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Drug Details

RAPIFEN

• Drug Class Description
  Narcotic analgesics.
• Generic Name
  Alfentanil
• Presentation
  Aqueous injection.
• Description
  Each ml of Rapifen contains alfentanil hydrochloride 544 micrograms, equivalent to 500 micrograms alfentanil base.
• Indications
  

  As an analgesic supplement for use before and during anaesthesia. It is indicated for:

  1. Short procedures and outpatient surgery.

  2. Procedures of medium and long duration when given as a bolus followed by supplemental doses or by continuous infusion. At very high doses, Rapifen may be used as an anaesthetic induction agent in ventilated patients.

• Adult Dosage
  

  For intravenous administration.

  Rapifen by the intravenous route can be administered to both adults and children. The dosage of Rapifen should be individualised according to age, bodyweight, physical status, underlying pathological condition, use of other drugs and type of surgery and anaesthesia. The usual recommended dosage regimen is as follows:

  Adults	Initial	Supplemental
  Spontaneous respiration	500 µg (1 ml)	250 µg (0.5 ml)
  Assisted ventilation	30-50 µg/kg	15 µg/kg
  Children	Initial	Supplemental
  Assisted ventilation	30-50 µg/kg	15 µg/kg

  If desired, Rapifen can be mixed with sodium chloride injection BP, dextrose injection BP or compound sodium lactate injection BP (Hartmann's solution). Such dilutions are compatible with plastic bags and giving sets. These dilutions should be used within 24 hours of preparation.

  Children may require higher or more frequent dosing owing to a shorter half-life of Rapifen in this age group. The elderly and debilitated may require lower or less frequent dosing owing to a longer half-life of Rapifen in this age group (dilution may be helpful).

  In spontaneously breathing patients, the initial bolus dose should be given slowly over about 30 seconds (dilution may be helpful).

  After intravenous administration in unpremedicated adult patients, 1 ml Rapifen may be expected to have a peak effect in 90 seconds and to provide analgesia for 5-10 minutes. Periods of more painful stimuli may be overcome by the use of small increments of Rapifen. For procedures of longer duration, additional increments will be required.

  In ventilated patients, the last dose of alfentanil should not be given later than about 10 minutes before the end of surgery to avoid the continuation of respiratory depression after surgery is complete.

  In ventilated patients undergoing longer procedures, Rapifen may be infused at a rate of 0.5-1 microgram/kg/minute. Adequate plasma concentrations of alfentanil will only be achieved rapidly if this infusion is preceded by a loading dose of 50-100 microgram/kg given as a bolus or fast infusion over 10 minutes.

  Lower doses may be adequate, for example, in geriatric patients or where anaesthesia is being supplemented by other agents.

  The infusion should be discontinued up to 30 minutes before the anticipated end of surgery.

  Increasing the infusion rate may prolong recovery. Supplementation of the anaesthetic, if required, for periods of painful stimuli, is best managed by extra bolus doses of Rapifen (1-2 ml) or low concentrations of a volatile agent for brief periods.

  Patients with severe burns presenting for dressing, etc, have received a loading dose of 18-28 µg/kg/min for up to 30 minutes without requiring mechanical ventilation. In heart surgery, when used as a sole anaesthetic, doses in the range of 12-50 mg/hour have been used.

• Contra Indications
  

  Obstructive airways disease or respiratory depression if not ventilating.

  Concurrent administration with monoamine oxidase inhibitors or within 2 weeks of their discontinuation.

  Administration in labour or before clamping of the cord during caesarean section due to the possibility of respiratory depression in the newborn infant.

  Patients with a known intolerance to alfentanil and other morphinomimetics.

• Special Precautions
  

  Warnings:

  Following administration of Rapifen, a fall in blood pressure may occur. The magnitude of this effect may be exaggerated in the hypovolaemic patient or in the presence of concomitant sedative medication. Appropriate measures to maintain a stable arterial pressure should be taken.

  Significant respiratory depression and loss of consciousness will occur following administration of Rapifen in doses in excess of 1 mg and is dose-related. This and the other pharmacological effects of Rapifen are usually of short duration and can be reversed by the specific opioid antagonists (e.g. naloxone). Additional doses of the antagonists may be necessary because the respiratory depression may last longer than the duration of action of the opioid antagonist.

  Like other opioids, alfentanil may cause bradycardia, an effect that may be marked and rapid in onset but which can be antagonised by atropine. Particular care must be taken following treatment with drugs which may depress the heart or increase vagal tone, such as anaesthetic agents or beta-blockers, since they may predispose to bradycardia or hypotension. Heart rate and blood pressure should therefore be monitored carefully. If hypotension or bradycardia occur, appropriate measures should be instituted.

  Cardiac arrest following bradycardia has been reported on very rare occasions in non-atropinised patients. Therefore it is advisable to be prepared to administer an anticholinergic drug.

  Precautions:

  It is wise to reduce the dosage in the elderly and debilitated patients. In hypothyroidism, pulmonary disease, decreased respiratory reserve, alcoholism and liver or renal impairment the dosage should be titrated with care and prolonged monitoring may be required.

  Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses.

  Rapifen may induce muscle rigidity during induction. Rigidity, which may also involve the thoracic muscles, can be avoided by the following measures:

  • Slow IV injection (usually sufficient for lower doses);

  • Premedication with a benzodiazepine;

  • Administration of a muscle relaxant just prior to administration of Rapifen.

  • Non-epileptic (myo)clonic movements can occur.

  As with all potent opioids, profound analgesia is accompanied by marked respiratory depression, which may persist into or recur in the early postoperative period. Care should be taken after infusions or large doses of alfentanil to ensure that adequate spontaneous breathing has been established and maintained in the absence of stimulation before discharging the patient from the recovery area. Resuscitation equipment and narcotic antagonists should be readily available. Hyperventilation during anaesthesia may alter the patient's response to CO₂, thus affecting respiration postoperatively.

  The use of rapid bolus injections of opioids should be avoided in patients with compromised intracerebral compliance; in such patients a transient decrease in the mean arterial pressure has occasionally been accompanied by a transient reduction of the cerebral perfusion pressure.

  This medicinal product contains less than 1 mmol sodium (23 mg) per 5 mg dose, i.e. essentially 'sodium-free'.

• Interactions
  

  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, 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 drugs requires special patient care and observation; in particular, it may be necessary to lower the dose of Rapifen.

  Treatment with drugs which may depress the heart or increase vagal tone, such as beta-blockers and anaesthetic agents, may predispose to bradycardia or hypotension. Bradycardia and possibly asystole can occur when Rapifen is combined with non-vagolytic muscle relaxants.

  The use of opioid premedication, barbiturates, benzodiazepines, neuroleptics, halogenic gases and other non-selective CNS depressants may enhance or prolong the respiratory depressant effects of alfentanil.

  If other narcotic or CNS depressant drugs are used concurrently with alfentanil, the effects of the drugs can be expected to be additive. When patients have received such drugs the dose of alfentanil required will be less than usual. Likewise, following the administration of alfentanil, the dose of other CNS depressant drugs should be reduced.

• Adverse Drug Reactions
  

  Adverse Drug Reactions

  The most frequently reported ADRs (incidence 10%) are: nausea and vomiting. Undesirable effects listed below in Table 1 have been reported in a clinical trial and/or from spontaneous reports from post-marketing experience. The following terms and frequencies are applied: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1000 to < 1/100), rare ( 1/10,000 to < 1/1000), very rare ( < 1/10,000), and not known (frequency cannot be estimated from the available data). Adverse drug reactions from spontaneous reports during worldwide postmarketing experience with Alfentanil that met threshold criteria are included. Unlike for clinical trials, precise frequencies cannot be provided for spontaneous reports. The frequency for these reports is therefore classified as 'not known'.

  Table 1 Adverse drug reactions reported in clinical trials and/or postmarketing
  Body System/Organ Class Frequency Category	Clinical trials	Spontaneous Reportsa
  Immune system disorders
  Uncommon	Allergic reactions (such as anaphylaxis, bronchospasm, urticaria)
  Psychiatric Disorders
  Common	Somnolence
  Uncommon	Disorientation, Agitation, Euphoria
  Nervous system disorders
  Common	Muscle rigidity (may also involve thoracic muscles), Myoclonic movements, Dizziness
  Uncommon	Headache
  Not known		Loss of consciousness (Postoperative period), Convulsion
  Eye disorders
  Uncommon	Blurred/double vision
  Not known		Miosis
  Cardiac disorders
  Common	Bradycardia, Tachycardia
  Uncommon	Arrhythmia
  Not known		Cardiac arrest
  Vascular Disorders
  Common	Hypotension, Hypertension
  Respiratory, thoracic, and mediastinal disorders
  Common	Apnoea, Respiratory depression
  Uncommon	Cough, Recurrence of respiratory depression, Laryngospasm, Hiccup
  Not known		Respiratory arrest (including fatal outcome)
  Gastrointestinal disorders
  Very common	Nausea, Vomiting
  Skin and subcutaneous tissue disorders
  Unommon	Pruritis, Sweating
  General disorders and administration site conditions
  Uncommon	Injection site pain, Shivering
  Not known		Pyrexia
  a: Listed are only those adverse drug reactions that were not identified in clinical trials