Medications for Allergy

A recent report concludes that Zeneca Pharmaceutical’s Accolate ® (zafirlukast) Tablets appear to be effective in helping to reduce symptoms and maintain airway function in asthmatics who are allergic to cat allergen. Accolate, which is already known to help control asthma symptoms, was tested in 18 asthmatic patients, ages 18-49, who tested positively for cat allergen to collect data. It was found that FEV1 (Forced Expiratory Volume in one second) was reduced by 25 percent when the participants were exposed to cats after they had been treated with a placebo, but only 15 percent during the treatment phase in which they were treated with Accolate. The report was presented by University of California-Los Angeles’ Sheldon Spector, MD, at the annual meeting of the American Academy of Allergy Asthma & Immunology (AAAAI) in Orlando, Florida.

Drug Nomenclature

Adverse Effects and Precautions

Headache, an increased incidence of respiratory-tract infection (in the elderly), and gastrointestinal disturbances have been reported with zafirlukast and other leukotriene antagonists. Other adverse effects have included generalised and abdominal pain, arthralgia, myalgia, fever, malaise, insomnia, and dizziness. Elevations in liver enzyme values have occurred, and rarely, symptomatic hepatitis or hyperbilirubinaemia (see also below) fatalities have occurred. Hyper sensitivity reactions, including rashes, pruritus, urticaria, and angioedema, have been reported. There have also been rare reports of agranulocytosis, bleeding, bruising and oedema. There have been a few reports of systemic eosinophilia consistent with Churg-Strauss syndrome in patients receiving zafirlukast (see below) treatment should be withdrawn in these patients. Zafirlukast and other leukotriene antagonists should not be used for the treatment of acute asthma attacks. Zafirlukast is contra-indicated in patients with hepatic impairment or cirrhosis.

Incidence of adverse effects. An observational study of 7976 patients prescribed zafirlukast found it to be generally well tolerated. Similarly to UK licensed product information, the most frequently reported adverse effects (1 to 2% of patients) were headache, rash, abdominal pain, malaise, and gastrointestinal disturbances such as nausea, diarrhoea, and dyspepsia. Dizziness and palpitations were more common in the first month of treatment. An increased incidence of depression was also noted.

Churg-Strauss syndrome. Pulmonary infiltrates and eosinophilia, resembling the Churg-Strauss syndrome, with dilated cardiomyopathy, were reported after withdrawal of corticosteroid therapy in 8 patients taking zafirlukast. Symptoms responded to withdrawal of zafirlukast and treatment with corticosteroids, with or without cyclophosphamide. It has been suggested that the patients original asthmatic symptoms had been part of an unrecognised vasculitic syndrome that was unmasked by stopping corticosteroids. However, others have reported Churg-Strauss syndrome associated with zafirlukast in those not receiving corticosteroids, although these cases were not inconsistent with the view that treatment with leukotriene antagonists was coincidental. It has also been noted that leukotriene receptor antagonists tend to be prescribed for patients with more severe asthma, which may be a precursor to the development of Churg-Strauss syndrome. In addition, eosinophilic syndromes have been reported for other anti-asthma drugs including inhaled fluticasone and sodium cromoglicate, evidence supporting a non-drug-related aetiology. However, the number of reports with zafirlukast and the other leukotriene antagonists, montelukast and pranlukast, means that a particular class-effect cannot be ruled out. It has been suggested that patients should be monitored carefully (e.g. by measuring erythrocyte sedimentation rate, C reactive protein, and eosinophil counts) if the introduction of an anti-asthma drug such as a leukotriene antagonist permits the reduction of oral corticosteroid dosage. In addition, in patients with asthma and features of multisystem disease, the possibility of underlying Churg-Strauss syndrome may be worth considering.

Effects on the liver. Severe hepatotoxicity has been associated with zafirlukast. The Canadian manufacturer reported in April 2004 that from worldwide postmarketing surveillance of zafirlukast there had been 46 reports of hepatitis, 14 of hepatic failure, 3 of which progressed to fulminant hepatitis, and 59 reports of other clinically significant hepatic dysfunction 7 fatalities had occurred. In most, but not all, cases symptoms had abated and liver enzymes had returned to normal after stopping zafirlukast. It was important that prescribers, patients and/or their carers were alert to the signs and symptoms of hepatotoxicity. Licensed product information for zafirlukast advises stopping treatment if hepatotoxicity is suspected, and performing liver function tests

Lupus. Zafirlukast was thought to be responsible for the development of lupus in a 9-year-old girl.

Renal impairment. The UK licensed product information states that zafirlukast should be used with caution in patients with moderate or severe renal impairment because of limited experience in this group. However, the US product information mentions no such caution, and states that the pharmacokinetics of zafirlukast in patients with renal impairment do not appear to differ from those in patients with normal renal function. Only about 10% of a dose is reported to be excreted in the urine.

Interactions

Zafirlukast is metabolised by hepatic cytochrome P450, specifically the CYP2C9 isoenzyme, and has been shown to inhibit the activity of isoenzymes CYP2C9 and CYP3A4. Therefore, use with other drugs that are metabolised by these hepatic enzymes may result in increases in plasma concentrations, and possibly, adverse effects. Patients receiving warfarin may develop prolongation of the prothrombin time and anticoagulant dosage should be adjusted accordingly. Erythromycin, terfenadine, and theophylline may reduce plasma concentrations of zafirlukast zafirlukast has rarely been reported to increase plasma-theophyl-line concentrations. Increased plasma concentrations of zafirlukast have been seen when given with high doses of aspirin.

Pharmacokinetics

Peak plasma concentrations of zafirlukast occur about 3 hours after oral doses. The absolute bioavailability is uncertain, but taking it with food reduces both the rate and extent of absorption, decreasing bioavailability by about 40%. Zafirlukast is about 99% bound to plasma proteins. It is extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP2C9, and excreted principally in faeces, as unchanged drug and metabolites. About 10% of a dose is excreted in urine as metabolites. The terminal elimination half-life of zafirlukast is about 10 hours. Studies in animals suggest that small amounts cross the placenta it is also distributed into breast milk.

Uses and Administration

Zafirlukast is a selective and competitive antagonist of the leukotriene C₄, D₄, and E₄ receptors, stimulation of which by circulating leukotrienes is thought to play a role in the pathogenesis of asthma. The drug suppresses both early and late bronchoconstrictor responses to inhaled antigens or irritants, but is not suitable for the management of acute attacks of asthma. Zafirlukast is used in the management of chronic asthma (see below). It is given orally in doses of 20 mg twice daily, taken at least 1 hour before or 2 hours after meals. For details of doses in children, see below.

Administration in children. In the management of chronic asthma, US licensed product information recommends a zafirlukast dose of 10 mg twice daily orally in children aged from 5 to 11 years. Children 12 years of age and over may be given the adult dose, see above. In the UK, zafirlukast is unlicensed in children under 12 years of age.

Asthma. Zafirlukast produces modest improvement in mild-to-moderate asthma, which was of a similar order to that seen with inhaled sodium cromoglicate in one study, but less than that of inhaled salmeterol in another It has also been found to be less effective than inhaled fluticasone in persistent asthma. Guidelines for the management of asthma permit the use of zafirlukast as an alternative to inhaled corticosteroids in patients with mild persistent asthma, who cannot be managed with inhaled beta₂ agonists on an asneeded basis alone. It can also be considered for use in moderate or severe persistent asthma, usually added to standard therapy of inhaled corticosteroids and long-acting inhaled beta₂ agonists. Combination of anti-leukotriene drugs with inhaled corticosteroids alone seems, however, to be less effective than a combination of the latter with long-acting inhaled beta₂ agonists. In a study in patients presenting to the emergency room with acute severe asthma, adding zafirlukast to standard therapy in hospital and for 28 days after discharge was associated with a reduced rate of relapse, and a reduction in the need for extended care.

Rhinitis. Although it was reported to improve symptoms of seasonal allergic rhinitis in one study, zafirlukast 20 mg twice daily was not effective when compared with placebo and intranasal beclometasone in another. Some benefits have been reported in perennial allergic rhinitis, in particular an improvement in nasal obstruction. A review of the role of leukotrienes in allergic rhinitis concluded that leukotriene receptor antagonists have modest efficacy given alone but can be usefully added to other treatments.

Urticaria. Leukotriene antagonists, such as zafirlukast, are reported to have some benefit in the management of chronic urticaria.

Proprietary Preparations

Argentina: Accolate Vanticon Zafinasmal

Australia: Accolate

Belgium: Accolate Resma

Brazil: Accolate

Canada: Accolate

Chile: Accolate

Czech Republic: Accolate

Finland: Accolate

Hong Kong: Accolate

Hungary: Accolate

India: Zuvair

Ireland: Accolate

Italy: Accoleit Zafirst

Mexico: Accolate

Philippines: Accolate

Poland: Accolate

Portugal: Accolate

Russia: Accolate

South Africa: Accolate

Singapore: Accolate

Spain: Accolate Aeronix Olmoran

Switzerland: Accolate

Thailand: Accolate

Turkey: Accolate

UK: Accolate

USA: Accolate

Venezuela: Accolate.