Methotrexate-RONC - instructions for use, doses, side effects, contraindications

Inhibits dihydrofolate reductase, which participates in the restoration of dihydrofolic acid to tetrahydrofolic acid (transporter carbon fragments required for synthesis of purine nucleotides and their derivatives).

It inhibits synthesis, DNA repair and cellular mitosis (in the S phase). Especially sensitive to the action of methotrexate tissue with high cell proliferation: tumor tissue, bone marrow, epithelial cells of the mucous membranes, embryonic cells.

Along with the antitumor has an immunosuppressive effect.

Pharmacokinetics:

With intramuscular injection, the maximum concentration of methotrexate in the blood plasma is reached in 30-60 minutes. Leukemia patients are characterized by a wide interindividual variability ranging from 1 to 3 hours.

After intravenous administration, it is quickly distributed within a volume equivalent to the total volume of body fluids.The initial volume of distribution is 0.18 l / kg (18% of body weight), the equilibrium volume of distribution is 0.4-0.8 l / kg (40-80% of body weight). 50-60% of the methotrexate circulating in the vascular bed is associated with proteins (mainly with albumin).

Through the BBB passes only to a limited extent (dose-dependent); after intrathecal administration in significant amounts enters the systemic circulation. It is secreted into breast milk, passes through the placenta (it has a teratogenic effect on the fetus).

The half-life in the initial phase is 2-4 hours, and in the final phase (which is prolonged) - 3-10 hours when using usual doses and 8-15 hours - when using high doses of the drug. In chronic renal failure, both phases of drug clearance can be significantly prolonged.

It is excreted mainly by the kidneys in unchanged form by glomerular filtration and tubular secretion (with intravenous administration of 80-90% is excreted within 24 hours), with bile is excreted up to 10% (followed by reabsorption in the intestine). Removal of the drug in patients with impaired renal function, expressed ascites or transudate is significantly slowed down. With repeated administration, it accumulates in tissues in the form of polyglutamates.

Indications:Acute leukemia (especially lymphoblastic and myeloblastic variants), non-Hodgkin's lymphomas, including lymphosarcoma, osteogenic sarcoma and soft tissue sarcoma.

Contraindications:

- Hypersensitivity to methotrexate and / or any other component of the drug.

- Pregnancy and lactation.

- severe anemia, leukopenia; neutropenia, thrombocytopenia.

- severe renal (creatinine clearance less than 30 ml / min) or hepatic (at a bilirubin concentration in the plasma of more than 5 mg / dL (85.5 μmol / l) insufficiency.

- alcoholism, alcoholic liver disease, other chronic liver diseases.

- immunodeficiency.

- parasitic and infectious diseases of a viral, fungal or bacterial nature - the risk of developing a severe generalized disease (currently or recently transferred, including recent contact with the patient).

Carefully:If there is a violation of the liver and kidney function, diabetes mellitus, oppression of bone marrow hematopoiesis, ascites, bleeding into the pleural cavity, peptic ulcer of stomach and duodenum, ulcerative colitis, dehydration, gout or nephrolithiasis in anamnesis, previous radiation therapy or chemotherapy, childhood or old age .

Pregnancy and lactation:

The use of methotrexate during pregnancy can cause serious malformations of the fetus (an increase in the frequency of malformations of the skull, cardiovascular system and limbs by a factor of 14), so methotrexate contraindicated during pregnancy.

If pregnancy occurred during methotrexate treatment, you should consult with experts regarding the risk of adverse effects of methotrexate on the fetus. Patients of reproductive age (both women and men) should use effective contraception during and for at least 6 months after the end of treatment with methotrexate.

Methotrexate penetrates into breast milk in concentrations dangerous to the baby. Therefore, during treatment with methotrexate, breastfeeding should be discontinued.

Dosing and Administration:

Methotrexate-RONTS® can be administered intramuscularly, intravenously, intraarterially.

Doses above 100 mg / m are administered only intravenously (IV) dropwise (the concentrate is preliminarily diluted with 5% dextrose solution (10 mg - 0.5-1.0 L dextrose solution)) followed by calcium folinate.

The following dosing regimens are used for adults and children:

Solid tumors: in combination with other antineoplastic agents 30-40 mg / m intravenously sprayed once a week.

Leukemia and lymphoma: 200 to 500 mg /m² by intravenous infusion once every 2-4 weeks.

High-dose therapy: from 2 to 15 g /m² in the form of a 4-6 hour intravenous infusion at intervals of 1-5 weeks with the obligatory subsequent administration of calcium folinate, which usually begins 24 hours after the onset of infusion of methotrexate and administered every 6 hours at a dose of 3-40 mg /m² (usually 15 mg /m²) and above, depending on the concentration of methotrexate in the blood serum for 48-72 hours (see instructions for the use of calcium folinate).

The specific features of methotrexate use in certain categories of patients

Application for violations of liver function: patients with severe hepatic impairment methotrexate appoint with caution. Methotrexate It should not be used with a plasma bilirubin concentration of more than 5 mg / dL (85.5 μmol / L).

Application for violations of kidney function: patients with severe renal dysfunction should adjust the dose depending on the creatinine clearance (with a creatinine clearance of 20-50 ml / min, the dose is reduced by 50%, with creatinine clearance less than 20 ml / min methotrexate should not be appointed).With caution should be used drug with nefrourolitiaz (including in the anamnesis).

Application in elderly patients: elderly patients (over 65 years of age) may need to reduce the dose of methotrexate, since the liver and kidney function worsens with age, and the amount of folate in the body decreases.

Side effects:

From the hematopoiesis: oppression hemopoiesis, leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, pancytopenia, agranulocytosis, eosinophilia, lymphadenopathy, hypogammaglobulinemia, development of lymphoproliferative diseases (including reversible diseases), anemia, aplastic anemia.

From the digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis; enteritis, diarrhea, bloody vomiting, melena, erosive-ulcerative lesions and bleeding from the gastrointestinal tract. With prolonged daily use, hepatotoxicity, liver dysfunction, acute hepatitis, hepatic insufficiency, increased activity of "hepatic" transaminases, hypoalbuminemia, periportal fibrosis and cirrhosis are possible; liver necrosis, fatty liver; pancreatitis.

From the nervous system: encephalopathy, especially when administering multiple doses intrathecally, as well as in patients who received radiation therapy on the skull region. There are also reports of mood changes, fatigue, drowsiness, insomnia, weakness, irritation, depression, dysarthria, aphasia, transient cognitive dysfunction, confusion, taste distortion (metallic taste in the mouth), meingism, myasthenia gravis, ataxia, tremor, convulsions, paresthesia in the limbs and coma. Acute side effects caused by the intrathecal administration of methotrexate may include dizziness, blurred vision, headache, back pain, stiff neck muscles, convulsions, paralysis, hemiparesis.

From the urinary system: cystitis, ulceration of the mucous membrane of the bladder, dysuria, oliguria, anuria, azotemia, proteinuria, impaired renal function (increased creatinine concentration, hematuria), renal failure, severe nephropathy.

On the part of the reproductive system: change in fertility, the process of oogenesis, spermatogenesis, teratogenic effects,menstrual dysfunction, vaginitis, vaginal discharge, gynaecomastia, oligospermia, impotence.

From the skin and skin appendages: itching, skin erythema and / or rash, Stevens-Johnson syndrome, alopecia, increased photosensitivity, ecchymosis, telangiectasia, furunculosis, depigmentation or pigmentation, acne, skin peeling, exfoliative dermatitis, blistering, folliculitis, skin ulceration, toxic epidermal necrolysis, necrosis of the skin.

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

From the sense organs: conjunctivitis, excessive lacrimation, cataract, photophobia, cortical blindness (at high doses), visual impairment.

From the respiratory system: respiratory failure, alveolitis, pleural effusion, interstitial pneumonitis, pulmonary fibrosis, pulmonary exacerbation of infections.

From the cardiovascular system: pericarditis, pericardial effusion, lowering blood pressure, thrombosis (including arterial thrombosis, cerebral vascular thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism).

From the musculoskeletal system: arthralgia, myalgia, osteoporosis, osteonecrosis, fractures.

Infections: opportunistic infections (up to a lethal outcome) - pneumonia, cytomegalovirus infection, sepsis, nocardiosis, histoplasmosis, cryptococcosis, shingles, infections caused by the herpes simplex virus.

Local reactions: when administered intramuscularly - sensations of burning, tissue damage (aseptic abscess, destruction of adipose tissue) at the injection site.

Other: immunosuppression (reduction of resistance to infectious diseases), deterioration of wound healing, malaise, hyperuricemia, vasculitis, soft tissue necrosis, benign, malignant and nonspecific neoplasms (including cysts and polyps), diabetes mellitus.

Overdose:

Symptoms: No, is diagnosed by the concentration of methotrexate in plasma.

Treatment: the introduction of a specific antidote - calcium folinate whenever possible immediately, 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 concentration of methotrexate in the blood serum.To prevent the precipitation of methotrexate and / or its metabolites in the renal tubules, the body is hydrated and alkalinized with urine, which accelerates the excretion of methotrexate.

Interaction:

Regular use of alcohol and simultaneous use with methotrexate hepatotoxic drugs increase the risk of hepatotoxicity of methotrexate.

With combined therapy with methotrexate and leflunomide, the incidence of pancytopenia and hepatotoxicity increases.

The simultaneous use of high doses of methotrexate with various non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid and other salicylates, azaprospan, diclofenac, indomethacin and ketoprofen, the toxicity of methotrexate may increase, and in some cases a potentially toxic effect, sometimes even fatal, is possible.

When treating patients with osteosarcoma, caution should be exercised when high doses of methotrexate are given in combination with potentially nephrotoxic drugs (for example, cisplatin). Methotrexate increases the concentration of mercaptopurine in the blood plasma, and may require a dose adjustment of mercaptopurine.

Simultaneous use of sulfonamides, sulfonylurea derivatives, phenytoin, phenylbutazone, aminobenzoic acid, probenicide, pyrimethamine or trimethoprim / sulfamethoxazole; a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and lipid-lowering drugs (colestramine) increases the toxicity of methotrexate.

Retinoids; azathioprine, sulfasalazine increase the risk of hepatotoxicity. Multivitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate therapy.

Asparaginase is a methotrexate antagonist.

Anesthesia using dinitrogen oxide can lead to unpredictable severe myelosuppression and stomatitis.

Amiodarone can promote skin ulceration.

Methotrexate reduces the clearance of theophylline.

Caution should be exercised with the simultaneous administration of erythrocyte mass and methotrexate.Hematotoxic drugs - increase the risk of hematotoxicity of methotrexate.

Drugs that block tubular secretion (for example, probenecid) increase the toxicity of methotrexate by reducing the excretion of it by the kidneys. The use of cytarabine 48 hours before or within 10 minutes after the initiation of methotrexate therapy may result in the development of a synergistic cytotoxic effect (correction of the dosing regimen is recommended based on hematologic parameters).

The combination with radiotherapy can increase the risk of soft tissue necrosis.

Methotrexate may reduce the immunological response to vaccination. With simultaneous administration with a live vaccine, severe antigenic reactions can develop.

With the simultaneous administration of proton pump inhibitors (omeprazole, pantoprazole, esomeprazole) with methotrexate (especially in high doses), the serum level of methotrexate may increase and the half-life of methotrexate and its metabolite, 7-hydroxymethotrexate, which determines the toxicity of methotrexate, will lengthen.

Special instructions:

- Methotrexate is a cytotoxic drug, so care must be taken when handling it.

- Dosage forms containing preservatives, in particular gasoline alcohol, are not allowed for high-dosage therapy.

- With the introduction of high doses of methotrexate, careful monitoring of the patient for early detection of the first signs of toxic reactions is necessary.

- High-dose therapy should be performed only by experienced chemotherapists under the control of methotrexate concentration in plasma under steady-state conditions followed by calcium folinate administration.

- During therapy with methotrexate in elevated and high doses, urine pH should be monitored: on the day of administration and in the next 2-3 days, the urine reaction should be alkaline. This is achieved by intravenous drip injection of a mixture consisting of 40 ml of 4.2% sodium bicarbonate solution and 0.9% sodium chloride solution on the eve, on the day of treatment and in the following 2-3 days.

- Treatment of methotrexate in high and high doses should be combined with increased hydration to 2 liters of fluid per day.

- Introduction of methotrexate in a dose of 2 g /m² and above are carried out under the control of its concentration in the blood serum.It is normal to reduce the content of methotrexate in the blood serum after 22 hours after the introduction of 2 times compared with the baseline. Increasing the creatinine concentration by 50% or more of the original content and / or increasing the concentration of bilirubin requires intensive detoxification therapy.

- To prevent toxicity during the treatment with methotrexate, a periodic blood test (once a week) is necessary to determine the concentration of leukocytes and platelets, monitoring the liver and kidney function.

- With special care apply methotrexate in patients with peptic ulcer, ulcerative colitis, in young patients, in the elderly.

- In patients with impaired liver function, the period of excretion of methotrexate is increased, so in such patients therapy should be carried out with extreme caution with the use of reduced doses.

- Impaired renal function is dose dependent. Risk of impairment is elevated in patients with reduced renal function or with dehydration, as well as in patients taking other nephrotoxic drugs.

- Methotrexate should be used with caution, if at all, in patients with bone marrow aplasia, leukopenia, thrombocytopenia and anemia (in the anamnesis).With the development of severe leukopenia, a bacterial infection may occur. Treatment of methotrexate in this case should be discontinued and appropriate antibiotic therapy initiated.

- In the development of severe myelosuppression, blood transfusions may be required.

- With early detection, most side effects are reversible. If side effects occur, reduce the dose of the drug or cancel it and take appropriate corrective measures.

- Side effects from the lungs, including pneumonitis and pulmonary fibrosis, may occur with any dose of the drug, even at a dose of 7.5 mg per week. The possibility of lung injury should be taken into account in patients with any pulmonary symptoms (for example, dry non-productive cough, shortness of breath) that appear against the background of taking the drug. When such symptoms appear methotrexate should be canceled and a thorough examination of the patient, including the exclusion of possible infection. Treatment of patients with manifestations of pulmonary toxicity of methotrexate is generally supportive and may include mechanical ventilation. In addition, the drug-induced pulmonary toxicity may not be completely reversible.

- For timely detection of symptoms of intoxication, it is necessary to monitor the state of peripheral blood (the number of leukocytes and platelets: first a day, then every 3-5 days for the first month, then 1 time for 7-10 days, in remission - 1 time in 1- 2 weeks), activity of "liver" transaminases, renal function (urea nitrogen, creatinine clearance and / or serum creatinine), uric acid concentration in the blood serum, and periodically perform chest X-ray. It is recommended to monitor the state of bone marrow hematopoiesis before treatment, 1 time during the treatment period and at the end of the course. In high-dose treatment, the plasma methotrexate concentration, urine pH (before each administration and every 6 hours during the entire period of calcium folinate as an antidote, must be determined, until the plasma methotrexate concentration is below 0.05 μmol / L, to ensure pH above 7, in order to minimize the risk of nephropathy, as a result of the formation of a sediment of the drug or its metabolites in the urine). After the treatment with high doses of methotrexate, the use of calcium folinate is recommended to reduce its toxicity.

- It is necessary to conduct a study of the oral cavity of the patient for the presence of ulcers before each use.

- With the development of diarrhea and ulcerative stomatitis, methotrexate therapy must be interrupted due to a high risk of hemorrhagic enteritis and perforation of the intestinal wall, which can lead to the death of the patient.

- Men and women of childbearing age should be treated with methotrexate and at least 3 months after the use of reliable methods of contraception.

Effect on the ability to drive transp. cf. and fur:Given that with the use of methotrexate in patients can develop nausea, vomiting, dizziness and other neurological symptoms that affect the overall condition, from driving the car and working with other mechanisms for this period, it is recommended to abstain.

Form release / dosage:Concentrate for the preparation of a solution for infusions of 100 mg / ml.

Packaging:

5 ml or 10 ml in a glass vial sealed with a bromobutyl rubber stopper under an aluminum cap or an aluminum cap with a plastic insert.

One bottle in a cardboard box with instructions for use.

Storage conditions:

In the dark place at a temperature of 15 to 25 ° C.

Keep out of the reach of children!

Do not freeze.

Shelf life:

2 years.

Do not use the product after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002821

Date of registration:14.01.2015 / 11.12.2017

Expiration Date:14.01.2020

The owner of the registration certificate:RNTS named after N.N. Blokhin RAMS RNTS named after N.N. Blokhin RAMS Russia

Manufacturer: & nbsp

RNTS named after N.N. Blokhin RAMS Russia

Information update date: & nbsp11.05.2018

Illustrated instructions

Instructions

Methotrexate-RONTS® (Methotrexate-RONTS®)