Combivent Information
Combivent (Albuterol sulfate; ipratropium bromide) Description
Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol is a combination of ipratropium bromide (as the monohydrate) and albuterol sulfate.
Ipratropium bromide is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo[3.2.1] octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-, bromide monohydrate, (3-endo, 8-syn)-: a synthetic quaternary ammonium compound chemically related to atropine. Ipratropium bromide is a white to off-white crystalline substance, freely soluble in water and methanol, sparingly soluble in ethanol, and insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons.
The structural formula is:
CHBrNO•HO ipratropium bromide Mol. Wt. 430.4
Albuterol sulfate, chemically known as (1,3-benzenedimethanol, α'-[[(1,1dimethylethyl) amino] methyl]-4-hydroxy, sulfate (2:1)(salt), (±)- is a relatively selective beta-adrenergic bronchodilator. Albuterol is the official generic name in the United States. The World Health Organization recommended name for the drug is salbutamol. Albuterol sulfate is a white to off-white crystalline powder, freely soluble in water and slightly soluble in alcohol, chloroform, and ether. The structural formula is:
(CHNO)•HSO albuterol sulfate Mol. Wt. 576.7
Combivent (Albuterol sulfate; ipratropium bromide) ® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol contains a microcrystalline suspension of ipratropium bromide and albuterol sulfate in a pressurized metered-dose aerosol unit for oral inhalation administration. The 200 inhalation unit has a net weight of 14.7 grams. Each actuation meters 21 mcg of ipratropium bromide and 120 mcg of albuterol sulfate from the valve and delivers 18 mcg of ipratropium bromide and 103 mcg of albuterol sulfate (equivalent to 90 mcg albuterol base) from the mouthpiece. The excipients are dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane as propellants and soya lecithin.
Combivent (Albuterol sulfate; ipratropium bromide) Clinical Pharmacology
Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol is a combination of the anticholinergic bronchodilator, ipratropium bromide, and the beta-adrenergic bronchodilator, albuterol sulfate.
In two 12-week randomized, double-blind, active-controlled clinical trials, 1067 patients with chronic obstructive pulmonary disease (COPD) were evaluated for the bronchodilator efficacy of Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol (358 patients) in comparison to its components, ipratropium bromide (362 patients) and albuterol sulfate (347 patients).
Serial FEV measurements (shown below as a percent change from test-day baseline) demonstrated that Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol produced significantly greater improvement in pulmonary function than either ipratropium bromide or albuterol sulfate when given separately. The median time to onset of a 15% increase in FEV was 15 minutes and the median time to peak FEV was one hour for Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol and its components. The median duration of effect as measured by FEV was 4 to 5 hours for Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol compared to 4 hours for ipratropium bromide and 3 hours for albuterol sulfate.
Percent Change in Adjusted Mean FEV from Test-Day Baseline - Endpoint Analysis of the Evaluable Data Set
These studies demonstrated that each component of Combivent (Albuterol sulfate; ipratropium bromide) ® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol contributed to the improvement in pulmonary function produced by the combination, especially during the first 4 to 5 hours after dosing, and that Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol was significantly more effective than ipratropium bromide or albuterol sulfate administered alone.
In the 2 controlled 12-week studies, Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol did not produce any change in the secondary efficacy parameters including symptom scores, physician global assessments and morning PEFR, all of which were monitored throughout the study period.
Combivent (Albuterol sulfate; ipratropium bromide) Indications And Usage
Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol is indicated 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.
Combivent (Albuterol sulfate; ipratropium bromide) Contraindications
Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol is also contraindicated in patients hypersensitive to any other components of the drug product or to atropine or its derivatives.
Combivent (Albuterol sulfate; ipratropium bromide) Warnings
If such a reaction occurs, therapy with Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol should be stopped at once and alternative treatment should be considered.
Combivent (Albuterol sulfate; ipratropium bromide) Precautions
Patients should be cautioned to avoid spraying the aerosol into their eyes and be advised that this may result in precipitation or worsening of narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Patients should also be advised that should any combination of these symptoms develop, they should consult their physician immediately.
The action of Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol should last 4 to 5 hours or longer. Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol without consulting your physician. If you find that treatment with Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, medical attention should be sought immediately. While you are taking Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol, other inhaled drugs should be taken only as directed by your physician. If you are pregnant or nursing, contact your physician about use of Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol. Appropriate use of Combivent (Albuterol sulfate; ipratropium bromide) ® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol includes an understanding of the way it should be administered (see ).
Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of Combivent (Albuterol sulfate; ipratropium bromide) , patients should be cautioned about engaging in activities requiring balance and visual acuity such as driving a car or operating appliances or machinery.
Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids, commonly used in the treatment of chronic obstructive pulmonary disease. With the exception of albuterol, there are no formal studies fully evaluating the interaction effects of Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol and these drugs with respect to safety and effectiveness.
Combivent (Albuterol sulfate; ipratropium bromide) Adverse Reactions
Adverse reaction information concerning Combivent (Albuterol sulfate; ipratropium bromide) ® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol) as seen in Table 1.
Additional adverse reactions, reported in less than two percent of the patients in the Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol treatment group include edema, fatigue, hypertension, dizziness, nervousness, paresthesia, tremor, dysphonia, insomnia, diarrhea, dry mouth, dyspepsia, vomiting, arrhythmia, palpitation, tachycardia, arthralgia, angina, increased sputum, taste perversion, and urinary tract infection/dysuria.
Allergic-type reactions such as skin reactions including rash, pruritus, and urticaria (including giant urticaria), angioedema including that of tongue, lips and face, laryngospasm and anaphylactic reaction have been reported with Combivent (Albuterol sulfate; ipratropium bromide) ® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol, with positive rechallenge in some cases. Many of these patients had a history of allergies to other drugs and/or foods including soybean (see ).
Combivent (Albuterol sulfate; ipratropium bromide) Overdosage
The effects of overdosage are expected to be related primarily to albuterol sulfate. Acute overdosage with ipratropium bromide by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after aerosol or oral administration. Oral median lethal doses of ipratropium bromide were greater than 1001 mg/kg in mice (approximately 19,000 times the maximum recommended daily inhalation dose in adults on a mg/m basis); 1663 mg/kg in rats (approximately 62,000 times the maximum recommended daily inhalation dose in adults on a mg/m basis); and 400 mg/kg in dogs (approximately 50,000 times the maximum recommended daily inhalation dose in adults, on a mg/m basis). Whereas the oral median lethal dose of albuterol sulfate in mice and rats was greater than 2000 mg/kg (approximately 6600 and 13,000 times the maximum recommended daily inhalation dose, respectively, in adults on a mg/m basis), the inhalational median lethal dose could not be determined. Manifestations of overdosage with albuterol may include anginal pain, hypertension, hypokalemia, tachycardia with rates up to 200 beats per minute and exaggeration of the pharmacologic effects listed in . As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse. Dialysis is not appropriate treatment for overdosage of albuterol as an inhalation aerosol; the judicious use of a cardiovascular beta-receptor blocker, such as metoprolol tartrate may be indicated.
Combivent (Albuterol sulfate; ipratropium bromide) Dosage And Administration
The dose of Combivent (Albuterol sulfate; ipratropium bromide) ® Inhalation Aerosol is two inhalations four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed 12 in 24 hours. Safety and efficacy of additional doses of Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol beyond 12 puffs/24 hours have not been studied. Also, safety and efficacy of extra doses of ipratropium or albuterol in addition to the recommended doses of Combivent (Albuterol sulfate; ipratropium bromide) ® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol have not been studied. It is recommended to “test-spray” three times before using for the first time and in cases where the aerosol has not been used for more than 24 hours.
Combivent (Albuterol sulfate; ipratropium bromide) How Supplied
Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol is supplied as a metered-dose inhaler with a white mouthpiece that has a clear, colorless sleeve and an orange protective cap.
The Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol canister is to be used only with the Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol mouthpiece and not with other mouthpieces.
This mouthpiece should not be used with other aerosol medications.
Each actuation meters 21 mcg of ipratropium bromide and 120 mcg of albuterol sulfate from the valve and delivers 18 mcg of ipratropium bromide and 103 mcg of albuterol sulfate (equivalent to 90 mcg albuterol base) from the mouthpiece.
Each 14.7 gram canister provides sufficient medication for 200 actuations (NDC 54868-4225-0).
Combivent (Albuterol sulfate; ipratropium bromide)
Combivent (Albuterol sulfate; ipratropium bromide) Patient's Instructions For Use
The contents of Combivent (Albuterol sulfate; ipratropium bromide) ® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol are under pressure. Do not puncture the canister. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw the container into a fire or incinerator.
Keep Combivent (Albuterol sulfate; ipratropium bromide) Inhalation Aerosol out of reach of children.
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Ipratropium bromide licensed from:
Boehringer Ingelheim International GmbH
Copyright 2010 Boehringer Ingelheim Pharmaceuticals, Inc.
ALL RIGHTS RESERVED
Revised: September 2010
IT9011GI2110
10004145/05
Combivent (Albuterol sulfate; ipratropium bromide)
