1. Paradoxical Bronchospasm: COMBIVENT Inhalation Aerosol can produce paradoxical bronchospasm that can be life-threatening. If it occurs, the preparation should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister.
2. Cardiovascular Effect: The albuterol sulfate contained in COMBIVENT Inhalation Aerosol, like other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure and/or symptoms. Although such effects are uncommon after administration of COMBIVENT Inhalation Aerosol at recommended doses, if they occur, discontinuation of the drug may be indicated. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischemia associated with albuterol. In addition, beta-adrenergic agents have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. Therefore, COMBIVENT Inhalation Aerosol should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias and hypertension.
3. Do Not Exceed Recommended Dose: Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs, in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.
4. Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of ipratropium bromide or albuterol sulfate, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.
5. Storage Conditions: The contents of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol are under pressure. Do not puncture. 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 out of reach of children.
1. Effects Seen with Anticholinergic Drugs: COMBIVENT Inhalation Aerosol contains ipratropium bromide and, therefore, should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.
2. Effects Seen with Sympathomimetic Drugs: Preparations containing sympathomimetic amines such as albuterol sulfate 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.
3. Use in Hepatic or Renal Disease: COMBIVENT Inhalation Aerosol has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in those patient populations.
Information for Patients
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 Inhalation Aerosol should last 4-5 hours or longer. COMBIVENT Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of COMBIVENT Inhalation Aerosol without consulting your physician. If you find that treatment with COMBIVENT 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 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 Inhalation Aerosol. Appropriate use of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol includes an understanding of the way it should be administered (see Patient’s Instructions for Use).
COMBIVENT 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 Inhalation Aerosol and these drugs with respect to effectiveness.
Anticholinergic agents: Although ipratropium bromide is minimally absorbed into the systemic circulation, there is some potential for an additive interaction with concomitantly used anticholinergic medications. Caution is therefore advised in the co-administration of COMBIVENT Inhalation Aerosol with other anticholinergic-containing drugs.
Beta-adrenergic agents: Caution is advised in the co-administration of COMBIVENT Inhalation Aerosol and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects.
Beta-receptor blocking agents and albuterol inhibit the effect of each other. Beta-receptor blocking agents should be used with caution in patients with hyperreactive airways.
Diuretics: The ECG changes and/or hypokalemia which may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of beta-agonist-containing drugs, such as COMBIVENT Inhalation Aerosol, with non-potassium sparing diuretics.
Monoamine oxidase inhibitors or tricyclic antidepressants: COMBIVENT Inhalation Aerosol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or within two weeks of discontinuation of such agents because the action of albuterol on the cardiovascular system may be potentiated.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to 6 mg/kg. This dose corresponds in rats and mice to approximately 230 and 110 times the maximum recommended daily inhalation dose of ipratropium bromide in adults, respectively, on a mg/m2 basis. Results of various mutagenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test and chromosome aberration of bone marrow in Chinese hamsters) were negative.
Fertility of male or female rats at oral doses up to 50 mg/kg (approximately 1,900 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis) was unaffected by ipratropium bromide administration. At an oral dose of 500 mg/kg (approximately 19,000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis), ipratropium bromide produced a decrease in the conception rate.
Like other agents in its class, albuterol caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium in a two-year study in the rat at dietary doses of 2, 10 and 50 mg/kg (approximately 15, 65 and 330 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). In another study this effect was blocked by the co-administration of propranolol. The relevance of these findings to humans is not known. An 18-month study in mice at dietary doses up to 500 mg/kg (approximately 1,600 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis) and a 99-week study in hamsters at oral doses up to 50 mg/kg (approximately 220 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis) revealed no evidence of tumorigenicity. Studies with albuterol revealed no evidence of mutagenesis.
Reproduction studies in rats with albuterol sulfate revealed no evidence of impaired fertility.
COMBIVENT Inhalation Aerosol
Teratogenic Effects: Pregnancy Category C.
There are no adequate and well-controlled studies of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol, ipratropium bromide or albuterol sulfate, in pregnant women. Animal reproduction studies have not been conducted with COMBIVENT Inhalation Aerosol. However, albuterol sulfate has been shown to be teratogenic in mice. COMBIVENT Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral reproduction studies were performed at doses of 10 mg/kg in mice, 1,000 mg/kg in rats and 125 mg/kg in rabbits. These doses correspond in each species, respectively, to approximately 190, 38,000, and 9,400 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis. Inhalation reproduction studies were conducted in rats and rabbits at doses of 1.5 and 1.8 mg/kg (approximately 55 and 140 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. At oral doses 90 mg/kg and above in rats (approximately 3,400 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis) embryotoxicity was observed as increased resorption. This effect is not considered relevant to human use due to the large doses at which it was observed and the difference in route of administration.
Albuterol has been shown to be teratogenic in mice. A reproduction study in CD-1 mice given albuterol subcutaneously (0.025, 0.25 and 2.5 mg/kg) showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (equivalent to the maximum recommended daily inhalation dose in adults on a mg/m2 basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately 8 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). None was observed at 0.025 mg/kg (less than the maximum recommended daily inhalation dose in adults). Cleft palate also occurred in 22 of 72 (30.5%) fetuses treated with 2.5 mg/kg isoproterenol (positive control). A reproduction study with oral albuterol in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses at 50 mg/kg (approximately 660 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
Labor and Delivery
Because of the potential for beta-agonist interference with uterine contractility, use of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol for the treatment of COPD during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
It is not known whether the components of COMBIVENT Inhalation Aerosol are excreted in human milk.
Although lipid-insoluble quaternary cations pass into breast milk, it is unlikely that the active component, ipratropium bromide, would reach the infant to an important extent, especially when taken by aerosol. However, because many drugs are excreted in human milk, caution should be exercised when COMBIVENT Inhalation Aerosol is administered to a nursing mother.
Because of the potential for tumorigenicity shown for albuterol 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.
Safety and effectiveness in the pediatric population have not been established.