Prescription Drug Information: Tolterodine Tartrate (Page 4 of 5)

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.


Following administration of a 5 mg oral dose of 14 C-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 3. These data were obtained following single and multiple doses of tolterodine extended-release administered daily to 17 healthy male volunteers (13 EM, 4 PM).

Table 3. Summary of Mean (± SD) Pharmacokinetic Parameters of Tolterodine Extended-Release and its Active Metabolite (5-Hydroxymethyl Tolterodine) in Healthy Volunteers
Data presented as median (range).
Parameter dose-normalized from 8 to 4 mg for the single-dose data.
not applicable.


5-Hydroxymethyl Tolterodine

t max *


C max


C avg


t 1/2


t max *


C max


C avg


t 1/2


Single dose

4 mg


4(2– to 6)









dose 4 mg EM














Cmax = Maximum serum concentration; tmax = Time of occurrence of Cmax; Cavg = Average serum concentration; t1/2 = Terminal elimination half-life.

Drug Interactions

Potent CYP2D6 Inhibitors

Fluoxetine is a selective serotonin reuptake inhibitor and a potent inhibitor of CYP2D6 activity. In a study to assess the effect of fluoxetine on the pharmacokinetics of tolterodine immediate release and its metabolites, it was observed that fluoxetine significantly inhibited the metabolism of tolterodine immediate release in extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in C max and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT, the pharmacologically active metabolite of tolterodine). Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be CYP2D6 extensive metabolizers of tolterodine immediate release to resemble the pharmacokinetic profile in poor metabolizers. The sums of unbound serum concentrations of tolterodine immediate release and 5-HMT are only 25% higher during the interaction. No dose adjustment is required when tolterodine and fluoxetine are co-administered.

Potent CYP3A4 Inhibitors

The effect of a 200 mg daily dose of ketoconazole on the pharmacokinetics of tolterodine immediate release was studied in 8 healthy volunteers, all of whom were CYP2D6 poor metabolizers. In the presence of ketoconazole, the mean C max and AUC of tolterodine increased by 2- and 2.5-fold, respectively. Based on these findings, other potent CYP3A4 inhibitors may also lead to increases of tolterodine plasma concentrations.

For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, miconazole, clarithromycin, ritonavir, the recommended dose of tolterodine tartrate extended-release capsules is 2 mg daily [see Dosage and Administration (2.3)] .


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.


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.


13.1 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 tolterodine tartrate extended-release capsules (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 tartrate extended-release capsules 2 mg were evaluated in 29 patients in a Phase 2 dose-effect study. Tolterodine tartrate extended-release capsules 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 extended-release capsules 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 tolterodine tartrate extended-release capsules 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 tolterodine tartrate extended-release capsules are summarized in Table 4.

Table 4. 95% Confidence Intervals (CI) for the Difference Between Tolterodine Tartrate Extended-Release Capsules (4 mg Daily) and Placebo for Mean Change at Week 12 from Baseline *
Intent-to-treat analysis.
1 to 2 patients missing in placebo group for each efficacy parameter.
The difference between tolterodine tartrate extended-release capsules and placebo was statistically significant.

Tolterodine Tartrate Extended-Release Capsules

(n = 507)


(n = 508)


Difference, vs. Placebo

(95% CI)

Number of incontinence episodes/week

Mean Baseline

Mean Change from Baseline


-11.8 (SD 17.8)


-6.9 (SD 15.4)


(-6.9, -2.8)

Number of micturitions/day

Mean Baseline

Mean Change from Baseline


-1.8 (SD 3.4)


-1.2 (SD 2.9)


(-1.0, -0.2)

Volume voided per micturition (mL)

Mean Baseline

Mean Change from Baseline


34 (SD 51)


14 (SD 41)


(14, 26)

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