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GlaxoSmithKline (Ireland) Ltd

12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland
Telephone: +353 1 495 5000
Fax: +353 1 4955225
Medical Information Direct Line: 1 800 244 255
Medical Information Facsimile: +353 1 495 5225
Summary of Product Characteristics last updated on medicines.ie: 15/12/2017
SPC Seretide Diskus

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

Updated on 15/12/2017 and displayed until Current
Reasons for adding or updating:
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Dec-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

SPC Section 2 - Qualitative and Quantitative Composition: to update excipients statement to introduce reference to lactose monohydrate
SPC Section 4.4 - Warnings & Precautions: to include headings as per QRD template and to include excipient warning for lactose monohydrate
Updated on 07/07/2017 and displayed until 15/12/2017
Reasons for adding or updating:
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   29-Dec-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

update Section 2 of the SmPC to remove Lactose Monohydrate

This SPC is being reinstated. This is because the recent live version on med.ie was from a Type IA variation and the Competent authority has requested the variation to be submitted as a Type IB. Therefore reinstating the previous version until we receive approval.
Updated on 24/05/2017 and displayed until 07/07/2017
Reasons for adding or updating:
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   28-Apr-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Update Section 2 of the SmPC to Introduce Lactose Monohydrate.
Updated on 10/01/2017 and displayed until 24/05/2017
Reasons for adding or updating:
  • 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:   29-Dec-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 4.4 Special Warnings and Precautions, A pneumonia warning for COPD patients has been added.
Section 4.8 Adverse Events, Has been updates to include pneumonia in COPD patients.
Updated on 21/07/2015 and displayed until 10/01/2017
Reasons for adding or updating:
  • Change to section 10 - Date of revision of the text
  • Change to MA holder contact details
Date of revision of text on the SPC:   01-Jul-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Update to MA holder contact details - Address change
Updated on 27/04/2015 and displayed until 21/07/2015
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   23-Apr-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section 4.8 – Addition of Oesophageal candidiasis as new adverse event with the frequency “rare”

Section 5.1 – Update to details on asthma studies due to alignment of wording with the definitions in the study of ‘well controlled’ and ‘total control’ of asthma

Updated on 24/04/2015 and displayed until 27/04/2015
Reasons for adding or updating:
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   16-Apr-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 5.1 - update to ATC Classification
Section 7 -  name of the MAH will be updated from “Glaxo Wellcome UK Limited, trading as Allen & Hanburys“ to “Glaxo Wellcome UK Limited, trading as GlaxoSmithKline UK“.
Updated on 09/12/2014 and displayed until 24/04/2015
Reasons for adding or updating:
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   04-Nov-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section 5.1 – Update ATC level name (Pharmacotherapeutic group)

Updated on 02/01/2014 and displayed until 09/12/2014
Reasons for adding or updating:
  • Change to section 6.3 - Shelf life
Date of revision of text on the SPC:   01-Nov-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



The shelf life has been extended from 18 months to 2 years

Updated on 03/09/2013 and displayed until 02/01/2014
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   10-Jun-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Changes to:

Section 4.4 - Special warnings and precautions for use,
Section 4.8 - Undesirable effects

Updated on 04/03/2013 and displayed until 03/09/2013
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   31-Jan-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



4.4     Special warnings and precautions for use

 

The management of asthma should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.

 

Seretide Diskus 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 medicinal product to be used for relief in an acute asthma attack available at all times.

 

Patients should not be initiated on Seretide 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 Seretide. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Seretide.

 

Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of 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. The patient should also be medically reviewed where the current dosage of Seretide has failed to give adequate control of asthma.

 

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Seretide. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Seretide should be used (see section 4.2).

 

For patients with asthma or COPD, consideration should be given to additional corticosteroid therapies.

 

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

 

As with all inhaled medication containing corticosteroids, Seretide should be administered with caution in patients with pulmonary tuberculosis.

 

Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Therefore Seretide should be used with caution in patients with severe cardiovascular disorders, heart rhythm abnormalities, 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.

 

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Seretide Diskus should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

 

Seretide contains lactose up to 12.5 milligram /dose. This amount does not normally cause problems in lactose intolerant people.

 

Care should be taken when transferring patients to Seretide therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.

 

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). 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.

 

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. 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.

 

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).

 

There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving Seretide 50/500 micrograms bd compared with placebo as well as in studies SCO40043 and SCO100250 comparing the lower non-approved COPD dose of Seretide, 50/250 micrograms bd, to salmeterol 50 micrograms bd only (see section 4.8 and section 5.1). A similar incidence of pneumonia in the Seretide group was seen across all studies. In TORCH, older patients, patients with a lower body mass index (<25kg/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 the treatment with Seretide should be re-evaluated.

 

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

 

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

 

Children and adolescents <16years taking high doses of fluticasone propionate (typically ³ 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.

 

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored. The dose of inhaled corticosteroid should be reduced to the lowest dose at which effective control of asthma is maintained.



4.8         Undesirable effects

 

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

 

Adverse events which have been associated with salmeterol/fluticasone propionate are given below, listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (³1/100 and <1/10), uncommon (³1/1000 and <1/100), rare (³1/10,000 to <1/1000) and not known (cannot be estimated from the available data). Frequencies were derived from clinical trial data. The incidence in placebo was not taken into account.

 

System Organ Class

Adverse Event

Frequency

Infections & Infestations

Candidiasis of the mouth and throat

 

Pneumonia

Bronchitis

 

Common

 

Common1,3,5

 

Common1,3

Immune System Disorders

Hypersensitivity reactions with the following manifestations:

Cutaneous hypersensitivity reactions

Angioedema (mainly facial and oropharyngeal oedema)

 

Respiratory symptoms (dyspnoea)

 

Respiratory symptoms (bronchospasm)

 

Anaphylactic reactions including anaphylactic shock

 




Rare

Rare

 

 

Uncommon

 

Rare

 

Rare

Endocrine Disorders

Cushing’s syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density

Rare4

Metabolism & Nutrition Disorders

Hypokalaemia

 

Hyperglycaemia

Common3

 

Rare4

Psychiatric Disorders

Anxiety

 

Sleep disorders and behavioural changes, including psychomotor hyperactivity and irritability (predominantly in children)

 

Depression, aggression (predominantly in children)

 

Uncommon

 

Rare

 

 

 

Not known

Nervous System Disorders

Headache

Tremor

 

Very Common1

Uncommon

Eye Disorders

Cataract, Glaucoma

 

Rare4

Cardiac Disorders

Palpitations

Tachycardia

Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles).

 

Angina pectoris

 

Uncommon

Uncommon

Rare

 

 

Uncommon

Respiratory, Thoracic & Mediastinal Disorders

Nasopharyngitis

Throat irritation

Hoarseness/dysphonia

Sinusitis

Paradoxical bronchospasm

 

Very Common2,3

Uncommon

Common

Common1,3


Rare4

Skin and subcutaneous tissue disorders

 

Contusions

Common1,3

Musculoskeletal & Connective Tissue Disorders

Muscle cramps

Traumatic fractures

Arthralgia

Myalgia

 

Uncommon

Common1,3

Common

Common

1.    Reported commonly in placebo

2.    Reported very commonly in placebo

3.    Reported over 3 years in a COPD study

4.    See section 4.4

5.    See section 5.1.

 

Description of selected adverse reactions

 

The pharmacological side effects of beta-2-agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.

 

Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Seretide Diskus.

 

Paediatric population

 

Possible systemic effects 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.

Updated on 13/08/2012 and displayed until 04/03/2013
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   29-Jun-2012
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Change to Section 4.8
Updated on 01/06/2012 and displayed until 13/08/2012
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   07-Mar-2012
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Changes to:

Section 4.4 - Special warnings and precautions for use,
Section 4.8 - Undesirable effects

Updated on 16/09/2011 and displayed until 01/06/2012
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
Date of revision of text on the SPC:   25-Jul-2011
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



SUMMARY OF PRODUCT CHARACTERISTICS

 

4.4     Special warnings and precautions for use

 

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, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. 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.

 

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.

 

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents <16years taking high doses of fluticasone propionate (typically ³ 1000mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000mcg. 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.

 

SUMMARY OF PRODUCT CHARACTERISTICS

 

4.4     Special warnings and precautions for use

 

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, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. 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.

 

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.

 

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents <16years taking high doses of fluticasone propionate (typically ³ 1000mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000mcg. 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.

 

 

4.4     Special warnings and precautions for use

(cont‘d)

 

……

 

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).

 

 

 

4.4     Special warnings and precautions for use

(cont‘d)

 

…..

 

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

 

Children and adolescents <16years taking high doses of fluticasone propionate (typically ³ 1000mcg/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.

 

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored. The dose of inhaled corticosteroid should be reduced to the lowest dose at which effective control of asthma is maintained.

 

 

4.6     Pregnancy and lactation

 

There are insufficient data on the use of salmeterol and fluticasone propionate during pregnancy and lactation in man to assess the possible harmful effects. In animal studies foetal abnormalities occur after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3).

 

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

 

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

 

There are no data available for human breast milk. Both salmeterol and fluticasone propionate are excreted into breast milk in rats. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

 

4.6     Fertility, pregnancy and lactation

 

Fertility

 

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

 

Pregnancy

 

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3).

 

There are insufficient data on the use of salmeterol and fluticasone propionate during pregnancy and lactation in man to assess the possible harmful effects. In animal studies foetal abnormalities occur after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3).

 

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

 

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

 

Lactation

 

There are no data available for human breast milk. Both salmeterol and fluticasone propionate are excreted into breast milk in rats. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

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

 

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

 

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

 

 

Updated on 13/05/2010 and displayed until 16/09/2011
Reasons for adding or updating:
  • Change to section 1 - Name of medicinal product
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
Date of revision of text on the SPC:   23-Apr-2010
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



1.       NAME OF THE MEDICINAL PRODUCT

 

Seretide 100 Diskus 50 microgram/100 microgram/dose inhalation powder, pre-dispensed.

 

Seretide 250 Diskus 50 microgram/250 microgram/dose inhalation powder, pre-dispensed.

 

Seretide 500 Diskus 50 microgram/500 microgram/dose inhalation powder, pre-dispensed.

                                                    

4.4     Special warnings and precautions for use

 

The management of asthma should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.

 

Seretide Diskus 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 medicinal product to be used for relief in an acute asthma attack available at all times.

 

Patients should not be initiated on Seretide 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 Seretide. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Seretide.

 

Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of 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. The patient should also be medically reviewed where the current dosage of Seretide has failed to give adequate control of asthma.

 

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Seretide. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Seretide should be used (see section 4.2).

 

For patients with asthma or COPD, consideration should be given to additional corticosteroid therapies.

 

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

 

As with all inhaled medication containing corticosteroids, Seretide should be administered with caution in patients with pulmonary tuberculosis.

 

Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Therefore Seretide should be used with caution in patients with severe cardiovascular disorders, heart rhythm abnormalities, 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.

 

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Seretide Diskus should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

 

Seretide contains lactose up to 12.5 milligram /dose. This amount does not normally cause problems in lactose intolerant people.

 

Care should be taken when transferring patients to Seretide therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.

 

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, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. 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.

 

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.

 

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents <16years taking high doses of fluticasone propionate (typically ³ 1000mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000mcg. 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. 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.

 

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).

 

There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving Seretide 50/500 micrograms bd compared with placebo as well as in studies SCO40043 and SCO100250 comparing the lower non-approved COPD dose of Seretide, 50/250 micrograms bd, to salmeterol 50 micrograms bd only (see section 4.8 and section 5.1). A similar incidence of pneumonia in the Seretide group was seen across all studies. In TORCH, older patients, patients with a lower body mass index (<25kg/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 the treatment with Seretide should be re-evaluated.

 

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

 

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).

 

4.8         Undesirable effects

 

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

 

Adverse events which have been associated with salmeterol/fluticasone propionate are given below, listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (³1/100 and <1/10), uncommon (³1/1000 and <1/100), rare (³1/10,000 to <1/1000), and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were derived from clinical trial data. The incidence in placebo was not taken into account. Very rare events were derived from post-marketing spontaneous data.

 

NOTE:

The changes to this table relate purely to sequence and layout issues.

There are no changes to the adverse events and/or frequency. 

System Organ Class

Adverse Event

Frequency

Infections & Infestations

 

 

 

 

Cardiac Disorders

Candidiasis of the mouth and throat

 

Pneumonia

Bronchitis

 

Palpitations

Tachycardia

Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles).

 

Common

 

Common1,3,5

 

Common1,3

 

Common

Uncommon

Very Rare

Immune System Disorders

 

 

 

 

 

 

 

 

Nervous System Disorders

Hypersensitivity reactions with the following manifestations:

Cutaneous hypersensitivity reactions

Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions including anaphylactic shock

 

Headache


Tremor

 




Uncommon

Very Rare

 

 

 

 

*Very Common

Common

Endocrine Disorders

 

 

 

Eye Disorders

Cushing’s syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density

Cataract, Glaucoma

 

Very Rare4

 

 

 

 

Very Rare

Metabolism & Nutrition Disorders

 

 

Respiratory, Thoracic & Mediastinal Disorders

Hypokalaemia

 

Hyperglycaemia

Nasopharyngitis


Throat irritation

Hoarseness/dysphonia

Sinusitis

Paradoxical bronchospasm

 

Common3

 

Very Rare4

 

**#Very Common

Common

Common

*#Common


Very Rare

Psychiatric Disorders

 

 

Skin and subcutaneous tissue disorders

 

Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children)

 

Contusions

 

Very Rare

 

 

 

*#Common

Nervous System Disorders

 

 

Musculoskeletal & Connective Tissue Disorders

Headache

Tremor

 

Muscle cramps

Traumatic fractures

Arthralgia

Myalgia

 

Very Common1

Common

 

Common

*#Common

Very Rare

Very Rare

Eye Disorders

 

Endocrine Disorders

 

Cataract, Glaucoma

 

Cushing’s syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density

Very Rare4

 

Very Rare

 

Cardiac Disorders

 

 

 

 

 

 

Metabolism & Nutrition Disorders

 

Palpitations

Tachycardia

Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles).

 

Hypokalaemia

 

Hyperglycaemia

Common

Uncommon

Very Rare

 

 

Common

 

Very Rare

 

 

Respiratory, Thoracic & Mediastinal Disorders

 

 

 

 

 

 

 

Infections & Infestations

 

Nasopharyngitis


Throat irritation

Hoarseness/dysphonia

Sinusitis

Paradoxical bronchospasm

 

Candidiasis of the mouth and throat

 

Pneumonia

Bronchitis

 

Very Common2,3

Common

Common

Common1,3


Very Rare4

 

Common

 

*#Common

 

*#Common

 

Skin and subcutaneous tissue disorders

 

Immune System Disorders

 

 

Contusions

 

 

 

Hypersensitivity reactions with the following manifestations:

Cutaneous hypersensitivity reactions

Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions including anaphylactic shock

 

Common1,3

 

 

 

 

 

 

Uncommon

Very Rare

Musculoskeletal & Connective Tissue Disorders

 

 

 

 

 

Psychiatric Disorders

 

Muscle cramps

Traumatic fractures

Arthralgia

Myalgia

 

Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children)

 

Common

Common1,3

Very Rare

Very Rare

 

Very Rare

 

1.    Reported commonly in placebo

2.    Reported very commonly in placebo

3.    Reported over 3 years in a COPD study

4.    See section 4.4

5.    See section 5.1.

 

Description of selected adverse reactions

 

The pharmacological side effects of beta-2-agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.

 

Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Seretide Diskus.

 

Pneumonia was reported in studies of patients with COPD (see section 5.1)

 

Paediatric population

 

Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, and growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.

 

There have been very rare reports of hyperglycaemia (see section 4.4).

 

As with other inhalation therapy, paradoxical broncospasm may occur (see section 4.4).

 

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic Group:   Adrenergics and other anti-asthmatics.

 

ATC Code:                                          R03AK06

 

Seretide 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 Seretide 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 Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose.

 

Well Controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Seretide compared to 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 Seretide treatment compared to 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/FP

FP

WC

TC

WC

TC

No ICS (SABA alone)

78%

50%

70%

40%

Low dose ICS ( ≤500mcg BDP or equivalent/day)

75%

44%

60%

28%

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

62%

29%

47%

16%

Pooled results across the 3 treatment levels

71%

41%

59%

28%

*Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus 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 lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy

 

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

 

A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide for up to 14 days resulted in a small increase in beta-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 to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy.

 

Seretide COPD clinical trials

 

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

 

 

Placebo

N = 1524

Salmeterol 50

N = 1521

FP 500

N = 1534

Seretide 50/500

N = 1533

All cause mortality at 3 years

Number of deaths (%)

231

(15.2%)

205

(13.5%)

246

(16.0%)

193

(12.6%)

Hazard Ratio vs Placebo (CIs)
p value

N/A

0.879
(0.73, 1.06)
0.180

1.060
(0.89, 1.27)
0.525

0.825
(0.68, 1.00 )
0.0521

Hazard Ratio Seretide 50/500 vs components (CIs)
p value

N/A

0.932
(0.77, 1.13)
0.481

0.774
(0.64, 0.93)
0.007

N/A

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 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/ FP 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 (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-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.

 

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

 

Mechanism of action:

 

Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below:

 

Salmeterol:

 

Salmeterol is a selective long-acting (12 hour) beta-2-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 beta-2-agonists.

 

Fluticasone propionate:

 

Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.

Updated on 16/11/2009 and displayed until 13/05/2010
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
Date of revision of text on the SPC:   01-Oct-2009
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



SUMMARY OF PRODUCT CHARACTERISTICS (changes in red)

 

4.4   Special warnings and precautions for use

 

…..

 

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

 

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).

 

 

4.5   Interaction with other medicinal products and other forms of interaction

 

Both non-selective and selective beta-blockers should be avoided unless there are compelling reasons for their use.

 

Concomitant use of other beta-adrenergic containing drugs can have a potentially additive effect.

 

Fluticasone Propionate

 

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

 

In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly potent cytochrome P450 3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma concentrations several hundred fold, resulting in markedly reduced serum cortisol concentrations. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing’s syndrome and adrenal suppression have been reported. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side-effects.

 

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

Salmeterol

 

Potent CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 mcg inhaled twice daily) in 15 healthy subjects for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This may lead to an increase in the incidence of other systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared with salmeterol or ketoconazole treatment alone (see Section 4.4).



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

 

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

 

Moderate CYP 3A4 inhibitors

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



Updated on 27/04/2009 and displayed until 16/11/2009
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   04/2009
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

 

SUMMARY OF CHANGES  TO SPC (Changes in Red)

 

4.4     Special warnings and precautions for use

 

.

 

There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving Seretide compared with placebo (see section 4.8 and 5.1). In TORCH, older patients, patients with a lower body mass index (<25kg/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 the treatment with Seretide should be re-evaluated.

 

.etc

 

 

4.8         Undesirable effects

 

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

 

Adverse events which have been associated with salmeterol/fluticasone propionate are given below, listed by system organ class and frequency. Frequencies are defined as: very common (1/10), common (1/100 and <1/10), uncommon (1/1000 and <1/100), rare (1/10,000 to <1/1000), and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were derived from clinical trial data. The incidence in placebo was not taken into account. Very rare events were derived from post-marketing spontaneous data.

 

Cataract & Glaucoma have been removed from Endocrine Disorders and moved to Eye Disorders, a new classification. In addition the order in which the System Order Classifications appear in the table below has been rearranged slightly, however there have been no changes made to the actual Adverse Events or the Frequency.


System Organ Class

Adverse Event

Frequency

Cardiac Disorders

Palpitations

Tachycardia

Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles).

Common

Uncommon

Very Rare

Nervous System Disorders

Headache

Tremor

*Very Common

Common

Eye Disorders

Cataract, Glaucoma

Very Rare

Respiratory, Thoracic & Mediastinal Disorders

Nasopharyngitis


Throat irritation

Hoarseness/dysphonia

Sinusitis

Paradoxical bronchospasm

**#Very Common

Common

Common

*#
Common


Very Rare

Skin and subcutaneous tissue disorders

Contusions

*#Common

Musculoskeletal & Connective Tissue Disorders

Muscle cramps

Traumatic fractures

Arthralgia

Myalgia

 

Common

*#Common

Very Rare

Very Rare

Endocrine Disorders

Cushings syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density.

Very Rare

Metabolism & Nutrition Disorders

Hypokalaemia

 

Hyperglycaemia

#Common

 

Very Rare

Infections & Infestations

Candidiasis of the mouth and throat

 

Pneumonia

Bronchitis

Common

 

*#Common

 

*#Common

Immune System Disorders

Hypersensitivity reactions with the following manifestations:

Cutaneous hypersensitivity reactions

Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions including anaphylactic shock




Uncommon

Very Rare

Psychiatric Disorders

Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children)

Very Rare

*Reported commonly in placebo

**Reported very commonly in placebo

#Reported over 3 years in a COPD study

 

.etc

 

Updated on 03/07/2008 and displayed until 27/04/2009
Reasons for adding or updating:
  • Change to section 1 - Name of medicinal product
  • Change to section 5.2 - Pharmacokinetic properties
Date of revision of text on the SPC:   05/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

1.         NAME OF THE MEDICINAL PRODUCT

Typo changes

 

5.2       Pharmacokinetic properties

 

Changed from   “The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies between approximately 5-11% of the nominal dose depending on the inhalation device used.

 

To  “The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies between approximately 10-30% of the nominal dose depending on the inhalation device used

 

 

Updated on 11/09/2007 and displayed until 03/07/2008
Reasons for adding or updating:
  • New SPC for medicines.ie

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Active Ingredients

 
   Fluticasone Propionate
   Salmeterol Xinafoate