Fesoterodine

Fesoterodine
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

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Overview

Fesoterodine is a muscarinic antagonist that is FDA approved for the {{{indicationType}}} of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Common adverse reactions include dry mouth and constipation.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Overactive bladder

• The recommended starting dose of Toviaz is 4 mg once daily. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily.

• The daily dose of Toviaz should not exceed 4 mg in the following populations:

• Patients with severe renal impairment (CLCR <30 mL/min).
• Patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Fesoterodine in adult patients.

Non–Guideline-Supported Use

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Fesoterodine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding FDA-Labeled Use of Fesoterodine in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Fesoterodine in pediatric patients.

Non–Guideline-Supported Use

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Fesoterodine in pediatric patients.

Contraindications

• Toviaz is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Toviaz is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules.

Warnings

Precautions

• Angioedema

• 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.

• 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.

• Central Nervous System Effects

• Toviaz is associated with anticholinergic central nervous sytem (CNS) effects. 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.

• Hepatic Impairment

• Toviaz has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population.

• Renal Impairment

• Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment.

• 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 CYP3A4 inhibitors.

• Myasthenia Gravis

• Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.

Adverse Reactions

Clinical Trials Experience

• The safety of Toviaz was evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder, of which 2288 were treated with fesoterodine. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase 2 or 3 studies with treatment periods of 8 or 12 weeks. Approximately 80% of these patients had >10 weeks exposure to Toviaz in these trials.

• A total of 1964 patients participated in two 12-week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these two studies combined, 554 patients received Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day.

• In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving Toviaz who reported one serious adverse event each: angina, chest pain, gastroenteritis, and QT prolongation on ECG.

• The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.

• The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg/day.

• Table 1 lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Toviaz 4 or 8 mg once daily for up to 12 weeks.

T1

• Patients also received Toviaz for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received Toviaz for at least 6 months, 1 year, 2 years, and 3 years, respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator and reported more than once during the open-label treatment period of up to 3 years, included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).

Postmarketing Experience

• The following events have been reported in association with fesoterodine use in worldwide post-marketing experience: Eye disorders: Blurred vision; Cardiac disorders: Palpitations; General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edema; Central nervous system disorders: Dizziness, headache, somnolence; Skin and subcutaneous tissue disorders: Urticaria, pruritus

• Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of fesoterodine in their causation cannot be reliably determined.

Drug Interactions

• Antimuscarinic Drugs

• 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.

• CYP3A4 Inhibitors

• Doses of Toviaz greater than 4 mg are not recommended in patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin. Coadministration of the potent CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a doubling of the maximum concentration (Cmax) and area under the concentration versus time curve (AUC) of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. Compared with CYP2D6 extensive metabolizers not taking ketoconazole, further increases in the exposure to 5-HMT were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole [see Clinical Pharmacology (12.3), Warnings and Precautions (5.8), and Dosage and Administration (2)].
• There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, the average (90% confidence interval) increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11% – 28%) and 27% (18% – 36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice).
• The effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors.

• CYP3A4 Inducers

• No dosing adjustments are recommended in the presence of CYP3A4 inducers, such as rifampin and carbamazepine. Following induction of CYP3A4 by coadministration of rifampin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed.

• CYP2D6 Inhibitors

• The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively.
• No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.

• Drugs Metabolized by Cytochrome P450

• In vitro data indicate that at therapeutic concentrations, the active metabolite of fesoterodine does not have the potential to inhibit or induce Cytochrome P450 enzyme systems.

• Oral Contraceptives

• In the presence of fesoterodine, there are no clinically significant changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel.

• Warfarin

• A clinical study has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity (PT/INR) of warfarin 25 mg. Standard therapeutic monitoring for warfarin should be continued

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• 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.

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fesoterodine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Fesoterodine during labor and delivery.

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.

Geriatic 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 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.

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.

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.

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.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Fesoterodine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Fesoterodine in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

Monitoring

There is limited information regarding Monitoring of Fesoterodine in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Fesoterodine in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Overdosage with Toviaz can result in severe anticholinergic effects.

Management

• Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended.

Chronic Overdose

There is limited information regarding Chronic Overdose of Fesoterodine in the drug label.

Pharmacology

There is limited information regarding Fesoterodine Pharmacology in the drug label.

Mechanism of Action

• Fesoterodine is a competitive muscarinic receptor antagonist. After oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active metabolite, 5-hydroxymethyl tolterodine, which is responsible for the antimuscarinic activity of fesoterodine and is also one of the active moieties of tolterodine tartrate tablets and tolterodine tartrate extended-release capsules.

• Muscarinic receptors play a role in contractions of urinary bladder smooth muscle and stimulation of salivary secretion. Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.

Structure

• Toviaz contains fesoterodine fumarate and is an extended-release tablet. Fesoterodine is rapidly de-esterified to its active metabolite (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxymethyl tolterodine, which is a muscarinic receptor antagonist.

• Chemically, fesoterodine fumarate is designated as isobutyric acid 2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate. The empirical formula is C30H41NO7 and its molecular weight is 527.66. The structural formula is:

This image is provided by the National Library of Medicine.

• Fesoterodine fumarate is a white to off-white powder, which is freely soluble in water. Each Toviaz extended-release tablet contains either 4 mg or 8 mg of fesoterodine fumarate and the following inactive ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Fesoterodine in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Fesoterodine in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Fesoterodine in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Fesoterodine in the drug label.

How Supplied

Storage

There is limited information regarding Fesoterodine Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Fesoterodine in the drug label.

Precautions with Alcohol

• Alcohol-Fesoterodine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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