Umeclidinium Drug Information

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). Limitations of Use: Not indicated for relief of acute bronchospasm or for the treatment of asthma.

• 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 )

• The following clinically significant adverse reactions are described elsewhere in labeling:
• Serious asthma-related events–hospitalizations, intubations, death [see Warnings and Precautions ( 5.1 )]
• Paradoxical bronchospasm [see Warnings and Precautions ( 5.5 )]
• Cardiovascular effects [see Warnings and Precautions ( 5.7 )]
• Worsening of narrow-angle glaucoma [see Warnings and Precautions ( 5.9 )]
• Worsening of urinary retention [see Warnings and Precautions ( 5.10 )] Most common adverse reactions (incidence ≥1% and more common than placebo) are pharyngitis, sinusitis, lower respiratory tract infection, constipation, diarrhea, pain in extremity, muscle spasms, neck pain, and chest pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 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. The clinical program for umeclidinium and vilanterol ELLIPTA included 8,138 subjects with COPD in four 6‑month lung function trials, one 12-month long-term safety study, and 9 other trials of shorter duration. A total of 1,124 subjects have received at least 1 dose of umeclidinium and vilanterol ELLIPTA (umeclidinium/vilanterol 62.5/25 mcg), and 1,330 subjects have received a higher dose of umeclidinium/vilanterol (125/25 mcg). The safety data described below are based on the four 6-month and one 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials. 6-Month Trials The incidence of adverse reactions associated with umeclidinium and vilanterol ELLIPTA in Table 1 is based on four 6-month trials: 2 placebo-controlled trials (Trial 1 and Trial 2); N = 1,532 and N = 1,489, respectively) and 2 active-controlled trials (Trial 3 and Trial 4); N = 843 and N = 869, respectively). Of the 4,733 subjects, 68% were male and 84% were white. They had a mean age of 63 years and an average smoking history of 45 pack-years, with 50% identified as current smokers. At screening, the mean postbronchodilator percent predicted forced expiratory volume in 1 second (FEV 1 ) was 48% (range: 13% to 76%), the mean postbronchodilator FEV 1 /forced vital capacity (FVC) ratio was 0.47 (range: 0.13 to 0.78), and the mean percent reversibility was 14% (range: -45% to 109%). Subjects received 1 dose once daily of the following: umeclidinium and vilanterol ELLIPTA, umeclidinium/vilanterol 125/25 mcg, umeclidinium 62.5 mcg, umeclidinium 125 mcg, vilanterol 25 mcg, active control, or placebo. Table 1. Adverse Reactions with Umeclidinium and Vilanterol ELLIPTA with ≥1% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease Adverse Reaction Umeclidinium and Vilanterol ELLIPTA (n = 842) % Umeclidinium 62.5 mcg (n = 418) % Vilanterol 25 mcg (n = 1,034) % Placebo (n = 555) % Infections and infestations Pharyngitis 2 1 2 <1 Sinusitis 1 <1 1 <1 Lower respiratory tract infection 1 <1 <1 <1 Gastrointestinal disorders Constipation 1 <1 <1 <1 Diarrhea 2 <1 2 1 Musculoskeletal and connective tissue disorders Pain in extremity 2 <1 2 1 Muscle spasms 1 <1 <1 <1 Neck pain 1 <1 <1 <1 General disorders and administration site conditions Chest pain 1 <1 <1 <1 Other adverse reactions with umeclidinium and vilanterol ELLIPTA observed with an incidence <1% but more common than placebo included the following: productive cough, dry mouth, dyspepsia, abdominal pain, gastroesophageal reflux disease, vomiting, musculoskeletal chest pain, chest discomfort, asthenia, atrial fibrillation, ventricular extrasystoles, supraventricular extrasystoles, myocardial infarction, pruritus, rash, and conjunctivitis. 12-Month Trial In a long-term safety trial (Trial 5), 335 subjects were treated for up to 12 months with umeclidinium/vilanterol 125/25 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo‑controlled efficacy trials described above. Adverse reactions observed with a frequency of ≥1% in the group receiving umeclidinium/vilanterol 125/25 mcg that exceeded that in placebo in this trial were: headache, back pain, sinusitis, cough, urinary tract infection, arthralgia, nausea, vertigo, abdominal pain, pleuritic pain, viral respiratory tract infection, toothache, and diabetes mellitus. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of umeclidinium and vilanterol 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 umeclidinium and vilanterol ELLIPTA or a combination of these factors. Cardiac Disorders Palpitations. Eye Disorders Blurred vision, eye pain, glaucoma, increased intraocular pressure. Immune System Disorders Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria. Nervous System Disorders Dysgeusia, tremor. Psychiatric Disorders Anxiety. Renal and Urinary Disorders Dysuria, urinary retention. Respiratory, Thoracic, and Mediastinal Disorders Dysphonia, paradoxical bronchospasm.

• 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 [see Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.3 )] . 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 [see Warnings and Precautions ( 5.9 , 5.10 )] .

Pregnancy Risk Summary There are insufficient data on the use of umeclidinium and vilanterol ELLIPTA or its individual components, umeclidinium and vilanterol, in pregnant women to inform a drug-associated risk. (See Clinical Considerations.) In animal reproduction studies, umeclidinium administered via inhalation or subcutaneously to pregnant rats and rabbits was not associated with adverse effects on embryofetal development at exposures approximately 50 and 200 times, respectively, the human exposure at the maximum recommended human daily inhaled dose (MRHDID). Vilanterol administered via inhalation to pregnant rats and rabbits produced no fetal structural abnormalities at exposures approximately 70 times the MRHDID. (See Data.) The estimated risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Labor or Delivery: Umeclidinium and Vilanterol ELLIPTA should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility.

Data Animal Data: The combination of umeclidinium and vilanterol has not been studied in pregnant animals. Studies in pregnant animals have been conducted with umeclidinium and vilanterol individually. Umeclidinium: In separate embryofetal developmental studies, pregnant rats and rabbits received umeclidinium during the period of organogenesis at doses up to approximately 50 and 200 times the MRHDID, respectively (on an AUC basis at maternal inhalation doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits). No evidence of teratogenic effects was observed in either species.

In a perinatal and postnatal developmental study in rats, dams received umeclidinium during late gestation and lactation periods with no evidence of effects on offspring development at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day). Vilanterol: In separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 450 times, respectively, the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 5,740 mcg/kg/day in rabbits). No evidence of structural abnormalities was observed at any dose in rats or in rabbits up to approximately 70 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 450 times the MRHDID (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. In a perinatal and postnatal developmental study in rats, dams received vilanterol during late gestation and the lactation periods at doses up to approximately 3,900 times the MRHDID (on a mcg/m 2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects in offspring development was observed.

Pediatric Use The safety and effectiveness of Umeclidinium and Vilanterol ELLIPTA have not been established in pediatric patients. Umeclidinium and Vilanterol ELLIPTA is not indicated for use in pediatric patients.

• 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 )

Umeclidinium and Vilanterol ELLIPTA contains both umeclidinium and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to Umeclidinium and Vilanterol ELLIPTA. Treatment of overdosage consists of discontinuation of Umeclidinium and Vilanterol ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.

Umeclidinium High doses of umeclidinium may lead to anticholinergic signs and symptoms. Vilanterol The expected signs and symptoms with overdosage of vilanterol are those of excessive beta‑adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol.