Yupelri (Revefenacin)
Dosage & administration
The recommended dosage is 175 mcg YUPELRI (one 175 mcg unit‑dose vial) administered by oral inhalation once daily by nebulizer using a mouthpiece.
YUPELRI should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor
The YUPELRI unit-dose vial should only be removed from the foil pouch and opened IMMEDIATELY BEFORE USE. The vial and any residual content should be discarded after use.
No dosage adjustment is required for geriatric patients, or patients with renal impairment
Based on available data, no adjustment of the dosage of YUPELRI in geriatric patients is necessary.
Clinical trials of YUPELRI included 441 subjects aged 65 years and older, and of those, 101 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
No dosage adjustment is required in patients with renal impairment. Monitor for systemic antimuscarinic side effects in COPD patients with severe renal impairment.
Revefenacin pharmacokinetic parameters are presented as the mean [standard deviation (SD)] unless otherwise specified. Following repeat dosing of inhaled YUPELRI, steady-state was achieved within 7 days with <1.6‑fold accumulation. Revefenacin exposure (Cmaxand AUC) in COPD patients is approximately 60% lower as compared to healthy subjects. Exposure (Cmaxand AUC) of the active metabolite in COPD patients is approximately 2-fold higher as compared to healthy subjects. Revefenacin Cmaxwas 0.16 ng/mL (0.11) and AUC was 0.22 ng·hr/mL (0.20) at steady-state after inhaled YUPELRI 175 mcg dose in COPD patients. Cmaxof the active metabolite was 0.20 ng/mL (0.13) and AUC was 0.69 ng·hr/mL (0.53) at steady-state after inhaled YUPELRI 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 of YUPELRI, both AUC and Cmaxof revefenacin and its active metabolite increased by approximately 11-fold over the 88 to 700 mcg (8‑fold) dose range.
Following inhaled administration of YUPELRI in healthy subjects or COPD patients, Cmaxof revefenacin and its active metabolite occurred at the first postdose sampling time which ranged from 14 to 41 minutes after start of nebulization. The absolute bioavailability following an oral dose of revefenacin is low (<3%).
Following intravenous administration to healthy subjects, the mean steady-state volume of distribution of revefenacin was 218 L suggesting extensive distribution to tissues.
The terminal half-life of revefenacin and its active metabolite after once-daily dosing of YUPELRI in COPD patients is 22 to 70 hours.
Following administration of a single intravenous dose of radiolabeled revefenacin to healthy male subjects, 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 <5% was present in urine, suggesting low oral absorption. There was minimal renal excretion (<1%) of revefenacin and its active metabolite following inhaled administration of YUPELRI in COPD patients.
Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (44 to 79 years), gender (59% male), smoking status (42% current smoker), or weight (46 to 155 kg) on systemic exposure of revefenacin and its active metabolite.
The pharmacokinetics of YUPELRI was evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no increase in Cmaxof revefenacin and 1.5-fold increase in Cmaxof the active metabolite. There was 1.2-fold increase in AUC of revefenacin and up to 4.7-fold increase in AUC of the active metabolite. YUPELRI has not been evaluated in subjects with severe hepatic impairment.
The pharmacokinetics of YUPELRI was evaluated in subjects with severe renal impairment (CrCl <30 mL/min). There was 1.5-fold increase in Cmaxof revefenacin and up to 2-fold increase in Cmaxof the active metabolite. There was up to 2.3‑fold increase in AUCinfof revefenacin; the active metabolite exposure (AUCinf) was increased by up to 2.5-fold. YUPELRI has not been evaluated in subjects with end-stage renal disease.
Neither revefenacin nor its active metabolite inhibits the following cytochrome P450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Neither revefenacin nor its active metabolite induces CYP1A2, CYP2B6, and CYP3A4/5.
Revefenacin is a substrate of P-gp and BCRP. Neither revefenacin nor its active metabolite is an inhibitor of these efflux transporters.
The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3. Neither revefenacin nor its active metabolite is an inhibitor of the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.
The drug compatibility (physical and chemical), efficacy, and safety of YUPELRI when mixed with other drugs in a nebulizer have not been established.
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Yupelri prescribing information
YUPELRI is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).
The recommended dosage is 175 mcg YUPELRI (one 175 mcg unit‑dose vial) administered by oral inhalation once daily by nebulizer using a mouthpiece.
YUPELRI should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor
The YUPELRI unit-dose vial should only be removed from the foil pouch and opened IMMEDIATELY BEFORE USE. The vial and any residual content should be discarded after use.
No dosage adjustment is required for geriatric patients, or patients with renal impairment
Based on available data, no adjustment of the dosage of YUPELRI in geriatric patients is necessary.
Clinical trials of YUPELRI included 441 subjects aged 65 years and older, and of those, 101 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
No dosage adjustment is required in patients with renal impairment. Monitor for systemic antimuscarinic side effects in COPD patients with severe renal impairment.
Revefenacin pharmacokinetic parameters are presented as the mean [standard deviation (SD)] unless otherwise specified. Following repeat dosing of inhaled YUPELRI, steady-state was achieved within 7 days with <1.6‑fold accumulation. Revefenacin exposure (Cmaxand AUC) in COPD patients is approximately 60% lower as compared to healthy subjects. Exposure (Cmaxand AUC) of the active metabolite in COPD patients is approximately 2-fold higher as compared to healthy subjects. Revefenacin Cmaxwas 0.16 ng/mL (0.11) and AUC was 0.22 ng·hr/mL (0.20) at steady-state after inhaled YUPELRI 175 mcg dose in COPD patients. Cmaxof the active metabolite was 0.20 ng/mL (0.13) and AUC was 0.69 ng·hr/mL (0.53) at steady-state after inhaled YUPELRI 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 of YUPELRI, both AUC and Cmaxof revefenacin and its active metabolite increased by approximately 11-fold over the 88 to 700 mcg (8‑fold) dose range.
Following inhaled administration of YUPELRI in healthy subjects or COPD patients, Cmaxof revefenacin and its active metabolite occurred at the first postdose sampling time which ranged from 14 to 41 minutes after start of nebulization. The absolute bioavailability following an oral dose of revefenacin is low (<3%).
Following intravenous administration to healthy subjects, the mean steady-state volume of distribution of revefenacin was 218 L suggesting extensive distribution to tissues.
The terminal half-life of revefenacin and its active metabolite after once-daily dosing of YUPELRI in COPD patients is 22 to 70 hours.
Following administration of a single intravenous dose of radiolabeled revefenacin to healthy male subjects, 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 <5% was present in urine, suggesting low oral absorption. There was minimal renal excretion (<1%) of revefenacin and its active metabolite following inhaled administration of YUPELRI in COPD patients.
Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (44 to 79 years), gender (59% male), smoking status (42% current smoker), or weight (46 to 155 kg) on systemic exposure of revefenacin and its active metabolite.
The pharmacokinetics of YUPELRI was evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no increase in Cmaxof revefenacin and 1.5-fold increase in Cmaxof the active metabolite. There was 1.2-fold increase in AUC of revefenacin and up to 4.7-fold increase in AUC of the active metabolite. YUPELRI has not been evaluated in subjects with severe hepatic impairment.
The pharmacokinetics of YUPELRI was evaluated in subjects with severe renal impairment (CrCl <30 mL/min). There was 1.5-fold increase in Cmaxof revefenacin and up to 2-fold increase in Cmaxof the active metabolite. There was up to 2.3‑fold increase in AUCinfof revefenacin; the active metabolite exposure (AUCinf) was increased by up to 2.5-fold. YUPELRI has not been evaluated in subjects with end-stage renal disease.
Neither revefenacin nor its active metabolite inhibits the following cytochrome P450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Neither revefenacin nor its active metabolite induces CYP1A2, CYP2B6, and CYP3A4/5.
Revefenacin is a substrate of P-gp and BCRP. Neither revefenacin nor its active metabolite is an inhibitor of these efflux transporters.
The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3. Neither revefenacin nor its active metabolite is an inhibitor of the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.
The drug compatibility (physical and chemical), efficacy, and safety of YUPELRI when mixed with other drugs in a nebulizer have not been established.
Inhalation solution: 175 mcg of revefenacin in 3 mL of sterile, clear, colorless, aqueous solution in unit dose vials.
Hepatic impairment: Avoid use of YUPELRI in patients with 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 YUPELRI has not been evaluated in COPD patients with mild-to-severe hepatic impairment. YUPELRI is not recommended in patients with any degree of hepatic impairment.
Revefenacin pharmacokinetic parameters are presented as the mean [standard deviation (SD)] unless otherwise specified. Following repeat dosing of inhaled YUPELRI, steady-state was achieved within 7 days with <1.6‑fold accumulation. Revefenacin exposure (Cmaxand AUC) in COPD patients is approximately 60% lower as compared to healthy subjects. Exposure (Cmaxand AUC) of the active metabolite in COPD patients is approximately 2-fold higher as compared to healthy subjects. Revefenacin Cmaxwas 0.16 ng/mL (0.11) and AUC was 0.22 ng·hr/mL (0.20) at steady-state after inhaled YUPELRI 175 mcg dose in COPD patients. Cmaxof the active metabolite was 0.20 ng/mL (0.13) and AUC was 0.69 ng·hr/mL (0.53) at steady-state after inhaled YUPELRI 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 of YUPELRI, both AUC and Cmaxof revefenacin and its active metabolite increased by approximately 11-fold over the 88 to 700 mcg (8‑fold) dose range.
Following inhaled administration of YUPELRI in healthy subjects or COPD patients, Cmaxof revefenacin and its active metabolite occurred at the first postdose sampling time which ranged from 14 to 41 minutes after start of nebulization. The absolute bioavailability following an oral dose of revefenacin is low (<3%).
Following intravenous administration to healthy subjects, the mean steady-state volume of distribution of revefenacin was 218 L suggesting extensive distribution to tissues.
The terminal half-life of revefenacin and its active metabolite after once-daily dosing of YUPELRI in COPD patients is 22 to 70 hours.
Following administration of a single intravenous dose of radiolabeled revefenacin to healthy male subjects, 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 <5% was present in urine, suggesting low oral absorption. There was minimal renal excretion (<1%) of revefenacin and its active metabolite following inhaled administration of YUPELRI in COPD patients.
Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (44 to 79 years), gender (59% male), smoking status (42% current smoker), or weight (46 to 155 kg) on systemic exposure of revefenacin and its active metabolite.
The pharmacokinetics of YUPELRI was evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no increase in Cmaxof revefenacin and 1.5-fold increase in Cmaxof the active metabolite. There was 1.2-fold increase in AUC of revefenacin and up to 4.7-fold increase in AUC of the active metabolite. YUPELRI has not been evaluated in subjects with severe hepatic impairment.
The pharmacokinetics of YUPELRI was evaluated in subjects with severe renal impairment (CrCl <30 mL/min). There was 1.5-fold increase in Cmaxof revefenacin and up to 2-fold increase in Cmaxof the active metabolite. There was up to 2.3‑fold increase in AUCinfof revefenacin; the active metabolite exposure (AUCinf) was increased by up to 2.5-fold. YUPELRI has not been evaluated in subjects with end-stage renal disease.
Neither revefenacin nor its active metabolite inhibits the following cytochrome P450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Neither revefenacin nor its active metabolite induces CYP1A2, CYP2B6, and CYP3A4/5.
Revefenacin is a substrate of P-gp and BCRP. Neither revefenacin nor its active metabolite is an inhibitor of these efflux transporters.
The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3. Neither revefenacin nor its active metabolite is an inhibitor of the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.
YUPELRI is contraindicated in patients with hypersensitivity to revefenacin or any component of this product.
• Do not initiate YUPELRI in acutely deteriorating COPD or to treat acute symptoms. ()5.1 Deterioration of Disease and Acute EpisodesYUPELRI should not be initiated in patients during acutely deteriorating or potentially life-threatening episodes of COPD. YUPELRI has not been studied in subjects with acutely deteriorating COPD. The initiation of YUPELRI in this setting is not appropriate.
YUPELRI is intended as a once-daily maintenance treatment for COPD and should not be used for relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes of bronchospasm, and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.
COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If YUPELRI no longer controls symptoms of bronchoconstriction, the patient's inhaled, short-acting beta2-agonist becomes less effective, or the patient needs more inhalations of a short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of YUPELRI beyond the recommended dose is not appropriate in this situation.
• If paradoxical bronchospasm occurs, discontinue YUPELRI and institute alternative therapy. ()5.2 Paradoxical BronchospasmAs with other inhaled medicines, YUPELRI can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs following dosing with YUPELRI, it should be treated immediately with an inhaled, short-acting bronchodilator; YUPELRI should be discontinued immediately and alternative therapy should be instituted.
• Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a healthcare provider immediately if symptoms occur. ()5.3 Worsening of Narrow-Angle GlaucomaYUPELRI should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for 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 consult a physician immediately if any of these signs or symptoms develops.
• Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact a healthcare provider immediately if symptoms occur. ()5.4 Worsening of Urinary RetentionYUPELRI should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g. difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.
• Immediate hypersensitivity reactions may occur. If such a reaction occurs, therapy with YUPELRI should be stopped at once and alternative treatments should be considered. ()5.5 Immediate Hypersensitivity ReactionsImmediate hypersensitivity reactions may occur after administration of YUPELRI. If such a reaction occurs, therapy with YUPELRI should be stopped at once and alternative treatments should be considered.