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Tolterodine Tartrate Extended Release Capsule

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Tolterodine tartrate extended release (ER) capsules contain tolterodine tartrate. The active moiety, tolterodine, is a muscarinic receptor antagonist.

The chemical name of tolterodine tartrate is (R)-N,Ndiisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine L-hydrogen tartrate. The empirical formula of tolterodine tartrate is C26H37NO7, and its molecular weight is 475.6. The structural formula of tolterodine tartrate is represented below:

Tolterodine tartrate is a white, crystalline powder. The pKa value is 9.87 and the solubility in water is 12 mg/mL. It is soluble in methanol, slightly soluble in ethanol, and practically insoluble in toluene. The partition coefficient (Log D) between noctanol and water is 1.83 at pH 7.3.

Tolterodine tartrate ER capsules for oral administration contain 2 mg or 4 mg of tolterodine tartrate. Inactive ingredients are sucrose, starch, hypromellose, ethylcellulose, medium chain triglycerides, oleic acid, gelatin, and FD&C Blue #2. The 2 mg capsules also contain yellow iron oxide. Both capsule strengths are imprinted with a pharmaceutical grade printing ink that contains shellac glaze, titanium dioxide, propylene glycol, and simethicone.

2. INDICATIONS AND USAGE

Tolterodine tartrate ER capsules are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

3. DOSAGE AND ADMINISTRATION

3.1 Dosing Information

The recommended dose of tolterodine ER 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 ER 2 mg.

3.2 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 ER is 2 mg once daily. Tolterodine ER is 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 ER in this population is not recommended [see WARNINGS AND PRECAUTIONS, USE IN SPECIFIC POPULATIONS].

3.3 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 ER is 2 mg once daily [see DRUG INTERACTIONS].

4. CONTRAINDICATIONS

Tolterodine ER is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Tolterodine ER is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like tolterodine ER, are metabolized to 5-hydroxymethyl tolterodine [see WARNINGS AND PRECAUTIONS].

5. MECHANISM OF ACTION

Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors.

After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels.

Tolterodine has a pronounced effect on bladder function. Effects on urodynamic parameters before and 1 and 5 hours after a single 6.4-mg dose of tolterodine immediate release were determined in healthy volunteers. The main effects of tolterodine at 1 and 5 hours were an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure. These findings are consistent with an antimuscarinic action on the lower urinary tract.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

At approximately 9-12 times the clinical exposure to the pharmacologically active components of tolterodine ER, no anomalies or malformations were observed in mice (based on the AUC of tolterodine and its 5-HMT metabolite at a dose of 20 mg/kg/day). At 14-18 times the exposure (doses of 30 to 40 mg/kg/day) in mice, tolterodine has been shown to be embryolethal and reduce fetal weight, and increase the incidence of fetal abnormalities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification). Pregnant rabbits treated 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. There are no studies of tolterodine in pregnant women. Therefore, tolterodine ER should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus.

6.2 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 ER should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue tolterodine ER in nursing mothers.

6.3 Pediatric Use

Efficacy in the pediatric population has not been demonstrated.

The pharmacokinetics of tolterodine extended release capsules have been evaluated in pediatric patients ranging in age from 11–15 years. The dose-plasma concentration relationship was linear over the range of doses assessed. Parent/metabolite ratios differed according to CYP2D6 metabolizer status. CYP2D6 extensive metabolizers had low serum concentrations of tolterodine and high concentrations of the active metabolite 5-HMT, while poor metabolizers had high concentrations of tolterodine and negligible active metabolite concentrations.

A total of 710 pediatric patients (486 on tolterodine ER, 224 on placebo) aged 5–10 with urinary frequency and urge incontinence were studied in two randomized, placebo-controlled, double-blind, 12-week studies. The percentage of patients with urinary tract infections was higher in patients treated with tolterodine ER (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 ER compared to 0.9% of children treated with placebo.

6.4 Geriatric Use

No overall differences in safety were observed between the older and younger patients treated with tolterodine.

In multiple-dose studies in which tolterodine immediate release 4 mg (2 mg bid) was administered, serum concentrations of tolterodine and of 5-HMT were similar in healthy elderly volunteers (aged 64 through 80 years) and healthy young volunteers (aged less than 40 years). In another clinical study, elderly volunteers (aged 71 through 81 years) were given tolterodine immediate release 2 or 4 mg (1 or 2 mg bid). Mean serum concentrations of tolterodine and 5-HMT in these elderly volunteers were approximately 20% and 50% higher, respectively, than concentrations reported in young healthy volunteers. However, no overall differences were observed in safety between older and younger patients on tolterodine in the Phase 3, 12-week, controlled clinical studies; therefore, no tolterodine dosage adjustment for elderly patients is recommended.

6.5 Renal Impairment

Renal impairment can significantly alter the disposition of tolterodine immediate release and its metabolites. In a study conducted in patients with creatinine clearance between 10 and 30 mL/min, tolterodine and 5-HMT levels were approximately 2–3 fold higher in patients with renal impairment than in healthy volunteers. Exposure levels of other metabolites of tolterodine (e.g., tolterodine acid, N-dealkylated tolterodine acid, N-dealkylated tolterodine, and N-dealkylated hydroxy tolterodine) were significantly higher (10–30 fold) in renally impaired patients as compared to the healthy volunteers. The recommended dose for patients with severe renal impairment (CCr: 10-30 mL/min) is tolterodine ER 2 mg daily. Patients with CCr < 10 mL/min have not been studied and use of tolterodine ER in this population is not recommended [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Tolterodine ER has not been studied in patients with mild to moderate renal impairment [CCr 30-80 mL/min].

6.6 Hepatic Impairment

Liver impairment can significantly alter the disposition of tolterodine immediate release. In a study of tolterodine immediate release conducted in cirrhotic patients (Child-Pugh Class A and B), the elimination half-life of tolterodine immediate release was longer in cirrhotic patients (mean, 7.8 hours) than in healthy, young, and elderly volunteers (mean, 2 to 4 hours). The clearance of orally administered tolterodine immediate release was substantially lower in cirrhotic patients (1.0 ± 1.7 L/h/kg) than in the healthy volunteers (5.7 ± 3.8 L/h/kg). The recommended dose for patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) is tolterodine ER 2 mg once daily. Tolterodine ER is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

6.7 Gender

The pharmacokinetics of tolterodine immediate release and 5-HMT are not influenced by gender. Mean Cmax of tolterodine immediate release (1.6 μg/L in males versus 2.2 μg/L in females) and the active 5-HMT (2.2 μg/L in males versus 2.5 μg/L in females) are similar in males and females who were administered tolterodine immediate release 2 mg. Mean AUC values of tolterodine (6.7 μg·h/L in males versus 7.8 μg·h/L in females) and 5-HMT (10 μg·h/L in males versus 11 μg·h/L in females) are also similar. The elimination half-life of tolterodine immediate release for both males and females is 2.4 hours, and the half-life of 5-HMT is 3.0 hours in females and 3.3 hours in males.

6.8 Race

Pharmacokinetic differences due to race have not been established.

7. WARNINGS AND PRECAUTIONS

7.1 Angioedema

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

7.2 Urinary Retention

Administer tolterodine ER capsules with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. [see CONTRAINDICATIONS].

7.3 Gastrointestinal Disorders

Administer tolterodine ER with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention.

Tolterodine ER, 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].

7.4 Controlled Narrow-Angle Glaucoma

Administer tolterodine ER with caution in patients being treated for narrow-angle glaucoma [see CONTRAINDICATIONS].

7.5 Central Nervous System Effects

Tolterodine ER is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions] 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.

7.6 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 ER is 2 mg once daily. Tolterodine ER is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see DOSAGE AND ADMINISTRATION and USE IN SPECIFIC POPULATIONS].

7.7 Renal Impairment

Renal impairment can significantly alter the disposition of tolterodine and its metabolites. The dose of tolterodine ER 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 ER in this population is not recommended [see DOSAGE AND ADMINISTRATION, and USE IN SPECIFIC POPULATIONS].

7.8 Myasthenia Gravis

Administer tolterodine ER with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.

7.9 Use in Patients with Congenital or Acquired QT Prolongation

In a study of the effect of tolterodine immediate release tablets on the QT interval 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 ER 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 or tolterodine ER.

8. 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.

8.1 Clinical Trials Experience

The efficacy and safety of tolterodine ER capsules was evaluated in 1073 patients (537 assigned to tolterodine ER; 536 assigned to placebo) who were treated with 2, 4, 6, or 8 mg/day for up to 15 months. These include a total of 1012 patients (505 randomized to tolterodine ER 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 ER and in 49% (n=247) of patients receiving placebo. The most common adverse events reported by patients receiving tolterodine ER were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported adverse event for patients treated with tolterodine ER occurring in 23.4% of patients treated with tolterodine ER 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 ER 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 ER 4 mg once daily.

Table 1. Incidence (%) of Adverse Events Exceeding Placebo Rate and Reported in ≥1% of Patients Treated with Tolterodine ER (4 mg daily) in a 12-week, Phase 3 Clinical Trial

The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Similar percentages of patients treated with tolterodine ER or placebo discontinued treatment due to adverse events. Dry mouth was the most common adverse event leading to treatment discontinuation among patients receiving tolterodine ER [n=12 (2.4%) vs. placebo n=6 (1.2%)].

8.2 Post-marketing Experience

The following events have been reported in association with tolterodine use in worldwide post-marketing experience:

General: anaphylactoid reactions, including 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.

9. OVERDOSAGE

A 27-month-old child who ingested 5 to 7 tolterodine immediate release tablets 2 mg was treated with a suspension of activated charcoal and was hospitalized overnight with symptoms of dry mouth. The child fully recovered.

Management of Overdosage

Overdosage with tolterodine tartrate capsules can potentially result in severe central anticholinergic effects and should be treated accordingly.

ECG monitoring is recommended in the event of overdosage. In dogs, changes in the QT interval (slight prolongation of 10% to 20%) were observed at a suprapharmacologic dose of 4.5 mg/kg, which is about 68 times higher than the recommended human dose. In clinical trials of normal volunteers and patients, QT interval prolongation was observed with tolterodine immediate release at doses up to 8 mg (4 mg twice daily) and higher doses were not evaluated.

10. 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. For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (e.g., itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of tolterodine tartrate is 2 mg daily (see DOSAGE AND ADMINISTRATION).

Fluoxetine: 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 Cmax and a 20% decrease in AUC of the 5-hydroxymethyl metabolite. Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be 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 the 5-hydroxymethyl metabolite are only 25% higher during the interaction. No dose adjustment is required when tolterodine and fluoxetine are coadministered.

Other Drugs Metabolized by Cytochrome P450 Isoenzymes: 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-hydroxymethyl metabolite are devoid of any significant inhibitory potential regarding the other isoenzymes.

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.

11. PHARMACOKINETICS

Absorption: In a study with 14C-tolterodine solution in healthy volunteers who received a 5-mg oral dose, at least 77% of the radiolabeled dose was absorbed. Cmax and area under the concentration-time curve (AUC) determined after dosage of tolterodine immediate release are dose-proportional over the range of 1 to 4 mg. Based on the sum of unbound serum concentrations of tolterodine and the 5-hydroxymethyl metabolite (“active moiety”), the AUC of tolterodine extended release 4 mg daily is equivalent to tolterodine immediate release 4 mg (2 mg twice daily). Cmax and Cmin levels of tolterodine extended release are about 75% and 150% of tolterodine immediate release, respectively. Maximum serum concentrations of tolterodine extended release are observed 2 to 6 hours after dose administration.

Effect of Food: There is no effect of food on the pharmacokinetics of tolterodine extended release.

Distribution: Tolterodine is highly bound to plasma proteins, primarily α1-acid glycoprotein. Unbound concentrations of tolterodine average 3.7% ± 0.13% over the concentration range achieved in clinical studies. The 5-hydroxymethyl metabolite is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%. The blood to serum ratio of tolterodine and the 5-hydroxymethyl metabolite averages 0.6 and 0.8, respectively, indicating that these compounds do not distribute extensively into erythrocytes. The volume of distribution of tolterodine following administration of a 1.28-mg intravenous dose is 113 ± 26.7 L.

Metabolism: Tolterodine is extensively metabolized by the liver following oral dosing. The primary metabolic route involves the oxidation of the 5-methyl group and is mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which account for 51% ± 14% and 29% ± 6.3% of the metabolites recovered in the urine, respectively.

Variability in Metabolism: A subset (about 7%) of the Caucasian population is devoid of CYP2D6, the enzyme responsible for the formation of the 5-hydroxymethyl metabolite of tolterodine. The identified pathway of metabolism for these individuals (“poor metabolizers”) is dealkylation via cytochrome P450 3A4 (CYP3A4) to Ndealkylated tolterodine. The remainder of the population is referred to as “extensive metabolizers.” Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers; this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite.

Excretion: Following administration of a 5-mg oral dose of 14C-tolterodine solution to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in feces in 7 days. Less than 1% (< 2.5% in poor metabolizers) of the dose was recovered as intact tolterodine, and 5% to 14% (<1% in poor metabolizers) was recovered as the active 5-hydroxymethyl metabolite.

Special Populations

Age: In Phase 1, multiple-dose studies in which tolterodine immediate release 4 mg (2 mg bid) was administered, serum concentrations of tolterodine and of the 5-hydroxymethyl metabolite were similar in healthy elderly volunteers (aged 64 through 80 years) and healthy young volunteers (aged less than 40 years). In another Phase 1 study, elderly volunteers (aged 71 through 81 years) were given tolterodine immediate release 2 or 4 mg (1 or 2 mg bid). Mean serum concentrations of tolterodine and the 5-hydroxymethyl metabolite in these elderly volunteers were approximately 20% and 50% higher, respectively, than reported in young healthy volunteers. However, no overall differences were observed in safety between older and younger patients on tolterodine in the Phase 3, 12-week, controlled clinical studies; therefore, no tolterodine dosage adjustment for elderly patients is recommended (see PRECAUTIONS, Geriatric Use).

Pediatric: Efficacy in the pediatric population has not been demonstrated.

The pharmacokinetics of tolterodine extended release capsules have been evaluated in pediatric patients ranging in age from 11–15 years. The dose-plasma concentration relationship was linear over the range of doses assessed. Parent/metabolite ratios differed according to CYP2D6 metabolizer status: EMs had low serum concentrations of tolterodine and high concentrations of the active 5-hydroxymethyl metabolite, while PMs had high concentrations of tolterodine and negligible active metabolite concentrations.

Gender: The pharmacokinetics of tolterodine immediate release and the 5-hydroxymethyl metabolite are not influenced by gender. Mean Cmax of tolterodine immediate release (1.6 μg/L in males versus 2.2 μg/L in females) and the active 5-hydroxymethyl metabolite (2.2 μg/L in males versus 2.5 μg/L in females) are similar in males and females who were administered tolterodine immediate release 2 mg. Mean AUC values of tolterodine (6.7 μg·h/L in males versus 7.8 μg·h/L in females) and the 5-hydroxymethyl metabolite (10 μg·h/L in males versus 11 μg·h/L in females) are also similar. The elimination half-life of tolterodine immediate release for both males and females is 2.4 hours, and the half-life of the 5-hydroxymethyl metabolite is 3.0 hours in females and 3.3 hours in males.

Race: Pharmacokinetic differences due to race have not been established.

Renal Insufficiency: Renal impairment can significantly alter the disposition of tolterodine immediate release and its metabolites. In a study conducted in patients with creatinine clearance between 10 and 30 mL/min, tolterodine immediate release and the 5-hydroxymethyl metabolite levels were approximately 2–3 fold higher in patients with renal impairment than in healthy volunteers. Exposure levels of other metabolites of tolterodine (e.g., tolterodine acid, N-dealkylated tolterodine acid, Ndealkylated tolterodine and N-dealkylated hydroxy tolterodine) were significantly higher (10–30 fold) in renally impaired patients as compared to the healthy volunteers. The recommended dose for patients with significantly reduced renal function is tolterodine 2 mg daily (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: Liver impairment can significantly alter the disposition of tolterodine immediate release. In a study of tolterodine immediate release conducted in cirrhotic patients, the elimination half-life of tolterodine immediate release was longer in cirrhotic patients (mean, 7.8 hours) than in healthy, young, and elderly volunteers (mean, 2 to 4 hours). The clearance of orally administered tolterodine immediate release was substantially lower in cirrhotic patients (1.0 ± 1.7 L/h/kg) than in the healthy volunteers (5.7 ± 3.8 L/h/kg). The recommended dose for patients with significantly reduced hepatic function is tolterodine 2 mg daily (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION).

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: DETROL LA, by PHARMACIA AND UPJOHN.

b) Generic drugs: None.

2) How Supplied:

DETROL LA Capsules 2 mg are blue-green with symbol and 2 printed in white ink. DETROL LA Capsules 4 mg are blue with symbol and 4 printed in white ink.

DETROL LA Capsules are supplied as follows:

3) Storage: Store at 20°–25°C (68°–77°F); excursions permitted to 15-30°C (59-86°F). Protect from light.

Rx only

Rev 08/12