Prescription Drug Information: Tolterodine Tartrate (Page 3 of 5)


Tolterodine tartrate extended-release capsules contain 2 mg or 4 mg of tolterodine tartrate. The active moiety, tolterodine, is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate is (+)-( R)-2-[I-[2-(Diisopropylamino)ethyl]benzyl]- p -cresol L-tartrate (1:1) (salt). The molecular formula of tolterodine tartrate is C 26 H 37 NO 7 . Its structure is:

Tolterodine Tartrate Strcutural Formula
(click image for full-size original)

Tolterodine tartrate, USP is a white to off-white colored solid with a molecular weight of 475.6. The pK a 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.

Each capsule contains 2 mg or 4 mg of tolterodine tartrate with the following inactive ingredients: ethylcellulose, FD&C Blue No. 2, gelatin, hypromellose, sodium lauryl sulfate, sugar spheres (corn starch and sucrose), talc and titanium dioxide. The 2 mg capsules also contain yellow iron oxide.

The imprinting ink contains the following: black iron oxide, potassium hydroxide, propylene glycol and shellac.


12.1 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.

12.2 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 tolterodine tartrate immediate release 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 Drug Interactions (7.2)] . 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 c F) and a population-specific (QT c P) 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.

Table 2. Mean (CI) Change in QT c from Baseline to Steady State (Day 4 of Dosing) at T max (Relative to Placebo)
At Tmax of 1 hr; 95% Confidence Interval.
At Tmax of 2 hr; 90% Confidence Interval.
The effect on QT interval with 4 days of moxifloxacin dosing in this QT trial may be greater than typically observed in QT trials of other drugs.



QT c F



QT c F



QT c P



QT c P




2 mg BID *



(0.28, 9.74)


(-2.99, 5.30)


(-0.37, 9.26)


(-1.81, 5.81)


4 mg BID *



(7.11, 16.58)


(1.48, 9.77)


(5.49, 15.12)


(4.53, 12.15)


400 mg QD



(15.49, 23.03)


(4.77, 13.03)


(15.32, 22.89)


(5.34, 13.24)

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 tolterodine tartrate tablets or tolterodine tartrate extended-release capsules [see Warnings and Precautions (5.9)] .

12.3 Pharmacokinetics


In a study with 14 C-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.


Tolterodine is highly bound to plasma proteins, primarily α 1 -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.


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.

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