VA Class:RE105

AHFS Class:

• Antimuscarinics/Antispasmodics 12:08.08

Generic Name(s):

• Ipratropium Bromide

• Ipratropium Bromide Anhydrous

Chemical Name:

• ( endo,syn -±-3-(3-Hydroxy-1-oxo-2-pheny lpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]octane bromide monohydrate

• ( endo,syn -±)-3-(3-Hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]octane bromide [anhydrous]

Molecular Formula:

• C₂₀H₃₀BrNO₃•H₂O

Ipratropium bromide is a synthetic quaternary ammonium antimuscarinic.1,2,3,4,6,7,12,13,14,224,281

Bronchospasm

Ipratropium bromide is used for the symptomatic treatment of reversible bronchospasm that may occur in association with chronic obstructive pulmonary disease (COPD),1,2,4,58,76,114,115,118,120,121,122,123,124,127,128,130,228,230,244,245,253,254,255,256,257,258,259,260,261,262,263,267,278,281,285,292,293,294,327,351,352,347 including chronic bronchitis1,2,4,36,55,61,76,90,116,117,119,120,121,124,125,129,131,281 and emphysema.1,2,4,90,91,119,120,125,281,332,333,334,343,344,347,351 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.320,327,347 Ipratropium bromide also is used for the symptomatic treatment of bronchial asthma†36,55,56,76,91,92,115,124,125,129,153,161,162,164,180,181,211,225,228,268,302,303,331 and for the prevention of exercise-induced bronchospasm†,32,167,202,228 and also has been used as a bronchodilator in patients with cystic fibrosis†.264,265,266

Chronic Obstructive Pulmonary Disease

Ipratropium bromide is used as a bronchodilator for the long-term symptomatic treatment of reversible bronchospasm associated with COPD,1,2,4,58,76,114,115,118,120,121,122,123,124,127,128,130,228,230,244,245,253,254,255,256,257,258,259,260,261,262,263,267,278,281,285,292,293,294,327,347,351,352 including chronic bronchitis1,2,4,36,55,61,76,90,116,117,119,120,121,124,125,129,131,281 and emphysema.1,2,4,90,91,119,120,125,281,332,333,334,343,344,347 Orally inhaled ipratropium is not indicated as a single agent for the initial treatment of acute episodes of bronchospasm or acute exacerbations of COPD;1,4,176,225,267,281,329,347,351 a drug with a more rapid onset of action (e.g., a β₂-adrenergic agonist) may be preferred in such cases.4,176,225,329,333,334,347,351 (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.197,225,267,320,327,332,335,343,344

The efficacy of ipratropium has been similar to122,123,124,125,126,129,130,131,132,133,134,135,138,148,151,152,153,332,334 or greater than120,121,127,128,191,332,334 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,1,2,4,120,121,225,228,244,255,267,281 ipratropium is a first-line maintenance bronchodilator for relief of chronic (e.g., daily) symptoms of bronchospasm in patients with mild COPD.190,191,197,244,254,255,256,267,268,292,334,343,344 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.338,339,342 (See Chronic Obstructive Pulmonary Disease under Uses: Bronchospasm, in Tiotropium Bromide 12:08.08.) 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.320,321,327,343,345,347

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.351,352 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).1,351,352 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).351,352

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.190,191,332,343,347

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.267,322,333,334,343,347 Alternatively, some clinicians initiate therapy with ipratropium inhalation aerosol.4,90,122,123,125,127,128,129,130,131,134,191,194,254,267,292,332,343,344,345,347 Patients with COPD who receive orally inhaled ipratropium generally have an increase in FEV₁ (at its peak) of 0.15-0.36 L114,120,124,126,146,151,158,225,333 and a decrease in functional residual capacity of 0.3-0.6 L.114,151,225 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,4,281,344 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).191,267,294,343,345

Low- to high-dose ipratropium bromide (6-16 inhalations daily)343 can be added to therapy with a selective β₂-agonist343,344,345,354 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).1,267,323,333,334,343,344,347,354 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.191,254,267,292,332,338,339,340,341,344,345,347 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.320,321 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.320,321

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.4,112,133,136,147,148,211,225,228,278,281,285,320,321,332,333,343,345,347 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,6,133,136,147,148,151,152,154,155,225,262 the duration of bronchodilation appears to be increased with such concomitant therapy, and the potential for adverse effects also may be minimized.4,188,190,191,225,228,260,267,278,281,285,320,321,332,333,347 The sequence of administration of ipratropium and a short-acting β₂-agonist generally does not alter the effectiveness of the bronchodilating action.334

Home management of COPD exacerbations involves increasing the dose and/or frequency of existing short-acting bronchodilator therapy, preferably with a B₂-adrenergic agonist.336 If response to a short-acting β₂-adrenergic agonist alone is inadequate, some clinicians recommend the addition of ipratropium.343,344,345,347 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.343,344,345,347

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.329,343,344,345,347

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,36,55,56,76,91,92,115,124,125,129,153,161,162,164,180,181,211,225,228,268,302,303,331,336,337 but the precise role of the drug in the management of this condition remains to be more fully elucidated.161,164,211,268,331,336 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.336 However, the efficacy of ipratropium in the long-term management of asthma has not been established.324,336 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.161,164,225,257,268,302,303,314,324,331,336,337 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.312,313,314,315,316,317,318,319,324,331,336,337 For additional information on the stepped-care approach for drug therapy in asthma,324 see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12.

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).324 During prolonged emergency transport, NAEPP recommends that other asthma therapies such as ipratropium bromide and oral corticosteroids also be available for use.324 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.161,164,193,211,268,314,324,331,336 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.1,4,164,225,331,337 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.331,336,337 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.324 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.324 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;193,205,222,242,269,314,331,336 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.193,331,336 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.324,336 Based on such data in children, NAEPP recommends discontinuance of ipratropium upon hospitalization for severe asthma exacerbations for patients of all age groups.324

The benefit of maintenance therapy with ipratropium in patients with chronic asthma† remains to be elucidated,161,164,268,324,331,336,337 but the drug may be useful as alternative therapy in adults experiencing adverse effects (e.g., tachycardia, arrhythmia, tremor) with a β₂-adrenergic agonist.331,336,337 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.324,331,336,337

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.31,191,194,225,268,324

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,32,167,202,228 orally inhaled β₂-adrenergic agonists are considered first-line agents in the management of this condition.161,167,302,331,324,336

Cystic Fibrosis

Orally inhaled ipratropium bromide has produced bronchodilation (i.e., increase in FEV₁) in a limited number of patients with cystic fibrosis†,264,265,266 but additional studies are needed to determine the clinical usefulness of such therapy in these patients.265

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†;191,290 to protect against bronchoconstriction in patients undergoing fiberoptic bronchoscopy†;191,299 and to improve pulmonary function in ventilator-dependent patients, including preterm infants†.227,295,300,301,304 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.308

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.298,325 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.297,298,326

Administration

Ipratropium bromide is administered by oral inhalation using an oral aerosol inhaler10,320,351 or via nebulization.4,281 Ipratropium bromide is administered in fixed combination with albuterol sulfate via a metered-dose aerosol inhaler320 or via nebulization.327 Patients should be advised that ipratropium must be used consistently throughout the course of therapy for maximum benefit.351 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.1,4,351

Oral Inhalation via Metered-Dose Aerosol

Ipratropium Bromide

Patients should be instructed carefully in the use of the ipratropium bromide metered-dose inhaler.10,351,353 To obtain optimum results, patients also should be given a copy of the patient instructions provided by the manufacturer.10,351,353 The aerosol inhaler should be actuated twice prior to the initial use or if it has not been used for more than 3 days.353 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;353 it also has been suggested that ipratropium aerosol not be administered using the open-mouth technique in patients at high risk for ocular toxicity.173,190,191 (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.353 The patient should then inhale slowly and deeply through the mouth while actuating the inhaler.353 After holding the breath for 10 seconds, the patient should remove the mouthpiece and exhale slowly.353 If additional inhalations are required, the patient should wait at least 15 seconds and repeat the procedure.353 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;353 nothing other than water should be used to wash the mouthpiece.353 The mouthpiece should be dried by shaking off the excess water and allowing the mouthpiece to air dry.353 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.353

Ipratropium Bromide and Albuterol Sulfate

Patients should insert the metal canister into the clear end of the mouthpiece.346 The aerosol inhaler should be shaken well for at least 10 seconds immediately prior to use320,346 and should be actuated 3 times prior to the initial use or if it has not been used for more than 24 hours.346 The mouthpiece provided for the inhalation aerosol of ipratropium bromide and albuterol sulfate should not be used for other aerosol drugs.346 Prior to use, the orange dust cap should be removed and the mouthpiece should be checked for foreign objects.346 Patients should avoid spraying ipratropium bromide and albuterol sulfate inhalation aerosol into their eyes.346 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.346 (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.346 The patient should then inhale slowly and deeply through the mouth while actuating the inhaler.346 After holding the breath for 10 seconds, the patient should remove the mouthpiece and exhale slowly.346 If additional inhalations are required, the patient should wait approximately 2 minutes and repeat the procedure.346 The manufacturer recommends that the ipratropium bromide and albuterol sulfate oral inhaler mouthpiece be cleaned as needed by rinsing the mouthpiece in hot water.346 If soap is used, the mouthpiece should be rinsed thoroughly with plain water.346 When dry, the cap on the mouthpiece should be replaced when the inhaler is not in use.346

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.190,191 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.4,349,350 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.1,2,4,10,225,250,275,327,349,350 (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.4

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.4,15,349 The patient should then breathe through the mouthpiece as calmly, deeply, and evenly as possible until the nebulizer stops producing mist.4,328,349 The duration of treatment for oral inhalation of a full dose of ipratropium usually is about 5-15 minutes.4,328,349 The nebulizer should be cleaned after use according to the manufacturer's instructions.4,328

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.4 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;4,190,209,215 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.4,190

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.328 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.328

The patient should place the mouthpiece of the nebulizer into the mouth.328 Alternatively, patients may put the face mask over the mouth and nose.328 The patient should then breathe through the mouth as calmly, deeply, and evenly as possible until the nebulizer stops producing mist.328 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.328 The nebulizer should be cleaned after use according to the manufacturer's instructions.328

Dosage

Oral Inhalation via Metered-Dose Aerosol

Dosage of ipratropium bromide oral inhalation aerosol (Atrovent^® HFA) is expressed in terms of the monohydrate.1,320 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.320

While some published studies and manufacturers have reported a dose of 20-21 mcg of ipratropium bromide per metered spray,225,228,233,351 this is the amount released from the valve stem during actuation of the inhaler;318 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.320,351 The commercially available aerosols deliver 200 metered sprays per canister.320,346,351 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.351 The inhaler should be discarded after 200 sprays have been used.320,346,351,353

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.351 If necessary, additional inhalations of ipratropium bromide may be used.191,254,351 The manufacturer of Atrovent^® HFA states that the dosage of ipratropium bromide should not exceed 204 mcg (12 inhalations) in 24 hours,351 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.191,254 The manufacturer recommends that 15 seconds elapse between successive inhalations of ipratropium.1,10,353

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.320 If necessary, additional inhalations of ipratropium bromide combined with albuterol sulfate may be used.191,254,320 The manufacturer recommends that approximately 2 minutes elapse between successive inhalations of ipratropium in fixed combination with albuterol.346 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.320 (See Cautions: Precautions and Contraindications, in Albuterol Sulfate 12:12.08.12.)

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.1,320 The dose or frequency of administration of ipratropium alone or in fixed combination with albuterol should not be increased without consultation with a clinician.1,320,346,353

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).324,351 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).324,351

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.324 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.324

Oral Inhalation via Nebulization

Dosage of ipratropium bromide inhalation solution for nebulization is expressed in terms of anhydrous drug.4,329,330 Dosage of ipratropium bromide in fixed combination with albuterol sulfate (as albuterol base) for nebulization is expressed as the monohydrate.327 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.327

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).4,329 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.4,329

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.327 The flow rate of the nebulizer should be adjusted so that the dose is delivered over a period of approximately 5-15 minutes.328 The manufacturer of DuoNeb^® recommends not exceeding 6 inhalations daily since such dosages have not been studied for the treatment of COPD.327

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.324 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.324 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.324 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.324,336 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.324,336 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.324,336

Adverse effects reported with orally inhaled ipratropium bromide are similar to those reported with other antimuscarinic drugs;1,2,4,14,16,35,60,75,90,120,127,281 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)6,102,103,104 less frequently than systemically administered antimuscarinic drugs.2,6,7,14,228,230,281 For further information on adverse effects reported with antimuscarinics, see Cautions in the Antimuscarinics/Antispasmodics General Statement 12:08.08. 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).351

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.1,4,190

Orally inhaled ipratropium therapy generally is well tolerated and has a low incidence of adverse effects.2,4,6,44,47,66,76,79,92,115,117,118,122,124,125,134,175,225,228,230,278,281 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.320,321 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.1 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.4 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.351

Respiratory Effects

Bronchitis4 or upper respiratory tract infection4 was reported in 14.6 or 13.2% of patients, respectively, receiving nebulized ipratropium in controlled studies,4 although these effects may not necessarily be attributable to the drug.4,190,191 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.320 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.351 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,1,2,4,87,120,285 and in 4.2% of patients receiving the fixed combination of albuterol and ipratropium inhalation aerosol.320 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.351 Exacerbation of respiratory symptoms1,2,62,213,225,271,272,273 occurred in about 2.4% of patients receiving ipratropium CFC aerosol (no longer commercially available in the US) in controlled studies1,2 and reportedly is more common in patients receiving nebulized dosages of 2 mg or more daily.4 Dyspnea,4 pharyngitis,4 or increase in sputum4 was reported in 9.6, 3.7, or 1.4% of patients, respectively, receiving nebulized ipratropium in controlled studies, while bronchospasm,4 sinusitis,4 or rhinitis4 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.320 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.351 Influenza was reported in 1.4% of patients receiving combined ipratropium and albuterol inhalation aerosol in controlled studies.320 Influenza-like symptoms occurred in 4-8% of patients receiving ipratropium HFA inhalation aerosol in clinical trials.351 Irritation from the aerosol occurred in about 2% of patients receiving ipratropium aerosol in controlled studies;1,2 drying of secretions or hoarseness was reported in 1% or less of patients receiving the aerosol.1 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.1,4,190,191,196,270,271,272,273,320,351 (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.320 Nasal congestion or wheezing also has been reported in patients receiving the fixed combination of albuterol and ipratropium inhalation aerosol.320

Unlike β₂-adrenergic agonists, inhalation of ipratropium does not aggravate hypoxemia in patients with airway obstruction.195,225,245

GI Effects

Dryness of the mouth,1,2,4,14,16,60,90,120,127 throat,1,75,90 or tongue87 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;1,329 dry mouth reportedly occurs more frequently with nebulized dosages of 2 mg or more daily.4 Nausea,1,2,4,75,120 GI distress,1,2,120 or constipation1,4,351 has been reported in about 4.1, 2.4, or 0.9% of patients receiving the drug.1,4 Nausea has been reported in 2% of patients receiving the fixed combination of albuterol and ipratropium inhalation aerosol.320 Paralytic ileus,224,274,280 thirst,35 bad/bitter taste,14,60,75,87,90,170,210 mucosal ulcers,1 and reduced appetite90 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.320 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.351

Ocular Effects

Blurred vision/difficulty in accommodation1,4,35,349 has been reported in about 1% of patients receiving orally inhaled ipratropium.1,4 Burning eyes,75 mydriasis,1,225,250,275 temporary blurred vision,1,2,4,10 ocular pain (sometimes acute),1,4,247,248,249,287,288,289,329,349,351 conjunctival or corneal congestion associated with visual halos or colored images,351 or precipitation or worsening of angle-closure glaucoma1,4,173,247,248,249,287,288,289,349,351 also has been reported, probably because of inadvertent contact of the drug with the eyes during administration.173,190,191,247,248,249,287,288,289,349 Increased intraocular pressure (IOP) has been reported in patients with angle-closure glaucoma receiving nebulized solutions of ipratropium alone173,289,296 or combined with albuterol, apparently as a result of the drug solution escaping from the face mask and entering the eyes.173,246,247,248,249,287,288,289,296 (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.173,351 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.286

Cardiovascular Effects

Ipratropium inhalation aerosol and solution for nebulization appear to cause adverse cardiovascular effects1,2,4,6,14 less frequently than β₂-adrenergic agonists or theophylline.2 Palpitation1,351 has occurred in up to 3% of patients receiving orally inhaled ipratropium.1,2,4,120 Chest pain4 has been reported in 3.2%, and induction or aggravation of hypertension4 in about 1% of patients receiving nebulized ipratropium in controlled studies.4 Angina was reported in less than 2% of patients receiving the fixed-combination inhalation aerosol of albuterol and ipratropium in controlled studies.320 Extrasystole,125 tachycardia,1,4,276,351 vasodilation,1 and hypotension1,351 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.1

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.356,357,358 (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.2,6 Nervousness,1,4,120,228 dizziness,1,2,4,120,228,285 and headache1,2,4,75,228 have occurred in about 0.5-6.4% of patients receiving orally inhaled ipratropium CFC inhalation aerosol (no longer commercially available in the US).1,4,320 Headache or dizziness occurred in 6-7 or 3%, respectively, of patients receiving ipratropium HFA inhalation aerosol in clinical trials.351 Headache occurs more frequently in patients receiving nebulized ipratropium bromide in total dosages of 2 mg or more daily.4 Fatigue1,35 or insomnia1,90 has been reported in less than 1% of patients receiving the drug. Paresthesia, drowsiness,1 coordination difficulty,1 and tremor1,4,125 also have been reported; tremor occurs less frequently with ipratropium than with β₂-adrenergic agonists or theophylline.6,14 Weakness or CNS stimulation has been reported in patients receiving albuterol and/or ipratropium inhalation aerosol.320

Dermatologic and Sensitivity Reactions

Immediate hypersensitivity reactions, including rash, angioedema of the tongue, lips, and face, urticaria (including giant urticaria), laryngospasm,351 bronchospasm, oropharyngeal edema, and anaphylactic reaction, have been reported in patients receiving orally inhaled ipratropium, with positive results upon rechallenge in some cases.1,4,196,213,277,285,320,329,351 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).4,190,196,277,320 Paradoxical bronchospasm has occurred occasionally with the use of ipratropium via nebulizer or oral aerosol.1,4,190,191,196,270,271,272,273,320,351 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,196,270,271,272,273,310,311 such reactions also have occurred following administration of isotonic, pH 7, preservative-free solutions of ipratropium.270

Rash was reported in 1.2%,1,2 and urticaria in less than 3%1,4 of patients receiving orally inhaled ipratropium in controlled studies. Pruritus,1 flushing,1 or alopecia1 has been reported in less than 1% of patients receiving ipratropium aerosol.1,4 Contact dermatitis has occurred in at least one patient receiving nebulized ipratropium.307

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,104 urinary retention/difficulty has been reported occasionally in patients receiving the drug.1,4,251,252 Urinary tract infection or dysuria also has been reported in patients receiving ipratropium.4,320,351

Other Effects

Pain,4 back pain,4 or flu-like symptoms4 have occurred in 4.1, 3.2, or 3.7% of patients, respectively, receiving nebulized ipratropium in controlled studies;4 arthritis has been reported in 0.9% of such patients.4 Back pain occurred in 2-7% of patients receiving ipratropium HFA inhalation aerosol in clinical trials.351 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.320 Tinnitus285 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.117

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.281 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.281

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,225,257,281 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).4,190,191,225,329,351 (See Cautions in the Antimuscarinics/Antispasmodics General Statement 12:08.08.)

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.320,327,346 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.320

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.1,4,351 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.4,225,267

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.4 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).346,351 The dosage or frequency of administration of ipratropium inhalation aerosol should not be increased without consultation with a clinician.351

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.356,357,358 (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.358 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.358 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.358

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.190,191,196,270,271,272,273,320,329,351 Ipratropium should be discontinued immediately if bronchoconstriction occurs, and alternative therapy instituted.216,227,320,351

Temporary blurred vision,1,2,4,10 mydriasis,225,250,275 ocular pain,4 conjunctival or corneal congestion associated with visual halos or colored images,1 or precipitation or worsening of angle-closure glaucoma4,173 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).4,190,191 In addition, patients should be instructed to close their eyes during oral inhalation of ipratropium aerosol.1,2 Patients should contact their clinician immediately if ocular symptoms develop after use of ipratropium inhalation aerosol.351

Orally inhaled ipratropium should be used with caution in patients with angle-closure glaucoma,1,4 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).102,103,246 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).173,190,191 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.173,190,191,286

The manufacturer states that ipratropium should be used with caution in patients with renal or hepatic impairment320 because the drug has not been evaluated systematically in these patient groups.320,351 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.320

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.1,4,320,351 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.277,320

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,320,351 although the drug has been used in such patients (generally in children with asthma) with no unusual risk.199,200,201,202,203,205,206,207,208,300,301 The safety and efficacy ipratropium bromide for oral inhalation via nebulization have not been established in patients younger than 12 years of age.329 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.327

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.351 No overall differences in efficacy or safety were observed between geriatric and younger patients in these studies.351

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.327 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.327

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,281,351 nor did the drug induce chromosomal aberrations in the bone marrow of Chinese hamsters.351

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.2,4,281,351

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/m² 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/m² basis), respectively, have not revealed evidence of harm to the fetus.219,351 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.351

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;351 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/m² basis).351 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.351

Lactation

It is not known whether ipratropium is distributed into milk in humans,4,351 but highly lipophobic quaternary bases are distributed slowly and at low concentrations into milk.2 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.1,4,351 The manufacturer recommends that orally inhaled ipratropium be used with caution in nursing women.2,4,351

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.2,190,191 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.346

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),4,59,115,124,129,132,133,136,137,138,139,140,141,142,143,144,145,146,147,148,150,151,152,153,154,155,156,169,233,262,278,285,305 theophylline derivatives,115,120,121,132,157,158,149,187,220,261,305 oral or inhaled corticosteroids,91,115,119,120,121,124,132,153,154,160,351 or cromolyn sodium132,159 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,4,6,133,147,152,155,225,228,262,278,279,285 such combined therapy usually increases the duration of bronchodilation.4,225,228,260,278,281,285,327 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.246,248,287,288,289,327 (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.320,327

Although ipratropium inhalation aerosol is minimally absorbed into the systemic circulation, there is some potential for additive interaction with concomitantly used antimuscarinic agents.320,351 Therefore, caution is advised when ipratropium aerosol is used concomitantly with other antimuscarinic agents.320,327,351

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

Acute Toxicity

Toxicology studies in animals indicate that ipratropium exhibits a low order of toxicity compared with that of other anticholinergic and bronchospasmolytic agents.281

Pathogenesis

The acute lethal dose of ipratropium bromide in humans is not known.190 The manufacturer states that ipratropium overdosage as a result of oral inhalation or oral administration is unlikely because systemic absorption of the drug is minimal after inhalation or oral administration of up to 4- or 40-fold the recommended oral inhalation dose, respectively.1,4

The IV LD₅₀ of ipratropium bromide in dogs, male rats, female rats, female mice, or male mice is approximately 17.5-20, 16, 15.7, 15, or 12.3 mg/kg, respectively.6,7,12,218 The oral LD₅₀ of ipratropium bromide in rats, mice, or dogs is 1700 mg/kg (approximately 68,000 times the maximum recommended human daily inhalation dosage on a mg/m² basis), in excess of 1 g/kg (approximately 20,000 times the maximum recommended human daily inhalation dosage on a mg/m² basis), or 400 mg/kg (approximately 53,000 times the maximum human daily inhalation dosage on a mg/m² basis), respectively.6,7,12,190,218,351 The subcutaneous LD₅₀ of ipratropium bromide in male or female mice is approximately 300 or 340 mg/kg, respectively.6,7 The inhalation LD₅₀ of ipratropium bromide is about 200 mg/kg in guinea pigs and about 1 mg/kg in monkeys.6,12,218,281 The oral lethal dose of ipratropium ranges from 1001-2010 mg/kg in mice (approximately 30,000 and 60,000 times the maximum recommended human daily inhalation dose on a mg/m² basis), from 1667-4000 mg/kg in rats (approximately 100,000 and 240,000 times the maximum recommended human daily inhalation dose on a mg/m² basis), and from 400-1300 mg/kg in dogs (approximately 80,000 and 260,000 times the maximum recommended human daily inhalation dose on a mg/m² basis).320 Death from ipratropium bromide overdosage in animals usually resulted from inhibition of ganglionic transmission, which produced curariform paralysis of skeletal muscle.6,12

Manifestations

In general, overdosage of ipratropium bromide may be expected to produce effects associated with antimuscarinic administration;7 however, the manufacturer states that because of the low systemic absorption of orally inhaled ipratropium bromide, acute overdosage of the drug is unlikely following oral administration or oral inhalation.1,4,318

For further information on acute overdosage reported with antimuscarinics, see Acute Toxicity in the Antimuscarinics/Antispasmodics General Statement 12:08.08.

Pharmacology

Ipratropium generally exhibits pharmacologic actions similar to those of other antimuscarinics.1,2,3,4,6,7,12,13,224 Similar to atropine, ipratropium is a nonselective competitive antagonist at muscarinic receptors present in airways and other organs.2,224,225,232 The drug relaxes smooth muscles of bronchi and bronchioles by blocking acetylcholine-induced stimulation of guanyl cyclase and thus reducing formation of cyclic guanosine monophosphate (cGMP), a mediator of bronchoconstriction.1,2,4,6 Ipratropium generally exhibits greater antimuscarinic activity on bronchial smooth muscle than on secretory (e.g., salivary, gastric) glands.6,7,12,16,18,34,225

Following IV administration in animals, the antimuscarinic activity of ipratropium (as measured by mydriasis, inhibition of salivary or gastric secretions, tachycardia, or spasmolysis) is similar to that of atropine; following oral administration, the antimuscarinic activity of ipratropium is only about 10-50% that of atropine.7 In animals, the relative bronchoselectivity of ipratropium is even more pronounced with oral inhalation of the drug than with IV administration.12,16,18,225

Respiratory Effects

Ipratropium is a potent bronchodilator,1,2,4,34,35,36,40,43,44,46,47,53,54,55,58,59,60,61,62,63,64,65,66,67,68,225,228,230 particularly in large bronchial airways;2,57,81,166,225 however, some evidence suggests that the drug also has bronchodilator activity in small airways.54,56,96,225,232,320 Bronchodilation results from relaxation of smooth muscles of the bronchial tree.7,14,113,225 The extent of bronchodilation produced by ipratropium appears to be determined by the level of cholinergic parasympathetic bronchomotor tone and by inhibition of bronchoconstriction resulting from neural reflex activation of cholinergic pathways.11,190,225,234 The importance of cholinergic tone and neural reflexes in producing bronchoconstriction in airway disease remains to be determined;225,234,244 however, limited evidence indicates that cholinergic tone may be increased in patients with chronic obstructive pulmonary disease (COPD).234,244,291 In animals, the bronchodilator activity of ipratropium is similar to or exceeds that of atropine2,7,12 or isoproterenol and exceeds that of albuterol or metaproterenol when these drugs are given via nebulization.12 In patients with COPD, ipratropium is at least as effective in producing bronchodilation as β-adrenergic agonists.2,55,58,88,118,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,146,198,225,228,244,245,253,254,255,256,258,259,263,292 Combined use of ipratropium and a β₂-adrenergic agonist (e.g., albuterol) results in greater bronchodilation than either drug alone.320,321,327

Ipratropium decreases airway resistance as measured by forced expiratory volume in 1 second (FEV₁)1,4,34,35,36,40,43,44,46,47,53,54,55,58,59,60,61,62,63,64,65,66,67,68,76,77,80,83,86,96,98,114,120,124,126,151,158,225 and forced expiratory flow during the middle half of forced vital capacity (FEF_25-75).1,163,165 Following oral inhalation of ipratropium in patients with pulmonary disease, FVC1,4,56,96,226 and specific airway conductance127 may increase and residual volume (RV) may decrease.61,96,127,225 In dose-ranging studies with ipratropium bromide inhalation aerosol in patients with chronic bronchitis, maximal bronchodilator effects reportedly were evident with ipratropium bromide doses of 36 mcg.2,221,225 Limited data suggest that in patients with COPD, the optimum dose (as determined by maximal increases in FEV₁ and forced vital capacity [FVC]) of nebulized ipratropium bromide is about 400 mcg.86 A 36-mcg dose (2 inhalations) of ipratropium bromide administered via a metered-dose inhaler appears to produce bronchodilation (defined as area under the FEV₁ curve) similar to that produced by a 100-mcg dose of ipratropium bromide administered via a nebulizer.86

While systemic administration of anticholinergic agents can reduce the volume and fluidity of bronchial secretions, orally inhaled ipratropium has little or no effect on respiratory secretions.1,6,197,216,225 Orally inhaled ipratropium does not appear to have any substantial effect on sputum viscosity75,76,77,78,79,80,120,197,212,216,230,281,351 or, unlike atropine,64,65,67,73,74 on mucociliary clearance.1,2,7,64,65,66,67,68,69,71,72,120,197,212,225,230,281,351 Ipratropium decreases ciliary activity in vitro but to a smaller extent than atropine.70 Volume of sputum usually remains unchanged during ipratropium therapy.67,76,77,78,79,80,191,197,212,281,351

Various mechanisms appear to be involved in irritant-, histamine-, exercise-, or allergen-induced bronchoconstriction,19,22,32,36,39,45,47,52,225,232,236,237,238,240 and the protective effect of ipratropium against a bronchoconstrictor stimulus appears to depend in part on the extent to which bronchospasm is mediated by vagal reflexes.10,11,19,20,21,22,23,24,25,26,27,28,32,33,34,35,36,37,38,39,40,41,42,43,44,46,47,48,49,190,191,225,226,232,235,236,237,238,239,240 As expected, orally inhaled ipratropium reliably prevents bronchospasm induced by cholinergic agonists such as methacholine11,20,21,22,23,24,28,48,49,189,225,232,235,238 or acetylcholine25,26,27 in both healthy individuals and asthmatic patients. Ipratropium also prevents bronchospasm induced by irritants such as sulfur dioxide, ozone, or cigarette smoke in healthy individuals,11,225,232 but generally is less effective in asthmatic patients whose airways are more reactive to such stimuli.11,14,26,51,225,232,238,241 Although in some asthmatic patients ipratropium may be effective in preventing bronchospasm provoked by allergens,20,29,49,225,226 histamine,11,30,49,50,189,225,235,237 exercise,19,26,32,33,34,35,36,37,38,39,40,41,42,43,44,46,47 bradykinin,11,235 prostaglandin F_2α,225,239 adenosine monophosphate,237 or substance P (a noncholinergic neurotransmitter),240 patients with asthma exhibit considerable interindividual variation in their response to ipratropium;11,32,33,34,189,225 asthmatic patients in whom bronchoconstriction is mediated principally by the vagal reflex may respond better to the drug than those in whom other mechanisms predominate.32,33,34,190,191,225,237,238,240 Usual doses of orally inhaled ipratropium bromide in asthmatic patients provide little or no protection against bronchospasm induced by serotonin25,26,225 or leukotrienes.11,225 However, the drug does appear to prevent bronchospasm induced by β₂-adrenergic blocking agents,31,194,225 pentamidine,243 or psychogenic stimuli.192,225 In patients with COPD, cholinergic bronchomotor tone is the principal determinant of reversible airway constriction.120,225,234,244,291 Therefore, while patients with asthma show a variable response to anticholinergic bronchodilators, patients with COPD generally respond to these agents.11,225,234,244,291

Inhalation of ipratropium does not appear to produce clinically important alterations in arterial oxygen1,77,81,82,83,98,225,245,309 or carbon dioxide tension;1,58,77,82,83,98,309 however, slight increases or decreases in arterial oxygen tension36,55,58,82,84,85,245 and slight decreases in carbon dioxide tension36,82,85 have been observed in some patients receiving the drug. In a limited number of studies in healthy adults95 or patients with COPD,82 no adverse effects on arterial pH,82,98,245 pulmonary blood pressure,82 or pulmonary diffusing capacity95 were observed following oral inhalation of ipratropium.

Tolerance to the bronchodilating effect of orally inhaled ipratropium does not appear to develop with prolonged use;4,14,90,91,92,115,116,117,118,119,120,121,168,225,278 the bronchodilator effect has been maintained throughout at least 5 years of continuous use in some patients.14,118,120

Cardiovascular Effects

Oral inhalation of ipratropium has not produced appreciable changes in heart rate,1,58,76,82,84,87,88,94,95,96,99,212 blood pressure,1,58,76,82,84,87,88,94,95,96 or cardiac rhythm87,95,99,212 in healthy adults,16,87,94,95 healthy adults with experimentally induced pulmonary hypertension,89 or patients with COPD58,76,82,84,96,99 or hypertension.97 Slight decreases in heart rate, accompanied by increases in stroke volume and ejection fraction, have been observed in healthy adults receiving high doses (e.g., up to 2.4 mg) of ipratropium bromide via a metered-dose inhaler;93,95 however, cardiac output in these patients remained unchanged, and these cardiovascular effects do not appear to be clinically important.93,95,225,228

GI Effects

Although orally inhaled ipratropium appears to have minimal effect on salivary secretions,2,7,12,16 the drug has produced inhibition of salivary secretions in animals7 and in healthy adults when given IV.16 Following oral administration of 15 mg of ipratropium bromide in healthy adults,6,17,100,101 basal gastric acid secretion decreased by 50% and gastric pH increased from 2.5 to 5 within 1 hour.6,17

Ocular Effects

Following IV administration of ipratropium in animals, the mydriatic activity of the drug is similar to that of atropine.7 When given by oral inhalation, ipratropium does not appear to produce mydriasis,102,103,214,286 increased intraocular pressure (IOP),6,102,103,211,246,286 or changes in ocular function2,103,214 in children286 or in adults with normal IOP102,246 or open-angle or angle-closure glaucoma.102,103,246 However, increased IOP and other adverse ocular effects have been reported during treatment with the drug, as a result of inadvertent exposure of the eyes during oral inhalation of ipratropium alone or combined with albuterol.190,191,212,246,247,248,249,287,288,289 (See Cautions: Ocular Effects.)β₂-Adrenergic agonists such as albuterol increase production of aqueous humor which, in combination with restricted outflow caused by anticholinergic-associated pupillary dilatation, may increase IOP and lead to acute angle-closure glaucoma in susceptible individuals (i.e., individuals with untreated or undiagnosed angle-closure glaucoma).246,248,287,288,289

Nervous System Effects

Because of its low lipid solubility, ipratropium, unlike atropine, does not appear to cross the blood-brain barrier.4,7,12,13 Current evidence indicates that the drug produces little or no CNS stimulation.7,12,13

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.4,6,14,106,228,229,230,351 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.4,229 Concomitant oral inhalation of ipratropium and albuterol in a fixed-combination aerosol did not alter the systemic absorption of either component.320 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;2,6,7,109 peak plasma concentrations of about 0.06 ng/mL (as total radioactivity) occurred in about 1-3 hours.6,106,109 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.351 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.351 The trough concentration of ipratropium 6 hours after inhalation in adult and geriatric patients was 28 pg/mL at steady state.351 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.320 Although most of a dose of an orally inhaled drug is actually swallowed,1,2,4,105,108,230 the bronchodilating action of ipratropium appears to result from a local action of the portion of the dose that reaches the bronchial tree.1,4,7,109

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.351,352 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.320 The median duration of bronchodilation was 4-5 hours with the fixed combination and 4 hours with ipratropium alone.320 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.2,162,163,165,166,221,225 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).190,191,225,254

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.4,86,281 In a dose-response study in patients with COPD, the optimal dose of nebulized ipratropium bromide was about 400 mcg.86 Bronchodilation with nebulized ipratropium generally persists for 4-5 hours, but may last up to 7-8 hours in some patients.4,86,281 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.4,281

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.6,7,8,106,109 However, peak plasma radioactivity following administration of radiolabeled ipratropium bromide appears to represent both the parent drug and its metabolites.8 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.229 In these individuals, approximately 3.3% (range: 0.9-6.1%) of the dose of ipratropium bromide was absorbed.229 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;7 plasma concentrations are approximately 1000 times higher following oral administration than following oral inhalation of equipotent doses.7,107,109,228,230 Plasma drug concentrations following oral inhalation of ipratropium bromide do not appear to correlate with pharmacologic effects.2,109

Distribution

Distribution of ipratropium bromide into human tissues and body fluids has not been elucidated.6,228 Quaternary ammonium antimuscarinics are completely ionized and possess poor lipid solubility; accordingly, they do not readily penetrate the CNS.2,4,12 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;6,8,107 the drug is minimally distributed into brain, lung, and muscle.6,8 High concentrations of ipratropium bromide in the gut in these animals may indicate biliary elimination or enterohepatic circulation.6,8,107,110

Ipratropium bromide reportedly is 0-9% bound to plasma albumin and α₁-acid glycoproteins in vitro.1,4

It is not known whether ipratropium bromide crosses the placenta or is distributed into milk.1,4,6

Elimination

Following IV administration of ipratropium bromide in healthy adults, plasma drug concentrations appear to decline in a biphasic manner.106,229 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.1,106,107,109,190 However, this method measures both ipratropium bromide and its metabolites.106,109,190,229 Using a radioreceptor assay that measures only unchanged ipratropium bromide, the initial distribution-phase half-life (t_½α) and the terminal elimination-phase half-life (t_½β) following a single 2-mg IV dose of the drug in healthy adults averaged about 0.07 and 1.6 hours, respectively.4,190,229

The exact metabolic fate of ipratropium bromide has not been fully determined.6,7,8,106,107,109 Following oral or IV administration or oral inhalation, the drug is partially metabolized to at least 8 metabolites.4,8,106 Metabolism appears to involve only the tropic acid moiety6,7,107 and usually consists of hydrolysis7,8 and conjugation.8,109 The main metabolites appear to be N -isopropylnortropium methobromide,106,109 which is formed by enzymatic hydrolysis of the ester;8,229α-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.229 In vitro, these metabolites have minimal or no antimuscarinic activity.6

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.1,8,106,109 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.320 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.2,3,6,7,107,109 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.6,106,109 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,6,7,106,109 and about 89 or 6% of the oral or IV dose was excreted in feces6,106,109 within 5-7 days;6,106 most excretion occurred within 24 hours.6,107,109 Ipratropium bromide undergoes biliary elimination110 and/or enterohepatic circulation in animals6 and appears to undergo some biliary elimination in humans.6,7

Chemistry and Stability

Chemistry

Ipratropium bromide is a synthetic quaternary ammonium antimuscarinic agent.1,2,3,4,6,7,12,13,14,224,281 Ipratropium is the quaternary N -methyl isopropyl derivative of noratropine.7,8 The drug is commercially available as the monobromide monohydrate (i.e., ipratropium bromide) in an oral aerosol formulation and in a solution for nebulization.1,3,4,5,7,8,282 Ipratropium bromide is also available in fixed combination with albuterol sulfate in an oral aerosol formulation and in a solution for nebulization.320,327 However, potencies of the commercially available preparations differ, the aerosol being expressed in terms of the monohydrate and the solution for nebulization being expressed in terms of anhydrous drug.1,4,329,330

Ipratropium bromide, which is hydrated, occurs as a white, bitter-tasting crystalline powder1,3,4,5,7,8,282,351 and has solubilities of 90 mg/mL in water and 28 mg/mL in alcohol.1,2,4,190,282 Like other quaternary ammonium compounds, ipratropium exists in an ionized state in aqueous solutions4 and is insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons.5,225,320,351 A 1% aqueous solution of ipratropium bromide has a pH of 5-7.5.2,190,281

Ipratropium bromide inhalation aerosol is commercially available as a solution of the drug in a vehicle containing a hydrofluoroalkane (tetrafluoroethane) propellant, water, dehydrated alcohol, and anhydrous citric acid.351 For oral inhalation, ipratropium bromide in fixed combination with albuterol sulfate, is commercially available as an aerosol containing a microcrystalline suspension of the drug (as the monohydrate) in a vehicle of chlorofluorocarbon propellants (dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane) and soya lecithin.190,320 Each actuation of the aerosol inhaler delivers 17 mcg of ipratropium bromide monohydrate from the mouthpiece.351 Each actuation of the combination aerosol inhaler delivers 18 mcg of ipratropium bromide monohydrate and 103 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) from the mouthpiece.320

For oral administration by nebulizer, ipratropium bromide is commercially available as a 0.02% solution (expressed in terms of anhydrous drug) in 0.9% sodium chloride; hydrochloric acid may be added to adjust the pH to 3.4 (3-4).4,282,329,330 Ipratropium bromide also is available in fixed combination with albuterol sulfate as a 0.017% solution (expressed in terms of the anhydrous drug) in sodium chloride; hydrochloric acid may be added to adjust the pH to 4.327,330 Each 3-mL unit-dose vial of ipratropium bromide in fixed combination with albuterol sulfate inhalation solution contains 0.5 mg of ipratropium bromide and 2.5 mg of albuterol (equivalent to 3 mg of albuterol sulfate).327 The commercially available solutions for nebulization are sterile, clear, colorless and do not contain preservatives.4,327

Stability

Commercially available ipratropium bromide alone or in fixed combination with albuterol sulfate oral inhalation aerosol should be stored at 25 °C but may be exposed to temperatures ranging from 15 to 30°C; exposure to excessive humidity should be avoided.320,346,351 For best results, the aerosol canister should be at room temperature before use;190,283,284,320,346,351 at colder temperatures, cooling of the propellants may decrease the internal pressure of the canister283 and result in delivery of particles too large to provide full therapeutic effect.190,284 Because the contents of ipratropium bromide inhalation aerosol are under pressure, the aerosol container should not be punctured, used or stored near heat or an open flame, or placed into a fire or incinerator for disposal;1,9,320,346,351 exposure to high temperatures (49°C) may cause the canister to burst.1,320,346,351 When stored as directed, commercially available ipratropium bromide inhalation aerosol is stable for 18 months from the date of manufacture.3

Commercially available ipratropium bromide inhalation solutions for nebulization should be stored at 15-30°C and protected from light, preferably in the manufacturer-supplied foil pouch.4,281 The commercially available inhalation solution of ipratropium bromide in fixed combination with albuterol sulfate should be stored at 2-30°C and be protected from light, preferably in the manufacturer-supplied foil pouch.327,328 When stored as directed, ipratropium bromide inhalation solution has an expiration date of 18 months following the date of manufacture.282

The manufacturer states that solutions containing ipratropium bromide and albuterol sulfate or metaproterenol sulfate for oral inhalation are stable for 1 hour when mixed extemporaneously in a nebulizer prior to administration.4,190 Ipratropium bromide oral inhalation solution also has been reported to be stable for 1 hour when mixed in a nebulizer with cromolyn sodium.190,209,215 The manufacturer states that the stability and safety of ipratropium bromide inhalation solution mixed with other drugs in a nebulizer have not been established.4,190

Additional Information

For further information on the chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, and drug interactions of ipratropium bromide, see the Antimuscarinics/Antispasmodics General Statement 12.08.08.

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