WARNINGS
See CONTRAINDICATIONS and
PRECAUTIONS
.
PRECAUTIONS
General
Risk of Urinary Retention and Gastric Retention:
DETROL 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).
Controlled Narrow-Angle Glaucoma:
DETROL should be used with caution in patients being treated
for narrow-angle glaucoma.
Reduced Hepatic and Renal Function:
Patients with significantly reduced hepatic function should
not receive doses of DETROL greater than 1 mg twice daily.
Patients with renal impairment should be treated with
caution (see CLINICAL PHARMACOLOGY, Pharmacokinetics in
Special Populations).
Information for Patients
Patients should be informed that antimuscarinic agents
such as tolterodine may produce blurred vision.
Drug Interactions
Cytochrome P450 3A4 Inhibitors: Pharmacokinetic studies
with patients concomitantly receiving cytochrome P450
3A4 inhibitors, such as macrolide antibiotics (erythromycin
and clarithromycin) or antifungal agents (ketoconazole,
itraconazole, and miconazole), have not been performed.
Patients receiving cytochrome P450 3A4 inhibitors should
not receive doses of DETROL greater than 1 mg twice daily.
Drug-Laboratory-Test Interactions
Interactions between tolterodine and laboratory tests
have not been studied.
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), AUC values obtained for tolterodine were
355, 291, and 462 ug h/L, respectively. In comparison,
the human AUC value for a 2-mg dose administered twice
daily is estimated at 34 ug h/L. Thus, tolterodine exposure
in the carcinogenicity studies was 9 to 10-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 four strains of Salmonella typhimurium
and in two 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 ug 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 cause embryolethality,
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 ug h/L, which is about three-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 should be used during pregnancy only
if the potential benefit for the mother justifies the
potential risk for the fetus.
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, administration of DETROL should
be discontinued during nursing.
Pediatric Use
The safety and effectiveness of DETROL in pediatric patients
have not been established.
Geriatric Use
Of the 1,120 patients who were treated in the four Phase
3, 12-week clinical studies of DETROL, 474 (42%) were
65 to 91 years of age. No overall differences in safety
were observed between the older and younger patients (see
CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations).
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