COMBIPRASAL

Uses

This Inhaler is used for use in patients with chronic obstructive pulmonary disease (COPD) on a regular aerosol bronchodilator who continue to have evidence of bronchospasm and who require a second bronchodilator.

COMBIPRASAL 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 COMBIPRASAL 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. Salbutamol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Salbutamol 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.

Salbutamol 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

COMBIPRASAL dosage

Inhaler puffs:2 puffs 4 times a day. Patients may take additional puffs as required; however, the total number of puffs should not exceed 12 in 24 hours.

Inhaler solution: Inhalation solution in ampoule may be administered from a suitable nebuliser or an intermittent positive pressure ventilator.

Adults (including elderly): One ampoule as required for the relief of symptoms or as directed. Up to three to four ampoules daily.

Patients should be advised to consult a doctor or the nearest hospital immediately in the case of acute or rapidly worsening dyspnoea if additional inhalations do not produce an adequate improvement.

Side Effects

Salbutamol: 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 angio-oedema, urticaria, bronchospasm, hypotension and collapse have been reported very rarely.

Ipratropium: Headache, pain, influenza, chest pain, nausea, bronchitis, dyspnea, coughing, pneumonia, and bronchospasm in lower part, and pharyngitis, sinusitis and rhinitis in the upper part have been reported.

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.

Salbutamol 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. Salbutamol 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

Ipratropium bromide containing inhaler should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction. Salbutamol sulphate containing inhaler should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines.

Beta-adrenergic agents may also produce significant hypokalemia in some patients (possibly through intracellular shunting) which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Combination of Ipratropium and Salbutamol Inhaler has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in those patient populations.

Interaction

Iprasol inhalation aerosol has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines and steroids, commonly used in the treatment of COPD, without adverse drug reactions. No formal drug interaction studies have been performed with Iprasol inhalation aerosol and these drugs or other medications commonly used in the treatment of COPD.

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

Pregnancy Category C. There are no adequate and well-controlled studies of ipratropium bromide and salbutamol sulfate inhaler, ipratropium bromide or salbutamol sulfate, in pregnant women. this Inhaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: It is not known whether the components of this Inhaler are excreted in human milk. this Inhaler should not be used by breastfeeding mothers, unless the expected benefit is thought to outweigh the risks.

Contraindication

This Inhaler is contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. This Inhaler is also contraindicated in patients hypersensitive to any component of the drug product or to atropine or its derivatives.

Special Warning

Use in children: Safety and effectiveness in the pediatric population have not been established.

Acute Overdose

The effects of overdosage are expected to be primarily related to Salbutamol because acute overdosage with Ipratropium Bromide is unlikely as it is not well absorbed systemically after inhalation or oral administration.

Symptoms: Manifestations of overdosage with Salbutamol may include tachycardia, anginal pain, hypertension, hypotension palpitations, tremor, widening of the pulse pressure, arrhythmia and flushing.

Therapy: Administration of sedatives, tranquillisers. In severe cases, intensive therapy. Beta-receptor blockers, preferably beta1- selective, are suitable as specific antidotes; however, a possible increase in bronchial obstruction must be taken into account and the dose should be adjusted carefully in patients suffering from bronchial asthma.

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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