Remifentanilo Mylan

Remifentanilo Mylan

Remifentanil Hydrochloride

Powder for concentrate for solution for injection or infusion

Remifentanilo Mylan is indicated as an analgesic agent for use during induction and/or maintenance of general anaesthesia under close supervision.

Remifentanilo Mylan is indicated for provision of analgesia and sedation in mechanically ventilated intensive care patients 18 years of age and over.

Remifentanilo Mylan should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by persons specifically trained in the use of anaesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.

< for additional information, including tables with examples of infusion rates by body weight to help titrate Remifentanilo Mylan to the patient's anaesthetic needs).

Remifentanilo Mylan may also be given by target controlled infusion (TCI) with an approved infusion device incorporating the Minto pharmacokinetic model with covariates for age and lean body mass (LBM).

Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual Remifentanilo Mylan after use.

Remifentanilo Mylan is for intravenous use only and must not be administered by epidural or intrathecal injection.

Dilution

<6 for storage conditions of the reconstituted/diluted product and the recommended diluents).

For manually-controlled infusion Remifentanilo Mylan can be diluted to concentrations of 20 to 250 micrograms/ml (50 micrograms/ml is the recommended dilution for adults and 20 to 25 micrograms/ml for paediatric patients aged 1 year and over).

For TCI the recommended dilution of Remifentanilo Mylan is 20 to 50 micrograms/ml.

<for additional information, including tables to help titrate Remifentanilo Mylan to the patient's anaesthetic needs).

4.2.1 General Anaesthesia

The administration of Remifentanilo Mylan must be individualised based on the patient's response.2 below.

4.2.1.1 Adults

Administration by Manually-Controlled Infusion

The following table summarises the starting infusion rates and dose range:

DOSING GUIDELINES FOR ADULTS

INDICATION	BOLUS INJECTION (micrograms/kg)	CONTINUOUS INFUSION (micrograms/kg/min)
		Starting Rate	Range
Induction of anaesthesia	1(give over not less than 30 seconds)	0.5 to 1	_
Maintenance of anaesthesia in ventilated patients
- Nitrous oxide (66%)	0.5 to 1	0.4	0.1 to 2
- Isoflurane (starting dose 0.5MAC)	0.5 to 1	0.25	0.05 to 2
- Propofol (Starting dose 100 micrograms/kg/min)	0.5 to 1	0.25	0.05 to 2

When given by bolus injection at induction Remifentanilo Mylan should be administered over not less than 30 seconds.

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects such as hypotension and bradycardia (see Concomitant medication below).

Induction of anaesthesia: Remifentanilo Mylan should be administered with a standard dose of an hypnotic agent, such as propofol, thiopentone, or isoflurane, for the induction of anaesthesia. Administering Remifentanilo Mylan after an hypnotic agent will reduce the incidence of muscle rigidity. Remifentanilo Mylan can be administered at an infusion rate of 0.5 to 1 micrograms/kg/min, with or without an initial slow bolus injection of 1 microgram/kg given over not less than 30 seconds. If endotracheal intubation is to occur more than 8 to 10 minutes after the start of the infusion of Remifentanilo Mylan, then a bolus injection is not necessary.

Maintenance of anaesthesia in ventilated patients: After endotracheal intubation, the infusion rate of Remifentanilo Mylan should be decreased, according to anaesthetic technique, as indicated in the above table. Due to the fast onset and short duration of action of Remifentanilo Mylan, the rate of administration during anaesthesia can be titrated upward in 25% to 100% increments or downward in 25% to 50% decrements, every 2 to 5 minutes to attain the desired level of mu-opioid response. In response to light anaesthesia, supplemental slow bolus injections may be administered every 2 to 5 minutes.

Anaesthesia in spontaneously breathing anaesthetised patients with a secured airway (e.g. laryngeal mask anaesthesia): In spontaneously breathing anaesthetised patients with a secured airway respiratory depression is likely to occur. Special care is needed to adjust the dose to the patient requirements and ventilatory support may be required. The recommended starting infusion rate for supplemental analgesia in spontaneously breathing anaesthetised patients is 0.04 micrograms/kg/min with titration to effect. A range of infusion rates from 0.025 to 0.1 micrograms/kg/min has been studied. Bolus injections are not recommended in spontaneously breathing anaesthetised patients.

Remifentanilo Mylan should not be used as an analgesic in procedures where patients remain conscious or do not receive any airway support during the procedure.

Concomitant medication: Remifentanilo Mylan decreases the amounts or doses of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia.

Doses of the following agents used in anaesthesia: isoflurane, thiopentone, propofol and temazepam have been reduced by up to 75% when used concurrently with remifentanil.

Guidelines for discontinuation/continuation into the immediate post-operative period: Due to the very rapid offset of action of Remifentanilo Mylan no residual opioid activity will be present within 5 to 10 minutes after discontinuation. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of Remifentanilo Mylan. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of post-operative care.

Care should be taken to avoid inadvertent administration of Remifentanilo Mylan remaining in IV lines and cannulae.

In the event that longer acting analgesia has not been established prior to the end of surgery, Remifentanilo Mylan may need to be continued to maintain analgesia during the immediate post-operative period until longer acting analgesia has reached its maximum effect.

<3 below.

In patients who are breathing spontaneously, the infusion rate of Remifentanilo Mylan should initially be decreased to a rate of 0.1 micrograms/kg/min. The infusion rate may then be increased or decreased by not greater than 0.025 micrograms/kg/min every five minutes, to balance the patient's level of analgesia and respiratory rate. Remifentanilo Mylan should only be used in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function, under the close supervision of persons specifically trained in the recognition and management of the respiratory effects of potent opioids.

The use of bolus injections of Remifentanilo Mylan to treat pain during the post-operative period is not recommended in patients who are breathing spontaneously.

Administration by Target-Controlled Infusion

Induction and maintenance of anaesthesia in ventilated patients: Remifentanilo Mylan TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see the table in Dosing Guidelines For Adults under 4.2.1.1). In association with these agents, adequate analgesia for induction of anaesthesia and surgery can generally be achieved with target blood remifentanil concentrations ranging from 3 to 8 nanograms/ml. Remifentanilo Mylan should be titrated to individual patient response. For particularly stimulating surgical procedures target blood concentrations up to 15 nanograms/ml may be required.

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects such as hypotension and bradycardia (see Table and Concomitant medication subsection in 4.2.1.1).

For information on blood remifentanil concentrations achieved with manually-controlled infusion see Table 6.

There are insufficient data to make recommendations on the use of TCI for spontaneous ventilation anaesthesia.

<1.1)

As there are insufficient data, the administration of Remifentanilo Mylan by TCI for the management of post-operative analgesia is not recommended.

4.2.1.2 Paediatric patients (1 to 12 years of age)

Co-administration of Remifentanilo Mylan and an intravenous anaesthetic agent for induction of anaesthesia has not been studied in detail and is therefore not recommended.

Remifentanilo Mylan TCI has not been studied in paediatric patients and therefore administration of Remifentanilo Mylan by TCI is not recommended in these patients.

When given by bolus injection Remifentanilo Mylan should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the Remifentanilo Mylan infusion, if a simultaneous bolus dose has not been given. For sole administration of nitrous oxide (70%) with Remifentanilo Mylan, typical maintenance infusion rates should be between 0.4 and 3 micrograms/kg/min, and although not specifically studied, adult data suggest that 0.4 micrograms/kg/min is an appropriate starting rate. Paediatric patients should be monitored and the dose titrated to the depth of analgesia appropriate for the surgical procedure.

Induction of anaesthesia: The use of remifentanil for induction of anaesthesia in patients aged 1 to 12 years is not recommended as there are no data available in this patient population.

Maintenance of anaesthesia: The following doses of Remifentanilo Mylan are recommended for maintenance of anaesthesia:

DOSING GUIDELINES FOR PAEDIATRIC PATIENTS (1 to 12 years of age)

*CONCOMITANT ANAESTHETIC AGENT	BOLUS INJECTION (micrograms/kg)	CONTINUOUS INFUSION (micrograms/kg/min)
		Starting Rate	Range
Halothane (starting dose 0.3MAC)	1	0.25	0.05 to 1.3
Sevoflurane (starting dose 0.3MAC)	1	0.25	0.05 to 0.9
Isoflurane (starting dose 0.5MAC)	1	0.25	0.06 to 0.9

*co-administered with nitrous oxide/oxygen in a ratio of 2:1

Concomitant medication: At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia.1.1 Adults- Concomitant medication).

Guidelines for patient management in the immediate post-operative period/ Establishment of alternative analgesia prior to discontinuation of Remifentanilo Mylan: Due to the very rapid offset of action of Remifentanilo Mylan, no residual activity will be present within 5 to 10 minutes after discontinuation. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of Remifentanilo Mylan. Sufficient time must be allowed to reach the therapeutic effect of the longer acting analgesic. The choice of agent(s), the dose and the time of administration should be planned in advance and individually tailored to be appropriate for the patient's surgical procedure and the level of post-operative care anticipated.

4.2.1.3 Neonates/infants (aged less than 1 year):

There is limited clinical trial experience of remifentanil in neonates and infants. The pharmacokinetic profile of remifentanil in neonates/infants (aged less than 1 year) is comparable to that seen in adults after correction for body weight differences. However, because there are insufficient clinical data, the administration of Remifentanilo Mylan is not recommended for this age group.

Use for Total Intravenous anaesthesia (TIVA): There is limited clinical trial experience of remifentanil of TIVA in infants. However, there are insufficient clinical data to make dosage recommendations.

4.2.2 Cardiac anaesthesia

Administration by Manually-Controlled Infusion

DOSING GUIDELINES FOR CARDIAC ANAESTHESIA

INDICATION	BOLUS INJECTION (micrograms/kg)	CONTINUOUS INFUSION (micrograms/kg/min)
		Starting Rate	Range
Induction of anaesthesia	Not recommended	1	_
Maintenance of anaesthesia in ventilated patients:
- Isoflurane (starting dose 0.4MAC)	0.5 to 1	1	0.003 to 4
- Propofol (Starting dose 50 micrograms/kg/min)	0.5 to 1	1	0.01 to 4.3
Continuation of post-operative analgesia, prior to extubation	Not recommended	1	0 to 1

Induction period of anaesthesia: After administration of hypnotic to achieve loss of consciousness, Remifentanilo Mylan should be administered at an initial infusion rate of 1 microgram/kg/min. The use of bolus injections of Remifentanilo Mylan during induction in cardiac surgical patients is not recommended. Endotracheal intubation should not occur until at least 5 minutes after the start of the infusion.

Maintenance period of anaesthesia: After endotracheal intubation the infusion rate of Remifentanilo Mylan can be titrated upward in 25% to 100% increments, or downward in 25% to 50% decrements, every 2 to 5 minutes according to patient need. Supplemental slow bolus doses, administered over not less than 30 seconds, may also be given every 2 to 5 minutes as required. High risk cardiac patients, such as those with poor ventricular function or undergoing valve surgery, should be administered a maximum bolus dose of 0.5 micrograms/kg. These dosing recommendations also apply during hypothermic cardiopulmonary bypass.

Concomitant medication: At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia.1.1 Adults - Concomitant medication).

Guidelines for post-operative patient management

Continuation of Remifentanilo Mylan post-operatively to provide analgesia prior to weaning for extubation: It is recommended that the infusion of Remifentanilo Mylan should be maintained at the final intra-operative rate during transfer of patients to the post-operative care area.3 for further information on management of intensive care patients).

Establishment of alternative analgesia prior to discontinuation of Remifentanilo Mylan: Due to the very rapid offset of action of Remifentanilo Mylan, no residual opioid activity will be present within 5 to 10 minutes after discontinuation. Prior to discontinuation of Remifentanilo Mylan, patients must be given alternative analgesic and sedative agents at a sufficient time in advance to allow the therapeutic effects of these agents to become established. It is therefore recommended that the choice of agent(s), the dose and the time of administration are planned, before weaning the patient from the ventilator.

Guidelines for discontinuation of Remifentanilo Mylan: Due to the very rapid offset of action of Remifentanilo Mylan, hypertension, shivering and aches have been reported in cardiac patients immediately following discontinuation of Remifentanilo Mylan. To minimise the risk of these occurring, adequate alternative analgesia must be established (as described above), before the Remifentanilo Mylan infusion is discontinued. The infusion rate should be reduced by 25% decrements in at least 10-minute intervals until the infusion is discontinued. During weaning from the ventilator the Remifentanilo Mylan infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics. Haemodynamic changes such as hypertension and tachycardia should be treated with alternative agents as appropriate.

When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.

Administration by Target-Controlled Infusion

Induction and maintenance of anaesthesia: Remifentanilo Mylan TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see table in Dosing Guidelines for Cardiac Anaesthesia under 4.2.2). In association with these agents, adequate analgesia for cardiac surgery is generally achieved at the higher end of the range of target blood remifentanil concentrations used for general surgical procedures. Following titration of remifentanil to individual patient response, blood concentrations as high as 20 nanograms/ml have been used in clinical studies. At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects such as hypotension and bradycardia (see Table and Concomitant medication subsection in 4.2.2).

For information on blood remifentanil concentrations achieved with manually-controlled infusion see Table 6.

<2.)

As there are insufficient data, the administration of Remifentanilo Mylan by TCI for the management of post-operative analgesia is not recommended.

4.2.3 Use in Intensive Care

Remifentanilo Mylan can be used for the provision of analgesia in mechanically ventilated intensive care patients. Sedative agents should be added as appropriate.

Remifentanilo Mylan has been studied in mechanically ventilated intensive care patients in well controlled clinical trials for up to three days. As patients were not studied beyond three days, no evidence of safety and efficacy for longer treatment has been established. Therefore, the use of Remifentanilo Mylan is not recommended for a duration of treatment greater than 3 days.

Remifentanilo Mylan TCI has not been studied in intensive care patients and therefore administration of Remifentanilo Mylan by TCI is not recommended in these patients.

In adults, it is recommended that Remifentanilo Mylan is initiated at an infusion rate of 0.1 micrograms/kg/min (6 micrograms/kg/h) to 0.15 micrograms/kg/min (9 micrograms/kg/h). The infusion rate should be titrated in increments of 0.025 micrograms/kg/min (1.5 micrograms/kg/h) to achieve the desired level of sedation and analgesia. A period of at least 5 minutes should be allowed between dose adjustments. The level of sedation and analgesia should be carefully monitored, regularly reassessed and the Remifentanilo Mylan infusion rate adjusted accordingly. If an infusion rate of 0.2 micrograms/kg/min (12 micrograms/kg/h) is reached and the desired level of sedation is not achieved, it is recommended that dosing with an appropriate sedative agent is initiated (see below). The dose of sedative agent should be titrated to obtain the desired level of sedation. Further increases to the Remifentanilo Mylan infusion rate in increments of 0.025 micrograms/kg/min (1.5 micrograms/kg/h) may be made if additional analgesia is required.

The following table summarises the starting infusion rates and typical dose range for provision of analgesia and sedation in individual patients:

DOSING GUIDELINES FOR USE OF Remifentanilo Mylan WITHIN THE INTENSIVE CARE SETTING

CONTINUOUS INFUSION micrograms/kg/min (micrograms/kg/h)
Starting Rate	Range
0.1 (6) to 0.15 (9)	0.006 (0.36) to 0.74 (44.4)

Bolus doses of Remifentanilo Mylan are not recommended in the intensive care setting.

The use of Remifentanilo Mylan will reduce the dosage requirement of any concomitant sedative agents. Typical starting doses for sedative agents, if required, are given below:

RECOMMENDED STARTING DOSE OF SEDATIVE AGENTS, IF REQUIRED

Sedative Agent	Bolus (mg/kg)	Infusion (mg/kg/h)
Propofol	Up to 0.5	0.5
Midazolam	Up to 0.03	0.03

To allow separate titration of the respective agents, sedative agents should not be prepared as one mixture in the same infusion bag.

Additional analgesia for ventilated patients undergoing stimulating procedures: An increase in the existing Remifentanilo Mylan infusion rate may be required to provide additional analgesic cover for ventilated patients undergoing stimulating and/or painful procedures such as endotracheal suctioning, wound dressing and physiotherapy. It is recommended that an Remifentanilo Mylan infusion rate of at least 0.1 micrograms/kg/min (6 micrograms/kg/h) should be maintained for at least 5 minutes prior to the start of the stimulating procedure. Further dose adjustments may be made every 2 to 5 minutes in increments of 25%-50% in anticipation of, or in response to, additional requirement for analgesia. A mean infusion rate of 0.25 micrograms/kg/min (15 micrograms/kg/h), maximum 0.75 micrograms/kg/min (45 micrograms/kg/h), has been administered for provision of additional analgesia during stimulating procedures.

Establishment of alternative analgesia prior to discontinuation of Remifentanilo Mylan: Due to the very rapid offset of action of Remifentanilo Mylan, no residual opioid activity will be present within 5 to 10 minutes after discontinuation regardless of the duration of infusion. Following administration of Remifentanilo Mylan, the possibility of tolerance and hyperalgesia should be considered. Therefore, prior to discontinuation of Remifentanilo Mylan, patients must be given alternative analgesic and sedative agents to prevent hyperalgesia and associated haemodynamic changes. These agents must be given at a sufficient time in advance to allow the therapeutic effects of these agents to become established. The range of options for analgesia includes long acting oral, intravenous, or regional analgesics controlled by the nurse or the patient. These techniques should always be titrated to individual patient needs as the infusion of Remifentanilo Mylan is reduced. It is recommended that the choice of agent(s), the dose, and the time of administration are planned prior to discontinuation of Remifentanilo Mylan.

There is a potential for the development of tolerance with time during prolonged administration of mu-opioid agonists.

Guidelines for extubation and discontinuation of Remifentanilo Mylan: In order to ensure a smooth emergence from an Remifentanilo Mylan-based regimen it is recommended that the infusion rate of Remifentanilo Mylan is titrated in stages to 0.1 micrograms/kg/min (6 micrograms/kg/h) over a period up to 1 hour prior to extubation.

Following extubation, the infusion rate should be reduced by 25% decrements in at least 10-minute intervals until the infusion is discontinued. During weaning from the ventilator the Remifentanilo Mylan infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics.

Upon discontinuation of Remifentanilo Mylan, the IV cannula should be cleared or removed to prevent subsequent inadvertent administration.

When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate analgesia must always be balanced against the potential risk of respiratory depression.

4.2.3.1 Paediatric intensive care patients

The use of remifentanil in intensive care patients under the age of 18 years is not recommended as there are no data available in this patient population.

4.2.3.2 Renally-impaired intensive care patients

No adjustments to the doses recommended above are necessary in renally-impaired patients, including those undergoing renal replacement therapy; however the clearance of the carboxylic acid metabolite is reduced in patients with renal impairment.

4.2.4 Special patient populations

4.2.4.1 Elderly (over 65 years of age)

General anaesthesia: The initial starting dose of remifentanil administered to patients over 65 should be half the recommended adult dose and then shall be titrated to individual patient need as an increased sensitivity to the pharmacological effects of remifentanil has been seen in this patient population. This dose adjustment applies to use in all phases of anaesthesia including induction, maintenance, and immediate post-operative analgesia.

Because of the increased sensitivity of elderly patients to Remifentanilo Mylan, when administering Remifentanilo Mylan by TCI in this population the initial target concentration should be 1.5 to 4 nanograms/ml with subsequent titration to response.

Cardiac anaesthesia: No initial dose reduction is required.

Intensive Care: No initial dose reduction is required.

4.2.4.2 Obese patients

For manually-controlled infusion it is recommended that for obese patients the dosage of Remifentanilo Mylan should be reduced and based upon ideal body weight as the clearance and volume of distribution of remifentanil are better correlated with ideal body weight than actual body weight.

With the calculation of lean body mass (LBM) used in the Minto model, LBM is likely to be underestimated in female patients with a body mass index (BMI) greater than 35 kg/m² and in male patients with BMI greater than 40 kg/m². To avoid underdosing in these patients, remifentanil TCI should be titrated carefully to individual response.

4.2.4.3 Renal impairment

On the basis of investigations carried out to date, a dose adjustment in patients with impaired renal function, including intensive care patients, is not necessary.

4.2.4.4 Hepatic impairment

Studies carried out with a limited number of patients with impaired liver function, do not justify any special dosage recommendations. However, patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of remifentanil. These patients shall be closely monitored and the dose of remifentanil shall be titrated to individual patient need.

4.2.4.5 Neurosurgery

Limited clinical experience in patients undergoing neurosurgery has shown that no special dosage recommendations are required.

4.2.4.6 ASA III/IV patients

General anaesthesia: As the haemodynamic effects of potent opioids can be expected to be more pronounced in ASA III/IV patients, caution should be exercised in the administration of Remifentanilo Mylan in this population. Initial dosage reduction and subsequent titration to effect is therefore recommended. In paediatric patients, there are insufficient data to make a dosage recommendation.

For TCI, a lower initial target of 1.5 to 4 nanograms/ml should be used in ASA III or IV patients and subsequently titrated to response.

Cardiac anaesthesia: No initial dose reduction is required.

As glycine is present in the formulation, Remifentanilo Mylan is contraindicated for epidural and intrathecal use.

Remifentanilo Mylan is contraindicated in patients with known hypersensitivity to any component of the preparation and other fentanyl analogues.

Remifentanilo Mylan is contraindicated for use as the sole agent for induction of anaesthesia.

Remifentanilo Mylan should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function, and by persons specifically trained in the use of anaesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include the establishment and maintenance of a patent airway and assisted ventilation. The use of Remifentanilo Mylan in mechanically ventilated intensive care patients is not recommended for a duration of treatment greater than 3 days.

Patients with a known hypersensitivity to opioids of a different class may exhibit a hypersensitivity reaction following administration of Remifentanilo Mylan. Caution should be exercised before using Remifentanilo Mylan in these patients.

Rapid offset of action /Transition to alternative analgesia

Due to the very rapid offset of action of Remifentanilo Mylan, no residual opioid activity will be present within 5 to 10 minutes after the discontinuation of Remifentanilo Mylan. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of Remifentanilo Mylan. The possibility of tolerance, hyperalgesia and associated haemodynamic changes should be considered when used in Intensive Care Unit. Prior to discontinuation of Remifentanilo Mylan, patients must be given alternative analgesic and sedative agents. Sufficient time must be allowed to reach the therapeutic effect of the longer acting analgesic. The choice of agent(s), the dose and the time of administration should be planned in advance and individually tailored to be appropriate for the patient's surgical procedure and the level of post-operative care anticipated. When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.

Discontinuation of Treatment

Symptoms following withdrawal of Remifentanilo Mylan including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days. Where reported, re-introduction and tapering of the infusion has been beneficial. The use of Remifentanilo Mylan in mechanically ventilated intensive care patients is not recommended for duration of treatment greater than 3 days.

Inadvertent administration

A sufficient amount of Remifentanilo Mylan may be present in the dead space of the IV line and/or cannula to cause respiratory depression, apnoea and/or muscle rigidity if the line is flushed with IV fluids or other drugs. This may be avoided by administering Remifentanilo Mylan into a fast flowing IV line or via a dedicated IV line which is removed when Remifentanilo Mylan is discontinued.

Muscle rigidity - prevention and management

At the doses recommended muscle rigidity may occur. As with other opioids, the incidence of muscle rigidity is related to the dose and rate of administration. Therefore, bolus injections should be administered over not less than 30 seconds.

Muscle rigidity induced by remifentanil must be treated in the context of the patient's clinical condition with appropriate supporting measures including ventilatory support. Excessive muscle rigidity occurring during the induction of anaesthesia should be treated by the administration of a neuromuscular blocking agent and/or additional hypnotic agents. Muscle rigidity seen during the use of remifentanil as an analgesic may be treated by stopping or decreasing the rate of administration of remifentanil. Resolution of muscle rigidity after discontinuing the infusion of remifentanil occurs within minutes. Alternatively an opioid antagonist may be administered, however this may reverse or attenuate the analgesic effect of remifentanil.

Respiratory depression - prevention and management

As with all potent opioids, profound analgesia is accompanied by marked respiratory depression. Therefore, remifentanil should only be used in areas where facilities for monitoring and dealing with respiratory depression are available. The appearance of respiratory depression should be managed appropriately, including decreasing the rate of infusion by 50%, or by a temporary discontinuation of the infusion. Unlike other fentanyl analogues, remifentanil has not been shown to cause recurrent respiratory depression even after prolonged administration. However, as many factors may affect post-operative recovery it is important to ensure that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area.

Cardiovascular effects

The risk of cardiovascular effects such as hypotension and bradycardia , which may rarely lead to asystole/cardiac arrest may be reduced by lowering the rate of infusion of Remifentanilo Mylan or the dose of concurrent anaesthetics or by using IV fluids, vasopressor or anticholinergic agents as appropriate.

Debilitated, hypovolaemic, and elderly patients may be more sensitive to the cardiovascular effects of remifentanil.

Neonates/infants

There is limited data available on use in neonates/infants under 1 year of age.

Drug abuse

As with other opioids remifentanil may produce dependency.

After anaesthesia with remifentanil the patient should not drive or operate machinery. The physician should decide when these activities may be resumed. It is advisable that the patient is accompanied when returning home and that alcoholic drink is avoided.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

- However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

The most common undesirable effects associated with remifentanil are direct extensions of mu-opioid agonist pharmacology. These adverse events resolve within minutes of discontinuing or decreasing the rate of remifentanil administration. The frequencies below are defined as 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) and very rare (<1/10,000), not known (cannot be estimated from the available data).

Immune System Disorders
Rare:	Allergic reactions including anaphylaxis have been reported in patients receiving remifentanil in conjunction with one or more anaesthetic agents.
Psychiatric disorders
Not known:	Drug dependence
Nervous System Disorders
Very common:	Skeletal muscle rigidity
Rare:	Sedation (during recovery from general anaesthesia)
Not known:	Convulsions
Cardiac Disorders
Common:	Bradycardia
Rare:	Asystole/cardiac arrest, usually preceded by bradycardia, has been reported in patients receiving remifentanil in conjunction with other anaesthetic agents.
Not known:	Atrioventricular block
Vascular Disorders
Very common:	Hypotension
Common:	Post-operative hypertension
Respiratory, Thoracic and Mediastinal Disorders
Common:	Acute respiratory depression, apnoea
Uncommon:	Hypoxia
Gastrointestinal Disorders
Very common:	Nausea, vomiting
Uncommon:	Constipation
Skin and Subcutaneous Tissue Disorders
Common:	Pruritus
General Disorders and Administration Site Conditions
Common:	Post-operative shivering
Uncommon:	Post-operative aches
Not known:	Drug tolerance

Discontinuation of treatment

Symptoms following withdrawal of remifentanil including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days.

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.

As with all potent opioid analgesics, overdose would be manifested by an extension of the pharmacologically predictable actions of remifentanil. Due to the very short duration of action of Remifentanilo Mylan, the potential for deleterious effects due to overdose is limited to the immediate time period following drug administration. Response to discontinuation of the drug is rapid, with return to baseline within ten minutes.

In the event of overdose, or suspected overdose, take the following actions: discontinue administration of Remifentanilo Mylan, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. If depressed respiration is associated with muscle rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressor agents for the treatment of hypotension and other supportive measures may be employed.

Intravenous administration of an opioid antagonist such as naloxone may be given as a specific antidote in addition to ventilatory support to manage severe respiratory depression. The duration of respiratory depression following overdose with Remifentanilo Mylan is unlikely to exceed the duration of action of the opioid antagonist.

Pharmacotherapeutic group: Opioid anaesthetics, ATC code: N01AH06

Remifentanil is a selective mu-opioid agonist with a rapid onset and very short duration of action. The mu-opioid activity, of remifentanil, is antagonised by narcotic antagonists, such as naloxone.

Assays of histamine in patients and normal volunteers have shown no elevation in histamine levels after administration of remifentanil in bolus doses up to 30 micrograms/kg.

Neonates/infants (aged less than 1 year):

In a randomised (ratio of 2:1, remifentanil:halothane), open label, parallel group, multicentre study in 60 young infants and neonates ≤8 weeks of age (mean 5.5 weeks) with an ASA physical status of I-II who were undergoing pyloromyotomy, the efficacy and safety of remifentanil (given as a 0.4 μg/kg/min initial continuous infusion plus supplemental doses or infusion rate changes as needed) was compared with halothane (given at 0.4% with supplemental increases as needed). Maintenance of anaesthesia was achieved by the additional administration of 70% nitrous oxide (N20) plus 30% oxygen. Recovery times were superior in the remifentanil relative to the halothane groups (not significant).

Use for Total Intravenous anaesthesia (TIVA) - children aged 6 months to 16 years

TIVA with remifenanil in paediatric surgery was compared to inhalation anaesthesia in three randomised, open-label studies. The results are summarised in the table below.

Surgical intervention	Age (y), (N)	Study condition (maintenance)	Extubation (min) (mean (SD))
Lower abdominal/urological surgery	0.5-16 (120)	TIVA: propofol (5 - 10 mg/kg/h) + remifentanil (0.125 - 1.0 μg/kg/min)	11.8 (4.2)
		Inhalation anaesthesia: sevoflurane (1.0 - 1.5 MAC) and remifentanil (0.125 - 1.0 μg/kg/min)	15.0 (5.6) (p<0.05)
ENT-surgery	4-11 (50)	TIVA: propofol (3 mg/kg/h) + remifentanil (0.5 μg/kg/min)	11 (3.7)
		Inhalation anaesthesia: desflurane (1.3 MAC) and N2O mixture	9.4 (2.9) Not significant
General or ENT surgery	2-12 (153)	TIVA: remifentanil (0.2 - 0.5 μg/kg/min) + propofol (100 - 200 μg/kg/min)	Comparable extubation times (based on limited data)
		Inhalation anaesthesia: sevoflurane (1 - 1.5 MAC) + N2O mixture

In the study in lower abdominal/urological surgery comparing remifentanil/propofol with remifentanil/sevoflurane, hypotension occurred significantly more often under remifentanil/sevoflurane, and bradycardia occurred significantly more often under remifentanil/propofol. In the study in ENT surgery comparing remifentanil/propofol with desflurane/nitrous oxide, a significantly higher heart rate was seen in subjects receiving desflurane/nitrous oxide compared with remifentanil/propofol and with baseline values.

Following administration of the recommended doses of remifentanil, the effective biological half-life is 3-10 minutes. The average clearance of remifentanil in young healthy adults is 40 ml/min/kg, the central volume of distribution is 100 ml/kg and the steady-state volume of distribution is 350 ml/kg. In children aged 1 to 12 years, remifentanil clearance and volume of distribution decreases with increasing age; the values of these parameters in neonates are approximately twice those of healthy young adults.

Blood concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. For every 0.1 micrograms/kg/min increase in infusion rate, the blood concentration of remifentanil will rise 2.5nanograms/ml. Remifentanil is approximately 70% bound to plasma proteins.

Metabolism

Remifentanil is an esterase metabolised opioid that is susceptible to metabolism by non-specific blood and tissue esterases. The metabolism of remifentanil results in the formation of an essentially inactive carboxylic acid metabolite (1/4600th as potent as remifentanil). The half life of the metabolite in healthy adults is 2 hours. Approximately 95% of remifentanil is recovered in the urine as the carboxylic acid metabolite. Remifentanil is not a substrate for plasma cholinesterase.

Cardiac anaesthesia

The clearance of remifentanil is reduced by approximately 20% during hypothermic (28°C) cardiopulmonary bypass. A decrease in body temperature lowers elimination clearance by 3% per degree centigrade.

Renal impairment

The rapid recovery from remifentanil-based sedation and analgesia is unaffected by renal status.

The pharmacokinetics of remifentanil are not significantly changed in patients with varying degrees of renal impairment even after administration for up to 3 days in the intensive care setting.

The clearance of the carboxylic acid metabolite is reduced in patients with renal impairment. Especially in intensive care patients with moderate/severe renal impairment, the concentration of the carboxylic acid metabolite may exceed 250-fold the level of remifentanil at steady-state in some patients. Clinical data demonstrate that the accumulation of the metabolite does not result in clinically relevant mu-opioid effects even after administration of remifentanil infusions for up to 3 days in these patients.

There is no evidence that remifentanil is extracted during renal replacement therapy.

The carboxylic acid metabolite is extracted during haemodialysis by 25 - 35 %.

Hepatic impairment

The pharmacokinetics of remifentanil are not changed in patients with severe hepatic impairment awaiting liver transplant, or during the anhepatic phase of liver transplant surgery. Patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of remifentanil. These patients should be closely monitored and the dose of remifentanil should be titrated to the individual patient need.

Paediatric patients

The average clearance and steady state volume of distribution of remifentanil are increased in younger children and decline to young healthy adult values by age 17. The elimination half-life of remifentanil in neonates is not significantly different from that of young healthy adults. Changes in analgesic effect after changes in infusion rate of remifentanil should be rapid and similar to those seen in young healthy adults. The pharmacokinetics of the carboxylic acid metabolite in paediatric patients 2-17 years of age are similar to those seen in adults after correcting for differences in body weight.

Elderly

The clearance of remifentanil is slightly reduced (approximately 25%) in elderly patients >65 years) compared to young patients. The pharmacodynamic activity of remifentanil increases with increasing age. Elderly patients have a remifentanil EC50 for formation of delta waves on the electroencephalogram (EEG) that is 50% lower than young patients; therefore, the initial dose of remifentanil should be reduced by 50% in elderly patients and then carefully titrated to meet the individual patient need.

Placental and milk transfer

In a human clinical trial, the mean ratio of maternal arterial to umbilical venous concentration indicated that the neonate was exposed to approximately 50% concentration of remifentanil to that in the mother. The mean umbilical arterio-venous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate.

Opioid anaesthetics, ATC code: N01AH06

Intrathecal administration of the glycine formulation without remifentanil to dogs caused agitation, pain and hind limb dysfunction and incoordination. These effects are believed to be secondary to the glycine excipient. Glycine is a commonly used excipient in intravenous products and this finding has no relevance for intravenous administration of Remifentanilo Mylan.

Remifentanil, like other opioid agonists, produced increases in action potential duration (APD) in dog isolated Purkinje fibres. For remifentanil, the effects were seen at concentrations of 1μM or higher (which are higher than plasma concentrations seen in clinical practice). There were no effects at a concentration of 0.1μM.

The major metabolite remifentanil acid had no effect on APD up to the maximum tested concentration of 10μM.

Reproductive toxicity studies

Remifentanil has been shown to reduce fertility in male rats when administered daily by intravenous injection for at least 70 days at a dose of 0.5mg/kg, or approximately 250 times the maximum recommended human bolus dose of 2 micrograms/kg. The fertility of female rats was not affected at doses up to 1mg/kg when administered for at least 15 days prior to mating. No teratogenic effects have been observed with remifentanil at doses up to 5 mg/kg in rats and 0.8 mg/kg in rabbits. Administration of remifentanil to rats throughout late gestation and lactation at doses up to 5 mg/kg IV had no significant effect on the survival, development, or reproductive performance of the F1 generation.

Genotoxicity

Remifentanil was devoid of genotoxic activity in bacteria and in rat liver or mouse bone marrow cells in vivo. However, a positive response was seen in vitro in different mammalian cell systems in the presence of a metabolic activation system. This activity was seen only at concentrations more than three orders of magnitude higher than therapeutic blood levels.

Remifentanilo Mylan should only be reconstituted and diluted with those infusion solutions recommended.

It should not be reconstituted, diluted or mixed with Lactated Ringer's Injection or Lactated Ringer's and 5% Dextrose Injection.

Remifentanilo Mylan should not be mixed with propofol in the same infusion bag prior to administration.

Administration of Remifentanilo Mylan into the same intravenous line with blood/serum/plasma is not recommended. Non-specific esterases in blood products may lead to the hydrolysis of remifentanil to its inactive metabolite.

Remifentanilo Mylan should not be mixed with other therapeutic agents prior to administration.

Remifentanilo Mylan should be prepared for intravenous use by adding, as appropriate 1, 2, or 5 ml of diluent to give a reconstituted solution with a concentration of 1 mg/ml remifentanil. The reconstituted solution is clear, colourless, and practically free from particulate material. After reconstitution, visually inspect the product (where the container permits) for particulate material, discolouration or damage of container. Discard any solution where such defects are observed. Reconstituted product is for single use only. Any unused material should be discarded.

Remifentanilo Mylan should not be administered by manually-controlled infusion without further dilution to concentrations of 20 to 250 micrograms/ml (50 micrograms/ml is the recommended dilution for adults and 20 to 25 micrograms/ml for paediatric patients aged 1 year and over).

Remifentanilo Mylan should not be administered by TCI without further dilution (20 to 50 micrograms/ml is the recommended dilution for TCI).

The dilution is dependent upon the technical capability of the infusion device and the anticipated requirements of the patient.

One of the following IV fluids listed below should be used for dilution:

Water for Injections

Glucose 5% solution for injection

Glucose 5% and Sodium Chloride 0.9% solution for injection

Sodium Chloride 0.9% solution for injection

Sodium Chloride 0.45% solution for injection

After dilution, visually inspect the product to ensure it is clear, colourless, practically free from particulate matter and the container is undamaged. Discard any solution where such defects are observed.

Remifentanilo Mylan has been shown to be compatible with the following intravenous fluids when administered into a running IV catheter:

Lactated Ringer's solution for injection

Lactated Ringer's and Glucose 5% solution for injection

Remifentanilo Mylan has been shown to be compatible with propofol when administered into a running IV catheter.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

The following tables give guidelines for infusion rates of Remifentanilo Mylan for manually-controlled infusion:

Table 1. Remifentanilo Mylan for Injection Infusion Rates (ml/kg/h)

Drug Delivery Rate (micrograms/kg/min)	Infusion Delivery Rate (ml/kg/h) for Solution Concentrations of
	20 micrograms/ml 1 mg/50 ml	25 micrograms/ml 1 mg/40 ml	50 micrograms/ml 1 mg/20 ml	250 micrograms/ml 10 mg/40 ml
0.0125	0.038	0.03	0.015	Not recommended
0.025	0.075	0.06	0.03	Not recommended
0.05	0.15	0.12	0.06	0.012
0.075	0.23	0.18	0.09	0.018
0.1	0.3	0.24	0.12	0.024
0.15	0.45	0.36	0.18	0.036
0.2	0.6	0.48	0.24	0.048
0.25	0.75	0.6	0.3	0.06
0.5	1.5	1.2	0.6	0.12
0.75	2.25	1.8	0.9	0.18
1.0	3.0	2.4	1.2	0.24
1.25	3.75	3.0	1.5	0.3
1.5	4.5	3.6	1.8	0.36
1.75	5.25	4.2	2.1	0.42
2.0	6.0	4.8	2.4	0.48

Table 2. Remifentanilo Mylan for Injection Infusion Rates (ml/h) for a 20 micrograms/ml Solution

Infusion Rate(micrograms/kg/min)	Patient Weight (kg)
	5	10	20	30	40	50	60
0.0125	0.188	0.375	0.75	1.125	1.5	1.875	2.25
0.025	0.375	0.75	1.5	2.25	3.0	3.75	4.5
0.05	0.75	1.5	3.0	4.5	6.0	7.5	9.0
0.075	1.125	2.25	4.5	6.75	9.0	11.25	13.5
0.1	1.5	3.0	6.0	9.0	12.0	15.0	18.0
0.15	2.25	4.5	9.0	13.5	18.0	22.5	27.0
0.2	3.0	6.0	12.0	18.0	24.0	30.0	36.0
0.25	3.75	7.5	15.0	22.5	30.0	37.5	45.0
0.3	4.5	9.0	18.0	27.0	36.0	45.0	54.0
0.35	5.25	10.5	21.0	31.5	42.0	52.5	63.0
0.4	6.0	12.0	24.0	36.0	48.0	60.0	72.0

Table 3. Remifentanilo Mylan for Injection Infusion Rates (ml/h) for a 25 micrograms/ml Solution

Infusion Rate (micrograms/kg/min)	Patient Weight (kg)
	10	20	30	40	50	60	70	80	90	100
0.0125	0.3	0.6	0.9	1.2	1.5	1.8	2.1	2.4	2.7	3.0
0.025	0.6	1.2	1.8	2.4	3.0	3.6	4.2	4.8	5.4	6.0
0.05	1.2	2.4	3.6	4.8	6.0	7.2	8.4	9.6	10.8	12.0
0.075	1.8	3.6	5.4	7.2	9.0	10.8	12.6	14.4	16.2	18.0
0.1	2.4	4.8	7.2	9.6	12.0	14.4	16.8	19.2	21.6	24.0
0.15	3.6	7.2	10.8	14.4	18.0	21.6	25.2	28.8	32.4	36.0
0.2	4.8	9.6	14.4	19.2	24.0	28.8	33.6	38.4	43.2	48.0

Table 4. Remifentanilo Mylan for Injection Infusion Rates (ml/h) for a 50 micrograms/ml Solution

Infusion Rate (micrograms/kg/min)	Patient Weight (kg)
	30	40	50	60	70	80	90	100
0.025	0.9	1.2	1.5	1.8	2.1	2.4	2.7	3.0
0.05	1.8	2.4	3.0	3.6	4.2	4.8	5.4	6.0
0.075	2.7	3.6	4.5	5.4	6.3	7.2	8.1	9.0
0.1	3.6	4.8	6.0	7.2	8.4	9.6	10.8	12.0
0.15	5.4	7.2	9.0	10.8	12.6	14.4	16.2	18.0
0.2	7.2	9.6	12.0	14.4	16.8	19.2	21.6	24.0
0.25	9.0	12.0	15.0	18.0	21.0	24.0	27.0	30.0
0.5	18.0	24.0	30.0	36.0	42.0	48.0	54.0	60.0
0.75	27.0	36.0	45.0	54.0	63.0	72.0	81.0	90.0
1.0	36.0	48.0	60.0	72.0	84.0	96.0	108.0	120.0
1.25	45.0	60.0	75.0	90.0	105.0	120.0	135.0	150.0
1.5	54.0	72.0	90.0	108.0	126.0	144.0	162.0	180.0
1.75	63.0	84.0	105.0	126.0	147.0	168.0	189.0	210.0
2.0	72.0	96.0	120.0	144.0	168.0	192.0	216.0	240.0

Table 5. Remifentanilo Mylan for Injection Infusion Rates (ml/h) for a 250 micrograms/ml Solution

Infusion Rate (micrograms/kg/min)	Patient Weight (kg)
	30	40	50	60	70	80	90	100
0.1	0.72	0.96	1.20	1.44	1.68	1.92	2.16	2.40
0.15	1.08	1.44	1.80	2.16	2.52	2.88	3.24	3.60
0.2	1.44	1.92	2.40	2.88	3.36	3.84	4.32	4.80
0.25	1.80	2.40	3.00	3.60	4.20	4.80	5.40	6.00
0.5	3.60	4.80	6.00	7.20	8.40	9.60	10.80	12.00
0.75	5.40	7.20	9.00	10.80	12.60	14.40	16.20	18.00
1.0	7.20	9.60	12.00	14.40	16.80	19.20	21.60	24.00
1.25	9.00	12.00	15.00	18.00	21.00	24.00	27.00	30.00
1.5	10.80	14.40	18.00	21.60	25.20	28.80	32.40	36.00
1.75	12.60	16.80	21.00	25.20	29.40	33.60	37.80	42.00
2.0	14.40	19.20	24.00	28.80	33.60	38.40	43.20	48.00

The following table provides the equivalent blood remifentanil concentration using a TCI approach for various manually-controlled infusion rates at steady state:

Table 6. Remifentanil Blood Concentrations (nanograms/ml) estimated using the Minto (1997) Pharmacokinetic Model in a 70 kg, 170 cm, 40 Year Old Male Patient for Various Manually-Controlled Infusion rates (micrograms/kg/min) at Steady State.

Remifentanilo Mylan Infusion Rate (micrograms/kg/min)	Remifentanil Blood Concentration (nanograms/ml)
0.05	1.3
0.10	2.6
0.25	6.3
0.40	10.4
0.50	12.6
1.0	25.2
2.0	50.5