Drugs

, Volume 40, Issue 3, pp 412–448 | Cite as

Ketotifen

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use in Asthma and Allergic Disorders
  • Susan M. Grant
  • Karen L. Goa
  • Andrew Fitton
  • Eugene M. Sorkin
Drug Evaluation

En

Summary

Synopsis

Ketotifen is an orally active prophylactic agent for the management of bronchial asthma and allergic disorders. Accumulated evidence indicates that after 6 to 12 weeks of administration, ketotifen significantly reduces respiratory symptoms and the need for concomitant antiasthmatic drugs in about 70% and 50%, respectively, of patients with mild to moderate bronchial asthma. However, absolute improvement in lung function is generally slight. Ketotifen also has pronounced antihistaminic and antianaphylactic properties which result in moderate to marked symptom improvement in the majority of patients with atopic dermatitis, seasonal or perennial rhinitis, allergic conjunctivitis, chronic or acute urticaria or food allergy.

Comparative trials with established agents — notably sodium cromoglycate (cromolyn sodium) in asthma and histamine H1- antagonists in allergic disorders — indicate that ketotifen has comparable clinical utility. Unlike inhaled sodium cromoglycate, ketotifen ameliorates the symptoms of asthma, rhinitis and dermatitis when present together in atopic patients.

Patient acceptance of ketotifen is good, although sedation can be troublesome in older children and adults for the initial 2 weeks of treatment. Weight gain is another notable effect in a small percentage of patients.

Thus, ketotifen appears to be a useful agent for the management of allergic disorders and bronchial asthma, particularly in patients for whom oral therapy is preferred. Although a lengthy run-in period is needed in the treatment of asthma, in those patients who respond, continued reduction in the frequency and severity of symptoms and in the use of additional antiasthmatic drugs can be anticipated.

Pharmacodynamic Properties

Ketotifen inhibits the bronchial response to inhaled histamine, allergen or aspirin, and the ocular, nasal and dermal responses to applied allergen in sensitised subjects. Ketotifen and clemastine have similar protective effects against histamine challenge, and ketotifen is generally as effective as sodium cromoglycate against both early and late reactions precipitated by inhalation of allergen extract in patients with extrinsic asthma. In contrast, ketotifen does not protect against methacholine- or exercise-induced bron-choconstriction.

Chronic inflammatory changes associated with the recruitment and activation of eosinophils within the tracheobronchial tree appear to underlie the changes in airway patency and reactivity in chronic asthma. Prior treatment with ketotifen attenuated airway eosinophilia and the ensuing hyperreactivity in animals, but similar data in humans are currently lacking. Inhibition of the release and/or activity of proinflammatory mediators, which has been demonstrated in vitro or in animals for histamine, platelet-activating factor (PAF), arachidonic acid metabolites, neutrophil chemotactic factor, and the cytotoxic oxygen intermediate O2 , may contribute to the prophylactic effect of ketotifen. Calcium may be integral to the generation and/or release of some of these compounds and a number of studies suggest that ketotifen interferes with calcium flux. It does not appear to affect smooth muscle contraction. Additional possible modes of action of ketotifen include its ability to reverse β2-agonist-induced reductions in β-adrenoceptor density and to alter the affinity of these receptors and increase intracellular concentrations of cyclic adenosine monophosphate (cAMP).

Exposure to ketotifen in vitro or in vivo had no clinically important effect on the number or function of lymphocytes in asthmatic children but the drug has been reported to decrease serum IgE levels and eosinophil counts in patients with bronchial asthma.

Pharmacokinetic Properties

Ketotifen is well absorbed after oral administration, achieving peak plasma concentrations within 2 to 4 hours of administration in conventional dosage forms. However, information regarding absorption from the once-daily slow-release tablet is lacking. Due to a ‘first pass’ effect, bioavailability of the drug is only about 50%. Peak plasma concentrations after multiple oral doses of 1mg twice daily were 1.92 mg/L in adults and 3.25 mg/L in children, with corresponding areas under the concentration-time curve of 16.98 mg/L· h and 20.72 mg/L· h. The drug is reported to be 75% protein bound.

Ketotifen is extensively metabolised to the inactive ketotifen-N-glucuronide and the pharmacologically active nor-ketotifen, and recovery of these metabolites in urine accounts for 50% and 10% of the administered dose, respectively. Only 1% is retrievable as the parent compound. Clearance of the drug from plasma is biphasic, with a half-life of distribution of 3 hours and a half-life of elimination of 22 hours in adults. Children exhibit a similar pattern of elimination. No data are available with regard to the effect of advanced age or disease on the pharmacokinetic profile of ketotifen.

Therapeutic Use

Although there is a large body of data available on the clinical use of ketotifen, poor study design, critical to the evaluation of a prophylactic drug, limits the usefulness of some studies. In well-designed trials the drug improved respiratory symptoms in about 70% of adults with asthma, based on patient diaries and physician assessment, and permitted a reduction in concomitant antiasthmatic drug requirements in about 50% of patients. The effects were apparent after 6 to 12 weeks and responding patients continued to improve with long term treatment. When initiated 6 to 8 weeks prior to peak pollen season, ketotifen attenuated the symptoms associated with seasonal asthma. Lung function, most frequently measured as peak expiratory flow, did not markedly improve in most studies but did remain stable as bronchodilators were withdrawn. Well-designed comparative trials are divided on whether ketotifen or sodium cromoglycate is statistically superior in patients with asthma. In general, the improvements in respiratory symptoms and bronchodilatbr requirements are clinically equivalent for these 2 agents and the preference of the individual and subsequent response will be the best guide when deciding on long term treatment. Limited comparative experience with ketotifen, azelastine and picumast suggests these 3 oral agents are similarly effective in the management of asthma.

Although some investigators reported ketotifen to be no more effective than placebo when used to treat children with asthma, when studies permitting concomitant sodium cromoglycate were excluded from analysis significant reductions in asthma symptoms and bronchodilator or theophylline requirements were demonstrated with the active drug. Well-designed comparisons with sodium cromoglycate are sparse but suggest that, in children as in adults, ketotifen reduces symptoms and drug requirements to a similar degree.

Several studies have addressed the possibility of corticosteroid withdrawal in ketotifen-treated patients with more severe steroid-dependent asthma. The results suggest that reduction in steroid dosage is possible in selected patients but there is currently little evidence that ketotifen can replace oral or inhaled corticosteroids in dependent patients. Prevention of asthma with ketotifen would be ideal; studies in at-risk infants hint at a protective effect for ketotifen and its use in this setting merits further study.

Ketotifen is effective in relieving the nasal and ocular symptoms of perennial and seasonal rhinitis in adults and children, the improvement being most pronounced in children with seasonal symptoms. The drug was at least as effective as clemastine, chlorpheniramine (chlorphenamine), terfenadine, loratadine or insufflated sodium cromoglycate in comparative trials but was less effective than astemizole in 1 study.

Good and sometimes dramatic improvement was noted in patients with chronic or cold- or exercise-induced urticaria treated with ketotifen for 1 to 4 weeks. The response in patients with urticaria pigmentosa or systemic mastocytosis was less impressive although good responses have been reported in individuals with this disorder and in small groups of patients with neurofibromatosis. Despite the variable nature of atopic dermatitis, a good response has been clearly demonstrated for ketotifen, including a decrease in skin lesions and pruritus over the course of 4 to 9 weeks’ treatment.

Food intolerance or allergy often appear as symptoms in several body systems (e.g. skin, gastrointestinal tract, lungs), and while elimination of the offending food(s) is effective it may impose unacceptable lifestyle and nutritional hardships. Prophylactic use of ketotifen appears to prevent bronchospasm, urticaria, skin lesions and gastrointestinal upset invoked by food allergens and may allow the reintroduction of poorly tolerated foods.

Adverse Effects

Ketotifen is generally well tolerated, especially in young children. The most frequent adverse effect is sedation, which occurs in about 10 to 20% of patients but declines after I to 2 weeks of continued use. Other reactions including dizziness, dry mouth, nausea and headache have been reported in 1 to 2% of patients after initiating therapy but do not appear to persist in patients continuing with long term treatment (up to 12 months). Weight gain may also occur in a small percentage of patients.

Dosage and Administration

For adult patients with bronchial asthma or allergic disease, the recommended dosage of ketotifen is 2 mg/day divided into 2 doseS or given as a single slow-release tablet. Patients should be cautioned against operating machinery or performing tasks requiring psychomotor skills until the sedative effects of the drug, if any, are known. If sedation is considered a problem, therapy should be initiated at half the daily dose or the drug should be given at bedtime.

Children aged 6 months to 3 years should be given ketotifen (tablet or syrup) in a dosage of 0.5mg twice daily, but older children should receive the full adult dose.

Keywords

Asthma Atopic Dermatitis Cromoglycate Peak Expiratory Flow Sodium Cromoglycate 

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© Adis International Limited 1990

Authors and Affiliations

  • Susan M. Grant
    • 1
  • Karen L. Goa
    • 1
  • Andrew Fitton
    • 1
  • Eugene M. Sorkin
    • 1
  1. 1.Adis Drug Information ServicesAucklandNew Zealand

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