ASTHALIN Respirator Solution (Salbutamol sulphate)

Table of Content

Composition

Each 1 ml contains:

Salbutamol Sulphate IP equivalent to Salbutamol IP…….. 5 mg

Dosage Form

Solution for inhalation via a nebulizer

Description

ASTHALIN Respirator Solution contain a racemic mixture of Salbutamol sulphate in equal amounts (50:50) of (R) and (S)-isomers. A white or almost white, crystalline powder. Clear solution in methanol. Sparingly soluble in water; soluble in ethanol (96%); slightly soluble in ether.

Pharmacology

Pharmacodynamics

Salbutamol is a selective beta2-agonist providing short-acting (4-6 hours) bronchodilation with a fast onset (within 5 minutes) in reversible airways obstruction. At therapeutic doses, it acts on the beta2-adrenoceptors of bronchial muscle. With its fast onset of action, it is particularly suitable for the management and prevention of attack in asthma.

Pharmacokinetics

Salbutamol administered intravenously has a half-life of 4-6 hours and is cleared partly renally and partly by metabolism to the inactive 4'-O-sulphate (phenolic sulphate), which is also excreted primarily in the urine. The faeces are a minor route of excretion. Most of a dose of salbutamol given intravenously, orally, or by inhalation is excreted within 72 hours. Salbutamol is bound to plasma proteins to the extent of 10%.

After administration by the inhaled route, between 10% and 20% of the dose reaches the lower airways. The remainder is retained in the delivery system or is deposited in the oropharynx from where it is swallowed. The fraction deposited in the airways is absorbed into the pulmonary tissues and circulation, but is not metabolized by the lungs. On reaching the systemic circulation, it becomes accessible to hepatic metabolism and is excreted, primarily in the urine, as unchanged drug and as phenolic sulphate.

The swallowed portion of an inhaled dose is absorbed from the gastrointestinal tract and undergoes considerable first-pass metabolism to phenolic sulphate. Both unchanged drug and conjugate are excreted primarily in the urine.

Indications

ASTHALIN Respirator Solution is indicated for use in the routine management of chronic bronchospasm unresponsive to conventional therapy, and in the treatment of acute severe asthma.

Dosage and Administration

ASTHALIN Respirator Solution is for inhalation use only, to be inhaled in through the mouth via a suitable nebulizer, as instructed by a physician.  The solution should not be injected or swallowed. ASTHALIN Respirator Solution may be administered intermittently or continuously. Salbutamol’s duration of action is 4-6 hours in most patients.

Intermittent Administration

Adults

ASTHALIN Respirator Solution 0.5 ml (2.5 mg of salbutamol) should be diluted to a final volume of 2 ml with sterile normal saline. This may be increased to 1 ml (5 mg of salbutamol), diluted to a final volume of 2.5 ml. The resulting solution is inhaled from a suitably driven nebulizer until aerosol generation ceases. When using a correctly matched nebulizer and driving source, this should take about 10 minutes.

ASTHALIN Respirator Solution may be used undiluted for intermittent administration. For this, 2 ml of ASTHALIN Respirator Solution (10 mg of salbutamol) is placed in the nebulizer and the patient allowed to inhale the nebulized solution until bronchodilation is achieved. This usually takes 3-5 minutes. Some adult patients may require higher doses of salbutamol up to 10mg, in which case, nebulization of the undiluted solution may continue until aerosol generation ceases.

Children

The same mode of administration for intermittent administration is also applicable to children. The minimum starting dosage for children below the age of 12 years is 0.5 ml (2.5 mg of salbutamol), diluted to 2-2.5 ml with sterile normal saline. Some children may, however, require higher doses of salbutamol up to 5 mg. Intermittent treatment may be repeated up to four times daily.

Continuous Administration

ASTHALIN Respirator Solution is diluted with sterile normal saline to contain 50-100 mcg of salbutamol per ml (1-2 ml solution made up to 100 ml with diluents). The diluted solution is administered as an aerosol by a suitably driven nebulizer. The usual rate of administration is 1-2 mg per hour.

In infants below 18 months of age, the clinical efficacy of nebulized salbutamol is uncertain. As transient hypoxaemia may occur, supplemental oxygen therapy should be considered.

Contraindications

ASTHALIN Respirator Solution is contraindicated in patients with a history of hypersensitivity to any of the components. Salbutamol preparations should not be used for managing premature labour and threatened abortion.

Warnings and Precautions

ASTHALIN Respirator Solution must only be used for inhalation, to be inhaled in through the mouth via a suitable nebulizer, and must not be injected or swallowed.

Bronchodilators should not be the only or main treatment in patients with severe or unstable asthma. Severe asthma requires regular medical assessment, including lung-function testing, as patients are at risk of severe attacks and, even, death. Physicians should consider using the maximum recommended dose of inhaled corticosteroid and/or oral corticosteroid therapy in these patients.

Patients receiving treatment at home should be warned to seek medical advice if treatment with ASTHALIN Respirator Solution becomes less effective. As there may be adverse effects associated with excessive dosing, the dosage or frequency of administration should only be increased on medical advice.

Patients being treated with ASTHALIN Respirator Solution may also be receiving other dosage forms of short-acting inhaled bronchodilators to relieve symptoms. Increasing use of bronchodilators, particular short-acting inhaled beta2-agonists, to relieve symptoms, indicates deterioration of asthma control. The patient should be instructed to seek medical advice if short-acting relief bronchodilator treatment becomes less effective or more inhalations than usual are required. In this situation, patients should be assessed and consideration given to the need for increased anti-inflammatory therapy (e.g., higher doses of inhaled corticosteroid or a course of oral corticosteroids).

Severe exacerbations of asthma must be treated in the normal way.

Salbutamol should be administered cautiously to patients suffering from thyrotoxicosis.

Salbutamol, like all other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salbutamol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, salbutamol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Immediate hypersensitivity reactions may occur after administration of salbutamol, as demonstrated by cases of urticaria, angio-oedema, rash, bronchospasm, anaphylaxis, and oropharyngeal oedema.

Cardiovascular effects may be seen with sympathomimetic drugs, including salbutamol. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with salbutamol. Patients with underlying severe heart disease (e.g. ischaemic heart disease, arrhythmia or severe heart failure) who are receiving salbutamol should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease. Attention should be paid to assessment of symptoms such as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin.

ASTHALIN Respirator Solution should be used with care in patients who are known to have received large doses of other sympathomimetic drugs. Potentially serious hypokalaemia may result from beta2-agonist therapy, mainly from parenteral and nebulized administration. Particular caution is advised in acute severe asthma as this effect may be potentiated by hypoxia and by concomitant treatment with xanthine derivatives, steroids, and diuretics. Serum potassium levels should be monitored in such situations.

Like other beta-adrenoceptor agonists, salbutamol can induce reversible metabolic changes such as increased blood glucose levels. Diabetic patients may be unable to compensate for the increase in blood glucose and the development of ketoacidosis has been reported. Concurrent administration of corticosteroids can exaggerate this effect.

Lactic acidosis has been reported in association with high therapeutic doses of intravenous and nebulised short-acting beta-agonist therapy, mainly in patients being treated for an acute asthma exacerbation. Increase in lactate levels may lead to dyspnoea and compensatory hyperventilation, which could be misinterpreted as a sign of asthma treatment failure and lead to inappropriate intensification of short-acting beta-agonist treatment. It is therefore recommended that patients are monitored for the development of elevated serum lactate and consequent metabolic acidosis in this setting.

In the following cases, salbutamol should only be used with caution and if strictly indicated: serious cardiac disorders, recent myocardial infarction, coronary heart disease, hypertrophic obstructive cardiomyopathy and tachyarrhythmia (due to the positive ionotropic effect of beta2-agonists) severe and untreated hypertension, aneurysm, hyperthyroidism, diabetes which is difficult to control, pheochromocytoma. The administration of salbutamol in patients with acute asthma may cause a further reduction of the O2 saturation. Exceeding the prescribed dose can be dangerous with resultant cardiac effects, hypokalaemia, taste alteration, nausea, restlessness, sweating, headache, or tremor.

There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischemia associated with salbutamol. Patients with underlying severe heart disease (e.g. ischemic heart disease, arrhythmia or severe heart failure) who are receiving salbutamol should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease.

A small number of cases of acute angle-closure glaucoma have been reported in patients treated with a combination of nebulized salbutamol and ipratropium bromide. A combination of nebulized salbutamol with nebulized anticholinergics should therefore be used cautiously. Patients should receive adequate instructions about correct usage and be warned not to let the solution or mist enter the eye.

Drug Interactions

Salbutamol preparations should be used with caution in patients suffering from thyrotoxicosis. ASTHALIN Respirator Solution and non-selective beta-blocking drugs such as propranolol should generally not be prescribed together. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to use beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.

Tricyclic antidepressants may increase the risk of cardiovascular side effects. Corticosteroids may increase the risk of hyperglycaemia.

The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical relevance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium sparing diuretics. Consider monitoring potassium levels.

Caution is advised in acute severe asthma as this effect may be potentiated by con­comitant treatment with xanthine deriva­tives, steroids, digoxin, diuretics, and by hypoxia. It is recommended that serum potassium levels be monitored in such situations.

ASTHALIN Respirator Solution should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or within 2 weeks discontinuation of such agents, because the action of salbutamol on the vascular system may be potentiated.

Pregnancy

Administration of ASTHALIN Respirator Solution during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

As with the majority of drugs, there is little published evidence of the safety of salbutamol in the early stages of human pregnancy, but in animal studies there was evidence of some harmful effects on the fetus at very high dose levels.

Lactation

As salbutamol is probably secreted in breast milk, its use in nursing mothers requires careful consideration. It is not known whether salbutamol has a harmful effect on the neonate, and so its use should be restricted to situations where it is felt that the expected benefit to the mother is likely to outweigh any potential risk to the neonate.

Undesirable Effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (1/10), common (1/100 and <1/10), uncommon (1/1000 and <1/100), rare (1/10,000 and <1/1000) and very rare (<1/10,000). Very common and common events were generally determined from clinical trial data. Rare, very rare and unknown events were generally determined from spontaneous data.

Immune System Disorders

Very rare: Hypersensitivity reactions including angioedema, urticaria, bronchospasm, hypotension and collapse.

Metabolism And Nutrition Disorders

Rare: Hypokalaemia, Hyperglycaemia

Potentially serious hypokalaemia may result from beta2-agonist therapy.

Unknown: Lactic acidosis

Psychiatric Disorders

Common: Restlessness

Nervous System Disorders

Common: Tremor, headache, dizziness

Very rare: Hyperactivity, Hyperexcitability, sleeping disturbances, hallucinations.

Cardiac Disorders

Common: Tachycardia

Uncommon: Palpitations, Angina pectoris, blood pressure effects (lowering/increase)

Very rare: Cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles

Unknown: Myocardial ischaemia*

Vascular Disorders

Rare: Peripheral vasodilatation, collapse

Respiratory, Thoracic and Mediastinal Disorders

Very rare: 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.

ASTHALIN Respirator Solution should be discontinued immediately, the patient assessed, and, if necessary, alternative therapy instituted.

Gastrointestinal Disorders

Uncommon: Mouth and throat irritation, Nausea, taste alteration

Musculoskeletal and Connective Tissue Disorders

Uncommon: Muscle cramps

Skin and Subcutaneous Tissue Disorders

Pruritis, rash, erythema, urticaria, angioedema

* reported spontaneously in post-marketing data therefore frequency regarded as unknown

If case of any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 180 3024.

By reporting side effects, you can help provide more information on the safety of this product.

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, headache, tremor, dry mouth, palpitation, nausea, dizziness, malaise, sleeplessness hypokalemia (serum potassium levels should be monitored), lactic acidosis and fatigue. Cardiac arrest and, even, death is associated with the abuse of ASTHALIN Respirator Solution.

Typical symptoms are: tachycardia, palpitations, arrhythmia, restlessness, sleep disturbances, chest pain and vigorous tremor, especially on hands but also on the whole body. Nausea, dizziness, increased systolic blood pressure and decreased diastolic blood pressure may also be observed.

Occasionally, psychotic reactions were observed after excessive doses of salbutamol. In the case of a salbutamol overdose there can increasingly be a shift of potassium into the intracellular space resulting in hypokalaemia, as well as hyperglycaemia, hyperlipidaemia, and hyperketonaemia.

Increased serum lactate levels and rarely, lactic acidosis, have been reported following therapy with salbutamol, particularly after high dose administration. Symptoms include deep, rapid breathing, cold and blue coloured fingers and toes, inability to concentrate and general malaise.

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.

If hypokalemia occurs, potassium replacement via the oral route should be given. In patients with severe hypokalemia, intravenous replacement may be necessary.

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.

Packaging Information

ASTHALIN Respirator Solution ………….Bottle of 15 ml

Last Updated: July 2018

Last Reviewed: July 2018