United Kingdom. Leukotriene antagonists are a new class of drugs for use in the treatment of asthma. Two products have been approved this year, montelukast (Singulair: MSD) and zafirlukast (Accolate: Zeneca). Leukotriene antagonists should be taken regularly to produce clinical benefit. It is important to note that:
Treatment with these drugs does not allow a reduction in existing corticosteroid treatment.
Leukotriene antagonists are not indicated for the treatment of acute asthma attacks; however, for patients already on therapy, they may be continued during an acute attack.
Adverse reactions. Churg-Strauss Syndrome (an eosinophilic infiltrative disorder) has been reported in association with both of these drugs. It is possible, however, that Churg-Strauss Syndrome predated leukotriene antagonist therapy in some of these patients and was unmasked when oral corticosteroid treatment was reduced.
Zafirlukast is contraindicated in patients with hepatic impairment or moderate to severe renal impairment and, in the absence of clinical data, in children under the age of 12. Elevations in serum transaminases can occur during treatment with zafirlukast and liver function tests should be performed in patients who develop symptoms of liver dysfunction. At doses greater than 20 mg twice daily, significant hepatotoxicity may occur. The most common adverse reactions in clinical trials were headache and nausea. Zafirlukast may also cause vomiting, diarrhoea, abdominal pain and hypersensitivity reactions including urticaria, angioedema and rashes. Zafirlukast inhibits the hepatic cytochrome P450 2C9. Due to an interaction with warfarin, the prothrombin time should be closely monitored if these drugs are co-administered. Zafirlukast also interacts with theophylline, terfenadine, acetylsalicylic acid and erythromycin, but the clinical significance of these interactions is not known.
Montelukast is metabolised by the hepatic cytochrome P450 CYP3A4 and co-administration of inducers of this enzyme (such as phenytoin, phenobarbital [phenobarbitone] and rifampicin) result in a marked reduction in its plasma levels. The most common adverse reactions in clinical trials were headache and abdominal pain. Other adverse reactions observed in clinical trials included nausea, diarrhoea, gastroenteritis, influenza, pharyngitis, sinusitis, cough, nasal congestion, dizziness, fatigue and insomnia.
Since the introduction of montelukast on the market in February 1998, 173 reports of 317 suspected ADRs have been received in the United Kingdom. Suspected ADRs not identified from clinical trials include; oedema (50), psychiatric reactions including agitation/restlessness (15), allergy including anaphylaxis, angioedema and urticaria (10), chest pain (7), tremor (5), dry mouth (5), vertigo (4) and arthralgia (3).
[See also Pharmaceuticals Newsletter Nos. 5&6, May & June 1998]
Reference: Current Problems in Pharmacovigilance Vol. 24, August 1998.