Fluticasone Furoate, Umeclidinium Bromide and Vilanterol Trifenatate

TRELEGY ELLIPTA is a combination of fluticasone furoate, an inhaled corticosteroid (ICS); 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). ( 1.1 )
• the maintenance treatment of asthma in patients aged 18 years and older. ( 1.2 ) Limitations of Use: Not indicated for relief of acute bronchospasm. ( 1.3 , 5.2 )

1.1 Maintenance Treatment of Chronic Obstructive Pulmonary Disease TRELEGY ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

1.2 Maintenance Treatment of Asthma TRELEGY ELLIPTA is indicated for the maintenance treatment of asthma in patients aged 18 years and older.

1.3 Limitations of Use TRELEGY ELLIPTA is NOT indicated for the relief of acute bronchospasm.

Inhalation powder:

• 100 mcg fluticasone furoate, 62.5 mcg umeclidinium, and 25 mcg vilanterol (100/62.5/25 mcg) per actuation.
• 200 mcg fluticasone furoate, 62.5 mcg umeclidinium, and 25 mcg vilanterol (200/62.5/25 mcg) per actuation. Inhalation powder:
• 100 mcg fluticasone furoate, 62.5 mcg umeclidinium, and 25 mcg vilanterol (100/62.5/25 mcg) per actuation. ( 3 )
• 200 mcg fluticasone furoate, 62.5 mcg umeclidinium, and 25 mcg vilanterol (200/62.5/25 mcg) per actuation. ( 3 )

TRELEGY ELLIPTA is contraindicated in the following conditions:

• Primary treatment of status asthmaticus or other acute episodes of COPD or asthma where intensive measures are required [see Warnings and Precautions ( 5.2 )] .
• Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone furoate, umeclidinium, vilanterol, or any of the excipients [see Warnings and Precautions ( 5.11 ), Description ( 11 )] .
• Primary treatment of status asthmaticus or acute episodes of COPD or asthma requiring intensive measures. ( 4 )
• Severe hypersensitivity to milk proteins or any ingredients. ( 4 )

• 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. […]

The following clinically significant adverse reactions are described elsewhere in labeling:

• Serious Asthma-Related Events – Hospitalizations, Intubations, Death [see Warnings and Precautions ( 5.1 )]
• Oropharyngeal Candidiasis [see Warnings and Precautions ( 5.4 )]
• Increased Risk of Pneumonia in COPD [see Warnings and Precautions ( 5.5 )]
• Immunosuppression and Risk of Infections [see Warnings and Precautions ( 5.6 )]
• Hypercorticism and Adrenal Suppression [see Warnings and Precautions ( 5.8 )]
• Paradoxical Bronchospasm [see Warnings and Precautions ( 5.10 )]
• Cardiovascular Effects [see Warnings and Precautions ( 5.12 )]
• Reduction in Bone Mineral Density [see Warnings and Precautions ( 5.13 )]
• Worsening of Narrow-Angle Glaucoma [see Warnings and Precautions ( 5.14 )]
• Worsening of Urinary Retention [see Warnings and Precautions ( 5.15 )] 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.
• COPD: Most common adverse reactions (incidence ≥1%) are upper respiratory tract infection, pneumonia, bronchitis, oral candidiasis, headache, back pain, arthralgia, influenza, sinusitis, pharyngitis, rhinitis, dysgeusia, constipation, urinary tract infection, diarrhea, gastroenteritis, oropharyngeal pain, cough, and dysphonia. ( 6.1 )
• Asthma: Most common adverse reactions (incidence ≥2%) are pharyngitis/nasopharyngitis, upper respiratory tract infection/viral upper respiratory tract infection, bronchitis, respiratory tract infection/viral respiratory tract infection, sinusitis/acute sinusitis, urinary tract infection, rhinitis, influenza, headache, and back pain. ( 6.2 ) 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 in Chronic Obstructive Pulmonary Disease The safety of TRELEGY ELLIPTA in COPD is based on the safety data from two 12-week treatment trials with coadministration of umeclidinium and the fixed-dose combination of fluticasone furoate/vilanterol and a 52-week long-term trial of TRELEGY ELLIPTA 100/62.5/25 mcg compared with the fixed-dose combinations of fluticasone furoate/vilanterol and umeclidinium/vilanterol [see Clinical Studies ( 14.1 )] . Trials 1 and 2 Two 12-week treatment trials (Trial 1 and Trial 2) evaluated the coadministration of umeclidinium + fluticasone furoate/vilanterol, the components of TRELEGY ELLIPTA, compared with placebo + fluticasone furoate/vilanterol. A total of 824 subjects with COPD across two 12-week, randomized, double-blind clinical trials received at least 1 dose of umeclidinium 62.5 mcg + fluticasone furoate/vilanterol 100/25 mcg or placebo + fluticasone furoate/vilanterol 100/25 mcg administered once daily (mean age: 64 years, 92% White, 66% male across all treatments) [see Clinical Studies ( 14.1 )] . The incidence of adverse reactions associated with the use of umeclidinium 62.5 mcg + fluticasone furoate/vilanterol 100/25 mcg presented in Table 2 is based on the two 12-week trials. Table 2. Adverse Reactions with Umeclidinium + Fluticasone Furoate/Vilanterol with ≥1% Incidence and More Common than Placebo + Fluticasone Furoate/Vilanterol in Subjects with COPD (Trials 1 and 2) Umec = Umeclidinium, FF/VI = Fluticasone Furoate/Vilanterol. Adverse Reaction Umec + FF/VI (n = 412) % Placebo + FF/VI (n = 412) % Nervous system disorders Headache 4 3 Dysgeusia 2 <1 Musculoskeletal and connective tissue disorders Back pain 4 2 Respiratory, thoracic, and mediastinal disorders Cough 1 <1 Oropharyngeal pain 1 0 Gastrointestinal disorders Diarrhea 2 <1 Infections and infestations Gastroenteritis 1 0 Trial 3 – Long-term Safety Data A 52-week trial (Trial 3) evaluated the long-term safety of TRELEGY ELLIPTA 100/62.5/25 mcg compared with the fixed-dose combinations of fluticasone furoate/vilanterol 100/25 mcg and umeclidinium/vilanterol 62.5/25 mcg. A total of 10,355 subjects with COPD with a history of moderate or severe exacerbations within the prior 12 months were randomized (2:2:1) to receive TRELEGY ELLIPTA 100/62.5/25 mcg, fluticasone furoate/vilanterol, or umeclidinium/vilanterol administered once daily in a double‑blind clinical trial (mean age: 65 years, 77% White, 66% male across all treatments) [see Clinical Studies ( 14.1 )] . The incidence of adverse reactions in the long-term trial were consistent with those in Trials 1 and 2. However, in addition to the adverse reactions shown in Table 2 , adverse reactions occurring in ≥1% of the subjects treated with TRELEGY ELLIPTA 100/62.5/25 mcg (n = 4,151) for up to 52 weeks also included upper respiratory tract infection, pneumonia [see Warnings and Precautions ( 5.5 )] , bronchitis, oral candidiasis [see Warnings and Precautions ( 5.4 )] , arthralgia, influenza, sinusitis, pharyngitis, rhinitis, constipation, urinary tract infection, and dysphonia.

6.2 Clinical Trials Experience in Asthma The safety of TRELEGY ELLIPTA in asthma is based on a randomized, double-blind, parallel‑group, active-controlled trial of 24 to 52 weeks’ duration (Trial 4) that enrolled 2,436 adult subjects inadequately controlled on their current treatment of combination therapy (ICS plus a LABA) [see Clinical Studies ( 14.2 )] . In the overall population, 62% were female and 80% were White; mean age was 53 years. The incidence of adverse reactions occurring in ≥1% of the subjects treated with TRELEGY ELLIPTA 100/62.5/25 mcg or TRELEGY ELLIPTA 200/62.5/25 mcg is shown in Table 3 . Adverse reactions observed for the groups treated with TRELEGY ELLIPTA were similar to those observed for the fluticasone furoate/vilanterol arms. Table 3. Adverse Reactions with TRELEGY ELLIPTA with ≥1% Incidence in Subjects with Asthma (Trial 4) FF/VI = Fluticasone Furoate/Vilanterol. Adverse Reaction TRELEGY ELLIPTA 200/62.5/25 mcg (n = 408) % TRELEGY ELLIPTA 100/62.5/25 mcg (n =406) % FF/VI 200/25 mcg (n = 406) % FF/VI 100/25 mcg (n = 407) % Infections and infestations Pharyngitis/nasopharyngitis 15 17 16 16 Upper respiratory tract infection/viral upper respiratory tract infection 7 5 6 7 Bronchitis 5 4 5 3 Respiratory tract infection/viral respiratory tract infection 3 4 2 4 Sinusitis/acute sinusitis 3 2 2 3 Urinary tract infection 2 <1 <1 1 Rhinitis 1 2 2 3 Influenza 1 4 2 3 Pneumonia <1 1 2 2 Nervous system disorders Headache 5 9 6 7 Musculoskeletal and connective tissue disorders Back pain 2 3 1 4 Respiratory, thoracic, and mediastinal disorders Dysphonia 1 1 2 1 Oropharyngeal pain 1 1 <1 <1 Cough 1 <1 1 1

6.3 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of TRELEGY 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 TRELEGY ELLIPTA or a combination of these factors. Cardiac Disorders Palpitations Eye Disorders Blurred vision, eye pain, glaucoma, and intraocular pressure increase Immune System Disorders Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria Metabolism and Nutrition Disorders Hyperglycemia Musculoskeletal and Connective Tissue Disorders Muscle spasms Nervous System Disorders Tremor Psychiatric Disorders Anxiety Renal and Urinary Disorders Dysuria, urinary retention.

• Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause systemic corticosteroid and 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 TRELEGY ELLIPTA with other anticholinergic-containing drugs. ( 7.5 )

7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol are substrates of CYP3A4. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of TRELEGY ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors [see Warnings and Precautions ( 5.9 ), 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 or asthma. Therefore, patients with COPD or asthma 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 TRELEGY ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions ( 5.14 , 5.15 )] .

Hepatic impairment: Fluticasone furoate systemic exposure may increase in patients with moderate or severe impairment. Monitor for systemic corticosteroid effects. ( 8.6 , 12.3 )

8.1 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 4.5 and 40 times the maximum recommended human daily inhalation doses (MRHDID) of 200 and 25 mcg, respectively in adults. (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 40 and 150 times, respectively, the human exposure at the MRHDID of 62.5 mcg. (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 Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control of asthma. Labor or 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 4.5 and 40 times the MRHDID of 200 and 25 mcg, respectively, alone or in combination (on a mcg/m 2 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 4.5 times and equal to, respectively, the MRHDID of 200 mcg (on a mcg/m 2 basis at maternal inhalation doses up to 91 and 8 mcg/kg/day, respectively). 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 1.5 times the MRHDID of 200 mcg (on a mcg/m 2 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 during the period of organogenesis at doses up to approximately 40 and 150 times, respectively the MRHDID of 62.5 mcg (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 20 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 760 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 120 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 760 or 840 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.

8.2 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 was detected in the plasma of offspring of lactating rats treated with umeclidinium, suggesting its presence in maternal 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 Subcutaneous administration of umeclidinium to lactating rats at greater than or equal to 60 mcg/kg/day resulted in a quantifiable level of umeclidinium in 2 of 54 pups, which may indicate transfer of umeclidinium in rat milk.

8.4 Pediatric Use The safety and effectiveness of TRELEGY ELLIPTA have not been established in pediatric patients (aged 17 years and younger). TRELEGY ELLIPTA is not indicated for use in pediatric patients. Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. Controlled clinical trials have shown that ICS may cause a reduction in growth in children. In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. A randomized, double-blind, parallel-group, multicenter, 1-year, placebo-controlled trial evaluated the effect of once-daily treatment with 110 mcg of fluticasone furoate in the nasal spray formulation on growth velocity assessed by stadiometry. The subjects were 474 prepubescent children (girls aged 5 to 7.5 years and boys aged 5 to 8.5 years). Mean growth velocity over the 52-week treatment period was lower in the subjects receiving fluticasone furoate nasal spray (5.19 cm/year) compared with placebo (5.46 cm/year). […]

TRELEGY ELLIPTA TRELEGY ELLIPTA contains fluticasone furoate, umeclidinium, and vilanterol. The mechanisms of action described below for the individual components apply to TRELEGY ELLIPTA. These drugs represent 3 different classes of medications (an ICS, an anticholinergic, and a LABA), each having different effects on clinical and physiological indices. Fluticasone Furoate Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects COPD and asthma symptoms is not known. Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. Umeclidinium Umeclidinium is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect. Vilanterol Vilanterol is a LABA. In vitro tests have shown the functional selectivity of vilanterol was similar to salmeterol. The clinical relevance of this in vitro finding is unknown. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenergic agonist drugs, including vilanterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3ʹ,5ʹ-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.