ZADITEN (ZADITOR) SRO
Ketotifen hydrogen fumarate.
Preventive treatment of bronchial asthma especially when associated with atopic symptoms.
ZADITEN (ZADITOR) is not effective in aborting established attacks of asthma. ZADITEN (ZADITOR) is not a substitute for corticosteroid treatment (inhaled or systemic) when corticosteroid is indicated in the treatment of asthma.
Prevention and treatment of multisystem allergic disorders eg, chronic urticaria, atopic dermatitis, allergic rhinitis and conjunctivitis.
Dosage & Administration:
1 tab (1 mg) twice daily (with morning and evening meals), or 1 SRO tab (1 mg) in the evening. In patients susceptible to sedation, slow increase in dose is recommended during the 1st week of treatment, starting with ½ tab twice daily and increasing to the full therapeutic dose. If necessary, the daily dose may be increased up to 4 mg ie, 2 ZADITEN (ZADITOR) tab twice daily or 2 ZADITEN (ZADITOR) tab once a day in the evening.
Adolescents and Children:
>3 years: 1 tab or 5 mL (1 teaspoonful) syr twice daily with morning and evening meal, or 1 SRO tab (2 mg) in the evening;
6 months to 3 years: 0.05 mg/kg body weight (0.25 mL syr) twice daily (morning and evening) [eg, an infant weighing 10 kg may receive 2.5 mL (½ teaspoonful) of ZADITEN (ZADITOR) syrup in the morning and evening].
Note: Clinical observations reflect pharmacokinetic findings and indicate that children >3 years may require a dosage regimen similar to adults in order to obtain optimal results (see Pharmacology: Pharmacokinetics under Actions).
Elderly: There is no evidence to suggest that the dosage needs to be adjusted in elderly patients.
Efficacy Guidance: In the prevention of bronchial asthma, it may take several weeks of treatment to achieve the full therapeutic effect. It is therefore recommended that for patients not adequately responding within a few weeks, treatment with ZADITEN (ZADITOR) should be maintained for a minimum of 2-3 months.
Concomitant Bronchodilator Therapy: If bronchodilators are used concomitantly with ZADITEN (ZADITOR), the frequency of bronchodilator usage can be reduced.
If it is necessary to withdraw ZADITEN (ZADITOR), this should be done gradually over a period of 2-4 weeks. Symptoms of asthma may recur.
Administration: ZADITEN (ZADITOR) SRO tablets should be swallowed whole.
The main symptoms of acute overdose include: Drowsiness to severe sedation, confusion and disorientation; tachycardia and hypotension; especially in children, hyperexcitability or convulsions; reversible coma.
Treatment: Treatment should be symptomatic. If excitation or convulsions are present, short-acting barbiturates or benzodiazepines may be given. Monitoring of the cardiovascular system are recommended. If ZADITEN (ZADITOR) has been taken very recently, emptying of the stomach may be considered. Administration of activated charcoal may be beneficial.
Known hypersensitivity to ketotifen or to any of the excipients of ZADITEN (ZADITOR)/ZADITEN (ZADITOR) SRO.
Epilepsy or history of seizures (see Precautions).
Convulsions have been reported during ZADITEN (ZADITOR) therapy. As ZADITEN (ZADITOR) may lower the seizure threshold, it is contraindicated in patients with a history of epilepsy (see Contraindications).
Symptomatic and prophylactic antiasthmatic drugs already in use should never be withdrawn abruptly when long-term treatment with ZADITEN (ZADITOR) is started. This applies especially to systemic corticosteroids, 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 1 year.
A reversible fall in the thrombocyte count in patients receiving ZADITEN (ZADITOR) concomitantly with oral antidiabetic agents has been observed in rare cases. Thrombocyte counts should therefore be measured out in patients concomitantly taking antidiabetics.
In diabetic patients, the carbohydrate content of the syrup (5 mL= carbohydrate 3 g) should be taken into consideration.
The tablets and SRO film-coated tablets contain lactose. This medicine is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
ZADITEN (ZADITOR) syrup contains maltitol liquid. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Effects on the Ability to Drive or Operate Machinery: During the 1st few days of treatment with ZADITEN (ZADITOR), the patient's reactions may be impaired and should therefore exercise care when driving a vehicle or operating machinery.
Impairment of Fertility: There is no data available on the effect of ZADITEN (ZADITOR)/ZADITEN (ZADITOR) SRO on fertility in humans (see Toxicology: Nonclinical Safety Data under Pharmacology under Actions).
Use in lactation:
Ketotifen is excreted in rat milk. While there are no human data available, it is likely that ZADITEN (ZADITOR) is also excreted in human breast milk, and therefore, mothers receiving ZADITEN (ZADITOR) should not breastfeed.
Use in pregnancy:
Although ketotifen was without effect on pregnancy and on peri- and postnatal development in animals at dose levels which were tolerated by the mother animals, its safety in human pregnancy has not been established. ZADITEN (ZADITOR) should not be given to pregnant women except if clearly needed and the benefits outweigh the potential risks.
Adverse Drug Reactions:
The following adverse reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent first. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000).
Infections and Infestations:
Immune System Disorders:
Very Rare: Erythema multiforme, Stevens-Johnson syndrome, severe skin reaction.
Metabolism and Nutrition Disorders:
Rare: Increased weight.
Common: Agitation, irritability, insomnia, nervousness.
Nervous System Disorders:
Uncommon: Dry mouth*.
Very Rare: Hepatitis, increased in liver enzymes.
*Sedation, dry mouth and dizziness may occur at the beginning of treatment, but usually disappear spontaneously with continued medication. In adults, the incidence of sedation is 14.1% during the first 3 months of treatment and 2.2% after 12 months.
**Symptoms of central nervous system stimulation eg, excitation, irritability, insomnia and nervousness, have been observed particularly in children.
Adverse drug reactions from spontaneous reports and literature cases (frequency not known). The following adverse drug reactions have been derived from post-marketing experience with ZADITEN (ZADITOR)/ZADITEN (ZADITOR) SRO via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known.
Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness: Nervous System Disorders: Convulsion, somnolence and headache.
Vomiting, nausea, diarrhoea.
Skin and Subcutaneous Tissue Disorders: Rash, urticaria.
Click to view ADR Monitoring Form
Observed Interaction resulting in a Concomitant Use Not Recommended: Oral Antidiabetic Agents: A reversible fall in the thrombocyte count in patients receiving ZADITEN (ZADITOR) concomitantly with oral antidiabetic agents has been observed in rare cases. Thrombocyte counts should therefore be measured in patients taking ZADITEN (ZADITOR) concomitantly with antidiabetics (see Precautions).
Anticipated Interactions to be Considered: Medicinal Products Causing Central Nervous System (CNS) Depression: ZADITEN (ZADITOR) may potentiate the effects of CNS depressants, antihistamines and alcohol.
Storage ZADITEN (ZADITOR):
Tablets: Do not store above 30°C. Syrup: Store below 25°C.
ZADITEN (ZADITOR) SRO: Store below 25°C.
ZADITEN (ZADITOR) tablet contains the following excipients: Magnesium stearate, maize starch, lactose and purified water.
ZADITEN (ZADITOR) SRO tablet also contains the following excipients: Magnesium stearate, silica, ethyl cellulose, polyvinylpyrrolidone, maize starch, glyceryl palmitostearate, lactose, polyethylene glycol 6000, talc, methylhydroxypropylcellulose, yellow iron oxide and titanium dioxide.
ZADITEN (ZADITOR) syrup contains ketotifen 1 mg (as the hydrogen fumarate) per 5 mL. It also contains the following excipients: Banana flavoring agent, propyl p-hydroxybenzoate, methyl p-hydroxybenzoate, citric acid, disodium hydrogen phosphate, maltitol liquid and purified water.
Mechanism of Action:
Pharmacology: Pharmacodynamics: Ketotifen is a non-bronchodilator antiasthmatic drug which inhibits the effects of certain endogenous substances known to be inflammatory mediators and thereby exerts antiallergic activity.
Laboratory experiments have revealed a number of properties of ketotifen, which may contribute to its antiasthmatic activity: Inhibition of the release of allergic mediators eg, histamine and leukotrienes; suppression of the priming of eosinophils by human recombinant cytokines and thereby suppression of the influx of eosinophils into inflammatory loci; inhibition of the development of airway hyperreactivity associated with activation of platelets by platelet-activating factor (PAF) or caused by neural activation following the use of sympathomimetic drugs or the exposure to allergen.
Ketotifen is an antiallergic substance possessing noncompetitive histamine (H1)-blocking properties.
Pharmacokinetics: Absorption: After oral administration, the absorption of ZADITEN (ZADITOR) is almost complete. Bioavailability amounts to approximately 50% owing to a first-pass effect of about 50% in the liver. Maximal plasma concentrations are reached within 2-4 hrs.
Distribution: Protein-binding is 75%.
Biotransformation: The main metabolite is the practically inactive ketotifen-N-glucuronide.
Elimination: Ketotifen is eliminated biphasically, with a short half-life (t½) of 3-5 hrs and a longer one of 21 hrs. About 1% of the substance is excreted unchanged in the urine within 48 hrs and 60-70% as metabolites.
Slow-Release (SRO) Formulation: The slow-release of ketotifen from ZADITEN (ZADITOR) SRO tablets results in a smoother pharmacokinetic profile with reduced daily variations in the plasma concentrations, which improves tolerability and allows once-a-day administration. The peak plasma levels attained with a single daily dose of ZADITEN (ZADITOR) SRO are lower (76%) than those found when the same daily amounts of ketotifen are given in 2 divided doses of other dosage forms. However, minimum plasma concentrations (trough levels) and relative bioavailability area under the concentration-time curve (AUC) are the same for both dose regimens.
Effect of Food: The bioavailability of either form of ZADITEN (ZADITOR) (immediate- or moidfied-release formulations) is not influenced by the intake of food. Therefore ZADITEN (ZADITOR) can be taken with or without food. However, smooth plasma concentration profile may be observed for the modified-release tablet when administered with meals.
Special Population: Children: The pattern of metabolism in children is the same as in adults, but the clearance is higher in children. Children >3 years therefore, require the same daily dose regimen as adults.
Hepatic Impairment: No relevant pharmacokinetic studies have been performed with ZADITEN (ZADITOR) in patients with hepatic impairment. Since ketotifen is metabolized in the liver and its glucuronidation may be impaired in hepatic impairment. The clearance of ketotifen will most likely be reduced in patients with hepatic impairment and the possibility of accumulation of unchanged drug cannot be excluded.
Renal Impairment: No relevant pharmacokinetic studies have been performed with ZADITEN (ZADITOR) in patients with renal impairment. However, considering that 60-70% the dose is excreted in urine as metabolites, an increased risk of adverse reactions due to accumulation of metabolites cannot be excluded. Thus, caution is required in administering ZADITEN (ZADITOR) in patients with mild to moderate renal impairment and, ZADITEN (ZADITOR) should not be administered with severe renal impairment.
Toxicology: Nonclinical Safety Data: Mutagenicity: Ketotifen and/or its metabolites were devoid of genotoxic potential, when investigated in vitro for induction of gene mutation in Salmonella typhimurium, for chromosome aberrations in V79 Chinese hamster cells or for primary DNA-damage in rat hepatocyte cultures. No clastogenic activity was observed in vivo (cytogenetic analysis of bone marrow cells in the Chinese hamster, bone marrow micronucleus assay in mice). Likewise, no mutagenic effects were evident on the germ cells of male mice in the dominant lethal test.
Carcinogenicity: In rats treated continuously in the diet for 24 months, maximum tolerated doses of ketotifen 71 mg/kg/day revealed no carcinogenic potential. No evidence of tumorigenic effects was obtained in mice treated with up to 88 mg/kg body weight in the diet for 74 weeks.
Reproductive Toxicity: No embryotoxic or teratogenic potential of ketotifen was revealed in rats or rabbits. In male rats treated for 10 weeks (ie, more than a complete spermatogenic cycle) before mating, fertility was unaffected at a tolerated dose of 10 mg/kg/day.
Treatment of male rats with a toxic oral dose of ketotifen (50 mg/kg/day) for 10 weeks prior to mating resulted in decreased fertility. Fertility was not impaired at doses relevant for human use.
The fertility of female rats as well as prenatal development, pregnancy and weaning of the offspring were not adversely affected by ketotifen treatment at oral dose levels of up to 50 mg/kg/day, although nonspecific toxicity to the pregnant females were observed at, and >10 mg/kg. Likewise, no adverse effect of treatment was found in the perinatal phase. Due to the maternal toxicity, some decrease in pup survival and weight gain was recorded during the 1st days of postnatal development at the high dose level of 50 mg/kg/day.