7.1Potent CYP2D6 Inhibitors Fluoxetine,
a potent inhibitor of CYP2D6 activity, significantly inhibited the metabolism of tolterodine immediate release in CYP2D6 extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in C max and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT), the pharmacologically active metabolite of tolterodine [see Clinical Pharmacology (12.1) ] . The sums of unbound serum concentrations of tolterodine and 5-HMT are only 25% higher during the interaction.
No dose adjustment is required when tolterodine and fluoxetine are co-administered [see Clinical Pharmacology (12.3) ].
7.2Potent CYP3A4 Inhibitors Ketoconazole
(200 mg daily), a potent CYP3A4 inhibitor, increased the mean C max and AUC of tolterodine by 2- and 2.5-fold, respectively, in CYP2D6 poor metabolizers. For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, clarithromycin, or ritonavir, the recommended dose of DETROL LA is 2 mg once daily [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] .
7.4Other Drugs Metabolized by Cytochrome P450 Isoenzymes
In vivo drug-interaction data show that tolterodine immediate release does not result in clinically relevant inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine, debrisoquine, S-warfarin, and omeprazole [see Clinical Pharmacology (12.3) ].
7.6Other Anticholinergics
The concomitant use of DETROL LA with other anticholinergic (antimuscarinic) agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, somnolence, and other anticholinergic pharmacological effects. Drug Interactions Potent CYP2D6 Inhibitors Fluoxetine is a selective serotonin reuptake inhibitor and a potent inhibitor of CYP2D6 activity. In a study to assess the effect of fluoxetine on the pharmacokinetics of tolterodine immediate release and its metabolites, it was observed that fluoxetine significantly inhibited the metabolism of tolterodine immediate release in extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC.
There was a 52% decrease in C max and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT, the pharmacologically active metabolite of tolterodine). Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be CYP2D6 extensive metabolizers of tolterodine immediate release to resemble the pharmacokinetic profile in poor metabolizers. The sums of unbound serum concentrations of tolterodine immediate release and 5-HMT are only 25% higher during the interaction.
No dose adjustment is required when tolterodine and fluoxetine are co-administered. Potent CYP3A4 Inhibitors The effect of a 200 mg daily dose of ketoconazole on the pharmacokinetics of tolterodine immediate release was studied in 8 healthy volunteers, all of whom were CYP2D6 poor metabolizers. In the presence of ketoconazole, the mean C max and AUC of tolterodine increased by 2- and 2.5-fold, respectively. Based on these findings, other potent CYP3A4 inhibitors may also lead to increases of tolterodine plasma concentrations.
For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, miconazole, clarithromycin, ritonavir, the recommended dose of DETROL LA is 2 mg daily [see Dosage and Administration (2.3) ] . Warfarin In healthy volunteers, coadministration of tolterodine immediate release 4 mg (2 mg bid) for 7 days and a single dose of warfarin 25 mg on day 4 had no effect on prothrombin time, Factor VII suppression, or on the pharmacokinetics of warfarin.
Oral Contraceptives Tolterodine immediate release 4 mg (2 mg bid) had no effect on the pharmacokinetics of an oral contraceptive (ethinyl estradiol 30 µg/levonorgestrel 150 µg) as evidenced by the monitoring of ethinyl estradiol and levonorgestrel over a 2-month period in healthy female volunteers. Diuretics Coadministration of tolterodine immediate release up to 8 mg (4 mg bid) for up to 12 weeks with diuretic agents, such as indapamide, hydrochlorothiazide, triamterene, bendroflumethiazide, chlorothiazide, methylchlorothiazide, or furosemide, did not cause any adverse electrocardiographic (ECG) effects.
Effect of Tolterodine on Other Drugs Metabolized by Cytochrome P450 Enzymes Tolterodine immediate release does not cause clinically significant interactions with other drugs metabolized by the major drug-metabolizing CYP enzymes. In vivo drug-interaction data show that tolterodine immediate release does not result in clinically relevant inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine, debrisoquine, S-warfarin, and omeprazole.
