Enablex Drug Interactions

Effects of other medicinal products on darifenacin: Darifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inhibitors of these enzymes may increase darifenacin exposure.
CYP2D6 inhibitors: In patients receiving drugs that are potent CYP2D6 inhibitors (e.g. paroxetine, terbinafine, cimetidine and quinidine) the recommended starting dose should be 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. Concomitant treatment with potent CYP2D6 inhibitors results in an increase in exposure (e.g. of 30% with paroxetine at the 30 mg dose of darifenacin).
CYP3A4 inhibitors: Darifenacin should not be used together with potent CYP3A4 inhibitors (see Contraindications) such as protease inhibitors, ketoconazole and itraconazole. Potent P-glycoprotein inhibitors such as cyclosporine and verapamil should also be avoided. Co-administration of darifenacin 7.5 mg with the potent CYP3A4 inhibitor ketoconazole 400 mg resulted in a 5-fold increase in steady-state darifenacin AUC. In subjects who are poor metabolisers, darifenacin exposure increased by approximately 10-fold. Due to a greater contribution of CYP3A4 after higher darifenacin doses, the magnitude of the effect is expected to be even more pronounced when combining ketoconazole with darifenacin 15 mg.
When co-administered with moderate CYP3A4 inhibitors such as erythromycin, clarithromycin, telithromycin, fluconazole and grapefruit juice, the recommended starting dose of darifenacin should be 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. Darifenacin AUC₂₄ and C_max from 30 mg od dosing in subjects who are extensive metabolisers were 95% and 128% higher, when erythromycin (moderate CYP3A4 inhibitor) was co-administered with darifenacin than when darifenacin was taken alone.
Enzyme inducers: Drugs that are inducers of CYP3A4 such as rifampicin, carbamazepine, barbiturates and St. John's wort (Hypericum perforatum) are likely to decrease the plasma concentrations of darifenacin.
Effects of darifenacin on other medicinal products: CYP2D6 substrates: Darifenacin is a moderate inhibitor of the enzyme CYP2D6. Caution should be exercised when darifenacin is used concomitantly with medicinal products that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine, or tricyclic antidepressants such as imipramine. The effects of darifenacin on the metabolism of CYP2D6 substrates are mainly clinically relevant for CYP2D6 substrate which are individually dose titrated.
CYP3A4 substrates: Darifenacin treatment resulted in a modest increase in the exposure of the CYP3A4 substrate midazolam. The interaction with midazolam lacks clinical relevance but is indicative of a slight CYP3A4 inhibition by darifenacin.
Warfarin: Standard therapeutic prothrombin time monitoring for warfarin should be continued. The effect of warfarin on prothrombin time was not altered when co-administered with darifenacin.
Digoxin: Therapeutic drug monitoring for digoxin should be performed when initiating and ending darifenacin treatment as well as changing the darifenacin dose. Darifenacin 30 mg once daily (two times greater than the recommended daily dose) co-administered with digoxin at steady state resulted in a small increase in digoxin exposure (AUC: 16% and C_max: 20%). The increase in digoxin exposure could be caused by competition between darifenacin and digoxin for P-glycoprotein. Other transporter-related interactions cannot be excluded.
Antimuscarinic agents: As with any other antimuscarinic agents, the concomitant medication with medicinal products that possess antimuscarinic properties, such as oxybutynin, tolterodine and flavoxate may result in more pronounced therapeutic and side effects. The potentiation of anticholinergic effects with anti-parkinson agents and tricyclic antidepressants may also occur if antimuscarinic agents are used concurrently with such medicinal products. However, no studies involving the interaction with anti-parkinson agents and tricyclic antidepressants have been performed.