Incruse Ellipta

— THERAPEUTIC CATEGORIES —
  • Asthma/COPD
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Incruse Ellipta Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Umeclidinium 62.5mcg; per inhalation; dry pwd for oral inhalation; contains lactose.

    Pharmacological Class

    Anticholinergic.

    How Supplied

    Dry pwd inhaler—30 doses

    How Supplied

    Incruse Ellipta is supplied as a disposable light grey and light green plastic inhaler containing a foil strip with:

    • 30 blisters or
    • 7 blisters (institutional pack).

    The inhaler is packaged in a moisture-protective foil tray with a desiccant and a peelable lid.

    Storage

    Incruse Ellipta should be stored at room temperature between 68°-77° F (20°-25° C); excursions permitted from 59°-86° F (15°-30° C). 

    Incruse Ellipta should be stored inside the unopened moisture-protective foil tray and only removed from the tray immediately before initial use. 

    Discard Incruse Ellipta 6 weeks after opening the foil tray or when the counter reads “0” (after all blisters have been used), whichever comes first. 

    The inhaler is not reusable. Do not attempt to take the inhaler apart.

    The product should be stored in a dry place away from direct heat or sunlight. 

    Keep out of reach of children.

    Manufacturer

    GlaxoSmithKline

    Generic Availability

    NO

    Mechanism of Action

    Umeclidinium 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 receptors at the smooth muscle leading to bronchodilation. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect.

    Incruse Ellipta Indications

    Indications

    Maintenance treatment of COPD.

    Incruse Ellipta Dosage and Administration

    Adult

    Take at same time every day. 1 inhalation every 24hrs.

    Children

    Not established.

    Incruse Ellipta Contraindications

    Contraindications

    Severe hypersensitivity to milk proteins.

    Incruse Ellipta Boxed Warnings

    Not Applicable

    Incruse Ellipta Warnings/Precautions

    Warnings/Precautions

    Not indicated for relief of acute bronchospasm. Do not initiate in rapidly or acutely deteriorating COPD. Do not exceed recommended dose. Reevaluate periodically. Prescribe a short-acting, inhaled β2-agonist for acute symptoms; monitor for increased need. Discontinue if paradoxical bronchospasm (use alternatives) or hypersensitivity reactions occur. Narrow-angle glaucoma. Urinary retention. Prostatic hyperplasia. Bladder-neck obstruction. Severe hepatic impairment. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Umeclidinium should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. Umeclidinium has not been studied in patients with acutely deteriorating COPD. The initiation of umeclidinium in this setting
    is not appropriate.

    Umeclidinium should not be used for the relief of acute symptoms, ie, as rescue therapy for the treatment of acute episodes of bronchospasm. Umeclidinium has not been studied in the relief of acute symptoms 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 umeclidinium no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of umeclidinium beyond the recommended dose is not appropriate in this situation.

    Umeclidinium can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with umeclidinium, it should be treated immediately with an inhaled, short-acting bronchodilator; umeclidinium should be discontinued immediately; and alternative therapy should be instituted.

    There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use umeclidinium.

    Umeclidinium should be used with caution in patients with narrow-angle glaucoma. Be alert for signs and symptoms of acute narrow-angle glaucoma (eg, eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema).

    Umeclidinium should be used with caution in patients with urinary retention. Be alert for signs and symptoms of urinary retention (eg, difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction.

    Pregnancy Considerations

    There are insufficient data on the use of umeclidinium in pregnant women to inform a drug-associated risk.

    Nursing Mother Considerations

    There are no data available on the presence of umeclidinium in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for umeclidinium and any potential adverse effects on the breastfed child from umeclidinium or from the underlying maternal condition.

    Pediatric Considerations

    Safety and effectiveness have not been established in pediatric patients.

    Geriatric Considerations

    No overall differences in safety or effectiveness were observed between geriatric patients (65 years and older) and younger patients. Greater sensitivity of some older individuals cannot be ruled out.

    Renal Impairment Considerations

    Patients with severe renal impairment (CrCl <30 mL/min) showed no relevant increases in Cmax or AUC, nor did protein binding differ between subjects with severe renal impairment and their healthy controls. No dosage adjustment is required in patients with renal impairment.

    Hepatic Impairment Considerations

    Patients with moderate hepatic impairment (Child-Pugh score of 7-9) showed no relevant increases in Cmax or AUC, nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls. Studies in subjects with severe hepatic impairment have not been performed.

    Incruse Ellipta Pharmacokinetics

    Absorption

    Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. 

    • Following inhaled administration of umeclidinium in healthy subjects, Cmax occurred at 5–15 minutes.

    • Following repeat dosing of inhaled Incruse Ellipta, steady state was achieved within 14 days with 1.8-fold accumulation.

    Distribution

    Following IV administration to healthy subjects, the mean volume of distribution was 86 L. Plasma protein bound: average 89%.

    Metabolism

    Primarily metabolized by the enzyme CYP2D6 and is a substrate for the P-gp transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (eg, glucuronidation). 

    Elimination

    The effective half-life of umeclidinium after once-daily inhaled dosing is 11 hours. Following IV dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. Following oral dosing to healthy male patients, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption. 

    Incruse Ellipta Interactions

    Interactions

    Additive effects with concomitant other anticholinergic-containing drugs; avoid.

    Incruse Ellipta Adverse Reactions

    Adverse Reactions

    Nasopharyngitis, URTI, cough, arthralgia; visual disturbances, paradoxical bronchospasm.

    Adverse Reactions

    Most common adverse reactions (≥2% incidence and more common than placebo): nasopharyngitis, upper respiratory tract infection, cough, arthralgia.

    Other adverse reactions with Incruse Ellipta observed with an incidence <1% but more common than placebo included atrial fibrillation.

    Results from a 52-week long-term safety trial in adults with COPD:

    • Double-blind, randomized, placebo-controlled.

    • Total of 336 patients: 227 to Incruse Ellipta 125 mcg for up to 52 weeks and 109 to placebo.

    Adverse reactions that occurred with a frequency ≥1% in patients receiving umeclidinium 125 mcg that exceeded that in placebo in this trial were:

    • nasopharyngitis, upper respiratory tract infection, urinary tract infection, pharyngitis, pneumonia, lower respiratory tract infection, rhinitis, supraventricular tachycardia, supraventricular extrasystoles, sinus tachycardia, idioventricular rhythm, headache, dizziness, sinus headache, cough, back pain, arthralgia, pain in extremity, neck pain, myalgia, nausea, dyspepsia, diarrhea, rash, depression, and vertigo.

    Incruse Ellipta Clinical Trials

    Clinical Trials

    The safety and efficacy of umeclidinium 62.5 mcg were evaluated in 3 dose-ranging trials, 2 placebo-controlled clinical trials (one 12-week trial and one 24-week trial), and a 12-month long-term safety trial. The efficacy of Incruse Ellipta is based primarily on the dose-ranging trials and the 2 placebo-controlled confirmatory trials in patients with COPD, including chronic bronchitis and/or emphysema.

    In the dose-ranging trials, dose selection for umeclidinium in COPD was supported by a 7-day, randomized, double-blind, placebo-controlled, crossover study evaluating 4 doses of umeclidinium (15.6 to 125 mcg) or placebo dosed once daily in the morning in 163 patients with COPD. A dose ordering was observed, with the 62.5- and 125-mcg doses demonstrating larger improvements in FEV1 over 24 hours compared with the lower doses of 15.6 and 31.25 mcg.

    The differences in trough FEV1 from baseline after 7 days for placebo and the 15.6-, 31.25-, 62.5-, and 125-mcg doses were -74 mL (95% CI: -118, -31), 38 mL (95% CI: -6, 83), 27 mL (95% CI: -18, 72), 49 mL (95% CI: 6, 93), and 109 mL (95% CI: 65, 152), respectively. Two additional dose-ranging trials in subjects with COPD demonstrated minimal additional benefit at doses above 125 mcg. The dose-ranging results supported the evaluation of 2 doses of umeclidinium, 62.5 and 125 mcg, in the confirmatory COPD trials to further assess dose response.

    The clinical development program for Incruse Ellipta included 2 randomized, double-blind, placebo-controlled, parallel-group confirmatory trials in patients with COPD designed to evaluate the efficacy of Incruse Ellipta on lung function. Trial 1 (NCT #01313650) was a 24-week placebo-controlled trial, and Trial 2 (NCT #01772147) was a 12-week placebo-controlled trial. These trials treated patients that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking ≥10 pack-years, had a post-albuterol FEV1 ≤70% of predicted normal values, had a ratio of FEV1/FVC of <0.7, and had a Modified Medical Research Council (mMRC) score ≥2. The majority of subjects (72%) reported not having a COPD exacerbation in the prior 12 months.

    Patient demographics: (n=1738)

    • Mean age: 63 years

    • Average smoking history: 46 pack-years (with 50% identified as current smokers)

    • Mean FEV1 (predicted): 47% (range: 13 to 74%)

    • Mean FEV1/FVC ratio: 0.47 (range: 0.20 to 0.74)

    • Mean percent reversibility: 15% (range: -35 to 109%)

    Trial 1 (n=418) evaluated umeclidinium 62.5 mcg and placebo. The primary endpoint was change from baseline in trough (predose) FEV1 at Day 169 (defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous dose on Day 168) compared with placebo. Incruse Ellipta 62.5 mcg demonstrated a larger increase in mean change from baseline in trough (predose) FEV1 relative to placebo (n=280; difference from placebo:  115 [95% CI: 76, 155]). Similar results were obtained from Trial 2. 

    The safety and efficacy of Incruse Ellipta in combination with an ICS/LABA were also evaluated in 4 randomized, double-blind, parallel-group trials involving 1,637 patients with COPD. These trials had similar study design and were of 12-weeks’ treatment duration. Patients were randomized to Incruse Ellipta 62.5 mcg + ICS/LABA or placebo + ICS/LABA. The primary endpoint for these trials was change from baseline in trough (predose) FEV1 at Day 85 (defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous dose on Day 84). Baseline FEV1 was measured while patients were on background ICS/LABA.

    In the combination with Fluticasone Furoate + Vilanterol (Trial 4 [NCT #01957163] and Trial 5 [NCT #02119286]):

    • Patients were randomly assigned to Incruse Ellipta 62.5 mcg + FF/VI 100 mcg/25 mcg given once daily or placebo + FF/VI 100 mcg/25 mcg given once daily.

    • Results in trial 4 (n=206), showed that Incruse Ellipta + FF/VI demonstrated a larger mean change from baseline in trough (predose) FEV1 relative to placebo + FF/VI (n=206; difference from placebo: 124 [95% CI: 93, 154]). Trial 5 results were similar.

    In the combination with Fluticasone Propionate + Salmeterol (Trial 6 [NCT #01772134] and Trial 7 [NCT #01772147]): 

    • Patients were randomly assigned to Incruse Ellipta 62.5 mcg + FP/SAL 250 mcg/50 mcg or placebo + FP/SAL 250 mcg/50 mcg. The treatments with Incruse Ellipta and placebo were given once daily, while the FP/SAL treatment was given twice daily. 

    • Results in trial 6 (n=204), showed that Incruse Ellipta + FP/SAL demonstrated a larger mean change from baseline in trough (predose) FEV1 relative to placebo + FP/SAL (n=205; difference from placebo: 147 [107, 187]). Results for Trial 7 were similar.

    Incruse Ellipta Note

    Not Applicable

    Incruse Ellipta Patient Counseling

    Patient Counseling

    Umeclidinium is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Treat acute symptoms with an inhaled, short-acting beta2-agonist such as albuterol. 

    Alert patients to seek medical attention immediately if experiencing any of the following:

    • Decreasing effectiveness of inhaled, short-acting beta2-agonists

    • Need for more inhalations than usual of inhaled, short-acting beta2-agonists

    • Significant decrease in lung function as outlined by the physician

    Tell patients they should not stop therapy with umeclidinium without physician/provider guidance since symptoms may recur after discontinuation.

    Umeclidinium can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, discontinue umeclidinium and contact a health care provider right away.

    Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (eg, eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Consult a health care provider immediately if any of these signs or symptoms develop.

    Instruct patients to be alert for signs and symptoms of urinary retention (eg, difficulty passing urine, painful urination); contact a health care provider if these develop.

    Cost Savings Program

    The Incruse Ellipta access and savings program is available here.

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