YUPELRI Inhalation solution Ref.[10186] Active ingredients: Revefenacin

5.1 Deterioration of Disease and Acute Episodes

YUPELRI 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.

5.2 Paradoxical Bronchospasm

As 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.

5.3 Worsening of Narrow-Angle Glaucoma

YUPELRI 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.

5.4 Worsening of Urinary Retention

YUPELRI 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.

5.5 Immediate Hypersensitivity Reactions

Immediate 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.

The following potential adverse reactions are described in greater detail in other sections:

• Paradoxical bronchospasm [see Warnings and Precautions (5.2)]
• Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.3)]
• Worsening of urinary retention [see Warnings and Precautions (5.4)]
• Immediate hypersensitivity reactions [see Warnings and Precautions (5.5)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The YUPELRI safety database included 2,285 subjects with COPD in two 12-week efficacy studies and one 52-week long-term safety study. A total of 730 subjects received treatment with YUPELRI 175 mcg once daily. The safety data described below are based on the two 12-week trials and the one 52-week trial.

12-Week Trials

YUPELRI was studied in two 12-week replicate placebo-controlled trials in patients with moderate to very severe COPD (Trials 1 and 2). In these trials, 395 patients were treated with YUPELRI at the recommended dose of 175 mcg once daily.

The population had a mean age of 64 years (range from 41 to 88 years), with 50% males, 90% Caucasian, and had COPD with a mean post-bronchodilator forced expiratory volume in one second (FEV₁) percent predicted of 55%. Of subjects enrolled in the two 12-week trials, 37% were taking concurrent LABA or ICS/LABA therapy. Patients with unstable cardiac disease, narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.

Table 1 shows the most common adverse reactions that occurred with a frequency of greater than or equal to 2% in the YUPELRI group and higher than placebo in the two 12‑week placebo-controlled trials.

The proportion of subjects who discontinued treatment due to adverse reactions was 13% for the YUPELRI-treated subjects and 19% for placebo-treated subjects.

Table 1. Adverse Events with YUPELRI ≥2% Incidence and Higher than Placebo:

Other adverse reactions defined as events with an incidence of ≥1.0%, less than 2.0%, and more common than with placebo included the following: hypertension, dizziness, oropharyngeal pain, and bronchitis.

52-Week Trial

YUPELRI was studied in one 52-week, open-label, active-control (tiotropium 18 mcg once daily) trial in 1,055 patients with COPD. In this trial, 335 patients were treated with YUPELRI 175 mcg once daily and 356 patients with tiotropium. The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo-controlled 12-week studies described, with the exception that concurrent LABA or LABA/ICS therapy was used in 50% of patients. The adverse reactions reported in the long-term safety trial for YUPELRI were consistent with those observed in the placebo-controlled studies of 12-weeks.

7.1 Anticholinergics

There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of YUPELRI with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.3, 5.4)].

7.2 Transporter-Related Drug Interactions

OATP1B1 and OATP1B3 inhibitors (e.g. rifampicin, cyclosporine, etc.) could lead to an increase in systemic exposure of the active metabolite. Therefore, coadministration with YUPELRI is not recommended [see Clinical Pharmacology (12.3)].

Risk Summary

There are no adequate and well-controlled studies with YUPELRI in pregnant women. Women should be advised to contact their physician if they become pregnant while taking YUPELRI. 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) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryo‑fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6 to 17, revefenacin was not teratogenic and did not affect fetal survival at exposures up to 209 times the MRHD (based upon summed AUCs for revefenacin and its active metabolite at maternal subcutaneous doses up to 500 mcg/kg/day).

In an embryo‑fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7 to 19, revefenacin was not teratogenic and did not affect fetal survival at exposures up to 694 times the MRHD (based upon summed AUCs for revefenacin and its active metabolite at maternal subcutaneous doses up to 500 mcg/kg/day).

Placental transfer of revefenacin and its active metabolite was observed in pregnant rabbits.

In a pre- and postnatal development (PPND) study in pregnant rats dosed during the periods of organogenesis and lactation from gestation day 6 to lactation day 20, revefenacin had no adverse developmental effects on pups at exposures up to 196 times the MRHD (based upon summed AUCs for revefenacin and its active metabolite at maternal subcutaneous doses up to 500 mcg/kg/day).

Risk Summary

There is no information regarding the presence of revefenacin in human milk, the effects on the breastfed infant, or the effects on milk production. However, revefenacin was present in the milk of lactating rats following dosing during pregnancy and lactation (see Data).

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for YUPELRI and any potential adverse effects on the breastfed infant from YUPELRI or from the underlying maternal condition.

Data

Animal Data

In a PPND study [see Pregnancy (8.1)], revefenacin and its active metabolite were present in milk of lactating rats on lactation day 22. Milk-to-plasma concentration ratios were up to 10 for revefenacin and its active metabolite.

YUPELRI is not indicated for use in children. The safety and efficacy in pediatric patients have not been established.

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 [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].