WARNINGS AND PRECAUTIONS
Bladder Outlet Obstruction
Toviaz should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention [ see
CONTRAINDICATIONS (4)
].
Decreased Gastrointestinal Motility
Toviaz, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility, such as those with severe constipation.
Controlled Narrow-Angle Glaucoma
Toviaz should be used with caution in patients being treated for narrow-angle glaucoma, and only where the potential benefits outweigh the risks [ see
CONTRAINDICATIONS (4)
].
Hepatic Impairment
Toviaz has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population [ see
USE IN SPECIFIC POPULATIONS
and
DOSAGE AND ADMINISTRATION (2)
].
Renal Impairment
Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment [ see
USE IN SPECIFIC POPULATIONS
and
DOSAGE AND ADMINISTRATION (2)
].
Concomitant Administration with CYP3A4 Inhibitors
Doses of Toviaz greater than 4 mg are not recommended in patients taking a potent CYP3A4 inhibitor (e.g. ketoconazole, itraconazole, clarithromycin).
In patients taking weak or moderate CYP3A4 inhibitors (e.g. erythromycin), careful assessment of tolerability at the 4 mg daily dose is advised prior to increasing the daily dose to 8 mg. While this specific interaction potential was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with potent CYP3A4 inhibitors [ see
DRUG INTERACTIONS
and
DOSAGE AND ADMINISTRATION (2)
].
Myasthenia Gravis
Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction .
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. There are no adequate and well-controlled studies using Toviaz in pregnant women.
No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at 6 to 27 times the expected exposure at the maximum recommended human dose (MRHD) of 8 mg based on AUC (75 mg/kg/day, oral), increased resorptions and decreased live fetuses were observed. One fetus with cleft palate was observed at each dose (15, 45 and 75 mg/kg/day), at an incidence within the background historical range. In rabbits treated at 3 to 11 times the MRHD (27 mg/kg/day, oral), incompletely ossified sternebrae (retardation of bone development) were observed in fetuses. In rabbits at 9 to 11 times the MRHD (4.5 mg/kg/day, subcutaneous), maternal toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence within the background historical range). In rabbits at 3 times the MRHD (1.5 mg/kg/day, subcutaneous), decreased maternal food consumption in the absence of any fetal effects was observed. Oral administration of 30 mg/kg/day fesoterodine to mice in a pre- and post-natal development study resulted in decreased body weight of the dams and delayed ear opening of the pups. No effects were noted on mating and reproduction of the F1 dams or on the F2 offspring.
Toviaz should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Nursing Mothers
It is not known whether fesoterodine is excreted in human milk. Toviaz should not be administered during nursing unless the potential benefit outweighs the potential risk to the neonate.
Pediatric Use
The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.
The safety and effectiveness of Toviaz in pediatric patients have not been established.
Geriatric Use
No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.
Of 1567 patients who received Toviaz 4mg/day or 8mg/day in the Phase 2 and 3, placebo-controlled, efficacy and safety studies, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies; however, the incidence of antimuscarinic adverse events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients. [ see
CLINICAL STUDIES
and
ADVERSE REACTIONS (6)
].
Renal Impairment
In patients with severe renal impairment (CLCR < 30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold, respectively. Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment. In patients with mild or moderate renal impairment (CLCR ranging from 30-80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and 1.8-fold respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate renal impairment [ see
WARNINGS AND PRECAUTIONS
and
DOSAGE AND ADMINISTRATION (2)
].
Hepatic Impairment
Patients with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz is not recommended for use in these patients. In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate hepatic impairment [ see
WARNINGS AND PRECAUTIONS
and
DOSAGE AND ADMINISTRATION (2)
].
Gender
No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are not significantly influenced by gender.
Race
Available data indicate that there are no differences in the pharmacokinetics of fesoterodine between Caucasian and Black healthy subjects following administration of Toviaz.
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