Combitide Starhaler^® (Powder) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

R03AK06 (Salmeterol and fluticasone)

Active Substances

Salmeterol (Rec.INN registered by WHO)

Fluticasone (Rec.INN registered by WHO)

Dosage Form

Combitide Starhaler®

Powder for inhalation, metered 25 mcg+250 mcg/1 dose: inhalers 60 doses

Dosage Form, Packaging, and Composition

Powder for inhalation, metered placed in a light blue plastic device (inhaler) with a blue cap, with a dose counter; inside the device is a plastic ring containing 60 cells with powder, sealed on top with aluminum foil on which the dose numbers are printed; the contents of the cells are a micronized white powder.

* the actual value is calculated based on 100% content of fluticasone propionate and salmeterol xinafoate (without recalculation to dry substance).

Excipients : lactose monohydrate micronized (Inhalation 120 MS or Lactohale 300) – 823 mcg, lactose monohydrate (Respitose SV001) – 8891 mcg.

60 doses – blister cells (60) – plastic inhalers with dose counter (1) – cardboard packs.

Clinical-Pharmacological Group

Drug with anti-inflammatory and bronchodilator action

Pharmacotherapeutic Group

Combined bronchodilator agent (selective beta₂-adrenomimetic + topical glucocorticosteroid)

Pharmacological Action

A combined preparation containing salmeterol and fluticasone propionate, which have different mechanisms of action. Salmeterol prevents the occurrence of bronchospasm symptoms, fluticasone propionate improves lung function and prevents disease exacerbation.

Salmeterol is a selective long-acting (up to 12 hours) agonist of β₂-adrenergic receptors, having a long side chain that binds to the external domain of the receptor. The pharmacological properties of salmeterol provide more effective protection against histamine-induced bronchoconstriction and longer bronchodilation (lasting at least 12 hours) than short-acting β₂-adrenergic receptor agonists.

In vitro studies have shown that salmeterol is a potent inhibitor of the release from human lungs of mast cell mediators such as histamine, leukotrienes, and prostaglandin D₂, and has a long duration of action.

Salmeterol inhibits the early and late phase response to inhaled allergens. Inhibition of the late phase response persists for more than 30 hours after a single dose, when the bronchodilator effect is no longer present. A single administration of salmeterol attenuates bronchial hyperreactivity. This indicates that salmeterol, in addition to bronchodilatory activity, has an additional action not related to bronchodilation, the clinical significance of which has not been definitively established. This mechanism of action differs from the anti-inflammatory effect of glucocorticosteroids.

Fluticasone – a glucocorticosteroid for topical application and when administered by inhalation in recommended doses, exerts a pronounced anti-inflammatory and anti-allergic effect in the lungs, leading to a reduction in clinical symptoms and a decrease in the frequency of exacerbations of bronchial asthma.

Pharmacokinetics

Salmeterol

It acts locally in lung tissues, so its plasma concentration does not correlate with therapeutic effects. Data on its pharmacokinetics are very limited, because when inhaled at therapeutic doses, its C_max in plasma is extremely low (about 200 pg/ml and below). After regular inhalations of salmeterol, hydroxynaphthoic acid can be detected in the blood, with C_ss of about 100 ng/ml. These concentrations are 1000 times lower than the C_ss observed in toxicity studies. Results of in vitro studies have shown that salmeterol is extensively metabolized by the cytochrome P450 isoenzyme CYP3A4 to α-hydroxysalmeterol via aliphatic oxidation.

Fluticasone

The absolute bioavailability of inhaled fluticasone propionate in healthy individuals varies depending on the inhaler used; when administering the combination of salmeterol and fluticasone propionate using a metered-dose aerosol inhaler, it is 5.3%. Patients with bronchial asthma and COPD have lower plasma concentrations of fluticasone propionate. Systemic absorption occurs primarily through the lungs. Initially, it is faster, but then its rate slows down. Part of the inhalation dose may be swallowed, but this part contributes minimally to systemic absorption due to the low solubility of fluticasone propionate in water and due to its presystemic metabolism; bioavailability from the gastrointestinal tract is less than 1%. As the inhalation dose increases, a linear increase in the plasma concentration of fluticasone propionate is observed. Fluticasone has a large V_d at steady state (about 300 L) and has a relatively high degree of binding to plasma proteins (91%). It is rapidly eliminated from the blood, mainly as a result of metabolism by the cytochrome P450 isoenzyme CYP3A4 to an inactive carboxylic metabolite. The distribution of fluticasone is characterized by rapid plasma clearance (1150 ml/min) and a terminal T_1/2 of approximately 8 hours. Renal clearance of unchanged fluticasone propionate is negligible (<0.2%), less than 5% of the dose is excreted in the urine as a metabolite.

Indications

For the regular treatment of bronchial asthma, if combination therapy with a long-acting beta₂-adrenergic agonist and an inhaled glucocorticosteroid is indicated.

For maintenance therapy in patients with COPD with a pre-bronchodilator FEV1 <60% of predicted and a history of repeated exacerbations, in whom significant disease symptoms persist despite regular bronchodilator therapy.

ICD codes

Dosage Regimen

For inhalation use only.

Individualize the dose and administration schedule based on disease severity and patient response.

For bronchial asthma in adults and adolescents (12 years and older): administer one inhalation twice daily.

The typical maintenance dose is 25 mcg salmeterol / 250 mcg fluticasone propionate per inhalation.

For patients requiring a higher dose of inhaled corticosteroid, a strength of 25 mcg/500 mcg may be used.

The maximum recommended daily dose is two inhalations of the 25 mcg/500 mcg strength.

For COPD maintenance therapy: administer one inhalation of 25 mcg/250 mcg twice daily.

For children (4 to 11 years): use only the 25 mcg/50 mcg strength; administer one inhalation twice daily.

Rinse the mouth with water after each inhalation to reduce the risk of oropharyngeal candidiasis.

Do not use this preparation for the relief of acute bronchospasm.

Ensure patients have access to a fast-acting bronchodilator for acute symptom relief.

Regularly assess patients and step down therapy to the lowest effective dose once asthma control is achieved.

Do not abruptly discontinue therapy; taper the dose gradually under medical supervision.

Adverse Reactions

Infections and parasitic diseases Common – oral and pharyngeal candidiasis, pneumonia (in patients with COPD); Rare – esophageal candidiasis.

Immune system disorders Hypersensitivity reactions: Uncommon – skin hypersensitivity reactions, dyspnea; Rare – anaphylactic reactions.

Endocrine system disorders Uncommon – cataract; Rare – glaucoma, Cushing’s syndrome, cushingoid symptoms, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density.

Metabolism and nutrition disorders: Uncommon – hyperglycemia; Very rare – hypokalemia.

Psychiatric disorders Uncommon – anxiety, sleep disorders; Rare – behavioral changes, including hyperactivity and irritability (especially in children).

Nervous system disorders Very common – headache; Uncommon – tremor.

Cardiac disorders Uncommon – palpitations, tachycardia, atrial fibrillation; Rare – arrhythmia, including ventricular extrasystole, supraventricular tachycardia and extrasystole.

Respiratory, thoracic and mediastinal disorders Common – hoarseness and/or dysphonia; Uncommon – pharyngeal irritation; Rare – paradoxical bronchospasm.

Skin and subcutaneous tissue disorders: Uncommon – bruising.

Musculoskeletal and connective tissue disorders Common – muscle spasms, arthralgia.

Contraindications

Hypersensitivity to the components of the drug; children under 4 years of age.

With caution patients with active or latent pulmonary tuberculosis; thyrotoxicosis; fungal, viral or bacterial respiratory tract infections; cardiovascular diseases, supraventricular tachycardia and extrasystole, ventricular extrasystole, atrial fibrillation; hypokalemia; glaucoma, cataract, osteoporosis; diabetes mellitus.

Use in Pregnancy and Lactation

Use during pregnancy and breastfeeding is only acceptable if the potential benefit to the mother outweighs the possible risk to the fetus or breastfed infant.

Special Precautions

This combination is not intended for the relief of acute symptoms, as a fast- and short-acting inhaled bronchodilator (e.g., salbutamol) should be used in such cases.

More frequent use of short-acting bronchodilators to relieve symptoms indicates worsening disease control, and in such situations, the patient should consult a doctor.

Sudden and increasing deterioration in bronchospastic syndrome control is a potential life-threatening situation, and in such situations, the patient should also consult a doctor.

Patients with asthma should not abruptly discontinue treatment with this combination; the dose of the drug should be reduced gradually under medical supervision. In patients with COPD, discontinuation of the drug may be accompanied by symptoms of decompensation and requires medical supervision.

Any inhaled glucocorticosteroid can cause systemic effects, especially with long-term use at high doses; however, the likelihood of such symptoms is much lower than with treatment with oral glucocorticosteroids. Possible systemic reactions include Cushing’s syndrome, cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract and glaucoma. Therefore, in the treatment of bronchial asthma, it is important to reduce the dose to the lowest dose that provides effective disease control.

In emergency and planned situations with a likelihood of stress, the possibility of adrenal cortex suppression and the need for glucocorticosteroid administration should always be considered.

During resuscitation or surgical interventions, assessment of the degree of adrenal insufficiency is required.

It is recommended to regularly measure the height of children receiving long-term therapy with inhaled glucocorticosteroids.

Due to the possibility of adrenal suppression, patients transferred from oral glucocorticosteroids to inhaled therapy with fluticasone propionate should be treated with particular caution and their adrenal cortex function should be regularly monitored.

After starting treatment with inhaled fluticasone, systemic glucocorticosteroids should be discontinued gradually, and such patients should carry a special patient card containing instructions about the possible need for additional glucocorticosteroid administration in stressful situations.

In patients with exacerbation of bronchial asthma, hypoxia, plasma potassium concentration should be monitored.

There are very rare reports of increased blood glucose levels; this should be taken into account when it is necessary to use this combination in patients with diabetes mellitus.

Drug Interactions

Due to the risk of bronchospasm, the use of selective and non-selective beta-blockers should be avoided, except in cases where they are absolutely necessary for the patient.

A drug interaction study has shown that ritonavir – a highly active inhibitor of the CYP3A4 isoenzyme – can cause a sharp increase in the plasma concentration of fluticasone propionate, resulting in a significant decrease in serum cortisol concentrations. There are reports of a clinically significant drug interaction between fluticasone and ritonavir, which led to systemic glucocorticosteroid effects, including Cushing’s syndrome and adrenal suppression. Therefore, it is recommended to avoid the concomitant use of fluticasone propionate and ritonavir, unless the potential benefit to the patient outweighs the risk associated with systemic glucocorticosteroid effects.

Studies have shown that other inhibitors of the CYP3A4 isoenzyme cause negligible (erythromycin) and slight (ketoconazole) increases in fluticasone plasma levels, with virtually no decrease in serum cortisol concentrations. Despite this, caution is recommended when co-administering fluticasone propionate and strong CYP3A4 inhibitors (e.g., ketoconazole), as such combinations may potentially increase fluticasone plasma concentrations, which could potentially increase its systemic effects.

In a drug interaction study, it was found that the use of ketoconazole as concomitant systemic therapy significantly increases the plasma concentration of salmeterol (increase in C_max by 1.4 times and AUC by 15 times). This may lead to prolongation of the QT_c interval. Caution should be exercised when co-administering strong CYP3A4 inhibitors (e.g., ketoconazole) and salmeterol.

Xanthine derivatives, glucocorticosteroids and diuretics increase the risk of hypokalemia (especially in patients with exacerbation of bronchial asthma, with hypoxia).

MAO inhibitors and tricyclic antidepressants increase the risk of adverse cardiovascular effects.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.