Detrol LA tolterodine tartrate 4 mg Capsule, Extended Release, 30-count

5 WARNINGS AND PRECAUTIONS • Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of DETROL LA. ( 5.1 ) • Urinary Retention: use caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. ( 5.2 ) • Gastrointestinal Disorders: use caution in patients with gastrointestinal obstructive disorders or decreased gastrointestinal motility because of the risk of gastric retention.

( 5.3 ) • Controlled Narrow-Angle Glaucoma: use caution in patients being treated for narrow-angle glaucoma. ( 5.4 ) • Central Nervous System Effects: Somnolence has been reported with Detrol LA. Advise patients not to drive or operate heavy machinery until they know how Detrol LA affects them ( 5.5 ). • Myasthenia Gravis: use caution in patients with myasthenia gravis.

( 5.8 ) • QT Prolongation: consider observations from the thorough QT study in clinical decisions to prescribe DETROL LA to patients with a known history of QT prolongation or to patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications. ( 5.9 )

5.1Angioedema Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of DETROL LA. In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, DETROL LA should be discontinued and appropriate therapy promptly provided.

5.2Urinary Retention Administer DETROL LA Capsules with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4) ] .

5.3Gastrointestinal Disorders Administer DETROL LA with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. DETROL LA, like other antimuscarinic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions associated with decreased gastrointestinal motility (e.g., intestinal atony) [ see Contraindications (4) ] .

5.4Controlled Narrow-Angle Glaucoma Administer DETROL LA with caution in patients being treated for narrow-angle glaucoma [see Contraindications (4) ] .

5.5Central Nervous System Effects Detrol LA is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2) ] including dizziness and somnolence [see Adverse Reactions (6.1) ] . 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 the drug’s effects have been determined.

If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

5.6Hepatic Impairment The clearance of orally administered tolterodine immediate release was substantially lower in cirrhotic patients than in the healthy volunteers. For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), the recommended dose for DETROL LA is 2 mg once daily. DETROL LA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6) ].

5.7Renal Impairment Renal impairment can significantly alter the disposition of tolterodine and its metabolites. The dose of DETROL LA should be reduced to 2 mg once daily in patients with severe renal impairment (CCr: 10-30 mL/min). Patients with CCr<10 mL/min have not been studied and use of DETROL LA in this population is not recommended [see Dosage and Administration (2.2) and Use in Specific Populations (8.7) ] .

5.8Myasthenia Gravis Administer DETROL LA with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.

5.9 Use in Patients with Cong…

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (incidence ≥4% and >placebo) were dry mouth, headache, constipation, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience The efficacy and safety of DETROL LA Capsules was evaluated in 1073 patients (537 assigned to DETROL LA; 536 assigned to placebo) who were treated with 2, 4, 6, or 8 mg/day for up to 15 months. These included a total of 1012 patients (505 randomized to DETROL LA 4 mg once daily and 507 randomized to placebo) enrolled in a randomized, placebo-controlled, double-blind, 12-week clinical efficacy and safety study. Adverse events were reported in 52% (n=263) of patients receiving DETROL LA and in 49% (n=247) of patients receiving placebo.

The most common adverse events reported by patients receiving DETROL LA were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported adverse event for patients treated with DETROL LA, occurring in 23.4% of patients treated with DETROL LA and 7.7% of placebo-treated patients. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and dry eyes are expected side effects of antimuscarinic agents.

A serious adverse event was reported by 1.4% (n=7) of patients receiving DETROL LA and by 3.6% (n=18) of patients receiving placebo. Table 1 lists the adverse events, regardless of causality, that were reported in the randomized, double-blind, placebo-controlled 12-week study at an incidence greater than placebo and in greater than or equal to 1% of patients treated with DETROL LA 4 mg once daily. Table 1.

Incidence in nearest integer. (%) of Adverse Events Exceeding Placebo Rate and Reported in ≥1% of Patients Treated with DETROL LA (4 mg daily) in a 12-week, Phase 3 Clinical Trial Body System Adverse Event % DETROL LA n=505 % Placebo n=507 Autonomic Nervous dry mouth 23 8 General headache 6 5 fatigue 2 1 Central/Peripheral Nervous dizziness 2 1 Gastrointestinal constipation 6 4 abdominal pain 4 2 dyspepsia 3 1 Vision xerophthalmia 3 2 vision abnormal 1 0 Psychiatric somnolence 3 2 anxiety 1 0 Respiratory sinusitis 2 1 Urinary dysuria 1 0 The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment.

Similar percentages of patients treated with DETROL LA or placebo discontinued treatment due to adverse events. Dry mouth was the most common adverse event leading to treatment discontinuation among patients receiving DETROL LA [n=12 (2.4%) vs. placebo n=6 (1.2%)].

6.2Post-marketing Experience The following events have been reported in association with tolterodine use in worldwide post-marketing experience: General: anaphylaxis and angioedema; Cardiovascular: tachycardia, palpitations, peripheral edema; Gastrointestinal: diarrhea; Central/Peripheral Nervous: confusion, disorientation, memory impairment, hallucinations. Reports of aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) have been reported after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia.

Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of tolterodine in their causation cannot be reliably determined.

7 DRUG INTERACTIONS • Potent CYP3A4 Inhibitors: Coadministration may increase systemic exposure to DETROL LA. Reduce DETROL LA dose to 2 mg once daily. ( 7.2 ) • Other Anticholinergics (antimuscarinics): Concomitant use with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, and other anticholinergic pharmacological effects. ( 7.6 )

7.1Potent CYP2D6 Inhibitors Fluoxetine, a potent inhibitor of CYP2D6 activity, significantly inhibited the metabolism of tolterodine immediate release in CYP2D6 extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in C max and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT), the pharmacologically active metabolite of tolterodine [see Clinical Pharmacology (12.1) ] . The sums of unbound serum concentrations of tolterodine and 5-HMT are only 25% higher during the interaction.

No dose adjustment is required when tolterodine and fluoxetine are co-administered [see Clinical Pharmacology (12.3) ].

7.2Potent CYP3A4 Inhibitors Ketoconazole (200 mg daily), a potent CYP3A4 inhibitor, increased the mean C max and AUC of tolterodine by 2- and 2.5-fold, respectively, in CYP2D6 poor metabolizers. For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, clarithromycin, or ritonavir, the recommended dose of DETROL LA is 2 mg once daily [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] .

7.3Other Interactions No clinically relevant interactions have been observed when tolterodine was co-administered with warfarin, with a combined oral contraceptive drug containing ethinyl estradiol and levonorgestrel, or with diuretics [see Clinical Pharmacology (12.3) ].

7.4Other Drugs Metabolized by Cytochrome P450 Isoenzymes In vivo drug-interaction data show that tolterodine immediate release does not result in clinically relevant inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine, debrisoquine, S-warfarin, and omeprazole [see Clinical Pharmacology (12.3) ].

7.5Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied.

7.6Other Anticholinergics The concomitant use of DETROL LA with other anticholinergic (antimuscarinic) agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, somnolence, and other anticholinergic pharmacological effects.

Drug Interactions Potent CYP2D6 Inhibitors Fluoxetine is a selective serotonin reuptake inhibitor and a potent inhibitor of CYP2D6 activity. In a study to assess the effect of fluoxetine on the pharmacokinetics of tolterodine immediate release and its metabolites, it was observed that fluoxetine significantly inhibited the metabolism of tolterodine immediate release in extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in C max and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT, the pharmacologically active metabolite of tolterodine).

Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be CYP2D6 extensive metabolizers of tolterodine immediate release to resemble the pharmacokinetic profile in poor metabolizers. The sums of unbound serum concentrations of tolterodine immediate release and 5-HMT are only 25% higher during the interaction. No dose adjustment is required when tolterodine and fluoxetine are co-administered.

Potent CYP3A4 Inhibitors The effect of a 200 mg daily dose of ketoconazole on the pharmacokinetics of tolterodine immediate release was studied in 8 healthy volunteers, all of whom were CYP2D6 poor metabolizers. In the presence of ketoconazole, the mean C max and AUC of tolterodine increased by 2- and 2.5-fold, respectively. Based on these findings, other potent CYP3A4 inhibitors may also lead to increases of tolterodine plasma concentrations.

For patients receiv…