Components:
Propofol
Propofol
Method of action:
Anesthesia, Anesthetic, General Anesthetizing
Anesthesia, Anesthetic, General Anesthetizing
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Name of the medicinal product

1% Propofol Maruishi

Qualitative and quantitative composition

Propofol

Therapeutic indications

The information provided in Therapeutic indications of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

1% Propofol Maruishi 1% is a short-acting intravenous general anaesthetic for:

• Induction and maintenance of general anaesthesia in adults and children >1 month.

• Sedation for diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia in adults and children >1 month.

• Sedation of ventilated patients >16 years of age in the intensive care unit.

1% Propofol Maruishi injectable emulsion is an I.V. sedative-hypnotic agent that can be used as described in the table below.

TABLE 3: INDICATIONS FOR 1% Propofol Maruishi INJECTABLE EMULSION

Indication Approved Patient Population
Initiation and maintenance of Monitored Anesthesia Care (MAC) sedation Adults only
Combined sedation and regional anesthesia Adults only (See PRECAUTIONS)
Induction of General Anesthesia Patients ≥ 3 years of age
Maintenance of General Anesthesia Patients ≥ 2 months of age
Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients Adults only

Safety, effectiveness and dosing guidelines for 1% Propofol Maruishi injectable emulsion have not been established for MAC Sedation in the pediatric population; therefore, it is not recommended for this use. (See PRECAUTIONS - Pediatric Use.)

1% Propofol Maruishi injectable emulsion is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness have not been established in those populations.

In the Intensive Care Unit (ICU), 1% Propofol Maruishi injectable emulsion can be administered to intubated, mechanically ventilated adult patients to provide continuous sedation and control of stress responses, only by persons skilled in the medical management of critically ill patients and trained in cardiovascular resuscitation and airway management.

1% Propofol Maruishi injectable emulsion is not indicated for use in Pediatric ICU sedation since the safety of this regimen has not been established. (See PRECAUTIONS - Pediatric Use.)

1% Propofol Maruishi injectable emulsion is not recommended for obstetrics, including Cesarean section deliveries. 1% Propofol Maruishi injectable emulsion crosses the placenta, and as with other general anesthetic agents, the administration of 1% Propofol Maruishi injectable emulsion may be associated with neonatal depression. (See PRECAUTIONS.)

1% Propofol Maruishi is not recommended for use in nursing mothers because 1% Propofol Maruishi injectable emulsion has been reported to be excreted in human milk and the effects of oral absorption of small amounts of 1% Propofol Maruishi are not known. (See PRECAUTIONS.)

DIPRIVAN Injectable Emulsion is an IV sedative-hypnotic agent that can be used as described in the table below.

Table 3:  Indications for DIPRIVAN Injectable Emulsion

Indication Approved Patient Population
Initiation and maintenance of Monitored Anesthesia Care (MAC) sedation Adults only
Combined sedation and regional anesthesia Adults only (see PRECAUTIONS)
Induction of General Anesthesia Patients ≥ 3 years of age
Maintenance of General Anesthesia Patients ≥ 2 months of age
Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients Adults only

Safety, effectiveness and dosing guidelines for DIPRIVAN Injectable Emulsion have not been established for MAC Sedation in the pediatric population; therefore, it is not recommended for this use (see PRECAUTIONS, Pediatric Use).

DIPRIVAN Injectable Emulsion is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness have not been established in those populations.

In the Intensive Care Unit (ICU), DIPRIVAN Injectable Emulsion can be administered to intubated, mechanically ventilated adult patients to provide continuous sedation and control of stress responses only by persons skilled in the medical management of critically ill patients and trained in cardiovascular resuscitation and airway management.

DIPRIVAN Injectable Emulsion is not indicated for use in Pediatric ICU sedation since the safety of this regimen has not been established (see PRECAUTIONS, Pediatric Use).

DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including Cesarean section deliveries. DIPRIVAN Injectable Emulsion crosses the placenta, and as with other general anesthetic agents, the administration of DIPRIVAN Injectable Emulsion may be associated with neonatal depression (see PRECAUTIONS).

DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because propofol has been reported to be excreted in human milk, and the effects of oral absorption of small amounts of propofol are not known (see PRECAUTIONS).

Dosage (Posology) and method of administration

The information provided in Dosage (Posology) and method of administration of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

Posology

<5. Such use is restricted to induction and maintenance of anaesthesia in adults. The 'Diprifusor' TCI system is not recommended for use in ICU sedation or sedation for surgical and diagnostic procedures, or in children.

4.2.1 Induction of General Anaesthesia

Adults

In unpremedicated and premedicated patients, it is recommended that 1% Propofol Maruishi 1% should be titrated (approximately 4 ml [40 mg] every 10 seconds in an average healthy adult by bolus injection or infusion) against the response of the patient until the clinical signs show the onset of anaesthesia. Most adult patients aged less than 55 years are likely to require 1.5–2.5 mg/kg of 1% Propofol Maruishi 1%. The total dose required can be reduced by lower rates of administration (2–5 ml/min [20–50 mg/min]). Over this age, the requirement will generally be less. In patients of ASA Grades 3 and 4, lower rates of administration should be used (approximately 2 ml [20 mg] every 10 seconds).

Older people

In older people the dose requirement for induction of anaesthesia with 1% Propofol Maruishi 1% is reduced. The reduction should take into account of the physical status and age of the patient. The reduced dose should be given at a slower rate and titrated against the response.

Paediatric population

1% Propofol Maruishi 1% is not recommended for induction of anaesthesia in children aged less than 1 month.

For induction of anaesthesia in children over 1 month of age, 1% Propofol Maruishi 1% should be titrated slowly until clinical signs show the onset of anaesthesia. The dose should be adjusted according to age and/or body weight. Most patients over 8 years of age require approximately 2.5 mg/kg body weight of 1% Propofol Maruishi 1% for induction of anaesthesia. In younger children, especially between the age of 1 month and 3 years, dose requirements may be higher (2.5–4 mg/kg body weight).

<).

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is not recommended for induction of general anaesthesia in children.

4.2.2 Maintenance of General Anaesthesia

Adults

Anaesthesia can be maintained by administering 1% Propofol Maruishi 1% either by continuous infusion or by repeat bolus injections to prevent the clinical signs of light anaesthesia. Recovery from anaesthesia is typically rapid and it is therefore important to maintain 1% Propofol Maruishi 1% administration until the end of the procedure.

Continuous Infusion

The required rate of administration varies considerably between patients, but rates in the region of 4–12 mg/kg/h usually maintain satisfactory anaesthesia.

Repeat Bolus Injections

If a technique involving repeat bolus injections is used, increments of 25 mg (2.5 ml) to 50 mg (5.0 ml) may be given according to clinical need.

Older people

When 1% Propofol Maruishi 1% is used for maintenance of anaesthesia the rate of infusion or 'target concentration' should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.

Paediatric population

1% Propofol Maruishi 1% is not recommended for maintenance of anaesthesia in children aged less than 1 month.

Anaesthesia can be maintained in children over 1 month of age by administering 1% Propofol Maruishi 1% by infusion or repeated bolus injection to maintain the depth of anaesthesia required. The required rate of administration varies considerably between patients, but rates in the region of 9–15 mg/kg/h usually achieve satisfactory anaesthesia. In younger children, especially between the age of 1 month and 3 years, dose requirements may be higher.

<).

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is not recommended for maintenance of general anaesthesia in children.

4.2.3 Sedation During Intensive Care

Adults

For sedation during intensive care it is advised that 1% Propofol Maruishi 1% should be administered by continuous infusion. The infusion rate should be determined by the desired depth of sedation. In most patients sufficient sedation can be obtained with a dosage of 0.3–4 mg/kg/h of 1% Propofol Maruishi 1% (See 4.4 Special warnings and precautions for use). 1% Propofol Maruishi 1% is not indicated for sedation in intensive care of patients of 16 years of age or younger (see

NOTE: CONTAINS BENZYL ALCOHOL (See PRECAUTIONS section.)

1% Propofol Maruishi blood concentrations at steady state are generally proportional to infusion rates, especially in individual patients. Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

When administering 1% Propofol Maruishi injectable emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates. When infusing 1% Propofol Maruishi injectable emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of 1% Propofol Maruishi injectable emulsion.

For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate 1% Propofol Maruishi injectable emulsion infusion to provide satisfactory anesthesia. With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of 1% Propofol Maruishi injectable emulsion and/or opioids should be increased in order to provide adequate anesthesia.

Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of 1% Propofol Maruishi injectable emulsion at rates higher than are clinically necessary. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery time.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by 1% Propofol Maruishi. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary 1% Propofol Maruishi injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.

Induction Of General Anesthesia

Adult Patients

Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of 1% Propofol Maruishi injectable emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, 1% Propofol Maruishi injectable emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of 1% Propofol Maruishi injectable emulsion.

Elderly, Debilitated, Or ASA-PS III Or IV Patients

It is important to be familiar and experienced with the intravenous use of 1% Propofol Maruishi injectable emulsion before treating elderly, debilitated, or ASA-PS III or IV patients. Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of 1% Propofol Maruishi injectable emulsion for induction of anesthesia according to their condition and responses. A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. (See DOSAGE AND ADMINISTRATION.)

Pediatric Patients

Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of 1% Propofol Maruishi injectable emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients. As with other sedativehypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of 1% Propofol Maruishi injectable emulsion. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Attention should be paid to minimize pain on injection when administering 1% Propofol Maruishi injectable emulsion to pediatric patients. Boluses of 1% Propofol Maruishi injectable emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins. (See PRECAUTIONS - General.)

Neurosurgical Patients

Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower boluses or infusions of 1% Propofol Maruishi injectable emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg). (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

Cardiac Anesthesia

1% Propofol Maruishi injectable emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited. As with other anesthetic and sedative-hypnotic agents, 1% Propofol Maruishi injectable emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

In addition, lower heart rates are observed during maintenance with 1% Propofol Maruishi injectable emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

As with other anesthetic agents, 1% Propofol Maruishi injectable emulsion reduces myocardial oxygen consumption. Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.

Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary 1% Propofol Maruishi injectable emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. The rate of 1% Propofol Maruishi injectable emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.

A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used. In order to assure adequate anesthesia, when 1% Propofol Maruishi injectable emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an opioid is used as the primary agent, 1% Propofol Maruishi injectable emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia. Higher doses of 1% Propofol Maruishi injectable emulsion will reduce the opioid requirements (see TABLE 4). When 1% Propofol Maruishi injectable emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONSCardiac Anesthesia).

TABLE 4: CARDIAC ANESTHESIA TECHNIQUES

Primary Asent Rate Secondary Aeent/Rate
1% Propofol Maruishi Injectable Emulsion   (Following Induction with Primary Agent) 0PI0IDa/0.05 - 0.075 mcg/kg/min (no bolus)
  Preinduction    
  Anxiolysis 25 mcg/kg/min  
  Induction 0.5 - 1.5 mg/kg  
  Over 60 sec  
  Maintenance (Titrated to Clinical Response) OPIOIDb 100 - 150 mcg/kg/min 1% Propofol Maruishi Injectable Emulsion/50 - 100 mcg/kg/min (no bolus)
  Induction 25 - 50 mcg/kg  
  Maintenance 0.2 - 0.3 mcg/kg/min  
a OPIOID is defined in terms of fentanyl equivalents, i.e.,
1 mcg of fentanyl = 5 mcg of alfentanil (for bolus)= 10 mcg of alfentanil (for maintenance)
OR
= 0.1 mcg of sufentanil
b Care should be taken to ensure amnesia.

Maintenance Of General Anesthesia

Adult Patients

In adults, anesthesia can be maintained by administering 1% Propofol Maruishi injectable emulsion by infusion or intermittent I.V. bolus injection. The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous Infusion

1% Propofol Maruishi injectable emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of 1% Propofol Maruishi injectable emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by 1% Propofol Maruishi.

Intermittent Bolus

Increments of 1% Propofol Maruishi injectable emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Pediatric Patients

1% Propofol Maruishi injectable emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

In general, for the pediatric population, maintenance by infusion of 1% Propofol Maruishi injectable emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose. Following the first halfhour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed. 1% Propofol Maruishi injectable emulsion should be titrated to achieve the desired clinical effect. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients. (See Clinical Trials - TABLE 2.)

1% Propofol Maruishi injectable emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

Monitored Anesthesia Care (MAC) Sedation

Adult Patients

When 1% Propofol Maruishi injectable emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of 1% Propofol Maruishi injectable emulsion administration will be in the range of 25 to 75 mcg/kg/min.

During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.) A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

Initiation Of MAC Sedation

For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be initiated by infusing 1% Propofol Maruishi injectable emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses. When 1% Propofol Maruishi injectable emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.) The rate of administration should be over 3-5 minutes and the dosage of 1% Propofol Maruishi injectable emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs. (See DOSAGE AND ADMINISTRATION.)

Maintenance Of MAC Sedation

For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of 1% Propofol Maruishi injectable emulsion at rates higher than are clinically necessary.

If the intermittent bolus dose method is used, increments of 1% Propofol Maruishi injectable emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.) The rate of administration and the dosage of 1% Propofol Maruishi injectable emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs. (See DOSAGE AND ADMINISTRATION.)

1% Propofol Maruishi injectable emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When 1% Propofol Maruishi injectable emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of 1% Propofol Maruishi injectable emulsion and may also result in a slower recovery profile. (See DRUG INTERACTIONS.)

ICU Sedation

(See WARNINGS and DOSAGE AND ADMINISTRATIONHandling Procedures.)

Abrupt discontinuation of 1% Propofol Maruishi injectable emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of 1% Propofol Maruishi injectable emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation. (See PRECAUTIONS.)

Adult Patients

For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. (See DOSAGE AND ADMINISTRATION.)

Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response. (See DOSAGE AND ADMINISTRATION.) With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation. These higher rates of administration may increase the likelihood of patients developing hypotension.

Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient's underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient. The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses. (See WARNINGS.)

1% Propofol Maruishi injectable emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs. (See PRECAUTIONS - Intensive Care Unit Sedation.) For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect. Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher. Dosages of 1% Propofol Maruishi injectable emulsion should be reduced in patients who have received large dosages of narcotics. Conversely, the 1% Propofol Maruishi injectable emulsion dosage requirement may be reduced by adequate management of pain with analgesic agents. As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time. (See Summary Of Dosage Guidelines.) Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of 1% Propofol Maruishi required for sedation (see Clinical Trials - Intensive Care Unit (ICU) Sedation). Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur. Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension. (See PRECAUTIONS.)

Summary Of Dosage Guidelines

Dosages and rates of administration in the following table should be individualized and titrated to clinical response. Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older. Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older.

For complete dosage information, see DOSAGE AND ADMINISTRATION.

INDICATION DOSAGE AND ADMINISTRATION
Induction of General Anesthesia: Healthy Adults Less Than 55 Years of Age: 40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).
Elderly, Debilitated, or ASA-PS III or IV Patients: 20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).
Cardiac Anesthesia: 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg).
Neurosurgical Patients: 20 mg every 10 seconds until induction onset (1 to 2 mg/kg).
Pediatric Patients - healthy, from 3 years to 16 years of age: 2.5 to 3.5 mg/kg administered over 20 to 30 seconds. (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)
Maintenance of General Anesthesia: Infusion
Healthy Adults Less Than 55 Years of Age: 100 to 200 mcg/kg/min (6 to 12 mg/kg/h).
Elderly, Debilitated, ASA-PS III or IV Patients: 50 to 100 mcg/kg/min (3 to 6 mg/kg/h).
Cardiac Anesthesia: Most patients require: Primary DIPRIVAN Injectable Emulsion with Secondary Opioid -100 to 150 mcg/kg/min.
Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid -50 to 100 mcg/kg/min. (see Table 4)
Neurosurgical Patients: 100 to 200 mcg/kg/min (6 to 12 mg/kg/h).
Pediatric Patients - healthy, from 2 months of age to 16 years of age: 125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h). Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased. (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)
Maintenance of General Anesthesia: Intermittent Bolus
Healthy Adults Less Than 55 Years of Age: Increments of 20 to 50 mg as needed.
Initiation of MAC Sedation: Healthy Adults Less Than 55 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Most patients require an infusion of 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3 to 5 minutes followed immediately by a maintenance infusion.
Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require dosages similar to healthy adults. Rapid boluses are to be avoided (see WARNINGS).
Maintenance of MAC Sedation: Healthy Adults Less Than 55 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique. Most patients require an infusion of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.
In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require 80% of the usual adult dose. A rapid (single or repeated) bolus dose should not be used (see WARNINGS). Sedation in Intubated, Mechanically Ventilated
Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least 5 minutes. Subsequent increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until desired clinical effect is achieved. Maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher may be required. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).
Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN Injectable Emulsion required for sedation.
The tubing and any unused DIPRIVAN Injectable Emulsion drug product should be discarded after 12 hours because DIPRIVAN Injectable Emulsion contains no preservatives and is capable of supporting growth of microorganisms (see WARNINGS).

Administration With Lidocaine

If lidocaine is to be administered to minimize pain on injection of 1% Propofol Maruishi, it is recommended that it be administered prior to 1% Propofol Maruishi administration or that it be added to 1% Propofol Maruishi immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg 1% Propofol Maruishi.

Compatibility And Stability

1% Propofol Maruishi injectable emulsion should not be mixed with other therapeutic agents prior to administration.

Dilution Prior To Administration

1% Propofol Maruishi injectable emulsion is provided as a ready-to-use formulation. However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

Administration With Other Fluids

Compatibility of 1% Propofol Maruishi injectable emulsion with the coadministration of blood/serum/plasma has not been established. (See WARNINGS.) When administered using a y-type infusion set, 1% Propofol Maruishi injectable emulsion has been shown to be compatible with the following intravenous fluids.

  • 5% Dextrose Injection, USP
  • Lactated Ringers Injection, USP
  • Lactated Ringers and 5% Dextrose Injection
  • 5% Dextrose and 0.45% Sodium Chloride Injection, USP
  • 5% Dextrose and 0.2% Sodium Chloride Injection, USP

Handling Procedures

General

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Clinical experience with the use of in-line filters and 1% Propofol Maruishi injectable emulsion during anesthesia or ICU/MAC sedation is limited. 1% Propofol Maruishi injectable emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of 1% Propofol Maruishi injectable emulsion and/or cause the breakdown of the emulsion. Filters should be used with caution and where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

Do not use if there is evidence of separation of the phases of the emulsion.

Rare cases of self-administration of 1% Propofol Maruishi injectable emulsion, by health care professionals have been reported, including some fatalities. (See Drug Abuse And Dependence.)

Strict aseptic technique must always be maintained during handling. 1% Propofol Maruishi injectable emulsion is a single-use parenteral product which contains benzyl alcohol 1.5 mg/mL and sodium benzoate 0.7 mg/mL to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination. However, 1% Propofol Maruishi injectable emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards. Accordingly, strict aseptic technique must still be adhered to. Do not use if contamination is suspected. Discard unused portions as directed within the required time limits (see DOSAGE AND ADMINISTRATION – Handling Procedures). There have been reports in which failure to use aseptic technique when handling 1% Propofol Maruishi injectable emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

1% Propofol Maruishi injectable emulsion, with benzyl alcohol, inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

Guidelines For Aseptic Technique For General Anesthesia/MAC Sedation

1% Propofol Maruishi should be prepared for use just prior to initiation of each individual anesthetic/sedative procedure. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. 1% Propofol Maruishi should be drawn into sterile syringes immediately after vials are opened. When withdrawing 1% Propofol Maruishi from vials, a sterile vent spike should be used. The syringe(s) should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vials have been opened.

1% Propofol Maruishi injectable emulsion should be prepared for single-patient use only. Any unused portions of 1% Propofol Maruishi injectable emulsion, reservoirs, dedicated administration tubing and/or solutions containing 1% Propofol Maruishi injectable emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The I.V. line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual 1% Propofol Maruishi injectable emulsion.

Guidelines For Aseptic Technique For ICU Sedation

1% Propofol Maruishi injectable emulsion should be prepared for single-patient use only. When 1% Propofol Maruishi injectable emulsion is administered directly from the vial, strict aseptic techniques must be followed. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of 1% Propofol Maruishi injectable emulsion. As with other lipid emulsions, the number of I.V. line manipulations should be minimized. Administration should commence promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused portions of 1% Propofol Maruishi injectable emulsion must be discarded after 12 hours.

If 1% Propofol Maruishi injectable emulsion is transferred to a syringe or other container prior to administration, the handling procedures for General Anesthesia/MAC Sedation should be followed and the product should be discarded and administration lines changed after 12 hours.

Propofol blood concentrations at steady-state are generally proportional to infusion rates, especially in individual patients. Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

Shake well before use. Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised. Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

When administering DIPRIVAN Injectable Emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates. When infusing DIPRIVAN Injectable Emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of DIPRIVAN Injectable Emulsion.

For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate DIPRIVAN Injectable Emulsion infusion to provide satisfactory anesthesia. With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of DIPRIVAN Injectable Emulsion and/or opioids should be increased in order to provide adequate anesthesia.

Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by propofol. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.

Induction Of General Anesthesia

Adult Patients

Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.

Elderly, Debilitated, or ASA-PS III or IV Patients

It is important to be familiar and experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients. Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses. A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation.

Pediatric Patients

Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric patients. Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

Neurosurgical Patients

Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS).

Cardiac Anesthesia

DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited. As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption. Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.

Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. The rate of DIPRIVAN Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.

A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used. In order to assure adequate anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia. Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 4). When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

Table 4: Cardiac Anesthesia Techniques

Primary Agent Rate Secondary Agent/Rate (Following Induction with Primary Agent)
DIPRIVAN Injectable Emulsion   OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)
  Preinduction Anxiolysis 25 mcg/kg/min  
  Induction 0.5 to 1.5 mg/kg over 60 sec
  Maintenance (Titrated to Clinical Response) 100 to 150 mcg/kg/min
OPIOIDb   DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min (no bolus)
  Induction 25 to 50 mcg/kg  
  Maintenance 0.2 to 0.3 mcg/kg/min
aOPIOID is defined in terms of fentanyl equivalents, i.e.,
1 mcg of fentanyl = 5 mcg of alfentanil (for bolus)
= 10 mcg of alfentanil (for maintenance)
or
= 0.1 mcg of sufentanil
bCare should be taken to ensure amnesia.

Maintenance Of General Anesthesia

DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

Adult Patients

In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by infusion or intermittent IV bolus injection. The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous Infusion

DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.

Intermittent Bolus

Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Pediatric Patients

DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose. Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed. DIPRIVAN Injectable Emulsion should be titrated to achieve the desired clinical effect. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients. (See Table 2 Clinical Trials.)

Monitored Anesthesia Care (MAC) Sedation

Adult Patients

When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

Initiation of MAC Sedation

For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses. When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). The rate of administration should be over 3 to 5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

Maintenance of MAC Sedation

For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.

If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). The rate of administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs.

DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS: DRUG INTERACTIONS).

ICU Sedation

(See WARNINGS and Handling Procedures.) Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

Adult Patients

For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.

Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response. With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation. These higher rates of administration may increase the likelihood of patients developing hypotension. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient's underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient. The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation). For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect. Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received large dosages of narcotics. The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents. As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see Summary Of Dosage Guidelines). Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation). Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur. Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

Summary Of Dosage Guidelines

Dosages and rates of administration in the following table should be individualized and titrated to clinical response. Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older. Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older.

For complete dosage information, see DOSAGE AND ADMINISTRATION.

INDICATION DOSAGE AND ADMINISTRATION
Induction of General Anesthesia: Healthy Adults Less Than 55 Years of Age: 40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).
Elderly, Debilitated, or ASA-PS III or IV Patients: 20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).
Cardiac Anesthesia: 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg).
Neurosurgical Patients: 20 mg every 10 seconds until induction onset (1 to 2 mg/kg).
Pediatric Patients - healthy, from 3 years to 16 years of age: 2.5 to 3.5 mg/kg administered over 20 to 30 seconds. (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)
Maintenance of General Anesthesia: Infusion
Healthy Adults Less Than 55 Years of Age: 100 to 200 mcg/kg/min (6 to 12 mg/kg/h).
Elderly, Debilitated, ASA-PS III or IV Patients: 50 to 100 mcg/kg/min (3 to 6 mg/kg/h).
Cardiac Anesthesia: Most patients require: Primary DIPRIVAN Injectable Emulsion with Secondary Opioid -100 to 150 mcg/kg/min.
Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid -50 to 100 mcg/kg/min. (see Table 4)
Neurosurgical Patients: 100 to 200 mcg/kg/min (6 to 12 mg/kg/h).
Pediatric Patients - healthy, from 2 months of age to 16 years of age: 125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h). Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased. (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)
Maintenance of General Anesthesia: Intermittent Bolus
Healthy Adults Less Than 55 Years of Age: Increments of 20 to 50 mg as needed.
Initiation of MAC Sedation: Healthy Adults Less Than 55 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Most patients require an infusion of 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3 to 5 minutes followed immediately by a maintenance infusion.
Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require dosages similar to healthy adults. Rapid boluses are to be avoided (see WARNINGS).
Maintenance of MAC Sedation: Healthy Adults Less Than 55 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique. Most patients require an infusion of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.
In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require 80% of the usual adult dose. A rapid (single or repeated) bolus dose should not be used (see WARNINGS). Sedation in Intubated, Mechanically Ventilated
Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least 5 minutes. Subsequent increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until desired clinical effect is achieved. Maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher may be required. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).
Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN Injectable Emulsion required for sedation.
The tubing and any unused DIPRIVAN Injectable Emulsion drug product should be discarded after 12 hours because DIPRIVAN Injectable Emulsion contains no preservatives and is capable of supporting growth of microorganisms (see WARNINGS).

Administration with Lidocaine

If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

Compatibility and Stability

DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

Dilution Prior to Administration

DIPRIVAN Injectable Emulsion is provided as a ready-to-use formulation. However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

Administration with Other Fluids

Compatibility of DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS). When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  • 5% Dextrose Injection, USP
  • Lactated Ringers Injection, USP
  • Lactated Ringers and 5% Dextrose Injection
  • 5% Dextrose and 0.45% Sodium Chloride Injection, USP
  • 5% Dextrose and 0.2% Sodium Chloride Injection, USP

Handling Procedures

General

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited. DIPRIVAN Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion. Filters should be used with caution and where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

Do not use if there is evidence of separation of the phases of the emulsion.

Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been reported, including some fatalities (see Drug Abuse And Dependence).

Strict aseptic technique must always be maintained during handling. DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination. However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons. DIPRIVAN Injectable Emulsion vials are never to be accessed more than once or used on more than one person.

Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used. The syringe should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

DIPRIVAN Injectable Emulsion must be prepared for single-patient use only. Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

Guidelines for Aseptic Technique for ICU Sedation

DIPRIVAN Injectable Emulsion must be prepared for single-patient use only. Strict aseptic techniques must be followed. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion. As with other lipid emulsions, the number of IV line manipulations should be minimized. Administration should commence promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used. The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened. DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

Contraindications

The information provided in Contraindications of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
more... close
Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion
). Administration of 1% Propofol Maruishi 1% by Diprifusor TCI system is not advised for sedation in the intensive care unit.

1% Propofol Maruishi 1% may be diluted with 5% Dextrose (see "Dilution and Co-administration" table below).

It is recommended that blood lipid levels be monitored should 1% Propofol Maruishi 1% be administered to patients thought to be at particular risk of fat overload. Administration of 1% Propofol Maruishi 1% should be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from the body. If the patient is receiving other intravenous lipid concurrently, a reduction in quantity should be made in order to take account of the amount of lipid infused as part of the 1% Propofol Maruishi 1% formulation; 1.0 ml of 1% Propofol Maruishi 1% contains approximately 0.1g of fat.

If the duration of sedation is in excess of 3 days, lipids should be monitored in all patients.

Older people

When 1% Propofol Maruishi 1% is used for sedation the rate of infusion should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.

Paediatric population

1% Propofol Maruishi 1% is contraindicated for the sedation of ventilated children aged 16 years or younger receiving intensive care.

4.2.4 Sedation For Surgical And Diagnostic Procedures

Adults

To provide sedation for surgical and diagnostic procedures, rates of administration should be individualised and titrated to clinical response.

Most patients will require 0.5–1 mg/kg over 1– 5 minutes for onset of sedation.

Maintenance of sedation may be accomplished by titrating 1% Propofol Maruishi 1% infusion to the desired level of sedation - most patients will require 1.5–4.5 mg/kg/h. In addition to the infusion, bolus administration of 10–20 mg may be used if a rapid increase in the depth of sedation is required. In patients of ASA Grades 3 and 4 the rate of administration and dosage may need to be reduced.

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is not recommended for sedation for surgical and diagnostic procedures.

Older people

When 1% Propofol Maruishi 1% is used for sedation the rate of infusion or 'target concentration' should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.

Paediatric population

1% Propofol Maruishi 1% is not recommended for surgical and diagnostic procedures in children aged less than 1 month.

In children over 1 month of age, doses and administration rates should be adjusted according to the required depth of sedation and the clinical response. Most paediatric patients require 1–2 mg/kg body weight of 1% Propofol Maruishi 1% for onset of sedation. Maintenance of sedation may be accomplished by titrating 1% Propofol Maruishi 1% infusion to the desired level of sedation. Most patients require 1.5–9 mg/kg/h 1% Propofol Maruishi 1%. The infusion may be supplemented by bolus administration of up to 1 mg/kg body weight if a rapid increase of depth of sedation is required.

In ASA 3 and 4 patients lower doses may be required.

4.2.5 Method of administration

1% Propofol Maruishi 1% has no analgesic properties and therefore supplementary analgesic agents are generally required in addition to 1% Propofol Maruishi 1%.

1% Propofol Maruishi 1% can be used for infusion undiluted from glass containers, plastic syringes or 1% Propofol Maruishi 1% pre-filled syringes or diluted with 5% Dextrose (Intravenous Infusion BP) only, in PVC infusion bags or glass infusion bottles. Dilutions, which must not exceed 1 in 5 (2 mg propofol per ml) should be prepared aseptically immediately before administration and must be used within 6 hours of preparation.

It is recommended that, when using diluted 1% Propofol Maruishi 1%, the volume of 5% Dextrose removed from the infusion bag during the dilution process is totally replaced in volume by 1% Propofol Maruishi 1% emulsion. (see "Dilution and Co-administration" table below).

The dilution may be used with a variety of infusion control techniques, but a giving set used alone will not avoid the risk of accidental uncontrolled infusion of large volumes of diluted 1% Propofol Maruishi 1%. A burette, drop counter or volumetric pump must be included in the infusion line. The risk of uncontrolled infusion must be taken into account when deciding the maximum amount of 1% Propofol Maruishi 1% in the burette.

When 1% Propofol Maruishi 1% is used undiluted to maintain anaesthesia, it is recommended that equipment such as syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

1% Propofol Maruishi 1% may be administered via a Y-piece close to the injection site into infusions of the following:

• Dextrose 5% Intravenous Infusion B.P.

• Sodium Chloride 0.9% Intravenous Infusion B.P.

• Dextrose 4% with Sodium Chloride 0.18% Intravenous Infusion B.P.

The glass pre-filled syringe (PFS) has a lower frictional resistance than plastic disposable syringes and operates more easily. Therefore, if 1% Propofol Maruishi 1% is administered using a hand held pre-filled syringe, the line between the syringe and the patient must not be left open if unattended.

When the pre-filled syringe presentation is used in a syringe pump appropriate compatibility should be ensured. In particular, the pump should be designed to prevent syphoning and should have an occlusion alarm set no greater than 1000 mm Hg. If using a programmable or equivalent pump that offers options for use of different syringes then choose only the 'B-D' 50/60 ml 'PLASTIPAK' setting when using the 1% Propofol Maruishi 1% pre-filled syringe.

1% Propofol Maruishi 1% may be premixed with alfentanil injection containing 500 micrograms/ml alfentanil in the ratio of 20:1 to 50:1 v/v. Mixtures should be prepared using sterile technique and used within 6 hours of preparation.

In order to reduce pain on initial injection, 1% Propofol Maruishi 1% may be mixed with preservative-free Lidocaine Injection 0.5% or 1%; (see "Dilution and Co-administration" table below).

Target Controlled Infusion - Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI System in Adults

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is restricted to induction and maintenance of general anaesthesia in adults. It is not recommended for use in ICU sedation or sedation for surgical and diagnostic procedures, or in children.

1% Propofol Maruishi 1% may be administered by TCI only with a 'Diprifusor' TCI system incorporating 'Diprifusor' TCI software. Such systems will operate only on recognition of electronically tagged pre-filled syringes containing 1% Propofol Maruishi 1% or 2% Injection. The 'Diprifusor' TCI system will automatically adjust the infusion rate for the concentration of 1% Propofol Maruishi recognised. Users must be familiar with the infusion pump users' manual, and with the administration of 1% Propofol Maruishi 1% by TCI and with the correct use of the syringe identification system.

The Diprifusor allows the anaesthetist to achieve and control a desired speed of induction and depth of anaesthesia by setting and adjusting target (predicted) blood concentrations of propofol. An alternative effect-site mode of administration may be accessible on some Diprifusors, but its safety and efficacy have not yet been established.

The 'Diprifusor' TCI system assumes that the initial blood propofol concentration in the patient is zero. Therefore, in patients who have received prior propofol, there may be a need to select a lower initial target concentration when commencing 'Diprifusor' TCI. Similarly, the immediate recommencement of 'Diprifusor' TCI is not recommended if the pump has been switched off.

Guidance on propofol target concentrations is given below. In view of interpatient variability in propofol pharmacokinetics and pharmacodynamics, in both premedicated and unpremedicated patients the target propofol concentration should be titrated against the response of the patient in order to achieve the depth of anaesthesia required.

Induction and Maintenance of General Anaesthesia

In adult patients under 55 years of age anaesthesia can usually be induced with target propofol concentrations in the region of 4–8 microgram/ml. An initial target of 4 microgram/ml is recommended in premedicated patients and in unpremedicated patients an initial target of 6 microgram/ml is advised. Induction time with these targets is generally within the range of 60–120 seconds. Higher targets will allow more rapid induction of anaesthesia but may be associated with more pronounced haemodynamic and respiratory depression.

A lower initial target concentration should be used in patients over the age of about 55 years and in patients of ASA grades 3 and 4. The target concentration can then be increased in steps of 0.5–1.0 microgram/ml at intervals of 1 minute to achieve a gradual induction of anaesthesia.

Supplementary analgesia will generally be required and the extent to which target concentrations for maintenance of anaesthesia can be reduced will be influenced by the amount of concomitant analgesia administered. Target propofol concentrations in the region of 3–6 microgram/ml usually maintain satisfactory anaesthesia.

The predicted propofol concentration on waking is generally in the region of 1.0–2.0 microgram/ml and will be influenced by the amount of analgesia given during maintenance.

Dilution and Co-Administration of 1% Propofol Maruishi 1% with Other Drugs or Infusion Fluids (see also 'Additional Precautions' Section)

Co-administration Technique

Additive or Diluent

Preparation

Precautions

Pre-mixing.

Dextrose 5% Intravenous Infusion

Mix 1 part of 1% Propofol Maruishi 1% with up to 4 parts of Dextrose 5% Intravenous Infusion B.P in either PVC infusion bags or glass infusion bottles. When diluted in PVC bags it is recommended that the bag should be full and that the dilution be prepared by withdrawing a volume of infusion fluid and replacing it with an equal volume of 1% Propofol Maruishi 1%.

Prepare aseptically immediately before administration. The mixture is stable for up to 6 hours.

Lidocaine hydrochloride injection (0.5% or 1% without preservatives).

Mix 20 parts of 1% Propofol Maruishi 1% with up to 1 part of either 0.5% or 1% lidocaine hydrochloride injection.

Prepare mixture aseptically immediately prior to administration. Use for Induction only.

Alfentanil injection (500 microgram/ml).

Mix 1% Propofol Maruishi 1% with alfentanil injection in a ratio of 20:1 to 50:1 v/v.

Prepare mixture aseptically; use within 6 hours of preparation.

Co-administration via a Y-piece connector.

Dextrose 5% intravenous infusion

Co-administer via a Y-piece connector.

Place the Y-piece connector close to the injection site.

Sodium chloride 0.9% intravenous infusion

As above

As above

Dextrose 4% with sodium chloride 0.18% intravenous infusion

As above

As above

4.3 Contraindications <

1% Propofol Maruishi 1% contains soya oil and should not be used in patients who are hypersensitive to peanut or soya.

1% Propofol Maruishi 1% must not be used in patients of 16 years of age or younger for sedation in intensive care .

1% Propofol Maruishi injectable emulsion is contraindicated in patients with a known hypersensitivity to 1% Propofol Maruishi injectable emulsion or any of its components.

1% Propofol Maruishi injectable emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

DIPRIVAN Injectable Emulsion is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN Injectable Emulsion components.

DIPRIVAN Injectable Emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

Special warnings and precautions for use

The information provided in Special warnings and precautions for use of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
more... close
Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion
). 1% Propofol Maruishi 1% is not indicated for sedation in intensive care of patients of 16 years of age or younger (see 4.3 Contraindications). Administration of 1% Propofol Maruishi 1% by Diprifusor TCI system is not advised for sedation in the intensive care unit.

1% Propofol Maruishi 1% may be diluted with 5% Dextrose (see "Dilution and Co-administration" table below).

It is recommended that blood lipid levels be monitored should 1% Propofol Maruishi 1% be administered to patients thought to be at particular risk of fat overload. Administration of 1% Propofol Maruishi 1% should be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from the body. If the patient is receiving other intravenous lipid concurrently, a reduction in quantity should be made in order to take account of the amount of lipid infused as part of the 1% Propofol Maruishi 1% formulation; 1.0 ml of 1% Propofol Maruishi 1% contains approximately 0.1g of fat.

If the duration of sedation is in excess of 3 days, lipids should be monitored in all patients.

Older people

When 1% Propofol Maruishi 1% is used for sedation the rate of infusion should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.

Paediatric population

1% Propofol Maruishi 1% is contraindicated for the sedation of ventilated children aged 16 years or younger receiving intensive care.

4.2.4 Sedation For Surgical And Diagnostic Procedures

Adults

To provide sedation for surgical and diagnostic procedures, rates of administration should be individualised and titrated to clinical response.

Most patients will require 0.5–1 mg/kg over 1– 5 minutes for onset of sedation.

Maintenance of sedation may be accomplished by titrating 1% Propofol Maruishi 1% infusion to the desired level of sedation - most patients will require 1.5–4.5 mg/kg/h. In addition to the infusion, bolus administration of 10–20 mg may be used if a rapid increase in the depth of sedation is required. In patients of ASA Grades 3 and 4 the rate of administration and dosage may need to be reduced.

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is not recommended for sedation for surgical and diagnostic procedures.

Older people

When 1% Propofol Maruishi 1% is used for sedation the rate of infusion or 'target concentration' should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.

Paediatric population

1% Propofol Maruishi 1% is not recommended for surgical and diagnostic procedures in children aged less than 1 month.

In children over 1 month of age, doses and administration rates should be adjusted according to the required depth of sedation and the clinical response. Most paediatric patients require 1–2 mg/kg body weight of 1% Propofol Maruishi 1% for onset of sedation. Maintenance of sedation may be accomplished by titrating 1% Propofol Maruishi 1% infusion to the desired level of sedation. Most patients require 1.5–9 mg/kg/h 1% Propofol Maruishi 1%. The infusion may be supplemented by bolus administration of up to 1 mg/kg body weight if a rapid increase of depth of sedation is required.

In ASA 3 and 4 patients lower doses may be required.

4.2.5 Method of administration

1% Propofol Maruishi 1% has no analgesic properties and therefore supplementary analgesic agents are generally required in addition to 1% Propofol Maruishi 1%.

1% Propofol Maruishi 1% can be used for infusion undiluted from glass containers, plastic syringes or 1% Propofol Maruishi 1% pre-filled syringes or diluted with 5% Dextrose (Intravenous Infusion BP) only, in PVC infusion bags or glass infusion bottles. Dilutions, which must not exceed 1 in 5 (2 mg propofol per ml) should be prepared aseptically immediately before administration and must be used within 6 hours of preparation.

It is recommended that, when using diluted 1% Propofol Maruishi 1%, the volume of 5% Dextrose removed from the infusion bag during the dilution process is totally replaced in volume by 1% Propofol Maruishi 1% emulsion. (see "Dilution and Co-administration" table below).

The dilution may be used with a variety of infusion control techniques, but a giving set used alone will not avoid the risk of accidental uncontrolled infusion of large volumes of diluted 1% Propofol Maruishi 1%. A burette, drop counter or volumetric pump must be included in the infusion line. The risk of uncontrolled infusion must be taken into account when deciding the maximum amount of 1% Propofol Maruishi 1% in the burette.

When 1% Propofol Maruishi 1% is used undiluted to maintain anaesthesia, it is recommended that equipment such as syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

1% Propofol Maruishi 1% may be administered via a Y-piece close to the injection site into infusions of the following:

• Dextrose 5% Intravenous Infusion B.P.

• Sodium Chloride 0.9% Intravenous Infusion B.P.

• Dextrose 4% with Sodium Chloride 0.18% Intravenous Infusion B.P.

The glass pre-filled syringe (PFS) has a lower frictional resistance than plastic disposable syringes and operates more easily. Therefore, if 1% Propofol Maruishi 1% is administered using a hand held pre-filled syringe, the line between the syringe and the patient must not be left open if unattended.

When the pre-filled syringe presentation is used in a syringe pump appropriate compatibility should be ensured. In particular, the pump should be designed to prevent syphoning and should have an occlusion alarm set no greater than 1000 mm Hg. If using a programmable or equivalent pump that offers options for use of different syringes then choose only the 'B-D' 50/60 ml 'PLASTIPAK' setting when using the 1% Propofol Maruishi 1% pre-filled syringe.

1% Propofol Maruishi 1% may be premixed with alfentanil injection containing 500 micrograms/ml alfentanil in the ratio of 20:1 to 50:1 v/v. Mixtures should be prepared using sterile technique and used within 6 hours of preparation.

In order to reduce pain on initial injection, 1% Propofol Maruishi 1% may be mixed with preservative-free Lidocaine Injection 0.5% or 1%; (see "Dilution and Co-administration" table below).

Target Controlled Infusion - Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI System in Adults

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is restricted to induction and maintenance of general anaesthesia in adults. It is not recommended for use in ICU sedation or sedation for surgical and diagnostic procedures, or in children.

1% Propofol Maruishi 1% may be administered by TCI only with a 'Diprifusor' TCI system incorporating 'Diprifusor' TCI software. Such systems will operate only on recognition of electronically tagged pre-filled syringes containing 1% Propofol Maruishi 1% or 2% Injection. The 'Diprifusor' TCI system will automatically adjust the infusion rate for the concentration of 1% Propofol Maruishi recognised. Users must be familiar with the infusion pump users' manual, and with the administration of 1% Propofol Maruishi 1% by TCI and with the correct use of the syringe identification system.

The Diprifusor allows the anaesthetist to achieve and control a desired speed of induction and depth of anaesthesia by setting and adjusting target (predicted) blood concentrations of propofol. An alternative effect-site mode of administration may be accessible on some Diprifusors, but its safety and efficacy have not yet been established.

The 'Diprifusor' TCI system assumes that the initial blood propofol concentration in the patient is zero. Therefore, in patients who have received prior propofol, there may be a need to select a lower initial target concentration when commencing 'Diprifusor' TCI. Similarly, the immediate recommencement of 'Diprifusor' TCI is not recommended if the pump has been switched off.

Guidance on propofol target concentrations is given below. In view of interpatient variability in propofol pharmacokinetics and pharmacodynamics, in both premedicated and unpremedicated patients the target propofol concentration should be titrated against the response of the patient in order to achieve the depth of anaesthesia required.

Induction and Maintenance of General Anaesthesia

In adult patients under 55 years of age anaesthesia can usually be induced with target propofol concentrations in the region of 4–8 microgram/ml. An initial target of 4 microgram/ml is recommended in premedicated patients and in unpremedicated patients an initial target of 6 microgram/ml is advised. Induction time with these targets is generally within the range of 60–120 seconds. Higher targets will allow more rapid induction of anaesthesia but may be associated with more pronounced haemodynamic and respiratory depression.

A lower initial target concentration should be used in patients over the age of about 55 years and in patients of ASA grades 3 and 4. The target concentration can then be increased in steps of 0.5–1.0 microgram/ml at intervals of 1 minute to achieve a gradual induction of anaesthesia.

Supplementary analgesia will generally be required and the extent to which target concentrations for maintenance of anaesthesia can be reduced will be influenced by the amount of concomitant analgesia administered. Target propofol concentrations in the region of 3–6 microgram/ml usually maintain satisfactory anaesthesia.

The predicted propofol concentration on waking is generally in the region of 1.0–2.0 microgram/ml and will be influenced by the amount of analgesia given during maintenance.

Dilution and Co-Administration of 1% Propofol Maruishi 1% with Other Drugs or Infusion Fluids (see also 'Additional Precautions' Section)

Co-administration Technique

Additive or Diluent

Preparation

Precautions

Pre-mixing.

Dextrose 5% Intravenous Infusion

Mix 1 part of 1% Propofol Maruishi 1% with up to 4 parts of Dextrose 5% Intravenous Infusion B.P in either PVC infusion bags or glass infusion bottles. When diluted in PVC bags it is recommended that the bag should be full and that the dilution be prepared by withdrawing a volume of infusion fluid and replacing it with an equal volume of 1% Propofol Maruishi 1%.

Prepare aseptically immediately before administration. The mixture is stable for up to 6 hours.

Lidocaine hydrochloride injection (0.5% or 1% without preservatives).

Mix 20 parts of 1% Propofol Maruishi 1% with up to 1 part of either 0.5% or 1% lidocaine hydrochloride injection.

Prepare mixture aseptically immediately prior to administration. Use for Induction only.

Alfentanil injection (500 microgram/ml).

Mix 1% Propofol Maruishi 1% with alfentanil injection in a ratio of 20:1 to 50:1 v/v.

Prepare mixture aseptically; use within 6 hours of preparation.

Co-administration via a Y-piece connector.

Dextrose 5% intravenous infusion

Co-administer via a Y-piece connector.

Place the Y-piece connector close to the injection site.

Sodium chloride 0.9% intravenous infusion

As above

As above

Dextrose 4% with sodium chloride 0.18% intravenous infusion

As above

As above

4.3 Contraindications <

1% Propofol Maruishi 1% contains soya oil and should not be used in patients who are hypersensitive to peanut or soya.

1% Propofol Maruishi 1% must not be used in patients of 16 years of age or younger for sedation in intensive care .

4.4 Special warnings and precautions for use

1% Propofol Maruishi 1% should be given by those trained in anaesthesia (or, where appropriate, doctors trained in the care of patients in Intensive Care).

Patients should be constantly monitored and facilities for maintenance of a patient airway, artificial ventilation, oxygen enrichment and other resuscitative facilities should be readily available at all times. 1% Propofol Maruishi 1% should not be administered by the person conducting the diagnostic or surgical procedure.

Abuse of, and dependence on 1% Propofol Maruishi 1%, predominantly by health care professionals, have been reported. As with other general anaesthetics, the administration of 1% Propofol Maruishi 1% without airway care may result in fatal respiratory complications.

When 1% Propofol Maruishi 1% is administered for conscious sedation, for surgical and diagnostic procedures, patients should be continually monitored for early signs of hypotension, airway obstruction and oxygen desaturation.

As with other sedative agents, when 1% Propofol Maruishi 1% is used for sedation during operative procedures, involuntary patient movements may occur. During procedures requiring immobility these movements may be hazardous to the operative site.

An adequate period is needed prior to discharge of the patient to ensure full recovery after use of 1% Propofol Maruishi 1%. Very rarely the use of 1% Propofol Maruishi 1% may be associated with the development of a period of postoperative unconsciousness, which may be accompanied by an increase in muscle tone. This may or may not be preceded by a period of wakefulness. Although recovery is spontaneous, appropriate care of an unconscious patient should be administered.

1% Propofol Maruishi 1% induced impairment is not generally detectable beyond 12 hours. The effects of 1% Propofol Maruishi 1%, the procedure, concomitant medications, the age and the condition of the patient should be considered when advising patients on:

• The advisability of being accompanied on leaving the place of administration

• The timing of recommencement of skilled or hazardous tasks such as driving

• The use of other agents that may sedate (Eg, benzodiazepines, opiates, alcohol.)

As with other intravenous anaesthetic agents, caution should be applied in patients with cardiac, respiratory, renal or hepatic impairment or in hypovolaemic or debilitated patients. 1% Propofol Maruishi 1% clearance is blood flow dependent, therefore, concomitant medication that reduces cardiac output will also reduce 1% Propofol Maruishi 1% clearance.

1% Propofol Maruishi 1% lacks vagolytic activity and has been associated with reports of bradycardia (occasionally profound) and also asystole. The intravenous administration of an anticholinergic agent before induction, or during maintenance of anaesthesia should be considered, especially in situations where vagal tone is likely to predominate, or when 1% Propofol Maruishi 1% is used in conjunction with other agents likely to cause a bradycardia.

As with other intravenous anaesthetic and sedative agents, patients should be instructed to avoid alcohol before and for at least 8 hours after administration of 1% Propofol Maruishi 1%.

During bolus administration for operative procedures, extreme caution should be exercised in patients with acute pulmonary insufficiency or respiratory depression.

Concomitant use of central nervous system depressants e.g., alcohol, general anaesthetics, narcotic analgesics will result in accentuation of their sedative effects. When 1% Propofol Maruishi 1% is combined with centrally depressant drugs administered parenterally, severe respiratory and cardiovascular depression may occur. It is recommended that 1% Propofol Maruishi 1% is administered following the analgesic and the dose should be carefully titrated to the patient's response .

During induction of anaesthesia, hypotension and transient apnoea may occur depending on the dose and use of premedicants and other agents.

Occasionally, hypotension may require use of intravenous fluids and reduction of the rate of administration of 1% Propofol Maruishi 1% during the period of anaesthetic maintenance.

When 1% Propofol Maruishi 1% is administered to an epileptic patient, there may be a risk of convulsion.

Appropriate care should be applied in patients with disorders of fat metabolism and in other conditions where lipid emulsions must be used cautiously .

Use is not recommended with electroconvulsive treatment.

As with other anaesthetics, sexual disinhibition may occur during recovery.

Paediatric population

The use of 1% Propofol Maruishi is not recommended in newborn infants as this patient population has not been fully investigated. Pharmacokinetic data indicate that clearance is considerably reduced in neonates and has a very high inter-individual variability. Relative overdose could occur on administering doses recommended for older children and result in severe cardiovascular depression.

1% Propofol Maruishi 2% is not recommended for use in children < 3 years of age due to difficulty in titrating small volumes.

Propofol must not be used in patients of 16 years of age or younger for sedation for intensive care as the safety and efficacy of propofol for sedation in this age group have not been demonstrated .

Advisory statements concerning Intensive Care Unit management

Use of propofol emulsion infusions for ICU sedation has been associated with a constellation of metabolic derangements and organ system failures that may result in death. Reports have been received of combinations of the following: Metabolic acidosis, Rhabdomyolysis, Hyperkalaemia, Hepatomegaly, Renal failure, Hyperlipidaemia, Cardiac arrhythmia, Brugada-type ECG (elevated ST-segment and coved T-wave) and rapidly progressive Cardiac failure usually unresponsive to inotropic supportive treatment. Combinations of these events have been referred to as the Propofol Infusion Syndrome. These events were mostly seen in patients with serious head injuries and children with respiratory tract infections who received dosages in excess of those advised in adults for sedation in the intensive care unit.

The following appear to be the major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents - vasoconstrictors, steroids, inotropes and/or 1% Propofol Maruishi 1% (usually at dose rates greater than 4mg/kg/h for more than 48 hours).

Prescribers should be alert to these events in patients with the above risk factors and promptly consider decreasing or stopping the 1% Propofol Maruishi 1% dosage when the above signs develop. All sedative and therapeutic agents used in the intensive care unit (ICU), should be titrated to maintain optimal oxygen delivery and haemodynamic parameters. Patients with raised intra-cranial pressure (ICP) should be given appropriate treatment to support the cerebral perfusion pressure during these treatment modifications.

Treating physicians are reminded if possible not to exceed the dosage of 4 mg/kg/h.

Appropriate care should be applied in patients with disorders of fat metabolism and in other conditions where lipid emulsions must be used cautiously.

It is recommended that blood lipid levels should be monitored if propofol is administered to patients thought to be at particular risk of fat overload. Administration of propofol should be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from the body. If the patient is receiving other intravenous lipid concurrently, a reduction in quantity should be made in order to take account of the amount of lipid infused as part of the propofol formulation; 1.0 mL of 1% Propofol Maruishi contains approximately 0.1 g of fat.

1% Propofol Maruishi 1% contains 0.0018 mmol sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Additional Precautions

Caution should be taken when treating patients with mitochondrial disease. These patients may be susceptible to exacerbations of their disorder when undergoing anaesthesia, surgery and ICU care. Maintenance of normothermia, provision of carbohydrates and good hydration are recommended for such patients. The early presentations of mitochondrial disease exacerbation and of the 'propofol infusion syndrome' may be similar.

1% Propofol Maruishi 1% contains no antimicrobial preservatives and supports growth of micro-organisms.

EDTA chelates metal ions, including zinc, and reduces microbial growth rates. The need for supplemental zinc should be considered during prolonged administration of 1% Propofol Maruishi 1%, particularly in patients who are predisposed to zinc deficiency, such as those with burns, diarrhoea and/or major sepsis.

When 1% Propofol Maruishi 1% is to be aspirated, it must be drawn aseptically into a sterile syringe or giving set immediately after opening the ampoule or breaking the vial seal. Administration must commence without delay. Asepsis must be maintained for both 1% Propofol Maruishi 1% and infusion equipment throughout the infusion period. Any infusion fluids added to the 1% Propofol Maruishi 1% line must be administered close to the cannula site. 1% Propofol Maruishi 1% must not be administered via a microbiological filter.

1% Propofol Maruishi 1% and any syringe containing 1% Propofol Maruishi 1% are for single use in an individual patient. In accordance with established guidelines for other lipid emulsions, a single infusion of propofol must not exceed 12 hours. At the end of the procedure or at 12 hours, whichever is the sooner, both the reservoir of propofol and the infusion line must be discarded and replaced as appropriate.

WARNINGS

Use of 1% Propofol Maruishi injectable emulsion has been associated with both fatal and life-threatening anaphylactic and anaphylactoid reactions.

For general anesthesia or monitored anesthesia care (MAC) sedation, 1% Propofol Maruishi injectable emulsion should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV patients.

For sedation of intubated, mechanically ventilated patients in the Intensive Care Unit (ICU), 1% Propofol Maruishi injectable emulsion should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.

Use of 1% Propofol Maruishi injectable emulsion for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as 1% Propofol Maruishi Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, cardiac and renal failure. The syndrome is most often associated with prolonged, high-dose infusions (> 5 mg/kg/h for > 48h) but has also been reported following large-dose, short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation, increasing 1% Propofol Maruishi dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a 1% Propofol Maruishi infusion, consideration should be given to using alternative means of sedation.

Abrupt discontinuation of 1% Propofol Maruishi injectable emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of 1% Propofol Maruishi injectable emulsion should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level. (See PRECAUTIONS.)

1% Propofol Maruishi injectable emulsion should not be coadministered through the same I.V. catheter with blood or plasma because compatibility has not been established. In vitro tests have shown that aggregates of the globular component of the emulsion vehicle have occurred with blood/plasma/serum from humans and animals. The clinical significance of these findings is not known.

There have been reports in which failure to use aseptic technique when handling 1% Propofol Maruishi injectable emulsion was associated with microbial contamination of the product and with fever, infection, sepsis, other life-threatening illness, and death. Do not use if contamination is suspected. Discard unused portions as directed within the required time limits (see DOSAGE AND ADMINISTRATION - Handling Procedures).

PRECAUTIONS

General

Adult And Pediatric Patients

A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients. (See DOSAGE AND ADMINISTRATION.) Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds. 1% Propofol Maruishi injectable emulsion use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.

Very rarely the use of 1% Propofol Maruishi injectable emulsion may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness. Recovery is spontaneous.

When 1% Propofol Maruishi injectable emulsion is administered to an epileptic patient, there is a risk of seizure during the recovery phase.

Attention should be paid to minimize pain on administration of 1% Propofol Maruishi injectable emulsion.  Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous injection may also be reduced by prior injection of I.V. lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to 1% Propofol Maruishi in quantities greater than 20 mg lidocaine/200 mg 1% Propofol Maruishi results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it is recommended that lidocaine be administered prior to 1% Propofol Maruishi administration or that it be added to 1% Propofol Maruishi immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg 1% Propofol Maruishi.

Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (< 1%). In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction.

Intra-arterial injection in animals did not induce local tissue effects. Accidental intra-arterial injection has been reported in patients, and other than pain, there were no major sequelae.

Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During the post-marketing period, there have been rare reports of local pain, swelling, blisters and/or tissue necrosis following accidental extravasation of 1% Propofol Maruishi injectable emulsion.

Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with 1% Propofol Maruishi injectable emulsion administration.

Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema and hypotension, occur rarely following 1% Propofol Maruishi injectable emulsion administration.

There have been rare reports of pulmonary edema in temporal relationship to the administration of 1% Propofol Maruishi injectable emulsion, although a causal relationship is unknown.

Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which 1% Propofol Maruishi injectable emulsion was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to 1% Propofol Maruishi injectable emulsion is unclear.

1% Propofol Maruishi injectable emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with 1% Propofol Maruishi injectable emulsion. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.

Intensive Care Unit Sedation

Adult Patients

(See WARNINGS and DOSAGE AND ADMINISTRATION - Handling Procedures.) The administration of 1% Propofol Maruishi injectable emulsion should be initiated as a continuous infusion and changes in the rate of administration made slowly (>5 min) in order to minimize hypotension and avoid acute overdosage. (See DOSAGE AND ADMINISTRATION.)

Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of 1% Propofol Maruishi injectable emulsion, I.V. fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III  or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression, including hypotension, apnea, airway obstruction, and oxygen desaturation.

As with other sedative medications, there is wide interpatient variability in 1% Propofol Maruishi injectable emulsion dosage requirements, and these requirements may change with time.

Failure to reduce the infusion rate in patients receiving 1% Propofol Maruishi injectable emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of 1% Propofol Maruishi injectable emulsion infusion for ICU sedation, especially when it is used for long durations.

Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of 1% Propofol Maruishi injectable emulsion should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilator support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression. Because of the rapid clearance of 1% Propofol Maruishi injectable emulsion, abrupt discontinuation of a patient's infusion may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of 1% Propofol Maruishi injectable emulsion be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes prior to extubation at which time the infusion can be discontinued.

Since 1% Propofol Maruishi injectable emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when 1% Propofol Maruishi injectable emulsion is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of 1% Propofol Maruishi injectable emulsion should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the 1% Propofol Maruishi injectable emulsion formulation; 1 mL of 1% Propofol Maruishi injectable emulsion contains approximately 0.1 g of fat (1.1 kcal).

The long-term administration of 1% Propofol Maruishi injectable emulsion to patients with renal failure and/or hepatic insufficiency has not been evaluated.

Neurosurgical Anesthesia

When 1% Propofol Maruishi injectable emulsion is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus of approximately 20 mg every 10 seconds should be utilized instead of rapid, more frequent, and/or larger boluses of 1% Propofol Maruishi injectable emulsion. Slower induction, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of 1% Propofol Maruishi injectable emulsion. (See DOSAGE AND ADMINISTRATION.)

Cardiac Anesthesia

Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Fluid deficits should be corrected prior to administration of 1% Propofol Maruishi injectable emulsion. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with 1% Propofol Maruishi injectable emulsion.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of 1% Propofol Maruishi.

Mutagenesis

1% Propofol Maruishi was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA 1538. 1% Propofol Maruishi was not mutagenic in either the gene mutation/gene conversion test using Saccharomyces cerevisiae, or in vitro cytogenetic studies in Chinese hamsters. In the in vivo mouse micronucleus assay with Chinese Hamsters 1% Propofol Maruishi administration did not produce chromosome aberrations.

Impairment Of Fertility

Female Wistar rats were administered either 0, 10, or 15 mg/kg/day 1% Propofol Maruishi intravenously from 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility. Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at intravenous doses of 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m² basis) and have revealed no evidence of impaired fertility or harm to the fetus due to 1% Propofol Maruishi. 1% Propofol Maruishi, however, has been shown to cause maternal deaths in rats and rabbits and decreased pup survival during the lactating period in dams treated with 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m² basis). The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, this drug should be used during pregnancy only if clearly needed.

Labor And Delivery

1% Propofol Maruishi injectable emulsion is not recommended for obstetrics, including cesarean section deliveries. 1% Propofol Maruishi injectable emulsion crosses the placenta, and as with other general anesthetic agents, the administration of 1% Propofol Maruishi injectable emulsion may be associated with neonatal depression.

Nursing Mothers

1% Propofol Maruishi injectable emulsion is not recommended for use in nursing mothers because 1% Propofol Maruishi injectable emulsion has been reported to be excreted in human milk and the effects of oral absorption of small amounts of 1% Propofol Maruishi are not known.

Pediatric Use

The safety and effectiveness of 1% Propofol Maruishi injectable emulsion have been established for induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2 months and older.

1% Propofol Maruishi injectable emulsion is not recommended for the induction of anesthesia in patients younger than 3 years of age and for the maintenance of anesthesia in patients younger than 2 months of age as safety and effectiveness have not been established.

In pediatric patients, administration of fentanyl concomitantly with 1% Propofol Maruishi injectable emulsion may result in serious bradycardia. (See PRECAUTIONSGeneral.)

1% Propofol Maruishi injectable emulsion is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established.

There have been anecdotal reports of serious adverse events and death in pediatric patients with upper respiratory tract infections receiving 1% Propofol Maruishi injectable emulsion for ICU sedation.

In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received 1% Propofol Maruishi injectable emulsion (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality has not been established, 1% Propofol Maruishi injectable emulsion is not indicated for sedation in pediatric patients until further studies have been performed to document its safety in that population. (See CLINICAL PHARMACOLOGY, PharmacokineticsPediatric Patients and DOSAGE AND ADMINISTRATION.)

In pediatric patients, abrupt discontinuation following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Geriatric Use

The effect of age on induction dose requirements for 1% Propofol Maruishi was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of 1% Propofol Maruishi injectable emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response. (See DOSAGE AND ADMINISTRATIONElderly, debilitated or ASA-PS III or IV patients and CLINICAL PHARMACOLOGYGeriatrics.)

WARNINGS

Use of DIPRIVAN Injectable Emulsion has been associated with both fatal and lifethreatening anaphylactic and anaphylactoid reactions.

For general anesthesia or monitored anesthesia care (MAC) sedation, DIPRIVAN Injectable Emulsion should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV patients.

For sedation of intubated, mechanically ventilated patients in the Intensive Care Unit (ICU), DIPRIVAN Injectable Emulsion should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.

Use of DIPRIVAN Injectable Emulsion infusions for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as Propofol Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes* and/or cardiac failure. The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or prolonged, high-dose infusions of propofol ( > 5 mg/kg/h for > 48h). The syndrome has also been reported following large-dose, short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation, increasing propofol dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a propofol infusion, consideration should be given to using alternative means of sedation.

*Coved ST segment elevation (similar to ECG changes of the Brugada syndrome).

Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level (see PRECAUTIONS).

DIPRIVAN Injectable Emulsion should not be coadministered through the same IV catheter with blood or plasma because compatibility has not been established. In vitro tests have shown that aggregates of the globular component of the emulsion vehicle have occurred with blood/plasma/serum from humans and animals. The clinical significance of these findings is not known.

There have been reports in which failure to use aseptic technique when handling Diprivan Injectable Emulsion was associated with microbial contamination of the product and with fever, infection, sepsis, other life-threatening illness, and death. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits (see DOSAGE AND ADMINISTRATION, Handling Procedures).

There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons. DIPRIVAN Injectable Emulsion vial is never to be accessed more than once or used on more than one person.

PRECAUTIONS

General

Adult and Pediatric Patients

A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients (see DOSAGE AND ADMINISTRATION). Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds. DIPRIVAN Injectable Emulsion use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.

Very rarely the use of DIPRIVAN Injectable Emulsion may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness. Recovery is spontaneous.

When DIPRIVAN Injectable Emulsion is administered to an epileptic patient, there is a risk of seizure during the recovery phase.

Attention should be paid to minimize pain on administration of DIPRIVAN Injectable Emulsion. Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous injection may also be reduced by prior injection of IV lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to DIPRIVAN Injectable Emulsion in quantities greater than 20 mg lidocaine/200 mg DIPRIVAN Injectable Emulsion results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it is recommended that lidocaine be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely ( < 1%). In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction.

Intra-arterial injection in animals did not induce local tissue effects. Accidental intraarterial injection has been reported in patients, and, other than pain, there were no major sequelae.

Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of DIPRIVAN Injectable Emulsion.

Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with DIPRIVAN Injectable Emulsion administration.

Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following DIPRIVAN Injectable Emulsion administration.

There have been rare reports of pulmonary edema in temporal relationship to the administration of DIPRIVAN Injectable Emulsion, although a causal relationship is unknown.

Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which DIPRIVAN Injectable Emulsion was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to DIPRIVAN Injectable Emulsion is unclear.

DIPRIVAN Injectable Emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with DIPRIVAN Injectable Emulsion. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.

Intensive Care Unit Sedation

Adult Patients

(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.) The administration of DIPRIVAN Injectable Emulsion should be initiated as a continuous infusion and changes in the rate of administration made slowly ( > 5 min) in order to minimize hypotension and avoid acute overdosage (see DOSAGE AND ADMINISTRATION).

Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of DIPRIVAN Injectable Emulsion, IV fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression, including hypotension, apnea, airway obstruction, and oxygen desaturation.

As with other sedative medications, there is wide interpatient variability in DIPRIVAN Injectable Emulsion dosage requirements, and these requirements may change with time.

Failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of DIPRIVAN Injectable Emulsion infusion for ICU sedation, especially when it is used for long durations.

Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilatory support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression. Because of the rapid clearance of DIPRIVAN Injectable Emulsion, abrupt discontinuation of a patient's infusion may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of DIPRIVAN Injectable Emulsion be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes prior to extubation, at which time the infusion can be discontinued.

Since DIPRIVAN Injectable Emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when DIPRIVAN Injectable Emulsion is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of DIPRIVAN Injectable Emulsion should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the DIPRIVAN Injectable Emulsion formulation; 1 mL of DIPRIVAN Injectable Emulsion contains approximately 0.1 g of fat (1.1 kcal).

EDTA is a strong chelator of trace metals - including zinc. Although with DIPRIVAN Injectable Emulsion there are no reports of decreased zinc levels or zinc deficiency-related adverse events, DIPRIVAN Injectable Emulsion should not be infused for longer than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses.

In clinical trials mean urinary zinc loss was approximately 2.5 to 3 mg/day in adult patients and 1.5 to 2 mg/day in pediatric patients.

In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major sepsis, the need for supplemental zinc should be considered during prolonged therapy with DIPRIVAN Injectable Emulsion.

At high doses (2 to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules. Studies to date in patients with normal or impaired renal function have not shown any alteration in renal function with DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation.

The long-term administration of DIPRIVAN Injectable Emulsion to patients with renal failure and/or hepatic insufficiency has not been evaluated.

Neurosurgical Anesthesia

When DIPRIVAN Injectable Emulsion is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus of approximately 20 mg every 10 seconds should be utilized instead of rapid, more frequent, and/or larger boluses of DIPRIVAN Injectable Emulsion. Slower induction, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of DIPRIVAN Injectable Emulsion (see DOSAGE AND ADMINISTRATION).

Cardiac Anesthesia

Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Fluid deficits should be corrected prior to administration of DIPRIVAN Injectable Emulsion. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with DIPRIVAN Injectable Emulsion.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of propofol.

Mutagenesis

Propofol was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. Propofol was not mutagenic in either the gene mutation/gene conversion test using Saccharomyces cerevisiae, or in vitro cytogenetic studies in Chinese hamsters. In the in vivo mouse micronucleus assay with Chinese Hamsters propofol administration did not produce chromosome aberrations.

Impairment of Fertility

Female Wistar rats were administered either 0, 10, or 15 mg/kg/day propofol intravenously from 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility. Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.

Pregnancy

Teratogenic Effects - Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at intravenous doses of 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m² basis) and have revealed no evidence of impaired fertility or harm to the fetus due to propofol. Propofol, however, has been shown to cause maternal deaths in rats and rabbits and decreased pup survival during the lactating period in dams treated with 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m² basis). The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, DIPRIVAN Injectable Emulsion should be used during pregnancy only if clearly needed.

Labor And Delivery

DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including cesarean section deliveries. DIPRIVAN Injectable Emulsion crosses the placenta, and as with other general anesthetic agents, the administration of DIPRIVAN Injectable Emulsion may be associated with neonatal depression.

Nursing Mothers

DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because DIPRIVAN Injectable Emulsion has been reported to be excreted in human milk and the effects of oral absorption of small amounts of propofol are not known.

Pediatric Use

The safety and effectiveness of DIPRIVAN Injectable Emulsion have been established for induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2 months and older.

DIPRIVAN Injectable Emulsion is not recommended for the induction of anesthesia in patients younger than 3 years of age and for the maintenance of anesthesia in patients younger than 2 months of age as safety and effectiveness have not been established.

In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN Injectable Emulsion may result in serious bradycardia (see PRECAUTIONS, General).

DIPRIVAN Injectable Emulsion is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established.

There have been anecdotal reports of serious adverse events and death in pediatric patients with upper respiratory tract infections receiving DIPRIVAN Injectable Emulsion for ICU sedation.

In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received DIPRIVAN Injectable Emulsion (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality has not been established, DIPRIVAN Injectable Emulsion is not indicated for sedation in pediatric patients until further studies have been performed to document its safety in that population (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Pediatric Patients and DOSAGE AND ADMINISTRATION).

In pediatric patients, abrupt discontinuation of DIPRIVAN Injectable Emulsion following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Geriatric Use

The effect of age on induction dose requirements for propofol was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of DIPRIVAN Injectable Emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response (see DOSAGE AND ADMINISTRATION, Elderly, Debilitated or ASA-PS III or IV Patients and CLINICAL PHARMACOLOGY, Geriatrics).

Effects on ability to drive and use machines

The information provided in Effects on ability to drive and use machines of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Effects on ability to drive and use machines in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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1% Propofol Maruishi 1% has moderate influence on the ability to drive and use machines. Patients should be advised that performance at skilled tasks, such as driving and operating machinery, may be impaired for some time after general anaesthesia.

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Undesirable effects

The information provided in Undesirable effects of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

General

Induction and maintenance of anaesthesia or sedation is generally smooth with minimal evidence of excitation. The most commonly reported ADRs are pharmacologically predictable side effects of an anaesthetic/sedative agent, such as hypotension. The nature, severity and incidence of adverse events observed in patients receiving 1% Propofol Maruishi 1% may be related to the condition of the recipients and the operative or therapeutic procedures being undertaken.

The following definitions of frequencies are used:

Very common (≥1/10), common (≥1/100 to <1/10), uncommon ((≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table of Adverse Drug Reactions

System Organ Class

Frequency

Undesirable Effects

Immune system disorders

Very rare

Anaphylaxis – may include angioedema, bronchospasm, erythema and hypotension

Metabolism and nutrition disorders

Not known (9)

Metabolic acidosis (5), hyperkalaemia (5), hyperlipidaemia (5)

Psychiatric disorders

Not known (9)

Euphoric mood. Drug abuse and drug dependence (8)

Nervous system disorders

Common

Headache during recovery phase

Rare

Epileptiform movements, including convulsions and opisthotonus during induction, maintenance and recovery

Very rare

Postoperative unconsciousness

Not known (9)

Involuntary movements

Cardiac disorders

Common

Bradycardia (1)

Very rare

Pulmonary oedema

Not known (9)

Cardiac arrhythmia (5), cardiac failure (5), (7)

Vascular disorders

Common

Hypotension (2)

Uncommon

Thrombosis and phlebitis

Respiratory, thoracic and mediastinal disorders

Common

Transient apnoea during induction

Not known (9)

Respiratory depression (dose dependent)

Gastrointestinal disorders

Common

Nausea and vomiting during recovery phase

Very rare

Pancreatitis

Hepatobiliary disorders

Not known (9)

Hepatomegaly (5)

Musculoskeletal and connective tissue disorders

Not known (9)

Rhabdomyolysis (3), (5)

Renal and urinary disorders

Very rare

Discolouration of urine following prolonged administration

Not known (9)

Renal failure (5)

Reproductive system and breast disorders

Very rare

Sexual disinhibition

General disorders and administration site conditions

Very common

Local pain on induction (4)

Very rare

Tissue necrosis (10) following accidental extravascular administration

Not known (9)

Local pain, swelling, following accidental extravascular administration

Investigations

Not known (9)

Brugada type ECG (5), (6)

Injury, poisoning and procedural complications

Very rare

Postoperative fever

(1) Serious bradycardias are rare. There have been isolated reports of progression to asystole.

(2) Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of 1% Propofol Maruishi.

(3) Very rare reports of rhabdomyolysis have been received where 1% Propofol Maruishi has been given at doses greater than 4 mg/kg/hr for ICU sedation.

(4) May be minimised by using the larger veins of the forearm and antecubital fossa. With 1% Propofol Maruishi 1% local pain can also be minimised by the co-administration of lidocaine.

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(6) Brugada-type ECG - elevated ST-segment and coved T-wave in ECG.

(7) Rapidly progressive cardiac failure (in some cases with fatal outcome) in adults. The cardiac failure in such cases was usually unresponsive to inotropic supportive treatment.

(8) Abuse of and drug dependence on propofol, predominantly by health care professionals.

(9) Not known as it cannot be estimated from the available clinical trial data.

(10) Necrosis has been reported where tissue viability has been impaired.

Dystonia/dyskinesia have been reported.

Local

The local pain which may occur during the induction phase of 1% Propofol Maruishi 1% anaesthesia can be minimised by the co-administration of lidocaine (see "Dosage and Administration") and by the use of the larger veins of the forearm and antecubital fossa. Thrombosis and phlebitis are rare. Accidental clinical extravasation and animal studies showed minimal tissue reaction. Intra-arterial injection in animals did not induce local tissue effects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

General

Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

Anesthesia And MAC Sedation In Adults

The following estimates of adverse events for 1% Propofol Maruishi injectable emulsion include data from clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with 1% Propofol Maruishi injectable emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship.

The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with 1% Propofol Maruishi during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.

Anesthesia In Pediatric Patients

Generally the adverse experience profile from reports of 506 1% Propofol Maruishi injectable emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with 1% Propofol Maruishi injectable emulsion during anesthesia in adults (see Pediatric percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

ICU Sedation In Adults

The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship.

Incidence greater than 1% - Probably Causally Related

  Anesthesia/MAC Sedation ICU Sedation
Cardiovascular: Bradycardia Arrhythmia [Peds: 1.2%] Tachycardia Nodal [Peds: 1.6%] Bradycardia
  Hypotension* [Peds: 17%] (see also CLINICAL PHARMACOLOGY) Decreased Cardiac Output
Central Nervous System: [Hypertension Peds: 8%] Movement* [Peds: 17%] Hypotension 26%
Injection Site: Burning/Stinging or Pain, 17.6% [Peds: 10%]  
Metabolic/Nutritional:   Hyperlipemia*
Respiratory: Apnea (see also CLINICAL PHARMACOLOGY) Respiratory Acidosis During Weaning*
Skin and Appendages: Rash [Peds: 5%]  
  Pruritus [Peds: 2%]  
Events without an * or % had an incidence of 1% to 3%
*Incidence of events 3% to 10%
  Incidence less than 1% - Probably Causally Related
  Anesthesia/MAC Sedation ICU Sedation
Body as a Whole: Anaphylaxis/Anaphylactoid Reaction, Perinatal Disorder, [Tachycardia], [Bigeminy], [Bradycardia], [Premature Ventricular Contractions], [Hemorrhage], [ECG Abnormal], [Arrhythmia Atrial], [Fever], [Extremities Pain], [Anticholinergic Syndrome]  
Cardiovascular: Premature Atrial Contractions, Syncope  
Central Nervous System: Hypertonia/Dystonia, Paresthesia Agitation
Digestive: [Hypersalivation], [Nausea]  
Hemic/Lymphatic: [Leukocytosis]  
Injection Site: [Phlebitis], [Pruritus]  
Metabolic: [Hypomagnesemia]  
Musculoskeletal: Myalgia  
Nervous: [Dizziness], [Agitation], [Chills], [Somnolence], [Delirium]  
Respiratory: Wheezing, [Cough], [Laryngospasm], [Hypoxia] Decreased Lung Function
Skin and Appendages: Flushing, Pruritus  
Special Senses: Amblyopia, [Vision Abnormal]  
Urogenital: Cloudy Urine Green Urine
  Incidence less than 1% - Causal Relationship Unknown
  Anesthesia/MAC Sedation ICU Sedation
Body as a Whole: Asthenia, Awareness, Chest Pain, Extremities Pain, Fever, Increased Drug Fever, Sepsis, Trunk Pain, Whole Body Weakness
Cardiovascular: Effect, Neck Rigidity/Stiffness, Trunk Pain Arrhythmia, Atrial Fibrillation, Atrioventricular Heart Block, Bigeminy, Bleeding, Bundle Branch Block, Cardiac Arrest, ECG Abnormal, Edema, Extrasystole, Heart Block, Hypertension, Myocardial Infarction, Myocardial Ischemia, Premature Ventricular Contractions, ST Segment Depression, Supraventricular Tachycardia, Tachycardia, Ventricular Fibrillation Arrhythmia, Atrial Fibrillation, Bigeminy, Cardiac Arrest, Extrasystole, Right Heart Failure, Ventricular Tachycardia
Central Nervous System: Abnormal Dreams, Agitation, Amorous Behavior, Anxiety, Bucking/Jerking/Thrashing, Chills/Shivering/Clonic/Myoclonic Movement, Combativeness, Confusion, Delirium, Depression, Dizziness, Emotional Lability, Euphoria, Fatigue, Hallucinations, Headache, Hypotonia, Hysteria, Insomnia, Moaning, Neuropathy, Opisthotonos, Rigidity, Seizures, Somnolence, Tremor, Twitching Chills/Shivering, Intracranial Hypertension, Seizures, Somnolence, Thinking Abnormal
Digestive: Cramping, Diarrhea, Dry Mouth, Enlarged Parotid, Nausea, Swallowing, Vomiting Ileus, Liver Function Abnormal
Hematologic/Lymphatic: Coagulation Disorder, Leukocytosis  
Injection Site: Hives/Itching, Phlebitis, Redness/Discoloration  
Metabolic/Nutritional: Hyperkalemia, Hyperlipemia BUN Increased, Creatinine Increased, Dehydration, Hyperglycemia, Metabolic Acidosis, Osmolality Increased
Respiratory: Bronchospasm, Burning in Throat, Cough, Dyspnea, Hiccough, Hyperventilation, Hypoventilation, Hypoxia, Laryngospasm, Pharyngitis, Sneezing, Tachypnea, Upper Airway Obstruction Hypoxia
Skin and Appendages: Conjunctival Hyperemia, Diaphoresis, Urticaria Rash
Special Senses: Diplopia, Ear Pain, Eye Pain, Nystagmus, Taste Perversion, Tinnitus  
Urogenital: Oliguria, Urine Retention Kidney Failure

General

Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent  US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

Anesthesia And MAC Sedation In Adults

The following estimates of adverse events for DIPRIVAN Injectable Emulsion include data from clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with DIPRIVAN Injectable Emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship.

The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with DIPRIVAN Injectable Emulsion during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.

Anesthesia In Pediatric Patients

Generally the adverse experience profile from reports of 506 DIPRIVAN Injectable Emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with DIPRIVAN Injectable Emulsion during anesthesia in adults (see Pediatric percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

ICU Sedation In Adults

The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship.

Incidence greater than 1% - Probably Causally Related

  Anesthesia/MAC Sedation ICU Sedation
Cardiovascular: Bradycardia Bradycardia
Arrhythmia [Peds: 1.2%]  
Tachycardia Nodal [Peds: 1.6%]
Hypotension* [Peds: 17%] (see also CLINICAL PHARMACOLOGY) Decreased Cardiac Output
  Hypertension [Peds: 8%] Hypotension 26%
Central Nervous System: Movement* [Peds: 17%]  
Injection Site: Burning/Stinging or Pain, 17.6% [Peds: 10%]  
Metabolic/Nutritional:   Hyperlipemia*
Respiratory: Apnea (see also CLINICAL PHARMACOLOGY) Respiratory Acidosis During Weaning*
Skin and Appendages: Rash [Peds: 5%] Pruritus [Peds: 2%]  
Events without an * or % had an incidence of 1% to 3%
*Incidence of events 3% to 10%

Incidence less than 1% - Probably Causally Related

  Anesthesia/MAC Sedation ICU Sedation
Body as a Whole: Anaphylaxis/Anaphylactoid Reaction Perinatal Disorder
[Tachycardia]
[Bigeminy]
[Bradycardia]
[Premature Ventricular Contractions]
[Hemorrhage]
[ECG Abnormal]
[Arrhythmia Atrial]
[Fever]
[Extremities Pain]
[Anticholinergic Syndrome]
 
Cardiovascular: Premature Atrial Contractions Syncope  
Central Nervous System: Hypertonia/Dystonia, Paresthesia Agitation
Digestive: [Hypersalivation]
[Nausea]
 
Hemic/Lymphatic: [Leukocytosis]  
Injection Site: [Phlebitis]
[Pruritus]
 
Metabolic: [Hypomagnesemia]  
Musculoskeletal: Myalgia  
Nervous: [Dizziness]
[Agitation]
[Chills]
[Somnolence]
[Delirium]
 
Respiratory: Wheezing
[Cough]
[Laryngospasm]
[Hypoxia]
Decreased Lung Function
Skin and Appendages: Flushing, Pruritus  
Special Senses: Amblyopia
[Vision Abnormal]
 
Urogenital: Cloudy Urine Green Urine

Incidence less than 1% - Causal Relationship Unknown

  Anesthesia/MAC Sedation ICU Sedation
Body as a Whole: Asthenia, Awareness, Chest Pain, Extremities Pain, Fever, Increased Drug Effect, Neck Rigidity/Stiffness, Trunk Pain Fever, Sepsis, Trunk Pain, Whole Body Weakness
Cardiovascular: Arrhythmia, Atrial Fibrillation, Atrioventricular Heart Block, Bigeminy, Bleeding, Bundle Branch Block, Cardiac Arrest, ECG Abnormal, Edema, Extrasystole, Heart Block, Hypertension, Myocardial Infarction, Myocardial Ischemia, Premature Ventricular Contractions, ST Segment Depression, Supraventricular Tachycardia, Tachycardia, Ventricular Fibrillation Arrhythmia, Atrial Fibrillation, Bigeminy, Cardiac Arrest, Extrasystole, Right Heart Failure, Ventricular Tachycardia
Central Nervous System: Abnormal Dreams, Agitation, Amorous Behavior, Anxiety, Bucking/Jerking/Thrashing, Chills/Shivering/Clonic/Myoclonic Movement, Combativeness, Confusion, Delirium, Depression, Dizziness, Emotional Lability, Euphoria, Fatigue, Hallucinations, Headache, Hypotonia, Hysteria, Insomnia, Moaning, Neuropathy, Opisthotonos, Rigidity, Seizures, Somnolence, Tremor, Twitching Chills/Shivering, Intracranial Hypertension, Seizures, Somnolence, Thinking Abnormal
Digestive: Cramping, Diarrhea, Dry Mouth, Enlarged Parotid, Nausea, Swallowing, Vomiting Ileus, Liver Function Abnormal
Hematologic/ Lymphatic: Coagulation Disorder, Leukocytosis  
Injection Site: Hives/Itching, Phlebitis, Redness/Discoloration  
Metabolic/ Nutritional: Hyperkalemia, Hyperlipemia BUN Increased, Creatinine Increased, Dehydration, Hyperglycemia, Metabolic Acidosis, Osmolality Increased
Respiratory: Bronchospasm, Burning in Throat, Cough, Dyspnea, Hiccough, Hyperventilation, Hypoventilation, Hypoxia, Laryngospasm, Pharyngitis, Sneezing, Tachypnea, Upper Airway Obstruction Hypoxia
Skin and Appendages: Conjunctival Hyperemia, Diaphoresis, Rash
  Urticaria  
Special Senses: Diplopia, Ear Pain, Eye Pain,  
  Nystagmus, Taste Perversion,  
  Tinnitus  
Urogenital: Oliguria, Urine Retention Kidney Failure

Drug Abuse And Dependence

There are reports of the abuse of propofol for recreational and other improper purposes, which have resulted in fatalities and other injuries. Instances of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have also been reported, which have resulted in fatalities and other injuries. Inventories of DIPRIVAN Injectable Emulsion should be stored and managed to prevent the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting.

Overdose

The information provided in Overdose of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

Accidental overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression would require lowering of the patient's head and, if severe, use of plasma expanders and pressor agents.

If overdosage occurs, 1% Propofol Maruishi injectable emulsion administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.

If overdosage occurs, DIPRIVAN Injectable Emulsion administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.

Pharmacodynamic properties

The information provided in Pharmacodynamic properties of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

Pharmacotherapeutic group: Other general anaesthetics

ATC code: N01AX10

Mechanism of action

Propofol (2, 6-diisopropylphenol) is a short-acting general anaesthetic agent with a rapid onset of action of approximately 30 seconds. Recovery from anaesthesia is usually rapid. The mechanism of action, like all general anaesthetics, is poorly understood. However, propofol is thought to produce its sedative/anaesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAA receptors.

Pharmacodynamic properties

In general, falls in mean arterial blood pressure and slight changes in heart rate are observed when 1% Propofol Maruishi 1% is administered for induction and maintenance of anaesthesia. However, the haemodynamic parameters normally remain relatively stable during maintenance and the incidence of untoward haemodynamic changes is low.

Although ventilatory depression can occur following administration of 1% Propofol Maruishi 1%, any effects are qualitatively similar to those of other intravenous anaesthetic agents and are readily manageable in clinical practice.

1% Propofol Maruishi 1% reduces cerebral blood flow, intracranial pressure and cerebral metabolism. The reduction in intracranial pressure is greater in patients with an elevated baseline intracranial pressure.

Clinical efficacy and safety

Recovery from anaesthesia is usually rapid and clear headed with a low incidence of headache and post-operative nausea and vomiting.

In general, there is less post-operative nausea and vomiting following anaesthesia with 1% Propofol Maruishi 1% than following anaesthesia with inhalational agents. There is evidence that this may be related to a reduced emetic potential of propofol.

1% Propofol Maruishi 1%, at the concentrations likely to occur clinically, does not inhibit the synthesis of adrenocortical hormones.

Paediatric population

Limited studies on the duration of propofol based anaesthesia in children indicate safety and efficacy is unchanged up to duration of 4 hours. Literature evidence of use in children documents use for prolonged procedures without changes in safety or efficacy.

Pharmacodynamic properties of 1% Propofol Maruishi are dependent upon the therapeutic blood 1% Propofol Maruishi concentrations. Steady-state 1% Propofol Maruishi blood concentrations are generally proportional to infusion rates. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dosage adjustments in order to assess clinical effects.

The hemodynamic effects of 1% Propofol Maruishi injectable emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of 1% Propofol Maruishi injectable emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of 1% Propofol Maruishi injectable emulsion during induction of anesthesia are generally more pronounced than with other intravenous (I.V.) induction agents.

Induction of anesthesia with 1% Propofol Maruishi injectable emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received 1% Propofol Maruishi injectable emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of 1% Propofol Maruishi injectable emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, 1% Propofol Maruishi injectable emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of 1% Propofol Maruishi injectable emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of 1% Propofol Maruishi injectable emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that 1% Propofol Maruishi injectable emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that 1% Propofol Maruishi injectable emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that 1% Propofol Maruishi injectable emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. 1% Propofol Maruishi injectable emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials - Neuroanesthesia).

Clinical studies indicate that 1% Propofol Maruishi injectable emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of 1% Propofol Maruishi injectable emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving 1% Propofol Maruishi injectable emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.

The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents.

Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASAPS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials, Neuroanesthesia).

Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacokinetic properties

The information provided in Pharmacokinetic properties of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

Absorption

When 1% Propofol Maruishi 1% is used to maintain anaesthesia, blood concentrations asymptotically approach the steady-state value for the given administration rate.

Distribution

Propofol is extensively distributed and rapidly cleared from the body (total body clearance 1.5–2 litres/minute).

Elimination

The decline in propofol concentrations following a bolus dose or following the termination of an infusion can be described by a three compartment open model with very rapid distribution (half-life 2 –4 minutes), rapid elimination (half-life 30 – 60 minutes), and a slower final phase, representative of redistribution of propofol from poorly perfused tissue.

Clearance occurs by metabolic processes, mainly in the liver where it is blood flow dependent, to form inactive conjugates of propofol and its corresponding quinol, which are excreted in urine.

After a single dose of 3 mg/kg intravenously, propofol clearance/kg body weight increased with age as follows: Median clearance was considerably lower in neonates <1 month old (n=25) (20 ml/kg/min) compared to older children (n= 36, age range 4 months–7 years). Additionally inter-individual variability was considerable in neonates (range 3.7–78 ml/kg/min). Due to this limited trial data that indicates a large variability, no dose recommendations can be given for this age group.

Median propofol clearance in older aged children after a single 3 mg/kg bolus was 37.5 ml/min/kg (4-24 months) (n=8), 38.7 ml/min/kg (11–43 months) (n=6), 48 ml/min/kg (1–3 years)(n=12), 28.2 ml/min/kg (4–7 years)(n=10) as compared with 23.6 ml/min/kg in adults (n=6).

Linearity

The pharmacokinetics are linear over the recommended range of infusion rates of 1% Propofol Maruishi 1%.

Pediatric Patients and DOSAGE AND ADMINISTRATION.)

In pediatric patients, abrupt discontinuation following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Geriatric Use

The effect of age on induction dose requirements for 1% Propofol Maruishi was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of 1% Propofol Maruishi injectable emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response. (See DOSAGE AND ADMINISTRATIONElderly, debilitated or ASA-PS III or IV patients and CLINICAL PHARMACOLOGYGeriatrics.)

Overdosage & Contraindications

OVERDOSE

If overdosage occurs, 1% Propofol Maruishi injectable emulsion administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.

CONTRAINDICATIONS

1% Propofol Maruishi injectable emulsion is contraindicated in patients with a known hypersensitivity to 1% Propofol Maruishi injectable emulsion or any of its components.

1% Propofol Maruishi injectable emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

General

1% Propofol Maruishi is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of 1% Propofol Maruishi induces hypnosis with minimal excitation, usually within 40 seconds from the start of injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia.

Pharmacodynamics

Pharmacodynamic properties of 1% Propofol Maruishi are dependent upon the therapeutic blood 1% Propofol Maruishi concentrations. Steady-state 1% Propofol Maruishi blood concentrations are generally proportional to infusion rates. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dosage adjustments in order to assess clinical effects.

The hemodynamic effects of 1% Propofol Maruishi injectable emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of 1% Propofol Maruishi injectable emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of 1% Propofol Maruishi injectable emulsion during induction of anesthesia are generally more pronounced than with other intravenous (I.V.) induction agents.

Induction of anesthesia with 1% Propofol Maruishi injectable emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received 1% Propofol Maruishi injectable emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of 1% Propofol Maruishi injectable emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, 1% Propofol Maruishi injectable emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of 1% Propofol Maruishi injectable emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of 1% Propofol Maruishi injectable emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that 1% Propofol Maruishi injectable emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that 1% Propofol Maruishi injectable emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that 1% Propofol Maruishi injectable emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. 1% Propofol Maruishi injectable emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials - Neuroanesthesia).

Clinical studies indicate that 1% Propofol Maruishi injectable emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of 1% Propofol Maruishi injectable emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving 1% Propofol Maruishi injectable emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacokinetics

The pharmacokinetics of 1% Propofol Maruishi are well described by a three compartment linear model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.

Following an I.V. bolus dose, there is rapid equilibration between the plasma and the brain, thus accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. Distribution accounts for about half of this decline following a bolus of 1% Propofol Maruishi.

However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion. When equilibration occurs there is no longer a net transfer of 1% Propofol Maruishi between tissues and plasma.

Discontinuation of the recommended doses of 1% Propofol Maruishi injectable emulsion after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood 1% Propofol Maruishi concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of 1% Propofol Maruishi, such that the reduction in circulating 1% Propofol Maruishi is slowed and the time to awakening is increased.

By daily titration of 1% Propofol Maruishi injectable emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, 1% Propofol Maruishi redistribution from fat and muscle to the plasma, can be significant and slow recovery.

The figure below illustrates the fall of plasma 1% Propofol Maruishi levels following infusions of various durations to provide ICU sedation.

The large contribution of distribution (about 50%) to the fall of 1% Propofol Maruishi plasma levels following brief infusions means that after very long infusions a reduction in infusion rate is appropriate by as much as half the initial infusion rate in order to maintain a constant plasma level. Therefore, failure to reduce the infusion rate in patients receiving 1% Propofol Maruishi injectable emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of 1% Propofol Maruishi injectable emulsion infusion for ICU sedation.

Adults

1% Propofol Maruishi clearance ranges from 23 to 50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults). It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. 1% Propofol Maruishi has a steady state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not been observed. The terminal half-life of 1% Propofol Maruishi after a 10-day infusion is 1 to 3 days.

Geriatrics

With increasing patient age, the dose of 1% Propofol Maruishi needed to achieve a defined anesthetic endpoint (dose-requirement) decreases. This does not appear to be an age-related change in pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing patient age, pharmacokinetic changes are such that for a given I.V. bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or arterial oxygen desaturation. The higher plasma levels reflect age-related decrease in volume of distribution and intercompartmental clearance. Lower doses are therefore recommended for initiation and maintenance of sedation and anesthesia in elderly patients. (See DOSAGE AND ADMINISTRATION.)

Pediatrics

The pharmacokinetics of 1% Propofol Maruishi were studied in children between 3 and 12 years of age who received 1% Propofol Maruishi injectable emulsion for periods of approximately 1 to 2 hours. The observed distribution and clearance of 1% Propofol Maruishi in these children were similar to adults.

Organ Failure

The pharmacokinetics of 1% Propofol Maruishi do not appear to be different in people with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of acute hepatic or renal failure on the pharmacokinetics of 1% Propofol Maruishi have not been studied.

Clinical Trials

Anesthesia And Monitored Anesthesia Care (MAC) Sedation

Pediatric Anesthesia

1% Propofol Maruishi injectable emulsion was studied in clinical trials which included cardiac surgical patients. Most patients were 3 years of age or older. The majority of the patients were healthy ASA-PS I or II patients. The range of doses in these studies are described in Tables 1 and 2.

TABLE 1: PEDIATRIC INDUCTION OF ANESTHESIA

Age Range Induction Dose Median (range) Injection Duration Median (range)
Birth through 16 years 2.5 mg/kg (1 - 3.6) 20 sec. (6 - 45)

TABLE 2: PEDIATRIC MAINTENANCE OF ANESTHESIA

Age Range Maintenance Dosage (mcg/kg/min) Duration (minutes)
2 months to 2 years 199 (82 - 394) 65 (12 - 282)
2 to 12 years 188 (12 - 1041) 69 (23 - 374)
>12 through 16 years 161 (84 - 359) 69 (26 - 251)

Neuroanesthesia

1% Propofol Maruishi injectable emulsion was studied in patients undergoing craniotomy for supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior x lateral) was 31 mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively. Anesthesia was induced with a median 1% Propofol Maruishi dose of 1.4 mg/kg (range: 0.9 to 6.9 mg/kg) and maintained with a median maintenance 1% Propofol Maruishi dose of 146 mcg/kg/min (range: 68 to 425 mcg/kg/min). The median duration of the 1% Propofol Maruishi maintenance infusion was 285 minutes (range: 48 to 622 minutes).

1% Propofol Maruishi injectable emulsion was administered by infusion in a controlled clinical trial to evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17% (mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), 1% Propofol Maruishi injectable emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.

Intensive Care Unit (ICU) Sedation

Adult Patients

1% Propofol Maruishi injectable emulsion was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received 1% Propofol Maruishi injectable emulsion and comprise the overall safety database for ICU sedation.

Across all clinical studies, the mean infusion maintenance rate for all 1% Propofol Maruishi injectable emulsion patients was 27 ± 21 mcg/kg/min. The maintenance infusion rates required to maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for analgesia. Some patients also received benzodiazepines and/or neuromuscular blocking agents. During long-term maintenance of sedation, some ICU patients were awakened once or twice every 24 hours for assessment of neurologic or respiratory function.

In Medical and Postsurgical ICU studies comparing 1% Propofol Maruishi injectable emulsion to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators, 1% Propofol Maruishi injectable emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect that 1% Propofol Maruishi injectable emulsion has been used safely in patients with a history of porphyria or malignant hyperthermia.

In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, adequate sedation was maintained with 1% Propofol Maruishi injectable emulsion or morphine. There were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery between the treatment groups. In literature reports of severely head-injured patients in Neurosurgical ICUs, 1% Propofol Maruishi injectable emulsion infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion pressure.

1% Propofol Maruishi injectable emulsion was found to be effective in status epilepticus which was refractory to the standard anticonvulsant therapies. For these patients, as well as for ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill patient populations.

Pediatric Patients

A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of 1% Propofol Maruishi versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either 1% Propofol Maruishi 2% (113 patients), 1% Propofol Maruishi 1% (109 patients), or an SSA (e.g., lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). 1% Propofol Maruishi therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The results of the study showed an increase in the number of deaths in patients treated with 1% Propofol Maruishi as compared to SSAs. Of the 25 patients who died during the trial or within the 28-day follow-up period: 12 (11% were) in the 1% Propofol Maruishi 2% treatment group, 9 (8% were) in the 1% Propofol Maruishi 1% treatment group, and 4% were (4%) in the SSA treatment group. The differences in mortality rate between the groups were not statistically significant. Review of the deaths failed to reveal a correlation with underlying disease status or a correlation to the drug or a definitive pattern to the causes of death.

Cardiac Anesthesia

1% Propofol Maruishi injectable emulsion was evaluated in clinical trials involving patients undergoing coronary artery bypass graft (CABG).

In post-CABG (coronary artery bypass graft) patients, the maintenance rate of 1% Propofol Maruishi administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving 1% Propofol Maruishi injectable emulsion required 35% less nitroprusside than midazolam patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular effects in patients with severely compromised ventricular function.

, Pediatric Patients and DOSAGE AND ADMINISTRATION).

In pediatric patients, abrupt discontinuation of DIPRIVAN Injectable Emulsion following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Geriatric Use

The effect of age on induction dose requirements for propofol was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of DIPRIVAN Injectable Emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response (see DOSAGE AND ADMINISTRATION, Elderly, Debilitated or ASA-PS III or IV Patients and CLINICAL PHARMACOLOGY, Geriatrics).

Overdosage & Contraindications

OVERDOSE

If overdosage occurs, DIPRIVAN Injectable Emulsion administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.

CONTRAINDICATIONS

DIPRIVAN Injectable Emulsion is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN Injectable Emulsion components.

DIPRIVAN Injectable Emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

General

DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol induces hypnosis, with minimal excitation, usually within 40 seconds from the start of injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia. The mechanism of action, like all general anesthetics, is poorly understood. However, propofol is thought to produce its sedative/anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAa receptors.

Pharmacodynamics

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.

The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents.

Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASAPS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials, Neuroanesthesia).

Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacokinetics

The pharmacokinetics of propofol are well described by a three compartment linear model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.

Following an IV bolus dose, there is rapid equilibration between the plasma and the brain, accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. Distribution accounts for about half of this decline following a bolus of propofol. However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion. When equilibration occurs there is no longer a net transfer of propofol between tissues and plasma.

Discontinuation of the recommended doses of DIPRIVAN Injectable Emulsion after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and the time to awakening is increased.

By daily titration of DIPRIVAN Injectable Emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, propofol redistribution from fat and muscle to the plasma can be significant and slow recovery.

The figure below illustrates the fall of plasma propofol levels following infusions of various durations to provide ICU sedation.

The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief infusions means that after very long infusions a reduction in the infusion rate is appropriate by as much as half the initial infusion rate in order to maintain a constant plasma level. Therefore, failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of DIPRIVAN Injectable Emulsion infusion for ICU sedation.

Adults

Propofol clearance ranges from 23 to 50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults). It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. Propofol has a steady-state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not been observed. The terminal half-life of propofol after a 10-day infusion is 1 to 3 days.

Geriatrics

With increasing patient age, the dose of propofol needed to achieve a defined anesthetic end point (dose-requirement) decreases. This does not appear to be an age-related change in pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing patient age, pharmacokinetic changes are such that, for a given IV bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or arterial oxygen desaturation. The higher plasma levels reflect an age-related decrease in volume of distribution and intercompartmental clearance. Lower doses are therefore recommended for initiation and maintenance of sedation and anesthesia in elderly patients (see DOSAGE AND ADMINISTRATION).

Pediatrics

The pharmacokinetics of propofol were studied in children between 3 and 12 years of age who received DIPRIVAN Injectable Emulsion for periods of approximately 1 to 2 hours. The observed distribution and clearance of propofol in these children were similar to adults.

Organ Failure

The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of acute hepatic or renal failure on the pharmacokinetics of propofol have not been studied.

Clinical Trials

Anesthesia and Monitored Anesthesia Care (MAC) Sedation

Pediatric Anesthesia

DIPRIVAN Injectable Emulsion was studied in clinical trials which included cardiac surgical patients. Most patients were 3 years of age or older. The majority of the patients were healthy ASA-PS I or II patients. The range of doses in these studies are described in Tables 1 and 2.

TABLE 1: PEDIATRIC INDUCTION OF ANESTHESIA

Age Range Induction Dose Median (range) Injection Duration Median (range)
Birth through 16 years 2.5 mg/kg (1 to 3.6) 20 sec. (6 to 45)

TABLE 2: PEDIATRIC MAINTENANCE OF ANESTHESIA

Age Range Maintenance Dosage (mcg/kg/min) Duration (minutes)
2 months to 2 years 199 (82 to 394) 65 (12 to 282)
2 to 12 years 188 (12 to 1041) 69 (23 to 374)
> 12 through 16 years 161 (84 to 359) 69 (26 to 251)

Neuroanesthesia

DIPRIVAN Injectable Emulsion was studied in patients undergoing craniotomy for supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior x lateral) was 31 mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively. Anesthesia was induced with a median DIPRIVAN dose of 1.4 mg/kg (range: 0.9 to 6.9 mg/kg) and maintained with a median maintenance DIPRIVAN dose of 146 mcg/kg/min (range: 68 to 425 mcg/kg/min). The median duration of the DIPRIVAN Injectable Emulsion maintenance infusion was 285 minutes (range: 48 to 622 minutes).

DIPRIVAN Injectable Emulsion was administered by infusion in a controlled clinical trial to evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17% (mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), DIPRIVAN Injectable Emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.

Intensive Care Unit (ICU) Sedation

Adult Patients

DIPRIVAN Injectable Emulsion was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received DIPRIVAN Injectable Emulsion and comprise the overall safety database for ICU sedation.

Across all clinical studies, the mean infusion maintenance rate for all DIPRIVAN Injectable Emulsion patients was 27 ± 21 mcg/kg/min. The maintenance infusion rates required to maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for analgesia. Some patients also received benzodiazepines and/or neuromuscular blocking agents. During long-term maintenance of sedation, some ICU patients were awakened once or twice every 24 hours for assessment of neurologic or respiratory function.

In Medical and Postsurgical ICU studies comparing DIPRIVAN Injectable Emulsion to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators, DIPRIVAN Injectable Emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect that DIPRIVAN Injectable Emulsion has been used safely in patients with a history of porphyria or malignant hyperthermia.

In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, adequate sedation was maintained with DIPRIVAN Injectable Emulsion or morphine. There were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery between the treatment groups. In literature reports of severely head injured patients in Neurosurgical ICUs, DIPRIVAN Injectable Emulsion infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion pressure.

DIPRIVAN Injectable Emulsion was found to be effective in status epilepticus which was refractory to the standard anticonvulsant therapies. For these patients, as well as for ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill patient populations.

Pediatric Patients

A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of DIPRIVAN Injectable Emulsion versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either DIPRIVAN Injectable Emulsion 2%, (113 patients), DIPRIVAN Injectable Emulsion 1%, (109 patients), or an SSA (eg, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). DIPRIVAN Injectable Emulsion therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The results of the study showed an increase in the number of deaths in patients treated with DIPRIVAN Injectable Emulsion as compared to SSAs. Of the 25 patients who died during the trial or within the 28-day followup period: 12 (11% were) in the DIPRIVAN Injectable Emulsion 2% treatment group, 9 (8% were) in the DIPRIVAN Injectable Emulsion 1% treatment group, and 4% were (4%) in the SSA treatment group. The differences in mortality rate between the groups were not statistically significant. Review of the deaths failed to reveal a correlation with underlying disease status or a correlation to the drug or a definitive pattern to the causes of death.

Cardiac Anesthesia

DIPRIVAN Injectable Emulsion was evaluated in clinical trials involving patients undergoing coronary artery bypass graft (CABG).

In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving DIPRIVAN Injectable Emulsion required 35% less nitroprusside than midazolam patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular effects in patients with severely compromised ventricular function.

Pharmacotherapeutic group

The information provided in Pharmacotherapeutic group of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Other general anaesthetics

Preclinical safety data

The information provided in Preclinical safety data of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Propofol is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

Incompatibilities

The information provided in Incompatibilities of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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The neuromuscular blocking agents, atracurium and mivacurium should not be given through the same intravenous line as 1% Propofol Maruishi 1% without prior flushing.

Special precautions for disposal and other handling

The information provided in Special precautions for disposal and other handling of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Special precautions for disposal and other handling in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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In-use precautions

Containers should be shaken before use.

Any portion of the contents remaining after use should be discarded.

1% Propofol Maruishi 1% should not be mixed prior to administration with injections or infusion fluids other than 5% Dextrose or Lidocaine Injection .

Name of the medicinal product
1% Propofol Maruishi
Qualitative and quantitative composition
Propofol
Therapeutic indications
The information provided in Therapeutic indications of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

1% Propofol Maruishi 1% is a short-acting intravenous general anaesthetic for:

• Induction and maintenance of general anaesthesia in adults and children >1 month.

• Sedation for diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia in adults and children >1 month.

• Sedation of ventilated patients >16 years of age in the intensive care unit.

1% Propofol Maruishi injectable emulsion is an I.V. sedative-hypnotic agent that can be used as described in the table below.

TABLE 3: INDICATIONS FOR 1% Propofol Maruishi INJECTABLE EMULSION

Indication Approved Patient Population
Initiation and maintenance of Monitored Anesthesia Care (MAC) sedation Adults only
Combined sedation and regional anesthesia Adults only (See PRECAUTIONS)
Induction of General Anesthesia Patients ≥ 3 years of age
Maintenance of General Anesthesia Patients ≥ 2 months of age
Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients Adults only

Safety, effectiveness and dosing guidelines for 1% Propofol Maruishi injectable emulsion have not been established for MAC Sedation in the pediatric population; therefore, it is not recommended for this use. (See PRECAUTIONS - Pediatric Use.)

1% Propofol Maruishi injectable emulsion is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness have not been established in those populations.

In the Intensive Care Unit (ICU), 1% Propofol Maruishi injectable emulsion can be administered to intubated, mechanically ventilated adult patients to provide continuous sedation and control of stress responses, only by persons skilled in the medical management of critically ill patients and trained in cardiovascular resuscitation and airway management.

1% Propofol Maruishi injectable emulsion is not indicated for use in Pediatric ICU sedation since the safety of this regimen has not been established. (See PRECAUTIONS - Pediatric Use.)

1% Propofol Maruishi injectable emulsion is not recommended for obstetrics, including Cesarean section deliveries. 1% Propofol Maruishi injectable emulsion crosses the placenta, and as with other general anesthetic agents, the administration of 1% Propofol Maruishi injectable emulsion may be associated with neonatal depression. (See PRECAUTIONS.)

1% Propofol Maruishi is not recommended for use in nursing mothers because 1% Propofol Maruishi injectable emulsion has been reported to be excreted in human milk and the effects of oral absorption of small amounts of 1% Propofol Maruishi are not known. (See PRECAUTIONS.)

DIPRIVAN Injectable Emulsion is an IV sedative-hypnotic agent that can be used as described in the table below.

Table 3:  Indications for DIPRIVAN Injectable Emulsion

Indication Approved Patient Population
Initiation and maintenance of Monitored Anesthesia Care (MAC) sedation Adults only
Combined sedation and regional anesthesia Adults only (see PRECAUTIONS)
Induction of General Anesthesia Patients ≥ 3 years of age
Maintenance of General Anesthesia Patients ≥ 2 months of age
Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients Adults only

Safety, effectiveness and dosing guidelines for DIPRIVAN Injectable Emulsion have not been established for MAC Sedation in the pediatric population; therefore, it is not recommended for this use (see PRECAUTIONS, Pediatric Use).

DIPRIVAN Injectable Emulsion is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness have not been established in those populations.

In the Intensive Care Unit (ICU), DIPRIVAN Injectable Emulsion can be administered to intubated, mechanically ventilated adult patients to provide continuous sedation and control of stress responses only by persons skilled in the medical management of critically ill patients and trained in cardiovascular resuscitation and airway management.

DIPRIVAN Injectable Emulsion is not indicated for use in Pediatric ICU sedation since the safety of this regimen has not been established (see PRECAUTIONS, Pediatric Use).

DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including Cesarean section deliveries. DIPRIVAN Injectable Emulsion crosses the placenta, and as with other general anesthetic agents, the administration of DIPRIVAN Injectable Emulsion may be associated with neonatal depression (see PRECAUTIONS).

DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because propofol has been reported to be excreted in human milk, and the effects of oral absorption of small amounts of propofol are not known (see PRECAUTIONS).

Dosage (Posology) and method of administration
The information provided in Dosage (Posology) and method of administration of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

Posology

<5. Such use is restricted to induction and maintenance of anaesthesia in adults. The 'Diprifusor' TCI system is not recommended for use in ICU sedation or sedation for surgical and diagnostic procedures, or in children.

4.2.1 Induction of General Anaesthesia

Adults

In unpremedicated and premedicated patients, it is recommended that 1% Propofol Maruishi 1% should be titrated (approximately 4 ml [40 mg] every 10 seconds in an average healthy adult by bolus injection or infusion) against the response of the patient until the clinical signs show the onset of anaesthesia. Most adult patients aged less than 55 years are likely to require 1.5–2.5 mg/kg of 1% Propofol Maruishi 1%. The total dose required can be reduced by lower rates of administration (2–5 ml/min [20–50 mg/min]). Over this age, the requirement will generally be less. In patients of ASA Grades 3 and 4, lower rates of administration should be used (approximately 2 ml [20 mg] every 10 seconds).

Older people

In older people the dose requirement for induction of anaesthesia with 1% Propofol Maruishi 1% is reduced. The reduction should take into account of the physical status and age of the patient. The reduced dose should be given at a slower rate and titrated against the response.

Paediatric population

1% Propofol Maruishi 1% is not recommended for induction of anaesthesia in children aged less than 1 month.

For induction of anaesthesia in children over 1 month of age, 1% Propofol Maruishi 1% should be titrated slowly until clinical signs show the onset of anaesthesia. The dose should be adjusted according to age and/or body weight. Most patients over 8 years of age require approximately 2.5 mg/kg body weight of 1% Propofol Maruishi 1% for induction of anaesthesia. In younger children, especially between the age of 1 month and 3 years, dose requirements may be higher (2.5–4 mg/kg body weight).

<).

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is not recommended for induction of general anaesthesia in children.

4.2.2 Maintenance of General Anaesthesia

Adults

Anaesthesia can be maintained by administering 1% Propofol Maruishi 1% either by continuous infusion or by repeat bolus injections to prevent the clinical signs of light anaesthesia. Recovery from anaesthesia is typically rapid and it is therefore important to maintain 1% Propofol Maruishi 1% administration until the end of the procedure.

Continuous Infusion

The required rate of administration varies considerably between patients, but rates in the region of 4–12 mg/kg/h usually maintain satisfactory anaesthesia.

Repeat Bolus Injections

If a technique involving repeat bolus injections is used, increments of 25 mg (2.5 ml) to 50 mg (5.0 ml) may be given according to clinical need.

Older people

When 1% Propofol Maruishi 1% is used for maintenance of anaesthesia the rate of infusion or 'target concentration' should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.

Paediatric population

1% Propofol Maruishi 1% is not recommended for maintenance of anaesthesia in children aged less than 1 month.

Anaesthesia can be maintained in children over 1 month of age by administering 1% Propofol Maruishi 1% by infusion or repeated bolus injection to maintain the depth of anaesthesia required. The required rate of administration varies considerably between patients, but rates in the region of 9–15 mg/kg/h usually achieve satisfactory anaesthesia. In younger children, especially between the age of 1 month and 3 years, dose requirements may be higher.

<).

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is not recommended for maintenance of general anaesthesia in children.

4.2.3 Sedation During Intensive Care

Adults

For sedation during intensive care it is advised that 1% Propofol Maruishi 1% should be administered by continuous infusion. The infusion rate should be determined by the desired depth of sedation. In most patients sufficient sedation can be obtained with a dosage of 0.3–4 mg/kg/h of 1% Propofol Maruishi 1% (See 4.4 Special warnings and precautions for use). 1% Propofol Maruishi 1% is not indicated for sedation in intensive care of patients of 16 years of age or younger (see

NOTE: CONTAINS BENZYL ALCOHOL (See PRECAUTIONS section.)

1% Propofol Maruishi blood concentrations at steady state are generally proportional to infusion rates, especially in individual patients. Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

When administering 1% Propofol Maruishi injectable emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates. When infusing 1% Propofol Maruishi injectable emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of 1% Propofol Maruishi injectable emulsion.

For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate 1% Propofol Maruishi injectable emulsion infusion to provide satisfactory anesthesia. With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of 1% Propofol Maruishi injectable emulsion and/or opioids should be increased in order to provide adequate anesthesia.

Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of 1% Propofol Maruishi injectable emulsion at rates higher than are clinically necessary. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery time.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by 1% Propofol Maruishi. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary 1% Propofol Maruishi injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.

Induction Of General Anesthesia

Adult Patients

Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of 1% Propofol Maruishi injectable emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, 1% Propofol Maruishi injectable emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of 1% Propofol Maruishi injectable emulsion.

Elderly, Debilitated, Or ASA-PS III Or IV Patients

It is important to be familiar and experienced with the intravenous use of 1% Propofol Maruishi injectable emulsion before treating elderly, debilitated, or ASA-PS III or IV patients. Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of 1% Propofol Maruishi injectable emulsion for induction of anesthesia according to their condition and responses. A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. (See DOSAGE AND ADMINISTRATION.)

Pediatric Patients

Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of 1% Propofol Maruishi injectable emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients. As with other sedativehypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of 1% Propofol Maruishi injectable emulsion. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Attention should be paid to minimize pain on injection when administering 1% Propofol Maruishi injectable emulsion to pediatric patients. Boluses of 1% Propofol Maruishi injectable emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins. (See PRECAUTIONS - General.)

Neurosurgical Patients

Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower boluses or infusions of 1% Propofol Maruishi injectable emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg). (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

Cardiac Anesthesia

1% Propofol Maruishi injectable emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited. As with other anesthetic and sedative-hypnotic agents, 1% Propofol Maruishi injectable emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

In addition, lower heart rates are observed during maintenance with 1% Propofol Maruishi injectable emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

As with other anesthetic agents, 1% Propofol Maruishi injectable emulsion reduces myocardial oxygen consumption. Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.

Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary 1% Propofol Maruishi injectable emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. The rate of 1% Propofol Maruishi injectable emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.

A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used. In order to assure adequate anesthesia, when 1% Propofol Maruishi injectable emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an opioid is used as the primary agent, 1% Propofol Maruishi injectable emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia. Higher doses of 1% Propofol Maruishi injectable emulsion will reduce the opioid requirements (see TABLE 4). When 1% Propofol Maruishi injectable emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONSCardiac Anesthesia).

TABLE 4: CARDIAC ANESTHESIA TECHNIQUES

Primary Asent Rate Secondary Aeent/Rate
1% Propofol Maruishi Injectable Emulsion   (Following Induction with Primary Agent) 0PI0IDa/0.05 - 0.075 mcg/kg/min (no bolus)
  Preinduction    
  Anxiolysis 25 mcg/kg/min  
  Induction 0.5 - 1.5 mg/kg  
  Over 60 sec  
  Maintenance (Titrated to Clinical Response) OPIOIDb 100 - 150 mcg/kg/min 1% Propofol Maruishi Injectable Emulsion/50 - 100 mcg/kg/min (no bolus)
  Induction 25 - 50 mcg/kg  
  Maintenance 0.2 - 0.3 mcg/kg/min  
a OPIOID is defined in terms of fentanyl equivalents, i.e.,
1 mcg of fentanyl = 5 mcg of alfentanil (for bolus)= 10 mcg of alfentanil (for maintenance)
OR
= 0.1 mcg of sufentanil
b Care should be taken to ensure amnesia.

Maintenance Of General Anesthesia

Adult Patients

In adults, anesthesia can be maintained by administering 1% Propofol Maruishi injectable emulsion by infusion or intermittent I.V. bolus injection. The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous Infusion

1% Propofol Maruishi injectable emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of 1% Propofol Maruishi injectable emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by 1% Propofol Maruishi.

Intermittent Bolus

Increments of 1% Propofol Maruishi injectable emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Pediatric Patients

1% Propofol Maruishi injectable emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

In general, for the pediatric population, maintenance by infusion of 1% Propofol Maruishi injectable emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose. Following the first halfhour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed. 1% Propofol Maruishi injectable emulsion should be titrated to achieve the desired clinical effect. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients. (See Clinical Trials - TABLE 2.)

1% Propofol Maruishi injectable emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

Monitored Anesthesia Care (MAC) Sedation

Adult Patients

When 1% Propofol Maruishi injectable emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of 1% Propofol Maruishi injectable emulsion administration will be in the range of 25 to 75 mcg/kg/min.

During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.) A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

Initiation Of MAC Sedation

For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be initiated by infusing 1% Propofol Maruishi injectable emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses. When 1% Propofol Maruishi injectable emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.) The rate of administration should be over 3-5 minutes and the dosage of 1% Propofol Maruishi injectable emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs. (See DOSAGE AND ADMINISTRATION.)

Maintenance Of MAC Sedation

For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of 1% Propofol Maruishi injectable emulsion at rates higher than are clinically necessary.

If the intermittent bolus dose method is used, increments of 1% Propofol Maruishi injectable emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation. (See WARNINGS.) The rate of administration and the dosage of 1% Propofol Maruishi injectable emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs. (See DOSAGE AND ADMINISTRATION.)

1% Propofol Maruishi injectable emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When 1% Propofol Maruishi injectable emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of 1% Propofol Maruishi injectable emulsion and may also result in a slower recovery profile. (See DRUG INTERACTIONS.)

ICU Sedation

(See WARNINGS and DOSAGE AND ADMINISTRATIONHandling Procedures.)

Abrupt discontinuation of 1% Propofol Maruishi injectable emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of 1% Propofol Maruishi injectable emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation. (See PRECAUTIONS.)

Adult Patients

For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. (See DOSAGE AND ADMINISTRATION.)

Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response. (See DOSAGE AND ADMINISTRATION.) With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation. These higher rates of administration may increase the likelihood of patients developing hypotension.

Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient's underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient. The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses. (See WARNINGS.)

1% Propofol Maruishi injectable emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs. (See PRECAUTIONS - Intensive Care Unit Sedation.) For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect. Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher. Dosages of 1% Propofol Maruishi injectable emulsion should be reduced in patients who have received large dosages of narcotics. Conversely, the 1% Propofol Maruishi injectable emulsion dosage requirement may be reduced by adequate management of pain with analgesic agents. As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time. (See Summary Of Dosage Guidelines.) Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of 1% Propofol Maruishi required for sedation (see Clinical Trials - Intensive Care Unit (ICU) Sedation). Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur. Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension. (See PRECAUTIONS.)

Summary Of Dosage Guidelines

Dosages and rates of administration in the following table should be individualized and titrated to clinical response. Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older. Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older.

For complete dosage information, see DOSAGE AND ADMINISTRATION.

INDICATION DOSAGE AND ADMINISTRATION
Induction of General Anesthesia: Healthy Adults Less Than 55 Years of Age: 40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).
Elderly, Debilitated, or ASA-PS III or IV Patients: 20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).
Cardiac Anesthesia: 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg).
Neurosurgical Patients: 20 mg every 10 seconds until induction onset (1 to 2 mg/kg).
Pediatric Patients - healthy, from 3 years to 16 years of age: 2.5 to 3.5 mg/kg administered over 20 to 30 seconds. (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)
Maintenance of General Anesthesia: Infusion
Healthy Adults Less Than 55 Years of Age: 100 to 200 mcg/kg/min (6 to 12 mg/kg/h).
Elderly, Debilitated, ASA-PS III or IV Patients: 50 to 100 mcg/kg/min (3 to 6 mg/kg/h).
Cardiac Anesthesia: Most patients require: Primary DIPRIVAN Injectable Emulsion with Secondary Opioid -100 to 150 mcg/kg/min.
Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid -50 to 100 mcg/kg/min. (see Table 4)
Neurosurgical Patients: 100 to 200 mcg/kg/min (6 to 12 mg/kg/h).
Pediatric Patients - healthy, from 2 months of age to 16 years of age: 125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h). Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased. (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)
Maintenance of General Anesthesia: Intermittent Bolus
Healthy Adults Less Than 55 Years of Age: Increments of 20 to 50 mg as needed.
Initiation of MAC Sedation: Healthy Adults Less Than 55 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Most patients require an infusion of 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3 to 5 minutes followed immediately by a maintenance infusion.
Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require dosages similar to healthy adults. Rapid boluses are to be avoided (see WARNINGS).
Maintenance of MAC Sedation: Healthy Adults Less Than 55 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique. Most patients require an infusion of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.
In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require 80% of the usual adult dose. A rapid (single or repeated) bolus dose should not be used (see WARNINGS). Sedation in Intubated, Mechanically Ventilated
Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least 5 minutes. Subsequent increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until desired clinical effect is achieved. Maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher may be required. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).
Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN Injectable Emulsion required for sedation.
The tubing and any unused DIPRIVAN Injectable Emulsion drug product should be discarded after 12 hours because DIPRIVAN Injectable Emulsion contains no preservatives and is capable of supporting growth of microorganisms (see WARNINGS).

Administration With Lidocaine

If lidocaine is to be administered to minimize pain on injection of 1% Propofol Maruishi, it is recommended that it be administered prior to 1% Propofol Maruishi administration or that it be added to 1% Propofol Maruishi immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg 1% Propofol Maruishi.

Compatibility And Stability

1% Propofol Maruishi injectable emulsion should not be mixed with other therapeutic agents prior to administration.

Dilution Prior To Administration

1% Propofol Maruishi injectable emulsion is provided as a ready-to-use formulation. However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

Administration With Other Fluids

Compatibility of 1% Propofol Maruishi injectable emulsion with the coadministration of blood/serum/plasma has not been established. (See WARNINGS.) When administered using a y-type infusion set, 1% Propofol Maruishi injectable emulsion has been shown to be compatible with the following intravenous fluids.

  • 5% Dextrose Injection, USP
  • Lactated Ringers Injection, USP
  • Lactated Ringers and 5% Dextrose Injection
  • 5% Dextrose and 0.45% Sodium Chloride Injection, USP
  • 5% Dextrose and 0.2% Sodium Chloride Injection, USP

Handling Procedures

General

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Clinical experience with the use of in-line filters and 1% Propofol Maruishi injectable emulsion during anesthesia or ICU/MAC sedation is limited. 1% Propofol Maruishi injectable emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of 1% Propofol Maruishi injectable emulsion and/or cause the breakdown of the emulsion. Filters should be used with caution and where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

Do not use if there is evidence of separation of the phases of the emulsion.

Rare cases of self-administration of 1% Propofol Maruishi injectable emulsion, by health care professionals have been reported, including some fatalities. (See Drug Abuse And Dependence.)

Strict aseptic technique must always be maintained during handling. 1% Propofol Maruishi injectable emulsion is a single-use parenteral product which contains benzyl alcohol 1.5 mg/mL and sodium benzoate 0.7 mg/mL to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination. However, 1% Propofol Maruishi injectable emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards. Accordingly, strict aseptic technique must still be adhered to. Do not use if contamination is suspected. Discard unused portions as directed within the required time limits (see DOSAGE AND ADMINISTRATION – Handling Procedures). There have been reports in which failure to use aseptic technique when handling 1% Propofol Maruishi injectable emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

1% Propofol Maruishi injectable emulsion, with benzyl alcohol, inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

Guidelines For Aseptic Technique For General Anesthesia/MAC Sedation

1% Propofol Maruishi should be prepared for use just prior to initiation of each individual anesthetic/sedative procedure. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. 1% Propofol Maruishi should be drawn into sterile syringes immediately after vials are opened. When withdrawing 1% Propofol Maruishi from vials, a sterile vent spike should be used. The syringe(s) should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vials have been opened.

1% Propofol Maruishi injectable emulsion should be prepared for single-patient use only. Any unused portions of 1% Propofol Maruishi injectable emulsion, reservoirs, dedicated administration tubing and/or solutions containing 1% Propofol Maruishi injectable emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The I.V. line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual 1% Propofol Maruishi injectable emulsion.

Guidelines For Aseptic Technique For ICU Sedation

1% Propofol Maruishi injectable emulsion should be prepared for single-patient use only. When 1% Propofol Maruishi injectable emulsion is administered directly from the vial, strict aseptic techniques must be followed. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of 1% Propofol Maruishi injectable emulsion. As with other lipid emulsions, the number of I.V. line manipulations should be minimized. Administration should commence promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused portions of 1% Propofol Maruishi injectable emulsion must be discarded after 12 hours.

If 1% Propofol Maruishi injectable emulsion is transferred to a syringe or other container prior to administration, the handling procedures for General Anesthesia/MAC Sedation should be followed and the product should be discarded and administration lines changed after 12 hours.

Propofol blood concentrations at steady-state are generally proportional to infusion rates, especially in individual patients. Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

Shake well before use. Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised. Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

When administering DIPRIVAN Injectable Emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates. When infusing DIPRIVAN Injectable Emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of DIPRIVAN Injectable Emulsion.

For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate DIPRIVAN Injectable Emulsion infusion to provide satisfactory anesthesia. With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of DIPRIVAN Injectable Emulsion and/or opioids should be increased in order to provide adequate anesthesia.

Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by propofol. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.

Induction Of General Anesthesia

Adult Patients

Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.

Elderly, Debilitated, or ASA-PS III or IV Patients

It is important to be familiar and experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients. Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses. A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation.

Pediatric Patients

Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric patients. Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

Neurosurgical Patients

Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS).

Cardiac Anesthesia

DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited. As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption. Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.

Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. The rate of DIPRIVAN Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.

A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used. In order to assure adequate anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia. Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 4). When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

Table 4: Cardiac Anesthesia Techniques

Primary Agent Rate Secondary Agent/Rate (Following Induction with Primary Agent)
DIPRIVAN Injectable Emulsion   OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)
  Preinduction Anxiolysis 25 mcg/kg/min  
  Induction 0.5 to 1.5 mg/kg over 60 sec
  Maintenance (Titrated to Clinical Response) 100 to 150 mcg/kg/min
OPIOIDb   DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min (no bolus)
  Induction 25 to 50 mcg/kg  
  Maintenance 0.2 to 0.3 mcg/kg/min
aOPIOID is defined in terms of fentanyl equivalents, i.e.,
1 mcg of fentanyl = 5 mcg of alfentanil (for bolus)
= 10 mcg of alfentanil (for maintenance)
or
= 0.1 mcg of sufentanil
bCare should be taken to ensure amnesia.

Maintenance Of General Anesthesia

DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

Adult Patients

In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by infusion or intermittent IV bolus injection. The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous Infusion

DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.

Intermittent Bolus

Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Pediatric Patients

DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose. Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed. DIPRIVAN Injectable Emulsion should be titrated to achieve the desired clinical effect. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients. (See Table 2 Clinical Trials.)

Monitored Anesthesia Care (MAC) Sedation

Adult Patients

When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

Initiation of MAC Sedation

For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses. When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). The rate of administration should be over 3 to 5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

Maintenance of MAC Sedation

For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.

If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). The rate of administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs.

DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS: DRUG INTERACTIONS).

ICU Sedation

(See WARNINGS and Handling Procedures.) Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

Adult Patients

For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.

Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response. With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation. These higher rates of administration may increase the likelihood of patients developing hypotension. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient's underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient. The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation). For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect. Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received large dosages of narcotics. The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents. As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see Summary Of Dosage Guidelines). Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation). Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur. Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

Summary Of Dosage Guidelines

Dosages and rates of administration in the following table should be individualized and titrated to clinical response. Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older. Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older.

For complete dosage information, see DOSAGE AND ADMINISTRATION.

INDICATION DOSAGE AND ADMINISTRATION
Induction of General Anesthesia: Healthy Adults Less Than 55 Years of Age: 40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).
Elderly, Debilitated, or ASA-PS III or IV Patients: 20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).
Cardiac Anesthesia: 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg).
Neurosurgical Patients: 20 mg every 10 seconds until induction onset (1 to 2 mg/kg).
Pediatric Patients - healthy, from 3 years to 16 years of age: 2.5 to 3.5 mg/kg administered over 20 to 30 seconds. (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)
Maintenance of General Anesthesia: Infusion
Healthy Adults Less Than 55 Years of Age: 100 to 200 mcg/kg/min (6 to 12 mg/kg/h).
Elderly, Debilitated, ASA-PS III or IV Patients: 50 to 100 mcg/kg/min (3 to 6 mg/kg/h).
Cardiac Anesthesia: Most patients require: Primary DIPRIVAN Injectable Emulsion with Secondary Opioid -100 to 150 mcg/kg/min.
Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid -50 to 100 mcg/kg/min. (see Table 4)
Neurosurgical Patients: 100 to 200 mcg/kg/min (6 to 12 mg/kg/h).
Pediatric Patients - healthy, from 2 months of age to 16 years of age: 125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h). Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased. (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)
Maintenance of General Anesthesia: Intermittent Bolus
Healthy Adults Less Than 55 Years of Age: Increments of 20 to 50 mg as needed.
Initiation of MAC Sedation: Healthy Adults Less Than 55 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Most patients require an infusion of 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3 to 5 minutes followed immediately by a maintenance infusion.
Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require dosages similar to healthy adults. Rapid boluses are to be avoided (see WARNINGS).
Maintenance of MAC Sedation: Healthy Adults Less Than 55 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique. Most patients require an infusion of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.
In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require 80% of the usual adult dose. A rapid (single or repeated) bolus dose should not be used (see WARNINGS). Sedation in Intubated, Mechanically Ventilated
Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least 5 minutes. Subsequent increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until desired clinical effect is achieved. Maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher may be required. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).
Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN Injectable Emulsion required for sedation.
The tubing and any unused DIPRIVAN Injectable Emulsion drug product should be discarded after 12 hours because DIPRIVAN Injectable Emulsion contains no preservatives and is capable of supporting growth of microorganisms (see WARNINGS).

Administration with Lidocaine

If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

Compatibility and Stability

DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

Dilution Prior to Administration

DIPRIVAN Injectable Emulsion is provided as a ready-to-use formulation. However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

Administration with Other Fluids

Compatibility of DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS). When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  • 5% Dextrose Injection, USP
  • Lactated Ringers Injection, USP
  • Lactated Ringers and 5% Dextrose Injection
  • 5% Dextrose and 0.45% Sodium Chloride Injection, USP
  • 5% Dextrose and 0.2% Sodium Chloride Injection, USP

Handling Procedures

General

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited. DIPRIVAN Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion. Filters should be used with caution and where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

Do not use if there is evidence of separation of the phases of the emulsion.

Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been reported, including some fatalities (see Drug Abuse And Dependence).

Strict aseptic technique must always be maintained during handling. DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination. However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons. DIPRIVAN Injectable Emulsion vials are never to be accessed more than once or used on more than one person.

Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used. The syringe should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

DIPRIVAN Injectable Emulsion must be prepared for single-patient use only. Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

Guidelines for Aseptic Technique for ICU Sedation

DIPRIVAN Injectable Emulsion must be prepared for single-patient use only. Strict aseptic techniques must be followed. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion. As with other lipid emulsions, the number of IV line manipulations should be minimized. Administration should commence promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used. The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened. DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

Contraindications
The information provided in Contraindications of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
more... close
Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion
). Administration of 1% Propofol Maruishi 1% by Diprifusor TCI system is not advised for sedation in the intensive care unit.

1% Propofol Maruishi 1% may be diluted with 5% Dextrose (see "Dilution and Co-administration" table below).

It is recommended that blood lipid levels be monitored should 1% Propofol Maruishi 1% be administered to patients thought to be at particular risk of fat overload. Administration of 1% Propofol Maruishi 1% should be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from the body. If the patient is receiving other intravenous lipid concurrently, a reduction in quantity should be made in order to take account of the amount of lipid infused as part of the 1% Propofol Maruishi 1% formulation; 1.0 ml of 1% Propofol Maruishi 1% contains approximately 0.1g of fat.

If the duration of sedation is in excess of 3 days, lipids should be monitored in all patients.

Older people

When 1% Propofol Maruishi 1% is used for sedation the rate of infusion should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.

Paediatric population

1% Propofol Maruishi 1% is contraindicated for the sedation of ventilated children aged 16 years or younger receiving intensive care.

4.2.4 Sedation For Surgical And Diagnostic Procedures

Adults

To provide sedation for surgical and diagnostic procedures, rates of administration should be individualised and titrated to clinical response.

Most patients will require 0.5–1 mg/kg over 1– 5 minutes for onset of sedation.

Maintenance of sedation may be accomplished by titrating 1% Propofol Maruishi 1% infusion to the desired level of sedation - most patients will require 1.5–4.5 mg/kg/h. In addition to the infusion, bolus administration of 10–20 mg may be used if a rapid increase in the depth of sedation is required. In patients of ASA Grades 3 and 4 the rate of administration and dosage may need to be reduced.

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is not recommended for sedation for surgical and diagnostic procedures.

Older people

When 1% Propofol Maruishi 1% is used for sedation the rate of infusion or 'target concentration' should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.

Paediatric population

1% Propofol Maruishi 1% is not recommended for surgical and diagnostic procedures in children aged less than 1 month.

In children over 1 month of age, doses and administration rates should be adjusted according to the required depth of sedation and the clinical response. Most paediatric patients require 1–2 mg/kg body weight of 1% Propofol Maruishi 1% for onset of sedation. Maintenance of sedation may be accomplished by titrating 1% Propofol Maruishi 1% infusion to the desired level of sedation. Most patients require 1.5–9 mg/kg/h 1% Propofol Maruishi 1%. The infusion may be supplemented by bolus administration of up to 1 mg/kg body weight if a rapid increase of depth of sedation is required.

In ASA 3 and 4 patients lower doses may be required.

4.2.5 Method of administration

1% Propofol Maruishi 1% has no analgesic properties and therefore supplementary analgesic agents are generally required in addition to 1% Propofol Maruishi 1%.

1% Propofol Maruishi 1% can be used for infusion undiluted from glass containers, plastic syringes or 1% Propofol Maruishi 1% pre-filled syringes or diluted with 5% Dextrose (Intravenous Infusion BP) only, in PVC infusion bags or glass infusion bottles. Dilutions, which must not exceed 1 in 5 (2 mg propofol per ml) should be prepared aseptically immediately before administration and must be used within 6 hours of preparation.

It is recommended that, when using diluted 1% Propofol Maruishi 1%, the volume of 5% Dextrose removed from the infusion bag during the dilution process is totally replaced in volume by 1% Propofol Maruishi 1% emulsion. (see "Dilution and Co-administration" table below).

The dilution may be used with a variety of infusion control techniques, but a giving set used alone will not avoid the risk of accidental uncontrolled infusion of large volumes of diluted 1% Propofol Maruishi 1%. A burette, drop counter or volumetric pump must be included in the infusion line. The risk of uncontrolled infusion must be taken into account when deciding the maximum amount of 1% Propofol Maruishi 1% in the burette.

When 1% Propofol Maruishi 1% is used undiluted to maintain anaesthesia, it is recommended that equipment such as syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

1% Propofol Maruishi 1% may be administered via a Y-piece close to the injection site into infusions of the following:

• Dextrose 5% Intravenous Infusion B.P.

• Sodium Chloride 0.9% Intravenous Infusion B.P.

• Dextrose 4% with Sodium Chloride 0.18% Intravenous Infusion B.P.

The glass pre-filled syringe (PFS) has a lower frictional resistance than plastic disposable syringes and operates more easily. Therefore, if 1% Propofol Maruishi 1% is administered using a hand held pre-filled syringe, the line between the syringe and the patient must not be left open if unattended.

When the pre-filled syringe presentation is used in a syringe pump appropriate compatibility should be ensured. In particular, the pump should be designed to prevent syphoning and should have an occlusion alarm set no greater than 1000 mm Hg. If using a programmable or equivalent pump that offers options for use of different syringes then choose only the 'B-D' 50/60 ml 'PLASTIPAK' setting when using the 1% Propofol Maruishi 1% pre-filled syringe.

1% Propofol Maruishi 1% may be premixed with alfentanil injection containing 500 micrograms/ml alfentanil in the ratio of 20:1 to 50:1 v/v. Mixtures should be prepared using sterile technique and used within 6 hours of preparation.

In order to reduce pain on initial injection, 1% Propofol Maruishi 1% may be mixed with preservative-free Lidocaine Injection 0.5% or 1%; (see "Dilution and Co-administration" table below).

Target Controlled Infusion - Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI System in Adults

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is restricted to induction and maintenance of general anaesthesia in adults. It is not recommended for use in ICU sedation or sedation for surgical and diagnostic procedures, or in children.

1% Propofol Maruishi 1% may be administered by TCI only with a 'Diprifusor' TCI system incorporating 'Diprifusor' TCI software. Such systems will operate only on recognition of electronically tagged pre-filled syringes containing 1% Propofol Maruishi 1% or 2% Injection. The 'Diprifusor' TCI system will automatically adjust the infusion rate for the concentration of 1% Propofol Maruishi recognised. Users must be familiar with the infusion pump users' manual, and with the administration of 1% Propofol Maruishi 1% by TCI and with the correct use of the syringe identification system.

The Diprifusor allows the anaesthetist to achieve and control a desired speed of induction and depth of anaesthesia by setting and adjusting target (predicted) blood concentrations of propofol. An alternative effect-site mode of administration may be accessible on some Diprifusors, but its safety and efficacy have not yet been established.

The 'Diprifusor' TCI system assumes that the initial blood propofol concentration in the patient is zero. Therefore, in patients who have received prior propofol, there may be a need to select a lower initial target concentration when commencing 'Diprifusor' TCI. Similarly, the immediate recommencement of 'Diprifusor' TCI is not recommended if the pump has been switched off.

Guidance on propofol target concentrations is given below. In view of interpatient variability in propofol pharmacokinetics and pharmacodynamics, in both premedicated and unpremedicated patients the target propofol concentration should be titrated against the response of the patient in order to achieve the depth of anaesthesia required.

Induction and Maintenance of General Anaesthesia

In adult patients under 55 years of age anaesthesia can usually be induced with target propofol concentrations in the region of 4–8 microgram/ml. An initial target of 4 microgram/ml is recommended in premedicated patients and in unpremedicated patients an initial target of 6 microgram/ml is advised. Induction time with these targets is generally within the range of 60–120 seconds. Higher targets will allow more rapid induction of anaesthesia but may be associated with more pronounced haemodynamic and respiratory depression.

A lower initial target concentration should be used in patients over the age of about 55 years and in patients of ASA grades 3 and 4. The target concentration can then be increased in steps of 0.5–1.0 microgram/ml at intervals of 1 minute to achieve a gradual induction of anaesthesia.

Supplementary analgesia will generally be required and the extent to which target concentrations for maintenance of anaesthesia can be reduced will be influenced by the amount of concomitant analgesia administered. Target propofol concentrations in the region of 3–6 microgram/ml usually maintain satisfactory anaesthesia.

The predicted propofol concentration on waking is generally in the region of 1.0–2.0 microgram/ml and will be influenced by the amount of analgesia given during maintenance.

Dilution and Co-Administration of 1% Propofol Maruishi 1% with Other Drugs or Infusion Fluids (see also 'Additional Precautions' Section)

Co-administration Technique

Additive or Diluent

Preparation

Precautions

Pre-mixing.

Dextrose 5% Intravenous Infusion

Mix 1 part of 1% Propofol Maruishi 1% with up to 4 parts of Dextrose 5% Intravenous Infusion B.P in either PVC infusion bags or glass infusion bottles. When diluted in PVC bags it is recommended that the bag should be full and that the dilution be prepared by withdrawing a volume of infusion fluid and replacing it with an equal volume of 1% Propofol Maruishi 1%.

Prepare aseptically immediately before administration. The mixture is stable for up to 6 hours.

Lidocaine hydrochloride injection (0.5% or 1% without preservatives).

Mix 20 parts of 1% Propofol Maruishi 1% with up to 1 part of either 0.5% or 1% lidocaine hydrochloride injection.

Prepare mixture aseptically immediately prior to administration. Use for Induction only.

Alfentanil injection (500 microgram/ml).

Mix 1% Propofol Maruishi 1% with alfentanil injection in a ratio of 20:1 to 50:1 v/v.

Prepare mixture aseptically; use within 6 hours of preparation.

Co-administration via a Y-piece connector.

Dextrose 5% intravenous infusion

Co-administer via a Y-piece connector.

Place the Y-piece connector close to the injection site.

Sodium chloride 0.9% intravenous infusion

As above

As above

Dextrose 4% with sodium chloride 0.18% intravenous infusion

As above

As above

4.3 Contraindications <

1% Propofol Maruishi 1% contains soya oil and should not be used in patients who are hypersensitive to peanut or soya.

1% Propofol Maruishi 1% must not be used in patients of 16 years of age or younger for sedation in intensive care .

1% Propofol Maruishi injectable emulsion is contraindicated in patients with a known hypersensitivity to 1% Propofol Maruishi injectable emulsion or any of its components.

1% Propofol Maruishi injectable emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

DIPRIVAN Injectable Emulsion is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN Injectable Emulsion components.

DIPRIVAN Injectable Emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

Special warnings and precautions for use
The information provided in Special warnings and precautions for use of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
more... close
Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion
). 1% Propofol Maruishi 1% is not indicated for sedation in intensive care of patients of 16 years of age or younger (see 4.3 Contraindications). Administration of 1% Propofol Maruishi 1% by Diprifusor TCI system is not advised for sedation in the intensive care unit.

1% Propofol Maruishi 1% may be diluted with 5% Dextrose (see "Dilution and Co-administration" table below).

It is recommended that blood lipid levels be monitored should 1% Propofol Maruishi 1% be administered to patients thought to be at particular risk of fat overload. Administration of 1% Propofol Maruishi 1% should be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from the body. If the patient is receiving other intravenous lipid concurrently, a reduction in quantity should be made in order to take account of the amount of lipid infused as part of the 1% Propofol Maruishi 1% formulation; 1.0 ml of 1% Propofol Maruishi 1% contains approximately 0.1g of fat.

If the duration of sedation is in excess of 3 days, lipids should be monitored in all patients.

Older people

When 1% Propofol Maruishi 1% is used for sedation the rate of infusion should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.

Paediatric population

1% Propofol Maruishi 1% is contraindicated for the sedation of ventilated children aged 16 years or younger receiving intensive care.

4.2.4 Sedation For Surgical And Diagnostic Procedures

Adults

To provide sedation for surgical and diagnostic procedures, rates of administration should be individualised and titrated to clinical response.

Most patients will require 0.5–1 mg/kg over 1– 5 minutes for onset of sedation.

Maintenance of sedation may be accomplished by titrating 1% Propofol Maruishi 1% infusion to the desired level of sedation - most patients will require 1.5–4.5 mg/kg/h. In addition to the infusion, bolus administration of 10–20 mg may be used if a rapid increase in the depth of sedation is required. In patients of ASA Grades 3 and 4 the rate of administration and dosage may need to be reduced.

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is not recommended for sedation for surgical and diagnostic procedures.

Older people

When 1% Propofol Maruishi 1% is used for sedation the rate of infusion or 'target concentration' should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.

Paediatric population

1% Propofol Maruishi 1% is not recommended for surgical and diagnostic procedures in children aged less than 1 month.

In children over 1 month of age, doses and administration rates should be adjusted according to the required depth of sedation and the clinical response. Most paediatric patients require 1–2 mg/kg body weight of 1% Propofol Maruishi 1% for onset of sedation. Maintenance of sedation may be accomplished by titrating 1% Propofol Maruishi 1% infusion to the desired level of sedation. Most patients require 1.5–9 mg/kg/h 1% Propofol Maruishi 1%. The infusion may be supplemented by bolus administration of up to 1 mg/kg body weight if a rapid increase of depth of sedation is required.

In ASA 3 and 4 patients lower doses may be required.

4.2.5 Method of administration

1% Propofol Maruishi 1% has no analgesic properties and therefore supplementary analgesic agents are generally required in addition to 1% Propofol Maruishi 1%.

1% Propofol Maruishi 1% can be used for infusion undiluted from glass containers, plastic syringes or 1% Propofol Maruishi 1% pre-filled syringes or diluted with 5% Dextrose (Intravenous Infusion BP) only, in PVC infusion bags or glass infusion bottles. Dilutions, which must not exceed 1 in 5 (2 mg propofol per ml) should be prepared aseptically immediately before administration and must be used within 6 hours of preparation.

It is recommended that, when using diluted 1% Propofol Maruishi 1%, the volume of 5% Dextrose removed from the infusion bag during the dilution process is totally replaced in volume by 1% Propofol Maruishi 1% emulsion. (see "Dilution and Co-administration" table below).

The dilution may be used with a variety of infusion control techniques, but a giving set used alone will not avoid the risk of accidental uncontrolled infusion of large volumes of diluted 1% Propofol Maruishi 1%. A burette, drop counter or volumetric pump must be included in the infusion line. The risk of uncontrolled infusion must be taken into account when deciding the maximum amount of 1% Propofol Maruishi 1% in the burette.

When 1% Propofol Maruishi 1% is used undiluted to maintain anaesthesia, it is recommended that equipment such as syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

1% Propofol Maruishi 1% may be administered via a Y-piece close to the injection site into infusions of the following:

• Dextrose 5% Intravenous Infusion B.P.

• Sodium Chloride 0.9% Intravenous Infusion B.P.

• Dextrose 4% with Sodium Chloride 0.18% Intravenous Infusion B.P.

The glass pre-filled syringe (PFS) has a lower frictional resistance than plastic disposable syringes and operates more easily. Therefore, if 1% Propofol Maruishi 1% is administered using a hand held pre-filled syringe, the line between the syringe and the patient must not be left open if unattended.

When the pre-filled syringe presentation is used in a syringe pump appropriate compatibility should be ensured. In particular, the pump should be designed to prevent syphoning and should have an occlusion alarm set no greater than 1000 mm Hg. If using a programmable or equivalent pump that offers options for use of different syringes then choose only the 'B-D' 50/60 ml 'PLASTIPAK' setting when using the 1% Propofol Maruishi 1% pre-filled syringe.

1% Propofol Maruishi 1% may be premixed with alfentanil injection containing 500 micrograms/ml alfentanil in the ratio of 20:1 to 50:1 v/v. Mixtures should be prepared using sterile technique and used within 6 hours of preparation.

In order to reduce pain on initial injection, 1% Propofol Maruishi 1% may be mixed with preservative-free Lidocaine Injection 0.5% or 1%; (see "Dilution and Co-administration" table below).

Target Controlled Infusion - Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI System in Adults

Administration of 1% Propofol Maruishi 1% by a 'Diprifusor' TCI system is restricted to induction and maintenance of general anaesthesia in adults. It is not recommended for use in ICU sedation or sedation for surgical and diagnostic procedures, or in children.

1% Propofol Maruishi 1% may be administered by TCI only with a 'Diprifusor' TCI system incorporating 'Diprifusor' TCI software. Such systems will operate only on recognition of electronically tagged pre-filled syringes containing 1% Propofol Maruishi 1% or 2% Injection. The 'Diprifusor' TCI system will automatically adjust the infusion rate for the concentration of 1% Propofol Maruishi recognised. Users must be familiar with the infusion pump users' manual, and with the administration of 1% Propofol Maruishi 1% by TCI and with the correct use of the syringe identification system.

The Diprifusor allows the anaesthetist to achieve and control a desired speed of induction and depth of anaesthesia by setting and adjusting target (predicted) blood concentrations of propofol. An alternative effect-site mode of administration may be accessible on some Diprifusors, but its safety and efficacy have not yet been established.

The 'Diprifusor' TCI system assumes that the initial blood propofol concentration in the patient is zero. Therefore, in patients who have received prior propofol, there may be a need to select a lower initial target concentration when commencing 'Diprifusor' TCI. Similarly, the immediate recommencement of 'Diprifusor' TCI is not recommended if the pump has been switched off.

Guidance on propofol target concentrations is given below. In view of interpatient variability in propofol pharmacokinetics and pharmacodynamics, in both premedicated and unpremedicated patients the target propofol concentration should be titrated against the response of the patient in order to achieve the depth of anaesthesia required.

Induction and Maintenance of General Anaesthesia

In adult patients under 55 years of age anaesthesia can usually be induced with target propofol concentrations in the region of 4–8 microgram/ml. An initial target of 4 microgram/ml is recommended in premedicated patients and in unpremedicated patients an initial target of 6 microgram/ml is advised. Induction time with these targets is generally within the range of 60–120 seconds. Higher targets will allow more rapid induction of anaesthesia but may be associated with more pronounced haemodynamic and respiratory depression.

A lower initial target concentration should be used in patients over the age of about 55 years and in patients of ASA grades 3 and 4. The target concentration can then be increased in steps of 0.5–1.0 microgram/ml at intervals of 1 minute to achieve a gradual induction of anaesthesia.

Supplementary analgesia will generally be required and the extent to which target concentrations for maintenance of anaesthesia can be reduced will be influenced by the amount of concomitant analgesia administered. Target propofol concentrations in the region of 3–6 microgram/ml usually maintain satisfactory anaesthesia.

The predicted propofol concentration on waking is generally in the region of 1.0–2.0 microgram/ml and will be influenced by the amount of analgesia given during maintenance.

Dilution and Co-Administration of 1% Propofol Maruishi 1% with Other Drugs or Infusion Fluids (see also 'Additional Precautions' Section)

Co-administration Technique

Additive or Diluent

Preparation

Precautions

Pre-mixing.

Dextrose 5% Intravenous Infusion

Mix 1 part of 1% Propofol Maruishi 1% with up to 4 parts of Dextrose 5% Intravenous Infusion B.P in either PVC infusion bags or glass infusion bottles. When diluted in PVC bags it is recommended that the bag should be full and that the dilution be prepared by withdrawing a volume of infusion fluid and replacing it with an equal volume of 1% Propofol Maruishi 1%.

Prepare aseptically immediately before administration. The mixture is stable for up to 6 hours.

Lidocaine hydrochloride injection (0.5% or 1% without preservatives).

Mix 20 parts of 1% Propofol Maruishi 1% with up to 1 part of either 0.5% or 1% lidocaine hydrochloride injection.

Prepare mixture aseptically immediately prior to administration. Use for Induction only.

Alfentanil injection (500 microgram/ml).

Mix 1% Propofol Maruishi 1% with alfentanil injection in a ratio of 20:1 to 50:1 v/v.

Prepare mixture aseptically; use within 6 hours of preparation.

Co-administration via a Y-piece connector.

Dextrose 5% intravenous infusion

Co-administer via a Y-piece connector.

Place the Y-piece connector close to the injection site.

Sodium chloride 0.9% intravenous infusion

As above

As above

Dextrose 4% with sodium chloride 0.18% intravenous infusion

As above

As above

4.3 Contraindications <

1% Propofol Maruishi 1% contains soya oil and should not be used in patients who are hypersensitive to peanut or soya.

1% Propofol Maruishi 1% must not be used in patients of 16 years of age or younger for sedation in intensive care .

4.4 Special warnings and precautions for use

1% Propofol Maruishi 1% should be given by those trained in anaesthesia (or, where appropriate, doctors trained in the care of patients in Intensive Care).

Patients should be constantly monitored and facilities for maintenance of a patient airway, artificial ventilation, oxygen enrichment and other resuscitative facilities should be readily available at all times. 1% Propofol Maruishi 1% should not be administered by the person conducting the diagnostic or surgical procedure.

Abuse of, and dependence on 1% Propofol Maruishi 1%, predominantly by health care professionals, have been reported. As with other general anaesthetics, the administration of 1% Propofol Maruishi 1% without airway care may result in fatal respiratory complications.

When 1% Propofol Maruishi 1% is administered for conscious sedation, for surgical and diagnostic procedures, patients should be continually monitored for early signs of hypotension, airway obstruction and oxygen desaturation.

As with other sedative agents, when 1% Propofol Maruishi 1% is used for sedation during operative procedures, involuntary patient movements may occur. During procedures requiring immobility these movements may be hazardous to the operative site.

An adequate period is needed prior to discharge of the patient to ensure full recovery after use of 1% Propofol Maruishi 1%. Very rarely the use of 1% Propofol Maruishi 1% may be associated with the development of a period of postoperative unconsciousness, which may be accompanied by an increase in muscle tone. This may or may not be preceded by a period of wakefulness. Although recovery is spontaneous, appropriate care of an unconscious patient should be administered.

1% Propofol Maruishi 1% induced impairment is not generally detectable beyond 12 hours. The effects of 1% Propofol Maruishi 1%, the procedure, concomitant medications, the age and the condition of the patient should be considered when advising patients on:

• The advisability of being accompanied on leaving the place of administration

• The timing of recommencement of skilled or hazardous tasks such as driving

• The use of other agents that may sedate (Eg, benzodiazepines, opiates, alcohol.)

As with other intravenous anaesthetic agents, caution should be applied in patients with cardiac, respiratory, renal or hepatic impairment or in hypovolaemic or debilitated patients. 1% Propofol Maruishi 1% clearance is blood flow dependent, therefore, concomitant medication that reduces cardiac output will also reduce 1% Propofol Maruishi 1% clearance.

1% Propofol Maruishi 1% lacks vagolytic activity and has been associated with reports of bradycardia (occasionally profound) and also asystole. The intravenous administration of an anticholinergic agent before induction, or during maintenance of anaesthesia should be considered, especially in situations where vagal tone is likely to predominate, or when 1% Propofol Maruishi 1% is used in conjunction with other agents likely to cause a bradycardia.

As with other intravenous anaesthetic and sedative agents, patients should be instructed to avoid alcohol before and for at least 8 hours after administration of 1% Propofol Maruishi 1%.

During bolus administration for operative procedures, extreme caution should be exercised in patients with acute pulmonary insufficiency or respiratory depression.

Concomitant use of central nervous system depressants e.g., alcohol, general anaesthetics, narcotic analgesics will result in accentuation of their sedative effects. When 1% Propofol Maruishi 1% is combined with centrally depressant drugs administered parenterally, severe respiratory and cardiovascular depression may occur. It is recommended that 1% Propofol Maruishi 1% is administered following the analgesic and the dose should be carefully titrated to the patient's response .

During induction of anaesthesia, hypotension and transient apnoea may occur depending on the dose and use of premedicants and other agents.

Occasionally, hypotension may require use of intravenous fluids and reduction of the rate of administration of 1% Propofol Maruishi 1% during the period of anaesthetic maintenance.

When 1% Propofol Maruishi 1% is administered to an epileptic patient, there may be a risk of convulsion.

Appropriate care should be applied in patients with disorders of fat metabolism and in other conditions where lipid emulsions must be used cautiously .

Use is not recommended with electroconvulsive treatment.

As with other anaesthetics, sexual disinhibition may occur during recovery.

Paediatric population

The use of 1% Propofol Maruishi is not recommended in newborn infants as this patient population has not been fully investigated. Pharmacokinetic data indicate that clearance is considerably reduced in neonates and has a very high inter-individual variability. Relative overdose could occur on administering doses recommended for older children and result in severe cardiovascular depression.

1% Propofol Maruishi 2% is not recommended for use in children < 3 years of age due to difficulty in titrating small volumes.

Propofol must not be used in patients of 16 years of age or younger for sedation for intensive care as the safety and efficacy of propofol for sedation in this age group have not been demonstrated .

Advisory statements concerning Intensive Care Unit management

Use of propofol emulsion infusions for ICU sedation has been associated with a constellation of metabolic derangements and organ system failures that may result in death. Reports have been received of combinations of the following: Metabolic acidosis, Rhabdomyolysis, Hyperkalaemia, Hepatomegaly, Renal failure, Hyperlipidaemia, Cardiac arrhythmia, Brugada-type ECG (elevated ST-segment and coved T-wave) and rapidly progressive Cardiac failure usually unresponsive to inotropic supportive treatment. Combinations of these events have been referred to as the Propofol Infusion Syndrome. These events were mostly seen in patients with serious head injuries and children with respiratory tract infections who received dosages in excess of those advised in adults for sedation in the intensive care unit.

The following appear to be the major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents - vasoconstrictors, steroids, inotropes and/or 1% Propofol Maruishi 1% (usually at dose rates greater than 4mg/kg/h for more than 48 hours).

Prescribers should be alert to these events in patients with the above risk factors and promptly consider decreasing or stopping the 1% Propofol Maruishi 1% dosage when the above signs develop. All sedative and therapeutic agents used in the intensive care unit (ICU), should be titrated to maintain optimal oxygen delivery and haemodynamic parameters. Patients with raised intra-cranial pressure (ICP) should be given appropriate treatment to support the cerebral perfusion pressure during these treatment modifications.

Treating physicians are reminded if possible not to exceed the dosage of 4 mg/kg/h.

Appropriate care should be applied in patients with disorders of fat metabolism and in other conditions where lipid emulsions must be used cautiously.

It is recommended that blood lipid levels should be monitored if propofol is administered to patients thought to be at particular risk of fat overload. Administration of propofol should be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from the body. If the patient is receiving other intravenous lipid concurrently, a reduction in quantity should be made in order to take account of the amount of lipid infused as part of the propofol formulation; 1.0 mL of 1% Propofol Maruishi contains approximately 0.1 g of fat.

1% Propofol Maruishi 1% contains 0.0018 mmol sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Additional Precautions

Caution should be taken when treating patients with mitochondrial disease. These patients may be susceptible to exacerbations of their disorder when undergoing anaesthesia, surgery and ICU care. Maintenance of normothermia, provision of carbohydrates and good hydration are recommended for such patients. The early presentations of mitochondrial disease exacerbation and of the 'propofol infusion syndrome' may be similar.

1% Propofol Maruishi 1% contains no antimicrobial preservatives and supports growth of micro-organisms.

EDTA chelates metal ions, including zinc, and reduces microbial growth rates. The need for supplemental zinc should be considered during prolonged administration of 1% Propofol Maruishi 1%, particularly in patients who are predisposed to zinc deficiency, such as those with burns, diarrhoea and/or major sepsis.

When 1% Propofol Maruishi 1% is to be aspirated, it must be drawn aseptically into a sterile syringe or giving set immediately after opening the ampoule or breaking the vial seal. Administration must commence without delay. Asepsis must be maintained for both 1% Propofol Maruishi 1% and infusion equipment throughout the infusion period. Any infusion fluids added to the 1% Propofol Maruishi 1% line must be administered close to the cannula site. 1% Propofol Maruishi 1% must not be administered via a microbiological filter.

1% Propofol Maruishi 1% and any syringe containing 1% Propofol Maruishi 1% are for single use in an individual patient. In accordance with established guidelines for other lipid emulsions, a single infusion of propofol must not exceed 12 hours. At the end of the procedure or at 12 hours, whichever is the sooner, both the reservoir of propofol and the infusion line must be discarded and replaced as appropriate.

WARNINGS

Use of 1% Propofol Maruishi injectable emulsion has been associated with both fatal and life-threatening anaphylactic and anaphylactoid reactions.

For general anesthesia or monitored anesthesia care (MAC) sedation, 1% Propofol Maruishi injectable emulsion should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV patients.

For sedation of intubated, mechanically ventilated patients in the Intensive Care Unit (ICU), 1% Propofol Maruishi injectable emulsion should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.

Use of 1% Propofol Maruishi injectable emulsion for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as 1% Propofol Maruishi Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, cardiac and renal failure. The syndrome is most often associated with prolonged, high-dose infusions (> 5 mg/kg/h for > 48h) but has also been reported following large-dose, short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation, increasing 1% Propofol Maruishi dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a 1% Propofol Maruishi infusion, consideration should be given to using alternative means of sedation.

Abrupt discontinuation of 1% Propofol Maruishi injectable emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of 1% Propofol Maruishi injectable emulsion should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level. (See PRECAUTIONS.)

1% Propofol Maruishi injectable emulsion should not be coadministered through the same I.V. catheter with blood or plasma because compatibility has not been established. In vitro tests have shown that aggregates of the globular component of the emulsion vehicle have occurred with blood/plasma/serum from humans and animals. The clinical significance of these findings is not known.

There have been reports in which failure to use aseptic technique when handling 1% Propofol Maruishi injectable emulsion was associated with microbial contamination of the product and with fever, infection, sepsis, other life-threatening illness, and death. Do not use if contamination is suspected. Discard unused portions as directed within the required time limits (see DOSAGE AND ADMINISTRATION - Handling Procedures).

PRECAUTIONS

General

Adult And Pediatric Patients

A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients. (See DOSAGE AND ADMINISTRATION.) Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds. 1% Propofol Maruishi injectable emulsion use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.

Very rarely the use of 1% Propofol Maruishi injectable emulsion may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness. Recovery is spontaneous.

When 1% Propofol Maruishi injectable emulsion is administered to an epileptic patient, there is a risk of seizure during the recovery phase.

Attention should be paid to minimize pain on administration of 1% Propofol Maruishi injectable emulsion.  Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous injection may also be reduced by prior injection of I.V. lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to 1% Propofol Maruishi in quantities greater than 20 mg lidocaine/200 mg 1% Propofol Maruishi results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it is recommended that lidocaine be administered prior to 1% Propofol Maruishi administration or that it be added to 1% Propofol Maruishi immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg 1% Propofol Maruishi.

Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (< 1%). In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction.

Intra-arterial injection in animals did not induce local tissue effects. Accidental intra-arterial injection has been reported in patients, and other than pain, there were no major sequelae.

Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During the post-marketing period, there have been rare reports of local pain, swelling, blisters and/or tissue necrosis following accidental extravasation of 1% Propofol Maruishi injectable emulsion.

Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with 1% Propofol Maruishi injectable emulsion administration.

Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema and hypotension, occur rarely following 1% Propofol Maruishi injectable emulsion administration.

There have been rare reports of pulmonary edema in temporal relationship to the administration of 1% Propofol Maruishi injectable emulsion, although a causal relationship is unknown.

Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which 1% Propofol Maruishi injectable emulsion was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to 1% Propofol Maruishi injectable emulsion is unclear.

1% Propofol Maruishi injectable emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with 1% Propofol Maruishi injectable emulsion. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.

Intensive Care Unit Sedation

Adult Patients

(See WARNINGS and DOSAGE AND ADMINISTRATION - Handling Procedures.) The administration of 1% Propofol Maruishi injectable emulsion should be initiated as a continuous infusion and changes in the rate of administration made slowly (>5 min) in order to minimize hypotension and avoid acute overdosage. (See DOSAGE AND ADMINISTRATION.)

Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of 1% Propofol Maruishi injectable emulsion, I.V. fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III  or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression, including hypotension, apnea, airway obstruction, and oxygen desaturation.

As with other sedative medications, there is wide interpatient variability in 1% Propofol Maruishi injectable emulsion dosage requirements, and these requirements may change with time.

Failure to reduce the infusion rate in patients receiving 1% Propofol Maruishi injectable emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of 1% Propofol Maruishi injectable emulsion infusion for ICU sedation, especially when it is used for long durations.

Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of 1% Propofol Maruishi injectable emulsion should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilator support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression. Because of the rapid clearance of 1% Propofol Maruishi injectable emulsion, abrupt discontinuation of a patient's infusion may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of 1% Propofol Maruishi injectable emulsion be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes prior to extubation at which time the infusion can be discontinued.

Since 1% Propofol Maruishi injectable emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when 1% Propofol Maruishi injectable emulsion is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of 1% Propofol Maruishi injectable emulsion should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the 1% Propofol Maruishi injectable emulsion formulation; 1 mL of 1% Propofol Maruishi injectable emulsion contains approximately 0.1 g of fat (1.1 kcal).

The long-term administration of 1% Propofol Maruishi injectable emulsion to patients with renal failure and/or hepatic insufficiency has not been evaluated.

Neurosurgical Anesthesia

When 1% Propofol Maruishi injectable emulsion is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus of approximately 20 mg every 10 seconds should be utilized instead of rapid, more frequent, and/or larger boluses of 1% Propofol Maruishi injectable emulsion. Slower induction, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of 1% Propofol Maruishi injectable emulsion. (See DOSAGE AND ADMINISTRATION.)

Cardiac Anesthesia

Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Fluid deficits should be corrected prior to administration of 1% Propofol Maruishi injectable emulsion. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with 1% Propofol Maruishi injectable emulsion.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of 1% Propofol Maruishi.

Mutagenesis

1% Propofol Maruishi was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA 1538. 1% Propofol Maruishi was not mutagenic in either the gene mutation/gene conversion test using Saccharomyces cerevisiae, or in vitro cytogenetic studies in Chinese hamsters. In the in vivo mouse micronucleus assay with Chinese Hamsters 1% Propofol Maruishi administration did not produce chromosome aberrations.

Impairment Of Fertility

Female Wistar rats were administered either 0, 10, or 15 mg/kg/day 1% Propofol Maruishi intravenously from 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility. Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at intravenous doses of 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m² basis) and have revealed no evidence of impaired fertility or harm to the fetus due to 1% Propofol Maruishi. 1% Propofol Maruishi, however, has been shown to cause maternal deaths in rats and rabbits and decreased pup survival during the lactating period in dams treated with 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m² basis). The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, this drug should be used during pregnancy only if clearly needed.

Labor And Delivery

1% Propofol Maruishi injectable emulsion is not recommended for obstetrics, including cesarean section deliveries. 1% Propofol Maruishi injectable emulsion crosses the placenta, and as with other general anesthetic agents, the administration of 1% Propofol Maruishi injectable emulsion may be associated with neonatal depression.

Nursing Mothers

1% Propofol Maruishi injectable emulsion is not recommended for use in nursing mothers because 1% Propofol Maruishi injectable emulsion has been reported to be excreted in human milk and the effects of oral absorption of small amounts of 1% Propofol Maruishi are not known.

Pediatric Use

The safety and effectiveness of 1% Propofol Maruishi injectable emulsion have been established for induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2 months and older.

1% Propofol Maruishi injectable emulsion is not recommended for the induction of anesthesia in patients younger than 3 years of age and for the maintenance of anesthesia in patients younger than 2 months of age as safety and effectiveness have not been established.

In pediatric patients, administration of fentanyl concomitantly with 1% Propofol Maruishi injectable emulsion may result in serious bradycardia. (See PRECAUTIONSGeneral.)

1% Propofol Maruishi injectable emulsion is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established.

There have been anecdotal reports of serious adverse events and death in pediatric patients with upper respiratory tract infections receiving 1% Propofol Maruishi injectable emulsion for ICU sedation.

In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received 1% Propofol Maruishi injectable emulsion (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality has not been established, 1% Propofol Maruishi injectable emulsion is not indicated for sedation in pediatric patients until further studies have been performed to document its safety in that population. (See CLINICAL PHARMACOLOGY, PharmacokineticsPediatric Patients and DOSAGE AND ADMINISTRATION.)

In pediatric patients, abrupt discontinuation following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Geriatric Use

The effect of age on induction dose requirements for 1% Propofol Maruishi was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of 1% Propofol Maruishi injectable emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response. (See DOSAGE AND ADMINISTRATIONElderly, debilitated or ASA-PS III or IV patients and CLINICAL PHARMACOLOGYGeriatrics.)

WARNINGS

Use of DIPRIVAN Injectable Emulsion has been associated with both fatal and lifethreatening anaphylactic and anaphylactoid reactions.

For general anesthesia or monitored anesthesia care (MAC) sedation, DIPRIVAN Injectable Emulsion should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV patients.

For sedation of intubated, mechanically ventilated patients in the Intensive Care Unit (ICU), DIPRIVAN Injectable Emulsion should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.

Use of DIPRIVAN Injectable Emulsion infusions for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as Propofol Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes* and/or cardiac failure. The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or prolonged, high-dose infusions of propofol ( > 5 mg/kg/h for > 48h). The syndrome has also been reported following large-dose, short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation, increasing propofol dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a propofol infusion, consideration should be given to using alternative means of sedation.

*Coved ST segment elevation (similar to ECG changes of the Brugada syndrome).

Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level (see PRECAUTIONS).

DIPRIVAN Injectable Emulsion should not be coadministered through the same IV catheter with blood or plasma because compatibility has not been established. In vitro tests have shown that aggregates of the globular component of the emulsion vehicle have occurred with blood/plasma/serum from humans and animals. The clinical significance of these findings is not known.

There have been reports in which failure to use aseptic technique when handling Diprivan Injectable Emulsion was associated with microbial contamination of the product and with fever, infection, sepsis, other life-threatening illness, and death. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits (see DOSAGE AND ADMINISTRATION, Handling Procedures).

There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons. DIPRIVAN Injectable Emulsion vial is never to be accessed more than once or used on more than one person.

PRECAUTIONS

General

Adult and Pediatric Patients

A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients (see DOSAGE AND ADMINISTRATION). Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds. DIPRIVAN Injectable Emulsion use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.

Very rarely the use of DIPRIVAN Injectable Emulsion may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness. Recovery is spontaneous.

When DIPRIVAN Injectable Emulsion is administered to an epileptic patient, there is a risk of seizure during the recovery phase.

Attention should be paid to minimize pain on administration of DIPRIVAN Injectable Emulsion. Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous injection may also be reduced by prior injection of IV lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to DIPRIVAN Injectable Emulsion in quantities greater than 20 mg lidocaine/200 mg DIPRIVAN Injectable Emulsion results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it is recommended that lidocaine be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely ( < 1%). In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction.

Intra-arterial injection in animals did not induce local tissue effects. Accidental intraarterial injection has been reported in patients, and, other than pain, there were no major sequelae.

Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of DIPRIVAN Injectable Emulsion.

Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with DIPRIVAN Injectable Emulsion administration.

Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following DIPRIVAN Injectable Emulsion administration.

There have been rare reports of pulmonary edema in temporal relationship to the administration of DIPRIVAN Injectable Emulsion, although a causal relationship is unknown.

Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which DIPRIVAN Injectable Emulsion was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to DIPRIVAN Injectable Emulsion is unclear.

DIPRIVAN Injectable Emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with DIPRIVAN Injectable Emulsion. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.

Intensive Care Unit Sedation

Adult Patients

(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.) The administration of DIPRIVAN Injectable Emulsion should be initiated as a continuous infusion and changes in the rate of administration made slowly ( > 5 min) in order to minimize hypotension and avoid acute overdosage (see DOSAGE AND ADMINISTRATION).

Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of DIPRIVAN Injectable Emulsion, IV fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression, including hypotension, apnea, airway obstruction, and oxygen desaturation.

As with other sedative medications, there is wide interpatient variability in DIPRIVAN Injectable Emulsion dosage requirements, and these requirements may change with time.

Failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of DIPRIVAN Injectable Emulsion infusion for ICU sedation, especially when it is used for long durations.

Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilatory support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression. Because of the rapid clearance of DIPRIVAN Injectable Emulsion, abrupt discontinuation of a patient's infusion may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of DIPRIVAN Injectable Emulsion be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes prior to extubation, at which time the infusion can be discontinued.

Since DIPRIVAN Injectable Emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when DIPRIVAN Injectable Emulsion is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of DIPRIVAN Injectable Emulsion should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the DIPRIVAN Injectable Emulsion formulation; 1 mL of DIPRIVAN Injectable Emulsion contains approximately 0.1 g of fat (1.1 kcal).

EDTA is a strong chelator of trace metals - including zinc. Although with DIPRIVAN Injectable Emulsion there are no reports of decreased zinc levels or zinc deficiency-related adverse events, DIPRIVAN Injectable Emulsion should not be infused for longer than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses.

In clinical trials mean urinary zinc loss was approximately 2.5 to 3 mg/day in adult patients and 1.5 to 2 mg/day in pediatric patients.

In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major sepsis, the need for supplemental zinc should be considered during prolonged therapy with DIPRIVAN Injectable Emulsion.

At high doses (2 to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules. Studies to date in patients with normal or impaired renal function have not shown any alteration in renal function with DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation.

The long-term administration of DIPRIVAN Injectable Emulsion to patients with renal failure and/or hepatic insufficiency has not been evaluated.

Neurosurgical Anesthesia

When DIPRIVAN Injectable Emulsion is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus of approximately 20 mg every 10 seconds should be utilized instead of rapid, more frequent, and/or larger boluses of DIPRIVAN Injectable Emulsion. Slower induction, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of DIPRIVAN Injectable Emulsion (see DOSAGE AND ADMINISTRATION).

Cardiac Anesthesia

Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Fluid deficits should be corrected prior to administration of DIPRIVAN Injectable Emulsion. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with DIPRIVAN Injectable Emulsion.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of propofol.

Mutagenesis

Propofol was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. Propofol was not mutagenic in either the gene mutation/gene conversion test using Saccharomyces cerevisiae, or in vitro cytogenetic studies in Chinese hamsters. In the in vivo mouse micronucleus assay with Chinese Hamsters propofol administration did not produce chromosome aberrations.

Impairment of Fertility

Female Wistar rats were administered either 0, 10, or 15 mg/kg/day propofol intravenously from 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility. Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.

Pregnancy

Teratogenic Effects - Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at intravenous doses of 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m² basis) and have revealed no evidence of impaired fertility or harm to the fetus due to propofol. Propofol, however, has been shown to cause maternal deaths in rats and rabbits and decreased pup survival during the lactating period in dams treated with 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m² basis). The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, DIPRIVAN Injectable Emulsion should be used during pregnancy only if clearly needed.

Labor And Delivery

DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including cesarean section deliveries. DIPRIVAN Injectable Emulsion crosses the placenta, and as with other general anesthetic agents, the administration of DIPRIVAN Injectable Emulsion may be associated with neonatal depression.

Nursing Mothers

DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because DIPRIVAN Injectable Emulsion has been reported to be excreted in human milk and the effects of oral absorption of small amounts of propofol are not known.

Pediatric Use

The safety and effectiveness of DIPRIVAN Injectable Emulsion have been established for induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2 months and older.

DIPRIVAN Injectable Emulsion is not recommended for the induction of anesthesia in patients younger than 3 years of age and for the maintenance of anesthesia in patients younger than 2 months of age as safety and effectiveness have not been established.

In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN Injectable Emulsion may result in serious bradycardia (see PRECAUTIONS, General).

DIPRIVAN Injectable Emulsion is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established.

There have been anecdotal reports of serious adverse events and death in pediatric patients with upper respiratory tract infections receiving DIPRIVAN Injectable Emulsion for ICU sedation.

In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received DIPRIVAN Injectable Emulsion (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality has not been established, DIPRIVAN Injectable Emulsion is not indicated for sedation in pediatric patients until further studies have been performed to document its safety in that population (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Pediatric Patients and DOSAGE AND ADMINISTRATION).

In pediatric patients, abrupt discontinuation of DIPRIVAN Injectable Emulsion following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Geriatric Use

The effect of age on induction dose requirements for propofol was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of DIPRIVAN Injectable Emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response (see DOSAGE AND ADMINISTRATION, Elderly, Debilitated or ASA-PS III or IV Patients and CLINICAL PHARMACOLOGY, Geriatrics).

Effects on ability to drive and use machines
The information provided in Effects on ability to drive and use machines of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Effects on ability to drive and use machines in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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1% Propofol Maruishi 1% has moderate influence on the ability to drive and use machines. Patients should be advised that performance at skilled tasks, such as driving and operating machinery, may be impaired for some time after general anaesthesia.

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Undesirable effects
The information provided in Undesirable effects of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

General

Induction and maintenance of anaesthesia or sedation is generally smooth with minimal evidence of excitation. The most commonly reported ADRs are pharmacologically predictable side effects of an anaesthetic/sedative agent, such as hypotension. The nature, severity and incidence of adverse events observed in patients receiving 1% Propofol Maruishi 1% may be related to the condition of the recipients and the operative or therapeutic procedures being undertaken.

The following definitions of frequencies are used:

Very common (≥1/10), common (≥1/100 to <1/10), uncommon ((≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table of Adverse Drug Reactions

System Organ Class

Frequency

Undesirable Effects

Immune system disorders

Very rare

Anaphylaxis – may include angioedema, bronchospasm, erythema and hypotension

Metabolism and nutrition disorders

Not known (9)

Metabolic acidosis (5), hyperkalaemia (5), hyperlipidaemia (5)

Psychiatric disorders

Not known (9)

Euphoric mood. Drug abuse and drug dependence (8)

Nervous system disorders

Common

Headache during recovery phase

Rare

Epileptiform movements, including convulsions and opisthotonus during induction, maintenance and recovery

Very rare

Postoperative unconsciousness

Not known (9)

Involuntary movements

Cardiac disorders

Common

Bradycardia (1)

Very rare

Pulmonary oedema

Not known (9)

Cardiac arrhythmia (5), cardiac failure (5), (7)

Vascular disorders

Common

Hypotension (2)

Uncommon

Thrombosis and phlebitis

Respiratory, thoracic and mediastinal disorders

Common

Transient apnoea during induction

Not known (9)

Respiratory depression (dose dependent)

Gastrointestinal disorders

Common

Nausea and vomiting during recovery phase

Very rare

Pancreatitis

Hepatobiliary disorders

Not known (9)

Hepatomegaly (5)

Musculoskeletal and connective tissue disorders

Not known (9)

Rhabdomyolysis (3), (5)

Renal and urinary disorders

Very rare

Discolouration of urine following prolonged administration

Not known (9)

Renal failure (5)

Reproductive system and breast disorders

Very rare

Sexual disinhibition

General disorders and administration site conditions

Very common

Local pain on induction (4)

Very rare

Tissue necrosis (10) following accidental extravascular administration

Not known (9)

Local pain, swelling, following accidental extravascular administration

Investigations

Not known (9)

Brugada type ECG (5), (6)

Injury, poisoning and procedural complications

Very rare

Postoperative fever

(1) Serious bradycardias are rare. There have been isolated reports of progression to asystole.

(2) Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of 1% Propofol Maruishi.

(3) Very rare reports of rhabdomyolysis have been received where 1% Propofol Maruishi has been given at doses greater than 4 mg/kg/hr for ICU sedation.

(4) May be minimised by using the larger veins of the forearm and antecubital fossa. With 1% Propofol Maruishi 1% local pain can also be minimised by the co-administration of lidocaine.

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(6) Brugada-type ECG - elevated ST-segment and coved T-wave in ECG.

(7) Rapidly progressive cardiac failure (in some cases with fatal outcome) in adults. The cardiac failure in such cases was usually unresponsive to inotropic supportive treatment.

(8) Abuse of and drug dependence on propofol, predominantly by health care professionals.

(9) Not known as it cannot be estimated from the available clinical trial data.

(10) Necrosis has been reported where tissue viability has been impaired.

Dystonia/dyskinesia have been reported.

Local

The local pain which may occur during the induction phase of 1% Propofol Maruishi 1% anaesthesia can be minimised by the co-administration of lidocaine (see "Dosage and Administration") and by the use of the larger veins of the forearm and antecubital fossa. Thrombosis and phlebitis are rare. Accidental clinical extravasation and animal studies showed minimal tissue reaction. Intra-arterial injection in animals did not induce local tissue effects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

General

Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

Anesthesia And MAC Sedation In Adults

The following estimates of adverse events for 1% Propofol Maruishi injectable emulsion include data from clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with 1% Propofol Maruishi injectable emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship.

The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with 1% Propofol Maruishi during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.

Anesthesia In Pediatric Patients

Generally the adverse experience profile from reports of 506 1% Propofol Maruishi injectable emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with 1% Propofol Maruishi injectable emulsion during anesthesia in adults (see Pediatric percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

ICU Sedation In Adults

The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship.

Incidence greater than 1% - Probably Causally Related

  Anesthesia/MAC Sedation ICU Sedation
Cardiovascular: Bradycardia Arrhythmia [Peds: 1.2%] Tachycardia Nodal [Peds: 1.6%] Bradycardia
  Hypotension* [Peds: 17%] (see also CLINICAL PHARMACOLOGY) Decreased Cardiac Output
Central Nervous System: [Hypertension Peds: 8%] Movement* [Peds: 17%] Hypotension 26%
Injection Site: Burning/Stinging or Pain, 17.6% [Peds: 10%]  
Metabolic/Nutritional:   Hyperlipemia*
Respiratory: Apnea (see also CLINICAL PHARMACOLOGY) Respiratory Acidosis During Weaning*
Skin and Appendages: Rash [Peds: 5%]  
  Pruritus [Peds: 2%]  
Events without an * or % had an incidence of 1% to 3%
*Incidence of events 3% to 10%
  Incidence less than 1% - Probably Causally Related
  Anesthesia/MAC Sedation ICU Sedation
Body as a Whole: Anaphylaxis/Anaphylactoid Reaction, Perinatal Disorder, [Tachycardia], [Bigeminy], [Bradycardia], [Premature Ventricular Contractions], [Hemorrhage], [ECG Abnormal], [Arrhythmia Atrial], [Fever], [Extremities Pain], [Anticholinergic Syndrome]  
Cardiovascular: Premature Atrial Contractions, Syncope  
Central Nervous System: Hypertonia/Dystonia, Paresthesia Agitation
Digestive: [Hypersalivation], [Nausea]  
Hemic/Lymphatic: [Leukocytosis]  
Injection Site: [Phlebitis], [Pruritus]  
Metabolic: [Hypomagnesemia]  
Musculoskeletal: Myalgia  
Nervous: [Dizziness], [Agitation], [Chills], [Somnolence], [Delirium]  
Respiratory: Wheezing, [Cough], [Laryngospasm], [Hypoxia] Decreased Lung Function
Skin and Appendages: Flushing, Pruritus  
Special Senses: Amblyopia, [Vision Abnormal]  
Urogenital: Cloudy Urine Green Urine
  Incidence less than 1% - Causal Relationship Unknown
  Anesthesia/MAC Sedation ICU Sedation
Body as a Whole: Asthenia, Awareness, Chest Pain, Extremities Pain, Fever, Increased Drug Fever, Sepsis, Trunk Pain, Whole Body Weakness
Cardiovascular: Effect, Neck Rigidity/Stiffness, Trunk Pain Arrhythmia, Atrial Fibrillation, Atrioventricular Heart Block, Bigeminy, Bleeding, Bundle Branch Block, Cardiac Arrest, ECG Abnormal, Edema, Extrasystole, Heart Block, Hypertension, Myocardial Infarction, Myocardial Ischemia, Premature Ventricular Contractions, ST Segment Depression, Supraventricular Tachycardia, Tachycardia, Ventricular Fibrillation Arrhythmia, Atrial Fibrillation, Bigeminy, Cardiac Arrest, Extrasystole, Right Heart Failure, Ventricular Tachycardia
Central Nervous System: Abnormal Dreams, Agitation, Amorous Behavior, Anxiety, Bucking/Jerking/Thrashing, Chills/Shivering/Clonic/Myoclonic Movement, Combativeness, Confusion, Delirium, Depression, Dizziness, Emotional Lability, Euphoria, Fatigue, Hallucinations, Headache, Hypotonia, Hysteria, Insomnia, Moaning, Neuropathy, Opisthotonos, Rigidity, Seizures, Somnolence, Tremor, Twitching Chills/Shivering, Intracranial Hypertension, Seizures, Somnolence, Thinking Abnormal
Digestive: Cramping, Diarrhea, Dry Mouth, Enlarged Parotid, Nausea, Swallowing, Vomiting Ileus, Liver Function Abnormal
Hematologic/Lymphatic: Coagulation Disorder, Leukocytosis  
Injection Site: Hives/Itching, Phlebitis, Redness/Discoloration  
Metabolic/Nutritional: Hyperkalemia, Hyperlipemia BUN Increased, Creatinine Increased, Dehydration, Hyperglycemia, Metabolic Acidosis, Osmolality Increased
Respiratory: Bronchospasm, Burning in Throat, Cough, Dyspnea, Hiccough, Hyperventilation, Hypoventilation, Hypoxia, Laryngospasm, Pharyngitis, Sneezing, Tachypnea, Upper Airway Obstruction Hypoxia
Skin and Appendages: Conjunctival Hyperemia, Diaphoresis, Urticaria Rash
Special Senses: Diplopia, Ear Pain, Eye Pain, Nystagmus, Taste Perversion, Tinnitus  
Urogenital: Oliguria, Urine Retention Kidney Failure

General

Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent  US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

Anesthesia And MAC Sedation In Adults

The following estimates of adverse events for DIPRIVAN Injectable Emulsion include data from clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with DIPRIVAN Injectable Emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship.

The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with DIPRIVAN Injectable Emulsion during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.

Anesthesia In Pediatric Patients

Generally the adverse experience profile from reports of 506 DIPRIVAN Injectable Emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with DIPRIVAN Injectable Emulsion during anesthesia in adults (see Pediatric percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

ICU Sedation In Adults

The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship.

Incidence greater than 1% - Probably Causally Related

  Anesthesia/MAC Sedation ICU Sedation
Cardiovascular: Bradycardia Bradycardia
Arrhythmia [Peds: 1.2%]  
Tachycardia Nodal [Peds: 1.6%]
Hypotension* [Peds: 17%] (see also CLINICAL PHARMACOLOGY) Decreased Cardiac Output
  Hypertension [Peds: 8%] Hypotension 26%
Central Nervous System: Movement* [Peds: 17%]  
Injection Site: Burning/Stinging or Pain, 17.6% [Peds: 10%]  
Metabolic/Nutritional:   Hyperlipemia*
Respiratory: Apnea (see also CLINICAL PHARMACOLOGY) Respiratory Acidosis During Weaning*
Skin and Appendages: Rash [Peds: 5%] Pruritus [Peds: 2%]  
Events without an * or % had an incidence of 1% to 3%
*Incidence of events 3% to 10%

Incidence less than 1% - Probably Causally Related

  Anesthesia/MAC Sedation ICU Sedation
Body as a Whole: Anaphylaxis/Anaphylactoid Reaction Perinatal Disorder
[Tachycardia]
[Bigeminy]
[Bradycardia]
[Premature Ventricular Contractions]
[Hemorrhage]
[ECG Abnormal]
[Arrhythmia Atrial]
[Fever]
[Extremities Pain]
[Anticholinergic Syndrome]
 
Cardiovascular: Premature Atrial Contractions Syncope  
Central Nervous System: Hypertonia/Dystonia, Paresthesia Agitation
Digestive: [Hypersalivation]
[Nausea]
 
Hemic/Lymphatic: [Leukocytosis]  
Injection Site: [Phlebitis]
[Pruritus]
 
Metabolic: [Hypomagnesemia]  
Musculoskeletal: Myalgia  
Nervous: [Dizziness]
[Agitation]
[Chills]
[Somnolence]
[Delirium]
 
Respiratory: Wheezing
[Cough]
[Laryngospasm]
[Hypoxia]
Decreased Lung Function
Skin and Appendages: Flushing, Pruritus  
Special Senses: Amblyopia
[Vision Abnormal]
 
Urogenital: Cloudy Urine Green Urine

Incidence less than 1% - Causal Relationship Unknown

  Anesthesia/MAC Sedation ICU Sedation
Body as a Whole: Asthenia, Awareness, Chest Pain, Extremities Pain, Fever, Increased Drug Effect, Neck Rigidity/Stiffness, Trunk Pain Fever, Sepsis, Trunk Pain, Whole Body Weakness
Cardiovascular: Arrhythmia, Atrial Fibrillation, Atrioventricular Heart Block, Bigeminy, Bleeding, Bundle Branch Block, Cardiac Arrest, ECG Abnormal, Edema, Extrasystole, Heart Block, Hypertension, Myocardial Infarction, Myocardial Ischemia, Premature Ventricular Contractions, ST Segment Depression, Supraventricular Tachycardia, Tachycardia, Ventricular Fibrillation Arrhythmia, Atrial Fibrillation, Bigeminy, Cardiac Arrest, Extrasystole, Right Heart Failure, Ventricular Tachycardia
Central Nervous System: Abnormal Dreams, Agitation, Amorous Behavior, Anxiety, Bucking/Jerking/Thrashing, Chills/Shivering/Clonic/Myoclonic Movement, Combativeness, Confusion, Delirium, Depression, Dizziness, Emotional Lability, Euphoria, Fatigue, Hallucinations, Headache, Hypotonia, Hysteria, Insomnia, Moaning, Neuropathy, Opisthotonos, Rigidity, Seizures, Somnolence, Tremor, Twitching Chills/Shivering, Intracranial Hypertension, Seizures, Somnolence, Thinking Abnormal
Digestive: Cramping, Diarrhea, Dry Mouth, Enlarged Parotid, Nausea, Swallowing, Vomiting Ileus, Liver Function Abnormal
Hematologic/ Lymphatic: Coagulation Disorder, Leukocytosis  
Injection Site: Hives/Itching, Phlebitis, Redness/Discoloration  
Metabolic/ Nutritional: Hyperkalemia, Hyperlipemia BUN Increased, Creatinine Increased, Dehydration, Hyperglycemia, Metabolic Acidosis, Osmolality Increased
Respiratory: Bronchospasm, Burning in Throat, Cough, Dyspnea, Hiccough, Hyperventilation, Hypoventilation, Hypoxia, Laryngospasm, Pharyngitis, Sneezing, Tachypnea, Upper Airway Obstruction Hypoxia
Skin and Appendages: Conjunctival Hyperemia, Diaphoresis, Rash
  Urticaria  
Special Senses: Diplopia, Ear Pain, Eye Pain,  
  Nystagmus, Taste Perversion,  
  Tinnitus  
Urogenital: Oliguria, Urine Retention Kidney Failure

Drug Abuse And Dependence

There are reports of the abuse of propofol for recreational and other improper purposes, which have resulted in fatalities and other injuries. Instances of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have also been reported, which have resulted in fatalities and other injuries. Inventories of DIPRIVAN Injectable Emulsion should be stored and managed to prevent the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting.

Overdose
The information provided in Overdose of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

Accidental overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression would require lowering of the patient's head and, if severe, use of plasma expanders and pressor agents.

If overdosage occurs, 1% Propofol Maruishi injectable emulsion administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.

If overdosage occurs, DIPRIVAN Injectable Emulsion administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.

Pharmacodynamic properties
The information provided in Pharmacodynamic properties of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

Pharmacotherapeutic group: Other general anaesthetics

ATC code: N01AX10

Mechanism of action

Propofol (2, 6-diisopropylphenol) is a short-acting general anaesthetic agent with a rapid onset of action of approximately 30 seconds. Recovery from anaesthesia is usually rapid. The mechanism of action, like all general anaesthetics, is poorly understood. However, propofol is thought to produce its sedative/anaesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAA receptors.

Pharmacodynamic properties

In general, falls in mean arterial blood pressure and slight changes in heart rate are observed when 1% Propofol Maruishi 1% is administered for induction and maintenance of anaesthesia. However, the haemodynamic parameters normally remain relatively stable during maintenance and the incidence of untoward haemodynamic changes is low.

Although ventilatory depression can occur following administration of 1% Propofol Maruishi 1%, any effects are qualitatively similar to those of other intravenous anaesthetic agents and are readily manageable in clinical practice.

1% Propofol Maruishi 1% reduces cerebral blood flow, intracranial pressure and cerebral metabolism. The reduction in intracranial pressure is greater in patients with an elevated baseline intracranial pressure.

Clinical efficacy and safety

Recovery from anaesthesia is usually rapid and clear headed with a low incidence of headache and post-operative nausea and vomiting.

In general, there is less post-operative nausea and vomiting following anaesthesia with 1% Propofol Maruishi 1% than following anaesthesia with inhalational agents. There is evidence that this may be related to a reduced emetic potential of propofol.

1% Propofol Maruishi 1%, at the concentrations likely to occur clinically, does not inhibit the synthesis of adrenocortical hormones.

Paediatric population

Limited studies on the duration of propofol based anaesthesia in children indicate safety and efficacy is unchanged up to duration of 4 hours. Literature evidence of use in children documents use for prolonged procedures without changes in safety or efficacy.

Pharmacodynamic properties of 1% Propofol Maruishi are dependent upon the therapeutic blood 1% Propofol Maruishi concentrations. Steady-state 1% Propofol Maruishi blood concentrations are generally proportional to infusion rates. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dosage adjustments in order to assess clinical effects.

The hemodynamic effects of 1% Propofol Maruishi injectable emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of 1% Propofol Maruishi injectable emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of 1% Propofol Maruishi injectable emulsion during induction of anesthesia are generally more pronounced than with other intravenous (I.V.) induction agents.

Induction of anesthesia with 1% Propofol Maruishi injectable emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received 1% Propofol Maruishi injectable emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of 1% Propofol Maruishi injectable emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, 1% Propofol Maruishi injectable emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of 1% Propofol Maruishi injectable emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of 1% Propofol Maruishi injectable emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that 1% Propofol Maruishi injectable emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that 1% Propofol Maruishi injectable emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that 1% Propofol Maruishi injectable emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. 1% Propofol Maruishi injectable emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials - Neuroanesthesia).

Clinical studies indicate that 1% Propofol Maruishi injectable emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of 1% Propofol Maruishi injectable emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving 1% Propofol Maruishi injectable emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.

The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents.

Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASAPS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials, Neuroanesthesia).

Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacokinetic properties
The information provided in Pharmacokinetic properties of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Emulsion for injection or for infusion; Emulsion for intravenous administration
Substance-liquid
Emulsion for infusion

Absorption

When 1% Propofol Maruishi 1% is used to maintain anaesthesia, blood concentrations asymptotically approach the steady-state value for the given administration rate.

Distribution

Propofol is extensively distributed and rapidly cleared from the body (total body clearance 1.5–2 litres/minute).

Elimination

The decline in propofol concentrations following a bolus dose or following the termination of an infusion can be described by a three compartment open model with very rapid distribution (half-life 2 –4 minutes), rapid elimination (half-life 30 – 60 minutes), and a slower final phase, representative of redistribution of propofol from poorly perfused tissue.

Clearance occurs by metabolic processes, mainly in the liver where it is blood flow dependent, to form inactive conjugates of propofol and its corresponding quinol, which are excreted in urine.

After a single dose of 3 mg/kg intravenously, propofol clearance/kg body weight increased with age as follows: Median clearance was considerably lower in neonates <1 month old (n=25) (20 ml/kg/min) compared to older children (n= 36, age range 4 months–7 years). Additionally inter-individual variability was considerable in neonates (range 3.7–78 ml/kg/min). Due to this limited trial data that indicates a large variability, no dose recommendations can be given for this age group.

Median propofol clearance in older aged children after a single 3 mg/kg bolus was 37.5 ml/min/kg (4-24 months) (n=8), 38.7 ml/min/kg (11–43 months) (n=6), 48 ml/min/kg (1–3 years)(n=12), 28.2 ml/min/kg (4–7 years)(n=10) as compared with 23.6 ml/min/kg in adults (n=6).

Linearity

The pharmacokinetics are linear over the recommended range of infusion rates of 1% Propofol Maruishi 1%.

Pediatric Patients and DOSAGE AND ADMINISTRATION.)

In pediatric patients, abrupt discontinuation following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Geriatric Use

The effect of age on induction dose requirements for 1% Propofol Maruishi was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of 1% Propofol Maruishi injectable emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response. (See DOSAGE AND ADMINISTRATIONElderly, debilitated or ASA-PS III or IV patients and CLINICAL PHARMACOLOGYGeriatrics.)

Overdosage & Contraindications

OVERDOSE

If overdosage occurs, 1% Propofol Maruishi injectable emulsion administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.

CONTRAINDICATIONS

1% Propofol Maruishi injectable emulsion is contraindicated in patients with a known hypersensitivity to 1% Propofol Maruishi injectable emulsion or any of its components.

1% Propofol Maruishi injectable emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

General

1% Propofol Maruishi is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of 1% Propofol Maruishi induces hypnosis with minimal excitation, usually within 40 seconds from the start of injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia.

Pharmacodynamics

Pharmacodynamic properties of 1% Propofol Maruishi are dependent upon the therapeutic blood 1% Propofol Maruishi concentrations. Steady-state 1% Propofol Maruishi blood concentrations are generally proportional to infusion rates. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dosage adjustments in order to assess clinical effects.

The hemodynamic effects of 1% Propofol Maruishi injectable emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of 1% Propofol Maruishi injectable emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of 1% Propofol Maruishi injectable emulsion during induction of anesthesia are generally more pronounced than with other intravenous (I.V.) induction agents.

Induction of anesthesia with 1% Propofol Maruishi injectable emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received 1% Propofol Maruishi injectable emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of 1% Propofol Maruishi injectable emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, 1% Propofol Maruishi injectable emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of 1% Propofol Maruishi injectable emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of 1% Propofol Maruishi injectable emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that 1% Propofol Maruishi injectable emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that 1% Propofol Maruishi injectable emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that 1% Propofol Maruishi injectable emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. 1% Propofol Maruishi injectable emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials - Neuroanesthesia).

Clinical studies indicate that 1% Propofol Maruishi injectable emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of 1% Propofol Maruishi injectable emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving 1% Propofol Maruishi injectable emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacokinetics

The pharmacokinetics of 1% Propofol Maruishi are well described by a three compartment linear model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.

Following an I.V. bolus dose, there is rapid equilibration between the plasma and the brain, thus accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. Distribution accounts for about half of this decline following a bolus of 1% Propofol Maruishi.

However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion. When equilibration occurs there is no longer a net transfer of 1% Propofol Maruishi between tissues and plasma.

Discontinuation of the recommended doses of 1% Propofol Maruishi injectable emulsion after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood 1% Propofol Maruishi concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of 1% Propofol Maruishi, such that the reduction in circulating 1% Propofol Maruishi is slowed and the time to awakening is increased.

By daily titration of 1% Propofol Maruishi injectable emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, 1% Propofol Maruishi redistribution from fat and muscle to the plasma, can be significant and slow recovery.

The figure below illustrates the fall of plasma 1% Propofol Maruishi levels following infusions of various durations to provide ICU sedation.

The large contribution of distribution (about 50%) to the fall of 1% Propofol Maruishi plasma levels following brief infusions means that after very long infusions a reduction in infusion rate is appropriate by as much as half the initial infusion rate in order to maintain a constant plasma level. Therefore, failure to reduce the infusion rate in patients receiving 1% Propofol Maruishi injectable emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of 1% Propofol Maruishi injectable emulsion infusion for ICU sedation.

Adults

1% Propofol Maruishi clearance ranges from 23 to 50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults). It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. 1% Propofol Maruishi has a steady state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not been observed. The terminal half-life of 1% Propofol Maruishi after a 10-day infusion is 1 to 3 days.

Geriatrics

With increasing patient age, the dose of 1% Propofol Maruishi needed to achieve a defined anesthetic endpoint (dose-requirement) decreases. This does not appear to be an age-related change in pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing patient age, pharmacokinetic changes are such that for a given I.V. bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or arterial oxygen desaturation. The higher plasma levels reflect age-related decrease in volume of distribution and intercompartmental clearance. Lower doses are therefore recommended for initiation and maintenance of sedation and anesthesia in elderly patients. (See DOSAGE AND ADMINISTRATION.)

Pediatrics

The pharmacokinetics of 1% Propofol Maruishi were studied in children between 3 and 12 years of age who received 1% Propofol Maruishi injectable emulsion for periods of approximately 1 to 2 hours. The observed distribution and clearance of 1% Propofol Maruishi in these children were similar to adults.

Organ Failure

The pharmacokinetics of 1% Propofol Maruishi do not appear to be different in people with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of acute hepatic or renal failure on the pharmacokinetics of 1% Propofol Maruishi have not been studied.

Clinical Trials

Anesthesia And Monitored Anesthesia Care (MAC) Sedation

Pediatric Anesthesia

1% Propofol Maruishi injectable emulsion was studied in clinical trials which included cardiac surgical patients. Most patients were 3 years of age or older. The majority of the patients were healthy ASA-PS I or II patients. The range of doses in these studies are described in Tables 1 and 2.

TABLE 1: PEDIATRIC INDUCTION OF ANESTHESIA

Age Range Induction Dose Median (range) Injection Duration Median (range)
Birth through 16 years 2.5 mg/kg (1 - 3.6) 20 sec. (6 - 45)

TABLE 2: PEDIATRIC MAINTENANCE OF ANESTHESIA

Age Range Maintenance Dosage (mcg/kg/min) Duration (minutes)
2 months to 2 years 199 (82 - 394) 65 (12 - 282)
2 to 12 years 188 (12 - 1041) 69 (23 - 374)
>12 through 16 years 161 (84 - 359) 69 (26 - 251)

Neuroanesthesia

1% Propofol Maruishi injectable emulsion was studied in patients undergoing craniotomy for supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior x lateral) was 31 mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively. Anesthesia was induced with a median 1% Propofol Maruishi dose of 1.4 mg/kg (range: 0.9 to 6.9 mg/kg) and maintained with a median maintenance 1% Propofol Maruishi dose of 146 mcg/kg/min (range: 68 to 425 mcg/kg/min). The median duration of the 1% Propofol Maruishi maintenance infusion was 285 minutes (range: 48 to 622 minutes).

1% Propofol Maruishi injectable emulsion was administered by infusion in a controlled clinical trial to evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17% (mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), 1% Propofol Maruishi injectable emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.

Intensive Care Unit (ICU) Sedation

Adult Patients

1% Propofol Maruishi injectable emulsion was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received 1% Propofol Maruishi injectable emulsion and comprise the overall safety database for ICU sedation.

Across all clinical studies, the mean infusion maintenance rate for all 1% Propofol Maruishi injectable emulsion patients was 27 ± 21 mcg/kg/min. The maintenance infusion rates required to maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for analgesia. Some patients also received benzodiazepines and/or neuromuscular blocking agents. During long-term maintenance of sedation, some ICU patients were awakened once or twice every 24 hours for assessment of neurologic or respiratory function.

In Medical and Postsurgical ICU studies comparing 1% Propofol Maruishi injectable emulsion to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators, 1% Propofol Maruishi injectable emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect that 1% Propofol Maruishi injectable emulsion has been used safely in patients with a history of porphyria or malignant hyperthermia.

In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, adequate sedation was maintained with 1% Propofol Maruishi injectable emulsion or morphine. There were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery between the treatment groups. In literature reports of severely head-injured patients in Neurosurgical ICUs, 1% Propofol Maruishi injectable emulsion infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion pressure.

1% Propofol Maruishi injectable emulsion was found to be effective in status epilepticus which was refractory to the standard anticonvulsant therapies. For these patients, as well as for ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill patient populations.

Pediatric Patients

A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of 1% Propofol Maruishi versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either 1% Propofol Maruishi 2% (113 patients), 1% Propofol Maruishi 1% (109 patients), or an SSA (e.g., lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). 1% Propofol Maruishi therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The results of the study showed an increase in the number of deaths in patients treated with 1% Propofol Maruishi as compared to SSAs. Of the 25 patients who died during the trial or within the 28-day follow-up period: 12 (11% were) in the 1% Propofol Maruishi 2% treatment group, 9 (8% were) in the 1% Propofol Maruishi 1% treatment group, and 4% were (4%) in the SSA treatment group. The differences in mortality rate between the groups were not statistically significant. Review of the deaths failed to reveal a correlation with underlying disease status or a correlation to the drug or a definitive pattern to the causes of death.

Cardiac Anesthesia

1% Propofol Maruishi injectable emulsion was evaluated in clinical trials involving patients undergoing coronary artery bypass graft (CABG).

In post-CABG (coronary artery bypass graft) patients, the maintenance rate of 1% Propofol Maruishi administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving 1% Propofol Maruishi injectable emulsion required 35% less nitroprusside than midazolam patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular effects in patients with severely compromised ventricular function.

, Pediatric Patients and DOSAGE AND ADMINISTRATION).

In pediatric patients, abrupt discontinuation of DIPRIVAN Injectable Emulsion following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Geriatric Use

The effect of age on induction dose requirements for propofol was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of DIPRIVAN Injectable Emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response (see DOSAGE AND ADMINISTRATION, Elderly, Debilitated or ASA-PS III or IV Patients and CLINICAL PHARMACOLOGY, Geriatrics).

Overdosage & Contraindications

OVERDOSE

If overdosage occurs, DIPRIVAN Injectable Emulsion administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.

CONTRAINDICATIONS

DIPRIVAN Injectable Emulsion is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN Injectable Emulsion components.

DIPRIVAN Injectable Emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

General

DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol induces hypnosis, with minimal excitation, usually within 40 seconds from the start of injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia. The mechanism of action, like all general anesthetics, is poorly understood. However, propofol is thought to produce its sedative/anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAa receptors.

Pharmacodynamics

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.

The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents.

Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASAPS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials, Neuroanesthesia).

Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacokinetics

The pharmacokinetics of propofol are well described by a three compartment linear model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.

Following an IV bolus dose, there is rapid equilibration between the plasma and the brain, accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. Distribution accounts for about half of this decline following a bolus of propofol. However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion. When equilibration occurs there is no longer a net transfer of propofol between tissues and plasma.

Discontinuation of the recommended doses of DIPRIVAN Injectable Emulsion after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and the time to awakening is increased.

By daily titration of DIPRIVAN Injectable Emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, propofol redistribution from fat and muscle to the plasma can be significant and slow recovery.

The figure below illustrates the fall of plasma propofol levels following infusions of various durations to provide ICU sedation.

The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief infusions means that after very long infusions a reduction in the infusion rate is appropriate by as much as half the initial infusion rate in order to maintain a constant plasma level. Therefore, failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of DIPRIVAN Injectable Emulsion infusion for ICU sedation.

Adults

Propofol clearance ranges from 23 to 50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults). It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. Propofol has a steady-state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not been observed. The terminal half-life of propofol after a 10-day infusion is 1 to 3 days.

Geriatrics

With increasing patient age, the dose of propofol needed to achieve a defined anesthetic end point (dose-requirement) decreases. This does not appear to be an age-related change in pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing patient age, pharmacokinetic changes are such that, for a given IV bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or arterial oxygen desaturation. The higher plasma levels reflect an age-related decrease in volume of distribution and intercompartmental clearance. Lower doses are therefore recommended for initiation and maintenance of sedation and anesthesia in elderly patients (see DOSAGE AND ADMINISTRATION).

Pediatrics

The pharmacokinetics of propofol were studied in children between 3 and 12 years of age who received DIPRIVAN Injectable Emulsion for periods of approximately 1 to 2 hours. The observed distribution and clearance of propofol in these children were similar to adults.

Organ Failure

The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of acute hepatic or renal failure on the pharmacokinetics of propofol have not been studied.

Clinical Trials

Anesthesia and Monitored Anesthesia Care (MAC) Sedation

Pediatric Anesthesia

DIPRIVAN Injectable Emulsion was studied in clinical trials which included cardiac surgical patients. Most patients were 3 years of age or older. The majority of the patients were healthy ASA-PS I or II patients. The range of doses in these studies are described in Tables 1 and 2.

TABLE 1: PEDIATRIC INDUCTION OF ANESTHESIA

Age Range Induction Dose Median (range) Injection Duration Median (range)
Birth through 16 years 2.5 mg/kg (1 to 3.6) 20 sec. (6 to 45)

TABLE 2: PEDIATRIC MAINTENANCE OF ANESTHESIA

Age Range Maintenance Dosage (mcg/kg/min) Duration (minutes)
2 months to 2 years 199 (82 to 394) 65 (12 to 282)
2 to 12 years 188 (12 to 1041) 69 (23 to 374)
> 12 through 16 years 161 (84 to 359) 69 (26 to 251)

Neuroanesthesia

DIPRIVAN Injectable Emulsion was studied in patients undergoing craniotomy for supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior x lateral) was 31 mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively. Anesthesia was induced with a median DIPRIVAN dose of 1.4 mg/kg (range: 0.9 to 6.9 mg/kg) and maintained with a median maintenance DIPRIVAN dose of 146 mcg/kg/min (range: 68 to 425 mcg/kg/min). The median duration of the DIPRIVAN Injectable Emulsion maintenance infusion was 285 minutes (range: 48 to 622 minutes).

DIPRIVAN Injectable Emulsion was administered by infusion in a controlled clinical trial to evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17% (mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), DIPRIVAN Injectable Emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.

Intensive Care Unit (ICU) Sedation

Adult Patients

DIPRIVAN Injectable Emulsion was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received DIPRIVAN Injectable Emulsion and comprise the overall safety database for ICU sedation.

Across all clinical studies, the mean infusion maintenance rate for all DIPRIVAN Injectable Emulsion patients was 27 ± 21 mcg/kg/min. The maintenance infusion rates required to maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for analgesia. Some patients also received benzodiazepines and/or neuromuscular blocking agents. During long-term maintenance of sedation, some ICU patients were awakened once or twice every 24 hours for assessment of neurologic or respiratory function.

In Medical and Postsurgical ICU studies comparing DIPRIVAN Injectable Emulsion to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators, DIPRIVAN Injectable Emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect that DIPRIVAN Injectable Emulsion has been used safely in patients with a history of porphyria or malignant hyperthermia.

In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, adequate sedation was maintained with DIPRIVAN Injectable Emulsion or morphine. There were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery between the treatment groups. In literature reports of severely head injured patients in Neurosurgical ICUs, DIPRIVAN Injectable Emulsion infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion pressure.

DIPRIVAN Injectable Emulsion was found to be effective in status epilepticus which was refractory to the standard anticonvulsant therapies. For these patients, as well as for ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill patient populations.

Pediatric Patients

A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of DIPRIVAN Injectable Emulsion versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either DIPRIVAN Injectable Emulsion 2%, (113 patients), DIPRIVAN Injectable Emulsion 1%, (109 patients), or an SSA (eg, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). DIPRIVAN Injectable Emulsion therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The results of the study showed an increase in the number of deaths in patients treated with DIPRIVAN Injectable Emulsion as compared to SSAs. Of the 25 patients who died during the trial or within the 28-day followup period: 12 (11% were) in the DIPRIVAN Injectable Emulsion 2% treatment group, 9 (8% were) in the DIPRIVAN Injectable Emulsion 1% treatment group, and 4% were (4%) in the SSA treatment group. The differences in mortality rate between the groups were not statistically significant. Review of the deaths failed to reveal a correlation with underlying disease status or a correlation to the drug or a definitive pattern to the causes of death.

Cardiac Anesthesia

DIPRIVAN Injectable Emulsion was evaluated in clinical trials involving patients undergoing coronary artery bypass graft (CABG).

In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving DIPRIVAN Injectable Emulsion required 35% less nitroprusside than midazolam patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular effects in patients with severely compromised ventricular function.

Pharmacotherapeutic group
The information provided in Pharmacotherapeutic group of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Other general anaesthetics
Preclinical safety data
The information provided in Preclinical safety data of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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Propofol is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

Incompatibilities
The information provided in Incompatibilities of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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The neuromuscular blocking agents, atracurium and mivacurium should not be given through the same intravenous line as 1% Propofol Maruishi 1% without prior flushing.

Special precautions for disposal and other handling
The information provided in Special precautions for disposal and other handling of 1% Propofol Maruishi is based on data of another medicine with exactly the same composition as the 1% Propofol Maruishi of the medicine (Propofol). Be careful and be sure to specify the information on the section Special precautions for disposal and other handling in the instructions to the drug 1% Propofol Maruishi directly from the package or from the pharmacist at the pharmacy.
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In-use precautions

Containers should be shaken before use.

Any portion of the contents remaining after use should be discarded.

1% Propofol Maruishi 1% should not be mixed prior to administration with injections or infusion fluids other than 5% Dextrose or Lidocaine Injection .

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