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. Buprenorphine HCl 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 buprenorphine HCl 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 BUPRENORPHINE HCl. 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 buprenorphine HCl 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
Buprenorphine HCl, 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. Buprenorphine HCl can produce miosis and changes in the level of consciousness which may interfere with patient evaluation.
Use in Ambulatory Patients
Buprenorphine HCl may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Therefore, buprenorphine HCl 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 buprenorphine HCl, use in the physically dependent individual may result in withdrawal effects.
PRECAUTIONS
General
Buprenorphine HCl 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 buprenorphine HCl is metabolized by the liver, the activity of buprenorphine HCl may be increased and/or extended in those individuals with impaired hepatic function or those receiving other agents known to decrease hepatic clearance.
Buprenorphine HCl 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 buprenorphine HCl, 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. Buprenorphine HCl 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 buprenorphine HCl 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 buprenorphine HCl. Particular care should be taken when buprenorphine HCl is used in combination with central nervous system depressant drugs (see WARNINGS). Although specific information is not presently available, caution should be exercised when buprenorphine HCl 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 buprenorphine HCl. A suspected interaction between buprenorphine HCl 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 buprenorphine HCl 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 buprenorphine HCl to patients receiving these medications and, if necessary, dose adjustments should be considered.
Carcinogenesis, Mutagenesis, 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 80 mg/kg (approximately 763 times the recommended human daily dose of 1.2 mg on a mg/22 basis) or up to 5 mg/kg I.M. or S.C. (approximately 48 times the recommended human daily dose of
1.2 mg on a mg/22 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 to 25 mg/kg/day) were not statistically significant.
There are no adequate and well-controlled studies in pregnant women. Buprenorphine HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The safety of buprenorphine HCl 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 buprenorphine HCl.
Pediatric Use
The safety and effectiveness of buprenorphine HCl have been established for children between 2 and 12 years of age. Use of buprenorphine HCl in children is supported by evidence from adequate and well-controlled trials of buprenorphine HCl 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 buprenorphine HCl may be used safely in children ranging from 2 to 12 years of age, and that it is of similar effectiveness in children as in adults.
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