Alfenta (Alfentanil HCl)

ALFENTA®

Janssen-Ortho

Alfentanil HCl

Opioid Analgesic – Adjunct to Anesthesia

Action And Clinical Pharmacology: Alfentanil is a potent opioid analgesic/anesthetic with a rapid onset and short duration of action. The analgesic potency of alfentanil is 1/4 to 1/3 that of fentanyl. Low to moderate doses of alfentanil in short-stay surgical procedures provide good analgesic protection against hemodynamic responses to surgical stress and rapid recovery. Hemodynamic stability and duration of action increase with increasing dosage. At high doses followed by continuous infusion in general surgery, alfentanil provides hemodynamic stability, rapid recovery and a reduced need for postoperative analgesics.

Alfentanil has an immediate onset of action and plasma levels decay according to a 3 compartment model with sequential half-lives of 1 minute for the fast distribution phase, 12 minutes for the redistribution phase and 90 minutes for the terminal elimination phase. It is extensively metabolized in the liver and small intestine. Approximately 88% of the administered dose is excreted in the urine within 48 hours with unchanged alfentanil accounting for only 0.2 to 0.5% of the recovered dose. The plasma protein binding of alfentanil is approximately 92%.

Pharmacokinetics: The pharmacokinetics of alfentanil are characterized by limited accumulation and extremely rapid elimination from tissue storage sites. The apparent volume of distribution is 0.59 to 1.0 L/kg and the plasma clearance is 5.1 to 7.7 mL/kg/min. This accounts for the rapid recovery seen following i.v. bolus injection or continuous infusion.

At dosages of 8 µg/kg to 40 µg/kg alfentanil produces analgesia in short-stay surgery. For longer procedures, doses up to 75 µg/kg in intubated patients provide better hemodynamic stability with recovery time comparable to fentanyl. A pre-intubation loading dose of 50 to 75 µg/kg attenuates the response to laryngoscopy, intubation and incision. Subsequent administration of alfentanil infusion administered at a rate of 0.5 to 1.5 µg/kg/min with nitrous oxide/oxygen dampens sympathetic responses to surgical stress and maintains hemodynamic stability, providing smooth and rapid postoperative recovery.

At doses of 105 to 119 µg/kg, alfentanil produces dependable hypnosis; an anesthetic ED90 of 182 µg/kg for alfentanil in unpremedicated patients has been determined, based upon the ability to block response to placement of a nasopharyngeal airway.

In one study of patients administered alfentanil with nitrous oxide/oxygen, a narrow range of alfentanil plasma concentrations, 312 to 338 ng/mL, was shown to provide adequate anesthesia for intra-abdominal surgery, while lower concentrations, approximately 250 ng/mL, blocked responses to abdominal closure. Levels from 100 to 200 ng/mL provide adequate anesthesia for superficial surgery.

Attenuation of the catecholamine response with alfentanil infusion was greater than or equal to that seen with a thiopental/enflurane technique.

Patients administered doses of up to 200 µg/kg of alfentanil have shown no elevation in plasma histamine levels and no indication of histamine release.

Indications And Clinical Uses: For Surgical Patients: As an analgesic adjunct to a barbiturate induction agent during short procedures. As an analgesic adjunct to barbiturate/nitrous oxide/oxygen anesthesia when given in incremental doses for the maintenance of anesthesia at dosages of 5 to 75 µg/kg in surgical procedures with an expected duration of up to 1 hour. As an analgesic adjunct given as a continuous infusion at a rate of 0.5 to 1.5 µg/kg/min with nitrous oxide/oxygen in the maintenance of general anesthesia (see Warnings and Precautions).

For Mechanically Ventilated Patients in the Intensive Care Unit: As an analgesic and suppressant of respiratory drive, to aid compliance with the ventilator and to facilitate toleration of the endotracheal tube, when given as a continuous infusion. As an additional analgesic during brief painful procedures, when given in bolus doses to supplement continuous infusion.

Contra-Indications: Patients with known hypersensitivity to the drug or to other morphinomimetics.

Manufacturers’ Warnings In Clinical States: As with other CNS depressants, patients who have received alfentanil should have appropriate surveillance. Resuscitation equipment and a narcotic antagonist should be readily available to manage apnea.

Intensive Care Patients: Alfentanil should not be used in spontaneously breathing patients in the Intensive Care Unit.

Alfentanil, even at the low doses used in the Intensive Care Unit, may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscular rigidity is related to dose and speed of administration of alfentanil, and may involve all skeletal muscles including those of the head and neck. A neuromuscular blocking agent may be necessary to allow intubation and mechanical ventilation. The onset of muscular rigidity occurs earlier with alfentanil than with other opioids.

The incidence may be reduced by 1) routine administration of neuromuscular blocking agents for balanced narcotic anesthesia; 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 75 µg/kg. The neuromuscular blocking agent used should be compatible with the patient’s cardiovascular status.

As with all potent opioids, profound analgesia is accompanied by marked respiratory depression, which may persist into or recur in the early postoperative or postinfusion period. If alfentanil has been used for prolonged sedation in the Intensive Care Unit, close observation of respiration should continue for at least 12 hours after discontinuation of the infusion. Care should be taken after infusions or large bolus doses of alfentanil to ensure that adequate spontaneous breathing has been established and maintained in the absence of ventilatory support or stimulation before close monitoring of the patient is discontinued. The adjunctive use of sedative hypnotics or other anesthetic agents may result in significant respiratory depression even with small doses of alfentanil.

Hyperventilation during anesthesia may alter the patient’s responses to CO2, thus affecting respiration postoperatively.

Adequate facilities should be available for monitoring and ventilation of all patients receiving alfentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression, including the use of neuromuscular blocking agents for tracheal intubation.

Nonepileptic myoclonic movements can occur.

Precautions: Alfentanil should be administered only by persons specifically trained in the use of i.v. anesthetics. Vital signs should be monitored routinely.

Skeletal muscle rigidity is related to the dose and speed of administration of alfentanil and administration of adequate doses of a muscle relaxant. At high doses, muscular rigidity will occur unless preventative measures are employed (see Warnings).

Geriatrics: In geriatric patients, the dose of alfentanil required to produce anesthesia, as determined by the appearance of delta waves in the EEG, was 40% lower than that needed in healthy young patients.

Patients with Impaired Hepatic Function: In patients with compromised liver function (and in geriatric patients), the plasma clearance of alfentanil may be reduced and postoperative recovery may be prolonged.

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 than 20% above ideal total body weight), the dosage should be determined on the basis of lean body weight.

Patients with Impaired Renal Function: Although the clearance of alfentanil does not appear to be altered in patients with renal impairment, it may be necessary to reduce dosage requirements due to an increased free fraction of the drug.

Patients with Impaired Respiration: Decreased respiratory drive and increased airway resistance occur with increasing doses of alfentanil. The degree and duration of respiratory depression is dose-related. At high doses, a pronounced decrease in pulmonary exchange and apnea may be produced. 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 anesthesia, this can be managed by assisted or controlled respiration. 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.

Patients with Compromised Cardiovascular Systems: Rapid administration may produce loss of vascular tone and hypotension. Management with fluid replacement should be considered in patients with compromised cardiovascular systems prior to induction.

In some patients administered alfentanil, bradycardia and possibly asystole can occur if the patient has received an insufficient amount of anticholinergic, or when alfentanil is combined with nonvagolytic muscle relaxants. Bradycardia can be treated with atropine.

Careful titration of dosage may be required in patients with special conditions, such as uncontrolled hypothyroidism or alcoholism (see Drug Interactions; alcohol can potentiate the respiratory depression of narcotics). In such cases, prolonged postoperative monitoring is required.

Patients on chronic opioid therapy or with a history of narcotic abuse, may require increased amounts of alfentanil.

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

In patients with compromised intracerebral compliance, the use of rapid bolus injections should be avoided. In such patients with opioid therapy, the decrease in mean arterial pressure has occasionally been accompanied by a short-lasting reduction of the cerebral perfusion pressure.

Pregnancy: There are no adequate well-controlled studies in pregnant women. Alfentanil should be used during pregnancy only if the potential benefits justify the potential risks.

Labor and Delivery: There are insufficient data to support the use of alfentanil in labor and delivery. Such use is not recommended.

Lactation: In one study of 9 women undergoing postpartum tubal ligation, minimal levels of alfentanil were detected in colostrum 4 hours after administration of 60 µg/kg alfentanil, with no detectable levels present after 28 hours. Caution should be exercised when alfentanil is administered to a nursing woman.

Children: There are insufficient data on the safety, efficacy and dosage regimen in children under 12 years of age, therefore the use of alfentanil is not recommended in this age group.

Drug Interactions: CNS Depressants: Both magnitude and duration of CNS and cardiovascular effects may be enhanced when alfentanil is administered to patients receiving barbiturates, tranquilizers, opioids, general anesthetics or other CNS depressants (e.g., alcohol). 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.

MAO Inhibitors: It is usually recommended to discontinue MAO inhibitors 2 weeks prior to any surgical or anesthetic procedure.

Diazepam: Administration of i.v. diazepam immediately prior to or following high doses of alfentanil has been shown to produce decreases in blood pressure that may be secondary to vasodilation; recovery may also be prolonged.

Hepatic Enzyme Inhibitors: The concomitant use of erythromycin with alfentanil can significantly inhibit the clearance of alfentanil and may increase the risk of prolonged or delayed respiratory depression. The concomitant use of cimetidine with a prolonged infusion of alfentanil may reduce clearance and extend the elimination half-life of alfentanil due to the inhibitory effects of cimetidine on microsomal enzymes. Therefore smaller doses of alfentanil may be required.

Drug Abuse and Dependence: Alfentanil can produce drug dependence of the morphine type and, therefore, has the potential for being abused.

Occupational Hazards: Effect on Driving Ability and Use of Machinery: Patients should be advised to allow sufficient time to elapse before operating a car or heavy machinery. Individual reactions vary. 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.

Adverse Reactions: The most frequent adverse reactions experienced in patients administered alfentanil were: Cardiovascular: bradycardia 2%, hypertension 2%, hypotension 2%.

Gastrointestinal: nausea 5%, vomiting 4%.

Musculoskeletal: chest wall rigidity 33% (incremental administration) and 22.5% (continuous infusion).

This incidence of chest wall rigidity can be significantly reduced by pretreatment with a nonparalyzing dose of a neuromuscular blocking agent (i.e., nondepolarizing muscle relaxant).

Other adverse reactions reported in £1% of the patients were:

Cardiovascular: tachycardia.

Respiratory: apnea, laryngospasm, postoperative respiratory depression.

CNS: dizziness, sleepiness.

Musculoskeletal: skeletal muscle movements.

In postmarketing data, myoclonic movements and respiratory depression have been reported.

Allergic reactions (such as anaphylaxis, bronchospasm, pruritus, urticaria) and asystole have been reported; since several drugs were coadministered during anesthesia, it is uncertain whether there is a causal relationship to the drug.

Symptoms And Treatment Of Overdose: Symptoms: There has been no clinical experience of overdosage with alfentanil in clinical trials to date. As with other potent opioid analgesics, overdosage is expected to be manifested by an extension of the pharmacological actions of alfentanil. The i.v. LD50 of alfentanil in male rats is 43.0 to 50.9 mg/kg.

An overdose of alfentanil injection is manifested as an extension of its pharmacologic actions.

Treatment: In the event of overdosage, oxygen should be administered and ventilation assisted or controlled as indicated for hypoventilation or apnea. A patent airway must be maintained and an oropharyngeal airway or endotracheal tube may be indicated.

I.V. administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression. The duration of respiratory depression following overdosage with alfentanil may be longer than the duration of action of the opioid antagonist; additional doses of the latter may be required. Administration of an opioid antagonist should not preclude more immediate countermeasures.

If depressed respiration is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled ventilation. I.V. fluids and vasopressors for the treatment of hypotension and other supportive measures may be employed.

Dosage And Administration: Adults: The dosage should be individualized according to body weight, physical status, underlying pathological condition, concomitant medication, and type and duration of surgical procedure and anesthesia. 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. The dose of alfentanil should be reduced in geriatric patients.

Vital signs should be monitored routinely.

Alfentanil may be administered: 1) by incremental injection as an analgesic adjunct with barbiturate/nitrous oxide/oxygen anesthesia for short surgical procedures (expected duration of less than 1 hour); 2) as an analgesic adjunct to barbiturate induction for general surgical procedures followed by continuous infusion as a maintenance analgesic with nitrous oxide/oxygen for general surgical procedures.

Dosage for Mechanically Ventilated Patients in the Intensive Care Unit: The dosage of alfentanil required in intensive care patients will depend on many factors including the underlying pathological condition, the severity of the pain, the type of mechanical ventilation, the individual patient’s response to the drug, and the use of concomitant medications, especially sedative hypnotics or major tranquilizers.

Continuous Infusion: The recommended initial infusion rate of alfentanil in mechanically ventilated adult patients is 0.5 µg/kg/min. The rate of infusion should be reassessed regularly and individualized to ensure that it is kept at the minimum necessary to achieve the desired clinical effect. The optimal infusion rate varies considerably from patient to patient. However, in the majority of patients, infusion rates in the range of 0.2 to 2.0 µg/kg/min effectively prevent pain and aid compliance with mechanical ventilation.

An initial loading dose of up to 50 µg/kg may be required in some patients, depending on their status prior to initiation of the infusion as well as previous analgesic or anesthetic therapy.

Supplemental Bolus Doses: Supplemental bolus doses of 10 to 20 µg/kg may be given during periods of increased stimulation due to painful procedures such as physiotherapy or endotracheal suction.

Patients should be closely monitored for at least 12 hours following cessation of the infusion to detect any evidence of respiratory depression. Care should be taken to ensure that adequate spontaneous ventilation has been established and maintained in the absence of ventilatory support or stimulation.

At the recommended dosage, alfentanil provides analgesia and suppression of respiratory drive but it may not provide sedation or induce sleep. The addition of an anxiolytic such as a benzodiazepine may be required to achieve sedation. Neuromuscular blocking agents may also be necessary for intubation or to settle patients who are difficult to manage on mechanical ventilation.

There is no clinical experience with infusions of more than 5 consecutive days.

Children: Not recommended, see Precautions.

Premedication: The selection of preanesthetic medication should be based upon the needs of the individual patient.

Neuromuscular Blocking Agents: The neuromuscular blocking agent selected should be compatible with the patient’s condition, taking into account the hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required (see Pharmacology, Warnings and Precautions).

Availability And Storage: Each mL of colorless, sterile, preservative-free aqueous solution contains: alfentanil HCl equivalent to 500 µg of alfentanil base and water for injection. Sodium chloride is added to produce an isotonic solution. pH range of 4.0 to 6.0. Ampuls of 2 and 5 mL (packages of 10), ampuls of 20 mL (packages of 5). Store at room temperature protected from light.

ALFENTA® Janssen-Ortho Alfentanil HCl Opioid Analgesic – Adjunct to Anesthesia

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