Combivent Respimat ipratropium bromide and albuterol 20 ug; 100 ug Spray, Metered
🆔 Identity & classification
Where does this data come from?
🏷️ RxNorm drug class
This medicine belongs to the beta2-Adrenergic Agonist class.
Where does this data come from?
🏭 Manufacturer & labeler
Where does this data come from?
🩺 Clinical
- This combination is used for COPD — a chronic lung condition — when one bronchodilator (airway opener) isn't enough to keep your airways open. Albuterol and ipratropium work in two...
- What exactly is this medicine for, and why do I need two drugs in one inhaler?
- This medicine is generally used several times a day as your doctor directs. Using more than prescribed is genuinely dangerous — there have been reports of serious heart problems an...
- How often should I use this, and can I take an extra dose if I'm struggling to breathe?
Patient education
Supplement & herbal interactions
Where does this data come from?
Ask a licensed pharmacist directly — free, answered by our team.
🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
Where does this data come from?
IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
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Can inactive ingredients matter?
💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per g | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $124.140 | — |
| Medicaid paysCMS SDUD · 12 mo | $122.32 | — |
| Medicare drug plans payPart D · Q2 2026 | $124.69 | — |
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Combivent Respimat 20 ug/1; 100 ugthis 00597-0024-02 | Boehringer | 1 cartridge | $124.140 | — | Availability likely | — |
Where does this data come from?
⏳ Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 7396341 ↗ delist req. | Drug product | — | Oct 10, 2026 |
| US 7837235 ↗ delist req. | Drug product | — | Mar 13, 2028 |
| US 8733341 ↗ delist req. | Drug product | — | Oct 16, 2030 |
| US 9027967 ↗ delist req. | Drug product | — | Mar 31, 2027 |
Is there a generic version of COMBIVENT RESPIMAT 20-100 MCG?
The FDA approved a generic — why can’t I get it at my pharmacy yet?
Why do different websites show different generic release dates?
What does “FDA listed” mean?
What does a patent or protection date mean here?
What does “current Orange Book estimate” mean?
Can a generic come out before the last patent expires?
Can a generic come out after the listed dates?
What is the difference between patents and exclusivity?
Why are there multiple patent dates?
Where does this data come from?
🗺️ Medicaid utilization & spend
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 00597-0024-02 You're viewing this | 1 CARTRIDGE in 1 CARTON (0597-0024-02) / 120 SPRAY, METERED in 1 CARTRIDGE | 2012-07-01 | Active |
📄 Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE COMBIVENT RESPIMAT is a combination of ipratropium bromide (an anticholinergic agent) and albuterol sulfate (a beta 2 -adrenergic agonist) 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 ipratropium bromide (an anticholinergic agent) and albuterol sulfate (a beta 2 ‑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)
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION The recommended dosage 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)
💊 Dosage Forms and Strengths ▾
3 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 (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.
Inhalation spray: 20 mcg ipratropium bromide (monohydrate) and 100 mcg albuterol (equivalent to 120 mcg albuterol sulfate) per actuation with the COMBIVENT RESPIMAT inhaler (3)
⛔ 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)
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Paradoxical bronchospasm: Discontinue COMBIVENT RESPIMAT immediately and treat with alternative therapy if paradoxical bronchospasm occurs (5.1) Patients with cardiovascular system disorders: Use with caution because of beta-adrenergic stimulation (5.2) Ocular effects: Advise patients to avoid spraying into eyes and to contact a physician if blurred vision, halos, or other visual disturbances occur. Monitor patients with narrow-angle glaucoma. (5.3) Urinary retention: Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction (5.4) Hypersensitivity reactions including anaphylaxis: Discontinue COMBIVENT RESPIMAT and institute alternative therapy if immediate hypersensitivity reactions such as urticaria, angioedema, rash, bronchospasm, anaphylaxis, or oropharyngeal edema occur (5.6) Coexisting conditions: Use with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus (5.7)
5.1Paradoxical 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.
5.2Cardiovascular Effects 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 postmarketing data and published literature of rare occurrences of myocardial ischemia associated with albuterol.
In addition, beta‑adrenergic agonists 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 [ see Drug Interactions (7.2) ].
5.3Ocular 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 [ see Drug Interactions (7.1) ].
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.
5.4Urinary 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 [ see Drug Interactions (7.1) ].
5.5Do Not Exceed Recommended Dosage 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 [ see Drug Interactions (7.2) ].
5.6Hypersensitivity 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 postmarketing 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 hav…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS Use of albuterol, a beta 2 -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 (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience COMBIVENT RESPIMAT 12-Week Clinical Trials The safety data described in Table 1 below are derived from one 12-week, randomized, multicenter, 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 1,460 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 FEV 1 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 separat…
🔄 Drug 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)
7.1Anticholinergic 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) ].
7.2Beta‑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) ].
7.3Beta-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.
7.4Diuretics 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 2 -agonists, especially when the recommended dosage of the beta 2 -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.
7.5Monoamine 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) ].
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS
8.1Pregnancy Risk Summary There are no randomized clinical studies of COMBIVENT RESPIMAT, or its individual components, ipratropium bromide and albuterol sulfate, in pregnant women. Ipratropium is negligibly absorbed systemically following oral inhalation; therefore, maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology (12.3) ] . Published literature, including cohort studies, case control studies and case series, over several decades have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes with ipratropium bromide.
Available data from published epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or, miscarriage. There are clinical considerations with the use of COMBIVENT RESPIMAT in pregnant women [see Clinical Considerations ] . Animal reproduction studies have not been conducted with COMBIVENT RESPIMAT, however, animal studies are available with its individual components, ipratropium bromide and albuterol sulfate.
Based on oral reproduction studies, no evidence of structural alterations was observed when ipratropium bromide was administered to pregnant mice, rats, and rabbits during organogenesis at doses approximately 340, 68,000 and 17,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults on a mg/m 2 basis. When albuterol was administered to pregnant mice during organogenesis there was evidence of cleft palate at doses approximately equivalent to the maximum recommended human daily inhalation dose (MRHDID) [see Data ] .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Consideration Labor or 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. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including albuterol. Data Animal Data Ipratropium bromide In animal reproduction studies, oral and inhalation administration of ipratropium bromide to pregnant mice, rats and rabbits during the period of organogenesis did not show evidence of fetal structural alterations.
The ipratropium dose in oral studies in mice, rats, and rabbits was up to approximately 340, 68,000 and 17,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mg/m 2 basis at maternal doses in each species of 10, 1,000 and 125 mg/kg/day, respectively). The ipratropium dose in inhalation studies in rats and rabbits was up to approximately 100 and 240 times, respectively, the MRHDID in adults (on a mg/m 2 basis at maternal doses of 1.5 and 1.8 mg/kg/day, respectively).
Embryotoxicity was observed as increased resorption in rats at oral doses approximately 6,100 times MRHDID in adults (on a mg/m 2 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 In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at a dose approximately equivalent to the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at approximately 14 times the MRHDID in adults (on…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary There are no randomized clinical studies of COMBIVENT RESPIMAT, or its individual components, ipratropium bromide and albuterol sulfate, in pregnant women. Ipratropium is negligibly absorbed systemically following oral inhalation; therefore, maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology (12.3) ] . Published literature, including cohort studies, case control studies and case series, over several decades have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes with ipratropium bromide.
Available data from published epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or, miscarriage. There are clinical considerations with the use of COMBIVENT RESPIMAT in pregnant women [see Clinical Considerations ] . Animal reproduction studies have not been conducted with COMBIVENT RESPIMAT, however, animal studies are available with its individual components, ipratropium bromide and albuterol sulfate.
Based on oral reproduction studies, no evidence of structural alterations was observed when ipratropium bromide was administered to pregnant mice, rats, and rabbits during organogenesis at doses approximately 340, 68,000 and 17,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults on a mg/m 2 basis. When albuterol was administered to pregnant mice during organogenesis there was evidence of cleft palate at doses approximately equivalent to the maximum recommended human daily inhalation dose (MRHDID) [see Data ] .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Consideration Labor or 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. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including albuterol. Data Animal Data Ipratropium bromide In animal reproduction studies, oral and inhalation administration of ipratropium bromide to pregnant mice, rats and rabbits during the period of organogenesis did not show evidence of fetal structural alterations.
The ipratropium dose in oral studies in mice, rats, and rabbits was up to approximately 340, 68,000 and 17,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mg/m 2 basis at maternal doses in each species of 10, 1,000 and 125 mg/kg/day, respectively). The ipratropium dose in inhalation studies in rats and rabbits was up to approximately 100 and 240 times, respectively, the MRHDID in adults (on a mg/m 2 basis at maternal doses of 1.5 and 1.8 mg/kg/day, respectively).
Embryotoxicity was observed as increased resorption in rats at oral doses approximately 6,100 times MRHDID in adults (on a mg/m 2 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 In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at a dose approximately equivalent to the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at approximately 14 times the MRHDID in adults (on a mg/m 2 basis at a maternal…
🧒 Pediatric Use ▾
8.4Pediatric 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 ▾
8.5Geriatric 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.
🆘 Overdosage ▾
10 OVERDOSAGE 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 [ see Adverse Reactions (6) ].
As with all beta 2 -adrenergic agonist aerosol medications, cardiac arrest and even death may be associated with abuse. Treatment of overdosage consists of discontinuation of COMBIVENT RESPIMAT together with institution of appropriate medical and supportive therapy. 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.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action COMBIVENT RESPIMAT: COMBIVENT RESPIMAT is a combination of the anticholinergic ipratropium bromide and the beta 2 -adrenergic agonist albuterol sulfate. The mechanisms of action described below for the individual components apply to COMBIVENT RESPIMAT. The two classes of medications (an anticholinergic and a beta 2 -adrenergic agonist) are both bronchodilators.
Simultaneous administration of both an anticholinergic (ipratropium bromide) and a beta 2 -sympathomimetic (albuterol sulfate) is designed to produce a greater bronchodilator effect than when either drug is utilized alone at its recommended dosage. The efficacy of COMBIVENT RESPIMAT is likely to be due to a local effect on the muscarinic and beta 2 -adrenergic receptors in the lung. Ipratropium bromide 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. Albuterol sulfate In vitro studies and in vivo pharmacology studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, recent data indicate that there is a population of beta 2 -receptors in the human heart which comprise between 10% and 50% of cardiac beta-adrenergic receptors.
The precise function of these receptors, however, is not yet established [ see Warnings and Precautions (5.2) ]. Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenylyl cyclase and to an increase in the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase, 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 agonist drugs, including albuterol sulfate, can produce a significant cardiovascular effect in some patients [ see Warnings and Precautions (5.2) ].
12.2Pharmacodynamics Ipratropium bromide Cardiovascular effects At recommended dosages, 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.
12.3Pharmacokinetics Ipratropium bromide Ipratropium bromide is a quaternary amine and hence, it is not read…
🧬 Mechanism of Action ▾
12.1Mechanism of Action COMBIVENT RESPIMAT: COMBIVENT RESPIMAT is a combination of the anticholinergic ipratropium bromide and the beta 2 -adrenergic agonist albuterol sulfate. The mechanisms of action described below for the individual components apply to COMBIVENT RESPIMAT. The two classes of medications (an anticholinergic and a beta 2 -adrenergic agonist) are both bronchodilators.
Simultaneous administration of both an anticholinergic (ipratropium bromide) and a beta 2 -sympathomimetic (albuterol sulfate) is designed to produce a greater bronchodilator effect than when either drug is utilized alone at its recommended dosage. The efficacy of COMBIVENT RESPIMAT is likely to be due to a local effect on the muscarinic and beta 2 -adrenergic receptors in the lung. Ipratropium bromide 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. Albuterol sulfate In vitro studies and in vivo pharmacology studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, recent data indicate that there is a population of beta 2 -receptors in the human heart which comprise between 10% and 50% of cardiac beta-adrenergic receptors.
The precise function of these receptors, however, is not yet established [ see Warnings and Precautions (5.2) ]. Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenylyl cyclase and to an increase in the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase, 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 agonist drugs, including albuterol sulfate, can produce a significant cardiovascular effect in some patients [ see Warnings and Precautions (5.2) ].
Ipratropium bromide 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.
Albuterol sulfate In vitro studies and in vivo pharmacology studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, recent data indicate that there is a population of beta 2 -receptors in the human heart which comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors, however, is not yet establishe…
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/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) 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 after preparation for use. 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 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 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Avoid freezing.
📋 Description ▾
11 DESCRIPTION COMBIVENT RESPIMAT is a combination of ipratropium bromide (monohydrate) and albuterol sulfate. Ipratropium bromide is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo[3.2.1] octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-, bromide monohydrate, (3-endo, 8-syn)-: a synthetic quaternary ammonium compound chemically related to atropine. Ipratropium bromide is a white to off-white crystalline substance, freely soluble in water and methanol, sparingly soluble in ethanol, and insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons.
The structural formula is: C 20 H 30 BrNO 3 •H 2 O ipratropium bromide Mol. Wt. 430.4 Albuterol sulfate, chemically known as (1,3-benzenedimethanol, α'-[[(1,1dimethylethyl) amino] methyl]-4-hydroxy, sulfate (2:1)(salt), (±)- is a relatively selective beta 2 -adrenergic bronchodilator.
Albuterol is the official generic name in the United States. The World Health Organization recommended name for the drug is salbutamol. Albuterol sulfate is a white to off-white crystalline powder, freely soluble in water and slightly soluble in alcohol, chloroform, and ether.
The structural formula is: (C 13 H 21 NO 3 ) 2 •H 2 SO 4 albuterol sulfate Mol. Wt. 576.7 The drug product, COMBIVENT RESPIMAT, is composed of a sterile, aqueous solution of ipratropium bromide and albuterol sulfate filled into a 4.5 mL plastic container crimped into an aluminum cylinder (COMBIVENT RESPIMAT cartridge) for use with the COMBIVENT RESPIMAT inhaler.
Excipients include benzalkonium chloride, edetate disodium, hydrochloric acid, and water for injection. The COMBIVENT RESPIMAT cartridge is only intended for use with the COMBIVENT RESPIMAT inhaler. The COMBIVENT RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow-moving aerosol cloud of medication from a metered volume of the drug solution.
The COMBIVENT RESPIMAT inhaler has an orange-colored cap. When used with the COMBIVENT RESPIMAT inhaler, each cartridge containing 4 grams of a sterile aqueous solution delivers the labeled number of metered actuations after preparation for use. Each actuation from the COMBIVENT RESPIMAT inhaler delivers 20 mcg ipratropium bromide (monohydrate) and 100 mcg albuterol (equivalent to 120 mcg albuterol sulfate) in 11.4 mcL of solution from the mouthpiece.
As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds). 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) ]. ipratropium-structure albuterol-structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Instructions for Use). 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.
Ocular Effects Caution patients to avoid spraying the aerosol into their eyes and advise 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 advise them to consult their physician if they experience difficulty with urination. Adverse Effects Associated with Beta 2 -agonists Inform patients of adverse effects associated with beta 2 -agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness [ see Warnings and Precautions (5.2 , 5.5) ]. 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 [ see Warnings and Precautions (5.5) ]. Hypersensitivity Reactions Inform patients that hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema, may occur after the administration of COMBIVENT RESPIMAT.
Advise patients to immediately discontinue COMBIVENT RESPIMAT and consult a physician [ see Warnings and Precautions (5.6) ]. Concomitant Drug Use Remind patients that while taking COMBIVENT RESPIMAT, other inhaled drugs should be taken only as directed by a physician [ see Drug Interactions (7.1) ]. Pregnancy Patients who are pregnant or nursing should contact their physician about the use of COMBIVENT RESPIMAT [ see Use in Specific Populations (8.1 , 8.2) ].
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.
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Licensed from: Boehringer Ingelheim International GmbH RESPIMAT® is a registered trademark of and used under license from Boehringer Ingelheim International GmbH COMBIVENT® is a register…