METHOTREXATE PILLS 5 MG

Mechanism of action

An antitumor drug from the group of antimetabolites - folic acid analogues. Along with antitumor has an immunosuppressive effect.

Inhibits 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.

Inhibits synthesis, DNA repair and cell mitosis (in the S-phase). Particularly sensitive to the action of Methotrexate tissue with high cell proliferation: tumor tissue, bone marrow, mucous membrane epithelium cells, embryonic cells. In addition, methotrexate has immunosuppressive properties.

Suction

Absorption from the gastrointestinal tract when administered orally depends on the dose: when taken 30 mg / m2 well absorbed, the average bioavailability - 50%. Absorption is reduced when taken in doses of> 80 mg / m2 (probably due to saturation). Food slows down the absorption of methotrexate and reduces Cmax. Tmax is 1-2 hours when taken orally and 30-60 minutes - with the / m introduction.

Distribution

Plasma protein binding is about 50%.

When taken in therapeutic doses, regardless of the route of administration, methotrexate practically does not penetrate through the BBB (after intrathecal administration, high concentrations are achieved in the cerebrospinal fluid). It is excreted in breast milk.

Metabolism

After oral administration, methotrexate is partially metabolized by the intestinal flora, the main part - in the liver (regardless of the route of administration) with the formation of a pharmacologically active polyglutamine form that inhibits dihydrofolate reducta and thymidine synthesis.

Removal

T1/2 in the initial phase is 2-4 hours, and in the final phase (which is long) is 3-10 hours with conventional doses and 8-15 hours with high doses. doses of the drug.

It is excreted unchanged predominantly with urine by glomerular filtration and tubular secretion (with intravenous administration 80-90% is excreted within 24 hours), with bile up to 10% is excreted (with subsequent reabsorption in the intestine). When repeated injections accumulates in the tissues in the form of metabolites.

Pharmacokinetics in special clinical situations

Have children with leukemia Absorption ranges from 23 to 95%.

At chronic renal failure both phases of drug withdrawal can be significantly prolonged. Removal of the drug in patients with impaired renal function, ascites or transudate expressed is significantly slowed down.

Indications and usage

- trophoblastic tumors;

- acute lymphoblastic and myeloblastic leukemias;

- neuroleukemia;

- non-Hodgkin lkmphomas, including lymphosarcomas;

- breast cancer, squamous cell head and neck cancer, lung cancer, skin cancer, cervical cancer, vulvar cancer, esophageal cancer, kidney cancer, bladder cancer, testicular cancer, ovarian cancer, penile cancer, retinoblastoma, medulloblastoma;

- osteogenic sarcoma and soft tissue sarcoma;

- mushroom mycosis (advanced stages);

- severe forms of psoriasis, psoriatic arthritis, rheumatoid arthritis, dermatomyositis, SLE, ankylosing spondylitis (with the ineffectiveness of standard therapy).

Methotrexate is a part of many chemotherapeutic treatment regimens, and therefore in choosing the route of administration, regimen and doses in each individual case, one should be guided by the data of special literature.

Methotrexate-Ebeve for injection can be injected in a / m, in / in, in / a or intrathecal. pills Methotrexate-Ebeve should be taken orally before eating, without chewing.

At trophoblastic tumors - 15-30 mg orally or intramuscularly, daily for 5 days with an interval of ≥1 week (depending on signs of toxicity). Or, 50 mg 1 time in 5 days with an interval of ≥1 month. The course of treatment is usually repeated from 3 to 5 times to a total dose of 300-400 mg.

At solid tumors in combination with other anticancer drugs - 30-40 mg / m2 in / in the jet 1 time per week.

At leukemia or lymphomas - 200-500 mg / m2 by iv infusion 1 time in 2-4 weeks.

At neuroleukemia - 12 mg / m2 intrathecally within 15-30 seconds 1 or 2 times a week.

When treating children, the dose is selected depending on age: children under 1 year prescribe 6 mg 1 year old children - 8 mg, children aged 2 years - 10 mg, children over 3 years old - 12 mg.

Before the introduction, the cerebrospinal fluid should be removed in a volume approximately equal to the volume of the medicinal product to be introduced.

When applied high-dose therapy - from 2 to 15 g / m2 in the form of a 4-6 hour intravenous infusion with an interval of 1-5 weeks with the mandatory subsequent administration of Calcium folinate, which usually starts 24 hours after the start of the infusion of methotrexate and is administered every 6 hours at a dose of 3-40 mg / m2 (usually 15 mg / m2) and higher, depending on the concentration of methotrexate in the serum for 48-72 hours

At rheumatoid arthritis The initial dose is usually 7.5 mg 1 time per week, which is administered simultaneously in /, in / m or orally - 2.5 mg every 12 hours (only 3 doses). Day to achieve the optimal effect of the weekly dose may be increased, but it should not exceed 20 mg. When the optimal clinical effect is achieved, the dose should be reduced to the lowest effective dose. The optimal duration of treatment is not known.

At psoriasis orally, intramuscularly or intravenously in a jet at doses of 10 to 25 mg per week. The dose is usually increased gradually, when the optimal clinical effect is reached, the dose reduction begins until the lowest effective dose is reached.

At mushroom mycosis V / m 50 mg 1 time per week or 25 mg 2 times per week or inside 2.5 mg / day. within a few weeks or months. Dose reduction or withdrawal of the drug is determined by the patient's response and hematological parameters.

Adverse reactions

From the hemopoietic system: leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia.

From the digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis; rarely - enteritis, diarrhea, gastrointestinal lesions, Gastrointestinal bleeding; in some cases (with long-term daily use) - abnormal liver function, increased activity of hepatic transaminases, periportal fibrosis and cirrhosis, hepatic necrosis, fatty degeneration of the liver, pancreatitis.

From the side of the central nervous system and peripheral nervous system: encephalopathy (with the introduction of multiple doses intrathecally, conducting radiotherapy in the skull), fatigue, weakness, confusion, ataxia, tremor, irritability, convulsions, coma; with intrathecal administration of methotrexate - dizziness, blurred vision, headache, pain in the back, stiff neck, convulsions, paralysis, hemiparesis.

On the part of the respiratory system: rarely - interstitial pneumonitis, pulmonary fibrosis, exacerbation of pulmonary infections.

From the urinary system: cystitis, nephropathy, renal dysfunction (increased creatinine, hematuria).

From the reproductive system: disruption of oogenesis, spermatogenesis, decreased libido / impotence, changes in fertility, teratogenic effects.

From the senses: conjunctivitis, excessive tearing, cataracts, photophobia, cortical blindness (when used in high doses), visual impairment.

Dermatological reactions: skin erythema and / or rash, pruritus, telangiectasia, furunculosis, depigmentation or hyperpigmentation, rye, peeling of the skin, folliculitis, alopecia (rare), exacerbation of radiation dermatitis.

Allergic reactions; fever, chills, rash, urticaria, anaphylaxis, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), photosensitization.

Other: immunosuppression (reduced resistance to infectious diseases), malaise, osteoporosis, hyperuricemia, vasculitis, arthralgia / myalgia.

- severe anemia, leukopenia, neutropenia, thrombocytopenia.

- renal failure;

- liver failure;

- pregnancy;

- breastfeeding period;

- hypersensitivity to methotrexate and / or any other component of the drug.

WITH caution the drug should be used for ascites, effusions in the pleural cavity, gastric ulcer and duodenal ulcer, ulcerative colitis, dehydration, gout or nephrolithiasis in history, previous radiation therapy or Chemotherapy , infectious diseases of viral, fungal or bacterial nature.

The drug is contraindicated in pregnancy and during breastfeeding.

during treatment with methotrexate and for at least 3 months after, reliable methods of contraception should be used.

Contraindicated use of the drug for liver failure.

The use of the drug is contraindicated in renal failure.

With caution should use the drug with a history of nephrolithiasis.

Caution must be exercised when using methotrexate.

Dosage forms containing preservatives (benzyl alcohol) cannot be used for intrathecal administration or with high-dose therapy.

With the introduction of high doses of methotrexate, careful monitoring of the patient is necessary for early detection of the first signs of toxic reactions.

High-dose therapy should be carried out only by experienced chemotherapists who can control the concentration of methotrexate in the blood plasma under inpatient conditions under the cover of folinate calcium.

During therapy with methotrexate in high and high doses, the urine of the patient should be monitored: on the day of administration and in the next 2-3 days, the urine reaction should be alkaline. This is achieved in / in the drip injection of a mixture consisting of 40 ml of 4.2% sodium bicarbonate solution and 400-800 ml of isotonic sodium chloride solution, the day before, on the day of treatment and in the next 2-3 days.

Treatment with methotrexate in high and high doses should be combined with enhanced hydration - up to 2 l / day.

The introduction of methotrexate dose ≥2 g / m3 should be carried out under the control of its concentration in the serum. It is considered normal to decrease the content of methotrexate in the serum 22 hours after the administration by 2 times compared with the initial level. Increasing the level of creatinine by ≥50% of the initial content and / or an increase in the level of bilirubin require intensive detoxification therapy.

For the treatment of psoriasis, methotrexate is prescribed only to patients with a severe form of the disease, which is not amenable to other types of therapy.

For the prevention of toxicity in the process of treatment with methotrexate should periodically conduct a blood test (1 time per week), determine the content of leukocytes and platelets, conduct liver and kidney function tests.

With the development of diarrhea and ulcerative stomatitis, therapy with methotrexate should be interrupted to avoid the development of hemorrhagic enteritis and patient death due to bowel perforation.

In patients with impaired liver function, the period of methotrexate elimination is increased, so drug therapy should be carried out with extreme caution, with lower doses.

Impaired renal function is dose dependent. The risk of impairment is increased in patients with reduced renal function or dehydration, as well as in patients taking other nephrotoxic drugs.

Influence on ability to drive motor transport and control mechanisms

Some side effects of the drug can adversely affect the ability to drive a car and perform potentially hazardous activities that require increased concentration and psychomotor speed.

Treatment: immediately, preferably within the first hour, the administration of a specific antidote, calcium folinate, should be started at a dose equal to or higher than that of methotrexate; Subsequent doses are administered as needed, depending on the serum concentration of methotrexate. To prevent the precipitation of methotrexate and / or its metabolites in the renal tubules spend the body's hydration and alkalinization of urine.

In case of overdose with intrathecal administration, repeated lumbar punctures should be immediately performed to ensure rapid drainage of the cerebrospinal fluid. Neurosurgical intervention with ventriculo lumbar perfusion is possible. All these procedures should be performed on the background of intensive maintenance therapy and systemic administration of calcium folinate in high doses.

With the simultaneous use of high doses of methotrexate with various NSAIDs (including Aspirin and other salicylates, azapropazone, dichlofenac, Indomethacin and ketoprofen), the toxicity of methotrexate can be enhanced. In some cases, possible severe toxic effects, sometimes even fatal. With special precautions and appropriate monitoring, the use of low-dose methotrexate (7.5–15 mg per week), in particular in the treatment of rheumatoid arthritis, in combination with NSAIDs is not contraindicated.

With simultaneous use with sulfonamides, sulfonylurea derivatives, phenytoin, phenylbutazone, ayrytohimbokanoic acid, probenecid, pyrimethamine or trimethoprim, a number of antibiotics (including penicillin, Tetracycline , chloramphenicol), indirect anti-coagulants, aryl pendulants, aloetima, aloetima, pyromethamine or trimethoprimum. Antibiotics poorly absorbed from the gastrointestinal tract (includingtetracyclines, chloramphenicol), reduce the absorption of methotrexate and disrupt its metabolism due to the suppression of the normal intestinal microflora.

With simultaneous use with methotrexate retinoids, azathioprine, Sulfasalazine increase the risk of developing hepatotoxicity. Parenteral use of Acyclovir on the background of intrathecal administration of methotrexate increases the risk of neurological disorders.

With simultaneous use of methotrexate with multivitamin preparations containing folic acid or its derivatives, it is possible to reduce the effectiveness of methotrexate therapy.

L-asparaginase is antagonist of methotrexate.

Anesthesia with dinitrogen oxide during therapy with methotrexate can lead to the development of unpredictable severe myelosuppression and stomatitis.

When used simultaneously with methotrexate, Amiodarone may contribute to ulceration of the skin.

Methotrexate reduces theophylline clearance.

A few patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (methoxalen and UFO) were diagnosed with skin cancer.

Caution should be exercised with the simultaneous use of erythrocyte mass and methotrexate.

The combination of methotrexate therapy with radiotherapy may increase the risk of soft tissue necrosis.

Methotrexate may reduce the immunological response to vaccination; with the simultaneous administration of the drug with a live vaccine, severe antigenic reactions may develop.

The drug is available on prescription.

List B. Solution for injection and concentrate for preparing the solution for infusion should be stored out of reach of children, protected from light at a temperature of 15 ° to 25 ° C. pills should be kept out of the reach of children, protected from light at a temperature not exceeding 25 ° C.