Ketaride

Ketaride is indicated in children and in adults.

Ketaride is recommended:

As an anaesthetic agent for diagnostic and surgical procedures. When used by intravenous or intramuscular injection, Ketaride is best suited for short procedures. With additional doses, or by intravenous infusion, Ketaride can be used for longer procedures. If skeletal muscle relaxation is desired, a muscle relaxant should be used and respiration should be supported.

For the induction of anaesthesia prior to the administration of other general anaesthetic agents. To supplement other anaesthetic agents.

Specific areas of application or types of procedures:

When the intramuscular route of administration is preferred.

Debridement, painful dressings, and skin grafting in burned patients, as well as other superficial surgical procedures.

Neurodiagnostic procedures such as pneumoencephalograms, ventriculograms, myelograms, and lumbar punctures.

Diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental extractions.

Note: Eye movements may persist during ophthalmological procedures.

Anaesthesia in poor-risk patients with depression of vital functions or where depression of vital functions must be avoided, if at all possible.

Orthopaedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.

Sigmoidoscopy and minor surgery of the anus and rectum, circumcision and pilonidal sinus.

Cardiac catheterization procedures.

Caesarean section; as an induction agent in the absence of elevated blood pressure.

Anaesthesia in the asthmatic patient, either to minimise the risks of an attack of bronchospasm developing, or in the presence of bronchospasm where anaesthesia cannot be delayed.

Ketaride injection is indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. Ketaride is best suited for short procedures but it can be used, with additional doses, for longer procedures.

Ketaride injection is indicated for the induction of anesthesia prior to the administration of other general anesthetic agents.

Ketaride injection is indicated to supplement low-potency agents, such as nitrous oxide.

Specific areas of application are described in the CLINICAL PHARMACOLOGY Section.

For intravenous infusion, intravenous injection or intramuscular injection.

NOTE: All doses are given in terms of Ketaride base

Adults, elderly (over 65 years) and children:

For surgery in elderly patients Ketaride has been shown to be suitable either alone or supplemented with other anaesthetic agents.

Preoperative preparations

Ketaride has been safely used alone when the stomach was not empty. However, since the need for supplemental agents and muscle relaxants cannot be predicted, when preparing for elective surgery it is advisable that nothing be given by mouth for at least six hours prior to anaesthesia.

Premedication with an anticholinergic agent (e.g. atropine, hyoscine or glycopyrolate) or another drying agent should be given at an appropriate interval prior to induction to reduce Ketaride- induced hypersalivation.

Midazolam, diazepam, lorazepam, or flunitrazepam used as a premedicant or as an adjunct to Ketaride, have been effective in reducing the incidence of emergence reactions.

Onset and duration

As with other general anaesthetic agents, the individual response to Ketaride is somewhat varied depending on the dose, route of administration, age of patient, and concomitant use of other agents, so that dosage recommendation cannot be absolutely fixed. The dose should be titrated against the patient's requirements.

Because of rapid induction following intravenous injection, the patient should be in a supported position during administration. An intravenous dose of 2 mg/kg of bodyweight usually produces surgical anaesthesia within 30 seconds after injection and the anaesthetic effect usually lasts 5 to10 minutes. An intramuscular dose of 10 mg/kg of bodyweight usually produces surgical anaesthesia within 3 to 4 minutes following injection and the anaesthetic effect usually lasts 12 to 25 minutes. Return to consciousness is gradual.

A. Ketaride as the sole anaesthetic agent

Intravenous Infusion

The use of Ketaride by continuous infusion enables the dose to be titrated more closely, thereby reducing the amount of drug administered compared with intermittent administration. This results in a shorter recovery time and better stability of vital signs.

A solution containing 1 mg/ml of Ketaride in dextrose 5% or sodium chloride 0.9% is suitable for administration by infusion.

General Anaesthesia Induction

An infusion corresponding to 0.5 - 2 mg/kg as total induction dose.

Maintenance of anaesthesia

Anaesthesia may be maintained using a microdrip infusion of 10 - 45 microgram/kg/min (approximately 1 - 3 mg/min).

The rate of infusion will depend on the patient's reaction and response to anaesthesia. The dosage required may be reduced when a long acting neuromuscular blocking agent is used.

Intermittent Injection

Induction

Intravenous Route

The initial dose of Ketaride administered intravenously may range from 1 mg/kg to 4.5 mg/kg (in terms of Ketaride base). The average amount required to produce 5 to 10 minutes of surgical anaesthesia has been 2.0 mg/kg. It is recommended that intravenous administration be accomplished slowly (over a period of 60 seconds). More rapid administration may result in respiratory depression and enhanced pressor response.

Dosage in Obstetrics

Intramuscular Route

The initial dose of Ketaride administered intramuscularly may range from 6.5 mg/kg to 13 mg/kg (in terms of Ketaride base). A low initial intramuscular dose of 4 mg/kg has been used in diagnostic manoeuvres and procedures not involving intensely painful stimuli. A dose of 10 mg/kg will usually produce 12 to 25 minutes of surgical anaesthesia.

Dosage in Hepatic Insufficiency:

Dosage in Obstetrics

Data are lacking for intramuscular injection and maintenance infusion of Ketaride in the parturient population, and recommendations cannot be made.

Maintenance of general anaesthesia

Lightening of anaesthesia may be indicated by nystagmus, movements in response to stimulation, and vocalization. Anaesthesia is maintained by the administration of additional doses of Ketaride by either the intravenous or intramuscular route.

Each additional dose is from ½ to the full induction dose recommended above for the route selected for maintenance, regardless of the route used for induction.

The larger the total amount of Ketaride administered, the longer will be the time to complete recovery.

Purposeless and tonic-clonic movements of extremities may occur during the course of anaesthesia. These movements do not imply a light plane and are not indicative of the need for additional doses of the anaesthetic.

B. Ketaride as induction agent prior to the use of other general anaesthetics

Induction is accomplished by a full intravenous or intramuscular dose of Ketaride as defined above. If Ketaride has been administered intravenously and the principal anaesthetic is slow- acting, a second dose of Ketaride may be required 5 to 8 minutes following the initial dose. If Ketaride has been administered intramuscularly and the principal anaesthetic is rapid-acting, administration of the principal anaesthetic may be delayed up to 15 minutes following the injection of Ketaride.

C. Ketaride as supplement to anaesthetic agents

Ketaride is clinically compatible with the commonly used general and local anaesthetic agents when an adequate respiratory exchange is maintained. The dose of Ketaride for use in conjunction with other anaesthetic agents is usually in the same range as the dosage stated above; however, the use of another anaesthetic agent may allow a reduction in the dose of Ketaride.

D. Management of patients in recovery

Following the procedure the patient should be observed but left undisturbed. This does not preclude the monitoring of vital signs. If, during the recovery, the patient shows any indication of emergence delirium, consideration may be given to the use of diazepam (5 to 10 mg I.V. in an adult). A hypnotic dose of a thiobarbiturate (50 to 100 mg I.V.) may be used to terminate severe emergence reactions. If any one of these agents is employed, the patient may experience a longer recovery period.

Note: Barbiturates and Ketaride, being chemically incompatible because of precipitate formation, should not be injected from the same syringe.

If the Ketaride dose is augmented with diazepam, the two drugs must be given separately. Do not mix ketamine hydrochloride and diazepam in syringe or infusion flask. For additional information on the use of diazepam, refer to the WARNINGS and DOSAGE AND ADMINISTRATION Sections of the diazepam insert.

Preoperative Preparations

1. While vomiting has been reported following ketamine hydrochloride administration, some airway protection may be afforded because of active laryngeal-pharyngeal reflexes. However, since aspiration may occur with Ketaride and since protective reflexes may also be diminished by supplementary anesthetics and muscle relaxants, the possibility of aspiration must be considered. Ketaride is recommended for use in the patient whose stomach is not empty when, in the judgment of the practitioner, the benefits of the drug outweigh the possible risks.
2. Atropine, scopolamine, or another drying agent should be given at an appropriate interval prior to induction.

Onset And Duration

Because of rapid induction following the initial intravenous injection, the patient should be in a supported position during administration.

The onset of action of Ketaride is rapid; an intravenous dose of 2 mg/kg (1 mg/lb) of body weight usually produces surgical anesthesia within 30 seconds after injection, with the anesthetic effect usually lasting five to ten minutes. If a longer effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia without producing significant cumulative effects.

Intramuscular doses, in a range of 9 to 13 mg/kg (4 to 6 mg/lb) usually produce surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes.

Dosage

As with other general anesthetic agents, the individual response to Ketaride is somewhat varied depending on the dose, route of administration, and age of patient, so that dosage recommendation cannot be absolutely fixed. The drug should be titrated against the patient's requirements.

Induction

Intravenous Route

The initial dose of Ketaride administered intravenously may range from 1 mg/kg to 4.5 mg/kg (0.5 to 2 mg/lb). The average amount required to produce five to ten minutes of surgical anesthesia has been 2 mg/kg (1 mg/lb).

Alternatively, in adult patients an induction dose of 1 mg to 2 mg/kg intravenous ketamine at a rate of 0.5 mg/kg/min may be used for induction of anesthesia. In addition, diazepam in 2 mg to 5 mg doses, administered in a separate syringe over 60 seconds, may be used. In most cases, 15 mg of intravenous diazepam or less will suffice. The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by this induction dosage program.

Note: The 100 mg/mL concentration of ketamine hydrochloride should not be injected intravenously without proper dilution. It is recommended the drug be diluted with an equal volume of either Sterile Water for injection, USP, Normal Saline, or 5% Dextrose in Water.

Rate of Administration

It is recommended that Ketaride be administered slowly (over a period of 60 seconds). More rapid administration may result in respiratory depression and enhanced pressor response.

Intramuscular Route

The initial dose of Ketaride administered intramuscularly may range from 6.5 to 13 mg/kg (3 to 6 mg/lb). A dose of 10 mg/kg (5 mg/lb) will usually produce 12 to 25 minutes of surgical anesthesia.

Maintenance Of Anesthesia

The maintenance dose should be adjusted according to the patient's anesthetic needs and whether an additional anesthetic agent is employed.

Increments of one-half to the full induction dose may be repeated as needed for maintenance of anesthesia. However, it should be noted that purposeless and tonic-clonic movements of extremities may occur during the course of anesthesia. These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic.

It should be recognized that the larger the total dose of Ketaride administered, the longer will be the time to complete recovery.

Adult patients induced with Ketaride augmented with intravenous diazepam may be maintained on Ketaride given by slow microdrip infusion technique at a dose of 0.1 to 0.5 mg/minute, augmented with diazepam 2 to 5 mg administered intravenously as needed. In many cases 20 mg or less of intravenous diazepam total for combined induction and maintenance will suffice. However, slightly more diazepam may be required depending on the nature and duration of the operation, physical status of the patient, and other factors. The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by this maintenance dosage program.

Dilution

To prepare a dilute solution containing 1 mg of ketamine per mL, aseptically transfer 10 mL from a 50 mg per mL vial or 5 mL from a 100 mg per mL vial to 500 mL of 5% Dextrose Injection, USP or Sodium Chloride (0.9%) Injection, USP (Normal Saline) and mix well. The resultant solution will contain 1 mg of ketamine per mL.

The fluid requirements of the patient and duration of anesthesia must be considered when selecting the appropriate dilution of Ketaride injection. If fluid restriction is required, Ketaride injection can be added to a 250 mL infusion as described above to provide a Ketaride concentration of 2 mg/mL. Ketaride injection 10 mg/mL vials are not recommended for dilution.

Supplementary Agents

Ketaride is clinically compatible with the commonly used general and local anesthetic agents when an adequate respiratory exchange is maintained.

The regimen of a reduced dose of Ketaride supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents such as nitrous oxide and oxygen.

Ketaride is contra-indicated in persons in whom an elevation of blood pressure would constitute a serious hazard.

Ketaride should not be used in patients with eclampsia or pre-eclampsia, severe coronary or myocardial disease, cerebrovascular accident or cerebral trauma.

Ketaride is contraindicated in those in whom a significant elevation of blood pressure would constitute a serious hazard and in those who have shown hypersensitivity to the drug.

To be used only in hospitals by or under the supervision of experienced medically qualified anaesthetists except under emergency conditions.

As with any general anaesthetic agent, resuscitative equipment should be available and ready for use.

Respiratory depression may occur with overdosage of Ketaride, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to the administration of analeptics.

The intravenous dose should be administered over a period of 60 seconds. More rapid administration may result in transient respiratory depression or apnoea and enhanced pressor response.

Because pharyngeal and laryngeal reflexes usually remain active, mechanical stimulation of the pharynx should be avoided unless muscle relaxants, with proper attention to respiration, are used.

Although aspiration of contrast medium has been reported during Ketaride anaesthesia under experimental conditions (Taylor, P A and Towey, R M, Brit. Med. J. 1971, 2: 688), in clinical practice aspiration is seldom a problem.

In surgical procedures involving visceral pain pathways, Ketaride should be supplemented with an agent which obtunds visceral pain.

When Ketaride is used on an outpatient basis, the patient should not be released until recovery from anaesthesia is complete and then should be accompanied by a responsible adult.

Ketaride should be used with caution in patients with the following conditions:

- Use with caution in the chronic alcoholic and the acutely alcohol-intoxicated patient.

- Ketaride is metabolised in the liver and hepatic clearance is required for termination of clinical effects. A prolonged duration of action may occur in patients with cirrhosis or other types of liver impairment. Dose reductions should be considered in these patients. Abnormal liver function tests associated with Ketaride use have been reported, particularly with extended use (>3 days) or drug abuse.

- Since an increase in cerebrospinal fluid (CSF) pressure has been reported during Ketaride anaesthesia, Ketaride should be used with special caution in patients with preanaesthetic elevated cerebrospinal fluid pressure.

- Use with caution in patients with globe injuries and increased intraocular pressure (e.g. glaucoma) because the pressure may increase significantly after a single dose of Ketaride.

- Use with caution in patients with neurotic traits or psychiatric illness (e.g. schizophrenia and acute psychosis)

- Use in caution in patients with acute intermittent porphyria.

- Use in caution in patients with seizures.

- Use in caution in patients with hyperthyroidism or patients receiving thyroid replacement (increased risk of hypertension and tachycardia)

- Use in caution in patients with pulmonary or upper respiratory infection (Ketaride sensitises the gag reflex, potentially causing laryngospasm)

- Use in caution in patients with intracranial mass lesions, a presence of head injury, or hydrocephalus.

Emergence Reaction

The psychological manifestations vary in severity between pleasant dream-like states, vivid imagery, hallucinations, nightmares and emergence delirium (often consisting of dissociative or floating sensations). In some cases these states have been accompanied by confusion, excitement, and irrational behaviour which a few patients recall as an unpleasant experience..

Emergence delirium phenomena may occur during the recovery period. The incidence of these reactions may be reduced if verbal and tactile stimulation of the patient is minimised during the recovery period. This does not preclude the monitoring of vital signs.

Cardiovascular

Because of the substantial increase in myocardial oxygen consumption, Ketaride should be used in caution in patients with hypovolemia, dehydration or cardiac disease, especially coronary artery disease (e.g. congestive heart failure, myocardial ischemia and myocardial infarction). In addition Ketaride should be used with caution in patients with mild-to-moderate hypertension and tachyarrhythmias.

Cardiac function should be continually monitored during the procedure in patients found to have hypertension or cardiac decompensation.

Elevation of blood pressure begins shortly after the injection of Ketaride, reaches a maximum within a few minutes and usually returns to preanaesthetic values within 15 minutes after injection. The median peak rise of blood pressure in clinical studies has ranged from 20 to 25 percent of preanaesthetic values. Depending on the condition of the patient, this elevation of blood pressure may be considered a beneficial effect, or in others, an adverse reaction.

Long-Term Use

Cases of cystitis including haemorrhagic cystitis have been reported in patients being given Ketaride on a long term basis. This adverse reaction develops in patients receiving long term Ketaride treatment after a time ranging from 1 month to several years. Ketaride is not indicated nor recommended for long term use. Hepatotoxicity has also been reported in patients with extended use (> 3 days).

Drug Abuse and Dependence

Ketaride has been reported as being a drug of abuse. Reports suggest that Ketaride produces a variety of symptoms including, but not limited to, flashbacks, hallucinations, dysphoria, anxiety, insomnia, or disorientation. Cases of cystitis including haemorrhagic cystitis and cases of hepatotoxicity have also been reported. If used on a daily basis for a few weeks, dependence and tolerance may develop, particularly in individuals with a history of drug abuse and dependence. Therefore the use of Ketaride should be closely supervised and it should be prescribed and administered with caution.

WARNINGS

Cardiac function should be continually monitored during the procedure in patients found to have hypertension or cardiac decompensation.

Postoperative confusional states may occur during the recovery period. (See Special Note.)

Respiratory depression may occur with overdosage or too rapid a rate of administration of Ketaride, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to administration of analeptics.

PRECAUTIONS

General

Ketaride injection should be used by or under the direction of physicians experienced in administering general anesthetics and in maintenance of an airway and in the control of respiration.

Because pharyngeal and laryngeal reflexes are usually active, Ketaride should not be used alone in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree. Mechanical stimulation of the pharynx should be avoided, whenever possible, if Ketaride is used alone. Muscle relaxants, with proper attention to respiration, may be required in both of these instances.

Resuscitative equipment should be ready for use.

The incidence of emergence reactions may be reduced if verbal and tactile stimulation of the patient is minimized during the recovery period. This does not preclude the monitoring of vital signs (see Special Note).

The intravenous dose should be administered over a period of 60 seconds. More rapid administration may result in respiratory depression or apnea and enhanced pressor response.

In surgical procedures involving visceral pain pathways, Ketaride should be supplemented with an agent which obtunds visceral pain.

Use with caution in the chronic alcoholic and the acutely alcohol-intoxicated patient.

An increase in cerebrospinal fluid pressure has been reported following administration of Ketaride. Use with extreme caution in patients with preanesthetic elevated cerebrospinal fluid pressure.

Usage In Pregnancy

Since the safe use in pregnancy, including obstetrics (either vaginal or abdominal delivery), has not been established, such use is not recommended (see Animal Pharmacology And Toxicology, Reproduction).

Geriatric Use

Clinical studies of Ketaride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 16 have not been established.

The following Adverse Events have been reported:

†Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Not known (frequency cannot be estimated from the available data)

* AE frequency estimated from post-marketing safety database

** Extended period use (> 3 days) or drug abuse

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 at: www.mhra.gov.uk/yellowcard.

Cardiovascular: Blood pressure and pulse rate are frequently elevated following administration of Ketaride alone. However, hypotension and bradycardia have been observed. Arrhythmia has also occurred.

Respiration: Although respiration is frequently stimulated, severe depression of respiration or apnea may occur following rapid intravenous administration of high doses of Ketaride. Laryngospasms and other forms of airway obstruction have occurred during ketamine hydrochloride anesthesia.

Eye: Diplopia and nystagmus have been noted following Ketaride administration. It also may cause a slight elevation in intraocular pressure measurement.

Genitourinary: Severe irritative and inflammatory urinary tract and bladder symptoms including cystitis have been reported in individuals with history of chronic ketamine use or abuse.

Psychological: (See Special Note.)

Neurological: In some patients, enhanced skeletal muscle tone may be manifested by tonic and clonic movements sometimes resembling seizures (see DOSAGE AND ADMINISTRATION Section).

Gastrointestinal: Anorexia, nausea and vomiting have been observed; however, this is not usually severe and allows the great majority of patients to take liquids by mouth shortly after regaining consciousness (see DOSAGE AND ADMINISTRATION Section).

General: Anaphylaxis. Local pain and exanthema at the injection site have infrequently been reported. Transient erythema and/or morbilliform rash have also been reported.

For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact JHP at 1-866-923-2547 or MEDWATCH at 1-800-FDA-1088 (1- 800-332-1088) or http://www.fda.gov/medwatch/.

Drug Abuse And Dependence

Ketamine has been reported being used as a drug of abuse.

Reports suggest that ketamine produces a variety of symptoms including, but not limited to anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations, and psychotic episodes.

Ketamine dependence and tolerance are possible following prolonged administration. A withdrawal syndrome with psychotic features has been described following discontinuation of long-term ketamine use. Therefore, ketamine should be prescribed and administered with caution.

Respiratory depression can result from an overdosage of Ketaride hydrochloride. Supportive ventilation should be employed. Mechanical support of respiration that will maintain adequate blood oxygen saturation and carbon dioxide elimination is preferred to administration of analeptics.

Ketaride has a wide margin of safety; several instances of unintentional administration of overdoses of Ketaride (up to 10 times that usually required) have been followed by prolonged but complete recovery.

Respiratory depression may occur with overdosage or too rapid a rate of administration of Ketaride, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to administration of analeptics.