METHOTREXATE INJECTION SOLUTION SYRINGE 10MG/ML 0.75ML

Composition

1 syringe for injection contains:

methotrexate 7.5 mg

Mechanism of action

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 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.

Along with antitumor has an immunosuppressive effect.

Oral absorption depends on the dose: when taken 30 mg / m is well absorbed, the average bioavailability is 50%. Absorption is reduced when taken in doses exceeding 80 mg / m (believed due to saturation).

In children with leukemia, absorption ranges from 23 to 95%.

The time to reach the maximum concentration (Cmax) - 1-2 hours with oral administration and 30-60 minutes - with i / m administration. Food slows down absorption and reduces Cmax. Communication with plasma proteins is about 50%. When taken in therapeutic doses, regardless of the route of administration, it practically does not penetrate through the BBB (after intrathecal administration, high concentrations are achieved in the cerebrospinal fluid). Penetrates into breast milk.

After oral administration, it 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 reductase and thymidine synthesis. The half-life in the initial phase is 2-4 hours, and in the final phase (which is long) - 3-10 hours using normal doses and 8-15 hours using high doses of the drug. In chronic renal failure, both phases of the elimination of the drug can be significantly prolonged.

Excreted mainly by the kidneys in unchanged form by glomerular filtration and tubular secretion (with intravenous injection 80-90% o is excreted within 24 hours), with bile up to 10% excreted (with subsequent reabsorption in the intestine). Removal of the drug in patients with impaired renal function, ascites or transudate expressed is significantly slowed down. When repeated injections accumulates in the tissues in the form of metabolites.

Adverse reactions

From the side of blood formation organs: leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia.

On the part of the digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis, rarely - enteritis, diarrhea, erosive-ulcerative lesions and bleeding from the gastrointestinal tract, in some cases (with prolonged daily use) - impaired liver function, increased activity of liver transaminases, periportal fibrosis and liver cirrhosis, liver necrosis, fatty degeneration of the liver, pancreatitis.

On the part of the nervous system: encephalopathy, especially with the introduction of multiple doses of intrathecal, as well as in patients who received radiation therapy on the skull. There are also reports of fatigue, weakness, confusion, ataxia, tremor, irritability, convulsions and coma. Acute adverse events caused by intrathecal administration of methotrexate may include dizziness, blurred vision, headache, back pain, stiff neck, convulsions, paralysis, hemiparesis.
On the part of the respiratory system: rarely - interstitial pneumonitis, pulmonary fibrosis, exacerbation of pulmonary infections.
On the part of the urinary system: cystitis, nephropathy, impaired renal function (increased creatinine levels, hematuria).
Reproductive system: impaired oogenesis, spermatogenesis, decreased libido / impotence, changes in fertility, teratogenic effects.
From the skin and skin appendages: skin erythema and / or rash, pruritus, urticaria, telangiectasia, furunculosis,depigmentation or hyperpigmentation, acne, peeling of the skin, folliculitis, alopecia (rare), increased photosensitivity, exacerbation of radiation dermatitis.
From the senses: conjunctivitis, excessive tearing, cataract, photophobia, cortical blindness (at high doses), visual impairment.

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

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

prescription

Methotrexate is a cytotoxic drug, so care must be taken when handling it. Dosage forms containing preservatives, in particular benzyl alcohol, should not 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 the 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 Calcium folinate. During therapy with methotrexate in high and high doses, it is necessary to monitor urine pH: on the day of administration and in the next 2-3 days, the urine reaction should be alkaline.This is achieved by intravenous drip administration 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 for the next 2-3 days.

Treatment with methotrexate in high and high doses should be combined with enhanced hydration of up to 2 liters of fluid per day. The introduction of methotrexate in a dose of 2 g / m2 and above is carried out under the control of its concentration in blood serum. It is considered normal to decrease the content of methotrexate in the serum after 22 hours after administration by 2 times compared with the initial level. Increasing the level of creatinine by 50% or more of the initial content and / or increasing the level of bilirubin requires intensive detoxification therapy.

For the treatment of psoriasis, methotrexate is prescribed only to patients with a severe form of the disease that cannot be treated with other types of therapy. For the prevention of toxicity in the process of treatment with methotrexate, a periodic blood test (1 time per week), the determination of leukocytes and platelets, and liver and kidney function tests are necessary.

With the development of diarrhea and ulcerative stomatitis, therapy with methotrexate must be interrupted, otherwise it may lead to the development of hemorrhagic enteritis and to the death of the patient due to bowel perforation. In patients with impaired liver function, the period of methotrexate elimination is increased, therefore, in such patients, therapy should be carried out with extreme caution, with the use of reduced 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. Men and women of childbearing age during treatment with methotrexate and for at least 3 months after should use reliable methods of contraception.

Some side effects of the drug may adversely affect the ability to drive and perform potentially hazardous activities that require increased concentration and psychomotor speed,

Overdosage

In case of an accidental overdose of methotrexate, it is recommended to use a specific antidote, calcium folinate. Calcium folinate administration should be started as soon as possible, preferably within the first hour, at a dose equal to or greater than the dose 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 after intrathecal administration, immediately after overdose has been identified, repeated lumbar punctures should be performed to ensure rapid drainage of the cerebrospinal fluid, possibly with neurosurgical intervention with ventriculo lumbar perfusion. All these procedures should be performed on the background of intensive maintenance therapy and systemic administration of large doses of calcium folinate.

• trophoblastic tumors
• acute leukemia (lymphoblastic and myeloblastic variants);
• neuroleukemia;
• non-Hodgkin lymphomas, 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, systemic lupus erythematosus, ankylosing spondylitis (with the ineffectiveness of standard therapy).

Hypersensitivity to methotrexate and / or any other component of the drug.
Severe anemia, leukopenia, neutropenia, thrombocytopenia.
Renal or hepatic failure.
Pregnancy and lactation period.

with ascites, pleural effusion, 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 simultaneous use of high doses of methotrexate with various nonsteroidal anti-inflammatory drugs (NSAIDs), including Aspirin and other salicylates, azapropazone, Diclofenac,indomethacin and Ketoprofen, the toxicity of methotrexate can be enhanced, and in some cases severe toxic effects are possible, 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. Simultaneous use of sulfonamides, sulfonylureas, phenytoin, phenylbutazone, aminobenzoic acid, probenicid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, Tetracycline, chloramphenicol), anticoagulants, and lipid lowering drugs (cholestyramine) enhances the toxicity of methotrexate. Antibiotics, poorly absorbed in the gastrointestinal tract (tetracyclines, chloramphenicol), reduce the absorption of methotrexate and disrupt its metabolism due to the suppression of the normal intestinal microflora.

Retinoids, azathioprine, sulfasalazin increase the risk of hepatotoxicity. Parenteral use of Acyclovir on the background of intrathecal administration of methotrexate increases the risk of neurological disorders.

Multivitamin preparations containing folic acid or its derivatives can reduce the effectiveness of methotrexate therapy.
L-asparaginase is antagonist of methotrexate.
Anesthesia with dinitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis.
Amiodarone may promote ulceration of the skin.
Methotrexate reduces theophylline clearance.

Several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (methoxen and ultraviolet radiation) were diagnosed with skin cancer.

Caution should be exercised with the simultaneous introduction of erythrocyte mass and methotrexate. Combination with radiotherapy may increase the risk of soft tissue necrosis. Methotrexate can reduce the immunological response to vaccination. When administered simultaneously with a live vaccine, severe antigen reactions can develop.