Consumer medicine information

Rapifen

Alfentanil

BRAND INFORMATION

Brand name

Rapifen

Active ingredient

Alfentanil

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rapifen.

What is in this leaflet

This leaflet answers some of the common questions people ask about RAPIFEN. It does not contain all the information that is known about RAPIFEN.

It does not take the place of talking to your doctor, anaesthetist or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given RAPIFEN against the benefits they expect it will have for you.

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

Keep this leaflet. You may need to read it again.

What RAPIFEN is for

RAPIFEN is a drug used to relieve pain and produce anaesthesia.

It can be used as a premedication before an operation, or with a general anaesthetic during an operation.

RAPIFEN belongs to a group of medicines called opioid analgesics.

RAPIFEN works by changing the messages that are sent to the brain about pain.

Your doctor will have explained why you are being given RAPIFEN.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Your doctor may prescribe this medicine for another use. Ask your doctor if you want more information.

RAPIFEN can be addictive, but when it is used only to relieve or prevent pain it is unlikely to become habit forming.

Before you are given RAPIFEN

When you must not use it

RAPIFEN should not be used for pain relief after surgery has taken place.

RAPIFEN should not be used if you have an allergy, intolerance or hypersensitivity to:

  • alfentanil
  • any ingredients listed at the end of this leaflet
  • other opioid analgesics (pain killers) e.g. morphine or pethidine.

Symptoms of an allergic or hypersensitivity reaction may include:

  • rash, itching or hives on the skin
  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body.

RAPIFEN is not generally given to children under 12 years of age.

RAPIFEN injection will only be used if the solution is clear, the package is undamaged and the use by (expiry) date marked on the pack has not passed.

Before you are given it

You must tell your doctor if you:

  • are pregnant or planning to become pregnant. Your doctor will decide if you can take RAPIFEN. It may affect your baby if it is given early in pregnancy or in the last weeks before your baby is due.
  • are breastfeeding or wish to breastfeed. RAPIFEN may be excreted in breast milk. Breast-feeding is not advisable for 24 hours after RAPIFEN has been given.
  • You or anyone in your family have ever abused or been dependent on alcohol, prescription medicines or illegal drugs (“addiction”).
  • You are a smoker.
  • You have ever had problems with your mood (depression, anxiety or a personality disorder) or have been treated by a psychiatrist for other mental illnesses.

This medicine contains alfentanil which is an opioid medicine. Repeated use of opioid painkillers may result in the drug being less effective (you become accustomed to it). It may also lead to dependence and abuse which may result in life-threatening overdose. If you have concern that you may become dependent on RAPIFEN, it is important that you consult your doctor.

Tell your doctor if you have any of the following medical conditions:

  • problems with your breathing such as severe asthma, severe bronchitis or emphysema
  • a history of fits or head injury
  • under-active thyroid
  • myasthenia gravis (muscle weakness)
  • heart problems
  • liver or kidney problems
  • are overweight or obese

Tell your doctor if you take any medicine that slows down your reactions (CNS depressants), especially benzodiazepines or related drugs or have problems with alcohol.

It may not be safe for you to be given RAPIFEN or you may be given a reduced dose if you have any of these conditions.

If you have not told your doctor about any of the above, tell them before you are given RAPIFEN.

Taking other medicines

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

Tell your doctor immediately and do not take RAPIFEN if you are taking:

  • medicines for depression called Monoamine Oxidase (MAO) Inhibitors. These medicines must not be taken in the 14 days before RAPIFEN is given.

Also tell your doctor if you are taking:

  • any anaesthetic agents such as propofol
  • any medicine that slows down your reactions (CNS depressants) such as benzodiazepines or related drugs, sleeping pills, tranquillizers, medicines for mental disorders, alcohol, some illegal drugs.
    If you receive a strong pain killer or other CNS depressant after receiving RAPIFEN during surgery, the dose of the painkiller or other CNS depressants may need to be lowered to reduce the risk of potentially serious side effects such as breathing difficulties, with slow or shallow breathing, severe drowsiness and decreased awareness, coma and death. The concomitant use of opioids and drugs used to treat epilepsy, nerve pain or anxiety (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression and may be life-threatening.
  • an antibiotic called erythromycin
  • an antifungal called fluconazole, voriconazole, ketoconazole or itraconazole
  • a medicine for the stomach called cimetidine
  • an antiviral called ritonavir
  • a heart medicine called diltiazem
  • medicines for depression known as selective serotonin re-uptake inhibitors (SSRIs) or serotonin norepinephrine re-uptake inhibitors (SNRIs)

RAPIFEN can increase the effects of alcohol. Tell your doctor about your consumption of alcohol and follow the doctor's advice.

If you have not told your doctor about any of these things, tell them before you are given RAPIFEN.

These medicines may be affected by RAPIFEN or may affect how well RAPIFEN works. Your doctor can tell you what to do if you are taking any of these medicines.

Addiction

You can become addicted to RAPIFEN even if you take it exactly as prescribed. RAPIFEN 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 RAPIFEN. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking RAPIFEN suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance

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

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.

RAPIFEN given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

Also, if women receive this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

How RAPIFEN is given

RAPIFEN will be given to you by injection by a specially trained anaesthetist.

The injection is given into the vein (intravenous use).

Your doctor will decide how much RAPIFEN you will need.

Elderly people may be given a smaller dose.

Overdose

The doctor or nurse giving you RAPIFEN will be experienced in its use, so it is extremely unlikely that you will be given too much.

In the unlikely event that an overdose occurs, your doctor or the anaesthetist will take the necessary actions. The symptoms of overdose could include:

  • Slow, unusual or difficult breathing
  • Drowsiness, dizziness or unconsciousness
  • Slow or weak heartbeat
  • Nausea or vomiting
  • Convulsions or fits
  • muscle stiffness
  • lowering of blood pressure
  • lowering of heart rate

If these symptoms occur, you may be administered another medicine (e.g. naloxone) to help reverse the effects.

If you think you or anybody else has been given too much RAPIFEN, contact your doctor or nurse immediately or phone the Poisons Information Centre (by calling 13 11 26).

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well after you have been given RAPIFEN. RAPIFEN helps most people suffering severe pain, but it may have unwanted side-effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

After you have been given RAPIFEN you will probably feel light-headed, dizzy, sleepy and you may feel quite strange, especially if you are not lying down.

Tell your doctor or nurse if you notice any of the following side effects and they worry you:

  • nausea and vomiting
  • dizziness
  • drowsiness or sleepiness
  • injection site pain or pain during the procedure

Tell your doctor or nurse as soon as possible if you have any of the following as you may need medical attention:

  • feeling of extreme happiness (euphoric mood)
  • visual disturbance such as blurred vision
  • chills
  • rash

Tell your doctor or nurse immediately if you experience:

  • breathing difficulties, which can last longer than its pain-killing effect.
  • slow, fast or irregular heartbeat.
  • tightening of the chest or heart attack
  • low or high blood pressure
  • muscle stiffness or involuntary muscle movements, including slow, stiff or jerking movements
  • spasm of the larynx (voice box)

RAPIFEN may affect your alertness and ability to drive. Therefore you should not drive or operate machinery until your doctor advised that you can.

Some people may get other side effects after being given RAPIFEN.

Tell your doctor or nurse if you notice anything else that is making you feel unwell.

Storage

RAPIFEN should be kept in a cool dry place, protected from light, where the temperature stays below 25 degrees C.

RAPIFEN will be kept in a locked cupboard in the hospital pharmacy or operating theatre.

RAPIFEN should not be used after the date (month and year) printed after "EXP". The anaesthetist will inspect RAPIFEN before use to determine that it is still within its use by date.

Disposal

The hospital staff looking after you will dispose of any remaining RAPIFEN appropriately.

Do not use this medicine after the expiry date.

Product description

RAPIFEN injection is a clear, colourless solution.

Ingredients

The active ingredient in RAPIFEN is alfentanil.

RAPIFEN contains 0.5 mg/mL of alfentanil, as the active ingredient

RAPIFEN also contains sodium chloride and water for injection.

RAPIFEN is available in two size glass ampoules: a 2 mL and a 10 mL ampoule.

A carton of RAPIFEN contains 5 ampoules.

5 x 2 mL and 5 x 10 mL

The 2 mL ampoule contains 1 mg of alfentanil.

The 10 mL ampoule contains 5 mg of alfentanil.

Sponsor

PIRAMAL CRITICAL CARE PTY LIMITED
Level 20, Tower A, The Zenith
821 Pacific Highway
Chatswood
NSW 2067
Australia
Tel: 1800413707

Australian Registration Numbers:

1 mg/2 mL ampoule AUSTR 50506

5 mg/10 mL ampoule AUSTR 50508

This leaflet was prepared in May 2023

®RAPIFEN is the registered trademark of PIRAMAL CRITICAL CARE PTY LIMITED for alfentanil hydrochloride injection

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Rapifen

Active ingredient

Alfentanil

Schedule

S8

 

1 Name of Medicine

Alfentanil hydrochloride.

2 Qualitative and Quantitative Composition

Each mL of Rapifen contains alfentanil hydrochloride equivalent to 0.5 mg alfentanil with 9.0 mg sodium chloride in water for injection to 1 mL.

3 Pharmaceutical Form

Rapifen solution for injection is a sterile, clear and colourless solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Rapifen is indicated for intravenous use by specialist anaesthetists and their trainees as:
an analgesic supplement given by incremental intravenous boluses or continuous infusion; and
an anaesthetic induction agent where in patients undergoing inpatient surgery, when endotracheal intubation and controlled ventilation are to be used.
Because of its rapid onset and short duration of action, intravenous Rapifen is particularly suited as a narcotic analgesic for short procedures and outpatients, provided that the patients are maintained under appropriate postoperative surveillance. However, intravenous Rapifen is also useful as an analgesic supplement for procedures of medium to long duration, since periods of very painful stimuli can be easily overcome by administration of small increments of Rapifen or by adapting the infusion rate.

4.2 Dose and Method of Administration

Rapifen should be administered intravenously (other routes of administration have not been evaluated). The dosage should be individualised taking into consideration factors such as age, bodyweight, physical status, underlying pathological condition (see Section 4.4 Special Warnings and Precautions for Use), use of other medicines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), type of anaesthesia to be used and type and duration of the surgical procedure. As a general principle, the lowest effective dose should be used.
To avoid bradycardia, a small I.V. dose of an anticholinergic (e.g. atropine) just before anesthetic induction may be administered.
Coadministration of droperidol or benzodiazepines may lengthen recovery from Rapifen, of importance in outpatients (a successful outpatient technique has consisted of an anticholinergic, a short acting induction hypnotic, Rapifen and nitrous oxide/ oxygen).
The initial dose of Rapifen should be appropriately reduced in the elderly (> 65 years of age) and in cirrhotic patients. The effect of the initial dose should be considered in determining supplemental doses. Monitoring of the patient should continue well after surgery in a recovery facility that conforms to the current guidelines of the Australian and New Zealand College of Anaesthetics.

Use as an analgesic supplement.

i. Spontaneous ventilation techniques.

Doses up to 7 microgram/kg, administered as a slow intravenous injection, may be used with increments of 2-3 microgram/kg at 10-15 minute intervals. At this dose with induction of anaesthesia, in particular with propofol (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), transient apnoea is frequent and the dosage may be adjusted downwards.

ii. Controlled ventilation techniques.

For attenuation of the hypertensive response to laryngoscopy, a dose prior to intubation of 20-50 microgram/kg is appropriate; such doses may have effect for up to 30-45 minutes.
For short procedures, an initial dose 7-15 microgram/kg at induction, with intermittent boluses up to 15 microgram/kg at 10-15 minute intervals are most useful.
For procedures of longer duration, a higher dose may be given at induction (see Table 1) and further increments titrated to effect.
When surgery is more prolonged or more traumatic, analgesia should be maintained by either increments of up to 15 microgram/kg (2 mL/70 kg) Rapifen when required (to avoid postoperative respiratory depression, no Rapifen should be administered during the last 10 minutes of surgery), or a Rapifen infusion at a rate of 0.5 to 1 microgram/kg/min (0.14 mL/70 kg/minute) until 5 to 10 minutes before the completion of surgery.
Continuous infusion is preferable for cases greater than 60 minutes duration.
Rapifen should not be given in the last 10 minutes prior to completion of surgery.
Periods of very painful stimuli can easily be overcome by small dose increments of Rapifen or by temporarily increasing the infusion rate. When Rapifen is used without nitrous oxide/ oxygen or another inhalation anaesthetic, a higher maintenance dose of Rapifen is required.
Rapifen may be administered as an infusion for more prolonged procedures with the following infusion solutions: 0.9% sodium chloride injection; 5.0% glucose injection; compound sodium lactate intravenous injection (Ringer lactate injection).

Warning.

The prepared infusion should commence as soon as possible after its preparation and in any case within 24 hours. Any storage of the prepared solution should be at 2-8°C.

Use as an induction agent.

An intravenous bolus dose of ≥ 120 microgram/kg (17 mL/70 kg) Rapifen will induce hypnosis and analgesia while maintaining good cardiovascular stability in patients with adequate muscle relaxation.
When postoperative nausea occurs it is of relatively short duration and easily controlled by conventional measures.

4.3 Contraindications

Rapifen is contraindicated in those with a known intolerance to the medicine, components of the formulation or to other opioid analgesics.
Contraindicated in postoperative analgesia.
Contraindicated for use in patients with severe respiratory disease, acute respiratory disease and respiratory depression.
Contraindicated for use in chronic (long-term) noncancer pain (CNCP).
Not for use by unapproved routes of administration.

4.4 Special Warnings and Precautions for Use

Alfentanil should be administered only by persons specifically trained in the use of intravenous and general anaesthetic agents and in the management of respiratory effects of potent opioids.
An opioid antagonist, resuscitative and intubation equipment, and oxygen should be readily available. Because of the possibility of delayed respiratory depression, monitoring of the patient must continue well after surgery in an approved recovery facility. (See Section 4.2 Dose and Method of Administration.)
Rapifen, also at doses below 20 microgram/kg, may cause skeletal muscular rigidity, particularly of the truncal muscles. The incidence and severity of muscular rigidity is usually dose related. Administration of Rapifen at anaesthetic induction dosages (above 120 microgram/kg) will consistently produce muscular rigidity with an immediate onset. The onset of muscular rigidity occurs earlier than with other opioids.

Hazardous and harmful use.

Rapifen contains the opioid alfentanil and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Rapifen 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 Rapifen.
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 Rapifen 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 Rapifen 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 existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma), and in patients with liver disease (see Use in hepatic impairment) and renal failure (see Use in renal impairment). 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, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.
As with other potent opioids, profound analgesia is accompanied by marked respiratory depression and loss of consciousness, which may persist or recur in the postoperative period. There is no reliable way of determining, a priori, which individuals are at risk. In the case of alfentanil, respiratory depression is dose related and usually of short duration, and can be reversed by specific opioid antagonists, but additional doses of the latter may be necessary because the respiratory depression may last longer than the duration of action of the opioid antagonist. Recovery room staff should be aware that marked respiratory depression has been reported as occurring after periods of up to several hours after the patient has been perceived to be alert, conversing coherently, and with normal respiration. The risk might be greater with patients on other depressant medicines, for example benzodiazepines and thiopental. As with other narcotic analgesics, patients who have received Rapifen should remain under appropriate surveillance. Vital signs should be monitored continuously. This should occur during, and must continue well after recovery (for at least two hours). Resuscitation equipment and a specific opioid antagonist, such as naloxone, should be readily available to manage apnoea. Naloxone administration may need to be repeated. Hyperventilation during anaesthesia may alter the patient's response to carbon dioxide, thus affecting respiration postoperatively.
Opioids should be titrated with caution in patients with pulmonary disease, decreased respiratory reserve, alcoholism and impaired hepatic and renal function. Such patients also require prolonged postoperative monitoring.

Risk 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 Rapifen 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 Rapifen 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 Rapifen.

Tolerance and opioid use disorder (abuse and dependence).

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance, physical dependence and opioid use disorder (OUD). Abuse or intentional misuse of opioids may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders). 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 Rapifen 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; see Section 4.2 Dose and Method of Administration).

Neonatal withdrawal syndrome.

There is a risk that newborn infants will experience neonatal withdrawal syndrome following prolonged use of opioids during pregnancy (also see Paediatric use below; see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Rapifen, especially by children, can result in a fatal overdose of alfentanil. Patients and their caregivers should be given information on safe storage and disposal of unused Rapifen (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 and opioid use disorder (abuse and dependence)). 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 and opioid use disorder (abuse and dependence)). 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.

Muscular rigidity.

Rapifen may induce muscle rigidity during induction, including thoracic muscular rigidity. Rigidity may be avoided by the following measures:
a) slow intravenous injection, especially when higher doses are indicated;
b) premedication with benzodiazepines;
c) administration of muscle relaxants prior to Rapifen administration.
Nonepileptic (myo)clonic movements can occur.

Cardiovascular effects.

When insufficient anticholinergic is administered, or when Rapifen is administered in combination with nonvagolytic muscle relaxants and induction agents, bradycardia, hypotension and sometimes cardiac arrest may occur.

Instructions for use and handling.

Wear gloves while opening ampoule.
Accidental dermal exposure should be treated by rinsing the affected area with water. Avoid usage of soap, alcohol, and other cleaning materials that may cause chemical or physical abrasions to the skin.

Special dosing conditions.

As with other opioids, Rapifen may induce hypotension, especially in hypovolaemic patients. Appropriate measures should be taken to maintain a stable arterial pressure.
The use of rapid bolus injections of opioids should be avoided in patients with compromised intracerebral compliance; in such patients the transient decrease in the mean arterial pressure has occasionally been accompanied by a short-lasting reduction of the cerebral perfusion pressure.
It is recommended to reduce the dosage in the elderly and in debilitated patients. As with other opioids, Rapifen should be titrated with caution in patients with any of the following conditions: uncontrolled hypothyroidism; pulmonary disease; decreased respiratory reserve; alcoholism; impaired hepatic or renal function. Such patients also require prolonged postoperative monitoring.

Head injury.

Rapifen may obscure the clinical course of patients with head injuries.

Use in hypothyroidism.

It is recommended that the dose of Rapifen is reduced in those patients with hypothyroidism, because of reduced clearance. The dosage should be titrated individually and adjusted according to the clinical response.

Use in obese patients.

It is recommended that the dosage of Rapifen is reduced in obese patients because of reduced clearance. The dosage should be titrated individually and adjusted according to the clinical response.

Use in hepatic impairment.

It is recommended that the dose of Rapifen is reduced in those patients with chronic liver disease, because of decreased plasma protein concentrations and reduced clearance possibly resulting in more prolonged and pronounced clinical effects. Because of the variable pharmacokinetics and pharmacodynamics, the dosage should be titrated individually and adjusted on the basis of the clinical response.

Use in renal impairment.

Due to an increased plasma free fraction of alfentanil in patients with renal failure, the clinical effects of Rapifen may be prolonged and more pronounced. Therefore, the dose of Rapifen should be titrated with caution in these patients.

Use in the elderly.

It is recommended that the dose of Rapifen is reduced in the elderly, because of reduced clearance. A dosage reduced by about a third has been effective, but in general, the dosage should be individualised, and based on the clinical response.

Paediatric use.

Adequate data to support the use of alfentanil in children under 12 years of age are presently not available. Infants and neonates exposed to opioids directly may experience withdrawal symptoms, particularly following abrupt cessation or following prolonged use.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Anaesthetic agents.

As with other opioids, the respiratory depressant and cardiovascular depressant effects of Rapifen may be potentiated by halogenated inhalation agents, and particularly propofol. Propofol also appears to alter the disposition of Rapifen pharmacokinetics, resulting in elevated plasma levels of alfentanil.

Central nervous system (CNS) depressants.

Rapifen may potentiate the respiratory and cardiovascular depressant effects of medicines such as barbiturates, benzodiazepines, phenothiazine derivatives, other nonselective hypnotics. Medicines such other opioid analgesics, barbiturates, benzodiazepines or related drugs, antihistamines, antipsychotics, neuroleptics, tricyclic antidepressants, centrally-active antiemetics, gabapentinoids, general anaesthetics, cannabis and other nonselective CNS depressants (e.g. alcohol) may potentiate the respiratory depression of narcotics. When patients have received such medicines, the dose of Rapifen required will be less than usual (see Section 4.4 Special Warnings and Precautions for Use).
Likewise, following the administration of Rapifen, the dose of other CNS-depressant medicines should be reduced. This is particularly important after surgery, because profound analgesia is accompanied by marked respiratory depression, which can persist or recur in the postoperative period. Administration of a CNS depressant, such as a benzodiazepine or related drugs, during this period may disproportionally increase the risk of respiratory depression (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant use with Rapifen in spontaneously breathing patients may increase the risk of respiratory depression, profound sedation, coma and death (see Section 4.4 Special Warnings and Precautions for Use). The concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression and death.

Cytochrome P450 3A4 (CYP3A4) inhibitors.

Alfentanil is metabolised mainly via the human cytochrome P450 3A4 enzyme. Available human pharmacokinetic data indicate that the metabolism of alfentanil may be inhibited by fluconazole, voriconazole, erythromycin, diltiazem and cimetidine (known cytochrome P450 3A4 enzyme inhibitors). In vitro data suggest that other potent cytochrome P450 3A4 enzyme inhibitors (e.g. ketoconazole, itraconazole, ritonavir) may also inhibit the metabolism of alfentanil. This could increase the risk of prolonged or delayed respiratory depression. The concomitant use of such medicines requires special patient care and observation; in particular, it may be necessary to lower the dose of Rapifen.

Monoamine oxidase inhibitors (MAOI).

Monoamine oxidase inhibitors have been reported to potentiate the effects of opioid analgesics, the use of Rapifen in patients who have received irreversible MAO inhibitors within two weeks should be avoided.

Serotonergic drugs.

Co-administration of alfentanil with a serotonergic agent, such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), or Monoamine Oxidase Inhibitors (MAOIs), may increase the risk of serotonin syndrome, a potentially life-threatening condition.

Effect of alfentanil on the metabolism of other medicines.

In combination with Rapifen, the blood concentrations of propofol are 17% higher than in the absence of Rapifen. The concomitant use of Rapifen and propofol may require a lower dose of Rapifen.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
A concern with narcotic analgesics in pregnancy is with their use during labour when they may cause respiratory depression in the newborn infant. These products should only be used during labour after weighing the needs of the mother against the risk to the foetus. I.V. administration during childbirth (including caesarean section) is not recommended, because Rapifen crosses the placenta and may suppress spontaneous respiration in the newborn period. If Rapifen is administered nevertheless, assisted ventilation equipment must be immediately available for use if required for the mother and infant. An opioid antagonist for the child must always be available. The half-life of the opioid antagonist may be shorter than the half-life of alfentanil, therefore, repeated administration of the opioid antagonist may be necessary. Respiratory depression and hypotension are basic pharmacological actions of alfentanil. Careful monitoring by trained personnel is routinely required.
Rapifen has been shown to have an embryocidal effect on rats and rabbits when given in doses of 1.25 mg/kg for a period of 10 days to over 30 days. These effects may have been due to maternal toxicity following prolonged administration of the medicine. No teratogenic effect has been observed after the administration of Rapifen to rats and rabbits at doses up to 1.25 mg/kg IV. It should be noted, however, that alfentanil crosses the placenta and may suppress spontaneous respiration in the newborn period.
The foetal respiratory centre is known to be more sensitive to opiates.
Withdrawal symptoms in newborn infants have been reported with prolonged use of opioids.
Prolonged use of an opioid during pregnancy may cause drug dependence in the neonate, leading to neonatal withdrawal syndrome. Consequently, it is necessary to consider potential risks and potential advantages before administering alfentanil to pregnant patients. Prolonged use of opioids in pregnant woman should only be considered if the benefits outweigh the risks associated with use. Prior to commencement of the treatment, patients should be advised of the risk of neonatal opioid withdrawal syndrome.
 Rapifen may be excreted in human milk. Therefore, breastfeeding or use of expressed breast milk is not recommended during the 24 hours following its administration.

4.7 Effects on Ability to Drive and Use Machines

Driving and the operation of machines can only be resumed when sufficient time has elapsed following the administration of Rapifen. Individual reactions vary greatly. It is recommended that patients not drive or use machines for at least 24 hours after administration of Rapifen.

4.8 Adverse Effects (Undesirable Effects)

The adverse reactions are those associated with the intravenous opioids, e.g. respiratory depression, apnoea, muscular rigidity (which may also involve the thoracic muscles), myoclonic movements, bradycardia, (transient) hypotension, nausea, vomiting and dizziness.
Other less frequently reported adverse reactions are:
Laryngospasm.
Allergic reactions (such as anaphylaxis, bronchospasm, urticaria) and asystole have been reported; since several medicines were coadministered during anaesthesia, it is uncertain whether there is a causal relationship to alfentanil.
Recurrence of respiratory depression after the operation has been observed in rare instances.
Also see Section 4.4 Special Warnings and Precautions for Use.
Although it is unlikely, alfentanil could cause opioid dependence and has a potential for being abused.

Clinical trial data.

The safety of Rapifen was evaluated in 1157 subjects who participated in 18 clinical trials. Rapifen was administered as an anaesthetic induction agent or as an analgesic/ anaesthesia adjuvant to regional and general anaesthesia, in short, medium, and long surgical procedures. These subjects took at least one dose of Rapifen and provided safety data. Adverse drug reactions (ADRs) that were reported for ≥ 1% of Rapifen treated subjects in these trials are shown in Table 2.
Additional ADRs that occurred in < 1% of Rapifen treated subjects in the 18 clinical trials are listed in Table 3.

Postmarketing data.

Adverse drug reactions first identified during postmarketing experience with Rapifen are included in Table 4. The frequencies are provided according to the following convention: very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1,000 and < 1/100; rare ≥ 1/10,000, < 1/1,000; very rare < 1/10,000, including isolated reports.

Reporting suspected adverse effects.

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

The manifestations of Rapifen overdose are an extension of its pharmacological actions. Depending on the individual sensitivity, the clinical picture will be determined primarily by respiratory depression, varying from bradypnoea to apnoea.
In the presence of hypoventilation or apnoea, oxygen should be administered and respiration should be assisted or controlled as indicated.
If depressed respiration is associated with muscular rigidity, an intravenous neuromuscular blocking agent might be required to facilitate assisted or controlled respiration. The patient should be carefully observed; body warmth and adequate fluid intake should be maintained. If hypotension is severe or if it persists, the possibility of hypovolaemia should be considered and controlled with appropriate parenteral fluid administration.
A specific narcotic antagonist, naloxone, should be available for use as indicated to control respiratory depression. This does not preclude the use of more immediate countermeasures. The respiratory depression may last longer than the effect of the antagonist; additional doses of the latter may therefore be required.
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.

Alfentanil is a potent, short acting opioid analgesic chemically related to fentanyl.
The onset of action of alfentanil is more rapid than that of an equianalgesic dose of fentanyl, and the maximal analgesic and respiratory depressant effect occurs within 1 to 2 minutes. The time to onset of analgesia was 55.7 (range 15-120) seconds for alfentanil, compared to 103.8 (range 30-120) seconds for fentanyl. Depth of analgesia can be adjusted to the pain level of the surgical procedure.
The duration of action of alfentanil is shorter than that of an equianalgesic dose of fentanyl, and is dose related. Durations of action for short, medium and long procedures are discussed under Section 4.2 Dose and Method of Administration. For analgesia lasting longer than 60 minutes, an infusion is preferable.
The duration of the analgesic effect may be shorter than that of the respiratory depression in some patients. The duration and degree of apnoea, respiratory depression and increased airway resistance usually increase with dose but have also been observed at lower doses (see Section 4.4 Special Warnings and Precautions for Use). The time course of respiratory depression is not related to the pharmacokinetics described below.
At higher doses (> 120 microgram/kg) alfentanil can be used as an anaesthetic induction agent. Induction is smooth, pain free and devoid of cardiovascular and hormonal stress response to intubation.
At induction, alfentanil may produce increased muscular tone, including thoracic muscular rigidity and limb movements. These and other typical signs and symptoms of narcotic analgesics, such as euphoria, miosis and bradycardia, may also be observed if alfentanil is given too rapidly or at too high a dosage.
All actions of alfentanil are rapidly and completely reversed by a specific narcotic antagonist, such as naloxone. A single dose of one of these agents may not be sufficient in prolonged respiratory depression. Repeat doses may be needed.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Alfentanil is a synthetic opioid with mu-opioid receptor agonist activity.
After intravenous administration of Rapifen, maximal analgesia, at the recommended dose, occurs after one minute. The low degree of ionisation (11% at pH 7.4) contributes significantly to a rapid distribution. The total volume of distribution varies from 0.4 to 1.0 L/kg, which is approximately one quarter to one tenth that of fentanyl, indicating a limited distribution to the tissues. The small volume of distribution is also attributable to the limited liposolubility and strong plasma protein binding of the drug, mainly to alpha1-acid glycoprotein.
Alfentanil is metabolised mainly by the liver with only 1% of the active substance found unaltered in the urine. It is metabolised by N and O-dealkylation. 70-80% of the metabolites are eliminated in the urine. The plasma clearance averages 356 mL/min. Clearance is decreased in obese patients. As with fentanyl, "secondary peaks" in plasma concentrations have been reported.
The sequential distribution half-lives are 1 and 14 minutes. Alfentanil elimination is rapid: the terminal elimination half-life is 90-111 minutes (range 50-150 minutes), which is significantly faster than for fentanyl.
During average to long lasting surgical procedures, analgesia can be maintained by repeated injection of Rapifen or by a continuous infusion, subsequent to a bolus dose. Repeated or prolonged administration of Rapifen produces increased plasma concentrations and accumulation of the drug.
Once steady-state has been reached after infusion, the elimination half-life remains unaltered, providing there has been no drug interaction with drugs such as erythromycin, and hepatic function is not unexpectedly impaired.
Patient recovery (i.e. return to consciousness) generally occurs rapidly on discontinuation of Rapifen.
Table 5 summarising pharmacokinetic parameters for alfentanil and fentanyl is shown.

Special populations.

Hepatic impairment.

After administration of a single intravenous dose of 50 microgram/kg, the terminal half-life in cirrhotic patients is significantly longer than in controls. The volume of distribution remains unchanged. The free fraction of alfentanil increases in cirrhotic patients to 18.5% compared with 11.5% in controls. This increase in free fraction together with a reduction in clearance from 3.06 mL/min/kg in controls to 1.60 mL/min/kg in cirrhotic patients will result in a more prolonged and pronounced effect (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

The volume of distribution and clearance of the free fraction is similar in renal failure patients and healthy controls. The free fraction of alfentanil in patients with renal failure is increased to 12.4 to 19% compared with 10.3 to 11% in controls. This may result in an increase in clinical effect of alfentanil (see Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenicity studies showed no evidence of mutagenic activity (Ames Salmonella assay) and chromosomal damage (micronucleus and dominant lethal tests).

Carcinogenicity.

No long-term animal studies of Rapifen have been performed to evaluate carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, water for injection.

6.2 Incompatibilities

See Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

5 years.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light. Ampoules should be removed only for immediate use.

6.5 Nature and Contents of Container

1 mg alfentanil in 2 mL glass ampoules in cartons of 5 ampoules. AUST R 50506.
5 mg alfentanil in 10 mL glass ampoules in cartons of 5 ampoules. AUST R 50508.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

71195-58-9.

7 Medicine Schedule (Poisons Standard)

Schedule 8 - Controlled Drug.

Summary Table of Changes