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Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.
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].
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].
Central Nervous System Effects
Toviaz is associated with anticholinergic central nervous sytem (CNS) effects [see ADVERSE REACTIONS]. A variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Toviaz affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
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].
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].
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).
No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice).
While the effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with moderate CYP3 A4 inhibitors [see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION].
Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.
Patient Counseling Information
See FDA-Approved Patient Labeling
Patients should be informed that fesoterodine may produce angioedema, which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue fesoterodine therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficult breathing.
Patients should be informed that Toviaz, like other antimuscarinic agents, may produce clinically significant adverse effects related to antimuscarinic pharmacological activity including constipation and urinary retention. Toviaz, like other antimuscarinics, may be associated with blurred vision, therefore, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects on the patient have been determined. Heat prostration (due to decreased sweating) can occur when Toviaz, like other antimuscarinic drugs, is used in a hot environment.
Patients should also be informed that alcohol may enhance the drowsiness caused by Toviaz, like other anticholinergic agents. Patients should read the patient leaflet entitled "Patient Information TOVIAZ" before starting therapy with Toviaz.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of drug-related carcinogenicity was found in 24-month studies with oral administration to mice and rats. The highest tolerated doses in mice (females 45 to 60 mg/kg/day, males 30 to 45 mg/kg/day) correspond to 11 to 19 times (females) and 4 to 9 times (males) the estimated human AUC values reached with fesoterodine 8 mg, which is the Maximum Recommended Human Dose (MRHD). In rats, the highest tolerated dose (45 to 60 mg/kg/day) corresponds to 3 to 8 times (females) and 3 to 14 times (males) the estimated human AUC at the MRHD.
Fesoterodine was not mutagenic or genotoxic in vitro (Ames tests, chromosome aberration tests) or in vivo (mouse micronucleus test).
Fesoterodine had no effect on reproductive function, fertility, or early embryonic development of the fetus at non-maternally toxic doses in mice. The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day. Based on AUC, the systemic exposure was 0.6 to 1.5 times higher in mice than in humans at the MRHD, whereas based on peak plasma concentrations, the exposure in mice was 5 to 9 times higher. The Lowest-Observed-Effect Level (LOEL) for maternal toxicity was 45 mg/kg/day.
Use In Specific Populations
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 FI dams or on the FI offspring.
Toviaz should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
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.
The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients. The safety and effectiveness of Toviaz in pediatric patients have not been established.
No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.
Of 1567 patients who received Toviaz 4 mg/day or 8 mg/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 8 mg 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].
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 DOSAGE AND ADMINISTRATION].
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 DOSAGE AND ADMINISTRATION].
No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are not significantly influenced by gender.
Available data indicate that there are no differences in the pharmacokinetics of fesoterodine between Caucasian and Black healthy subjects following administration of Toviaz.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 8/13/2012
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