BULMOL

Uses

BULMOL Respirator Solution is used for the treatment of severe acute asthma (status asthmaticus) and also forms of bronchospasm.

BULMOL tablet/injection is used for a bronchodilator for use in Asthma, Chronic Bronchitis, Emphysema and other conditions associated with airways obstruction.

BULMOL inhaler is used for the treatment and prophylaxis of bronchial asthma and for the treatment of reversible airways obstruction associated with bronchitis and emphysema.

BULMOL inhaler may be used to relieve attacks of acute dyspnoea and may also be taken prophylactically before exertion or to prevent exercise-induced asthma.

BULMOL inhaler is suitable for treating bronchospasm in patients with coexisting heart disease or hypertension, including those taking beta blockers, because of its selective action on the bronchial receptors and lack of effects on the cardiovascular system. At therapeutic levels, it has little effect on cardiac receptors.

BULMOL is also used to associated treatment for these conditions: Asthma, Asthmatic Bronchitis, Bronchial Asthma, Bronchospasm, Chronic Asthma, Chronic Bronchitis, Cough, Emphysema, Exercise-Induced Bronchospasm, Hyperkalemia, Wheezing, Excess mucus or phlegm, Airway secretion clearance therapy, Bronchodilation

How BULMOL works

In vitro studies and in vivo pharmacologic studies have shown that salbutamol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. Although beta2­ adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1 adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta2-agonists may have cardiac effects.

Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase and to an increase in the intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. BULMOL relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. BULMOL acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

BULMOL has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

A measurable decrease in airway resistance is typically observed within 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.

Dosage

BULMOL dosage

BULMOL Oral-

Children:

• 2-6 years: 2.5 ml syrup, 3-4 times daily
• 6-12 years: 5 ml syrup, 3-4 times daily
• Over 12 years: 5-10 ml syrup, 3-4 times daily (2-4 mg tablet, 3-4 times daily)

Adults: 2-4 mg tablet, 3-4 times daily. Maximum single dose is 8 mg tablet.

Injection-

salbutamol Injection may be administered by the subcutaneous, intramuscular or intravenous route, under the direction of a physician.

Adults:

• Subcutaneous route:500 mcg (8 mcg/kg) and repeated every four hours as required.
• Intramuscular route:500 mcg (8 mcg/kg) and repeated every four hours as required.

Slow intravenous injection: 250 mcg (4 mcg/kg) injected slowly. If necessary the dose may be repeated. The use of salbutamol Injection 500 mcg in 1 ml (500 mcg/ml, for intravenenous administration may be facilitated by dilution to 10 ml with Water for Injection BP (final concentration of 50 mcg/ml) and 5 ml of the diluted preparation (250 mcg/5 ml) administered by slow intravenous injection.

PediatricPopulation:The safety and efficacy of salbutamol Injection in children under the age of 12 has not been established. From the available data no recommendation on posology can be made.

Children aged 12 years and over: Dose as per adult population

BULMOL inhaler is administered by the inhaled route only. Shake BULMOLInhaler well before each spray. As there may be adverse effects associated with excessive dosing, the dosage or frequency of administration should only be increased on medical advice.

Adults:

• For the relief of acute bronchospasm and for managing intermittent episodes of asthma: One or two puffs as a single dose
• For chronic maintenance or prophylactic therapy: Two puffs three or four times daily
• For prevention of exercise induced bronchospasm: Two puffs before exertion
• For prevention of exercise induced bronchospasm: Two puffs should be taken at least 15 minutes before exertion

Children:

• For the relief of acute bronchospasm, management of episodic asthma and for prevention of exercise induced bronchospasm: One puff may be administered as a single dose. Only for the use of medical professionals
• For routine maintenance and prophylaxis: One puff three or four times daily, increasing if necessary to two puffs three or four times daily

Elderly: The dosage is the same as that for adults.

By Intermittent Administration:

Adult: salbutamol Respirator Solution 0.5-4.0 ml should be diluted to final volume of 2.0-4.0 ml with normal saline for injection. The resulting solution is inhaled from a suitably driven nebuliser until aerosol generation ceases. Using a correctly matched nebuliser and driving source this should take about 10 minutes.BULMOL Respirator Solution may be used undiluted for intermittent administration. For this 2.0 ml of the solution is placed in the nebuliser and the patient allowed to inhale until bronchodilatation is achieved. This usually takes 3-5 minutes. Some adult patients may require higher doses of salbutamol upto 10 mg in which case nebulisation may continue until aerosol generation ceases.

Children under 12 years age: 0.5 ml of the solution diluted to 2-4 ml with normal saline. Some children may however require higher doses of upto 1 ml of the solution. Intermittent treatment may be repeated four times a day.

By Continuous Administration:

BULMOL Respirator Solution is diluted with normal saline for injection, 1-2 ml solution made upto 100 ml with diluent. The diluted solution is administered as an aerosol by a suitably driven nebuliser. The usual rate of administration is 1 to 2 mg/hour. Delivery of the aerosol may be by face mask or via an endotracheal tube. Intermittent positive pressure may be used but is rarely necessary. When there is risk of anoxia through hypoventilation, oxygen should be added to the inspired air.

Side Effects

BULMOL may cause fine tremor of skeletal muscles (particularly the hands), palpitations and muscle cramps. Tachycardia, tenseness, headaches and peripheral vasodilatation have been reported after large doses.

Mild tremor and headache have been rarely reported. These usually disappear with continuous treatment. There have been very rare reports of transient muscle cramp. Hypersensitivity reactions including angioedema, urticaria, bronchospasm, hypotension and collapse have been reported very rarely. As with other inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, the preparation should be discontinued immediately and alternative therapy should be instituted.

Toxicity

The expected signs and symptoms with overdosage of albuterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). In particular, the signs of salbutamol overdosage are significant tachycardia and/or significant muscle tremor.

Hypokalaemia may occur following overdosage with salbutamol. Serum potassium levels should be monitored.

Lactic acidosis has been reported in association with high therapeutic doses as well as overdoses of short-acting beta-agonist therapy, therefore monitoring for elevated serum lactate and consequent metabolic acidosis (particularly if there is persistence or worsening of tachypnea despite resolution of other signs of bronchospasm such as wheezing) may be indicated in the setting of overdose.

BULMOL is categorized as Pregnancy Category C. There are no adequate and well-controlled trials with salbutamolc or albuterol sulfate in pregnant women. During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients being treated with salbutamol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between salbutamol use and congenital anomalies has not been established. Animal reproduction studies in mice and rabbits revealed evidence of teratogenicity. BULMOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetusLabel]. Women should be advised to contact their physicians if they become pregnant while taking salbutamol.

Since there exists a potential for beta-agonist interference with uterine contractility, the use of salbutamol during labour should be restricted to those patients in whom the benefits clearly outweigh the risk.

Plasma levels of albuterol sulfate and HFA-134a after inhaled therapeutic doses are very low in humans, but it is not known whether the components of salbutamol are excreted in human milk. Because of the potential for tumorigenicity shown for albuterol in animal studies and lack of experience with the use of salbutamol by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when salbutamol is administered to a nursing woman.

The safety and effectiveness of salbutamol in children younger than 4 years of age has not yet been established.

Clinical trials of VENTOLIN HFA did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The LD₅₀ value was determined to be 1100 mg/kg (orally in mice).

Precaution

BULMOL should be used with caution in patients with hyperthyroidism, cardiovascular disease, occlusive vascular disorders, hypertension and aneurysms. Hypokalaemia associated with high doses of BULMOL may result in increased susceptibility to digitalis-induced cardiac arrhythmia. Tachyphylaxis with resistance may occur with prolonged use of high dosage. Care is necessary when treating patients with diabetes mellitus or closed-angle glaucoma, and in those receiving antihypertensive therapy.

BULMOL should be administered cautiously to patients suffering from thyrotoxicosis. In the event of previously effective dose of salbuatmol inhaler failing to give relief for at least three hours, the patient should be advised to seek medical advice in order that any necessary additional steps may be taken.

The management of asthma should normally a stepwise programme, and patient response should be monitored clinically and by lung function test. Increasing use of short acting inhaled agonists to control symptoms indicates deterioration of asthma control. Under these conditions, the patient’s therapy plan should be reassessed. Sudden and progressive deterioration in asthma control is potentially life threatening and consideration should be given to starting or increasing corticosteroid therapy. In patients considered at risk, daily peak flow monitoring may be instituted. Patients inhaler techinique should be checked to make sure that aerosl actuation is synchronized with inspiration of breath for optimum delivery of the drugs to the lungs.

Interaction

BULMOL and non-selective beta-blocking drugs such as propranolol should generally not be prescribed together. Potentially serious hypokalaemia may result from beta2-agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids, diuretics, and by hypoxia. It is recommended that serum potassium levels are monitored in such situations.

Food Interaction

Volume of Distribution

The volume of distribution recorded for intravenously administered salbutamol has been recorded as 156 +/- 38 L.

Elimination Route

Following inhalation, salbutamol acts topically on bronchial smooth muscle and the drug is initially undetectable in the blood. After 2 to 3 hours low concentrations are seen, due presumably to the portion of the dose which is swallowed and absorbed in the gut.

In particular, the systemic levels of salbutamol are low after inhalation of recommended doses. A trial conducted in 12 healthy male and female subjects using a higher dose (1,080 mcg of albuterol base) showed that mean peak plasma concentrations of approximately 3 ng/mL occurred after dosing when salbutamol was delivered using propellant HFA-134a. The mean time to peak concentrations (Tmax) was delayed after administration of VENTOLIN (salbutamol) HFA (Tmax = 0.42 hours) as compared with CFC-propelled salbutamol inhaler (Tmax = 0.17 hours).

Half Life

The elimination half-life of inhaled or oral salbutamol has been recorded as being between 2.7 and 5 hours while the apparent terminal plasma half-life of albuterol has been documented as being approximately 4.6 hours.

Clearance

The renal clearance of salbutamol has been documented as 272 +/- 38 ml/min after oral administration and 291 +/- 70 ml/min after intravenous administration. Furthermore, the renal clearance of the predominant sulfate conjugate metabolite was recorded as 98.5 +/- 23.5 ml/min following oral administration.

Elimination Route

After oral administration, 58-78% of the dose is excreted in the urine in 24 hours, approximately 60% as metabolites. A small fraction is excreted in the feces.

Pregnancy & Breastfeeding use

BULMOL is known to cross the placental barrier in humans. Safety for use in pregnancy has not been demonstrated, therefore the drug should not be used in pregnant women, or those likely to become pregnant, unless the expected benefit outweighs any potential risk. Oral administration of salbutamol to rats and rabbits during pregnancy showed no teratogenic effects in offspring, but evidence of retardation of fetal development was recorded in an inhalational teratology study in rabbits at an estimated dose of 149 μg/kg/day. Although intravenous salbutamol and occasionally salbutamol tablets are used in the management of uncomplicated premature labour, BULMOL presentations should not be used for threatened abortion during the first or second trimesters of pregnancy.

Intravenous salbutamol is contra-indicated in cases of ante-partum haemorrhage because of the risk of further haemorrhage from an atonic uterus and there is the risk of the same problem arising inadvertently in asthmatics using salbutamol. Profuse uterine bleeding following spontaneous abortion has been reported after the use of salbutamol. Special care is required in pregnant diabetic women. As salbutamol is probably secreted in breast milk, its use in nursing mothers is not recommended unless the expected benefit to the mother is greater than any possible risk to the infant.

Contraindication

History of hypersensitivity to any of its components. BULMOL presentation should not be used for threatened abortion during the first or second trimester of pregnancy. It should be used with care in patients known to have received large doses of other sympathomimetic drugs.

BULMOL tablet/injection is contraindicated in patients with a history of hypersensitivity to BULMOL or any of its components.

Salbuatmol inhaler is contraindicated in patients with a history of hypersensitivity to any of its components. Although intravenous salbutamol, and occasionally salbutamol tablets, is used in the management of premature labour uncomplicated by conditions such as placenta praevia, ante-partum haemorrhage or toxaemia of pregnancy, salbutamol inhaler preparations are not appropriate for managing premature labour. BULMOL preparation should not be used for threatened abortion during the first or second trimesters of pregnancy.

Acute Overdose

The symptoms with overdosage are angina, headache, nausea, vomiting, tremor etc. The preferred antidote for overdosage with BULMOL is a cardio-selective beta-blocking agent but beta-blocking drugs should be used with caution in patients with a history of bronchospasm.

Storage Condition

Store at a cool & dry place, protected from light. Once a bottle has been opened the contents should be discarded after one month.

Innovators Monograph

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