Fesoterodine Fumarate (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

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.

Mutagenesis

Fesoterodine was not mutagenic or genotoxic in vitro (Ames tests, chromosome aberration tests) or in vivo (mouse micronucleus test).

Impairment of Fertility

Fesoterodine had no effect on male reproductive function or fertility at doses up to 45 mg/kg/day in mice. At 45 mg/kg/day, a lower number of corpora lutea, implantation sites and viable fetuses was observed in female mice administered fesoterodine for 2 weeks prior to mating and continuing through day 7 of gestation. The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day. At the NOEL, the systemic exposure, based on AUC, 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.

14 CLINICAL STUDIES

14.1 Adult Overactive Bladder

The efficacy of fesoterodine fumarate extended-release tablets was evaluated in two, Phase 3, randomized, double-blind, placebo-controlled, 12-week studies for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Entry criteria required that patients have symptoms of overactive bladder for ≥ 6-months duration, at least 8 micturitions per day, and at least 6 urinary urgency episodes or 3 urge incontinence episodes per 3-day diary period. Patients were randomized to a fixed dose of fesoterodine fumarate 4 or 8 mg/day or placebo. In one of these studies, 290 patients were randomized to an active control arm (an oral antimuscarinic agent). For the combined studies, a total of 554 patients received placebo, 554 patients received fesoterodine fumarate 4 mg/day, and 566 patients received fesoterodine fumarate 8 mg/day. The majority of patients were Caucasian (91%) and female (79%) with a mean age of 58 years (range 19 to 91 years).

The primary efficacy endpoints were the mean change in the number of urge urinary incontinence episodes per 24 hours and the mean change in the number of micturitions (frequency) per 24 hours. An important secondary endpoint was the mean change in the voided volume per micturition.

Results for the primary endpoints and for mean change in voided volume per micturition from the two 12 week clinical studies of fesoterodine fumarate are reported in Table 10.

Table 10: Mean baseline and change from baseline to Week 12 for urge urinary incontinence episodes, number of micturitions, and volume voided per micturition

Study 1				Study 2
Parameter	Placebo N=279	Fesoterodine Fumarate 4 mg/day N=265	Fesoterodine Fumarate 8 mg/day N=276	Placebo N=266	Fesoterodine Fumarate 4 mg/day N=267	Fesoterodine Fumarate 8 mg/day N=267
Number of urge incontinence episodes per 24 hoursa
Baseline	3.7	3.8	3.7	3.7	3.9	3.9
Change from baseline	-1.20	-2.06	-2.27	-1	-1.77	-2.42
p-value vs. placebo	–	0.001	<0.001	–	<0.003	<0.001
Number of micturitions per 24 hours
Baseline	12	11.6	11.9	12.2	12.9	12
Change from baseline	-1.02	-1.74	-1.94	-1.02	-1.86	-1.94
p-value vs. placebo	–	<0.001	<0.001	–	0.032	<0.001
Voided volume per micturition (mL)
Baseline	150	160	154	159	152	156
Change from baseline	10	27	33	8	17	33
p-value vs. placebo	–	<0.001	<0.001	–	0.150	<0.001

vs. = versus

^a Only those patients who were urge incontinent at baseline were included for the analysis of number of urge incontinence episodes per 24 hours: In Study 1, the number of these patients was 211, 199, and 223 in the placebo, fesoterodine fumarate 4 mg/day and fesoterodine fumarate 8 mg/day groups, respectively. In Study 2, the number of these patients was 205, 228, and 218, respectively.

Figures 1-4: The following figures show change from baseline over time in number of micturitions and urge urinary incontinence episodes per 24 h in the two studies.

A reduction in number of urge urinary incontinence episodes per 24 hours was observed for both doses as compared to placebo as early as two weeks after starting fesoterodine fumarate therapy.

Pediatric use information is approved for Pfizer Inc.’s TOVIAZ® (fesoterodine fumarate) extended-release tablets. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

16 HOW SUPPLIED/STORAGE AND HANDLING

Fesoterodine fumarate extended-release tablets, 4 mg are light blue colored, oval shaped, biconvex, film-coated, debossed with ‘ ’ on one side and ‘FS’ on the other side and are supplied in bottles of 30’s, and 90’s.

Bottles of 30 NDC 43598-247-30

Bottles of 90 NDC 43598-247-90

Fesoterodine fumarate extended-release tablets, 8 mg are blue colored, oval shaped, biconvex, film-coated, debossed with ‘ ’ on one side and ‘FT’ on the other side and are supplied in bottles of 30’s, and 90’s.

Bottles of 30 NDC 43598-248-30

Bottles of 90 NDC 43598-248-90

Store fesoterodine fumarate extended-release tablets, at 20º to 25°C (68º to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-Approved Patient Labeling (Patient Information)

Angioedema

Inform patients and/or their caregivers that fesoterodine fumarate extended-release tablets may cause angioedema, which could result in life-threatening airway obstruction. Advise patients and/or their caregivers to promptly discontinue fesoterodine fumarate extended-release tablets and seek immediate medical attention if they experience edema of the lips, tongue or laryngopharynx, or difficulty breathing.

Antimuscarinic Effects

Inform patients that fesoterodine fumarate, like other antimuscarinic agents, may produce clinically significant adverse effects related to antimuscarinic pharmacological activity including constipation and urinary retention. Fesoterodine fumarate, 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 fesoterodine fumarate, like other antimuscarinic drugs, is used in a hot environment.

Alcohol

Patients should also be informed that alcohol may enhance the drowsiness caused by fesoterodine fumarate, like other anticholinergic agents. Patients should read the patient leaflet entitled “Patient Information Fesoterodine Fumarate Extended-release Tablets” before starting therapy with fesoterodine fumarate.

R_X only

Distributor:

Dr. Reddy’s Laboratories Inc.,

Princeton, NJ 08540

Made in India

Issued: 03/2022