1mg & 2mg tablet.Â Tolterodine tartrate 2mg & 4mg extended release capsule.
Tolterodine tartrate ER Capsules contain tolterodine tartrate. The active moiety,
tolterodine, is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate is
(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine L-hydrogen tartrate. The empirical formula of tolterodine tartrate is
C26H37NO7,Â and its molecular weight is 475.6. The structural formula of tolterodine
tartrate is represented below:
Tolterodine tartrate is a white, crystalline powder. The pKa value is 9.87 and the solubility in water is 12 mg/mL. It is soluble in methanol,
slightly soluble in ethanol, and practically insoluble in toluene. The partition coefficient (Log D) between n-octanol and water is 1.83 at pH 7.3.
TolterodineÂ tartrate ER capsuleÂ for oral administration contains 2 mg or 4 mg of tolterodine tartrate. Inactive
ingredients are sucrose, starch, hypromellose, ethylcellulose, medium chain triglycerides, oleic acid, gelatin, and FD&C Blue #2. The 2 mg capsules also
contain yellow iron oxide. Both capsule strengths are imprinted with a pharmaceutical grade printing ink that contains shellac glaze, titanium dioxide,
propylene glycol, and simethicone.
of Urinary Retention and Gastric Retention
Tolterodine tartrate should be administered with caution to patients with clinically significant bladder
outflow obstruction because of the risk of urinary retention and to patients with gastrointestinal obstructive disorders, such as pyloric stenosis, because
of the risk of gastric retention (seeÂ CONTRAINDICATIONS).
Decreased Gastrointestinal Motility
Tolterodine tartrate, like
other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility.
Controlled Narrow-Angle Glaucoma
Tolterodine tartrate should be used with caution in patients being treated for narrow-angle glaucoma.
Reduced Hepatic and Renal Function
For patients with significantly reduced hepatic function or renal function, the recommended dose for Tolterodine tartrateÂ is 2 mg daily (seeÂ CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations).
Tolterodine tartrateÂ should be used with caution in patients with
myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.
Congenital or Acquired QT Prolongation
In a study of the effect of tolterodine immediate release tablets on
the QT interval (seeÂ CLINICAL PHARMACOLOGY, Cardiac Electrophysiology), the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day and was more pronounced in
CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs). The effect of tolterodine 8 mg/day was not as large as that observed after four days of
therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped. These observations should be considered in clinical
decisions to prescribe Tolterodine tartrate ER capsule for patients
with a known history of QT prolongation or patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol)
antiarrhythmic medications (seeÂ PRECAUTIONS, Drug Interactions).
There has been no association of Torsade de Pointes in the international post-marketing experience with Tolterodine tartrate or Tolterodine tartrate ER
Information for Patients
should be informed that antimuscarinic agents such as Tolterodine tartrate ER capsule may produce the following effects: blurred vision, dizziness, or drowsiness. Patients should be advised to exercise caution in
decisions to engage in potentially dangerous activities until the drug's effects have been determined.
Ketoconazole, an inhibitor
of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor
metabolizers (seeÂ CLINICAL PHARMACOLOGY, Variability in MetabolismÂ andÂ Drug-Drug Interactions). For patients receiving
ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (e.g., itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin,
clarithromycin) or cyclosporine or vinblastine, the recommended dose of Tolterodine tartrateÂ is 2 mg daily (seeÂ DOSAGE AND ADMINISTRATION).
Interactions between tolterodine
and laboratory tests have not been studied.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with tolterodine immediate release were conducted in mice and rats. At the maximum tolerated dose in
mice (30 mg/kg/day), female rats (20 mg/kg/day), and male rats (30 mg/kg/day), AUC values obtained for tolterodine were 355, 291, and 462 Âµgâˆ™h/L,
respectively. In comparison, the human AUC value for a 2-mg dose administered twice daily is estimated at 34 Âµgâˆ™h/L. Thus, tolterodine exposure in the
carcinogenicity studies was 9- to 14-fold higher than expected in humans. No increase in tumors was found in either mice or rats.
mutagenic effects of tolterodine were detected in a battery of inÂ vitro tests, including bacterial mutation assays (Ames test) in 4 strains
ofÂ Salmonella typhimuriumÂ and in 2 strains ofÂ Escherichia coli,Â a gene mutation assay in L5178Y mouse lymphoma cells, and chromosomal
aberration tests in human lymphocytes. Tolterodine was also negativeÂ in vivoÂ in the bone marrow micronucleus test in the mouse.
female mice treated for 2 weeks before mating and during gestation with 20 mg/kg/day (corresponding to AUC value of about 500 Âµgâˆ™h/L), neither effects on
reproductive performance or fertility were seen. Based on AUC values, the systemic exposure was about 15-fold higher in animals than in humans. In male mice,
a dose of 30 mg/kg/day did not induce any adverse effects on fertility.
Pregnancy Category C. At oral doses of 20 mg/kg/day (approximately 14 times the human exposure), no anomalies or malformations were observed in
mice. When given at doses of 30 to 40 mg/kg/day, tolterodine has been shown to be embryolethal and reduce fetal weight, and increase the incidence of fetal
abnormalities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification) in mice.
At these doses, the AUC values were about 20- to 25-fold higher than in humans. Rabbits treated subcutaneously at a dose of 0.8 mg/kg/day achieved an AUC of
100 Âµgâˆ™h/L, which is about 3-fold higher than that resulting from the human dose. This dose did not result in any embryotoxicity or teratogenicity. There
are no studies of tolterodine in pregnant women. Therefore, Tolterodine tartrate ER capsule should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the
Tolterodine immediate release is excreted into the milk in
mice. Offspring of female mice treated with tolterodine 20 mg/kg/day during the lactation period had slightly reduced body weight gain. The offspring
regained the weight during the maturation phase. It is not known whether tolterodine is excreted in human milk; therefore, Tolterodine tartrateÂ should not be administered during nursing. A decision should be made whether to
discontinue nursing or to discontinue Tolterodine tartrate ER capsule
in nursing mothers.
Efficacy in the pediatric population has not
A total of 710 pediatric patients (486 on Tolterodine tartrate ER capsule, 224 on placebo) aged 5â€“10 with urinary
frequency and urge incontinence were studied in two Phase 3 randomized, placebo-controlled, double-blind, 12-week studies. The percentage of patients with
urinary tract infections was higher in patients treated with Tolterodine tartrate ER capsule (6.6%) compared to patients who received placebo (4.5%).
Aggressive, abnormal and hyperactive behavior and attention disorders occurred in 2.9% of children treated with Tolterodine tartrate ER capsule compared to
0.9% of children treated with placebo.
No overall differences in safety
were observed between the older and younger patients treated with tolterodine (seeÂ CLINICAL PHARMACOLOGY,
Pharmacokinetics in Special Populations).
|Adverse Drug Reactions
Tolterodine tartrate 1-2 mg tablet
The Phase 2 and 3 clinical trial program
for Tolterodine tartrate Tablets included 3071 patients who were treated with Tolterodine tartrate (N=2133) or placebo (N=938). The patients were treated
with 1, 2, 4, or 8 mg/day for up to 12 months. No differences in the safety profile of tolterodine were identified based on age, gender, race, or
The data described below reflect exposure to Tolterodine tartrate 2 mg bid in 986 patients and to placebo in 683 patients
exposed for 12 weeks in five Phase 3, controlled clinical studies. Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to
be related to drug use and approximating rates.
Sixty-six percent of patients receiving Tolterodine tartrate 2 mg bid reported
adverse events versus 56% of placebo patients. The most common adverse events reported by patients receiving Tolterodine tartrate were dry mouth, headache,
constipation, vertigo/dizziness, and abdominal pain. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and
xerophthalmia are expected side effects of antimuscarinic agents.
Dry mouth was the most frequently reported adverse event for
patients treated with Tolterodine tartrate 2 mg bid in the Phase 3 clinical studies, occurring in 34.8% of patients treated with Tolterodine tartrate and
9.8% of placebo-treated patients. One percent of patients treated with Tolterodine tartrate discontinued treatment due to dry mouth.
The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Seven percent of patients treated with
Tolterodine tartrate 2 mg bid discontinued treatment due to adverse events versus 6% of placebo patients. The most common adverse events leading to
discontinuation of Tolterodine tartrate were dizziness and headache.
Three percent of patients treated with Tolterodine tartrate 2 mg
bid reported a serious adverse event versus 4% of placebo patients. Significant ECG changes in QT and QTc have not been demonstrated in clinical-study
patients treated with Tolterodine tartrate 2 mg bid. Table 5 lists the adverse events reported in 1% or more of the patients treated with Tolterodine
tartrate 2 mg bid in the 12-week studies. The adverse events are reported regardless of causality.
Tolterodine tartrate 2-4mg extended release capsule
The Phase 2 and 3 clinical
trial program for Tolterodine tartrate ER Capsules included 1073 patients who were treated with Tolterodine tartrate ER capsule (n=537) or placebo (n=536).
The patients were treated with 2, 4, 6, or 8 mg/day for up to 15 months. Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the
rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that
appear to be related to drug use and for approximating rates. The data described below reflect exposure to Tolterodine tartrate ER capsule 4 mg once daily
every morning in 505 patients and to placebo in 507 patients exposed for 12 weeks in the Phase 3, controlled clinical study.
Adverse events were
reported in 52% (n=263) of patients receiving Tolterodine tartrate ER capsule and in 49% (n=247) of patients receiving placebo. The most common adverse
events reported by patients receiving Tolterodine tartrate ER capsule were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most
frequently reported adverse event for patients treated with Tolterodine tartrate ER capsule occurring in 23.4% of patients treated with Tolterodine tartrate
ER capsule and 7.7% of placebo-treated patients. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and dry eyes are
expected side effects of antimuscarinic agents. A serious adverse event was reported by 1.4% (n=7) of patients receiving Tolterodine tartrate ER capsule and
by 3.6% (n=18) of patients receiving placebo.
The frequency of discontinuation due to adverse events was highest during the first 4 weeks of
treatment. Similar percentages of patients treated with Tolterodine tartrate ER capsule or placebo discontinued treatment due to adverse events. Treatment
was discontinued due to adverse events and dry mouth was reported as an adverse event in 2.4% (n=12) of patients treated with Tolterodine tartrate ER capsule
and in 1.2% (n=6) of patients treated with placebo.
The adverse events reported in 1% or more of patients treated with Tolterodine tartrate ER
capsule 4 mg once daily in the 12-week study. The adverse events were reported regardless of causality.
The following events have been reported in
association with tolterodine use in worldwide post-marketing experience:Â General:Â anaphylactoid reactions, including angioedema;Â Cardiovascular:Â tachycardia, palpitations, peripheral edema;Â Gastrointestinal:Â diarrhea;Â Central/Peripheral Nervous:Â confusion, disorientation,
memory impairment, hallucinations.Â
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.
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.
Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated
via cholinergic muscarinic receptors.
After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the
5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to
that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for
muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as
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.
In a study withÂ 14C-tolterodine solution in healthy volunteers
who received a 5-mg oral dose, at least 77% of the radiolabeled dose was absorbed. Cmaxand area under the concentration-time curve (AUC) determined after dosage of tolterodine immediate release are
dose-proportional over the range of 1 to 4 mg. Based on the sum of unbound serum concentrations of tolterodine and the 5-hydroxymethyl metabolite ("active
moiety"), the AUC of tolterodine extended release 4 mg daily is equivalent to tolterodine immediate release 4 mg (2 mg bid). CmaxÂ and CminÂ 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.
Tolterodine is highly bound to plasma proteins, primarily Î±1-acid glycoprotein. Unbound concentrations of tolterodine average 3.7% Â± 0.13% over the concentration range achieved in
clinical studies. The 5-hydroxymethyl metabolite is not extensively protein bound, with unbound fraction concentrations averaging 36% Â± 4.0%. The blood to
serum ratio of tolterodine and the 5-hydroxymethyl metabolite averages 0.6 and 0.8, respectively, indicating that these compounds do not distribute
extensively into erythrocytes. The volume of distribution of tolterodine following administration of a 1.28-mg intravenous dose is 113 Â± 26.7 L.
Tolterodine is extensively metabolized by the liver following oral dosing. The primary metabolic
route involves the oxidation of the 5-methyl group and is mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a pharmacologically
active 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid andÂ N-dealkylated 5-carboxylic acid metabolites, which account for 51% Â± 14% and 29% Â± 6.3% of the metabolites recovered in the
Variability in Metabolism
A subset (about 7%) of the Caucasian
population is devoid of CYP2D6, the enzyme responsible for the formation of the 5-hydroxymethyl metabolite of tolterodine. The identified pathway of
metabolism for these individuals ("poor metabolizers") is dealkylation via cytochrome P450 3A4 (CYP3A4) toÂ 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 the 5-hydroxymethyl metabolite.
Following administration of a 5-mg oral dose ofÂ 14C-tolterodine solution to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in feces in 7
days. Less than 1% (< 2.5% in poor metabolizers) of the dose was recovered as intact tolterodine, and 5% to 14% (<1% in poor metabolizers) was
recovered as the active 5-hydroxymethyl metabolite.
Pharmacokinetics in Special
In Phase 1, multiple-dose studies in which tolterodine immediate release 4 mg (2 mg bid) was administered, serum
concentrations of tolterodine and of the 5-hydroxymethyl metabolite were similar in healthy elderly volunteers (aged 64 through 80 years) and healthy young
volunteers (aged less than 40 years). In another Phase 1 study, elderly volunteers (aged 71 through 81 years) were given tolterodine immediate release 2 or 4
mg (1 or 2 mg bid). Mean serum concentrations of tolterodine and the 5-hydroxymethyl metabolite in these elderly volunteers were approximately 20% and 50%
higher, respectively, than reported in young healthy volunteers. However, no overall differences were observed in safety between older and younger patients
on tolterodine in the Phase 3, 12-week, controlled clinical studies; therefore, no tolterodine dosage adjustment for elderly patients is recommended
(seeÂ PRECAUTIONS, Geriatric Use).
Efficacy in the pediatric population has
not been demonstrated.
The pharmacokinetics of tolterodine extended release capsules have been evaluated in pediatric patients ranging in
age from 11â€“15 years. The dose-plasma concentration relationship was linear over the range of doses assessed. Parent/metabolite ratios differed according
to CYP2D6 metabolizer status: EMs had low serum concentrations of tolterodine and high concentrations of the active 5-hydroxymethyl metabolite, while PMs had
high concentrations of tolterodine and negligible active metabolite concentrations.
pharmacokinetics of tolterodine immediate release and the 5-hydroxymethyl metabolite are not influenced by gender. Mean CmaxÂ of tolterodine immediate release (1.6 Âµg/L in males versus 2.2 Âµg/L in females) and the active
5-hydroxymethyl metabolite (2.2 Âµg/L in males versus 2.5 Âµg/L in females) are similar in males and females who were administered tolterodine immediate
release 2 mg. Mean AUC values of tolterodine (6.7 Âµgâˆ™h/L in males versus 7.8 Âµgâˆ™h/L in females) and the 5-hydroxymethyl metabolite (10 Âµgâˆ™h/L in
males versus 11 Âµgâˆ™h/L in females) are also similar. The elimination half-life of tolterodine immediate release for both males and females is 2.4 hours,
and the half-life of the 5-hydroxymethyl metabolite is 3.0 hours in females and 3.3 hours in males.
Pharmacokinetic differences due to race have not been established.
Renal impairment can significantly alter the disposition of tolterodine immediate release and its metabolites. In a study conducted in patients with
creatinine clearance between 10 and 30 mL/min, tolterodine immediate release and the 5-hydroxymethyl metabolite levels were approximately 2â€“3 fold higher
in patients with renal impairment than in healthy volunteers. Exposure levels of other metabolites of tolterodine (e.g., tolterodine acid,Â N-dealkylated tolterodine acid,Â N-dealkylated tolterodine andÂ N-dealkylated
hydroxy tolterodine) were significantly higher (10â€“30 fold) in renally impaired patients as compared to the healthy volunteers. The recommended dose for
patients with significantly reduced renal function is tolterodine 2 mg daily (seePRECAUTIONS,
GeneralÂ andÂ DOSAGE AND ADMINISTRATION).
Liver impairment can significantly alter
the disposition of tolterodine immediate release. In a study of tolterodine immediate release conducted in cirrhotic patients, the elimination half-life of
tolterodine immediate release was longer in cirrhotic patients (mean, 7.8 hours) than in healthy, young, and elderly volunteers (mean, 2 to 4 hours). The
clearance of orally administered tolterodine immediate release was substantially lower in cirrhotic patients (1.0 Â± 1.7 L/h/kg) than in the healthy
volunteers (5.7 Â± 3.8 L/h/kg). The recommended dose for patients with significantly reduced hepatic function is tolterodine 2 mg daily (seeÂ PRECAUTIONS, GeneralÂ andÂ DOSAGE AND
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 CmaxÂ and a 20% decrease in AUC of the
5-hydroxymethyl metabolite. Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be extensive metabolizers of tolterodine immediate
release to resemble the pharmacokinetic profile in poor metabolizers. The sums of unbound serum concentrations of tolterodine immediate release and the
5-hydroxymethyl metabolite are only 25% higher during the interaction. No dose adjustment is required when tolterodine and fluoxetine are
Other Drugs Metabolized by Cytochrome P450 Isoenzymes
release does not cause clinically significant interactions with other drugs metabolized by the major drug metabolizing CYP enzymes.Â In vivoÂ 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.Â In vitroÂ data show that tolterodine immediate release is
a competitive inhibitor of CYP2D6 at high concentrations (Ki 1.05 ÂµM), while tolterodine immediate release as well as the 5-hydroxymethyl metabolite are
devoid of any significant inhibitory potential regarding the other isoenzymes.
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 poor metabolizers (seeÂ Pharmacokinetics, Variability in MetabolismÂ for discussion of poor metabolizers). In the presence of ketoconazole, the mean CmaxÂ and AUC of tolterodine increased by 2 and 2.5 fold, respectively. Based on these findings, other
potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or
cyclosporine or vinblastine may also lead to increases of tolterodine plasma concentrations (seeÂ PRECAUTIONSÂ andÂ DOSAGE AND ADMINISTRATION).
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.
Tolterodine immediate release 4 mg (2 mg bid) had no effect on the
pharmacokinetics of an oral contraceptive (ethinyl estradiol 30 Âµg/levo-norgestrel 150 Âµg) as evidenced by the monitoring of ethinyl estradiol and
levo-norgestrel over a 2-month period in healthy female volunteers.
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.
The effect of 2 mg BID and 4 mg BID of Tolterodine tartrate 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 18â€“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
(seeÂ PRECAUTIONS, Drug Interactions). QT interval was measured
over a 12-hour period following dosing, including the time of peak plasma concentration (Tmax) of tolterodine and at steady state (Day 4 of dosing).
Both Fridericia's (QTcF) and a population-specific
(QTcP) 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.Â 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 QTc 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 Tolterodine tartrate or Tolterodine
tartrate ER capsule (seeÂ PRECAUTIONS, Patients with Congenital or Acquired QT Prolongation).
Tolterodine tartrate 1-2mg FC
DETROL Tablets were evaluated for the treatment of
overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in four randomized, double-blind, placebo-controlled, 12-week studies.
A total of 853 patients received DETROL 2 mg twice daily and 685 patients received placebo. The majority of patients were Caucasian (95%) and female (78%),
with a mean age of 60 years (range, 19 to 93 years). At study entry, nearly all patients perceived they had urgency and most patients had increased frequency
of micturitions and urge incontinence. These characteristics were well balanced across treatment groups for the studies.
endpoints for study 007 included the change from baseline for:
- Number of incontinence episodes per
- Number of micturitions per 24 hours (averaged over 7 days)
- Volume of urine voided per micturition (averaged over 2
Tolterodine tartrate 2-4mg ER Capsule
Tolterodine tartrate ER Capsules 2mg were evaluated in 29 patients in a Phase 2 dose-effect study. Tolterodine tartrate ER capsule 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 Tolterodine tartrate ER capsule 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 endpoint was change in mean number of incontinence episodes per week at week 12 from
baseline. Secondary efficacy endpoints included change in mean number of micturitions per day and mean volume voided per micturition at week 12 from