Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2021 Publisher: GlaxoSmithKline NZ Limited, Private Bag 106600, Downtown, Auckland, New Zealand
SERETIDE is contraindicated in patients with a history of hypersensitivity to salmeterol xinafoate, fluticasone propionate or any of the excipients listed in Section 6.1 List of excipients.
SERETIDE should not be initiated in patients during an exacerbation, or if they have unstable or acutely deteriorating asthma.
SERETIDE Inhaler is not for relief of acute symptoms for which a fast and shortacting bronchodilator (e.g. salbutamol) is required. Patients should be advised to have their relief medication available at all times.
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 of SERETIDE.
Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control.
Sudden and progressive deterioration in control of asthma is potentially lifethreatening and the patient should be reviewed by a physician. Consideration should be given to increasing corticosteroid therapy. Also, where the current dosage of SERETIDE has failed to give adequate control of ROAD, the patient should be reviewed by a physician.
Patients should be advised to seek medical attention if sudden deterioration of their asthma occurs, if they find that short-acting relief bronchodilator treatment becomes less effective or if they need more inhalations than usual.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast and short-acting inhaled bronchodilator. Salmeterol-fluticasone propionate ACCUHALER or Inhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary (see Section 4.8 Undesirable effects).
The pharmacological side-effects of beta-2 agonist treatment, such as tremor, subjective palpitations and headaches have been reported, but tend to be transient and to reduce with regular therapy (see Section 4.8 Undesirable effects).
There was an increased reporting of pneumonia in studies of patients with COPD receiving SERETIDE (see Section 4.8 Undesirable effects). Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbation frequently overlap.
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.
Treatment with SERETIDE should not be stopped abruptly in patients with asthma due to risk of exacerbation; therapy should be titrated-down under physician supervision.
For patients with COPD cessation of therapy may be associated with symptomatic decompensation and should be supervised by a physician.
SERETIDE contains an inhaled corticosteroid (fluticasone propionate).
Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods; however, these effects are much less likely to occur than with oral corticosteroids (see Section 4.9 Overdose). Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation and (very rarely) behavioural disturbances in children and adolescents, decrease in bone mineral density, cataract, glaucoma and central serous chorioretinopathy. Therefore, it is important, that the patient is reviewed regularly and the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained.
The possibility of impaired adrenal response should always be borne in mind in emergency and elective situations likely to produce stress and appropriate corticosteroid treatment considered (see Section 4.9 Overdose).
Because of the possibility of impaired adrenal response, patients transferring from oral steroid therapy to inhaled fluticasone propionate therapy should be treated with special care, and adrenocortical function regularly monitored.
Following introduction of inhaled fluticasone propionate, withdrawal of systemic therapy should be gradual and patients encouraged to carry a steroid warning card indicating the possible need for additional therapy in times of stress.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.
In rare cases inhaled therapy may unmask underlying eosinophilic conditions (e.g. Churg Strauss syndrome). These cases have usually been associated with reduction or withdrawal of oral corticosteroid therapy. A direct causal relationship has not been established.
As with all inhaled medication containing corticosteroids, SERETIDE should be administered with caution in patients with active or quiescent pulmonary tuberculosis.
SERETIDE should be administered with caution in patients with thyrotoxicosis.
Cardiovascular effects, such as increases in systolic blood pressure and heart rate, may occasionally be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. Rarely, SERETIDE may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation. Therefore, SERETIDE should be used with caution in patients with pre-existing cardiovascular disorders.
A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher therapeutic doses. Therefore, SERETIDE should be used with caution in patients predisposed to low levels of serum potassium.
There have been very rare reports of increases in blood glucose levels (see Section 4.8 Undesirable effects) and this should be considered when prescribing to patients with a history of diabetes mellitus.
During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects (see Section 4.5 Interaction with other medicines and other forms of interaction).
It was observed in a drug interaction study that concomitant use of systemic ketoconazole increases exposure to salmeterol. This may lead to prolongation in the QTc interval. Caution should be exercised when strong CYP3A4 inhibitors (e.g. ketoconazole) are co-administered with salmeterol (see Section 4.5 Interaction with other medicines and other forms of interaction and Section 5.2 Pharmacokinetic properties).
Patients that have poor inhaler technique may benefit from the consistent use of a spacer device with their metered dose inhaler (MDI or ‘puffer’). Use of a spacer will also decrease the amount of drug deposited in the mouth and back of the throat, and therefore reduce the incidence of local side effects such as ‘thrush’ and a hoarse voice.
A change in the make of spacer may be associated with alterations in the amount of drug delivered to the lungs. The clinical significance of these alterations is uncertain. However, in these situations, the person should be monitored for any loss of asthma control.
If using a spacer, there are two potential techniques that can be described to the patient:
Static on the walls of the spacer may cause variability in drug delivery. Patients should be instructed to wash the spacer in warm water and detergent and allow it to air dry without rinsing or drying with a cloth. This should be performed before initial use of the spacer and at least monthly thereafter.
Both non-selective and selective beta-blockers should be avoided, unless there are compelling reasons for their use.
Co-administration of ketoconazole and salmeterol resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This may lead to prolongation of the QTc interval. Due to the potential increased risk of cardiovascular adverse events, the concomitant use of salmeterol with strong CYP3A43 inhibitors (e.g. ketoconazole, atazanavir, ritonavir, clarithromycin, indinavir, intraconazole, nefazodone, nelfinavir and saquinavir) is not recommended (see Section 4.4 Special warnings and precautions for use and Section 5.2 Pharmacokinetic properties ).
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.
A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects.
Studies have shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. Nevertheless, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.
There are limited data in pregnant women. Administration during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
An observational retrospective epidemiological cohort study utilising electronic health records from the United Kingdom was conducted to evaluate the risk of MCMs following first trimester exposure to inhaled fluticasone propionate alone and salmeterol-fluticasone propionate relative to non-fluticasone propionate containing inhaled corticosteroids. No placebo comparator was included in this study.
Within the asthma cohort of 5362 first trimester inhaled corticosteroids-exposed pregnancies, 131 diagnosed MCMs were identified; 1612 (30%) were exposed to fluticasone propionate or salmeterol-fluticasone propionate of which 42 diagnosed MCMs were identified. The adjusted odds ratio for MCMs diagnosed by 1 year was 1.1 (95%CI: 0.5-2.3) for fluticasone propionate exposed vs non-fluticasone propionate inhaled corticosteroid exposed women with moderate asthma and 1.2 (95%CI: 0.7-2.0) for women with considerable to severe asthma. No difference in the risk of MCMs was identified following first trimester exposure to fluticasone propionate alone versus salmeterol-fluticasone propionate. Absolute risks of MCM across the asthma severity strata ranged from 2.0 to 2.9 per 100 fluticasone propionate-exposed pregnancies which is comparable to results from a study of 15,840 pregnancies unexposed to asthma therapies in the General Practice Research Database (2.8 MCM events per 100 pregnancies).
Results from the retrospective epidemiological study did not find an increased risk of major congenital malformations (MCMs) following exposure to fluticasone propionate when compared to other inhaled corticosteroids, during the first trimester of pregnancy.
Reproductive toxicity studies in animals, either with single agent or in combination, revealed the foetal effects expected at excessive systemic exposure levels of a potent beta-2-adrenoreceptor agonist and glucocorticosteroid.
Extensive clinical experience with agents in these classes has revealed no evidence that the effects are relevant at therapeutic doses.
Administration during lactation should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
There is insufficient experience of the use of salmeterol xinafoate and fluticasone propionate in human lactation. Salmeterol and fluticasone propionate concentrations in plasma after inhaled therapeutic doses are very low and therefore concentrations in human breast milk are likely to be correspondingly low. This is supported by studies in lactating animals, in which low agent concentrations were measured in milk. There are no data available for human breast milk.
There are no data on human fertility. Animal studies indicate no effects of fluticasone propionate or salmeterol xinofoate on male or female fertility.
There have been no specific studies of the effect of SERETIDE on the above activities, but the pharmacology of both agents does not indicate any effect.
All of the adverse reactions associated with the individual components, salmeterol xinafoate and fluticasone propionate, are listed below. There are no additional adverse reactions attributed to the combination product when compared to the adverse event profiles of the individual components.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1000 to <1/100), Rare (>1/10,000 to <1/1000), Very rare (<1/10,000) including isolated reports.
The majority of frequencies were determined from pooled clinical trial data from 23 asthma and 7 COPD studies. Not all events were reported in clinical trials. For these events, the frequency was calculated based on spontaneous data.
Common: Candidiasis of mouth and throat, pneumonia (in COPD patients)
Rare: Oesophageal candidiasis
Hypersensitivity Reactions:
Uncommon: Cutaneous hypersensitivity reactions, dyspnoea
Rare: Anaphylactic reactions
Possible systemic effects include (see Section 4.4 Special warnings and precautions for use):
Uncommon: Cataract
Rare: Glaucoma
Uncommon: Hyperglycaemia
Uncommon: Anxiety, sleep disorders
Rare: Behavioural changes, including hyperactivity and irritability (predominantly in children)
Very common: Headache (see Section 4.4 Special warnings and precautions for use)
Uncommon: Tremor (see Section 4.4 Special warnings and precautions for use)
Uncommon: Palpitations (see Section 4.4 Special warnings and precautions for use), tachycardia, atrial fibrillation
Rare: Cardiac arrhythmias including supraventricular tachycardia and extrasystoles
Common: Hoarseness/dysphonia
Uncommon: Throat irritation
Uncommon: Contusions
Common: Muscle cramps, arthralgia
Hypersensitivity reactions manifesting as:
Rare: Angioedema (mainly facial and oropharyngeal oedema) and bronchospasm
Possible systemic effects include (see Section 4.4 Special warnings and precautions for use):
Rare: Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density
Rare: Paradoxical bronchospasm (see Section 4.4 Special warnings and precautions for use).
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via: https://nzphvc.otago.ac.nz/reporting/.
None reported.
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