WARNINGS:
Impaired Respiration: As with other potent opioids, clinically significant respiratory depression may occur within the recommended dose range in patients receiving therapeutic doses of buprenorphine. Buprenex should be used with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression). Particular caution is advised if Buprenex is administered to patients taking or recently receiving drugs with CNS/respiratory depressant effects. In patients with the physical and/or pharmacological risk factors above, the dose should be reduced by approximately one-half.
NALOXONE MAY NOT BE EFFECTIVE IN REVERSING THE RESPIRATORY DEPRESSION PRODUCED BY BUPRENEX. THEREFORE, AS WITH OTHER POTENT OPIOIDS, THE PRIMARY MANAGEMENT OF OVERDOSE SHOULD BE THE REESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL ASSISTANCE OF RESPIRATION, IF REQUIRED.
Interaction with Other Central Nervous System Depressants: Patients receiving Buprenex in the presence of other narcotic analgesics, general anesthetics, antihistamines, benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics or other CNS depressants (including alcohol) may exhibit increased CNS depression. When such combined therapy is contemplated, it is particularly important that the dose of one or both agents be reduced.
Head Injury and Increased Intracranial Pressure: Buprenex, like other potent analgesics, may itself elevate cerebrospinal fluid pressure and should be used with caution in head injury, intracranial lesions and other circumstances where cerebrospinal pressure may be increased. Buprenex can produce miosis and changes in the level of consciousness which may interfere with patient evaluation.
Use in Ambulatory Patients: Buprenex may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Therefore, Buprenex should be administered with caution to ambulatory patients who should be warned to avoid such hazards.
Use in Narcotic-Dependent Patients: Because of the narcotic antagonist activity of Buprenex, use in the physically dependent individual may result in withdrawal effects.
PRECAUTIONS:
General: Buprenex should be administered with caution in the elderly, debilitated patients, in children and those with severe impairment of hepatic, pulmonary, or renal function; myxedema or hypothyroidism; adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.
Because Buprenex is metabolized by the liver, the activity of Buprenex may be increased and/or extended in those individuals with impaired hepatic function or those receiving other agents known to decrease hepatic clearance.
Buprenex has been shown to increase intracholedochal pressure to a similar degree as other opioid analgesics, and thus should be administered with caution to patients with dysfunction of the biliary tract.
Information for Patients: The effects of Buprenex, particularly drowsiness, may be potentiated by other centrally acting agents such as alcohol or benzodiazepines. It is particularly important that in these circumstances patients must not drive or operate machinery. Buprenex has some pharmacologic effects similar to morphine which in susceptible patients may lead to self-administration of the drug when pain no longer exists. Patients must not exceed the dosage of Buprenex prescribed by their physician. Patients should be urged to consult their physician if other prescription medications are currently being used or are prescribed for future use.
Drug Interactions: Drug interactions common to other potent opioid analgesics also may occur with Buprenex. Particular care should be taken when Buprenex is used in combination with central nervous system depressant drugs (see WARNINGS). Although specific information is not presently available, caution should be exercised when Buprenex is used in combination with MAO inhibitors. There have been reports of respiratory and cardiovascular collapse in patients who received therapeutic doses of diazepam and Buprenex. A suspected interaction between Buprenex and phenprocoumon resulting in purpura has been reported.
CYP3A4 Inhibitors: Since the metabolism of buprenorphine is mediated by the CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of buprenorphine. Thus patients coadministered with inhibitors of CYP3A4 such as macrolide antibiotics (e.g., erythromycin), azole antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritanovir) while receiving Buprenex should be carefully monitored and dosage adjustment made if warranted.
CYP3A4 Inducers: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and as such may cause increased clearance of buprenorphine. Caution is advised when administering Buprenex to patients receiving these medications and if necessary dose adjustments should be considered
Carcinogenesis, Mutagenesis and Impairment of Fertility:
Carcinogenesis: Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet at doses of 0.6, 5.5, and 56 mg/kg/day for 27 months in rats. These doses were approximately equivalent to 5.7, 52 and 534 times the recommended human dose (1.2 mg) on a mg/m2 body surface area basis. Statistically significant dose-related increases in testicular interstitial (Leydig's) cell tumors occurred, according to the trend test adjusted for survival. Pairwise comparison of the high dose against control failed to show statistical significance. In the mouse study, buprenorphine was administered in the diet at doses of 8, 50, and 100 mg/kg/day for 86 weeks.
The high dose was approximately equivalent to 477 times the recommended human dose (1.2 mg) on a mg/m2 basis. Buprenorphine was not carcinogenic in mice.
Mutagenesis: Buprenorphine was studied in a series of tests. Results were negative in Chinese hamster bone marrow and spermatogonia cells, and negative in mouse lymphoma L5178Y assay. Results were equivocal in the Ames test: negative in studies in two laboratories, but positive in frame shift mutation at high dose (5 mg/plate) in a third study.
Impairment of Fertility: Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at daily oral doses up to 80mg/kg (approximately 763 times the recommended human daily dose of 1.2 mg on a mg/m2 basis) or up to 5mg/kg I.M. or S.C. (approximately 48 times the recommended human daily dose of 1.2 mg on a mg/m2 basis)
Pregnancy: Pregnancy Category C.
Teratogenic effects: Buprenorphine was not teratogenic in rats or rabbits after I.M. or S.C. doses up to 5 mg/kg/day (approximately 48 and 95 times the recommended human daily dose of 1.2 mg on a mg/m2 basis), I.V. doses up to 0.8 mg/kg/day (approximately 8 times and 15 times the recommended human daily dose of 1.2 mg on a mg/m2 basis), or oral doses up to 160 mg/kg/day in rats (approximately 1525 times the recommended human daily dose of 1.2 mg on a mg/m2 basis) and 25 mg/kg/day in rabbits (approximately 475 times the recommended human daily dose of 1.2 mg on a mg/m2 basis). Significant increases in skeletal abnormalities (e.g. extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after S.C. administration of 1 mg/kg/day and up (approximately 9.5 times the recommended human daily dose of 1.2 mg on a mg/m2 basis) and in rabbits after I.M. administration of 5 mg/kg/day (approximately 95 times the recommended human daily dose of 1.2 mg on a mg/m2 basis), but these increases were not statistically significant. Increases in skeletal abnormalities after oral administration were not observed in rats, and increases in rabbits (1-25 mg/kg/day) were not statistically significant.
There are no adequate and well-controlled studies in pregnant women. Buprenex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The safety of Buprenex given during labor and delivery has not been established.
Nursing Mothers: An apparent lack of milk production during general reproduction studies with buprenorphine in rats caused decreased viability and lactation indices. Use of high doses of sublingual buprenorphine in pregnant women showed that buprenorphine passes into the mother's milk. Breast-feeding is therefore not advised in nursing mothers treated with Buprenex.
Pediatric Use: The safety and effectiveness of Buprenex have been established for children between 2 and 12 years of age. Use of Buprenex in children is supported by evidence from adequate and well controlled trials of Buprenex in adults, with additional data from studies of 960 children ranging in age from 9 months to 18 years of age. Data is available from a pharmacokinetic study, several controlled clinical trials, and several large post-marketing studies and case series. The available information provides reasonable evidence that Buprenex may be used safely in children ranging from 2-12 years of age, and that it is of similar effectiveness in children as in adults.
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