Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Pharmacological interactions
Caution should be exercised in coadministration of fesoterodine with other antimuscarinics and medicinal products with anticholinergic properties (e.g. amantadine, tri-cyclic antidepressants, certain neuroleptics ) as this may lead to more pronounced therapeutic- and side-effects (e.g. constipation, dry mouth, drowsiness, urinary retention).
Fesoterodine may reduce the effect of medicinal products that stimulate the motility of the gastro-intestinal tract, such as metoclopramide.



Pharmacokinetic interactions
In vitro data demonstrate that the active metabolite of fesoterodine does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 at clinically relevant plasma concentrations. Thus fesoterodine is unlikely to alter the clearance of medicinal products that are metabolised by these enzymes.

CYP3A4 inhibitors

Potent CYP3A4 inhibitors
Following inhibition of CYP3A4 by co-administration of ketoconazole 200 mg twice daily, Cmax and AUC of the active metabolite of fesoterodine increased 2.0 and 2.3-fold in CYP2D6 extensive metabolisers and 2.1 and 2.5-fold in CYP2D6 poor metabolisers, respectively. Therefore, the maximum dose of fesoterodine should be restricted to 4 mg when used concomitantly with potent CYP3A4 inhibitors (e.g. atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir (and all ritonavir boosted PI-regimens), saquinavir and telithromycin (see sections 4.2 and 4.4)).

Moderate CYP3A4 inhibitors
Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, Cmax and AUC of the active metabolite of fesoterodine increased approximately 19% and 27%, respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice).

Weak CYP3A4 inhibitors
The effect of weak CYP3A4 inhibitors (e.g. cimetidine), was not examined; it is not expected to be in excess of the effect of moderate inhibitor.

CYP3A4 inducers
Following induction of CYP3A4 by coadministration of rifampicin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of fesoterodine 8 mg.

Induction of CYP3A4 may lead to subtherapeutic plasma levels. Concomitant use with CYP3A4 inducers (e.g. carbamazepine, rifampicin, phenobarbital, phenytoin, St John’s Wort) is not recommended (see section 4.4).

CYP2D6 inhibitors
The interaction with CYP2D6 inhibitors was not tested clinically. Mean Cmax and AUC of the active metabolite are 1.7 and 2-fold higher, respectively, in CYP2D6 poor metabolisers as compared to extensive metabolisers. Co-administration of a potent CYP2D6 inhibitor may result in increased exposure and adverse events. A dose reduction to 4 mg may be needed (see section 4.4).

Oral contraceptives
Fesoterodine does not impair the suppression of ovulation by oral hormonal contraception. In the presence of fesoterodine there are no changes in the plasma concentrations of combined oral contraceptives containing ethinylestradiol and levonorgestrel.

Warfarin
A clinical study in healthy volunteers has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity of a single dose of warfarin.

Paediatric population
Interaction studies have only been performed in adults.