Antitumor drug from the group of antimetabolites – analogues of folic acid. Along with anti-tumor, it has immunosuppressive activity.
Inhibits dihydrofolate reductase, which participates in the reduction of dihydrofolic acid to tetrahydrofolic acid – the carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives.
Inhibits synthesis, DNA repair and cellular mitosis (in S-phase). Tissues with high cell proliferation are particularly sensitive to the action of methotrexate: tumor tissue, bone marrow, mucosal epithelial cells, embryonic cells. In addition, methotrexate has immunosuppressive properties.
Gastrointestinal absorption when taken orally depends on the dose: When taken 30 mg/m2 absorption is good, average bioavailability is 50%. Absorption is reduced at doses >80 mg/m2 (probably due to saturation). Food slows absorption of methotrexate and decreases Cmax. Tmax is 1-2 h when administered orally and 30-60 min when administered by injection.
The binding to plasma proteins is about 50%.
When administered in therapeutic doses, regardless of the route of administration, methotrexate has almost no penetration through the BBB (after intrathecal administration high concentrations are reached in the cerebrospinal fluid). It is excreted with breast milk.
After oral administration methotrexate is partially metabolized by the intestinal flora, the main part – in the liver (regardless of route of administration) with the formation of pharmacologically active polyglutamine form, which inhibits dihydrofolatreductase and thymidine synthesis.
T1/2 in the initial phase is 2-4 h, and in the final phase (which is prolonged) is 3-10 h when using conventional doses and 8-15 h when using high doses of the drug.
It is excreted unchanged mainly with urine by glomerular filtration and tubular secretion (when administered intravenously 80-90% is excreted within 24 hours), with bile up to 10% is excreted (with subsequent reabsorption in the intestine). In repeated administration it is accumulated in tissues as metabolites.
Pharmacokinetics in special clinical cases
In children with leukemia absorption ranges from 23 to 95%.
In chronic renal failure, both phases of drug excretion may be significantly prolonged. Excretion of the drug is significantly delayed in patients with impaired renal function, marked ascites or transudate.
Rheumatoid arthritis, cancer, breast cancer, psoriasis
- Trophoblastic tumors;
- .Acute lymphoblastic and myeloblastic leukemia;
- Non-Hodgkin’s lymphoma, including lymphosarcoma;
- 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 sarcomas;
- fungal mycosis (advanced stages);
1 syringe for injection contains:
Methotrexate 7.5 mg
How to take, the dosage
Methotrexate is included in many chemotherapy regimens, and therefore the route of administration, regimen, and dosages should be guided by the literature in each individual case.
Methotrexate-Ebeve Injection can be given by injection, intravenously, intravenously, or intrathecally. Methotrexate-Ebeve tablets should be taken orally before meals, without chewing.
In trophoblastic tumors, 15-30 mg orally or intramuscularly, daily for 5 days at ≥1 week intervals (depending on signs of toxicity). Or 50 mg once every 5 days at intervals of ≥1 month. Treatment courses are usually repeated 3 to 5 times up to a total dose of 300-400 mg.
In solid tumors in combination with other antitumor drugs, 30-40 mg/m2 by IV infusion once a week.
In leukemia or lymphoma, 200-500 mg/m2 by IV infusion once every 2-4 weeks.
In neuroleukemia, 12 mg/m2 intrathecal for 15-30 seconds once or twice a week.
When treating children, the dose is adjusted according to age:
- children under 1 year of age are prescribed 6 mg;
- children aged 1 year are prescribed 8 mg;
- children aged 2 years are prescribed 10 mg;
- children over 3 years are prescribed 12 mg.
Spinal fluid should be removed before administration in an amount approximately equal to the volume of the drug to be injected.
When using high-dose therapy, 2 to 15 g/m2 as a 4-6-hour IV infusion at 1-5 week intervals, followed by mandatory calcium folinate infusion, which usually begins 24 h after the start of methotrexate infusion and is given every 6 h at a dose of 3-40 mg/m2 (usually 15 mg/m2) or higher depending on the serum concentration of methotrexate for 48-72 h.
In rheumatoid arthritis, the starting dose is usually 7.5 mg once a week, which is administered once in a single dose by IV, IV/m, or intravenously at 2.5 mg every 12 hours (3 doses total). The weekly dose may be increased, but should not exceed 20 mg, to achieve optimal effect. When optimal clinical effect is achieved, dose reduction should be initiated until the lowest effective dose is achieved. The optimal duration of therapy is not known.
In psoriasis, oral, intravenous, or intravenous doses of 10 to 25 mg per week are given. The dose is usually increased gradually; when optimal clinical effect is achieved, dose reduction is initiated until the lowest effective dose is achieved.
In fungal mycosis, 50 mg once weekly or 25 mg twice weekly, or orally at 2.5 mg/day for several weeks or months. Dose reduction or discontinuation of the drug is determined by the patient’s response and hematologic parameters.
When concomitant use of high doses of methotrexate with various NSAIDs (including aspirin and other salicylates, azapropazon, dichlofenac, indomethacin and ketoprofen) toxicity of methotrexate may increase. In some cases severe toxic effects are possible, sometimes even fatal. With observance of special precautions and proper monitoring the use of methotrexate in low doses (7.5-15 mg per week), in particular in treatment of rheumatoid arthritis, in combination with NSAIDs is not contraindicated.
When used concomitantly with sulfonamides, sulfonylurea derivatives, phenytoin, phenylbutazone, aminobenzoic acid, probenecid, pyrimethamine or trimethoprim, a number of antibiotics (including penicillin and penicillin).including penicillin, tetracycline, chloramphenicol), indirect anticoagulants and hypolipidemic drugs (colestyramine) increases toxicity of methotrexate. Antibiotics poorly absorbed from the gastrointestinal tract (including tetracyclines, chloramphenicol) decrease absorption of methotrexate and impair its metabolism due to suppression of normal intestinal microflora.
The retinoids, azathioprine, sulfasalazine increase the risk of hepatotoxicity when concomitantly used with methotrexate. Parenteral use of acyclovir against intrathecal administration of methotrexate increases the risk of neurological disorders.
The simultaneous use of methotrexate with multivitamin preparations containing folic acid or its derivatives may decrease the effectiveness of therapy with methotrexate.
L-asparaginase is an antagonist of methotrexate.
The administration of dinitrogen oxide anesthesia with methotrexate therapy may result in unpredictable severe myelosuppression and stomatitis.
In concomitant use with methotrexate, amiodarone may contribute to skin ulceration.
Methotrexate decreases clearance of theophylline.
A few patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (methoxalen and UVA) have been found to have skin cancer.
Caution should be exercised when using red blood cell mass and methotrexate concomitantly.
The combination of methotrexate therapy with radiotherapy may increase the risk of soft tissue necrosis.
Methotrexate may decrease the immunological response to vaccination; severe antigenic reactions may develop if the drug is given concomitantly with live vaccine.
Caution should be exercised when using methotrexate.
Drug forms containing preservatives (benzyl alcohol) should not be used for intrathecal administration and high-dose therapy.
When administering high doses of methotrexate, close monitoring of the patient is necessary for early detection of the first signs of toxic reactions.
High-dose therapy should only be given by experienced chemotherapists who can monitor plasma concentrations of methotrexate in a hospital setting under the cover of calcium folinate.
During therapy with methotrexate at higher and higher doses, the patient’s urine pH should be monitored: on the day of injection and the following 2-3 days, the urine reaction should be alkaline. This is achieved by intravenous drop infusion 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, the day of treatment and the next 2-3 days.
Treatment with methotrexate in higher and higher doses should be combined with increased hydration – up to 2 liters per day.
The administration of methotrexate at a dose of ≥2 g/m3 should be performed under control of its serum concentration. Normal is considered to be a 2-fold decrease in methotrexate serum level in 22 hours after injection compared to the initial level. Creatinine level increase by ≥50% from the initial level and/or bilirubin level increase requires intensive detoxification therapy.
To treat psoriasis, methotrexate is indicated only for patients with a severe form of the disease that does not respond to other therapies.
In order to prevent toxicity during treatment with methotrexate, periodic blood tests (once a week), white blood cell and platelet counts, and liver and kidney function tests should be performed.
In case of development of diarrhea and ulcerative stomatitis therapy with methotrexate should be discontinued to prevent development of hemorrhagic enteritis and patient death due to intestinal perforation.
In patients with impaired liver function, the elimination time of methotrexate is prolonged; therefore, therapy with the drug should be given with extreme caution with decreasing doses.
The impairment of renal function depends on the dose. The risk of impairment is increased in patients with decreased renal function or dehydration, as well as in patients taking other nephrotoxic drugs.
Impact on ability to drive vehicles and other mechanisms requiring increased concentration
Some side effects of the drug may adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and quick psychomotor reactions.
- Severe anemia, leukopenia, neutropenia, thrombocytopenia;
- renal insufficiency;
- hepatic insufficiency;
- breastfeeding period;
- high sensitivity to methotrexate and/or any other component of the drug.
With caution: The drug should be used in cases of ascites, pleural effusion, peptic ulcer, ulcerative colitis, dehydration, history of gout or nephrolithiasis, previous radiation therapy or chemotherapy, infectious diseases of viral, fungal or bacterial origin.
Hematopoietic system: leukopenia, neutropenia, lymphopenia (especially T lymphocytes), thrombocytopenia, anemia.
Digestive system disorders: Anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis; rarely – enteritis, diarrhea, gastrointestinal ulcers, gastrointestinal bleeding; in individual cases (with long-term daily use) – liver function disorders, increased activity of liver transaminases, periportal fibrosis and cirrhosis, liver necrosis, fatty liver degeneration, pancreatitis.
CNS and peripheral nervous system disorders: Encephalopathy (when multiple doses are given intrathecally, cranial radiation therapy), fatigue, weakness, confusion, ataxia, tremor, irritability, seizures, coma; when methotrexate is given intrathecally, dizziness, blurred vision, headache, back pain, neck muscle rigidity, seizures, paralysis, hemiparesis.
Respiratory system disorders: rarely – interstitial pneumonitis, pulmonary fibrosis, exacerbation of lung infections.
Urinary system disorders: cystitis, nephropathy, renal dysfunction (increased creatinine level, hematuria).
Reproductive system disorders: disruption of oogenesis, spermatogenesis, decreased libido/impotence, changes in fertility, teratogenic effects.
Sensory organs: conjunctivitis, excessive lacrimation, cataracts, photophobia, cortical blindness (in high doses), visual impairment.
Dermatological reactions: erythema and/or rash, skin itching, telangiectasia, furunculosis, depigmentation or hyperpigmentation, acne, skin peeling, folliculitis, alopecia (rare), exacerbation of radiation dermatitis.
Allergic reactions: fever, chills, rash, urticaria, anaphylaxis, erythema malignant exudative (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), photosensitization.
Others: immunosuppression (decreased resistance to infectious diseases), malaise, osteoporosis, hyperuricemia, vasculitis, arthralgia/myalgia.
Symptoms: mainly symptoms associated with suppression of the hematopoietic system are observed.
Treatment: a specific antidote to methotrexate is calcium folinate. It neutralizes the adverse toxic effects.
In case of accidental overdose no later than one hour after methotrexate administration, calcium folinate is administered (IV or IV/m) in a dose equal to or greater than the dose of methotrexate. Calcium folinate administration is continued until methotrexate serum concentration decreases below 10-7 mmol/L.
In significant overdose, hydration of the body and alkalization of the urine (pH greater than 7) may be required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Hemodialysis and peritoneal dialysis do not improve methotrexate elimination. Intensive intermittent hemodialysis using “high-flux” dialyzers can provide effective clearance of methotrexate.
In case of overdose during intrathecal administration, repeated lumbar punctures should be performed immediately to ensure rapid drainage of cerebrospinal fluid, possibly neurosurgical intervention with ventriculolumbar perfusion. All these procedures should be performed against a background of intensive supportive therapy and systemic administration of high doses of calcium folinate.
Methotrexate, Metodect, Metodect, Metodect solution for p/dermal injection. 50 mg/ml 0.25 ml (12.5 mg) syringe, 1 pc.
See on the package.
|Conditions of storage|
Store out of reach of children, protected from light at a temperature not exceeding 25 ° C.
Fareva Untereh GmbH, Austria
solution for injection
Fareva Untereh GmbH
Buy Methotrexate-Ebeve, 10 mg/ml 0.75 ml with delivery to USA, UK, Europe and over 120 other countries.