Incruse Ellipta

Dosage Forms And Strengths

Inhalation Powder. Disposable light grey and light green plastic inhaler containing a foil blister strip of powder intended for oral inhalation only. Each blister contains umeclidinium 62.5 mcg.

Storage And Handling

INCRUSE ELLIPTA is supplied as a disposable light grey and light green plastic inhaler containing a foil strip with 30 blisters (NDC 0173-0873-10) or 7 blisters (institutional pack) (NDC 0173-0873-06).

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

Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C). Store in a dry place away from direct heat or sunlight. Keep out of reach of children.

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.

GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: June 2017

INCRUSE® ELLIPTA® is indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

INCRUSE ELLIPTA (umeclidinium 62.5 mcg) should be administered as 1 inhalation once daily by the orally inhaled route only.

INCRUSE ELLIPTA should be used at the same time every day. Do not use INCRUSE ELLIPTA more than 1 time every 24 hours.

No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with moderate hepatic impairment.

The use of INCRUSE ELLIPTA is contraindicated in the following conditions:

• Severe hypersensitivity to milk proteins
• Hypersensitivity to umeclidinium or any of the excipients

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Deterioration Of Disease And Acute Episodes

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

INCRUSE ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. INCRUSE ELLIPTA 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 INCRUSE ELLIPTA 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 INCRUSE ELLIPTA beyond the recommended dose is not appropriate in this situation.

Paradoxical Bronchospasm

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

Hypersensitivity Reactions

Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, rash, and urticaria may occur after administration of INCRUSE ELLIPTA. Discontinue INCRUSE ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not use INCRUSE ELLIPTA.

Worsening Of Narrow-angle Glaucoma

INCRUSE ELLIPTA 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 healthcare provider immediately if any of these signs or symptoms develops.

Worsening Of Urinary Retention

INCRUSE ELLIPTA 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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Not For Acute Symptoms

Inform patients that INCRUSE ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medicine and instruct them in how it should be used.

Instruct patients to seek medical attention immediately if they experience 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 INCRUSE ELLIPTA without healthcare provider guidance since symptoms may recur after discontinuation.

Paradoxical Bronchospasm

As with other inhaled medicines, INCRUSE ELLIPTA can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue INCRUSE ELLIPTA.

Worsening Of Narrow-angle Glaucoma

Instruct patients to 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 healthcare provider immediately if any of these signs or symptoms develops.

Worsening Of Urinary Retention

Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively).

Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay.

No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC basis).

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C. There are no adequate and well-controlled trials with INCRUSE ELLIPTA in pregnant women. Because animal reproduction studies are not always predictive of human response, INCRUSE ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their healthcare providers if they become pregnant while taking INCRUSE ELLIPTA.

There were no teratogenic effects in rats and rabbits at approximately 50 and 200 times, respectively, the maximum recommended human daily inhaled dose (MRHDID) in adults (on an AUC basis at maternal inhaled doses up to 278 mcg/kg/day in rats and maternal subcutaneous doses up to 180 mcg/kg/day in rabbits).

Nonteratogenic Effects

There were no effects on perinatal and postnatal developments in rats at approximately 80 times the MRHDID in adults (on an AUC basis at maternal subcutaneous doses up to 180 mcg/kg/day).

Labor And Delivery

There are no adequate and well-controlled human trials that have investigated the effects of INCRUSE ELLIPTA during labor and delivery. INCRUSE ELLIPTA should be used during labor only if the potential benefit justifies the potential risk.

Nursing Mothers

It is not known whether umeclidinium is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when INCRUSE ELLIPTA is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of INCRUSE ELLIPTA by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue INCRUSE ELLIPTA, taking into account the importance of INCRUSE ELLIPTA to the mother.

Subcutaneous administration of umeclidinium to lactating rats at approximately 25 times the MRHDID in adults resulted in a quantifiable level of umeclidinium in 2 pups, which may indicate transfer of umeclidinium in milk.

Pediatric Use

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

Geriatric Use

Based on available data, no adjustment of the dosage of INCRUSE ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

Clinical trials of INCRUSE ELLIPTA included 810 subjects aged 65 years and older, and, of those, 183 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 subjects.

Hepatic Impairment

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.

Renal Impairment

Patients with severe renal impairment (creatinine clearance less than 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.

Umeclidinium and P-glycoprotein Transporter: Umeclidinium is a substrate of P-gp. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium was assessed in healthy subjects. No effect on umeclidinium Cmax was observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed (Figure 1).

Umeclidinium and Cytochrome P450 2D6: In vitro metabolism of umeclidinium is mediated primarily by CYP2D6. However, no clinically meaningful difference in systemic exposure to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing to normal (ultrarapid, extensive, and intermediate metabolizers) and CYP2D6 poor metabolizer subjects (Figure 1).

Teratogenic Effects

Pregnancy Category C. There are no adequate and well-controlled trials with INCRUSE ELLIPTA in pregnant women. Because animal reproduction studies are not always predictive of human response, INCRUSE ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their healthcare providers if they become pregnant while taking INCRUSE ELLIPTA.

There were no teratogenic effects in rats and rabbits at approximately 50 and 200 times, respectively, the maximum recommended human daily inhaled dose (MRHDID) in adults (on an AUC basis at maternal inhaled doses up to 278 mcg/kg/day in rats and maternal subcutaneous doses up to 180 mcg/kg/day in rabbits).

Nonteratogenic Effects

There were no effects on perinatal and postnatal developments in rats at approximately 80 times the MRHDID in adults (on an AUC basis at maternal subcutaneous doses up to 180 mcg/kg/day).

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

• Paradoxical bronchospasm
• Worsening of narrow-angle glaucoma
• Worsening of urinary retention

Clinical Trials 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the 8 clinical trials conducted to support initial approval of INCRUSE ELLIPTA, a total of 1,663 subjects with COPD (mean age: 62.7 years; 89% white; 65% male across all treatments, including placebo) received at least 1 inhalation dose of umeclidinium at doses of 62.5 or 125 mcg. In the 4 randomized, double-blind, placebo-or active-controlled, efficacy clinical trials, 1,185 subjects received umeclidinium for up to 24 weeks, of which 487 subjects received the recommended dose of umeclidinium 62.5 mcg. In a 12-month, randomized, double-blind, placebo-controlled, long-term safety trial, 227 subjects received umeclidinium 125 mcg for up to 52 weeks.

The incidence of adverse reactions associated with INCRUSE ELLIPTA in Table 1 is based upon 2 placebo-controlled efficacy trials: one 12-week trial and one 24-week trial.

Table 1: Adverse Reactions with INCRUSE ELLIPTA with ≥ 1% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease

Other adverse reactions with INCRUSE ELLIPTA observed with an incidence less than 1% but more common than placebo included atrial fibrillation.

In a long-term safety trial, 336 subjects (n = 227 umeclidinium 125 mcg, n = 109 placebo) were treated for up to 52 weeks with umeclidinium 125 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the efficacy trials described above. Adverse reactions that occurred with a frequency greater than or equal to 1% in subjects 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.

The safety and efficacy of INCRUSE ELLIPTA in combination with an inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA) were also evaluated in four 12-week clinical trials. A total of 1,637 subjects with COPD across four 12-week, randomized, double-blind clinical trials received at least 1 dose of INCRUSE ELLIPTA (62.5 mcg) or placebo administered once daily in addition to background ICS/LABA (mean age: 64 years, 88% white, 65% male across all treatments). Two trials (Trials 1 and 2) evaluated INCRUSE ELLIPTA in combination with fluticasone furoate/vilanterol (FF/VI) 100 mcg/25 mcg administered once daily, and 2 trials (Trials 3 and 4) evaluated INCRUSE ELLIPTA administered once daily in combination with fluticasone propionate/salmeterol (FP/SAL) 250 mcg/50 mcg administered twice daily. Adverse reactions that occured with INCRUSE ELLIPTA in combination with an ICS/LABA were similar to those reported with INCRUSE ELLIPTA as monotherapy. In addition to the umeclidinium monotherapy adverse reactions reported above, adverse reactions occurring with INCRUSE ELLIPTA in combination with an ICS/LABA, at an incidence of greater than or equal to 1% and exceeding ICS/LABA alone, were oropharyngeal pain and dysgeusia.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of INCRUSE ELLIPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to INCRUSE ELLIPTA or a combination of these factors.

Immune System Disorders

Hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, and urticaria.

No case of overdose has been reported with INCRUSE ELLIPTA.

High doses of umeclidinium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD.

Treatment of overdosage consists of discontinuation of INCRUSE ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy.

Cardiac Electrophysiology

QTc interval prolongation was studied in a double-blind, multiple dose, placebo-and positive-controlled, crossover trial in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent.

Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg).

Absorption

Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, Cmax occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled INCRUSE ELLIPTA, steady state was achieved within 14 days with 1.8-fold accumulation.

Distribution

Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on average 89%.

Metabolism

In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

Elimination

Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was less than 1% of the total dose, suggesting negligible oral absorption. The effective half-life after once-daily dosing is 11 hours.