Remifentanil

Registered South African indications:

• Narcotic analgesic or adjuvant for use during induction and/or maintenance of inhalational anaesthesia during surgical procedures, including cardiac surgery
• Provision of analgesia and as an aid to sedation (up to 72 hours sedation) in mechanically ventilated intensive care patients (safety and efficacy beyond 72 hours have not been demonstrated)

Remifentanil should be administered only by persons specifically trained in the use of anaesthetic medicines and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation such as the establishment and maintenance of a patent airway and assisted ventilation.

Registered South African contraindications

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

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other fentanyl analogues
• Pregnancy
• Breastfeeding
• Coadministration with nitrous oxide and oxygen alone, at altitudes above sea level
• Do not use unless artificial ventilation is planned

South African recommendations

Caution in the following patient groups:

• Severe hepatic impairment
• Elderly (general anaesthesia)

Obese patients

• For obese patients (greater than 30% over their ideal body weight) the dosage of remifentanil 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 in this population

Neurosurgery

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

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 remifentanil in this population. Initial dosage reduction and subsequent titration to effect is therefore recommended
• Cardiac anaesthesia: No initial dose reduction is required (see Cardiac anaesthesia dosing guidelines)
• Long-term use in the ICU: No data are available on the long-term (longer than 72 hours) use of remifentanil in ICU patients

Monotherapy

• Remifentanil is not recommended for use as the sole medicine in general anaesthesia

Mechanically ventilated intensive care patients

• The use of remifentanil in mechanically ventilated intensive care patients is not recommended for a duration of treatment greater than 3 days

Hypersensitivity

• Patients with a known hypersensitivity to opioids of a different class may experience a hypersensitivity reaction following administration of remifentanil. Caution should be exercised when using remifentanil in these patients

Interference with daily activities

• Interference with daily activities may continue for up to 24 hours and no legal/contractual decisions should be entered into for 24 hours after receiving anaesthetic/conscious sedation. Alcohol use should also be avoided for the same time period

Rapid offset of action/ Transition to alternative analgesia

• Due to the very rapid offset of action of remifentanil (within 5-10 minutes of discontinuation), administer analgesics prior to or immediately following the cessation of remifentanil in patients with anticipated post-operative pain
• In the intensive care unit, consider the possibility of tolerance, hyperalgesia, and associated haemodynamic changes, and ensure alternative, longer-acting analgesic and sedative medicines are given sufficient time to reach maximum effect before stopping remifentanil
• When transitioning, balance the need for adequate post-operative analgesia with the risk of respiratory depression from other opioids

Risk from concomitant use of sedative medicines such as benzodiazepines or related medicines

• The concomitant use of remifentanil and sedative medicines (such as benzodiazepines or related medicines) may cause sedation, respiratory depression, coma, and death; therefore, reserve concomitant prescribing for when alternative treatment options are not possible
• If co-administered, use the lowest effective dose for the shortest duration possible, and closely monitor patients for signs of respiratory depression and sedation

Discontinuation of treatment

• Abrupt cessation of remifentanil, particularly after prolonged administration of more than 3 days, has infrequently resulted in withdrawal symptoms including tachycardia, hypertension, and agitation
• The use of remifentanil in mechanically ventilated intensive care patients is not recommended for treatment durations greater than 3 days

Inadvertent administration

• A sufficient amount of remifentanil may remain in the dead space of the IV line or cannula to cause respiratory depression, apnoea, or muscle rigidity if the line is flushed
• Administer remifentanil into a fast-flowing IV line or a dedicated IV line that is adequately cleared of residual medicine or removed upon discontinuation to avoid this risk

Muscle rigidity prevention and management

• Muscle rigidity, which is dose and rate-related, may occur with remifentanil; therefore, administer bolus infusions over no less than 30 seconds. Treat excessive rigidity during induction with a neuromuscular blocking agent and/or additional hypnotic medicines
• Rigidity during use as an analgesic may be managed by stopping or decreasing the infusion rate, and an opioid antagonist may be used, though this may reverse or attenuate analgesia

Respiratory depression management

• Remifentanil causes marked respiratory depression, so it should only be used where monitoring and management facilities are available. Manage respiratory depression by decreasing the infusion rate by 50% or discontinuing the infusion
• Patients with impaired lung function and severe hepatic impairment are more sensitive to these effects. Ensure full consciousness and adequate spontaneous ventilation before discharge from recovery

Cardiovascular effects

• Remifentanil may cause hypotension and bradycardia, leading to asystole and cardiac arrest. Manage these by reducing the remifentanil infusion rate or the dose of concurrent anaesthetics, or by using IV fluids, vasopressors, or anticholinergic medicines
• Debilitated, hypovolaemic, and elderly patients are more sensitive to remifentanil's cardiovascular effects

Serotonin Syndrome

• Serotonin syndrome, a potentially life-threatening condition, has been reported with the concomitant use of remifentanil and serotonergic medicines (such as SSRIs, SNRIs, TCAs, triptans, 5-HT3 receptor antagonists, and MAO inhibitors including linezolid and intravenous methylene blue)
• Symptoms may include mental status changes, autonomic instability, neuromuscular aberrations, and gastrointestinal symptoms. If suspected, rapid discontinuation of remifentanil should be considered

Dependency

• As with other opioids, remifentanil may produce dependency, and the risk of addiction is increased in patients with a personal or family history of substance abuse or mental health disorders

Paediatric population

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

Effects on ability to drive and use machines

• Remifentanil has a major influence on the ability to drive and use machines by impairing cognitive function. Patients should be advised not to drive or operate machinery, should be accompanied when returning home, and should avoid alcoholic drinks if an early discharge is planned

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Remifentanil should be administered only by persons specifically trained in the use of anaesthetic medicines and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation such as the establishment and maintenance of a patent airway and assisted ventilation.

General anaesthesia

The administration of remifentanil must be individualised based on the patient’s response

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

Indication	Bolus Infusion of remifentanil (µg/kg)	Continuous infusion of remifentanil (µg/kg/min)
		Starting Rate	Range
With induction of anaesthesia in ventilated patients	1 (given over not less than 30 seconds)	0.5 to 1.0	-
Maintenance of anaesthesia in ventilated patients
Isoflurane (starting dose 0.5 MAC)	0.5 to 1.0	0.25	0.05 to 0.5
Propofol (starting dose 100 µg/kg/min)	0.5 to 1.0	0.25	0.05 to 0.5

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At the doses recommended, remifentanil significantly reduced the amount of hypnotic medicine required to maintain anaesthesia. Therefore, isoflurane should be administered as recommended above to avoid excessive depth of anaesthesia

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Induction of anaesthesia

Remifentanil should be administered with a hypnotic medicine, such as isoflurane, for the induction of anaesthesia

• IV: 0.5-1μg/kg/min, as an infusion with or without an initial bolus infusion of 1µg/kg given in no less than 30secs; If endotracheal intubation is to occur more than 8-10mins after the start of the infusion, then a bolus infusion is not necessary

Maintenance of anaesthesia

After endotracheal intubation, the infusion rate of remifentanil should be decreased, according to the anaesthetic technique, as indicated in the above table

• IV: Due to the fast onset and short duration of action of remifentanil, the rate of administration during anaesthesia can be titrated upward in 25-100% increments OR downward in 25-50% decrements, every 2-5mins to obtain the desired level of µ-opioid receptor response; In response to light anaesthesia, supplemental bolus infusions may be administered every 2-5mins

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The use of remifentanil to treat pain during the post-operative period is not recommended in patients who are breathing spontaneously

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Guidelines for discontinuation
Due to the very rapid offset of action of remifentanil, residual opioid activity will be reduced within 5-10 minutes after discontinuation. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to, or immediately following 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

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Concomitant medication
Remifentanil decreases the amounts or doses of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia

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Cardiac anaesthesia

Cardiac anaesthesia: Adults: Dosing guidelines for cardiac anaesthesia
Indication	Bolus infusion of remifentanil (μg/kg)	Continuous infusion of remifentanil (μg/kg/min)
		Starting Rate	Typical Infusion Rates
Intubation	Not recommended	1	-
Maintenance of anaesthesia
Isoflurane (starting dose 0.4 MAC)	0.5 to 1	1	0.003 to 4
Propofol (starting dose 50μg/kg/min)	0.5 to 1	1	0.01 to 4.3
Continuation of postoperative analgesia, prior to extubation	Not recommended	1	0 to 1

Induction period of anaesthesia

After administration of a hypnotic medicine to achieve loss of consciousness,

• IV: Admin. at an initial infusion rate of 1µg/kg/min; The use of bolus infusions of remifentanil during induction in cardiac surgical patients is not recommended; Endotracheal intubation should not occur until at least 5mins after the start of the infusion

Maintenance period of anaesthesia

• IV: After endotracheal intubation: The infusion rate of remifentanil should be titrated according to patient need; Supplemental bolus doses may also be given as required; High risk cardiac patients, such as those with poor ventricular function: Max bolus dose: 0.5µg/kg
  These dosing recommendations also apply during hypothermic cardiopulmonary bypass

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Concomitant medication
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic medicine required to maintain anaesthesia. Therefore, isoflurane, halothane and sevoflurane should be administered as recommended above to avoid excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil

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Continuation of post-operative analgesia prior to 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. Upon arrival into this area, the infusion should be maintained initially at a rate of 1µg/kg/min until the patient is ready to be weaned from the ventilator

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Guidelines for discontinuation
Prior to discontinuation of remifentanil, patients must be given alternative analgesic and sedative medicine at a sufficient time in advance. The choice and dose of medicine(s) should be appropriate for the patient’s level of post-operative care. It is recommended that the remifentanil infusion is discontinued by reducing the infusion rate in three to four steps of 50% at 10 minute intervals. During weaning from the ventilator, the remifentanil infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics. It is recommended that haemodynamic changes such as hypertension and tachycardia should be treated with alternative medicines, as appropriate.

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Intensive care use

When used for the provision of analgesia for up to 72hrs and as an aid to short-term sedation in mechanically ventilated intensive care patients

• IV: Initial: Infusion rate: 0.1µg/kg/min (6µg/kg/hr) to 0.15µg/kg/min (9µg/kg/hr); The infusion rate should be titrated in increments of 0.025µg/kg/min (1.5µg/kg/hr) to achieve the desired level of analgesia; A period of at ≥5mins should be allowed between dose adjustments; The level of analgesia should be carefully monitored, regularly reassessed and the infusion rate adjusted accordingly; If an infusion rate of 0.2µg/kg/min (12µg/kg/hr) is reached and the desired level of sedation is not achieved; It is recommended that dosing with an appropriate sedative medicine is initiated (see below); The dose of sedative medicine should be titrated to obtain the desired level of sedation; Further increases to the infusion rate in increments of 0.025µg/kg/min (1.5µg/kg/hr) may be made if additional analgesia is required
   

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

Dosing guidelines for use of remifentanil within the intensive care setting
Continuous Infusion μg/kg/min (μg/kg/hr)
Starting rate	Range
0.1 (6) to 0.15 (9)	0.006 (0.36) to 0.74 (44.4)

Bolus doses of remifentanil are not recommended in the intensive care setting. The use of remifentanil will reduce the dosage requirements of any concomitant sedative medicine by approximately 50%. Typical starting doses for sedative medicine, if required are given in the table below

Recommended starting dose of sedative medicines, if required
Sedative medicine	Bolus (mg/kg)	Infusion (mg/kg/hr)
Propofol	Up to 0.5	0.5
Midazolam	Up to 0.03	0.03

To allow separate titration of the respective medicines, sedative medicines should not be administered as an admixture

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Additional analgesia for ventilated patients undergoing stimulating procedures
An increase in the existing remifentanil 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 remifentanil infusion rate of at least 0.1µg/kg/min (6µg/kg/hr) 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 0.25µg/kg/min (15µg/kg/hr), maximum 0.75µg/kg/min (45µg/kg/h), has been administered for provision of additional anaesthesia during stimulating procedures

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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 regardless of the duration of infusion. Prior to discontinuation of remifentanil, patients must be given alternative analgesic and sedative medicines at a sufficient time in advance, to allow the therapeutic effects of these medicines to become established. It is therefore recommended that the choice of medicine(s), the dose and the time of administration, are planned prior to discontinuation of remifentanil

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Guidelines for extubation and discontinuation of remifentanil
In order to ensure a smooth emergence from a remifentanil-based regimen, it is recommended that the infusion rate of remifentanil is titrated in stages to 0.1µg/kg/min (6µg/kg/hr) 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 remifentanil infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics. Upon discontinuation of remifentanil, the IV cannula should be cleared or removed to prevent subsequent inadvertent administration. When other opioid medicines 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 with these medicines

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See method of administration in Additional Prescribing Points

Paed. forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Remifentanil should be administered only by persons specifically trained in the use of anaesthetic medicines and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation such as the establishment and maintenance of a patent airway and assisted ventilation.

Induction of anaesthesia in paediatric patients aged 1-12 years: Remifentanil is not recommended for the induction of anaesthesia, as insufficient data are available

Maintenance of anaesthesia

Younger than 1 year

• Not established for use (see red notes below)

Between 1-12 years

Dosing guidelines for maintenance of anaesthesia in paediatric patients

Dosing guidelines for maintenance of anaesthesia in paediatric patients (1 - 12 years of age)
Concomitant anaesthetic medicine	Bolus infusion of remifentanil (μg/kg)	Continuous infusion of remifentanil (μg/kg/min)
		Starting Rate	Typical Maintenance Rates
Halothane (starting dose 0.3 MAC)	1	0.25	0.05 to 1.3
Sevoflurane (starting dose 0.3 MAC)	1	0.25	0.05 to 0.9
Isoflurane (starting dose 0,5 MAC)	1	0.25	0.06 to 0.09

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When given by bolus infusion, remifentanil should be administered over not less than 30 seconds

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Surgery should not commence until at least 5 minutes after the start of remifentanil infusion, if a simultaneous bolus dose has not been given. Paediatric patients should be monitored and the dose titrated to the depth of analgesia appropriate for the surgical procedure

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Concomitant medication
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic medicine required to maintain anaesthesia. Therefore, isoflurane, halothane and sevoflurane should be administered as recommended above to avoid excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil

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Guidelines for discontinuation
Following discontinuation of the infusion, the offset of analgesic effect of remifentanil is rapid and similar to that seen in adult patients. Appropriate post-operative analgesic requirements should be anticipated and implemented (see Adult Dosages – Guidelines for discontinuation)

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Neonates/infants (aged less than 1 year)
The pharmacokinetic profile of remifentanil in neonates/infants (aged less than 1 year) is comparable to that seen in adults after correction of body weight differences. However, there are insufficient clinical data to make dosage recommendations for this age group

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Cardiac anaesthesia
There are insufficient data to make a dosage recommendation for use during cardiac surgery

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Paediatric intensive care patients
There are no data available on use in paediatric patients

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See method of administration in Additional prescribing points

Pregnancy

South African recommendations

• Contraindicated
• Safety of remifentanil in pregnancy has not been established and is therefore not recommended

Labour and delivery

• The safety profile of remifentanil during labour or delivery has not been demonstrated
• There are insufficient data to recommend remifentanil for use during labour and caesarean section
• Remifentanil, crosses the placental barrier, and fentanyl analogues can cause respiratory depression in the child

Breastfeeding

South African recommendations

• Contraindicated
• Safety of remifentanil in lactation has not been established and is therefore not recommended
• It is not known whether remifentanil, is excreted in human milk
• However, because fentanyl analogues are excreted in human milk and remifentanil-related material was found in rat milk after dosing with remifentanil, nursing mothers should be advised to discontinue breastfeeding for 24 hours following administration of remifentanil

Fertility

South African recommendations

• There is no data on fertility with remifentanil

South African recommendations

• No dose adjustment recommended
  No adjustments to the recommended doses are necessary in renally impaired patients, including those undergoing renal replacement therapy or g intensive care patients

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adustment recommended
  May be 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

South African recommendations

• General anaesthesia: Caution: dose adjustment recommended
  The initial starting dose of remifentanil should be half the recommended adult dose and then 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
• Cardiac anaesthesia: No dose adjustment recommended
  No initial dose reduction is required (see Cardiac anaesthesia dosing guidelines in Adult Dosages)
• Intensive care: No dose adjustment recommended
  No initial dose reduction is required (see Intensive care use in Adult Dosages)

Central Nervous System Disorders

• Sedation
• Seizures
• Dependence

Cardiovascular Disorders

• Bradycardia
• Asystole
• Cardiac arrest
• Atrioventricular block
• Hypotension
• Hypertension

Respiratory Disorders

• Acute respiratory depression
• Apnoea
• Hypoxia

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation

Musculoskeletal Disorders

• Skeletal muscle rigidity  

Skin and Subcutaneous Tissue Disorders

• Pruritus

Immune System Disorders

• Hypersensitivity reactions

• Central nervous system depressants
• Benzodiazepines
• Cardiac depressant agents
• Beta-blockers
• Calcium channel blockers

• Respiratory function
• Cardiac function  
• Blood pressure

Method of administration

• After reconstitution, solutions of remifentanil are clear and colourless
• Continuous infusion of remifentanil must be administered by a calibrated infusion device into a fast-flowing IV line or via a dedicated IV line
• This infusion line should be connected at, or close to, the venous cannula and primed, to minimise the potential dead space
• Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual remifentanil after use
• Remifentanil is for intravenous use only and must not be administered by epidural or intrathecal injection

Reconstitution

• Remifentanil should be prepared for intravenous use by adding, as appropriate 1, 2, or 5ml of diluent (refer below to the list of IV fluids) to give a reconstituted solution with a concentration of 1mg/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
• The reconstituted solution is stable for 24 hours at room temperature (25 ⁰C) and further dilution to 20 to 250μg/ml (50μg/ml is the recommended dilution for adults and 20 - 25μg/ml for paediatric patients aged 1 year and over) with one of the following IV fluids below:
  • Sterilised water for injections
  • 5% Dextrose injection
  • 5% Dextrose and 0.9% sodium chloride injection
  • 0.9% Sodium chloride injection
  • 0.45% Sodium chloride 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

Remifentanil is a mu-opioid receptor agonist with rapid onset and peak effect, and short duration of action.

Injection (per ml) 1mg

• Mylan Remifentanil (Mylan)

Injection (per 2ml) 2mg

• Mylan Remifentanil (Mylan)

Injection (per 3ml) 3mg

• Mylan Remifentanil (Mylan)

Injection (per 3ml) 1mg

• Fortiva (Pharmacare)
• Ultiva (Pharmacare) originator

Injection (per 5ml) 2mg

• Fortiva (Pharmacare)
• Ultiva (Pharmacare) originator

Injection (per 10ml) 5mg

• Fortiva (Pharmacare)
• Ultiva (Pharmacare) originator