Ipratropium Bromide And Albuterol

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# Overview
Ipratropium Bromide And Albuterol is a combination of an anticholinergic and beta-adrenergic that is FDA approved for the {{{indicationType}}} of chronic obstructive pulmonary disease (COPD).   Common adverse reactions include upper respiratory infection, nasopharyngitis, cough, bronchitis, headache, and dyspnea.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- 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
- Dosing Information
- 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 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 cartridge delivers 120 metered actuations after preparation for use, the equivalent of 30 days 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ipratropium Bromide And Albuterol in adult patients.

### NonGuideline-Supported Use
- Dosing Information
- Ipratropium 0.5 mg/albuterol 2.5 mg (usually given once).

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ipratropium Bromide And Albuterol in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ipratropium Bromide And Albuterol in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ipratropium Bromide And Albuterol in pediatric patients.

# Contraindications
- 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

### 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.
- Use of albuterol, a beta-adrenergic agonist, may be associated with the following:
- Paradoxical bronchospasm
- Cardiovascular effects
- Hypersensitivity reactions, including anaphylaxis
- Use of ipratropium bromide, an anticholinergic, may result in the following:
- Ocular effects
- Urinary retention

# Adverse Reactions

## Clinical Trials Experience
- 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.
- 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.
- 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.

## Postmarketing 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
- 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- 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).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ipratropium Bromide And Albuterol in women who are pregnant.

### 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
- 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.

### Geriatic 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.

### Gender
There is no FDA guidance on the use of Ipratropium Bromide And Albuterol with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ipratropium Bromide And Albuterol with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Ipratropium Bromide And Albuterol in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Ipratropium Bromide And Albuterol in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ipratropium Bromide And Albuterol in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Ipratropium Bromide And Albuterol in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Respiratory(Inhalation)

### Monitoring
- Electrocardiographic changes and/or hypokalemia associated with diuretics may worsen with concomitant use of beta-agonists. Consider monitoring potassium levels.

# IV Compatibility
There is limited information regarding IV Compatibility of Ipratropium Bromide And Albuterol in the drug label.

# Overdosage

## Acute Overdose

### Signs and Symptoms
- 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.

### Management
- 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.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Ipratropium Bromide And Albuterol in the drug label.

# Pharmacology
There is limited information regarding Ipratropium Bromide And Albuterol Pharmacology in the drug label.

## Mechanism of Action
- COMBIVENT RESPIMAT is a combination of the anticholinergic ipratropium bromide and the beta2-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 beta2-adrenergic agonist) are both bronchodilators. Simultaneous administration of both an anticholinergic (ipratropium bromide) and a beta2-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 beta2-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 beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, recent data indicate that there is a population of beta2-receptors in the human heart which comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors, however, is not yet established.
- Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylyl cyclase and to an increase in the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.
- Albuterol has been shown in most clinical trials to have more bronchial smooth muscle relaxation effect than isoproterenol at comparable doses while producing fewer cardiovascular effects. However, all beta-adrenergic drugs, including albuterol sulfate, can produce a significant cardiovascular effect in some patients.

## Structure
- COMBIVENT RESPIMAT is a combination of ipratropium bromide (as the monohydrate) and albuterol sulfate.
- Ipratropium bromide is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo 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:
- C20H30BrNO3H2O    ipratropium bromide    Mol. Wt. 430.4
- Albuterol sulfate, chemically known as (1,3-benzenedimethanol, '- methyl]-4-hydroxy, sulfate (2:1)(salt), ()- is a relatively selective beta2-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:
- (C13H21NO3)2H2SO4    albuterol sulfate    Mol. Wt. 576.7

## Pharmacodynamics
- Ipratropium bromide
- Cardiovascular effects
At recommended doses, ipratropium bromide does not produce clinically significant changes in pulse rate or blood pressure.
- 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.
- 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.
- 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.
- 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.

## Pharmacokinetics
- 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 1-acid glycoprotein. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half of the dose is excreted unchanged in the urine.
- 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.
- Specific Populations
- Age
- Consistent with CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg), patients receiving COMBIVENT RESPIMAT (20/100 mcg) aged 65 years and over had higher steady state systemic exposures than patients aged under 65 years for both ipratropium (AUC = 166 vs. 105 pghr/mL, Cmax = 38.5 vs. 30.1 pg/mL) and albuterol (AUC = 5.44 vs. 3.27 nghr/mL, Cmax = 1.19 vs. 0.74 ng/mL).
- Gender
- The AUC- and Cmax-values for ipratropium were 131 pg.hr/mL and 35.4 pg/mL in males and 123 pg.hr/mL and 31.7 pg/mL in females, respectively. The AUC- and Cmax-values for albuterol were 4.0 nghr/mL and 0.89 ng/mL in males and 4.2 nghr/mL and 0.93 ng/mL in females, respectively.
- Hepatic and Renal Impairment
- The pharmacokinetics of COMBIVENT RESPIMAT or ipratropium bromide has not been studied in patients with hepatic or renal insufficiency.
- Drug-Drug Interactions
- No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions with other medications.

## Nonclinical Toxicology
- 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.
- 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.

# Clinical Studies
- The efficacy of COMBIVENT RESPIMAT (20/100 mcg) was evaluated in COPD patients in one randomized, double-blind, double-dummy parallel group trial. This was a 12-week trial in a total of 1460 adult patients (955 males and 505 females) conducted to demonstrate the efficacy and safety of COMBIVENT RESPIMAT (20/100 mcg) in COPD. All patients were required to have a clinical diagnosis of COPD, be at least 40 years of age or older, to have an FEV1 of less than or equal to 65% predicted and an FEV1/FVC ratio of less than or equal to 0.7 at screening, and a smoking history of greater than 10 pack-years prior to entering the trial. Patients with narrow-angle glaucoma, symptomatic prostatic hypertrophy, or bladder neck obstruction were excluded from the trial. The majority of the patients (89%) were Caucasian, had a mean age of 64 years, a mean percent predicted pre-bronchodilator FEV1 of 41% and FEV1/FVC ratio of 0.45. The patients were randomized to one of the following active treatments COMBIVENT RESPIMAT (20/100 mcg) (n=486), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) (n=491), and ipratropium bromide delivered by the RESPIMAT (20 mcg) (n=483) administered four times a day. Data from 1424 patients were used in the efficacy analyses.
- There were three primary efficacy variables: (i) Mean FEV1 over 0 to 6 hours post-dose defined as the AUC of the change from test-day baseline in FEV1 over 0 to 6 hours post-dose divided by 6 hours (FEV1 AUC0-6h); (ii) Mean FEV1 over 0 to 4 hours post-dose defined as the AUC of the change from test-day baseline in FEV1 over 0 to 4 hours post-dose divided by 4 hours (FEV1 AUC0-4h), and (iii) Mean FEV1 over 4 to 6 hours post-dose defined as the AUC of the change from test-day baseline in FEV1 over 4 to 6 hours post-dose divided by 2 hours (FEV1 AUC4-6h). Test-day baseline was the FEV1 recorded prior to inhaling the dose of randomized treatment on test day.
- The three primary efficacy comparisons were: (i) Non-inferiority of COMBIVENT RESPIMAT (20/100 mcg) to CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) for the FEV1 AUC0-6h on Test Day 85; (ii) Superiority of COMBIVENT RESPIMAT (20/100 mcg) to ipratropium RESPIMAT (20 mcg) for the FEV1 AUC0-4h on Test Day 85, to demonstrate the contribution of albuterol in the combination product, and (iii) Non-inferiority of COMBIVENT RESPIMAT (20/100 mcg) in comparison to ipratropium RESPIMAT (20 mcg) for FEV1 AUC4-6h on Test Day 85, to demonstrate the contribution of ipratropium in the combination product. Non-inferiority was declared if the lower bound of the 95% confidence interval for the point estimate for the difference of COMBIVENT RESPIMAT minus the comparator was more than -50 mL.
- COMBIVENT RESPIMAT (20/100 mcg) was shown to be non-inferior to CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) in terms of mean FEV1 AUC0-6h. The LS mean (mL) (95% CI) of the treatment difference was -3 (-22, 15). The FEV1 AUC0-4h for COMBIVENT RESPIMAT (20/100 mcg), was superior to that of ipratropium bromide  and the mean FEV1 AUC4-6h for COMBIVENT RESPIMAT (20/100 mcg) was non-inferior to that of ipratropium bromide . The FEV1 results on Test Days 1, 29, 57, and 85 are shown in Figure 1.
- In this trial, COMBIVENT RESPIMAT (20/100 mcg) was shown to be clinically comparable (statistically non-inferior) to CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg).
- Additionally, in this trial, no differences in these efficacy comparisons were identified in males and females or in patients over 65 years of age versus those under 65 years of age. There were too few African-American subjects to adequately assess differences in effects in that population.
- The median time to onset of bronchodilation, defined as an FEV1 increase of 15% or greater from test-day baseline, for the COMBIVENT RESPIMAT (20/100 mcg) group occurred at 13 minutes post-dose on Day 1.
- The means are adjusted for treatment baseline and investigator site. A separate ANCOVA was fitted for each time point.
- The imputation method for data missing because the patient withdrew from the trial was Last Visit Carried Forward.
- The imputation method for data missing at the end of test days depends on why the data were missing.
- A second study was conducted in 1118 COPD patients using a higher than approved dose of COMBIVENT RESPIMAT. 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 study was supportive, particularly for safety.

# How Supplied
- COMBIVENT RESPIMAT Inhalation Spray is supplied in a carton containing one COMBIVENT RESPIMAT cartridge and one COMBIVENT RESPIMAT inhaler (NDC 0597-0024-02).
- 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 grey inhaler body indicate that it is labeled for use with the COMBIVENT RESPIMAT cartridge.
- The COMBIVENT RESPIMAT cartridge has a net fill weight of 4 grams and when used with the COMBIVENT RESPIMAT inhaler, is designed to deliver 120 metered actuations after preparation for use; the equivalent of 30 days 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) 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 (120 actuations), whichever comes first.
- Keep out of reach of children. Do not spray into eyes.
- Storage
- Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F). Avoid freezing.

## Storage
There is limited information regarding Ipratropium Bromide And Albuterol Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- 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.

# Precautions with Alcohol
- Alcohol-Ipratropium Bromide And Albuterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- COMBIVENT RESPIMAT

# Look-Alike Drug Names
There is limited information regarding Ipratropium Bromide And Albuterol Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price