Methodical instructions for use, testimonials, analogs and forms of release (injections in ampoules for injection 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg) drugs for the treatment of cancer and oncology, psoriasis, arthritis in adults, children and during pregnancy. Composition

In this article, you can read the instructions for using the drug Methodic. There are reviews of visitors to the site - consumers of this medication, as well as opinions of doctors of specialists on the use of Methodic in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Analogues of the Methodic in the presence of existing structural analogs. Use for the treatment of cancer and oncology, psoriasis, rheumatoid arthritis in adults, children, as well as during pregnancy and lactation.Composition of the preparation.

Methodic - immunosuppressant, antitumor drug, antimetabolite, antagonist of folic acid. Competitively inhibits the enzyme dihydrofolate reductase involved in the reduction of dihydrofolic acid to tetrahydrofolic acid (a carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives). It inhibits synthesis, DNA repair and cellular mitosis.

The action of Methotrexate is particularly sensitive to rapidly proliferating cells: malignant tumor cells, bone marrow, embryonic cells, mucosal epithelial cells. Along with the antitumor has an immunosuppressive effect.

It remains unclear why the effectiveness of methotrexate in the treatment of psoriasis, psoriatic arthritis and rheumatoid arthritis (including juvenile chronic arthritis): its anti-inflammatory or immunosuppressive effect. Also, it is not established to what extent the effectiveness of therapy is explained by the increase in extracellular adenosine concentration caused by methotrexate in places of inflammation.

With psoriasis, the formation of skin epithelial cells is significantly accelerated compared with the norm. The use of methotrexate can slow the formation of skin epithelial cells, which justifies the use of the drug for the treatment of psoriasis.

Composition

Methotrexate disodium + excipients.

Pharmacokinetics

The binding to plasma proteins is about 50%. After distribution in tissues, high concentrations of methotrexate in the form of polyglutamates are found in the liver, kidneys and especially in the spleen, in which methotrexate can be retained for several weeks or even months. When used in small doses penetrates into the cerebrospinal fluid only in minimal amounts. About 10% of the administered dose is metabolized in the liver, the main metabolite is 7-hydroxymethotrexate, and also has some pharmacological activity. About 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate is excreted with bile (followed by reabsorption in the intestine). It is excreted mainly unchanged in kidneys by glomerular filtration and tubular secretion. About 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate is excreted with bile (followed by reabsorption in the intestine).

Removal of the drug in patients with impaired renal function is significantly slowed down.There is no evidence of a delay in excretion of methotrexate with insufficient liver function.

Indications

• acute lymphocytic leukemia;
• trophoblastic disease;
• skin cancer;
• cancer of the cervix and vulva;
• esophageal carcinoma;
• squamous cell carcinoma of the head and neck;
• cancer of the renal pelvis and ureters;
• osteogenic and soft cell sarcoma;
• Ewing's sarcoma;
• lung cancer;
• mammary cancer;
• germinogenous tumors of testis and ovaries;
• liver cancer;
• kidney cancer;
• retinoblastoma;
• medulloblastoma;
• cancer of the penis;
• lymphogranulomatosis;
• severe forms of psoriasis (in case of ineffectiveness of standard therapy);
• severe form of rheumatoid arthritis (in case of ineffectiveness of standard therapy).

Forms of release

Solution for subcutaneous, intravenous and intramuscular administration 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 27.5 mg (injections in injections).

Other dosage forms, be it tablets, capsules or syrup, do not exist.

Instructions for use and dosing regimen

Methodic designate subcutaneously, intramuscularly or intravenously.

The needle for injection included in the package is intended only for the introduction of the Methodic. For the introduction of the drug in / m and / in the need to use suitable for these methods of introducing needles.

The drug is used once a week.The doctor determines the total duration of treatment individually.

The drug should appoint a doctor who has experience in the use of methotrexate and knowledge about the properties of the drug and the characteristics of its action.

In rheumatoid arthritis for adults, the recommended initial dose of the drug is 7.5 mg once a week IM, IV or SC. Depending on the severity of the disease and the tolerability of methotrexate, the dose can be gradually increased - by 2.5 mg per week. The maximum dose is 25 mg per week. The therapeutic effect usually develops 4-8 weeks after the start of the drug. After achieving the optimal therapeutic effect, the dose should be reduced to the lowest effective maintenance dose. The duration of therapy with the drug may exceed 10 years.

In psoriasis and psoriatic arthritis, a parenteral test dose of 5-10 mg of methotrexate is recommended a week before the start of treatment to identify intolerance reactions. The recommended initial dose is 7.5 mg once a week IM, IV or SC. The dose should be gradually increased. In most cases, do not exceed the dose of 25 mg per week, but in any case, the maximum dose is 30 mg per week.The therapeutic effect usually develops 2-6 weeks after the start of the drug. After achieving the desired response, the dose should be reduced to the lowest effective maintenance dose.

In elderly patients Methodic should be used with caution, it is often necessary to correct the dose downwards due to the age-related decline in liver and kidney function, as well as a decrease in the folate reserve in the body.

Children under the age of 16 years with the polyarteritis form of juvenile chronic arthritis, the recommended dose of methotrexate is 10-15 mg / m2 body surface per week. With insufficient effectiveness of treatment, the dose can be increased up to 20 mg / m2 per week. Due to the limited data on sc and to / in the use of children in juvenile arthritis should be used in / m.

When switching from methotrexate intake to parenteral administration, a dose reduction may be required due to the difference in bioavailability of the drug for different modes of administration.

During therapy, Methodic should consider the simultaneous administration of folic acid preparations in accordance with existing treatment standards.

Side effect

• stomatitis;
• dyspepsia;
• nausea, vomiting;
• loss of appetite;
• increased transaminase activity;
• ulcers in the oral cavity;
• diarrhea;
• enteritis;
• cirrhosis, fibrosis and fatty liver;
• hepatotoxicity (acute hepatitis, hepatic insufficiency);
• erosive and ulcerative lesions of the gastrointestinal tract;
• vomiting with an admixture of blood, bleeding from the digestive tract (including melena, hematemesis);
• pancreatitis;
• leukopenia, anemia (including aplastic), neutropenia, thrombocytopenia, pancytopenia, agranulocytosis;
• severe oppression of bone marrow function;
• exanthema;
• erythema;
• dermatitis;
• itching;
• photosensitization;
• baldness;
• increased rheumatic nodes;
• vasculitis;
• infections caused by the herpes virus;
• herpetiform eruptions on the skin;
• hives;
• increased pigmentation;
• changes in the pigmentation of the nails;
• sharp paronychia;
• Stevens-Johnson syndrome;
• toxic epidermal necrolysis (Lyell's syndrome);
• various allergic manifestations up to anaphylactic shock;
• allergic vasculitis;
• pericarditis;
• pericardial effusion;
• pericardial tamponade;
• a decrease in blood pressure;
• thromboembolism (incl.arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism);
• headache;
• feeling tired;
• drowsiness;
• dizziness;
• a sense of confusion;
• depression;
• muscle weakness or paresthesia of the limbs;
• the violation of taste sensations (metallic taste);
• convulsions;
• paralysis;
• diabetes;
• conjunctivitis;
• impaired vision, (including transient blindness);
• tinnitus;
• interstitial alveolitis / pneumonia;
• pharyngitis;
• pulmonary fibrosis;
• pulmonary pneumocystis;
• pulmonary insufficiency and bronchial asthma;
• pleural effusion;
• nose bleed;
• inflammation and ulceration of the bladder;
• painful urination;
• hematuria;
• hyperuricemia;
• kidney failure;
• oliguria;
• anuria;
• inflammation and ulceration of the vagina;
• vaginal discharge;
• loss of sexual desire;
• impotence;
• oligospermia;
• menstrual cycle disorders;
• infertility;
• arthralgia;
• myalgia;
• osteoporosis;
• osteonecrosis;
• increased risk of fractures;
• necrosis of soft tissues;
• increased sweating;
• Life-threatening opportunistic infections (incl.pneumocystis pneumonia), cytomegalovirus infections (CMV) (including CMV pneumonia), sepsis (including fatal), nocardiosis, histoplasmosis, cryptococcosis;
• deterioration of wound healing;
• the appearance of lymphomas;
• burning sensation at the injection site, the formation of an aseptic abscess, the destruction of fatty tissue.

Contraindications

• marked violation of liver function;
• alcoholism;
• renal failure of severe degree (CC less than 20 ml / min);
• haemorrhage in the anamnesis, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, severe anemia;
• severe acute or chronic infectious diseases, such as tuberculosis, HIV infection;
• ulcerous lesions of the oral cavity;
• ulcerative gastrointestinal lesion in the active phase;
• severe immunodeficiency;
• pregnancy;
• lactation period (breastfeeding);
• simultaneous vaccination with live vaccines;
• hypersensitivity to the components of the drug.

Application in pregnancy and lactation

The method is contraindicated in pregnancy and during breastfeeding.

Methotrexate affects fertility, is embryo, fetotoxic and teratogenic.When used in humans, methotrexate displays teratogenic properties, is capable of causing fetal death, congenital malformations.

Limited use in pregnant women led to an increase in the frequency of malformations (cranial, cardiovascular, extremities). In cases of interruption of methotrexate therapy, normal pregnancy was observed before fertilization.

Patients of childbearing age of both sexes and their partners should apply reliable contraceptive measures during treatment with methotrexate and, at least, within 6 months after its termination.

If pregnancy occurs during methotrexate therapy, the risk of a side effect on the fetus should be assessed.

Methotrexate is excreted in breast milk in quantities that are harmful to the baby, so before starting methotrexate, breastfeeding should be discontinued and refrained from it during the course of treatment.

Use in children

Children under the age of 16 years with the polyarteritis form of juvenile chronic arthritis, the recommended dose of methotrexate is 10-15 mg / m2 body surface per week.With insufficient effectiveness of treatment, the dose can be increased up to 20 mg / m2 per week. Due to the limited data on sc and to / in the use of children in juvenile arthritis should be used in / m.

Application in elderly patients

With caution should be used in elderly patients.

special instructions

Patients should be clearly informed that the drug should be used once a week, not every day.

Methotrexate is cytotoxic, so care must be taken when handling it.

For patients undergoing therapy with Methodic, patients should be properly monitored so that signs of possible toxic effects and adverse reactions are detected and evaluated with minimal delay.

In view of the possible development of severe, or even fatal, adverse reactions, patients should be fully informed of the possible risks and recommended safety measures by the doctor.

Recommended research and safety measures

Before starting or resuming treatment with methotrexate, you need to complete a complete blood count with a determination of platelet count; biochemical blood test with determination of liver enzymes activity, bilirubin concentration,serum albumin; X-ray examination of the chest, examination of the kidney function. If necessary, conduct tests for tuberculosis and hepatitis.

During treatment (at least once a month in the first 6 months of treatment, then at least once every 2 months), the following studies should be carried out:

1. Examination of the oral and pharyngeal mucosa.

2. Complete blood count with determination of the number of platelets. Suppression of hemopoiesis, caused by methotrexate, can occur suddenly, incl. when using the drug in small doses. In any case, a significant reduction in the number of white blood cells or platelets should immediately stop treatment with methotrexate and conduct adequate maintenance therapy. Patients should be advised to report any signs and symptoms of possible infections. Patients who simultaneously receive drugs that depress hemopoiesis (eg leflunomide) require close monitoring with monitoring of blood counts and the number of platelets.

3. Investigation of liver function. Particular attention should be given to identifying possible toxic effects on the liver.Treatment should not be initiated or interrupted if liver function abnormalities present prior to treatment or developed during treatment are detected during appropriate examinations. Usually, the disorders that develop during treatment return to normal within 2 weeks after the interruption of methotrexate therapy, then, at the discretion of the treating physician, treatment can be resumed.

When using methotrexate in rheumatoid arthritis, there is no obvious need for a liver biopsy to monitor hepatic toxicity.

Particular attention should be paid to patients with risk factors, such as excessive alcohol consumption, a steady increase in liver enzyme activity, a history of liver disease, diabetes, obesity, the use of hepatotoxic drugs or drugs that affect hematopoiesis in the anamnesis.

Control of hepatic enzymes in blood serum: 13-20% of patients reported transitory 2-3-fold excess of normal values ​​of transaminases. In the case of a sustained increase in hepatic enzyme activity, the question of dose reduction or cessation of treatment should be considered.

Due to the toxic effect of the drug on the liver during treatment, patients, with the exception of cases of obvious necessity, should refrain from the simultaneous use of other hepatotoxic drugs; alcohol should also be avoided.

In patients using other hepatotoxic drugs or drugs that depress hematopoiesis (eg leflunomide), liver enzyme activity and general blood counts should be carefully monitored with platelet count.

4. Control of kidney function and urinalysis. Because Methotrexate is excreted mainly by the kidneys, in the case of insufficient kidney function, an increase in plasma methotrexate concentration should be expected, which can lead to serious undesirable side effects. In cases of possible reduction in kidney function (for example, in elderly patients), follow-up examinations should be conducted more often. This also applies to the simultaneous administration of drugs that affect the excretion of methotrexate, drugs that can lead to kidney damage (eg, NSAIDs), as well as drugs that can affect the hematopoiesis system.Dehydration can also increase the toxicity of methotrexate.

5. Examination of the respiratory system. Particular attention should be paid to the symptoms of worsening lung function, if necessary, appropriate tests should be carried out. Symptoms of respiratory damage (especially dry non-productive cough), nonspecific pneumonitis that occur during methotrexate therapy, may indicate a potentially dangerous disease and require discontinuation of treatment and thorough examination for the diagnosis. The clinical symptoms of methotrexate-induced lung injury are diverse, but typical symptoms are fever, cough, shortness of breath, hypoxemia. X-ray examination of the chest is mandatory to exclude the presence of infiltrates or infection. The possibility of a respiratory disease caused by the use of methotrexate does not depend on the applied doses of the drug.

If the dose of methotrexate is increased, the frequency of the examinations should be increased.

The method influences the immune system, can worsen the response to vaccination and influence the results of immunological tests.Particular caution is required when using the drug in patients with chronic infectious diseases outside the periods of exacerbation (Herpes zoster, tuberculosis, hepatitis B or C) because of the possibility of exacerbation of the disease. It is necessary to refuse immunization. The interval between the use of methotrexate and the introduction of live and inactivated viral vaccines should be at least 3 months, possibly up to 12 months (depending on the patient's immune status).

With the development of diarrhea and ulcerative stomatitis, methotrexate therapy must be discontinued.

Do not expose unprotected skin to prolonged sun exposure or ultraviolet radiation (a photosensitization reaction is possible).

Patients receiving methotrexate in low doses may develop malignant lymphoma; in these cases, treatment should be discontinued. In the absence of signs of spontaneous regression of lymphoma, cytotoxic therapy is necessary.

With the use of methotrexate, the development of osteonecrosis and osteoporosis is possible, which increases the risk of fractures.

It shows mutagenic activity. The study of carcinogenicity in rodents did not reveal an increase in the incidence of tumors inuse of methotrexate.

Impact on the ability to drive vehicles and manage mechanisms

Since methotrexate is able to influence the central nervous system (fatigue, dizziness) during treatment, the patient should refrain from driving and working with machinery.

Drug Interactions

Regular use of alcohol and simultaneous use with methotrexate hepatotoxic drugs increase the risk of hepatotoxicity of methotrexate. Patients using other hepatotoxic drugs (eg leflunomide) should be carefully monitored. This also applies to the simultaneous prescription of drugs that oppress hemopoiesis, which increases the risk of developing hematotoxicity of methotrexate. With the simultaneous administration of leflunomide and methotrexate, the risk of pancytopenia and hepatotoxicity increases.

Such antibiotics as penicillins, glycopeptides, ciprofloxacin, cephalothin, and sulfonamides can in some cases reduce the excretion of methotrexate by the kidneys, which leads to an increase in its concentration in the plasma and, thus, to the risk of manifestations of hematologic and gastrointestinal toxicity.

Probenecid, weak organic acids (such as loop diuretics) and pyrazolone series (phenylbutazone) reduce the excretion of methotrexate and can lead to an increase in its concentration in the plasma and, thus, to an increase in hematological toxicity.

The risk of an increase in toxicity occurs when a combination of methotrexate with non-steroidal anti-inflammatory drugs (NSAIDs) (because there may be a decrease in excretion of methotrexate by renal tubules) or salicylates. Care should be taken with these combinations.

Simultaneous administration of salicylates, phenylbutazone, phenytoin, sulfonamides, sulfonylurea derivatives, aminobenzoic acid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and lipid-lowering agents (colestyramine) increases toxicity by displacing methotrexate from binding to albumins and / or a decrease in tubular secretion, which in some cases may cause the development of severe toxic effects, sometimes even fatal.

In the case of drugs that can affect the bone marrow (incl.as an adverse event) (eg, sulfonamides, trimethoprim, sulfamethoxazole, chloramphenicol, pyrimethamine), the possibility of oppression of hematopoiesis must be taken into account.

The combination of methotrexate with Sulfasalazine can increase the effectiveness of methotrexate and, as a result, increase the side effects associated with inhibiting the synthesis of folic acid by sulfasalazine. However, such side effects were observed only in a few rare cases in a number of studies.

With the simultaneous administration of proton pump inhibitors (omeprazole, pantoprazole), the excretion of methotrexate may change. The simultaneous use of methotrexate and Omeprazole increases the time to excrete methotrexate. One case of decreasing the excretion of methotrexate metabolite, 7-hydroxymethotrexate, was reported, which was accompanied by myalgia and tremor.

During the treatment, the method should avoid the use of large quantities of caffeine-containing (including coffee, tea) and theophylline-containing beverages. Methotrexate reduces the clearance of theophylline.

Simultaneous administration of drugs that can inhibit bone marrow hematopoiesis (for example, sulfonamides, trimethoprim, sulfamethoxazole), may lead to an increase in the toxicity of methotrexate.Therefore, it is recommended that special care be taken when prescribing such drugs in order to avoid the development of a deficiency of folic acid.

Folate-containing medicines (including multivitamins) reduce the toxic effect of methotrexate on the bone marrow.

Methotrexate increases the anticoagulant activity of coumarin or indanedione derivatives and / or increases the risk of bleeding due to decreased synthesis in the liver of procoagulant factors and platelet abnormalities.

In the treatment of patients with concomitant hyperuricemia and gout, correction of the dose of antidotal agents (allopurinol, colchicine, sulfinpyrazone) may be required.

Anesthesia using dinitrogen oxide can lead to unpredictable severe myelosuppression and stomatitis.

Several patients with psoriasis who were treated with methotrexate in combination with PUVA therapy (metoxalen and ultraviolet irradiation) were diagnosed with skin cancer.

Methotrexate can reduce the immune response to vaccination, so the interval between the use of methotrexate and the introduction of live and inactivated viral vaccines should be at least 3 months, possibly up to 12 months (depending on the patient's immune status).

Pharmaceutical incompatibility

Compatibility with other drugs used parenterally has not been studied.

Do not mix Method with other drugs and solvents.

Analogs of the drug Methodic

Structural analogs for the active substance:

• Zexate;
• Métortrite;
• Methotrexate;
• Methotrexate for injection;
• Methotrexate sodium;
• Treksan;
• Evetrex.

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