Tolterodine precautions

List of precautions
General Patients with congenital/acquired QT prolongation Lab test interactions Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Nursing mothers Pediatric use Geriatric use
 * Risk of urinary retention/gastric retention
 * Decreased gastrointestinal motility
 * Controlled narrow-angle glaucoma
 * Reduced hepatic/renal function
 * Myasthenia gravis

Risk of urinary retention/gastric retention
Tolterodine Tablets 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. Return to top

Decreased gastrointestinal motility
Tolterodine, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility. Return to top

Controlled narrow-angle glaucoma
Tolterodine should be used with caution in patients being treated for narrow-angle glaucoma. Return to top

Reduced hepatic/renal function
For patients with significantly reduced hepatic function or renal function, the recommended dose of Tolterodine is 1 mg twice daily. Return to top

Myasthenia gravis
Tolterodine should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction. Return to top

Patients with congenital/acquired QT prolongation
In a study of the effect of tolterodine immediate release tablets on the QT interval, 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 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. There has been no association of Torsade de Pointes in the international post-marketing experience with Tolterodine or Tolterodine LA. Return to top

Lab test interactions
Interactions between tolterodine and laboratory tests have not been studied. Return to top

Carcinogenesis
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), AUC values obtained for tolterodine were 355, 291, and 462 µg∙h/L, respectively. In comparison, the human AUC value for a 2-mg dose administered twice daily is estimated at 34 µg∙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. Return to top

Mutagenesis
No mutagenic 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. Return to top

Impairment of fertility
In female mice treated for 2 weeks before mating and during gestation with 20 mg/kg/day (corresponding to AUC value of about 500 µg∙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. Return to top

Pregnancy
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, 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 µg∙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 should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus. Return to top

Nursing mothers
Tolterodine 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 should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue Tolterodine in nursing mothers. Return to top

Pediatric use
Efficacy in the pediatric population has not been demonstrated. Two pediatric phase 3 randomized, placebo-controlled, double-blind, 12-week studies were conducted using tolterodine extended release (Tolterodine LA) capsules. A total of 710 pediatric patients (486 on Tolterodine LA and 224 on placebo) aged 5–10 years with urinary frequency and urge urinary incontinence were studied. The percentage of patients with urinary tract infections was higher in patients treated with Tolterodine LA (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 LA compared to 0.9% of children treated with placebo. Return to top

Geriatric use
Of the 1120 patients who were treated in the four Phase 3, 12-week clinical studies of Tolterodine, 474 (42%) were 65 to 91 years of age. No overall differences in safety were observed between the older and younger patients. Return to top