VA Class:AU350
ATC Class:G04BD07
Tolterodine, a synthetic tertiary amine antimuscarinic agent, is a genitourinary antispasmodic.17,19
Tolterodine tartrate is used in the treatment of overactive bladder for the relief of symptoms associated with voiding such as urge urinary incontinence, urgency, and frequency.1,3,9,10,19,23 Efficacy of the drug has not been established in pediatric patients.1,23
According to the International Continence Society (ICS), overactive bladder disorder is characterized by involuntary detrusor contractions that may occur spontaneously or may be provoked (by rapid filling, alterations of posture, coughing, walking, jumping).15 An overactive bladder of neurogenic origin usually has been referred to as a hyperflexic disorder, whereas one that is nonneurogenic is referred to as an unstable disorder.2,15,19 The hyperflexic overactive bladder disorder usually involves a neurologic disorder.2,10,15 Tolterodine tartrate is used for the management of symptoms associated with both neurogenic and nonneurogenic overactive bladder.17,18
Results of several 12-week placebo-controlled studies in patients with an overactive bladder indicate that tolterodine tartrate (1 or 2 mg twice daily as conventional tablets) is more effective than placebo in relieving urinary symptoms (e.g., urinary frequency, urgency, urge incontinence).1,2,3,9 Patients receiving tolterodine tartrate 2 mg twice daily (as conventional tablets) or placebo experienced mean decreases in the number of micturitions per 24 hours of 1.7-2.7 or 1.2-1.6, respectively, and mean increases in the volume of urine voided per micturition of 29-38 or 6-14 mL, respectively.1 In these studies, therapy with tolterodine was not associated with substantial decreases in the mean number of episodes of incontinence per 24 hours or per week compared with placebo (1.3-1.7 or 10.6, respectively, versus 0.9-1.3 or 6.9, respectively).1 However, analysis of pooled data that excluded patients with no episodes of incontinence at baseline from several studies of 12 weeks' duration indicate that tolterodine therapy was associated with a statistically significant decrease in the mean number of episodes of incontinence per 24 hours compared with placebo (1.7, 1.6, and 1.1 with tolterodine tartrate 1 mg twice daily, tolterodine tartrate 2 mg twice daily, and placebo, respectively).2,8,10
Tolterodine tartrate dosages of 1 or 2 mg twice daily (as conventional tablets) appear to have similar efficacy concerning number of micturitions per 24 hours, episodes of incontinence, and volume of urine voided per micturition.2,8 However, in one 4-week study in which cystometry was used to evaluate outcomes, only the 2-mg dosage was more effective than placebo in increasing the volume at first contraction and the maximum cystometric capacity, although both dosages increased the residual volume compared with placebo.2,8,16 In addition, in several studies, patients' perceptions concerning improvement of symptoms also were substantially greater using the higher dosage of tolterodine.2,8
Extended-release tolterodine tartrate also appears to be more effective than placebo in relieving urinary symptoms (e.g., urinary frequency, urgency, urge incontinence) in patients with overactive bladder.23 In a 12-week randomized, double-blind, placebo-controlled study in previously treated (i.e., with conventional tolterodine tartrate tablets or other anticholinergic agents) and untreated patients, treatment with tolterodine tartrate 4 mg once daily in the morning (as extended-release capsules) or placebo resulted in median decreases in the number of micturitions per 24 hours of 1.8 or 1.2, respectively, median increases in the volume of urine voided per micturition of 34 or 14 mL, respectively, and median decreases in the number of incontinence episodes per week of 11.8 or 6.9, respectively.23
Limited data indicate that efficacy of tolterodine (in reducing the number of micturitions and episodes of incontinence per 24 hours and increasing the volume voided per micturition) has been maintained after 6 and 12 months of therapy.2,3,8
Single daily doses of extended-release capsules of tolterodine tartrate appear to be slightly more effective in relieving certain urinary symptoms (i.e., urge incontinence) than 2 daily doses of conventional tablets of the drug.24,25 In a 12-week comparative, randomized, double-blind, placebo-controlled study in patients with overactive bladder, treatment with tolterodine tartrate extended-release capsules (4 mg once daily), tolterodine tartrate conventional tablets (2 mg twice daily), or placebo resulted in median decreases in the number of micturitions per 24 hours of 1.8, 1.7, or 1.2, respectively, median increases in the volume of urine voided per micturition of 34, 29, or 14 mL, respectively, and median decreases in the number of incontinence episodes per week of 11.8, 10.6, or 6.9, respectively.24,25
In one randomized, double-blind, placebo-controlled study of 12 weeks' duration evaluating the comparative efficacy and safety of tolterodine tartrate (2 mg twice daily as conventional tablets) and oxybutynin (5 mg 3 times daily) in patients with overactive bladder, efficacy of the 2 drugs appeared to be similar in reducing urinary symptoms of the disorder.3,12 Administration of tolterodine tartrate, oxybutynin, or placebo was associated with decreased number of micturitions per 24 hours in 21, 19.5, or 10.5% of patients, respectively, while the mean number of episodes of incontinence decreased by 47, 71, or 19%, respectively.12 In addition, increases in the volume of urine voided per micturition were similar in patients receiving tolterodine (mean increase of 27%) and oxybutynin (mean increase of 31%) compared with a 7% increase in patients receiving placebo.12 It appears that tolterodine was better tolerated than oxybutynin; tolterodine was associated with a lower incidence of dry mouth than oxybutynin.2,3,9,12,21 (See Cautions.) Analysis of pooled data from other comparative studies of 12 weeks' duration using the same dosages of tolterodine tartrate and oxybutynin also indicate that efficacy of tolterodine is similar to that of oxybutynin in decreasing the mean number of micturitions per 24 hours and the mean number of episodes of incontinence;2,3,8,10,19,21 although both drugs increased the mean volume voided per micturition, such increases were greater with oxybutynin than with tolterodine.2,8,21 Some clinicians, however, consider tolterodine to be less effective but better tolerated than older agents (e.g., oxybutynin) in the management of overactive bladder.9
Tolterodine tartrate (administered twice daily as conventional tablets) appeared to be less effective in relieving urinary symptoms than a single daily dose of extended-release oxybutynin in one study.26 In this 12-week comparative, randomized, double-blind study in patients with overactive bladder, treatment with tolterodine tartrate conventional tablets (2 mg twice daily) or oxybutynin chloride extended-release tablets (10 mg once daily) resulted in decreased micturition frequency (from a mean of 91.8 to 67.1 episodes per week with extended-release oxybutynin or from a mean of 91.6 to 71.5 episodes per week with conventional tolterodine tartrate), a decreased number of urge incontinence episodes (from a mean of 25.6 to 6.1 or from a mean of 24.1 to 7.8 episodes per week, respectively), and a decreased number of total incontinence episodes (from a mean of 28.6 to 7.1 or from a mean of 27 to 9.3 episodes per week, respectively).25,26 The incidence of adverse effects (e.g., dry mouth) was similar between patients receiving conventional tolterodine tartrate and extended-release oxybutynin.26
Tolterodine tartrate is administered orally.1,2,3,10,23 Tolterodine tartrate extended-release capsules should be administered with adequate amounts of fluid and swallowed whole.23
For the management of urge urinary incontinence, urgency, and frequency in patients with overactive bladder, the usual initial adult dosage of tolterodine tartrate is 2 mg twice daily as conventional tablets or 4 mg once daily as extended-release capsules.1,2,3,9,10,23 Dosage may be reduced to 1 mg twice daily (as conventional tablets) or 2 mg once daily (as extended-release capsules) according to individual response and tolerance.1,2,10,23 In addition, patients receiving drugs that inhibit the cytochrome P-450 isoenzyme 3A4 should receive a reduced dosage of 1 mg of tolterodine tartrate twice daily (as conventional tablets) or 2 mg once daily (as extended-release capsules).1,2,9,10,23 (See Cytochrome P-450 Isoenzyme 3A4 Inhibitors under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) However, the manufacturer states that efficacy data for the lower dosage (i.e., 2 mg) of extended-release capsules are limited.23
Dosage in Renal and Hepatic Impairment
Renal or hepatic impairment may substantially affect the disposition of tolterodine.1,23 Therefore, the recommended dosage of tolterodine tartrate is 1 mg twice daily (as conventional tablets) or 2 mg once daily (as extended-release capsules) in patients with substantially reduced renal or hepatic function.1,2,3,9,10,23
Tolterodine tartrate is an antimuscarinic agent.1,2,3,4,5,6,7,8,9,23 Adverse effects frequently associated with these agents include dry mouth, constipation, abnormal vision (including abnormal accommodation), urinary retention, and xerophthalmia.1,2,23 Dry mouth,1,2,3,4,5,6,7,8,9,10,12,16,19,20,21,23 constipation,1,2,3,9,10,19,21,23 xerophthalmia,1,2,9,10,23 abnormal ocular accommodation,1,2,6,10,19 and urinary retention1,2,10 have been reported in patients receiving tolterodine tartrate.1,2,23 However, in controlled studies, the incidence of visual accommodation abnormalities and urinary retention generally was similar or less in patients receiving usual dosages of tolterodine than in those receiving placebo.1,2,10
In therapeutic dosages, tolterodine tartrate generally is well tolerated.3,5,6,17,18,20 In placebo-controlled, phase III clinical studies of 12 weeks' duration, adverse effects were reported in 74, 66, 52, or 49-56% of patients receiving tolterodine tartrate 1 mg twice daily as conventional tablets, tolterodine tartrate 2 mg twice daily as conventional tablets, tolterodine tartrate 4 mg once daily as extended-release capsules, or placebo, respectively.1,2,23 Most adverse effects of tolterodine were mild to moderate.3,17,18 The most frequent adverse effect in these patients was dry mouth,1,2,3,4,5,23 occurring in about 24, 35, 23, or 8-10% of patients, respectively.1,2,23 In one study, single daily doses of extended-release capsules were better tolerated than 2 daily doses of conventional tablets; dry mouth occurred in 23% of patients receiving extended-release capsules and in 30% of those receiving conventional tablets of the drug.24 When tolterodine tartrate was compared with oxybutynin (another antimuscarinic agent used for overactive bladder), dry mouth was reported in about 40 or 78% of patients receiving tolterodine (2 mg twice daily as conventional tablets) or oxybutynin (5 mg 3 times daily), respectively.1,2,9,19,21 Discontinuance of therapy because of dry mouth has been reported in about 1-2% of patients receiving tolterodine tartrate.1,2,23 There are no studies to date comparing safety of tolterodine tartrate with that of extended-release oxybutynin chloride or other antimuscarinic agents recommended for the treatment of overactive bladder.17,18
Other adverse effects reportedly associated with tolterodine tartrate therapy include headache,1,2,3,7,8,9,10,16,19,23 and constipation.1,2,3,9,10,16,19 The incidence of these adverse effects also was dose related, occurring more frequently in those receiving 2 mg of tolterodine tartrate twice daily than in those receiving 1 mg twice daily.2,23 Vertigo/dizziness1 and abdominal pain1,23 also have been reported. Serious adverse effects occurred in 3, 1, or 4% of patients receiving tolterodine tartrate 2 mg twice daily as conventional tablets, tolterodine tartrate 4 mg once daily as extended-release capsules, or placebo, respectively.1,23 Discontinuance of tolterodine because of adverse effects (mainly secondary to headache and dizziness) occurred most frequently during the first 4 weeks of therapy.1,23 Discontinuance of therapy because of adverse effects has been reported in 1.7, 7, 2, or 1-6% of patients receiving tolterodine tartrate 1 mg twice daily as conventional tablets, tolterodine tartrate 2 mg twice daily as conventional tablets, tolterodine tartrate 4 mg once daily as extended-release capsules, or placebo, respectively.1,2,23
In long-term studies (up to 12 months' duration), the incidence of adverse effects was similar to that observed in the phase III controlled studies of 12 weeks' duration, and no new adverse effects of clinical importance were observed.2 The safety of tolterodine tartrate was not influenced by age, gender, race, or the oxidizer phenotype in these studies.1,17,23
Headache was reported in 6.6, 7, 6, or 4-7% of patients receiving tolterodine tartrate 1 mg twice daily as conventional tablets, tolterodine tartrate 2 mg twice daily as conventional tablets, tolterodine tartrate 4 mg once daily as extended-release capsules, or placebo, respectively.1,2,23 Other adverse nervous system effects of tolterodine include vertigo/dizziness,1,2,3,23 fatigue,1,2,3,23 or somnolence,1,2,23 occurring in 5, 4, or 3%, respectively, of patients receiving tolterodine tartrate 2 mg twice daily as conventional tablets1 and in 2, 2, or 3%, respectively, of those receiving tolterodine tartrate 4 mg once daily as extended-release capsules.23 Anxiety23 was reported in 1% of patients receiving tolterodine tartrate 4 mg once daily as extended-release capsules.23 However, a causal relationship of the drug to some of these adverse effects has not been established.17,18,23
Confusion, disorientation, memory impairment, and hallucinations have been reported during postmarketing experience with tolterodine, although a causal relationship to the drug for these effects has not been established.1,23,30,31,32,38 In addition, aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) has been reported during postmarketing experience after tolterodine therapy was initiated in patients taking acetylcholinesterase inhibitors for the treatment of dementia.1,23,35
The most frequent adverse GI effect reported in patients receiving tolterodine tartrate is dry mouth,1,2,3,4,5,6,8,12,20,23 occurring in about 24, 35, 23, or 8-16% of patients receiving 1 mg twice daily as conventional tablets, 2 mg twice daily as conventional tablets, tolterodine tartrate 4 mg once daily as extended-release capsules, or placebo, respectively.1,2,23
Abdominal pain has been reported in about 6, 5, 4, or 2-3% of patients receiving tolterodine 1 mg twice daily as conventional tablets, tolterodine tartrate 2 mg twice daily as conventional tablets, tolterodine tartrate 4 mg once daily as extended-release capsules, or placebo, respectively.1,2,23 Constipation was reported in about 6, 7, 6, or 4-5% of patients receiving tolterodine tartrate 1 mg twice daily as conventional tablets, tolterodine tartrate 2 mg twice daily as conventional tablets, tolterodine tartrate 4 mg once daily as extended-release capsules, or placebo, respectively.1,2,23 Dyspepsia,1,2,23 diarrhea,1,2,23 and weight gain1,2 also have been reported in patients receiving tolterodine.1,2,23 However, a causal relationship of the drug to some of these adverse effects has not been established.17,23
Xerophthalmia has been reported in 3, 3, or 2% of patients receiving tolterodine tartrate 2 mg twice daily as conventional tablets, tolterodine tartrate 4 mg once daily as extended-release capsules, or placebo, respectively.1,2,23 Abnormal accommodation and other visual abnormalities also have been reported among patients receiving the drug.1,2,6,7,16,19,23
Dermatologic and Sensitivity Reactions
Dry skin1,2 has been reported in approximately 1% of patients receiving tolterodine tartrate dosages of 2 mg twice daily as conventional tablets.1,2 Anaphylactoid reactions (e.g., angioedema) have been reported in patients receiving tolterodine during postmarketing surveillance.1,2,23 However, a causal relationship of the drug to some of these effects has not been established.17,18
In a study evaluating the effect of tolterodine tartrate on cardiac electrophysiology in healthy individuals, a dosage of 4 mg twice daily (twice the maximum recommended dosage) (as conventional tablets) appeared to have a greater effect in prolonging the QTc interval (5.63 or 11.84 msec increase from baseline as measured by machine or manually, respectively) than a dosage of 2 mg twice daily (1.16 or 5.01 msec increase from baseline as measured by machine or manually, respectively).1,23 Prolongation of the QTc interval was found to correlate with plasma tolterodine concentration and was more pronounced in individuals with the poor-oxidizer phenotype than in those with the extensive-oxidizer phenotype.1,23 (See Pharmacokinetics: Elimination.) Heart rate increased by a mean of 2 or 6.3 beats/minute following administration of tolterodine 2 mg twice daily or 4 mg twice daily, respectively.1,23 Associated torsades de pointes has not been reported during postmarketing experience with tolterodine conventional tablets or extended-release capsules.1,23 (See Cautions: Precautions and Contraindications.)
Tachycardia, palpitations, and peripheral edema have been reported in patients receiving tolterodine during postmarketing surveillance;1,23 however, a causal relationship to the drug has not been established.1,23
Other adverse effects that have been reported in at least 1% of patients receiving tolterodine tartrate include arthralgia,1,2 chest pain,1,2 dysuria,1,23 infection,1,2 flu-like symptoms,1,2 and sinusitis.23 However, a causal relationship of the drug to some of these adverse effects has not been established.17,18 Hyponatremia also has been reported in at least 2 geriatric patients receiving tolterodine.33,34
Precautions and Contraindications
Because of the possibility of urinary or gastric retention, tolterodine tartrate should be used with caution in patients with clinically important bladder outflow obstruction or GI obstructive disorders (e.g., pyloric stenosis); like other antimuscarinic agents, tolterodine should be used with caution in patients with decreased GI motility.1,2,10,23 The drug also should be used with caution in patients receiving therapy for angle-closure glaucoma and in patients with myasthenia gravis, which is characterized by decreased cholinergic activity at the neuromuscular junction.1,2,23
Patients should be informed that tolterodine, like other antimuscarinic agents, may cause blurred vision, dizziness, or drowsiness;1,2,23 patients should be advised to exercise caution when engaging in potentially hazardous activities until the drug's effects have been determined.1,23
Renal or hepatic impairment may substantially affect the disposition of tolterodine; therefore, dosage should be reduced in patients with substantially reduced renal or hepatic function.1,23 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
Prolongation of the QTc interval has been observed following administration of therapeutic (2 mg twice daily) and supratherapeutic (4 mg twice daily) dosages of tolterodine tartrate in healthy adults.1,23 Prolongation of the QTc interval was more pronounced in individuals with the poor-oxidizer phenotype than in those with the extensive-oxidizer phenotype.1,23 (See Cautions: Cardiovascular Effects.) These observations should be considered when use of tolterodine is contemplated in patients with a history of QT interval prolongation or in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents.1,23
Tolterodine tartrate is contraindicated in patients with urinary retention,1,2,9,10,23 gastric retention,1,2,10,23 or uncontrolled angle-closure glaucoma.1,2,9,10,23 Tolterodine tartrate also is contraindicated in patients who are hypersensitive to the drug or any ingredient in its formulations.1,2,23
Efficacy of tolterodine tartrate in children younger than 18 years of age has not been established.1,2,17,23
In pediatric patients 5-10 years of age with urinary frequency and urge incontinence, the incidence of urinary tract infections was higher in patients receiving tolterodine tartrate extended-release capsules (6.6%) than in those receiving placebo (4.5%).1,23 Aggressive, abnormal, and hyperactive behavior and attention disorders were reported in 2.9% of pediatric patients receiving tolterodine extended-release capsules compared with 0.9% of those receiving placebo.1,23
While safety and efficacy of tolterodine tartrate in geriatric patients have not been studied specifically, several hundred patients receiving the drug in clinical studies were 65-91 years of age.1 Although in one phase I clinical study higher serum concentrations of tolterodine and its 5-hydroxymethyl metabolite were reported in healthy geriatric individuals (71-81 years of age) compared with those reported in young healthy adults, overall differences in safety were not observed between geriatric and younger patients.1,23 Therefore, dosage adjustment solely on the basis of age is not required for otherwise healthy geriatric patients.1,17,18 Aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) has been reported during postmarketing experience after tolterodine therapy was initiated in patients taking acetylcholinesterase inhibitors for the treatment of dementia. 1,23,35 (See Cautions: Nervous System Effects.) Hyponatremia also has been reported in at least 2 geriatric patients receiving tolterodine.33,34
Mutagenicity and Carcinogenicity
Tolterodine was not mutagenic in several in vitro tests including the bacterial mutation assay (Ames test) in 4 strains of Salmonella typhimurium and 2 strains of Escherichia coli , a gene mutation assay in L5178Y mouse lymphoma cells, and chromosomal aberration tests in human lymphocytes.1,23 No evidence of mutagenicity was observed in vivo in the bone marrow micronucleus test in mice.1,23
No evidence of increased incidence of tumors was observed in carcinogenicity studies in mice, female rats, and male rats receiving tolterodine tartrate dosages of 30, 20, and 30 mg/kg daily, respectively (9-14 times the human systemic exposure at the recommended oral dosage of 2 mg twice daily (as conventional tablets) based on area under the concentration-time curve [AUC] comparisons).1,23
Pregnancy, Fertility, and Lactation
Reproduction studies in mice using tolterodine tartrate dosages of 20 mg/kg daily (about 14 times the usual human exposure based on unbound tolterodine concentrations) have not revealed evidence of fetal anomalies or malformations.1,23 However, embryolethality, reduced fetal weight, and increased incidence of fetal abnormalities (e.g., cleft palate, digital abnormalities, intra-abdominal hemorrhage, skeletal abnormalities including reduced ossification) were observed in mice receiving tolterodine tartrate dosages of 30-40 mg/kg daily (20-25 times the human systemic exposure based on AUC comparisons).1,2,10,23 In addition, no evidence of embryotoxicity or teratogenicity was observed in rabbits receiving tolterodine tartrate dosages of 0.8 mg/kg daily subcutaneously (approximately 3 times the human systemic exposure at the recommended human dosage based on AUC comparisons).1,2,10,23 There are no adequate and controlled studies to date using tolterodine tartrate in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risk to the fetus.1,23
When administered for 2 weeks prior to mating and during gestation in female mice, tolterodine tartrate dosages of 20 mg/kg daily (about 15 times the human systemic exposure based on AUC comparisons) were not associated with impairment of fertility or reproductive performance.1,23 In addition, in male mice receiving tolterodine tartrate dosages of 30 mg/kg daily, no adverse effects on fertility were observed.1,23
It is not known whether tolterodine is distributed into human milk.1,10,23 However, the drug is distributed into milk in mice.1,10,23 Administration of tolterodine tartrate dosages of 20 mg/kg to nursing mice resulted in slightly decreased body weight gain, although offspring regained the weight during maturation.1,23 The manufacturer states that tolterodine tartrate should not be used in nursing women, and a decision should be made whether to discontinue nursing or the drug in these patients.1,23
Drugs Affecting Hepatic Microsomal Enzymes
The manufacturer states that tolterodine does not appear to cause clinically important interactions with drugs metabolized by major microsomal cytochrome P-450 (CYP) isoenzymes.1,23 Data from in vivo studies indicate that tolterodine does not inhibit CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4, as evidenced by a lack of effects on the pharmacokinetics of caffeine, debrisoquin, S -warfarin, and omeprazole when these agents were used concomitantly with tolterodine.1,23 However, tolterodine has been shown to inhibit CYP2D6 in vitro at high concentrations (KI 1.05 µM).1,23
Since metabolism of tolterodine is mediated by CYP2D6 in individuals with the extensive-oxidizer phenotype (see Pharmacokinetics: Elimination), concomitant administration with drugs that inhibit this isoenzyme may result in increased concentrations of tolterodine and decreased concentrations of the active 5-hydroxymethyl metabolite.1,2
Fluoxetine, a potent inhibitor of CYP2D6, substantially inhibits the oxidation pathway responsible for tolterodine's metabolism in extensive metabolizers; therefore, the pharmacokinetic profile of patients receiving fluoxetine and tolterodine concomitantly resembles that of poor metabolizers.1,2 The area under the serum concentration-time curve (AUC) of tolterodine has increased 4.8-fold and peak serum concentrations and AUC of the 5-hydroxymethyl metabolite (the main metabolite of tolterodine in extensive-oxidizer phenotypes) have been reduced by approximately 52 and 20%, respectively, in patients with the extensive-oxidizer phenotype who received concomitant fluoxetine.1,2,10 However, since the sum of the serum concentrations of unbound tolterodine and the 5-hydroxymethyl metabolite was only 25% higher than that in patients receiving tolterodine without fluoxetine, the manufacturer states that adjustment of tolterodine tartrate dosage is not necessary in patients receiving concomitant fluoxetine therapy.1,2
Cytochrome P-450 Isoenzyme 3A4 Inhibitors
Concomitant use of ketoconazole (200 mg daily) with tolterodine (as conventional tablets) in healthy individuals with poor-oxidizer phenotypes (see Pharmacokinetics: Elimination) has resulted in a 2- or 2.5-fold increase in peak plasma concentrations or AUC, respectively, of tolterodine.1,23 Therefore, the manufacturer states that concomitant use of tolterodine with other potent CYP3A4 inhibitors, such as azole antifungals (e.g., itraconazole, miconazole), macrolide antibiotics (e.g., erythromycin, clarithromycin), cyclosporine, or vinblastine, also may result in increased plasma tolterodine concentrations and recommends that the dosage of tolterodine tartrate not exceed 1 mg twice daily (as conventional tablets) or 2 mg once daily (as extended-release capsules) when these drugs are used concomitantly.1,23 (See Dosage and Administration.)
ECG abnormalities were not reported in patients receiving a diuretic (e.g., bendroflumethiazide, chlorothiazide, furosemide, indapamide, hydrochlorothiazide, methyclothiazide, triamterene) concomitantly with tolterodine tartrate (administered as conventional tablets at dosages up to 4 mg twice daily for up to 12 weeks).1,2,23
Limited data indicate that tolterodine has no effect on the pharmacokinetics of oral estrogen-progestin contraceptives (e.g., those containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel).1,2 In healthy premenopausal women receiving oral contraceptives and tolterodine tartrate dosages of 2 mg twice daily (as conventional tablets) for a 2-month cycle, no changes in the pharmacokinetics of either steroid were observed.1,2,17,23
Acetylcholinesterase Inhibitors
When tolterodine therapy was initiated in patients taking acetylcholinesterase inhibitors for the treatment of dementia, aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) has been reported.1,23,35 Some clinicians recommend avoidance of tolterodine in dementia patients receiving acetylcholinesterase inhibitors.35
The potential for tolterodine to cause prolongation of the QTc interval should be considered when used concomitantly with class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents.23 (See Cautions: Cardiovascular Effects.)
In a study in healthy individuals receiving 2 mg of tolterodine tartrate twice daily (as conventional tablets) for 7 days, no effect on prothrombin time, suppression of factor VII, or warfarin pharmacokinetics was observed when a single 25-mg dose of warfarin was administered on day 4 of the study.1,2,23 However, increases in international normalized ratios (INR) have been reported in several patients receiving warfarin concomitantly with tolterodine.36,37
When tolterodine tartrate is administered with other antimuscarinic agents, the antimuscarinic effects of the drug may be increased.2,10
Studies on potential interactions between tolterodine tartrate and laboratory tests have not been performed to date.1,23
Limited information is available on the acute toxicity of tolterodine tartrate.17,18 The acute lethal dose of the drug in humans is not known.17,18
In general, overdosage of tolterodine tartrate may be expected to produce effects that are extensions of the drug's pharmacologic and adverse effects.17,18 Overdosage of tolterodine may result in severe central anticholinergic effects (e.g., hallucinations, severe excitation).1,2,23 A 27-month-old child who ingested 10-14 mg of tolterodine tartrate (five to seven 2-mg conventional tablets) developed symptoms of dry mouth.1,23 Treatment consisted of administration of activated charcoal and overnight observation in a hospital setting; the patient recovered completely.1,23 In healthy individuals who received single maximum oral tolterodine tartrate doses up to 12.8 mg and multiple tolterodine tartrate dosages of 1-6 mg twice daily for up to 28 days, dry mouth, difficulty in visual accommodation, and micturition disorders (which persisted for up to 16 hours after administration of 12.8 mg of tolterodine) were the adverse effects most frequently reported.2,6
Slight prolongation of the QT interval (10-20%) was observed in dogs receiving high doses (4.5 mg/kg [about 68 times higher than the recommended human dose]).1,2,23 Prolongation of the QTc interval also has been observed in healthy adults following administration of therapeutic (2 mg twice daily) and supratherapeutic (4 mg twice daily) dosages of tolterodine tartrate.23 (See Cautions: Cardiovascular Effects.)
Treatment of tolterodine overdosage generally involves symptomatic and supportive care.1,2,17,18 Gastric lavage and administration of activated charcoal may be useful in minimizing further GI absorption of the drug.2 It is not known whether tolterodine is removed by hemodialysis or peritoneal dialysis, but the drug's extensive protein binding suggests that dialysis is not likely to be beneficial in removing tolterodine from the body.17 ECG monitoring is recommended in patients who ingest an overdose of tolterodine tartrate.1,2 Although physostigmine salicylate may be useful as adjunctive treatment if severe anticholinergic toxicity is present,2 the drug should not be used routinely because of its potential adverse effects.13,14 An anticonvulsant (e.g., diazepam) may be used to control excitement and seizures.2 Supportive treatment may include catheterization for patients experiencing urinary retention and mechanically assisted respiration for patients who develop respiratory insufficiency.2 In addition, a β-adrenergic blocking agent may be used for tachycardia.2 Conjunctival application of pilocarpine may be used to counteract mydriasis, or, alternatively, the patient may be placed in a dark room.2
Tolterodine tartrate generally exhibits pharmacologic actions similar to those of other antimuscarinics.17,18 The drug is a nonselective competitive antagonist at muscarinic receptors present in the bladder, salivary glands, and other organs.1,2,3,4,5,6,7,8,9,10,22,23 Tolterodine tartrate decreases contraction of the detrusor muscle of normal and overactive urinary bladder.17,18 In vitro data indicate that the drug may inhibit electrically induced contractions of human detrusor muscle from stable and overactive bladders.2,3 Tolterodine has been shown to exhibit functional selectivity for urinary bladder over secretory (e.g., salivary) glands.2,3,19 In animal studies, tolterodine demonstrated greater selectivity for the urinary bladder than for salivary glands.1,3,5,10,16,22,23
The pharmacologic effects of tolterodine result from the parent drug and its 5-hydroxymethyl metabolite (DD 01), which exhibits antimuscarinic activity similar to that of tolterodine.1,2,3,5,9,19,23 Animal data indicate that tolterodine and its 5-hydroxymethyl metabolite have little or no activity at receptors other than muscarinic receptors, including α-adrenergic receptors, histaminergic receptors, calcium-channel receptors, and the neuromuscular junction.1,2,19,23
Genitourinary and Renal Effects
The precise mechanism of the inhibitory action of tolterodine on the contraction of the urinary bladder has not been fully elucidated, but it may involve antagonism of several muscarinic receptors.2,5,11,17,18 Five types of muscarinic receptors have been identified, although only 3 types of these receptors (M1/m1, M2/m2, M3/m3) appear to exist in the urinary bladder.2,5,11,22 M2/m2 muscarinic receptors are the predominant (about 80%) muscarinic receptors in the bladder; however, in vitro data indicate that contraction of smooth muscle, including muscles in the urinary bladder, is mediated mainly by M3/m3 receptors.2,5,11,19,22 In in vitro binding studies, tolterodine demonstrated no specificity for any subtype of muscarinic receptors while oxybutynin (another antimuscarinic drug used for the management of overactive bladder) demonstrated high binding specificity for M3/m3 receptors.2,3,5,10,22 In vitro, the relative binding affinity of tolterodine at the muscarinic receptors in the bladder is similar to that of oxybutynin,2,3,22 while at the muscarinic receptors in the parotid gland the potency of oxybutynin appears to be eightfold greater than that of tolterodine.2,3,5,10,19,22
Cystometric studies in healthy individuals (receiving a single 6.4-mg oral dose of tolterodine tartrate as conventional tablets) indicate that the drug increases volumes of residual urine (reflecting an incomplete emptying of the bladder) and decreases maximum detrusor pressure, effects that are consistent with a powerful antimuscarinic action of the drug on the lower urinary tract.1,4,10,17,23 In a dose-ranging, double-blind study in which patients with detrusor instability received tolterodine tartrate 0.5, 1, 2, or 4 mg or placebo twice daily for 2 weeks, dose-related increases in volume at first contraction and residual urine volume were observed.20 In a cystometric study in patients with overactive bladder, after 4 weeks of therapy tolterodine increased volume at first bladder contraction, residual volume, and maximum cystometric capacity.2,8,16
Similar to other antimuscarinic agents, tolterodine may cause inhibition of salivation.2,3,4,6,9,10,19 Tolterodine decreased stimulated or basal whole-mouth salivation in healthy individuals.4,6,7 Following IV administration of a single dose or oral administration of single or multiple doses of tolterodine in healthy men, maximum effects on salivation occurred within 1-2 hours and then declined gradually thereafter.4,6,7
Tolterodine has not produced appreciable changes in blood pressure.2,3,4 However, therapeutic (2 mg twice daily) and supratherapeutic (4 mg twice daily) dosages of tolterodine tartrate have been shown to cause prolongation of the QTc interval in healthy adults.1,23 Although slight increases in heart rate have been reported following tolterodine administration,1,2,4,7,20,23 such increases are not considered clinically important.2 (See Cautions: Cardiovascular Effects.)
The pharmacokinetics of tolterodine have been studied in healthy individuals and in patients with liver cirrhosis or renal impairment.1,2,3,4,6,7,23 Pharmacokinetic studies to date have not revealed gender- or race-related differences in the pharmacokinetics of tolterodine.1,2,23
Studies in adults with renal impairment or liver cirrhosis indicate that the pharmacokinetics of tolterodine are affected substantially by renal or hepatic impairment.1 (See Absorption and see Elimination, in Pharmacokinetics.)
In healthy individuals, at least 77% of a radiolabeled dose of tolterodine tartrate is rapidly absorbed from the GI tract.1,23 Peak serum concentrations of the drug usually occur within 1-2 or 2-6 hours after administration of a dose as conventional tablets or extended-release capsules, respectively.1,2,3,4,6,7,10,19,23 However, because of extensive first-pass metabolism in the liver,1,23 the absolute oral bioavailability of tolterodine is variable (10-74%)2,3,6,10,19 and may depend on a patient's genetically determined ability to metabolize the drug.1,2,6,10,23 (See Pharmacokinetics: Elimination.)
In most patients (those with the extensive-oxidizer phenotype), tolterodine undergoes extensive first-pass metabolism in the liver, producing the major active 5-hydroxymethyl metabolite.1,3,6,7,10,23 However, in a small fraction of patients (those with the poor-oxidizer phenotype), the drug undergoes only limited first-pass metabolism.1,7 In these patients, the absolute bioavailability of tolterodine is higher than that in patients with the extensive-oxidizer phenotype.1,17,18,23 Peak and average serum concentrations of the parent drug vary according to the metabolic (oxidizer) phenotype of a patient.1,23
In healthy men with extensive- or poor-oxidizer phenotypes, when using data normalized for a single 2-mg dose of tolterodine tartrate (as conventional tablets), peak serum tolterodine concentrations of 1.6 or 10 ng/mL were achieved within 1.6 or 1.4 hours, respectively, while average serum concentrations of the drug were 0.5 or 8.3 ng/mL, respectively.1 In addition, in healthy men with extensive- or poor-oxidizer phenotypes receiving multiple doses (twice daily) of tolterodine tartrate (as conventional tablets), when using data normalized for a 2-mg dose, peak serum tolterodine concentrations of 2.6 or 19 ng/mL were achieved within 1.2 or 1.9 hours, respectively, while average serum concentrations were 0.58 or 12 ng/mL, respectively.1 In healthy men with extensive-oxidizer phenotypes receiving single doses of tolterodine tartrate, when using data normalized for a single 2-mg dose (as conventional tablets), peak serum 5-hydroxymethyl metabolite concentrations of 1.8 ng/mL were achieved within 1.8 hours, while serum concentrations of the metabolite averaged 0.62 ng/mL; only negligible amounts of the metabolite were detected in individuals with poor-oxidizer phenotypes.1 In addition, using data normalized for 2-mg doses (as conventional tablets), in healthy men with extensive-oxidizer phenotypes receiving multiple doses (twice daily) of tolterodine tartrate, peak serum 5-hydroxymethyl metabolite concentrations of 2.4 ng/mL were achieved within 1.2 hours, while serum 5-hydroxymethyl metabolite concentrations averaged 0.92 ng/mL; only negligible amounts of the metabolite were detected in the poor-oxidizer phenotypes.1
In healthy men with the extensive-oxidizer phenotype, when using data normalized for a single 4-mg dose of tolterodine tartrate (administered as extended-release capsules), peak serum tolterodine concentrations of 1.3 ng/mL were achieved within 4 hours, while serum concentrations of the drug averaged 0.8 ng/mL.23 In addition, in healthy men with extensive- or poor-oxidizer phenotypes receiving multiple 4-mg doses of tolterodine tartrate as extended-release capsules, peak serum tolterodine concentrations of 3.4 or 19 ng/mL, respectively, were achieved within 4 hours, while average serum concentrations were 1.7 or 13 ng/mL, respectively.23 In healthy men with extensive-oxidizer phenotypes receiving single doses of tolterodine tartrate, using data normalized for a single 4-mg dose (as extended-release capsules), peak serum 5-hydroxymethyl metabolite concentrations of 1.6 ng/mL were achieved within 4 hours, while serum concentrations of the metabolite averaged 1 ng/mL.23 In addition, in healthy men with the extensive-oxidizer phenotype receiving multiple 4-mg doses of tolterodine tartrate as extended-release capsules, peak serum 5-hydroxymethyl metabolite concentrations of 2.7 ng/mL were achieved within 4 hours, while serum 5-hydroxymethyl metabolite concentrations averaged 1.4 ng/mL.23
In one phase I study, following oral administration of tolterodine tartrate dosages of 2 mg twice daily (as conventional tablets) in healthy geriatric adults (64-80 years of age), serum concentrations of tolterodine and its 5-hydroxymethyl metabolite were similar to those observed in healthy individuals younger than 40 years of age.1,23 In another phase I study, when tolterodine tartrate was administered in a dosage of 1 or 2 mg twice daily (as conventional tablets), average serum concentrations of tolterodine and its 5-hydroxymethyl metabolite were about 20 and 50% higher, respectively, in healthy geriatric individuals (71-81 years of age) compared with those reported in young healthy adults.1,23 However, overall differences in safety were not observed between geriatric and younger patients in phase III, controlled clinical studies of 12 weeks' duration.1,23 Therefore, dosage adjustment solely on the basis of age generally is not required for otherwise healthy geriatric patients.1,17,18,23
In pediatric patients 11-15 years of age receiving tolterodine tartrate (as extended-release capsules), the dose-plasma concentration relationship was linear over the range of doses assessed.23 Patients with the extensive-oxidizer phenotype had low serum concentrations of tolterodine and high concentrations of the active 5-hydroxymethyl metabolite, while patients with the poor-oxidizer phenotype had high concentrations of tolterodine and negligible concentrations of the active metabolite.23
Peak serum concentration and area under the serum concentration-time curve (AUC) of tolterodine and its 5-hydroxymethyl metabolite were similar in males and females.1,23 Following oral administration of 2 mg of tolterodine tartrate (as conventional tablets), the average peak serum concentrations of the drug in males and females were 1.6 and 2.2 ng/mL, respectively, while the average peak serum concentrations of the 5-hydroxymethyl metabolite were 2.2 and 2.5 ng/mL in males and females, respectively.1,17,23 The mean AUC of tolterodine was 6.7 and 7.8 nghour/mL in males and females, respectively, while the mean AUC of the 5-hydroxymethyl metabolite was 10 and 11 nghour/mL in males and females, respectively.1,17,23
Serum concentrations of tolterodine tartrate and its metabolites appear to be higher in patients with renal impairment than in healthy individuals.1,23 Following administration of conventional tablets of tolterodine tartrate, serum concentrations of tolterodine and its 5-hydroxymethyl metabolite were approximately 2- to 3-fold higher in patients with renal impairment (creatinine clearance of 10-30 mL/minute) compared with those observed in healthy individuals.1,23 Serum concentrations of other metabolites (e.g., tolterodine acid) were approximately 10- to 30-fold higher in these patients than in healthy individuals.1,23 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
Tolterodine tartrate (administered as conventional tablets) generally exhibits linear dose-dependent pharmacokinetics over the dosage range of 1-4 mg;1,3,23 however, absorption of the drug appears to be dose proportional following single oral doses of 1-12.8 mg.2,6,10,17,18 Based on the sum of the unbound serum concentrations of tolterodine and the 5-hydroxymethyl metabolite, the AUC of tolterodine tartrate following daily administration of the 4-mg extended-release capsules is expected to be approximately equivalent to that of twice-daily administration of the 2-mg conventional tablets.23 Peak and trough serum tolterodine concentrations achieved with extended-release capsules are approximately 75 and 150%, respectively, of those achieved with conventional tablets.23
Oral bioavailability of conventional tolterodine tartrate tablets may be increased (e.g., by an average of 53%) when the drug is administered with food; however, the manufacturer states that such changes are not expected to be clinically important.1 Food does not appear to alter the pharmacokinetics of extended-release tolterodine.23 Therefore, the manufacturer states that tolterodine tartrate conventional tablets or extended-release capsules can be taken without regard to meals.1,17,18,23 However, some clinicians state that patients should be advised to take tolterodine tartrate in a consistent manner relative to food intake.18 Food does not appear to affect serum concentrations of the 5-hydroxymethyl metabolite of tolterodine in individuals who are extensive metabolizers of tolterodine.1 (See Pharmacokinetics: Elimination.)
Following oral administration of a single 6.4-mg dose of tolterodine tartrate as an aqueous solution in healthy men, inhibitory effects on urinary bladder function (as measured by residual urine volume, volume at which the first sensation of bladder filling was experienced, volume at which the normal desire to void occurred, and maximum detrusor pressure during micturition) were observed within 1 hour and persisted for at least 5 hours.4
Distribution of tolterodine into most body tissues and fluids has not been fully characterized.17,18 Tolterodine and its 5-hydroxymethyl metabolite do not appear to distribute extensively into erythrocytes, as indicated by average blood-to-serum ratios of 0.6 and 0.8 for tolterodine and the 5-hydroxymethyl metabolite, respectively.1,23 Following IV administration of a single 1.28-mg dose of tolterodine tartrate in humans, the volume of distribution of tolterodine is about 113 L.1,17,23
Tolterodine is highly bound to plasma proteins, principally to α1-acid glycoprotein;1,2,10,23 at concentrations of tolterodine achieved in clinical studies, about 96.3% of tolterodine reportedly was protein bound.1,2,3,10,17,18,23 The 5-hydroxymethyl metabolite has a lower affinity for binding to plasma proteins compared with the parent drug; about 64% of the metabolite reportedly is bound to protein.1,2,3,5,10,23
It is not known whether tolterodine crosses the placenta or is distributed into breast milk in humans; 1,17,23 however, the drug is distributed into milk in mice.1,2,23
There are 2 major patterns of tolterodine metabolism.1,3,9,10,23 The patterns are related to a genetically determined ability to metabolize the drug by an oxidation pathway.1,23 The ability to metabolize tolterodine via oxidation, leading to the formation of the 5-hydroxymethyl metabolite, 5-hydroxymethyl tolterodine, is related to the cytochrome P-450 (CYP) isoenzyme 2D6,1,3,7,9,10,19,23,28,29 which is under genetic control and is associated with the ability to oxidatively metabolize debrisoquin.1,7,23 (Fesoterodine, another antimuscarinic agent used in the treatment of overactive bladder, also is metabolized to 5-hydroxymethyl tolterodine; however, fesoterodine metabolism to 5-hydroxymethyl tolterodine is via nonspecific esterases.)27,28,29 Individuals who extensively metabolize tolterodine via the oxidation pathway exhibit the extensive-oxidizer phenotype, while those who have an impaired ability to metabolize the drug by this pathway exhibit the poor-oxidizer phenotype.1,3,9,10,17,18,19,23 Approximately 93% of Caucasians exhibit the extensive-oxidizer phenotype and about 7% the poor-oxidizer phenotype.1,3,7,9,10,17,18,19,23
Following oral administration of 2-mg doses of tolterodine tartrate (as conventional tablets) in men and women, the elimination half-life of tolterodine is about 2.4 hours while the elimination half-life of the 5-hydroxymethyl metabolite is 3 or 3.3 hours in females or males, respectively.1,23 Following single or multiple oral doses of tolterodine tartrate (as conventional tablets) in healthy men with the extensive-oxidizer phenotype, the elimination half-life of tolterodine is about 2 or 2.2 hours, respectively,1 but the half-life of tolterodine is prolonged to about 6.5 or 9.6 hours, respectively, in men with the poor-oxidizer phenotype.1 Following single or multiple oral doses of tolterodine tartrate (as conventional tablets), the elimination half-life of the 5-hydroxymethyl metabolite in healthy men is about 3.1 or 2.9 hours, respectively.1 Following single or multiple oral doses of tolterodine tartrate (as extended-release capsules) in healthy men with the extensive-oxidizer phenotype, the elimination half-life of tolterodine is about 8.4 or 6.9 hours, respectively;23 however, the half-life of tolterodine is prolonged to about 13 hours following multiple oral doses in men with the poor-oxidizer phenotype.23 Following single or multiple oral doses of tolterodine tartrate, the elimination half-life of the 5-hydroxymethyl metabolite in healthy men is about 8.8 or 9.9 hours, respectively.23
The elimination half-life of tolterodine is prolonged in patients with hepatic impairment.1,10 In one study in patients with liver cirrhosis, the mean half-life of tolterodine was 8.7 hours compared with 2-4 hours reported in healthy young and geriatric individuals.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
Following oral administration of tolterodine tartrate in individuals with the extensive-oxidizer phenotype, tolterodine is extensively metabolized in the liver principally by CYP2D6 to the 5-hydroxymethyl metabolite, which is formed through oxidation of the 5-methyl group of the parent drug.1,9,10,19,23 This metabolite exhibits antimuscarinic activity similar to that of tolterodine and contributes substantially to the therapeutic effects of the drug.1,9,23 The 5-hydroxymethyl metabolite undergoes further metabolism to form the 5-carboxylic acid and the N -dealkylated 5-carboxylic acid metabolites, which do not have clinically important antimuscarinic activity.1,17,23
In individuals with the poor-oxidizer phenotype, tolterodine is metabolized by the CYP isoenzyme 3A4 to form N -dealkylated tolterodine which does not exhibit clinically important antimuscarinic activity.1,9,10,17,23 In pharmacokinetic studies, tolterodine was metabolized at a slower rate in poor metabolizers than in extensive metabolizers.1,2,23 In addition, serum concentrations of tolterodine were substantially higher and serum concentrations of the 5-hydroxymethyl metabolite were negligible in individuals with the poor-oxidizer phenotype compared with those observed in extensive metabolizers of the drug.1,2,7,10,19,23 (See Pharmacokinetics: Absorption.)
Following oral administration of a 5-mg dose of radiolabeled tolterodine tartrate solution in healthy individuals, approximately 77 and 17% of administered radioactivity was recovered within 7 days in urine and feces, respectively, principally within the first 24 hours.1,6,17,23 In individuals with the extensive-oxidizer phenotype, less than 1 and 5-14% of the administered dose were excreted as unchanged tolterodine and as the 5-hydroxymethyl metabolite, respectively.1,2,6,7,17,23 The 5-carboxylic acid and N -dealkylated 5-carboxylic acid metabolites account for about 51 and 29%, respectively, of the metabolites recovered in urine.1,6,23 In those with poor-oxidizer phenotype, less than 2.5% of the dose was excreted as unchanged tolterodine and less than 1% as the 5-hydroxymethyl metabolite.1,7,23
In healthy men with the extensive-oxidizer phenotype, apparent oral clearance of tolterodine is about 8900 or 6917 mL/minute following single (4 mg) or multiple (4 mg twice daily) oral doses of the drug (administered as conventional tablets), respectively, while in healthy men with the poor-oxidizer phenotype, apparent oral clearance of tolterodine under the same conditions reportedly is about 283 or 183 mL/minute, respectively.1 Clearance of oral tolterodine (administered as conventional tolterodine tartrate tablets) was about 17 or 95 mL/minute per kg in patients with liver cirrhosis or healthy individuals, respectively.1,23
Tolterodine is a synthetic tertiary amine antimuscarinic agent1,17,19,23 and is structurally similar to other tertiary amine muscarinic receptor antagonists (e.g., flavoxate, oxybutynin).17 Tolterodine tartrate occurs as a white, crystalline powder, has a solubility of 12 mg/mL in water at 25°C, and is slightly soluble in alcohol at 25°C.1,2,17,23 The drug has a pKa of 9.9.2
Tolterodine tartrate conventional tablets and extended-release capsules should be stored at a temperature of 25°C but may be exposed to temperatures ranging from 15-30°C.1,23 The conventional tablets are stable for at least 36 months following the date of manufacture when stored at room temperature (below 25°C).2
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions January 1, 2010. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Pfizer. Detrol® (tolterodine tartrate) tablets prescribing information. New York, NY; 2008 Mar.
2. Pharmacia & Upjohn. Detrol® (tolterodine) immediate-release tablets and Detrol® LA extended-release capsulesgeneral review. Kalamazoo, MI; 2001 Apr.
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8. Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology . 1997; 50(Suppl 6A):90-6. [PubMed 9426760]
9. Anon. Tolterodine for overactive bladder. Med Lett Drugs Ther . 1998; 40:101-2. [PubMed 9813595]
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14. Goldfrank LR, Lewin NA, Flomenbaum NE et al. Psychotropics. Antidepressants: tricyclics, tetracyclics, monoamine oxidase inhibitors, and others. In: Goldfrank LR, Flomenbaum NE, Lewin NA et al, eds. Goldfrank's toxicologic emergencies. 3rd ed. Norwalk, CT: Appleton-Century-Crofts; 1986:351-9.
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17. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication.
18. Reviewers' comments (personal observations).
19. Ruscin JR, Morgenstern NE. Tolterodine use for symptoms of overactive bladder. Ann Pharmacother . 1999; 33:1073-82. [PubMed 10534221]
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22. Nilvebrant L, Andersson KE, Gillberg PG et al. Tolterodinea new bladder-selective antimuscarinic agent. Eur J Pharmacol . 1997; 327:195-207. [PubMed 9200560]
23. Pfizer. Detrol® LA (tolterodine tartrate) extended-release capsules prescribing information. New York, NY; 2008 Mar.
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