Source: Medicines Authority (MT) Revision Year: 2022 Publisher: Glenmark Pharmaceuticals Nordic AB, Propellergatan 2, SE-211 15 Malmö, Sweden
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Salmex is for use in patients with severe asthma only. It should not be used to treat acute asthma symptoms for which a fast- and short- acting bronchodilator is required.
Patients should be advised to have their inhaler to be used for relief in an acute asthma attack available at all times.
Patients should not be initiated on Salmex 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 Salmex. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Salmex.
Increased requirements for use of reliever medication (short-acting bronchodilators), or decreased response to reliever medication indicate deterioration of control and patients should be reviewed by a physician.
Sudden and progressive deterioration in control of asthma is potentially lifethreatening and the patient should undergo urgent medical assessment. Consideration should be given to increasing corticosteroid therapy.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of the inhaled corticosteroid and therefore a change to an alternative fixed-dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled corticosteroid is required. Regular review of patients as treatment is stepped down is important. The lowest dose of inhaled corticosteroid should be used.
For patients with COPD experiencing exacerbations, treatment with systemic corticosteroids is typically indicated, therefore patients should be instructed to seek medical attention if symptoms deteriorate with Salmex .
Treatment with Salmex 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, Salmex should be administered with caution in patients with active or quiescent pulmonary tuberculosis and fungal, viral or other infections of the airway. Appropriate treatment should be promptly instituted, if indicated.
Rarely, Salmex may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Salmex should be used with caution in patients with severe cardiovascular disorders or heart rhythm abnormalities and in patients with diabetes mellitus, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium.
There have been very rare reports of increases in blood glucose levels (see section 4.8) and this should be considered when prescribing to patients with a history of diabetes mellitus.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Salmex should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
The pharmacological side effects of β2 agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.
Salmex contains lactose up to 13.3 milligram /dose. This amount does not normally cause problems in lactose intolerant people.
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 adolescents) (see Paediatric population sub-heading below for information on the systemic effects of inhaled corticosteroids in adolescents). 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. Therefore these patients should be treated with special care and adrenocortical function regularly monitored. Patients who have required high dose emergency corticosteroid therapy in the past may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures.
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).
An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.
There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.
Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.
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).
Adolescents <16 years taking high doses of fluticasone propionate (typically ≥ 1000 micrograms/day) may be at particular risk. Systemic effects may occur, particularly at high doses prescribed for long periods. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, acute adrenal crisis and growth retardation in adolescents and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression. Consideration should be given to referring the adolescent to a paediatric respiratory specialist.
It is recommended that the height of adolescents 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.
β adrenergic blockers may weaken or antagonise the effect of salmeterol. Both nonselective and selective β blockers should be avoided unless there are compelling reasons for their use. Potentially serious hypokalaemia may result from β2 agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics.
Concomitant use of other β adrenergic containing drugs can have a potentially additive effect.
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 CYP3A4 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 CYP3A4 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 and cobicistat-containing products, and moderate CYP3A inhibitors, such as erythromycin, is also expected to increase the systemic fluticasone propionate exposure and the risk of systemic side effects. Combinations should be avoided unless the benefit outweighs the potential increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.
Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 micrograms 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).
Co-administration of erythromycin (500 mg orally three times a day) and salmeterol (50 micrograms 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.
A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicates no malformative or feto/neonatal toxicity related to salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of β2 adrenoreceptor agonists and glucocorticosteroids (see section 5.3).
Administration of Salmex to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.
The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women.
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 Salmex therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility.
Salmex has no or negligible influence on the ability to drive and use machines.
As Salmex 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 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 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 (in COPD patients) Bronchitis Oesophageal candidiasis | Common Common1,3,5 Common1,3 Rare |
| 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 | Uncommon Rare Uncommon Rare Rare |
| Endocrine Disorders | Cushing’s syndrome, Cushingoid features, Adrenal suppression, Growth retardation in adolescents, Decreased bone mineral density | Rare4 |
| Metabolism & Nutrition Disorders | Hypokalaemia Hyperglycaemia | Common3 Uncommon4 |
| Psychiatric Disorders | Anxiety Sleep disorders Behavioural changes, including psychomotor hyperactivity and irritability (predominantly in adolescents) Depression, aggression (predominantly in adolescents) | Uncommon Uncommon Rare Not Known |
| Nervous System Disorders | Headache Tremor | Very Common1 Uncommon |
| Eye Disorders | Cataract Glaucoma Vision, blurred | Uncommon Rare4 Not known4 |
| Cardiac Disorders | Palpitations Tachycardia Cardiac arrhythmias (including supraventricular tachycardia and extrasystoles). Atrial fibrillation Angina pectoris | Uncommon Uncommon Rare Uncommon Uncommon |
| Respiratory, Thoracic & Mediastinal Disorders | Nasopharyngitis Throat irritation Hoarseness/dysphonia Sinusitis Paradoxical bronchospasm | Very Common2,3 Common Common Common1,3 Rare4 |
| Skin and subcutaneous tissue disorders | Contusions | Common1,3 |
| Musculoskeletal & Connective Tissue Disorders | Muscle cramps Traumatic fractures Arthralgia Myalgia | Common 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.
The pharmacological side effects of β2 agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Salmex should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat and, rarely, of the oesophagus can occur in some patients. Both hoarseness and incidence of mouth and throat candidiasis may be relieved by rinsing the mouth with water and/or brushing the teeth after using the product. Symptomatic mouth and throat candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Salmex inhaler.
Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression and growth retardation in adolescents (see section 4.4). Adolescents may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal
Not applicable.
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