Ventolin (Salbutamol)

VENTOLIN® VENTODISK® VENTODISK® DISKHALER® VENTOLIN® ROTACAPS® VENTOLIN® ROTAHALER® VENTOLIN® RESPIRATOR SOLUTION VENTOLIN® NEBULES P.F.

Glaxo Wellcome

Salbutamol

Bronchodilator – Beta2-adrenergic Stimulant

Action And Clinical Pharmacology: Salbutamol produces bronchodilation through stimulation of beta2-adrenergic receptors in bronchial smooth muscle, thereby causing relaxation of bronchial muscle fibres. This action is manifested by an improvement in pulmonary function as demonstrated by spirometric measurements. At therapeutic doses, salbutamol has little action on the beta1-adrenergic receptors in cardiac muscle (Ventolin, Ventodisk and Ventolin Rotacaps).

A measurable decrease in airway resistance is typically observed 5 to 15 minutes after inhalation of salbutamol. The maximum improvement in pulmonary function usually occurs 60 to 90 minutes after salbutamol treatment, and significant bronchodilator activity has been observed to persist for 3 to 6 hours.

Indications And Clinical Uses: Salbutamol inhalation aerosol and powder for inhalation are indicated for the symptomatic relief and prevention of bronchospasm due to bronchial asthma, chronic bronchitis and other chronic bronchopulmonary disorders in which bronchospasm is a complicating factor. In addition, salbutamol inhalation aerosol and powder for inhalation are indicated for the prevention of exercise-induced asthma.

Salbutamol respirator solutions are indicated for the treatment of severe bronchospasm associated with exacerbations of chronic bronchitis and bronchial asthma. They can be used by “wet” nebulization. When administered through a nebulizer, salbutamol respirator solutions should be used with compressed air or oxygen.

Contra-Indications: Patients with a hypersensitivity to any of the ingredients and in patients with tachyarrhythmias.

Manufacturers’ Warnings In Clinical States: Use of Anti-inflammatory Agents: In accordance with the present practice for asthma treatment, concomitant anti-inflammatory therapy (e.g., corticosteroids) should be part of the regimen if inhaled salbutamol needs to be used on a regular daily basis (see Dosage). It is essential that the physician instruct the patient in the need for further evaluation if the patient’s asthma becomes worse.

Deterioration of Asthma: The management of asthma should normally follow a stepwise program and patient response should be monitored clinically and by lung function tests. The increasing use of fast-acting, short-duration inhaled beta2-adrenergic agonists to control symptoms indicates deterioration of asthma control and the patient’s therapy plan should be reassessed. Sudden or progressive deterioration in asthma control is potentially life-threatening; the treatment plan must be re-evaluted, and consideration be given to corticosteroid therapy.

Cardiovascular Effects: In individual patients, any beta2-adrenergic agonist, including salbutamol, may have a clinically significant cardiac effect. Care should be taken with patients suffering from cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias and hypertension. Special care and supervision are required in patients with idiopathic hypertrophic subvalvular aortic stenosis, in whom an increase in the pressure gradient between the left ventricle and the aorta may occur, causing increased strain on the left ventricle.

Hypokalemia: In common with other beta-adrenergic agents, salbutamol can induce reversible metabolic changes such as potentially serious hypokalemia, particularly following nebulized or especially infused administration. Particular caution is advised in acute severe asthma since hypokalemia may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics and by hypoxia. Hypokalemia will increase the susceptibility of digitalis-treated patients to cardiac arrhythmias. It is recommended that serum potassium levels be monitored in such situations.

Diabetes: Care should be taken with patients with diabetes mellitus. Salbutamol can induce reversible hyperglycemia during nebulized administration or especially during infusions of the drug. The diabetic patient may be unable to compensate for this and the development of ketoacidosis has been reported. Concurrent administration of corticosteroids can exaggerate this effect.

Paradoxical Bronchospasm: With repeated excessive use of sympathomimetic inhalation preparations, some patients have been reported to have developed severe paradoxical bronchospasm, occasionally leading to death. The cause of either the refractory state or death is unknown. However, it is suspected in the fatal episodes that cardiac arrest occurred following the unexpected development of a severe acute asthmatic crisis and subsequent hypoxia. Several cases have been reported in which intermittent positive pressure ventilation in acute asthma attacks was related to lethal episodes of hypoxia and pneumothorax. This method of drug administration may be ineffective in patients with severe obstruction and greatly increased airway resistance, and it may induce severe hypercapnia and hypoxia. During intermittent ventilation therapy, the monitoring of arterial blood gases is highly desirable. It is advisable that in the event of either hypoxia and pneumothorax or paradoxical bronchospasm the use of the preparation should be discontinued immediately and alternate therapy instituted, since in the reported cases the patients did not respond to other forms of therapy until the drug was withdrawn.

Care should be taken with patients with convulsive disorders, hyperthyroidism or in patients who are unusually responsive to sympathomimetic amines.

Do Not Exceed Recommended Dose: Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.

Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of salbutamol or salbutamol sulfate, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.

Precautions: General: If therapy does not produce a significant improvement or if the patient’s condition worsens, medical advice must be sought to determine a new plan of treatment. In the case of acute or rapidly worsening dyspnea, a doctor should be consulted immediately.

Failure to respond for at least 3 hours to a previously effective dose of salbutamol indicates a deterioration of the condition and the physician should be contacted promptly. Patients should be warned not to exceed recommended dose. Increasing use of beta2-agonists to control symptoms is usually a sign of worsening asthma. In worsening asthma it is inadequate to increase beta2-agonist use only, especially over an extended period of time. Instead, a reassessment of the patient’s therapy plan is required and concomitant anti-inflammatory therapy should be considered (see Dosage).

Patients should always carry their salbutamol aerosol or dry powder to use immediately if an episode of asthma is experienced.

To ensure administration of the proper dose of the drug, the patient should be instructed by the physician or other health professional in the proper use of the inhaler, Diskhaler, Rotahaler or nebulizer systems. The application of these inhalation systems in children depends on the ability of the individual child to learn the proper use of the devices. During inhalation, children should be assisted or supervised by an adult who knows the proper use of the devices.

Pregnancy: Salbutamol has been in widespread use for many years in human beings without apparent ill consequence. However, there are no adequate and well-controlled studies in pregnant women, and there is little published evidence of its safety in the early stages of human pregnancy. Administration of any drug to pregnant women should only be considered if the anticipated benefits to the expectant woman are greater than any possible risks to the fetus.

A reproducton study in CD-1 mice with salbutamol showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg. None was observed at 0.025 mg/kg. Cleft palate also occurred in 22 of 72 (30.5%) fetuses treated with 2.5 mg/kg isoproterenol positive control. A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses at 50 mg/kg, corresponding to 78 times the maximum human oral dose of salbutamol.

Labor and Delivery: Although there have been no reports concerning the use of inhaled salbutamol formulations during labor and delivery, i.v. administered salbutamol given at high doses may inhibit uterine contractions. While this effect is extremely unlikely as a consequence of using inhaled formulations, it should be kept in mind. Oral salbutamol has been shown to delay preterm labor in some reports, but there are no well-controlled studies which demonstrate that it will stop preterm labor or prevent labor at term. When given to pregnant patients for relief of bronchospasm, cautious use of Ventolin products is required to avoid interference with uterine contractility.

Lactation: Since salbutamol is probably excreted in breast milk and because of its observed tumorigenicity in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother. It is not known whether salbutamol in breast milk has a harmful effect on the neonate.

Drug Interactions: MAO Inhibitors or Tricyclic Antidepressants: Salbutamol should be administered with extreme caution to patients being treated with MAO inhibitors or tricyclic antidepressants since the action of salbutamol on the cardiovascular system may be potentiated.

Other Inhaled Sympathomimetic Bronchodilators or Epinephrine: Other inhaled sympathomimetic bronchodilators or epinephrine should not be used concomitantly with salbutamol. If additional adrenergic drugs are to be administered by any route to the patient using inhaled salbutamol, the adrenergic drugs should be used with caution to avoid deleterious cardiovascular effects. Such concomitant use must be individualized and not given on a routine basis. If regular coadministration is required then alternative therapy must be considered.

Beta-blockers: Beta-adrenergic blocking drugs, especially the noncardioselective ones, may effectively antagonize the action of salbutamol, and therefore, salbutamol and nonselective beta-blocking drugs, such as propranolol, should not usually be prescribed together.

Ipratropium Bromide: 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. Therefore, a combination of nebulized salbutamol with nebulized anticholinergics should be used cautiously. Patients should receive adequate instruction in correct administration and be warned not to let the solution or mist enter the eye.

Diuretics: The ECG changes and/or hypokalemia that may result from the administration of nonpotassium 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 significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium sparing diuretics.

Digoxin: Mean decreases of 16 to 22% in serum digoxin levels were demonstrated after single dose i.v. and oral administration of salbutamol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airways disease who are receiving salbutamol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate serum digoxin levels in patients who are currently receiving digoxin and salbutamol.

Adverse Reactions: The most frequent adverse reactions associated with salbutamol inhalation aerosol, dry powder or respirator solution formulations are nervousness and tremor. In some patients inhaled salbutamol may cause a fine tremor of skeletal muscle, particularly in the hands. This effect is common to all beta2-adrenergic stimulants. Adaptation occurs during the first few days of dosing, and the tremor usually disappears as treatment continues. Headache, palpitations, transient muscle cramps, insomnia, nausea, weakness and dizziness have been reported as untoward effects following salbutamol administration. Peripheral vasodilation and a compensatory small increase in heart rate may occur in some patients.

Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles) have been reported, usually in susceptible patients.

Rarely reported adverse effects include drowsiness, flushing, restlessness, irritability, chest discomfort, difficulty in micturition, hypertension, angina, vomiting, vertigo, CNS stimulation, hyperactivity in children, unusual taste and drying or irritation of the oropharynx.

Immediate hypersensitivity reactions including angioedema, urticaria, bronchospasm, hypotension, rash, oropharyngeal edema, anaphylaxis and collapse have been reported very rarely.

As with other bronchodilator inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, the preparation should be discontinued immediately and alternative therapy instituted.

Potentially serious hypokalemia may result from beta2-agonist therapy, primarily from parenteral and nebulized routes of administration.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage may cause tachycardia, cardiac arrhythmia, hypokalemia, hypertension and, in extreme cases, sudden death. To antagonize the effect of salbutamol, the judicious use of a cardioselective beta-adrenergic blocking agent (e.g., metoprolol, atenolol) may be considered, bearing in mind the danger of inducing an asthmatic attack. Serum potassium levels should be monitored.

Dosage And Administration: Dosage should be individualized, and the patient’s response should be monitored by the prescribing physician on an ongoing basis.

In accordance with the present practice for asthma treatment, if salbutamol is required for relief of symptoms more than twice a day on a regular daily basis or for an extended period of time, anti-inflammatory therapy (e.g., corticosteroid) should be part of the regimen.

Increasing demand for salbutamol preparations in bronchial asthma is usually a sign of worsening asthma and indicates that the treatment plan should be reviewed.

If a previously effective dose fails to provide the usual relief, or the effects of a dose last for less than 3 hours, patients should seek prompt medical advice since this is usually a sign of worsening asthma.

As there may be adverse effects associated with excessive dosing the dosage or frequency of administration should only be increased on medical advice. However, if a more severe attack has not been relieved by the usual dose, additional doses may be required. In these cases, patients should immediately consult their doctors or the nearest hospital.

Ventodisk blisters and Ventolin Rotacaps capsules are alternative inhalation forms of salbutamol to the metered-dose pressurized aerosol. The Ventodisk Diskhaler and Ventolin Rotacaps/Rotahaler systems are particularly useful in patients who are unable to use properly the pressurized aerosol form of salbutamol or who prefer an alternative delivery system. Ventodisk blisters and Ventolin Rotacaps capsules are for inhalation use only, using only a Ventodisk Diskhaler or Ventolin Rotahaler inhalation device, respectively.

Ventolin Respirator Solution may be preferred in the treatment of severe bronchospasm associated with exacerbations of chronic bronchitis and bronchial asthma.

Ventolin Inhalation Aerosol: Experience is insufficient for recommending the treatment of children under 6 years of age.

Acute Symptoms: Adults: 1 to 2 puffs (100 to 200 g salbutamol).

Children (6 years or older): 1 puff (100 g salbutamol).

If a more severe attack has not been relieved by the usual dose (1 to 2 puffs), further puffs may be required. In these cases, patients should immediately consult their doctors or the nearest hospital.

Intermittent and Long-term Treatment: If despite appropriate anti-inflammatory therapy (e.g., corticosteroid), regular daily use of the inhalation aerosol remains necessary for the control of bronchospasm, the recommended dose is: Adults: 1 or 2 puffs (100 to 200 g salbutamol) 3 to 4 times daily, not exceeding 8 puffs (800 g salbutamol)/day.

Children (6 years or older): 1 puff (100 g salbutamol) 3 to 4 times daily, not exceeding 4 puffs (400 g salbutamol)/day.

Prevention of Exercise-induced Asthma: Adults: 2 puffs (200 g salbutamol) before exertion.

Children (6 years or older): 1 puff (100 g salbutamol) before exertion.

Total Daily Dose Should Not Exceed: Adults: 8 puffs (800 g salbutamol).

Children (6 years or older): 4 puffs (400 g salbutamol).

Ventodisk Blisters/Diskhaler and Ventolin Rotacaps/Rotahaler: Experience is insufficient for recommending the treatment of children under 6 years of age.

Acute Symptoms: Adults: 200 to 400 g salbutamol (1 to 2 Ventodisk blisters or Ventolin Rotacaps capsules).

Children (6 years or older): 200 g salbutamol (1 Ventodisk blister or Ventolin Rotacaps capsule).

If a more severe attack has not been relieved by the usual dose (1 to 2 Ventodisk blisters or Ventolin Rotacaps capsules), additional blisters or capsules may be required. In these cases, patients should immediately consult their doctors or the nearest hospital.

Intermittent and Long-term Treatment: If despite appropriate anti-inflammatory therapy (e.g., corticosteroid) regular daily use of Ventodisk blisters remains necessary for the control of bronchospasm, the recommended dose is: Adults: 200 to 400 g salbutamol (1 to 2 Ventodisk blisters or Ventolin Rotacaps capsules) 3 to 4 times daily, not exceeding 1 600 g salbutamol daily.

Children (6 years or older): 200 g salbutamol (1 Ventodisk blister or Ventolin Rotacaps capsule) 3 to 4 times daily, not exceeding 800 g salbutamol daily.

Prevention of Exercise-induced Asthma: Adults: 200 to 400 g salbutamol (1 or 2 Ventodisk blisters or Ventolin Rotacaps capsules) before exertion.

Children (6 years or older): 200 g salbutamol (1 Ventodisk blister or Ventolin rotacaps capsule) before exertion.

Total Daily Dose Should Not Exceed: Adults: 1 600 g salbutamol (8´200 g Ventodisk blisters or 4´400 g Ventodisk blisters or 8´200 g Ventolin Rotacaps capsules or 4´400 g Ventolin Rotacaps capsules).

Children (6 years or older): 800 g salbutamol (4´200 g Ventodisk blisters or 4´200 g Ventolin Rotacaps capsules).

Ventolin Respirator Solution Regimens: Experience is insufficient for recommending the treatment of children under 5 years of age.

Ventolin Respirator Solution: Adults: In adults, 0.5 to 1 mL (2.5 to 5 mg of salbutamol) should be diluted in 2 to 5 mL or more of sterile normal saline. Treatment may be repeated 4 times a day if necessary.

Children (5 to 12 years): The average dose for a single treatment is 0.25 to 0.5 mL (1.25 to 2.5 mg of salbutamol) diluted in 2 to 5 mL or more of sterile normal saline. For more refractory cases, the single dose of Ventolin Respirator Solution may be increased to 1 mL (5 mg of salbutamol). Treatment may be repeated 4 times a day if necessary.

Ventolin Nebules P.F.: Adults: Patients requiring single doses of 2.5 mg or 5 mg may be administered the contents of a single unit dose (Ventolin Nebules P.F. 2.5 or 5 mg of salbutamol). Treatment may be repeated 4 times a day if necessary.

Children (5 to 12 years): Children requiring single doses of 1.25 mg or 2.5 mg may be administered the contents of a single unit dose (Ventolin Nebules P.F. 1.25 or 2.5 mg of salbutamol). For more refractory cases children may use a 5 mg unit dose (see dosage above). Treatment may be repeated 4 times a day if necessary.

If a more severe attack has not been relieved by a treatment, further treatments may be required. In these cases, patients should immediately consult their doctor or the nearest hospital.

Use of Ventolin Respirator Solution: Ventolin Respirator Solution is to be used only under the direction of a physician employing either a respirator or nebulizer. Ventolin Respirator Solution can be taken by either the nebulization or intermittent positive pressure ventilation method. When used in a nebulizer, a mouthpiece or a face mask may be applied. The nebulizer should be connected to a compressed air or oxygen pump. Gas flow should be in the range of 6 to 10 L/minute. With an average volume of 3 mL, a single treatment lasts approximately 10 minutes. It is advisable to prepare 1 dose at a time or to utilize the unit dose (Ventolin Nebules P.F.) presentation. When administered through intermittent positive pressure ventilation, the inspiratory pressure is usually 10 to 20 cm H2O and the duration of administration varies from 5 to 20 minutes, depending upon the patient and the control of the apparatus. This length of administration provides a more gradual and more complete lysis of bronchospasm. In several cases it has been reported that the use of intermittent positive pressure ventilation in acute asthma attacks was related to lethal episodes of hypoxia and pneumothorax. This method of drug administration may be ineffective in patients with severe obstruction and may greatly increase airway resistance and possibly induce severe hypercapnia and hypoxia. It is highly desirable to monitor arterial blood gases during intermittent positive pressure ventilation therapy.

In hospitals, Ventolin Respirator Solution, diluted (1:5 or 1:10) with sterile normal saline, should be used within 24 hours from time of dilution when stored at room temperature or within 48 hours when stored under refrigeration.

Cleansing and maintenance of the nebulizer must be carefully exercised by strict adherence to the manufacturer’s instructions.

The respirator solution must not be injected.

Availability And Storage: Ventolin Inhalation Aerosol: Each metered-dose aerosol unit for oral inhalation contains: a microcrystalline suspension of salbutamol in propellants. Each actuation delivers to the patient salbutamol 100 g. Nonmedicinal ingredients: dichlorodifluoromethane (propellant), oleic acid and trichloromonofluoromethane (propellant). Dose format of 200. Store at a temperature between 2 to 30°C. Protect from direct sunlight.

The canister should not be punctured, broken or burnt, even when apparently empty.

Ventodisk Blisters: Each blister contains: microfine salbutamol (as the sulfate) 200 g (pale blue disk) or 400 g (dark blue disk). Each double-foil disk contains 8 sealed blisters. Also contains lactose. Disks of 8, cartons of 15. Store below 30°C, in a dry place.

The contents of each Ventodisk blister are inhaled using the specially designed plastic device called the Ventodisk Diskhaler. The Ventodisk Diskhaler is available separately from the Ventodisk disks.

Ventolin Rotacaps Capsules: Each Rotacaps capsule contains: microfine salbutamol sulfate 200 g (pale blue) or 400 g (dark blue). Also contains lactose. Polypropylene bottles of 100, closed with polythene snap caps. Store below 30°C, in a dry place.

The contents of each Ventolin Rotacaps capsule are inhaled using the specially designed plastic device called the Ventolin Rotahaler. The Ventolin Rotahaler comes in a plastic box and is available separately from the Ventolin Rotacaps capsules.

Ventolin Respirator Solution: Each mL of isotonic solution contains: salbutamol sulfate, equivalent to salbutamol base 5 mg. Adjusted to pH 3.4 to 4.4. Preserved with benzalkonium chloride 0.01% w/v. Bottles of 10 and 100 mL. Store below 25°C. Protect from light.

Ventolin Respirator Solution Unit Dose (Ventolin Nebules P.F.): Each unit dose of sterile, isotonic solution contains: salbutamol sulfate equivalent to salbutamol base 1.25, 2.5 or 5 mg in 2.5 mL. Adjusted to pH 3.5 to 4.5. Boxes of 20. Overwrapped nebule: Store below 25°C. Nebule removed from overwrap: Store below 25°C. Protect from light. Use within 3 months.

VENTOLIN® VENTODISK® VENTODISK® DISKHALER® VENTOLIN® ROTACAPS® VENTOLIN® ROTAHALER® VENTOLIN® RESPIRATOR SOLUTION VENTOLIN® NEBULES P.F. Glaxo Wellcome Salbutamol Bronchodilator – Beta2-adrenergic Stimulant

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