Consumer medicine information

Remifentanil-AFT

Remifentanil

BRAND INFORMATION

Brand name

Remifentanil-AFT

Active ingredient

Remifentanil

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Remifentanil-AFT.

What is in this leaflet

This leaflet answers some common questions about Remifentanil-AFT. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Remifentanil-AFT against the benefits this medicine is expected to have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Remifentanil-AFT is used for

Remifentanil-AFT is an anaesthetic used with other anaesthetic medicines, to produce and/or maintain heavy sleep during your operation. If you are a cardiac patient, it may also be used to help relieve any pain immediately after your operation.

Remifentanil-AFT may also be used for patients in the Intensive Care unit to maintain sedation and relieve pain.

Remifentanil-AFT belongs to a group of medicines called opioids. It differs from other medicines in this group by its very quick onset and very short duration of action.

Your doctor may have prescribed Remifentail-AFT for another reason. Ask your doctor if you have any questions about why Remifentanil-AFT has been prescribed for you.

Remifentanil-AFT can be addictive but this is unlikely to happen when it is only used during your operation.

Before you are given Remifentanil-AFT

When you must not be given it

You must not be given Remifentanil-AFT if you have severe respiratory disease, acute respiratory disease and respiratory depression or chronic (long-term) non-cancer pain or if you have ever had an allergic reaction to remifentanil hydrochloride or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following:

  • wheezing,
  • swelling of the lips/mouth,
  • difficulty in breathing,
  • hayfever, rash ("hives") or
  • fainting

Before you are given Remifentanil-AFT

You must tell your doctor if:

  • you have had any adverse reactions during an operation.
  • You are using any opioid medicine, benzodiazepines or alcohol
  • you have had any type of allergic reaction to any opioid medicine e.g. morphine, fentanyl, pethidine, codeine, or to any medicine used during an operation. You may have an increased risk of being allergic to Remifentanil-AFT if you are allergic to other opioids.
  • you are allergic to any other medicine or any other substance, e.g. foods, dyes or preservatives.
  • you have or have had any of the following medical conditions:
    - slow heart beat,
    - low blood pressure,
    - chest or breathing problems.
  • you are pregnant, intend to become pregnant, are breast feeding or plan to breast feed. Remifentanil-AFT is not recommended during pregnancy or when breast-feeding. Your doctor will discuss the potential risks and benefits of you being given Remifentanil-AFT if you are pregnant or breast-feeding.

If you have not told your doctor about any of the above, make sure you tell him/her before you are given Remifentanil-AFT.

Taking other medicines:

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

Tell your doctor if you have recently been taking medicines for blood pressure or heart problems e.g. beta blockers or calcium channel blockers.

Some medicines, such as benzodiazepines, may interfere with how Remifentanil-AFT works. Your doctor or pharmacist will be able to tell you what to do when being given Remifentanil-AFT with other medicines.

How Remifentanil-AFT is given

Remifentanil-AFT is given into a vein as either:

  • a slow injection, or
  • a slow infusion.

by an anaesthetist or other highly trained doctor. You will never be expected to give yourself this medication. The dosage will vary according to many factors e.g. your body weight and the type of operation you are having.

While using Remifentanil-AFT

If you are discharged early following treatment with Remifentanil-AFT or any other anaesthetic agents, do not drive or operate machinery.

Withdrawal

Continue taking your medicine for as long as your doctor tells you. If you stop having this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

  • nervousness, restlessness, agitation, trouble sleeping or anxiety
  • body aches, weakness or stomach cramps
  • loss of appetite, nausea, vomiting or diarrhoea
  • increased heart rate, breathing rate or pupil size
  • watery eyes, runny nose, chills or yawning
  • increased sweating.

Side effects

Check with your doctor as soon as possible if you have any concerns after being given Remifentanil-AFT, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like all medicines, Remifentanil-AFT can have side-effects.

The most common side-effects are:

  • slow breathing
  • breathlessness
  • slow heart beat
  • drop in blood pressure
  • increased blood pressure which may cause a headache or sensation of warmth or flushing.
  • muscle stiffness
  • shivering
  • nausea
  • vomiting
  • aches

This is not a complete list of all possible side-effects. Others may occur in some people and there may be some side-effects not yet known.

Addiction
You can become addicted to Remifentanil-AFT even if you take it exactly as prescribed. Remifentanil-AFT may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Dependence
As with all other opioid containing products, your body may become used to you taking Remifentanil-AFT. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking Remifentanil-AFT suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance
Tolerance to Remifentanil-AFT may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

Your doctor or pharmacist will be able to answer any questions you may have. Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Do not be alarmed by this list of possible side-effects. You may not experience any of them.

Overdose

Because Remifentanil-AFT will only be given by a doctor trained in its use, it is unlikely that you will receive an overdose. Should the doctor think you have received more Remifentanil-AFT than you need, he/she will either slow down the rate at which he/she is giving you the medicine or stop giving it to you altogether. Tell your doctor if you experience any of the following symptoms:

  • Slow, unusual or difficult breathing
  • Drowsiness, dizziness or unconsciousness
  • Slow or weak heartbeat
  • Nausea or vomiting
  • Convulsions or fits

Storage

Remifentanil-AFT powder for injection should be stored at or below 25 ºC.

To reduce microbiological hazards, reconstituted Remifentanil-AFT solutions should be used as soon as practicable after reconstitution. If storage is necessary, hold at 2-8 °C for not more than 24 hours.

Remifentanil-AFT contains no antimicrobial preservative. Use in one patient on one occasion only.

Other ingredients

Remifentanil-AFT also contains glycine and hydrochloric acid which is used to adjust the pH.

If you want to know more

Talk to your doctor or pharmacist if you have any questions about Remifentanil-AFT. Remifentanil is available in glass vials in three strengths:

  • Remifentanil-AFT 1 mg, powder for injection containing remifentanil (as hydrochloride) 1 mg: packs of 5 vials per carton: AUST R 193697
  • Remifentanil-AFT 2 mg, powder for injection containing remifentanil (as hydrochloride) 2 mg; packs of 5 vials per carton: AUST R 194069
  • Remifentanil-AFT 5 mg, powder for injection containing remifentanil (as hydrochloride) 5 mg; packs of 5 vials per carton: AUST R 193698

Sponsor

Australia

AFT Pharmaceuticals Pty Ltd
113 Wicks Road
North Ryde
NSW 2113

New Zealand

AFT Pharmaceuticals Ltd
Auckland

Date of Preparation

This CMI was revised in November 2020.

Published by MIMS January 2021

BRAND INFORMATION

Brand name

Remifentanil-AFT

Active ingredient

Remifentanil

Schedule

S8

 

1 Name of Medicine

Remifentanil-AFT.

2 Qualitative and Quantitative Composition

Remifentanil-AFT powder for injection is a sterile, nonpyrogenic, preservative-free white to off-white lyophilised powder for intravenous administration.
The product is formulated in glycine and requires reconstitution and dilution before use.
Three strengths are available:
Remifentanil-AFT 1 mg powder for injection contains remifentanil (as hydrochloride) 1 mg: packs of 5 vials per carton: AUST R 193697.
Remifentanil-AFT 2 mg powder for injection contains remifentanil (as hydrochloride) 2 mg: packs of 5 vials per carton: AUST R 194069.
Remifentanil-AFT 5 mg powder for injection contains remifentanil (as hydrochloride) 5 mg: packs of 5 vials per carton: AUST R 193698.
Three strengths are available; 1 mg, 2 mg and 5 mg of remifentanil base (as the hydrochloride salt).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Remifentanil-AFT is indicated:
as an opioid adjunct for use during induction and/or maintenance of general anaesthesia during surgical procedures including cardiac surgery in adults;
as an opioid adjunct for use during induction and/or maintenance of general anaesthesia during surgical but not cardiac procedures in children aged 1 to 12 years;
for continuation as an analgesic into the immediate post-operative period under the close supervision of medically qualified persons trained in the use of anaesthetic drugs, during transition to longer acting analgesia following adult cardiac surgery - when endotracheal intubation and controlled ventilation are anticipated;
for provision of analgesia and sedation in mechanically ventilated intensive care patients.

4.2 Dose and Method of Administration

Remifentanil-AFT should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by medically qualified 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 intubation, and assisted ventilation.
Continuous infusions of remifentanil must be administered by a calibrated infusion device, where possible via a dedicated intravenous line, otherwise into a fast flowing IV line. The remifentanil infusion line should be connected at, or close to, the intravenous cannula and primed, to minimise the potential dead space (see Section 4.2 Dose and Method of Administration, Instructions for use) for additional information, including tables with examples of infusion rates by body weight to help titrate remifentanil to the patient's anaesthetic needs.
Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual remifentanil after use (see Section 4.4 Special Warnings and Precautions for Use). Failure to clear the intravenous tubing to remove residual remifentanil has been associated with the appearance of respiratory depression, apnoea and muscle rigidity upon later administration of fluids or medications through the same IV tubing.
Remifentanil-AFT is for intravenous use only and must not be administered by epidural or intrathecal injection (see Section 4.3 Contraindications).
The administration of Remifentanil-AFT must be individualised based on the patient's response. It is not recommended for use as the sole agent in general anaesthesia.

1. General anaesthesia.

1.1 Dosage in adults.

Table 1 summarises the starting infusion rates and dose range for various anaesthetic situations.
(See Section 4.2 Dose and Method of Administration, Instructions for use for additional information, including tables to help titrate Remifentanil-AFT to the patient's anaesthetic needs).
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 excessive depth of anaesthesia (see Section 4.2 Dose and Method of Administration, Concomitant medication).
No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil.

Induction of anaesthesia.

Remifentanil-AFT should be administered with a hypnotic agent, such as propofol, thiopentone or isoflurane, for the induction of anaesthesia (see Section 4.4 Special Warnings and Precautions for Use, Muscle rigidity - prevention and management). Remifentanil-AFT can be administered at an infusion rate of 0.5 to 1 microgram/kg/min with or without an initial bolus injection of 1 microgram/kg over 60 seconds. If endotracheal intubation is to occur more than 8 to 10 minutes after the start of the infusion of remifentanil, then a bolus infusion 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 Table 1. 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 mu-opioid response. In response to light anaesthesia, supplemental bolus infusions may be administered every 2 to 5 minutes.

Analgesia.

On cessation of infusion, remifentanil has a short-lasting analgesic effect. Post-operative pain management should be considered and, where appropriate, begun prior to the termination of Remifentanil-AFT infusion.

Guidelines for discontinuation.

Upon discontinuation of remifentanil the intravenous tubing should be cleared to prevent the inadvertent administration of remifentanil at a later point in time (see Section 4.4 Special Warnings and Precautions for Use). Due to the 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 post-operative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of Remifentanil-AFT. 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 follow-up care.

Concomitant medication.

Remifentanil decreases the dose of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
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.

1.2 Dosage in paediatric patients (1-12 years of age).

Induction of anaesthesia.

There are insufficient data to make a dosage recommendation.

Maintenance of anaesthesia.

See Table 2.
When given by bolus injection remifentanil should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the 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.

Concomitant medication.

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent 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 (see Dosage in adults, Concomitant medication).

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 Dosage in adults, Guidelines for discontinuation).

Paediatric patients aged less than 1 year.

The pharmacokinetic profile of remifentanil in paediatric patients aged more than 2 months is comparable to that seen in adults after correction for body weight differences. However, there are insufficient pharmacokinetic and clinical data to make dosage recommendations for patients aged less than 1 year.

2. Cardiac anaesthesia.

2.1 Dosage in adults.

See Table 3.

Induction period of anaesthesia.

After administration of hypnotic to achieve loss of consciousness, remifentanil should be administered at an initial infusion rate of 1 microgram/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 6 minutes after the start of infusion in order to minimise the response to intubation.

Maintenance period of anaesthesia.

After endotracheal intubation the infusion rate of Remifentanil-AFT 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, should be administered a maximum bolus dose of 0.5 microgram/kg. These dosing recommendations also apply during hypothermic cardiopulmonary bypass (see Section 5.1 Pharmacodynamic Properties, Cardiac anaesthesia).

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 excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see General anaesthesia, Dosage in adults, Concomitant medication).

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 patient's level of analgesia and sedation should be closely monitored and the remifentanil rate adjusted to meet the individual patient's requirements.

Guidelines for discontinuation.

Remifentanil-AFT should only be continued as an analgesic in the immediate post-operative period, and subsequently discontinued during transition to longer acting analgesia, in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by medically qualified 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 intubation, and assisted ventilation. Prior to discontinuation of remifentanil, patients must be given alternative analgesic and sedative agents at a sufficient time in advance. The choice and dose of agent(s) should be appropriate for the patient's level of post-operative care (see Dosage in adults, Guidelines for discontinuation).
It is recommended that the remifentanil infusion is discontinued by reducing the infusion rate 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.
It is recommended that haemodynamic changes such as hypertension and tachycardia should be treated with alternative agents as appropriate.

2.2 Dosage in paediatric patients.

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

3. Special patient populations.

3.1 Dosage in elderly patients (over 65 years of age).

(a) General anaesthesia.

The initial starting dose of remifentanil administered to patients over 65 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.

(b) Cardiac anaesthesia.

No initial dose reduction is required (see Cardiac anaesthesia -dosing guidelines for cardiac anaesthesia).

3.2 Dosage in obese patients.

It is recommended that for obese patients 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.

3.3 Dosage in patients with renal impairment.

No dosage adjustment, relative to that used in healthy adults, is necessary as the pharmacokinetic profile of remifentanil is unchanged in this patient population.

3.4 Dosage in patients with hepatic impairment.

No adjustment of the initial dose, relative to that used in healthy adults, is necessary as the pharmacokinetic profile of remifentanil is unchanged in this patient population. However, 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 titrated to individual patient needs.

3.5 Neurosurgery.

There is limited clinical experience with patients undergoing neurosurgery.

3.6 ASA III/IV patients.

(a) 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.

(b) Cardiac anaesthesia.

No initial dose reduction is required (see Cardiac anaesthesia -dosing guidelines for cardiac anaesthesia).

(c) Intensive care.

No initial dose reduction is required (see Use in intensive care).

Instructions for use.

Reconstitution and dilution.

To reconstitute the powder, add 1 mL of diluent (see Physical compatibilities for recommended diluents) per mg of remifentanil. Shake well to dissolve. When reconstituted as directed, the solution contains approximately 1 mg of remifentanil activity per 1 mL.
Remifentanil-AFT should be diluted to a final concentration of 20, 25, 50, or 250 microgram/mL prior to administration (see Table 4).
50 microgram/mL is the recommended dilution for adults and 20-25 microgram/mL for paediatric patients aged 1 year and over. The dilution is dependent upon the technical capability of the infusion device and the expected requirements of the patient. Remifentanil-AFT should not be administered without dilution.

Physical compatibilities.

Remifentanil-AFT is chemically and physically stable and should be used within 24 hours of preparation and storage at 2-8°C, after reconstitution and further dilution to concentrations of 20 to 250 microgram/mL with one of the following recommended intravenous fluids: sterile water for injection, 5% glucose injection, 5% glucose and 0.9% sodium chloride injection, 0.9% sodium chloride injection, 0.45% sodium chloride injection.
Remifentanil-AFT contains no antimicrobial preservative and care must be taken to assure the sterility of prepared solutions. Reconstituted product should be used promptly and any unused material discarded. If storage is necessary, hold at 2-8°C for not more than 24 hours to reduce microbiological hazard.
(Also see Physical incompatibilities.)
Remifentanil-AFT has been shown to be compatible with the following intravenous fluids when administered into a running intravenous line: lactated Ringer's injection, lactated Ringer's and 5% glucose injection.
Remifentanil has been shown to be compatible with propofol when administered into a running intravenous line.

Physical incompatibilities.

Continuous infusions of remifentanil must be administered by a calibrated infusion device, where possible via a dedicated intravenous line, otherwise into a fast flowing IV line.
Remifentanil-AFT should only be admixed with those infusion solutions recommended (also see Physical compatibilities).
Remifentanil-AFT should not be admixed with lactated Ringer's injection or lactated Ringer's and 5% glucose injection.
Remifentanil-AFT should not be mixed with propofol in the same intravenous admixture solution.
Administration of Remifentanil-AFT into the same intravenous line with blood/serum/plasma is not recommended. Non-specific esterase in blood products may lead to the hydrolysis of remifentanil to its inactive metabolite.
Remifentanil-AFT should not be mixed with other therapeutic agents prior to administration.
Tables 5, 6, 7, 8 and 9 give guidelines for infusion rates of remifentanil.

Discontinuation.

Upon discontinuation of Remifentanil-AFT sufficient drug may remain in intravenous lines or in the dead space of cannulae to cause opioid-related effects (e.g. respiratory depression) if the line is flushed. Therefore, appropriate measures should be taken to avoid such inadvertent administration of remifentanil (see Section 4.4 Special Warnings and Precautions for Use).

3.7 Use in intensive care.

Remifentanil-AFT can be initially used alone for the provision of analgesia and sedation in mechanically ventilated intensive care patients.
It is recommended that Remifentanil-AFT is initiated at an infusion rate of remifentanil 0.1 microgram/kg/min to 0.15 microgram/kg/min. The infusion rate should be titrated in increments of 0.025 microgram/kg/min to achieve the desired level of analgesia and sedation. A period of at least 5 minutes should be allowed between dose adjustments. The level of analgesia and sedation should be carefully monitored, regularly reassessed and the remifentanil infusion rate adjusted accordingly. If an infusion rate of 0.2 microgram/kg/min is reached and the desired level of sedation is not achieved, it is recommended that dosing with an appropriate sedative agent is initiated. The dose of sedative agent should be titrated to obtain the desired level of sedation. Further increases to the remifentanil infusion rate in increments of 0.025 microgram/kg/min may be made if additional analgesia is required.
Remifentanil has been studied in intensive care patients in well controlled clinical trials for up to three days (see Clinical trials, Intensive care unit).
Table 10 summarises the starting infusion rates and typical dose range for provision of analgesia and sedation in individual patients.
The use of Remifentanil-AFT will reduce the dosage requirement of any concomitant sedative agents. Typical starting doses for sedative agents, if required, are given in Table 11.
To allow separate titration of the respective agents sedative agents should not be administered as an admixture.

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 a remifentanil infusion rate of at least 0.1 microgram/kg/min 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 microgram/kg/min, maximum 0.75 microgram/kg/min, has been administered for provision of additional anaesthesia during stimulating procedures.

Establishment of alternative analgesia prior to discontinuation of Remifentanil-AFT.

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-AFT, 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. The range of options for analgesia includes long acting oral, intravenous, or regional analgesics controlled by the nurse of the patient. These techniques should always be titrated to individual patient need as the infusion of remifentanil is reduced (see below). It is recommended that the choice of agent(s), the dose, and the time of administration are planned prior to discontinuation of Remifentanil-AFT.
In order to ensure a smooth emergence from a remifentanil-based regimen it is recommended that the infusion rate of remifentanil is titrated down in stages to 0.1 microgram/kg/min 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.

3.8 Paediatric intensive care patients.

There are no data available on use in paediatric patients.

3.9 Renally-impaired intensive care patients.

No adjustments to the doses recommended above are necessary in renally-impaired patients including those undergoing renal replacement therapy.
Recovery following discontinuation of a remifentanil infusion may be slightly prolonged in moderate to severe renal impairment (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with renal impairment).

4.3 Contraindications

Remifentanil-AFT is not suitable as the sole agent for induction of general anaesthesia.
Remifentanil-AFT is not recommended for use in spontaneous ventilation anaesthesia or as an analgesic in the immediate post-operative period due to inadequate safety data in such uses, except in ventilated cardiac surgery patients (see Section 4.1 Therapeutic Indications; Section 4.2 Dose and Method of Administration, 2. Cardiac anaesthesia).
As glycine is present in the formulation, Remifentanil-AFT is contraindicated for epidural and intrathecal use.
Remifentanil-AFT is contraindicated for use in patients with severe respiratory disease, acute respiratory disease and respiratory depression.
Remifentanil-AFT is contraindicated for use in chronic (long-term) non-cancer pain.
Remifentanil-AFT is contraindicated in patients with known hypersensitivity to any component of the preparation and to other fentanyl analogues.

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Remifentanil-AFT contains the opioid remifentanil and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Remifentanil-AFT at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Remifentanil-AFT.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Remifentanil-AFT with anyone else.

Respiratory depression.

Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Remifentanil-AFT but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients, in patients with severe hepatic impairment and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma). Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, (see Section 4.2 Dose and Method of Administration), together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.
The use of remifentanil may be associated with apnoea and respiratory depression. Remifentanil-AFT should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by medically qualified 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 intubation and assisted ventilation.

Respiratory depression - management.

The use of remifentanil may be associated with apnoea and respiratory depression. Therefore remifentanil should only be used where facilities for monitoring and treating respiratory depression are available. The occurrence of respiratory depression should be managed appropriately, including decreasing the rate of infusion by 50% or a temporary discontinuation of the infusion. Remifentanil has not been shown tocause recurrent respiratory depression even after prolonged administration. However, respiratory depression may occur in some patients up to 30 minutes after cessation of the remifentanil infusion due to residual effects of concomitant anaesthetics, and therefore it is important to ensure that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area (also see Inadvertent administration).

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Remifentanil-AFT with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Remifentanil-AFT concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Remifentanil-AFT.

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
When discontinuing Remifentanil-AFT in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; Section 4.2 Dose and Method of Administration).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Remifentanil-AFT, especially by children, can result in a fatal overdose of remifentanil. Patients and their caregivers should be given information on safe storage and disposal of unused Remifentanil-AFT (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Muscle rigidity - prevention and management.

At the recommended doses, remifentanil can cause muscle rigidity. Profound chest wall rigidity and inability to ventilate the patient has occurred during induction, and following inadvertent boluses after intravenous line flushing. The incidence of muscle rigidity is related to the dose and rate of administration. Therefore, boluses should be administered slowly, over 60 seconds.
Muscle rigidity induced by remifentanil must be treated in the context of the patient's clinical condition with appropriate supporting measures. 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 and may require intubation for ventilation. Muscle rigidity seen during the use of remifentanil as an analgesic may be treated by stopping or decreasing the rate of administration of Remifentanil-AFT. 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. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or an opioids antagonist may be administered.

Cardiovascular effects.

Remifentanil causes dose-dependent hypotension and bradycardia. These effects may be attenuated by the pre-administration of an appropriate anticholinergic agent such as glycopyrrolate or atropine. Hypotension and bradycardia may be managed by reducing the rate of infusion of remifentanil or the dose of concurrent anaesthetics, and by using intravenous fluids, vasopressor or anticholinergic agents as appropriate.
Debilitated, hypovolaemic, and elderly patients may be more sensitive to the cardiovascular effects of remifentanil.

Rapid offset of action.

Within 5 to 10 minutes after the discontinuation of Remifentanil-AFT no residual opioid activity will be present. For those patients undergoing surgical procedures where post-operative pain is generally anticipated alternative analgesics should be administered prior to the 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 follow-up care.

Discontinuation of treatment.

Symptoms including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of remifentanil. Where reported, re-introduction and tapering of the infusion has been beneficial.

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. Remifentanil-AFT should be administered, where possible via a dedicated IV line which is removed when Remifentanil-AFT is discontinued, otherwise into a fast flowing IV line at or close to the venous cannula and primed, in order to avoid administration of drug into the single dead space.

Awareness.

Intraoperative awareness has been reported when remifentanil has been administered with propofol infusion rates less than 75 microgram/kg/min for TIVA.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Special patient populations, Dosage in elderly patients (over 65 years of age).

Paediatric use.

Paediatric patients under 1 year of age.

There are insufficient data available on use in paediatric patients under 1 year of age.

Effects on laboratory tests.

See Section 5.3 Preclinical Safety Data.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Remifentanil is not metabolised by plasma cholinesterase therefore interactions with drugs metabolised by this enzyme are not anticipated.
As with other opioids, remifentanil decreases the dose of inhaled and intravenous anaesthetics and benzodiazepines required for anaesthesia (see Section 4.2 Dose and Method of Administration). If doses of concomitantly administered CNS depressant drugs are not reduced, patients may experience an increased incidence of adverse effects associated with these agents. Also see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants including alcohol.
The cardiovascular effects of remifentanil (hypotension and bradycardia), may be exacerbated in patients receiving concomitant cardiac depressant drugs, such as beta-blockers and calcium channel blocking agents.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Daily administration of remifentanil to male rats was associated with pathological changes in the epididymides at exposures to remifentanil and its major metabolite GR90291 of < 1 and > 200 fold, respectively, the anticipated clinical exposure, and pathological changes in the testes and reduced fertility and pregnancies at exposures to remifentanil and GR90291 of 1-2 and > 600 fold, respectively, the anticipated clinical exposure.
(Category C)
Although placental transfer of remifentanil and its major metabolite GR90291 was found in rats, rabbits and monkeys, there was no evidence of teratogenicity in rats at exposures to remifentanil and its major metabolite of 6 and > 200 fold, respectively, the anticipated clinical exposure. In rabbits, teratogenicity was observed only at remifentanil doses greater than those producing maternotoxicity and foetotoxicity, with remifentanil exposures of about 200 fold anticipated human remifentanil exposure. However, there are no adequate and well-controlled studies in pregnant women. The use of Remifentanil-AFT in pregnant women is 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, caution should be exercised when Remifentanil-AFT is administered to mothers who are breastfeeding.

Use in obstetrics.

The safety profile of remifentanil during labour or delivery has not been demonstrated. Remifentanil should not be used during labour and caesarean sections because it is known that remifentanil crosses the placental barrier and fentanyl analogues can cause respiratory depression in the infant.

4.7 Effects on Ability to Drive and Use Machines

Following treatment using anaesthetic agents, patients should be advised not to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

The most common adverse events associated with remifentanil are direct extensions of mu-opioid agonist pharmacology, such as respiratory depression, bradycardia, hypotension and skeletal muscle rigidity. These are dose dependent events and hence dissipate within minutes of discontinuing or decreasing the infusion rate of remifentanil. Hypotension may be relatively more common in the elderly (> 65 years).
Approximately 3,800 patients have been exposed to remifentanil in controlled clinical trials.
The frequencies of adverse events during general anaesthesia with the recommended doses of remifentanil are given in Table 12. Each patient was counted once for each type of adverse event.

Cardiac anaesthesia.

The side-effect profile of remifentanil was consistent with the known pharmacology of mu-opioid agonists. Hypotension observed in maintenance regimens (4% vs. 1%); and hypertension (2% vs. 0%), shivering (4% vs. 2%) and aches (2% vs. 0%) observed post-operatively; occurred at a greater frequency with remifentanil compared to "fast-track" comparator opioid (fentanyl and sufentanil) regimens. Although there was a higher frequency of the above adverse events, the incidence of adverse cardiac outcomes in each of the randomised, double-blind trials was similar for remifentanil and comparator opioid.

Paediatric anaesthesia.

Remifentanil was well tolerated and the incidence of adverse events at the recommended doses was similar to that reported for adults.

Intensive care unit.

The overall incidence of drug-related adverse events across treatment groups was: remifentanil 22% vs. fentanyl 17% vs. morphine 16%. The incidence of hypotension was comparable between groups (remifentanil 9% vs. fentanyl 9% vs. morphine 7%); the majority of hypotensive reports being drug-related (remifentanil 6% vs. fentanyl 6% vs. morphine 6%). Episodes of hypotension (defined as a mean arterial pressure, 50 mmHg) were more frequent with remifentanil (11% - 17% compared with morphine 2% and fentanyl 10%) however this was not associated with an increase in adverse event reporting (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular effects). In the remifentanil group the majority of drug-related episodes of hypotension were mild or moderate in severity and in the majority of cases, the average duration was less than 20 minutes.
Pruritus was one of the most commonly reported drug-related adverse events in the remifentanil group (2% incidence).

Other adverse events.

Less commonly reported adverse clinical events (incidence < 1%) from all controlled studies are presented below.

Digestive.

Constipation, abdominal discomfort, xerostomia, gastro-oesophageal reflux, dysphagia, diarrhoea, heartburn, ileus.

Cardiovascular.

Various atrial and ventricular arrhythmias, heart block, ECG change consistent with myocardial ischaemia, elevated CPK-MB level, syncope.

Musculoskeletal.

Muscle stiffness, musculoskeletal chest pain, post-operative aches.

Respiratory.

Cough, dyspnoea, bronchospasm, laryngospasm, rhonchi, stridor, nasal congestion, pharyngitis, pleural effusion, hiccups, pulmonary oedema, rales, bronchitis, rhinorrhoea.

Nervous.

Anxiety, involuntary movement, prolonged emergence from anaesthesia, confusion, awareness under anaesthesia without pain, rapid awakening from anaesthesia, tremors, disorientation, dysphoria, nightmares, hallucinations, paraesthesia, nystagmus, twitch, sleep disorder, seizure, amnesia.

Body as a whole.

Decreased body temperature, anaphylactic reaction, delayed recovery from neuromuscular block.

Skin.

Rash, urticaria.

Urogenital.

Urine retention, oliguria, dysuria, urine incontinence.

Infusion site reactions.

Erythema, pruritus, rash.

Metabolic and nutrition.

Abnormal liver function, hyperglycaemia, electrolyte disorders, increased CPK level.

Haematologic and lymphatic.

Anaemia, lymphopaenia, leukocytosis, thrombocytopaenia.

Observed during clinical practice.

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of remifentanil in conjunction with one or more anaesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to remifentanil.

Non-site specific.

Very rarely, allergic reactions including anaphylaxis have been reported in patients receiving remifentanil in conjunction with one or more anaesthetic agents.

Cardiovascular.

Rare cases of asystole/cardiac arrest, usually preceded by bradycardia, have been reported in patients receiving remifentanil in conjunction with other anaesthetic agents.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdosage is manifested by an extension of the pharmacologically predictable actions of remifentanil.
In the event of overdosage or suspected overdosage, take the following actions: Discontinue administration of remifentanil, 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 naloxone may be given as a specific antidote to manage severe respiratory depression and muscle rigidity.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Remifentanil is a potent, selective, 4-anilidopiperidine mu-opioid agonist with pharmacological action typical of this class of compound. It is distinguished from other 4-anilidopiperidines (fentanyl analogues) by its rapid onset and very short duration of action. The mu-opioid activity of remifentanil is antagonised by naloxone. Remifentanil in humans has a rapid blood-brain equilibration half-time of 1 ± 1 minutes (mean ± SD) and a rapid onset of action. The pharmacodynamic effects of remifentanil closely follow the measured blood concentrations, allowing direct correlation between dose, blood levels, and response. Blood concentration decreases 50% in 3 to 6 minutes after a 1-minute infusion or after prolonged continuous infusion due to rapid distribution and elimination processes and is independent of duration of drug administration. Recovery from the effects of remifentanil occurs rapidly (within 5 to 10 minutes). New steady-state concentrations occur within 5 to 10 minutes after changes in infusion rate. When used as a component of an anaesthetic technique, remifentanil can be rapidly titrated to the desired depth of anaesthesia/analgesia (e.g. as required by varying levels of intraoperative stress) by changing the continuous infusion rate or by administering an IV bolus injection. Remifentanil is a potent opioid, therefore careful adherence to the sections (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration) of this document is essential to avoid unacceptable adverse events.

Haemodynamics.

In premedicated patients undergoing anaesthesia, 1-minute infusions of < 2 microgram/kg of remifentanil caused dose-dependent hypotension and bradycardia. While additional doses > 2 microgram/kg (up to 30 microgram/kg) do not produce any further decreases in heart rate or blood pressure, the duration of the haemodynamic change is increased in proportion to the blood concentrations achieved. Peak haemodynamic effects occur within 3 to 5 minutes of a single dose of remifentanil or an infusion rate increase. Glycopyrrolate, atropine, and vagolytic neuromuscular blocking agents attenuate the haemodynamic effects associated with remifentanil. When appropriate, bradycardia and hypotension can be reversed by reduction of the rate of infusion of remifentanil, or the dose of concurrent anaesthetics, or by the administration of fluids or vasopressors.

Respiration.

Remifentanil depresses respiration in a dose-related fashion. Unlike other fentanyl analogues, the duration of action of remifentanil at a given dose does not increase with increasing duration of administration, due to lack of drug accumulation.
When remifentanil and alfentanil were dosed to equal levels of respiratory depression, recovery of respiratory drive after 3-hour infusions was more rapid and less variable with remifentanil (see Figure 1).
Spontaneous respiration occurs at blood concentrations of 4 to 5 nanogram/mL in the absence of other anaesthetic agents, for example, after discontinuation of a 0.25 microgram/kg/min infusion of remifentanil, these blood concentrations would be reached in 2 to 4 minutes. In patients undergoing general anaesthesia, the rate of respiratory recovery depends upon the concurrent anaesthetic; it is fastest after N2O, slower with propofol, and slowest after isoflurane.

Muscle rigidity.

Skeletal muscle rigidity can be caused by remifentanil and is related to the dose and speed of administration. Remifentanil may cause chest wall rigidity (inability to ventilate) after single doses of > 1 microgram/kg administered over 30 to 60 seconds or infusion rates > 0.1 microgram/kg/min. Administration of doses < 1 microgram/kg may cause chest wall rigidity when given concurrently with a continuous infusion of remifentanil.

Histamine release.

Assays of histamine in patients and normal volunteers have shown no elevation in histamine levels after administration of remifentanil in doses up to 30 microgram/kg over 60 seconds.

Clinical trials.

Clinical trials have demonstrated that remifentanil is unsuitable as a sole agent for induction. For induction, remifentanil should only be used as an opioid adjunct where intubation and mechanical ventilation are intended. Remifentanil is not recommended for use in post-operative analgesia, except for ventilated cardiac surgery patients in an environment where the patient is under the close supervision of medically qualified persons trained in the use of anaesthetic drugs (see Section 4.1 Therapeutic Indications; Section 4.3 Contraindications).
Remifentanil was evaluated in 3,562 patients undergoing general anaesthesia (n = 2,923) and monitored anaesthesia care (n = 639). These patients were evaluated in the following settings: inpatient (n = 2,213) which included cardiovascular (n = 675) and neurosurgical (n = 61), and outpatient (n = 1,349). Three hundred and seventy-seven (377) elderly patients (age range 66 to 90 years) and 440 paediatric patients received remifentanil. Of the general anaesthesia patients, 1,132 also received remifentanil as an IV analgesic agent during the immediate post-operative period.

Induction and maintenance of general anaesthesia - inpatient/outpatient.

The efficacy of remifentanil was investigated in 1562 patients in 15 randomised, controlled trials as the analgesic component for the induction and maintenance of general anaesthesia. Eight of these studies compared remifentanil to alfentanil, and two studies compared remifentanil to fentanyl. In these studies, doses of remifentanil up to the ED90 were compared to recommended doses (approximately ED50) of alfentanil or fentanyl.

Induction of anaesthesia.

Remifentanil was administered with isoflurane, propofol, or thiopentone for the induction of anaesthesia (n = 1,562). The majority of patients (80%) received propofol as the concurrent agent. Remifentanil reduced the propofol and thiopentone requirements for loss of consciousness. Compared to alfentanil and fentanyl, a higher relative dose of remifentanil resulted in fewer responses to intubation (see Table 13). Overall, hypotension occurred in 5% of patients receiving remifentanil compared to 2% of patients receiving the other opioids.
Remifentanil has been used as a primary agent for the induction of anaesthesia; however, it should not be used as a sole agent because loss of consciousness cannot be assured and because of a high incidence of apnoea, muscle rigidity, and tachycardia. The administration of an induction dose of propofol or thiopentone or a paralysing dose of a muscle relaxant prior to or concurrently with remifentanil during the induction of anaesthesia markedly decreased the incidence of muscle rigidity from 20% to < 1%.

Use during maintenance of anaesthesia.

Remifentanil was investigated in 929 patients in seven well-controlled general surgery studies in conjunction with nitrous oxide, isoflurane, or propofol in both inpatient and outpatient settings. These studies demonstrated that remifentanil could be dosed to high levels of opioid effect and rapidly titrated to optimise analgesia intraoperatively without delaying or prolonging recovery. Remifentanil was inadequate as a sole agent for maintenance of anaesthesia.
Compared to alfentanil and fentanyl, these higher relative doses (ED90) of remifentanil resulted in fewer responses to intraoperative stimuli (see Table 14) and a higher frequency of hypotension (16% compared to 5% for the other opioids). Remifentanil was infused to the end of surgery, while alfentanil was discontinued 5 to 30 minutes before the end of surgery as recommended. The mean final infusion rates of remifentanil were between 0.25 and 0.48 microgram/kg/min.
In three randomised, controlled studies (n = 407) during general anaesthesia, remifentanil attenuated the signs of light anaesthesia within a median time of 3 to 6 minutes after bolus doses of 1 microgram/kg with or without infusion rate increases of 50% to 100% (up to a maximum rate of 2 microgram/kg/min).
In an additional double-blind, randomised study (n = 103), a constant rate (0.25 microgram/kg/min) of remifentanil was compared to doubling the rate to 0.5 microgram/kg/min approximately 5 minutes before the start of the major surgical stress event. Doubling the rate decreased the incidence of signs of light anaesthesia from 67% to 8% in patients undergoing abdominal hysterectomy, and from 19% to 10% in patients undergoing radical prostatectomy. In patients undergoing laminectomy the lower dose was adequate.

Recovery.

In 2,169 patients receiving remifentanil for periods up to 16 hours, recovery from anaesthesia was rapid, predictable, and independent of the duration of the infusion of remifentanil. In the seven controlled, general surgery studies, extubation occurred in a median of 5 minutes (range: -3 to 17 minutes in 95% of patients) in outpatient anaesthesia and 10 minutes (range: 0 to 32 minutes in 95% of patients) in inpatient anaesthesia. Recovery in studies using nitrous oxide or propofol was faster than in those using isoflurane as the concurrent anaesthetic. There was no case of remifentanil-induced delayed respiratory depression (occurring more than 30 minutes after discontinuation of remifentanil).
In a double-blind, randomised study, administration of morphine sulfate (0.15 mg/kg) intravenously 20 minutes before the anticipated end of surgery to 98 patients did not delay recovery of respiratory drive in patients undergoing major surgery with remifentanil-propofol total IV anaesthesia.

Paediatric anaesthesia.

The safety, efficacy and pharmacokinetics of remifentanil have been established in five studies which included 687 paediatric patients (aged 5 days to 17 years). Of these, 437 patients received remifentanil: 65 patients were enrolled in pharmacokinetic studies and 372 paediatric patients were studied undergoing general anaesthesia for routine surgical procedures in the inpatient (n=190) and outpatient (n=182) settings. Two hundred and fifty patients were administered comparator anaesthetic regimens. Four of these studies were open-labelled.
One randomised, double-blind, parallel comparator-controlled study consisted of 206 patients, of which 103 received remifentanil. This study found the median time to extubation was 9 minutes vs. 10 minutes for fentanyl. The overall incidences of adverse events were 38% for remifentanil and 39% for fentanyl, drug-related adverse events were 19% and 22% respectively.
The studies confirmed the effectiveness of the initial adult dosing in paediatric patients > 1 year of age with subsequent titration to clinical effect according to individual patient requirements. Remifentanil based anaesthesia was shown to be as effective as conventional anaesthetic regimens in attenuation of responses to stimulating procedures and the provision of intra-operative haemodynamic stability. Remifentanil could be continued until the end of surgery and recovery from anaesthesia was rapid, predictable and similar to conventional anaesthetic regimens. Generally higher post-operative pain scores were observed when using remifentanil, consistent with the rapid offset of action of remifentanil. This highlights that longer acting analgesia must be established at an appropriate time in advance of the discontinuation of remifentanil to minimise post-operative pain (see Guidelines for discontinuation).
No relationship was found between age and the final infusion rate of remifentanil, indicating that the starting dose was appropriate across the range of ages studied. There were no clinically significant differences in time to extubation or other recovery parameters between remifentanil based anaesthesia and conventional anaesthetic regimens. Remifentanil was well tolerated and the incidence of adverse events at the recommended maintenance doses in combination with inhalational anaesthetics was similar to that reported in adults.

Cardiac surgery.

In preliminary investigations of cardiac anaesthesia, two studies evaluated the pharmacokinetics of remifentanil in patients (n=25) undergoing hypothermic coronary artery bypass graft (CABG) surgery; and two dose ranging studies were conducted which included a total of 217 ASA II-IV patients undergoing CABG surgery. The data indicated that high dose remifentanil (starting doses 1-3 microgram/kg/min) effectively attenuated responses to major surgical stress and was associated with rapid recovery profile. However, none of these studies included comparator opioids.
Subsequently remifentanil was evaluated in four randomised, double blind studies including a total of 830 patients (450 remifentanil, 380 comparator opioid) undergoing coronary artery bypass graft (CABG) or valve replacement/repair surgery. This was initiated to develop dosing guidelines for use of remifentanil in cardiac patients, establish the safety and efficacy of remifentanil compared with the use of fentanyl and sufentanil in 'fast-track' cardiac anaesthesia; and especially in 'higher risk' cardiac patients - those with impaired left ventricular function (ejection fraction < 0.35) or undergoing valve surgery.
A high dose remifentanil based regimen was generally more effective in attenuating major surgical stress responses compared to conventional opioid regimens (low/medium intermittent dose) used for 'fast-track' cardiac surgery (e.g. attenuation of response to Maximal Sternal Spread was 11-21% with remifentanil vs. 44-52% fentanyl and 39% sufentanil). Comparable haemodynamic stability was observed during surgery with remifentanil and comparator opioids regimens. After induction and during maintenance, remifentanil was associated with a higher incidence of hypotension or requirement for treatment of excessive anaesthesia than comparator opioid regimens.
Continuation of a remifentanil regimen at a fixed rate of 1 microgram/kg/min into the immediate post-operative period (ICU) was effective in managing patient comfort. The protocol regimen for transition to alternative analgesia in advance of down titration and discontinuation from remifentanil during weaning for extubation, was effective. Although sedation was increased it did not result in significant delay in post-operative recovery. Times to discharge from an intensive care setting were comparable to 'fast-track' opioid regimens.
For the side-effect profile in cardiac surgery, see Section 4.8 Adverse Effects (Undesirable Effects).

Neurosurgery.

Remifentanil was administered to 61 patients undergoing craniotomy for removal of a supratentorial mass lesion. In these studies, ventilation was controlled to maintain a predicted PaCO2 of approximately 28 mmHg. In one study (n = 30) with remifentanil and 66% nitrous oxide, the median time to extubation and to patient response to verbal commands was 5 minutes (range 1 to 19 minutes). Intracranial pressure and cerebrovascular responsiveness to carbon dioxide were normal.
A randomised, controlled study compared remifentanil (n = 31) to fentanyl (n = 32). Remifentanil (1 microgram/kg/min) and fentanyl (2 microgram/kg/min) were administered after induction with thiopentone and pancuronium. A similar number of patients (6%) receiving remifentanil and fentanyl had hypotension during induction. Anaesthesia was maintained with nitrous oxide and remifentanil at a mean infusion rate of 0.23 microgram/kg/min (range 0.1 to 0.4) compared with a fentanyl mean infusion rate of 0.04 microgram/kg/min (range 0.02 to 0.07). Supplemental isoflurane was administered as needed. The patients receiving remifentanil required a lower mean isoflurane dose (0.07 MAC-hours) compared with 0.64 MAC-hours for the fentanyl patients (P = 0.04). Remifentanil was discontinued at the end of anaesthesia, whereas fentanyl was discontinued at the time of bone flap replacement (a median time of 44 minutes before the end of surgery). Median time to extubation was similar (5 and 3.5 minutes, respectively, with remifentanil and fentanyl). None of the patients receiving remifentanil required naloxone compared to seven of the fentanyl patients (P = 0.01). Eighty-one percent (81%) of patients receiving remifentanil recovered (awake, alert, and oriented) within 30 minutes after surgery compared with 59% of fentanyl patients (P = 0.06). At 45 minutes, recovery rates were similar (81% and 69% respectively for remifentanil and fentanyl, P = 0.27). Patients receiving remifentanil required an analgesic for headache sooner than fentanyl patients (median of 35 minutes compared with 136 minutes, respectively [P = 0.04]). No adverse cerebrovascular effects were seen in this study.

Intensive care unit.

Three clinical studies were conducted to determine the safety and efficacy of remifentanil in a clinically relevant Intensive Care population requiring mechanical ventilation for up to three days. Two of these studies (USA 03206 and USA 30207) were randomised, double-blind, controlled, parallel group studies, the third of these (USA 30212) was an open labelled, non-comparator study. A total of 261 patients received remifentanil, 81 received fentanyl and 83 received morphine. Of those receiving remifentanil, 32 were treated for ≥ 48 hours, 12 of whom had moderate/severe renal impairment.
The randomized, double-blind studies compared a remifentanil-based analgesia/sedation regimen with fentanyl or morphine based regimens. The opioid was initially titrated to achieve adequate levels for sedation (a patient who was calm, easily rousable and followed commands) and analgesia (no or mild pain). Frequent monitoring of the depth of sedation and analgesia was undertaken. Administration of sedative agent was initiated only if the target level of sedation could not be achieved with opioid alone.
A remifentanil-based regimen was effective in providing optimal sedation for the majority (82%-90%) of the maintenance phase. Fentanyl and morphine comparator regimens provided similar efficacy in terms of duration of optimal sedation. Remifentanil infusion alone provided optimal sedation in the majority (65% in USA 30206, 78% in USA 30207 and 43% in USA 30212) of patients without the need for a supplementary sedative agent.
The primary end point, between patient variability in the percentage of hours of optimal sedation, was not statistically significantly different for remifentanil compared with fentanyl (study USA 30206) or morphine (study USA 30207).
Remifentanil was effective in providing adequate analgesia (no pain/mild pain) for the majority (> 94%) of the maintenance phase. Fentanyl and morphine provided similar efficacy in terms of duration of adequate analgesia. Moderate/severe pain was reported in a higher percentage of patients administered remifentanil compared to those administered morphine and fentanyl subsequent to down titration and discontinuation of the opioid. This was consistent with the rapid offset of the analgesic effects of remifentanil.
The time to extubation was rapid and comparable between remifentanil and the comparator regimens (median values ≤ 1.3 h in studies USA 30206 and USA 30207).
Remifentanil was associated with acceptable haemodynamic stability during the maintenance phase, which was similar to that observed in patients administered morphine or fentanyl. A greater incidence of haemodynamic changes were reported in the extubation, post-extubation and post-treatment phases in the remifentanil group, which were related to a greater incidence of pain.
The data indicate that a remifentanil-based regimen (starting infusion rate 0.1-0.15 microgram/kg/min), was very effective for establishing and maintaining optimal analgesia and sedation in a wide range of IC patients, including those with severe renal impairment. In the majority of patients (≥ 60%) in the comparator studies there was no requirement for infusion of supplementary sedative agents (midazolam or propofol) to maintain optimal sedation (SAS 4). In study USA 30212, where patients could be more deeply sedated (SAS 2-4), there was a greater requirement for supplementary use of sedative i.e. 58% of patients required propofol infusion. Use of a remifentanil-based regimen resulted in rapid extubation of the patients, similar to the comparator opioid regimens.

5.2 Pharmacokinetic Properties

Absorption.

Following administration of the recommended doses of remifentanil, the effective biological half-life is 3-10 minutes due to redistribution. The terminal half-life of the unchanged drug is 10 to 20 minutes. The average clearance of remifentanil in young healthy adults is 40 mL/min/kg. Clearance generally correlates with total body weight (with the exception of severely obese patients in whom it correlates with ideal body weight).

Distribution.

The central volume of distribution is 100 mL/kg, and the steady-state volume of distribution is 350 mL/kg. Blood concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. For every 0.1 microgram/kg/min increase in infusion rate, the blood concentration of remifentanil will rise 2.5 nanogram/mL. Unlike other fentanyl analogues, the duration of action does not increase with prolonged administration. Remifentanil is approximately 70% bound to plasma proteins.

Metabolism.

Remifentanil is an esterase metabolised opioid. It is rapidly and extensively metabolised by non-specific esterases in blood and tissues to the carboxylic acid derivative, GR90291. This metabolite is 4,600 times less active than the parent compound in quantitative EEG analysis of opioid activity. It is unlikely that there is any clinically significant activity of the metabolite. 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.

Excretion.

Placental and milk transfer.

Placental transfer studies in rats and rabbits showed that pups are exposed to remifentanil and/or its metabolites during growth and development. Remifentanil-related material is transferred to the milk of lactating rats. In a human clinical trial, the concentration of remifentanil in foetal blood was approximately 50% of that in maternal blood. The foetal arterio-venous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate.

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 Celsius.

Pharmacokinetics in patients with renal impairment.

After 72 hours of infusion, the rapid recovery from remifentanil-based sedation and analgesia is unaffected by mild renal impairment and may be slightly prolonged in patients with moderate/severe renal impairment (median time to off-set of effects of remifentanil was 30 minutes in patients with moderate/severe renal impairment compared with 13.5 minutes in mild renal impairment).
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. In intensive care patients with moderate/severe renal impairment, the concentration of the carboxylic acid metabolite is expected to reach approximately 100-fold the level of remifentanil at steady-state. There is no evidence that the metabolite produces clinically relevant mu-opioid effects even after administration of remifentanil infusions for up to three days in these patients. However, due to the limited data available, it is not known whether the accumulated metabolite has any other clinically relevant effects. (See Section 5.1 Pharmacodynamic Properties, Clinical trials, Intensive care unit).
There is no evidence that remifentanil is extracted during renal replacement therapy.
The carboxylic acid metabolite is extracted during haemodialysis by at least 30%.

Pharmacokinetics in patients with 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. Individuals with severe hepatic impairment demonstrated statistically significant, reduced sensitivity to carbon dioxide stimulation of minute ventilation, which may indicate an increased sensitivity 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's need.

Pharmacokinetics in paediatric patients.

In paediatric patients 5 days to 17 years of age, 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 half life of remifentanil is not significantly different in neonates suggesting that changes in analgesic effect after changes in infusion rate of remifentanil should be rapid and similar to that 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.

Pharmacokinetics in elderly patients.

The clearance of remifentanil is reduced (approximately 25%) in elderly patients (> 65 years) compared to young patients. The pharmacodynamics activity of remifentanil increases with increasing age. The EC50 for formation of delta waves on the electroencephalogram (EEG) in elderly patients receiving remifentanil is 50% lower than in 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's need.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenesis.

There is no information currently available on the carcinogenic potential of remifentanil. Remifentanil was not mutagenic in bacterial assays for gene mutations (Salmonella typhimurium histidine reversion assay), chromosomal aberrations (mouse micronucleus and Chinese hamster ovary chromosome) and a DNA repair assay (rat hepatocytes). However, a positive result was obtained in the mouse lymphoma L5178Y/tk+/- assay in the presence of metabolic activation.
Daily administration of remifentanil to male rats was associated with pathological changes in the epididymides at exposures to remifentanil and its major metabolite GR90291 of < 1 and > 200 fold, respectively, the anticipated clinical exposure, and pathological changes in the testes and reduced fertility and pregnancies at exposures to remifentanil and GR90291 of 1-2 and > 600 fold, respectively, the anticipated clinical exposure.

6 Pharmaceutical Particulars

6.1 List of Excipients

Glycine, hydrochloric acid.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.
In situations in which the medicine and the diluent have been mixed, but not immediately administered to the patient, the admixture may be stored for up to 24 hours if stored under refrigeration (2-8°C).
Do not freeze reconstituted Remifentanil-AFT.
To reduce microbiological hazards, use as soon as practicable after reconstitution. If storage is necessary, hold at 2-8°C for not more than 24 hours. Remifentanil-AFT contains no antimicrobial preservative. Use in one patient on one occasion only.

6.5 Nature and Contents of Container

Three strengths are available: 1 mg, 2 mg and 5 mg of remifentanil base (as the hydrochloride salt) packed in clear glass vials with siliconised stoppers and overseals.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


The chemical name of remifentanil hydrochloride is 1-(2- methoxycarbonyl-ethyl)-4 (phenylpropionyl-amino)- piperidine- 4-carboxylic acid methyl ester hydrochloride. The log P n-octanol/water is 17.9. Remifentanil HCl possesses no chiral centres.
It has the chemical formula C20H28N2O5.HCl with a molecular weight of 412.9.

CAS number.

The CAS Number is 13539-07-2.

7 Medicine Schedule (Poisons Standard)

S8 Controlled Drug.

Summary Table of Changes