Ketotifen

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETOTIFEN (KETOTIFEN)

Composition:

Active substance: ketotifen fumarate;

5 ml of syrup contain 1 mg of ketotifen fumarate (calculated as ketotifen and 100 % dry substance);

Excipients: sodium benzoate (E 211), maltitol liquid, sodium saccharin, sodium hydrogen phosphate dodecahydrate, citric acid monohydrate, fumaric acid, glycerin, hydroxyethylcellulose, banana flavoring, purified water.

Pharmaceutical form. Syrup.

Main physicochemical properties: colorless or slightly yellowish clear viscous liquid with a specific odor.

Pharmacotherapeutic group. Antihistamines for systemic use.

ATC code R06AX17.

Pharmacological properties.

Pharmacodynamics.

Ketotifen exerts membrane-stabilizing, anti-allergic, and antihistaminic effects. The mechanism of action of ketotifen is due to inhibition of the release of biologically active substances from mast cells and basophils (histamine, leukotrienes), suppression of cytokine-induced eosinophil granulocyte sensitization, and inhibition of their migration into inflammatory foci. The drug suppresses the development of airway hyperreactivity caused by platelet activation under the influence of platelet-activating factor (PAF) or allergens. The drug inhibits phosphodiesterase and increases intracellular cAMP levels. Ketotifen induces non-competitive blockade of H₁-histamine receptors. It effectively prevents bronchospasm and reduces the need for corticosteroids and bronchodilators. It does not exert bronchodilatory action. The therapeutic effect of the drug develops slowly over 1–2 months.

Pharmacokinetics.

After oral administration, ketotifen is almost completely absorbed. The main metabolite of ketotifen, N-glucuronide, is almost non-toxic. Maximum plasma concentration is reached within 2–4 hours. Protein binding is approximately 75%. Elimination of ketotifen from the body is biphasic: the first half-life period is 3–5 hours, the second – 21 hours. 60–70% of the drug is excreted by the kidneys and 20–30% by the liver in the form of metabolites; 10% of the drug is excreted unchanged. Within 48 hours, the majority of a single administered dose is excreted in the urine.

Clinical characteristics.

Indications.

• Prophylactic treatment of bronchial asthma, especially atopic asthma.
• Symptomatic treatment of allergic conditions, including allergic rhinitis and conjunctivitis.

Contraindications.

• Hypersensitivity to ketotifen or to any other components of the drug.
• Concomitant use of ketotifen and oral antidiabetic agents should be avoided (risk of developing reversible thrombocytopenia) until this phenomenon is sufficiently studied.

Interaction with other medicinal products and other forms of interaction.

Atropine (agents with atropine-like effects): increases the risk of adverse reactions such as urinary retention, constipation, dry mouth.

Sedatives, hypnotics: ketotifen may potentiate the effects of other medicinal products that depress the central nervous system (CNS).

Antihistamines: may lead to mutual potentiation of their effects.

Ethanol: enhances the CNS depressant effect of ketotifen.

Oral antidiabetic agents: may cause reversible thrombocytopenia.

The use of ketotifen may reduce the need for beta-adrenergic agonists, corticosteroids, and methylxanthines.

Special precautions for use.

The drug is not intended for emergency treatment of asthma attacks.

The maximum therapeutic effect of the drug is achieved after several weeks of regular use.

At the beginning of therapy with Ketotifen, anti-asthmatic medications, especially systemic glucocorticosteroids, should not be discontinued abruptly due to the risk of developing adrenal insufficiency. In such cases, the period required for restoration of normal hypothalamic-pituitary-adrenal axis response to stress may last up to 1 year.

To prevent sedative effects, treatment may be initiated at half the recommended dose during the first few days.

During Ketotifen therapy, the need for glucocorticoids and bronchodilators may decrease in patients with bronchial asthma.

In case of intercurrent infection, specific anti-infective therapy should be administered.

Ketotifen should be used with caution in patients with a predisposition to seizures (e.g., history of epilepsy), as the drug may lower the seizure threshold.

Alcohol consumption should be avoided during Ketotifen treatment, as it enhances the CNS depressant effect of Ketotifen.

The therapeutic effect develops gradually, within 2–4 weeks after initiation of treatment; therefore, treatment should be prolonged (2–3 months or longer). Discontinuation of therapy should be gradual over a period of 2–4 weeks, during which asthma symptoms may recur.

Caution is advised when administering ketotifen to patients with impaired liver function.

When used concomitantly with antidiabetic drugs, platelet counts in peripheral blood should be monitored (transient thrombocytopenia is possible).

Patients with carbohydrate intolerance (e.g., glucose-galactose malabsorption) and those with diabetes mellitus should be aware that the formulation contains carbohydrates (the syrup contains 0.06 g of carbohydrates per 1 ml). The syrup contains maltitol (hydrated glucose syrup) in liquid form. This preparation must not be used by patients with rare hereditary fructose intolerance.

Frequent and prolonged use of the syrup may be harmful to teeth (risk of caries development).

Experience with ketotifen use indicates that no special recommendations are required for elderly patients.

Clinical observations are consistent with pharmacokinetic characteristics and show that children may require a higher dose per kilogram of body weight than adults to achieve optimal therapeutic effect. Such higher doses are as well tolerated as the minimal doses.

Use during pregnancy or breastfeeding.

Ketotifen has no embryotoxic or teratogenic effects in animals. During pregnancy, ketotifen is contraindicated in the first trimester. In the second and third trimesters, it should be prescribed only after strict assessment of direct indications and when the expected benefit of treatment outweighs the potential risk to the fetus.

Ketotifen passes into breast milk; therefore, breastfeeding should be discontinued during treatment.

Ability to affect reaction speed when driving or operating machinery.

At the beginning of treatment, Ketotifen may slow reaction times. Patients should therefore exercise increased caution when driving or operating machinery.

Dosage and Administration.

For children aged 6 months to 3 years: administer the syrup at a dose of 0.25 ml (0.05 mg of ketotifen) per 1 kg of body weight. The frequency of administration is twice daily (in the morning and evening). Measure the required dose using the dosing spoon provided.

For example, a child weighing 10 kg can be given 2.5 ml (according to the mark on the dosing spoon) of syrup twice daily (with morning and evening meals).

For children aged 3 years and older: administer 5 ml/1 mg of ketotifen (1 dosing spoon) of syrup twice daily (in the morning and evening, with meals).

The therapeutic effect of the drug develops gradually, within 2–4 weeks after the start of treatment; therefore, the treatment course should be prolonged (2–3 months). Discontinuation of treatment should be gradual over 2–4 weeks, during which a recurrence of asthma symptoms may occur.

Children.

The drug may be used in children aged 6 months and older.

Overdose.

Symptoms. May manifest as pronounced sedative effects (including marked drowsiness), faintness, confusion, disorientation, nystagmus, headache, tachycardia, bradycardia, arrhythmia, respiratory center depression, arterial hypotension, and coma. Symptoms of CNS stimulation (especially in children) may also occur, such as increased excitability and seizures.

Treatment. Provide symptomatic therapy: gastric lavage (if the drug was recently ingested), administration of activated charcoal.

If necessary, monitor cardiovascular and respiratory functions. In cases of agitation or seizures, administer short-acting barbiturates or benzodiazepines.

Adverse Reactions.

Adverse reactions during the use of therapeutic doses are usually mild, occur generally at the beginning of treatment, and spontaneously resolve after several days of continued use.

Infections and infestations: cystitis.

Immune system: skin rashes are possible, including erythema multiforme, Stevens-Johnson syndrome, and other severe skin reactions.

Metabolism and nutrition disorders: weight gain due to increased appetite may occur.

Psychiatric disorders: symptoms of CNS stimulation such as restlessness, irritability, insomnia, and anxiety are rarely observed (more frequently in children).

Nervous system: sedative effect (including drowsiness), dizziness, seizures.

Gastrointestinal tract: dry mouth, stomach pain, constipation, nausea, vomiting, dyspeptic disorders.

Hepatobiliary system: increased liver enzymes, hepatitis.

Renal and urinary system: dysuria.

Laboratory findings: thrombocytopenia.

Dry mouth and dizziness may appear at the beginning of treatment but usually resolve spontaneously during continued therapy. Symptoms of CNS stimulation such as restlessness, irritability, insomnia, and anxiety are rarely observed, particularly in children.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. After opening the bottle, the shelf life of the medication is 30 days at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 50 ml in bottles, 100 ml in bottles and jars, with a dosing spoon, in a carton.

Prescription status. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchagov Chemical and Pharmaceutical Plant".

Manufacturer's address and location of manufacturing activities.

17, Miru Street, Kyiv, 03134, Ukraine.