Tolterodine Tartrate

INDICATIONS AND USAGE Tolterodine tartrate tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

DOSAGE AND ADMINISTRATION The initial recommended dose of tolterodine tartrate tablets is 2 mg twice daily. The dose may be lowered to 1 mg twice daily based on individual response and tolerability. For patients with significantly reduced hepatic or renal function or who are currently taking drugs that are potent inhibitors of CYP3A4, the recommended dose of tolterodine tartrate tablets is 1 mg twice daily (see PRECAUTIONS, General , PRECAUTIONS, Reduced Hepatic and Renal Function , and PRECAUTIONS, Drug Interactions ).

CONTRAINDICATIONS Tolterodine tartrate tablets are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Tolterodine tartrate tablets are also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like tolterodine tartrate tablets, are metabolized to 5-hydroxymethyl tolterodine.

WARNINGS Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of tolterodine tartrate tablets. In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, tolterodine tartrate tablets should be discontinued and appropriate therapy promptly provided.

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 (e.g., erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of tolterodine tartrate tablets is 1 mg twice daily (see DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS The Phase 2 and 3 clinical trial program for tolterodine tartrate tablets included 3071 patients who were treated with tolterodine tartrate tablets (N=2133) or placebo (N=938). The patients were treated with 1, 2, 4, or 8 mg/day for up to 12 months. No differences in the safety profile of tolterodine were identified based on age, gender, race, or metabolism. The data described below reflect exposure to tolterodine tartrate tablets 2 mg bid in 986 patients and to placebo in 683 patients exposed for 12 weeks in five Phase 3, controlled clinical studies. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and approximating rates. Sixty-six percent of patients receiving tolterodine tartrate tablets 2 mg bid reported adverse events versus 56% of placebo patients. The most common adverse events reported by patients receiving tolterodine tartrate tablets were dry mouth, headache, constipation, vertigo/dizziness, and abdominal pain. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and xerophthalmia are expected side effects of antimuscarinic agents. Dry mouth was the most frequently reported adverse event for patients treated with tolterodine tartrate tablets 2 mg bid in the Phase 3 clinical studies, occurring in 34.8% of patients treated with tolterodine tartrate tablets and 9.8% of placebo-treated patients. One percent of patients treated with tolterodine tartrate tablets discontinued treatment due to dry mouth. The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Seven percent of patients treated with tolterodine tartrate tablets 2 mg bid discontinued treatment due to adverse events versus 6% of placebo patients. The most common adverse events leading to discontinuation of tolterodine tartrate tablets were dizziness and headache. Three percent of patients treated with tolterodine tartrate tablets 2 mg bid reported a serious adverse event versus 4% of placebo patients. Significant ECG changes in QT and QTc have not been demonstrated in clinical-study patients treated with tolterodine tartrate tablets 2 mg bid. Table 5 lists the adverse events reported in 1% or more of the patients treated with tolterodine tartrate tablets 2 mg bid in the 12-week studies. The adverse events are reported regardless of causality. Table 5. Incidence in nearest integer. (%) of Adverse Events Exceeding Placebo Rate and Reported in >1% of Patients Treated with Tolterodine TartrateTablets (2 mg bid) in 12-week, Phase 3 Clinical Studies Body System Adverse Event % Tolterodine Tartrate Tablets N=986 % Placebo N=683 Autonomic Nervous accommodation abnormal 2 1 dry mouth 35 10 General chest pain 2 1 fatigue 4 3 headache 7 5 influenza-like symptoms 3 2 Central/Peripheral Nervous vertigo/dizziness 5 3 Gastrointestinal abdominal pain 5 3 constipation 7 4 diarrhea 4 3 dyspepsia 4 1 Urinary dysuria 2 1 Skin/Appendages dry skin 1 0 Musculoskeletal arthralgia 2 1 Vision xerophthalmia 3 2 Psychiatric somnolence 3 2 Metabolic/Nutritional weight gain 1 0 Resistance Mechanism infection 1 0 Post-marketing Surveillance The following events have been reported in association with tolterodine use in worldwide post-marketing experience: General: anaphylaxis and angioedema; Cardiovascular: tachycardia, palpitations, peripheral edema; Central/Peripheral Nervous: confusion, disorientation, memory impairment, hallucinations. Reports of aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) have been reported after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of tolterodine in their causation cannot be reliably determined.

Pregnancy Tolterodine, administered at oral doses of 20 mg/kg/day (approximately 14 times the human exposure), showed no anomalies or malformations 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 tartrate tablets should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus.