Salmeterol/ Fluticasone Propionate

Registered South African indications:

• Atopic asthma
• Chronic obstructive pulmonary disease (COPD) (acc)

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active ingredients or any of the excipients in this combination product

Cautions
South African recommendations

50/100 (μg) acc and inh

• Pregnancy
• Breastfeeding
• Acute asthma symptoms for which a fast and short-acting bronchodilator is required
• Uncontrolled or worsening asthma symptoms after initiation
• Increased requirements for reliever medication (short-acting bronchodilators) or decreased response to reliever agent
• Sudden and progressive deterioration in control of asthma
• Abrupt withdrawal
• Active or quiescent pulmonary tuberculosis
• Thyrotoxicosis
• High doses for prolonged periods
• Need for supplementary systemic steroid during periods of stress
  - Worsening asthma attacks
  - Chest infections
  - Major intercurrent illness
  - Surgery
  - Trauma
• Patients transferred from other inhaled steroids or oral steroids
• Patients who have required high-dose emergency corticosteroid therapy in the past (inh)
• Patients who require high doses of inhaled steroids and/or intermittent treatment with oral steroids in a medical or surgical emergency (inh)

50/250 (μg) and 50/500 (μg) acc

• Pregnancy
• Breastfeeding
• Acute asthma symptoms for which a fast and short-acting bronchodilator is required
• Initiation during an exacerbation, significantly worsening or acutely deteriorating asthma
• Uncontrolled or worsening asthma symptoms after initiation
• Increased requirements for reliever medication (short-acting bronchodilators) or decreased response to reliever agent
• Sudden and progressive deterioration in control of asthma
• Children and adolescents below 16 years taking high doses of fluticasone propionate (typically ≥1000μg/day)
• Patients with chronic obstructive pulmonary disease (COPD) experiencing exacerbations
• During periods of stress or elective surgery
• Abrupt withdrawal
• Active or quiescent pulmonary tuberculosis
• Fungal, viral or other infections of the airway
• Severe cardiovascular disorders or heart rhythm abnormalities 
• Diabetes mellitus 
  - History of diabetes mellitus
• Thyrotoxicosis
• Uncorrected hypokalaemia 
• Predisposition to low serum potassium levels
• High doses for prolonged periods
• Doses of fluticasone propionate  500-<1000μg
• Situations which could potentially trigger acute adrenal crisis
  - Trauma
  - Surgery
  - Infection
  - Rapid reduction in dosage
• Patients transferring from oral steroids
• Patients who have required high-dose emergency corticosteroid therapy in the past
• Risk factors associated with pneumonia in patients with chronic obstructive pulmonary disease (COPD)
  - Smoking
  - Elderly
  - Low body mass index (BMI)
  - Severe chronic obstructive pulmonary disease (COPD) 
• Fructose intolerance
• Galactose intolerance
• Galactosaemia
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Hepatic impairment
• Children and adolescents below 16 years taking high doses of fluticasone propionate (typically ≥1000μg/day)
• Acute asthma symptoms for which a fast and short-acting bronchodilator is required
• Exacerbation, significantly worsening or acutely deteriorating asthma
• Uncontrolled or worsening asthma symptoms after initiation
• Increased requirements for reliever medication (short-acting bronchodilators) or decreased response to reliever agent
• Sudden and progressive deterioration in control of asthma
• Patients with chronic obstructive pulmonary disease (COPD) experiencing exacerbations (acc, in certain formulations)
• Abrupt withdrawal
• Active or quiescent pulmonary tuberculosis
• Fungal, viral or other infections of the airway
• Severe cardiovascular disorders or heart rhythm abnormalities
• Diabetes mellitus
  - History of diabetes mellitus
• Thyrotoxicosis
• Uncorrected hypokalaemia
• Predisposition to low serum potassium levels
• High doses for prolonged period
• Doses of fluticasone propionate  500-<1000μg
• During periods of stress or elective surgery
• Emergency and elective situations likely to produce stress
• Use of a spacer device with a metered dose inhaler (inh)
• Patients transferring from oral steroids
• Patients who have required high-dose emergency corticosteroid therapy in the past
• Risk factors associated with pneumonia in patients with chronic obstructive pulmonary disease (COPD) (inh)
  - Elderly
  - Lower body mass index (<25kg/m²)
  - Very severe COPD (FEV1 <30% predicted)
• Risk factors associated with pneumonia in patients with chronic obstructive pulmonary disease (COPD) (acc, in certain formulations)
  - Smoking
  - Elderly
  - Low body mass index (BMI)
  - Severe COPD (acc, in certain formulations) 
• Pneumonia and other lower respiratory tract infections in patients with chronic obstructive pulmonary disease (COPD) (inh)
• Pneumonia in patients with chronic obstructive pulmonary disease (COPD) (acc, in certain formulations)
• Situations which could potentially trigger acute adrenal crisis (acc, in certain formulations) 
  - Trauma
  - Surgery
  - Infection
  - Rapid reduction in dosage
• Galactose intolerance (acc)
• Total lactase deficiency (acc)
• Glucose-galactose malabsorption (acc)

Forms avail. in SA and covered in this monograph: acc, inh

South African registered indications and dosages

Atopic asthma
- Regular prophylactic treatment in those who have been stabilised on identical dosages of the components of salmeterol/ fluticasone propionate given concurrently

Salmeterol/ Fluticasone Propionate
25/50 (μg)
25/125 (μg)
25/250 (μg)

• Inhaled (inh): 2 inhalations, twice daily 

50/100 (μg)
50/250 (μg)
50/500 (μg)

• Inhaled (acc): 1 inhalation, twice daily

Chronic obstructive pulmonary disease (COPD)
- Regular treatment of COPD including chronic bronchitis and emphysema
- Symptomatic treatment of severe COPD (forced expiratory volume (FEV1) <50% predicted normal) and a history of repeated exacerbations, with significant symptoms despite regular bronchodilator therapy

Salmeterol/ Fluticasone Propionate
50/250 (μg)
50/500 (μg)

• Inhaled (acc): 1 inhalation, twice daily

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Salmeterol/ fluticasone propionate is for oral inhalation use only

---

Salmeterol/ fluticasone propionate must be used regularly for optimum benefit, even when asymptomatic

---

Patients should be regularly reassessed by a doctor so that the dosage of salmeterol/ fluticasone propionate they are receiving remains optimal and is only changed on medical advice (inh)

---

The dose should be titrated to the lowest dose at which effective control of symptoms is maintained

---

Salmeterol/ fluticasone propionate is not for the relief of asthma symptoms for which a fast and short-acting bronchodilator is required. Patients should have their relief medication available at all times

---

Increasing use of short-acting bronchodilators to relieve asthma symptoms indicates deterioration of asthma control

---

Sudden and progressive deterioration in control of asthma is potentially life-threatening and the patient should be reviewed. Consideration should be given to increasing corticosteroid therapy. Also, the patient should be reviewed when the current dosage of salmeterol/ fluticasone propionate has failed to give adequate control of reversible obstructive airways disease. Consideration should be given to additional corticosteroid therapies and to including administration of antibiotics if an infection is present

---

Treatment with salmeterol/ fluticasone propionate should not be stopped abruptly

---

Shake the inhaler well before use (inh)

Paed. forms avail. in SA and covered in this monograph: acc, inh

South African registered indications and dosages

Atopic asthma
- Regular prophylactic treatment in those who have been stabilised on identical dosages of the components of salmeterol/ fluticasone propionate given concurrently

Salmeterol/ Fluticasone Propionate
25/50 (μg)
25/125 (μg)
25/250 (μg)

• Younger than 12 years: No information available
• 12 years and older: See adult dosage

50/100 (μg)

• Younger than 4 years: Not established for use
• Older than 4 years: Inhaled (acc): 1 inhalation, twice daily

50/100 (μg)
50/250 (μg)
50/500 (μg)

• 12 years and older: See adult dosage

---

Salmeterol/ fluticasone propionate is for oral inhalation use only

---

Salmeterol/ fluticasone propionate must be used regularly for optimum benefit, even when asymptomatic

---

Patients should be regularly reassessed by a doctor

---

Patients should be regularly reassessed by a doctor so that the dosage of salmeterol/ fluticasone propionate they are receiving remains optimal and is only changed on medical advice (inh)

---

The dose should be titrated to the lowest dose at which effective control of symptoms is maintained

---

Salmeterol/ fluticasone propionate is not for the relief of asthma symptoms for which a fast and short-acting bronchodilator is required. Patients should have their relief medication available at all times

---

Increasing use of short-acting bronchodilators to relieve asthma symptoms indicates deterioration of asthma control

---

Sudden and progressive deterioration in control of asthma is potentially life-threatening and the patient should be reviewed. Consideration should be given to increasing corticosteroid therapy. Also, the patient should be reviewed when the current dosage of salmeterol/ fluticasone propionate has failed to give adequate control of reversible obstructive airways disease. Consideration should be given to additional corticosteroid therapies and to including administration of antibiotics if an infection is present

---

Treatment with salmeterol/ fluticasone propionate should not be stopped abruptly

---

Shake the inhaler well before use (inh)

Pregnancy

South African recommendations

• Caution; positive evidence of risk in animal studies
• Safety in pregnancy has not been established
• A large amount of data on pregnant women (>1000 pregnancy outcomes) indicates no malformative or foeto/neonatal toxicity related to salmeterol/ fluticasone propionate. Animal studies have shown reproductive toxicity after administration of beta-2 adrenoreceptor agonists and glucocorticosteroids (50/250 (μg) and 50/500 (μg) (acc))
• Fluticasone propionate: Corticosteroids have been shown to be teratogenic in animals. As these agents are absorbed when inhaled, teratogenicity following inhalation cannot be excluded (50/100 (μg) acc, inh)

Recommendations in other jurisdictions

• Caution; positive evidence of risk in animal studies
• A large amount of data on pregnant women (>1000 pregnancy outcomes) indicates no malformative or foeto/neonatal toxicity related to salmeterol/ fluticasone propionate. Animal studies have shown reproductive toxicity after administration of beta-2 adrenoreceptor agonists and glucocorticosteroids
• Administration of salmeterol/ fluticasone propionate 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

Breastfeeding

South African recommendations

• Caution 
• Safety in breastfeeding has not been established
• 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 (50/250 (μg) and 50/500 (μg) (acc))
• Salmeterol: There is no experience of the use of salmeterol in breastfeeding mothers (50/100 (μg) acc, inh)

Recommendations in other jurisdictions

• Caution 
• 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 breastfeeding or to discontinue salmeterol/ fluticasone propionate therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

South African recommendations

• There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility (50/250 (μg) and 50/500 (μg) (acc))
• No information available (50/100 (μg) acc, inh)

Recommendations in other jurisdictions

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

Renal Impairment

• No dose adjustment recommended 

Hepatic Impairment

South African recommendations

• No dose adjustment recommended 

Recommendations in other jurisdictions

• Caution; no information available 

Elderly

• No dose adjustment recommended 

Porphyria Information

• Probably not porphyrinogenic (PNP) 

Drugs in Sport

• Permitted - With warnings
  Prohibited substance: Salmeterol - refer to section S3 (Beta-2 agonists) of the world anti-doping agency (WADA) 2022 prohibited list
  All selective and non-selective beta-2 agonists, including all optical isomers, are prohibited except for
  - Inhaled salbutamol: maximum 1600μg over 24 hours in divided doses not to exceed 600μg over 8 hours starting from any dose
  - Inhaled formoterol: maximum delivered dose of 54μg over 24 hours
  - Inhaled salbutamol: maximum 200μg over 24 hours
  - Inhaled vilanterol: maximum 25μg over 24 hours
  Salmeterol, a beta-2-agonist was included in the WADA 2022 monitoring program to assess patterns and prevalence of misuse

  in- and out-of-competition below the minimum reporting level

Central Nervous System Disorders 

• Headache
• Tremor
• Anxiety
• Sleep disorders
• Behavioural changes (predominantly in children)
  - Psychomotor hyperactivity
  - Irritability
• Depression (predominantly in children)
• Aggression (predominantly in children)

Cardiovascular Disorders 

• Palpitations
• Tachycardia
• Atrial fibrillation
• Angina pectoris
• Cardiac arrhythmias
  - Supraventricular tachycardia
  - Extrasystoles

Respiratory Disorders 

• Respiratory symptoms
  - Dyspnoea
  - Bronchospasm
• Nasopharyngitis
• Pneumonia (in COPD patients)
• Bronchitis
• Throat irritation
• Hoarseness/dysphonia
• Sinusitis
• Paradoxical bronchospasm
  - Immediate increase in wheezing
  - Shortness of breath 

Gastrointestinal  Disorders 

• Candidiasis of the mouth and throat
• Oesophageal candidiasis

Endocrine and Metabolic Disorders

• Cushing's syndrome
• Cushingoid features
• Adrenal suppression
• Growth retardation in children and adolescents
• Hypokalaemia
• Hyperglycaemia

Musculoskeletal Disorders

• Muscle cramps
• Traumatic fractures
• Arthralgia
• Myalgia
• Decreased bone mineral density

Skin and Subcutaneous Tissue Disorders 

• Contusions

Immune, Blood and Lymphatic System Disorder

• Hypersensitivity reactions
• Cutaneous hypersensitivity reactions
• Angioedema
  - Facial oedema
  - Oropharyngeal oedema
• Anaphylactic reactions
  - Anaphylactic shock

Sensory Disorders 

• Cataract
• Glaucoma
• Blurred vision

Salmeterol/ fluticasone propionate

• Beta-adrenergic blockers
• Other beta adrenergic-containing agents
• Non-selective beta-blockers
• Selective beta blockers
• Beta-2 agonist
• Xanthine derivatives
• Steroids
• Diuretics

Salmeterol

• Potent CYP3A4 inhibitors
• Ketoconazole
• Itraconazole
• Telithromycin
• Ritonavir

Fluticasone propionate

• Ritonavir
• Potent CYP3A inhibitors
• Ketoconazole
• Itraconazole
• Cobicistat-containing agents
• Moderate CYP3A inhibitors
• Erythromycin

• Pulmonary function 
  - Forced expiratory volume (FEV1)
  - Peak flow
• Blood pressure
• Heart rate
• Central nervous system (CNS) stimulation
• Ophthalmic examination
  - Glaucoma 
  - Cataracts
• Bone mineral density 

Specific cases may require

• Serum potassium (hypokalemic patients)
• Blood glucose (diabetic patients)
• Growth (adolescents and children via stadiometry)

Additional observations

• Signs/symptoms of 
  - Oral candidiasis
  - Hypothalamic-pituitary-adrenal (HPA) axis suppression/adrenal insufficiency 

Salmeterol and fluticasone propionate have different modes of action. 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, with less adverse effects than when corticosteroids are administered systemically.

COMBINATION PREPARATIONS

Salmeterol/ Fluticasone Propionate

Inhaler 25μg/50μg

• Foxair 25/50 inhaler (GSK)
• Sereflo 25/50 HFA (Cipla Medpro)
• Sereflo 25/50 HFA (Syncrobreathe) (Cipla Medpro)
• Seretide 25/50 inhaler (GSK) originator

Inhaler 25μg/125μg

• Foxair 25/125 inhaler (GSK) 
• Sereflo 25/125 HFA (Cipla Medpro)
• Sereflo 25/125 HFA (Syncrobreathe) (Cipla Medpro)
• Seretide 25/125 inhaler (GSK) originator

Inhaler 25μg/250μg

• Foxair 25/250 inhaler (GSK) 
• Sereflo 25/250 HFA (Cipla Medpro)
• Sereflo 25/250 HFA (Syncrobreathe) (Cipla Medpro)
• Seretide 25/250 (GSK) originator

Accuhaler 50μg/100μg

• Foxair 50/100 accuhaler (GSK) 
• Sereflo DPI 50/100 (Cipla Medpro) 
• Seretide 50/100 accuhaler (GSK) originator

Accuhaler 50μg/250μg

• Airflusal Forspiro 50/250 (Sandoz SA) 
• Foxair 50/250 accuhaler (GSK)
• Sereflo DPI 50/250 (Cipla Medpro)
• Seretide 50/250 accuhaler (GSK) originator

Accuhaler 50μg/500μg

• Airflusal Forspiro 50/500 (Sandoz SA) 
• Foxair 50/500 accuhaler (GSK) 
• Seretide 50/500 accuhaler (GSK) originator