UMECLIDINIUM: 6,321 Adverse Event Reports & Safety Profile

Umeclidinium and Vilanterol ELLIPTA is an inhalation powder drug product for delivery of a combination of umeclidinium (an anticholinergic) and vilanterol (a LABA) to patients by oral inhalation. Umeclidinium bromide has the chemical name 1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azoniabicyclo[2.2.2]octane bromide and the following chemical structure: Umeclidinium bromide is a white powder with a molecular weight of 508.5, and the empirical formula is C 29 H 34 NO 2

• Br (as a quaternary ammonium bromide compound). It is slightly soluble in water. Vilanterol trifenatate has the chemical name triphenylacetic acid-4-{(1 R )-2-[(6-{2-[(2,6-dicholorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (1:1) and the following chemical structure: Vilanterol trifenatate is a white powder with a molecular weight of 774.8, and the empirical formula is C 24 H 33 Cl 2 NO 5
• C 20 H 16 O 2 . It is practically insoluble in water. Umeclidinium and Vilanterol ELLIPTA is a light grey and red plastic inhaler containing 2 foil blister strips. Each blister on one strip contains a white powder blend of micronized umeclidinium bromide (74.2 mcg equivalent to 62.5 mcg of umeclidinium), magnesium stearate (75 mcg), and lactose monohydrate (to 12.5 mg), and each blister on the other strip contains a white powder blend of micronized vilanterol trifenatate (40 mcg equivalent to 25 mcg of vilanterol), magnesium stearate (125 mcg), and lactose monohydrate (to 12.5 mg). The lactose monohydrate contains milk proteins. After the inhaler is activated, the powder within both blisters is exposed and ready for dispersion into the airstream created by the patient inhaling through the mouthpiece. Under standardized in vitro test conditions, Umeclidinium and Vilanterol ELLIPTA delivers 55 mcg of umeclidinium and 22 mcg of vilanterol per dose when tested at a flow rate of 60 L/min for 4 seconds. In adult subjects with obstructive lung disease and severely compromised lung function (COPD with FEV 1 /FVC <70% and FEV 1 <30% predicted or FEV 1 <50% predicted plus chronic respiratory failure), mean peak inspiratory flow through the ELLIPTA inhaler was 66.5 L/min (range: 43.5 to 81.0 L/min). The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. Umeclidinium bromide chemical structure Vilanterol trifenatate chemical structure

AND USAGE Umeclidinium and Vilanterol ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Limitations of Use Umeclidinium and Vilanterol ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma. The safety and effectiveness of Umeclidinium and Vilanterol ELLIPTA in asthma have not been established. Umeclidinium and Vilanterol ELLIPTA is a combination of umeclidinium, an anticholinergic, and vilanterol, a long-acting beta 2 -adrenergic agonist (LABA), indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). ( 1 ) Limitations of Use: Not indicated for relief of acute bronchospasm or for the treatment of asthma. ( 1 , 5.2 )

AND ADMINISTRATION The recommended dosage of Umeclidinium and Vilanterol ELLIPTA for maintenance treatment of COPD is 62.5 mcg umeclidinium and 25 mcg vilanterol (1 actuation of Umeclidinium and Vilanterol ELLIPTA 62.5/25 mcg) once daily by oral inhalation.

• Umeclidinium and Vilanterol ELLIPTA should be used at the same time every day. Do not use Umeclidinium and Vilanterol 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 [see Clinical Pharmacology ( 12.3 )] .
• For oral inhalation only. ( 2 )
• Maintenance treatment of COPD: 1 actuation of Umeclidinium and Vilanterol ELLIPTA once daily administered by oral inhalation. ( 2 )

Umeclidinium and Vilanterol ELLIPTA is contraindicated in:

• patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to umeclidinium, vilanterol, or any of the excipients [see Warnings and Precautions ( 5.6 ), Description ( 11 )] .
• use of a long-acting beta 2 -adrenergic agonist (LABA), including vilanterol, one of the active ingredients in Umeclidinium and Vilanterol ELLIPTA, without an inhaled corticosteroid (ICS), in patients with asthma [see Warnings and Precautions ( 5.1 )] . Umeclidinium and Vilanterol ELLIPTA is not indicated for the treatment of asthma.
• Severe hypersensitivity to milk proteins or any ingredients. ( 4 )
• Use of a LABA, including Umeclidinium and Vilanterol ELLIPTA, without an inhaled corticosteroid is contraindicated in patients with asthma. ( 4 )

REACTIONS The following 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 ( 5.4 )]
• Worsening of urinary retention [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (incidence ≥2% and more common than placebo) include nasopharyngitis, upper respiratory tract infection, cough, arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . The incidence of adverse reactions associated with INCRUSE ELLIPTA in Table 1 is based upon 2 placebo-controlled trials: one 24-week trial (Trial 1) and one 12-week trial (Trial 2) [ see Clinical Studies (14.2)].

Table

1.

Adverse

Reactions with INCRUSE ELLIPTA with ≥1% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease Adverse Reaction INCRUSE ELLIPTA (n = 487) % Placebo (n = 348) % Infections and infestations Nasopharyngitis 8% 7% Upper respiratory tract infection 5% 4% Pharyngitis 1% <1% Viral upper respiratory tract infection 1% <1% Respiratory, thoracic, and mediastinal disorders Cough 3% 2% Musculoskeletal and connective tissue disorders Arthralgia 2% 1% Myalgia 1% <1% Gastrointestinal disorders Abdominal pain upper 1% <1% Toothache 1% <1% Injury, poisoning, and procedural complications Contusion 1% <1% Cardiac disorders Tachycardia 1% <1% Other adverse reactions with INCRUSE ELLIPTA observed with an incidence <1% but more common than placebo included atrial fibrillation. In a long-term safety trial (Trial 3), 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 ≥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 beta 2 -adrenergic agonist (ICS/LABA) were also evaluated in four 12‑week clinical trials (Trial 4, Trial 5, Trial 6, and Trial 7). 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 4 and 5) evaluated INCRUSE ELLIPTA in combination with fluticasone furoate/vilanterol (FF/VI) 100 mcg/25mcg administered once daily, and 2 trials (Trials 6 and 7) evaluated INCRUSE ELLIPTA administered once daily in combination with fluticasone propionate/salmeterol (FP/SAL) 250 mcg/50 mcg administered twice daily [see Clinical Studies ( 14.3 )] . Adverse reactions that occurred 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 ≥1% and exceeding ICS/LABA alone, were oropharyngeal pain and dysgeusia.

6.2 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.

Eye Disorders

Eye pain, glaucoma, vision blurred.

Immune System Disorders

Hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, and urticaria. Renal and Urinary Disorders Dysuria, urinary retention. Respiratory, Thoracic and Mediastinal Disorders Dysphonia, oropharyngeal pain.

AND PRECAUTIONS

• LABA monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. ( 5.1 )
• Do not initiate in acutely deteriorating COPD. Do not use to treat acute symptoms. ( 5.2 )
• Do not use in combination with additional therapy containing a LABA because of risk of overdose. ( 5.3 )
• If paradoxical bronchospasm occurs, discontinue Umeclidinium and Vilanterol ELLIPTA and institute alternative therapy. ( 5.5 )
• Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.7 )
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.8 )
• 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. ( 5.9 )
• 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. ( 5.10 )
• Be alert to hypokalemia and hyperglycemia. ( 5.11 )

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death The safety and effectiveness of Umeclidinium and Vilanterol ELLIPTA in patients with asthma have not been established. Umeclidinium and Vilanterol ELLIPTA is not indicated for the treatment of asthma <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

Salmeterol Multicenter Asthma Research

Trial (SMART) A 28-week, placebo-controlled, U.S. trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma‑related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABAs, including vilanterol, one of the active ingredients in Umeclidinium and Vilanterol ELLIPTA. No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with Umeclidinium and Vilanterol ELLIPTA has been conducted. Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

5.2 Deterioration of Disease and Acute Episodes Umeclidinium and Vilanterol ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. Umeclidinium and Vilanterol ELLIPTA has not been studied in subjects with acutely deteriorating COPD. The initiation of Umeclidinium and Vilanterol ELLIPTA in this setting is not appropriate.

If

Umeclidinium and Vilanterol ELLIPTA no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta 2 -agonist becomes less effective; or the patient needs more short-acting beta 2 ‑agonist than usual, these may be markers of deterioration of disease. In this setting, re‑evaluate the patient and the COPD treatment regimen at once. The daily dose of Umeclidinium and Vilanterol ELLIPTA should not be increased. Increasing use of inhaled, short-acting beta 2 -agonists is a signal of deteriorating disease. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the need for additional therapeutic options. Patients should not use more than 1 inhalation of Umeclidinium and Vilanterol ELLIPTA once daily. Umeclidinium and Vilanterol ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Umeclidinium and Vilanterol 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 beta 2 -agonist. When beginning treatment with Umeclidinium and Vilanterol ELLIPTA, patients who have been taking oral or inhaled, short-acting beta 2 -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing Umeclidinium and Vilanterol ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist and instruct the patient on how it should be used.

5.3 Avoid Excessive Use of Umeclidinium and Vilanterol ELLIPTA and Avoid Use with Other Long-Acting Beta 2 -Agonists Umeclidinium and Vilanterol ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other therapies containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using Umeclidinium and Vilanterol ELLIPTA should not use another therapy containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.4 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of Umeclidinium and Vilanterol ELLIPTA with ketoconazole and other known strong cytochrome P450 3A4 (CYP3A4) inhibitors (including, but not limited to, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased cardiovascular adverse effects may occur <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span> .

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

5.6 Hypersensitivity Reactions, including Anaphylaxis Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of Umeclidinium and Vilanterol ELLIPTA.

Discontinue

Umeclidinium and Vilanterol ELLIPTA if such reactions occur. 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 and Vilanterol ELLIPTA [see Contraindications ( 4 ), Adverse Reactions ( 6.2 )] .

5.7 Cardiovascular Effects Vilanterol, like other beta 2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, Umeclidinium and Vilanterol ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Umeclidinium and Vilanterol ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. In a 52-week trial of subjects with COPD, the exposure-adjusted rates for any on-treatment major adverse cardiac event, including non-fatal central nervous system hemorrhages and cerebrovascular conditions, non-fatal myocardial infarction, non-fatal acute myocardial infarction, and adjudicated on-treatment death due to cardiovascular events, was 2.2 per 100 patient-years for fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg (n = 4,151), 1.9 per 100 patient-years for fluticasone furoate/vilanterol 100/25 mcg (n = 4,134), and 2.2 per 100 patient-years for umeclidinium and vilanterol ELLIPTA (n = 2,070). Adjudicated on‑treatment deaths due to cardiovascular events occurred in 20 of 4,151 patients (0.54 per 100 patient-years) receiving fluticasone furoate/umeclidinium/vilanterol, 27 of 4,134 patients (0.78 per 100 patient-years) receiving fluticasone furoate/vilanterol, and 16 of 2,070 patients (0.94 per 100 patient-years) receiving umeclidinium and vilanterol ELLIPTA.

5.8 Coexisting Conditions Umeclidinium and Vilanterol ELLIPTA, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.9 Worsening of Narrow-Angle Glaucoma Umeclidinium and Vilanterol ELLIPTA should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should also 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 develop.

5.10 Worsening of Urinary Retention Umeclidinium and Vilanterol ELLIPTA, like all therapies containing an anticholinergic, 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 develop.

5.11 Hypokalemia and Hyperglycemia Beta-adrenergic agonist therapies may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist therapies may produce transient hyperglycemia in some patients.

In

4 clinical trials of 6-month duration evaluating umeclidinium and vilanterol ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

INTERACTIONS

• Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause cardiovascular effects. ( 7.1 )
• Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of vilanterol on cardiovascular system. ( 7.2 )
• Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.3 )
• Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. ( 7.4 )
• Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of Umeclidinium and Vilanterol ELLIPTA with other anticholinergic-containing drugs. ( 7.5 )

7.1 Inhibitors of Cytochrome P450 3A4 Vilanterol is a substrate of CYP3A4. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to vilanterol. Caution should be exercised when considering the coadministration of Umeclidinium and Vilanterol ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.3 )]</span> .

7.2 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and QTc Prolonging Drugs Vilanterol, like other beta 2 -agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

7.3 Beta-Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, but may also produce severe bronchospasm in patients with COPD. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta‑adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 Non–Potassium-Sparing Diuretics The electrocardiographic changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics.

7.5 Anticholinergics There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of Umeclidinium and Vilanterol ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.9 , 5.10 )]</span> .