Drug Safety-related Labeling Changes (SrLC)

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TRELEGY ELLIPTA (NDA-209482)

(FLUTICASONE FUROATE; UMECLIDINIUM BROMIDE; VILANTEROL TRIFENATATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/02/2023 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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.

12/02/2022 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Immunosuppression and Risk of Infections

Additions and/or revisions underlined:

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 …

6 Adverse Reactions

In the 2nd bullet in the bulleted line listing, ‘Oropharyngeal Candidiasis’ replaces ‘Candida albicans infection’

6.3 Postmarketing Experience

Newly added information:

Renal and Urinary Disorders

Dysuria, urinary retention.

05/11/2022 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.18 Effect on Growth

Newly added information:

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).]

 

5.6 Immunosuppression and Risk Infections

Newly added information:

The safety and effectiveness of TRELEGY have not been established in pediatric patients and TRELEGY is not indicated for use in this population.

6 Adverse Reactions

6.3 Postmarketing Experience

Newly added information:

Eye Disorders

Blurred vision, eye pain, glaucoma.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

Before using TRELEGY ELLIPTA, tell your healthcare provider about all of your medical conditions, including if you:

…

• are breastfeeding or plan to breastfeed. It is not known if the medicines in TRELEGY ELLIPTA pass into your breast milk and if they can harm your baby.

09/09/2020 (SUPPL-10)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

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)].

5 Warnings and Precautions

5.2 Deterioration of Disease and Acute Episodes

Additions and/or revisions underlined:

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 beta2-agonist becomes less effective; or the patient needs shorter-more acting beta2-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 beta2-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 …

… 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. When prescribing TRELEGY ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-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 Beta2-agonists

‘therapy(ies)’ replaces ‘medicine(s)’ throughout subsection.

5.4 Oropharyngeal Candidiasis

Additions and/or revisions underlined:

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

Additions and/or revisions underlined:

… 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 …

5.6 Immunosuppression and Risk of Infections subtitle revised only

5.7 Transferring Patients from Systemic Corticosteroid Therapy

Additions and/or revisions underlined:

HPA Suppression/Adrenal Insufficiency

Particular care is needed for patients who have been transferred …

…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 …

… Lung function (FEV1), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids …

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 …

Corticosteroid Withdrawal Symptoms

During withdrawal from oral corticosteroids, some patients may experience symptoms …

5.8 Hypercortism and Adrenal Suppression

Additions and/or revisions underlined:

… 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

Additions and/or revisions underlined:

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 …

5.14 Glaucoma and Cataracts, Worsening of Narrow-Angle Glaucoma

Additions and/or revisions underlined:

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration …

Newly added subsection:

5.18 Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. [See Use in Specific Populations (8.4).]

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death

Additions and/or revisions underlined:

… 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 Beta2-adrenergic Agonists).

Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-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 Newly added table; please refer to label for complete information.

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 versus 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.

6 Adverse Reactions

Additions underlined in bulleted line listing:

• Immunosuppression and risk of infections [see Warnings and Precautions (5.6)]

Additions and/or revisions underlined:

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, NCT #01957163 and Trial 2, NCT #02119286) evaluated the coadministration of umeclidinium + fluticasone furoate/vilanterol, the components of TRELEGY ELLIPTA …

… 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 greater than or equal to 1% Incidence and More Common than Placebo + Fluticasone Furoate/Vilanterol in Subjects with COPD This used to be labeled Table 1; only change is underlined in the table title.

A 52-week trial (Trial 3, NCT #02164513) 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 …

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 …

Newly added subsection:

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, NCT #02924688) 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 greater than or equal to 1% Incidence in Subjects with Asthma (Trial 4) Newly added table; please refer to label for complete information.

7 Drug Interactions

Additions and/or revisions underlined:

7.2 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and QTc Prolonging Drugs

7.3 Beta-Adrenergic Receptor Blocking Agents

Addition of ‘or asthma’ following COPD throughout subsection.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

… 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.) …

… 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 …

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/m2 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/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 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) …

8.2 Lactation

Additions and/or revisions underlined:

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.) …

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

Additions and/or revisions underlined:

TRELEGY ELLIPTA is not indicated for use in children and adolescents. The safety and efficacy in pediatric patients (aged 17 years and younger) have not been established.

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). The mean reduction in growth velocity was 0.27 cm/year (95% CI: 0.06, 0.48) [see Warnings and Precautions (5.18)].

8.5 Geriatric Use

Additions and/or revisions underlined:

… In COPD 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 100/25 mcg. In COPD Trial 3, 2,265 subjects aged 65 years and older, of which 565 subjects were aged 75 years and older, were administered TRELEGY ELLIPTA. In an asthma clinical trial (Trial 4), 159 subjects aged 65 years and older, of which 27 subjects were aged 75 years and older, were administered TRELEGY ELLIPTA 100/62.5/25 mcg or TRELEGY ELLIPTA 200/62.5/25 mcg. No overall differences in safety or effectiveness were observed …

8.6 Hepatic Impairment

Additions and/or revisions underlined:

… 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. Use TRELEGY ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects [see Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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

Serious Asthma-Related Events

Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization or asthma-related death. Available data show that when ICS and LABA are used together, such as with TRELEGY ELLIPTA, there is not a significant increase in the risk of these events. [See Warnings and Precautions (5.1).]

Not for Acute Symptoms

Inform patients that TRELEGY ELLIPTA is not meant to relieve acute symptoms of COPD or asthma and extra doses should not be used for that purpose …

Do Not Use Additional Long-acting Beta2-agonists

Instruct patients not to use other LABA for COPD and asthma. [See Warnings and Precautions (5.3).]

Oropharyngeal Candidiasis

Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients …

Immunosuppression and Risk of Infections

…

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. Instruct patients to consult a health care practitioner immediately should any of these signs and symptoms develop. [See Warnings and Precautions (5.12).]

PATIENT INFORMATION

What is TRELEGY ELLIPTA?

Additions and/or revisions underlined:

TRELEGY ELLIPTA is not used to relieve sudden breathing problems and will not replace a rescue inhaler.

• TRELEGY ELLIPTA is a prescription medicine used long term (chronic) to treat people with:

Chronic Obstructive Pulmonary Disease (COPD) …

Asthma:

• TRELEGY ELLIPTA is a prescription medicine used to prevent and control symptoms of asthma for better breathing and to prevent symptoms such as wheezing.

• TRELEGY ELLIPTA contains vilanterol. LABA medicines such as vilanterol when used alone increase the risk of hospitalizations and death from asthma problems. TRELEGY ELLIPTA contains an ICS, an anticholinergic, and a LABA. When an ICS and LABA are used together, there is not a significant increased risk in hospitalizations and death from asthma problems.

TRELEGY ELLIPTA should not be used in children younger than 18 years of age.

It is not known if TRELEGY ELLIPTA is safe and effective in children younger than 18 years of age.

Do not use TRELEGY ELLIPTA:

• to treat sudden, severe symptoms of COPD or asthma.

How should I use TRELEGY ELLIPTA?

Read the step-by-step instructions for using TRELEGY ELLIPTA at the end of this Patient Information.

• TRELEGY ELLIPTA comes in 2 different strengths. Your healthcare provider prescribed the strength that is best for you.

• TRELEGY ELLIPTA does not relieve sudden symptoms of COPD or asthma and you should not take extra doses of TRELEGY ELLIPTA to relieve these sudden symptoms …

What are the possible side effects of TRELEGY ELLIPTA?

TRELEGY ELLIPTA can cause serious side effects, including:

• slowed growth in children.

Common side effects of TRELEGY ELLIPTA include:

COPD was added above the 17 side effects already listed. The following is newly added:

Asthma:

• runny nose and sore throat

• painful and frequent urination

• upper respiratory tract infection (signs of a urinary tract infection)

• bronchitis

• flu

• respiratory tract infection

• headache

• inflammation of the sinuses

• back pain

09/09/2020 (SUPPL-11)

Approved Drug Label (PDF)

6 Adverse Reactions

Newly added subsection:

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.

Immune System Disorders

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticarial.

05/15/2019 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection title to existing information:

5.10 Paradoxical Bronchospasm

As with other inhaled medicines …

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

Vilanterol:

… approximately 13,000 and 760 times …

… approximately 120 times the MRHDID …

… in rabbits at approximately 760 or 840 times the MRHDID …

8.2 Lactation

Data

Animal Data:

… lactating rats at approximately 20 times the MRHDID …

01/07/2019 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.14 Glaucoma and Cataracts, Worsening of Narrow- Angle Glaucoma

(additions underlined)

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 develop. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use TRELEGY ELLIPTA long term.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Glaucoma and Cataracts

Advise 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 develop.

…

PATIENT INFORMATION

(additions underlined)

…

Before using TRELEGY ELLIPTA, tell your healthcare provider about all of your medical conditions, including if you:

…

 

• have eye problems such as glaucoma, increased pressure in your eye, cataracts, blurred vision, or other changes in vision. TRELEGY ELLIPTA may make your glaucoma worse.

 

…

 

What are the possible side effects of TRELEGY ELLIPTA? TRELEGY ELLIPTA can cause serious side effects, including:

…

• eye problems including glaucoma, increased pressure in your eye, cataracts, blurred vision, worsening of narrow-angle glaucoma, or other changes in vision. You should have regular eye exams while using TRELEGY ELLIPTA. Acute narrow-angle glaucoma can cause permanent loss of vision if not treated. Symptoms of acute narrow-angle

…

04/24/2018 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death

(Additions and/or revisions are underlined)

Use of long-acting beta2-adrenergic agonists (LABA) as monotherapy [without inhaled corticosteroid (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.

Available data from clinical trials in subjects with COPD do not suggest an increased risk of death with use of LABA in patients with COPD.

5.12 Cardiovascular Effects

(Additions and/or revisions are underlined)

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 mcg/25 mcg (n = 4,134), and 2.2 per 100 patient-years for umeclidinium/vilanterol 62.5 mcg/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.

5.5 Pneumonia

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In a 52-week trial of subjects with COPD (N = 10,355), the incidence of pneumonia was 8% for TRELEGY ELLIPTA (n = 4,151), 7% for fluticasone furoate/vilanterol 100 mcg/25 mcg (n = 4,134), and 5% for umeclidinium/vilanterol 62.5 mcg/25 mcg (n = 2,070). Fatal pneumonia occurred in 12 of 4,151 patients (0.35 per 100 patient-years) receiving TRELEGY ELLIPTA, 5 of 4,134 patients (0.17 per 100 patient-years) receiving fluticasone furoate/vilanterol, and 5 of 2,070 patients (0.29 per 100 patient-years) receiving umeclidinium/vilanterol.

6 Adverse Reactions

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The following adverse reactions are described in greater detail in other sections:

• Serious asthma-related events – hospitalizations, intubations, death

6.1 Clinical Trials Experience

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The safety of TRELEGY ELLIPTA 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 compared with the fixed-dose combinations of fluticasone furoate/vilanterol and umeclidinium/vilanterol.

Trial 3 - Long-term Safety Data

TheA 52-week trial (Trial 3) evaluated the long-term safety of TRELEGY ELLIPTA compared with the fixed-dose combinations of fluticasone furoate/vilanterol 100 mcg/25 mcg and umeclidinium/vilanterol 62.5 mcg/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, fluticasone furoate/vilanterol powder), or umeclidinium/vilanterol administered once daily in a double-blind clinical trial (mean age: 65 years, 77% white, 66% male across all treatments).

8 Use in Specific Populations

8.5 Geriatric Use

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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. In Trial 3, 2,265 subjects aged 65 years and older, of which 565 subjects were aged 75 years and older, were administered TRELEGY ELLIPTA…