opioid anesthetics - ATC code: N01AH02

alfentanil hydrochloride

Each 1 ml of Alfentanil 500 micrograms/ml solution for injection contains: Alfentanil hydrochloride, monohydrate 543.8 micrograms, equivalent to 500 micrograms alfentanil base

Solution for Injection The product is a clear and colourless solution

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, Alfentanil 500 micrograms/ml solution for injection may be used as an anaesthetic induction agent in ventilated patients.

Alfentanil 500 micrograms/ml by the intravenous route can be administered to both adults and children. The dosage of Alfentanil 500 micrograms/ml 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 shown in Table 1 Dosage regimen:

Table 1 Dosage regimen

If desired, Alfentanil 500 micrograms/ml can be mixed with sodium chloride injection BP, glucose injection BP or Ringer-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.

In obese patients (more than 20 % above ideal total body weight), the dosage of alfentanil should be determined on the basis of lean body weight.

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 Alfentanil 500 micrograms/ml 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 Alfentanil 500 micrograms/ml. For procedures of longer duration, additional increments will be required.

In ventilated patients, the last dose of Alfentanil 500 micrograms/ml 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, Alfentanil 500 micrograms/ml may be infused at a rate of 0.5 – 1 µg/kg/minute. Adequate plasma concentrations of alfentanil will only be achieved rapidly if this infusion is preceded by a loading dose of 50 – 100 µg/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 Alfentanil 500 micrograms/ml (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.

Patients with renal impairment: No dosage adjustment is needed.

Patients with hepatic impairment: Dose should be modified depending on the clinical response and degree of hepatic impairment however no quantitative recommendations are available.

Administration Guidelines

Alfentanil is administered intravenously by injection or infusion and should only be given by individuals trained in the administration of general anaesthetics and the management of the respiratory effects of potent opioids. Pulse oximetry or some other means for measuring respiratory function is recommended. Visually inspect parenteral products for particulate matter and discoloration prior to administration.

Infuse iv slowly over 3 minutes. Injections rates of < 1 minute are associated with an increased incidence of hypotension.

Continuous infusions longer than 4 days have not been studied.

Children may require higher or more frequent dosing owing to a shorter half-life of Alfentanil 500 micrograms/ml in this age group (dilution may be helpful).

Alfentanil hydrochloride is contraindicated in patients with known hypersensitivity to the drug and other opioids.

Obstructive airway 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 new-born infant.

Warnings

Alfentanil should be administered only by persons specifically trained in the use of intravenous and general anaesthetic agents and 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.

Alfentanil hydrochloride administered in initial dosages up to 20 µg/kg may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is usually dose-related. Administration of alfentanil at anaesthetic induction dosages (above 130 µg/kg) will consistently produce muscular rigidity with an immediate onset. The onset of muscular rigidity occurs earlier than with other opioids. Alfentanil may produce muscular rigidity that involves all skeletal muscles, including those of the neck and extremities. The incidence may be reduced by: 1) routine methods of administration of neuromuscular blocking agents for balanced opioid anaesthesia; 2) administration of up to 1/4 of the full paralyzing dose of a neuromuscular blocking agent just prior to administration of alfentanil at dosages up to 130 µg/kg; following loss of consciousness, a full paralyzing dose of a neuromuscular blocking agent should be administered; or 3) simultaneous administration of alfentanil and a full paralyzing dose of a neuromuscular blocking agent when alfentanil is used in rapidly administered anaesthetic dosages (above 130 µg/kg).

The neuromuscular blocking agent used should be appropriate for the patient's cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered alfentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression.

Patients receiving monitored anaesthesia care should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure; oxygen supplementation should be immediately available and provided where clinically indicated; oxygen saturation should be continuously monitored; the patient should be observed for early signs of hypertension, apnea, upper airway obstruction and/or oxygen desaturation.

Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported for other opioid analgesics, and rarely with alfentanil. Therefore when alfentanil is administered to patients who have received MAO inhibitors within 14 days, appropriate monitoring and ready availability of vasodilators and beta-blockers for the treatment of hypertension is recommended.

Precautions

Delayed respiration depression, respiratory arrest, bradycardia, asystole, arrhythmias and hypotension have also been reported. Therefore, vital signs must be monitored continuously.

In patients with hypothyroidism the dosage should be titrated with care and prolonged monitoring may be required.

General

The initial dose of alfentanil should be appropriately reduced in elderly and debilitated patients. The effect of the initial dose should be considered in determining supplemental doses. In obese patients (more then 20% above ideal total body weight) the dosage of alfentanil should be determined on the basis of lean body weight. In one clinical trial, the dose of alfentanil required to produce anaesthesia, as determined by appearance of delta waves in EEG, was 40% lower in geriatric patients than that needed in healthy young patients.

In patients with compromised liver function and in geriatric patients, the plasma clearance of alfentanil may be reduced and postoperative recovery may be prolonged.

Induction doses of alfentanil should be administered slowly (over three minutes). Administration may produce loss of vascular tone and hypotension. Consideration should be given to fluid replacement prior to induction.

Diazepam administered immediately prior to or in conjunction with high doses of alfentanil may produce vasodilation, hypotension and result in delayed recovery.

Bradycardia produced by alfentanil may be treated with atropine. Severe bradycardia and asystole have been successfully treated with atropine and conventional resuscitative methods.

The hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required should be considered in the selection of a neuromuscular blocking agent.

Following an anaesthetic induction dose of alfentanil, requirements for volatile inhalation anaesthetics of alfentanil infusion are reduced by 30 to 50% for the first hour of maintenance.

Alfentanil infusions should be discontinued at least 10-15 minutes prior to the end of surgery during general anaesthesia. During administration of alfentanil for monitored anaesthesia care, infusions may be continued to the end of the procedure.

Respiratory depression caused by opioid analgesics can be reversed by opioid antagonists such as naloxone. Because the duration of respiratory depression produced by alfentanil may last longer than the duration of the opioid antagonist action, appropriate surveillance should be maintained. As with all potent opioids, profound analgesia is accompanied by respiratory depression and diminished sensitivity to CO₂ stimulation which may persist into or recur in the postoperative period.

Intraoperative hyperventilation may further add to respiratory depression. Appropriate postoperative monitoring should be employed, particularly after infusions and large doses of alfentanil, to ensure that adequate spontaneous breathing is established and maintained in the absence of stimulation prior to discharging the patient from the recovery area.

Head injuries

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

Impaired respiration

Alfentanil should be used with caution in patients with pulmonary disease, decreased respiratory reserve or potentially compromised respiration. In such patients, opioids may additionally decrease respiratory drive and increase airway resistance. During anaesthesia, this can be managed by assisted or controlled respiration.

Impaired hepatic or renal function

In patients with liver or kidney dysfunction, alfentanil should be administered with caution due to the importance of these organs in the metabolism and excretion of alfentanil.

Paediatric use

Adequate data to support the use of alfentanil in children under 12 years of age are not presently available.

Monoamine oxidase (MAO) inhibitors may potentiate the effects of narcotics. It is not recommended to take alfentanil who have received MAO inhibitors within 14 days.

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 P450 3A4 enzyme inhibitors (e.g. ketoconazole, ritonavir) may also inhibit the metabolism of alfentanil. This could increase the risk of prolonged or delayed respiratory depression. The concomitant use of such active substances requires special patient care and observation, in particular, it may be necessary to lower the dose of alfentanil.

Both the magnitude and duration of central nervous system and cardiovascular effects may be enhanced when alfentanil is administered in combination with other CNS depressants such as barbiturates, tranquilizers, opioids, or inhalation general anaesthetics. Postoperative respiratory depression may be enhanced or prolonged by these agents. In such cases of combined treatment, the dose of one or both agents should be reduced. Limited clinical experience indicates that requirements for volatile inhalation anaesthetics are reduced by 30 to 50% for the first sixty (60) minutes following alfentanil induction.

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

Perioperative administration of drugs affecting hepatic blood flow or enzyme function may reduce plasma clearance and prolong recovery.

Undesirable effects in patients receiving alfentanil are generally mild and transient.

The most common adverse reactions of opioids are respiratory depression and skeletal muscle rigidity, particularly of the truncal muscles. Alfentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities.

The adverse experience profile from patients receiving alfentanil for monitored anaesthesia care is similar to the profile established with alfentanil during general anaesthesia. Respiratory events reported during monitored anaesthesia care included hypoxia, apnea, and bradypnea. Other adverse events reported by patients receiving alfentanil for monitored anaesthesia care, in order of decreasing frequency, were nausea, hypotension, vomiting, pruritus, confusion, somnolence and agitation.

Summarising the adverse effects reported in the currently available literature (clinical trials and case reports, representing 2029 patients), the incidence of adverse reactions probably or possibly related to alfentanil sorted according to the affected organ system is shown in Table 1.

Table 1. Adverse reactions probably or possibly related to alfentanil sorted by frequency and organ system

A more detailed summary of probably or possibly to alfentanil use related adverse events is compiled in Table 2. Nausea and vomiting are the most frequent observed adverse events, then cardiovascular reactions and respiratory effects. All other adverse events reported are uncommon and rare.

Table 2: Frequency of adverse reactions possibly or probably related to alfentanil, reported in clinical trials

hameln pharmaceuticals ltd

(POM)

16 February 2012