Methotrexate side effects
Application: Horionkartsinoma cancer, acute lymphocytic leukemia, CNS tumors (leukemoid infiltration of the meninges), breast cancer, cancer of the head and neck, lung, bladder, stomach, Hodgkin’s disease, non-Hodgkin’s lymphoma, retinoblastoma, osteosarcoma, Ewing’s sarcoma, soft tissue sarcoma ; refractory psoriasis (only at diagnosis in the case of resistance to other types of therapy), rheumatoid arthritis.
Contraindications: Hypersensitivity, immune deficiency, anemia (including hypo-and aplastic), leukopenia, thrombocytopenia, leukemia with hemorrhagic syndrome, hepatic or renal insufficiency.
Restrictions apply to: Infectious diseases, ulcers of the mouth and digestive tract, has recently transferred the operation, gout or kidney concrements a history of (risk of hyperuricemia), the elderly and children’s age.
Application of pregnancy and breastfeeding: Contraindicated in pregnancy (may cause fetal death or cause of congenital malformations). At the time of treatment should stop breastfeeding.
Side effects: Since the nervous system and sensory organs: encephalopathy (especially with the introduction of multiple doses of intrathecal as well as in patients after irradiation of the brain), dizziness, headache, blurred vision, drowsiness, aphasia, pain in the back, stiffness in the muscles of the back of the neck, convulsions, paralysis, hemiparesis, and in some cases – fatigue, weakness, confusion, ataxia, tremor, irritability, coma, conjunctivitis, excessive lacrimation, cataract, photophobia, cortical blindness (at high doses).
Since the cardiovascular system (hematopoiesis, hemostasis): anemia, leukopenia, thrombocytopenia, neutropenia, lymphopenia (especially T-lymphocytes), hypogammaglobulinemia, hemorrhage, septicemia due to leucopenia, rarely – pericarditis, pericardial effusion, hypotension, thromboembolic changes (arterial thrombosis , cerebral thrombosis, deep vein thrombosis, renal vein thrombosis, thrombophlebitis, pulmonary embolism).
From the respiratory system: rarely – interstitial pneumonitis, pulmonary fibrosis, exacerbation of lung infections.
On the part of the digestive tract: gingivitis, pharyngitis, ulcerative stomatitis, anorexia, nausea, vomiting, diarrhea, difficulty swallowing, melena, ulceration of the mucous membrane of the digestive tract, gastrointestinal bleeding, enteritis, liver damage, fibrosis and cirrhosis of the liver (the probability is increased in patients receiving continuous or long-term therapy).
The part of the urogenital system: cystitis, nephropathy, azotemia, hematuria, or severe hyperuricemia nephropathy, dysmenorrhea, transitory oligospermia, violation of the process of oogenesis and spermatogenesis, fetal defects.
For the skin: skin erythema, itching, hair loss (rare), photosensitivity, ecchymosis, ugrevidnoe rash, abrasions, peeling, de-or hyperpigmentation of the skin, blistering, folliculitis, telangiectasia, toxic epidermal necrolysis, a syndrome of Stevens – Johnson.
Allergic reactions: fever, chills, rash, urticaria, anaphylaxis.
Other: immunosuppression, rarely – opportunistic infections (bacterial, viral, fungal, protozoal), osteoporosis, vasculitis.
Interaction: Intensified and prolonged action of methotrexate, leading to intoxication facilitates the simultaneous use of NSAIDs, barbiturates, sulfonamides, corticosteroids, tetracyclines, trimethoprim, chloramphenicol, para-aminobenzoic and para-aminogippurovoy acids, probenecid. Folic acid and its derivatives reduce efficiency. Enhances the effect of indirect anticoagulants (coumarin derivatives or indandiona) and increases the risk of bleeding. Preparations of penicillin reduces the renal clearance of methotrexate. If concomitant use of methotrexate and asparaginase possible blocking action of methotrexate. Neomycin (for ingestion) may reduce the absorption of methotrexate (for ingestion). Drugs that cause pathological changes in the blood, strengthen leukopenia and / or thrombocytopenia, if these drugs have the same, like methotrexate, the effect on bone marrow function. Other drugs that cause depression of bone marrow function, or radiation therapy potentiated the effect of additive and inhibit the function of bone marrow. Possible synergistic cytotoxic effect with cytarabine, when used together. With simultaneous application of methotrexate (intrathecal) and acyclovir (parenteral) are possible neurological disorders. In combination with live virus vaccines can cause an intensification of the process of replication of vaccinia virus, increased side effects of vaccines and decrease antibody response to the introduction of both living and inactivated vaccines.
Overdose: Symptoms: No specific symptoms.
Treatment: immediate introduction of calcium folinate to neutralize the myelotoxic action of methotrexate (oral, in / m or /). The dose of calcium folinate should be at least equal to the dose of methotrexate, it should be entered within the first hour, subsequent doses given as needed. Increase hydration of the body, hold alkalization of urine to prevent precipitation of the drug and its metabolites in the urinary tract.
Dosing and dose: Inside, parenterally (in / m / w, vnutriarterialno, intrathecally), depending on the evidence.
Individualise dose depending on the type of tumor, stage of disease, treatment efficacy, tolerability.
The applied dose in accordance with schemes of treatment is divided into ordinary (low) dose (single dose below 100 mg / m 2), medium (single dose of 100-1000 mg / m 2) and high (single dose greater than 1000 mg / m 2).
Conventional-dose therapy (without cover calcium folinate): w / 15-20 mg / m 2 2 times a week, or 30-50 mg/m2 once a week, or i / m, in / in the 15 mg/m2 per day 5 days with repetition in 2-3 weeks.
Medium-dose therapy: in / at 50-150 mg/m2 (no cover calcium folinate) with repetition in 2-3 weeks or 240 mg/m2 (i / v infusion over 24 hours under the guise of calcium folinate) c repeated after 4-7 days, or 500-1000 mg / m 2 (i / v infusion over 36-42 h under the guise of calcium folinate) with repetition in 2-3 weeks.
Treatment with high doses (under the guise of calcium folinate): 1000-1200 mg / m 2 (i / v infusion of 1.6 h) with repetition after 1-3 weeks (requires monitoring of methotrexate in serum).
Intrathecal 0,2-0,5 mg / kg of body weight or 8.12 mg / m 2 every 2-3 days. The maximum dose for intrathecal administration – 15 mg/m2. After reducing the symptoms of the intervals between courses of therapy is week, then – a month until the normalized rates of cerebrospinal fluid. Prophylactic intrathecal administration shows every 6-8 weeks.
In severe cases, generalized resistant psoriasis, including psoriatic arthritis and other autoimmune diseases, parenteral 10-50 mg of methotrexate weekly intervals. In resistant rheumatoid arthritis – a / m 5-15 mg 1 time per week, the maximum dose per week – 25 mg.
Inside (before eating). Typically, the initial dose – 2,5-5 mg, then gradually increase the dose until 7,5-25 mg / week, weekly dose – 10-25 mg, maximum total dose – 25 mg per week. Typically, 2.5 mg of methotrexate taken 3 times a week with a 12-hour intervals and with a break in a week (Monday – morning and evening, Tuesday – morning, then – a break until next Monday).
Precautions: Apply under close medical supervision. For early detection of symptoms of intoxication necessary to monitor the status of peripheral blood (number of leukocytes and platelets: first, through the day, then every 3-5 days during the first month, then 1 time is 7-10 days, during remission – 1 time in 1-2 weeks), the activity of hepatic transaminases, renal function, periodic X-rays of the chest. MTX therapy is stopped if the number of lymphocytes in the blood is less than 1,5 Ї109 / l, neutrophil count – less than 0,2 Ї109 / L, platelet count less than 75Ї109 / liter. Increased serum creatinine by 50% or more original content requires re-measurement of creatinine clearance. Increased bilirubin desintoxication requires intensive therapy. Investigation of bone marrow hematopoiesis is recommended before treatment, 1 time during the treatment period and at the end of the course. The level of methotrexate in plasma determined immediately after the infusion, and after 24, 48 and 72 h (to detect signs of intoxication, that suppresses the introduction of calcium folinate).
During treatment at elevated and high doses necessary to monitor urine pH (alkaline reaction should be the day of administration and in the next 2-3 days). To do this, / in (drip) injected a mixture of 40 ml 4.2% solution of sodium bicarbonate and 400-800 ml isotonic sodium chloride solution before the day of treatment and in the next 2-3 days. Methotrexate in the treatment of elevated and high doses combined with enhanced hydration (up to 2 liters of fluid a day).
Should pay particular attention to cases of reduction of hematopoietic function of bone marrow, caused by the use of radiation therapy, chemotherapy, or prolonged use of certain drugs (sulfonamides, derivatives amidopirina, chloramphenicol, indomethacin). In such cases, usually worsens the general condition that poses the greatest danger to patients young and old.
In the development of diarrhea and ulcerative stomatitis therapy with MTX should stop, otherwise it could lead to the development of hemorrhagic enteritis. When signs of pulmonary toxicity (especially a dry cough without sputum) treatment with MTX is recommended to stop because of the risk, perhaps, irreversible toxic effect on the lungs. With care given to patients with impaired liver function and / or kidneys (lower dose).
Avoid use of alcohol and drugs with hepatotoxicity, because their use in the treatment of methotrexate increases the risk of liver injury, prolonged sun exposure. In the combined treatment should take each medication at the scheduled time, with missed doses of the drug is not taken, the dose does not double.
In the period of treatment is not recommended vaccination virus vaccines, should avoid contact with people who received the vaccine against polio, with patients bacterial infections. Use live virus vaccine in patients with leukemia in remission should not be for at least 3 months after the last course of chemotherapy. Immunization with oral polio vaccine persons who are 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 stool, blood in urine or feces or point red spots on the skin requires immediate medical advice.
Observe caution to avoid accidental cuts with sharp objects (safety razor, scissors), avoid contact sports lessons or other situations which are likely to hemorrhage or trauma.
The presence of ascites, pleural fluid, effusion in the field of surgical wounds contributes to the accumulation of methotrexate in tissues and enhance its action, which can lead to intoxication.
Dental procedures should be completed before the beginning of therapy or deferred until the normalization of the blood picture (possibly increasing the risk of microbial infections, slow process of healing, bleeding gums). In the course of treatment to be cautious when using the toothbrush, toothpicks, or thread.
In patients with developing as a result of methotrexate thrombocytopenia are advised to observe special precautionary measures (restriction of the frequency venopunktsy, non-i / m injection, testing of urine, feces, and secrets for occult blood, preventing constipation, withdrawal from the use of acetylsalicylic acid, etc. ), with leukopenia – carefully monitor the development of infections. In patients with neutropenia with increasing temperature the use of antibiotics should be started empirically.
Cautions: Methotrexate for injection in the form of dried powder in the presence of the preservative is not suitable for intrathecal administration.
Should avoid conception during treatment with methotrexate and after (men – 3 months after treatment, women – at least one ovulatory cycle). After treatment with MTX is recommended that the use of calcium folinate to reduce the toxic effects of high doses of the drug.
It is necessary to comply with rules on the use and destruction of the drug.
