nalysis of Phase I studies with immediate-release tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers,” while M1 concentrations were 40% lower.
Drug Interaction Studies
CYP2D6 Inhibitors
In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 (fluoxetine, norfluoxetine, amitriptyline, and quinidine) inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown.
Quinidine
Tramadol is metabolized to M1 by CYP2D6. A study was conducted to examine the effect of quinidine, a selective inhibitor of CYP2D6, on the pharmacokinetics of tramadol by administering 200 mg quinidine two hours before the administration of 100 mg tramadol extended release tablet. The results demonstrated that the exposure of tramadol increased 50 to 60% and the exposure of M1 decreased 50 to 60%. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism [see WARNINGS AND PRECAUTIONS (5.4) and DRUG INTERACTIONS (7)].
Cimetidine
Concomitant administration of tramadol and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the tramadol hydrochloride and acetaminophen dosage regimen is recommended.
CYP3A4 Inhibitors and Inducers
Tramadol is metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or CYP3A4 inducers, such as rifampin and St. John’s Wort, with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure [see WARNINGS AND PRECAUTIONS (5.2 and 5.4) and DRUG INTERACTIONS (7)].
Carbamazepine
Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Concomitant administration of tramadol and carbamazepine is not recommended.
Potential for Tramadol to Affect Other Drugs
In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic 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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
There are no animal or laboratory studies on the combination product (tramadol and acetaminophen) to eva luate carcinogenesis, mutagenesis, or impairment of fertility. Data on the individual components are described below.
Carcinogenesis
A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in an NMRI mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg in the drinking water (0.5 times the maximum recommended daily human dosage or MRHD) 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 evidence of carci |
