Trelegy Ellipta

Trelegy Ellipta is a combination inhaled corticosteroid/anticholinergic/long-acting beta2-adrenergic agonist indicated for the long-term, once-daily, maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema, who are on a fixed-dose combination of fluticasone furoate and vilanterol for airflow obstruction and reducing exacerbations in whom additional treatment of airflow obstruction is desired or for patients who are already receiving umeclidinium and a fixed-dose combination of fluticasone furoate and vilanterol.

Important Limitations of Use

Trelegy Ellipta is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

Asthma-Related Death

Data from a large placebo-controlled trial in subjects with asthma showed that LABA may increase the risk of asthma-related death.

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 LABA, including vilanterol, one of the active ingredients in Trelegy Ellipta.

No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with Trelegy Ellipta has been conducted. The safety and efficacy of Trelegy Ellipta in patients with asthma have not been established. Trelegy Ellipta is not indicated for the treatment of asthma.

Deterioration of Disease and Acute Episodes

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

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 beta2-agonist.

When beginning treatment with Trelegy Ellipta, patients who have been taking oral or inhaled, short-acting beta2-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.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If Trelegy 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 Trelegy Ellipta beyond the recommended dose is not appropriate in this situation.

Excessive Use of Trelegy Ellipta and Use with Other Long-acting Beta2-agonists

Trelegy Ellipta should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines 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 medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

Local Effects of Inhaled Corticosteroids

Trelegy Ellipta contains fluticasone furoate, an inhaled corticosteroid (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, but at times therapy with Trelegy Ellipta may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

Pneumonia

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as clinical features of pneumonia and exacerbations frequently overlap. Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids.

In two 12-week trials of subjects with COPD (N = 824), the incidence of pneumonia was less than 1% for both treatment arms: umeclidinium 62.5 mcg + fluticasone furoate/vilanterol 100 mcg/25 mcg or placebo + fluticasone furoate/vilanterol 100 mcg/25 mcg. Fatal pneumonia occurred in 1 subject receiving placebo + fluticasone furoate/vilanterol 100 mcg/25 mcg. 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 pneumonia was 3.4 per 100 patient-years for fluticasone furoate/vilanterol 100 mcg/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 mcg/25 mcg, 9 subjects receiving placebo, 10 subjects receiving fluticasone furoate 100 mcg, and 6 subjects receiving vilanterol 25 mcg (less than 0.2 per 100 patient-years for each treatment group).

Immunosuppression

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, 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 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 package inserts for complete VZIG and IG prescribing information.) 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.

Transferring Patients from Systemic Corticosteroid Therapy

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 with asthma 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 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 or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians 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 or a severe COPD exacerbation.

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 (forced expiratory volume in 1 second [FEV1]), beta-agonist use, and COPD 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.

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).

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.

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, appropriate therapy should be considered.

Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the coadministration of Trelegy Ellipta with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., 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)].

Paradoxical Bronchospasm

As with other inhaled medicines, 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.

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)].

Cardiovascular Effects

Vilanterol, like other beta2-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 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 mcg/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 mcg/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).

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 medicine to treat or prevent osteoporosis should be strongly considered.

Glaucoma and Cataracts, Worsening of Narrow-Angle Glaucoma

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD 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 develops. Close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, narrow- or open-angle glaucoma, and/or cataracts.

Worsening of Urinary Retention

Trelegy Ellipta, like all medicines 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 develops.

Coexisting Conditions

Trelegy Ellipta, like all medicines 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 beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia and Hyperglycemia

Beta-adrenergic agonist medicines 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 medications may produce transient hyperglycemia in some patients.

Pregnancy

Risk Summary

There are insufficient data on the use of Trelegy Ellipta or its individual components, fluticasone furoate, umeclidinium, and vilanterol, in pregnant women to inform a drug-associated risk. [See Clinical Considerations.] In an animal reproduction study, fluticasone furoate and vilanterol administered by inhalation alone or in combination to pregnant rats during the period of organogenesis produced no fetal structural abnormalities. The highest fluticasone furoate and vilanterol doses in this study were approximately 9 and 40 times the maximum recommended human daily inhalation doses (MRHDID) of 100 and 25 mcg in adults, respectively. [See Data.] Umeclidinium administered via inhalation or subcutaneously to pregnant rats and rabbits was not associated with adverse effect on embryofetal development at exposures approximately 50 and 200 times, respectively, the human exposure at the MRHDID.

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 and Delivery: Trelegy 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 fluticasone furoate, umeclidinium, and vilanterol has not been studied in pregnant animals. Studies in pregnant animals have been conducted with fluticasone furoate and vilanterol in combination and individually with fluticasone furoate, umeclidinium, or vilanterol.

Fluticasone Furoate and Vilanterol: In an embryofetal developmental study, pregnant rats received fluticasone furoate and vilanterol during the period of organogenesis at doses up to approximately 9 and 40 times the MRHDID, respectively, alone or in combination (on a mcg/m2 basis at inhalation doses up to approximately 95 mcg/kg/day). No evidence of structural abnormalities was observed.

Fluticasone Furoate: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received fluticasone furoate during the period of organogenesis at doses up to approximately 9 and 2 times the MRHDID, respectively (on a mcg/m2 basis at maternal inhalation doses up to 91 and 8 mcg/kg/day). No evidence of structural abnormalities in fetuses was observed in either species. In a perinatal and postnatal developmental study in rats, dams received fluticasone furoate during late gestation and lactation periods at doses up to approximately 3 times the MRHDID (on a mcg/m2 basis at maternal inhalation doses up to 27 mcg/kg/day). No evidence of effects on offspring development was observed.

Umeclidinium: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received umeclidinium via inhalation 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 at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day). No evidence of effects on offspring development was observed.

Vilanterol: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 1,000 times, respectively, the MRHDID (on a mcg/m2 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 160 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day). However, fetal skeletal variations were observed in rabbits at approximately 1,000 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/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects in offspring development was observed.

Lactation

Risk Summary

There is no information available on the presence of fluticasone furoate, umeclidinium, or vilanterol in human milk; the effects on the breastfed child; or the effects on milk production. Umeclidinium is present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Trelegy Ellipta and any potential adverse effects on the breastfed child from fluticasone furoate, umeclidinium, or vilanterol or from the underlying maternal condition.

Data

Animal Data: Subcutaneous administration of umeclidinium to lactating rats at approximately 25 times the MRHDID resulted in a quantifiable level of umeclidinium in 2 of 54 pups, which may indicate transfer of umeclidinium in rat milk.

Pediatric Use

Trelegy 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 Trelegy Ellipta in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

In Trials 1 and 2 (coadministration trials), 189 subjects aged 65 years and older, of which 39 subjects were aged 75 years and older, were administered umeclidinium 62.5 mcg + fluticasone furoate/vilanterol 100 mcg/25 mcg. 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

Trelegy Ellipta has not been studied in subjects with hepatic impairment. Information on the individual components is provided below.

Fluticasone Furoate/Vilanterol

Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Monitor patients for corticosteroid-related side effects [see Clinical Pharmacology (12.3)].

Umeclidinium

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 [see Clinical Pharmacology (12.3)].

Renal Impairment

Trelegy Ellipta has not been studied in subjects with renal impairment. Information on the individual components is provided below.

Fluticasone Furoate/Vilanterol

There were no significant increases in either fluticasone furoate or vilanterol exposure in subjects with severe renal impairment (CrCl less than 30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].

Umeclidinium

Patients with severe renal impairment (CrCl 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 [see Clinical Pharmacology (12.3)].

No human overdosage data has been reported for Trelegy Ellipta.

Trelegy Ellipta contains fluticasone furoate, umeclidinium, and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to Trelegy Ellipta. Treatment of overdosage consists of discontinuation of Trelegy 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.

Fluticasone Furoate

Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur [see Warnings and Precautions (5.8)].

Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have been studied in human subjects. Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days.

Umeclidinium

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.

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.

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

Asthma-Related Death

Inform patients that LABA, such as vilanterol, one of the active ingredients in Trelegy Ellipta, increase the risk of asthma-related death. Trelegy Ellipta is not indicated for the treatment of asthma.

Not for Acute Symptoms

Inform patients that Trelegy 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 medication and instruct them in how it should be used.

Instruct patients to seek medical attention immediately if they experience any of the following:

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

Do Not Use Additional Long-acting Beta2-agonists

Instruct patients not to use other LABA.

Local Effects

Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with Trelegy Ellipta, but at times therapy with Trelegy Ellipta may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

Pneumonia

Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare providers if they develop symptoms of pneumonia.

Immunosuppression

Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Hypercorticism and Adrenal Suppression

Advise patients that Trelegy Ellipta may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to Trelegy Ellipta.

Paradoxical Bronchospasm

As with other inhaled medicines, Trelegy Ellipta can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue Trelegy Ellipta and contact their healthcare provider right away.

Hypersensitivity Reactions, including Anaphylaxis

Advise patients that hypersensitivity reactions (e.g., anaphylaxis, angioedema, rash, urticaria) may occur after administration of Trelegy Ellipta. Instruct patients to 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.

Reduction in Bone Mineral Density

Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk.

Ocular Effects

Inform patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

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 physician 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 physician immediately if any of these signs or symptoms develops.

Risks Associated with Beta-agonist Therapy

Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Trademarks are owned by or licensed to the GSK group of companies.

Trelegy Ellipta was developed in collaboration with Innoviva.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2017 GSK group of companies or its licensor.

TRL:2PI

This Instructions for Use has been approved by the U.S. Food and Drug Administration               Revised: September 2017

PRINCIPAL DISPLAY PANEL

NDC 0173-0887-10

Trelegy ELLIPTA

(fluticasone furoate, umeclidinium, and vilanterol inhalation powder)

100 mcg/62.5 mcg/25 mcg

Rx Only

FOR ORAL INHALATION ONLY

Trelegy Ellipta contains 2 foils strips of 30 blisters each. Each blister on one strip contains 100 mcg of fluticasone furoate and lactose monohydrate. Each blister on the other strip contains 62.5 mcg of umeclidinum, 25 mcg of vilanterol, magnesium stearate, and lactose monohydrate.

Federal Law requires the dispensing of Trelegy Ellipta with the Medication Guide inside the carton.

1 ELLIPTA Inhaler containing 30 doses (60 blisters total)

Made in UK

©2017 GSK group of companies or its licensor.

10000000145265

Rev. 5/17

Read this Medication Guide before you start treatment. Talk with your healthcare provider if you have questions about your health condition or treatment. Reading this Medication Guide does not take the place of talking with your healthcare provider.

Trelegy Ellipta is approved only for use in chronic obstructive pulmonary disease (COPD).

It is not approved for the treatment of asthma.

Trelegy Ellipta can cause serious side effects, including:

• People with asthma who take long-acting beta2sup>-adrenergic agonist (LABA) medicines, such as vilanterol (one of the medicines in Trelegy Ellipta), have an increased risk of death from asthma problems. It is not known whether fluticasone furoate, one of the other medicines in Trelegy Ellipta, reduces the risk of death from asthma problems seen with LABA medicines.
• It is not known if LABA medicines, such as vilanterol, increase the risk of death in people with COPD.
• Call your healthcare provider if breathing problems worsen over time during treatment. You may need to change to a different medication.
• Get emergency medical care if:
  • your breathing problems worsen quickly.
  • you use your rescue inhaler, but it does not relieve your breathing problems.

Do not use Trelegy Ellipta if you:

• have a severe allergy to milk proteins. Ask your healthcare provider if you are not sure.
• are allergic to fluticasone furoate, umeclidinium, vilanterol, or any of the other ingredients. See the end of this Medication Guide for a complete list of ingredients.

Use Trelegy Ellipta as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Follow how to use as you have been told by the doctor or read the package insert.
• For breathing in only.
• Take this medicine at the same time of day.
• To gain the most benefit, do not miss doses.
• Keep using Trelegy Ellipta as you have been told by your doctor or other health care provider, even if you feel well.
• Do not take out the inhaler from the foil tray until right before first use.
• Do not take the device apart or wash it. Do not use it with a spacer. Do not breathe out into the device.
• Close the device after each dose. Do not open the device unless a dose is being used.
• Rinse out mouth after each use. Do not swallow the rinse water. Spit it out.
• If using more than 1 type of puffer (inhaler), ask the doctor which puffer to use first.
• Have your puffer (inhaler) use checked with your doctor at each visit. Read and follow facts on how to use the puffer. Make sure you use the puffer the right way.

What do I do if I miss a dose?

• Use a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not use 2 doses at the same time or extra doses.
• Do not use more than 1 time a day.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Signs of low potassium levels like muscle pain or weakness, muscle cramps, or a heartbeat that does not feel normal.
• Signs of a weak adrenal gland like a very bad upset stomach or throwing up, very bad dizziness or passing out, muscle weakness, feeling very tired, mood changes, not hungry, or weight loss.
• Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
• Chest pain or pressure or a fast heartbeat.
• A heartbeat that does not feel normal.
• Feeling nervous and excitable.
• Shakiness.
• Change in eyesight, eye pain, or very bad eye irritation.
• Seeing halos or bright colors around lights.
• Trouble passing urine.
• Pain when passing urine.
• Passing urine in a weak stream or drips.
• Redness or white patches in mouth or throat.
• Bone pain.
• This medicine can cause very bad breathing problems right after you take a dose. Sometimes, this may be life-threatening. If you have trouble breathing, breathing that is worse, wheezing, or coughing after using this medicine, use a rescue inhaler and get medical help right away.

Dosage Forms & Strengths

fluticasone furoate/umeclidinium/vilanterol

powder for inhalation

• (100 mcg/62.5 mcg/25 mcg)/blister

Chronic Obstructive Pulmonary Disease

Indicated for maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), who are on a fixed-dose combination of fluticasone furoate (FF) and vilanterol (VI) for airflow obstruction and reducing exacerbations in whom additional treatment of airflow obstruction is desired, as well as for patients who are already receiving umeclidinium (UMEC) and a fixed-dose combination of FF and VI

1 inhalation PO qDay

See Administration

Dosage Modifications

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

Studies in subjects with moderate-to-severe hepatic impairment have not been performed; monitor for corticosteroid-related adverse effects

Safety and efficacy not established

Fluticasone is a steroid that prevents the release of substances in the body that cause inflammation.

Umeclidinium is an anticholinergic. Vilanterol is a bronchodilator. These medications work by relaxing muscles in the airways to improve breathing.

Fluticasone, umeclidinium, and vilanterol is a combination medicine used to improve symptoms and prevent bronchospasm in adults with COPD (chronic obstructive pulmonary disease), including bronchitis and emphysema.

Fluticasone, umeclidinium, and vilanterol may also be used for purposes not listed in this medication guide.

Fluticasone is a steroid that prevents the release of substances in the body that cause inflammation.

Umeclidinium is an anticholinergic. Vilanterol is a bronchodilator. These medications work by relaxing muscles in the airways to improve breathing.

Fluticasone, umeclidinium, and vilanterol is a combination medicine used to prevent airflow obstruction and reduce flare-ups in adults with COPD (chronic obstructive pulmonary disease), including bronchitis and bysema.

Fluticasone, umeclidinium, and vilanterol may also be used for purposes not listed in this medication guide.

This medicine is for use only in people with chronic obstructive pulmonary disease (COPD) and should not be used to treat asthma.

Fluticasone, umeclidinium, and vilanterol is not a rescue medicine. It will not work fast enough to treat a bronchospasm attack.

Seek medical attention if your breathing problems get worse quickly, or if you think your medications are not working as well.

You should not use this medicine if you are allergic to fluticasone, umeclidinium, vilanterol, or milk proteins. This medicine is for use only in people with COPD and should not be used to treat asthma.

Tell your doctor if you have ever had:

• heart disease, high blood pressure;
• a seizure;
• a weak immune system;
• any type of infection, including tuberculosis, herpes infection of the eyes, or an infection caused by parasites;
• liver disease;
• glaucoma or cataracts;
• diabetes (or ketoacidosis);
• osteoporosis;
• a thyroid disorder; or
• an enlarge prostate, bladder obstruction, or urination problems.

If you also use an oral steroid medication, you should not stop using it suddenly. Follow your doctor's instructions about tapering your dose.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It may not be safe to breast-feed while using this medicine. Ask your doctor about any risk.

This medicine is not approved for use by anyone younger than 18 years old.BasicDescription Back to TopTrelegy Ellipta Side Effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• tremors, nervousness, chest pain, fast or pounding heartbeats;
• fever, chills, cough with mucus, feeling short of breath;
• nausea, vomiting, feeling weak or light-headed;
• sores or white patches in your mouth and throat, pain when swallowing;
• wheezing, choking, or other breathing problems after using this medicine;
• painful or difficult urination;
• blurred vision, tunnel vision, eye pain, or seeing halos around lights;
• increased thirst or increased urination; or
• low potassium level--leg cramps, constipation, irregular heartbeats, fluttering in your chest, numbness or tingling, muscle weakness or limp feeling.

Common side effects may include:

• cold or flu symptoms such as runny or stuffy nose, sore throat, cough;
• nausea, vomiting, stomach pain;
• constipation, diarrhea;
• joint pain;
• hoarse voice;
• headache, back pain; or
• mouth pain, changes in your sense of taste.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed. Using this medicine improperly can cause death or serious side effects on the heart.

Use the medicine at the same time each day, and not more than once in a 24-hour period.

Read and follow all patient instructions provided with the inhaler device. Ask your doctor or pharmacist if you do not understand these instructions.

To prevent yeast infection in your mouth, rinse with water (but do not swallow) after using this medicine.

This medicine is not a rescue medicine for bronchospasm attacks. Use only fast-acting inhalation medicine for an attack. Seek medical attention if your breathing problems get worse quickly, or if you think your medications are not working as well.

Your dose needs may change due to surgery, illness, stress, or worsened COPD. Do not change your dose or dosing schedule without your doctor's advice.

You may need frequent medical tests. Your vision and your bone mineral density may also need to be checked.

Store at room temperature away from moisture, heat, and light. Keep the inhaler device in the sealed foil tray until ready to start using it.

Throw the inhaler device away 6 weeks after you have taken it out of the foil pouch, or if the dose indicator shows a zero, whichever comes first.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include chest pain, fast heart rate, and feeling shaky or short of breath.

Use the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not use two doses at one time.

Do not use more than 1 inhalation in a single day.