REMIFENTANIL

Remifentanil shall 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. Continuous infusions of remifentanil must be administered by a calibrated infusion device into a fast flowing IV line or via a dedicated IV line.

6 for additional information, for tables with examples of infusion rates by body weight to help titrate remifentanil to the patient`s anaesthetic needs see below). 4). IV lines/infusion system should be removed after cessation of use to avoid inadvertent administration.

Remifentanil may 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). 3). Dilution Remifentanil may be further diluted after reconstitution of the lyophilized powder.

6 for recommended diluents and instructions on reconstitution / dilution of the product before administration. 1 General Anaesthesia The administration of remifentanil must be individualised based on the patient's response. 05 to 2 When given by bolus injection at induction remifentanil 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 (hypotension and bradycardia) of remifentanil (see Concomitant medication).

No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with remifentanil. Induction of anaesthesia Remifentanil should be administered with a standard dose of hypnotic agent, such as propofol, thiopentone, or isoflurane, for the induction of anaesthesia.

Administering remifentanil after a hypnotic agent will reduce the incidence of muscle rigidity. 5 to 1 μg/kg/min, with or without an initial bolus injection of 1 μg/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 remifentanil, then a bolus injection is not necessary.

Maintenance of anaesthesia in ventilated patients After endotracheal intubation, the infusion rate of remifentanil should be decreased, according to anaesthetic technique, as indicated in the above table. Due to the fast onset and short duration of action of remifentanil, 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 μ-opioid response.

In response to light anaesthesia, supplemental bolus injections may be administered every 2 to 5 minutes. g. laryngeal mask anaesthesia) In spontaneously breathing anaesthetised patients with a secured airway respiratory depression is likely to occur.

Therefore attention must be given to respiratory effects possibly combined with muscular rigidity. Special care is needed to adjust the dose to the patient requirements and ventilatory support may be required. Adequate facilities should be available for monitoring of patients administered remifentanil.

4). 04 μg/kg/min with titration to effect. 1 μg/kg/min has been studied. Bolus injections are not recommended in spontaneously breathing anaesthetised patients. Remifentanil should not be used as an analgesic in procedures where patients remain conscious or do not receive any airway support during the procedure.

5). 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 postoperative period Due to the very rapid offset of action of remifentanil no residual opioid activity will be present within 5 to 10 minutes after discontinuation.

For those patients undergoing surgical procedures where […]

The most common undesirable effects associated with remifentanil are direct extensions of μ-opioid agonist activities. These adverse events resolve within minutes of discontinuing or decreasing the rate of remifentanil administration.

4). 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.

uk/yellowcard.

Remifentanil 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. As mechanically ventilated, intensive care patients were not studied beyond three days, no evidence of safety and efficacy for longer treatment has been established.

Therefore, a longer usage is not recommended in intensive care patients. Rapid offset of action/transition to alternative analgesia Due to the very rapid offset of action of remifentanil, patients may emerge rapidly from anaesthesia and no residual opioid activity will be present within 5-10 minutes after the discontinuation of remifentanil.

During administration of remifentanil as a μ-opioid agonists the potential for the development of tolerance and hyperalgesia should be paid attention to. Therefore, prior to discontinuation of remifentanil, 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 and to prevent hyperalgesia and concomitant haemodynamic changes.

For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of remifentanil. 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. 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 and withdrawal syndrome Repeated administration at short term intervals for prolonged periods may result in the development of withdrawal syndrome after cessation of therapy. 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.

Where reported, re-introduction and tapering of the infusion has been beneficial. The use of Remifentanil in mechanically ventilated intensive care patients is not recommended for duration of treatment greater than 3 days. 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, a μ-opioid antagonist may be administered; however this may reverse or attenuate the analgesic effect of remifentanil.

Respiratory depression – preventive measures and treatment 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.

Special care should be taken in patients with impaired lung function and with severe hepatic impairment. These patients may be slightly more sensitive to the respiratory depressant effects of remifentanil. These patients should be closely monitored and the dose of remifentanil titrated to individual patient need.

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.

g. inadvertent administration of bolus doses (see section below) and administration of concomitant longer acting opioids), respiratory depression occurring up to 50 minutes after discontinuation of infusion has been reported. 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.

8) may be managed by reducing the rate of infusion of remifentanil 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.

Inadvertent administration A sufficient amount of remifentanil 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 remifentanil into a fast flowing IV line or via a dedicated IV line which is removed when remifentanil is discontinued. Neonates/infants There is limited data […]

3 Continuation of post-operative analgesia, prior to extubation Not recommended 1 0 to 1 Induction period of anaesthesia After administration of a hypnotic to achieve loss of consciousness, remifentanil should be administered at an initial infusion rate of 1 μg/kg/min.

The use of bolus injections of remifentanil 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 remifentanil should be titrated according to patient need.

Supplemental bolus doses may also be given as required. 5 μg/kg. 2). Concomitant medication 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 (hypotension and bradycardia) of remifentanil.

No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see in section above: Administration by Manually Controlled Infusion (MCI), Concomitant medication). Guidelines for postoperative patient management Continuation of remifentanil post-operatively to provide analgesia prior to weaning for extubation It is recommended that the infusion of remifentanil should be maintained at the final intra-operative rate during transfer of patients to the post-operative care area.

3). Establishment of alternative analgesia prior to discontinuation of remifentanil Due to the very rapid offset of action of remifentanil, no residual opioid activity will be present within 5 to 10 minutes after discontinuation. Prior to discontinuation of remifentanil, 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. 8). To minimise the risk of these occurring, adequate alternative analgesia must be established (as described above), before the remifentanil 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 remifentanil 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. 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 ng/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 (hypotension and bradycardia) of remifentanil (see table 4 Dosing Guidelines for Cardiac Anaesthesia above).

1). Guidelines for discontinuation / continuation into the immediate post- operative period At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the region of 1 to 2 ng/ml.

1). As there are insufficient data, the administration of remifentanil by TCI for the management of post-operative analgesia is not recommended. 1 Adults Remifentanil can be used for the provision of analgesia in mechanically ventilated intensive care patients.

If required, additionally sedating drugs should be applied. Remifentanil has been studied in intensive care patients in well […]