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 alter darifenacin pharmacokinetics (see also PHARMACOLOGY under Actions).
CYP2D6 Inhibitors: No special dosing requirements are necessary in the presence of CYP2D6 inhibitors. Darifenacin exposure following 30 mg once daily (two times greater than the recommended daily dose) at steady state was 33% higher in the presence of potent CYP2D6 inhibitor, paroxetine 20 mg.
CYP3A4 Inhibitors: Darifenacin should not be used together with potent CYP3A4 inhibitors (see CONTRAINDICATIONS) such as protease inhibitors (e.g. ritonavir), ketoconazole and itraconazole. Potent P-glycoprotein inhibitors such as ciclosporin 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 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 Cmax from 30 mg once daily 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: Substances 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.
CYP450 mixed inhibitor: The mean Cmax and AUC of darifenacin following 30 mg once daily at steady state were 42% and 34% higher, respectively, in the presence of cimetidine, a mixed CYP450 enzyme inhibitor.
P-glycoprotein inhibitors: Darifenacin is a substrate of the drug efflux transporter P-glycoproteins. The in vivo effect of P-glycoproteins inhibition on darifenacin exposure has not been studied.
Effects of darifenacin on other medicinal products: CYP2D6 substrates: Caution should be exercised when darifenacin is used concomitantly with medications that are predominantly metabolised by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine, or tricyclic antidepressants such as imipramine.
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.
Other medicinal products: 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 Cmax: 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: The concomitant use of Enablex with other antimuscarinic agents may increase the frequency and/or severity of antimuscarinic pharmacological effects such as dry mouth, constipation and blurred vision.