Combivent_Aerosol (Ipratropium Bromide – Salbutamol Sulfate)

COMBIVENT® Inhalation Aerosol

Boehringer Ingelheim

Ipratropium Bromide – Salbutamol Sulfate

Bronchodilator

Action And Clinical Pharmacology: Combivent Inhalation Aerosol is a combination of the anticholinergic bronchodilator, ipratropium bromide, and the b2-adrenergic bronchodilator, salbutamol sulfate. Each actuation from the valve delivers 20 µg ipratropium bromide and 120 µg salbutamol sulfate (equivalent to 100 µg salbutamol base).

Ipratropium bromide is a quaternary ammonium derivative of atropine and is an anticholinergic with bronchodilator properties. On inhalation of ipratropium bromide the onset of action is noted within 5 to 15 minutes with a peak response between 1 and 2 hours, lasting about 2 additional hours with subsequent decline. An inhaled dose of 40 µg of ipratropium bromide inhalation aerosol induced bronchodilatation lasting for some 6 hours.

Salbutamol produces bronchodilation through stimulation of b2-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.

In a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pattern of absorption and excretion of 2 inhalations of Combivent Inhalation Aerosol to the 2 active components individually, the coadministration of ipratropium bromide and salbutamol sulfate in a single canister did not potentiate the systemic absorption of either component. From a pharmacokinetic perspective, the synergistic efficacy of Combivent Inhalation Aerosol is due to a local effect on the muscarinic and b2-adrenergic receptors in the lung.

In two 12-week controlled clinical trials, 1 067 patients with chronic obstructive pulmonary disease (COPD) were evaluated for the bronchodilator efficacy of Combivent Inhalation Aerosol (358 patients) in comparison to its components, ipratropium bromide (362 patients) and salbutamol sulfate (347 patients). In these studies Combivent Inhalation Aerosol produced significant improvements in pulmonary function as demonstrated by increases in FEV1 of 15% or more compared with baseline. The median time to onset of a 15% increase was 15 minutes and the median time to peak was 1 hour for Combivent Inhalation Aerosol and its components. The median duration of effect was 4 to 5 hours for Combivent Inhalation Aerosol compared to 4 hours for ipratropium bromide and 3 hours for salbutamol sulfate. These studies demonstrated that each component of Combivent Inhalation Aerosol contributed to the efficacy of the combination, especially during the first 4 to 5 hours after dosing, and that Combivent Inhalation Aerosol was significantly more effective than ipratropium bromide or salbutamol sulfate administered alone.

Indications And Clinical Uses: Treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).

Contra-Indications: In patients with cardiac tachyarrhythmias, hypertrophic obstructive cardiomyopathy and in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. Combivent should also not be taken by patients hypersensitive to salbutamol sulfate, ipratropium bromide, atropinics or any other aerosol components.

Manufacturers’ Warnings In Clinical States: Pregnancy: The safety of Combivent Inhalation Aerosol in pregnancy has not been established. The benefits of using Combivent when pregnancy is present or suspected must be weighed against possible hazards caused to the fetus.

Salbutamol, a component of Combivent Inhalation Aerosol, has been shown to be teratogenic in mice when given in doses corresponding to 14 times the human aerosol dose; 5 times the human inhalation dose, 0.2 times the maximum human (child weighing 21 kg) oral dose; and 0.4 times the maximum human oral dose and at doses corresponding to the human nebulization dose.

Lactation: It is not known whether the components of Combivent Inhalation Aerosol are excreted in human milk. As salbutamol is probably secreted in breast milk and because of the potential for tumorigenicity shown for salbutamol in animal studies, 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. It is not known whether salbutamol in breast milk has a harmful effect on the neonate. No specific studies have been conducted on the excretion of ipratropium in breast milk. The benefits of Combivent Inhalation Aerosol use during lactation should therefore be weighed against possible effects on the infant.

Children: The efficacy and safety in children younger than 12 years has not been established.

General: Care should be taken to ensure that Combivent Inhalation Aerosol does not reach the eye. There have been isolated reports of ocular complications (i.e., mydriasis, increased intraocular pressure, glaucoma and eye pain) when aerosolized ipratropium has been released into the eyes. Ocular events have occurred when ipratropium aerosol was used with the standard mouthpiece or with a spacing device. In the event that glaucoma is precipitated or worsened, treatment should include standard measures for this condition.

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.

Care should be taken with patients suffering from cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias and hypertension; in patients with convulsive disorders, diabetes mellitus, hyperthyroidism and in patients who are usually responsive to sympathomimetic amines. Fatalities have been reported following excessive use of inhaled sympathomimetic, the exact cause of which is unknown.

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

In common with other beta-adrenergic agents, salbutamol can induce reversible metabolic changes; these are more pronounced during infusions of the drug and include hyperglycemia and hypokalemia.

Potentially serious hypokalemia may result from b2-agonist therapy, mainly from parenteral and nebulized administration. Hypokalemia will increase the susceptibility of digitalis-treated patients to cardiac arrhythmias. It is recommended that serum potassium levels be monitored in such situations. Large doses of i.v. salbutamol have been reported to aggravate pre-existing diabetes mellitus and may precipitate ketoacidosis. The relevance of these observations to the use of Combivent is unknown.

Some patients receiving b2-adrenergic agonist have been reported to have developed severe paradoxical bronchospasm which has been life threatening. The cause of this refractory state is unknown. In this event, 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.

Combivent Inhalation Aerosol inhaler 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.

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

Precautions: General: To ensure optimal delivery of Combivent Inhalation Aerosol to the bronchial tree, the patient should be properly instructed by the physician or other health professional in the use of the inhaler.

In patients with glaucoma, prostatic hypertrophy or urinary retention Combivent should be used with caution. In patients with glaucoma or narrow anterior chambers, care should be taken to ensure that aerosol does not reach the eye. Due care should be taken when a spacing device is employed. There have been isolated reports of ocular complications (i.e., mydriasis, increased intraocular pressure, angle closure glaucoma) when ipratropium bromide either alone or in combination with an adrenergic b2-agonist has been released into the eyes. In the event that glaucoma is precipitated or worsened, treatment should include standard measure for this condition.

Like other pressurized aerosol formulations, Combivent Inhalation Aerosol contains fluorocarbon propellants dichlorodifluoromethane, dichlorotetrafluoroethane, trichloromonofluoromethane. Such propellants may be hazardous if they are deliberately abused. Inhalation of high concentrations of aerosol sprays has brought about toxic cardiovascular effects and even death, especially under conditions of hypoxia. However, evidence attests to the relative safety of aerosols when used properly and with adequate ventilation. The recommended dose of Combivent Inhalation Aerosol should not be exceeded and the patient should be so informed.

The concomitant use of Combivent with other sympathomimetic agents is not recommended since such combined use may lead to deleterious cardiovascular effects.

Drug Interactions: In patients receiving other anticholinergic drugs, Combivent should be used with caution because of possible additive effects.

Xanthine derivatives and b2-adrenergic agents may enhance the effect of Combivent Inhalation Aerosol.

Other sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with Combivent Inhalation Aerosol. If additional adrenergic drugs are to be administered by any route, they 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.

Combivent Inhalation Aerosol should be administered with extreme caution to patients being treated with MAO inhibitors or tricyclic antidepressants because the action of salbutamol on the vascular system may be potentiated.

Beta-receptor blocking agents and salbutamol inhibit the effect of each other.

Labor and Delivery: It has been reported that high doses of salbutamol, administered i.v., inhibits uterine contractions. Although this effect is extremely unlikely as a consequence of the use of inhaled formulations, it should be kept in mind.

Oral salbutamol has been shown to delay preterm labor in some reports. There are presently no well-controlled studies which demonstrated that it will stop preterm labor or prevent labor at term. Therefore, cautious use of Combivent Inhalation Aerosol is required in pregnant patients when it is given for relief of bronchospasm so as to avoid interference with uterine contractility.

Adverse Reactions: Adverse reaction information concerning Combivent Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for Combivent Inhalation Aerosol).

Adverse reactions, judged by the investigator to be possibly related to drug treatment, occurring in 1% or more of patients in any group in the two 12-week controlled clinical trials.

Additional adverse reactions reported in less than 1% of the patients considered possibly due to Combivent include fatigue, enlarged abdomen, hypertension, nervousness, paresthesia, tremor, dyspepsia, nausea, tachycardia, palpitation, abscess, sinusitis, dysuria and urinary retention.

Additional information is derived from the literature on the use of ipratropium or salbutamol inhalation aerosol singly or in combination. Cases of precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, nasal congestion, hoarseness, voice changes, drying of secretions, unusual taste, mucosal ulcers, irritation from aerosol, paradoxical bronchospasm, wheezing, exacerbation of COPD symptoms, angina, arrhythmia, heartburn, lightheadedness, drowsiness, insomnia, dizziness, vertigo, CNS stimulation, coordination difficulty, weakness, itching, rash, hives, giant urticaria, angioedema, flushing, alopecia, hypotension, increased blood pressure, indigestion, gastrointestinal distress, burning in stomach, vomiting, diarrhea, constipation and urinary difficulty have been reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The effects of overdosage are expected to be related primarily to salbutamol because acute overdosage with ipratropium is unlikely since ipratropium is not well absorbed systemically after aerosol or oral administration. However, should signs of serious anticholinergic toxicity appear, cholinesterase inhibitors may be considered.

Salbutamol 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 patient response should be monitored to determine the requirement for more than a single bronchodilator by the prescribing physician on an ongoing basis.

Counselling on smoking cessation should be the first step in treating patients with chronic bronchitis who smoke. Smoking cessation produces symptomatic benefits and has been shown to confer a survival advantage by slowing or stopping the progression of chronic bronchitis and emphysema.

The recommended dosage is 2 inhalations 4 times/day. The maximum daily dose should not exceed 12 inhalations.

Availability And Storage: Each actuation delivers from the valve: ipratropium bromide 20 µg and salbutamol sulfate 120 µg (equivalent to 100 µg salbutamol base). Nonmedicinal ingredients: propellants (dichlorodifluoromethane, dichlorotetrafluoroethane and trichloromonofluoromethane) and soya lecithin. Metal canisters containing 100 or 200 doses of Combivent with mouthpiece (oral adaptor).

The aerosol canisters should be stored at room temperature (15 to 30°C). Avoid excessive humidity. Caution. Contents under pressure. Container may explode if heated. Do not place in hot water or near radiators, stoves or other sources of heat. Do not puncture or incinerate container or store at temperatures over 30°C.

COMBIVENT® Inhalation Aerosol Boehringer Ingelheim Ipratropium Bromide – Salbutamol Sulfate Bronchodilator

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