Detrusitol/Detrusitol SR

Detrusitol: The film-coated tablets are white, round and biconvex. The 2 mg tablet is engraved with arcs above and below the letters DT.
Each film-coated tablet contains tolterodine tartrate 2 mg corresponding to 1.37 mg tolterodine.
Detrusitol SR: DETRUSITOL SR Capsules 4 mg are blue with symbol and 4 printed in white ink.
Each extended release capsule contains tolterodine tartrate 4 mg equivalent to 2.74 mg tolterodine.
Excipients/Inactive Ingredients: Detrusitol: Tablet Core: Microcrystalline cellulose, Calcium hydrogen phosphate dihydrate, Sodium starch glycollate (Type B), Magnesium stearate, Colloidal anhydrous silica.
Film coating: Coating granules containing Hypromellose, Microcrystalline cellulose, Stearic acid, Titanium dioxide E171.
Detrusitol SR: Inactive ingredients are sucrose, maize starch, ethylcellulose, medium chain triglycerides, oleic acid, hypromellose, gelatin. Capsule strength is imprinted with a pharmaceutical grade printing ink that contains shellac glaze, titanium dioxide (E171), indigo carmine (E132), propylene glycol, and simethicone.

Pharmacotherapeutic group: Urinary antispasmodics. ATC code: G04B D07.
Pharmacology: Detrusitol: Pharmacodynamics: Mechanism of action: Tolterodine is a competitive, specific muscarinic receptor antagonist with a selectivity for the urinary bladder over salivary glands in vivo.
Pharmacodynamic effects: One of the tolterodine metabolites (5-hydroxymethyl derivative) exhibits a pharmacological profile similar to that of the parent compound. In extensive metabolisers this metabolite contributes significantly to the therapeutic effect (see Pharmacokinetics as follows).
Clinical efficacy and safety: Effect of the treatment can be expected within 4 weeks.
Effect of treatment with tolterodine 2 mg twice daily after 4 and 12 weeks, respectively, compared with placebo (pooled data). Absolute change and percentage change relative to baseline. (See Table 1.)

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The effect of tolterodine was evaluated in patients, examined with urodynamic assessment at baseline and, depending on the urodynamic result, they were allocated to a urodynamic positive (motor urgency) or a urodynamic negative (sensory urgency) group. Within each group, the patients were randomised to receive either tolterodine or placebo. The study could not provide convincing evidence that tolterodine had effects over placebo in patients with sensory urgency.
The clinical effects of tolterodine on QT interval were studied in ECGs obtained from over 600 treated patients, including the elderly and patients with pre-existing cardiovascular disease. The changes in QT intervals did not significantly differ between placebo and treatment groups.
The effect of tolterodine on QT-prolongation was investigated further in 48 healthy male and female volunteers aged 18-55 years. Subjects were administered 2 mg twice daily and 4 mg twice daily tolterodine as the immediate release formulations. The results (Fridericia corrected) at peak tolterodine concentration (1 hour) showed mean QTc interval increases of 5.0 and 11.8 msec for tolterodine doses of 2 mg twice daily and 4 mg twice daily respectively and 19.3 msec for moxifloxacin (400 mg) which was used as an active, internal control. A pharmacokinetic/pharmacodynamic model estimated that QTc interval increases in poor metabolisers (devoid of CYP2D6) treated with tolterodine 2 mg twice daily are comparable to those observed in extensive metabolisers receiving 4 mg twice daily. At both doses of tolterodine, no subject, irrespective of their metabolic profile, exceeded 500 msec for absolute QTcF or 60 msec for change from baseline that are considered thresholds of particular concern. The 4 mg twice daily dose corresponds to a peak exposure (C_max) of three times that obtained with the highest therapeutic dose of tolterodine extended release capsules.
Detrusitol SR: Mechanism of Action: Tolterodine acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors. 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 5-hydroxymethyl tolterodine (5-HMT), the major pharmacologically active metabolite. 5-HMT, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and 5-HMT 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.
Pharmacodynamics: 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.
Cardiac Electrophysiology: The effect of 2 mg BID and 4 mg BID of DETRUSITOL immediate release (tolterodine IR) tablets on the QT interval was evaluated in a 4-way crossover, double-blind, placebo- and active-controlled (moxifloxacin 400 mg QD) study in healthy male (N=25) and female (N=23) volunteers aged 18-55 years. Study subjects [approximately equal representation of CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs)] completed sequential 4-day periods of dosing with moxifloxacin 400 mg QD, tolterodine 2 mg BID, tolterodine 4 mg BID, and placebo. The 4 mg BID dose of tolterodine IR (two times the highest recommended dose) was chosen because this dose results in tolterodine exposure similar to that observed upon coadministration of tolterodine 2 mg BID with potent CYP3A4 inhibitors in patients who are CYP2D6 poor metabolizers [see Interactions]. QT interval was measured over a 12-hour period following dosing, including the time of peak plasma concentration (T_max) of tolterodine and at steady state (Day 4 of dosing).
Table 2 summarizes the mean change from baseline to steady state in corrected QT interval (QT_c) relative to placebo at the time of peak tolterodine (1 hour) and moxifloxacin (2 hour) concentrations. Both Fridericia's (QT_cF) and a population-specific (QT_cP) method were used to correct QT interval for heart rate. No single QT correction method is known to be more valid than others. QT interval was measured manually and by machine, and data from both are presented. The mean increase of heart rate associated with a 4 mg/day dose of tolterodine in this study was 2.0 beats/minute and 6.3 beats/minute with 8 mg/day tolterodine. The change in heart rate with moxifloxacin was 0.5 beats/minute. (See Table 2.)

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The reason for the difference between machine and manual read of QT interval is unclear.
The QT effect of tolterodine immediate release tablets appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day. 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.
Tolterodine's effect on QT interval was found to correlate with plasma concentration of tolterodine. There appeared to be a greater QT_c interval increase in CYP2D6 poor metabolizers than in CYP2D6 extensive metabolizers after tolterodine treatment in this study.
This study was not designed to make direct statistical comparisons between drugs or dose levels. There has been no association of Torsade de Pointes in the international post-marketing experience with DETRUSITOL or DETRUSITOL SR [see Precautions].
Clinical Studies: DETRUSITOL SR Capsules 2 mg were evaluated in 29 patients in a Phase 2 dose-effect study. DETRUSITOL SR 4 mg was evaluated for the treatment of overactive bladder with symptoms of urge urinary incontinence and frequency in a randomized, placebo-controlled, multicenter, double-blind, Phase 3, 12-week study. A total of 507 patients received DETRUSITOL SR 4 mg once daily in the morning and 508 received placebo. The majority of patients were Caucasian (95%) and female (81%), with a mean age of 61 years (range, 20 to 93 years). In the study, 642 patients (42%) were 65 to 93 years of age. The study included patients known to be responsive to tolterodine immediate release and other anticholinergic medications, however, 47% of patients never received prior pharmacotherapy for overactive bladder. At study entry, 97% of patients had at least 5 urge incontinence episodes per week and 91% of patients had 8 or more micturitions per day.
The primary efficacy assessment was change in mean number of incontinence episodes per week at week 12 from baseline. Secondary efficacy measures included change in mean number of micturitions per day and mean volume voided per micturition at week 12 from baseline.
Patients treated with DETRUSITOL SR experienced a statistically significant decrease in number of urinary incontinence per week from baseline to last assessment (week 12) compared with placebo as well as a decrease in the average daily urinary frequency and an increase in the average urine volume per void.
Mean change from baseline in weekly incontinence episodes, urinary frequency, and volume voided between placebo and DETRUSITOL SR are summarized in Table 3. (See Table 3.)

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Pharmacokinetics: Detrusitol: Pharmacokinetic characteristics specific for this formulation: Tolterodine is rapidly absorbed. Both tolterodine and the 5-hydroxymethyl metabolite reach maximal serum concentrations 1-3 hours after dose. The half-life for tolterodine given as the tablet is 2-3 hours in extensive and about 10 hours in poor metabolisers (devoid of CYP2D6). Steady state concentrations are reached within 2 days after administration of the tablets.
Food does not influence the exposure to the unbound tolterodine and the active 5-hydroxymethyl metabolite in extensive metabolisers, although the tolterodine levels increase when taken with food. Clinically relevant changes are likewise not expected in poor metabolisers.
Absorption: After oral administration, tolterodine is subject to CYP2D6 catalysed first-pass metabolism in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically equipotent metabolite.
The absolute bioavailability of tolterodine is 17% in extensive metabolisers, the majority of the patients, and 65% in poor metabolisers (devoid of CYP2D6).
Distribution: Tolterodine and the 5-hydroxymethyl metabolite bind primarily to orosomucoid. The unbound fractions are 3.7% and 36%, respectively. The volume of distribution of tolterodine is 113 L.
Elimination: Tolterodine is extensively metabolised by the liver following oral dosing. The primary metabolic route is mediated by the polymorphic enzyme CYP2D6 and leads to the formation of the 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which account for 51% and 29% of the metabolites recovered in the urine, respectively. A subset (about 7%) of the population is devoid of CYP2D6 activity. The identified pathway of metabolism for these individuals (poor metabolisers) is dealkylation via CYP3A4 to N-dealkylated tolterodine, which does not contribute to the clinical effect. The remainder of the population is referred to as extensive metabolisers. The systemic clearance of tolterodine in extensive metabolisers is about 30 L/h. In poor metabolisers, the reduced clearance leads to significantly higher serum concentrations of tolterodine (about 7-fold) and negligible concentrations of the 5-hydroxymethyl metabolite are observed.
The 5-hydroxymethyl metabolite is pharmacologically active and equipotent with tolterodine. Because of the differences in the protein-binding characteristics of tolterodine and the 5-hydroxymethyl metabolite, the exposure (AUC) of unbound tolterodine in poor metabolisers is similar to the combined exposure of unbound tolterodine and the 5-hydroxymethyl metabolite in patients with CYP2D6 activity given the same dosage regimen. The safety, tolerability and clinical response are similar irrespective of phenotype.
The excretion of radioactivity after administration of [¹⁴C]-tolterodine is about 77% in urine and 17% in faeces. Less than 1% of the dose is recovered as unchanged drug, and about 4% as the 5-hydroxymethyl metabolite. The carboxylated metabolite and the corresponding dealkylated metabolite account for about 51% and 29% of the urinary recovery, respectively.
Linearity/non-linearity: The pharmacokinetics is linear in the therapeutic dosage range.
Hepatic impairment: About 2-fold higher exposure of unbound tolterodine and the 5-hydroxymethyl metabolite is found in subjects with liver cirrhosis (see Dosage & Administration and Precautions).
Impaired renal function: The mean exposure of unbound tolterodine and its 5-hydroxymethyl metabolite is doubled in patients with severe renal impairment (inulin clearance GFR ≤30 ml/min). The plasma levels of other metabolites were markedly (up to 12-fold) increased in these patients. The clinical relevance of the increased exposure of these metabolites is unknown. There is no data in mild to moderate renal impairment (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data: In toxicity, genotoxicity, carcinogenicity and safety pharmacology studies no clinically relevant effects have been observed, except those related to the pharmacological effect of the drug.
Reproduction studies have been performed in mice and rabbits.
In mice, there was no effect of tolterodine on fertility or reproductive function. Tolterodine produced embryo death and malformations at plasma exposures (C_max or AUC) 20 or 7 times higher than those seen in treated humans.
In rabbits, no malformative effect was seen, but the studies were conducted at 20 or 3 times higher plasma exposure (C_max or AUC) than those expected in treated humans.
Tolterodine, as well as its active human metabolites, prolong action potential duration (90% repolarisation) in canine purkinje fibres (14 - 75 times therapeutic levels) and block the K+-current in cloned human ether-a-go-go-related gene (hERG) channels (0,5 - 26,1 times therapeutic levels). In dogs, prolongation of the QT interval has been observed after application of tolterodine and its human metabolites (3,1 - 61,0 times therapeutic levels). The clinical relevance of these findings is unknown.
Detrusitol SR: 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. C_max 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 5-HMT ("active moiety"), the AUC of tolterodine extended release 4 mg daily is equivalent to tolterodine immediate release 4 mg (2 mg bid). C_max and C_min 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. 5-HMT is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%. The blood to serum ratio of tolterodine and 5-HMT 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 metabolite, 5-HMT. 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 of individuals (approximately 7% of Caucasians and approximately 2% of African Americans) are poor metabolizers for CYP2D6, the enzyme responsible for the formation of 5-HMT from tolterodine. The identified pathway of metabolism for these individuals ("poor metabolizers") is dealkylation via cytochrome P450 3A4 (CYP3A4) to N-dealkylated 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 5-HMT.
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 5-HMT.
A summary of mean (±standard deviation) pharmacokinetic parameters of tolterodine extended release and 5-HMT in extensive (EM) and poor (PM) metabolizers is provided in Table 4. These data were obtained following single and multiple doses of tolterodine extended release administered daily to 17 healthy male volunteers (13 EM, 4 PM). (See Table 4.)

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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 DETRUSITOL SR is 2 mg daily [see Dosage & Administration].
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/levo-norgestrel 150 μg) as evidenced by the monitoring of ethinyl estradiol and levo-norgestrel 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 (K_i 1.05 μM), while tolterodine immediate release as well as the 5-HMT are devoid of any significant inhibitory potential regarding the other isoenzymes.
Pharmacokinetics in Special Populations: Pediatric: The effectiveness of DETRUSITOL SR has not been established in pediatric patients.
Efficacy was not established in two randomized, placebo-controlled, double-blind, 12-week studies that enrolled 710 pediatric patients (486 on DETRUSITOL SR, 224 on placebo) aged 5-10 years with urinary frequency and urge incontinence. The percentage of patients with urinary tract infections was higher in patients treated with DETRUSITOL SR (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 DETRUSITOL SR compared to 0.9% of children treated with placebo.
Geriatric: 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.
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 DETRUSITOL SR 2 mg daily. Patients with CCr<10 mL/min have not been studied and use of DETRUSITOL SR in this population is not recommended [see Dosage & Administration and Precautions]. DETRUSITOL SR has not been studied in patients with mild to moderate renal impairment [CCr 30-80 mL/min].
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 DETRUSITOL SR 2 mg once daily. DETRUSITOL SR is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Dosage & Administration and Precautions].
Toxicology: Nonclinical Toxicology: 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), exposure margins were approximately 6-9 times, 7 times, and 11 times the clinical exposure to the pharmacologically active components of DETRUSITOL SR (based on AUC of tolterodine and its 5-HMT metabolite). At these exposure margins, no increase in tumors was found in either mice or rats.
No mutagenic or genotoxic 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 (about 9-12 times the clinical exposure via AUC), neither effects on reproductive performance or fertility were seen. In male mice, a dose of 30 mg/kg/day did not induce any adverse effects on fertility.

Tolterodine is indicated for the treatment of overactive bladder with symptoms of urinary urgency, frequency, or urge incontinence.

Detrusitol: Adults (including the Elderly): The recommended total daily dose is 4 mg. Dosage with tolterodine tablets is 2 mg twice daily. The total daily dose may be reduced to 2 mg, based on individual tolerability.
Use in Children: Safety and effectiveness in children have not been established.
Use in Impaired Renal Function: The recommended total daily dose is 2 mg (i.e., tolterodine tablets 1 mg twice daily) for patients with impaired renal function (see Precautions).
Use in Impaired Hepatic Function: The recommended total daily dose is 2 mg (i.e., tolterodine tablets 1 mg twice daily) for patients with impaired hepatic function (see Precautions).
Use with Potent CYP3A4 Inhibitors: The recommended total daily dose is 2 mg (i.e., tolterodine tablets 1 mg twice daily) for patients receiving concomitant ketoconazole or other potent CYP3A4 inhibitors (see Precautions and Interactions).
Detrusitol SR: The recommended dose of DETRUSITOL SR 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 DETRUSITOL SR 2 mg [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
Dosage Adjustment in Specific Populations: Hepatic and Renal Impairment: 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 DETRUSITOL SR is 2 mg once daily. DETRUSITOL SR 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 DETRUSITOL SR in this population is not recommended [see Precautions and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions].
Pediatric Use: Efficacy in the pediatric population has not been demonstrated.
Geriatric Use: No overall differences in safety were observed between the older and younger patients treated with tolterodine.
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 DETRUSITOL SR is 2 mg once daily [see Interactions].

Detrusitol: Symptoms: The highest dose given to human volunteers of tolterodine L-tartrate is 12.8 mg as single dose. The most severe adverse events observed were accommodation disturbances and micturition difficulties.
Management: In the event of tolterodine overdose, treat with gastric lavage and give activated charcoal. Treat symptoms as follows: Severe central anticholinergic effects (e.g. hallucinations, severe excitation): treat with physostigmine.
Convulsions or pronounced excitation: treat with benzodiazepines.
Respiratory insufficiency: treat with artificial respiration.
Tachycardia: treat with beta-blockers.
Urinary retention: treat with catheterization.
Mydriasis: treat with pilocarpine eye drops and/or place patient in dark room.
An increase in QT interval was observed at a total daily dose of 8 mg immediate release tolterodine (twice the recommended daily dose of the immediate release formulation and equivalent to three times the peak exposure of the prolonged release capsule formulation) administered over four days. In the event of tolterodine overdose, standard supportive measures for managing QT prolongation should be adopted.
Detrusitol SR: Overdosage with DETRUSITOL SR 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 bid) and higher doses were not evaluated [see Precautions and Pharmacology under Actions].
A 27-month-old child who ingested 5 to 7 tolterodine immediate release 2 mg tablets was treated with a suspension of activated charcoal and was hospitalized overnight with symptoms of dry mouth. The child fully recovered.

Detrusitol: Tolterodine is contraindicated in patients with: Urinary retention; Uncontrolled narrow angle glaucoma; Myasthenia gravis; Known hypersensitivity to tolterodine or to any of the excipients (see Description); Severe ulcerative colitis; Toxic megacolon.
Detrusitol SR: DETRUSITOL SR is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. DETRUSITOL SR is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like DETRUSITOL SR, are metabolized to 5-hydroxymethyl tolterodine [see Precautions].

Detrusitol: Tolterodine shall be used with caution in patients with: Significant bladder outlet obstruction at risk of urinary retention; Gastrointestinal obstructive disorders, e.g. pyloric stenosis; Renal impairment (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions); Hepatic disease (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions); Autonomic neuropathy; Hiatus hernia; Risk for decreased gastrointestinal motility.
Multiple oral total daily doses of immediate release 4 mg (therapeutic) and 8 mg (supratherapeutic) tolterodine have been shown to prolong the QTc interval (see Pharmacology: Pharmacodynamics under Actions). The clinical relevance of these findings is unclear and will depend on individual patient risk factors and susceptibilities present. Tolterodine should be used with caution in patients with risk factors for QT-prolongation including: Congenital or documented acquired QT prolongation; Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia; Bradycardia; Relevant pre-existing cardiac diseases (i.e. cardiomyopathy, myocardial ischaemia, arrhythmia, congestive heart failure); Concomitant administration of drugs known to prolong QT-interval including Class IA (e.g. quinidine, procainamide) and Class III (e.g. amiodarone, sotalol) anti-arrhythmics.
This especially holds true when taking potent CYP3A4 inhibitors (see Pharmacology: Pharmacodynamics under Actions).
Concomitant treatment with potent CYP3A4 inhibitors should be avoided (see Interactions).
Urinary retention: As with all treatments for symptoms of urgency and urge incontinence, organic reasons for urge and frequency should be considered before treatment.
Excipient information: Detrusitol 2 mg film-coated tablets contain less than 1 mmol sodium (23 mg) per tablet. Patients on low sodium diets can be informed that this medicinal product is essentially 'sodium free'.
Effects on Ability to Drive and Use Machines: Since this drug may cause accommodation disturbances and influence reaction time, the ability to drive and use machines may be negatively affected.
Detrusitol SR: Angioedema: Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of DETRUSITOL SR. In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, DETRUSITOL SR should be discontinued and appropriate therapy promptly provided.
Urinary Retention: Administer DETRUSITOL SR Capsules with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications].
Gastrointestinal Disorders: Administer DETRUSITOL SR with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention.
DETRUSITOL SR, 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].
Controlled Narrow-Angle Glaucoma: Administer DETRUSITOL SR with caution in patients being treated for narrow-angle glaucoma [see Contraindications].
Central Nervous System Effects: DETRUSITOL SR is associated with anticholinergic central nervous system (CNS) effects [see Post-marketing Experience under Adverse Reactions] including dizziness and somnolence [see Clinical Trials Experience under 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.
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 DETRUSITOL SR is 2 mg once daily. DETRUSITOL SR is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions].
Renal Impairment: Renal impairment can significantly alter the disposition of tolterodine and its metabolites. The dose of DETRUSITOL SR 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 DETRUSITOL SR in this population is not recommended [see Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions].
Myasthenia Gravis: Administer DETRUSITOL SR with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.
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 Pharmacology under Actions] 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 DETRUSITOL SR 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 DETRUSITOL or DETRUSITOL SR.

Detrusitol: Pregnancy: There are no adequate data from the use of tolterodine in pregnant women.
Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). The potential risk for humans is unknown.
Consequently, tolterodine is not recommended during pregnancy.
Lactation: No data concerning the excretion of tolterodine into human milk are available. Tolterodine should be avoided during lactation.
Fertility: Animal studies do not show an effect of tolterodine on fertility (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). There are no human data.
Detrusitol SR: Pregnancy: Risk Summary: There are no available data with DETRUSITOL SR use in pregnant women to inform drug-associated risks. In animal reproduction studies, oral administration of tolterodine and its 5-HMT metabolite to pregnant mice during organogenesis did not produce adverse developmental outcomes at doses approximately 9 to 12 times the clinical exposure at a dose of 20 mg/kg/day; however, higher doses produced adverse developmental outcomes (see Data as follows).
In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data: Animal Data: No anomalies or malformations were observed after oral administration of tolterodine to pregnant mice during organogenesis at approximately 9-12 times the clinical exposure to the pharmacologically active components of DETRUSITOL SR (based on the AUC of tolterodine and its 5-HMT metabolite at a dose of 20 mg/kg/day). At 14-18 times the clinical exposure (doses of 30 to 40 mg/kg/day) in mice, tolterodine was embryo-lethal, caused reduced fetal weight, and increased the incidence of fetal abnormalities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification). Pregnant rabbits administered tolterodine subcutaneously at about 0.3 - 2.5 times the clinical exposure (dose of 0.8 mg/kg/day) did not show any embryotoxicity or teratogenicity.
Lactation: Risk Summary: There is no information on the presence of tolterodine or its 5-HMT metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Based on limited data, tolterodine is excreted into the milk in mice in low amounts (see Animal Data as follows). The development and health benefits of breastfeeding should be considered along with the mother's clinical need for DETRUSITOL SR and any potential adverse effects on the breastfed infant from DETRUSITOL SR or from the underlying maternal condition.
Animal Data: The use of radiolabeled tolterodine in pregnant mice produced milk: plasma ratios that ranged between 0.0 and 0.7.

Detrusitol: Summary of the safety profile: Due to the pharmacological effect of tolterodine it may cause mild-to-moderate antimuscarinic effects, like dryness of the mouth, dyspepsia, and dry eyes.
Table 5 as follows reflects the data obtained with tolterodine in clinical trials and from post-marketing experience. The most commonly reported adverse reaction was dry mouth, which occurred in 35% of patients treated with tolterodine and in 10% of placebo treated patients. Headaches were also reported very commonly and occurred in 10.1% of patients treated with tolterodine and in 7.4% of placebo treated patients.
Tabulated list of adverse reactions: The adverse drug reactions listed in the table as follows are presented by System Organ Class (SOC) and frequency categories, defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 5.)

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Cases 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.
Detrusitol SR: 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.
Clinical Trials Experience: The efficacy and safety of DETRUSITOL SR Capsules was evaluated in 1073 patients (537 assigned to DETRUSITOL SR; 536 assigned to placebo) who were treated with 2, 4, 6, or 8 mg/day for up to 15 months. These included a total of 1012 patients (505 randomized to DETRUSITOL SR 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 DETRUSITOL SR and in 49% (n=247) of patients receiving placebo. The most common adverse events reported by patients receiving DETRUSITOL SR were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported adverse event for patients treated with DETRUSITOL SR occurring in 23.4% of patients treated with DETRUSITOL SR 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 DETRUSITOL SR and by 3.6% (n=18) of patients receiving placebo.
Table 6 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 DETRUSITOL SR 4 mg once daily. (See Table 6.)

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The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Similar percentages of patients treated with DETRUSITOL SR or placebo discontinued treatment due to adverse events. Dry mouth was the most common adverse event leading to treatment discontinuation among patients receiving DETRUSITOL SR [n=12 (2.4%) vs. placebo n=6 (1.2%)].
Post-marketing Experience: The following events have been reported in association with tolterodine use in worldwide post-marketing experience: General: anaphylaxis and angioedema;
Cardiovascular: tachycardia, palpitations, peripheral edema;
Gastrointestinal: diarrhea;
Central/Peripheral Nervous: confusion, disorientation, memory impairment, hallucinations.
Reports of aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) have been reported after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia.
Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of tolterodine in their causation cannot be reliably determined.

Detrusitol: Concomitant systemic medication with potent CYP3A4 inhibitors such as macrolide antibiotics (e.g. erythromycin and clarithromycin), antifungal agents (e.g. ketoconazole and itraconazole) and antiproteases is not recommended due to increased serum concentrations of tolterodine in poor CYP2D6 metabolisers with (subsequent) risk of overdosage (see Precautions).
Concomitant medication with other drugs that possess antimuscarinic properties may result in more pronounced therapeutic effect and side-effects. Conversely, the therapeutic effect of tolterodine may be reduced by concomitant administration of muscarinic cholinergic receptor agonists.
The effect of prokinetics like metoclopramide and cisapride may be decreased by tolterodine.
Concomitant treatment with fluoxetine (a potent CYP2D6 inhibitor) does not result in a clinically significant interaction since tolterodine and its CYP2D6-dependent metabolite, 5-hydroxymethyl tolterodine are equipotent.
Drug interaction studies have shown no interactions with warfarin or combined oral contraceptives (ethinyl estradiol/levonorgestrel).
A clinical study has indicated that tolterodine is not a metabolic inhibitor of CYP2D6, 2C19, 2C9, 3A4 or 1A2. Therefore an increase of plasma levels of drugs metabolised by these isoenzymes is not expected when dosed in combination with tolterodine.
Detrusitol SR: Potent CYP2D6 Inhibitors: Fluoxetine, a potent inhibitor of CYP2D6 activity, significantly inhibited the metabolism of tolterodine immediate release in CYP2D6 extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in C_max and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT), the pharmacologically active metabolite of tolterodine [see Pharmacology under Actions]. The sums of unbound serum concentrations of tolterodine and 5-HMT are only 25% higher during the interaction. No dose adjustment is required when tolterodine and fluoxetine are co-administered [see Pharmacology under Actions].
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 DETRUSITOL SR is 2 mg once daily [see Dosage & Administration and Pharmacology under Actions].
Other Interactions: No clinically relevant interactions have been observed when tolterodine was co-administered with warfarin, with a combined oral contraceptive drug containing ethinyl estradiol and levonorgestrel, or with diuretics [see Pharmacology under Actions.]
Other Drugs Metabolized by Cytochrome P450 Isoenzymes: In vivo drug-interaction data show that tolterodine immediate release does not result in clinically relevant inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine, debrisoquine, S-warfarin, and omeprazole [see Pharmacology under Actions].
Drug-laboratory Test Interactions: Interactions between tolterodine and laboratory tests have not been studied.
Other Anticholinergics: The concomitant use of DETRUSITOL SR with other anticholinergic (antimuscarinic) agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, somnolence and other anticholinergic pharmacological effects.

Incompatibilities: Not applicable.
Special Precautions for Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store below 30°C. Keep tablets in the original package, protected from moisture.

Drugs for Bladder & Prostate Disorders

G04BD07 - tolterodine ; Belongs to the class of urinary antispasmodics.

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