Revefenacin (Monograph)

Brand name: Yupelri
Drug class: Antimuscarinics/Antispasmodics
VA class: RE105
Chemical name: 1-(2-{4-[(4-carbamoylpiperidin-1-yl)methyl]-N-methylbenzamido}ethyl) piperidin-4-yl –({1,1’-biphenyl}-2-yl) carbamate
Molecular formula: C₃₅H₄₃N₅O₄
CAS number: 864750-70-9

Medically reviewed by Drugs.com on Oct 23, 2023. Written by ASHP.

Introduction

Bronchodilator; a synthetic tertiary amine long-acting antimuscarinic agent.

Uses for Revefenacin

COPD

Long-term maintenance treatment of reversible bronchospasm associated with COPD, including chronic bronchitis and emphysema.

Not indicated for treatment of acute episodes of bronchospasm (i.e., as rescue therapy) or acute exacerbations of COPD.

Revefenacin Dosage and Administration

Administration

Administer by oral inhalation via nebulization only using a standard jet nebulizer (with mouthpiece) connected to an air compressor.

Oral Inhalation

Administer once daily at the same time every day.

Store single-dose vials of revefenacin oral inhalation solution in the foil pouch provided; remove immediately before use.

For specific information on administration of the oral inhalation solution via nebulization, consult the manufacturer’s instructions for use.

In clinical trials, a Pari LC Sprint nebulizer with a Pari Trek S compressor was used to deliver revefenacin oral inhalation solution. Safety and efficacy of the drug delivered from a nebulizer system without a compressor not established.

Do not mix with other inhalation solutions. Do not administer inhalation solution orally or by injection.

Dosage

Each 3-mL single-dose vial of revefenacin oral inhalation solution contains 175 mcg of revefenacin.

Dilution not required prior to administration by nebulization.

Amount of drug delivered to the lungs depends on patient factors, type of nebulization system used, and compressor performance.

Adults

COPD

Oral Inhalation

175 mcg (entire contents of 1 single-dose vial) once daily via nebulization.

Prescribing Limits

Adults

COPD

Oral Inhalation

Maximum 175 mcg daily.

Special Populations

Hepatic Impairment

Not recommended in patients with hepatic impairment. (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required. (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustment required. (See Geriatric Use under Cautions.)

Cautions for Revefenacin

Contraindications

Hypersensitivity to revefenacin or any ingredient in the formulation.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur. If such a reaction occurs, discontinue drug immediately and consider alternative therapy.

Deterioration of Disease and Acute Episodes

Do not initiate in patients with acutely deteriorating or substantially worsening COPD, which may be life-threatening.

Indicated only for maintenance treatment of bronchospasm associated with COPD; do not use for treatment of acute bronchospasm (i.e., as rescue therapy). Treat acute symptoms with an inhaled, short-acting β₂-agonist.

Failure to respond to a previously effective dosage of revefenacin or to a supplemental short-acting, inhaled β₂-agonist may indicate deterioration of COPD. Immediately reevaluate the patient and treatment regimen. Do not increase revefenacin dosage in such situations.

Paradoxical Bronchospasm

Possible life-threatening paradoxical bronchospasm may occur upon inhalation of revefenacin.

If paradoxical bronchospasm occurs, discontinue drug immediately and consider alternative therapy.

Ocular Effects

Use with caution in patients with narrow-angle glaucoma. May worsen signs and/or symptoms of narrow-angle glaucoma (e.g., ocular pain or discomfort, blurred vision, visual halos, colored images in association with red eyes from conjunctival congestion and corneal edema). (See Advice to Patients.)

GU Effects

Use with caution in patients with urinary retention. May worsen signs and symptoms of urinary retention (e.g., difficulty passing urine, dysuria) associated with prostatic hyperplasia or bladder neck obstruction. (See Advice to Patients.)

Cardiovascular Effects

No effect on QT interval observed in healthy individuals following single dose of revefenacin.

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women. Advise women to contact their clinician if they become pregnant while using revefenacin.

In animal reproduction studies, subcutaneous administration of the drug to pregnant rats and rabbits during the period of organogenesis produced no evidence of fetal harm at approximately 209 and 694 times the exposure at the maximum recommended human dose, respectively. Placental transfer of revefenacin and its active metabolite observed in pregnant rabbits.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Data not available on effects of the drug on the breast-fed child or on milk production.

Unlikely to affect the breast-fed child since revefenacin is less than 3% absorbed orally. Long-term use of revefenacin has potential to reduce milk production; observe nursing women receiving the drug for signs of decreased lactation (e.g., insatiety, poor weight gain in the nursing infant). Consider benefits of breast-feeding along with importance of the drug to the woman and any potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Safety and efficacy not established.

Moderate hepatic impairment: Systemic exposure of revefenacin unchanged while that of its active metabolite is increased.

Severe hepatic impairment: Not recommended. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Severe renal impairment: Monitor for adverse anticholinergic effects. (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Cough, nasopharyngitis, upper respiratory tract infection, headache, back pain.

Drug Interactions

Revefenacin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Revefenacin and its active metabolite are not inhibitors of P-gp or BCRP.

Revefenacin and its active metabolite do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 and do not induce CYP1A2, 2B6, or 3A4/5.

The active metabolite of revefenacin is a substrate of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Inhibitors of OATP1B1 and OATP1B3 may increase systemic exposure of the active metabolite; concomitant use with revefenacin not recommended.

Revefenacin and its active metabolite are not inhibitors of uptake membrane transporters, including OATP1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, or organic cation transporter (OCT)2.

Specific Drugs

Drug	Interaction	Comments
Anticholinergic agents	Possible additive anticholinergic effects	Avoid concomitant use
Cyclosporine	Possible increase in systemic exposure of active metabolite	Concomitant use not recommended
Rifampin	Possible increase in systemic exposure of active metabolite	Concomitant use not recommended

Revefenacin Pharmacokinetics

Absorption

Bioavailability

Following oral administration, absolute bioavailability is <3%.

Following oral inhalation, peak plasma concentrations of revefenacin and its active metabolite reached within 14–41 minutes after initiation of nebulization.

Following repeated dosing of orally inhaled revefenacin, steady-state concentrations achieved within 7 days.

Onset

Peak FEV₁ effect: 2–3 hours post oral inhalation dose.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

In vitro protein binding of drug and its active metabolite: 71 and 42%, respectively.

Elimination

Metabolism

Metabolized principally via hydrolysis of the primary amide to a carboxylic acid forming its major active metabolite.

Conversion to active metabolite occurs rapidly; plasma exposures of active metabolite exceed those of revefenacin by approximately 4- to 6-fold (based on AUC).

Active metabolite formed by hepatic metabolism possesses activity at target muscarinic receptors that is lower (approximately one-third to one-tenth) than that of revefenacin.

Elimination Route

Following IV administration, 54% of drug recovered in feces and 27% in urine. Approximately 19% recovered in feces as active metabolite.

Following single radiolabeled oral dose, 88% recovered in feces and <5% in urine.

Following oral inhalation, minimal renal excretion (<1%) of drug and its active metabolite in patients with COPD.

Half-life

Following once-daily oral inhalation in patients with COPD, terminal half-life of drug and active metabolite is 22–70 hours.

Special Populations

Moderate hepatic impairment: No increase in peak concentrations of revefenacin and a 1.5-fold increase in peak concentrations of its active metabolite. AUCs of revefenacin and its active metabolite increased 1.2- and up to 4.7-fold, respectively.

Severe hepatic impairment: Not evaluated.

Severe renal impairment (Cl_cr <30 mL/minute): For revefenacin, 1.5- and 2.3-fold increase in peak concentrations and AUC, respectively. For the active metabolite, up to 2- and 2.5-fold increase in peak concentrations and AUC, respectively.

End-stage renal disease: Not evaluated.

No clinically important differences in exposure based on age, gender, weight, and smoking status.

Stability

Storage

Oral Inhalation

Solution, for Nebulization

Single-dose vials: 20–25°C (may be exposed to 15–30°C). Protect from sunlight and excessive heat.

Actions

Synthetic tertiary amine antimuscarinic agent.
Long-acting, orally inhaled bronchodilator.
Nonselective competitive antagonist at muscarinic receptors M₁ to M₅.
Competitively and reversibly inhibits actions of cholinergic stimuli at M₃ receptors in the smooth muscle of the respiratory tract leading to bronchodilation.
Prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects is dose-dependent and lasts up to 24 hours; clinical relevance of these findings is unknown.

Advice to Patients

Provide a copy of the manufacturer’s patient information to all patients each time the drug is dispensed. Importance of instructing patients to read the patient information prior to initiation of therapy and each time the prescription is refilled.
Importance of adequate understanding of proper storage and inhalation techniques, including use of a standard jet nebulizer.
Importance of not using revefenacin to relieve acute symptoms or exacerbations of COPD.
Importance of informing clinician immediately if signs and/or symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos, or colored images in association with red eyes from conjunctival congestion or corneal edema) occur.
Importance of discontinuing revefenacin and informing clinician if paradoxical bronchospasm occurs.
Importance of informing clinician immediately if urinary retention or dysuria occurs.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., urinary retention, enlarged prostate, narrow-angle glaucoma).
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing 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.