For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Qualitative and Quantitative Composition

Each 2.5 ml respule contains:

Salbutamol Sulphate IP equivalent to Salbutamol IP .… 2.5 mg

Normal saline solution …….q.s.

Dosage Form and Strength

Solution for inhalation via a nebulizer of Salbutamol Sulphate 2.5 mg

Clinical Particulars

Therapeutic Indications

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

Posology and Method of Administration

ASTHALIN Respules are 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 Respules are intended to be used undiluted. However, if prolonged delivery time (more than 10 minutes) is required, the solution may be diluted with sterile normal saline.

Adults (including the elderly):

The usual starting dose is 2.5mg as a single dose. This may be increased to 5mg. Treatment may be repeated up to four times a day. For the treatment of severe airways obstruction in adult hospitalised patients, higher dose up to 40mg per day can be given under strict medical supervision in hospital.

In domiciliary practice the benefits of increasing the dosage should be weighed against the risk that a deterioration in the patient's underlying condition may be masked. In this case a medical assessment should be considered and alternative therapy instituted where indicated.

Paediatric Population

Children (12 years and above)

Dose as per adult population.

Children (4 years to 11 years)

2.5mg to 5mg up to four times a day.

Infants (under 18 months old)

Clinical efficacy of nebulised salbutamol in infants under 18 months is uncertain. As transient hypoxia may occur supplemental oxygen therapy should be considered.

ASTHALIN respule is designed to be used undiluted. However, if a prolonged delivery time is indicated (more than 10 minutes) then dilution with Sodium Chloride Solution (0.9%w/v) for nebulisation or sterile sodium chloride injection (normal saline) may be required.

Contraindications

ASTHALIN Respules is contraindicated in patients with a history of hypersensitivity to any of the components. Although some forms of salbutamol sulphate have been used in the management of premature labour, Salbutamol inhalation should not be used for this purpose. Salbutamol inhalation should not be used in threatened abortion.

Special Warnings and Precautions for Use

ASTHALIN Respules must only be used for inhalation, to be inhaled in through the mouth via a suitable nebulizer, and must not be injected or swallowed. In patients with severe or unstable asthma, bronchodilators should not be the only or main treatment. Regular medical assessment is required including lung function testing, as they are at risk of severe attacks and even death. Oral corticosteroid therapy and/or inhaled corticosteroids should be considered. Increasing use of bronchodilators to relieve symptoms indicates deterioration of asthma control.

In the following cases, salbutamol should only be used with caution and if strictly indicated:

• serious cardiac disorders, in particular recent myocardial infarction
• coronary heart disease, hypertrophic obstructive cardiomyopathy and tachyarrhythmia (due to the positive ionotropic effect of ?2 – agonists) severe and untreated hypertension
• aneurysm
• hyperthyroidism
• diabetes which is difficult to control
• pheochromocytoma

Daily self assessment of asthma control following instructions regarding the use of Salbutamol respules and any other drugs required for the management of asthma is important in order that the course of the disease can be followed and the success of both bronchodilator and anti inflammatory therapy monitored. The patient should be instructed in the regular measurement of peak expiratory flow rate (PEFR) using a portable peak flow meter. Patients receiving treatment with Salbutamol respule at home should be warned that, if asthma control does not improve satisfactorily or deteriorates, or if the short-acting relief bronchodilator treatment becomes less effective, or more inhalations than usual are required, medical advice must be sought in order that the clinical condition can be reassessed and therapeutic management revised appropriately. In this situation anti-inflammatory therapy may be required, the dose of anti – inflammatory therapy may need to be increased or a short course of oral glucocorticoids may be needed. Increasing use of bronchodilators and in particular short-acting inhaled beta₂ adrenergic agonists to relieve symptoms indicates deterioration of asthma control. A sudden and increasing deterioration of asthma symptoms can be life threatening. Therefore, medical assistance must be sought immediately. The administration of salbutamol in patients with acute asthma may cause a further reduction of the O₂ saturation. The dose and frequency of inhalation of short-acting beta2 agonists should only be increased following medical advice and if a previously effective dose fails to give the expected relief the patient should be advised to seek medical advice. Exceeding the prescribed dose can be dangerous with resultant cardiac effects, hypokalaemia, taste alteration, nausea, restlessness, sweating, headache, or tremor. 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 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. Attention should be paid to assessment of symptoms such as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin. Potentially serious hypokalaemia may result from beta₂-agonist therapy, mainly from parenteral and inhalation 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. Due to the hyperglycaemic effects of beta₂ – stimulants, additional blood glucose measurements are initially recommended when treatment with Salbutamol respules is started in diabetic patients. Inhalation of high doses of salbutamol can increase the blood glucose level. Therefore, blood glucose levels in diabetic patients should be monitored closely. The use of salbutamol respule in combination with anticholinergic agents has been reported to precipitate acute angle closure glaucoma. This combination should be used with caution, in particular in patients with actual or potential glaucoma. Patients should be warned

Drug Interactions

ASTHALIN respules should be used with caution in patients receiving other sympathomimetics. Salbutamol and non-selective beta-receptor blocking drugs should not usually be prescribed together. In patients with asthma administration of beta-receptor blocking drugs is associated with a risk of severe bronchoconstriction. Treatment with salbutamol can lead to hypokalaemia. This effect may be potentiated by the concomitant administration of other drugs, in particular xanthine derivatives, glucocorticoids, diuretics and cardiac glycosides (digoxin). Serum potassium levels should be monitored in these situations. Tricyclic antidepressants may increase the risk of cardiovascular side effects.  Corticosteroids may increase the risk of hyperglycaemia. A few cases have been reported where the combination of salbutamol and ipratropium bromide has given rise to acute angle-closure glaucoma.

Use in Special Population

Pregnancy

Based on preclinical studies and long-term clinical experience, salbutamol has not been shown to have any teratogenic effects. If the mother uses salbutamol during pregnancy, the pulse rate of the foetus may increase. Although salbutamol is considered the first line treatment to relieve bronchospasm in asthmatic pregnant women, use during pregnancy, especially in the first trimester, and lactation should only be considered once the benefits have been carefully weighed against the risks.

Lactation
Since salbutamol is passively excreted in breast milk, high doses may induce drug effect in the breast-fed infant.

Effects on Ability to Drive and Use Machines

Not known

Undesirable Effects

Up to approximately 10% of patients can be expected to experience adverse reactions. These depend upon the dose and the individual sensitivity. Most commonly reported are: taste alteration (bad, unpleasant and unusual taste) and application site reaction (mouth and throat irritation, burning sensation of the tongue), fine tremor (usually of the hands) nausea, sweating, restlessness, headache, dizziness and muscle cramps. These undesirable effects may subside on continuation of treatment within 1-2 weeks. As with other inhalation therapies, in rare cases paradoxical bronchospasm may occur, manifest by an immediate increase in wheezing after dosing. Paradoxical bronchospasm should be treated immediately with an alternative presentation or a different fast-acting inhaled bronchodilator. ASTHALIN respules should be discontinued immediately, the patient should be assessed, and if necessary, alternative therapy instituted. Hypersensitivity reactions such as rash, urticaria, dermatitis, pruritus and erythema have been observed. There have been very rare reports of angioedema (oedema of the face, lips, eyes and throat), bronchospasm, hypotension and collapse.

Tachycardia, with or without peripheral vasodilation, may occur. In common with other beta₂ agonists, cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles), palpitations, angina pectoris, and blood pressure effects have been reported in association with the use of salbutamol, usually in susceptible patients. There are reports about stimulating effects on the central nervous system after inhalation of salbutamol which manifest themselves in hyperexcitability, hyperactive behaviour, sleeping disturbances and hallucinations. These observations were predominantly made in children up to 12 years of age.

The following definitions apply to the incidence of undesirable effects: Frequencies are defined as: common (≥1/100 to <1/10); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Immune system disorders

Very rare: Hypersensitivity reactions

Metabolism disorders

Rare: Hypokalaemia, Hyperglycaemia

Psychiatric Disorders

Common: Restlessness

Nervous system disorders

Common: Tremor, dizziness

Rare: Hyperactive behaviour

Very rare: Hyperexcitability, sleeping disturbances, hallucinations.

Cardiac disorders

Rare: Tachycardia, Cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles, Palpitations, Angina pectoris, blood pressure effects (lowering/increase)

Unknown: Myocardial ischaemia*

Vascular disorders

Rare: Peripheral vasodilatation

Very rare: Collapse

Respiratory, thoracic and mediastinal disorders

Very rare: Paradoxical bronchospasm

Gastrointestinal disorders

Common: Nausea, taste alteration

Musculoskeletal and connective tissue disorders

Rare: Muscle cramps

Skin and subcutaneous tissue disorders

Pruritis, rash, erythema, urticaria, angioedema

General disorders and administration site condition

Common: Headache, application site reaction (mouth and throat irritation, burning sensation of the tongue)

* 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 program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting adverse events, you can help provide more information on the safety of this product.

Overdose

Symptoms of an overdose

In the case of an overdose, the above-mentioned undesirable effects (see 4.8, Undesirable effects) occur very quickly and with increased severity. 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

Management of an overdose

Treatment after an overdose of a ?-sympathomimetic is mainly symptomatic. The following measures may be considered, depending upon the individual circumstances:

• If large amounts of the drug are swallowed, irrigation of the stomach should be considered. Activated charcoal and laxatives can have favourable effects on the undesired absorption of the ?-sympathomimetic.
• For the cardiac symptoms of overdosage with salbutamol a cardioselective beta-blocking agent may be considered, but beta-blocking drugs should only be used with caution and be avoided as far as possible in patients with a history of bronchospasm. ECG monitoring is indicated in such patients.
• In the case of fairly pronounced lowering of the blood pressure, volume substitution (e.g. plasma expanders) is recommended.
• If hypokalaemia develops, electrolyte balance should be monitored and, if appropriate, electrolytes may need to be administered

Pharmacological Properties

Mechanism of Action

Salbutamol activates adenyl cyclase, the enzyme that stimulates the production of cyclic adenosine-3', 5'-monophosphate (cAMP). Increased cAMP leads to activation of protein kinase A, which inhibits phosphorylation of myosin and lowers intracellular ionic Ca⁺² concentrations, resulting in smooth muscle relaxation.

Pharmacodynamic Properties

Salbutamol is a selective beta₂-adrenoceptor agonist. At therapeutic doses it acts on the beta2-adrenoceptors of bronchial muscle to provide bronchodilation. With its fast onset of action (within 5 minutes) it is particularly suitable for the management and prevention of attacks in asthma. Salbutamol has a duration of action of 4 to 6 hours in most patients.

Pharmacokinetic Properties

Absorption and metabolism of salbutamol in lungs and gastrointestinal tract differ. After inhalation, between 10 and 20 % of the active substance reaches the lower airways. The remainder is retained in the delivery system or is deposited in the oropharynx where it is swallowed. The fraction deposited in the airways is absorbed into the pulmonary tissues and circulation, but is not metabolised by the lung. On reaching the systemic circulation it becomes accessible to hepatic metabolism and is excreted, primarily in the urine, as unchanged drug and as the phenolic sulfate.

The swallowed portion of an inhaled dose is absorbed from the gastrointestinal tract and undergoes considerable first-pass metabolism to the phenolic sulfate. Both unchanged drug and conjugate are excreted primarily in the urine. Approximately 90% of an oral dose is excreted in urine and 10% in faeces. Salbutamol administered intravenously has a half-life of 4 to 6 hours and is cleared partly renally, and partly by metabolism to the inactive 4'-O-sulfate (phenolic sulfate) which is also excreted primarily in the urine.

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%.

Nonclinical Properties

Animal Toxicology or Pharmacology

Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. Effects seen in toxicity studies were related to the beta-adrenergic activity of salbutamol.

Description

ASTHALIN respule contain a clear, colourless to light yellow solution. On visual examination, there is no sign of leakage and physical damage.

Pharmaceutical Particulars

Incompatibility

Not applicable.

Shelf-life

See on pack.

Packaging Information

ASTHALIN respules 2.5mg is available as unit-dose vial of 2.5 ml.

Available in a pack of 5 strips [20 respules]. Each strip contains 4 unit-dose vials of 2.5ml [4 x 5 x 2.5ml].

Storage and Handling instructions

Keep out of the sight and reach of children.

Store the product below 25°C. Store in the original package.

Patient Counseling Information

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

1. What ASTHALIN respules is and what it is used for?

Salbutamol belongs to a group of medicines called bronchodilators which help to open up the air passages in your lungs so that you can breathe more easily.

ASTHALIN respules helps to make breathing easier in patients who have long-standing breathing difficulties. It is also given to treat severe attacks of asthma.

2. Before you take ASTHALIN respules

Do not take ASTHALIN respules

• If you are allergic (hypersensitive) to salbutamol
• If you are allergic to any of the other ingredients

Some forms of Salbutamol are used to help control premature labour. ASTHALIN respules is not to be used for this purpose.

Take special care with ASTHALIN respules

Talk to your doctor if any of the following apply to you:

• if you have diabetes
• if you have a heart condition or have recently had a heart attack
• if you have high blood pressure
• if you have an overactive thyroid gland
• if you have a history of heart disease, irregular heartbeat/rhythm including a very fast pulse or angina
• if you have an aneurysm (a widening of the wall of a blood vessel)
• if you suffer from glaucoma (excessive pressure inside your eyes)
• if you have ever been told that you suffer from pheochromocytoma. This is a rare tumour which produces chemicals that can cause restlessness, high blood pressure, and your heart to beat faster.

Taking other medicines

Tell your doctor if you are taking any of the following as they may interact with ASTHALIN respules:

• steroids including prednisolone
• medicines called xanthines such as theophylline
• medicines called beta blockers, as these can reduce the effectiveness of your medicine
• diuretic medicines (commonly known as “water tablets” including non-sparing potassium diuretics such as furosemide and indapamide)
• digoxin, which is used in the treatment of heart failure
• tricyclic antidepressants (for depression)
• ipratropium bromide (for asthma)

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

If you are pregnant, think you are pregnant or are breast-feeding, you should not use ASTHALIN respules unless your doctor tells you to. If you become pregnant whilst taking this medicine you should tell your doctor as soon as possible.

Driving and using machines

ASTHALIN respules has no known effects on the ability to drive and use machines.

3. HOW TO TAKE ASTHALIN respules?

 ASTHALIN respules are 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.

Adults and adolescents aged 12 years and over

• the usual starting dose is 2.5mg up to four times daily. Your doctor may increase this to 5mg up to four times daily.

Children aged 4 to 11 years

• the usual dose is 2.5mg to 5mg up to four times a day.

Contact your doctor immediately if:

• You are not getting relief from your current dose or you are having to take more inhalations
• Your breathing is not improving or is getting worse
• Your chest feels tight

These are signs that your condition is not being controlled and you may need different or additional treatment.

If you use more ASTHALIN respules than you should you may feel unwell and overtired, shaky, dizzy, have chest pains and feel that your heart is beating faster than usual. Call your doctor immediately or go to the nearest hospital casualty department. If you feel shaky you should not drive. Take this leaflet or an ampoule with you so the hospital will know what you have taken.

If you forget to use ASTHALIN respules, take the next dose when it is due or before you become wheezy. Do not take a double dose to make up for the one you missed.

If you stop using ASTHALIN respules this may make your condition worse. Do not stop taking your medicine unless your doctor tells you to do so.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, ASTHALIN respules can cause side effects, although not everybody gets them.

All medicines can cause allergic reactions, although serious allergic reactions are very rare. Tell your doctor immediately if you get any sudden wheeziness, difficulty in breathing, swelling of the eyelids, face, lips or throat, or a rash or itching especially affecting the whole body.

Rarely, inhaled medicines such as salbutamol can cause acute wheezing and/or shortness of breath. If this occurs, stop using your medicine immediately and seek medical help.

The following side effects have also been reported:

Common side effects (probably affecting less than 1 person in 10):

• restlessness
• sweating
• headache
• tremor (shaking)
• dizziness
• mouth and throat irritation
• nausea
• rash
• taste alteration (bad, unpleasant or unusual taste)
• hives
• burning sensation of the tongue
• itching
• redness of the skin

Rare side effects (probably affecting less than 1 person in 1,000):

• an awareness of your heartbeat
• hyperactive behaviour
• increase in heart rate
• muscle cramp
• an irregular heart rhythm or chest pain
• increased blood flow or pain in the arms and legs

Sometimes this medicine can cause a lowering of potassium levels in the blood which can make you feel generally unwell and over-tired. You may also experience frequent urination (passing water). If you notice any of these effects, tell your doctor who may arrange for you to have a blood test.

Very rare side effects (probably affecting less than 1 person in 10,000):

• hyperexcitability
• swelling of the face, lips, eyes and throat
• skin rashes
• sleep disturbances
• feeling faint and collapsing
• hallucinations

Although it is not known exactly how often this happens, some people may occasionally experience chest pain (due to heart problems such as angina).

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 program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting adverse events, you can help provide more information on the safety of this product.

5. How to Store ASTHALIN respules?

Keep out of the sight and reach of children.

Store the product below 25°C. Store in the original package

6. What Salbutamol Nebuliser Solution contains?

• The active substance is Salbutamol 2.5mg/2.5ml (as salbutamol sulphate).
• The other ingredients are sodium chloride, water for injections and sulfuric acid.

7.   What Salbutamol Nebuliser Solution looks like and contents of the pack?

Salbutamol Nebuliser Solutions is free from visible particles filled in 2.5 ml FFS respules.

Details of Manufacturer

Mfg By Cipla Ltd.

Registered Office: Cipla House,

Peninsula Business Park, Ganpatrao Kadam,

Marg Lower Parel, Mumbai – 400 013, India.

Details of Permission or Licence Number with Date

M/447/2007 Dated: 23/12/16

Date of Revision

20^th May 2020