carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol concomitant administration of Ultram and carbamazepine is not recommended Use With Quinidine Tramadol is metabolized to M1 by CYP2D6 Quinidine is a selective inhibitor of that isoenzyme so that concomitant administration of quinidine and Ultram results in increased concentrations of tramadol and reduced concentrations of M1 The clinical consequences 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 amitriptyline could result in some inhibition of the metabolism of tramadol Use With Cimetidine Concomitant administration of Ultram with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics Therefore no alteration of the Ultram dosage regimen 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 and Warfarin Post-marketing surveillance has revealed rare reports of digoxin toxicity and alteration of warfarin effect including elevation of prothrombin times Carcinogenesis Mutagenesis 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 m2 or times the maximum daily human dosage of 246 mg m2 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 a rat carcinogenicity study dosing orally up to 30 mg kg 180 mg m2 or times the maximum daily human dosage Tramadol was not mutagenic in the following assays Ames Salmonella microsomal activation test CHO HPRT mammalian cell