General
Risk of Urinary Retention and Gastric Retention: DETROL LA Capsules
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 (see CONTRAINDICATIONS).
Decreased Gastrointestinal Motility: DETROL LA, like other antimuscarinic
drugs, should be used with caution in patients with decreased gastrointestinal motility.
Controlled Narrow-Angle Glaucoma: DETROL LA 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 DETROL LA is
2 mg daily (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations).
Myasthenia Gravis: DETROL LA should be used with caution in patients
with myasthenia gravis, a disease characterized by decreased cholinergic activity
at the neuromuscular junction.
Patients with Congenital or Acquired QT Prolongation
In a study of the effect of tolterodine immediate release tablets on the QT interval
(see 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 DETROL LA 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 (See PRECAUTIONS,
Drug Interactions). There has been no association of Torsade de Pointes
in the international post-marketing experience with DETROL or DETROL LA.
Information for Patients
Patients should be informed that antimuscarinic agents such as DETROL LA 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.
Drug Interactions
CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing
enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when
coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY,Variability
in Metabolism and 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 DETROL LA is 2 mg daily
(see DOSAGE AND ADMINISTRATION).
Drug-Laboratory-Test Interactions
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 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.
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.
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.
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 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 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, DETROL LA should be used during pregnancy only if the potential
benefit for the mother justifies the potential risk to the fetus.
Nursing Mothers
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,
DETROL LA should not be administered during nursing. A decision should be made whether
to discontinue nursing or to discontinue DETROL LA in nursing mothers.
Pediatric Use
Efficacy in the pediatric population has not been demonstrated.
A total of 710 pediatric patients (486 on DETROL LA, 224 on placebo) aged 5–10 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 DETROL 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 DETROL LA compared
to 0.9% of children treated with placebo.
Geriatric Use
No overall differences in safety were observed between the older and younger patients
treated with tolterodine (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special
Populations).