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ipratropium 0.03% spray generic atrovent

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Uses

Bronchospasm

Ipratropium bromide is used for the symptomatic treatment of reversible bronchospasm that may occur in association with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Ipratropium bromide in fixed combination with albuterol sulfate is used by oral inhalation for the symptomatic management of bronchospasm associated with COPD in patients who continue to have evidence of bronchospasm despite the regular use of an orally inhaled bronchodilator and who require a second bronchodilator. Ipratropium bromide also is used for the symptomatic treatment of bronchial asthma and for the prevention of exercise-induced bronchospasm, and also has been used as a bronchodilator in patients with cystic fibrosis.

Chronic Obstructive Pulmonary Disease

Ipratropium bromide is used as a bronchodilator for the long-term symptomatic treatment of reversible bronchospasm associated with COPD, including chronic bronchitis and emphysema. Orally inhaled ipratropium is not indicated as a single agent for the initial treatment of acute episodes of bronchospasm or acute exacerbations of COPD; a drug with a more rapid onset of action (e.g., a β2-adrenergic agonist) may be preferred in such cases.(See Cautions: Precautions and Contraindications.) However, some clinicians consider combined therapy with a β2-agonist bronchodilator and ipratropium to be useful in selected patients with acute exacerbations of COPD.

The efficacy of ipratropium has been similar to or greater than that of β2-adrenergic agonists (e.g., albuterol, metaproterenol) in comparative studies in which these drugs were administered via metered-dose inhaler or nebulization. As orally inhaled ipratropium produces fewer adverse effects than these drugs, ipratropium is a first-line maintenance bronchodilator for relief of chronic (e.g., daily) symptoms of bronchospasm in patients with mild COPD. However, in a few long-term studies comparing ipratropium bromide and tiotropium bromide, another long-acting orally inhaled anticholinergic agent, ipratropium bromide (36 mcg 4 times daily) oral inhalation aerosol with chlorofluorocarbon (CFC) propellants (preparation with CFC propellants no longer commercially available in the US) was less effective than tiotropium (18 mcg once daily) in improving lung function (e.g., as determined by changes in forced expiratory volume in 1 second [FEV1] and peak expiratory flow rate [PEFR]) in patients with COPD. Short-term (e.g., 3-month) controlled studies indicate that the fixed combination of albuterol and ipratropium results in greater bronchodilation following oral inhalation than either agent given alone in patients with COPD.

The efficacy and safety of ipratropium bromide with a hydrofluoroalkane propellant (Atrovent HFA) have been shown to be comparable to that of ipratropium bromide with chlorofluorocarbon propellants (Atrovent, no longer commercially available in the US) in patients with COPD. In 2 randomized, comparative clinical trials in patients with COPD, therapy with ipratropium bromide inhalation aerosol with a hydrofluoroalkane (HFA) propellant (Atrovent HFA 34 or 68 mcg [dose delivered from the mouthpiece] 4 times daily) produced similar improvements in FEV1 and forced vital capacity (FVC) over the 12-week study period and had similar adverse effects as therapy with ipratropium bromide with chlorofluorocarbon propellants (Atrovent 36 mcg [dose delivered from the mouthpiece] 4 times daily). In one of these studies, the mean peak improvement in FEV1 relative to baseline on day 85 of therapy (one of the primary end points) was 0.295 L after a single dose of Atrovent HFA (34 mcg or 2 inhalations) compared with 0.14 L observed with placebo (HFA propellant vehicle only).

Administration of nebulized ipratropium generally is reserved for patients with severe disease who do not respond adequately to conventional therapy and for those who find it difficult or are unable to optimally inhale the drug orally via a metered-dose inhaler.

In the stepped-care approach to COPD drug therapy, mild intermittent symptoms and minimal lung impairment (e.g., FEV1 at least 80% of predicted) can be treated with a short-acting selective inhaled β2-agonist as needed during acute exacerbations, but use should not exceed 8-12 inhalations daily. Alternatively, some clinicians initiate therapy with ipratropium inhalation aerosol. Patients with COPD who receive orally inhaled ipratropium generally have an increase in FEV1 (at its peak) of 0.15-0.36 L and a decrease in functional residual capacity of 0.3-0.6 L. Although ipratropium produces objective bronchodilation (i.e., increase in FEV1 and FVC) in patients with COPD, a beneficial effect on subjective symptom or quality-of-life scores has not been demonstrated in short-term (e.g., 3-month) clinical studies, and current evidence indicates that ipratropium therapy does not alter the disease process (neither accelerates nor slows the age-related decline in FEV1 associated with COPD).

Low- to high-dose ipratropium bromide (6-16 inhalations daily) can be added to therapy with a selective β2-agonist in patients with mild to moderate symptoms of COPD, with the frequency of inhalation dosing with either agent not to exceed 4 times daily; the highest dosage of ipratropium bromide included in some guidelines for COPD exceeds the manufacturer's recommended maximum daily dosage (12 inhalations). Therapy with anticholinergic and/or β2-adrenergic agonist bronchodilators increases airflow and exercise tolerance and reduces dyspnea in patients with symptoms of COPD, and these drugs are used in the long-term management of airflow limitation in such patients. The mean peak FEV1 increase was 0.37 L following short-term (approximately 3 months) administration of the fixed combination of albuterol sulfate (180 mcg as albuterol base) and ipratropium bromide monohydrate (36 mcg) 4 times daily. The fixed combination of ipratropium and albuterol did not affect morning PEFR after short-term administration (i.e., less than 3 months) in these patients.

Current evidence indicates that concomitant or sequential administration of inhaled ipratropium and an inhaled β2-adrenergic agonist in patients with COPD generally produces additional bronchodilation compared with that achieved with either agent alone. Although the improvement in bronchodilation produced by combined therapy with ipratropium and a β2-adrenergic agonist often may not exceed that which could be achieved with larger dosages of either agent alone, the duration of bronchodilation appears to be increased with such concomitant therapy, and the potential for adverse effects also may be minimized. The sequence of administration of ipratropium and a short-acting β2-agonist generally does not alter the effectiveness of the bronchodilating action.

Home management of COPD exacerbations involves increasing the dose and/or frequency of existing short-acting bronchodilator therapy, preferably with a B2-adrenergic agonist. If response to a short-acting β2-adrenergic agonist alone is inadequate, some clinicians recommend the addition of ipratropium. In a severe exacerbation treated at home, administration of these agents by nebulization or metered-dose inhalation with a spacer device may be used as needed for short-term therapy.

Following initiation of oxygen therapy in hospitalized patients with COPD, therapy with a short-acting β2-adrenergic agonist and/or ipratropium (administered separately or in fixed combination) should be used for acute exacerbations of COPD, although the effectiveness of such combination therapy remains controversial.

Asthma

Orally inhaled ipratropium bromide has been used effectively for the symptomatic treatment of acute or chronic bronchial asthma and can potentiate the bronchodilatory effects of β2-adrenergic agonists, but the precise role of the drug in the management of this condition remains to be more fully elucidated. Ipratropium is suggested by some experts as an alternative to short-acting inhaled β2-agonists for relief of asthma symptoms, particularly in patients who experience adverse effects with β2-adrenergic agonists. However, the efficacy of ipratropium in the long-term management of asthma has not been established. Because the onset of action of ipratropium is slower than that of β2-adrenergic agonist bronchodilators and the peak bronchodilator effects generally are less pronounced, β2-adrenergic agonist bronchodilators generally are preferred initially for the symptomatic relief of bronchospasm in patients with asthma. Current guidelines for the management of asthma and many clinicians recommend concomitant anti-inflammatory therapy with orally inhaled corticosteroids as first-line therapy for long-term management of asthma in adults and children whose symptoms are not controlled by intermittent use of a short-acting β2-adrenergic agonist alone. For additional information on the stepped-care approach for drug therapy in asthma,.

Orally inhaled, selective short-acting β2-adrenergic agonists currently are recommended by an expert panel of the National Asthma Education and Prevention Program (NAEPP) for prehospital management of asthma exacerbations (e.g., in emergency medicine facilities and/or ambulances). During prolonged emergency transport, NAEPP recommends that other asthma therapies such as ipratropium bromide and oral corticosteroids also be available for use. In patients with acute exacerbations of asthma, ipratropium generally has been reserved for use as an adjunct to other therapy, usually in combination with a β2-adrenergic agonist bronchodilator. Because of its delayed onset, ipratropium generally should not be used alone for the management of acute bronchospasm, particularly if a prompt response is required. Some clinicians suggest that adjunctive therapy with ipratropium be considered in the emergency department in patients with moderate or severe exacerbations (peak expiratory flow [PEF] 60-80% or less than 60%, respectively, of predicted or personal best) of asthma who fail to respond adequately to β2-adrenergic agonists and corticosteroids. NAEPP recommends adjunctive therapy with ipratropium (via nebulization or a metered-dose inhaler) and oral corticosteroids in patients with severe asthma exacerbations (FEV1 or PEF less than 40% of predicted or personal best) who fail to respond adequately to short-acting, inhaled β2-agonists. In patients with impending respiratory failure in the emergency department, ipratropium in combination with a short-acting β2-adrenergic agonist (via nebulization) and an IV corticosteroid is recommended. In certain children with acute exacerbations of asthma, some evidence suggests that orally inhaled ipratropium (via nebulization) in conjunction with an orally inhaled β2-adrenergic agonist (via nebulization) may be more effective than therapy with the β2-agonist alone; in one study in children with severe acute asthma, children with the most severe bronchospasm (defined as baseline FEV1 not exceeding 30% of predicted) who received via nebulization repeated doses of ipratropium in conjunction with albuterol were less likely to require hospitalization or additional bronchodilator therapy than children receiving albuterol alone. However, ipratropium does not appear to confer additional benefit in children once they have been hospitalized and treated with an intensive regimen including a nebulized β2-agonist and systemic corticosteroids. Based on such data in children, NAEPP recommends discontinuance of ipratropium upon hospitalization for severe asthma exacerbations for patients of all age groups.

The benefit of maintenance therapy with ipratropium in patients with chronic asthma remains to be elucidated, but the drug may be useful as alternative therapy in adults experiencing adverse effects (e.g., tachycardia, arrhythmia, tremor) with a β2-adrenergic agonist. Some experts currently consider orally inhaled anticholinergics to have a limited role or no role in the long-term management of asthma in children because of a lack of data on safety and efficacy.

Orally inhaled ipratropium may be particularly useful for preventing or reversing bronchospasm induced by β2-adrenergic blocking agents (e.g., propranolol) in asthmatic patients; β2-adrenergic bronchodilators generally are ineffective for this indication in such patients.

Prevention of Exercise-Induced Bronchospasm

Although orally inhaled ipratropium bromide has been effective in the prevention of exercise-induced asthma in a limited number of patients, orally inhaled β2-adrenergic agonists are considered first-line agents in the management of this condition.

Cystic Fibrosis

Orally inhaled ipratropium bromide has produced bronchodilation (i.e., increase in FEV1) in a limited number of patients with cystic fibrosis, but additional studies are needed to determine the clinical usefulness of such therapy in these patients.

Other Uses

Ipratropium also has been used in a limited number of patients to minimize increases in lung resistance following anesthetic induction and tracheal intubation; to protect against bronchoconstriction in patients undergoing fiberoptic bronchoscopy; and to improve pulmonary function in ventilator-dependent patients, including preterm infants. In a few patients with COPD and myasthenia gravis, ipratropium has been used to counteract the bronchoconstriction and the increase in respiratory secretions associated with cholinesterase inhibitor (e.g., pyridostigmine) therapy in these patients.

Ipratropium bromide is used as a 0.03% nasal spray for the symptomatic relief of rhinorrhea associated with allergic and nonallergic perennial rhinitis in adults and children 6 years of age or older. The drug also is used as a 0.06% nasal spray for the symptomatic relief of rhinorrhea associated with the common cold in adults and children 5 years of age or older.

Dosage and Administration

Administration

Ipratropium bromide is administered by oral inhalation using an oral aerosol inhaler or via nebulization. Ipratropium bromide is administered in fixed combination with albuterol sulfate via a metered-dose aerosol inhaler or via nebulization. Patients should be advised that ipratropium must be used consistently throughout the course of therapy for maximum benefit. In addition, patients should be advised that the drug will not provide immediate symptomatic relief and should not be used for the relief of acute bronchospasm.

Oral Inhalation via Metered-Dose Aerosol

Ipratropium Bromide

Patients should be instructed carefully in the use of the ipratropium bromide metered-dose inhaler. To obtain optimum results, patients also should be given a copy of the patient instructions provided by the manufacturer. The aerosol inhaler should be actuated twice prior to the initial use or if it has not been used for more than 3 days. To avoid inadvertent contact of the drug with the eyes and subsequent adverse effects, patients should be advised to close their eyes during inhalation of ipratropium aerosol; it also has been suggested that ipratropium aerosol not be administered using the open-mouth technique in patients at high risk for ocular toxicity.(See Cautions: Precautions and Contraindications and also see Cautions: Ocular Effects.)

After the patient exhales slowly and completely, the inhaler should be held upright and the mouthpiece of the inhaler placed well into the mouth with the lips closed firmly around it. The patient should then inhale slowly and deeply through the mouth while actuating the inhaler. After holding the breath for 10 seconds, the patient should remove the mouthpiece and exhale slowly. If additional inhalations are required, the patient should wait at least 15 seconds and repeat the procedure. The manufacturer recommends that the ipratropium oral inhaler be cleaned at least once a week by removing the canister and dust cap from the mouthpiece and rinsing the mouthpiece in warm water for at least 30 seconds; nothing other than water should be used to wash the mouthpiece. The mouthpiece should be dried by shaking off the excess water and allowing the mouthpiece to air dry. When the mouthpiece is dry, the mouthpiece and the canister should be reassembled; patients should make sure that the canister is fully inserted into the mouthpiece.

Ipratropium Bromide and Albuterol Sulfate

Patients should insert the metal canister into the clear end of the mouthpiece. The aerosol inhaler should be shaken well for at least 10 seconds immediately prior to use and should be actuated 3 times prior to the initial use or if it has not been used for more than 24 hours. The mouthpiece provided for the inhalation aerosol of ipratropium bromide and albuterol sulfate should not be used for other aerosol drugs. Prior to use, the orange dust cap should be removed and the mouthpiece should be checked for foreign objects. Patients should avoid spraying ipratropium bromide and albuterol sulfate inhalation aerosol into their eyes. To avoid inadvertent contact of the drug with the eyes and subsequent adverse effects (e.g., temporary blurred vision, precipitation or worsening of narrow-angle glaucoma, ocular pain), patients should be advised to close their eyes during inhalation of ipratropium bromide and albuterol sulfate aerosol.(See Cautions: Precautions and Contraindications and also see Cautions: Ocular Effects.)

The patient should exhale deeply within 30 seconds of shaking the aerosol inhaler and the mouthpiece of the inhaler should be placed into the mouth with the canister held upright. The patient should then inhale slowly and deeply through the mouth while actuating the inhaler. After holding the breath for 10 seconds, the patient should remove the mouthpiece and exhale slowly. If additional inhalations are required, the patient should wait approximately 2 minutes and repeat the procedure. The manufacturer recommends that the ipratropium bromide and albuterol sulfate oral inhaler mouthpiece be cleaned as needed by rinsing the mouthpiece in hot water. If soap is used, the mouthpiece should be rinsed thoroughly with plain water. When dry, the cap on the mouthpiece should be replaced when the inhaler is not in use.

Oral Inhalation via Nebulization

Ipratropium Bromide

Prior to administration of ipratropium bromide inhalation solution for nebulization, the nebulizer manufacturer's information should be reviewed to ensure thorough familiarity with the use and maintenance of the nebulizer. For administration of ipratropium bromide alone via a nebulizer, the entire contents of the single-use vial of solution should be emptied into the nebulizer reservoir and the reservoir attached to the mouthpiece or face mask and to the compressor according to the manufacturer's instructions. When a face mask is used to deliver the drug during nebulization, care should be taken to avoid leakage around the mask because transient blurred vision and other adverse effects may result if the drug enters the eyes.(See Cautions: Ocular Effects.) To avoid inadvertent entry of drug into the eye, it may be preferable to administer nebulized ipratropium bromide using a mouthpiece rather than a face mask.

The patient should place the mouthpiece of the nebulizer between the teeth and on top of the tongue and close the lips firmly around it, taking care not to block the airflow from the mouthpiece with the tongue. The patient should then breathe through the mouthpiece as calmly, deeply, and evenly as possible until the nebulizer stops producing mist. The duration of treatment for oral inhalation of a full dose of ipratropium usually is about 5-15 minutes. The nebulizer should be cleaned after use according to the manufacturer's instructions.

Ipratropium bromide inhalation solution contains no preservatives; the manufacturer states that once the single-use vial is opened, the entire contents must be used or the remainder discarded. When ipratropium bromide is mixed extemporaneously in a nebulizer with albuterol sulfate, metaproterenol sulfate, or cromolyn sodium solution for oral inhalation, the resulting solutions are stable for 1 hour; the manufacturer states that the drug stability and safety of ipratropium bromide inhalation solution mixed with other drugs in a nebulizer have not been established.

Ipratropium Bromide and Albuterol Sulfate

Prior to administration of ipratropium bromide and albuterol sulfate inhalation solution for nebulization, the nebulizer manufacturer's information should be reviewed to assess any changes in administration. For administration of ipratropium bromide in fixed combination with albuterol sulfate (DuoNeb) via a nebulizer, the entire contents of the single-use vial of solution should be emptied into the nebulizer reservoir and the reservoir attached to the mouthpiece or face mask and to the compressor according to the manufacturer's instructions.

The patient should place the mouthpiece of the nebulizer into the mouth. Alternatively, patients may put the face mask over the mouth and nose. The patient should then breathe through the mouth as calmly, deeply, and evenly as possible until the nebulizer stops producing mist. The duration of treatment for oral inhalation of a full dose of ipratropium and albuterol sulfate in fixed combination usually is about 5-15 minutes. The nebulizer should be cleaned after use according to the manufacturer's instructions.

Dosage

Oral Inhalation via Metered-Dose Aerosol

Dosage of ipratropium bromide oral inhalation aerosol (Atrovent HFA) is expressed in terms of the monohydrate. Dosage of ipratropium bromide in fixed combination with albuterol sulfate is expressed in terms of the monohydrate and dosage of albuterol sulfate is expressed in terms of albuterol.

While some published studies and manufacturers have reported a dose of 20-21 mcg of ipratropium bromide per metered spray, this is the amount released from the valve stem during actuation of the inhaler; the dose of ipratropium bromide alone or in fixed combination with albuterol sulfate delivered to the patient through the mouthpiece (actuator) is approximately 17 or 18 mcg, respectively, per metered spray. The commercially available aerosols deliver 200 metered sprays per canister. The actual amount of drug delivered to the lung via a metered-dose aerosol inhaler may depend on patient factors, such as coordination between actuation of the device and inspiration through the delivery system. The inhaler should be discarded after 200 sprays have been used.

COPD

For the management of bronchospasm associated with COPD, the usual initial dosage of ipratropium bromide administered via a metered-dose aerosol (Atrovent HFA) in adults is 34 mcg (2 inhalations) 4 times daily. If necessary, additional inhalations of ipratropium bromide may be used. The manufacturer of Atrovent HFA states that the dosage of ipratropium bromide should not exceed 204 mcg (12 inhalations) in 24 hours, although some clinicians suggest that even higher dosages of ipratropium bromide (up to 6 inhalations 4 times daily) may be used without notable adverse effects. The manufacturer recommends that 15 seconds elapse between successive inhalations of ipratropium.

The usual initial dosage of ipratropium bromide administered in fixed combination with albuterol sulfate (90 mcg of albuterol base per inhalation) via a metered-dose aerosol (Combivent) in adults is 36 mcg (2 inhalations) 4 times daily. If necessary, additional inhalations of ipratropium bromide combined with albuterol sulfate may be used. The manufacturer recommends that approximately 2 minutes elapse between successive inhalations of ipratropium in fixed combination with albuterol. Since fatalities have been reported in association with excessive use of inhaled β2-adrenergic agents in patients with asthma, the manufacturer of the fixed combination of ipratropium bromide and albuterol sulfate recommends not exceeding 12 inhalations (216 mcg of ipratropium bromide) in 24 hours.

When COPD symptoms are not controlled with ipratropium alone or in fixed combination with albuterol (e.g., if there is a need to increase the dose or frequency of administration of the drug), medical assistance should be sought immediately. The dose or frequency of administration of ipratropium alone or in fixed combination with albuterol should not be increased without consultation with a clinician.

Asthma

For initial management of severe asthma exacerbations (forced expiratory volume in 1 second [FEV1] or peak expiratory flow [PEF] of less than 40% of predicted or personal best) in the emergency department in adolescents 12 years of age or older and adults receiving ipratropium bromide as the metered-dose aerosol (Atrovent HFA), an expert panel of the National Asthma Education and Prevention Program (NAEPP) recommends a dose of 136 mcg (8 inhalations, 17 mcg per inhalation) every 20 minutes as needed for up to 3 hours, given in conjunction with a short-acting inhaled β2-adrenergic agonist (administered separately). In children younger than 12 years of age with severe asthma exacerbations, NAEPP recommends an ipratropium bromide dose of 68-136 mcg (4-8 inhalations, 17 mcg per inhalation) as the metered-dose aerosol every 20 minutes as needed for up to 3 hours, given in conjunction with a short-acting inhaled β2-adrenergic agonist (administered separately).

For initial management of severe asthma exacerbations (FEV1 or PEF of less than 40% of predicted or personal best) in the emergency department in adolescents 12 years of age or older and adults receiving the fixed combination of ipratropium bromide and albuterol sulfate (90 mcg of albuterol base per inhalation) as the metered-dose aerosol, NAEPP recommends an ipratropium bromide dose of 144 mcg (8 inhalations, 18 mcg per inhalation) every 20 minutes as needed for up to 3 hours. For initial management of severe asthma exacerbations in children younger than 12 years of age, NAEPP recommends an ipratropium bromide dose of 72-144 mcg (4-8 inhalations, 18 mcg per inhalation) every 20 minutes as needed for up to 3 hours.

Oral Inhalation via Nebulization

Dosage of ipratropium bromide inhalation solution for nebulization is expressed in terms of anhydrous drug. Dosage of ipratropium bromide in fixed combination with albuterol sulfate (as albuterol base) for nebulization is expressed as the monohydrate. Using in vitro testing at an average flow rate of 3.6 L per minute for an average of 15 minutes or less, the Pari-LC Plus nebulizer delivered at the mouthpiece approximately 46 or 42% of the original dosage of albuterol or ipratropium bromide, respectively.

COPD

For administration via a nebulizer, the usual dosage of ipratropium bromide in adults with COPD is 500 mcg 3 or 4 times daily (i.e., every 6-8 hours). To administer 500 mcg of the drug, the contents of a single-use vial (2.5 mL) of the commercially available 0.02% solution of ipratropium bromide may be used.

The usual dosage of ipratropium bromide in fixed combination with albuterol sulfate (as 2.5 mg of albuterol base) for nebulization (DuoNeb) in adults with COPD is 500 mcg 4 times daily, with up to 2 additional inhalations allowed daily. The flow rate of the nebulizer should be adjusted so that the dose is delivered over a period of approximately 5-15 minutes. The manufacturer of DuoNeb recommends not exceeding 6 inhalations daily since such dosages have not been studied for the treatment of COPD.

Asthma

For initial management of severe asthma exacerbations in the emergency department, an expert panel of the NAEPP recommends an ipratropium bromide dosage of 500 mcg via nebulization every 20 minutes for 3 doses initially (i.e., for the first hour) in adults and adolescents 12 years of age or older in conjunction with a short-acting inhaled β2-adrenergic agonist. For initial management of severe asthma exacerbations in children younger than 12 years of age, 250-500 mcg of ipratropium bromide may be given via nebulization every 20 minutes for 3 doses initially (i.e., for the first hour), in conjunction with a short-acting inhaled β2-adrenergic agonist. Alternatively, ipratropium bromide via nebulization may be used continuously for the first hour after admittance to the emergency department in patients with severe asthma exacerbations. If there is no improvement after the first hour of treatment, ipratropium bromide in conjunction with a short-acting inhaled β2-adrenergic agonist may be continued for no more than 2 additional hours for a total duration of 3 hours in the emergency department, with the frequency of administration after the first hour based on improvement in airflow obstruction and other symptoms and occurrence of adverse effects. Similarly, if a severe exacerbation develops after the first hour of treatment with a short-acting β2-adrenergic agonist and an oral corticosteroid, ipratropium bromide in conjunction with a short-acting inhaled β2-adrenergic agonist may be initiated and continued for no more than 2 additional hours. If the patient is admitted to the hospital, ipratropium bromide should be discontinued since benefit of the drug in conjunction with short-acting inhaled β2-adrenergic agonist therapy (e.g., albuterol) has not been established once patients with severe asthma exacerbations are hospitalized.

Cautions

Adverse effects reported with orally inhaled ipratropium bromide are similar to those reported with other antimuscarinic drugs; however, because of the drug's limited systemic absorption, oral inhalation of ipratropium bromide produces anticholinergic adverse effects (e.g., increased intraocular pressure, mydriasis, urinary retention) less frequently than systemically administered antimuscarinic drugs. For further information on adverse effects reported with antimuscarinics, . In comparative clinical trials, adverse effects reported with ipratropium inhalation aerosol employing a hydrofluoroalkane (HFA) propellant (ipratropium HFA) were similar to those reported with the drug in a preparation containing chlorofluorocarbon (CFC) propellants (ipratropium CFC aerosol; no longer commercially available in the US).

Unless otherwise stated, adverse effects mentioned in the Cautions section are those reported in patients receiving orally inhaled (via metered-dose inhaler or nebulizer) ipratropium and may or may not be directly attributable to the drug.

Orally inhaled ipratropium therapy generally is well tolerated and has a low incidence of adverse effects. No additive effect on the incidence of adverse effects was observed after short-term oral inhalation therapy with the fixed combination of albuterol and ipratropium as an aerosol. In a large, uncontrolled study in seriously ill patients receiving ipratropium inhalation aerosol, about 7% of patients required discontinuance of the drug because of adverse effects. In controlled clinical studies with nebulized ipratropium, adverse effects resulting in discontinuance of the drug most frequently included respiratory effects such as bronchitis, dyspnea, and bronchospasm. In controlled clinical studies with orally inhaled ipratropium HFA via a metered-dose inhaler, the most frequent drug-related adverse effects included dry mouth and taste perversion.

Respiratory Effects

Bronchitis or upper respiratory tract infection was reported in 14.6 or 13.2% of patients, respectively, receiving nebulized ipratropium in controlled studies, although these effects may not necessarily be attributable to the drug. Bronchitis or upper respiratory tract infection was reported in 12.3 or 10.9%, respectively, of patients receiving the fixed combination of albuterol and ipratropium inhalation aerosol. Bronchitis was reported in 10-23%, and upper respiratory tract infection in 9-34% of patients receiving ipratropium HFA inhalation aerosol in controlled clinical trials. Cough following inhalation of ipratropium CFC inhalation aerosol (no longer commercially available in the US) has been reported in about 4.6-5.9% of patients with chronic obstructive pulmonary disease (COPD) in controlled clinical studies, and in 4.2% of patients receiving the fixed combination of albuterol and ipratropium inhalation aerosol. Coughing or exacerbation of COPD symptoms has been reported in 3-5 or 8-23%, respectively, of patients receiving ipratropium HFA inhalation aerosol in controlled clinical trials. Exacerbation of respiratory symptoms occurred in about 2.4% of patients receiving ipratropium CFC aerosol (no longer commercially available in the US) in controlled studies and reportedly is more common in patients receiving nebulized dosages of 2 mg or more daily. Dyspnea, pharyngitis, or increase in sputum was reported in 9.6, 3.7, or 1.4% of patients, respectively, receiving nebulized ipratropium in controlled studies, while bronchospasm, sinusitis, or rhinitis each was reported in 2.3% of such patients. Dyspnea, pharyngitis, sinusitis, bronchospasm, or rhinitis was reported in 4.5, 2.2, 2.3, 0.3, or 1.1%, respectively, of patients receiving the fixed combination of ipratropium and albuterol inhalation aerosol in controlled studies. Dyspnea, rhinitis, or sinusitis has been reported in 7-8, 4-6, or 1-11%, respectively, of patients receiving ipratropium bromide HFA inhalation aerosol in clinical trials. Influenza was reported in 1.4% of patients receiving combined ipratropium and albuterol inhalation aerosol in controlled studies. Influenza-like symptoms occurred in 4-8% of patients receiving ipratropium HFA inhalation aerosol in clinical trials. Irritation from the aerosol occurred in about 2% of patients receiving ipratropium aerosol in controlled studies; drying of secretions or hoarseness was reported in 1% or less of patients receiving the aerosol. As with other inhaled drugs for asthma, paradoxical bronchospasm has been reported in a few patients receiving ipratropium nebulized solution, inhalation aerosol, or the fixed combination (with albuterol) inhalation aerosol, although a causal relationship to the drug has not been definitely established.(See Cautions: Dermatologic and Sensitivity Reactions.) Lower respiratory tract disorders or pneumonia was reported in 2.5 or 1.4% of patients, respectively, receiving orally inhaled albuterol and ipratropium in fixed combination. Nasal congestion or wheezing also has been reported in patients receiving the fixed combination of albuterol and ipratropium inhalation aerosol.

Unlike β2-adrenergic agonists, inhalation of ipratropium does not aggravate hypoxemia in patients with airway obstruction.

GI Effects

Dryness of the mouth, throat, or tongue occurred in up to 5% of patients receiving orally inhaled ipratropium CFC inhalation aerosol (no longer commercially available in the US) or ipratropium via nebulization; dry mouth reportedly occurs more frequently with nebulized dosages of 2 mg or more daily. Nausea, GI distress, or constipation has been reported in about 4.1, 2.4, or 0.9% of patients receiving the drug. Nausea has been reported in 2% of patients receiving the fixed combination of albuterol and ipratropium inhalation aerosol. Paralytic ileus, thirst, bad/bitter taste, mucosal ulcers, and reduced appetite have occurred rarely with ipratropium therapy. Diarrhea, dyspepsia, or vomiting has been reported in less than 2% of patients receiving combined albuterol and ipratropium inhalation aerosol. Dyspepsia, dry mouth, or nausea has been reported in 1-5, 2-4, or 4%, respectively, of patients receiving ipratropium HFA inhalation aerosol in clinical trials.

Ocular Effects

Blurred vision/difficulty in accommodation has been reported in about 1% of patients receiving orally inhaled ipratropium. Burning eyes, mydriasis, temporary blurred vision, ocular pain (sometimes acute), conjunctival or corneal congestion associated with visual halos or colored images, or precipitation or worsening of angle-closure glaucoma also has been reported, probably because of inadvertent contact of the drug with the eyes during administration. Increased intraocular pressure (IOP) has been reported in patients with angle-closure glaucoma receiving nebulized solutions of ipratropium alone or combined with albuterol, apparently as a result of the drug solution escaping from the face mask and entering the eyes.(See Cautions: Precautions and Contraindications.) Increased IOP also has been reported with ipratropium inhalation aerosol and with concomitant administration of ipratropium aerosol (using the open-mouth technique) and nebulized albuterol. While blurred vision has been reported in children given nebulized ipratropium and albuterol via face mask, acute angle-closure glaucoma as a result of environmental exposure to these drugs apparently has not occurred in parents, nurses, or respiratory therapists caring for children undergoing such therapy.

Cardiovascular Effects

Ipratropium inhalation aerosol and solution for nebulization appear to cause adverse cardiovascular effects less frequently than β2-adrenergic agonists or theophylline. Palpitation has occurred in up to 3% of patients receiving orally inhaled ipratropium. Chest pain has been reported in 3.2%, and induction or aggravation of hypertension in about 1% of patients receiving nebulized ipratropium in controlled studies. Angina was reported in less than 2% of patients receiving the fixed-combination inhalation aerosol of albuterol and ipratropium in controlled studies. Extrasystole, tachycardia, vasodilation, and hypotension have been reported infrequently with orally inhaled ipratropium therapy. Hospitalizations for supraventricular tachycardia and atrial fibrillation occurred in 0.5% of patients receiving ipratropium inhalation aerosol.

Data from an observational study involving over 32,000 patients and another pooled analysis of 17 studies enrolling almost 15,000 patients have shown an increased risk of mortality and/or cardiovascular events (e.g., myocardial infarction, stroke, transient ischemic attacks) in patients receiving inhaled anticholinergic agents, including ipratropium.(See Cautions: Precautions and Contraindications.)

Nervous System Effects

Because of the drug's low lipid solubility, orally inhaled ipratropium produces adverse nervous system effects less frequently than orally inhaled atropine or β2-adrenergic agonists. Nervousness, dizziness, and headache have occurred in about 0.5-6.4% of patients receiving orally inhaled ipratropium CFC inhalation aerosol (no longer commercially available in the US). Headache or dizziness occurred in 6-7 or 3%, respectively, of patients receiving ipratropium HFA inhalation aerosol in clinical trials. Headache occurs more frequently in patients receiving nebulized ipratropium bromide in total dosages of 2 mg or more daily. Fatigue or insomnia has been reported in less than 1% of patients receiving the drug. Paresthesia, drowsiness, coordination difficulty, and tremor also have been reported; tremor occurs less frequently with ipratropium than with β2-adrenergic agonists or theophylline. Weakness or CNS stimulation has been reported in patients receiving albuterol and/or ipratropium inhalation aerosol.

Dermatologic and Sensitivity Reactions

Immediate hypersensitivity reactions, including rash, angioedema of the tongue, lips, and face, urticaria (including giant urticaria), laryngospasm, bronchospasm, oropharyngeal edema, and anaphylactic reaction, have been reported in patients receiving orally inhaled ipratropium, with positive results upon rechallenge in some cases. Many of these patients had a history of allergies to other drugs and/or foods, including peanuts and soybeans (soya lecithin is present as an excipient in the fixed-combination inhalation aerosol containing ipratropium and albuterol sulfate). Paradoxical bronchospasm has occurred occasionally with the use of ipratropium via nebulizer or oral aerosol. While it has been suggested that such bronchospasm may result from hypersensitivity to the active drug or other ingredients in the formulation, altered bronchial reactivity in atopic individuals with asthma, or the acidity of the nebulized solution, such reactions also have occurred following administration of isotonic, pH 7, preservative-free solutions of ipratropium.

Rash was reported in 1.2%, and urticaria in less than 3% of patients receiving orally inhaled ipratropium in controlled studies. Pruritus, flushing, or alopecia has been reported in less than 1% of patients receiving ipratropium aerosol. Contact dermatitis has occurred in at least one patient receiving nebulized ipratropium.

Genitourinary Effects

Although no alteration in micturition function was observed in a controlled study in a small number of geriatric men receiving orally inhaled ipratropium, urinary retention/difficulty has been reported occasionally in patients receiving the drug. Urinary tract infection or dysuria also has been reported in patients receiving ipratropium.

Other Effects

Pain, back pain, or flu-like symptoms have occurred in 4.1, 3.2, or 3.7% of patients, respectively, receiving nebulized ipratropium in controlled studies; arthritis has been reported in 0.9% of such patients. Back pain occurred in 2-7% of patients receiving ipratropium HFA inhalation aerosol in clinical trials. Pain or arthralgia also has been reported in 2.5 or less than 2% of patients, respectively, receiving albuterol and ipratropium in fixed combination in controlled studies. Tinnitus also has occurred with ipratropium therapy. Although a causal relationship has not been established, a slight elevation of serum ALT (SGPT) has been reported during therapy with the drug.

Long-term toxicology studies in monkeys using orally inhaled ipratropium bromide dosages of up to 1.6 mg daily for 6 months did not reveal gross or microscopic changes consistent with systemic anticholinergic activity. Food consumption was reduced and body weight decreased in purebred beagles given oral ipratropium bromide dosages of up to 75 mg/kg daily for 1 year.

Precautions and Contraindications

Although the toxic potential of orally inhaled ipratropium generally is less than that of other antimuscarinics because of its poor systemic absorption, the usual precautions of antimuscarinic therapy should be considered during therapy with ipratropium (e.g., the drug should be used with caution in patients with angle-closure glaucoma, bladder neck obstruction or prostatic hyperplasia).

When the preparation containing ipratropium bromide in fixed combination with albuterol sulfate is used, the cautions, precautions, and contraindications applicable to albuterol sulfate should be considered. Adverse cardiovascular effects (e.g., alterations in heart rate, blood pressure, or other manifestations) have been noted with albuterol in fixed combination with ipratropium as an inhalation aerosol; the combination aerosol should be discontinued if such effects occur.

The manufacturer warns that orally inhaled ipratropium is not indicated for the initial treatment of acute episodes of bronchospasm when a rapid response is required. For additional information on the use of ipratropium in asthma, see Asthma under Uses: Bronchospasm. In addition, use of orally inhaled ipratropium as a single agent for the management of bronchospasm in patients experiencing an acute exacerbation of COPD has not been adequately studied, and an agent with a faster onset of action (e.g., a β2-adrenergic agonist) may be preferred as initial therapy in such patients.

Patients should be reminded that orally inhaled ipratropium is not intended for occasional use; it should be used consistently throughout the course of therapy for maximum effectiveness. Patients should contact their clinician if symptoms of COPD are not relieved by ipratropium or if a previously effective dosage regimen fails to provide the usual relief (i.e., the frequency of administration of the drug needs to be increased). The dosage or frequency of administration of ipratropium inhalation aerosol should not be increased without consultation with a clinician.

Data from an observational study involving over 32,000 patients and another pooled analysis have shown an increased risk of mortality and/or cardiovascular events, including stroke or transient ischemic attacks, in patients receiving inhaled anticholinergic agents, including ipratropium.(See Cautions: Cardiovascular Effects.) While data are conflicting, a possible increased risk of stroke has also been identified from ongoing safety monitoring and pooled analysis of placebo-controlled trials in patients receiving another anticholinergic agent, tiotropium. However, preliminary analysis of a placebo-controlled trial in approximately 6000 patients with COPD did not reveal an increased risk of stroke with tiotropium bromide. FDA has not yet confirmed the results of these analyses and is currently reviewing postmarketing adverse event reports and preliminary results of a recently completed placebo-controlled trial to assess additional long-term safety data and further evaluate the risk of stroke with tiotropium.

As with other inhaled drugs, paradoxical bronchospasm has been reported in a few patients receiving ipratropium nebulized solution, inhalation aerosol, or the fixed-combination (with albuterol) inhalation aerosol, although a causal relationship to the drug has not been definitely established. Ipratropium should be discontinued immediately if bronchoconstriction occurs, and alternative therapy instituted.

Temporary blurred vision, mydriasis, ocular pain, conjunctival or corneal congestion associated with visual halos or colored images, or precipitation or worsening of angle-closure glaucoma may occur following inadvertent contact of ipratropium with the eyes; therefore, when the drug is administered via a nebulizer, procedures to minimize ocular exposure should be employed (e.g., using a mouthpiece rather than a face mask to deliver the drug). In addition, patients should be instructed to close their eyes during oral inhalation of ipratropium aerosol. Patients should contact their clinician immediately if ocular symptoms develop after use of ipratropium inhalation aerosol.

Orally inhaled ipratropium should be used with caution in patients with angle-closure glaucoma, although the drug has been used in patients with open-angle glaucoma without clinically important effects on pupil size, accommodation, visual acuity, or intraocular pressure (IOP). Since the risk of ocular toxicity of ipratropium is associated with local exposure of the eye to aerosolized/nebulized drug, care to avoid such exposure is particularly important in patients who are at increased risk from the ocular consequences of exposure. Therefore, some clinicians suggest that ipratropium aerosol should not be administered using the open-mouth technique in patients at high risk for ocular toxicity (e.g., those with angle-closure glaucoma). It also has been suggested that children with blindness (e.g., marked retinal detachment secondary to retinopathy of prematurity, infantile or childhood glaucoma, traumatic cataracts, or dislocation of the lens) should not receive ipratropium via nebulization.

The manufacturer states that ipratropium should be used with caution in patients with renal or hepatic impairment because the drug has not been evaluated systematically in these patient groups. Albuterol and ipratropium inhalation aerosol should be used with caution in patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias, or hypertension), seizure disorders, hyperthyroidism, diabetes mellitus, and in those who are unusually responsive to β2-adrenergic agents.

Ipratropium aerosol and inhalation solution for nebulization are contraindicated in patients with known hypersensitivity to the drug or any other component of the respective formulation, or to atropine or its derivatives. Ipratropium aerosol in fixed combination with albuterol sulfate also is contraindicated in patients with known hypersensitivity to soya lecithin or related food products, including soybeans and peanuts.

Pediatric Precautions

The manufacturer states that safety and efficacy of orally inhaled ipratropium via a metered-dose inhaler in pediatric patients have not been established, although the drug has been used in such patients (generally in children with asthma) with no unusual risk. The safety and efficacy ipratropium bromide for oral inhalation via nebulization have not been established in patients younger than 12 years of age. The safety and efficacy of albuterol sulfate in fixed combination with ipratropium bromide for oral inhalation via nebulization have not been established in patients younger than 18 years of age.

Geriatric Precautions

When the total number of patients studied in clinical trials of ipratropium HFA inhalation aerosol is considered, 57% were 65 years of age or older. No overall differences in efficacy or safety were observed between geriatric and younger patients in these studies.

Safety and efficacy of ipratropium bromide in fixed combination with albuterol sulfate inhalation solution in geriatric patients have not been specifically studied to date; however, in clinical studies of the combination for the treatment of bronchospasm, approximately 62% of the patients were 65 years of age or older and 19% were 75 years of age or older. Although no overall differences were observed between geriatric and younger patients in the safety and efficacy of the combination in clinical studies, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was seen with ipratropium in an in vitro microbial mutagen test (Ames test), the mouse micronucleus test, or the mouse dominant lethal assay, nor did the drug induce chromosomal aberrations in the bone marrow of Chinese hamsters.

No evidence of carcinogenic potential was seen in rats or mice receiving oral ipratropium bromide at dosages up to 6 mg/kg daily for 2 years.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in mice, rats, and rabbits receiving oral ipratropium bromide dosages of 10, 1000, and 125 mg/kg daily (approximately 200, 40,000, and 10,000 times the maximum recommended human daily inhalation dosage on a mg/m basis), respectively, and in rats or rabbits receiving orally inhaled ipratropium bromide dosages of 1.5 or 1.8 mg/kg (approximately 60 or 140 times the maximum recommended human daily inhalation dosage on a mg/m basis), respectively, have not revealed evidence of harm to the fetus. There are no adequate and controlled studies to date using orally inhaled ipratropium in pregnant women, and the drug should be used during pregnancy only when clearly needed.

Fertility

Reproduction studies in male and female rats using oral ipratropium bromide dosages up to 50 mg/kg daily have not revealed evidence of impaired fertility; however, the drug was associated with impaired fertility (i.e., increased resorption) when given at an oral dosage exceeding 90 mg/kg in rats (approximately 3600 times the maximum recommended human daily inhalation dosage on a mg/m basis). As these results were not obtained at dosages and a route of administration that were clinically relevant, the manufacturer states that such embryotoxic effects in rats are not considered clinically important.

Lactation

It is not known whether ipratropium is distributed into milk in humans, but highly lipophobic quaternary bases are distributed slowly and at low concentrations into milk. Because ipratropium is not well absorbed systemically following oral inhalation, the manufacturer states that ingestion of substantial amounts of the drug by an infant during breast-feeding is unlikely. The manufacturer recommends that orally inhaled ipratropium be used with caution in nursing women.

Drug Interactions

The manufacturer states that because of the limited systemic absorption and low plasma drug concentrations associated with oral inhalation of ipratropium, it is unlikely that the drug would interact with systemically administered drugs. The manufacturer states that patients taking ipratropium bromide in fixed combination with albuterol sulfate should not use other inhaled agents unless directed by a clinician.

Adverse drug interactions have not been reported with concomitant administration of orally inhaled ipratropium and a β-adrenergic agonist bronchodilator (e.g., albuterol, fenoterol [currently not commercially available in the US], isoproterenol, metaproterenol), theophylline derivatives, oral or inhaled corticosteroids, or cromolyn sodium in clinical studies in patients with chronic obstructive pulmonary disease (COPD) or asthma.

While concomitant inhalation of ipratropium and a β2-adrenergic agonist may not always result in substantial additional bronchodilation compared with inhalation of either agent alone, such combined therapy usually increases the duration of bronchodilation. Concomitant administration of ipratropium and albuterol via nebulization has been reported to increase intraocular pressure (IOP) and precipitate acute angle-closure glaucoma in susceptible individuals (i.e., individuals with untreated or undiagnosed angle-closure glaucoma), probably as a result of inadvertent contact of the drugs with the eyes.(See Cautions: Ocular Effects.) Caution is advised if the fixed combination of albuterol and ipratropium inhalation aerosol is used concomitantly with other β2-adrenergic agents since the risk for adverse cardiovascular effects increases.

Although ipratropium inhalation aerosol is minimally absorbed into the systemic circulation, there is some potential for additive interaction with concomitantly used antimuscarinic agents. Therefore, caution is advised when ipratropium aerosol is used concomitantly with other antimuscarinic agents.

For further information on drug interactions reported with antimuscarinics, see Drug Interactions in the Antimuscarinics/Antispasmodics General Statement 12:08.08.

Pharmacokinetics

Absorption

Following oral inhalation, ipratropium bromide is only minimally absorbed into systemic circulation from the surface of the lungs or from the GI tract. Following oral inhalation of 2 mg of ipratropium bromide via nebulization in healthy adults, approximately 7% (range: 1.4-16.3%) of the dose was absorbed into systemic circulation. Concomitant oral inhalation of ipratropium and albuterol in a fixed-combination aerosol did not alter the systemic absorption of either component. Following oral inhalation of 555 mcg of radiolabeled ipratropium bromide in healthy adults, radioactivity was detected in blood within 2 minutes, indicating rapid buccal and/or pulmonary absorption; peak plasma concentrations of about 0.06 ng/mL (as total radioactivity) occurred in about 1-3 hours. Following oral inhalation of a single, higher-than-recommended dose (4 inhalations, total dose 68 mcg) of ipratropium bromide (with a hydrofluoroalkane [HFA] propellant), mean peak plasma concentrations of ipratropium in a limited number of adult or geriatric patients with chronic obstructive pulmonary disease (COPD) were 59 or 56 pg/mL, respectively. Following administration of a higher-than-recommended dosage (4 inhalations 4 times daily, 272 mcg total daily dosage) of ipratropium (with HFA propellant) for 1 week, mean peak plasma ipratropium bromide concentrations in adult or geriatric patients increased to 82 or 84 pg/mL, respectively. The trough concentration of ipratropium 6 hours after inhalation in adult and geriatric patients was 28 pg/mL at steady state. Following oral inhalation of the fixed combination of albuterol sulfate (180 mcg as albuterol base) and ipratropium bromide monohydrate (36 mcg), peak plasma concentration of ipratropium bromide remained below detectable limits (less than 100 pg/mL); peak plasma concentrations of albuterol of about 492 pg/mL occurred within 3 hours after administration. Although most of a dose of an orally inhaled drug is actually swallowed, the bronchodilating action of ipratropium appears to result from a local action of the portion of the dose that reaches the bronchial tree.

Following oral aerosol inhalation of 34 mcg of ipratropium bromide (with HFA propellant) in patients with COPD, bronchodilation (as determined by an increase of 15% or more in FEV1) is evident within 14-17.5 minutes, is maximal within 1-2 hours, and generally persists for 2-4 hours. The onset to a 15% increase in FEV1 after oral inhalation of albuterol sulfate (180 mcg as albuterol base) and ipratropium bromide monohydrate (36 mcg) in fixed combination in patients with COPD was 15 minutes; median time to peak FEV1 was 1 hour. The median duration of bronchodilation was 4-5 hours with the fixed combination and 4 hours with ipratropium alone. In dose-ranging studies in patients with bronchospasm, ipratropium bromide doses of 36-72 mcg given via a metered-dose inhaler generally have provided optimal clinical benefit. Because penetration of orally inhaled particles into airways is impaired when airways are severely obstructed, some clinicians suggest that higher doses of ipratropium bromide may be needed for maximal effect in some patients (e.g., those with severe airway disease).

Following oral inhalation via nebulization of 400-600 mcg of ipratropium bromide, bronchodilation (defined as increases of 15% or more in FEV1) usually is evident within 15-30 minutes with peak effect in approximately 1-2 hours. In a dose-response study in patients with COPD, the optimal dose of nebulized ipratropium bromide was about 400 mcg. Bronchodilation with nebulized ipratropium generally persists for 4-5 hours, but may last up to 7-8 hours in some patients. Following concomitant administration via nebulization of a β2-adrenergic agonist (i.e., albuterol, metaproterenol) and ipratropium in patients with COPD, bronchodilation persists for 5-7 hours compared with 3-4 hours in patients given a β2-adrenergic agonist alone.

Following oral administration of a single 30-mg dose of radiolabeled ipratropium bromide in healthy adults, peak plasma ipratropium bromide concentrations of about 25 ng/mL (as total radioactivity) occurred within 2-4 hours. However, peak plasma radioactivity following administration of radiolabeled ipratropium bromide appears to represent both the parent drug and its metabolites. Peak plasma drug concentrations of about 1 ng/mL (determined by a radioreceptor assay that does not measure metabolites of ipratropium bromide) occurred within 2 hours following administration of a single 10-mg oral dose of ipratropium bromide in healthy adults. In these individuals, approximately 3.3% (range: 0.9-6.1%) of the dose of ipratropium bromide was absorbed. Oral administration of 15 mg of ipratropium bromide appears to produce bronchodilation similar to that produced by 36 or 150 mcg of the drug given by oral aerosol inhalation or IV, respectively; plasma concentrations are approximately 1000 times higher following oral administration than following oral inhalation of equipotent doses. Plasma drug concentrations following oral inhalation of ipratropium bromide do not appear to correlate with pharmacologic effects.

Distribution

Distribution of ipratropium bromide into human tissues and body fluids has not been elucidated. Quaternary ammonium antimuscarinics are completely ionized and possess poor lipid solubility; accordingly, they do not readily penetrate the CNS. Following IV administration of ipratropium bromide in rats, the drug is distributed throughout the body with highest concentrations appearing in the stomach, intestines, liver, and kidneys; the drug is minimally distributed into brain, lung, and muscle. High concentrations of ipratropium bromide in the gut in these animals may indicate biliary elimination or enterohepatic circulation.

Ipratropium bromide reportedly is 0-9% bound to plasma albumin and α1-acid glycoproteins in vitro.

It is not known whether ipratropium bromide crosses the placenta or is distributed into milk.

Elimination

Following IV administration of ipratropium bromide in healthy adults, plasma drug concentrations appear to decline in a biphasic manner. Using radiolabeled ipratropium bromide, an elimination half-life of about 2-4 hours (determined by measurement of total radioactivity) generally has been reported following administration of the drug orally, IV, or by oral inhalation in animals and healthy adults. However, this method measures both ipratropium bromide and its metabolites. Using a radioreceptor assay that measures only unchanged ipratropium bromide, the initial distribution-phase half-life (t½α) and the terminal elimination-phase half-life (t½β) following a single 2-mg IV dose of the drug in healthy adults averaged about 0.07 and 1.6 hours, respectively.

The exact metabolic fate of ipratropium bromide has not been fully determined. Following oral or IV administration or oral inhalation, the drug is partially metabolized to at least 8 metabolites. Metabolism appears to involve only the tropic acid moiety and usually consists of hydrolysis and conjugation. The main metabolites appear to be N-isopropylnortropium methobromide, which is formed by enzymatic hydrolysis of the ester; α-phenylacrylic acid-N-isopropylnortropine-ester methobromide, which is formed by enzymatic loss of a water; and phenylacetic acid-N-isopropylnortropine-ester methobromide, which is formed by enzymatic loss of a CH3OH-group. In vitro, these metabolites have minimal or no antimuscarinic activity.

After oral inhalation, oral administration, or IV injection of radiolabeled ipratropium bromide, unchanged drug recovered in urine within 4 hours (as total radioactivity) averaged 13, 24, or 50% of the dose, respectively. After administration of albuterol sulfate (180 mcg as albuterol base) and ipratropium bromide monohydrate (36 mcg) in fixed combination, 27.1% of the estimated mouthpiece dose is excreted unchanged in urine within 24 hours. Following oral administration or oral inhalation of ipratropium bromide in healthy adults, most of the dose is excreted in feces within 24 hours, principally as unchanged drug. In healthy individuals receiving 555 mcg of radiolabeled ipratropium bromide by oral inhalation, about 69 and 3.2% of the dose was excreted in feces and urine, respectively, within 6-7 days. Following administration of radiolabeled ipratropium bromide in healthy adults, about 9 or 72% of a single oral or IV dose, respectively, was excreted in urine, and about 89 or 6% of the oral or IV dose was excreted in feces within 5-7 days; most excretion occurred within 24 hours. Ipratropium bromide undergoes biliary elimination and/or enterohepatic circulation in animals and appears to undergo some biliary elimination in humans.

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