Ipratropium Bromide

(BAN, USAN, rINN)
Ipratropium Bromide Chemical formula
Synonyms: Bromuro de ipratropio; Ipratropii bromidum; Ipratropii Bromidum Monohydricum; Ipratropio bromidas; Ipratropiowy bromek; Ipratropium bromid monohydrát; Ipratropium, bromure d’; Ipratropiumbromid; Ipratropium-bromid; Ipratropiumbromidi; Ipratropyum Bromür; Sch-1000; Sch-1000-Br-monohydrate. (1R,3r,5S,8r)-8-Isopropyl-3-[(±)-tropoyloxy]tropanium bromide monohydrate.
Cyrillic synonym: Ипратропия Бромид.

💊 Chemical information

Chemical formula: C20H30BrNO3,H2O = 430.4.
CAS — 22254-24-6 (anhydrous ipratropium bromide); 66985-17-9 (ipratropium bromide monohydrate).
ATC — R01AX03; R03BB01.
ATC Vet — QR01AX03; QR03BB01.

Pharmacopoeias.

In Eur., Jpn, and US.

Ph. Eur. 6.2

(Ipratropium Bromide). White or almost white crystalline powder. Soluble in water; slightly soluble in alcohol; freely soluble in methyl alcohol. The pH of a 1% solution in water is 5.0 to 7.5.

USP 31

(Ipratropium Bromide). A white to off-white, crystalline powder. Soluble in water; slightly soluble in alcohol; freely soluble in methyl alcohol. A 10% solution has a pH of 5 to 7. Store in airtight containers.

Stability.

In a study 1 of the stability of admixtures of ipratropium and salbutamol nebuliser solutions equal ratio mixtures were found to retain more than 90% of their initial concentrations after storage for 5 days at 4° or 22° in the dark or at 22° under continuous fluorescent lighting. 1. Jacobson GA, Peterson GM. Stability of ipratropium bromide and salbutamol nebuliser admixtures. Int J Pharm Pract 1995; 3: 169–73.

💊 Adverse Effects and Precautions

Ipratropium and other inhaled antimuscarinic bronchodilators commonly cause dry mouth and constipation, and rarely, urinary retention. They should be used with care in prostatic hyperplasia. Acute angle-closure glaucoma has been reported; the mist or solution should not be allowed to enter the eyes, particularly in patients susceptible to glaucoma. As with other bronchodilators, paradoxical bronchospasm has occurred. Tachycardia, palpitations, and arrhythmias have been reported with ipratropium. Hypersensitivity reactions, including urticaria, angioedema, rash, and anaphylaxis have occurred rarely. Nausea and vomiting, dyspepsia, headaches, and dizziness have also been reported. Intranasal ipratropium has been associated with nasal dryness, irritation, and epistaxis. For details of the adverse effects of, and precautions for, antimuscarinics in general, see Atropine.

Buccal ulceration.

A report1 of inflammation and ulceration of the buccal mucosa associated with the use of an ipratropium bromide inhaler.
1. Spencer PA. Buccal ulceration with ipratropium bromide. BMJ 1986; 292: 380.

Effects on the eyes.

Ocular complications have been reported with the use of aerosolised ipratropium. A patient with a history of glaucoma developed angle-closure glaucoma after use of ipratropium from a metered dose inhaler (MDI) with nebulised salbutamol.1 Pupillary dilatation2 and blurred vision3 have been reported in association with ipratropium given through a spacer device in patients also given salbutamol therapy, and a 4-year-old child who attempted to self-administer an ipratropium MDI developed anisocoria (unequal dilatation of the pupils) and ataxia.4Angle-closure glaucoma,5-7 pupillary dilatation,7-10 and anisocoria11,12 have been reported in patients given nebulised ipratropium, usually with salbutamol, through a poorly fitting face mask. The antimuscarinic effects of ipratropium can lead to impaired drainage of aqueous humour in the eyes of patients predisposed to angle-closure glaucoma; use with salbutamol may intensify this problem by increasing the production of aqueous humour.6 Studies13,14 suggest that patients with a history of angle-closure glaucoma might be at an increased risk of developing glaucoma when nebulised ipratropium and salbutamol are used together.
1. Hall SK. Acute angle-closure glaucoma as a complication of combined β-agonist and ipratropium bromide therapy in the emergency department. Ann Emerg Med 1994; 23: 884–7
2. Weir REP, et al. Pupil blown by a puffer. Lancet 2004; 363: 1853
3. Kizer KM, et al. Blurred vision from ipratropium bromide inhalation. Am J Health-Syst Pharm 2000; 57: 996–7
4. Bond DW, et al. Mydriasis due to self-administered inhaled ipratropium bromide. Eur J Pediatr 2002; 161: 178
5. Packe GE, et al. Nebulised ipratropium bromide and salbutamol causing closed-angle glaucoma. Lancet 1984; ii: 691
6. Shah P, et al. Acute angle closure glaucoma associated with nebulised ipratropium bromide and salbutamol. BMJ 1992; 304: 40–1
7. Mulpeter KM, et al. Ocular hazards of nebulized bronchodilators. Postgrad Med J 1992; 68: 132–3
8. Roberts TE, Pearson DJ. Wide eyed and breathless. BMJ 1989; 299: 1348
9. Woelfle J, et al. Unilateral fixed dilated pupil in an infant after inhalation of nebulized ipratropium bromide. J Pediatr 2000; 136: 423–4
10. Openshaw H. Unilateral mydriasis from ipratropium in transplant patients. Neurology 2006; 67: 914–15
11. Lust K, Livingstone I. Nebulizer-induced anisocoria. Ann Intern Med 1998; 128: 327
12. Iosson N. Nebulizer-associated anisocoria. N Engl J Med 2006; 354: e8
13. Watson WTA, et al. Effect of nebulized ipratropium bromide on intraocular pressures in children. Chest 1994; 105: 1439–41
14. Kalra L, Bone MF. The effect of nebulized bronchodilator therapy on intraocular pressures in patients with glaucoma. Chest 1988; 93: 739–41.

Effects on the gastrointestinal tract.

Paralytic ileus developed shortly after starting ipratropium therapy in 2 patients, apparently due to the inadvertent swallowing of the drug during inhalation.1,2 Both patients also had other predisposing factors for paralytic ileus (cystic fibrosis,1 spastic diplegia2).
1. Mulherin D, FitzGerald MX. Meconium ileus equivalent in association with nebulised ipratropium bromide in cystic fibrosis. Lancet 1990; 355: 552
2. Markus HS. Paralytic ileus associated with ipratropium. Lancet 1990; 355: 1224.

Effects on the respiratory tract.

Antimuscarinics typically inhibit mucociliary clearance and inhibit secretions of the nose, mouth, pharynx, and bronchi. However, inhaled ipratropium bromide has virtually no effect on sputum viscosity or volume and, in contrast to atropine, it does not affect mucociliary function in the respiratory tract.1,2
1. Gross NJ. Ipratropium bromide. N Engl J Med 1988; 319: 486–94
2. Mann KV, et al. Use of ipratropium bromide in obstructive lung disease. Clin Pharm 1988; 7: 670–80.
BRONCHOSPASM. Paradoxical bronchoconstriction occurring after the use of ipratropium was reported in 3 patients.1 A further report2 of paradoxical bronchoconstriction after nebulised salbutamol and ipratropium suggested that this adverse effect might have been caused by benzalkonium chloride present in the nebuliser solutions. Nebuliser solutions of ipratropium in some countries contain benzalkonium chloride as a preservative. Solutions available in the UK are preservativefree but licensed product information still recommends that the first doses of ipratropium nebuliser solution should be inhaled under medical supervision.
1. Connolly CK. Adverse reaction to ipratropium bromide. BMJ 1982; 285: 934–5
2. Boucher M, et al. Possible associations of benzalkonium chloride in nebulizer solutions with respiratory arrest. Ann Pharmacother 1992; 26: 772–4.

Effects on the urinary tract.

Treatment with nebulised ipratropium bromide has resulted in urinary retention in elderly men especially those with prostatic hyperplasia.1,2
1. Lozewicz S. Bladder outflow obstruction induced by ipratropium bromide. Postgrad Med J 1989; 65: 260–1
2. Pras E, et al. Urinary retention associated with ipratropium bromide. DICP Ann Pharmacother 1991; 25: 939–40.

Increased mortality.

A case-control study found an unexpected association between death from asthma and treatment with ipratropium, which was not explained by co-morbidity due to chronic obstructive airways disease.1 A retrospective cohort study2 of elderly patients found no increase in all-cause mortality associated with the use of ipratropium for chronic obstructive pulmonary disease (COPD). In patients with asthma there was a slight increase in the risk of death, but this may have been due to the confounding effect of disease severity. A later longitudinal cohort study of 1100 patients with obstructive lung disease found an increased risk of premature death associated with ipratropium in both asthma and COPD patients.3 After adjusting for confounding factors such as forced expiratory volume, smoking status, BMI, and presence of cor pulmonale, ipratropium was associated with a mortality risk ratio (RR) of 2.4 in asthmatic patients and 1.6 in COPD patients. Again, residual confounding by disease severity could not be ruled out.
1. Guite HF, et al. Risk factors for death from asthma, chronic obstructive pulmonary disease, and cardiovascular disease after a hospital admission for asthma. Thorax 1999; 54: 301–7
2. Sin DD, Tu JV. Lack of association between ipratropium bromide and mortality in elderly patients with chronic obstructive airway disease. Thorax 2000; 55: 194–7
3. Ringbæk T, Viskum K. Is there any association between inhaled ipratropium and mortality in patients with COPD and asthma? Respir Med 2003; 97: 264–72.

💊 Interactions

For interactions associated with antimuscarinics in general, see Atropine. However, these interactions are not usually seen with antimuscarinics, such as ipratropium, given by inhalation.

Salbutamol.

For reference to nebulised salbutamol exacerbating the adverse effects of nebulised ipratropium in patients predisposed to angle-closure glaucoma, see under Effects on the Eyes, above.

💊 Pharmacokinetics

After inhalation, around 10 to 30% of a dose is deposited in the lungs where it exerts its therapeutic effect. Only a small amount of ipratropium reaches the systemic circulation. The majority of a dose is swallowed but is poorly absorbed from the gastrointestinal tract. Ipratropium and its metabolites are eliminated in the urine and faeces.
1. Ensing K, et al. Pharmacokinetics of ipratropium bromide after single dose inhalation and oral and intravenous administration. Eur J Clin Pharmacol 1989; 36: 189–94.

💊 Uses and Administration

Ipratropium bromide is a quaternary ammonium antimuscarinic. It is used by inhalation as a bronchodilator in the treatment of reversible airways obstruction, as in asthma and chronic obstructive pulmonary disease (see below). In the UK the dose of ipratropium bromide from the metered-dose aerosol is expressed in terms of the amount of drug released from the valve into the mouthpiece (20 micrograms) whereas in the USA it is expressed in terms of the dose emitted from the mouthpiece (17 micrograms, equivalent to 21 micrograms released from the valve); recommended doses may therefore appear lower in the USA. For reversible airways obstruction, the usual UK dose from a metered-dose aerosol is 1 or 2 inhalations (20 or 40 micrograms) three or four times daily; single doses of up to 4 inhalations may be required. Comparable doses are used in the USA, but it is recommended that the daily dose should not exceed 12 inhalations. Dry powder inhalation capsules are also available; the usual dose is 40 micrograms three or four times daily, to a maximum of 320 micrograms daily. Ipratropium bromide may be given by inhalation as a nebulised solution in doses of 250 to 500 micrograms up to 4 times daily. Ipratropium bromide, given intranasally, is also used in the management of rhinorrhoea associated with rhinitis. A dose of 42 micrograms is given into each nostril by metered-dose nasal spray 2 or 3 times daily. US licensing also permits higher doses of 84 micrograms into each nostril 3 or 4 times daily, for up to 4 days when rhinorrhoea is associated with the common cold; doses of 84 micrograms may be given into each nostril 4 times daily, for up to 3 weeks when rhinorrhoea is associated with seasonal allergic rhinitis. For details of doses in children, see Administration in Children, below.

Administration in children.

Children may be given ipratropium bromide via a metered dose aerosol in the treatment of reversible airways obstruction. UK licensed product information recommends doses by age as follows:
under 6 years: 1 inhalation of 20 micrograms three times daily
6 to 12 years: 1 or 2 inhalations of 20 micrograms three times daily
12 years and over: adult doses, see above Dry powder inhalation capsules are also available, and are licensed for use in children from 12 years of age using the adult dose, see above. Ipratropium bromide may also be given by inhalation as a nebulised solution. UK licensed product information recommends the following doses:
under 6 years, for the treatment of acute asthma only: 125 to 250 micrograms, given no more often than every 6 hours up to a total daily dose of 1 mg
6 to 12 years, for the treatment of acute or chronic asthma: 250 micrograms, repeated if necessary up to a total daily dose of 1 mg
12 years and over: adult doses, see above. Ipratropium bromide is used in the management of rhinorrhoea associated with rhinitis. A dose of 42 micrograms may be given into both nostrils two or three times daily. In the UK this dose may be given to children from 12 years of age, but in the USA this dose is licensed in children from 6 years of age. US licensing also permits higher doses for up to 4 days when rhinorrhoea is associated with the common cold:
5 to 11 years: 84 micrograms into each nostril three times daily
12 years and over: adult doses, see above Higher doses are also permitted in the USA for up to 3 weeks when rhinorrhoea is associated with seasonal allergic rhinitis. Children 5 years of age and over may be given the same dose as adults, see above.

Asthma.

Ipratropium bromide is currently recommended as an adjunct to beta2 agonists in the management of acute severe asthma. Antimuscarinic drugs, mainly ipratropium but also including oxitropium, glycopyrronium and atropine, have been reviewed in the treatment of both acute and chronic asthma. A systematic review and meta-analysis1 of the effectiveness of antimuscarinics in the treatment of acute asthma in children and adults, found they produced significant reductions in hospital admissions. Combined treatment with an inhaled beta2 agonist also produced a significant increase in respiratory function. Systematic reviews of antimuscarinic drugs have concluded that there is currently insufficient evidence to justify their routine use in adults2 or children3 with chronic asthma.
1. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax 2005; 60: 740–6
2. Westby M, et al. Anticholinergic agents for chronic asthma in adults. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2004 (accessed 18/02/08)
3. McDonald NJ, et al. Anticholinergic therapy for chronic asthma in children over 2 years of age. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2003 (accessed 18/02/08).

Chronic obstructive pulmonary disease.

Inhaled antimuscarinics, such as ipratropium bromide, are currently recommended as bronchodilators in chronic obstructive pulmonary disease with treatment using regular short-acting beta2 agonists in stable COPD;1 it found small benefits on lung function outcomes and quality of life with ipratropium compared with a short-acting beta2 agonist; a reduction in the requirements for oral corticosteroids was also seen. Combination therapy with ipratropium and a short-acting beta2 agonist was associated with some clinically meaningful lung function outcomes compared with the beta2agonist alone, but these were not reflected in subjective improvements or symptom scores. A systematic review comparing ipratropium with a long-acting beta2 agonist in stable COPD,2 found that salmeterol had more effect than ipratropium on lung function, but no major differences were seen between symptom responses to ipratropium and salmeterol. Combination treatment with these two drugs was better than salmeterol alone in terms of quality of life.
1. Appleton S, et al. Ipratropium bromide versus short acting beta2 agonists for stable chronic obstructive pulmonary disease. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2006 (accessed 18/02/08)
2. Appleton S, et al. Ipratropium bromide versus long-acting beta2 agonists for stable chronic obstructive pulmonary disease. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2006 (accessed 18/02/08).

Rhinitis.

Ipratropium bromide is used intranasally for the treatment of rhinorrhoea in allergic and non-allergic rhinitis. It has also relieved rhinorrhoea and sneezing associated with the common cold.
1. Georgitis JW, et al. Ipratropium bromide nasal spray in non-allergic rhinitis: efficacy, nasal cytological response and patient evaluation on quality of life. Clin Exp Allergy 1994; 24: 1049–55
2. Hayden FG, et al. Effectiveness and safety of intranasal ipratropium bromide in common colds: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996; 125: 89–97
3. Dockhorn R, et al. Ipratropium bromide nasal spray 0.03% and beclomethasone nasal spray alone and in combination for the treatment of rhinorrhea in perennial rhinitis. Ann Allergy Asthma Immunol 1999; 82: 349–59
4. Bonadonna P, et al. Cold-induced rhinitis in skiers—clinical aspects and treatment with ipratropium bromide nasal spray: a randomized controlled trial. Am J Rhinol 2001; 15: 297–301
5. Kim KT, et al. Pediatric Atrovent Nasal Spray Study Group. Use of 0.06% ipratropium bromide nasal spray in children aged 2 to 5 years with rhinorrhea due to a common cold or allergies. Ann Allergy Asthma Immunol 2005; 94: 73–9.

💊 Preparations

BP 2008: Ipratropium Nebuliser Solution; Ipratropium Powder for Inhalation; Ipratropium Pressurised Inhalation.

Proprietary Preparations

Arg.: Aerotrop; Atrovent; Iprabron; Austral.: Aeron; Apoven; Atrovent; Ipratrin; Ipravent; Austria: Atrovent; Itrop; Belg.: Atronase; Atrovent; Braz.: Alvent†; Ares; Atrovent; Bromovent; Iprabon; Ipraneo; Canad.: Apo-Ipravent; Atrovent; Novo-Ipramide; Chile: Atrovent; Neorinol†; Cz.: Atrovent; Itrop†; Denm.: Atrovent; Fin.: Atrovent; Fr.: Atrovent; Ger.: Atrovent; Itrop; Gr.: Atrovent; Hong Kong: Atrovent; Cyclovent; Ipravent†; Hung.: Atrovent; India: Ipranase; Ipravent; Indon.: Atrovent; Irl.: Atrovent; Rinatec; Israel: Aerovent; Apovent; Atrovent; Ital.: Atem; Rinovagos; Jpn: Atrovent; Malaysia: Atrovent; Mex.: Atrovent; Neth.: Atrovent; Ipraxa; Norw.: Atrovent; Respontin†; NZ: Apo-Ipravent; Atrovent; Ipra†; Philipp.: Atrovent; Pol.: Atrovent; Port.: Atrovent; Rus.: Atrovent (Атровент); S.Afr.: Atrovent; Ipvent; Singapore: Atrovent; Spain: Atrovent; Swed.: Atrovent; Switz.: Atrovent; Rhinovent; Thai.: Atrovent; Turk.: Atrovent; UAE: Atropulm; UK: Atrovent; Respontin; Rinatec; USA: Atrovent; Venez.: Alovent. Multi-ingredient: Arg.: Berodual; Combivent; Ipradual; Iprasalb; Salbutral AC; Salbutrop†; Austral.: Combivent; Austria: Berodual; Berodualin; Combivent; Di-Promal; Belg.: Combivent; Duovent; Braz.: Combivent; Duovent; Canad.: Combivent; Duovent; ratio-Ipra Sal UDV; Chile: Berodual; Combivent; Salbutral AC; Cz.: Berodual; Combivent†; Denm.: Berodual; Combivent; Fin.: Atrodual; Atrovent Comp; Fr.: Bronchodual; Combivent; Ger.: Berodual; Gr.: Berodual; Berovent; Hong Kong: Berodual†; Combivent; Hung.: Berodual; India: Duolin; Fenovent; Indon.: Berodual; Combivent; Irl.: Combivent; Duovent; Ipramol; Ital.: Breva; Duovent; Iprafen; Malaysia: Berodual; Combivent; Duovent; Ipramol; Mex.: Berodual; Combivent; Neth.: Berodual; Combivent; NZ: Combivent; Duolin; Philipp.: Berodual; Combipul; Combivent; Duavent; Pol.: Berodual; Port.: Berodual; Combivent; Rus.: Berodual (Беродуал); S.Afr.: Atrovent Beta; Berodual; Combivent; Duolin; Duovent; Sabax Combineb; Sabax Nebrafen; Singapore: Berodual; Combivent; Duovent; Spain: Berodual†; Combivent; Legis†; Swed.: Combivent; Switz.: Berodual; Dospir; Thai.: Berodual; Combivent; Inhalex; Punol; Turk.: Combivent; UK: Combivent; Duovent; Ipramol; USA: Combivent; DuoNeb; Venez.: Berodual; Combivent; Duolin; Duovent; Ipralin; Respidual.
Published November 22, 2018.