DARIFENACIN HYDROBROMIDE Drug Interactions: What You Need to Know

INTERACTIONS Caution should be taken when darifenacin extended-release tablets are used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine and tricyclic antidepressants ( 7.2 ) The concomitant use of darifenacin extended-release tablets with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects of gastrointestinal motility ( 7.3 )

7.1 CYP3A4 Inhibitors The systemic exposure of darifenacin from darifenacin extended-release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of darifenacin extended-release tablet should not exceed 7.5 mg when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (for example, erythromycin, fluconazole, diltiazem and verapamil) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12.3 )]</span> .

7.2 CYP2D6 Inhibitors No dosing adjustments are recommended in the presence of CYP2D6 inhibitors (for example, paroxetine, fluoxetine, quinidine and duloxetine) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.3 CYP2D6 Substrates Caution should be taken when darifenacin extended-release tablet is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window (for example, flecainide, thioridazine and tricyclic antidepressants) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.4 CYP3A4 Substrates Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.5 Combination oral contraceptives Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of the combination oral contraceptives containing levonorgestrel and ethinyl estradiol <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.6 Warfarin Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with darifenacin (30 mg daily) at steady-state. Standard therapeutic prothrombin time monitoring for warfarin should be continued.

7.7 Digoxin Darifenacin (30 mg daily) did not have a clinically relevant effect on the pharmacokinetics of digoxin (0.25 mg) at steady-state. Routine therapeutic drug monitoring for digoxin should be continued <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.8 Other Anticholinergic Agents The concomitant use of darifenacin extended-release tablets with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects on gastrointestinal motility.

Darifenacin extended-release tablets are contraindicated in patients with, or at risk for, the following conditions ( 4 ): urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Darifenacin extended-release tablets are contraindicated in patients with, or at risk for, the following conditions: urinary retention gastric retention, or uncontrolled narrow-angle glaucoma.

AND PRECAUTIONS Darifenacin extended-release tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention ( 5.1 ) Darifenacin extended-release tablets should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention ( 5.2 ) Darifenacin extended-release tablets should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks ( 5.3 )

Central Nervous System

Effects: Somnolence has been reported with darifenacin extended-release tablets. Advise patients not to drive or operate heavy machinery until they know how darifenacin extended-release tablets affects them ( 5.5 )

5.1 Risk of Urinary Retention Darifenacin extended-release tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

5.2 Decreased Gastrointestinal Motility Darifenacin extended-release tablets should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Darifenacin extended-release tablets, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as severe constipation, ulcerative colitis, and myasthenia gravis.

5.3 Controlled Narrow-Angle Glaucoma Darifenacin extended-release tablets should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks.

5.4 Angioedema Angioedema of the face, lips, tongue, and/or larynx have been reported with darifenacin. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, darifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

5.5 Central Nervous System Effects Darifenacin extended-release tablets are associated with anticholinergic central nervous system (CNS) effects <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations 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 darifenacin extended-release tablets affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

5.6 Patients with Hepatic Impairment The daily dose of darifenacin extended-release tablet should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Darifenacin extended-release tablet has not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore is not recommended for use in this patient population <span class="opacity-50 text-xs">[see Dosage and Administration ( 2 ) Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span> .