Combivent precautions

List of precautions
General Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Labor & delivery Nursing mothers Pediatric use Warnings
 * Effects seen with anticholinergic drugs
 * Effects seen with sympathomimetic drugs
 * Use in hepatic/renal disease
 * Combivent Inhalation Aerosol
 * Ipratropium bromide
 * Albuterol
 * Paradoxical bronchospasm
 * Cardiovascular effect
 * Do not exceed recommended dose
 * Immediate hypersensitivity reactions
 * Storage conditions

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. Return to top

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. Return to top

Use in hepatic/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. Return to top

Carcinogenesis
Two-year oral carcinogenicity studies in rats and mice for ipratropium bromide 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. 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 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 1600 times the maximum recommended daily inhalation dose on a mg/m2 basis) and a 99-week study in hamsters at oral doses up to 50 mg/kg (approximately 270 times the maximum recommended daily inhalation dose on a mg/m2 basis) revealed no evidence of tumorigenicity. Return to top

Mutagenesis
Results of various mutagenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test and chromosome aberration of bone marrow in Chinese hamsters) of ipratropium bromide were negative. Studies with albuterol revealed no evidence of mutagenesis. Return to top

Impairment of fertility
Studies with albuterol revealed no evidence of mutagenesis. Reproduction studies in rats with albuterol sulfate revealed no evidence of impaired fertility. Return to top

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. Because animal reproduction studies are not always predictive of human response, Combivent Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Return to top

Ipratropium bromide
Teratogenic Effects: Pregnancy Category B'' 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, 38000, and 9400 times the maximum recommended daily inhalation dose 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 on a mg/m2 basis). These studies have 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. Return to top''

Albuterol
Teratogenic Effects: Pregnancy Category C 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 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 on a mg/m2 basis). None was observed at 0.025 mg/kg (approximately one-tenth the maximum recommended daily inhalation dose). 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 on a mg/m2 basis). Return to top

Labor & 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. Return to top

Nursing mothers
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. Return to top

Pediatric use
Safety and effectiveness in the pediatric population have not been established. Return to top

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. Return to top

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. 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. Return to top

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. Return to top

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. Return to top

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. Return to top