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Product
Anti-asthmatic Products (Aerocort Inhaler)
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Anti-asthmatic Products (Aerocort Inhaler)
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Aerocort Inhaler
Beclomethasone Dipropionate and Levosalbutamol
COMPOSITION
AEROCORT Inhaler
Each actuation delivers:
Beclomethasone Dipropionate IP…………. 50 mcg
Levosalbutamol Sulphate IP equivalent to Levosalbutamol …..50 mcg
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 Levosalbutamol and beclomethasone dipropionate.
Levosalbutamol is the active (R)-enantiomer of the racemate, salbutamol. It is a single- isomer, beta 2 -agonist that differs from racemic salbutamol by the elimination of (S)-salbutamol, which is inactive. Levosalbutamol has a highly selective action on the recep-tors in bronchial muscle, resulting in bronchodilation.
Beclomethasone dipropionate is a synthetic gluco¬corticoid with a potent anti-inflammatory activity and weak mineralocorticoid acti¬vity. This combination of levosalbutamol and beclomethasone dipropionate is specially provided for those patients who require regular doses of both drugs for treatment of their obstructive airways disease. |
PHARMACOLOGY
AEROCORT Inhaler is a combination of beclomethasone dipropionate and levosalbutamol, which have different modes of action and show additive effects.
Pharmacodynamics
Levosalbutamol:
Levosalbutamol leads to activation of beta 2 -adrenergic receptors on airways smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of cAMP. The increase in cAMP is associated with the activation of protein kinase A, which in turn, inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation and bronchodilation. Levosalbutamol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Increased cAMP concentrations are also associated with the inhibition of the release of mediators from mast cells in the airways.
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
Levosalbutamol:
A population pharmacokinetics (PPK) model was developed using plasma concentrations of (R)-salbutamol obtained from 632 asthmatic patients, aged 4 to 81 years, in three large trials. The PPK model-derived pharmacokinetic parameters for (R)-salbutamol in paediatric and adolescent/adult patients receiving a 90 mcg dose of inhaled levosalbutamol or a 180 mcg dose of inhaled racemic salbutamol are presented in Table 1.
These pharmacokinetic data indicate that mean exposure to (R)-salbutamol was 13–16% less in adult and 30–32% less in paediatric patients given inhaled levosalbutamol as compared to those given a comparable dose of racemic salbutamol. When compared to adult patients, paediatric patients given 90 mcg of levosalbutamol had a 17% lower mean exposure to (R)-salbutamol.
Metabolism and Elimination:
Information available in published literature suggests that the primary enzyme responsible for the metabolism of salbutamol enantiomers in humans is sulphotranferase 1A 3 (SULT1A3). When racemic salbutamol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration time curves (AUC) between the (R)- and (S)-salbutamol enantiomers, with (S)-salbutamol concentrations being consistently higher. However, after either inhalation or oral administration without charcoal pre-treatment, the differences were 8- to 24-fold, suggesting that (R)-salbutamol is preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3.
Table 1: Mean Model-Predicted (R)-Salbutamol Pharmacokinetic Parameters
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Treament |
| Study Population |
Parameters |
Levosalbutamol |
Racemic Salbutamol
HFA MDI |
| Adolescent/Adult Patients |
C max (ng/mL) |
0.199 |
0.238 |
| t max (hr) |
0.54 |
0.53 |
| AUC (0-6) (ng•hr/mL) |
0.695 |
0.798 |
Paediatric Patients
(4–11 years old) |
C max (ng/mL) |
0.163 |
0.238 |
| t max (hr) |
0.76 |
0.78 |
| AUC (0-6) (ng•hr/mL) |
0.579 |
0.828 |
The primary route of elimination of salbutamol enantiomers is through renal excretion (80–100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the faeces. Following intravenous administration of racemic salbutamol, between 25–46% of the (R)-salbutamol fraction of the dose was excreted as unchanged (R)-salbutamol in the urine.
Beclomethasone dipropionate :
Absorption:
When administered via inhalation, there is extensive conversion of beclomethasone dipropionate to the active metabolite, 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 was negligible, but pre-systemic conversion to B-17-MP resulted in 41% of the dose being available as B-17-MP.
Distribution:
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%).
Metabolism:
It 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.
Excretion:
The elimination of beclomethasone dipropionate and B-17-MP are characterized by high plasma clearance (150 and 120 L/h), with corresponding terminal elimination half-lives of 0.5 hours and 2.7 hours. Following oral administration of titrated 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 corticoteroid and bronchodilator therapy has been established.
DOSAGE AND ADMINISTRATION
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
Hypersensitivity to any of the components of the formulation
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, sur¬gery 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
Levosalbutamol:
Levosalbutamol and non-selective beta-blocking drugs such as propranolol, should not usually be prescribed together.
Beclomethasone dipropionate :
No interactions have been reported.
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 contain levosalbutamol and beclomethasone dipropionate , the type and severity of adverse reactions associated with each of the compounds may be expected.
Levosalbutamol:
Mild tremor and headache have been reported. Paradoxical bronchospasm, hypokalaemia, and muscle cramps may occur.
Beclomethasone dipropionate:
Candidiasis of the mouth and throat (thrush) may occur in some patients, the incidence of which is increased with doses greater than 400 mcg of beclomethasone dipropionate per day. Gargling with water after inhalation may relieve this.
OVERDOSAGE
The expected symptoms of overdosage are those of excessive beta-adrenergic stimulation, viz., seizures, angina, hypertension or hypotension, tachycardia (with rates up to 200 beats/min), arrhythmias, nervousness, and fatigue. Cardiac arrest and, even, death is associated with the abuse of levosalbutamol.
PACKAGING INFORMATION
AEROCORT Inhaler Sales pack available in 200 metered doses
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