Fesoterodine (Monograph)

Brand name: Toviaz
Drug class: Genitourinary Smooth Muscle Relaxants
ATC class: G04BD11
VA class: AU350
Chemical name: isobutyric acid 2-((R)-3diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate
Molecular formula: C₂₆H₃₇NO₃
CAS number: 286930-03-8

Introduction

Genitourinary antispasmodic; an antimuscarinic agent.

Uses for Fesoterodine

Overactive Bladder

Relief of symptoms associated with voiding (e.g., urge urinary incontinence, urgency, frequency).

Fesoterodine Dosage and Administration

Administration

Oral Administration

Administer orally once daily with liquids without regard to meals.

Swallow extended-release tablets whole; do not chew, divide, or crush.

Dosage

Available as fesoterodine fumarate; dosage expressed in terms of the salt.

Adults

Overactive Bladder

Oral

Initially, 4 mg once daily. Depending on individual response and tolerability, may increase to 8 mg once daily.

Prescribing Limits

Adults

Overactive Bladder

Oral

Maximum 8 mg daily.

Special Populations

Hepatic Impairment

Manufacturer does not recommend dosage adjustments for patient with mild or moderate hepatic impairment. Some clinicians recommend caution when increasing dosage from 4 mg to 8 mg daily in patients with mild hepatic impairment (Child-Pugh class A) and a maximum dosage of 4 mg daily in patients with moderate hepatic impairment (Child-Pugh class B). (See Absorption: Special Populations, under Pharmacokinetics.)

Use not recommended in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Manufacturer does not recommend dosage adjustments for patient with mild or moderate renal impairment (Cl_cr 30–80 mL/minute); some clinicians recommend caution when increasing dosage from 4 mg to 8 mg daily in such patients. (See Absorption: Special Populations, under Pharmacokinetics.)

In patients with severe renal impairment (Cl_cr <30 mL/minute), maximum dosage 4 mg daily.

Geriatric Patients

No dosage adjustment required.

Cautions for Fesoterodine

Contraindications

• Urinary retention, gastric retention, or uncontrolled angle-closure glaucoma.

• Known hypersensitivity to fesoterodine fumarate or any ingredient in the formulation.

Warnings/Precautions

General Precautions

Urinary Retention

Risk of urinary retention; use with caution in patients with clinically important bladder outflow obstruction.

Decreased GI Motility

Use with caution in patients with decreased GI motility (e.g., patients with severe constipation).

Controlled Angle-closure Glaucoma

Use with caution in patients being treated for angle-closure glaucoma and only when potential benefits outweigh risks. (See Cautions: Contraindications.)

Myasthenia Gravis

Use with caution in patients with myasthenia gravis.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether fesoterodine is distributed into milk in humans; do not use unless benefit to woman outweighs potential risk to the infant.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.

Incidence of adverse antimuscarinic events (e.g., dry mouth, constipation, dyspepsia, increase in residual urine, dizziness [only at a dosage of 8 mg daily]) and urinary tract infection was higher in patients ≥75 years of age compared with younger patients.

Hepatic Impairment

Not studied in patients with severe hepatic impairment (Child-Pugh class C); use not recommended in these patients. (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Dosage adjustment recommended in patients with severe renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Dry mouth, constipation.

Drug Interactions

Rapidly metabolized to active metabolite, 5-hydroxymethyl tolterodine (5-HMT), by nonspecific esterases; active metabolite is further metabolized, principally via CYP2D6 and CYP3A4. 5-HMT does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP isoenzymes 1A2, 2B6, 2C9, 2C19, or 3A4.

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma 5-HMT concentrations). Do not exceed 4 mg daily when used concomitantly with potent CYP3A4 inhibitors.

Weak or moderate inhibitors of CYP3A4: Effects on 5-HMT pharmacokinetics not studied; pharmacokinetic interaction is expected, albeit less than that observed with potent CYP3A4 inhibitors. Carefully assess tolerability at 4-mg daily dosage of fesoterodine fumarate prior to increasing dosage to 8 mg daily in patients concomitantly receiving weak or moderate CYP3A4 inhibitors.

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma 5-HMT concentrations); no dosage adjustments are recommended.

Inhibitors of CYP2D6: Effects on 5-HMT pharmacokinetics not tested clinically. However, increased plasma 5-HMT concentrations observed in subjects with poor metabolizer phenotype for CYP2D6; no dosage adjustments recommended when CYP2D6 inhibitors are used concomitantly.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1isoenzymeA2 s, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4: Pharmacokinetic interactions unlikely.

Orally Administered Drugs

Potential pharmacokinetic interaction (altered absorption because of anticholinergic effects on GI motility). (See Decreased GI Motility under Cautions.)

Specific Drugs

Fesoterodine Pharmacokinetics

Absorption

Bioavailability

Following oral administration of fesoterodine, peak plasma concentrations of active metabolite, 5-hydroxymethyl tolterodine (5-HMT), are achieved in approximately 5 hours; because of rapid metabolism, fesoterodine itself is not detected in plasma.

Bioavailability of 5-HMT is 52%.

Onset

Symptomatic improvement (i.e., reduction in number of urge incontinence episodes) observed as early as 2 weeks after starting fesoterodine therapy.

Food

Food has no clinically important effect on fesoterodine pharmacokinetics.

Special Populations

In individuals with poor metabolizer phenotypes of CYP2D6 (approximately 7% of Caucasians and 2% of African Americans), peak plasma concentrations of 5-HMT increased by 1.7-fold and AUC increased twofold as compared with extensive metabolizers.

In patients with mild or moderate renal insufficiency (Cl_cr 30–80 mL/minute), peak plasma concentrations and AUC of 5-HMT were increased up to 1.5- and 1.8-fold, respectively, as compared with those in healthy subjects. In patients with severe renal impairment (Cl_cr <30 mL/minute), peak plasma concentrations and AUC of 5-HMT were increased twofold and 2.3-fold, respectively. (See Renal Impairment under Dosage and Administration.)

In patients with moderate (Child-Pugh class B) hepatic impairment, peak plasma concentrations and AUC of 5-HMT were increased 1.4 and 2.1-fold, respectively, as compared with those in healthy subjects. Subjects with severe hepatic impairment (Child-Pugh class C) have not been studied. (See Hepatic Impairment under Dosage and Administration.)

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

5-HMT: Approximately 50%, principally to albumin and α₁-acid glycoprotein.

Elimination

Metabolism

Fesoterodine is a prodrug: rapidly and extensively hydrolyzed by nonspecific esterases to 5-HMT, which is responsible for the antimuscarinic effects of fesoterodine. Tolterodine, another antimuscarinic agent used in the treatment of overactive bladder, also is metabolized to 5-HMT; however, tolterodine metabolism to 5-HMT is via CYP2D6.

5-HMT is further metabolized to various metabolites in the liver, principally via CYP2D6 and CYP3A4. None of these metabolites contribute substantially to the antimuscarinic activity of fesoterodine.

Elimination Route

Recovered in urine (70%) and feces (7%) as various active and inactive metabolites.

Half-life

Terminal half-life of 5-HMT following oral administration of fesoterodine fumarate is approximately 7 hours.

Special Populations

Pharmacokinetics not substantially affected by gender or age; pharmacokinetics not studied in pediatric patients.

Available data indicate no differences in pharmacokinetics between Caucasian and black subjects.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C). Protect from moisture.

Actions

• Fesoterodine is a competitive antimuscarinic agent.

• Fesoterodine is a prodrug: rapidly and extensively hydrolyzed to 5-hydroxymethyl tolterodine (5-HMT), which is responsible for the antimuscarinic effects of fesoterodine.

• Fesoterodine and 5-HMT inhibit contraction of the urinary bladder smooth muscle.

• In urodynamic study, fesoterodine administration increased volume at first detrusor contraction and bladder capacity in dose-dependent manner.

Advice to Patients

• Importance of reading manufacturer’s patient information before beginning fesoterodine therapy.

• Risk of dry mouth, constipation, dry eyes, urinary retention, decreased sweating and heat prostration (when used in a hot environment).

• May cause blurred vision and drowsiness. Use caution when driving or performing dangerous activities until effects are known. Alcohol may enhance the drowsiness caused by fesoterodine.

• Importance of taking fesoterodine with liquids and swallowing the extended-release tablet whole; do not chew, divide, or crush.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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