Vilanterol

LAVENTAIR ELLIPTA is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).

Posology The recommended and maximum dose is one inhalation once daily. LAVENTAIR ELLIPTA should be administered at the same time of the day each day to maintain bronchodilation. If a dose is missed the next dose should be inhaled at the usual time the next day.

2). 2). 3 Hepatic impairment No dose adjustment is required in patients with mild or moderate hepatic impairment. 2). Paediatric population There is no relevant use of LAVENTAIR ELLIPTA in the paediatric population (under 18 years of age) for the indication of COPD.

Method of administration For inhalation use only. The following instructions for the 30 dose inhaler (30 day supply) also apply to the 7 dose inhaler (7 day supply). The ELLIPTA inhaler contains pre-dispensed doses and is ready to use.

The inhaler is packaged in a tray containing a desiccant sachet, to reduce moisture. The desiccant sachet should be thrown away and it should not be opened, eaten or inhaled. The patient should be advised to not open the tray until they are ready to inhale a dose.

The inhaler will be in the ‘closed’ position when it is first taken out of its sealed tray. The “Discard by” date should be written on the inhaler label in the space provided. The “Discard by” date is 6 weeks from the date of opening the tray.

After this date the inhaler should no longer be used. The tray can be discarded after first opening. If the inhaler cover is opened and closed without inhaling the medicinal product, the dose will be lost. The lost dose will be securely held inside the inhaler, but it will no longer be available to be inhaled.

It is not possible to accidentally take extra medicinal product or a double dose in one inhalation. Instructions for use: a) Prepare a dose Open the cover when ready to inhale a dose. The inhaler should not be shaken. Slide the cover down until a “click” is heard.

The medicinal product is now ready to be inhaled. The dose counter counts down by 1 to confirm. If the dose counter does not count down as the “click” is heard, the inhaler will not deliver a dose and should be taken back to a pharmacist for advice.

b) How to inhale the medicinal product The inhaler should be held away from the mouth breathing out as far as is comfortable. But not breathing out into the inhaler. The mouthpiece should be placed between the lips and the lips should then be closed firmly around it.

The air vents should not be blocked with fingers during use. • Inhale with one long, steady, deep breath in. This breath should be held in for as long as possible (at least 3-4 seconds). • Remove the inhaler from the mouth. • Breathe out slowly and gently.

4 The medicinal product may not be tasted or felt, even when using the inhaler correctly. The mouthpiece of the inhaler may be cleaned using a dry tissue before closing the cover. c) Close the inhaler Slide the cover upwards as far as it will go, to cover the mouthpiece.

Summary of the safety profile The most frequently reported adverse reaction is nasopharyngitis (9%). Tabulated list of adverse reactions The safety profile of LAVENTAIR ELLIPTA is based on safety experience with umeclidinium/vilanterol and the individual components from the clinical development program comprising of 6 855 patients with COPD and from spontaneous reporting.

The clinical development programme included 2 354 patients who received umeclidinium/vilanterol once daily in the Phase III clinical studies of 24 weeks or more, of whom 1 296 patients received the recommended dose of 55/22 micrograms in 24-week studies, 832 patients received a higher dose of 113/22 micrograms in 24-week studies and 226 patients received 113/22 micrograms in a 12-month study.

The frequencies assigned to the adverse reactions identified in the table below include crude incidence rates observed in the integration of five 24-week studies and in the 12-month safety study. The frequency of adverse reactions is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000) and not known (cannot be estimated from available data).

8 System Organ Class Adverse reactions Frequency Infections and infestations Urinary tract infection Sinusitis Nasopharyngitis Pharyngitis Upper respiratory tract infection Common Common Common Common Common Immune system disorders Hypersensitivity reactions including: Rash Anaphylaxis, angioedema, and urticaria Uncommon Rare Nervous system disorders Headache Tremor Dysgeusia Dizziness Common Uncommon Uncommon Not known Eye disorders Vision blurred Glaucoma Intraocular pressure increased Eye pain Rare Rare Rare Rare Cardiac disorders Atrial fibrillation Supraventricular tachycardia Rhythm idioventricular Tachycardia Supraventricular extrasystoles Palpitations Uncommon Uncommon Uncommon Uncommon Uncommon Uncommon Respiratory, thoracic and mediastinal disorders Cough Oropharyngeal pain Dysphonia Paradoxical bronchospasm Common Common Uncommon Rare Gastrointestinal disorders Constipation Dry mouth Common Common Musculoskeletal and connective tissue disorders Muscle spasms Uncommon Renal and urinary disorders Urinary retention Dysuria Bladder outlet obstruction Rare Rare Rare Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

1.

AND CLINICAL USE ............................................................................ 3 CONTRAINDICATIONS ................................................................................................ 4 WARNINGS AND PRECAUTIONS................................................................................

5 ADVERSE REACTIONS .............................................................................................. 14 DRUG INTERACTIONS .............................................................................................. 23 DOSAGE AND ADMINISTRATION ............................................................................

26 OVERDOSAGE............................................................................................................ 28 ACTION AND CLINICAL PHARMACOLOGY ............................................................ 29 STORAGE AND STABILITY .......................................................................................

38 SPECIAL HANDLING INSTRUCTIONS ...................................................................... 38 DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................. 39 PART II: SCIENTIFIC INFORMATION..............................................................................

40 PHARMACEUTICAL INFORMATION ........................................................................ 40 CLINICAL TRIALS...................................................................................................... 41 DETAILED PHARMACOLOGY ..................................................................................

56 TOXICOLOGY ............................................................................................................ 58 REFERENCES .............................................................................................................

66 PART III: CONSUMER INFORMATION ............................................................................ 67 Page 3 of 74 PrBREO ELLIPTA fluticasone furoate/vilanterol dry powder for oral inhalation PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form/Strength Nonmedicinal Ingredients Oral Inhalation Dry powder for oral inhalation/ 100 and 200 mcg fluticasone furoate/ 25 mcg vilanterol Lactose monohydrate (which contains milk protein) and magnesium stearate INDICATIONS AND CLINICAL USE COPD BREO ELLIPTA (fluticasone furoate/vilanterol) 100/25 mcg is a combination of an inhaled corticosteroid (ICS) and a long-acting beta2-adrenergic agonist (LABA), indicated for the long-term once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema, and to reduce exacerbations of COPD in patients with a history of exacerbations.

BREO ELLIPTA 100/25 mcg once daily is the only strength indicated for the treatment of COPD. BREO ELLIPTA 200/25 mcg is not indicated for patients with COPD. There is no additional benefit of the 200/25 mcg dose compared to the 100/25 mcg dose and there is a potential increased risk of pneumonia and systemic corticosteroid-related adverse reactions.

BREO ELLIPTA is not indicated for the relief of acute bronchospasm (see WARNINGS AND PRECAUTIONS, General). Page 4 of 74 Asthma BREO ELLIPTA 100/25 mcg and BREO ELLIPTA 200/25 mcg are indicated for the once-daily maintenance treatment of asthma in patients aged 18 years and older with reversible obstructive airways disease.

BREO ELLIPTA, an ICS/LABA combination, should be prescribed for patients not adequately controlled on a long-term asthma control medication, such as an ICS, or whose disease severity clearly warrants treatment with both an ICS and a LABA.

BREO ELLIPTA is not indicated for patients whose asthma can be managed by occasional use of a rapid onset, short duration, inhaled beta2-agonist or for patients whose asthma can be successfully managed by ICS along with occasional use of a rapid onset, short duration, inhaled beta2-agonist.

BREO ELLIPTA is not indicated for the relief of acute bronchospasm (see WARNINGS AND PRECAUTIONS, General).

Geriatrics:

No dosage adjustment is required in patients 65 years of age and older.

Pediatrics:

The safety and efficacy in pediatric patients younger than 18 years have not been established. CONTRAINDICATIONS  Patients who are hypersensitive to fluticasone furoate, vilanterol, or any ingredient in the formulation or component of the container (see DOSAGE FORMS, COMPOSITION AND PACKAGING).

 Patients with severe hypersensitivity to milk proteins (see WARNINGS AND PRECAUTIONS, Hypersensitivity).  In the primary treatment of status asthmaticus or other acute episodes of asthma. Page 5 of 74 WARNINGS AND PRECAUTIONS General Serious Asthma-Related Events – Hospitalizations, Intubations, Death Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death (see Salmeterol Multicenter Asthma Research Trial (SMART)).

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 Beta2-adrenergic Agonist Combination Products).

Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2- adrenergic Agonist Combination Products 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 […]

Dosing Considerations COPD and Asthma As with other inhaled drugs containing beta2-adrenergic agents, BREO 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.

d) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief if they develop acute respiratory symptoms while taking BREO ELLIPTA. It is crucial to inform patients that BREO ELLIPTA should not be used to treat acute symptoms of asthma or COPD.

, salbutamol) to relieve the acute symptoms such as shortness of breath and advised to have this available for use at all times. Patients should be made aware that for optimum benefit, BREO ELLIPTA must be used regularly, even when asymptomatic.

If a previously effective dose of BREO ELLIPTA fails to provide adequate control of asthma symptoms, patients should seek medical advice as this indicates worsening of their underlying condition. Asthma When treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants treatment with both an inhaled corticosteroid and LABA.

Patients with asthma should be regularly re-assessed by a healthcare professional so that the dose of BREO ELLIPTA they are receiving remains optimal and is only changed on medical advice. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained.

Page 27 of 74 Recommended Dose and Dosage Adjustment The recommended dose of BREO ELLIPTA in adults 18 years of age and older is: COPD Asthma BREO ELLIPTA 100/25 mcg One inhalation once daily One inhalation once daily BREO ELLIPTA 200/25 mcg Not indicated One inhalation once daily COPD The recommended dose is one inhalation of BREO ELLIPTA 100/25 mcg once daily.

The maximum recommended dose is one inhalation of BREO ELLIPTA 100/25 mcg once daily. BREO ELLIPTA 200/25 mcg is not indicated for the treatment of COPD. Asthma The recommended dose is one inhalation of BREO ELLIPTA 100/25 mcg or 200/25 mcg once-daily.

The maximum recommended dose is one inhalation of BREO ELLIPTA 200/25 mcg once daily. The starting dose is based on patients’ asthma severity. For patients previously treated with low- to mid-dose corticosteroid-containing treatment, BREO ELLIPTA 100/25 mcg should be considered.

For patients previously treated with mid- to high-dose corticosteroid-containing treatment, BREO ELLIPTA 200/25 mcg should be considered. For patients who do not respond adequately to one inhalation of BREO ELLIPTA 100/25 mcg once-daily, switching to one inhalation of BREO ELLIPTA 200/25 mcg once-daily may provide additional asthma control.

Administration BREO ELLIPTA should be administered once-daily at the same time every day (morning or evening) by oral inhalation only. Do not use BREO ELLIPTA more than once every 24 hours. After inhalation, patients should rinse their mouth with water (without swallowing).

Dosing in Special Populations Geriatrics No dosage adjustment is required in patients 65 years of age and older (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics). Page 28 of 74 Renal Insufficiency No dose adjustment is required for patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

Hepatic Insufficiency Fluticasone furoate systemic exposure (Cmax and AUC) increased by up to 3-fold in subjects with mild, moderate and severe hepatic impairment. Caution should be exercised when dosing patients with hepatic impairment as they may be more at risk of systemic adverse reactions associated with corticosteroids.

Patients should be monitored for corticosteroid-related side effects. No dosage adjustment is required for patients with mild hepatic impairment. For patients with moderate or severe hepatic impairment, the maximum dose is 100/25 mcg (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Missed Dose If a dose is missed, the patient should be instructed to take the next dose when it is due. The patient should be instructed not to take an extra dose. OVERDOSAGE BREO ELLIPTA contains both fluticasone furoate and vilanterol.

There is no specific treatment for an overdose with fluticasone furoate/vilanterol combination therapy. The risks associated with overdosage for the individual components described below therefore apply to BREO ELLIPTA. Further management should be as clinically indicated or as recommended by regional Poison Control centres, where available.

Fluticasone Furoate Chronic overdosage (use at excessive doses for prolonged periods) may result in signs/symptoms of hypercorticism (see WARNINGS AND PRECAUTIONS). The potential for acute toxic corticosteroid effects following overdosage with BREO ELLIPTA is low.

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. Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have shown fluticasone furoate to be well tolerated.

Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days. , angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, QTc […]