TRELEGY ELLIPTA

• LABA monotherapy increases the risk of serious asthma-related events. ( 5.1 ) • Do not initiate in acutely deteriorating COPD or asthma. 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 ) • Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) • Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.6 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids. Wean patients slowly from systemic corticosteroids if transferring to TRELEGY ELLIPTA. ( 5.7 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue TRELEGY ELLIPTA slowly. ( 5.8 ) • If paradoxical bronchospasm occurs, discontinue TRELEGY ELLIPTA and institute alternative therapy. ( 5.10 ) • Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 ) • Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) • Glaucoma and cataracts may occur with long-term use of ICS. 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. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use TRELEGY ELLIPTA long term. ( 5.14 ) • 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. ( 5.15 ) • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.16 ) • Be alert to hypokalemia and hyperglycemia. ( 5.17 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death Use of long-acting beta 2 -adrenergic agonists (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 (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long ‑ acting Beta 2 -adrenergic Agonists) . Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta 2 -adrenergic Agonists Four (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: 1 trial compared budesonide/formoterol with budesonide, 1 trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder, and 1 trial compared mometasone furoate/formoterol with mometasone furoate. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related. The 3 adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone ( Table 1 ). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS. Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12 Years and Older ICS = Inhaled Corticosteroid, LABA = Long-acting Beta 2 -adrenergic Agonist. a Randomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis. b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials. c Number of subjects with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Subjects can have 1 or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma related. ICS/LABA (n = 17,537)a ICS (n = 17,552) a ICS/LABA vs. ICS Hazard Ratio (95% CI) b Serious asthma-related event c 116 105 1.10 (0.85, 1.44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24-hour stay) 115 105 The pediatric safety trial included 6,208 pediatric subjects aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) subjects randomized to ICS/LABA and 21/3,101 (0.7%) subjects randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27). TRELEGY ELLIPTA is not indicated for use in pediatric patients aged 17 years and younger. Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled, U.S. trial that compared the safety of 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]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy. 5.2 Deterioration of Disease and Acute Episodes TRELEGY ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma. TRELEGY ELLIPTA has not been studied in subjects with acutely deteriorating COPD or asthma. The initiation of TRELEGY ELLIPTA in this setting is not appropriate. If TRELEGY ELLIPTA 100/62.5/25 mcg 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. For COPD, the daily dose of TRELEGY ELLIPTA 100/62.5/25 mcg should not be increased. Increasing use of inhaled, short-acting beta 2 -agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the need for additional therapeutic options. Patients should not use more than 1 inhalation once daily of TRELEGY ELLIPTA. TRELEGY ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. TRELEGY 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 TRELEGY 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 TRELEGY 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 TRELEGY ELLIPTA and Avoid Use with Other Long-acting Beta 2 -agonists TRELEGY ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other therapies containing LABA, 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 TRELEGY ELLIPTA should not use another therapy containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. 5.4 Oropharyngeal Candidiasis TRELEGY ELLIPTA contains fluticasone furoate, an ICS. Localized infections of the mouth and pharynx with Candida albicans have occurred in subjects treated with orally inhaled drug products containing fluticasone furoate. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with TRELEGY ELLIPTA continues. In some cases, therapy with TRELEGY ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following administration of TRELEGY ELLIPTA to help reduce the risk of oropharyngeal candidiasis. 5.5 Pneumonia Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as clinical features of pneumonia and exacerbations frequently overlap. In two 12-week trials of subjects with COPD (N = 824), the incidence of pneumonia was <1% for both treatment arms: umeclidinium 62.5 mcg + fluticasone furoate/vilanterol 100/25 mcg or placebo + fluticasone furoate/vilanterol 100/25 mcg. Fatal pneumonia occurred in 1 subject receiving placebo + fluticasone furoate/vilanterol 100/25 mcg. In a 52-week trial of subjects with COPD (N = 10,355), the incidence of pneumonia was 8% for TRELEGY ELLIPTA 100/62.5/25 mcg (n = 4,151), 7% for fluticasone furoate/vilanterol 100/25 mcg (n = 4,134), and 5% for umeclidinium/vilanterol 62.5/25 mcg (n = 2,070). Fatal pneumonia occurred in 12 of 4,151 patients (0.35 per 100 patient-years) receiving TRELEGY ELLIPTA 100/62.5/25 mcg; 5 of 4,134 patients (0.17 per 100 patient-years) receiving fluticasone furoate/vilanterol 100/25 mcg; and 5 of 2,070 patients (0.29 per 100 patient-years) receiving umeclidinium/vilanterol 62.5/25 mcg. In a mortality trial with fluticasone furoate/vilanterol 100/25 mcg with a median treatment duration of 1.5 years in 16,568 subjects with moderate COPD and cardiovascular disease, the annualized incidence rate of pneumonia was 3.4 per 100 patient-years for fluticasone furoate/vilanterol 100/25 mcg, 3.2 for placebo, 3.3 for fluticasone furoate 100 mcg, and 2.3 for vilanterol 25 mcg. Adjudicated, on‑treatment deaths due to pneumonia occurred in 13 subjects receiving fluticasone furoate/vilanterol 100/25 mcg, 9 subjects receiving placebo, 10 subjects receiving fluticasone furoate 100 mcg, and 6 subjects receiving vilanterol 25 mcg (<0.2 per 100 patient-years for each treatment group). 5.6 Immunosuppression and Risk of Infections Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The safety and effectiveness of TRELEGY have not been established in pediatric patients and TRELEGY is not indicated for use in this population. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective Prescribing Information for VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered. ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.7 Transferring Patients from Systemic Corticosteroid Therapy HPA Suppression/Adrenal Insufficiency Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although TRELEGY ELLIPTA may control COPD or asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their health care practitioner for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to TRELEGY ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with TRELEGY ELLIPTA. Lung function (FEV 1 ), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids Transfer of patients from systemic corticosteroid therapy to TRELEGY ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Corticosteroid Withdrawal Symptoms During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. 5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of fluticasone furoate in TRELEGY ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions ( 5.9 ), Drug Interactions ( 7.1 )] . Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with TRELEGY ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, reduce the dose of TRELEGY ELLIPTA slowly, consistent with accepted procedures for reducing systemic corticosteroids, and consider other treatments for management of COPD or asthma symptoms. 5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of TRELEGY ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors (including, but not limited to, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . 5.10 Paradoxical Bronchospasm As with other inhaled therapies, TRELEGY ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with TRELEGY ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; TRELEGY ELLIPTA should be discontinued immediately; and alternative therapy should be instituted. 5.11 Hypersensitivity Reactions, including Anaphylaxis Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of TRELEGY ELLIPTA. Discontinue TRELEGY 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 TRELEGY ELLIPTA [see Contraindications ( 4 ), Adverse Reactions ( 6.3 )] . 5.12 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, TRELEGY 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 [see Clinical Pharmacology ( 12.2 )] . Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. TRELEGY 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 (MI), non-fatal acute MI, and adjudicated on-treatment death due to cardiovascular events, was 2.2 per 100 patient-years for TRELEGY ELLIPTA (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/vilanterol 62.5/25 mcg (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 TRELEGY ELLIPTA; 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/vilanterol. In a mortality trial with fluticasone furoate/vilanterol with a median treatment duration of 1.5 years in 16,568 subjects with moderate COPD and cardiovascular disease, the annualized incidence rate of adjudicated cardiovascular events (composite of myocardial infarction, stroke, unstable angina, transient ischemic attack, or on-treatment death due to cardiovascular events) was 2.5 per 100 patient-years for fluticasone furoate/vilanterol 100/25 mcg, 2.7 for placebo, 2.4 for fluticasone furoate 100 mcg, and 2.6 for vilanterol 25 mcg. Adjudicated, on-treatment deaths due to cardiovascular events occurred in 82 subjects receiving fluticasone furoate/vilanterol 100/25 mcg, 86 subjects receiving placebo, 80 subjects receiving fluticasone furoate 100 mcg, and 90 subjects receiving vilanterol 25 mcg (annualized incidence rate ranged from 1.2 to 1.3 per 100 patient-years for the treatment groups). 5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long‑term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating TRELEGY ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and TRELEGY ELLIPTA is still considered medically important for that patient’s COPD therapy, use of therapy to treat or prevent osteoporosis should be strongly considered. 5.14 Glaucoma and Cataracts, Worsening of Narrow-Angle Glaucoma Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of ICS or with use of inhaled anticholinergics. TRELEGY 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. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use TRELEGY ELLIPTA long term. 5.15 Worsening of Urinary Retention TRELEGY 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. 5.16 Coexisting Conditions TRELEGY 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. 5.17 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. 5.18 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. The safety and effectiveness of TRELEGY have not been established in pediatric patients (aged 17 years and younger) and TRELEGY is not indicated for use in this population. [See Use in Specific Populations ( 8.4 ).]