RAPIFEN® 2 mL IV injection; RAPIFEN® 10 mL IV injection

INDICATIONS CONTRA-INDICATIONS DOSAGE SIDE-EFFECTS PREGNANCY OVERDOSE IDENTIFICATION PATIENT INFORMATION

RAPIFEN® 2 mL IV injection
RAPIFEN® 10 mL IV injection

SCHEDULING STATUS
Schedule 7.

PROPRIETARY NAME
(and dosage form)

RAPIFEN^® 2 mL IV injection
RAPIFEN^® 10 mL IV injection

COMPOSITION
Each mL contains alfentanil hydrochloride 0,544 mg (equivalent to alfentanil base 0,50 mg) and sodium chloride 9,0 mg in water for injection.

PHARMACOLOGICAL CLASSIFICATION
A.2.7 Central nervous system depressants. Narcotic analgesics.

PHARMACOLOGICAL ACTION
Pharmacodynamics
RAPIFEN* injection is a narcotic analgesic with a pharmacologic profile similar to that of fentanyl. It differs from fentanyl, however, in that its analgesic potency is four times less than that of fentanyl.
Its depressant effects on the respiratory rate and alveolar ventilation are also shorter than those of fentanyl and in most cases the clinical analgesic effect lasts longer than significant respiratory depression. The onset of action of RAPIFEN* is four times more rapid than that of an equi-analgesic dose of fentanyl; the peak analgesic and respiratory depressant effects occur within 1 minute. The duration of action of RAPIFEN* is three times shorter than that of an equi-analgesic dose of fentanyl but is clearly dose-related.
The onset of the analgesic action of RAPIFEN* is rapid, the peak effect being reached within 1 minute. The duration of action is short, 11 minutes at twice and 17 minutes at four times the lowest ED₅₀.
At high doses (> 120 µg/kg), RAPIFEN* induces sleep and can be used as an anaesthetic induction agent. The induction is smooth, pain-free and devoid of cardiovascular and hormonal stress responses to intubation.
Recovery after RAPIFEN* administration is rapid and smooth. All actions of RAPIFEN* are immediately and completely reversed by the specific narcotic antagonist naloxone hydrochloride.
RAPIFEN* maintains cardiovascular stability. RAPIFEN* has not been shown to cause histamine release (in doses used clinically).
Pharmacokinetics
RAPIFEN* has a low degree of ionisation (11% at pH = 7,4) which significantly contributes to a rapid distribution. Tissue distribution is limited : the total distribution volume varies from 0,4 to 1,0 L/kg. RAPIFEN*'s limited liposolubility and strong plasma protein binding (92%) contribute to its limited volume of distribution.
RAPIFEN* is metabolised mainly in the liver. Only 1% of the active substance is found unaltered in the urine. The plasma clearance averages 356 mL/minute. The metabolites are inactive and 70-80% of them are eliminated in the urine.
Elimination is very rapid; the sequential distribution half-lives are 1 and 14 minutes and the terminal half-life is 90-111 minutes (range 50-150 minutes). Accumulation of alfentanil may occur under the following circumstances: With prolonged continuous infusion or with repeated administration of single doses and in patients with reduced plasma clearance e.g. patients with compromised liver function and patients over the age of 65 years.
During average length to long-lasting surgery, analgesia can be maintained by repeating RAPIFEN* injections or by continuous infusion, subsequent to a bolus dose. Once steady-state has been reached after infusion, the elimination half-life remains unaltered.

INDICATIONS
RAPIFEN* is indicated for use as a narcotic analgesic in general anaesthesia for both short (bolus injections) and long (bolus, supplemented by increments or by infusion) surgical procedures. It may also be used as an anaesthetic induction agent.

CONTRA-INDICATIONS
RAPIFEN* is contra-indicated in patients with a known intolerance to the medicine or to morphinomimetics in general.
As is the case with any narcotic analgesic, it should not be used in patients who may be particularly susceptible to respiratory depression such as comatose patients who may have head injury or brain tumour.
Patients with a history of myasthenia gravis and myopathies.

WARNINGS
Alfentanil may cause bradycardia, an effect that may be marked and rapid in onset, but that can be antagonized by atropine. Bradycardia may be more pronounced when alfentanil is combined with other anaesthetic agents which depress the heart rate or increase vagal activity. Heart rate should therefore be monitored carefully.
As asystole has been reported on occasions in non-atropinised patients, it is advisable to be prepared to administer an anticholinergic drug if the heart rate is considered low.
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 cerebral perfusion pressure.

Use in pregnancy and lactation:
The safe use of RAPIFEN* in pregnancy has not been established.
Administration (IM or IV) during childbirth (including caesarian section) is not recommended, because RAPIFEN* crosses the placenta and because the fetal respiratory centre is more sensitive to opiates. Nevertheless, if RAPIFEN* is administered, an antidote for the child should always be at hand.
RAPIFEN* may enter the maternal milk. Therefore nursing is not recommended during 24 hours following the administration of RAPIFEN*.

DOSAGE AND DIRECTIONS FOR USE

WARNING: Must only be administered when adequate facilities for the use of ventilators and muscle relaxants are close at hand.

The dosage should be individualized. Some of the factors to be considered in determining the dose are age, body mass, physical status, underlying pathological condition, use of other medicines, type of anaesthesia to be used and type and duration of the surgical procedure.
The initial dose should be reduced in the elderly and debilitated patients. In children it should be increased. The effect of the initial dose should be taken into account in determining supplemental doses.
To avoid bradycardia, it is recommended to administer a small intravenous dose of an anticholinergic just before induction. Droperidol may be given to prevent nausea and vomiting.

(a).	For short procedures and use in outpatients: RAPIFEN* in small doses is useful for minor, short but painful surgical procedures and for outpatients, provided good monitoring equipment is available in the operating room. A bolus dose of 7-15 µg/kg given intravenously should be adequate for procedures lasting less than 10 minutes. If this dose is injected slowly, respiration may be maintained at a decreased level. Should the duration of the procedure exceed 10 minutes, further increments of 7-15 µg/kg should be given every 10-15 minutes or as required. Outpatients: An anticholinergic, a short-acting induction agent (eg. RAPIFEN*) and N₂0/O₂ are recommended. Should post-operative nausea occur it is mostly of short duration and easily controlled by conventional measures. The use of droperidol or benzodiazepines is not recommended in outpatients as these drugs may lengthen the recovery period.
(b).	For procedures of medium duration:
	WARNING: Respiration will be depressed and ventilation will be required.
	The dose of the initial intravenous bolus should be adapted to the expected duration of the surgical procedure as follows:
Duration of the procedure (minutes)		RAPIFEN* (0,5 mg/mL) IV bolus dose
		(µg/kg)	mL per 70 kg
10-30		20-40	3-6
30-60		40-80	6-12
>60		80-150	12-20

When surgery is more prolonged or aggressive, analgesia should be maintained by:

–	increments of 15 µg/kg of RAPIFEN* when required (to avoid post-operative respiratory depression, the last dose of RAPIFEN* should not be administered within the last 10 minutes of surgery).

–	RAPIFEN* infusion at a rate of 1 µg/kg/min (0,14 mL of RAPIFEN* 0,5 mg/mL per 70 kg/min) until 5-10 minutes before the end of surgery. Periods of very painful stimuli can easily be overcome by small increments of RAPIFEN* or by temporarily increasing the infusion rate. When using RAPIFEN* without N₂O/O₂ or other inhalational anaesthetic agents, the maintenance dose of RAPIFEN* should be increased.
(c).	For long procedures:
	WARNING: Respiration will be depressed and ventilation will be required.
	RAPIFEN* may be used as the analgesic component of anaesthesia for surgical procedures of long duration especially when rapid extubation is indicated. Optimum analgesia and a stable autonomic condition are maintained by means of an individually adapted initial intravenous dose and by varying the infusion rate according to the surgical stimuli and the clinical reactions of the patient.
(d).	Induction:
	WARNING: Respiration will be depressed and ventilation will be required.
	An intravenous bolus dose of > 120 µg/kg (17 mL of RAPIFEN* 0,5 mg/mL per 70 kg) RAPIFEN* will induce hypnosis and analgesia while maintaining good cardiovascular stability in patients with adequate muscle relaxation.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Adverse reactions:

The most common adverse reaction that may occur with RAPIFEN* is respiratory depression. This reaction is more likely when the intravenous dosage is given too rapidly. Should respiratory depression occur during anaesthesia, assisted or controlled respiration will provide adequate ventilation without reversing analgesia.

Respiratory depression and analgesia which may persist into or recur in the post-operative period, can be immediately and completely reversed by the specific narcotic antagonist, naloxone hydrochloride.
Because the duration of respiratory depression may exceed the duration of action of the antagonist, the patient should be monitored closely and repeated treatment with the antagonist may be indicated.

RAPIFEN* may induce myoclonic movements and muscle rigidity, particularly of the chest wall during induction. Rigidity may be avoided by the following measures:
–        Slow intravenous injection: this should be adequate for lower doses of RAPIFEN*.
–        Benzodiazepine premedication: should reduce muscle rigidity.
–        Muscle relaxants, at full paralysing dose, administered just prior to RAPIFEN* should completely eliminate muscle rigidity.

Other adverse reactions reported to occur with RAPIFEN* are apnoea, (transient) hypotension, bradycardia, euphoria, miosis, dizziness, post-operative nausea and vomiting and less frequently laryngospasm, allergic reactions (such as anaphylaxis, bronchospasm and urticaria), asystole and arrhythmias.
Nausea and vomiting can be controlled with anti-emetics.

Precautions:
Patients who have received RAPIFEN* should remain under appropriate surveillance.

Resuscitation equipment and a narcotic antagonist should be available to manage apnoea. The duration of respiratory depression is dose-related, but short and is immediately reversed by the specific narcotic antagonist, naloxone hydrochloride.

Because of its weak cholinergic activity, RAPIFEN* should be used with caution in patients with cardiac arrhythmias.
Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses.
Hyperventilation during anaesthesia may alter the patient's response to CO₂, thus affecting respiration postoperatively.
Opioids may induce hypotension, especially in hypovolaemic patients. Appropriate measures to maintain a stable arterial pressure should be taken.
It is recommended to reduce the dosage in the elderly or debilitated patients. Opioids 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.

Effects on driving ability and use of machinery:
Car driving and the operation of machinery can only be resumed when sufficient time has elapsed after administration of RAPIFEN*. Individual reactions vary greatly. On average, the patient should wait 3 to 6 hours after doses of 1 to 3 mL and 12 to 24 hours after higher doses and infusions.

Interactions:
Since MAO inhibitors have been reported to potentiate narcotic analgesics, the use of RAPIFEN* in patients who have received MAO inhibitors within 2 weeks should be avoided.
However, several reports describe the uneventful use of fentanyl (a related opioid) during surgical or anaesthetic procedures in patients on MAO-inhibitors.
When insufficient anticholinergic is administered or when RAPIFEN* is given in combination with non-vagolytic muscle relaxants, bradycardia may occur.
Medicines such as barbiturates, benzodiazepines, neuroleptics, halogenic gases and other non-selective central nervous 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. Likewise, following the administration of RAPIFEN*, the dose of the other central nervous system depressant drugs should be reduced.
The concomitant use of erythromycin with RAPIFEN* may significantly inhibit RAPIFEN* clearance and may increase the risk of prolonged or delayed respiratory depression. Cimetidine reduces the distribution volume and impairs the clearance of RAPIFEN*. Therefore, smaller doses of RAPIFEN* will be required and the duration of action may be extended in patients receiving erythromycin or cimetidine. Theoretically, similar consideration may apply to other hepatic enzyme inhibitors.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Symptoms:
The manifestations of RAPIFEN* overdosage are an extension of its pharmacologic actions. Depending on the individual sensitivity, the clinical picture will be determined primarily by respiratory depression, varying from bradypnoea to apnoea.
Treatment:
In the presence of hypoventilation or apnoea, oxygen should be administered and respiration should be assisted or controlled as indicated. Endotracheal intubation will be necessary for the administration of oxygen in apnoea. The specific narcotic antagonist (naloxone hydrochloride) should be available for use as indicated to manage respiratory depression. The adult dose of naloxone hydrochloride is 0,4 mg intravenously and in children the dosage is 0,01 mg/kg body mass, repeated at 2-3 minute intervals until sufficient reversal is obtained. This does not preclude the use of more immediate countermeasures.
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 occurs and is severe or persists, the possibility of hypovolaemia should be considered and managed with appropriate parenteral fluid therapy.

IDENTIFICATION
A clear colourless solution in 2 mL or 10 mL glass ampoules.

PRESENTATION
Cartons containing 5 x 2 mL and 5 x 10 mL ampoules.

STORAGE INSTRUCTIONS
Store below 25°C. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
2 mL: Q/2.7/327.
10 mL: Q/2.7/328.

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No. 80/11122/07)
15th Road, HALFWAY HOUSE 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
15 May 1992.

Z-Afrika - 272136/V1 V