Methotrexate

When ATH:
L01BA01

Characteristic.

Antimetabolite group of structural analogs of folic acid. Yellow or orange-yellow crystalline powder. Practically insoluble in water and alcohol, hygroscopic and unstable to light. Available in a dried mass of yellow to yellow-brown, soluble in water. Molecular weight 454,45.

Pharmacological action.
Antitumor, cytostatic, immunosuppressive.

Application.

Horionkartsinoma uterus, acute lymphocytic leukemia, CNS tumor (leukemoid infiltration of the meninges), mammary cancer, head and neck cancer, lung cancer, Bladder, stomach; Hodgkin's disease, nehodzhkinskaya lymphoma, retinoblastoma, osteosarcoma, sarkoma Juinga, soft tissue sarcoma; refractory psoriasis (only when the diagnosis in the case of resistance to other therapies), rheumatoid arthritis.

Contraindications.

Hypersensitivity, Immunodeficiency, anemia (incl. Hypo- and aplastic), leukopenia, thrombocytopenia, leukemia with hemorrhagic syndrome, liver or kidney failure.

Restrictions apply.

Infectious diseases, ulcers of the mouth and gastrointestinal tract, recently transferred operations, gout or renal calculi in history (the risk of hyperuricemia), the elderly and children's age.

Pregnancy and breast-feeding.

Contraindicated in pregnancy (may cause fetal death or cause of congenital malformations).

Category actions result in FDA - X. (Animal tests or clinical trials revealed a violation of the fetus and / or there is evidence of the risk of adverse effects on the human fetus, obtained in research or practice; risk, associated with the use of drugs in pregnancy, greater than the potential benefits.)

At the time of treatment should stop breastfeeding.

Side effects.

From the nervous system and sensory organs: encephalopathy (particularly when administered intrathecally multiple doses, and in patients after brain irradiation), dizziness, headache, blurred vision, drowsiness, afazija, Pain in the back, muscle rigidity back of the neck, convulsions, paralysis, gemiparez; in some cases - fatigue, weakness, confusion, ataxia, tremor, irritability, coma; conjunctivitis, excessive tearing, Cataract, photophobia, korkovaya blindness (at high doses).

Cardio-vascular system (hematopoiesis, hemostasis): anemia, leukopenia, thrombocytopenia, neutropenia, lymphopenia (especially T lymphocytes), hypogammaglobulinemia, gemorragija, septicemia due leykopenii; rarely - pericarditis, pericardial effusion, gipotenziya, thromboembolic changes (arteryalnыy thrombosis, cerebral thrombosis, deep vein thrombosis, thrombosis of renal vein, tromboflebit, pulmonary embolism).

From the respiratory system: rarely - interstitial pneumonitis, fibrosis lyegkikh, worsening of pulmonary infections.

From the digestive tract: gingivitis, pharyngitis, ulcerative stomatitis, anorexia, nausea, vomiting, diarrhea, difficulty swallowing, ground, ulceration of the gastrointestinal mucosa, gastrointestinal bleeding, enteritis, liver, fibrosis and cirrhosis (increased the likelihood of patients, receiving continuous or long-term therapy).

With the genitourinary system: cystitis, nephropathy, azotemia, hematuria, hyperuricemia or severe nephropathy, dysmenorrhoea, unstable oligospermatism, violation of oogenesis and spermatogenesis, fetal defects.

For the skin: each erythema, itch, hair loss (rarely), photosensitivity, ecchymosis, acne-like rash, furunculosis, peeling, where- or hyperpigmentation, bullation, folliculitis, teleangiэktaziya, toxic epidermal necrolysis, Syndrome Stevens - Johnson.

Allergic reactions: fever, chills, rash, hives, anaphylaxis.

Other: immunosuppression, rarely - opportunistic infection (Bacterial, Viral, Fungus, protozoal), osteoporosis, vasculitis.

Cooperation.

Gain and prolonged action of methotrexate, leading to intoxication, It facilitates the simultaneous use of NSAIDs, ʙarʙituratov, sulfonamides, corticosteroids, tetracyclines, Trimethoprim, chloramphenicol, para-amino benzoic and para-aminogippurovoy acids, probenecid. Folic acid and its derivatives reduce the efficiency. It enhances the effect of indirect anticoagulants (coumarin derivatives or indandiona) and increases the risk of bleeding. Drugs group penicillin reduced renal clearance of methotrexate. With simultaneous use of methotrexate and asparaginase may block the action of methotrexate. Neomycin (orally) may reduce the absorption of methotrexate (orally). Preparations, causing blood dyscrasias, enhance leukopenia and / or thrombocytopenia, if these drugs have the same, how and methotrexate, action on the bone marrow. Other drugs, causing depression of bone marrow function, or potentiate the effect of radiation therapy and additive depress bone marrow function. Possible synergistic cytotoxic effect with cytarabine while using. With simultaneous use of methotrexate (intrathecal) acyclovir (parenterally) possible neurological disorders. In combination with live viral vaccines may cause intensification of the process of replication of vaccine virus, increased side effects of vaccines and reducing the production of antibodies in response to both live, and inactivated vaccines.

Overdose.

Symptoms: There are no specific symptoms.

Treatment: Immediate administration of calcium folinate to neutralize myelotoxic action of methotrexate (inside, w / o or w / w). The dose of calcium folinate should be at least equal to the dose of methotrexate, it must enter within the first hour; subsequent doses are administered as required. Increase the hydration of the body, urinary alkalization is carried out to prevent precipitation of the drug and its metabolites in the urinary tract.

Dosing and Administration.

Inside, parenterally (/ m, I /, intraarterially, intrathecal), depending on the evidence.

The dose is individualized, depending on the type of tumor, stage of the disease, efficacy, Portability.

The applied dose according to the regimens separated into ordinary (low) dose (a single dose of below 100 mg / m²), average (single dose of 100-1000 mg / m²) and high (a single dose of the above 1000 mg / m²).

Therapy usual doses (without cover calcium folinate): / in 15-20 mg / m² 2 twice a week, or 30-50 mg / m² once a week, or / m, I / 15 mg / m² in a day 5 days with repetition in 2-3 weeks.

Therapy average doses: I / 50-150 mg / m² (without cover calcium folinate) Repeat after 2-3 weeks, or 240 mg / m² (in / infusion over 24 h under the guise of calcium folinate) c repeated every 4-7 days; or 500-1000 mg / m² (in / infusion over 36-42 hours, under the guise of calcium folinate) Repeat 2-3 weeks.

Treatment with high doses (under the guise of calcium folinate): 1000-1200 Mg / m² (in / in infusion 1-6 pm) Repeat after 1-3 weeks (It requires monitoring of methotrexate in serum).

Intrathecally 0.2-0.5 mg / kg body weight or 8-12 mg / m² every 2-3 days. The maximum dose for intrathecal administration - 15 mg / m². After reducing the symptoms of the intervals between courses of treatment up week, then - a month, until they normalize CSF. Prophylactic intrathecal administration shows every 6-8 weeks.

In severe cases of generalized resistant psoriasis, including psoriatic arthritis, and other autoimmune diseases, parenteral methotrexate 10-50 mg at weekly intervals. When resistant rheumatoid arthritis - a / m 5-15 mg 1 once a week, the maximum dose per week - 25 mg.

Inside (before eating). Typically, the initial dose - 2.5-5 mg, Further dose gradually increased to 7,5-25 mg per week, weekly dose - 10-25 mg, maximum total dose - 25 mg per week. Usually 2,5 mg methotrexate take 3 twice a week with a 12-hour intervals, and with a break in the week (Monday - morning and evening, Tuesday - morning, further - a break until next Monday).

Precautions.

Apply under close medical supervision. For early detection of symptoms of intoxication necessary to monitor the peripheral blood (the number of leukocytes and platelets: first through the day, then every 3-5 days during the first month, further 1 every 7-10 days, in remission - 1 every 1-2 weeks), the activity of hepatic transaminases, renal function, periodic X-rays of the chest. Methotrexate therapy is stopped, если число лимфоцитов в крови составляет менее 1,5·10⁹/l, количество нейтрофилов — менее 0,2·10⁹/l, количество тромбоцитов менее 75·10⁹/l. Increased creatinine 50% more original content and requires re-measurement of creatinine clearance. Increasing the level of bilirubin require intensive detoxification therapy. The study of bone marrow hematopoiesis is recommended prior to treatment, 1 time during the treatment period and at the end of the course. The level of methotrexate in plasma is determined immediately after the infusion, and through 24, 48 and 72 no (for signs of intoxication, which cropped administration of calcium folinate).

During treatment at elevated and high doses necessary to monitor the pH of urine (alkaline reaction should be the day of administration, and the next 2-3 days). To this I / (drop) injected a mixture of 40 ml 4,2% sodium hydrogen carbonate and 400-800 ml of isotonic sodium chloride solution eve, day of treatment and in the next 2-3 days. Treatment with methotrexate in high doses and high combined with enhanced hydration (to 2 liters per day).

We should pay particular attention to cases of reduction of hematopoietic function of bone marrow, caused by the use of radiation therapy, chemotherapy or long-term use of some drugs (sulfonamides, derivatives amidopirina, chloramphenicol, Indomethacin). In such cases, the general condition usually worsens, that poses the greatest danger to patients young and old.

With the development of diarrhea and ulcerative stomatitis methotrexate therapy should be interrupted, otherwise it can lead to hemorrhagic enteritis. If signs of pulmonary toxicity (especially a dry cough without phlegm) Methotrexate is recommended to stop because of the risk, perhaps, irreversible toxic effect on the lungs. Be wary appoint patients with impaired function of the liver and / or kidney (reduce dose).

Avoid the use of alcohol and drugs, having hepatotoxicity, tk. their use in the treatment of methotrexate increases the risk of liver damage; prolonged sun exposure. In the combined treatment should take each medication at the scheduled time; a missed dose of the drug is not taken, do not double the dose.

During the period of treatment is not recommended vaccination virus vaccines, Avoid contact with people, received the vaccine against polio, patients with bacterial infections. Use live virus vaccine in patients with leukemia in remission should not be at least 3 months after the last cycle of chemotherapy. Immunization of oral polio vaccine people, It is in close contact with the patient, especially family members, should be postponed.

The appearance of signs of depression of bone marrow function, unusual bleeding or hemorrhage, black tarry stools, blood in the urine or feces or point of red spots on the skin requires immediate doctor's advice.

Use caution to avoid accidental cuts with sharp objects (safety razor, scissors), Avoid contact sports or other situations, which are likely to hemorrhage or trauma.

The presence of ascites, pleural exudates, effusion in the field of surgical wounds promotes the accumulation of MTX in tissues and enhance its action, which may lead to intoxication.

Dental procedures should be completed before the start of therapy or deferred until the normalization of the blood picture (may increase the risk of microbial infection, slowing the healing process, krovotochivosty right). During treatment caution when using toothbrushes, threads or toothpicks.

In patients who develop the application of methotrexate is recommended thrombocytopenia special precautions (limit frequency venipuncture, the rejection of the / m injection, a urine test, feces and secret occult blood; prevent constipation, refusal of the use of acetylsalicylic acid, etc.), when leukopenia - carefully monitor the development of infections. Patients with neutropenia as the temperature increases the use of antibiotics should be started empirically.

Cautions.

Methotrexate injection as a lyophilized powder due to the presence of preservative is not suitable for intrathecal.

You should avoid conception during treatment with methotrexate and after (men - 3 months after treatment, women - at least one ovulatory cycle). After a course of treatment with methotrexate is recommended that the use of calcium folinate to reduce the toxic effects of high doses of the drug.

Observe the necessary rules for the use and destruction of the drug.

Cooperation