Pirimetamine - instructions for use, doses, side effects, contraindications

Clinical and pharmacological group: & nbsp

Included in the formulation

АТХ:

P.01.B.D.01 Pyrimethamine

Pharmacodynamics:

The pharmacological action is antiprotozoal.

It inhibits dihydrofolate reductase, disrupts the formation of tetrahydrofolic acid, and stops the catalyzed processes (transfer of single-carbon fragments).

Effective against toxoplasm, leishmania, malarial plasmodium (P. falciparum, P. vivax, P. malariae). Affects the asexual erythrocyte, tissue pre-erythrocyte forms and damages the gamonts of all kinds of plasmodia, blocks sporogony in the mosquito and prevents cyclical spread of malaria; The plasmodium resistance to pyrimethamine develops rapidly. It acts on leishmanias in the flagellate stage and disrupts their development in the body of a mosquito.

Pharmacokinetics:

It is well absorbed from the digestive tract. The volume of distribution is 2.3-3.1 l / kg. After oral intake is absorbed slowly, the maximum concentration is recorded after 2-7 hours. Continuously circulates in the blood (within 1 week after a single application). It is distributed in the body, mainly accumulating in the blood cells, kidneys, lungs, liver, spleen. Penetrates into the cerebrospinal fluid, where the concentration is 13-26% of that in the blood plasma. The ratio of concentrations in cells and blood plasma is 0.87.Penetrates through the placenta and into breast milk (peak concentration - after 6 hours). The connection with plasma proteins is high (87%). Biotransformation occurs in the liver. Half-lifein adults - 96 hours; when AIDS is shortened to 23 hours, which may indicate genetic variations in metabolism in cases of impaired liver function. Half-life in children of the first year of life an average of 64 hours (52-87 hours). Time to reach the maximum concentration of 3 hours (2-6 hours). The maximum concentration in children of the first year of life after taking a dose of 1 mg / kg per day is 1.3 μg / ml; 0.7 μg / ml - 4 hours after taking 1 mg / kg every Monday, Wednesday, Friday. The maximum concentration in adults after taking in a dose of 25 mg is 0.13-0.31 μg / ml. Elimination is carried out by the kidneys (20-30% in unchanged form, can be stored in the blood for 30 days or more). After peritoneal dialysis, the concentration of pyrimethamine in blood plasma in one patient decreased by 47%.

Indications:

Treatment and chemoprophylaxis of malaria, toxoplasmosis.

Primary polycythemia (in case of ineffectiveness of radiation therapy).

ICD-10

I.B50-B64.B54 Malaria, unspecified

I.B50-B64.B52 Malaria caused by Plasmodium malariae

I.B50-B64.B51 Malaria caused by Plasmodium vivax

I.B50-B64.B50 Malaria caused by Plasmodium falciparum

I.B50-B64.B58 Toxoplasmosis

II.D37-D48.D45 Polycythemia true

Contraindications:

Hypersensitivity to pyrimethamine or any component of the dosage form. Megaloblastic anemia (pyrimethamine contraindicated due to a deficiency of folate), diseases of the hematopoietic organs and kidneys. I trimester of pregnancy, breast-feeding, breast age (up to 2 months).

Carefully:Use with caution in patients with hepatic insufficiency.

Pregnancy and lactation:

Recommendations FDA category C. Controlled studies in humans have not been conducted. It should be used only in situations where the potential benefit of treatment exceeds its risk. It is necessary to simultaneously take folates.

High doses of pyrimethamine are prescribed for the prevention of toxoplasmosis in the fetus and the mother. When using standard doses of pyrimethamine, an increase in the total number of congenital anomalies has not been established, but individual cases have been reported.

Penetrates into breast milk. In the case of a single admission by the mother at a dose of 75 mg, the child receives 3-4 mg of the drug for 48 hours or more. Negative impact on children is not described, but pyrimethamine can affect the metabolism of folate in a child (especially when prescribed in high doses, necessary for the treatment of toxoplasmosis).Due to the possibility of serious adverse reactions in the child (especially when combined with sulfonamides in the treatment of toxoplasmosis), it is recommended to stop either breastfeeding or treatment (depending on its importance for the mother).

Dosing and Administration:

Inside (after eating). For chemoprophylaxis of malaria: once a week, adults and children over 10 years - 25 mg, children from 4 to 10 years - 12.5 mg, newborns and children up to 4 years - 6.25 mg (after returning to the area where there is no risk of contracting malaria, taking the drug for 4 weeks).

Treatment of malaria (together with sulfonamides): within 2-4 days, adults - 50 - 75 mg; children from 10 to 14 years - 50 mg; from 4 to 10 years - 25 mg.

In acute and chronic toxoplasmosis: cycles of 5 days with a break of 7-10 days, adults and children over 6 years (together with sulfonamides) - 50 mg, then - 25 mg per day, children from 2 to 6 years - 2 mg / kg (maximum 50 mg), then - 1 mg / kg (maximum - 25 mg), children under 2 years - 1 mg / kg per day.

For prophylaxis of toxoplasmosis: 3-5 days before the onset of the risk of infection, then once a week for the entire epidemiologically unfavorable period and 4-6 weeks after the danger of infection has disappeared.

For the prevention of congenital toxoplasmosis in women with acute and subacute toxoplasmosis: 2 cycles of treatment are carried out with a break of 10 days, starting from the 16th week of pregnancy (no earlier than the second trimester). If necessary, the third cycle can be carried out after 1 month.

Side effects:

Nausea, vomiting, anorexia, abdominal cramps, dry mouth and throat, diarrhea (early stages of treatment), malaise, headache, weakness, dizziness, insomnia, depression, convulsions, fever, thrombocytopenia, pulmonary eosinophilia, dermatitis, rash, skin pigmentation disorder.

At a dose of 75 mg and above - violations of the heart rhythm, hematuria, in higher doses - circulatory collapse, ulceration in the oral cavity, megaloblastic anemia, leukopenia, atrophic glossitis.

In newborns with congenital toxoplasmosis - hyperphenylalaninemia, with long-term treatment of toxoplasmosis - the risk of developing tumors.

Overdose:

Symptoms: nausea, vomiting, diarrhea, convulsions.

Treatment: gastric lavage, with convulsions - intravenous administration of seduksen or barbiturates.

Interaction:

Hingamin, sulfonamide preparations and other antimalarial drugs increase (mutually) activity. Quinidine and warfarin increase toxicity.Antifolia drugs and cytotoxic agents (sulfonamides, trimethoprim, methotrexate, daunorubicin and others) potentiate myelosuppression, daunorubicin and cytosine arabinoside - the risk of bone marrow aplasia. Prevents the binding of warfarin with proteins. In children with leukemia and CNS lesions, the combination with methotrexate increases the risk of seizures.

Cases of unexplained hepatotoxicity when combining lorazepam with pyrimethamine are described.

Special instructions:

Use with caution in patients with renal and / or liver failure, with a deficiency in the body of folic acid.

During the treatment period, a large amount of liquid should be consumed, additionally prescribed preparations of folic acid and vitamin B12, once a week, monitoring of peripheral blood counts, platelet counts (weekly for high-dosage therapy, for example, toxoplasmosis, and within 2 weeks after it ), the concentration of phenylalanine (it is possible to increase it by combining pyrimethamine with sulfonamide).

Do not recommend applying pyrimethamine in monotherapy for the treatment of acute attacks of malaria in non-immune patients (quick-actingshizototsidnye funds, for example, 4-aminoquinolones, quinine).

Preparation of dosage form. If you can not swallow the tablets, you can grind and dissolve in a 0.9% solution of sodium chloride to obtain a 1% solution. The latter is stable for 24 hours at room temperature. Solvents may be sucrose solutions (immediately after preparation).

When taken in high doses pyrimethamine may cause irritation of the gastrointestinal tract and vomiting. To minimize these effects, it is recommended to take the drug while eating or lower the dose.

It is necessary to stop treatment with pyrimethamine in the development of folic acid deficiency. For its prevention, it is possible to simultaneously take calcium folinate, which does not affect the antiprotozoic activity of pyrimethamine: adults - 5-15 mg orally, intramuscularly or intravenously every 3 days or 9 mg 2-3 times a week (in AIDS patients increase dose up to 50 mg per day); children under the age of 7 years - 1 mg per day. Since malarial plasmodia can not utilize folic acid, the latter also should not affect the antimalarial activity of pyrimethamine, but it can alter its activity against Toxoplasma gondii, so at the same time take folic acid in the treatment of toxoplasmosis is not recommended.

Instructions

Pyrimethamine (Pyrimethaminum)