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° The patient should understand the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures, hepatic toxicity and death. Drug Interactions In vitro studies indicate that tramadol is unlikely to in-hibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at thera-peutic doses. Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data.
Tramadol is a mild inducer of selected drug metabolism pathways measured in animals. Text Continues Below
Use With Carbamazepine Patients taking carbamazepine may have a signifi-cantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRACET and carba-mazepine is not recommended. Use With Quinidine Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme; so that con-comitant administration of quinidine and tramadol re-sults in increased concentrations of tramadol and reduced concentrations of M1. The clinical conse-quences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. Use With Inhibitors of CYP2D6 In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitripty-line could result in some inhibition of the metabolism of tramadol. Use With Cimetidine Concomitant administration of ULTRACET and cime-tidine
has not been studied. Concomitant administra-tion of tramadol and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRACET dosage reg-imen is recommended. Use With MAO Inhibitors Interactions with MAO Inhibitors, due to interference with detoxification mechanisms, have been reported for some centrally acting drugs (see WARNINGS, Use With MAO Inhibitors). Use With Digoxin Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. Use With Warfarin Like Compounds Post-marketing surveillance of both tramadol and acetaminophen individual products have revealed rare alterations of warfarin effect, including elevation of pro-thrombin times. While such changes have been generally of limited clin-ical significance for the individual products, periodic evaluation of prothrombin time should be performed when ULTRACET and warfarin-like compounds are administered concurrently. Carcinogenesis, Mutagenesis, Impairment of Fertility There are no animal or laboratory studies on the com-bination product (tramadol and acetaminophen) to evaluate carcinogenesis, mutagenesis, or impairment of fertility. A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/ kg (90 mg/ m 2 or 0.5 times the maximum daily human tramadol dosage of 185 mg/ m 2 ) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in rat carcinogenic-ity study (dosing orally up to 30 mg/ kg, 180 mg/ m 2 , or 1 time the maximum daily human tramadol dosage).
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/ HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mu-tation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans. No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/ kg (350 mg/ m 2 ) in male rats and 75 mg/ kg (450 mg/ m 2 ) in female rats. These dosages are 1.6 and 2.4 times the maximum daily human tram-adol dosage of 185 mg/ m 2 . Pregnancy Teratogenic Effects
Pregnancy Category C No drug-related teratogenic effects were observed in the progeny of rats treated orally with tramadol and acetaminophen. The tramadol/ acetaminophen combi-nation product was shown to be embryotoxic and
fetotoxic in rats at a maternally toxic dose, 50/ 434 mg/ kg tramadol/ acetaminophen (300/ 2604 mg/ m 2 or 1.6 times the maximum daily human tramadol/ acetaminophen dosage of 185/ 1591 mg/ m 2 ), but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Non-teratogenic effects
Tramadol alone was evaluated in peri-and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/ kg (300 mg/ m 2 or 1.6 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/ kg (480 mg/ m 2 or 2.6 times the maximum daily human tramadol dosage). There are no adequate and well-controlled studies in pregnant women. ULTRACET should be used during pregnancy only if the potential benefit justifies the po-tential risk to the fetus. Neonatal seizures, neonatal with-drawal syndrome, fetal death and still birth have been reported with tramadol hydrochloride during post-marketing. Labor and Delivery ULTRACET should not be used in pregnant women prior to or during labor unless the potential benefits out-weigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn. (See DRUG ABUSE AND DEPENDENCE.) Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the um-bilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. The effect of ULTRACET, if any, on the later growth, development, and functional maturation of the child is unknown. Nursing Mothers ULTRACET is not recommended for obstetrical pre-operative medication or for post-delivery analgesia in nursing mothers because its safety in infants and new-borns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 µg of tramadol (0.1% of the maternal dose) and 27 µg of M1. Page: << Prev | 1 | 2 | 3 | 4 | 5
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