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/m² basis); 1663 mg/kg in rats (approximately 62,000 times the maximum recommended daily inhalation dose in adults on a mg/m² basis); and 400 mg/kg in dogs (approximately 50,000 times the maximum recommended daily inhalation dose in adults, on a mg/m² 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/m² 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, metabolic acidosis, and exaggeration of the pharmacologic effects listed in ADVERSE REACTIONS. 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.
Adverse reaction information concerning Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for COMBIVENT Inhalation Aerosol) as seen in Table 1.
Table 1 : All Adverse Events (in percentages), from Two
Large Double-blind, Parallel, 12-Week Studies of Patients with COPD*
| COMBIVENT Ipratropium Bromide 36 mcg/Albuterol Sulfate 206 mcg QID N = 358 |
Ipratropium Bromide 36 mcg QID N = 362 |
Albuterol Sulfate 206 mcg QID N = 347 |
|
| Body as a Whole-General Disorders | |||
| Headache | 5.6 | 3.9 | 6.6 |
| Pain | 2.5 | 1.9 | 1.2 |
| Influenza | 1.4 | 2.2 | 2.9 |
| Chest Pain | 0.3 | 1.4 | 2.9 |
| Gastrointestinal System Disorders | |||
| Nausea | 2.0 | 2.5 | 2.6 |
| Respiratory System Disorders (Lower) | |||
| Bronchitis | 12.3 | 12.4 | 17.9 |
| Dyspnea | 4.5 | 3.9 | 4 |
| Coughing | 4.2 | 2.8 | 2.6 |
| Respiratory Disorders | 2.5 | 1.7 | 2.3 |
| Pneumonia | 1.4 | 2.5 | 0.6 |
| Bronchospasm | 0.3 | 3.9 | 1.7 |
| Respiratory System Disorders (Upper) | |||
| Upper Respiratory Tract Infection | 10.9 | 12.7 | 13 |
| Pharyngitis | 2.2 | 3.3 | 2.3 |
| Sinusitis | 2.3 | 1.9 | 0.9 |
| Rhinitis | 1.1 | 2.5 | 2.3 |
| *All adverse events, regardless of drug relationship, reported by two percent or more patients in one or more treatment group in the 12-week controlled clinical trials. | |||
Additional adverse reactions, reported in less than two percent of the patients in the COMBIVENT 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® (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 CONTRAINDICATIONS).
Post-Marketing ExperienceIn a 5-year placebo-controlled trial, hospitalizations for supraventricular tachycardia and/or atrial fibrillation occurred with an incidence rate of 0.5% in COPD patients receiving Atrovent® (ipratropium bromide) Inhalation Aerosol CFC.
Additional side effects identified from the published literature and/or post-marketing surveillance on the use of ipratropium bromide-containing products (singly or in combination with albuterol), include: hypersensitivity, pharyngeal edema, mouth edema, urinary retention, mydriasis, bronchospasm (including paradoxical bronchospasm), cases of precipitation or worsening of narrow-angle glaucoma, glaucoma, intraocular pressure increased, acute eye pain, halo vision, blurred vision, accommodation disorder, ocular irritation, corneal edema, conjunctival hyperaemia, nasal congestion, drying of secretions, mucosal ulcers, stomatitis, irritation from aerosol, throat irritation, dry throat, wheezing, exacerbation of COPD symptoms, hoarseness, palpitations, heartburn, drowsiness, CNS stimulation, coordination difficulty, flushing, alopecia, hypotension, edema, gastrointestinal distress (diarrhea, nausea, vomiting), gastrointestinal motility disorder, constipation, hypokalemia, mental disorder, hyperhidrosis, muscle spasms, muscular weakness, myalgia, asthenia, myocardial ischemia, diastolic blood pressure decreased, and systolic blood pressure increased.
Metabolic acidosis has been reported with use of albuterol-containing products.
Much of an administered dose is swallowed as shown by fecal excretion studies. Ipratropium bromide is a quaternary amine. It is not readily absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract as confirmed by blood level and renal excretion studies. Plasma levels of ipratropium bromide were below the assay sensitivity limit of 100 pg/mL.
The half-life of elimination is about 2 hours after inhalation or intravenous administration. Ipratropium bromide is minimally bound (0 to 9% in vitro) to plasma albumin and α1-acid glycoprotein. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half of the dose is excreted unchanged in the urine. Autoradiographic studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier.
Albuterol sulfateAlbuterol is longer acting than isoproterenol in most patients because it is not a substrate for the cellular uptake processes for catecholamines nor for metabolism by catechol-O-methyl transferase. Instead, the drug is conjugatively metabolized to albuterol 4'-O-sulfate.
In a pharmacokinetic study in 12 healthy male volunteers of two inhalations of albuterol sulfate, 103 mcg dose/inhalation through the mouthpiece, peak plasma albuterol concentrations ranging from 419 to 802 pg/mL (mean 599 ± 122 pg/mL) were obtained within three hours post-administration. Following this single-dose administration, 30.8 ± 10.2% of the estimated mouthpiece dose was excreted unchanged in the 24-hour urine. Since albuterol sulfate is rapidly and completely absorbed, this study could not distinguish between pulmonary and gastrointestinal absorption.
Intravenous pharmacokinetics of albuterol were studied in a comparable group of 16 healthy male volunteers; the mean terminal half-life following a 30-minute infusion of 1.5 mg was 3.9 hours with a mean clearance of 439 mL/min/1.73 m².
Intravenous albuterol studies in rats demonstrated that albuterol crossed the blood-brain barrier and reached brain concentrations amounting to about 5% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), the drug achieved concentrations more than 100 times those in whole brain.
Studies in pregnant rats with tritiated albuterol demonstrated that approximately 10% of the circulating maternal drug was transferred to the fetus. Disposition in fetal lungs was comparable to maternal lungs, but fetal liver disposition was 1% of maternal liver levels.
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were administered concurrently. The significance of these findings when applied to humans is unknown.
COMBIVENT Inhalation AerosolIn a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pattern of absorption and excretion of two inhalations of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol to the two active components individually, the coadministration of ipratropium bromide and albuterol sulfate from a single canister did not significantly alter the systemic absorption of either component.
Ipratropium bromide levels remained below detectable limits ( < 100 pg/mL). Peak albuterol level obtained within 3 hours post-administration was 492 ± 132 pg/mL. Following this single administration, 27.1 ± 5.7% of the estimated mouthpiece dose was excreted unchanged in the 24-hour urine. From a pharmacokinetic perspective, the synergistic efficacy of COMBIVENT Inhalation Aerosol is likely to be due to a local effect on the muscarinic and beta2-adrenergic receptors in the lung.
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 and rabbits. COMBIVENT Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Ipratropium bromideTeratogenic Effects
Oral reproduction studies were performed at doses of 10 mg/kg in mice, 1000 mg/kg in rats, and 125 mg/kg in rabbits. These doses correspond in each species, respectively, to approximately 190, 38,000, and 9400 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.
AlbuterolTeratogenic Effects
Albuterol has been shown to be teratogenic in mice and rabbits. 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).
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 to 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).
Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of COMBIVENT, patients should be cautioned about engaging in activities requiring balance and visual acuity such as driving a car or operating appliances or machinery.
Carcinogenesis, Mutagenesis, Impairment of Fertility Ipratropium bromideTwo-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 1900 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.
AlbuterolLike other agents in its class, albuterol caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium in a 2-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 1600 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.
Pregnancy COMBIVENT Inhalation AerosolTeratogenic 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 and rabbits. COMBIVENT Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Ipratropium bromideTeratogenic Effects
Oral reproduction studies were performed at doses of 10 mg/kg in mice, 1000 mg/kg in rats, and 125 mg/kg in rabbits. These doses correspond in each species, respectively, to approximately 190, 38,000, and 9400 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.
AlbuterolTeratogenic Effects
Albuterol has been shown to be teratogenic in mice and rabbits. 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 DeliveryBecause 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.
Nursing MothersIt is not known whether the components of COMBIVENT Inhalation Aerosol are excreted in human milk.
Ipratropium bromideBecause lipid-insoluble quaternary cations pass into breast milk, caution should be exercised when COMBIVENT Inhalation Aerosol is administered to a nursing mother.
AlbuterolBecause 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.
Pediatric UseSafety and effectiveness in the pediatric population have not been established.
Adverse reaction information concerning Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for COMBIVENT Inhalation Aerosol) as seen in Table 1.
Table 1 : All Adverse Events (in percentages), from Two
Large Double-blind, Parallel, 12-Week Studies of Patients with COPD*
| COMBIVENT Ipratropium Bromide 36 mcg/Albuterol Sulfate 206 mcg QID N = 358 |
Ipratropium Bromide 36 mcg QID N = 362 |
Albuterol Sulfate 206 mcg QID N = 347 |
|
| Body as a Whole-General Disorders | |||
| Headache | 5.6 | 3.9 | 6.6 |
| Pain | 2.5 | 1.9 | 1.2 |
| Influenza | 1.4 | 2.2 | 2.9 |
| Chest Pain | 0.3 | 1.4 | 2.9 |
| Gastrointestinal System Disorders | |||
| Nausea | 2.0 | 2.5 | 2.6 |
| Respiratory System Disorders (Lower) | |||
| Bronchitis | 12.3 | 12.4 | 17.9 |
| Dyspnea | 4.5 | 3.9 | 4 |
| Coughing | 4.2 | 2.8 | 2.6 |
| Respiratory Disorders | 2.5 | 1.7 | 2.3 |
| Pneumonia | 1.4 | 2.5 | 0.6 |
| Bronchospasm | 0.3 | 3.9 | 1.7 |
| Respiratory System Disorders (Upper) | |||
| Upper Respiratory Tract Infection | 10.9 | 12.7 | 13 |
| Pharyngitis | 2.2 | 3.3 | 2.3 |
| Sinusitis | 2.3 | 1.9 | 0.9 |
| Rhinitis | 1.1 | 2.5 | 2.3 |
| *All adverse events, regardless of drug relationship, reported by two percent or more patients in one or more treatment group in the 12-week controlled clinical trials. | |||
Additional adverse reactions, reported in less than two percent of the patients in the COMBIVENT 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® (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 CONTRAINDICATIONS).
Post-Marketing ExperienceIn a 5-year placebo-controlled trial, hospitalizations for supraventricular tachycardia and/or atrial fibrillation occurred with an incidence rate of 0.5% in COPD patients receiving Atrovent® (ipratropium bromide) Inhalation Aerosol CFC.
Additional side effects identified from the published literature and/or post-marketing surveillance on the use of ipratropium bromide-containing products (singly or in combination with albuterol), include: hypersensitivity, pharyngeal edema, mouth edema, urinary retention, mydriasis, bronchospasm (including paradoxical bronchospasm), cases of precipitation or worsening of narrow-angle glaucoma, glaucoma, intraocular pressure increased, acute eye pain, halo vision, blurred vision, accommodation disorder, ocular irritation, corneal edema, conjunctival hyperaemia, nasal congestion, drying of secretions, mucosal ulcers, stomatitis, irritation from aerosol, throat irritation, dry throat, wheezing, exacerbation of COPD symptoms, hoarseness, palpitations, heartburn, drowsiness, CNS stimulation, coordination difficulty, flushing, alopecia, hypotension, edema, gastrointestinal distress (diarrhea, nausea, vomiting), gastrointestinal motility disorder, constipation, hypokalemia, mental disorder, hyperhidrosis, muscle spasms, muscular weakness, myalgia, asthenia, myocardial ischemia, diastolic blood pressure decreased, and systolic blood pressure increased.
Metabolic acidosis has been reported with use of albuterol-containing products.
DRUG INTERACTIONSCOMBIVENT 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 safety and effectiveness.
Anticholinergic agentsThere is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid co-administration of COMBIVENT Inhalation Aerosol with other anticholinergic-containing drugs.
Beta-adrenergic agentsCaution 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.
DiureticsThe 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. Consider monitoring potassium levels.
Monoamine oxidase inhibitors or tricyclic antidepressantsCOMBIVENT 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. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants.
