Ketotifen

Pharmacological properties

Antiallergic, membrane stabilizing, antihistamine. inhibits the release of histamine, leukotrienes, lymphokines and other biologically active substances from mast cells and basophils. non-competitively blocks n1-histamine receptors, inhibits phosphodiesterase, increases the level of cAMP in cells. reduces the sensitization of eosinophils by recombinant human cytokines and their accumulation in target organs. when used internally, the drug is absorbed almost completely, its bioavailability is about 50% due to the effect of the primary passage through the liver.

Ketotifen is excreted from the body in two phases, with the half-life of the short phase being 3-5 hours and the long half-life of 21 hours. Most of the dose taken is excreted in the urine for 48 hours as metabolites (60–70%).

Indications

Prevention and treatment of acute, subacute and chronic allergic conjunctivitis and keratoconjunctivitis, seasonal (spring) conjunctivitis, ocular manifestations of hay fever. in the form of tablets is used to prevent the development of bronchospasm, asthmatic attacks and acute allergic reactions, to reduce the dose and / or withdrawal of hormonal drugs (glucocorticosteroids) and bronchodilators with their combined use.

Application

The drug in the form of drops for adults and children over the age of 12 years is prescribed 1 drop in the conjunctival sac of each eye 2 times a day. prophylactic administration in subacute and chronic processes should begin 3 weeks before contact with the allergen. treatment continues throughout the period of exposure to allergens. the duration of the use of eye drops depends on the type and severity of the disease. The vial should be carefully closed after each use.

In the form of tablets, 1 tablet is prescribed for adults inside, 2 times a day - in the morning and in the evening with meals. If necessary, the daily dose is increased to 4 mg, divided into 2 doses. For children over 3 years of age, the drug is prescribed 1 mg 2 times a day.

Contraindications

Hypersensitivity to ketotifen and other components of the drug, the period of pregnancy and lactation; children under 3 years old.

Side effects

Burning and tingling sensation in the eyes, blurred vision immediately after instillation. irritation of the mucous membrane of the eye, skin rash around the eyes; hypersensitivity. when taking the drug inside, drowsiness, dry mouth, dizziness, slowing of mental reactions, which usually disappear after several days of administration, are possible. occasionally noted an increase in body weight due to increased appetite.

special instructions

In acute inflammation and during an exacerbation of the chronic process, it is possible to use the drug in combination with corticosteroids. the patient should be warned about the need for regular use of the drug. treatment begins before contact with the allergen and continues the entire period of the allergen.

The drug should not be used simultaneously with antidiabetic agents.

When using eye drops, soft contact lenses cannot be used due to the presence of chloride in benzalkonium. Hard contact lenses should be removed from the eyes immediately before instillation of the drops and inserted no earlier than 15 minutes after application of the drug.

The use of the drug during lactation. It is recommended only as directed by a doctor.

Influence on the ability to drive vehicles and control mechanisms. When using tablets, patients should refrain from performing potentially hazardous activities that require increased attention. For some time after dropping drops into the eyes, one should refrain from doing work that requires increased attention.

Interactions

With the simultaneous use of ketotifen and antihistamines, a potentiation effect is possible.concomitant use with oral antidiabetic drugs increases the possibility of thrombocytopenia.

Overdose

Cases of overdose in the form of drops have not been established. when taking in the form of tablets, confusion and disorientation, tachycardia and a decrease in hell, convulsions and increased irritability (especially in children), drowsiness and severe sedation, coma are possible. treatment: gastric lavage, monitoring of indicators of the cardiovascular system. in the case of psychomotor agitation and the development of convulsive syndrome, barbiturates with a short period of action and benzodiazepines are prescribed.

Storage conditions

In the dark place at a temperature of 15-25 ° C.

Actual information

Ketotifen as the first successful (from a preventive point of view) anti-asthma drug was described in 1965. The scientific world learned about this new progress in the treatment of bronchial asthma, followed by research and publications in this direction. the drug is recognized as effective for the treatment of not only bronchial asthma, but also allergic rhinitis and conjunctivitis.

Physical properties

Fine crystalline powder from white to brownish yellow. Soluble in water; very slightly soluble in acetonitrile (acetic acid nitrile); slightly soluble in methyl alcohol.

Pharmacokinetics

Ketotifen is almost completely absorbed from the gastrointestinal tract after oral administration, but bioavailability is only about 50% due to hepatic metabolism of the first passage. The maximum concentration in blood plasma after oral administration is achieved after 2–4 hours. As a rule, the drug is excreted in the urine in the form of inactive metabolites and a small amount of the drug unchanged; T ^1/₂ - about 21 hours

Application

According to the ATC classification, it belongs to the group “Antihistamines for systemic use”. Ketotifen It is a sedative antihistamine that also has a stabilizing effect on mast cells. It is used in the treatment of allergic conditions, including allergic rhinitis and conjunctivitis. Ketotifen It is also used in the prevention of asthma, it may take several weeks for its full therapeutic effect to manifest. For the treatment of acute attacks of bronchial asthma is not used. It is also used in the form of eye drops.

Studies on the efficacy of ketotifen in asthma have been controversial. Although some researchers found it effective in reducing the severity of symptoms, the use of other anti-asthma drugs was also reduced during its use, but some studies have shown no significant benefits. In the British asthma guidelines, ketotifen is considered ineffective. When writing some systematic reviews, it was found that the prescription of the drug was effective for controlling asthma and shortness of breath in children with mild to moderate disease severity, but noted that the high prevalence of atopy in some studies meant that the results could not be extended to children with bronchial asthma in general. Studies conducted with children have shown that prolonged ketotifen therapy reduces the risk of bronchial asthma.

Experimental data

The obtained experimental data justify the use of ketotifen as a prophylactic for asthma (inhibition of the release of anaphylaxis mediators, especially SRS-A, the prevention of bronchospasm caused by SRS-A in vivo, the effect of calcium antagonist). The relevant reviews briefly discussed and reviewed the results of experimental and therapeutic studies conducted over 6 years in several countries on several thousand patients.Some important features of oral asthma prophylaxis with ketotifen were identified, namely the effect Ketotifen the characteristic hyperreactivity of bronchial asthma, the types of asthma that respond best to ketotifen treatment; the effect of ketotifen with a decrease in the concomitant use of corticosteroids and bronchodilators, comparison of ketotifen with specific antihistamines, as well as side effects and safety of the drug with prolonged use (Craps L., 1981).

Allergic conjunctivitis is an IgE-mediated inflammation of the conjunctiva. Despite the fact that histamine is the main mediator in this condition, the use of local antihistamines often provides only temporary relief. Therapeutic agents aimed at inflammatory cascades of the disease are necessary, especially in cases with prolonged and severe allergic conjunctivitis. Ketotifen has been considered for the treatment of allergic conjunctivitis in terms of its mechanism of action and clinical efficacy. Thus, eye drops were recommended for the treatment of this type of disease.

A drug Ketotifen as a second-generation antihistamine, it demonstrated anti-inflammatory properties, such as inhibiting the release of histamine from mast cells, as well as interfering with the production of cytokines and adhesion molecules from cord blood and conjunctival mast cells. Currently, several options for immunomodulation are available for the treatment of allergic conjunctivitis. These therapeutic options provide the best therapeutic result for patients with allergic conjunctivitis, especially those who are in serious condition (Pacharn R., 2013).

The therapeutic efficacy of ketotifen for prophylaxis in children and adolescents with bronchial asthma was also considered. Conclusions are drawn based on the results of 4 double-blind, placebo-controlled trials in 194 patients, 2 double-blind, controlled trials with clemastine in 86 patients and 5 double-trials. Long-term use of oral ketotifen allowed to reduce the intake of corticosteroids and bronchodilators while improving clinical symptoms and maintaining respiratory function. Optimal results were obtained after 8-12 weeks of therapy. Comparative studies with clemastine specific H₁-blocking agent, showed that the antihistamine properties of ketotifen do not have a prophylactic effect in bronchial asthma. In addition, it was found that for optimal results, a double dose in milligrams per kilogram of body weight, based on the recommended dose for adults, or that a dose for adults can be used in children, will be required. These clinical observations correspond to the results of pharmacokinetics in children, which indicates a faster metabolism without changing the nature of biotransformation. Comparative studies between ketotifen and disodium chromoglycate showed comparable efficacy, although this does not mean that the response pattern was the same for the two drugs. Long-term treatment with oral ketotifen was as well tolerated in children as in adults. The main adverse effect was the sedation that occurred in 6% of children at the beginning of treatment, which took place after several days of using the drug (Craps L., 1983).

Efficiency and safety Ketotifen in the treatment of recurrent bronchitis were studied in 20 Thai children, whose average age was 5.3 years. The symptoms studied were cough, increased secretion, and shortness of breath, and rating points were assigned to each of the symptoms (maximum 4 points). The frequency, severity and duration of the disease were taken into account, and scores for the dose of symptomatic drugs used were also assigned.Symptoms during the use of symptomatic drugs were recorded throughout the year before therapy with ketotifen and throughout the following year. Evaluation of effectiveness was carried out by comparing the symptoms (evaluated for a month) and the effects of drugs during the study period with the average value of these indicators for the previous year. Thirteen children received ketotifen throughout the year, while seven children who showed almost no symptoms after a 4-month treatment with ketotifen were observed only for 8 months. At the end of the study period of ketotifen therapy, treatment was rated as very good and good in 85% of children, satisfactory in 10% and poor in 5%. Drowsiness was the only side effect reported in several cases, but only at the initial stage of therapy. There were no deviations in laboratory indicators (Suwanjutha S., 1985).

17 children with neurodermatitis aged 2 to 14 years received Ketotifen at a dose of 1 mg 2 times a day. In 7 children, multivalent therapy was performed. Ketotifen therapy caused marked relief of itching for only two weeks; patients were completely relieved of itching after an average of 20 days. Improvements in the skin were recorded after 2 months of treatment. Patients were completely cured of skin diseases after 7–9 months. In three patients, skin deterioration was caused by infection. Regarding long-term therapy with ketotifen, no serious side effects were observed (Kikindjanin V., 1990).

In a double-blind study, half of the 56 adult patients with atopic dermatitis were treated systemically for 3 months with ketotifen capsules of 1 mg twice daily, while the other half was given placebo. The health status of patients in the ketotifen group significantly improved during treatment according to all clinical estimates. The overall treatment efficacy was significantly higher in the ketotifen group. No serious side effects were observed (Falk E.S., 1993).

Adverse effects

They relate to the entire class of antihistamines: drowsiness, dry mouth and dizziness may occur at the beginning of treatment, but usually these symptoms disappear with further use of the drug. Information was reported on weight gain, as well as on individual cases of severe skin reactions, cystitis and hepatitis. Irritation, pain and acne keratitis were usually observed after instillation in the eyes. So that the full therapeutic effect is manifested Ketotifen, it is necessary to carry out therapy for several weeks. And in the case of anti-asthma treatment, it should not be suddenly canceled after the start of ketotifen therapy. This drug should not be prescribed for the treatment of acute asthma attacks.

Children

Ketotifen It can be prescribed to children for the treatment of allergic conditions, such as rhinitis or conjunctivitis, and is used to prevent bronchial asthma. Oral doses equivalent to 1 mg of ketotifen 2 times a day with meals can be used from 3 years. A dose equivalent to 500 micrograms of ketotifen twice a day has been suggested for children aged 6 months to 3 years. Ketotifen also used in the form of eye drops 2 times a day.

Overdose

Overdose Ketotifen while taking a dose of 10–120 mg was recorded in 8 patients. Symptoms included drowsiness, confusion, shortness of breath, disorientation. The most serious manifestations were loss of consciousness, convulsions, bradycardia and tachycardia, as well as a severe hypotensive reaction. In such cases, the stomach should be washed. Next, symptomatic maintenance therapy is prescribed.

Interactions

A reversible decrease in platelet count was observed in several patients receiving ketotifen combined with oral administration of antidiabetic drugs, and therefore it was suggested to avoid this combination.

Dosage regimen

Adults: 1 tablet 2 times a day (morning and evening), if necessary, the daily dose of the drug can be increased to 4 mg (this is the maximum daily dose).

Children: 1 tablet 2 times a day; at the age of 6 months - 3 years at 500 mcg 2 times a day.

Ketotifen also applied topically, as eye drops is equivalent to 0.025% ketotifen, is prescribed twice a day.

The therapeutic effect develops slowly. Therapy with the drug is carried out for 2-3 months. Finish taking the drug should be gradual, within 2-4 weeks.