rsi ad
 
drx ad
 
ad space

Revefenacin Inhalation Solution

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Revefenacin inhalation solution is a sterile, clear, colorless, aqueous solution of revefenacin. Revefenacin, the active component of revefenacin inhalation solution, is an anticholinergic. The chemical name for revefenacin is 1-(2-{4- [(4-carbamoylpiperidin-1-yl)methyl]-N-methylbenzamido}ethyl)piperidin-4-yl N-({1,1’- biphenyl}-2-yl)carbamate; its structural formula is:

Empirical formula: C35H43N5O4 - Molecular weight: 597.76 g/mol

Revefenacin is a white to off-white crystalline powder and is slightly soluble in water.

Revefenacin inhalation solution is supplied as 3 mL of revefenacin solution packaged in a unit-dose low-density polyethylene vial overwrapped in a foil pouch. Each vial contains 175 mcg of revefenacin in 3 mL of an isotonic, sterile aqueous solution containing sodium chloride, citric acid, sodium citrate, and water for injection at pH 5.0.

Revefenacin inhalation solution does not require dilution prior to administration by nebulization. Like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the nebulization system used, and compressor performance.

Using the PARI LC® Sprint nebulizer connected to a PARI Trek® S compressor under in vitro conditions, the mean delivered dose from the mouthpiece was approximately 62 mcg (35% of label claim), at a mean flow rate of 4 LPM. The mean nebulization time was 8 minutes. Revefenacin inhalation solution should only be administered via a standard jet nebulizer connected to an air compressor with an adequate airflow, and equipped with a mouthpiece.

2. INDICATIONS AND USAGE

Revefenacin inhalation solution is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

3. DOSAGE AND ADMINISTRATION

The recommended dose of revefenacin inhalation solution is one 175 mcg unit-dose vial administered once daily by nebulizer using a mouthpiece.

Revefenacin inhalation solution should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor (See Medication Guide). The safety and efficacy of revefenacin inhalation solution have been established in clinical trials when administered using the PARI LC® Sprint nebulizer with a mouthpiece and the PARI Trek® S compressor. The safety and efficacy of revefenacin inhalation solution delivered from non-compressor based nebulizer systems have not been established.

The revefenacin inhalation solution 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 [see Clinical Pharmacology].

The drug compatibility (physical and chemical), efficacy, and safety of revefenacin inhalation solution when mixed with other drugs in a nebulizer have not been established.

4. CONTRAINDICATIONS

Revefenacin inhalation solution is contraindicated in patients with hypersensitivity to revefenacin or any component of this product.

5. WARNINGS AND PRECAUTIONS

5.1. Deterioration of Disease and Acute Episodes

Revefenacin inhalation solution should not be initiated in patients during acutely deteriorating or potentially life-threatening episodes of COPD. Revefenacin has not been studied in subjects with acutely deteriorating COPD. The initiation of revefenacin in this setting is not appropriate.

Revefenacin inhalation solution 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 revefenacin inhalation solution 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 revefenacin inhalation solution beyond the recommended dose is not appropriate in this situation.

5.2. Paradoxical Bronchospasm

As with other inhaled medicines, revefenacin inhalation solution can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs following dosing with revefenacin inhalation solution, it should be treated immediately with an inhaled, short-acting bronchodilator; revefenacin inhalation solution should be discontinued immediately and alternative therapy should be instituted.

5.3. Worsening of Narrow-Angle Glaucoma

Revefenacin inhalation solution 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

Revefenacin inhalation solution 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 revefenacin inhalation solution. If such a reaction occurs, therapy with revefenacin inhalation solution should be stopped at once and alternative treatments should be considered.

6. ADVERSE REACTIONS

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)]

6.1. Clinical Trial Experience

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 revefenacin 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 revefenacin 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

Revefenacin inhalation solution 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 revefenacin inhalation solution 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 revefenacin inhalation solution 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 revefenacin inhalation solution-treated subjects and 19% for placebo-treated subjects.

Table 1: Adverse Events with Revefenacin Inhalation Solution ≥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

Revefenacin inhalation solution 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 revefenacin inhalation solution 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 revefenacin inhalation solution were consistent with those observed in the placebo controlled studies of 12-weeks.

7. DRUG INTERACTIONS

7.1. Anticholinergics

There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of revefenacin inhalation solution 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 revefenacin inhalation solution is not recommended [see Clinical Pharmacology].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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

8.2. Lactation

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 revefenacin inhalation solution and any potential adverse effects on the breastfed infant from revefenacin inhalation solution or from the underlying maternal condition.

Data

Animal Data

In a PPND study (see Section 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.

8.4. Pediatric Use

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

8.5. Geriatric Use

Based on available data, no adjustment of the dosage of revefenacin inhalation solution in geriatric patients is necessary.

Clinical trials of revefenacin inhalation solution 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.

8.6. 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 inhalation solution has not been evaluated in COPD patients with mild-to-severe hepatic impairment. Revefenacin inhalation solution is not recommended in patients with any degree of hepatic impairment. [see Clinical Pharmacology].

8.7. 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. [see Clinical Pharmacology

9. OVERDOSAGE

An overdose of revefenacin inhalation solution may lead to anticholinergic signs and symptoms such as nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure (causing pain, vision disturbances, or reddening of the eye), obstipation or difficulties in voiding. In COPD patients, orally inhaled administration of revefenacin inhalation solution at a once daily dose of up to 700 mcg (4 times the maximum recommended daily dose) for 7 days was well tolerated.

Treatment of overdosage consists of discontinuation of revefenacin inhalation solution along with institution of appropriate symptomatic and/or supportive therapy.

10. MECHANISM OF ACTION

Revefenacin is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of 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.

11. PHARMACODYNAMICS

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, double-blind, placebo- and positive-controlled, single dose, crossover trial in 48 healthy subjects. Following a single dose of revefenacin 700 mcg (4 times the recommended dosage), no effects on prolongation of QTc interval were observed.

12. PHARMACOKINETICS

Revefenacin pharmacokinetic parameters are presented as the mean [standard deviation (SD)] unless otherwise specified. Following repeat dosing of inhaled revefenacin inhalation solution, steady state was achieved within 7 days with <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 in COPD patients is approximately 2-fold higher as compared to healthy subjects. Revefenacin Cmax was 0.16 ng/mL (0.11) and AUC was 0.22 ng·hr/mL (0.20) at steady-state after inhaled revefenacin inhalation solution 175 mcg dose in COPD patients. Cmax of 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 revefenacin inhalation solution 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 revefenacin inhalation solution, both AUC and Cmax of revefenacin and its active metabolite increased by approximately 11-fold over the 88 to 700 mcg (8-fold) dose range.

Absorption

Following inhaled administration of revefenacin inhalation solution in healthy subjects or COPD patients, Cmax of 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%).

Distribution

Following intravenous administration to healthy subjects, the mean steady-state volume of distribution of revefenacin was 218 L suggesting extensive distribution to tissues. In vitro protein binding of revefenacin and its active metabolite in human plasma was on average 71% and 42%, respectively.

Elimination

The terminal half-life of revefenacin and its active metabolite after once-daily dosing of revefenacin inhalation solution in COPD patients is 22 to 70 hours.

Metabolism

In vitro and in vivo data showed that revefenacin is primarily metabolized via hydrolysis of the primary amide to a carboxylic acid forming its major active metabolite. Following inhaled administration of revefenacin inhalation solution 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. It could potentially contribute to systemic antimuscarinic effects at therapeutic doses.

Excretion

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 revefenacin inhalation solution in COPD patients.

Specific Populations

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.

Patients with Hepatic Impairment: The pharmacokinetics of revefenacin inhalation solution was evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no increase in Cmax of revefenacin and 1.5-fold increase in Cmax of 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. Revefenacin inhalation solution has not been evaluated in subjects with severe hepatic impairment.

Patients with Renal Impairment: The pharmacokinetics of revefenacin inhalation solution was evaluated in subjects with severe renal impairment (CrCl <30 mL/min). There was 1.5-fold increase in Cmax of revefenacin and up to 2-fold increase in Cmax of the active metabolite. There was up to 2.3-fold increase in AUCinf of revefenacin; the active metabolite exposure (AUCinf) was increased by up to 2.5-fold. Revefenacin inhalation solution has not been evaluated in subjects with end stage renal disease.

Drug Interactions

Revefenacin and Cytochrome P450: 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 and Efflux Transporters: Revefenacin is a substrate of P-gp and BCRP. Neither revefenacin nor its active metabolite is an inhibitor of these efflux transporters.

Revefenacin and Uptake 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.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

YUPELRI (revefenacin) inhalation solution is supplied as a 175 mcg/3 mL sterile, clear, colorless, aqueous solution in unit-dose low-density polyethylene vials. Each vial is overwrapped in a foil pouch and supplied in cartons containing 30 individually pouched unit-dose vials (NDC 49502-806-93).

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

• Store YUPELRI in the protective foil pouch. Protect from direct sunlight and excessive heat.

• The YUPELRI solution 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.

• Discard any solution that is not clear and colorless.

• YUPELRI should only be administered via a standard jet nebulizer connected to an air compressor with an adequate airflow, and equipped with a mouthpiece.

• Do not swallow or inject YUPELRI.

Rx only

Rev 11/18