Metoject, 50 mg/ml 0.5 ml

Pharmacodynamics

Antitumor, cytostatic agent of the group of antimetabolites – analogues of folic acid.

Inhibits dihydrofolate reductase, involved in the reduction of dihydrofolic acid to tetrahydrofolic acid (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.

. The mechanism of action in rheumatoid arthritis is connected with the immunomodulatory and anti-inflammatory action of the preparation and is caused by the induction of apoptosis of the rapidly proliferating cells (activated T-lymphocytes, fibroblasts, synoviocytes), inhibition of anti-inflammatory cytokine synthesis (interleukin (IL)-1, tumor necrosis factor alpha), enhancement of anti-inflammatory cytokine synthesis IL-4, IL-10 and suppression of metalloproteinases activity.

In patients with rheumatoid arthritis, methotrexate reduces symptoms of inflammation (pain, swelling, stiffness), but there are limited studies on long-term use (regarding the ability to maintain remission in rheumatoid arthritis).

The growth rate of keratinocytes in psoriatic plaques is increased in psoriasis compared to normal skin cell proliferation. This difference in cell proliferation is the basis for the use of methotrexate to treat psoriasis.

Pharmacokinetics

When administered in m/m, C_max methotrexate in plasma is reached after 30-60 min. Systemic absorption of methotrexate after injection under the skin of the abdomen and thigh is the same. After IV administration, it is rapidly distributed within a volume equivalent to the total volume of body fluids. Initial V_d is 0.18 L/kg (18% of body weight), equilibrium distribution volume is 0.4-0.8 L/kg (40-80% of body weight). 50-60% of methotrexate circulating in the vascular stream is bound to proteins (mainly to albumin). Competitive displacement is possible when concomitant use with sulfonamides, salicylates, tetracyclines, chloramphenicols, phenytoin. Methotrexate does not penetrate the BBB when used in therapeutic doses. High concentrations of methotrexate in the CNS may be achieved by intrathecal administration. Methotrexate undergoes hepatic and intracellular metabolism to form pharmacologically active polyglutamine form, which also inhibits dihydrofolate reductase and thymidine synthesis. Small amounts of polyglutamate methotrexate can remain in tissues for a long period of time. The persistence and prolongation of the action of active methotrexate metabolites varies by cell type, tissue type, and tumor type. The average T_1/2 values for methotrexate at doses less than 30 mg/m² are 6-7 h. In patients receiving high-dose methotrexate, T_1/2 is 8-17 h. In chronic renal failure, both phases of methotrexate excretion may be significantly prolonged. It is excreted mainly unchanged by the kidneys through glomerular filtration and tubular secretion (when administered intravenously 80-90% is eliminated within 24 hours), up to 10% is excreted with the bile (with subsequent reabsorption in the intestine). Methotrexate cumulates in the liver, kidneys and organs for several weeks or months. With repeated injections it accumulates in tissues as polyglutamates.

Indications

Trophoblastic tumors; acute leukemia (especially lymphoblastic and myeloblastic variants); neuroleukemia; non-Hodgkin’s lymphoma (including lymphosarcoma); breast cancer, squamous cell head and neck cancer, lung cancer, skin cancer, cervical cancer, vulvar cancer, esophageal cancer, bladder cancer, testicular cancer, ovarian cancer, penile cancer, retinoblastoma, medulloblastoma; osteogenic sarcoma and soft tissue sarcoma; fungal mycosis (advanced stages);

Severe forms of psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile chronic arthritis, dermatomyositis, systemic lupus erythematosus, ankylosing spondylitis (if standard therapy is not effective).

Active ingredient

Composition

Active ingredient:
methotrexate dinatrium 54.84 mg (equivalent to 50 mg of methotrexate)
prepared according to the prescription: methotrexate – 50 mg; sodium hydroxide – 9.6 mg
excipients: sodium chloride – 4 mg; sodium hydroxide – q.s. (to pH 8.5-8.9), water for injection – up to 1 ml.

How to take, the dosage

It is taken orally, administered intravenously, intramuscularly, intralumbarly. The dosing regimen is established individually, depending on the indication and stage of the disease, the patient’s age, the state of the hematopoiesis system, the scheme of anti-tumor therapy, the dosage form used.

The directions in the methotrexate formulation instructions for appropriate dosage forms and routes of administration of methotrexate must be strictly followed, depending on the indication.

Interaction

Concomitant use with vitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate.

Concomitant use of NSAIDs in high doses may lead to increased plasma concentrations of methotrexate and prolongation of its T1/2, as well as increased concentration of methotrexate not bound to plasma albumin, which in turn increases toxic effects of methotrexate (especially on gastrointestinal and circulatory system).

In concomitant use with penicillins of methotrexate (even in low doses) it is possible to increase its toxic effects.

In concomitant use with sulfonamides, especially with co-trimoxazole, there is a risk of increased myelodepressive effects.

The use of nitrous oxide in patients receiving methotrexate may result in severe unpredictable myelodepression, stomatitis.

When concomitant use of valproic acid with methotrexate, its plasma concentrations may decrease.

Colestyramine binds methotrexate, reduces its enterohepatic recirculation, which leads to a decrease in its plasma concentrations.

Concomitant use with mercaptopurine may increase its bioavailability due to impaired metabolism during “first passage” through the liver.

Neomycin and paramomycin decrease absorption of methotrexate from the gastrointestinal tract.

In patients receiving omeprazole, increased plasma concentrations of methotrexate may occur.

In concomitant use with probenecid a 3-4-fold increase in plasma concentration of methotrexate is possible due to decreased renal excretion.

Concomitant use of methotrexate with retinoids may increase the risk of hepatotoxic effects.

Salicylates potentiate the effects of methotrexate due to decreased renal excretion.

Methotrexate, even at low doses, may have toxic effects after tetracycline treatment.

When methotrexate and fluorouracil are administered sequentially, synergism is possible; fluorouracil administered before methotrexate may reduce its toxicity.

Cisplatin has a nephrotoxic effect and therefore may decrease renal excretion of methotrexate, resulting in increased toxicity.

The concomitant use of indirect anticoagulants and hypolipidemic agents (cholestyramine) increases methotrexate toxicity.

The likelihood of hepatotoxic effect of methotrexate increases in case of regular alcohol consumption and concomitant use of other hepatotoxic drugs.

The incidence of pancytopenia and hepatotoxic effects increases with combined therapy with methotrexate and leflunomide.

There may be increased toxicity when using cyclosporine in patients who received methotrexate.

The concomitant use of indirect anticoagulants and hypolipidemic drugs (colestyramine) increases the toxicity of methotrexate.

When treating with methotrexate, excessive consumption of beverages containing caffeine and theophylline (coffee, sweet drinks containing caffeine, black tea) should be avoided.

Methotrexate decreases theophylline clearance.

Methotrexate should not be mixed with other medicinal products and solvents.

Special Instructions

Methotrexate is cytotoxic, so caution should be exercised and the rules for handling cytotoxic drugs should be followed when handling the drug Metodect.

Contact of the drug with the skin and mucous membranes should be avoided except when injected. In case of contact, the areas of skin and mucous membranes concerned should be washed immediately with plenty of water, the areas of skin afterwards should be washed with soap and water.

In case of accidental spillage of the drug, collect the spilled solution with a disposable absorbent cloth, then treat the contacted surface with detergent and wipe it with a disposable wet cloth, after which the hands should be thoroughly washed with soap.

The product is for single use only.

Unused product and used materials must be disposed of in accordance with the rules for handling cytotoxic drugs.

The use of Metodect in children. The use of the drug Metodect in children under 3 years of age is not recommended because of insufficient data on the effectiveness and safety of the drug in this group of patients.

Patients with juvenile rheumatoid arthritis should be monitored by a rheumatologist specializing in the treatment of children and adolescents.

The effect on the ability to drive vehicles and use machinery. Methotrexate can affect the CNS (causing symptoms such as fatigue, drowsiness, and dizziness) and thus adversely affect the ability to drive, operate machinery, and perform other activities requiring quick psychomotor reactions.

Contraindications

Side effects

In the digestive system: ulcerative stomatitis, anorexia, gingivitis, pharyngitis, nausea; rarely – diarrhea, melena, enteritis, pancreatitis; in individual cases (with long-term daily use) – liver necrosis, cirrhosis, fatty atrophy, periportal liver fibrosis.

With the hematopoietic system:leukopenia, anemia, thrombocytopenia.

CNS side:fatigue, dizziness; rarely – headache, aphasia, somnolence, seizures.

Reproductive system disorders:disorders of oogenesis and spermatogenesis, oligospermia, menstrual disorders, decreased libido, impotence.

In the urinary system:hematuria, cystitis, marked renal dysfunction.

Allergic reactions:chills, decreased resistance to infection; rarely – urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Cardiovascular system disorders: infrequently – vasculitis; rarely – pericarditis, pericardial effusion, cardiac tamponade, decreased BP, thromboembolic complications (including cerebral and arterial thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis, pulmonary thromboembolism).

Blood and lymphatic system disorders: frequent – leukopenia, thrombocytopenia, anemia; infrequent – pancytopenia, agranulocytosis, hematopoietic disorders; rare – megaloblastic anemia; very rare – severe suppression of bone marrow function, aplastic anemia, enlarged lymph nodes, lymphoproliferative diseases (partially reversible), eosinophilia, neutropenia. The first signs of these complications, which are life-threatening, are fever, sore throat, mouth ulcers, flu-like symptoms, nosebleeds, and skin hemorrhages. Use of methotrexate should be stopped immediately if the blood cell count decreases significantly.

Injury to the immune system: infrequently – allergic reactions, anaphylactic shock, immunosuppression.

Infectious diseases: very rarely – sepsis, opportunistic infections (may be fatal in some cases), infections caused by Cytomegalovirus; frequency unknown – reported cases of nocardiasis, histoplasmosis and cryptococcal fungal infections, disseminated form of herpes simplex.

Nervous system disorders: frequent – headache, increased fatigue, drowsiness; infrequent – depression, confusion, dizziness, seizures; rare – change in mood; very rare – pain, muscle weakness or paresthesia in the extremities, taste disturbance (metallic taste), acute aseptic meningitis with meningism (paralysis, vomiting), insomnia; frequency unknown – ringing in the ears.

Visual side: rarely – severe visual impairment; very rare – conjunctivitis, retinopathy.

Benign, malignant and unspecified neoplasms: infrequent – isolated cases of lymphoma, which regress when treatment with methotrexate is discontinued.

Injuries to the respiratory system: frequent – pulmonary complications due to interstitial pneumonitis/alveolitis, including fatal – regardless of the dose and duration of methotrexate treatment (typical symptoms: malaise, dry nonproductive cough, shortness of breath. progressing to shortness of breath at rest, chest pain, fever. If the above adverse reactions are suspected, use of methotrexate should be stopped immediately, infections, including pneumonia, should be excluded); infrequent – pulmonary fibrosis; rare – pharyngitis, apnea, bronchial asthma, dyspnea, abnormal results of lung function instrument tests; very rare – pneumonia caused by Pneumocystis carinii and other lung infections, difficulty in breathing, chronic obstructive pulmonary disease, pleural effusion.

Digestive system disorders: very often – decreased appetite, nausea, vomiting (especially during the first 24-48 h after methotrexate administration), abdominal pain, inflammation and ulcers in the mucosa of the mouth and throat, stomatitis, dyspepsia; frequently – diarrhea (especially during the first 24-48 hours after methotrexate administration); infrequently – ulcers, gastrointestinal bleeding; rarely – enteritis, melena, gingivitis, malabsorption syndrome; very rarely – vomiting with blood, toxic megacolon.

With the liver and biliary tract: very often – increased activity of “liver” enzymes (ALT, ACT), increased ALP activity, increased concentration of bilirubin; infrequently – liver steatosis, liver fibrosis, liver cirrhosis (may appear even in case of regular detection while monitoring normal values of “liver” transaminases); rarely – acute hepatitis and hepatotoxicity; very rarely – reactivation of chronic hepatitis, acute liver dystrophy, liver failure (the most common is hepatitis caused by herpes simplex virus and accompanied by liver failure).

Skin and subcutaneous tissue side: frequently – exanthema, erythema, skin itching; infrequent – urticaria, photosensitization, increased skin pigmentation, hair loss, abnormal wound healing, increased rheumatic nodules, shingles, painful psoriatic plaques (plaque psoriasis may worsen during UV therapy and concomitant use of methotrexate), severe toxic reactions, vasculitis, allergic vasculitis, herpetiform skin rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome); rarely – changes in the pigmentation of the nails, onycholisis, petechiae, ecchymosis, erythema multiforme, erythematous skin rash; very rare – acute paronychia, furunculosis, telangiectasia, hydradenitis.

Muscular system disorders: infrequently – arthralgia, myalgia, osteoporosis; rarely – stress fractures, osteonecrosis.

With the urinary system: infrequent – inflammation and ulceration of the bladder (possibly with hematuria), dysuria; rare – renal failure, oliguria, anuria, azotemia; very rare – proteinuria.

As to the sexual system: infrequent – vaginitis; rare – oligospermia, menstrual disorders; very rare – decreased libido, impotence, vaginal discharge, infertility, gynecomastia; frequency unknown – violation of oogenesis and spermatogenesis, teratogenic effect.

From the endocrine system: frequency unknown – diabetes mellitus, metabolic disorders.

Local reactions: injection, infrequent – burning or tissue damage (formation of sterile abscesses, destruction of fatty deposits) at the injection site.

Very rare: fever. Usually, when injected subcutaneously, methotrexate is well tolerated; only mild local reactions have been reported so far, which decreased during treatment.

Others: infrequent – decreased serum albumin concentration, hypogammaglobulinemia; rarely – fever

The frequency and severity of adverse reactions to methotrexate depend on the dose and frequency of use. Because serious adverse reactions can also occur at low doses, it is extremely important that patients be evaluated by a physician regularly and at short intervals.

Pregnancy use

Methotrexate is contraindicated in pregnancy. Breast-feeding should be stopped if it is necessary to use during lactation.

Women of childbearing age should use reliable contraception while using methotrexate.

In experimental studies established the embryotoxic and teratogenic effects of methotrexate.

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