Combivent Respimat

Dosage Forms And Strengths

COMBIVENT RESPIMAT consists of a COMBIVENT RESPIMAT inhaler and an aluminum cylinder (COMBIVENT RESPIMAT cartridge) containing a combination of ipratropium bromide (as the monohydrate) and albuterol sulfate. The COMBIVENT RESPIMAT cartridge is only intended for use with the COMBIVENT RESPIMAT inhaler.

Each actuation from the COMBIVENT RESPIMAT inhaler delivers 20 mcg ipratropium bromide (monohydrate) and 100 mcg albuterol (equivalent to 120 mcg albuterol sulfate) from the mouthpiece.

Storage And Handling

COMBIVENT RESPIMAT Inhalation Spray is supplied in a carton containing one COMBIVENT RESPIMAT cartridge and one COMBIVENT RESPIMAT inhaler.

The COMBIVENT RESPIMAT cartridge is provided as an aluminum cylinder with a tamper protection seal on the cap. The COMBIVENT RESPIMAT cartridge is only intended for use with the COMBIVENT RESPIMAT inhaler.

The COMBIVENT RESPIMAT inhaler is a cylindrical shaped plastic inhalation device with a gray colored body and a clear base. The clear base is removed to insert the cartridge. The inhaler contains a dose indicator. The orange colored cap and the written information on the label of the gray inhaler body indicate that it is labeled for use with the COMBIVENT RESPIMAT cartridge.

COMBIVENT RESPIMAT Inhalation Spray is available as:

COMBIVENT RESPIMAT Inhalation Spray: 120 metered actuations (NDC 0597-0024-02)

COMBIVENT RESPIMAT Inhalation Spray: 60 metered actuations (NDC 0597-0024-58) (institutional pack)

The COMBIVENT RESPIMAT cartridge has a net fill weight of 4 grams and when used with the COMBIVENT RESPIMAT inhaler, is designed to deliver the labeled number of metered actuations (120 or 60) after preparation for use; which is, respectively, equivalent to 30 or 15 days of medication when used as one inhalation four times a day. Each actuation from the COMBIVENT RESPIMAT inhaler delivers 20 mcg ipratropium bromide (monohydrate) and 100 mcg albuterol (equivalent to 120 mcg albuterol sulfate) from the mouthpiece.

When the labeled number of metered actuations (120 or 60) has been dispensed from the inhaler, the RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed.

After assembly, the COMBIVENT RESPIMAT inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first.

Keep out of reach of children. Do not spray into eyes.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) . Avoid freezing.

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA. Revised: October 2014

COMBIVENT RESPIMAT 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.

The recommended dose of COMBIVENT RESPIMAT is one inhalation four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed six in 24 hours.

Prior to first use, the COMBIVENT RESPIMAT cartridge is inserted into the COMBIVENT RESPIMAT inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.

Safety and efficacy of additional doses of COMBIVENT RESPIMAT beyond six inhalations/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 RESPIMAT have not been studied.

COMBIVENT RESPIMAT is contraindicated in the following conditions :

• Hypersensitivity to any of the ingredients in COMBIVENT RESPIMAT
• Hypersensitivity to atropine or any of its derivatives

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Paradoxical Bronchospasm

COMBIVENT RESPIMAT can produce paradoxical bronchospasm that can be life-threatening. If it occurs, therapy with COMBIVENT RESPIMAT should be discontinued immediately and alternative therapy instituted.

Cardiovascular Effect

The albuterol sulfate contained in COMBIVENT RESPIMAT, 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. If these symptoms occur, COMBIVENT RESPIMAT may need to be discontinued. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischemia associated with albuterol. In addition, beta-adrenergic agents have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. Therefore, COMBIVENT RESPIMAT should be used with caution in patients with cardiovascular disorders; especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Ocular Effects

Ipratropium bromide, a component of COMBIVENT RESPIMAT, is an anticholinergic and may increase intraocular pressure. This may result in precipitation or worsening of narrow-angle glaucoma. Therefore, COMBIVENT RESPIMAT should be used with caution in patients with narrow-angle glaucoma.

Patients should avoid spraying COMBIVENT RESPIMAT into the eyes. If a patient sprays COMBIVENT RESPIMAT into their eyes they may cause acute eye pain or discomfort, temporary blurring of vision, mydriasis, visual halos, or colored images in association with red eyes from conjunctival or corneal congestion. Advise patients to consult their physician immediately if any of these symptoms develop while using COMBIVENT RESPIMAT.

Urinary Retention

Ipratropium bromide, a component of COMBIVENT RESPIMAT, is an anticholinergic and may cause urinary retention. Therefore, caution is advised when administering this medication to patients with prostatic hyperplasia or bladder-neck obstruction.

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.

Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema may occur after administration of ipratropium bromide or albuterol sulfate. In clinical trials and post-marketing experience with ipratropium containing products, hypersensitivity reactions such as skin rash, pruritus, angioedema of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported If such a reaction occurs, therapy with COMBIVENT RESPIMAT should be stopped at once and alternative treatment should be considered.

Coexisting Conditions

COMBIVENT RESPIMAT contains albuterol sulfate, a beta-adrenergic sympathomimetic amine and, therefore, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus, and in patients who are unusually responsive to sympathomimetic amines.

Hypokalemia

Beta-adrenergic agents may 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.

Patient Counseling Information

See FDA-approved Patient Labeling

Ocular Effects

Caution patients 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.

Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of COMBIVENT RESPIMAT, patients should be cautioned about engaging in activities requiring balance and visual acuity such as driving a car or operating appliances or machinery.

Urinary Retention

Inform patients that COMBIVENT RESPIMAT may cause urinary retention and should be advised to consult their physician if they experience difficulty with urination.

Frequency Of Use

The action of COMBIVENT RESPIMAT should last 4 to 5 hours or longer. COMBIVENT RESPIMAT should not be used more frequently than recommended. Safety and efficacy of additional doses of COMBIVENT RESPIMAT beyond six inhalations in 24 hours have not been studied. Patients should be told not to increase the dose or frequency of COMBIVENT RESPIMAT without consulting a physician. Patients should be instructed that if they find that treatment with COMBIVENT RESPIMAT becomes less effective for symptomatic relief, their symptoms become worse, and/or they need to use the product more frequently than usual, medical attention should be sought immediately.

Preparation For Use And Priming

Instruct patients that priming COMBIVENT RESPIMAT is essential to ensure appropriate content of the medication in each actuation.

When using the unit for the first time, the COMBIVENT RESPIMAT cartridge is inserted into the COMBIVENT RESPIMAT inhaler and the unit is primed. COMBIVENT RESPIMAT patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use..

Concomitant Drug Use

Remind patients that while taking COMBIVENT RESPIMAT, other inhaled drugs should be taken only as directed by a physician.

Paradoxical Bronchospasm

Inform patients that COMBIVENT RESPIMAT can produce paradoxical bronchospasm that can be life-threatening. If paradoxical bronchospasm occurs, patients should discontinue using COMBIVENT RESPIMAT.

Adverse Effects Associated With Beta2-agonists

Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Pregnancy

Patients who are pregnant or nursing should contact their physician about the use of COMBIVENT RESPIMAT.

FDA-approved Patient Labeling

Instructions for Use is supplied as a tear-off following the full prescribing information.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Ipratropium Bromide

Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to 6 mg/kg/day (approximately 400 and 200 times the maximum recommended human daily inhalation dose of ipratropium bromide (MRHDID) in adults on a mg/m² basis, respectively).

Results of various mutagenicity/clastogenicity 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 3400 times the MRHDID in adults on a mg/m² basis) was unaffected by ipratropium bromide administration. At an oral dose of 500 mg/kg/day (approximately 34,000 times the MRHDID in adults on a mg/m² basis), ipratropium bromide produced a decrease in the conception rate.

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 2-year study in the rat at dietary doses of 2, 10, and 50 mg/kg/day (approximately 20, 110, and 560 times the MRHDID on a mg/m² basis). In another study this effect was blocked by the coadministration 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 2800 times the MRHDID on a mg/m² basis) and a 99-week study in hamsters at oral doses up to 50 mg/kg/day (approximately 470 times the MRHDID 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.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C.

COMBIVENT RESPIMAT Inhalation Spray

There are no adequate and well-controlled studies of COMBIVENT RESPIMAT (ipratropium bromide and albuterol sulfate) Inhalation Spray, ipratropium bromide, or albuterol sulfate, in pregnant women. Animal reproduction studies have not been conducted with COMBIVENT RESPIMAT. However, albuterol sulfate has been shown to be teratogenic in mice and rabbits. COMBIVENT RESPIMAT Inhalation Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Ipratropium bromide

Oral reproduction studies were performed in mice, rats and rabbits at doses approximately 340, 68,000 and 17,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mg/m² basis at maternal doses in each species of 10, 1000 and 125 mg/kg/day, respectively). Inhalation reproduction studies were conducted in rats and rabbits at approximately 100 and 240 times, respectively, the MRHDID in adults (on a mg/m² basis at maternal doses of 1.5 and 1.8 mg/kg/day, respectively). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. Embryotoxicity was observed as increased resorption in rats at oral doses approximately 6100 times MRHDID in adults (on a mg/m² basis at maternal doses of 90 mg/kg/day and above). This effect is not considered relevant to human use due to the large doses at which it was observed and the difference in route of administration.

Albuterol

Albuterol has been shown to be teratogenic in mice and rabbits. A reproduction study in CD-1 mice given albuterol subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at approximately equivalent to the MRHDID in adults (on a mg/m² basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 183 (9.3%) fetuses at approximately 14 times the MRHDID in adults (on a mg/m² basis a maternal dose of 2.5 mg/kg/day). None was observed at less than MRHDID in adults (on a mg/m² basis at a maternal dose of 0.025 mg/kg/day). Cleft palate also occurred in 22 of 72 (30.5%) fetuses treated with 2.5 mg/kg/day isoproterenol (positive control). A reproductive study with oral albuterol in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses at approximately 1,100 times the MRHDID in adults (on a mg/m² basis at a maternal dose of 50 mg/kg/day).

Labor And Delivery

Because of the potential for beta-agonist interference with uterine contractility, use of COMBIVENT RESPIMAT 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 RESPIMAT are excreted in human milk.

Ipratropium bromide

Because lipid-insoluble quaternary cations pass into breast milk, caution should be exercised when COMBIVENT RESPIMAT 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.

Pediatric Use

Safety and effectiveness of COMBIVENT RESPIMAT in pediatric patients have not been established. COMBIVENT RESPIMAT is indicated for use in patients with COPD on a regular aerosol bronchodilator who continue to have evidence of bronchospasm and who require a second bronchodilator. This disease does not normally occur in children.

Geriatric Use

In the 12-week trial in COPD, 48% of COMBIVENT RESPIMAT clinical trial patients were 65 years of age or over. In general, there were no marked differences between the proportion of patients with adverse reactions for the COMBIVENT RESPIMAT and CFC-propelled COMBIVENT Inhalation Aerosol treated patients. Cardiac and lower respiratory disorders occurred less frequently in the patients under the age of 65 and were balanced across treatment groups.

No overall differences in effectiveness were observed among treatment groups. Based on available data, no adjustment of COMBIVENT RESPIMAT dosage in geriatric patients is warranted.

SIDE EFFECTS

Use of albuterol, a beta-adrenergic agonist, may be associated with the following:

• Paradoxical bronchospasm
• Cardiovascular effects
• Hypersensitivity reactions, including anaphylaxis
• Hypokalemia

Albuterol is a component of COMBIVENT RESPIMAT.

Use of ipratropium bromide, an anticholinergic, may result in the following:

• Ocular effects
• Urinary retention

Ipratropium bromide is a component of COMBIVENT RESPIMAT.

Clinical Trials Experience

COMBIVENT RESPIMAT 12-Week Clinical Trials

The safety data described in Table 1 below are derived from one 12-week, randomized, multi-center, double-blind, double-dummy, parallel-group trial that compared COMBIVENT RESPIMAT (20/100 mcg), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg), and ipratropium bromide delivered by the RESPIMAT inhaler (20 mcg) administered four times a day in 1460 adult COPD patients (955 males and 505 females) 40 years of age and older. Of these patients, 486 were treated with COMBIVENT RESPIMAT. The COMBIVENT RESPIMAT group was composed of mostly Caucasian (88.5%) patients with a mean age of 63.8 years, and a mean percent predicted FEV₁ at screening of 41.5%. Patients with narrow-angle glaucoma, symptomatic prostatic hypertrophy or bladder-neck obstruction were excluded from the trial.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 1 shows all adverse reactions that occurred with a frequency of ≥ 2% in the COMBIVENT RESPIMAT treatment group in the 12-week COPD trial. The frequency of the corresponding adverse reactions in the CFC-propelled COMBIVENT Inhalation Aerosol and ipratropium bromide delivered by the RESPIMAT inhaler groups is included for comparison. The rates are derived from all reported adverse reactions of that type not present at baseline, whether considered drug-related or not by the clinical investigator.

Table 1: Adverse Reactions in ≥ 2% of Patients in the COMBIVENT RESPIMAT Group in a 12-Week COPD Clinical Trial

Adverse reactions that occurred in < 2% in the COMBIVENT RESPIMAT (20/100 mcg) group observed in this 12-week trial include: Vascular disorders: hypertension; Nervous system disorders: dizziness and tremor; Musculoskeletal and connective tissue disorder: muscle spasms and myalgia; Gastrointestinal disorders: diarrhea, nausea, dry mouth, constipation, and vomiting; General disorders and administration site conditions: asthenia, influenza-like illness, and chest discomfort; Eye disorders: eye pain; Metabolism and nutritional disorders: hypokalemia; Cardiac disorders: palpitations and tachycardia; Skin and subcutaneous tissue disorders: pruritus and rash; Respiratory, thoracic and mediastinal disorders; pharyngolaryngeal pain and wheezing.

A separate 12-week trial evaluated a higher than approved dose of COMBIVENT RESPIMAT in 1118 COPD patients. Patients were randomized to COMBIVENT RESPIMAT (40/200 mcg) (n=345), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) (n=180), ipratropium delivered by the RESPIMAT (40 mcg) (n=252) or placebo (n=341). The overall incidence and nature of adverse reactions observed were similar to the adverse reactions seen with COMBIVENT RESPIMAT 20/100 mcg.

COMBIVENT RESPIMAT Long Term (48-week) Safety Trial

Long term chronic use safety data for COMBIVENT RESPIMAT were obtained from one 48-week, randomized, multi-center, open-label, parallel-group trial that compared COMBIVENT RESPIMAT (20/100 mcg), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) and the free combination of ipratropium bromide (34 mcg) and albuterol (180 mcg) HFA inhalation aerosols administered 4 times a day in 465 adult COPD patients (273 males and 192 females) 40 years of age and older. Of these patients, 157 were treated with COMBIVENT RESPIMAT. The COMBIVENT RESPIMAT group was composed of mostly Caucasian (93.5%) patients with a mean age of 62.9 years, and a mean percent predicted FEV₁ at screening of 47.0%. An evaluation of the safety data from the trial revealed that most adverse reactions were similar in type and rate between treatment groups. However, cough occurred more frequently in patients enrolled in the COMBIVENT RESPIMAT group (7.0%) compared to those in the CFC-propelled COMBIVENT Inhalation Aerosol (2.6%) or the free combination of ipratropium bromide and albuterol HFA inhalation aerosols (3.9%) groups.

In addition to the adverse reactions reported in the controlled clinical trial with COMBIVENT RESPIMAT, adverse reaction information concerning CFC-propelled COMBIVENT Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for CFC-propelled COMBIVENT Inhalation Aerosol). Adverse reactions reported in ≥ 2% of patients in the CFC-propelled COMBIVENT Inhalation Aerosol treatment group include: bronchitis, upper respiratory tract infection, headache, dyspnea, cough, pain, respiratory disorder, sinusitis, pharyngitis and nausea. Adverse reactions reported in < 2% of patients in the CFC-propelled COMBIVENT Inhalation Aerosol treatment group include: edema, fatigue, hypertension, dizziness, nervousness, tremor, dysphonia, insomnia, diarrhea, dry mouth, dyspepsia, vomiting, arrhythmia, palpitation, tachycardia, arthralgia, angina, increased sputum, taste perversion, urinary tract infection, dysuria, dry throat and bronchospasm.

Post-Marketing Experience

In addition to the adverse reactions reported during clinical trials, the following adverse reactions have been identified during post approval use of CFC-propelled COMBIVENT Inhalation Aerosol. Since CFC-propelled Combivent Inhalation Aerosol and Combivent Respimat contain the same active ingredients, one should take into account the fact that the adverse reactions seen with CFC-propelled Combivent Inhalation Aerosol could also occur with Combivent Respimat. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye disorders: glaucoma, blurred vision, mydriasis, conjunctival hyperemia, halo vision, accommodation disorder ocular irritation and corneal edema

Gastrointestinal disorders: gastrointestinal motility disorder, drying of secretions, stomatitis and mouth edema

Immune system disorders: hypersensitivity;

Investigations: intraocular pressure increased, blood pressure diastolic decreased and blood pressure systolic increased

Musculoskeletal and connective tissue disorders: muscular weakness

Psychiatric disorders: CNS stimulation, mental disorder

Respiratory, thoracic, and mediastinal disorders: throat irritation, paradoxical bronchospasm, wheezing, nasal congestion and pharyngeal edema

Skin and subcutaneous tissue disorders: angioedema, hyperhidrosis, and skin reaction

Urinary disorders: urinary retention

Cardiac disorders: myocardial ischemia

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 also been reported with CFC-propelled COMBIVENT Inhalation Aerosol, with positive re-challenge in some cases.

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 CFC-propelled Atrovent® (ipratropium bromide) Inhalation Aerosol.

Metabolic acidosis has been reported with use of albuterol-containing products.

DRUG INTERACTIONS

COMBIVENT RESPIMAT has been used concomitantly with other drugs, including beta-adrenergic bronchodilators, methylxanthines, and oral and inhaled steroids, commonly used in the treatment of chronic obstructive pulmonary disease. There are no formal studies fully evaluating the interaction effects of COMBIVENT RESPIMAT and these drugs with respect to safety and effectiveness.

Anticholinergic Agents

There is the potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of COMBIVENT RESPIMAT with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Beta-adrenergic Agents

Caution is advised in the coadministration of COMBIVENT RESPIMAT and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects.

Beta-receptor Blocking Agents

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 coadministration of beta-agonist-containing drugs, such as COMBIVENT RESPIMAT, with non-potassium sparing diuretics. Consider monitoring potassium levels.

Monoamine Oxidase Inhibitors Or Tricyclic Antidepressants

COMBIVENT RESPIMAT should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or within 2 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.

Teratogenic Effects

Pregnancy Category C.

COMBIVENT RESPIMAT Inhalation Spray

There are no adequate and well-controlled studies of COMBIVENT RESPIMAT (ipratropium bromide and albuterol sulfate) Inhalation Spray, ipratropium bromide, or albuterol sulfate, in pregnant women. Animal reproduction studies have not been conducted with COMBIVENT RESPIMAT. However, albuterol sulfate has been shown to be teratogenic in mice and rabbits. COMBIVENT RESPIMAT Inhalation Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Ipratropium bromide

Oral reproduction studies were performed in mice, rats and rabbits at doses approximately 340, 68,000 and 17,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mg/m² basis at maternal doses in each species of 10, 1000 and 125 mg/kg/day, respectively). Inhalation reproduction studies were conducted in rats and rabbits at approximately 100 and 240 times, respectively, the MRHDID in adults (on a mg/m² basis at maternal doses of 1.5 and 1.8 mg/kg/day, respectively). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. Embryotoxicity was observed as increased resorption in rats at oral doses approximately 6100 times MRHDID in adults (on a mg/m² basis at maternal doses of 90 mg/kg/day and above). This effect is not considered relevant to human use due to the large doses at which it was observed and the difference in route of administration.

Albuterol

Albuterol has been shown to be teratogenic in mice and rabbits. A reproduction study in CD-1 mice given albuterol subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at approximately equivalent to the MRHDID in adults (on a mg/m² basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 183 (9.3%) fetuses at approximately 14 times the MRHDID in adults (on a mg/m² basis a maternal dose of 2.5 mg/kg/day). None was observed at less than MRHDID in adults (on a mg/m² basis at a maternal dose of 0.025 mg/kg/day). Cleft palate also occurred in 22 of 72 (30.5%) fetuses treated with 2.5 mg/kg/day isoproterenol (positive control). A reproductive study with oral albuterol in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses at approximately 1,100 times the MRHDID in adults (on a mg/m² basis at a maternal dose of 50 mg/kg/day).

Use of albuterol, a beta-adrenergic agonist, may be associated with the following:

• Paradoxical bronchospasm
• Cardiovascular effects
• Hypersensitivity reactions, including anaphylaxis
• Hypokalemia

Albuterol is a component of COMBIVENT RESPIMAT.

Use of ipratropium bromide, an anticholinergic, may result in the following:

• Ocular effects
• Urinary retention

Ipratropium bromide is a component of COMBIVENT RESPIMAT.

Clinical Trials Experience

COMBIVENT RESPIMAT 12-Week Clinical Trials

The safety data described in Table 1 below are derived from one 12-week, randomized, multi-center, double-blind, double-dummy, parallel-group trial that compared COMBIVENT RESPIMAT (20/100 mcg), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg), and ipratropium bromide delivered by the RESPIMAT inhaler (20 mcg) administered four times a day in 1460 adult COPD patients (955 males and 505 females) 40 years of age and older. Of these patients, 486 were treated with COMBIVENT RESPIMAT. The COMBIVENT RESPIMAT group was composed of mostly Caucasian (88.5%) patients with a mean age of 63.8 years, and a mean percent predicted FEV₁ at screening of 41.5%. Patients with narrow-angle glaucoma, symptomatic prostatic hypertrophy or bladder-neck obstruction were excluded from the trial.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 1 shows all adverse reactions that occurred with a frequency of ≥ 2% in the COMBIVENT RESPIMAT treatment group in the 12-week COPD trial. The frequency of the corresponding adverse reactions in the CFC-propelled COMBIVENT Inhalation Aerosol and ipratropium bromide delivered by the RESPIMAT inhaler groups is included for comparison. The rates are derived from all reported adverse reactions of that type not present at baseline, whether considered drug-related or not by the clinical investigator.

Table 1: Adverse Reactions in ≥ 2% of Patients in the COMBIVENT RESPIMAT Group in a 12-Week COPD Clinical Trial

Adverse reactions that occurred in < 2% in the COMBIVENT RESPIMAT (20/100 mcg) group observed in this 12-week trial include: Vascular disorders: hypertension; Nervous system disorders: dizziness and tremor; Musculoskeletal and connective tissue disorder: muscle spasms and myalgia; Gastrointestinal disorders: diarrhea, nausea, dry mouth, constipation, and vomiting; General disorders and administration site conditions: asthenia, influenza-like illness, and chest discomfort; Eye disorders: eye pain; Metabolism and nutritional disorders: hypokalemia; Cardiac disorders: palpitations and tachycardia; Skin and subcutaneous tissue disorders: pruritus and rash; Respiratory, thoracic and mediastinal disorders; pharyngolaryngeal pain and wheezing.

A separate 12-week trial evaluated a higher than approved dose of COMBIVENT RESPIMAT in 1118 COPD patients. Patients were randomized to COMBIVENT RESPIMAT (40/200 mcg) (n=345), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) (n=180), ipratropium delivered by the RESPIMAT (40 mcg) (n=252) or placebo (n=341). The overall incidence and nature of adverse reactions observed were similar to the adverse reactions seen with COMBIVENT RESPIMAT 20/100 mcg.

COMBIVENT RESPIMAT Long Term (48-week) Safety Trial

Long term chronic use safety data for COMBIVENT RESPIMAT were obtained from one 48-week, randomized, multi-center, open-label, parallel-group trial that compared COMBIVENT RESPIMAT (20/100 mcg), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) and the free combination of ipratropium bromide (34 mcg) and albuterol (180 mcg) HFA inhalation aerosols administered 4 times a day in 465 adult COPD patients (273 males and 192 females) 40 years of age and older. Of these patients, 157 were treated with COMBIVENT RESPIMAT. The COMBIVENT RESPIMAT group was composed of mostly Caucasian (93.5%) patients with a mean age of 62.9 years, and a mean percent predicted FEV₁ at screening of 47.0%. An evaluation of the safety data from the trial revealed that most adverse reactions were similar in type and rate between treatment groups. However, cough occurred more frequently in patients enrolled in the COMBIVENT RESPIMAT group (7.0%) compared to those in the CFC-propelled COMBIVENT Inhalation Aerosol (2.6%) or the free combination of ipratropium bromide and albuterol HFA inhalation aerosols (3.9%) groups.

In addition to the adverse reactions reported in the controlled clinical trial with COMBIVENT RESPIMAT, adverse reaction information concerning CFC-propelled COMBIVENT Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for CFC-propelled COMBIVENT Inhalation Aerosol). Adverse reactions reported in ≥ 2% of patients in the CFC-propelled COMBIVENT Inhalation Aerosol treatment group include: bronchitis, upper respiratory tract infection, headache, dyspnea, cough, pain, respiratory disorder, sinusitis, pharyngitis and nausea. Adverse reactions reported in < 2% of patients in the CFC-propelled COMBIVENT Inhalation Aerosol treatment group include: edema, fatigue, hypertension, dizziness, nervousness, tremor, dysphonia, insomnia, diarrhea, dry mouth, dyspepsia, vomiting, arrhythmia, palpitation, tachycardia, arthralgia, angina, increased sputum, taste perversion, urinary tract infection, dysuria, dry throat and bronchospasm.

Post-Marketing Experience

In addition to the adverse reactions reported during clinical trials, the following adverse reactions have been identified during post approval use of CFC-propelled COMBIVENT Inhalation Aerosol. Since CFC-propelled Combivent Inhalation Aerosol and Combivent Respimat contain the same active ingredients, one should take into account the fact that the adverse reactions seen with CFC-propelled Combivent Inhalation Aerosol could also occur with Combivent Respimat. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye disorders: glaucoma, blurred vision, mydriasis, conjunctival hyperemia, halo vision, accommodation disorder ocular irritation and corneal edema

Gastrointestinal disorders: gastrointestinal motility disorder, drying of secretions, stomatitis and mouth edema

Immune system disorders: hypersensitivity;

Investigations: intraocular pressure increased, blood pressure diastolic decreased and blood pressure systolic increased

Musculoskeletal and connective tissue disorders: muscular weakness

Psychiatric disorders: CNS stimulation, mental disorder

Respiratory, thoracic, and mediastinal disorders: throat irritation, paradoxical bronchospasm, wheezing, nasal congestion and pharyngeal edema

Skin and subcutaneous tissue disorders: angioedema, hyperhidrosis, and skin reaction

Urinary disorders: urinary retention

Cardiac disorders: myocardial ischemia

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 also been reported with CFC-propelled COMBIVENT Inhalation Aerosol, with positive re-challenge in some cases.

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 CFC-propelled Atrovent® (ipratropium bromide) Inhalation Aerosol.

Metabolic acidosis has been reported with use of albuterol-containing products.

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 inhalation or oral administration. 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 the Adverse Reactions section. As with all beta-adrenergic 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.

Ipratropium Bromide

Cardiovascular Effects

At recommended doses, ipratropium bromide does not produce clinically significant changes in pulse rate or blood pressure.

Ocular Effects

In studies without a positive control, ipratropium bromide did not alter pupil size, accommodation or visual acuity.

Mucociliary Clearance and Respiratory Secretions

Controlled clinical studies have demonstrated that ipratropium bromide does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions.

Albuterol Sulfate

Cardiovascular Effects

Controlled clinical trials and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

Ipratropium Bromide

Ipratropium bromide is a quaternary amine and hence, 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.

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.

Albuterol Sulfate

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.

Intravenous pharmacokinetics of albuterol was 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.

COMBIVENT RESPIMAT Inhalation Spray

In a 12-week randomized, multicenter, double-blind, double-dummy parallel group trial, 108 US patients with COPD receiving either COMBIVENT RESPIMAT (20/100 mcg) or CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) four times daily participated in pharmacokinetic evaluations. Plasma ipratropium concentrations were low with an average peak plasma concentration of 33.5 pg/mL from COMBIVENT RESPIMAT. The majority of the study participants exhibited levels below the lower limit of quantitation ( < 10 pg/mL) by 4 to 6 hours following dosing. The steady state systemic exposure obtained for ipratropium bromide following COMBIVENT RESPIMAT was comparable to that of CFC-propelled COMBIVENT Inhalation Aerosol. Ipratropium plasma AUC and total amount of drug excreted unchanged in urine (Ae) ratios for COMBIVENT RESPIMAT/CFC-propelled COMBIVENT Inhalation Aerosol were 1.04 and 1.18, respectively. For albuterol the steady-state systemic exposure was less from COMBIVENT RESPIMAT compared to that of CFC-propelled COMBIVENT Inhalation Aerosol. Albuterol plasma AUC and urine Ae ratios for COMBIVENT RESPIMAT/CFC-propelled COMBIVENT Inhalation Aerosol were 0.74 and 0.86, respectively.

Pharmacokinetic drug-drug interaction between ipratropium bromide and albuterol sulfate was evaluated in a crossover study in 12 healthy male volunteers who received CFC-propelled COMBIVENT Inhalation Aerosol and the two active components separately as individual treatments. Results from this study indicated that the coadministration of these two components from a single canister did not significantly alter the systemic absorption of either component, indicating lack of any pharmacokinetic interaction between these two drugs.