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    Respiratory Long-Acting Muscarinic Antagonists (LAMA)

    DEA CLASS

    Rx

    DESCRIPTION

    Respiratory long-acting antimuscarinic agent (LAMA); available as an inhalation solution
    Used in adults for the long-term maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema
    Administered once-daily via nebulizer

    COMMON BRAND NAMES

    YUPELRI

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the maintenance treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
    Oral inhalation dosage (Yupelri, inhalation solution for nebulizer)
    Adults

    Inhale 175 mcg (contents of 1 vial) once daily by nebulizer using a mouthpiece for oral inhalation. Max: 1 dose per 24 hours. Revefenacin is 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]

    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.

    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.

    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.

    STORAGE

    YUPELRI:
    - Avoid excessive heat (above 104 degrees F)
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from direct sunlight
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original unopened pouch
    - Store unused product in foil pouch

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The use of revefenacin is contraindicated in any patient with a known or suspected hypersensitivity to revefenacin or any of the inactive ingredients. Immediate hypersensitivity reactions may occur after administration of revefenacin. If such a reaction occurs, discontinue therapy and consider alternative treatments.[63742]

    Acute bronchospasm

    Inhaled revefenacin is not indicated for the relief of acute bronchospasm. It is crucial to properly educate patients and prescribe an inhaled, short-acting beta agonist (SABA), such as albuterol, for symptomatic relief of acute respiratory symptoms. Inform patients that increasing SABA use is a signal of deteriorating pulmonary disease for which prompt medical attention is warranted. Do not initiate revefenacin in patients with acutely deteriorating or potentially life-threatening episodes of chronic obstructive pulmonary disease (COPD). COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If symptoms of bronchospasm worsen or if SABA use becomes less effective or more frequent, patients should be instructed to seek immediate medical attention so the COPD treatment regimen can be re-evaluated.[63742]

    Paradoxical bronchospasm

    Like other inhaled medications, revefenacin can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, treat immediately with an inhaled short-acting bronchodilator, discontinue revefenacin immediately, and institute alternative therapy.

    Closed-angle glaucoma, ocular exposure

    All anticholinergics may increase intraocular pressure and aqueous outflow resistance in patients with closed-angle glaucoma. Use revefenacin with caution in patients with narrow-angle glaucoma and avoid inadvertent ocular exposure. Educate patients on the signs and 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 and corneal edema). Instruct patients to seek immediate medical attention if such symptoms occur.

    Prostatic hypertrophy, urinary retention, urinary tract obstruction

    Revefenacin can exacerbate urinary retention in patients with known urinary tract obstruction (e.g., bladder neck obstruction, such as might occur with hypertrophy of the prostate). Use revefenacin with caution in patients with a predisposition for urinary retention, particularly those with prostatic hypertrophy since anticholinergic drugs may aggravate these conditions. Instruct patients to seek immediate medical attention if signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination) occur.[63742]

    Hepatic disease

    Revefenacin is not recommended in patients with any degree of hepatic disease or hepatic impairment. The systemic exposure of revefenacin is unchanged while that of its active metabolite is increased in subjects with moderate hepatic impairment. The safety of revefenacin has not been evaluated in COPD patients with mild-to-severe hepatic impairment.[63742]

    Cardiac disease

    Use revefenacin with caution in patients with known cardiac disease. Patients with unstable cardiac disease were excluded from the pre-marketing clinical trials of the drug.[63742]

    Driving or operating machinery

    Revefenacin may rarely cause blurred vision. Although not recommended by the manufacturer, it may be prudent for patients to use caution in driving or operating machinery until the effects of the drug are known.

    Anticholinergic medications, geriatric

    No overall differences in safety or effectiveness were observed during the revefenacin clinical trial between geriatric subjects and younger adult subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. A greater sensitivity of some older individuals cannot be ruled out. Geriatric patients should be monitored carefully due to a potential increased susceptibility to anticholinergic effects. The effects of other anticholinergic medications are additive to the effects of revefenacin, and should be considered in prescribing for all patients, especially the older adult.[63742]

    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).

    Breast-feeding

    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.

    Children, infants

    Safety and efficacy of revefenacin has not been established in neonates, infants, children, or adolescents less than 18 years of age.

    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

    DRUG INTERACTIONS

    Amoxicillin; Clarithromycin; Lansoprazole: (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.
    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; 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.
    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.
    Atropine; Diphenoxylate: (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; Edrophonium: (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; Hyoscyamine; Phenobarbital; 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.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (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.
    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) Coadministration of revefenacin is not recommended with daclatasvir 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; daclatasvir 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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of revefenacin is not recommended with paritaprevir 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; paritaprevir 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.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for revefenacin-related adverse reactions during coadministration of elexacaftor; tezacaftor; ivacaftor as concurrent use may increase exposure of revefenacin. Revefenacin is a substrate for the transporters OATP1B1 and OATP1B3; elexacaftor; tezacaftor; ivacaftor may inhibit uptake of OATP1B1 and OATP1B3.
    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.
    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.
    Erythromycin; Sulfisoxazole: (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.
    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.
    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.
    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.
    Mepenzolate: (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.
    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.
    Obeticholic Acid: (Major) Coadministration of revefenacin is not recommended with obeticholic acid 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; obeticholic acid and its conjugates appear to inhibit OATP1B1 and OATP1B3 (the clinical significance of which is unknown).
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of revefenacin is not recommended with paritaprevir 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; paritaprevir is an inhibitor of OATP1B1 and OATP1B3.
    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.
    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.
    Simeprevir: (Major) Coadministration of revefenacin is not recommended with simeprevir 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; simeprevir is an inhibitor of OATP1B1 and OATP1B3.
    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.
    Telithromycin: (Major) Coadministration of revefenacin is not recommended with telithromycin 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; telithromycin 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.

    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.

    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.