Biwind

Biwind 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 Inhalation Aerosol 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.

Biwind (ipratropium bromide and albuterol sulfate) is indicated for the treatment of bronchospasm associated with COPD in patients requiring more than one bronchodilator.

The recommended dose of Biwind 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 Biwind cartridge is inserted into the Biwind 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 Biwind 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 Biwind have not been studied.

The dose of COMBIVENT® Inhalation Aerosol is two inhalations four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed 12 in 24 hours. Safety and efficacy of additional doses of COMBIVENT Inhalation Aerosol beyond 12 puffs/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® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol have not been studied. It is recommended to “test-spray” three times before using for the first time and in cases where the aerosol has not been used for more than 24 hours. Avoid spraying into eyes.

The recommended dose of Biwind (ipratropium bromide and albuterol sulfate) is one 3 mL vial administered 4 times per day via nebulization with up to 2 additional 3 mL doses allowed per day, if needed. Safety and efficacy of additional doses or increased frequency of administration of Biwind (ipratropium bromide and albuterol sulfate) beyond these guidelines has not been studied and the safety and efficacy of extra doses of albuterol sulfate or ipratropium bromide in addition to the recommended doses of Biwind (ipratropium bromide and albuterol sulfate) have not been studied.

The use of Biwind (ipratropium bromide and albuterol sulfate) can be continued as medically indicated to control recurring bouts of bronchospasm. If a previously effective regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of worsening COPD, which would require reassessment of therapy.

A Pari-LC-Plus™ nebulizer (with face mask or mouthpiece) connected to a PRONEB™ compressor was used to deliver Biwind (ipratropium bromide and albuterol sulfate) to each patient in one U.S. clinical study. The safety and efficacy of Biwind (ipratropium bromide and albuterol sulfate) delivered by other nebulizers and compressors have not been established.

Biwind (ipratropium bromide and albuterol sulfate) should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask.

El viento bi está contraindicado en las siguientes condiciones:

• Hipersensibilidad a cualquiera de los ingredientes en Biwind
• Hipersensibilidad a la atropina o cualquiera de sus derivados

COMBIVENTE Inhalación El aerosol está contraindicado en pacientes con antecedentes de hipersensibilidad a la lecitina de soja o productos alimenticios relacionados como la soja y el maní. COMBIVENTE Inhalación Aerosol también está contraindicado en pacientes hipersensibles a cualquier otro componente del medicamento o a la atropina o sus derivados.

El biwind (bromuro de ipratropio y sulfato de albuterol) está contraindicado en pacientes con antecedentes de hipersensibilidad a cualquiera de sus componentes, o a la atropina y sus derivados.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Paradoxical Bronchospasm

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

Cardiovascular Effect

The albuterol sulfate contained in Biwind, 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, Biwind should be used with caution in patients with cardiovascular disorders; especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Ocular Effects

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

Patients should avoid spraying Biwind into the eyes. If a patient sprays Biwind 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 Biwind, 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

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

Hypokalemia

Beta-adrenergic agents may produce significant hypokalemia in some patients (possibly through intracellular shunting) which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.

Patient Counseling Information

See FDA-approved Patient Labeling

Ocular Effects

Caution patients to avoid spraying the aerosol into their eyes and be advised that this may result in precipitation or worsening of narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Patients should also be advised that should any combination of these symptoms develop, they should consult their physician immediately.

Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of Biwind, 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 Biwind may cause urinary retention and should be advised to consult their physician if they experience difficulty with urination.

Frequency Of Use

The action of Biwind should last 4 to 5 hours or longer. Biwind should not be used more frequently than recommended. Safety and efficacy of additional doses of Biwind beyond six inhalations in 24 hours have not been studied. Patients should be told not to increase the dose or frequency of Biwind without consulting a physician. Patients should be instructed that if they find that treatment with Biwind 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 Biwind 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 Biwind inhaler and the unit is primed. Biwind 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 Biwind, other inhaled drugs should be taken only as directed by a physician.

Paradoxical Bronchospasm

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

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 Biwind.

FDA-approved Patient Labeling

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Ipratropium Bromide

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

Results of various mutagenicity/clastogenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test, and chromosome aberration of bone marrow in Chinese hamsters) were negative.

Fertility of male or female rats at oral doses up to 50 mg/kg/day (approximately 3400 times the MRHDID in adults on a mg/m² basis) was unaffected by ipratropium bromide administration. At an oral dose of 500 mg/kg/day (approximately 34,000 times the MRHDID in adults on a mg/m² basis), ipratropium bromide produced a decrease in the conception rate.

Albuterol

Like other agents in its class, albuterol caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium in a 2-year study in the rat at dietary doses of 2, 10, and 50 mg/kg/day (approximately 20, 110, and 560 times the MRHDID on a mg/m² basis). In another study this effect was blocked by the coadministration of propranolol. The relevance of these findings to humans is not known. An 18-month study in mice at dietary doses up to 500 mg/kg/day (approximately 2800 times the MRHDID on a mg/m² basis) and a 99-week study in hamsters at oral doses up to 50 mg/kg/day (approximately 470 times the MRHDID on a mg/m² basis) revealed no evidence of tumorigenicity. Studies with albuterol revealed no evidence of mutagenesis.

Reproduction studies in rats with albuterol sulfate revealed no evidence of impaired fertility.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C.

Biwind Inhalation Spray

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

Ipratropium bromide

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

Albuterol

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

Labor And Delivery

Because of the potential for beta-agonist interference with uterine contractility, use of Biwind for the treatment of COPD during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Nursing Mothers

It is not known whether the components of COMBIVENT RESPIMAT are excreted in human milk.

Ipratropium bromide

Because lipid-insoluble quaternary cations pass into breast milk, caution should be exercised when Biwind 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 Biwind in pediatric patients have not been established. Biwind is indicated for use in patients with COPD on a regular aerosol bronchodilator who continue to have evidence of bronchospasm and who require a second bronchodilator. This disease does not normally occur in children.

Geriatric Use

In the 12-week trial in COPD, 48% of Biwind 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 Biwind 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.

WARNINGS

1. Paradoxical Bronchospasm: COMBIVENT Inhalation Aerosol can produce paradoxical bronchospasm that can be life-threatening. If it occurs, the preparation should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister.
2. Cardiovascular Effect: The albuterol sulfate contained in COMBIVENT Inhalation Aerosol, 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, discontinuation of the drug may be indicated. 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 Inhalation Aerosol should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias and hypertension.
3. 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.
4. Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of ipratropium bromide or albuterol sulfate, as demonstrated by urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. If such a reaction occurs, therapy with COMBIVENT Inhalation Aerosol should be stopped at once and alternative treatment should be considered.
5. Storage Conditions: The contents of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw the container into a fire or incinerator. Keep out of reach of children.

PRECAUTIONS

General

1. Effects Seen with Anticholinergic Drugs: COMBIVENT Inhalation Aerosol contains ipratropium bromide and, therefore, should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction.
2. Effects Seen with Sympathomimetic Drugs: Preparations containing sympathomimetic amines such as albuterol sulfate should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines. Beta-adrenergic agents may also produce significant hypokalemia in some patients (possibly through intracellular shunting) which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.
3. Use in Hepatic or Renal Disease: COMBIVENT Inhalation Aerosol has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in those patient populations.

Information for Patients

Patients should be cautioned to avoid spraying the aerosol into their eyes and be advised that this may result in precipitation or worsening of narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Patients should also be advised that should any combination of these symptoms develop, they should consult their physician immediately.

The action of COMBIVENT Inhalation Aerosol should last 4 to 5 hours or longer. COMBIVENT Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of COMBIVENT Inhalation Aerosol without consulting your physician. If you find that treatment with COMBIVENT Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, medical attention should be sought immediately. While you are taking COMBIVENT Inhalation Aerosol, other inhaled drugs should be taken only as directed by your physician. If you are pregnant or nursing, contact your physician about use of COMBIVENT Inhalation Aerosol. Appropriate use of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol includes an understanding of the way it should be administered (see Patient's Instructions for Use).

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ipratropium bromide

Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to 6 mg/kg. This dose corresponds in rats and mice to approximately 230 and 110 times the maximum recommended daily inhalation dose of ipratropium bromide in adults, respectively, on a mg/m² basis. Results of various mutagenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test and chromosome aberration of bone marrow in Chinese hamsters) were negative.

Fertility of male or female rats at oral doses up to 50 mg/kg (approximately 1900 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) was unaffected by ipratropium bromide administration. At an oral dose of 500 mg/kg (approximately 19,000 times the maximum recommended daily inhalation dose in adults on a mg/m² basis), ipratropium bromide produced a decrease in the conception rate.

Albuterol

Like other agents in its class, albuterol caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium in a 2-year study in the rat at dietary doses of 2, 10, and 50 mg/kg (approximately 15, 65, and 330 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). In another study this effect was blocked by the co-administration of propranolol. The relevance of these findings to humans is not known. An 18-month study in mice at dietary doses up to 500 mg/kg (approximately 1600 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) and a 99-week study in hamsters at oral doses up to 50 mg/kg (approximately 220 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) revealed no evidence of tumorigenicity. Studies with albuterol revealed no evidence of mutagenesis.

Reproduction studies in rats with albuterol sulfate revealed no evidence of impaired fertility.

Pregnancy

COMBIVENT Inhalation Aerosol

Teratogenic Effects: Pregnancy Category C

Ipratropium bromide

Teratogenic Effects

Oral reproduction studies were performed at doses of 10 mg/kg in mice, 1000 mg/kg in rats, and 125 mg/kg in rabbits. These doses correspond in each species, respectively, to approximately 190, 38,000, and 9400 times the maximum recommended daily inhalation dose in adults on a mg/m² basis. Inhalation reproduction studies were conducted in rats and rabbits at doses of 1.5 and 1.8 mg/kg (approximately 55 and 140 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. At oral doses 90 mg/kg and above in rats (approximately 3,400 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) embryotoxicity was observed as increased resorption. This effect is not considered relevant to human use due to the large doses at which it was observed and the difference in route of administration.

Albuterol

Teratogenic Effects

Albuterol has been shown to be teratogenic in mice and rabbits. A reproduction study in CD-1 mice given albuterol subcutaneously (0.025, 0.25, and 2.5 mg/kg) showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (equivalent to the maximum recommended daily inhalation dose in adults on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately 8 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). None was observed at 0.025 mg/kg (less than the maximum recommended daily inhalation dose in adults). Cleft palate also occurred in 22 of 72 (30.5%) fetuses treated with 2.5 mg/kg isoproterenol (positive control). A reproduction study with oral albuterol in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses at 50 mg/kg (approximately 660 times the maximum recommended daily inhalation dose in adults on a mg/m² basis).

Labor and Delivery

Because of the potential for beta-agonist interference with uterine contractility, use of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol for the treatment of COPD during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Nursing Mothers

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

Ipratropium bromide

Because lipid-insoluble quaternary cations pass into breast milk, caution should be exercised when COMBIVENT Inhalation Aerosol 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 in the pediatric population have not been established.

WARNINGS

Paradoxical Bronchospasm

In the clinical study of Biwind (ipratropium bromide and albuterol sulfate) , paradoxical bronchospasm was not observed. However, paradoxical bronchospasm has been observed with both inhaled ipratropium bromide and albuterol products and can be life-threatening. If this occurs, Biwind (ipratropium bromide and albuterol sulfate) should be discontinued immediately and alternative therapy instituted.

Do Not Exceed Recommended Dose

Fatalities have been reported in association with excessive use of inhaled products containing sympathomimetic amines and with the home use of nebulizers.

Cardiovascular Effect

Biwind (ipratropium bromide and albuterol sulfate) , 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. Although such effects are uncommon for Biwind (ipratropium bromide and albuterol sulfate) at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta agonists have been reported to produce ECG changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, Biwind (ipratropium bromide and albuterol sulfate) , like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions to albuterol and/or ipratropium bromide may occur after the administration of Biwind (ipratropium bromide and albuterol sulfate) as demonstrated by rare cases of urticaria, angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, and anaphylaxis.

PRECAUTIONS

General

1. Effects Seen with Sympathomimetic Drugs: As with all products containing sympathomimetic amines, Biwind (ipratropium bromide and albuterol sulfate) should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous albuterol have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. Additionally, β-agonists may cause a decrease in serum potassium in some patients, possibly through intracellular shunting. The decrease is usually transient, not requiring supplementation.
2. Effects Seen with Anticholinergic Drugs: Due to the presence of ipratropium bromide in Biwind (ipratropium bromide and albuterol sulfate) , it should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction.
3. Use in Hepatic or Renal Disease: Biwind (ipratropium bromide and albuterol sulfate) has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in these patient populations.

Information for Patients

The action of Biwind (ipratropium bromide and albuterol sulfate) should last up to 5 hours. Biwind (ipratropium bromide and albuterol sulfate) should not be used more frequently than recommended. Patients should be instructed not to increase the dose or frequency of Biwind (ipratropium bromide and albuterol sulfate) without consulting their healthcare provider. If symptoms worsen, patients should be instructed to seek medical consultation.

Patients must avoid exposing their eyes to this product as temporary papillary dilation, blurred vision, eye pain, or precipitation or worsening of narrow-angle glaucoma may occur, and therefore proper nebulizer technique should be assured, particularly if a mask is used.

If a patient becomes pregnant or begins nursing while on Biwind (ipratropium bromide and albuterol sulfate) , they should contact their healthcare provider about use of Biwind.

See the illustrated Patient's Instruction for Use in the product package insert.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Albuterol sulfate

In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m² basis). In another study, this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist.

In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 140 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). In a 22-month study in Golden hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 20 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleous assay.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of albuterol sulfate up to 50 mg/kg (approximately 25 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

Ipratropium bromide

In 2-year studies in Sprague-Dawley rats and CD-1 mice, ipratropium bromide showed no evidence of tumorigenicity at oral doses up to 6 mg/kg (approximately 15 times and 8 times the maximum recommended daily inhalation dose for adults in rats and mice respectively, on a mg/m² basis).

Ipratropium bromide was not mutagenic in the Ames test and mouse dominant lethal test. Ipratropium bromide was not clastogenic in a mouse micronucleous assay.

A reproduction study in rats demonstrated decreased conception and increased resorptions when ipratropium bromide was administered orally at a dose of 90 mg/kg (approximately 240 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). These effects were not seen with a dose of 50 mg/kg (approximately 140 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

Pregnancy

Teratogenic Effects: Pregnancy Category C

Albuterol sulfate

Pregnancy Category C. Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice given albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m² basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis). Cleft palate formation also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg isoproterenol (positive control).

A reproduction study in Stride rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol was administered orally at a dose of 50 mg/kg (approximately 55 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, a relationship between albuterol use and congenital anomalies has not been established.

Ipratropium bromide

Pregnancy Category B. Reproduction studies in CD-1 mice, Sprague-Dawley rats and New Zealand rabbits demonstrated no evidence of teratogenicity at oral doses up to 10, 100, and 125 mg/kg, respectively (approximately 15, 270, and 680 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). Reproduction studies in rats and rabbits demonstrated no evidence of teratogenicity at inhalation doses up to 1.5 and 1.8 mg/kg, respectively (approximately 4 and 10 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). There are no adequate and well-controlled studies of the use of Biwind (ipratropium bromide and albuterol sulfate) , albuterol sulfate, or ipratropium bromide in pregnant women. Biwind (ipratropium bromide and albuterol sulfate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

Oral albuterol sulfate has been shown to delay preterm labor in some reports. Because of the potential of albuterol to interfere with uterine contractility, use of Biwind (ipratropium bromide and albuterol sulfate) during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

It is not known whether the components of Biwind (ipratropium bromide and albuterol sulfate) are excreted in human milk. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that ipratropium bromide would reach the infant to an important extent, especially when taken as a nebulized solution. Because of the potential for tumorigenicity shown for albuterol sulfate in some animals, a decision should be made whether to discontinue nursing or discontinue Biwind (ipratropium bromide and albuterol sulfate) , taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Biwind (ipratropium bromide and albuterol sulfate) in patients below 18 years of age have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of Biwind (ipratropium bromide and albuterol sulfate) , 62 percent were 65 and over, while 19 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

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

Albuterol is a component of Biwind.

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

• Ocular effects
• Urinary retention

Ipratropium bromide is a component of Biwind.

Clinical Trials Experience

Biwind 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 Biwind (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 Biwind. The Biwind 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 Biwind 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 Biwind Group in a 12-Week COPD Clinical Trial

Adverse reactions that occurred in < 2% in the Biwind (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 Biwind in 1118 COPD patients. Patients were randomized to Biwind (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 Biwind 20/100 mcg.

Biwind Long Term (48-week) Safety Trial

Long term chronic use safety data for Biwind were obtained from one 48-week, randomized, multi-center, open-label, parallel-group trial that compared Biwind (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 Biwind. The Biwind 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 Biwind 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 Biwind, adverse reaction information concerning CFC-propelled COMBIVENT Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for CFC-propelled COMBIVENT Inhalation Aerosol). Adverse reactions reported in ≥ 2% of patients in the CFC-propelled COMBIVENT Inhalation Aerosol treatment group include: bronchitis, upper respiratory tract infection, headache, dyspnea, cough, pain, respiratory disorder, sinusitis, pharyngitis and nausea. Adverse reactions reported in < 2% of patients in the CFC-propelled COMBIVENT Inhalation Aerosol treatment group include: edema, fatigue, hypertension, dizziness, nervousness, tremor, dysphonia, insomnia, diarrhea, dry mouth, dyspepsia, vomiting, arrhythmia, palpitation, tachycardia, arthralgia, angina, increased sputum, taste perversion, urinary tract infection, dysuria, dry throat and bronchospasm.

Post-Marketing Experience

In addition to the adverse reactions reported during clinical trials, the following adverse reactions have been identified during post approval use of CFC-propelled COMBIVENT Inhalation Aerosol. Since CFC-propelled Combivent Inhalation Aerosol and Biwind 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 Biwind. 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.

Adverse reaction information concerning Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for COMBIVENT Inhalation Aerosol) as seen in Table 1.

Table 1 : All Adverse Events (in percentages), from Two Large Double-blind, Parallel, 12-Week Studies of Patients with COPD*

Additional adverse reactions, reported in less than two percent of the patients in the COMBIVENT Inhalation Aerosol treatment group include edema, fatigue, hypertension, dizziness, nervousness, paresthesia, tremor, dysphonia, insomnia, diarrhea, dry mouth, dyspepsia, vomiting, arrhythmia, palpitation, tachycardia, arthralgia, angina, increased sputum, taste perversion, and urinary tract infection/dysuria.

Allergic-type reactions such as skin reactions including rash, pruritus, and urticaria (including giant urticaria), angioedema including that of tongue, lips and face, laryngospasm and anaphylactic reaction have been reported with Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol, with positive rechallenge in some cases. Many of these patients had a history of allergies to other drugs and/or foods including soybean (see CONTRAINDICATIONS).

Post-Marketing Experience

In a 5-year placebo-controlled trial, hospitalizations for supraventricular tachycardia and/or atrial fibrillation occurred with an incidence rate of 0.5% in COPD patients receiving Atrovent® (ipratropium bromide) Inhalation Aerosol CFC.

Additional side effects identified from the published literature and/or post-marketing surveillance on the use of ipratropium bromide-containing products (singly or in combination with albuterol), include: hypersensitivity, pharyngeal edema, mouth edema, urinary retention, mydriasis, bronchospasm (including paradoxical bronchospasm), cases of precipitation or worsening of narrow-angle glaucoma, glaucoma, intraocular pressure increased, acute eye pain, halo vision, blurred vision, accommodation disorder, ocular irritation, corneal edema, conjunctival hyperaemia, nasal congestion, drying of secretions, mucosal ulcers, stomatitis, irritation from aerosol, throat irritation, dry throat, wheezing, exacerbation of COPD symptoms, hoarseness, palpitations, heartburn, drowsiness, CNS stimulation, coordination difficulty, flushing, alopecia, hypotension, edema, gastrointestinal distress (diarrhea, nausea, vomiting), gastrointestinal motility disorder, constipation, hypokalemia, mental disorder, hyperhidrosis, muscle spasms, muscular weakness, myalgia, asthenia, myocardial ischemia, diastolic blood pressure decreased, and systolic blood pressure increased.

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

Adverse reaction information concerning Biwind (ipratropium bromide and albuterol sulfate) was derived from the 12-week controlled clinical trial.

ADVERSE EVENTS OCCURRING IN ≥ 1% OF ≥ 1 TREATMENT GROUP(S) AND WHERE THE COMBINATION TREATMENT SHOWED THE HIGHEST PERCENTAGE

Additional adverse reactions reported in more than 1% of patients treated with Biwind (ipratropium bromide and albuterol sulfate) included constipation and voice alterations.

In the clinical trial, there was a 0.3% incidence of possible allergic-type reactions, including skin rash, pruritus, and urticaria.

Additional information derived from the published literature on the use of albuterol sulfate and ipratropium bromide singly or in combination includes precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of COPD symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain, sore throat, and metabolic acidosis. Because these reactions 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.

Se espera que los efectos de la sobredosis estén relacionados principalmente con el sulfato de albuterol. La sobredosis aguda con bromuro de ipratropio por inhalación es poco probable ya que el bromuro de ipratropio no se absorbe bien sistémicamente después de la inhalación o la administración oral. Las manifestaciones de sobredosis con albuterol pueden incluir dolor anginal, hipertensión, hipocalemia, taquicardia con tasas de hasta 200 latidos por minuto, acidosis metabólica y exageración de los efectos farmacológicos enumerados en la sección Reacciones adversas. Al igual que con todos los medicamentos en aerosol beta-adrenérgicos, el paro cardíaco e incluso la muerte pueden estar asociados con el abuso. La diálisis no es un tratamiento apropiado para la sobredosis de albuterol como aerosol por inhalación; Se puede indicar el uso juicioso de un bloqueador cardiovascular del beta-receptor, como el tartrato de metoprolol.

Se espera que los efectos de la sobredosis estén relacionados principalmente con el sulfato de albuterol. La sobredosis aguda con bromuro de ipratropio por inhalación es poco probable ya que el bromuro de ipratropio no se absorbe bien sistémicamente después de la administración en aerosol u oral. Las dosis letales medias orales de bromuro de ipratropio fueron mayores a 1001 mg / kg en ratones (aproximadamente 19,000 veces la dosis máxima recomendada de inhalación diaria en adultos en mg / m²) 1663 mg / kg en ratas (aproximadamente 62,000 veces la dosis máxima recomendada de inhalación diaria en adultos en mg / m²) y 400 mg / kg en perros (aproximadamente 50,000 veces la dosis máxima recomendada de inhalación diaria en adultos, en mg / m² base). Mientras que la dosis letal media oral de sulfato de albuterol en ratones y ratas fue mayor a 2000 mg / kg (aproximadamente 6600 y 13,000 veces la dosis máxima recomendada de inhalación diaria, respectivamente, en adultos en mg / m²), la dosis letal media por inhalación No se pudo determinar. Las manifestaciones de sobredosis con albuterol pueden incluir dolor anginal, hipertensión, hipocalemia, taquicardia con tasas de hasta 200 latidos por minuto, acidosis metabólica y exageración de los efectos farmacológicos enumerados en las REACCIONES ADVERSAS. Como con todos los medicamentos simpaticomiméticos en aerosol, el paro cardíaco e incluso la muerte pueden estar asociados con el abuso. La diálisis no es un tratamiento apropiado para la sobredosis de albuterol como aerosol por inhalación; Se puede indicar el uso juicioso de un bloqueador cardiovascular del beta-receptor, como el tartrato de metoprolol.

Se espera que los efectos de la sobredosis con Biwind (bromuro de ipratropio y sulfato de albuterol) estén relacionados principalmente con el sulfato de albuterol, ya que el bromuro de ipratropio no se absorbe bien sistémicamente después de la administración oral o en aerosol. Los síntomas esperados con sobredosis son los de estimulación beta-adrenérgica excesiva y / o aparición o exageración de síntomas como las convulsiones, angina, hipertensión o hipotensión, taquicardia con velocidades de hasta 200 latidos por minuto, arritmia, nerviosismo, dolor de cabeza, temblor, boca seca, palpitación, náuseas, mareo, fatiga, malestar general, insomnio, y exageración de los efectos farmacológicos enumerados en REACCIONES ADVERSAS. La hipocalemia también puede ocurrir. Al igual que con todos los medicamentos simpaticomiméticos para aerosoles, el paro cardíaco e incluso la muerte pueden estar asociados con el abuso de Biwind (bromuro de ipratropio y sulfato de albuterol). El tratamiento consiste en la interrupción de Biwind (bromuro de ipratropio y sulfato de albuterol) junto con la terapia sintomática adecuada. Se puede considerar el uso juicioso de un bloqueador cardioselectivo del beta-receptor, teniendo en cuenta que dicho medicamento puede producir broncoespasmo. No hay pruebas suficientes para determinar si la diálisis es beneficiosa para la sobredosis de Biwind (bromuro de ipratropio y sulfato de albuterol).

La dosis letal media oral de sulfato de albuterol en ratones es superior a 2000 mg / kg (aproximadamente 540 veces la dosis máxima recomendada de inhalación diaria de Biwind (bromuro de ipratropio y sulfato de albuterol) en mg / m²). La dosis letal media subcutánea de sulfato de albuterol en ratas maduras y ratas jóvenes pequeñas es de aproximadamente 450 y 2000 mg / kg respectivamente (aproximadamente 240 y 1100 veces la dosis máxima recomendada de inhalación diaria de Biwind (bromuro de ipratropio y sulfato de albuterol) en mg / m² base, respectivamente). La dosis letal media de inhalación no se ha determinado en animales. La dosis letal media oral de bromuro de ipratropio en ratones, ratas y perros es mayor que 1000 mg / kg, aproximadamente 1700 mg / kg y aproximadamente 400 mg / kg, respectivamente (aproximadamente 1400, 4600 y 3600 veces la dosis diaria máxima recomendada de inhalación en adultos en mg / m², respectivamente).

Bromuro de ipratropio

El bromuro de ipratropio es una amina cuaternaria y, por lo tanto, no se absorbe fácilmente en la circulación sistémica ni desde la superficie del pulmón ni desde el tracto gastrointestinal, como lo confirman los estudios de nivel sanguíneo y excreción renal.

La vida media de eliminación es de aproximadamente 2 horas después de la inhalación o la administración intravenosa. El bromuro de ipratropio se une mínimamente (0% a 9% in vitro) a la albúmina plasmática y a la α₁-glicoproteína ácida. Se metaboliza parcialmente a productos de hidrólisis de éster inactivo. Después de la administración intravenosa, aproximadamente la mitad de la dosis se excreta sin cambios en la orina.

Sulfato de albuterol

El albuterol actúa más tiempo que el isoproterenol en la mayoría de los pacientes porque no es un sustrato para los procesos de absorción celular de catecolaminas, ni para el metabolismo por catecol-O-metil transferasa. En cambio, el fármaco se metaboliza conjugativamente a albuterol 4'-O-sulfato.

Se estudió la farmacocinética intravenosa de albuterol en un grupo comparable de 16 voluntarios varones sanos; La vida media terminal media después de una infusión de 30 minutos de 1,5 mg fue de 3,9 horas con un aclaramiento medio de 439 ml / min / 1,73 m².

Spray de inhalación de viento

En un ensayo grupal paralelo aleatorizado, multicéntrico, doble ciego, doble simulado de 12 semanas, 108 pacientes estadounidenses con EPOC que recibieron Biwind (20/100 mcg) o Erosol de inhalación COMBIVENTE impulsado por CFC (36/206 mcg) cuatro veces al día participó en evaluaciones farmacocinéticas. Las concentraciones plasmáticas de ipratropio fueron bajas con una concentración plasmática máxima promedio de 33.5 pg / ml de Biwind. La mayoría de los participantes del estudio exhibieron niveles por debajo del límite inferior de cuantificación (<10 pg / ml) entre 4 y 6 horas después de la dosificación. La exposición sistémica en estado estacionario obtenida para el bromuro de ipratropio después de Biwind fue comparable a la del aerosol de inhalación COMBIVENTE impulsado por CFC. El AUC plasmático de ipratropio y la cantidad total de fármaco excretado sin cambios en las proporciones de orina (Ae) para el COMBIVENTE RESPIMAT / COMBIVENTE propulsado por CFC Inhalation Aerosol fueron 1.04 y 1.18, respectivamente. Para el albuterol, la exposición sistémica en estado estacionario fue menor que la de Biwind en comparación con la de la aerosol de inhalación COMBIVENTE propulsada por CFC. AUC plasmático de albuterol y orina Las relaciones Ae para RESPIMAT COMBIVENTE / COMBIVENTE propulsado por CFC Inhalación Aerosol fueron 0.74 y 0.86, respectivamente.

La interacción farmacocinética fármaco-fármaco entre el bromuro de ipratropio y el sulfato de albuterol se evaluó en un estudio cruzado en 12 voluntarios varones sanos que recibieron aerosol de inhalación COMBIVENTE impulsado por CFC y los dos componentes activos por separado como tratamientos individuales. Los resultados de este estudio indicaron que la administración conjunta de estos dos componentes de un solo recipiente no alteró significativamente la absorción sistémica de ninguno de los componentes, lo que indica la falta de interacción farmacocinética entre estos dos medicamentos.

Bromuro de ipratropio

Gran parte de una dosis administrada se ingiere como lo demuestran los estudios de excreción fecal. El bromuro de ipratropio es una amina cuaternaria. No se absorbe fácilmente en la circulación sistémica ni desde la superficie del pulmón ni desde el tracto gastrointestinal, como lo confirman los estudios de nivel sanguíneo y excreción renal. Los niveles plasmáticos de bromuro de ipratropio estaban por debajo del límite de sensibilidad del ensayo de 100 pg / ml

La vida media de eliminación es de aproximadamente 2 horas después de la inhalación o la administración intravenosa. El bromuro de ipratropio se une mínimamente (0 a 9% in vitro) a la albúmina plasmática y a la glucoproteína ácida α1. Se metaboliza parcialmente a productos de hidrólisis de éster inactivo. Después de la administración intravenosa, aproximadamente la mitad de la dosis se excreta sin cambios en la orina. Los estudios autorradiográficos en ratas han demostrado que el bromuro de ipratropio no penetra en la barrera hematoencefálica.

Sulfato de albuterol

El albuterol actúa más tiempo que el isoproterenol en la mayoría de los pacientes porque no es un sustrato para los procesos de absorción celular de catecolaminas ni para el metabolismo por catecol-O-metil transferasa. En cambio, el fármaco se metaboliza conjugativamente a albuterol 4'-O-sulfato.

En un estudio farmacocinético en 12 voluntarios varones sanos de dos inhalaciones de sulfato de albuterol, dosis de 103 mcg / inhalación a través de la boquilla, se obtuvieron concentraciones máximas de albuterol en plasma que van desde 419 a 802 pg / ml (media 599 ± 122 pg / ml) dentro de las tres horas posteriores a la administración. Después de esta administración de dosis única, 30.8 ± 10.2% de la dosis estimada de la boquilla se excretó sin cambios en la orina de 24 horas. Dado que el sulfato de albuterol se absorbe rápida y completamente, este estudio no pudo distinguir entre absorción pulmonar y gastrointestinal.

Se estudió la farmacocinética intravenosa de albuterol en un grupo comparable de 16 voluntarios varones sanos; La vida media terminal media después de una infusión de 30 minutos de 1,5 mg fue de 3,9 horas con un aclaramiento medio de 439 ml / min / 1,73 m².

Los estudios de albuterol intravenoso en ratas demostraron que el albuterol cruzó la barrera hematoencefálica y alcanzó concentraciones cerebrales que representan aproximadamente el 5% de las concentraciones plasmáticas. En estructuras fuera de la barrera hematoencefálica (glándulas pineales y pituitarias), el fármaco alcanzó concentraciones más de 100 veces mayores que en todo el cerebro.

Los estudios en ratas preñadas con albuterol tritiado demostraron que aproximadamente el 10% de la droga materna circulante se transfirió al feto. La disposición en los pulmones fetales fue comparable a los pulmones maternos, pero la disposición del hígado fetal fue del 1% de los niveles del hígado materno.

Los estudios en animales de laboratorio (minipigs, roedores y perros) han demostrado la aparición de arritmias cardíacas y muerte súbita (con evidencia histológica de necrosis miocárdica) cuando se administraron beta-agonistas y metilxantinas simultáneamente. Se desconoce la importancia de estos hallazgos cuando se aplica a humanos.

COMBIVENTE Inhalación Aerosol

En un estudio farmacocinético cruzado en 12 voluntarios varones sanos que comparan el patrón de absorción y excreción de dos inhalaciones de Combivent® (bromuro de ipratropio y sulfato de albuterol) Inhalación de aerosol a los dos componentes activos individualmente, La administración conjunta de bromuro de ipratropio y sulfato de albuterol de un solo recipiente no alteró significativamente la absorción sistémica de ninguno de los componentes.

Los niveles de bromuro de ipratropio se mantuvieron por debajo de los límites detectables (<100 pg / ml). El nivel máximo de albuterol obtenido dentro de las 3 horas posteriores a la administración fue de 492 ± 132 pg / ml. Después de esta administración única, 27.1 ± 5.7% de la dosis estimada de la boquilla se excretó sin cambios en la orina de 24 horas. Desde una perspectiva farmacocinética, es probable que la eficacia sinérgica de COMBIVENT Inhalation Aerosol se deba a un efecto local sobre la muscarínica y la beta₂-receptores adrenérgicos en el pulmón.