Last Updated on eMC 08-12-2017 View medicine  | Sandoz Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text
  • Change to section 4.8 - Undesirable effects - how to report a side effect

Date of revision of text on the SPC:24-11-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Amended text within each sections are tracked:

 

4.4     Special warnings and special precautions for use

 

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

 

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.

 

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 symptoms remain uncontrolled or worsen whilst using AirFluSal Forspiro.

 

 

4.8       Undesirable effects

 

System Organ Class

Adverse Event

Frequency

Psychiatric Disorders

Anxiety

Sleep disorders

 

Behavioural changes, including psychomotor hyperactivity and irritability (predominantly in children)

 

Depression, aggression (predominantly in children)

 

Uncommon

 

Uncommon

 

Rare

 

 

 

Not known

Nervous System Disorders

Headache

Tremor

 

Very Common1

Uncommon

Eye Disorders

Cataract

 

Glaucoma

 

Vision, blurred (see also section 4.4)

Uncommon

 

Rare4

 

Not known

 

Cardiac Disorders

Palpitations

Tachycardia

Cardiac arrhythmias (including supraventricular tachycardia and extrasystoles).

 

Atrial fibrillation

 

Angina pectoris

 

Uncommon

Uncommon

Rare

 

 

 

Uncommon

 

Uncommon

 

 

 

 

10      Date of revision of the summary of the text

24/11/2017

 

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:29-06-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



 

Complete SmPC revision change.

Please use the uploaded SmPC for the update.

Reasons for adding or updating:

  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:17-02-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Amended text within each sections are shown in colour, deleted texts are crossed out:

4.1       Therapeutic indications

AirFluSal Forspiro is indicated for use in adults 18 years of age and older only.

 

Asthma

AirFluSal Forspiro is indicated in the regular treatment of adults with severe asthma where use of a combination product (long-acting β2 agonist [LABA] and inhaled corticosteroid [ICS]) 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 β2 agonist.

 

Chronic Obstructive Pulmonary Disease (COPD)

AirFluSal Forspiro is indicated for the symptomatic treatment of adults with COPD, with a forced expiratory volume in one second (FEV1) <60% predicted normal (pre-bronchodilator) and a history of repeated exacerbations and who have significant symptoms despite regular bronchodilator therapy.

 

AirFluSal Forspiro is indicated for the symptomatic treatment of adults with Chronic Obstructive Pulmonary Disease (COPD), with a FEV1 <60% predicted normal (pre-bronchodilator) and a history of repeated exacerbations and who have significant symptoms despite regular bronchodilator therapy.

 

AirFluSal Forspiro is intended for use by adults 18 years of age and older only.

 

4.2       Posology and method of administration

 

AirFluSal Forspiro is indicated in adults 18 years of age and older only.

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

 

Method Route of administration: Inhalation use

 

Patients should be made aware that AirFluSal Forspiro must be used regularly, every dayregularly, every day 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.

 

In patients with asthma, the dose should always be titrated to the lowest dose at which effective control of symptoms is maintained.

 

To Note: AirFluSal Forspiro is available on the market in the strength of 50 micrograms of salmeterol and 500 micrograms of fluticasone propionate per metered dose only; AirFluSal Forspiro is not available in any is available in the strengths lower thanof 50 micrograms of salmeterol and 500 micrograms of fluticasone propionate per metered dose only. Therefore, when it is appropriate to titrate down to a lower strength not available for AirFluSal Forspiro, a change to an alternative fixed dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled corticosteroid is required.

 

Patients should be given a strength of salmeterol/fluticasone propionate inhaler containing the appropriate fluticasone propionate dosage for the severity of their disease. AirFluSal Forspiro 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 β2 agonist and/or corticosteroid should be prescribed.

 

 

Posology

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. 

The lowest effective dose of the inhaled corticosteroid should be used.

 

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.

 

AirFluSal Forspiro 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 β2 agonist has been established previously.

 

AirFluSal Forspiro 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.

 

 

COPD

 

There are no data available foron the use of AirFluSal Forspiro in patients with hepatic impairment.

 

Paediatric population:

AirFluSal Forspiro is not recommended for use in either children aged 12 years and youngerand or in adolescents less than 18 years of aged 13 to 17 years.

The safety and efficacy of AirFluSal Forspiro in children and adolescents aged less than 18 years of age has not been established. No data are available.

 

4.4       Special warnings and precautions for use

 

Asthma

AirFluSal Forspiro is for use in patients with severe asthma only.

 

AirFluSal Forspiro should not be used in patients with mild or mild to moderate asthma.

AirFluSal Forspiro should not be used as initial maintenance therapy in patients with moderate persistent asthma.

AirFluSal Forspiro should not be used 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 β2 agonist has been established previously.

AirFluSal Forspiro should not be used in children and adolescents less than 18 years of age with asthma.

 

AirFluSal Forspiro 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 AirFluSal Forspiro during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

 

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

 

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. As AirFluSal Forspiro is available in the strength of 50 micrograms of salmeterol and 500 micrograms of fluticasone propionate per metered dose only, a change to an alternative fixed dose combination product of salmeterol and fluticasone propionate containing a lower dose of the inhaled corticosteroid is required when it is appropriate to titrate down to a lower dose of the inhaled corticosteroid.

Regular review of patients as treatment is stepped down is important. The lowest effective dose of the inhaled corticosteroid should be used (see Section 4.2).

 

COPD

 

Cessation of therapy

Treatment with AirFluSal Forspiro should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision (see above).

 

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

Paradoxical bronchospasm
Beta 2 adrenoreceptor agonists

 

Systemic effects

 

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 paragraphs under the sub-heading Paediatric Population, below). 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 the diseaseasthma is maintained.

 

Adrenal function

Interactions with other medicinal products

 

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 side 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.

 

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 AirFluSal Forspiro should be re-evaluated.

 

If a patient with severe COPD has experienced pneumonia, treatment with AirFluSal Forspiro should be re-evaluated.

 

Ethnic populations

 

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 side effects of salmeterol treatment (see section 4.5).

 

Paediatric Population

AirFluSal Forspiro 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.

 

To Note: AirFluSal Forspiro is only available in one high strength, it is not available as either a low strength product containing salmeterol 50 microgram and fluticasone propionate 100 microgram, or a mid-strength product containing salmeterol 50 microgram and fluticasone propionate 250 microgram. The maximum authorised dose of fluticasone propionate formulated as an inhalation powder for use in children is 100 microgram twice daily – as is available in the low strength product – and therefore this high strength product would not be appropriate, in any event, for use in children 12 years of age and younger.

 

Furthermore the safety and efficacy of AirFluSal Forspiro in children, 12 years of age and younger and adolescents, 13-17 years of age have not been established. No data are available.

 

Therefore AirFluSal Forspiro is not recommended for use in children and adolescents under 18 years of age at this time (see Section 4.2).

 

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 AirFluSal Forspiro.

 

Excipients

AirFluSal Forspiro contains 11.95 mg lactose/dose. This amount does not normally cause problems in lactose intolerant people. However 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

 

βBeta adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and selective β blockers should be avoided unless there are compelling reasons for their use.

Potentially serious hypokalaemia may result from β2 agonist therapy. Particular caution is advised in acute severe asthma as Tthis effect may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics.

 

Concomitant use of other β adrenergic containing drugsmedicinal products can have a potentially additive effect.

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

 

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 sSection 4.4).

 

4.6       Fertility, pregnancy and lactation

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

 

4.8       Undesirable effects

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 mouth and throat candidiasis may be relieved by rinsing the mouth with water and spitting the water out and/or brushing the teeth after using the product. Symptomatic mouth and throat candidiasis can be treated with topical anti-fungal therapy whilst still continuing with a fixed-dose combination of salmeterol/ and fluticasone propionate.

 

Paediatric population

AirFluSal Forspiro is not indicated for use in children and adolescents under the age of 18 years (see Section 4.2). Possible systemic effects in these age groups include Cushing's syndrome, Cushingoid features, adrenal suppression and growth retardation in children and adolescents (see Section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.

 

4.9       Overdose

There are no data available from clinical trials on overdose with AirFluSal Forspiro; however data on overdose with both active substancesdrugs are given below:

 

Salmeterol

The signs and symptoms of salmeterol overdose are dizziness, increases in systolic blood pressure, tremor, headache and tachycardia. If AirFluSal Forspiro therapy has to be withdrawn due to overdose of the β agonist component of the medicinal productdrug, 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 overdose: Acute inhalation of fluticasone propionate doses in excess of those recommended may lead to 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 of inhaled fluticasone propionate: Refer to section 4.4: risk of adrenal suppression: 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: risk of adrenal suppression.

In cases of both acute and chronic fluticasone propionate overdose, AirFluSal Forspiro therapy should be continued at a suitable dosage dose for symptom control.

 

5.1       Pharmacodynamic properties

Mechanism of action:

AirFluSal Forspiro contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both active substancesdrugs are discussed below:

 

Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting β2 agonists (SABA).

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 AirFluSal Forspiro.

 

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:

Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months

Pre-Study Treatment

salmeterol/ fluticasone propionate

fluticasone propionate

WC

TC

WC

TC

No ICS (SABA alone)

78%

50%

70%

40%

Low dose ICS (500  micrograms BDP or

 equivalent/day)

75%

44%

60%

28%

Medium dose ICS (>500-1000 micrograms BDP or equivalent/day)

62%

29%

47%

16%

Pooled results across the 3 treatment levels

71%

41%

59%

28%

 

*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 50/100 microgram twice daily may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential.

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 β 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 β 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 short-term (up to 14 days) inhaled corticosteroid therapy.

 

Salmeterol/fluticasone propionate – Chronic obstructive pulmonary disease (COPD) clinical trials

TORCH was a 3-year study to assess the effect of treatment with salmeterol/fluticasone propionate 50/500 microgram bdtwice daily, salmeterol 50 micrograms bdtwice daily, fluticasone propionate 500 micrograms bdtwice 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.

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


The mean number of moderate to severe exacerbations per year was significantly reduced with salmeterol/fluticasone propionate as compared with treatment with salmeterol, fluticasone propionate and placebo (mean rate in the salmeterol/fluticasone propionate group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the fluticasone propionate group and 1.13 in the placebo group).

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 fluticasone propionate and 19.6% for salmeterol/fluticasone propionate (Hhazard ratio for salmeterol/fluticasone propionate vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001).

There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% fluticasone propionate and 6.3% salmeterol/fluticasone propionate; Hhazard ratio for salmeterol/fluticasone propionate vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.

Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of salmeterol/fluticasone propionate 50/250 micrograms bdtwice daily (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bdtwice daily on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations.

 

The trials had a 4 -week run-in period during which all subjects received open-label salmeterol/ fluticasone propionate 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ fluticasone propionate 50/250 (total ITT n=776) or salmeterol (total ITT n=778).  Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (β2- agonist and anticholinergic drugs), salbutamol/ipratropium/salbutamol bromide combination products, oral β2- 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 guidelines for use.  Subjects used salbutamol on an as-needed basis throughout the studies.

 

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 bdtwice 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 bdtwice daily group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the salmeterol/fluticasone propionate 50/250 micrograms bdtwice daily group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with salmeterol/fluticasone propionate 50/250 micrograms bdtwice daily appears to be of similar magnitude to the incidence reported following treatment with salmeterol/fluticasone propionate 50/500 micrograms bdtwice 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

Patient group

Number of primary endpoint events /number of patients

Relative Risk

(95% confidence intervals)

salmeterol

placebo

All patients

50/13,176

36/13,179

1.40 (0.91, 2.14)

Patients using inhaled steroids

23/6,127

19/6,138

1.21 (0.66, 2.23)

Patients not using inhaled steroids

27/7,049

17/7,041

1.60 (0.87, 2.93)

African-American patients

20/2,366

5/2,319

4.10 (1.54, 10.90)

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

Key findings from SMART by inhaled steroid use at baseline: secondary endpoints

Number of secondary endpoint events /number of patients

Relative Risk

(95% confidence intervals)

salmeterol

placebo

Respiratory-related death

Patients using inhaled steroids

10/6127

5/6138

2.01 (0.69, 5.86)

Patients not using inhaled steroids

14/7049

6/7041

2.28 (0.88, 5.94)

Combined asthma-related death or life-threatening experience

Patients using inhaled steroids

16/6127

13/6138

1.24 (0.60, 2.58)

Patients not using inhaled steroids

21/7049

9/7041

2.39 (1.10, 5.22)

Asthma-related death

Patients using inhaled steroids

4/6127

3/6138

1.35 (0.30, 6.04)

Patients not using inhaled steroids

9/7049

0/7041

*

(*=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.

 

Paediatric population

AirFluSal Forspiro is not recommended for use in children and adolescents aged less than 18 years. The safety and efficacy of AirFluSal Forspiro 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 AirFluSal Forspiro. The studies described were carried out with a previously authorised product available in three different strengths; the studies were not carried out with AirFluSal Forspiro.

 

In a study in 158 children aged 6 to 16 years with symptomatic asthma, the combination of fluticasone propionate/salmeterol 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 fluticasone propionate/salmeterol 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

In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picogram/mlL or less) achieved after inhaled dosing.

Distribution:

The disposition of fluticasone propionate is characterised by high plasma clearance (1150 mlL/min), a large volume of distribution at steady-state (approximately 300  lL) and a terminal half-life of approximately 8 hours.

 

Paediatric population

AirFluSal Forspiro is not recommended for use in children and adolescents aged less than 18 years. The safety and efficacy of AirFluSal Forspiro 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 AirFluSal Forspiro.

 

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.

 

The effect of 21 days of treatment with salmeterol/fluticasone propionate pressurised inhaler 25/50 microgram (2 inhalations twice daily with or without a spacer) or salmeterol/fluticasone propionate 50/100 microgram, inhalation powder (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma.

 

Systemic exposure to fluticasone propionate was similar for salmeterol/fluticasone propionate pressurised inhaler with spacer (107 pg hr/mL [95% CI: 45.7, 252.2]) and salmeterol/fluticasone propionate, inhalation powder (138 pg hr/mL [95% CI: 69.3, 273.2]), but lower for salmeterol/fluticasone propionate pressurised inhaler without spacer (24 pg hr/mL [95% CI: 9.6, 60.2]). Systemic exposure to salmeterol was similar for salmeterol/fluticasone propionate pressurised inhaler without spacer, salmeterol/fluticasone propionate pressurised inhaler with spacer, and salmeterol/fluticasone propionate, inhalation powder (126 pg hr/mL [95% CI: 70, 225], 103 pg hr/mL [95% CI: 54, 200], and 110 pg hr/mL [95% CI: 55, 219], respectively).


 

 

 

10      DATE OF REVISION OF THE TEXT

 

09/11/201607/2016 to be amended upon approval17/02/2017

 

 

 

 

 

 

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:17-02-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Amended text within each sections are shown in colour, deleted texts are crossed out:

4.2       Posology and method of administration

Note: As the inhaler is used the side chamber will gradually fill up with used strip. The foil strips with black bars don’t contain medication. Eventually the numbered sections of the strip will appear in the side chamber. There should never be more than 23 sections of foil strip in the side chamber as they may cause the inhaler to jam. The strip should be torn away carefully as shown above, and disposed of safely.


10      DATE OF REVISION OF THE TEXT

17/02/2017

Reasons for adding or updating:

  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:03-02-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Emboldened text has been added. Text crossed out has been removed.


Section 3

 

The pre-dispensed powder, contained in blister, is delivered by a purple plastic dry

 

- powder inhalation device.

 

 

 

Section 4.1

AirFluSal Forspiro is indicated for use in adults 18 years of age and older only.

 

Asthma

AirFluSal Forspiro is indicated in the regular treatment of adults with severe asthma where use of a combination product (long-acting β2 agonist [LABA] and inhaled corticosteroid [ICS]) 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 β2 agonist.

 

Chronic Obstructive Pulmonary Disease (COPD)

AirFluSal Forspiro is indicated for the symptomatic treatment of adults with COPD, with a forced expiratory volume in one second (FEV1) <60% predicted normal (pre-bronchodilator) and a history of repeated exacerbations and who have significant symptoms despite regular bronchodilator therapy.

Section 4.2

AirFluSal Forspiro is indicated in adults 18 years of age and older only.

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

 

Route of administration: Inhalation use

 

Patients should be made aware that AirFluSal Forspiro must be used regularly, every day 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.

 

In patients with asthma, the dose should always be titrated to the lowest dose at which effective control of symptoms is maintained.

 

To Note: AirFluSal Forspiro is available on the market in the strength of 50 micrograms of salmeterol and 500 micrograms of fluticasone propionate per metered dose only; AirFluSal Forspiro is not available in any strengths lower than 50 micrograms of salmeterol and 500 micrograms of fluticasone propionate per metered dose. Therefore, when it is appropriate to titrate down to a lower strength not available for AirFluSal Forspiro, a change to an alternative fixed dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled corticosteroid is required.

 

Patients should be given a strength of salmeterol/fluticasone propionate inhaler containing the appropriate fluticasone propionate dosage for the severity of their disease. AirFluSal Forspiro 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 β2 agonist and/or corticosteroid should be prescribed.

 

 

Posology

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.

The lowest effective dose of the inhaled corticosteroid should be used.

 

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.

 

AirFluSal Forspiro 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 β2 agonist has been established previously.

 

AirFluSal Forspiro 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.

 

 

COPD

Adults:

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 AirFluSal Forspiro in patients with hepatic impairment.

 

Paediatric population:

AirFluSal Forspiro is not recommended for use in either children aged 12 years and younger or in adolescents aged 13 to 17 years.

The safety and efficacy of AirFluSal Forspiro in children and adolescents aged less than 18 years of age has not been established. No data are available.


Section 4.4

Signification changes have been made to this section. Please find the final text below:

Asthma

AirFluSal Forspiro is for use in patients with severe asthma only.

 

AirFluSal Forspiro should not be used in patients with mild or mild to moderate asthma.

AirFluSal Forspiro should not be used as initial maintenance therapy in patients with moderate persistent asthma.

AirFluSal Forspiro should not be used 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 β2 agonist has been established previously.

AirFluSal Forspiro should not be used in children and adolescents less than 18 years of age with asthma.

 

AirFluSal Forspiro 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 AirFluSal Forspiro during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

 

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

 

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. As AirFluSal Forspiro is available in the strength of 50 micrograms of salmeterol and 500 micrograms of fluticasone propionate per metered dose only, a change to an alternative fixed dose combination product of salmeterol and fluticasone propionate containing a lower dose of the inhaled corticosteroid is required when it is appropriate to titrate down to a lower dose of the inhaled corticosteroid.

Regular review of patients as treatment is stepped down is important. The lowest effective dose of the inhaled corticosteroid should be used (see Section 4.2).

 

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 AirFluSal Forspiro.

 

Cessation of therapy

Treatment with AirFluSal Forspiro should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision (see above).

 

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

As with all inhaled medication containing corticosteroids, AirFluSal Forspiro 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.

 

Rarely, AirFluSal Forspiro may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. AirFluSal Forspiro 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

As with other inhalation therapy 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. AirFluSal Forspiro should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

 

Beta 2 adrenoreceptor agonists

The pharmacological side effects of β2 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 paragraphs under the sub-heading Paediatric Population, below). 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.

 

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 side 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 side 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.

 

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 AirFluSal Forspiro 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 AirFluSal Forspiro 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 symptoms remain uncontrolled or worsen whilst using AirFluSal Forspiro.

 

 

 

Paediatric Population

AirFluSal Forspiro 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.

 

To Note: AirFluSal Forspiro is only available in one high strength, it is not available as either a low strength product containing salmeterol 50 microgram and fluticasone propionate 100 microgram, or a mid-strength product containing salmeterol 50 microgram and fluticasone propionate 250 microgram. The maximum authorised dose of fluticasone propionate formulated as an inhalation powder for use in children is 100 microgram twice daily – as is available in the low strength product – and therefore this high strength product would not be appropriate, in any event, for use in children 12 years of age and younger.

 

Furthermore the safety and efficacy of AirFluSal Forspiro in children, 12 years of age and younger and adolescents, 13-17 years of age have not been established. No data are available.

 

Therefore AirFluSal Forspiro is not recommended for use in children and adolescents under 18 years of age at this time (see Section 4.2).

 

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 AirFluSal Forspiro.

 

Excipients

AirFluSal Forspiro contains 11.95 mg lactose/dose. This amount does not normally cause problems in lactose intolerant people. However lactose may contain small amounts of milk proteins which may cause allergic reactions in those with severe hypersensitivity or allergy to milk protein.


Section 4.5

 

 

 

 

Beta adrenergic blockers may weaken or antagonise the effect of salmeterol. Both

 

non-selective and selective

 

β blockers should be avoided unless there are compelling

 

reasons for their use.

Potentially serious hypokalaemia may result from

 

β2 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

 

β adrenergic containing drugsmedicinal products can have a potentially additive effect.

 

 

 


 

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.

 

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).

 

 

 

 

 



Section 4.6

 

The lowest effective dose of fluticasone propionate needed to maintain adequate

 

asthma control should be used in the treatment of pregnant women.

 

 

 

Section 4.8

 

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 mouth and throat candidiasis may be relieved by rinsing the mouth with water and spitting the water out and/or brushing the teeth after using the product. Symptomatic mouth and throat candidiasis can be treated with topical anti-fungal therapy whilst still continuing with a fixed-dose combination of salmeterol and fluticasone propionate.

 

 

 

 

Paediatric population

AirFluSal Forspiro is not indicated for use in children and adolescents under the age of 18 years (see Section 4.2). Possible systemic effects in these age groups include Cushing's syndrome, Cushingoid features, adrenal suppression and growth retardation in children and adolescents (see Section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.

 

 

 


Section 4.9

 

There are no data available from clinical trials on overdose with AirFluSal Forspiro; however data on 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 AirFluSal Forspiro therapy has to be withdrawn due to overdose of the

 

β 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

 

overdose: Acute inhalation of fluticasone propionate doses in excess of those

 

recommended may lead to 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: risk of adrenal suppression.

 

In cases of both acute and chronic fluticasone propionate overdose, AirFluSal Forspiro therapy should be continued at a suitable

 

dose for symptom control.

 

 

 


Section 5.1

 

Mechanism of action:

AirFluSal Forspiro 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)

 

β2 -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

 

β2 agonists (SABA).

 

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 AirFluSal Forspiro.

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 naïve 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:

<<table has been inserted>>

 

 

 

 

 

*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 50/100 microgram twice daily may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential.

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 β 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 β 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 short-term (up to 14 days) inhaled corticosteroid therapy.

 

 

 

 

 

 

 

 

Salmeterol/fluticasone propionate – Chronic obstructive pulmonary disease

(

 

 

COPD) clinical trials

 

TORCH was a 3-year study to assess the effect of treatment with salmeterol/fluticasone propionate 50/500 microgram

 

twice daily, salmeterol 50 micrograms twice daily, fluticasone propionate 500 micrograms twice daily or placebo on all-cause mortality in patients

 

 

 

 

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

 

 

 


 

The mean number of moderate to severe exacerbations per year was significantly reduced with salmeterol/fluticasone propionate as compared with treatment with salmeterol, fluticasone propionate and placebo (mean rate in the salmeterol/fluticasone propionate group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the fluticasone propionate group and 1.13 in the placebo

 

group).

 

hazard ratio

 



 

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 use of concurrent inhaled long-acting bronchodilators (

 

β2- agonist and anticholinergic drugs), salbutamol/ipratropium bromide combination products, oral β2 agonists, and theophylline preparations were not allowed during the treatment period.

 

twice daily

 

 

 



 

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

 

 

 

<<table has been inserted>>

(*=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.

 

Paediatric population

AirFluSal Forspiro is not recommended for use in children and adolescents aged less than 18 years. The safety and efficacy of AirFluSal Forspiro 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 AirFluSal Forspiro. The studies described were carried out with a previously authorised product available in three different strengths; the studies were not carried out with AirFluSal Forspiro.

 

In a study in 158 children aged 6 to 16 years with symptomatic asthma, the combination of fluticasone propionate/salmeterol 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 fluticasone propionate/salmeterol 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.

Section 5.2

m L

 

Paediatric population

AirFluSal Forspiro is not recommended for use in children and adolescents aged less

than 18 years. The safety and efficacy of AirFluSal Forspiro 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 AirFluSal Forspiro.

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.

The effect of 21 days of treatment with salmeterol/fluticasone propionate pressurised

inhaler 25/50 microgram (2 inhalations twice daily with or without a spacer) or

salmeterol/fluticasone propionate 50/100 microgram, inhalation powder (1 inhalation

twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma.

Systemic exposure to fluticasone propionate was similar for salmeterol/fluticasone

propionate pressurised inhaler with spacer (107 pg hr/mL [95% CI: 45.7, 252.2]) and

salmeterol/fluticasone propionate, inhalation powder (138 pg hr/mL [95% CI: 69.3,

273.2]), but lower for salmeterol/fluticasone propionate pressurised inhaler without

spacer (24 pg hr/mL [95% CI: 9.6, 60.2]). Systemic exposure to salmeterol was

similar for salmeterol/fluticasone propionate pressurised inhaler without spacer,

salmeterol/fluticasone propionate pressurised inhaler with spacer, and

salmeterol/fluticasone propionate, inhalation powder (126 pg hr/mL [95% CI: 70,

225], 103 pg hr/mL [95% CI: 54, 200], and 110 pg hr/mL [95% CI: 55, 219],

respectively).

 

 

 

 

 

 

Section 10
03/02/2017

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:09-11-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Text crossed out has been removed. Emboldened text has been added.


Section 4.2

Posology

Route Method

 

 

of administration: Inhalation use

 

Posology



Section 4.4

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.

Risk factors for pneumonia in patients with COPD include current smoking, older

age, low body mass index (BMI) and severe COPD.


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 bd compared with placebo as

well as in studies SCO40043 and SCO100250 comparing the lower non-approved

COPD dose of salmeterol/fluticasone propionate, 50/250 micrograms bd, to

salmeterol 50 micrograms bd only (see sections 4.8 and 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 (<25kg/m

 

 

2) and

 

patients with very severe disease (FEV

 

 

1<30% predicted) were at greatest risk of

 

developing pneumonia regardless of treatment. 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 the

treatment with AirFluSal Forspiro should be re-evaluated.



Section 4.8

Pneumonia

 

(in COPD patients)

 

Section 10
10/2015
09/11/2016

Reasons for adding or updating:

  • New SPC for new product

Date of revision of text on the SPC:01-01-0001

Legal Category:POM

Black Triangle (CHM): NO