FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA 250 µg/50 µg/dose Inhalation Powder in Unit-Dose Container 1 Available/60 dose

Inhalation powder in single-dose container.

Molded plastic device containing an aluminium strip with 60 blisters, placed at regular intervals. Each blister contains a measured dose of a white to off-white inhalation powder.

Each inhalation delivers a dose (at the mouthpiece) of 229 micrograms of fluticasone propionate and 45 micrograms of salmeterol (as salmeterol xinafoate), which corresponds to a metered dose of 250 micrograms of fluticasone propionate and 50 micrograms of salmeterol (as salmeterol xinafoate).

Excipient with known effect

Each delivered dose contains approximately 13 milligrams of lactose (monohydrate).

For the full list of excipients, see section Composition.

Excipients:

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA is indicated in adults and adolescents aged 12 years and over.

Asthma

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA is indicated for the continuous treatment of asthma, in situations where inhaled administration of a medicine combining a corticosteroid and a long-acting β2 agonist bronchodilator is justified:

• in patients inadequately controlled by inhaled corticosteroid therapy and the "as-needed" use of an inhaled short-acting β2 agonist bronchodilator

or

• in patients controlled by inhaled corticosteroid administration combined with continuous treatment with an inhaled long-acting β2 agonist.

Note: the FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA 100 micrograms/50 micrograms/dose strength is not suitable for the treatment of severe asthma in adults and children.

Dosage

The patient should be informed that, in order to achieve an optimal effect of treatment, FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA must be administered daily even when symptoms have improved.

The physician should regularly check that the prescribed dose of FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA is well suited to the patient's clinical condition. It should only be modified on medical advice. The minimum effective dosage should always be sought. When symptoms are controlled by the lowest recommended dosage in two intakes per day, administration of an inhaled corticosteroid alone will then be considered.

It may also be considered to reduce the dosage of FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA to one intake per day, if the physician deems it necessary to maintain a long-acting β2 mimetic treatment for symptom control. The timing of the intake of FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA will then depend on the frequency of symptom occurrence. If the symptoms predominantly occur at night, FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA will be administered in the evening; if they predominantly occur during the day, FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA will be administered in the morning.

The strength of FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA prescribed to the patient should correspond to the dose of fluticasone propionate adapted to the severity of their asthma. If the available strengths of this fixed combination do not meet the needs to adjust dosages according to the patient's condition, β2 agonists and/or corticosteroids should be prescribed individually.

Recommended doses:

Asthma

Adults and adolescents aged 12 years and older:

• One inhalation of 250 micrograms of fluticasone propionate and 50 micrograms of salmeterol twice daily.

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA may be considered as initiation treatment during a short trial period in adults and adolescents with moderate persistent asthma (defined by daytime symptoms, daily use of a short-acting bronchodilator as rescue symptomatic treatment, and moderate to severe bronchial obstruction) in whom rapid control of asthma is considered essential. In these cases, the recommended initial dose is one inhalation of 100 micrograms of fluticasone propionate and 50 micrograms of salmeterol, twice daily. Once control of asthma is achieved, treatment should be reassessed with a view to reducing therapy to an inhaled corticosteroid alone. It is important that patients are followed up regularly during the treatment reduction period.

No clear benefit has been established compared with treatment with fluticasone propionate inhaled alone, when one to two of the severity criteria mentioned above are not present. In the majority of cases, the first-line treatment remains the administration of inhaled corticosteroids alone.

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA is not intended for first-line treatment of mild asthma. The 100 microgram/50 microgram strength of FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA is not suitable for adults and children with severe asthma; the appropriate dose of inhaled corticosteroids should be adjusted individually before initiating treatment with a fixed combination in patients with severe asthma.

Paediatric population

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA is not recommended in children under 12 years of age. The safety and efficacy of FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA in children under 12 years of age have not been established.

Special patient groups

No dose adjustment is necessary in elderly subjects or in patients with renal impairment.

No data are available on the use of FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA in patients with hepatic impairment.

Method of administration

Inhalation route.

Training required

FLUTICASONE/SALMETEROL ZENTIVA must be used correctly to allow effective treatment. It is therefore advisable to recommend that patients read the leaflet carefully and follow the instructions for use detailed therein. The prescribing healthcare professional must provide the patient with appropriate instructions for correct use of FLUTICASONE/SALMETEROL ZENTIVA, particularly if the inhalation device is being used for the first time. It is important to verify that the patient uses the inhaler correctly.

Using FLUTICASONE/SALMETEROL ZENTIVA involves three simple steps, described below:

1. The device must be opened by pressing the red safety button and primed by sliding the cover of the pink mouthpiece until a click is heard.

2. The patient must first breathe out. The mouthpiece must be placed in the mouth and the lips must be closed tightly around it. The patient must then breathe in deeply through the mouth and as forcefully as possible. The patient must then remove the inhaler from the mouth and hold their breath for 10 seconds or for as long as they can without discomfort.

3. The patient must then breathe out gently and close the inhaler cover until a click is heard.

The patient must then rinse the mouth with water, then spit out the water and/or brush the teeth.

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

Deterioration of the disease

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA must not be used to treat acute asthma symptoms that require a fast-acting, short-acting bronchodilator. The patient should be warned of the need to always have their inhaler available to relieve an acute asthma attack.

Treatment with FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA must not be initiated during an asthma exacerbation or during a period of significant worsening or acute deterioration of asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA. Patients should be informed that if asthma symptoms persist or worsen during treatment with FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA, they should continue treatment but seek advice from their doctor.

An increase in the consumption of fast-acting, short-acting bronchodilator medicines (called "rescue medicines") or a decrease in the response to them is a sign of destabilisation of the disease. In this case, the patient should consult their doctor.

A more or less rapid deterioration in symptom control should raise concern about progression to asthma that may be life-threatening and therefore requires urgent medical consultation. Consideration should then be given to increasing corticosteroid therapy.

Once asthma symptoms are controlled, a gradual reduction of the FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA dose should be considered. It is important that patients are monitored regularly during the period of treatment reduction. The minimum effective dose of FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA should be used (see section Dosage and administration).

Discontinuation of treatment

In asthmatic patients, treatment with FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA must not be stopped abruptly due to the risk of exacerbation. Furthermore, the minimum effective dose should always be sought under medical supervision.

Precautions with certain associated diseases

As with other corticosteroids intended for inhaled administration, FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA should be used with caution in patients with active or quiescent pulmonary tuberculosis, fungal and viral infections, or other respiratory tract infections. Appropriate treatment should be initiated promptly, if necessary.

Cardiovascular effects

Rarely, FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA may cause cardiac rhythm disturbances such as supraventricular tachycardia, extrasystoles and atrial fibrillation, as well as a moderate and transient decrease in serum potassium at high therapeutic doses. FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA should be used with caution in patients with severe cardiovascular disease or cardiac rhythm disorders, and in patients with diabetes, hyperthyroidism, uncorrected hypokalaemia, or at risk of hypokalaemia.

Hyperglycaemia

Increases in blood glucose have very rarely been reported (see section Adverse effects). This should be taken into account when prescribing to patients with a history of diabetes.

Paradoxical bronchospasm

As with other inhaled treatments, paradoxical bronchospasm may occur, characterised by an increase in wheezing and shortness of breath immediately after administration. Paradoxical bronchospasm must be treated immediately with a fast-acting, short-acting bronchodilator. Administration of FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA should then be stopped immediately, the patient's condition assessed, and an alternative treatment initiated if necessary.

Beta-2 adrenergic receptor agonists

The pharmacological adverse effects of β2 agonists, such as tremors, palpitations and headaches have been reported, but these effects are generally transient and diminish with regular treatment.

Excipients

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA contains approximately 13 mg/dose of lactose monohydrate. This amount does not normally cause problems in people with lactose intolerance. The lactose excipient contains small amounts of milk proteins, which may cause allergic reactions.

Systemic effects of corticosteroid therapy

Inhaled corticosteroid therapy may cause systemic effects, particularly during long-term treatment at high doses. However, the occurrence of these effects is less likely than during oral corticosteroid therapy. Cushing's syndrome, Cushingoid features, adrenal suppression, decreased bone mineral density, cataract and glaucoma may be observed and, more rarely, various psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children) (see the subsection Paediatric population below for more information on the systemic effects of inhaled corticosteroids in children and adolescents). Consequently, the patient should be monitored regularly and the minimum effective dose ensuring effective asthma control should always be sought.

Adrenal function

Prolonged administration of high doses of corticosteroids by inhalation may cause inhibition of adrenal function and acute adrenal insufficiency. Cases of inhibition of adrenal function and acute adrenal insufficiency have also been very rarely reported with doses of fluticasone propionate between 500 and 1 000 micrograms. Episodes of acute adrenal insufficiency may be triggered by trauma, surgery, infection or any rapid reduction in dosage. The clinical picture is usually atypical and may include anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, hypotension, impaired consciousness, hypoglycaemia and convulsions. In cases of stress or when surgery is planned, systemic corticosteroid supplementation should be considered.

Administration of fluticasone propionate by inhalation promotes a reduction in the need for oral corticosteroids to treat asthma, but it does not prevent the risk of adrenal insufficiency occurring when patients on long-term oral corticosteroid therapy are weaned. Consequently, these patients should be treated with caution and their corticosteroid-adrenal function should be regularly monitored. This risk also exists in patients who have received high doses of corticosteroids in emergency situations.

The risk of persistent inhibition of adrenal function should be kept in mind in emergency situations and/or situations likely to trigger a state of stress. Appropriate replacement corticosteroid therapy should be considered. The extent of adrenal insufficiency may require specialist advice before non-urgent procedures.

Interactions with other medicinal products

Ritonavir may considerably increase the plasma concentration of fluticasone propionate. Therefore, concomitant administration of these medicines should be avoided, unless the expected benefit to the patient outweighs the risk of systemic corticosteroid adverse effects. The risk of systemic adverse effects is also increased when fluticasone propionate is combined with other potent CYP3A inhibitors (see section Interactions).

Concomitant systemic administration of ketoconazole significantly increases systemic exposure to salmeterol, which may lead to an increased risk of systemic effects (for example, QTc interval prolongation and palpitations). Therefore, concomitant administration of ketoconazole or other potent CYP3A4 inhibitors should be avoided unless the expected benefits outweigh the potential risk of systemic salmeterol effects (see section Interactions).

Visual disorders

Visual disturbances may occur with systemic or topical corticosteroid therapy. If blurred vision or any other visual symptoms occur during corticosteroid therapy, an ophthalmological examination is required to look for cataract, glaucoma or rarer conditions such as central serous chorioretinopathy (CSC), which have been described with systemic or topical corticosteroid administration.

Paediatric population

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA is not recommended in children under 12 years (see section Dosage and administration).

Adolescents under 16 years receiving high doses of fluticasone propionate (generally ≥ 1 000 micrograms/day) are particularly at risk. Systemic effects may occur, particularly during long-term treatment at high doses. Cushing's syndrome, Cushingoid features, adrenal suppression, acute adrenal insufficiency and growth retardation in adolescents may be observed and, more rarely, various psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression. The adolescent should then be referred to a paediatric specialist in pulmonology.

The growth of adolescents receiving long-term inhaled corticosteroid therapy should be regularly monitored. Inhaled corticosteroid therapy should be reduced to the lowest dose ensuring effective asthma control.

Adrenergic β-blockers may reduce or antagonise the effect of salmeterol. β-blockers, whether selective or non-selective, should be avoided in patients with asthma, unless absolutely necessary. Potentially serious hypokalaemia may occur following treatment with β-agonists2. Particular attention is recommended in cases of severe acute asthma because of the risk of aggravation of this hypokalaemia by concomitant treatment with xanthine derivatives, steroids and diuretics.

Concomitant administration of other β-adrenergics may potentiate the effects of β2-mimetics.

Fluticasone propionate

Under normal conditions of use, plasma concentrations of fluticasone propionate reached after inhaled administration are low due to a significant presystemic first-pass effect (hepatic and intestinal) and a high plasma clearance through extensive metabolism mediated by cytochrome CYP3A4. Consequently, clinically significant interactions with other active substances mediated by fluticasone propionate are unlikely.

An interaction study in healthy volunteers receiving intranasal fluticasone propionate showed that ritonavir (a very potent inhibitor of cytochrome CYP3A4) at a dose of 100 mg twice daily increased plasma concentrations of fluticasone propionate several hundred-fold, resulting in a marked decrease in plasma cortisol concentrations.

There is no data documenting the interaction with inhaled fluticasone propionate, but a substantial increase in plasma concentrations of fluticasone propionate is expected. Cases of Cushing's syndrome and adrenal suppression have been reported. Concomitant administration of fluticasone propionate and ritonavir should therefore be avoided, unless the benefit outweighs the increased risk of systemic corticosteroid effects.

A small study in healthy volunteers showed that ketoconazole, a somewhat less potent inhibitor of CYP3A4, increased the systemic exposure to a dose of inhaled fluticasone propionate by 150 %. The reduction in plasma cortisol was greater than that observed after administration of fluticasone propionate alone. An increase in systemic exposure and in the risk of systemic adverse effects is expected with concomitant administration of other potent CYP3A4 inhibitors (for example, itraconazole and cobicistat-containing medicinal products) and moderate CYP3A inhibitors (for example, erythromycin). Concomitant administration should be avoided, unless the expected benefits outweigh the increased risk of systemic corticosteroid side effects. In that case, patients should be monitored for possible systemic corticosteroid side effects.

Salmeterol

Potent inhibitors of CYP3A4

Concomitant administration of ketoconazole (400 mg orally once daily) and salmeterol (50 micrograms by inhalation twice daily) in 15 healthy volunteers for 7 days resulted in a significant increase in plasma salmeterol concentrations (maximum concentration [Cmax] increased by a factor of 1,4 and area under the curve [AUC] increased by a factor of 15). This observation therefore suggests an increased risk of occurrence of systemic salmeterol effects, such as QTc interval prolongation and palpitations, compared with administration of salmeterol or ketoconazole alone (see section Warnings and precautions).

No clinically significant effect on blood pressure, heart rate, blood glucose and serum potassium was observed. Concomitant administration of ketoconazole did not result in prolongation of the elimination half-life of salmeterol nor its accumulation after repeated administration.

Co-administration of ketoconazole with salmeterol treatment should be avoided unless the expected benefit outweighs the potential risk of systemic salmeterol effects. A similar interaction risk is expected with other potent CYP3A4 inhibitors (for example, itraconazole, telithromycin, ritonavir).

Moderate inhibitors of CYP3A4

Concomitant administration of erythromycin (500 mg orally three times daily) and salmeterol (50 micrograms by inhalation twice daily) in 15 healthy volunteers for 6 days resulted in a slight, but not statistically significant, increase in plasma salmeterol concentrations (Cmax increased by a factor of 1,4 and AUC increased by a factor of 1,2). No serious adverse effects were associated with concomitant administration of erythromycin.

Fertility

No data are available in humans. However, animal studies showed no effect of fluticasone propionate or salmeterol on fertility.

Pregnancy

A large amount of data obtained in pregnant women (more than 1 000 documented pregnancies) does not report malformative or foetal/neonatal toxicity associated with fluticasone propionate and salmeterol. Animal reproduction studies have shown toxicity of β2 mimetics and glucocorticoids (see section Preclinical safety).

The use of FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA during pregnancy should only be considered if the expected benefit to the mother outweighs any potential risk to the foetus.

In pregnant women, the minimum effective dose of fluticasone propionate providing satisfactory control of asthma symptoms should always be sought.

Breast-feeding

The passage of fluticasone propionate and salmeterol and their metabolites into breast milk is not known.

Studies have shown that fluticasone propionate and salmeterol, and their metabolites, are excreted in the milk of lactating rats.

A risk to breastfed newborns/infants cannot be excluded. The decision to discontinue breastfeeding or treatment with FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA should be made taking into account the expected benefit of breastfeeding for the child against the benefit of treatment for the breastfeeding woman.

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA contains fluticasone propionate and salmeterol, whose adverse effects (type and severity) associated with each of these active substances are expected. No new adverse events are observed after concomitant administration of the two active substances.

Adverse events attributed to the fluticasone propionate/salmeterol combination are listed below, by system organ class and by frequency. Frequencies are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1 000, < 1/100), rare (≥ 1/10 000, < 1/1 000) and not known (cannot be estimated from the available data). Frequencies were defined based on clinical trials. The corresponding incidence in the placebo arm was not taken into consideration.

System organ class	Adverse event	Frequency
Infections and infestations	Oral and pharyngeal candidiasis	Common
	Oesophageal candidiasis	Rare
Immune system disorders	Hypersensitivity reactions of the following types:
	Cutaneous hypersensitivity reactions	Uncommon
	Angioedema (mainly facial and oropharyngeal edema)	Rare
	Respiratory symptoms (dyspnea)	Uncommon
	Respiratory symptoms (bronchospasm)	Rare
	Anaphylactic reactions including anaphylactic shock	Rare
Endocrine disorders	Cushing's syndrome, Cushingoid appearance, inhibition of adrenal function, slowing of growth in children and adolescents, decreased bone mineral density	Rare2
Metabolism and nutrition disorders	Hyperglycaemia	Uncommon4
Psychiatric disorders	Anxiety	Uncommon
	Sleep disturbances	Uncommon
	Behavioral changes including psychomotor hyperactivity and irritability (mainly in children)	Rare
	Depression, aggressiveness (mainly in children)	Frequency not known
Nervous system disorders	Headache	Very common1
	Tremors	Uncommon
Eye disorders	Cataract	Uncommon
	Glaucoma	Rare2
	Blurred vision (see also section Warnings and precautions)	Frequency not known4
Cardiac disorders	Palpitations	Uncommon
	Tachycardia	Uncommon
	Cardiac arrhythmias (including supraventricular tachycardia and extrasystoles)	Rare
	Atrial fibrillation	Uncommon
	Angina pectoris	Uncommon
Respiratory, thoracic and mediastinal disorders	Pharyngeal discomfort	Common
	Hoarseness of voice/dysphonia	Common
	Paradoxical bronchospasm	Rare2
Musculoskeletal and systemic disorders	Muscle cramps	Common
	Arthralgia	Common
	Myalgia	Common

1 Frequently reported in placebo groups.

2 See section Warnings and precautions.

Description of selected adverse reactions

Side effects related to the β-mimetic pharmacological properties have been reported, such as tremor, palpitations and headache.2 They are most often transient and decrease with continued treatment.

As with other inhaled treatments, paradoxical bronchospasm may occur, characterised by an increase in wheezing and shortness of breath immediately after administration. Paradoxical bronchospasm must be treated immediately with a fast-acting, short-acting bronchodilator. All administration of PROPIONATE DE FLUTICASONE/SALMETEROL ZENTIVA should then be stopped, the patient's condition assessed, and an alternative treatment initiated if necessary.

Adverse effects associated with fluticasone propionate, such as hoarseness of voice and oral and pharyngeal candidiasis (thrush) and, rarely, oesophageal candidiasis, may occur in some patients. Hoarseness and the incidence of candidiasis may be relieved by rinsing the mouth with water and/or brushing the teeth after use of the product. Symptomatic oral and pharyngeal candidiasis may be treated with local antifungals while continuing treatment with PROPIONATE DE FLUTICASONE/SALMETEROL ZENTIVA.

Paediatric population

Systemic effects such as Cushing's syndrome, cushingoid appearance, inhibition of adrenal function and growth retardation in children and adolescents are possible (see section Warnings and precautions). Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability, may also occur in children.

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: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

No overdose has been described in the clinical trials conducted with PROPIONATE DE FLUTICASONE/SALMETEROL ZENTIVA. Nevertheless, information on overdose with each of the active substances is described below:

Salmeterol

Signs and symptoms of an overdose with salmeterol include dizziness, increases in systolic blood pressure, tremor, headache and tachycardia. Initiation of appropriate replacement corticosteroid therapy should be considered if it proves necessary to interrupt treatment with PROPIONATE DE FLUTICASONE/SALMETEROL ZENTIVA due to an overdose of the β agonist contained in the medicine. Hypokalaemia is also possible, which may require monitoring of serum potassium levels and possibly potassium supplementation.

Fluticasone propionate

Acute overdose: administration of fluticasone propionate by inhalation at doses higher than those recommended may lead to temporary inhibition of adrenal function. No emergency measure is required as adrenal function recovers within a few days, as shown by plasma cortisol measurements.

Chronic overdose of inhaled fluticasone propionate: adrenal function should be monitored and systemic corticosteroid treatment may then be necessary. Once stabilised, treatment should be continued with an inhaled corticosteroid at the recommended dose. Refer to section Warnings and precautions : risk of adrenal suppression.

In the case of acute or chronic overdose of fluticasone propionate, treatment with PROPIONATE DE FLUTICASONE/SALMETEROL ZENTIVA should be continued, adjusting the dosage to the levels sufficient for optimal control of asthma symptoms.

Pharmacotherapeutic class: Adrenergics in combination with corticosteroids or other drugs, excluding anticholinergics, ATC code: R03AK06.

Mechanism of action and pharmacodynamic effects

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA contains fluticasone propionate and salmeterol, which have different modes of action. The respective mechanisms of action of these two active substances are presented below.

Salmeterol:

Salmeterol is a selective long-acting (12 hours) agonist of β2 adrenergic receptors. It has a long side chain that binds it to the exo-site of the receptor.

Salmeterol produces bronchodilation that persists for at least 12 hours. This duration is longer than that generally observed with short-acting β2 mimetics administered at the recommended doses.

Fluticasone propionate:

Fluticasone propionate administered by inhalation at the recommended doses exerts glucocorticoid activity resulting in a local anti-inflammatory effect at the level of the bronchial mucosa. Consequently, asthma symptoms and exacerbations are reduced, while systemic effects are limited compared with the administration of corticosteroids by the systemic route.

Clinical efficacy and tolerability

The studies described below (GOAL and SMART) were carried out with this same fixed-dose combination of fluticasone propionate and salmeterol xinafoate, but with a previously authorised product; the studies described were not carried out with the specialty FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA.

Clinical studies conducted with fluticasone propionate/salmeterol in asthma

A study of 12 months (Gaining Optimal Asthma controL, GOAL) conducted in 3 416 adult and adolescent patients with persistent asthma compared the tolerability and efficacy of fluticasone propionate/salmeterol with inhaled corticosteroid therapy alone (fluticasone propionate) in order to assess the possibility of achieving asthma management goals. The treatment dose was increased every 12 weeks until total control** was obtained or the highest dose of the study was reached. GOAL showed that more patients achieved asthma control when treated with fluticasone propionate/salmeterol than with inhaled corticosteroids (ICS) alone, this control being obtained with a lower corticosteroid dose. total control** was obtained or the highest dose of the study was reached. GOAL showed that more patients achieved asthma control when treated with fluticasone propionate/salmeterol than with inhaled corticosteroids (ICS) alone, this control being obtained with a lower corticosteroid dose.

A good control* of asthma was achieved more rapidly in patients treated with fluticasone propionate/salmeterol than in patients treated with ICS alone. The time required for 50% of subjects included in the study to reach their first week of good control* was 16 days for subjects treated with fluticasone propionate/salmeterol and 37 days for those treated with ICS. In the subgroup of asthma patients not previously treated with inhaled corticosteroids, this time was 16 days (fluticasone propionate/salmeterol) and 23 days (ICS), respectively.

The overall results of the study were as follows:

Percentage of patients achieving Good Control (GC)* and Total Control** (TC) of asthma over 12 months
Treatment before study inclusion	FP/salmeterol		FP
	GC	TC	GC	TC
No ICS (β2 SABA alone)	78 %	50 %	70 %	40 %
Low-dose ICS (≤ 500 micrograms of BDP or equivalent per day)	75 %	44 %	60 %	28 %
Moderate-dose ICS (> 500 to 1 000 micrograms of BDP or equivalent per day)	62 %	29 %	47 %	16 %
Overall results (regardless of prior treatment)	71 %	41 %	59 %	28 %

* Good asthma control: no more than 2 days per week with a symptom score greater than 1 (a symptom score of 1 is defined as "presence of symptoms for a short period during the day"), use of a short-acting beta-2 agonist bronchodilator: maximum of 2 days per week and maximum of 4 times per week, morning peak expiratory flow value ≥ 80 % of the predicted value, no nocturnal awakening, no exacerbation, and no adverse effect leading to a change in treatment.

** Total asthma control: no symptoms, no use of a short-acting beta-2 agonist bronchodilator, morning peak expiratory flow value greater than or equal to 80 % of the predicted value, no nocturnal awakening, no exacerbation, and no adverse effect leading to a change in treatment.

The results of this study suggest that fluticasone propionate/salmeterol 100/50 micrograms/dose, twice daily, may be considered for initiation of maintenance therapy in patients with moderate persistent asthma in whom rapid asthma control is considered essential (see section Dosage and administration).

A double-blind, randomised, parallel-group study conducted in 318 patients aged at least 18 years with persistent asthma evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of fluticasone propionate/salmeterol for two weeks. This study showed that doubling the dose of fluticasone propionate/salmeterol (regardless of strength), over a duration of up to 14 days, results, compared with administration of one inhalation twice daily, in a slight increase in adverse events related to beta-mimetic activity (tremor: 1 patient [1 %] vs 0, palpitations: 6 [3 %] vs 1 [< 1 %], muscle cramps: 6 [3 %] vs 1 [< 1 %]) and a similar incidence of adverse events related to inhaled corticosteroid (oral candidiasis: 6 [6 %] vs 16 [8 %], hoarseness of voice: 2 [2 %] vs 4 [2 %]). The slight increase in adverse effects related to beta-mimetic activity should be taken into consideration if doubling the prescribed dose of fluticasone propionate/salmeterol is considered in adult patients who would require an increase in inhaled corticosteroid therapy for a short period (up to 14 days).

Asthma

Multicentre asthma trial with salmeterol (" Salmeterol Multi-Center Asthma Research Trial, SMART »)

The SMART study (Salmeterol Multi-center Asthma Research Trial) was a 28-week study conducted in the United States in adult and adolescent patients to evaluate the safety of salmeterol versus placebo added to usual treatment. Although no significant difference was observed for the primary endpoint, a combined endpoint associating the number of deaths from respiratory causes and the number of life-threatening respiratory crises, the study showed a significant increase in the number of asthma-related deaths in patients receiving salmeterol (13 deaths among 13 176 patients treated with salmeterol versus 3 deaths among 13 179 patients receiving placebo). The study was not designed to assess the impact of inhaled corticosteroids administered in parallel; at inclusion, use of ICS was reported in only 47 % of patients.

Safety and efficacy of the PF/salmeterol combination versus PF monotherapy in asthma

Two multicentre studies of 26 weeks were conducted to compare the safety and efficacy of the PF/salmeterol combination versus PF monotherapy: one in adult and adolescent patients (AUSTRI study) and the other in paediatric patients aged 4 to 11 years (VESTRI study). In both studies, included patients had moderate to severe persistent asthma, associated with a history of asthma-related hospitalisations or exacerbation episodes during the previous year. The primary objective of each study was to determine whether adding LABA to ICS treatment (PF/salmeterol) was non-inferior to ICS (PF) given alone in terms of the risk of serious asthma-related adverse events (asthma-related hospitalisation, endotracheal intubation and death). The secondary efficacy objective of these studies was to assess whether the ICS/LABA combination (PF/salmeterol) was superior to ICS alone (PF) in terms of severe asthma exacerbation (defined as asthma deterioration requiring the use of systemic corticosteroids for at least 3 days or a hospitalisation or emergency department visit for asthma requiring the use of systemic corticosteroids).

A total of 11 679 and 6 208 patients, respectively, were randomised to receive the treatment defined in the AUSTRI and VESTRI studies. For the primary endpoint, non-inferiority was demonstrated in both studies (see table below).

Serious asthma-related adverse events reported in the 26 -week AUSTRI and VESTRI studies

	AUSTRI		VESTRI
	FP/salmeterol (n = 5 834)	PF monotherapy (n = 5 845)	FP/salmeterol (n = 3 107)	PF monotherapy (n = 3 101)
Composite efficacy endpoint (asthma-related hospitalisation, endotracheal intubation or death)	34 (0,6 %)	33 (0,6 %)	27 (0,9 %)	21 (0,7 %)
Risk ratio PF-salmeterol/PF (95% CI)	1,029 (0,638–1,662)a		1,285 (0,726–2,272)b
Deaths	0	0	0	0
Asthma-related hospitalisation	34	33	27	21
Endotracheal intubation	0	2	0	0

a Obtaining an upper estimate of the 95% CI of the relative risk below 2,0 allowed the conclusion of non-inferiority.

b Obtaining an upper estimate of the 95% CI of the relative risk below 2,675 allowed the conclusion of non-inferiority.

For the secondary efficacy endpoint, a reduction in the time to onset of the first asthma exacerbation with the PF/salmeterol combination compared with PF alone was observed in both studies; however, this reduction was statistically significant only in the AUSTRI study.

	AUSTRI		VESTRI
	FP/salmeterol (n = 5 834)	PF monotherapy (n = 5 845)	FP/salmeterol (n = 3 107)	PF monotherapy (n = 3 101)
Number of subjects presenting an asthma exacerbation	480 (8 %)	597 (10 %)	265 (9 %)	309 (10 %)
Risk ratio PF-salmeterol/PF (95% CI)	0,787 (0,698 ; 0,888)		0,859 (0,729 ; 1,012)

Paediatric population

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA is not indicated in children under 12 years (see section Dosage and administration). The studies described below were conducted with a previously authorised product; the studies described were not conducted with FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA.

In the SAM101667 study, conducted in 158 children aged 6 to 16 years with symptomatic asthma, the fluticasone propionate/salmeterol combination was as effective as a double dose of fluticasone propionate in terms of symptom control and lung function. This study was not designed to study the effect on exacerbations.

In a 12-week study conducted in children aged 4 to 11 years [n = 257] treated with the fluticasone propionate/salmeterol combination 100/50 micrograms 2 times daily or with salmeterol 50 micrograms and fluticasone propionate 100 micrograms 2 times daily, a mean increase of 14% in peak expiratory flow rate (PEF or Peak expiratory flow rate) as well as an improvement in symptom severity scores and a decrease in use of so-called "rescue" medication (salbutamol) were observed in the 2 groups compared. No difference was observed between the two treatment groups. Likewise, no difference was demonstrated between the 2 treatment groups in terms of tolerability.

A 12-week, randomised, 2-group parallel study, whose primary objective was to assess tolerability, was conducted in children aged 4 to 11 years [n = 203] with persistent asthma who remained symptomatic despite treatment with inhaled corticosteroids. Children received either the fluticasone propionate/salmeterol combination (100/50 micrograms) or fluticasone propionate (100 micrograms) alone, twice daily. Two children in the fluticasone propionate/salmeterol group and 5 children in the fluticasone propionate alone group discontinued the study due to worsening of their asthma. After 12 weeks, none of the children in either treatment group had abnormal urinary cortisol excretion over 24 hours. There was no difference in the tolerability profile between the two treatment groups.

Anti-asthmatic medicines containing fluticasone propionate used during pregnancy

A retrospective observational epidemiological cohort study was conducted using electronic medical records from the United Kingdom to assess the risk of major congenital malformations (MCM) following exposure to inhaled PF alone and to the PF/salmeterol combination, compared with treatment with ICS not containing PF, during the first trimester of pregnancy. No placebo comparator was included in this study.

Within the "asthma" cohort of 5 362 pregnancies exposed to ICS during the first trimester, 131 diagnosed MCM were identified; 1 612 (30%) pregnancies were exposed to PF or the PF/salmeterol combination, among which 42 diagnosed MCM were identified. The adjusted odds ratios for diagnosed MCM within one year were 1,1 (95% CI; 0,5 – 2,3) for women with moderate asthma exposed to PF compared with ICS treatment without PF, and 1,2 (95% CI; 0,7 – 2,0) for women with severe to significant asthma. No difference in the risk of MCM was identified following exposure to PF monotherapy during the first trimester of pregnancy compared with the PF/salmeterol combination. Absolute risks of MCM, regardless of asthma severity, ranged between 2,0 and 2,9 for 100 pregnancies exposed to PF, which is comparable to the results of a study of 15 840 pregnancies not exposed to asthma treatment according to the " General Practice Research Database " (2,8 MCM for 100 pregnancies).

The pharmacokinetics of each component may be considered separately.

Salmeterol

As salmeterol acts locally in the lungs, plasma levels are not correlated with therapeutic effects. Furthermore, few data are available on the pharmacokinetics of salmeterol after inhaled administration, as plasma concentrations observed at therapeutic doses are low (at most 200 picograms/mL) and difficult to measure.

Fluticasone propionate

Absolute bioavailability after a single dose of inhaled fluticasone propionate in healthy volunteers ranges approximately from 5 to 11% of the nominal dose depending on the inhalation device used.

Lower systemic exposure to fluticasone propionate has been observed in asthmatic patients.

Absorption

Absorption is essentially pulmonary. It is rapid initially and then continues more slowly. The remainder of the dose may be swallowed but contributes only minimally to systemic exposure due to low aqueous solubility and extensive first-pass metabolism. Oral bioavailability is thus less than 1%. Systemic exposure increases linearly with increasing inhaled dose.

Distribution

Elimination of fluticasone propionate is characterised by high plasma clearance (1 150 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 eliminated very rapidly from systemic circulation. The product is mainly metabolised to an inactive carboxylic acid derivative, by the isoenzyme CYP3A4 of cytochrome P450. Other unidentified metabolites are also found in faeces.

Elimination

Renal clearance of fluticasone propionate is negligible. Less than 5 % of the dose is excreted in urine, mainly as metabolites. The majority of the dose is eliminated in faeces, as metabolites and as unchanged substance.

Paediatric population

FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA is not indicated in children under 12 years. The studies described below were carried out with a previously authorised product; the studies described were not carried out with FLUTICASONE PROPIONATE/SALMETEROL ZENTIVA.

In a population pharmacokinetic analysis pooling data from 9 controlled clinical studies, conducted with different inhalation devices (dry powder inhaler, metered-dose inhaler) and including 350 patients with asthma aged 4 to 77 years (of whom 174 patients were aged 4 to 11 years), systemic exposure to fluticasone propionate after treatment with fluticasone/salmeterol 100/50 was higher compared with the fluticasone propionate dry powder inhaler 100.

Geometric mean ratio [CI at 90 %] for fluticasone propionate/salmeterol dry powder inhaler versus fluticasone propionate. Comparison in the paediatric population versus the adult/adolescent population.

Treatment (tested versus reference)	Population	AUC	Cmax
Fluticasone propionate/salmeterol dry powder inhaler 100/50 Fluticasone propionate dry powder inhaler 100	Children (4–11 years)	1,20 [1,06 – 1,37]	1,25 [1,11 – 1,41]
Fluticasone propionate/salmeterol dry powder inhaler 100/50 Fluticasone propionate dry powder inhaler 100	Adolescent/Adult (≥ 12 years)	1,52 [1,08 – 2,13]	1,52 [1,08 – 2,16]

The effect of 21 days of treatment with fluticasone/salmeterol inhaler 50/25 micrograms (2 inhalations twice daily with or without a spacer device) or with fluticasone/salmeterol dry powder inhaler 100/50 micrograms (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma. Systemic exposure to salmeterol was similar for the fluticasone/salmeterol inhaler (126 picograms/h/mL [CI at 95 %: 70; 225]), the fluticasone/salmeterol inhaler without a spacer device (103 picograms/h/mL [CI at 95 %: 54; 200]) and the fluticasone/salmeterol dry powder inhaler (110 picograms/h/mL [CI at 95 %: 55; 219]). Systemic exposure to fluticasone propionate was similar for the fluticasone/salmeterol inhaler without a spacer device (107 picograms/h/mL [CI at 95 %: 45,7; 252,2]) and for the fluticasone/salmeterol dry powder inhaler (138 picograms/h/mL [CI at 95 %: 69,3; 273,2]) but lower for the fluticasone/salmeterol inhaler (24 picograms/h/mL [CI at 95 %: 9,6; 60,2]).

The effects observed in animal studies are related to exaggerated pharmacological effects of fluticasone propionate and salmeterol administered separately when used in humans.

In animal reproduction studies, malformations were observed after administration of glucocorticoids (cleft palate, skeletal malformations). However, these experimental findings in animals do not appear predictive of a malformative effect in humans at the recommended doses. Animal studies with salmeterol showed embryofoetal toxicity only after exposure to high doses. After concomitant administration of both active substances, an increased frequency of transposition of the umbilical artery and incomplete ossifications of the occipital bone was observed in rats receiving doses of glucocorticoids known to induce abnormalities. Neither fluticasone propionate nor salmeterol xinafoate showed potential genotoxicity.

3 years.

Store at a temperature not exceeding 30 °C.

FLUTICASONE/SALMETEROL ZENTIVA delivers a powder that is inhaled into the lungs. A dose indicator on FLUTICASONE/SALMETEROL ZENTIVA shows the number of doses remaining. For detailed information on use, see the patient leaflet.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

List I

Marketing authorisation (AMM)

CIP 3400930222942 (1 available/60 dose).

Price:

19,07 euros (1 available/60 dose).

Social security reimbursement at 65% under the indications:

• Indication(s) appearing in the marketing authorisation at the date of publication of this decree

Collection.