YUPELRI

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YUPELRI

Classes

Respiratory Long-Acting Muscarinic Antagonists (LAMA)

Administration
Inhalation Administration Oral Inhalation Administration

Nebulized inhalation solution (Yupieri)
Administer by oral inhalation via nebulizer only; do not swallow.
No dilution necessary. Single-dose vials are ready-to-use.
Only remove the unit-dose vial from the foil pouch immediately before use.
Revefenacin should be colorless; discard any vial if the solution is not colorless.
Do not mix with other drugs. The compatibility of revefenacin inhalation solution with other drugs administered by nebulization has not been established.
Give the inhalation solution via a standard jet nebulizer connected to an air compressor. During clinical trials, safety and efficacy were established when administered via PARI LC Sprint nebulizer and PARI Trek S compressor. Safety and efficacy of delivering the drug from non-compressor based nebulizer systems have not been established.
Deliver solution by nebulization over about 8 minutes.
Discard the vial and any residual solution after use.

Adverse Reactions
Severe

angioedema / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
ocular hypertension / Delayed / Incidence not known

Moderate

hypertension / Early / 1.0-2.0
cycloplegia / Early / Incidence not known
blurred vision / Early / Incidence not known
urinary retention / Early / Incidence not known
dysuria / Early / Incidence not known

Mild

pharyngitis / Delayed / 4.0-4.0
headache / Early / 4.0-4.0
cough / Delayed / 4.0-4.0
infection / Delayed / 1.0-3.0
back pain / Delayed / 2.0-2.0
dizziness / Early / 1.0-2.0
urticaria / Rapid / Incidence not known
pruritus / Rapid / Incidence not known
mydriasis / Early / Incidence not known
xerostomia / Early / Incidence not known

Common Brand Names

YUPELRI

Dea Class

Rx

Description

Respiratory long-acting antimuscarinic agent (LAMA); available as a nebulized inhalation solution
Used in adults for the maintenance treatment of chronic obstructive lung disease (COPD), including chronic bronchitis and emphysema
Administered once-daily via nebulizer

Dosage And Indications
For the maintenance treatment of chronic obstructive pulmonary disease (COPD) (e.g., chronic bronchitis and emphysema). Nebulized Inhalation dosage (nebulizer solution, i.e., Yupelri) Adults

175 mcg (1 vial) via nebulizer once daily using a mouthpiece for oral inhalation. Max: 1 dose per 24 hours. Not indicated for the relief of acute bronchospasm. Use an inhaled short-acting beta-2 agonist (SABA) for immediate relief of acute symptoms. Do not use other long-acting muscarinic antagonists (LAMAs) concurrently.[63742] According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, revefenacin may be used as initial monotherapy in all groups of COPD patients; however, combination therapy with a long-acting beta-agonist (LABA) or inhaled corticosteroid (ICS) may be needed in patients in Group D or those patients still experiencing dyspnea or exacerbations upon follow-up.[63765]

Dosing Considerations
Hepatic Impairment

Revefenacin is not recommended in patients with any degree of hepatic impairment. The systemic exposure of revefenacin is unchanged while that of its active metabolite is increased in subjects with moderate hepatic impairment. Safety has not been evaluated in COPD patients with mild-to-severe hepatic impairment.

Renal Impairment

No dosage adjustment is required in patients with renal impairment. Monitor for systemic antimuscarinic side effects in COPD patients with severe renal impairment.

Drug Interactions

Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of revefenacin is not recommended with clarithromycin because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increase in potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; clarithromycin is an inhibitor of OATP1B1 and OATP1B3.
Anticholinergics: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Atazanavir: (Major) Coadministration of revefenacin with atazanavir is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increase in potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; atazanavir is an in vitro inhibitor of OATP1B1.
Atazanavir; Cobicistat: (Major) Coadministration of revefenacin is not recommended with cobicistat because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; cobicistat is an inhibitor of OATP1B1 and OATP1B3. (Major) Coadministration of revefenacin with atazanavir is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increase in potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; atazanavir is an in vitro inhibitor of OATP1B1.
Atropine: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Atropine; Difenoxin: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Belladonna; Opium: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Benztropine: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Chlordiazepoxide; Clidinium: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Clarithromycin: (Major) Coadministration of revefenacin is not recommended with clarithromycin because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increase in potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; clarithromycin is an inhibitor of OATP1B1 and OATP1B3.
Cobicistat: (Major) Coadministration of revefenacin is not recommended with cobicistat because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; cobicistat is an inhibitor of OATP1B1 and OATP1B3.
Cyclosporine: (Major) Coadministration of revefenacin with cyclosporine is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; cyclosporine is an inhibitor of OATP1B1/1B3.
Daclatasvir: (Major) Avoid concomitant use of revefenacin and daclatasvir. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1/3; daclatasvir is an inhibitor of OATP1B1/3.
Darolutamide: (Major) Avoid concomitant use of revefenacin and darolutamide. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; darolutamide is an inhibitor of OATP1B1 and OATP1B3.
Darunavir; Cobicistat: (Major) Coadministration of revefenacin is not recommended with cobicistat because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; cobicistat is an inhibitor of OATP1B1 and OATP1B3.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of revefenacin is not recommended with cobicistat because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; cobicistat is an inhibitor of OATP1B1 and OATP1B3.
Dicyclomine: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Diphenoxylate; Atropine: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Elexacaftor; tezacaftor; ivacaftor: (Major) Avoid concomitant use of revefenacin and elexacaftor. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1/3; elexacaftor is an inhibitor of OATP1B1/3.
Eltrombopag: (Major) Coadministration of revefenacin is not recommended with eltrombopag because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; eltrombopag is an inhibitor of OATP1B1.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of revefenacin is not recommended with cobicistat because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; cobicistat is an inhibitor of OATP1B1 and OATP1B3.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of revefenacin is not recommended with cobicistat because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; cobicistat is an inhibitor of OATP1B1 and OATP1B3.
Enasidenib: (Major) Avoid concomitant use of revefenacin and enasidenib. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; enasidenib is an inhibitor of OATP1B1 and OATP1B3.
Encorafenib: (Major) Avoid concomitant use of revefenacin and encorafenib. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1/3; encorafenib is an inhibitor of OATP1B1/3.
Erythromycin: (Major) Coadministration of revefenacin is not recommended with erythromycin because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; erythromycin is an inhibitor of OATP1B1 and OATP1B3.
Flavoxate: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Fostemsavir: (Major) Concomitant use of revefenacin with fostemsavir is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; fostemsavir is an inhibitor of OATP1B1/1B3.
Gemfibrozil: (Major) Coadministration of revefenacin with gemfibrozil is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; gemfibrozil is an inhibitor of OATP1B1.
Glecaprevir; Pibrentasvir: (Major) Coadministration of revefenacin is not recommended with glecaprevir because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; glecaprevir is an inhibitor of OATP1B1 and OATP1B3. (Major) Coadministration of revefenacin is not recommended with pibrentasvir because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; pibrentasvir is an inhibitor of OATP1B1 and OATP1B3.
Glycopyrrolate: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Glycopyrrolate; Formoterol: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Homatropine; Hydrocodone: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Hyoscyamine: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Indacaterol; Glycopyrrolate: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of revefenacin with rifampin is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; rifampin is an inhibitor of OATP1B1/1B3 when given as a single dose; when rifampin is given chronically, the hepatic enzyme induction effects of rifampin may supercede the OATP effects.
Isoniazid, INH; Rifampin: (Major) Coadministration of revefenacin with rifampin is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; rifampin is an inhibitor of OATP1B1/1B3 when given as a single dose; when rifampin is given chronically, the hepatic enzyme induction effects of rifampin may supercede the OATP effects.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Coadministration of revefenacin is not recommended with clarithromycin because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increase in potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; clarithromycin is an inhibitor of OATP1B1 and OATP1B3.
Leflunomide: (Major) Coadministration of revefenacin is not recommended with leflunomide because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; leflunomide is an inhibitor of OATP1B1 and OATP1B3.
Leniolisib: (Major) Avoid concomitant use of revefenacin and leniolisib. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1/3; leniolisib is an inhibitor of OATP1B1/3.
Letermovir: (Major) Coadministration of revefenacin is not recommended with letermovir because it may result in clinically relevant increases in plasma concentrations of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; letermovir is an inhibitor of OATP1B1 and OATP1B3.
Lopinavir; Ritonavir: (Major) Coadministration of revefenacin is not recommended with lopinavir because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; lopinavir is an inhibitor of OATP1B1.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Methscopolamine: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Midostaurin: (Major) Avoid concomitant use of revefenacin and midostaurin. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; midostaurin is an inhibitor of OATP1B1.
Neostigmine; Glycopyrrolate: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Oxybutynin: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Propantheline: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Rifampin: (Major) Coadministration of revefenacin with rifampin is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; rifampin is an inhibitor of OATP1B1/1B3 when given as a single dose; when rifampin is given chronically, the hepatic enzyme induction effects of rifampin may supercede the OATP effects.
Scopolamine: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Sofosbuvir; Velpatasvir: (Major) Coadministration of revefenacin is not recommended with velpatasvir because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; velpatasvir is an inhibitor of OATP1B1 and OATP1B3.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Coadministration of revefenacin is not recommended with velpatasvir because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; velpatasvir is an inhibitor of OATP1B1 and OATP1B3. (Major) Coadministration of revefenacin is not recommended with voxilaprevir because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; voxilaprevir is an inhibitor of OATP1B1 and OATP1B3.
Teriflunomide: (Major) Coadministration of revefenacin is not recommended with teriflunomide because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; teriflunomide is an inhibitor of OATP1B1 and OATP1B3.
Trihexyphenidyl: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Trofinetide: (Major) Avoid concomitant use of revefenacin and trofinetide. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1/3; trofinetide is an inhibitor of OATP1B1/3.
Vibegron: (Moderate) Vibegron should be administered with caution in patients taking anticholinergics because of potential for an increased risk of urinary retention. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
Voclosporin: (Major) Avoid concomitant use of revefenacin and voclosporin. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1; voclosporin is an inhibitor of OATP1B1.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Coadministration of revefenacin is not recommended with clarithromycin because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increase in potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; clarithromycin is an inhibitor of OATP1B1 and OATP1B3.

How Supplied

YUPELRI Respiratory (Inhalation) Sol: 3mL, 175mcg

Maximum Dosage
Adults

175 mcg/day via nebulizer for oral inhalation.

Geriatric

175 mcg/day via nebulizer for oral inhalation.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Mechanism Of Action

Revefenacin is a long-acting muscarinic antagonist (LAMA), which has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of the M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of M3 antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo models, prevention of methacholine-and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of revefenacin is predominantly a site-specific effect.[63742]

Pharmacokinetics

Revefenacin is administered via oral inhalation using nebulization. The absolute oral bioavailability of revefenacin is low (less than 3%) vai this route. Revefenacin is extensively distributed to tissues. In vitro protein binding of revefenacin and its active metabolite in human plasma is on average 71% and 42%, respectively. The terminal half-life of revefenacin and its active metabolite after once-daily dosing in COPD patients is 22 to 70 hours. Revefenacin is primarily metabolized via hydrolysis of the primary amide to a carboxylic acid forming its major active metabolite. Following inhaled administration in COPD patients, conversion to its active metabolite occurred rapidly, and plasma exposures of the active metabolite exceeded those of revefenacin by approximately 4-to 6-fold (based on AUC). The active metabolite is formed by hepatic metabolism and possesses activity at target muscarinic receptors that is lower (approximately one-third to one-tenth) than that of revefenacin. The active metabolite could potentially contribute to systemic antimuscarinic effects at therapeutic doses. Following administration of a single intravenous dose of radiolabeled revefenacin, approximately 54% of total radioactivity was recovered in the feces and 27% was excreted in the urine; approximately 19% of the administered radioactive dose was recovered in the feces as the active metabolite. Following administration of a single radiolabeled oral dose of revefenacin, 88% of total radioactivity was recovered in the feces and less than 5% was present in urine, suggesting low oral absorption. There was minimal renal excretion (less than 1%) of revefenacin and its active metabolite following inhaled administration in COPD patients.[63742]
 
Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: OATP1B1, OATP1B3, P-gp, BCRP
The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3. Coadministration of revefenacin with OATP1B1 and OATP1B3 inhibitors is not recommended because it could lead to an increase in systemic exposure of the active revefenacin metabolite. Neither revefenacin nor its active metabolite is an inhibitor of the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Revefenacin is a substrate of P-gp and BCRP, but no significant drug interactions related to these transporters have been identified. Neither revefenacin nor its active metabolite is an inhibitor of these efflux transporters. Neither revefenacin nor its active metabolite inhibits the following CYP450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Neither revefenacin nor its active metabolite induces CYP1A2, CYP2B6, or CYP3A4/5.[63742]

Inhalation Route

Following orally inhaled administration of revefenacin by nebulizer in healthy subjects or COPD patients, the maximum concentration (Cmax) of revefenacin and its active metabolite occurred at the first postdose sampling time which ranged from 14 to 41 minutes after the start of nebulization. The absolute bioavailability of revefenacin is low (less than 3%). With repeat dosing, steady-state was achieved within 7 days with less than 1.6-fold accumulation. Revefenacin exposure (Cmax and AUC) in COPD patients is approximately 60% lower as compared to healthy subjects. Exposure (Cmax and AUC) of the active metabolite of revefenacin in COPD patients is approximately 2-fold higher as compared to healthy subjects. Revefenacin mean Cmax (SD) was 0.16 ng/mL (0.11) and mean AUC (SD) was 0.22 ng x hour/mL (0.20) and the mean Cmax (SD) of the active metabolite was 0.20 ng/mL (0.13) and mean AUC (SD) was 0.69 ng x hour/mL (0.53) at steady-state after a nebulized orally inhaled 175 mcg dose in COPD patients. Revefenacin and its active metabolite exposure increased in a slightly greater than dose proportional manner with increasing revefenacin dose. After single or multiple once-daily dosing, both the AUC and Cmax of revefenacin and its active metabolite increased by approximately 11-fold over the 88 to 700 mcg (8-fold) dose range.

Pregnancy And Lactation
Pregnancy

Use revefenacin with caution during pregnancy. There are no adequate and well-controlled studies of revefenacin use in pregnant women. Women should be advised to contact their physician if they become pregnant while taking revefenacin. In animal reproduction studies, subcutaneous administration of revefenacin to pregnant rats and rabbits during the period of organogenesis produced no evidence of fetal harm at respective exposures approximately 209 times the exposure at the maximum recommended human dose (MRHD) (on an area under the curve [AUC] basis).

Caution must be exercised in the administration of revefenacin to a breast-feeding woman since many drugs are excreted in human milk. There is no information regarding the presence of revefenacin in human milk, the effects on the breast-fed infant, or the effects on milk production. Revefenacin was present in the milk of lactating rats following dosing during pregnancy and lactation. Milk-to-plasma concentration ratios were up to 10 for revefenacin and its active metabolite. Due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from revefenacin or the underlying maternal condition.[63742] Drugs with strong anticholinergic properties may suppress lactation, particularly when lactation is starting to be established.