Zaditen (Ketotifen Fumarate)

ZADITEN®

Novartis

Ketotifen Fumarate

Pediatric Asthma Prophylactic – Antiallergic Agent

Action And Clinical Pharmacology: Ketotifen is a nonbronchodilator antiasthmatic drug which inhibits the effects of certain endogenous substances known to be inflammatory mediators, and thereby exerts antiallergic activity. Preclinical studies indicated that ketotifen’s anti-H1 effect seems to be distinct from its antiallergic properties.

The effectiveness of ketotifen in the chronic management of mild atopic pediatric asthma has been shown in clinical trials. Continued use of ketotifen results in a partial reduction in the frequency, severity and duration of asthma symptoms and attacks, and may lead to the reduction in the daily requirements of concomitant antiasthmatic medication such as theophyllines and b2-agonists, without the deterioration in pulmonary function (FEV1, FVC and PEFR). Clinical improvements have been observed in some cases within the first weeks of treatment and generally reach statistical significance after ten weeks. Ketotifen may have an anti-inflammatory effect in the lungs and the time of onset of clinical efficacy may reflect the recovery period of the lungs from inflammation.

Pharmacological studies have revealed a number of properties of ketotifen which may contribute to its antiallergic activity and its ability to affect the underlying pathology of asthma:

In Vivo Results: Inhibition of the development of airway hyperreactivity associated with activation of platelets by PAF (Platelet Activating Factor) or caused by neural activation following the use of sympathomimetic drugs or the exposure to allergen; inhibition of PAF-induced accumulation of eosinophils and platelets in the airways; suppression of the priming of eosinophils by human recombinant cytokines and thereby suppression of the influx of eosinophils into inflammatory loci; antagonism of bronchoconstriction due to leukotrienes.

In Vitro Results: Inhibition of the release of allergic mediators such as histamine, leukotrienes C4 and D4 (SRS-A) and PAF.

In addition, ketotifen is a potent antiallergic substance possessing a powerful and sustained noncompetitive histamine (H1) blocking property.

In humans, the absorption of ketotifen from an oral administration was demonstrated to be at least 60%, and possibly even greater. The rate of absorption of ketotifen in humans was assessed as rather rapid, since the plasma concentration reached its maximum 3 hours after oral administration; the absorption half-life was calculated to be 1 hour. Bioavailability amounts to approximately 50% due to a large first pass effect. Maximum plasma concentrations are reached within 2 to 4 hours. The percentage of protein binding in humans is 75% and is also concentration-independent. Ketotifen is eliminated biphasically; there are two disposition half-lives of 3 to 5 hours and 21 hours for distribution and disappearance phases respectively. Within 48 hours, urinary excretion amounts to 1% as unchanged drug and 60 to 70% as metabolites. The main metabolite in the urine is the inactive ketotifen-N-glucuronide. The bioavailability of the various forms of ketotifen is not influenced by the intake of food.

The pattern of metabolism in children is the same as in adults, but the clearance is higher in children. Children over the age of 3 years therefore require the same daily dosage regimen as adults. In infants aged less than 3 years, however, the dosage must be adjusted, since the mean levels of the drug in infants are higher than those found in children, when the same dose is given.

Indications And Clinical Uses: As an add-on medication in the chronic treatment of mild atopic asthmatic children.

Ketotifen is a prophylactic agent to be used on a continuous basis and is not effective in the acute prevention or treatment of acute asthma attacks. Continuous use of ketotifen may reduce the frequency, severity and duration of asthmatic symptoms or attacks, and lead to a reduction in daily requirements of concomitant antiasthmatic medication, like theophyllines and b2-agonists.

Several weeks of ketotifen therapy may be necessary before the therapeutic effect becomes clinically evident. Full clinical effectiveness is generally reached after 10 weeks of treatment. Ketotifen may have an anti-inflammatory effect in the lungs and the time of onset of clinical efficacy may reflect the recovery period of the lungs from inflammation. It is therefore recommended that for patients not adequately responding within a few weeks, treatment with ketotifen should be maintained for a minimum of 2 to 3 months. If it is necessary to withdraw ketotifen, this should be done progressively over a period of 2 to 4 weeks. Symptoms of asthma may recur.

Contra-Indications: Hypersensitivity to ketotifen or any other components of the formulations. Patients sensitive to benzoate compounds should not take ketotifen syrup.

Precautions: General: Symptomatic and prophylactic antiasthmatic drugs (xanthine derivatives, b2-agonists, sodium cromoglycate, corticosteroids) already in use should not be reduced immediately when treatment with ketotifen is initiated. This applies especially to systemic corticosteroids and ACTH injections because of the possible existence of adrenocortical insufficiency in steroid-dependent patients; in such cases recovery of a normal pituitary-adrenal response to stress may take up to one year.

Occupational Hazards: Since drowsiness may occur in the early stages of therapy, patients engaging in activities requiring rapid and precise responses should be cautioned.

Drug Interactions: A reversible fall in the thrombocyte count in patients receiving ketotifen concomitantly with oral antidiabetic agents has been observed in rare cases. Thrombocyte counts should therefore be carried out in patients taking oral antidiabetic agents concomitantly.

Ketotifen may potentiate the effects of sedatives, hypnotics, antihistamines and alcohol.

Pregnancy: Although ketotifen was without effect on pregnancy and on peri- and post-natal development at dose levels which were tolerated by the mother animals, its safety in human pregnancy has not been established. Ketotifen should therefore be given to pregnant women only in compelling circumstances.

Lactation: Ketotifen is excreted in breast milk; therefore mothers receiving ketotifen should not breast-feed.

Patients with Special Diseases and Conditions: Ketotifen syrup should not be administered to patients sensitive to benzoate compounds. Ketotifen tablets are benzoate-free and can be administered alternatively to such patients.

In diabetic patients, the carbohydrate content of the syrup (5 mL: 4 g carbohydrate) should be taken into consideration.

Adverse Reactions: Table I illustrates the adverse reactions which were reported in a Canadian Multicentre Trial involving 196 asthmatic children aged 5 to 17 years. This double-blind, placebo controlled study lasted 30 weeks.

There was a relatively low incidence of adverse reactions reported. These were similar in both the ketotifen and placebo treated groups of patients. The reports for CNS and gastrointestinal symptoms in the placebo group are side effects known to be associated with xanthine administration, which was being used concomitantly by some patients during the study.

Thrombocytopenia has been reported when ketotifen is combined with oral hypoglycemic agents (see Precautions).

Occasional, isolated, instances of elevated liver enzyme levels have been seen during clinical trials. No definite relationship to ketotifen therapy has been established.

Sedation and, rarely, dry mouth or slight dizziness may occur at the beginning of treatment, but usually disappear spontaneously with continued medication. Occasionally, symptoms of CNS stimulation, such as excitation, irritability, insomnia and nervousness have been observed, particularly in children. Weight gain has also been reported.

Cystitis has been rarely described in association with ketotifen. Isolated cases of severe skin reactions (erythema multiforme, Stevens Johnson syndrome), have been reported, the occurrence being approximately 1 case in 2 million patients exposed to ketotifen.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosages with up to 120 mg ketotifen have been reported. The main symptoms of acute overdosage include: drowsiness to severe sedation; confusion and disorientation; tachycardia and hypotension; convulsions, especially in children; hyperexcitability in children; reversible coma. Treatment should be symptomatic. If ingestion is very recent, emptying of the stomach may be considered. Administration of activated charcoal may be beneficial. If necessary, specific or symptomatic treatment and monitoring of the cardiovascular system and physostigmine for anticholinergic effects are recommended; if excitation or convulsions are present, short-acting barbiturates or benzodiazepines may be given.

Dosage And Administration: Children older than 3 years of age: The drug should be given at a dose of 1 mg twice daily, in the morning and evening; 6 months to 3 years: 0.05 mg (0.25 mL of syrup) per kg of body weight given twice daily, in the morning and evening.

To minimize the initial sedation with ketotifen, a slow increase in dosage is recommended during the first week of treatment commencing with one half the daily recommended dosage given in 2 divided doses or in a single dose given in the evening, followed within 5 days, by an increase to the full therapeutic dose.

Concomitant Therapy: Existing asthma therapy should be maintained. A progressive reduction in dosage of other asthma drugs, where clinically indicated, should be attempted only after 6 to 12 weeks of ketotifen therapy.

Reduction of Corticosteroids: It is not fully established, but some patients may be able to reduce corticosteroids.

The reduction in the daily maintenance dosage of steroids should be stepwise according to the recommended methods. The gradual reduction should be continued until either the patient cannot tolerate a further reduction, or it is found possible to withdraw corticosteroids completely.

If troublesome symptoms recur during the period of reduction, the daily dose of corticosteroids should be raised immediately. A larger increase in the steroid dose may be essential at times, as a temporary measure, to control a severe relapse induced by antigen challenge, infection or stress. (The increased physical or mental activity resulting from subjective improvement can also constitute a stress.) When symptoms are brought under control, a progressive reduction may be attempted as before.

Any reduction should be gradual while maintaining close surveillance and frequent examination of the patient. The ability of these patients to react to stress is usually impaired. Acute adrenal insufficiency and severe asthma can be precipitated by an increase in stress and/or reduction of either steroid or ACTH therapy. It is advisable to assess adrenal and pituitary function before reducing steroid dosage in patients who have received long-term therapy.

Method of Withdrawing ACTH: The same principles as discussed above.

Availability And Storage: Syrup: Each 5 mL of strawberry-flavored syrup contains: ketotifen fumarate 1 mg. Nonmedicinal ingredients: alcohol, citric acid, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, sodium phosphate, sorbitol solution, strawberry flavor, sucrose and water. Bottles of 250 mL. To be administered orally. Store at temperatures not exceeding 25°C.

Tablets: Each scored white tablet embossed with the name “ZADITEN” contains: ketotifen fumarate 1 mg. Tablets are to be swallowed. Nonmedicinal ingredients: calcium hydrogen phosphate, magnesium stearate and maize starch. Packs of 56 tablets containing 4 blister strips of 14 tablets each. Store at temperatures not exceeding 25°C, in a dry place.

ZADITEN® Novartis Ketotifen Fumarate Pediatric Asthma Prophylactic – Antiallergic Agent

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