GSK gets EU approval for labelling update to Relvar Ellipta for asthma

London: GlaxoSmithKline plc (GSK) and Innoviva, Inc. announced that the European Commission has approved a label update for the use of once-daily Relvar Ellipta (fluticasone furoate/vilanterol, FF/VI), an inhaled corticosteroid (ICS) / long-acting β2-agonist (LABA) combination, in patients whose asthma is already adequately controlled on both an inhaled corticosteroid and long-acting β2-agonist.

The Type II variation regulatory approval has been supported by data from a non-inferiority lung function study, which demonstrated that patients with adequately controlled asthma were able to switch to the once-daily FF/VI 100/25, from the twice-daily Seretide Accuhaler (fluticasone propionate /salmeterol, FP/SAL) 250/50, without compromising their lung function. No new safety signals were identified and the adverse event data were consistent with the known safety profile for FF/VI established in patients with asthma.

Jonathan Sweeting, SVP, and Head of Global Respiratory Franchise GSK said: "Patients with asthma can continue to experience symptoms despite being adequately controlled and these symptoms can impact their lives. This label update gives doctors the option of switching appropriate patients from their current ICS/LABA to once-daily Relvar Ellipta.”

Dr. Theodore J. Witek Jr., Senior Vice President and Chief Scientific Officer of Innoviva, Inc., added: “The evidence supporting this regulatory update means doctors can be confident that patients taking once-daily Relvar Ellipta will experience comparable benefit in lung function and safety profile, as with a twice-daily ICS/LABA. We welcome this approval, which signifies an important milestone for Relvar Ellipta.”

The updated marketing authorization by the European Commission will be reflected in the label for Relvar Ellipta for countries in the European Union.

About Relvar Ellipta (fluticasone furoate + vilanterol)

Relvar Ellipta is a once-daily dual combination treatment comprising fluticasone furoate, an inhaled corticosteroid and vilanterol, a long-acting β2-agonist, in a single inhaler, the Ellipta®.

Relvar Ellipta is indicated in Europe for the regular treatment of asthma in adults and adolescents aged 12 years and older where use of a combination medicinal product (long-acting beta2–agonist, and inhaled corticosteroid) is appropriate: patients not adequately controlled with inhaled corticosteroids and 'as-needed' inhaled short-acting beta2-agonists; patients already adequately controlled on both inhaled corticosteroid and long-acting beta2-agonist.

Important safety information for Relvar Ellipta in Europe

FF/VI is contraindicated in patients with hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients.

FF/VI should not be used to treat acute asthma symptoms or an acute exacerbation in COPD, for which a short-acting bronchodilator is required. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.

Patients should not stop therapy with FF/VI in asthma or COPD, without physician supervision since symptoms may recur after discontinuation.

Asthma-related adverse events and exacerbations may occur during treatment with FF/VI. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of treatment with FF/VI.

Paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a short-acting inhaled bronchodilator. FF/VI should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Cardiovascular effects, such as cardiac arrhythmias e.g. supraventricular tachycardia and extrasystoles may be seen with sympathomimetic medicinal products including FF/VI. Therefore fluticasone furoate/vilanterol should be used with caution in patients with severe cardiovascular disease.

For patients with moderate to severe hepatic impairment, the 92/22 mcg dose should be used and patients should be monitored for systemic corticosteroid-related adverse reactions. FF/VI 184/22 mcg is not indicated for patients with COPD. There is no additional benefit of the 184/22 mcg dose compared to the 92/22 mcg dose and there is a potential increased risk of pneumonia and systemic corticosteroid-related adverse reactions.

An increase in the incidence of pneumonia has been observed in subjects with COPD receiving FF/VI. There was also an increased incidence of pneumonias resulting in hospitalisation. In some instances these pneumonia events were fatal.

The incidence of pneumonia in patients with asthma was common at the higher dose. In a previous study of FF/VI in asthma the incidence of pneumonia in patients with asthma taking FF/VI 184/22 mcg was numerically higher compared with those receiving FF/VI 92/22 mcg or placebo.

Hyperglycaemia: There have been reports of increases in blood glucose levels in diabetic patients and this should be considered when prescribing to patients with a history of diabetes mellitus.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

FF/VI should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections. Data from large asthma and COPD clinical trials were used to determine the frequency of adverse reactions associated with FF/VI.

Very common adverse reactions (occurring in >1/10 patients) with FF/VI were headache and nasopharyngitis. Common adverse reactions (occurring in >1/100 to <1/10 patients) were pneumonia, upper respiratory tract infection, bronchitis, influenza, candidiasis of mouth and throat, oropharyngeal pain, sinusitis, pharyngitis, rhinitis, cough, dysphonia, abdominal pain, arthralgia, back pain, fractures, and pyrexia and muscle spasms.

Extrasystoles were observed as an uncommon adverse reaction (occurring in >1/1,000 to <1/100 patients). Rare adverse reactions (occurring in >1/10,000 to < 1/1,000) were hypersensitivity reactions (including anaphylaxis, angioedema, rash and urticaria), anxiety, tremor, palpitations, tachycardia and paradoxical bronchospasm.

With the exception of pneumonia and fractures, the safety profile was similar in patients with asthma and COPD. During clinical studies, pneumonia and fractures were more frequently observed in patients with COPD.

Relvar Ellipta is known as Breo Ellipta in the United States.

Full US prescribing information is available at us.gsk.com or US Prescribing Information for Breo Ellipta.

About Seretide Accuhaler (fluticasone propionate + salmeterol)

Seretide Accuhaler is a twice-daily dual combination treatment comprising fluticasone propionate /salmeterol, in the Accuhaler inhaler.

Seretide Accuhaler is indicated in Europe in the regular treatment of patients aged 4 and over with asthma, where use of a combination product (long-acting β2–agonist, LABA, and inhaled corticosteroid, ICS) is appropriate: Patients not adequately controlled on both ICS and 'as-needed' short-acting β2-agonist (SABA); Patients already adequately controlled on both ICS and LABA.

Important safety information for Seretide Accuhaler

Uses: Asthma: Regular treatment of asthma, where a long-acting β2 agonist and inhaled corticosteroid is appropriate, i.e. patients uncontrolled on inhaled corticosteroids and 'as needed' short-acting inhaled bronchodilator or patients controlled on inhaled corticosteroid and long-acting β2 agonist.

Lowest strength Seretide (salmeterol 25mcg/fluticasone propionate 50 mcg and salmeterol 50mcg/fluticasone propionate 100 mcg) not appropriate in severe asthma. COPD: Symptomatic treatment of patients with COPD with a FEV1 <60% predicted normal (pre-bronchodilator) and a history of repeated exacerbations, who have significant symptoms despite regular bronchodilator therapy.

Dosage and administration: Inhalation only. Asthma: Adults and adolescents 12 years and over: Seretide Accuhaler - one inhalation b.d. of: Seretide 100 (salmeterol 50 mcg/fluticasone propionate 100 mcg) or Seretide 250 (salmeterol 50 mcg/fluticasone propionate 250 mcg) or Seretide 500 (salmeterol 50 mcg/fluticasone propionate 500 mcg), Seretide Evohaler – two puffs b.d. of:

Seretide 50 (salmeterol 25 mcg/fluticasone propionate 50 mcg) or Seretide 125 (salmeterol 25 mcg/fluticasone propionate 125mcg) or Seretide 250 (salmeterol 25 mcg/fluticasone propionate 250 mcg). Children 4-11 years: Seretide 50 Evohaler (salmeterol 25 mcg/fluticasone propionate 50 mcg): two puffs b.d. Spacer recommended for co-ordination. Seretide 100 Accuhaler (salmeterol 50 mcg/fluticasone propionate 100 mcg) one inhalation b.d. Regularly review patients and reduce dose to lowest that maintains effective symptom control.

Where the control of symptoms is maintained with the lowest strength of the combination, patients may be prescribed an inhaled corticosteroid alone, or if a long-acting β2 agonist is required, Seretide may be given once daily.

If rapid control of asthma in adults or adolescents with moderate persistent asthma (defined as patients with daily symptoms, daily rescue use and moderate to severe airflow limitation) is essential, an initial dose of two inhalations b.d of Seretide 50 Evohaler (salmeterol 25 mcg/fluticasone propionate 50 mcg) or one inhalation b.d of Seretide 100 Accuhaler (salmeterol 50 mcg/fluticasone propionate 100 mcg) may be considered on a short-term basis.

Once control of asthma is attained treatment should be regularly reviewed and stepped down. Doubling the dose of all strengths of Seretide may be considered when adult patients require additional short-term (up to 14 days) inhaled corticosteroid therapy but this causes a small increase in β-agonist-related adverse events. COPD: one inhalation b.d. of Seretide 500 Accuhaler (salmeterol 50mcg/fluticasone propionate 500 mcg).

Contraindications: Hypersensitivity to the active ingredients or to any of the excipients.

Precautions: Pulmonary tuberculosis, fungal, viral or other infections of the airway, severe cardiovascular disorders, heart rhythm abnormalities, diabetes mellitus, hypokalaemia and thyrotoxicosis. Increased reporting of pneumonia and bronchitis in patients with COPD receiving Seretide compared with placebo.

If a patient with severe COPD has experienced pneumonia, treatment with Seretide should be re-evaluated. Paradoxical bronchospasm post dose. Severe unstable asthma: Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases. Consider increased inhaled/additional corticosteroid therapy. Acute symptoms: Not for acute symptoms.

Use short-acting inhaled bronchodilator. Systemic effects: Systemic effects of inhaled corticosteroids may occur, particularly at high doses for prolonged periods, but much less likely than with oral corticosteroids. May include Cushing’s syndrome, cushingoid features, adrenal suppression, adrenal crisis, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma and, more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

Monitor height of children on prolonged inhaled corticosteroid therapy. Tremor, palpitations and headache, have been reported with β2 agonist treatment. In asthma, therapy should be down titrated under physician supervision to lowest effective dose and treatment should not be abruptly stopped due to risk of exacerbation. Serious asthma-related adverse events and exacerbations may occur during treatment with Seretide.

Patients should not be initiated on Seretide during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma. Data from a large asthma trial suggested patients of black African or Afro-Caribbean ancestry were at increased risk of serious respiratory-related events or deaths when using salmeterol.

All patients should continue treatment but seek medical advice if asthma symptoms remain uncontrolled or worsen when initiated on Seretide or using Seretide. In COPD cessation of therapy may also be associated with decompensation and should be supervised by a physician. Transfer from oral steroids: Special care needed. Consider appropriate steroid therapy in stressful situations.

Drug interactions: Avoid beta-blockers. Avoid concomitant administration of ketoconazole or other potent (e.g. itraconazole, telithromycin, ritonavir) and moderate (erythromycin) CYP3A4 inhibitors unless benefits outweigh potential risk. β2 adrenergic blockers may weaken or antagonise the effect of salmeterol.

Potentially serious hypokalaemia may result from 2 agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics.

Pregnancy and lactation: Experience limited. Balance risks against benefits.

Side effects: Very Common: headache, nasopharyngitis. Common: candidiasis of the mouth and throat, hoarseness/dysphonia, throat irritation, pneumonia, bronchitis, hypokalaemia, sinusitis, contusions, traumatic fractures, arthralgia, myalgia, muscle cramps.

Uncommon: respiratory symptoms (dyspnoea), anxiety, tremor, palpitations, tachycardia, angina pectoris, atrial fibrillation, cutaneous hypersensitivity reactions, hyperglycaemia, sleep disorders, cataract.

Rare: angioedema, respiratory symptoms (bronchospasm), anaphylactic reactions including anaphylactic shock, Cushings syndrome, cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, oesophageal candidiasis, behavioural changes including psychomotor hyperactivity and irritability (predominately in children), glaucoma, cardiac arrhythmias and paradoxical bronchospasm. Not known: depression or aggression (particularly in children). Paradoxical bronchospasm: substitute alternative therapy.