Aerocort Inhaler Beclomethasone Dipropionate and Salbutamol Inhaler COMPOSITION AEROCORT Inhaler Each actuation delivers: Beclomethasone Dipropionate IP…………. 50 mcg Salbutamol Sulphate IP equivalent to Salbutamol …..100mcg Suspended in propellant HFA 134a….q.s. contains absolute alcohol 3.75% v/v DOSAGE FORM Inhalation aerosol DESCRIPTION AEROCORT Inhaler is a combination of salbutamol and beclomethasone dipropionate. Salbutamol is a beta-adrenergic stimulant that has a highly selective action on the receptors in bronchial muscle, resulting in bronchodilation. Beclomethasone dipropionate is a synthetic glucocorticoid with a potent anti-inflammatory activity and weak mineralocorticoid activity. This association of salbutamol and beclomethasone dipropionate is specially provided for those patients who require regular doses of both drugs for treatment of their obstructive airways disease. PHARMACOLOGY Pharmacodynamics AEROCORT Inhaler is a combination of beclomethasone dipropionate and salbutamol, which have different modes of action and show additive effects. Salbutamol The primary action of beta-adrenergic drugs, including salbutamol, is to stimulate adenyl cyclase, the enzyme which catalyses the formation of cyclic-3`,5`-adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP) in beta-adrenergic cells. The cyclic AMP thus formed mediates the cellular responses. Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. Beclomethasone dipropionate The precise mechanisms of glucocorticoid action in asthma are unknown. Inflammation is recognized as an important component in the pathogenesis of asthma. Glucocorticoids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These anti-inflammatory actions of glucocorticoids may contribute to their efficacy in asthma. Pharmacokinetics Salbutamol Because of its gradual absorption from the bronchi, systemic levels of salbutamol are low after inhalation at recommended doses. Administration of tritiated salbutamol by inhalation to four subjects resulted in maximum plasma concentrations within 2 to 4 hours. Due to the insensitivity of the assay method, the metabolic rate and half-life of elimination of salbutamol in plasma could not be determined. However, data from urinary excretion studies indicated that salbutamol has an elimination half-life of 3.8 hours. Approximately 72% of the inhaled dose is excreted in the urine within 24 hours – 28% as unchanged drug and 44% as metabolite. Beclomethasone dipropionate When administered via inhalation there is extensive conversion of beclomethasone dipropionate to the active metabolite, beclomethasone 17-monopropionate (B-17-MP), within the lungs prior to systemic absorption. The systemic absorption of B-17-MP arises from both lung deposition and oral absorption of the swallowed dose. When administered orally in healthy male volunteers, the bioavailability of beclomethasone dipropionate is negligible, but pre-systemic conversion to B-17-MP results in 41% (95% CI 27-62 %) of the dose being available as B-17-MP. Beclomethasone dipropionate is cleared very rapidly from the systemic circulation, owing to extensive first-pass metabolism. The main product of metabolism is the active metabolite (B-17-MP). Minor inactive metabolites, beclomethasone-21-monopropionate (B-21-MP) and beclomethasone (BOH), are also formed, but these contribute little to systemic exposure. The tissue distribution at steady state for beclomethasone dipropionate is moderate (20L), but more extensive for B-17-MP (424L). Plasma protein binding is moderately high (87%). The elimination of beclomethasone dipropionate and B-17-MP are characterised by high plasma clearance (150 and 120L/h), with corresponding terminal elimination half-lives of 0.5 hours and 2.7 hours. Following oral administration of tritiated beclomethasone dipropionate, approximately 60% of the dose was excreted in the faeces within 96 hours, mainly as free and conjugated polar metabolites. Approximately 12% of the dose was excreted as free and conjugated polar metabolites in the urine. INDICATIONS AEROCORT Inhaler is indicated in the treatment of asthma, once the need for inhaled corticosteroid and bronchodilator therapy has been established. DOSAGE AND ADMINISTRATION Asthma Adults Two inhalations, three or four times daily, titrated to the lowest effective dose. Children One or two inhalations, two, three or four times daily. CONTRAINDICATIONS AEROCORT Inhaler is contraindicated in patients with a history of hypersensitivity to any of the components of the drug product. WARNINGS AND PRECAUTIONS AEROCORT Inhaler is not for use in acute attacks, but for routine long-term management; so, some patients will require a separate Asthalin Inhaler for relief of acute bronchospasm. For those patients who are steroid-dependent, it is advisable to commence therapy with beclomethasone diproprionate ( Beclate Inhaler ) as a separate inhaler. Patients who have been weaned in the previous few months from long-term systemic corticosteroids need special consideration until the hypothalamic-pituitary-adrenal system has recovered sufficiently to enable the patient to cope with emergencies such as trauma, surgery, or infections. These patients should also be given a supply of oral steroids to use in an emergency when their airways obstruction worsens. Drug Interactions Beclomethasone dipropionate No interactions have been reported. Salbutamol Salbutamol and non-selective, beta-blocking drugs such as propranolol should not usually be prescribed together. Pregnancy Administration of this combination of drugs during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus. Lactation This combination should be used only if the expected benefit to the mother is likely to outweigh any potential risk to the neonate. UNDESIRABLE EFFECTS As AEROCORT Inhaler contains salbutamol and beclomethasone dipropionate, the type and severity of undesirable effects associated with each of the compounds may be expected. Salbutamol Potentially serious hypokalaemia may result from beta 2 agonist therapy. Common undesirable effects are tremor, headache, and tachycardia. Rare undesirable effects are hypokalaemia, and peripheral vasodilatation. Very rare undesirable effects are hypersensitivity reactions including angio-oedema, urticaria, bronchospasm, hypotension and collapse , hyperactivity, cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia, and extrasystoles), and paradoxical bronchospasm. As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. This should be treated immediately with an alternative presentation or a different, fast-acting inhaled bronchodilator. Therapy should be discontinued immediately, the patient assessed, and, if necessary, alternative therapy instituted. Uncommon undesirable effects are palpitations, mouth and throat irritation, and muscle cramps. Beclomethasone dipropionate Very common undesirable effects are candidiasis of the mouth and throat, and hoarseness/throat irritation. Candidiasis of the mouth and throat (thrush) occurs in some patients, the incidence of which is increased with doses greater than 400 mcg beclomethasone dipropionate per day. Patients with high blood levels of Candida precipitins , indicating a previous infection, are most likely to develop this complication. Patients may find it helpful to rinse out their mouth with water after using the inhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy while continuing with beclomethasone dipropionate treatment. In some patients, inhaled beclomethasone dipropionate may cause hoarseness or throat irritation. It may be helpful to rinse out the mouth with water immediately after inhalation. Very rare undesirable effects are oedema of the eyes, face, lips and throat, respiratory symptoms (dyspnoea and/or bronchospasm), anaphylactoid/anaphylactic reactions, Cushing`s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma, paradoxical bronchospasm, anxiety, sleep disorders, and behavioural changes, including hyperactivity and irritability (predominantly in children). 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-acting inhaled bronchodilator. The beclomethasone dipropionate preparation should be discontinued immediately, the patient assessed, and if necessary, alternative therapy instituted. Uncommon undesirable effects are rashes, urticaria, pruritis, and erythema. OVERDOSAGE Beclomethasone dipropionate Acute: Inhalation of the drug in doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not necessitate any emergency action to be taken. In these patients, treatment with beclomethasone dipropionate by inhalation should be continued at a dose sufficient to control asthma; adrenal function recovers in a few days and can be verified by measuring plasma cortisol. Chronic: Use of inhaled beclomethasone dipropionate in daily doses in excess of 1,500 mcg over prolonged periods may lead to adrenal suppression. Monitoring of adrenal reserve may be indicated. Treatment with inhaled beclomethasone dipropionate should be continued at a dose sufficient to control asthma. Salbutamol Hypokalaemia may occur following overdose with salbutamol. Serum potassium levels should be monitored. The preferred antidote for overdosage with salbutamol is a cardioselective beta-blocking agent, but beta-blocking drugs should be used with caution in patients with a history of bronchospasm. SHELF-LIFE 3 years STORAGE AND HANDLING INSTRUCTIONS Store below 30°C. Do not freeze PACKAGING INFORMATION AEROCORT Inhaler Sales pack available in 120 metered doses