Aerivio Spiromax - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Aerivio Spiromax 50 micrograms/500 micrograms inhalation powder

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each metered dose contains 50 micrograms of salmeterol (as salmeterol xinafoate) and 500 micrograms of fluticasone propionate.

Each delivered dose (the dose from the mouthpiece) contains 45 micrograms of salmeterol (as salmeterol xinafoate) and 465 micrograms of fluticasone propionate.

Excipient(s) with known effect :

Each dose contains approximately 10 milligrams of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Inhalation powder.

White powder.

White inhaler with a semi-transparent yellow mouthpiece cover.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Aerivio Spiromax is indicated for

ults aged 18 years and older only.

Asthma

Aerivio Spiromax is indicated for the regular treatment of patients with severe asthma where use of a combination product (inhaled corticosteroid and long-acting P2 agonist) is appropriate:

• – patients not adequately controlled on a lower strength corticosteroid combination product or

• – patients already controlled on a high dose inhaled corticosteroid and long-acting P2 agonist.

Chronic Obstructive Pulmonary Disease (COPD)

Aerivio Spiromax is indicated for the 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.

4.2 Posology and method of administration

Aerivio Spiromax is indicated in adults 18 years of age and older only.

Aerivio Spiromax is not indicated for use in children, 12 years of age and younger or adolescents, 13 to 17 years of age.

Posology

Route of administration: Inhalation use

Patients should be made aware that Aerivio Spiromax must be used daily for optimum benefit, even when asymptomatic.

Patients should be regularly reassessed by a doctor, so that the strength of the salmeterol/flu­ticasone propionate inhaler 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. Aerivio Spiromax is not available on the market at strengths lower than 50/500 microgram. When it is appropriate to titrate down to a lower strength not available for Aerivio Spiromax, a change to an alternative fixed-dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled required.

Patients should be given a strength of salmeterol/flu­ticasone propionate inhaler containing the appropriate fluticasone propionate dosage for the severity of their disease. Aerivio Spiromax is only appropriate for use in the treatment of patients with severe asthma. If an individual patient should require dosages outside the recommended regimen, appropriate doses of P2 agonist and/or corticosteroid should be prescribed

Recommended doses:

Asthma

Adults aged 18 years and older.

One inhalation of 50 micrograms salmeterol and 500 micrograms fluticasone propionate twice daily.

Once control of asthma is attained treatment should be reviewed and consideration given as to whether patients should be stepped down to an alternative fixed-dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled corticosteroid and then ultimately to an inhaled corticosteroid alone. Regular review of patients as treatment is stepped down is important.

A clear benefit has not been shown as compared with inhaled fluticasone propionate alone used as initial maintenance therapy when one or two of the criteria of severity are missing. In general inhaled corticosteroids remain the first line treatment for most patients.

Aerivio Spiromax is for the treatment of patients with severe asthma only. It should not be used for the treatment of patients with mild or moderate asthma or for the initiation of treatment for patients with severe asthma unless the requirement for such a high dose of the corticosteroid together with a long-acting P2 agonist has been established previously.

Aerivio Spiromax is not intended as the treatment of asthma when a fixed-dose combination of salmeterol and fluticasone propionate is required for the first time. Patients should commence treatment with a fixed-

dose combination containing a lower dose of the corticosteroid component and will then be titrated up in respect of the corticosteroid dose until control of asthma is achieved. Once control of asthma is achieved patients should be reviewed regularly and the dose of inhaled corticosteroid titrated downwards as appropriate to maintain disease control.

It is recommended to establish the appropriate dosage of inhaled corticosteroid before any fixed-dose combination can be used in patients with severe asthma.

Paediatric population

Aerivio Spiromax is not recommended for use in either children aged 12 years of age and younger or in adolescents aged 13 to 17 years. The safety and efficacy of Aerivio Spiromax in children and adolescents aged less than 18 years of age has not been established.

No data are available.

COPD

One inhalation of 50 micrograms salmeterol and 500 micrograms fluticasone propionate twice daily.

Special patient groups

There is no need to adjust the dose in elderly patients or in those with renal impairment.

There are no data available on the use of Aerivio Spiromax in patients with hepatic impairmen

Method of administration/In­structions for use

The Spiromax device is a breath actuated, inspiratory flow-driven inhaler, which means that the active substances are delivered into the airways when the patient inhales through the mouthpiece. Patients with severe asthma and COPD were shown to be able to generate sufficient inspiratory flow rate when they breathed in forcefully through the Spiromax device to enable the delivery of the required therapeutic dose to the lungs (see also section 5.1 – last five paragraphs)

Required training

Aerivio Spiromax should be used correctly in order to achieve effective treatment. As such, the patients should be advised to read the patient information leaflet carefully and follow the instructions for use as detailed in the leaflet. All patients should be provided with training by the prescribing Health Care Professional on how to use Aerivio Spiromax. This is to ensure that they understand how to use the inhaler correctly, and so that they understand the need to breathe in forcefully when inhaling to obtain the required dose. It is important to inhale forcefully to ensure optimal dosing.

The use of Aerivio Spiromax follows three simple steps: open, breathe and close which are outlined below.

Open: Hold the Spiromax with the mouthpiece cover at the bottom and open the mouthpiece cover by folding it down until it is fully opened when one click is heard.

Breathe: Breathe out gently (as far as is comfortable). Do not breathe through your inhaler. Place the mouthpiece between the teeth with the lips closed around the mouthpiece, do not bite the mouthpiece of the inhaler. Breathe in forcefully and deeply through the mouthpiece. Remove the Spiromax device from the mouth and hold the breath for 10 seconds or as long as comfortable for the patients.

Close: Breathe out gently and close the mouthpiece cover.

Patients should not block the air vents at any time, or breathe out through the Spiromax device when they are preparing the “Breathe” step. Patients are not required to shake the inhaler prior to use.

Patients should also be advised to rinse their mouth with water and spit the water out, and/or brush their teeth

Patients may notice a taste when using Aerivio Spiromax due to the lactose excipient.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Asthma

Aerivio Spiromax is for use in patients with severe asthma only. It should not be used to treat acute asthma symptoms for which a fast- and short-acting bronchodilator is required. Patients should be advised to have their inhaler to be used for relief in an acute asthma attack available at all times.

Patients should not be initiated on Aerivio Spiromax during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

♦ c

Serious asthma-related adverse events and exacerbations may occur during treatment with Aerivio Spiromax. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Aerivio Spiromax.

Increased requirements for use of reliever medication (short-acting bronchodilators), or decreased response to reliever medication indicate deterioration of asthma control and patients should be reviewed by a physician.

Sudden and progressive deterioration in control of asthma is potentially life-threatening and the patient should undergo urgent medical assessment. Consideration should be given to increasing corticosteroid therapy.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of the inhaled corticosteroid and therefore a change to an alternative fixed-dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled corticosteroid is required. Regular review of patients as treatment is stepped down is important. The lowest dose of inhaled corticosteroid should be used.

COPD

For patients with COPD experiencing exacerbations, treatment with systemic corticosteroids is typically indicated, therefore patients should be instructed to seek medical attention if symptoms deteriorate with Aerivio Spiromax.

Cessation of therapy

Treatment with Aerivio Spiromax should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision. For patients with COPD cessation of therapy may also be associated with symptomatic decompensation and should be supervised by a physician.

Caution with special diseases

Aerivio Spiromax should be administered with caution in patients with active or quiescent pulmonary tuberculosis and fungal, viral or other infections of the airway. Appropriate treatment should be promptly instituted, if indicated.

♦J

Rarely, Aerivio Spiromax may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Aerivio Spiromax should be used with caution in patients with severe cardiovascular disorders or heart rhythm abnormalities and in patients with diabetes mellitus, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium.

There have been very rare reports of increases in blood glucose levels (see section 4.8) and this should be considered when prescribing to patients with a history of diabetes mellitus.

Paradoxical bronchospasm

Paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Aerivio Spiromax should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Peta 2 adrenoreceptor agonists

The pharmacological effects of p2 agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.

Systemic effects

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, 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) (see Paediatric population sub-heading below for information on the systemic effects of inhaled corticosteroids in children and adolescents). It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Adrenal function

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000 micrograms. Situations, which could potentially trigger acute adrenal crisis include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Therefore these patients should be treated with special care and adrenocortical function regularly monitored. Patients who have required high dose emergency corticosteroid therapy in the past may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures.

Interactions with other medicinal products

Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. There is also an increased risk of systemic undesirable effects when combining fluticasone propionate with other potent CYP3A inhibitors (see section 4.5).

Concomitant use of systemic ketoconazole significantly increases systemic exposure to salmeterol. This may lead to an increase in the incidence of systemic effects (e.g. prolongation in the QTc interval and palpitations). Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should therefore be avoided unless the benefits outweigh the potentially increased risk of systemic undesirable effects of salmeterol treatment (see section 4.5).

Respiratory tract infections

There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving salmeterol/flu­ticasone propionate 50/500 micrograms twice daily compared with placebo as well as in studies SCO40043 and SCO100250 comparing a lower dose of salmeterol/flu­ticasone propionate 50/250 micrograms twice daily, (a dose not authorised for use in COPD) with salmeterol 50 micrograms twice daily only (see section 4.8 and section 5.1). A similar incidence of pneumonia in the salmeterol/flu­ticasone propionate group was seen across all studies. In TORCH, older patients, patients with a lower body mass index (<25 kg/m2) and patients with very severe disease (FEV1<30% predicted) were at greatest risk of developing pneumonia regardless of treatment.

♦ c

Physicians should remain vigilant for the possible development of pneumonia and other lower respiratory tract infections in patients with COPD as the clinical features of such infections and exacerbation frequently overlap. If a patient with severe COPD has experienced pneumonia, treatment with Aerivio Spiromax should be re-evaluated.

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. If a patient with severe COPD has experienced pneumonia, treatment with Aerivio Spiromax should be re-evaluated.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Ethnic populations

Data from a large clinical trial (the Salmeterol Multi-Center Asthma Research Trial, SMART) suggested African-American patients were at increased risk of serious respiratory-related events or deaths when using salmeterol compared with placebo (see section 5.1). It is not known if this was due to pharmacogenetic or other factors. Patients of black African or Afro-Caribbean ancestry should therefore be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen whilst using Aerivio Spiromax.

Aerivio Spiromax is not indicated for use in children and adolescents under the age of 18 years (see Section 4.2). However, it should be noted that children and adolescents less than 16 years taking high doses of fluticasone propionate (typically > 1000 micrograms/day) may be at particular risk. Systemic effects may occur, particularly at high doses prescribed for long periods. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, acute adrenal crisis and growth retardation in children and adolescents and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression. Consideration should be given to referring the child or adolescent to a paediatric respiratory specialist. It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. The dose of inhaled corticosteroid should always be reduced to the lowest dose at which effective control of asthma is maintained.

Oral infections

Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat and, rarely of the oesophagus, can occur in some patients. Both hoarseness and the incidence of candidiasis of the mouth and throat may be relieved by rinsing the mouth with water and spitting the water out and/or brushing the teeth after using the product. Symptomatic candidiasis of the mouth and throat can be treated with topical anti-fungal therapy whilst still continuing with Aerivio Spiromax.

Excipients

This medicinal product contains lactose. Patients with severe lactose intolerance should use this medicine with caution and those with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. The excipient lactose may contain small amounts of milk proteins which may cause allergic reactions in those with severe hypersensitivity or allergy to milk protein.

4.5 Interaction with other medicinal products and other forms of interaction

Beta adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective an p blockers should be avoided unless there are compelling reasons for their use. Potentially serious hypokalaemia may result from p2 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.

Concomitant use of other p adrenergic-containing medicinal products can have a potentially additive effect.

Salmeterol

Potent CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and sal daily) in 15 healthy subjects for 7 days resulted in a significant increa fold Cmax and 15-fold AUC). This may lead to an increase in the incidence of other systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared with salmeterol or ketoconazole treatment alone (see section 4.4).

Clinically significant effects were not seen on blood pressure, heart rate, blood glucose and blood potassium levels. Co-administration with ketoconazole did not increase the elimination half-life of salmeterol or increase salmeterol accumulation with repeat dosing.

The concomitant administration of ketoconazole should be avoided, unless the benefits outweigh the potentially increased risk of systemic effects of salmeterol treatment. There is likely to be a similar risk of interaction with other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin, ritonavir).

Moderate CYP 3A4 inhibitors

Co-administration of erythromycin (500 mg orally three times a day) and salmeterol (50 micrograms inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically significant increase in salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.

Fluticasone propionate

Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.

In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly potent cytochrome P450 3A4 inhibitor) 100 mg twice daily increased the fluticasone propionate plasma concentrations several hundred fold, resulting in markedly reduced serum cortisol concentrations.

Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing’s syndrome and adrenal suppression have been reported. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid undesirable effects.

In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole increased the exposure of fluticasone propionate after a single inhalation by 150%. This resulted in a greater reduction of plasma cortisol as compared with fluticasone propionate alone. Co-treatment with other potent CYP3A inhibitors, such as itraconazole, and moderate CYP3A inhibitors, such as erythromycin, is also expected to increase the systemic fluticasone propionate exposure and the risk of systemic undesirable effects. Caution is

recommended and long-term treatment with such drugs should if possible be avoided.

Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increase risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid effects.

4.6 Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300 to 1000 pregnancy outcomes) indicates no malformative or feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of P2 adrenoreceptor agonists and glucocorticos­teroids (see section 5.3).

Administration of Aerivio Spiromax to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.

The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women.

Breastfeeding

It is unknown whether salmeterol and fluticasone propionate /metabolites are excreted in human milk.

e propionate and their metabolites, are excreted into the

A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue Aerivio Spiromax therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility.

4.7 Effects on ability to drive and use machines

erivio Spiromax has no or negligible influence on the ability to drive and use machines.

Summary of safety profile

As Aerivio Spiromax contains salmeterol and fluticasone propionate, the type and severity of adverse reactions associated with each of the active substance may be expected. There is no incidence of additional adverse events following concurrent administration of the two active substances.

Adverse reactions which have been associated with salmeterol/flu­ticasone propionate are given below, listed by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 to

<1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000) and not known (frequency cannot be estimated from the available data). Frequencies were derived from clinical trial data. The incidence in placebo was not taken into account.

• 1. Reported commonly in placebo

• 2. Reported very commonly in placebo

• 3. Reported over 3 years in a COPD study

• 4. See section 4.4

• 5. See section 5.1.

4.9 Overdose

There are no data available from clinical trials on overdose with Aerivio Spiromax, however data on

4.9 Overdose overdose with both active substances are given below:

Salmeterol

The signs and symptoms of salmeterol overdose are dizziness, increases in systolic blood pressure, tremor, headache and tachycardia. If Aerivio Spiromax therapy has to be withdrawn due to overdose of the p agonist component of the medicinal product, provision of appropriate replacement steroid therapy should be considered. Additionally, hypokalaemia can occur and therefore serum potassium levels should be monitored. Potassium replacement should be considered.

Fluticasone propionate

Acute: Acute inhalation of fluticasone propionate doses in ex temporary suppression of adrenal function. This does not need emergency action as adrenal function is recovered in a few days, as verified by plasma cortisol measurements.

Chronic overdose: Adrenal reserve should be monitored and treatment with a systemic corticosteroid may be necessary. When stabilised, treatment should be continued with an inhaled corticosteroid at the recommended dose. See section 4.4: “Adrenal function”.

In cases of both acute and chronic fluticasone propionate overdose Aerivio Spiromax therapy should be continued at a suitable dose for symptom control.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with corticosteroids or other drugs, excl. anticholinergics, ATC code: R03AK06

Mechanism of action and pharmacodynamic effects

Aerivio Spiromax contains salmeterol and fluticasone propionate, which have differing modes of action.

The respective mechanisms of action of both active substances are discussed below.

Salmeterol:

Salmeterol is a selective long-acting (12 hour) p2 adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor.

Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting p2 agonists.

Fluticasone propionate:

Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, with less adverse effects than when corticosteroids are administered systemically.

Clinical efficacy and safety

The studies described below (GOAL, TORCH and SMART) were carried out with this same fixed-dose combination, salmeterol xinafoate and fluticasone propionate, but studied a previously authorised product; the studies described were not carried out with Aerivio Spiromax.

Salmeterol/Flu­ticasone propionate – Asthma clinical trials

A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of salmeterol/flu­ticasone propionate versus inhaled corticosteroid (fluticasone propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with salmeterol/flu­ticasone propionate achieved asthma control than patients treated with inhaled corticosteroid (ICS) alone and this control was attained at a lower corticosteroid do­se.

Well controlled asthma was achieved more rapidly with salmeterol/flu­ticasone propionate than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual well controlled week was 16 days for salmeterol/flu­ticasone propionate compared with 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual well controlled week was 16 days in the salmeterol/flu­ticasone propionate treatment compared with 23 days following treatment with ICS.

The overall study results showed:

*Well controlled asthma – less than or equal to 2 days with symptom score greater than 1 (symptom score 1 defined as ‘symptoms for one short period during the day’), SABA use on less than or equal to 2 days and less than or equal to 4 occasions/week, greater than or equal to 80% predicted morning peak expiratory flow, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy

Total control of asthma – no symptoms, no SABA use, greater than or equal to 80% predicted morning peak expiratory flow, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy

The results of this study suggest that salmeterol/flu­ticasone propionate 50/100 micrograms twice daily may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2).

A double blind, randomised, parallel group study in 318 patients with persistent asthma aged >18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of salmeterol/flu­ticasone propionate for two weeks. The study showed that doubling the inhalations of each strength of salmeterol/flu­ticasone propionate for up to 14 days resulted in a small increase in P agonist-related adverse events (tremor – 1 patient [1%] vs 0, palpitations – 6 [3%] vs 1 [<1%], muscle cramps –6 [3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis – 6 [6%] vs 16 [8%], hoarseness – 2 [2%] vs 4 [2%]) compared with one inhalation twice daily. The small increase in P agonist-related adverse events should be taken into account if doubling the dose of salmeterol/flu­ticasone propionate is considered by the physician in adult patients requiring additional shortterm (up to 14 days) inhaled corticosteroid therapy.

Salmeterol/flu­ticasone propionate COPD – clinical trials

TORCH was a 3-year study to assess the effect of treatment with salmeterol/flu­ticasone propionate inhalation powder 50/500 micrograms twice daily, salmeterol inhalation powder 50 micrograms twice daily, fluticasone propionate (FP) inhalation powder 500 micrograms twice daily or placebo on all-cause mortality in patients with COPD. COPD patients with a baseline (pre-bronchodilator) FEV1 <60% of predicted normal were randomised to double-blind medication. During the study, patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids, long-acting bronchodilators and long-term systemic corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal from study medication. The primary endpoint was reduction in all-cause mortality at 3 years for salmeterol/flu­ticasone propionate vs placebo.

1. Non-significant p value after adjustment for 2 interim analyses on the primary efficacy comparison from a log-rank analysis stratified by smoking status

There was a trend towards improved survival in subjects treated with salmeterol/flu­ticasone propionate compared with placebo over 3 years however this did not achieve the statistical significance level p<0.05.

The percentage of patients who died within 3 years due to COPD-related causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for salmeterol/flu­ticasone propionate.

The mean number of moderate to severe exacerbations per year was significantly reduced with salmeterol/flu­ticasone propionate (FP) as compared with treatment with salmeterol, FP and placebo (mean rate in the salmeterol/flu­ticasone propionate group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the placebo). This translates to a reduction in the rate of moderate to severe exacerbations of 25% (95% CI: 19% to 31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively.

Health Related Quality of Life, as measured by the St George’s Respi­ratory Questionnaire (SGRQ) was improved by all active treatments in comparison with placebo. The average improvement over three years for salmeterol/flu­ticasone propionate compared with placebo was –3.1 units (95% CI: –4.1 to –2.1; p<0.001) and when compared with salmeterol was –2.2 units (p<0.001) and when compared with FP was –1.2 units (p=0.017). A 4-unit decrease is considered clinically relevant.

The estimated 3-year probability of having pneumonia reported as an adverse event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for FP and 19.6% for salmeterol/flu­ticasone propionate (hazard ratio for salmeterol/flu­ticasone propionate vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9 for salmeterol, 13 for FP and 8 for salmeterol/flu­ticasone propionate. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% salmeterol/flu­ticasone propionate; hazard ratio for salmeterol/flu­ticasone propionate vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.

Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of salmeterol/flu­ticasone propionate 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication.

Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of salmeterol/flu­ticasone propionate 50/250 micrograms twice daily (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms twice daily, on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation.

The trials had a 4 week run-in period during which all subjects received o standardize COPD pharmacotherapy and stabilise disease prior to random for 52 weeks. Subjects were randomised 1:1 to salmeterol/FP 50/250 (tota

ITT n=778). Prior to run-in, subjects discontinued use of previous bronchodilators. The use of concurrent inhaled long-acting P2 agoi

salbutamol/ipra­tropium bromide combination products, oral P2 agonists and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific g ines for use. Subjects used salbutamol on an as-needed basis throughout the studies.

The results of both studies showed that treatment with salmeterol/flu­ticasone propionate 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured salmeterol/flu­ticasone propionate 50/250 micrograms twice daily over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the salmeterol/flu­ticasone propionate 50/250 micrograms twice daily group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the salmeterol/flu­ticasone propionate 50/250 micrograms twice daily group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with salmeterol/flu­ticasone propionate 50/250 micrograms twice daily appears to be of similar magnitude to the incidence reported following treatment with salmeterol/flu­ticasone propionate 50/500 micrograms twice daily in TORCH.

The Salmeterol Multi-center Asthma Research Trial (SMART)

SMART was a multi-centre, randomised, double blind, placebo-controlled, parallel group 28-week study in the US which randomised 13,176 patients to salmeterol (50 micrograms twice daily) and 13,179 patients to placebo in addition to the patients’ usual asthma therapy. Patients were enrolled if >12 years of age, with asthma and if currently using asthma medication (but not a LABA). Baseline ICS use at study entry was recorded, but not required in the study. The primary endpoint in SMART was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences.

Key findings from SMART: primary endpoint

(Risk in bold is statistically significant at the 95% level.)

srP

(*=could not be calculated because of no events in placebo group. Risk in bold figures is statistically significant at the 95% level. The secondary endpoints in the table above reached statistical significance in the whole population.) The secondary endpoints of combined all cause death or life-threatening experience, all cause death, or all cause hospitalisation did not reach statistical significance in the whole population.

Peak Inspiratory Flow Rate through the Spiromax Device

A randomised, open-label cross-over study was performed in children and adolescents with asthma (aged 417 years), adults with asthma (aged 18–45 years), adults with chronic obstructive pulmonary disease (COPD) (aged older than 55 years) and healthy volunteers (aged 18–45 years) to evaluate the peak inspiratory flow rate (PIFR) and other related inhalation parameters following inhalation from a Spiromax device (containing placebo) compared with inhalation from an already marketed multi-dose dry powder inhaler device (containing placebo). The impact of optimal training (i.e. breathing in forcefully upon inhalation) in dry powder inhaler inhalation technique on inhalation speed and volume was assessed in these subject groups, together with assessment of potential differences in inhalation outputs according to the devices used.

The data from the study indicated that regardless of age and underlying disease severity, children, adolescents and adults with asthma as well as patients with COPD were able to achieve inspiratory flow rates through the Spiromax device that were similar to those generated through the marketed multi-dose dry powder inhaler device. The mean PIFR achieved by patients with asthma or COPD with optimal training (i.e. forceful inhalation) was over 60 L/min, a flow rate at which both devices studied are known to deliver comparable amounts of drug to the lungs.

All subjects with asthma or COPD achieved PIFR values greater than 60L/min after optimal training. It is important to inhale forcefully to ensure optimal dosing.

A flow rate of greater than 60L/min is required for optimal delivery of drugs to the lungs through the multidose dry powder Spiromax inhaler.

In order to ensure that patients achieve the PIFR needed to deliver the required dose, the patient is required to

be trained on the use of the Spiromax device including instruction on the need to inhale forcefully (see Section 4.2).

Paediatric population

Aerivio Spiromax is not recommended for use in children and adolescents aged less than 18 years. The safety and efficacy of Aerivio Spiromax in this young population have not been established. The data

presented below refer to a lower dose of the fixed-dose combination containing these two actives, a dose and strength which is not available for Aerivio Spiromax. The studies described were carried out with a previously authorised product available in three different strengths; the studies were not carr Aerivio Spiromax.

In a study in 158 children aged 6 to 16 years with symptomatic asthma, the combination of salmeterol/ fluticasone propionate is as efficacious as doubling the dose of fluticasone propionate in respect of symptom control and lung function. This study was not designed to investigate the effect on exacerbations.

In a 12-week trial of children aged 4 to 11 years [n=257] treated with either salmeterol/flu­ticasone propionate 50/100 or salmeterol 50 micrograms + fluticasone propionate 100 micrograms both twice daily, both treatment arms experienced a 14% increase in peak expiratory flow rate as well as improvements in symptom score and rescue salbutamol use. There were no differences between the two treatment arms. There were no differences in safety parameters between the two treatment arms.

In a 12-week trial of children 4 to 11 years of age [n=203] randomized in a parallel-group study with persistent asthma and who were symptomatic on inhaled corticosteroid, safety was the primary objective. Children received either salmeterol/flu­ticasone propionate (50/100 micrograms) or fluticasone propionate (100 micrograms) alone twice daily. Two children on salmeterol/flu­ticasone propionate and 5 children on fluticasone propionate withdrew because of worsening asthma. After 12 weeks no children in either treatment arm had abnormally low 24-hour urinary cortisol excretion. There were no other differences in safety profile between the treatment arms.

5.2 Pharmacokinetic properties

For pharmacokinetic purposes each component can be considered separately.

Salmeterol

Salmeterol acts l             lung therefore plasma levels are not an indication of therapeutic effects. In

addition there      ly limited data available on the pharmacokinetics of salmeterol because of the technical

difficulty of as       the drug in plasma due to the low plasma concentrations at therapeutic doses

(approximately 200 picogram/mL or less) achieved after inhaled dosing.

one propionate

olute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies approximately 5 to 11% of the nominal dose depending on the inhalation device used. In patients with asthma or COPD a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed.

Absorption

Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose of fluticasone propionate may be swallowed but contributes minimally to systemic exposure due to the low aqueous solubility and presystemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose.

Distribution

The disposition of fluticasone propionate is characterised by high plasma clearance (1150 mL/min), a large volume of distribution at steady-state (approximately 300 L) and a terminal half-life of approximately 8 hours. Plasma protein binding is 91%.

Biotransformation

Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in the faeces.

Elimination

The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted in mainly as metabolites. The main part of the dose is excreted in faeces as metabolites and unchanged drug.

Paediatric population

Aerivio Spiromax is not recommended for use in children and adolescents aged less than 18 years. The safety and efficacy of Aerivio Spiromax in this young population have not been established. The data presented below refer to a lower dose of the fixed-dose combination containing these two actives, a dose and strength which is not available for Aerivio Spiromax.

In a population pharmacokinetic analysis from 9 controlled clinical trials of 350 patients with asthma aged 4 to 77 years (174 patients 4 to 11 years of age) higher fluticasone propionate systemic exposure following treatment with salmeterol/flu­ticasone propionate inhalation powder 50/100 compared with fluticasone propionate inhalation powder 100 was seen.

5.3 Preclinical safety data

The only safety concerns for human use derived from animal studies of salmeterol and fluticasone propionate given separately were effects associated with exaggerated pharmacological actions.

In animal reproduction studies, glucocorticos­teroids have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant for man given recommended doses. Animal studies with salmeterol have shown embryofetal toxicity only at high exposure levels. Following co-administration, increased incidences of transposed umbilical artery and incomplete ossification of occipital bone were found in rats at doses associated with known glucocorticoid-induced abnormalities.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Lactose monohydrate.

.2 Incompatibilities

6.3 Shelf life 2 years.

After opening the foil wrap: 3 months.

6.4 Special precautions for storage

Do not store above 25°C.

Keep the mouthpiece cover closed after removal of the foil wrap.

6.5 Nature and contents of container

The inhaler is white with a semi-transparent yellow mouthpiece cover. The drug/mucosal contact parts of the inhaler are made of acrylonitrile butadiene styrene (ABS), polyethylene (PE) , and polypropylene (PP). Each inhaler contains 60 doses and is foil-wrapped.

Pack sizes of 1 or 3 inhalers.

Not all pack-sizes may be marketed.

6.6 Special precautions for disposal and other handlingNo special requirements.

7. MARKETING AUTHORISATION HOLDER

Teva B.V., Swensweg 5, 2031 GA Haarlem Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1122/001

EU/1/16/1122/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18th August 2016