Rapifen^® Intensive Care

Alfentanil hydrochloride 5.44 mg equivalent to 5 mg alfentanil base per ml.

Solution for injection.

Rapifen Intensive Care is a potent opioid analgesic with a very rapid onset of action. It is indicated for analgesia and suppression of respiratory activity in mechanically ventilated patients on intensive care and to provide analgesic cover for painful manoeuvres. It will aid compliance with mechanical ventilation, and tolerance of the endotracheal tube. Intravenous bolus doses of Rapifen (0.5 mg/ml) may be used to provide additional pain relief during brief painful procedures such as physiotherapy, endotracheal suction, etc. Despite being mechanically ventilated, patients may be awake in the presence of adequate analgesia.

At the proposed doses, Rapifen Intensive Care has no sedative activity. Therefore supplementation with an appropriate hypnotic or sedative agent is recommended. Admixture is not advisable due to the need to individually titrate both agents.

Alfentanil given by infusion should only be given in areas where facilities are available to deal with respiratory depression and where continuous monitoring is performed. Alfentanil should only be prescribed by physicians familiar with the use of potent opioids when given by continuous IV infusion.

Method of Administration

For intravenous infusions.

Dosage

Rapifen Intensive Care should be diluted with sodium chloride intravenous infusion BP, glucose intravenous infusion BP, or compound sodium lactate intravenous infusion BP (Hartmann's solution). Such dilutions are compatible with plastic bags and giving sets. These dilutions should be used within 24 hours of preparation.

Once the patient has been intubated, mechanical ventilation can be initiated using the following dosage regimen:

The recommended initial infusion rate for mechanically ventilated adult patients is 2 mg per hour (equivalent to 0.4 ml per hour of undiluted Rapifen Intensive Care). For a 70 kg patient, this corresponds to approximately 30 micrograms per kilogram per hour.

More rapid control may initially be gained by using a loading dose. For example, a dose of 5 mg may be given in divided doses over a period of 10 minutes, during which time careful monitoring of blood pressure and heart rate should be performed. If hypotension or bradycardia occurs, the rate of administration should be reduced accordingly and other appropriate measures instituted.

The dose to produce the desired effects should then be individually determined and reassessed regularly to ensure that the optimum dose is being used.

In clinical trials, patient requirements have generally been met with doses of 0.5 to 10 mg alfentanil per hour.

Additional bolus doses of 0.5-1.0 mg alfentanil may be given to provide analgesia during short painful procedures.

The elderly and those patients with liver impairment and hypothyroidism will require lower doses. Obese patients may require a dose based on their lean body mass.

Adolescents and young adults will require higher than average doses. There is little experience of use of alfentanil to treat children in intensive care.

The maximum recommended duration of treatment with alfentanil infusions is 4 days.

Present data suggest that clearance of alfentanil is unaltered in renal failure. However there is an increased free fraction and hence dosage requirements may be less than in the patient with normal renal function.

Known intolerance of alfentanil or other morphinomimetics. Pregnancy, and concurrent administration with monoamine oxidase inhibitors.

Warnings:

Following administration of Rapifen Intensive Care, 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.

Like other opioids, alfentanil may cause bradycardia, an effect which 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 occurs, the rate of administration of alfentanil should be reduced and other appropriate measures 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.

Care must be taken if the patient has received monoamine oxidase inhibitors within the previous 2 weeks.

Significant respiratory depression and loss of consciousness will occur following administration of alfentanil in doses in excess of 1 mg and is dose-related. If necessary for assessment purposes, naloxone or other specific antagonists may be administered to reverse the opioid respiratory depression and other pharmacological effects of alfentanil. More than one dose of naloxone may be required in view of its short half life.

Muscle rigidity (morphine-like effect) may occur, in which case neuromuscular blocking drugs may be helpful.

Precautions:

It is wise to reduce the dosage in the elderly and debilitated patient. 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.

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 post infusion period. Care should therefore be taken throughout the weaning period and adequate spontaneous respiration should be established and maintained in the absence of stimulation or ventilatory support. Following cessation of the infusion, the patient should be closely observed for at least 6 hours. Prior use of opioid medication may enhance or prolong the respiratory depressant effects of alfentanil.

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'.

Potential for Rapifen to affect other medicinal products

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

Potential for other medicinal products to affect Rapifen

Alfentanil is metabolised mainly via the human cytochrome P450 3A4 enzyme. In vitro data suggest that potent cytochrome P450 3A4 enzyme inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may inhibit the metabolism of alfentanil. Available human pharmacokinetic data indicate that the metabolism of alfentanil is inhibited by fluconazole, erythromycin, diltiazem and cimetidine (known cytochrome P450 3A4 enzyme inhibitors). 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 cardiac arrest can occur when Rapifen Intensive Care 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.

Although no teratogenic or acute embryotoxic effects have been observed in animal experiments, insufficient data are available to evaluate any harmful effects in man.

Consequently, it is necessary to consider possible risks and potential advantages before administering this drug to pregnant patients.

IV administration during childbirth (including Caesarian section) is not recommended, because alfentanil crosses the placenta and because the foetal respiratory centre is particularly sensitive to opiates. If, however, Rapifen is administered, an antidote should always be at hand for the child.

Alfentanil may appear in breast milk. It is therefore recommended that breast feeding is not initiated within 24 hours of treatment.

Where early discharge is envisaged, patients should be advised not to drive or operate machinery for the 24 hours following administration.

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 clinical trials (1157 subjects) 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 (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial 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'.

The manifestations of alfentanil overdose are generally an extension of its pharmacological action, which include the following:-

The suggested treatments given above do not preclude the use of other clinically indicated counter measures.

Body temperature and adequate fluid intake should be maintained and the patient observed for 24 hours.

A specific narcotic antagonist (e.g. naloxone) should be available to treat respiratory depression.

In man, alfentanil at therapeutic doses has no detrimental effects on myocardial performance. The cardiovascular stability is remarkable both in healthy and poor-risk patients. The only changes seen in blood pressure and heart rate were transient, slight decreases occurring immediately after induction. The incidence and degree of respiratory depression is less and of shorter duration after alfentanil than with fentanyl. Like other narcotic analgesics, alfentanil increases the amplitude of the EEG and reduces its frequency. Alfentanil reduces intraocular pressure by about 45%. It blocks increases in plasma cortisol and in plasma antidiuretic and growth hormones throughout surgery, and prevents increases in plasma catecholamines up to, but not during or after, cardiopulmonary bypass in patients undergoing open heart surgery.

Alfentanil is a synthetic opioid with µ-agonist pharmacological effects.

After bolus injections ranging from 2.4 to 125 µg/kg, plasma levels in man decay triexponentially with a terminal half life of approx. 90 minutes. Total distribution volume varies from 0.4 to 1.0 l/kg, indicating a limited distribution of alfentanil to the tissues. Plasma clearance, varying from 3.3 to 8.3 ml/kg/min represents approximately one third of liver plasma flow indicating that elimination of alfentanil is not flow dependent. Since only 0.4% of the dose is excreted with the urine as unchanged drug, elimination of alfentanil occurs mainly by metabolism.

These main parameters in patients undergoing surgery are similar to those in healthy volunteers. Only when the drug was given as the sole anaesthetic in a continuous high infusion over about 5 hours was the clearance of alfentanil reduced resulting in a plasma half-life of about 200 minutes, the distribution volume not being markedly changed.

Plasma protein binding of alfentanil is 92%, mainly due to a strong binding to the 'acute phase' α₁-acid-glycoprotein. It is not bound to the blood cells. Pharmacokinetics were comparable in rats, dogs and man. The elderly show a longer half-life for alfentanil, after IV bolus doses.

Special Populations

Paediatric patients

Protein binding in newborns is 75% and increases in children to 85%. The plasma clearance in newborns is approximately 7.2 ± 3.2mL/kg/min and 4.7 ± 1.7 mL/kg/min in children between 4.5 to 7.75 years. The volume of distribution at steady state was 1230 ± 520 mL/kg in newborns and 163.5 ± 110 mL/kg in children. The half-life is 146 ± 57 minutes in newborns and 40.2 ± 8.9 minutes in children.

Hepatic Impairment

After administration of a single intravenous dose of 50 µg/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.).

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 effects of alfentanil (see Section 4.4.).

Preclinical effects observed were only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Sodium chloride

Water for injections

Sodium hydroxide 0.1 N

Hydrochloric acid 0.1 N

See Section 4.2 Posology and Method of administration.

60 months.

Store in the controlled drug store, at or below 25°C.

Type I USP clear glass ampoules containing 1 ml, packed in 5s or 10s.

For single use only. Discard any unused contents.

Janssen-Cilag Limited

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

PL 0242/0137

Date of first Authorisation: 31/07/89

Date of Renewal: 23/06/05

26^th May 2010