Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 12 January 2017

Indication(s)

1 INDICATIONS AND USAGE 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. COMBIVENT RESPIMAT Inhalation Spray is a combination of an anticholinergic and beta2‑adrenergic agonist indicated for: 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 (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS COMBIVENT RESPIMAT is contraindicated in the following conditions [ see Warnings and Precautions (5.6) ]: Hypersensitivity to any of the ingredients in COMBIVENT RESPIMAT Hypersensitivity to atropine or any of its derivatives Hypersensitivity to any of the ingredients in COMBIVENT RESPIMAT (4) Hypersensitivity to atropine or any of its derivatives (4)
Adverse reactions
6 ADVERSE REACTIONS Use of albuterol, a beta2-adrenergic agonist, may be associated with the following: Paradoxical bronchospasm [ see Warnings and Precautions (5.1) ] Cardiovascular effects [ see Warnings and Precautions (5.2) ] Hypersensitivity reactions, including anaphylaxis [ see Contraindications (4) and Warnings and Precautions (5.6) ] Hypokalemia [ see Warnings and Precautions (5.8) ] Albuterol is a component of COMBIVENT RESPIMAT. Use of ipratropium bromide, an anticholinergic, may result in the following: Ocular effects [ see Warnings and Precautions (5.3) ] Urinary retention [ see Warnings and Precautions (5.4) ] Ipratropium bromide is a component of COMBIVENT RESPIMAT. Most common (≥2%) adverse reactions for COMBIVENT RESPIMAT (20/100 mcg) are upper respiratory infection, nasopharyngitis, cough, bronchitis, headache, and dyspnea (6) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 Body System (Event) 12-Week Ipratropium-Controlled Trial COMBIVENT RESPIMAT (20/100 mcg) CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) Ipratropium bromide by the RESPIMAT Inhaler (20 mcg) [n=486] [n=491] [n=483] Patients with any adverse reaction 46 52 45 Respiratory, thoracic and mediastinal disorders Cough Dyspnea 3 2 2 2 2 3 Nervous system disorders Headache 3 2 3 Infections and infestations Bronchitis Nasopharyngitis Upper Respiratory infection 3 4 3 3 3 4 1 4 3 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. 6.2 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 [ see Warnings and Precautions (5.6) ]. 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION 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 [see Patient Counseling Information (17)]. 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. For oral inhalation only One inhalation four times a day, not to exceed six inhalations in 24 hours (2)
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 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 at 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). 8.2 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. 8.3 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. 8.4 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. 8.5 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.
Pregnancy and lactation
8.3 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.

Interactions

7 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. Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of COMBIVENT RESPIMAT with other anticholinergic-containing drugs (7.1) Beta-adrenergic agonists: May increase the risk of adverse cardiovascular effects. Avoid coadministration of COMBIVENT RESPIMAT and other sympathomimetic agents (7.2) Beta-blockers: Inhibit the effect of albuterol. Consider alternative therapy in patients with hyperreactive airways (7.3) Diuretics: Electrocardiographic changes and/or hypokalemia associated with diuretics may worsen with concomitant use of beta-agonists. Consider monitoring potassium levels. (7.4) Monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants: May potentiate effect of albuterol on the vascular system. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants. (7.5) 7.1 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 [ see Warnings and Precautions (5.3, 5.4) ]. 7.2 Beta‑adrenergic Agonists Caution is advised in the coadministration of COMBIVENT RESPIMAT and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects [ see Warnings and Precautions (5.2, 5.5) ]. 7.3 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. 7.4 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 beta2-agonists, especially when the recommended dose of the beta2-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. 7.5 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 [ see Warnings and Precautions (5.2) ].

More information

Category Value
Authorisation number NDA021747
Orphan designation No
Product NDC 0597-0024
Date Last Revised 23-06-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 1190220
Marketing authorisation holder Boehringer Ingelheim Pharmaceuticals Inc.