Sublimaze (Fentanyl Citrate) - Description and Clinical Pharmacology

CLINICAL PHARMACOLOGY

SUBLIMAZE (fentanyl citrate) is a narcotic analgesic. A dose of 100 mcg (0.1 mg) (2.0 ml) is approximately equivalent in analgesic activity to 10 mg of morphine or 75 mg of meperidine. The principal actions of therapeutic value are analgesia and sedation. Alterations in respiratory rate and alveolar ventilation, associated with narcotic analgesics, may last longer than the analgesic effect. As the dose of narcotic is increased, the decrease in pulmonary exchange becomes greater. Large doses may produce apnea. SUBLIMAZE appears to have less emetic activity than either morphine or meperidine. Histamine assays and skin wheal testing in man indicate that clinically significant histamine release rarely occurs with SUBLIMAZE. Recent assays in man show no clinically significant histamine release in dosages up to 50 mcg/kg (0.05 mg/kg) (1 ml/kg). SUBLIMAZE preserves cardiac stability, and blunts stress-related hormonal changes at higher doses.

The pharmacokinetics of SUBLIMAZE can be described as a three-compartment model, with a distribution time of 1.7 minutes, redistribution of 13 minutes and a terminal elimination half-life of 219 minutes. The volume of distribution for SUBLIMAZE is 4 L/kg.

SUBLIMAZE plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. It accumulates in skeletal muscle and fat, and is released slowly into the blood. SUBLIMAZE, which is primarily transformed in the liver, demonstrates a high first pass clearance and releases approximately 75% of an intravenous dose in urine, mostly as metabolites with less than 10% representing the unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites.

The onset of action of SUBLIMAZE is almost immediate when the drug is given intravenously; however, the maximal analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration of action of the analgesic effect is 30 to 60 minutes after a single intravenous dose of up to 100 mcg (0.1 mg) (2.0 ml). Following intramuscular administration, the onset of action is from seven to eight minutes, and the duration of action is one to two hours. As with longer acting narcotic analgesics, the duration of the respiratory depressant effect of SUBLIMAZE may be longer than the analgesic effect. The following observations have been reported concerning altered respiratory response to CO₂ stimulation following administration of SUBLIMAZE to man.

1. DIMINISHED SENSITIVITY TO CO₂ STIMULATION MAY PERSIST LONGER THAN DEPRESSION OF RESPIRATORY RATE. (Altered sensitivity to CO₂ stimulation has been demonstrated for up to four hours following a single dose of 600 mcg (0.6 mg) (12 ml) SUBLIMAZE to healthy volunteers.) SUBLIMAZE frequently slows the respiratory rate, duration and degree of respiratory depression being dose related.
2. The peak respiratory depressant effect of a single intravenous dose of SUBLIMAZE is noted 5 to 15 minutes following injection. See also WARNINGS and PRECAUTIONS concerning respiratory depression.