| COMBIVENTŪ Inhalation Solution |
|Boehringer Ingelheim |
|Ipratropium Bromide - Salbutamol Sulfate |
|Action And Clinical Pharmacology: Combivent Inhalation Solution is a combination of the anticholinergic bronchodilator, ipratropium bromide, and the beta2-adrenergic bronchodilator, salbutamol sulfate.
Ipratropium bromide is a quaternary ammonium derivative of atropine and is an anticholinergic drug which has bronchodilator properties. On inhalation, 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 from the peak. Bronchodilation is still evident 8 hours after inhalation.
Salbutamol produces bronchodilation through stimulation of beta2-adrenergic receptors in bronchial smooth muscle, thereby causing relaxation of muscle fibres. This action is manifested by an increase in pulmonary function as demonstrated by spirometric measurements. 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 after 60 to 90 minutes, and significant bronchodilator activity has been observed to persist from 3 to 6 hours.
In a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pattern of absorption and excretion of a single-dose of Combivent Inhalation Solution to the 2 active components individually, the co-nebulization of ipratropium bromide and salbutamol sulfate does not potentiate the systemic absorptions of either component.
In another 85 day multi-center, randomized, double-blind, parallel trial, 652 patients with chronic obstructive pulmonary disease (COPD) were evaluated for the bronchodilator efficacy of Combivent Inhalation Solution (222 patients) in comparison to its components, ipratropium bromide (214 patients) and salbutamol sulfate (216 patients). In this study, Combivent Inhalation Solution 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 in FEV1 was 15 minutes for each treatment group. The median time to peak was 1 hour for Combivent, and ranged from 1 to 2 hours for the ipratropium group and 30 minutes to 1 hour for the salbutamol group. The median duration of effect was 3 to 5 hours for Combivent Inhalation Solution compared to 4 hours for ipratropium bromide and 2 to 3 hours for salbutamol sulfate.
These studies demonstrated that each component of Combivent Inhalation Solution contributed to the efficacy of the combination, especially during the first 4 hours after administration, and that Combivent Inhalation Solution was significantly more effective than ipratropium or salbutamol administered alone.
Indications And Clinical Uses: For the management of bronchospasm in patients suffering from chronic obstructive pulmonary disease (COPD) who require regular treatment with both ipratropium and salbutamol.
Contra-Indications: Patients with cardiac tachyarrhythmias, hypertrophic obstructive cardiomyopathy and patients with a history of hypersensitivity to any of its components or to atropine or its derivatives. tag_WarningWarnings
Manufacturers' Warnings In Clinical States: Pregnancy: The safety 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 Solution, 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 Solution 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 Solution use during lactation should therefore be weighed against possible effects on the infant.
Children: The efficacy and safety in children under 12 years has not been established.
General: Care should be taken to ensure that the nebulizer mask fits the patient's face properly and that nebulized solution does not escape into the eyes. In patients with glaucoma or narrow anterior chambers, the administration by nebulizer of a combined ipratropium/beta2-agonist solution should be avoided unless measures (e.g., use of swimming goggles or use of a nebulizer with a mouthpiece) are taken to ensure that nebulized solution does not reach the eye. There have been isolated reports of ocular complications (i.e., mydriasis, increased intraocular pressure, angle closure glaucoma) when nebulized ipratropium either alone or in combination with an adrenergic beta2-agonist solution has escaped into the eyes. 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 amines, the exact cause of which is unknown.
Patients with cystic fibrosis may be more prone to gastrointestinal motility disturbances.
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 beta2-agonist therapy, mainly from parenteral and nebulized administration.
Particular caution is advised in acute severe asthma as hypokalemia may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics: the adverse effects of hypokalemia may be exacerbated 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. 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 beta2-adrenergic agonist have been reported to have developed severe paradoxical bronchospasm which has been life threatening.
Precautions: General: Patients must be instructed in the correct use of Combivent Inhalation Solution and warned not to allow the solution or mist to enter the eyes. Acute angle glaucoma has been reported rarely when nebulized solutions of ipratropium have been used in conjunction with beta2-agonist bronchodilators. Protection of the eyes appears to prevent any increase in intraocular pressure and patients who may be susceptible to glaucoma should be warned specifically on the need for ocular protection.
In the following conditions Combivent Inhalation Solution should only be used after careful risk/benefit assessment: hypertrophic obstructive cardiomyopathy, tachyarrhythmia, inadequately controlled diabetes mellitus, recent myocardial infarction and/or severe organic heart or vascular disorders, hyperthyroidism, prostatic hypertrophy, urinary retention, or bladder-neck obstruction.
The patient should be instructed to consult a doctor immediately in the event of acute, rapidly worsening dyspnea. In addition, the patient should be warned to seek medical advice should a reduced response become apparent.
The concomitant use of Combivent with other sympathomimetic agents is not recommended since such combined use may lead to deleterious cardiovascular effects.
Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.
Drug Interactions: In patients receiving other anticholinergic drugs, Combivent should be used with caution because of possible additive effects.
Xanthine derivatives and beta2-adrenergic agents may enhance the effect of Combivent Inhalation Solution.
Other sympathomimetic bronchodilators or epinephrine should not be used concomitantly with Combivent Inhalation Solution. 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 co-administration is required then alternative therapy must be considered.
Combivent Inhalation Solution 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.
Inhalation of halogenated hydrocarbon anesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of beta-agonists.
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 Solution is required in pregnant patients when it is given for relief of bronchospasm so as to avoid interference with uterine contractility.
Adverse Reactions: COPD: Adverse reaction information concerning Combivent Inhalation Solution is derived from a total of 1 068 COPD patients randomized and treated with either Combivent (222 patients); ipratropium bromide+salbutamol sulfate (100 patients); ipratropium bromide (327 patients) or salbutamol sulfate (421 patients).
Adverse reactions, judged by the investigator to be possibly related to drug treatment, occurring in 1 or more patients in any group in the controlled clinical trials, appear in Table I.
Additional adverse reactions reported and considered possibly due to Combivent include fatigue, abdominal pain, hypertension, dyspepsia, tachycardia, sinusitis, dysuria, and urinary retention.
Additional information is derived from the literature on the use of ipratropium or salbutamol inhalation solution singly or in combination. Cases of blurred vision, taste perversion, dry mouth, paradoxical bronchospasm, bronchitis, angina, arrhythmia, lightheadedness, drowsiness, insomnia, dizziness, vertigo, CNS stimulation, weakness, itching, rash, flushing, alopecia, hypotension, increased blood pressure, gastrointestinal distress, vomiting, diarrhea, edema, 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.
Counseling 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.
Adults and Children over 12 years: COPD: Combivent Inhalation solution in unit dose vials (UDVs) may be administered from a suitable nebulizer or an intermittent positive pressure ventilator. The recommended dosage is 1 UDV vial 3 or 4 times daily.
Dilution Instructions: If necessary, before use, doses may be diluted to a total nebulization volume of 3 to 5 mL with preservative-free 0.9% sterile sodium chloride solution and used immediately. Discard any unused solution. Nebulize over 10 to 15 minutes at gas flow of 6 to 10 L/min. Repeat every 6 hours as necessary.
Availability And Storage: Each unit dose vial contains: ipratropium bromide anhydrous (as monohydrate) 0.5 mg and salbutamol sulfate 3 mg (equivalent to salbutamol base 2.5 mg). Nonmedicinal ingredients: hydrochloric acid, purified water and sodium chloride. Plastic, single dose units in strips of 10, 20 unit dose vials per box. Unopened unit dose vials should be stored at controlled room temperature (between 15 and 25°C) and protected from light and heat. Do not use if solution is discolored. Keep out of reach of children.