TOLTERODINE: 2,422 Adverse Event Reports & Safety Profile

Tolterodine tartrate extended-release capsules contain tolterodine tartrate. The active moiety, tolterodine, is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate is (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3 phenylpropanamine L-hydrogen tartrate. The empirical formula of tolterodine tartrate is C26H37NO7,. Its structure is: Tolterodine tartrate is a white, crystalline powder with a molecular weight of 475.6. The pKa value is 9.87 and the solubility in water is 14 mg/mL. It is sparingly soluble in water, slightly soluble in anhydrous ethanol, practically insoluble in heptane. The partition coefficient (Log D) between n-octanol and water is 1.83 at pH 7.3. Tolterodine tartrate extended-release capsules 2 mg capsule for oral administration contains 2 mg of Tolterodine Tartrate USP, and the following inactive ingredients are sugar spheres (which contain sucrose and corn starch), hypromellose, ethylcellulose dispersion type B (which contain ethylcellulose, medium chain triglycerides and oleic acid), talc, gelatin, titanium dioxide, iron oxide yellow, FD & C blue #1 and FD & C red #40. Tolterodine tartrate extended-release capsules 4 mg capsule for oral administration contains 4 mg of Tolterodine Tartrate USP. Inactive ingredients are sugar spheres (which contain sucrose and corn starch), hypromellose, ethylcellulose dispersion type B (which contain ethylcellulose, medium chain triglycerides and oleic acid), talc, gelatin, titanium dioxide, FD & C blue #1 and D & C red #28. Both the 2 mg and 4 mg capsule strengths are imprinted with a pharmaceutical grade printing ink that contains shellac, propylene glycol, black iron oxide, potassium hydroxide. Structure

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)

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 mL/min to 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 less than10 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 capsule 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 <span class="opacity-50 text-xs">[see CLINICAL STUDIES ( 14 )]</span>.

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 mL/min to 30 mL/min), the recommended dose of tolterodine tartrate extended-release capsule 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 less than 10 mL/min have not been studied and use of tolterodine tartrate extended-release capsules in this population is not recommended <span class="opacity-50 text-xs">[see WARNINGS AND PRECAUTIONS ( 5.6 ) and USE IN SPECIFIC POPULATIONS ( 8.6 , 8.7 )]</span>.

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 capsule is 2 mg once daily <span class="opacity-50 text-xs">[see DRUG INTERACTIONS ( 7.2 )]</span>.

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 ) 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 ) ] .

ADVERSE REACTIONS The Phase 2 and 3 clinical trial program for tolterodine tartrate tablets included 3071 patients who were treated with tolterodine tartrate tablets (N=2133) or placebo (N=938). The patients were treated with 1, 2, 4, or 8 mg/day for up to 12 months. No differences in the safety profile of tolterodine were identified based on age, gender, race, or metabolism. The data described below reflect exposure to tolterodine tartrate tablets 2 mg bid in 986 patients and to placebo in 683 patients exposed for 12 weeks in five Phase 3, controlled clinical studies. 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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and approximating rates. Sixty-six percent of patients receiving tolterodine tartrate tablets 2 mg bid reported adverse events versus 56% of placebo patients. The most common adverse events reported by patients receiving tolterodine tartrate tablets were dry mouth, headache, constipation, vertigo/dizziness, and abdominal pain. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and xerophthalmia are expected side effects of antimuscarinic agents. Dry mouth was the most frequently reported adverse event for patients treated with tolterodine tartrate tablets 2 mg bid in the Phase 3 clinical studies, occurring in 34.8% of patients treated with tolterodine tartrate tablets and 9.8% of placebo-treated patients. One percent of patients treated with tolterodine tartrate tablets discontinued treatment due to dry mouth. The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Seven percent of patients treated with tolterodine tartrate tablets 2 mg bid discontinued treatment due to adverse events versus 6% of placebo patients. The most common adverse events leading to discontinuation of tolterodine tartrate tablets were dizziness and headache. Three percent of patients treated with tolterodine tartrate tablets 2 mg bid reported a serious adverse event versus 4% of placebo patients. Significant ECG changes in QT and QTc have not been demonstrated in clinical-study patients treated with tolterodine tartrate tablets 2 mg bid.

Table

5 lists the adverse events reported in 1% or more of the patients treated with tolterodine tartrate tablets 2 mg bid in the 12-week studies. The adverse events are reported regardless of causality.

Table

5. Incidence* (%) of Adverse Events Exceeding Placebo Rate and Reported in >1% of Patients Treated with Tolterodine Tartrate Tablets (2 mg bid) in 12-week, Phase 3 Clinical Studies Body System Adverse Event % Tolterodine Tartrate Tablets N=986 % Placebo N=683 Autonomic Nervous accommodation abnormal dry mouth 2 35 1 10 General chest pain fatigue headache influenza-like symptoms 2 4 7 3 1 3 5 2 Central/Peripheral Nervous vertigo/dizziness 5 3 Gastrointestinal abdominal pain constipation diarrhea dyspepsia 5 7 4 4 3 4 3 1 Urinary dysuria 2 1 Skin/Appendages dry skin 1 0 Musculoskeletal arthralgia 2 1 Vision xerophthalmia 3 2 Psychiatric somnolence 3 2 Metabolic/Nutritional weight gain 1 0 Resistance Mechanism infection 1 0 * in nearest integer. Post-marketing Surveillance 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; 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.

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> including dizziness and somnolence <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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&apos;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 to 30 mL/min). Patients with CCr&lt;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 tartrate immediate release tablets or tolterodine tartrate extended-release capsules.

PRECAUTIONS General Risk of Urinary Retention and Gastric Retention Tolterodine tartrate tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention and to patients with gastrointestinal obstructive disorders, such as pyloric stenosis, because of the risk of gastric retention (see CONTRAINDICATIONS ).

Decreased Gastrointestinal Motility

Tolterodine tartrate tablets, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility.

Controlled

Narrow-Angle Glaucoma Tolterodine tartrate tablets should be used with caution in patients being treated for narrow-angle glaucoma.

Central Nervous

System (CNS)

Effects

Tolterodine tartrate tablets are associated with anticholinergic central nervous system (CNS) effects including dizziness and somnolence (see Adverse Reactions ). 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.

Reduced

Hepatic and Renal Function For patients with significantly reduced hepatic function or renal function, the recommended dose of tolterodine tartrate tablets 1 mg twice daily (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations ).

Myasthenia

Gravis: Tolterodine tartrate tablets should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction. 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, Cardiac Electrophysiology ) , 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 tablets for patients with a known history of QT prolongation or patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications (see PRECAUTIONS, Drug Interactions ) .There has been no association of Torsade de Pointes in the international post-marketing experience with tolterodine tartrate tablets or tolterodine tartrate extended-release capsules. Information for Patients Patients should be informed that antimuscarinic agents such as tolterodine tartrate tablets may produce the following effects: blurred vision, dizziness, or drowsiness. Patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects have been determined.

Drug

Interactions CYP3A4 Inhibitors Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions ). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (e.g., itraconazole, miconazole) or macrolide antibiotics (e.g., erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of tolterodine tartrate tablets is 1 mg twice daily (see DOSAGE AND ADMINISTRATION ). Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with tolterodine were conducted in mice and rats. At the maximum tolerated dose in mice (30 mg/kg/day), female rats (20 mg/kg/day), and male rats (30 mg/kg/day), AUC values obtained for tolterodine were 355, 291, and 462 µg∙h/L, respectively. In comparison, the human AUC value for a 2 mg dose administered twice daily is estimated at 34 µg∙h/L. Thus, tolterodine exposure in the carcinogenicity studies was 9- to 14-fold higher than expected in humans. No increase in tumors was found in either mice or rats. No mutagenic effects of tolterodine were detected in a battery of in vitro tests, including bacterial mutation assays (Ames test) in 4 strains of Salmonella typhimurium and in 2 strains of Escherichia coli , a gene mutation assay in L5178Y mouse lymphoma cells, and chromosomal aberration tests in human lymphocytes. Tolterodine was also negative in vivo in the bone marrow micronucleus test in the mouse. In female mice treated for 2 weeks before mating and during gestation with 20 mg/kg/day (corresponding to AUC value of about 500 µg∙h/L), neither effects on reproductive performance or fertility were seen. Based on AUC values, the systemic exposure was about 15-fold higher in animals than in humans. In male mice, a dose of 30 mg/kg/day did not induce any adverse effects on fertility.

Pregnancy Pregnancy

Category C. At oral doses of 20 mg/kg/day (approximately 14 times the human exposure), no anomalies or malformations were observed in mice. When given at doses of 30 to 40 mg/kg/day, tolterodine has been shown to be embryolethal, reduce fetal weight, and increase the incidence of fetal abnormalities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification) in mice. At these doses, the AUC values were about 20- to 25-fold higher than in humans. Rabbits treated subcutaneously at a dose of 0.8 mg/kg/day achieved an AUC of 100 μg·h/L, which is about 3-fold higher than that resulting from the human dose. This dose did not result in any embryotoxicity or teratogenicity. There are no studies of tolterodine in pregnant women. Therefore, tolterodine tartrate tablets should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus.

Nursing Mothers

Tolterodine is excreted into the milk in mice. Offspring of female mice treated with tolterodine 20 mg/kg/day during the lactation period had slightly reduced body weight gain. The offspring regained the weight during the maturation phase. It is not known whether tolterodine is excreted in human milk; therefore, tolterodine tartrate tablets should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue tolterodine tartrate tablets in nursing mothers.

Pediatric Use

Efficacy in the pediatric population has not been demonstrated. Two pediatric phase 3 randomized, placebo-controlled, double-blind, 12-week studies were conducted using tolterodine extended-release capsules. A total of 710 pediatric patients (486 on tolterodine tartrate extended-release capsules and 224 on placebo) aged 5–10 years with urinary frequency and urge urinary incontinence were studied. The percentage of patients with urinary tract infections was higher in patients treated with tolterodine tartrate extended-release capsules (6.6%) compared to patients who received placebo (4.5%). Aggressive, abnormal, and hyperactive behavior and attention disorders occurred in 2.9% of children treated with tolterodine tartrate extended-release capsules compared to 0.9% of children treated with placebo.

Geriatric

Use Of the 1120 patients who were treated in the four Phase 3, 12-week clinical studies of tolterodine tartrate tablets 474 (42%) were 65 to 91 years of age. No overall differences in safety were observed between the older and younger patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations ).

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 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 receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, miconazole, clarithromycin, ritonavir, the recommended dose of tolterodine tartrate extended-release capsules is 2 mg daily [see Dosage and Administration (2.3) ] . Warfarin In healthy volunteers, coadministration of tolterodine immediate release 4 mg (2 mg bid) for 7 days and a single dose of warfarin 25 mg on day 4 had no effect on prothrombin time, Factor VII suppression, or on the pharmacokinetics of warfarin.

Oral Contraceptives

Tolterodine immediate release 4 mg (2 mg bid) had no effect on the pharmacokinetics of an oral contraceptive (ethinyl estradiol 30 µg/levonorgestrel 150 µg) as evidenced by the monitoring of ethinyl estradiol and levonorgestrel over a 2-month period in healthy female volunteers.

Diuretics

Coadministration of tolterodine immediate release up to 8 mg (4 mg bid) for up to 12 weeks with diuretic agents, such as indapamide, hydrochlorothiazide, triamterene, bendroflumethiazide, chlorothiazide, methylchlorothiazide, or furosemide, did not cause any adverse electrocardiographic (ECG) effects. Effect of Tolterodine on Other Drugs Metabolized by Cytochrome P450 Enzymes Tolterodine immediate release does not cause clinically significant interactions with other drugs metabolized by the major drug-metabolizing CYP enzymes. 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. In vitro data show that tolterodine immediate release is a competitive inhibitor of CYP2D6 at high concentrations (Ki 1.05 µM), while tolterodine immediate release as well as the 5-HMT are devoid of any significant inhibitory potential regarding the other isoenzymes.