Ketotifen

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETOTIFEN

Composition:

Active substance: ketotifen;

1 tablet contains ketotifen fumarate equivalent to ketotifen 1 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, magnesium stearate, talc, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white tablets with a slightly greyish tint.

Pharmacotherapeutic group. Antihistamines for systemic use. ATC code R06AX17.

Pharmacological properties.

Pharmacodynamics. Ketotifen belongs to the cycloheptothienone group and has a pronounced antihistaminic effect. It belongs to the group of non-bronchodilating antiasthmatic agents. Its mechanism of action is associated with inhibition of histamine and other mediator release from mast cells, blockade of histamine H1-receptors, and inhibition of phosphodiesterase enzyme, resulting in increased cAMP levels in mast cells. It suppresses the effects of PAF (platelet-activating factor). When used alone, it does not terminate asthma attacks but prevents their occurrence and reduces their duration and intensity; in some cases, attacks may completely disappear.

Pharmacokinetics. It is almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 2–4 hours. Steady state is achieved after administration of the minimum daily dose of 2 mg. It is approximately 75% bound to plasma proteins.

Volume of distribution – 2.7 L/kg.

Approximately 60% of the administered dose is metabolized in the liver via three pathways (demethylation, N-oxidation, N-glucuronidation) into the following metabolites: ketotifen-N-glucuronide (pharmacologically inactive), nor-ketotifen (pharmacologically active, with activity similar to unchanged ketotifen), ketotifen N-oxide, and 10-hydroxyketotifen (pharmacological activity unknown).

Elimination is biphasic, with a short half-life of 3 to 5 hours and a longer one of 21 hours. Approximately 1% is excreted unchanged in urine within 48 hours, and 60–70% is excreted as metabolites.

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 of the excipients.

Avoid concomitant use of ketotifen and oral antidiabetic agents (risk of developing reversible thrombocytopenia) until this phenomenon has been sufficiently studied.

Interaction with other medicinal products and other forms of interaction. Concomitant use of ketotifen and oral antidiabetic agents may increase the risk of reversible thrombocytopenia; therefore, such combination should be avoided.

Concomitant use of ketotifen with atropine or atropine-like agents increases the risk of adverse effects such as urinary retention, constipation, and dry mouth.

Ketotifen may potentiate the effects of other medicinal products that depress the central nervous system (e.g., sedatives, hypnotics).

Concomitant administration of ketotifen with other antihistamines may lead to mutual potentiation of their effects.

Ethanol enhances the CNS-depressant effect of ketotifen.

Special precautions for use.

The drug is ineffective in the treatment of acute allergic reactions and asthma attacks.

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

Normalization of the hypothalamic-pituitary-adrenal system function may take up to 1 year. Therefore, during the first weeks of ketotifen therapy, previous treatment should be continued and discontinued gradually and over a prolonged period.

At the beginning of long-term ketotifen therapy, other anti-asthmatic drugs, especially corticosteroids, should not be abruptly discontinued. In patients dependent on steroids, adrenal cortical insufficiency may develop.

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

Very rarely, seizures have been reported during treatment with ketotifen. Since ketotifen lowers the seizure threshold, it should be used with particular caution in patients with a history of seizures. Treatment with this drug should be conducted under physician supervision due to the potential risk of seizures.

Ketotifen should be prescribed cautiously to patients with a history of epilepsy due to the possibility of lowering the seizure threshold during treatment.

Alcohol should not be consumed during ketotifen therapy, as it enhances the central nervous system depressant effects of ketotifen.

The drug should be discontinued 10–14 days prior to performing skin tests for allergy diagnosis.

If discontinuation of ketotifen therapy is necessary, the dose should be gradually reduced over 2–4 weeks to prevent recurrence of asthma symptoms.

Caution should be exercised when administering ketotifen to patients with impaired liver function.

Since concomitant use with oral hypoglycemic agents may cause thrombocytopenia, such combination should be avoided or platelet levels should be carefully monitored if such combination therapy is recommended.

If a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

Use during pregnancy or breastfeeding. Although there is no evidence of teratogenic effects, recommendations for the use of the drug during pregnancy cannot be provided. Ketotifen passes into breast milk; therefore, mothers receiving the drug should not breastfeed.

Ability to influence reaction speed when driving or operating machinery. At the beginning of treatment, the drug may slow reaction time, requiring patients to exercise increased caution when driving or operating automated machinery.

Method of Administration and Dosage

Tablets should be taken orally during meals with water.

Dosing. Adults: 1 tablet (1 mg) twice daily, in the morning and evening, during meals. For patients experiencing a pronounced sedative effect during the first days of treatment, it is recommended to take ketotifen as 1 tablet (1 mg) once daily only in the evening.

If necessary, the daily dose may be increased to 4 mg, i.e., 2 tablets twice daily. When a higher dose is used, a faster onset of therapeutic effect may be expected.

Children aged 3 years and older: 1 tablet (1 mg) twice daily, in the morning and evening, during meals.

Elderly patients: no special recommendations are required for elderly patients.

Duration of treatment. Treatment is long-term, and therapeutic effect is achieved after several weeks of therapy. Treatment should last at least 2–3 months, especially in patients who do not experience symptom improvement during the first weeks.

Concomitant bronchodilator therapy: concomitant use of ketotifen with bronchodilators may reduce the frequency of bronchodilator use.

Discontinuation of therapy. Ketotifen treatment should be discontinued gradually over 2–4 weeks to avoid the risk of recurrence of asthmatic symptoms.

Children. To be used in children aged 3 years and older.

Clinical observations confirm the pharmacokinetic characteristics of ketotifen and indicate that children may require a higher dose in mg/kg than adult patients. Higher doses are tolerated as well as lower doses.

Overdose. Symptoms: possible marked disturbances in psychomotor reactions, drowsiness progressing to pronounced sedation, headache, disorientation, tachycardia, decreased arterial pressure, coma (especially in children), symptoms of central nervous system excitation, including seizures.

Bradycardia, arrhythmia, respiratory center depression, and nystagmus may also occur.

In the event of the above-mentioned symptoms, the patient should be thoroughly examined.

Treatment: general measures to eliminate the non-absorbed amount of drug from the gastrointestinal tract: induce vomiting, gastric lavage. Administration of activated charcoal may be beneficial. If necessary, symptomatic treatment and monitoring of cardiovascular and respiratory systems are recommended. In cases of excitation, short-acting barbiturates or benzodiazepines may be used.

Adverse Reactions

Infections and infestations: cystitis.

Immune system disorders: skin rashes, severe skin reactions, erythema multiforme, Stevens-Johnson syndrome.

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

Psychiatric disorders: psychomotor agitation, irritability, insomnia, restlessness, nervousness, disorientation, somnolence.

Nervous system disorders: dizziness, sedative effect, seizures.

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

Hepatobiliary disorders: increased liver enzyme levels, hepatitis.

Renal and urinary disorders: dysuria.

Dry mouth and dizziness may occur at the beginning of treatment, but usually resolve spontaneously during therapy. Rarely, symptoms of CNS stimulation such as agitation, irritability, insomnia, and anxiety may occur, particularly in children.

Shelf life. 4 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging. Tablets, 30 in containers; 10×3 in blisters in a carton.

Prescription status. Prescription only.

Manufacturer

Limited Liability Company "Research Plant "GNCLS", or

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA", or

Limited Liability Company "FARMEKS GROUP".

Manufacturer's location and address of business activity.

Ukraine, Kharkiv region, city of Kharkiv, Vorobiova Street, building 8.

(Limited Liability Company "Research Plant "GNCLS")

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, building 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, building 100.

(Limited Liability Company "FARMEKS GROUP")