How Much Does Tolterodine Cost in Mexico vs the USA?

1. INDICATIONS AND USAGE Tolterodine tartrate extended-release capsules, USP are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency [see CLINICAL STUDIES (14) ] . Tolterodine tartrate extended-release capsules, USP are an antimuscarinic indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. (1)

2. DOSAGE AND ADMINISTRATION 4 mg capsules taken orally once daily with water and swallowed whole ( 2.1 ) 2 mg capsules taken orally once daily with water and swallowed whole in the presence of: mild to moderate hepatic impairment (Child-Pugh class A or B ( 2.2 ) severe renal impairment [Creatinine Clearance (CCr) 10-30 mL/min] ( 2.2 ) drugs that are potent CYP3A4 inhibitors. ( 2.2 ) Tolterodine tartrate extended-release capsules are not recommended for use in patients with CCr <10 mL/min. ( 2.2 ) Tolterodine tartrate extended-release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C). ( 2.2 ) 2.1 Dosing Information The recommended dose of tolterodine tartrate extended-release capsules is 4 mg once daily with water and swallowed whole. The dose may be lowered to 2 mg daily based on individual response and tolerability; however, limited efficacy data are available for tolterodine tartrate extended-release capsules 2 mg [see CLINICAL STUDIES (14) ] . 2.2 Dosage Adjustment in Specific Populations For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) or severe renal impairment (CCr 10 - 30 mL/min), the recommended dose of tolterodine tartrate extended-release capsules is 2 mg once daily. Tolterodine tartrate extended-release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C). Patients with CCr<10 mL/min have not been studied and use of tolterodine tartrate extended-release capsules in this population is not recommended [see WARNINGS AND PRECAUTIONS (5.6) and USE IN SPECIFIC POPULATIONS (8.6, 8.7) ]. 2.3 Dosage Adjustment in Presence of Concomitant Drugs For patients who are taking drugs that are potent inhibitors of CYP3A4 [e.g. ketoconazole, clarithromycin, ritonavir], the recommended dose of tolterodine tartrate extended-release capsules is 2 mg once daily [see DRUG INTERACTIONS (7.2) ].

4. CONTRAINDICATIONS Tolterodine tartrate extended-release capsules are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Tolterodine tartrate extended-release capsules are also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like tolterodine tartrate extended-release capsules, are metabolized to 5-hydroxymethyl tolterodine [see WARNINGS AND PRECAUTIONS (5.2), (5.3), (5.4) ]. Tolterodine tartrate extended-release capsules are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Tolterodine tartrate extended-release capsules are also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like tolterodine tartrate extended-release capsules, are metabolized to 5-hydroxymethyl tolterodine. ( 4 )

5. WARNINGS AND PRECAUTIONS Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of tolterodine tartrate extended-release capsules. ( 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 tolterodine tartrate extended-release capsules. Advise patients not to drive or operate heavy machinery until they know how tolterodine tartrate extended-release capsules affect 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 tolterodine tartrate extended-release capsules 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 ) 5.1 Angioedema Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of tolterodine tartrate extended-release capsules. In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, tolterodine tartrate extended-release capsules should be discontinued and appropriate therapy promptly provided. 5.2 Urinary Retention Administer tolterodine tartrate extended-release capsules with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see CONTRAINDICATIONS (4) ]. 5.3 Gastrointestinal Disorders Administer tolterodine tartrate extended-release capsules with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Tolterodine tartrate extended-release capsules, 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) ]. 5.4 Controlled Narrow-Angle Glaucoma Administer tolterodine tartrate extended-release capsules with caution in patients being treated for narrow-angle glaucoma [see CONTRAINDICATIONS (4) ]. 5.5 Central Nervous System Effects Tolterodine tartrate extended-release capsules are 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. 5.6 Hepatic 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 tolterodine tartrate extended-release capsules is 2 mg once daily. Tolterodine tartrate extended release-capsules are 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) ]. 5.7 Renal Impairment Renal impairment can significantly alter the disposition of tolterodine and its metabolites. The dose of tolterodine tartrate extended-release capsules 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 tolterodine tartrate extended-release capsules in this population is not recommended [see DOSAGE AND ADMINISTRATION (2.2) and USE IN SPECIFIC POPULATIONS (8.7) ] . 5.8 Myasthenia Gravis Administer tolterodine tartrate extended-release capsules with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction . 5.9 Use in Patients with Congenital or Acquired QT Prolongation In a study of the effect of tolterodine immediate release tablets on the QT interval [see CLINICAL PHARMACOLOGY (12.2) ] , the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day and was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs). The effect of tolterodine 8 mg/day was not as large as that observed after four days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped. These observations should be considered in clinical decisions to prescribe tolterodine tartrate extended-release capsules 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. There has been no association of Torsade de Pointes in the international post-marketing experience with tolterodine immediate release tablets or tolterodine tartrate extended-release capsules.

7. DRUG INTERACTIONS Potent CYP3A4 inhibitors: Coadministration may increase systemic exposure to tolterodine tartrate extended-release capsules. Reduce tolterodine tartrate extended-release capsules 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 ) 7.1 Potent 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) ]. 7.2 Potent 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 tolterodine tartrate extended release capsules is 2 mg once daily [see DOSAGE AND ADMINISTRATION (2.2) and CLINICAL PHARMACOLOGY (12.3) ] . 7.3 Other 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) ]. 7.4 Other 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) ]. 7.5 Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. 7.6 Other Anticholinergics The concomitant use of tolterodine tartrate extended-release capsules with other anticholinergic (antimuscarinic) agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, somnolence and other anticholienrgic pharmacological effects.

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 Inventia Healthcare Limited, at 1-800-270-7585 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The efficacy and safety of tolterodine tartrate extended-release capsules was evaluated in 1073 patients (537 assigned to tolterodine tartrate extended-release capsules; 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 tolterodine tartrate extended-release capsules 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 tolterodine tartrate extended-release capsules and in 49% (n=247) of patients receiving placebo. The most common adverse events reported by patients receiving tolterodine tartrate extended-release capsules were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported adverse event for patients treated with tolterodine tartrate extended-release capsules, occurring in 23.4% of patients treated with tolterodine tartrate extended-release capsules 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 tolterodine tartrate extended-release capsules 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 tolterodine tartrate extended-release capsules 4 mg once daily. Table 1. Incidence* (%) of Adverse Events Exceeding Placebo Rate and Reported in ≥1% of Patients Treated with Tolterodine Tartrate Extended-Release Capsules (4 mg daily) in a 12-week, Phase 3 Clinical Trial * in nearest integer. Body System Adverse Event % Tolterodine tartrate extended-release capsules 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 tolterodine tartrate extended-release capsules or placebo discontinued treatment due to adverse events. Dry mouth was the most common adverse event leading to treatment discontinuation among patients receiving tolterodine tartrate extended-release capsules [n=12 (2.4%) vs. placebo n=6 (1.2%)]. 6.2 Post-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.

8.1 Pregnancy Risk Summary There are no available data with tolterodine tartrate extended-release capsules use in pregnant women to inform drug-associated risks. In animal reproduction studies, oral administration of tolterodine and its 5-HMT metabolite to pregnant mice during organogenesis did not produce adverse developmental outcomes at doses approximately 9 to 12 times the clinical exposure at a dose of 20 mg/kg/day; however, higher doses produced adverse developmental outcomes (see Data) . In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data No anomalies or malformations were observed after oral administration of tolterodine to pregnant mice during organogenesis at approximately 9-12 times the clinical exposure to the pharmacologically active components of tolterodine tartrate extended-release capsules (based on the AUC of tolterodine and its 5-HMT metabolite at a dose of 20 mg/kg/day). At 1418 times the clinical exposure (doses of 30 to 40 mg/kg/day) in mice, tolterodine was embryo-lethal, caused reduced fetal weight, and increased the incidence of fetal abnormalities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification). Pregnant rabbits administered tolterodine subcutaneously at about 0.3-2.5 times the clinical exposure (dose of 0.8 mg/kg/day) did not show any embryotoxicity or teratogenicity.