 |
Prescribing Information
Combivent® Inhalation Aerosol is a combination of ipratropium bromide 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 (endo,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 lower alcohols but insoluble in lipophilic solvents such as ether, chloroform and fluorocarbons. The structural formula is:
|
|
Albuterol sulfate, chemically known as (1,3-benzenedimethanol, (alpha)'-[[(1,1-dimethylethyl) amino] methyl]-4-hydroxy, sulfate (2:1)(salt), (±)- is a relatively selective beta 2 -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, soluble in water and slightly soluble in ethanol. The structural formula is:
 |
Combivent 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 Inhalation Aerosol is a combination of the anticholinergic bronchodilator, ipratropium bromide, and the beta 2 -adrenergic bronchodilator, albuterol sulfate.
Ipratropium bromide is an anticholinergic (parasympatholytic) agent which, based on animal studies, appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) which are caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.
The bronchodilation following inhalation of ipratropium bromide is primarily a local, site-specific effect, not a systemic one. 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 (alpha) 1 -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. Studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier.
The pharmacokinetics of Combivent Inhalation Aerosol or ipratropium bromide have not been studied in patients with hepatic or renal insufficiency or in the elderly (See PRECAUTIONS ).
Controlled clinical studies have demonstrated that ipratropium bromide does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions. In studies without a positive control, ipratropium bromide did not alter pupil size, accommodation or visual acuity (See ADVERSE REACTIONS ). Ventilation/perfusion studies have shown no clinically significant effects on pulmonary gas exchange or arterial oxygen tension. At recommended doses, ipratropium bromide does not produce clinically significant changes in pulse rate or blood pressure.
In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, recent data indicate that there is a population of beta 2 -receptors in the human heart which comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors, however, is not yet established (See WARNINGS ).
Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenylyl cyclase and to an increase in the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.
Albuterol has been shown in most clinical trials to have more bronchial smooth muscle relaxation effect than isoproterenol at comparable doses while producing fewer cardiovascular effects. However, all beta-adrenergic drugs, including albuterol sulfate, can produce a significant cardiovascular effect in some patients (See PRECAUTIONS ).
Pharmacokinetics Albuterol 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 m 2 .
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 Aerosol:
Mechanism of Action Combivent Inhalation Aerosol is expected to maximize the response to treatment in patients with chronic obstructive pulmonary disease (COPD) by reducing bronchospasm through two distinctly different mechanisms, anticholinergic (parasympatholytic) and sympathomimetic. Simultaneous administration of both an anticholinergic (ipratropium bromide) and a beta 2 -sympathomimetic (albuterol sulfate) is designed to benefit the patient by producing a greater bronchodilator effect than when either drug is utilized alone at its recommended dosage.
Pharmacokinetics In a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pattern of absorption and excretion of two inhalations of Combivent Inhalation Aerosol to the two active components individually, the co-administration 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 beta 2 -adrenergic receptors in the lung.
Clinical Trials 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 Inhalation Aerosol (358 patients) in comparison to its components, ipratropium bromide (362 patients) and albuterol sulfate (347 patients).
Serial FEV 1 measurements (shown below as a percent change from test-day baseline) demonstrated that Combivent 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 1 was 15 minutes and the median time to peak FEV 1 was one hour for Combivent Inhalation Aerosol and its components. The median duration of effect as measured by FEV 1 was 4-5 hours for Combivent Inhalation Aerosol compared to 4 hours for ipratropium bromide and 3 hours for albuterol sulfate.
 |
 |
 |
 |
These studies demonstrated that each component of Combivent Inhalation Aerosol contributed to the improvement in pulmonary function produced by the combination, especially during the first 4-5 hours after dosing, and that Combivent Inhalation Aerosol was significantly more effective than ipratropium bromide or albuterol sulfate administered alone.
In the two controlled twelve-week studies, CombiventInhalation 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 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 Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut.Combivent Inhalation Aerosol is also contraindicated in patients hypersensitive to any other components of the drug product or to atropine or its derivatives.
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, eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Should any combination of these symptoms develop, consult your 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 InhalationAerosol 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 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 steroids, commonly used in the treatment of COPD, without adverse drug reactions. No formal drug interaction studies have been performed with Combivent Inhalation Aerosol and these or other medications commonly used in the treatment of COPD.
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.
Ipratropium bromide: Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic potential at doses up to 6 mg/kg/day. This dose corresponds to approximately 360 and 180 times the maximum recommended human daily inhalation dose in rats and mice respectively, on a mg/m 2 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/day (approximately 3000 times the maximum recommended human daily inhalation dose on a mg/m 2 basis) was unaffected by ipratropium bromide administration. At doses above 90 mg/kg/day (approximately 5400 times the maximum recommended human daily inhalation dose on a mg/m 2 basis), increased resorption and decreased conception rates were observed.
Albuterol: 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/day (approximately 20, 100 and 500 times the maximum recommended human daily inhalation dose on a mg/m 2 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/day (approximately 2500 times the maximum recommended human daily inhalation dose on a mg/m 2 basis) and a 99-week study in hamsters at oral doses up to 50 mg/kg/day (approximately 375 times the maximum recommended human daily inhalation dose on a mg/m 2 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.
TERATOGENIC EFFECTS Pregnancy Category C.
Ipratropium bromide: Pregnancy Category B. Oral reproduction studies were performed at doses of 10 mg/kg in mice, 100 mg/kg in rats and 125 mg/kg in rabbits. These doses correspond, in each species, respectively, to approximately 300, 600 and 15,000 times the maximum recommended human daily inhalation dose on a mg/m 2 basis. Inhalation reproduction studies were conducted in rats and rabbits at doses of 1.5 and 1.8 mg/kg/day (approximately 90 and 210 times the maximum recommended human daily inhalation dose on a mg/m 2 basis). These studies have demonstrated no evidence of teratogenic effects as a result of ipratropium bromide.
Albuterol: 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 human daily inhalation dose on a mg/m 2 basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately 10 times the maximum recommended human daily inhalation dose on a mg/m 2 basis). None was observed at 0.025 mg/kg (approximately one-tenth the maximum recommended human 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 1000 times the maximum recommended human daily inhalation dose on a mg/m 2 basis).
There are, however, no adequate and well-controlled studies of Combivent 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.
Because of the potential for beta-agonist interference with uterine contractility, use of Combivent 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.
Ipratropium bromide: Although lipid-insoluble quaternary bases 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 CombiventInhalation Aerosol is administered to a nursing mother.
Albuterol: 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 of Combivent Inhalation Aerosol in pediatric patients have not been established.
Adverse reaction information concerning Combivent Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for Combivent Inhalation Aerosol).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 rash, angioedema of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reaction have been reported, 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 ).
Additional information derived from the published literature and post-marketing surveillance on the use of ipratropium or albuterol inhalation aerosol singly or in combination that is not included in the lists above includes: cases of precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, nasal congestion, drying of secretions, mucosal ulcers, irritation from aerosol, paradoxical bronchospasm, wheezing, exacerbation of COPD symptoms, heartburn, drowsiness, CNS stimulation, coordination difficulty, weakness, itching, flushing, alopecia, hypotension, gastrointestinal distress, constipation, and urinary difficulties.
The effects of overdosage are expected to be related primarily to albuterol sulfate. Acute overdosage with ipratropium bromide is unlikely since ipratropium bromide is not well absorbed systemically after aerosol or oral administration. The oral median lethal dose of ipratropium bromide ranged between 1001 and 2010 mg/kg in mice (approximately 30,000 and 60,000 times the maximum recommended human daily inhalation dose on a mg/m 2 basis, respectively); between 1667 and 4000 mg/kg in rats approximately 100,000 and 240,000 times the maximum recommended human daily inhalation dose, respectively, on a mg/m 2 basis); and between 400 and 1300 mg/kg (approximately 80,000 and 260,000 times the maximum recommended human daily inhalation dose, respectively, on a mg/m 2 basis) in dogs. Whereas the oral median lethal dose of albuterol sulfate in mice and rats was greater than 2,000 mg/kg (approximately 10,000 and 20,000 times the maximum recommended human daily inhalation dose, respectively, on a mg/m 2 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 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.
The dose of Combivent 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 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 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® Inhalation Aerosol is supplied as a metered-dose inhaler with a white mouthpiece which has a clear, colorless sleeve and an orange protective cap. The Combivent Inhalation Aerosol canister should be used with theCombivent Inhalation Aerosol actuator only. The actuator 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 inhalations (NDC 0597-0013-14).
The canister should be discarded after the labeled number of actuations have been used. The amount of medication in each actuation cannot be assured after this point.
Store between 59°F (15° C) and 86° F (30° C). Avoid excessive humidity. For optimal results, the canister should be at room temperature before use. Shake well before using.
Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs):
Warning: Contains trichloromonofluoromethane (CFC-11), dichlorodifluoromethane (CFC-12) and dichlorotetrafluoroethane (CFC-114), substances which harm public health and the environment by destroying ozone in the upper atmosphere.
A notice similar to the above Warning has been placed in the information for the patient of this product under the Environmental Protection Agency's (EPA's) regulations. The patient's warning states that the patient should consult his or her physician if there are any questions about alternatives.
Rx only
Manufactured by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877, USA
Ipratropium bromide licensed from: Boehringer Ingelheim International GmbH
© Copyright Boehringer Ingelheim Pharmaceuticals, Inc.
2001, ALL RIGHTS RESERVED
Revised 9/01
10000291/03 10000291/US/03
 |
Combivent®
(ipratropium bromide and albuterol sulfate)
Inhalation Aerosol
Read complete instructions carefully before using
 |
 |
 |
 |
Store between 59°F (15°C) and 86°F (30°C). Avoid excessive humidity.
Manufactured by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
Ipratropium bromide licensed from:
Boehringer Ingelheim International GmbH
© Copyright Boehringer Ingelheim Pharmaceuticals, Inc.
2001, ALL RIGHTS RESERVED
Revised 9/01
10000291/03 10000291/US/03