IPRATROPIUM BROMIDE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Inhalation Administration
Oral Inhalation Administration
Aerosol Inhalation (metered-dose inhaler [MDI])
-Instruct patient and/or caregiver on proper inhalation technique. Make sure the canister is firmly seated in the plastic mouthpiece actuator before each use. The inhaler does not need to be shaken. Prime the inhaler prior to the initial use by releasing 2 sprays into the air, away from the face and other people. If not used for > 3 days, re-prime the inhaler.
-For patients of any age unable to coordinate inhalation and actuation, a spacer or valved holding chamber (VHC) may be beneficial.
-The choice of using a mouthpiece versus a face mask with a spacer/VHC device must be made based on the skills and understanding of each individual patient. However, in general, children < 4 years require administration with a tight fitting face mask and spacer/VHC device to achieve optimal delivery. If a face mask is used, allow 5-6 inhalations per actuation.
-After administration, instruct patient to rinse mouth with water to minimize dry mouth.
-Clean the plastic mouthpiece of the inhaler at least once a week. After removing the medication canister, wash the mouthpiece in warm running water for at least 30 seconds. Shake excess water from the mouthpiece and verify that all medication build-up has been rinsed away. Allow the mouthpiece to air-dry completely before next use (e.g., overnight).
-Some products may have an actuation counter. Discard medication and inhaler after expiration date or once the labeled number of actuations have been expelled, whichever comes first.
-To avoid the spread of infection, do not use the inhaler for more than 1 person.

Inhalation Solution for Nebulization
-Nebulization solution may be mixed with albuterol in the nebulizer if used within one hour.
-Do not mix ipratropium with cromolyn nebulizer solutions; they are not compatible.
-Deliver solution by nebulization over 5-15 minutes.
-The choice of using a mouthpiece versus a face mask must be made based on the skills and understanding of each individual patient. If a face mask is used, care should be taken to avoid leakage around the mask to avoid local ocular side effects.
-Using the 'blow by' technique (i.e., holding the face mask or open tube near the patient's nose and mouth) is not recommended.
-Storage: Unit-dose vials should be stored in the protective foil pouch at all times. Protect from light.



Other Administration Route(s)
Intranasal Administration
-Instruct patient and/or caregiver on the proper use of the nasal spray.
-Prime the bottle prior to the initial use by pumping the activator 7 times into the air, away from the face and other people, until a fine wide spray appears. If not used for > 24 hours, re-prime the bottle with 2 sprays. If not used for > 7 days, re-prime as if new.
-The patient should blow their nose, close one nostril, and tilt head slightly forward. After placing the applicator toward to back outer side of the open nostril, press down firmly and quickly on the applicator while breathing in. Expiration should occur through the mouth. After administration, tilt head backwards momentarily to let spray spread over back of nose. Repeat for other nostril.
-After administration, rinse the tip of the spray bottle with warm water for 1 minute, taking care not to suck water into the bottle, and dry with a clean tissue. Re-prime the nasal spray pump and replace the cap.
-To avoid the spread of infection, do not use the sprayer for more than 1 person.

Incidences of adverse reactions specifically in pediatric populations are not available. Adverse reaction data for the orally inhaled ipratropium products are derived from adult trials of chronic obstructive pulmonary disease (COPD), as reported by the manufacturer. The safety profile of ipratropium nasal spray is reported to be similar to that in adults. The adverse reaction profile of ipratropium varies with route of administration. Adverse reactions may represent local or systemic anticholinergic effects.

Paradoxical bronchospasm can occur after treatment with ipratropium aerosol and can be life threatening. If this occurs, ipratropium should be discontinued immediately. Rare cases of anaphylactoid reactions have occurred with the use of ipratropium. In clinical trials, some cases were confirmed by re-challenge with the medication. Reactions included pruritus, urticaria, rash (unspecified), oropharyngeal edema, angioedema, and laryngospasm. Many of the affected patients had documented allergies to other drugs and foods, including soybeans, legumes, or soya lecithin. Atrovent HFA no longer contains soya lecithin or any soy ingredient. Preservatives and additives (e.g., benzalkonium chloride, edetate disodium) that were commonly found in earlier formulations of nebulized bronchodilator solutions have been implicated as a cause of administration-induced bronchospasm.

Gastrointestinal (GI) complaints associated with the use of ipratropium in adult patients include nausea (4%), vomiting, dyspepsia (1-5%), diarrhea (2%), bowel obstruction, constipation (1%), gastroparesis, and GI obstruction. Mild complaints include xerostomia (1.5-4%), hoarseness/throat irritation (< 1%), polydipsia (< 1%), and dysgeusia (1-4%). Rarely, oral ulceration or stomatitis has been reported. Many of these symptoms are related to the anticholinergic properties of ipratropium.

Anticholinergic agents, like ipratropium, may increase intraocular pressure and aqueous outflow resistance and may precipitate or worsen ocular hypertension, corneal edema, or closed-angle glaucoma. Inadvertent ocular exposure may cause temporary ocular pain, ocular irritation, mydriasis, cycloplegia, blurred vision, conjunctivitis, or visual impairment (e.g., halo vision, accomodation disorder). Care should be taken not to spray ipratropium in the eyes; use of a nebulizer with mouthpiece rather than a face mask may be preferable to reduce the risk of solution reaching the eyes during nebulization. Patients wearing contact lenses may experience blurred vision related to xerophthalmia. The use of lubricating drops may alleviate these symptoms. In addition, less than 1% of patients receiving ipratropium nasal spray reported tinnitus during clinical trials.

Anticholinergic agents may cause urinary retention. Urinary retention (< 3%), urinary tract infection (<= 10%), and prostate disorders have been reported in adult patients taking orally inhaled or intranasal ipratropium. Ipratropium should be used with caution in patients with preexisting urinary tract or bladder obstruction.

Intranasal ipratropium causes nasal dryness in about 5% of patients. The most common adverse effect after intranasal use of ipratropium is epistaxis or blood-tinged nasal mucus, occurring in about 6-8% of patients. Epistaxis rarely requires medical attention; local application of pressure and the application of an emollient such as petrolatum adequately treats most episodes. Nasal congestion (1%) and general nasal irritation (burning, itching and ulcerative rhinitis) have also been reported with nasal product use. There has been no evidence of nasal rebound after intranasal use of ipratropium. Rhinitis (>= 2%) and sinusitis (1-11%) have been reported with use of intranasal and oral inhalation products.

Symptoms affecting the nervous system after ipratropium use in adult patients include dizziness (2-3%) and headache (4-7%), and to a lesser extent insomnia (1%), tremor (1%), and nervousness (0.5%).

Supraventricular tachycardia (SVT) and atrial fibrillation have been reported after use of ipratropium oral inhalation products in adult patients. Additionally, there have been reports of palpitations, sinus tachycardia, chest pain (unspecified) (3%), and edema possibly associated with ipratropium use. Young patients receiving inhaled anticholinergic agents may also be at increased risk of arrhythmia or arrhythmia exacerbation. In a cohort of 283,429 asthmatics (age range: 5-24 years) with no history of arrhythmia or congenital heart disease, active use of an inhaled anticholinergic was associated with a 1.56-fold increase in arrhythmia risk compared to non-use or non-active use (adjusted OR 1.56, 95% CI 1.08-2.25). Risk was highest among active users of ipratropium; however, tiotropium sample size was limited. In addition, risk was increased in those receiving high-dose therapy (defined as > 0.114 mg of ipratropium equivalents; adjusted OR 1.69, 95% CI 1.1-2.59) and monotherapy (adjusted OR 1.59, 95% CI 1.08-2.33) compared to those receiving low-dose therapy (defined as <= 0.114 mg ipratropium equivalents; adjusted OR 1.22, 95% CI 0.53-2.65) and combination ipratropium/short-acting beta agonist therapy (adjusted OR 1.2, 95% CI 0.74-1.94), respectively. Rarely, hypotension may occur as a result of the anticholinergic effects of ipratropium.

Various respiratory and infectious adverse events have been reported in patients receiving ipratropium. Cough (>= 3%), upper respiratory tract infection (>= 3%), bronchitis (10-23%), dyspnea (7-10%), pharyngitis (4%), symptoms of influenza (4-8%), and increased sputum (1.5%) have been reported during clinical trials of oral inhalation products in adults with chronic obstructive pulmonary disease (COPD). Cough (< 1%), pharyngitis (5%), and wheezing have also been reported with nasal spray use.

Back pain (2-7%), musculoskeletal pain (2-4%), arthralgia (1%), and paresthesias have been reported during ipratropium clinical trials.

Do not use ipratropium products in patients with ipratropium bromide hypersensitivity. Ipratropium is a derivative of and structurally similar to atropine; as such, use is contraindicated in patients with atropine hypersensitivity or atropine derivative hypersensitivity. Immediate hypersensitivity reactions may occur after administration, as demonstrated by rare cases of urticaria, angioedema, oropharyngeal edema, laryngospasm, and anaphylaxis. In addition, ipratropium aerosols can produce paradoxical bronchospasm, which may be life threatening. If hypersensitivity or paradoxical bronchospasm occurs, discontinue ipratropium immediately and alternative therapy instituted (e.g., albuterol). It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, most frequently occurs with the first use of a new canister.

The National Asthma Education and Prevention Program (NAEPP) Expert Panel considers ipratropium a quick-relief medication to treat acute bronchospasm and exacerbations of asthma; however, it recommends using ipratropium for additive benefit in combination with a short-acting beta2-agonist (SABA) only in the emergency care setting (e.g., not the hospital). Though ipratropium may be used as an alternative bronchodilator in patients who do not tolerate SABAs, SABAs are the preferred pharmacologic treatment to relieve acute bronchospasm.

Anticholinergics should be used with caution in patients with closed-angle glaucoma. While significant systemic absorption of ipratropium is unlikely, use may increase intraocular pressure and aqueous outflow resistance in patients with closed-angle glaucoma, particularly if the medication gets into the eyes (i.e., inadvertent ocular exposure). Temporary pain, mydriasis, cycloplegia, blurred vision, conjunctivitis, or visual impairment may result from inadvertent ophthalmic administration. Care should be taken not to spray ipratropium in the eyes; use of a nebulizer with a mouthpiece rather than a face mask may be preferable to reduce risk of solution reaching the eyes during nebulization. The anticholinergic effects of ipratropium may make the eyes dry, causing irritation or blurred vision for wearers of contact lenses. The use of lubricating drops may be necessary.

Anticholinergics may cause urinary retention and should be used with caution in patients with preexisting urinary tract or bladder obstruction. Although inhaled ipratropium is only minimally absorbed into the systemic circulation, the effects of ipratropium may be additive to other concomitantly administered anticholinergic medications.

Use ipratropium with caution in patients at risk for cardiac arrhythmias. In a cohort of 283,429 asthmatics (age range: 5-24 years) with no history of arrhythmia or congenital heart disease, active use of an inhaled anticholinergic was associated with a 1.56-fold increase in arrhythmia risk compared to non-use or non-active use (adjusted OR 1.56, 95% CI 1.08-2.25). Risk was highest among active users of ipratropium; however, tiotropium sample size was limited. In addition, risk was increased in those receiving high-dose therapy (defined as > 0.114 mg of ipratropium equivalents; adjusted OR 1.69, 95% CI 1.1-2.59) and monotherapy (adjusted OR 1.59, 95% CI 1.08-2.33) compared to those receiving low-dose therapy (defined as <= 0.114 mg ipratropium equivalents; adjusted OR 1.22, 95% CI 0.53-2.65) and combination ipratropium/short-acting beta agonist therapy (adjusted OR 1.2, 95% CI 0.74-1.94), respectively.

Description: Ipratropium bromide is a quaternary anticholinergic amine used as a nasal spray for symptoms of allergic rhinitis or other forms of rhinitis in pediatric patients. Ipratropium is often also used in combination with other bronchodilators (e.g., albuterol) by oral inhalation or nebulization for the treatment of bronchospasm. Ipratropium has been studied in the treatment of asthma; a disadvantage of ipratropium vs. SABAs includes a slower onset of action. Ipratropium provides some additive benefits during short-term use to treat moderate-severe acute asthma exacerbation when administered along with a SABA. There is a lowered incidence of hospitalization and a greater improvement in FEV1 if ipratropium is combined with SABAs vs. use of SABAs alone in the emergency department in children with severe asthma exacerbation; however, if a child is hospitalized, there appears to be no benefit of continued combined ipratropium/SABA use vs. use of a SABA alone in terms of length of stay. Ipratropium is not recommended as an asthma maintenance treatment as an additive benefit to standard controller medications has not been demonstrated. Ipratropium is much less effective than a SABA as an agent to prevent exercise-induced bronchospasm (EIB). Ipratropium nasal spray is FDA-approved for children as young as 5 years old; while inhalation dosage forms are not approved for use for pediatric patients, ipratropium inhalations are used off-label in children in combination with SABAs for asthma exacerbation.

For the treatment of asthma exacerbation*:
Respiratory (Inhalation) dosage (inhalation aerosol; e.g., Atrovent HFA):
Infants and Children 1 to 5 years: 160 mcg (approximately 9 actuations of 17 mcg/actuation) inhaled by mouth every 20 minutes for up to 1 hour has been recommended for moderate to severe asthma exacerbation in the emergency care setting in addition to a short-acting beta-agonist (SABA) if poor response to initial SABA alone. Alternately, 68 to 136 mcg (4 to 8 actuations of 17 mcg/actuation) every 20 minutes as needed for up to 3 hours has been used. Data suggest that ongoing use of ipratropium in addition to SABA beyond 1 hour is unlikely to confer additional benefit vs. as-needed use of the SABA alone in this population.
Children 6 to 12 years: 68 to 136 mcg (4 to 8 actuations of 17 mcg/actuation) inhaled by mouth every 20 minutes as needed for up to 3 hours has been recommended for severe asthma exacerbation in the emergency care setting in addition to a short-acting beta-agonist (SABA). Adding ipratropium to albuterol has not been shown to provide further benefit once the patient is hospitalized.
Adolescents: 136 mcg (8 actuations of 17 mcg/actuation) inhaled by mouth every 20 minutes as needed for up to 3 hours has been recommended for severe asthma exacerbation in the emergency care setting in addition to a short-acting beta-agonist (SABA). Adding ipratropium to albuterol has not been shown to provide further benefit once the patient is hospitalized.
Respiratory (Inhalation) dosage (inhalation solution):
Infants and Children 1 to 5 years: 250 mcg inhaled by nebulizer every 20 minutes for up to 1 hour has been recommended for moderate to severe asthma exacerbation in the emergency care setting in addition to a short-acting beta-agonist (SABA) in patients with poor response to initial SABA alone. Alternately, 250 to 500 mcg inhaled by nebulizer every 20 minutes for 3 doses, then as needed for up to 3 hours has been used. Data suggest that ongoing use of ipratropium in addition to SABA beyond 1 hour is unlikely to confer additional benefit vs. as-needed use of the SABA alone in this population.
Children 6 to 12 years: 250 to 500 mcg inhaled by nebulizer every 20 minutes for 3 doses, then as needed for up to 3 hours for initial management of severe asthma exacerbation in the emergency care setting in addition to a short-acting beta-agonist (SABA). Adding ipratropium to albuterol has not been shown to provide further benefit once the patient is hospitalized.
Adolescents: 500 mcg inhaled by nebulizer every 20 minutes for 3 doses, then as needed for up to 3 hours for initial management of severe asthma exacerbation in the emergency care setting in addition to a short-acting beta-agonist (SABA). Adding ipratropium to albuterol has not been shown to provide further benefit once the patient is hospitalized.

For exercise-induced bronchospasm prophylaxis*:
Oral Inhalation dosage (inhalation aerosol; e.g., Atrovent HFA):
Children and Adolescents 9 to 17 years: 34 mcg (2 actuations of 17 mcg/actuation) via oral inhalation 15 to 30 minutes before exercise. Due to low-quality clinical evidence, ipratropium should not be used as a first-line treatment; it has a slower onset than short-acting beta agonists and is less effective than short-acting beta-agonists and controller therapies.

For the management of rhinorrhea due to the common cold, seasonal allergies, or perennial allergies, including nonallergic and allergic rhinitis:
-for rhinorrhea due to seasonal allergies or the common cold:
Nasal dosage (0.06% nasal solution):
Children 5 to 11 years: For common cold: 2 sprays (84 mcg) per nostril 3 times per day; do not exceed 4 days of use. For seasonal allergic rhinitis, 2 sprays (84 mcg) per nostril 4 times per day; limit use to 3 weeks.
Children and Adolescents 12 years and older : For common cold: 2 sprays (84 mcg) per nostril 3 or 4 times per day; do not exceed 4 days of use. For seasonal allergic rhinitis, 2 sprays (84 mcg) per nostril 4 times per day; limit use to 3 weeks.
-for rhinorrhea due to allergic or nonallergic perennial rhinitis:
Nasal dosage (0.03% nasal solution):
Children and Adolescents 6 years and older: 2 sprays (42 mcg) per nostril 2 or 3 times per day.

For adjunctive treatment of neonatal respiratory illness, such as those with suspected airway reactivity*, bronchopulmonary dysplasia*, or chronic lung disease (CLD)*:
Nebulized Inhalation dosage (solution for nebulization):
Neonates: 175 mcg alone or in combination with albuterol or 25 mcg/kg/dose via nebulizer has been studied. Frequency of administration has not been established in neonates, but has been administered safely 3 times a day in older infants. A significant reduction of respiratory system resistance compared to baseline was seen after a single 25 mcg/kg dose in ventilator dependent premature neonates (n = 5; mean gestational age, 26 weeks; mean weight at study, 1.1 kg). A single 175 mcg dose was the only studied dose to lead to a significant decrease in respiratory system resistance and increased compliance 1 to 2 hours after administration in a dose finding study (n = 10; mean gestational age, 27 weeks; mean weight, 985 grams). The 175 mcg dose in combination with albuterol provided the largest decrease in respiratory system resistance.
Oral Inhalation dosage (inhalation aerosol):
Neonates: 4 oral inhalations of 17 mcg/actuation (approximate total: 72 mcg) via metered dose inhaler and spacer has been shown to improve respiratory mechanics short term in a small study of mechanically ventilated patients with respiratory distress syndrome (n = 10; median gestational age, 28 weeks; median weight, 880 grams). Alternatively, 2 oral inhalations of 20 mcg/actuation given every 20 minutes for a total of 2 doses was shown to significantly improve respiratory system resistance in the highest proportion of patients studied (38%; n = 21; mean gestational age, 27 weeks; mean weight at study, 1 kg). Frequency of administration has not been established in neonates, but has been administered safely 3 times a day in older infants.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; oral inhalation maximum dependent on patient response and formulation used.
-Infants
Safety and efficacy have not been established; oral inhalation maximum dependent on patient response and formulation used.
-Children
1 to 4 years: Safety and efficacy have not been established; oral inhalation maximum dependent on patient response and formulation used.
5 to 11 years: 504 mcg/day intranasally. Safety and efficacy of orally inhaled formulations have not been established; oral inhalation maximum dependent on patient response and formulation used.
12 years: 672 mcg/day intranasally. In general, a maximum of 12 puffs/day for HFA inhaler has been reported; FDA-approved labeling for nebulizer solution for oral inhalation recommends not exceeding 4 doses/day or 2,000 mcg/day (0.02% nebulizer solution). Higher maximum dosages for inhalation products have been recommended in NAEPP guidelines for acute exacerbations of asthma in the emergency care setting.
-Adolescents
672 mcg/day intranasally. In general, a maximum of 12 puffs/day for HFA inhaler has been reported; FDA-approved labeling for nebulizer solution for oral inhalation recommends not exceeding 4 doses/day or 2,000 mcg/day (0.02% nebulizer solution). Higher maximum dosages for inhalation products have been recommended in NAEPP guidelines for acute exacerbations of asthma in the emergency care setting.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Ipratropium antagonizes the action of acetylcholine by blocking muscarinic cholinergic receptors. Blockade of cholinergic receptors decreases the formation of cyclic guanosine monophosphate (cGMP). In the airways, this ultimately results in decreased contractility of smooth muscle, perhaps due to actions of cGMP on intracellular calcium. Ipratropium is not selective for specific subtypes of muscarinic receptors.

The actions of ipratropium parallel those of atropine on the bronchial smooth muscle, salivary glands, GI tract, and heart when administered by the intravenous route. When administered by oral inhalation, however, ipratropium exhibits greater antimuscarinic activity on the bronchial smooth muscle; systemic effects are minimal. Compared with atropine, ipratropium is roughly twice as potent as a bronchodilator, and it exhibits a more favorable ratio of bronchodilation to inhibition of salivary secretion. Bronchodilation after inhalation of ipratropium is secondary to local effects rather than a systemic effect. Ipratropium does not possess antiinflammatory properties.

Intranasal administration of ipratropium produces a localized parasympatholytic effect. This action reduces watery hypersecretion from mucosal glands of the nose thereby relieving rhinorrhea associated with the common cold or allergic or nonallergic seasonal rhinitis.

Pharmacokinetics: Ipratropium bromide is administered via oral inhalation or intranasal spray. Minimal protein binding (0-9% in vitro) of ipratropium occurs to albumin and alpha1-acid glycoprotein. Ipratropium penetrates the central nervous system (CNS) poorly, which relates to ipratropium being a quaternary compound rather than a tertiary one (e.g., atropine). Metabolism occurs by ester hydrolysis to inactive metabolites. Approximately 50% of the absorbed drug is excreted unchanged in the urine. The systemic elimination half-life of ipratropium is about 2 hours.


-Route-Specific Pharmacokinetics
Inhalation Route
After oral inhalation of ipratropium, most of the dose is swallowed and excreted unchanged in the feces. Ipratropium bromide is not readily absorbed into the systemic circulation after inhalation either from the surface of the lung or from the gastrointestinal tract as confirmed by blood concentration and renal excretion studies. In adult patients with chronic obstructive pulmonary disease (COPD), serial FEV1 measurements demonstrate that the median time to onset of ipratropium inhalation (i.e., a 15% increase in FEV1) is 15-30 minutes and the median time to peak FEV1 is 1-2 hours. The median duration of effect as measured by FEV1 is 4-5 hours.

Other Route(s)
Intranasal Route
After intranasal dosing, less than 20% of an ipratropium dose is absorbed from the nasal mucosa into the systemic circulation. After administration of 84 mcg of ipratropium per nostril three times daily in pediatric patients 5-18 years of age, plasma concentrations were low, ranging from undetectable to 0.62 ng/ml.