General
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).
Reduced Hepatic Function
There are no dosing adjustments for patients with mild or moderate 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 CLINICAL PHARMACOLOGY,
Pharmacokinetics in Special Populations and DOSAGE AND ADMINISTRATION).
Myasthenia Gravis
TOVIAZ should be used with caution in patients with myasthenia gravis, a disease
characterized by decreased cholinergic activity at the neuromuscular junction.
Reduced Renal Function
There are no dosing adjustments for patients with mild or moderate renal insufficiency.
Doses of TOVIAZ greater than 4 mg are not recommended in patients with severe renal
insufficiency (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special 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).
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 CLINICAL PHARMACOLOGY, Drug-Drug
Interactions and DOSAGE AND ADMINISTRATION).
Information for Patients
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 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.
Drug Interactions
Coadministration of TOVIAZ with other antimuscarinic agents that produce dry mouth,
constipation, urinary retention, and other anticholinergic pharmacological effects
may increase the frequency and/or severity of such effects. Anticholinergic agents
may potentially alter the absorption of some concomitantly administered drugs due
to anticholinergic effects on gastrointestinal motility. Also see PRECAUTIONS, Concomitant
Administration with CYP3A4 Inhibitors.
Drug-Laboratory Test Interactions
Interactions between TOVIAZ and laboratory tests have not been studied.
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-fold (females)
and 4- to 9-fold (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-fold (females) and 3- to 14-fold
(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-fold
higher in mice than in humans at the MRHD, whereas based on peak plasma concentrations,
the exposure in mice was 5- to 9-fold higher. The Lowest-Observed-Effect Level (LOEL)
for maternal toxicity was 45 mg/kg/day.
Pregnancy
Pregnancy Category C
Reproduction studies have been performed in mice and rabbits. No dose-related teratogenicity
was observed at oral doses up to 75 mg/kg/day in mice (6 to 27 times the expected
exposure at the MRHD based on AUC and greater than 77 times the expected Cmax)
and up to 27 mg/kg/day in rabbits (3- to 11- fold by AUC and 19- to 62– fold by
Cmax) or at subcutaneous doses up to 4.5 mg/kg/day in
rabbits (9- to 11- fold by AUC and 43 to 56-fold by Cmax).
In mice treated orally with 75 mg/kg/day (6- to 27-times the expected exposure at
the MRHD based on AUC and greater than 77-times the expected Cmax),
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 orally with 27 mg/kg/day (3
to 11- fold by AUC and 19 to 62- fold by Cmax), incompletely
ossified sternebrae (retardation of bone development) were observed in fetuses.
In rabbits treated by subcutaneous (sc) administration with 4.5 mg/kg/day (9 to
11- fold by AUC and 43 to 53- fold by Cmax), maternal
toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence
within the background historical range). At 1.5 mg/kg/day s.c., (3-fold by AUC and
11 to 13- fold by Cmax), 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.
There are no adequate and well-controlled studies using TOVIAZ in pregnant women.
Therefore, 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 safety and effectiveness of TOVIAZ in pediatric patients have not been established.
Geriatric Use
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 PHARMACOLOGY, Pharmacokinetics
in Special Populations, and CLINICAL STUDIES and ADVERSE REACTIONS).