Medications for Allergy

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Pharmacopoeias. In Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Ipratropium Bromide). White or almost white crystalline powder. Soluble in water slightly soluble in alcohol freely soluble in methyl alcohol. ThepHofa 1 % solution in water is 5.0 to 7.5.

The United States Pharmacopeia 31, 2008 (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 apH of 5 to 7. Store in airtight containers.

Stability. In a study 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.

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 report of inflammation and ulceration of the buccal mucosa associated with the use of an ipratropium bromide inhaler.

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. Pupillary dilatation and blurred vision 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. Angle-closure glaucoma, pupillary dilatation, and anisocoria 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. Studies 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.

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. Both patients also had other predisposing factors for paralytic ileus (cystic fibrosis, spastic diplegia).

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.

BRONCHOSPASM. Paradoxical bronchoconstriction occurring after the use of ipratropium was reported in 3 patients. A further report 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 preservative-free but licensed product information still recommends that the first doses of ipratropium nebuliser solution should be inhaled under medical supervision.

Effects on the urinary tract. Treatment with nebulised ipratropium bromide has resulted in urinary retention in elderly men especially those with prostatic hyperplasia.

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. A retrospective cohort study 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. 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.

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.

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:

• under6years: 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-analysis 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 adults or children with chronic asthma.

Chronic obstructive pulmonary disease. Inhaled antimuscarinics, such as ipratropium bromide, are currently recommended as bronchodilators in chronic obstructive pulmonary disease (COPD) guidelines. A systematic review compared regular treatment with ipratropium (given for at least 4 weeks) with treatment using regular short-acting beta₂ agonists in stable COPD 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 corticoster-oids 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 beta₂ agonist 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, 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.

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. References.

Preparations

British Pharmacopoeia 2008: Ipratropium Nebuliser Solution; Ipratropium Powder for Inhalation; Ipratropium Pressurised Inhalation.

Proprietary Preparations

Argentina: Aerotrop Atrovent Iprabron

Australia: Aeron Apoven Atrovent Ipratrin Ipravent

Austria: Atrovent Itrop

Belgium: Atronase Atrovent

Brazil: Alventf Ares Atrovent Bromovent Iprabon Ipraneo

Canada: Apo-lpravent Atrovent Novo-lpramide

Chile: Atrovent Neorinoll

Czech Republic: Atrovent Itrop

Denmark: Atrovent

Finland: Atrovent

France: Atrovent

Germany: Atrovent Itrop

Greece: Atrovent

Hong Kong: Atrovent Cyclovent Ipravent

Hungary: Atrovent

India: Ipranase Ipravent

Indonesia: Atrovent

Ireland: Atrovent Rinatec

Israel: Aerovent Apovent Atrovent

Italy: Atem Rinovagos

Japan: Atrovent

Malaysia: Atrovent

Mexico: Atrovent

The Netherlands: Atrovent Ipraxa

Norway: Atrovent Respontin

New Zealand: Apo-lpravent Atrovent Ipra †

Philippines: Atrovent

Poland: Atrovent

Portugal: Atrovent

Russia: Atrovent

South Africa: Atrovent Ipvent

Singapore: Atrovent

Spain: Atrovent

Sweden: Atrovent

Switzerland: Atrovent Rhinovent

Thailand: Atrovent

Turkey: Atrovent

United Arab Emirates: Atropulm

UK: Atrovent Respontin Rinatec

USA: Atrovent

Venezuela: Alovent

Multi-ingredient

Australia: Combivent

Austria: Berodual Berodualin Combivent Di-Promal

Belgium: Combivent Duovent

Brazil: Combivent Duovent

Canada: Combivent Duovent ratio-lpra Sal UDV

Chile: Berodual Combivent Salbutral AC

Czech Republic: Berodual Combivent †

Denmark: Berodual Combivent

Finland: Atrodual Atrovent Comp

France: Bronchodual Combivent

Germany: Berodual

Greece: Berodual Berovent

Hong Kong: Berodual Combivent

Hungary: Berodual

India: Duolin Fenovent

Indonesia: Berodual Combivent

Ireland: Combivent Duovent Ipramol

Italy: Breva Duovent Iprafen

Mexico: Berodual Combivent

The Netherlands: Berodual Combivent

New Zealand: Combivent Duolin

Poland: Berodual

Portugal: Berodual Combivent

Russia: Berodual

Spain: Berodualf Combivent Legis †

Sweden: Combivent

Switzerland: Berodual Dospir

Turkey: Combivent

UK: Combivent Duovent Ipramol

USA: Combivent DuoNeb

Cromolyn sodium

Cromolyn sodium [Rynacrom(UK), Nasalcrom, Prevalin (Netherlands)] stabilizes mast cells and thereby prevents the degranulation of chemical mediators upon antigen presentation. Intranasal cromolyn ameliorates symptoms such as sneezing, rhinorrhea, and nasal pruritis but lacks efficacy for nasal congestion. Cromolyn is generally less efficacious than intranasal corticos-teroids. Therapy adherence may be problematic, as it necessitates frequent dosing (3 to 4 times daily). However, cromolyn may be safely administered, even to very young children, with negligible side effects. Intranasal cromolyn is now available without prescription. Patients should be advised to initiate therapy with cromolyn before the start of the allergy season or in anticipation of allergen exposure.

Ipratropium bromide

Ipratropium bromide [Atrovent, Apovent] is a well-tolerated topical anti-cholinergic agent that is available in a 0.03% nasal formulation. It is indicated for rhinorrhea associated with allergic and nonallergic perennial rhinitis. (A 0.06% formulation is approved for rhinorrhea associated with the common cold.) This agent quickly and effectively reduces nasal hypersecretion but has no effect on other symptoms of rhinitis such as sneezing and congestion. The most commonly reported adverse effects are nasal dryness and epistaxis. The recommended dose of intranasal ipratropium bromide is 2 sprays per nostril 2 to 3 times daily.

Conclusion

Pharmacotherapy remains the mainstay of management in patients with allergic rhinitis. Given the wide selection of available agents, the ideal regimen should be individualized to reflect disease severity and specific symptoms. Factors such as the potential for side effects, risk for drug interactions, ease of administration, and cost should also be considered. Most importantly, patients should be routinely followed to assess therapeutic response and to monitor for side effects or complications.