Combivent

Combivent is a prescription medication used to prevent symptoms associated with chronic obstructive pulmonary disease (COPD). Symptoms of COPD include wheezing, difficulty breathing, chest tightness, and coughing.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X - are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Combivent falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Use Combivent exactly as prescribed.

Combivent is supplied as an aerosol spray to inhale by mouth. It is usually inhaled 4 times a day.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Combivent at the same time.

In the U.S.

• Combivent
• Combivent Respimat
• Duoneb

In Canada

• Ratio-Ipra Sal Udv

Available Dosage Forms:

• Aerosol Powder
• Solution
• Spray
• Aerosol Liquid

Therapeutic Class: Bronchodilator

Pharmacologic Class: Ipratropium

This section provides information on the proper use of a number of products that contain ipratropium and albuterol. It may not be specific to Combivent. Please read with care.

This medicine usually comes with patient directions or instructions. Read them carefully before using the medicine. If you do not understand the directions or you are not sure how to use the inhaler or nebulizer, ask your doctor to show you how to use it.

Use this medicine only as directed by your doctor. Do not use more of it and do not use it more often than your doctor ordered. Also, do not stop using this medicine without telling your doctor. To do so may cause your lung condition to become worse.

When you use the inhalation solution, make sure you use a jet nebulizer that is connected to an air compressor with a good air flow. Use a face mask or mouthpiece to inhale the medicine.

Keep the spray away from your eyes. This medicine may cause eye pain or discomfort, irritation, blurred vision, or start seeing halos or odd colors when you look at things. If it does come into contact with your eyes, check with your doctor right away.

To use the Combivent® inhaler:

• Insert the metal canister firmly and fully into the clear end of the Combivent® Inhalation Aerosol mouthpiece. This mouthpiece should not be used with other inhaled medicines.
• Remove the cap and look at the mouthpiece to make sure it is clean.
• Shake the inhaler for at least 10 seconds and test spray it in the air 3 times before using it for the first time or if the inhaler has not been used for 24 hours.
• To inhale this medicine, breathe out fully, trying to get as much air out of the lungs as possible. Put the mouthpiece just in front of your mouth with the canister upright.
• Open your mouth and breathe in slowly and deeply (like yawning), and at the same time firmly press down once on the top of the canister.
• Hold your breath for about 10 seconds, then breathe out slowly.
• If you are supposed to use more than one puff, wait 1 to 2 minutes before inhaling the second puff. Repeat these steps for the second puff, starting with shaking the inhaler.
• When you have finished all of your doses, rinse your mouth with water.
• Clean the inhaler mouthpiece every day with hot water. Dry it thoroughly before use.

To use the Combivent® Respimat® spray:

• Insert the cartridge into the Combivent® Respimat® inhaler.
• Before using the inhaler, prime it by spraying the medicine towards the ground (away from your face), until an aerosol cloud is visible. Repeat 3 more times. The inhaler is now ready for use.
• If the inhaler is not used for more than 3 days, prime the inhaler once to prepare it for use. If it not used for more than 21 days, prime the inhaler 3 times.
• To inhale this medicine, breathe out fully, trying to get as much air out of the lungs as possible.
• Open your mouth and breathe in slowly and deeply (like yawning), and at the same time firmly press down once the release button of the inhaler.
• Hold your breath for about 10 seconds, then breathe out slowly.
• After using the inhaler, clean the mouthpiece with a damp cloth or tissue at least once a week.
• This inhaler has a dose indicator window that shows how much medicine is left. When the pointer enters the red area of the scale, it is time that you need to refill your prescription.
• Throw away the inhaler 3 months from its first use or when the inhaler is locked (after 60 or 120 puffs).

Use only the brand of this medicine that your doctor prescribed. Different brands may not work the same way.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For symptoms of chronic obstructive pulmonary disease (COPD):
  • For inhalation aerosol dosage form (used with an inhaler):
    • Adults—2 puffs four times a day and as needed. Do not use more than 12 puffs in any 24-hour period.
    • Children—Use and dose must be determined by your doctor.
  • For inhalation solution dosage form (used with a nebulizer):
    • Adults—Use one 3 milliliter (mL) vial in the nebulizer four times a day. You may use 2 additional treatments per day if needed.
    • Children—Use and dose must be determined by your doctor.
  • For inhalation spray dosage form (used with an inhaler):
    • Adults—One puff four times a day. You may take additional doses per day if needed. Do not use more than 6 puffs in any 24-hour period.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the canister at room temperature, away from heat and direct light. Do not freeze. Do not keep this medicine inside a car where it could be exposed to extreme heat or cold. Do not poke holes in the canister or throw it into a fire, even if the canister is empty.

Keep the medicine in the foil pouch until you are ready to use it. Store at room temperature, away from heat and direct light. Do not freeze.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Body aches or pain
• chills
• cough
• cough producing mucus
• difficulty with breathing
• ear congestion
• fever
• headache
• loss of voice
• runny nose
• sneezing
• sore throat
• stuffy nose
• tightness in the chest
• unusual tiredness or weakness

• Bladder pain
• bloody or cloudy urine
• blurred vision
• burning while urinating burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain
• congestion
• diarrhea
• difficult, burning, or painful urination
• dizziness
• fainting
• fast, slow, irregular, pounding, or racing heartbeat or pulse
• frequent urge to urinate
• general feeling of discomfort or illness
• hoarseness
• increased sputum
• joint pain
• loss of appetite
• lower back or side pain
• muscle aches and pains
• nausea
• nervousness
• noisy breathing
• pain
• pain or tenderness around the eyes and cheekbones
• pounding in the ears
• shakiness in the legs, arms, hands, or feet
• shivering
• sweating
• swelling
• tender, swollen glands in the neck
• trembling or shaking of the hands or feet
• trouble sleeping
• trouble swallowing
• voice changes
• vomiting

• Skin rash or hives
• swelling of the face, lips, eyelids, mouth, or throat

• Chest discomfort
• decrease in the frequency of urination
• decrease in urine volume
• difficulty in passing urine (dribbling)
• itching skin
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• pain or discomfort in the arms, jaw, back, or neck
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• redness of the skin
• welts

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• bad, unusual, or unpleasant (after) taste
• belching
• change in taste
• diarrhea
• difficulty with moving
• dry mouth
• heartburn
• indigestion
• muscle pain or stiffness
• stomach discomfort, upset, or pain
• voice changes

• Bigger, dilated, or enlarged pupils (black part of the eye)
• blindness
• change in near or distance vision
• decreased vision
• difficulty in focusing eyes
• dry throat
• eye pain
• increased sensitivity of the eyes to light
• itching, redness, tearing, or other sign of eye irritation not present before use of this medicine or becoming worse during use
• lack or loss of strength
• noisy breathing
• redness of the white part of the eyes or inside of the eyelids
• swelling of the eye
• swelling or inflammation of the mouth
• tearing

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Combivent Inhalation Aerosol is a combination of the anticholinergic bronchodilator, ipratropium bromide, and the beta2-adrenergic bronchodilator, albuterol sulfate.

Mechanism of Action

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 at the neuromuscular junctions in the lung. Anticholinergics prevent the increases in intracellular concentration of Ca++ which is caused by interaction of acetylcholine with the muscarinic receptors on bronchial smooth muscle.

In vitro studies and in vivo pharmacology studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, recent data indicate that there is a population of beta2-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 beta2-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).

Combivent® (ipratropium bromide and albuterol sulfate) 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 beta2-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

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 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.

In 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 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 beta2-adrenergic receptors in the lung.

Special Populations

The pharmacokinetics of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol or ipratropium bromide have not been studied in patients with hepatic or renal insufficiency or in the elderly (see PRECAUTIONS).

Drug-Drug Interactions

No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions.

Pharmacodynamics

The bronchodilation following inhalation of ipratropium bromide is primarily a local, site-specific effect, not a systemic one.

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.

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 FEV1 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 FEV1 was 15 minutes and the median time to peak FEV1 was one hour for Combivent Inhalation Aerosol and its components. The median duration of effect as measured by FEV1 was 4 to 5 hours for Combivent Inhalation Aerosol compared to 4 hours for ipratropium bromide and 3 hours for albuterol sulfate.

Percent Change in Adjusted Meana FEV1 from Test-Day Baseline - Endpoint Analysis of the Evaluable Data Set

These studies demonstrated that each component of Combivent® (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 Inhalation Aerosol was significantly more effective than ipratropium bromide or albuterol sulfate administered alone.

In the 2 controlled 12-week studies, Combivent 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.

General

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 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.

Drug Interactions

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 safety and effectiveness.

Anticholinergic agents: There 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 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. Consider monitoring potassium levels.

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. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants.

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 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.

Like 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

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.

Teratogenic 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.

Teratogenic 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 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.

Nursing Mothers

It is not known whether the components of Combivent Inhalation Aerosol are excreted in human milk.

Because lipid-insoluble quaternary cations pass into breast 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.

Pediatric Use

Safety 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.

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 Experience

In 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.

If this medication gets in your eyes, rinse with water and seek medical attention.

This medication may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.