What information is available on long term treatment with ketotifen for bronchial asthma? Of partic

Fråga: What information is available on long term treatment with ketotifen for bronchial asthma? Of particular interest is the maximum dose and duration it has been administered. Basic pharmacokinetic data relevant for dosage recommendations would be appreciated.

Sammanfattning: Short-term treatment with ketotifen seems effective in the prophylactic treatment of adult asthma but not more than conventional treatments. Concerning long-term prophylaxis, there are still very few controlled clinical trials.

Svar: Ketotifen is a tricyclic compound belonging to the benzocyclo- heptathiophene group. Structurally this compound is not related to sodium cromoglicate, antihistaminic drugs or theophylline.

This drug has antiallergic properties inhibiting the liberation of leukotrienes from neutrophils and basophils. It is also a histamin (H1) receptor blocker (1).

Due to these properties and to the advantage that it can be taken by mouth, its efficacy in preventing different types of asthma attacks has been tested.

Asthma in children often has an allergic component and would be expected to respond well to an effective oral antiallergic drug. However, several controlled clinical trials show that ketotifen does not seem to be effective as a prophylactic agent in childhood asthma (2).

Ketotifen (0.5 mg twice daily) has been compared with theophylline in a double-blind crossover study of 16 asthmatic children and was less effective in reducing symptoms than theophylline but did appear to reduce the need for additional prednisolone (3). It should be mentioned that in this study the theophylline dosage but not the ketotifen one was preadjusted in individual patients.

This drug has not shown any protection against bronchial hyperreactivity or exercise-induced asthma in children (4,5).

The efficacy of ketotifen has also been tested in adult asthmatic patients after short and long-term prophylactic treatment.

In 43 patients with atopic asthma, ketotifen (1 mg twice daily) and sodium cromoglicate were compared in a double-blind crossover trial (3 months treatment with each drug), pulmonary function tests showed significant improvement which did not differ between the two drugs (6).

Concerning long-term treatment (up to 12 months), 13 patients with bronchial asthma were treated with ketotifen (1 mg twice daily) in a double-blind manner. In 9 of them the pulmonary function improved. These responders were within the young patients and had mild to moderate asthma (7).

In an open study, a large number of patients were treated with ketotifen (1 mg twice daily) and followed up to 12 months, 57 per cent dropouts were recorded and 38 per cent of them were due to lack of efficacy (8). The most common side effects reported were sedation, tiredness, weight gain and dry mouth.

Very few pharmacokinetic data are available in the literature probably because of methodological difficulties in measuring the drug.

In man, ketotifen is hydroxylated and demethylated and those derivatives are glucuronidated (9).

After a single oral dose of 2 mg, ketotifen reaches a maximum plasma concentration 2 hours after administration. The mean value of this maximum concentration is lower than 0.6 ng/ml. The unconjugated metabolites are in the same concentration range whereas the conjugated metabolites are present in plasma at levels 5-20 times higher than the unconjugated form (9).

Ketotifen is registered in some European countries such as Switzerland (1978) and England (1979) but not in the nordic countries or in USA. In Sweden the application for registration was rejected in 1982 by the authorities because of insufficient documentation (10).