FESOTERODINE Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Antimuscarinic Drugs Coadministration of fesoterodine fumarate extended-release tablets with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.

7.2 CYP3A4 Inhibitors Doses of fesoterodine fumarate extended-release tablets greater than 4 mg are not recommended in adult patients taking strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span>. The fesoterodine fumarate extended-release tablets dose in pediatric patients taking strong CYP3A4 inhibitors is recommended to be reduced to 4 mg once daily in patients &gt;35 kg and is not recommended in patients weighing greater than 25 kg and up to 35 kg <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span>. In a study in adults, coadministration of the strong CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a doubling of the maximum concentration (C max ) and area under the concentration versus time curve (AUC) of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. Compared with CYP2D6 extensive metabolizers not taking ketoconazole, further increases in the exposure to 5-HMT were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, the average (90% confidence interval) increase in C max and AUC of the active metabolite of fesoterodine was approximately 19% (11% to 28%) and 27% (18% to 36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). 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 inhibitors <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

7.3 CYP3A4 Inducers No dosing adjustments are recommended in the presence of CYP3A4 inducers, such as rifampin and carbamazepine. Following induction of CYP3A4 by coadministration of rifampin 600 mg once a day, C max and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of fesoterodine fumarate extended-release tablets 8 mg. The terminal half-life of the active metabolite was not changed.

7.4 CYP2D6 Inhibitors The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, C max and AUC of the active metabolite are increased 1.7- and 2-fold, respectively. No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.

7.5 Drugs Metabolized by Cytochrome P450 In vitro data indicate that at therapeutic concentrations, the active metabolite of fesoterodine does not have the potential to inhibit or induce Cytochrome P450 enzyme systems <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

7.6 Oral Contraceptives In the presence of fesoterodine, there are no clinically significant changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

7.7 Warfarin A clinical study has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity (PT/INR) of warfarin 25 mg. Standard therapeutic monitoring for warfarin should be continued <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

7.8 Drug-Laboratory Test Interactions Interactions between fesoterodine fumarate extended-release tablets and laboratory tests have not been studied.

Fesoterodine fumarate extended-release tablets are contraindicated in patients with any of the following, known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules [s ee Clinical Pharmacology ( 12.1 ) ]. Reactions have included angioedema [ see Warnings and Precautions ( 5.1 ) ]. urinary retention [ see Warnings and Precautions ( 5.2 ) ] gastric retention [ see Warnings and Precautions ( 5.3 ) ] uncontrolled narrow-angle glaucoma [ see Warnings and Precautions ( 5.4 ) ]

• Known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules. ( 4 )
• Urinary retention ( 4 )
• Gastric retention ( 4 )
• Uncontrolled narrow-angle glaucoma. ( 4 )

AND PRECAUTIONS Angioedema : Promptly discontinue fesoterodine fumarate extended-release tablets and provide appropriate therapy. ( 5.1 )

Urinary

Retention : Fesoterodine fumarate extended-release tablets are not recommended in patients with clinically significant bladder outlet obstruction because of the risk of urinary retention. ( 5.2 )

Decreased Gastrointestinal

Motility : Fesoterodine fumarate extended-release tablets are not recommended for use in patients with decreased gastrointestinal motility, such as those with severe constipation. ( 5.3 ) Worsening of Narrow-Angle Glaucoma : Use fesoterodine fumarate extended-release tablets with caution in patients being treated for narrow-angle glaucoma. ( 5.4 )

Central Nervous System

Effects : Somnolence has been reported with fesoterodine fumarate extended-release tablets. Advise patients not to drive or operate heavy machinery until they know how fesoterodine fumarate extended-release tablets affect them. ( 5.5 ) Worsening of Myasthenia Gravis Symptoms : Use fesoterodine fumarate extended-release tablets with caution in patients with myasthenia gravis. ( 5.6 )

5.1 Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine fumarate extended-release tablets. In some cases, angioedema occurred after the first dose; however, cases have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life-threatening. Fesoterodine fumarate extended-release tablets are contraindicated in patients with a known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>. If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine fumarate extended-release tablets should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.

5.2 Urinary Retention in Adult Patients With Bladder Outlet Obstruction The use of fesoterodine fumarate extended-release tablets, like other antimuscarinic drugs, in patients with clinically significant bladder outlet obstruction, including patients with urinary retention, may result in further urinary retention and kidney injury. The use of fesoterodine fumarate extended-release tablets are not recommended in patients with clinically significant bladder outlet obstruction, and is contraindicated in patients with urinary retention <span class="opacity-50 text-xs">[see Contraindications (4) and Adverse Reactions (6.1) ]</span> .

5.3 Decreased Gastrointestinal Motility Fesoterodine fumarate extended-release tablets are associated with decreased gastric motility. Fesoterodine fumarate extended-release tablets are contraindicated in patients with gastric retention <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>. The use of fesoterodine fumarate extended-release tablets are not recommended in patients with decreased gastrointestinal motility, such as those with severe constipation.

5.4 Worsening of Narrow-Angle Glaucoma Fesoterodine fumarate extended-release tablets can worsen controlled narrow-angle glaucoma. Fesoterodine fumarate extended-release tablets are contraindicated in patients with uncontrolled narrow-angle glaucoma <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>. Fesoterodine fumarate extended-release tablets should be used with caution in patients being treated for narrow-angle glaucoma.

5.5 Central Nervous System Effects Fesoterodine fumarate extended-release tablets are associated with anticholinergic central nervous system (CNS) adverse reactions <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . A variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how fesoterodine fumarate extended-release tablets affect them. If a patient experiences anticholinergic CNS effects, fesoterodine fumarate extended-release tablets dose reduction or discontinuation should be considered.

5.6 Worsening of Myasthenia Gravis Symptoms Fesoterodine fumarate extended-release tablets should be used with caution in patients with myasthenia gravis due to the risk of worsening of symptoms of the disease.