Metodect solution for injection 10mg/ml 2ml ( 20mg) syringe, 1pc

Composition

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1 ml (1 syringe) contains:

Active ingredients:

disodium methotrexate is 10.96 mg (21.92 mg), which corresponds to a methotrexate content of 10 mg (20 mg).

Auxiliary substances:

sodium chloride,

sodium hydroxide,

d/i water.

In a 2 ml colorless glass syringe.

The blister contains 1 colorless glass syringe complete with a d/i needle. There is 1 blister in a cardboard box.

Pharmacological action

Pharmacodynamics

Immunosuppressant, antitumor drug, antimetabolite, folic acid antagonist. Competitively inhibits the enzyme dihydrofolate reductase, which is involved in the reduction of dihydrofolic acid to tetrahydrofolic acid (a carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives). Inhibits DNA synthesis, repair, and cellular mitosis.

Rapidly proliferating cells, such as malignant tumor cells, bone marrow cells, embryonic cells, and epithelial cells of the mucous membranes, are particularly sensitive to the action of methotrexate. Along with antitumor, it has an immunosuppressive effect.

It remains unclear what causes the effectiveness of methotrexate in the treatment of psoriasis, psoriatic arthritis and rheumatoid arthritis (including juvenile chronic arthritis): its anti-inflammatory or immunosuppressive effects. It has also not been established to what extent the effectiveness of therapy is explained by the increase in the extracellular concentration of adenosine caused by methotrexate at the sites of inflammation.

With psoriasis, the formation of skin epithelial cells is significantly accelerated compared to the norm. The use of methotrexate can slow down the formation of skin epithelial cells, which justifies the use of the drug for the treatment of psoriasis.

Pharmacokinetics

Distribution

Binding to plasma proteins is about 50%.

After distribution to tissues, high concentrations of methotrexate in the form of polyglutamates are found in the liver, kidneys, and especially in the spleen, where methotrexate can be retained for several weeks or even months.

When used in small doses, it penetrates the cerebrospinal fluid only in minimal quantities.

Metabolism

About 10% of the administered dose is metabolized in the liver, the main metabolite-7-hydroxymethotrexate, also has some pharmacological activity. About 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate are excreted in the bile (followed by intestinal reabsorption).

Elimination

of T_1/2 is on average 6-7 hours and is characterized by high variability (3-17 hours).

It is mainly excreted unchanged by the kidneys by glomerular filtration and tubular secretion. About 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate are excreted in the bile (followed by intestinal reabsorption).

Pharmacokinetics in special clinical cases

, T_1/2 may increase to values 4 times higher than the average values in patients with an additional volume of distribution (the presence of pleural effusion, ascites).

Elimination of the drug in patients with impaired renal function is significantly slowed down. There are no data on slowing the elimination of methotrexate in patients with insufficient liver function.

Indications

• Rheumatoid arthritis in adults;
• polyarthritis in patients with severe juvenile chronic arthritis in active form;
• severe generalized forms of psoriasis and psoriatic arthritis in adults with ineffectiveness of standard therapy.

Use during pregnancy and lactation

Metodject is contraindicated during pregnancy and lactation.

Methotrexate affects the fertility function, is an embryo -, fetotoxic and teratogenic drug. When used in humans, methotrexate exhibits teratogenic properties, can cause intrauterine fetal death, and congenital deformities.

Limited use in pregnant women (42) resulted in an increased incidence (1: 14) of malformations (cranial, cardiovascular, and limb). In cases of interruption of methotrexate therapy before fertilization, a normal course of pregnancy was observed.

Patients of childbearing age of both sexes and their partners should use reliable contraceptive measures during treatment with methotrexate and for at least 6 months after it ends.

If pregnancy occurs during methotrexate therapy, the risk of adverse effects on the fetus should be evaluated.

Methotrexate is excreted in breast milk in amounts that are dangerous for the child, so before starting treatment with methotrexate, breastfeeding should be stopped and abstained from during the entire course of treatment.

Contraindications

• Expressed by the liver;
• alcoholism;
• renal failure severe (CC less than 20 ml/min);
• blood violations in history, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, severe anemia;
• severe acute or chronic infectious diseases such as tuberculosis, HIV infection;
• ulcerative lesions of the oral cavity;
• ulcerative lesions of the gastrointestinal tract in the active phase;
• pronounced immunodeficiency;
• pregnancy;
• lactation (breastfeeding);
• concurrent vaccination with live vaccines;
• hypersensitivity to the components of the drug.

With caution: the drug should be used in patients with ascites, dehydration, obstructive gastrointestinal diseases, pleural or peritoneal effusion, with chronic renal failure; with parasitic and infectious diseases of a viral, fungal or bacterial nature (currently or recently transferred, including recent contact with the patient) – herpes simplex, herpes zoster in the viremic phase, chickenpox, measles, amoebiasis, strongyloidosis, or suspected (risk of developing severe generalized disease); gout (including a history) or urate nephrourolithiasis (including a history), infection and inflammation of the oral mucosa, vomiting and diarrhea (loss of fluid due to severe vomiting and diarrhea can lead to increased toxicity of methotrexate), gastric and duodenal ulcers, ulcerative colitis, with previous chemotherapy or radiation therapy, asthenia, in elderly patients.

Side effects

The most common side effects when using Metodject are reactions from the hematopoietic system and the digestive system.

Determining the frequency of side effects:

• very common (≥ 1/10);
• common (≥ 1/100, < 1/10);
• sometimes (≥ 1/1000, < 1/100);
• rare (≥ 1/10 000, < 1/1000);
• very rare (

From the digestive system: very often – stomatitis, dyspepsia, nausea, loss of appetite, increased transaminase activity; often – oral ulcers, diarrhea; sometimes – enteritis, vomiting, cirrhosis, fibrosis and fatty degeneration of the liver, hepatotoxicity (acute hepatitis, liver failure); rarely – erosive and ulcerative lesions of the gastrointestinal tract; very rarely-vomiting with blood admixture, bleeding from the gastrointestinal tract (including melena, hematemesis); possibly – pancreatitis.

From the hematopoietic system: often-leukopenia, anemia (including aplastic), neutropenia, thrombocytopenia; sometimes-pancytopenia; very rarely-agranulocytosis, severe suppression of bone marrow function.

Dermatological reactions: often-exanthema, erythema, dermatitis, pruritus; sometimes-photosensitization, baldness, enlarged rheumatic nodes, vasculitis, infections caused by Herpes zoster, herpetiform rashes on the skin, urticaria; rarely-increased pigmentation; very rarely-changes in nail pigmentation, acute paronychia, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome). In the treatment of psoriasis – a burning sensation of the skin, rarely-painful erosive plaques on the skin.

Allergic reactions: various manifestations up to anaphylactic shock; allergic vasculitis, fever.

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

From the central nervous system and peripheral nervous system: often-headache, fatigue, drowsiness; sometimes-dizziness, confusion, depression; very rarely-pain, muscle weakness or paresthesia of the extremities, impaired taste (metallic taste), convulsions, meningism, paralysis.

From the endocrine system: possibly – diabetes mellitus.

From the sensory organs: conjunctivitis; very rarely-visual impairment (including temporary blindness); possibly-tinnitus.

From the respiratory system: often-interstitial alveolitis / pneumonia, symptoms of potentially serious interstitial pneumonia (dry, unproductive cough, shortness of breath and fever); sometimes – pharyngitis; rarely – pulmonary fibrosis, pulmonary pneumocystis, pulmonary insufficiency and bronchial asthma; possibly – pleural effusion, nosebleeds.

From the urinary system: sometimes-inflammation and ulcerative lesions of the bladder, painful urination, hematuria, hyperuricemia, renal failure; rarely-severe renal failure, oliguria, anuria, azotemia.

From the genital system: less often-inflammation and ulcerative lesions of the vagina; very rarely-vaginal discharge, loss of sexual desire, impotence, oligospermia, menstrual disorders, infertility.

Musculoskeletal disorders: rarely-arthralgia, myalgia, osteoporosis, osteonecrosis, increased risk of fractures; possibly-soft tissue necrosis.

From the side of metabolism: increased sweating, hypogammaglobulinemia; rarely-electrolyte balance disorders.

Infections: possibly life-threatening opportunistic infections (including pneumocystis pneumonia), cytomegalovirus infections (CMV) (including CMV-pneumonia), sepsis (including fatal), nocardiosis, histoplasmosis, cryptococcosis, infections caused by Herpes zoster and Herpes simplex (including disseminated), deterioration of wound healing.

Neoplasms: in some cases – the appearance of lymphomas. In a recent study, methotrexate therapy was not found to increase the incidence of lymphomas.

Local reactions: when used in / m use – burning sensation at the injection site, formation of an aseptic abscess, destruction of adipose tissue.

The frequency and severity of side effects of methotrexate treatment depends on the dose and frequency of use. However, severe side effects can also occur when using methotrexate in low doses, so it is necessary that patients receiving methotrexate regularly undergo medical examinations at short intervals.

Interaction

Regular alcohol consumption and concomitant use of hepatotoxic drugs with methotrexate increase the risk of methotrexate hepatotoxicity. Patients using other hepatotoxic drugs (for example, leflunomide) should be carefully monitored. This also applies to cases of simultaneous use of drugs that inhibit hematopoiesis, which increases the risk of developing hematotoxicity of methotrexate. Concomitant use of leflunomide and methotrexate increases the risk of pancytopenia and hepatotoxicity.

Antibiotics such as penicillins, glycopeptides, ciprofloxacin, cephalotin, and sulfonamides can in some cases reduce the excretion of methotrexate by the kidneys, which leads to an increase in its concentration in plasma and, thus, to the risk of hematological and gastrointestinal toxicity.

Probenecid, weak organic acids (such as loop diuretics) and pyrazolone-type drugs (phenylbutazone) reduce the elimination of methotrexate and may lead to an increase in its concentration in plasma and, thus, to an increase in hematological toxicity.

The risk of increased toxicity occurs when methotrexate is combined with NSAIDs (since there may be a decrease in the excretion of methotrexate by the renal tubules) or salicylates. Caution is required with these combinations.

Concomitant use of salicylates, phenylbutazone, phenytoin, sulfonamides, derivatives of sulfonylureas, aminobenzoic acid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and lipid-lowering agents (colestyramine) increases toxicity by displacing methotrexate from the connection with albumins and/or reducing tubular activity. secretions, which in some cases can lead to the development of severe toxic effects, sometimes even with a fatal outcome.

When using drugs that can affect the bone marrow (including as a side effect) (for example, sulfonamides, trimethoprim, sulfamethoxazole, chloramphenicol, pyrimethamine), it is necessary to take into account the possibility of hematopoiesis suppression.

The combination of methotrexate with sulfasalazine may increase the effectiveness of methotrexate and, as a result, increase the side effects associated with the inhibition of folic acid synthesis by sulfasalazine. However, such side effects have only been observed in a few rare cases in a number of studies.

Concomitant use of proton pump inhibitors (omeprazole, pantoprazole) may alter the excretion of methotrexate. Concomitant use of methotrexate and omeprazole increases the elimination time of methotrexate. One case of decreased excretion of the methotrexate metabolite,7 – hydroxymethotrexate, was reported, which was accompanied by myalgia and trembling.

During treatment with methotrexate, avoid consuming large amounts of caffeinated (including coffee, tea) and theophylline-containing beverages. Methotrexate reduces theophylline clearance.

Concomitant use of drugs that can inhibit bone marrow hematopoiesis (for example, sulfonamides, trimethoprim, sulfamethoxazole) may lead to an increase in methotrexate toxicity. Therefore, it is recommended to take special care when prescribing such drugs in order to avoid the development of folic acid deficiency.

Folate-containing medications (including multivitamins) reduce the toxic effect of methotrexate on the bone marrow.

Methotrexate increases the anticoagulant activity of coumarin or indanedione derivatives and / or increases the risk of bleeding due to reduced synthesis of procoagulant factors in the liver and impaired platelet formation.

When treating patients with concomitant hyperuricemia and gout, it may be necessary to adjust the dose of an anti-gouty agent (allopurinol, colchicine, sulfinpyrazone).

Performing anesthesia using dinitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis.

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

Methotrexate can reduce the immune response to vaccination, so the interval between the use of methotrexate and the introduction of live and inactivated viral vaccines should be at least 3 months, possibly up to 12 months (depending on the patient’s immune status).

Pharmaceutical incompatibilities

Compatibility with other parenteral medications has not been studied.

Do not mix Metodject with other medicines and solvents.

How to take, course of use and dosage

Metodject is prescribed by subcutaneous injection, intravenous injection, or intravenous injection.

The injection needle included in the package is intended only for subcutaneous injection of Metodject. For intravenous and intravenous use of the drug, it is necessary to use needles suitable for these methods of use.

The drug is used once a week. The doctor determines the total duration of treatment individually.

The drug should be prescribed by a doctor who has experience with the use of methotrexate and knowledge of the properties of the drug and the features of its action.

For adults with rheumatoid arthritis, the recommended starting dose is 7.5 mg once a week in/m, iv or subcutaneous injection. Depending on the severity of the disease and tolerability of methotrexate, the dose can be gradually increased – 2.5 mg/week. The maximum dose is 25 mg / week. The therapeutic effect usually develops 4-8 weeks after the start of the drug. Once the optimal therapeutic effect is achieved, the dose should be reduced to the lowest effective maintenance dose. The duration of therapy with the drug may exceed 10 years.

For psoriasis and psoriatic arthritis, a week before the start of treatment, it is recommended to enter a parenteral test dose of 5-10 mg of methotrexate to detect intolerance reactions. The recommended starting dose is 7.5 mg 1 time / week in / m, iv or subcutaneous. The dose should be gradually increased. In most cases, the dose should not exceed 25 mg / week, but in any case, the maximum dose is 30 mg / week. The therapeutic effect usually develops 2-6 weeks after the start of the drug. Once the desired response is achieved, the dose should be reduced to the lowest effective maintenance dose.

In patients with renal insufficiency, Metodject should be used with caution. Correction of the dose of the drug depending on the creatinine clearance value is shown in the table.

Patients with hepatic insufficiency: in patients with severe liver diseases currently or in the anamnesis, especially caused by alcohol intake, Metodject should be used with great caution. Methotrexate is contraindicated in patients with bilirubin concentrations > 5 mg/dl (85.5 mmol/L).

In elderly patients, Metodject should be used with caution, often it is necessary to adjust the dose downward due to age-related decline in liver and kidney function, as well as a decrease in the folate reserve in the body.

In children under 16 years of age with polyarthritic juvenile chronic arthritis, the recommended dose of methotrexate is 10-15 mg / m2 of body surface area per week. If the treatment is not effective enough, the dose can be increased up to 20 mg / m%^%2 / week. Due to limited data on subcutaneous and intravenous use in children, the drug should be used intravenously for juvenile arthritis.

When switching from oral methotrexate to parenteral use, a dose reduction may be required due to differences in the bioavailability of the drug with different methods of use.

During therapy with Metodject, consideration should be given to concomitant use of folic acid preparations in accordance with existing treatment standards.

Overdose

Symptoms: the toxic effect of methotrexate is mainly manifested by the hematopoietic system.

Treatment: use of a specific antidote-folinic acid preparations (if possible immediately) to neutralize the toxic effects of methotrexate. In case of accidental overdose – within the first hour after use of methotrexate, a specific antidote – folinic acid-should be administered intravenously or intramuscularly at a dose equal to or exceeding the dose of methotrexate.Further, as necessary, the use of folinic acid preparations should be continued until the concentration of methotrexate in the blood serum is below 10-7 mol/l.

In case of a significant overdose, the body is hydrated and urine is alkalinized to prevent precipitation of methotrexate and/or its metabolites in the renal tubules, which accelerates the elimination of methotrexate. Hemodialysis and peritoneal dialysis do not accelerate the elimination of methotrexate. The effectiveness of intermittent (periodic) hemodialysis using a high-speed dialysis machine has been reported.

Special instructions

Patients should be clearly informed that the drug should be used once a week, and not daily.

Methotrexate is cytotoxic, so caution should be exercised when handling it.

Patients undergoing Metodject therapy should be properly monitored so that signs of possible toxic effects and adverse reactions are identified and evaluated with minimal delay.

Due to the potential for severe or even fatal adverse reactions, patients should be fully informed by their doctor about the possible risks and recommended safety measures.

Recommended research and safety measures

Before starting or resuming treatment with methotrexate, it is necessary to perform a complete general blood test to determine the level of platelets; a biochemical blood test to determine the activity of liver enzymes, bilirubin concentration, serum albumin; X-ray examination of the chest, study of kidney function. If necessary, perform tests for tuberculosis and hepatitis.

During treatment (at least once a month for the first 6 months of treatment, then at least once every 2 months), the following studies should be conducted:

1. Examination of the oral and pharyngeal mucosa.

2. Complete general blood test with platelet count determination. Suppression of hematopoiesis caused by methotrexate may occur suddenly, including when using the drug in small doses. In any case of a significant decrease in the number of white blood cells or platelets, treatment with methotrexate should be stopped immediately and adequate maintenance therapy should be provided. Patients should be advised to report any signs and symptoms of possible infections. Patients receiving concomitant medications that inhibit hematopoiesis (such as leflunomide) should be carefully monitored for blood counts and platelet counts.

3. Study of liver function. Special attention should be paid to identifying possible toxic effects on the liver. Treatment should not be initiated or interrupted if liver function disorders that were present before the start of treatment or developed during treatment are detected during appropriate examinations. Usually, the disorders that developed during treatment return to normal within 2 weeks after the interruption of methotrexate therapy, after which, at the discretion of the attending physician, treatment can be resumed.

When using methotrexate in rheumatoid arthritis, there is no obvious need for a liver biopsy to control liver toxicity. Special attention should be paid to patients with risk factors such as excessive alcohol consumption, persistent increase in liver enzyme activity, a history of liver disease, diabetes mellitus, obesity, the use of hepatotoxic drugs or drugs that affect hematopoiesis in the anamnesis.

Control of liver enzymes in blood serum: in 13-20% of patients, a transient 2-3-fold excess of normal transaminase values was reported. In the event of a sustained increase in liver enzyme activity, dose reduction or discontinuation of treatment should be considered.

Due to the toxic effects of the drug on the liver, patients should refrain from concomitant use of other hepatotoxic drugs during treatment, except in cases of obvious necessity; alcohol consumption should also be avoided.

In patients using other hepatotoxic drugs or drugs that inhibit hematopoiesis (for example, leflunomide), the activity of liver enzymes and indicators of a general blood test with determination of the number of platelets should be carefully monitored.

4. Monitoring of renal function and urinalysis. Since methotrexate is mainly excreted by the kidneys, in case of renal insufficiency, an increase in the concentration of methotrexate in plasma should be expected, which can lead to serious undesirable side effects. In cases of possible decline in renal function (for example, in elderly patients), follow-up examinations should be performed more frequently. This also applies in cases of simultaneous use of drugs that affect the elimination of methotrexate, drugs that can lead to kidney damage (for example, NSAIDs), as well as drugs that can affect the hematopoietic system. Dehydration can also increase the toxicity of methotrexate.

5. Examination of the respiratory system. Special attention should be paid to symptoms of worsening lung function, and appropriate tests should be performed if necessary. Symptoms of respiratory damage (especially dry, unproductive cough), non-specific pneumonitis that occur during methotrexate therapy may indicate a potentially dangerous disease and require discontinuation of treatment and a thorough examination in order to make a diagnosis. The clinical symptoms of methotrexate-induced lung damage are diverse, but typical signs are fever, cough, difficulty breathing, and hypoxemia. An X-ray examination of the chest is mandatory to rule out the presence of infiltrates or infection. The possibility of respiratory diseases caused by the use of methotrexate does not depend on the doses of the drug used.

If the dose of methotrexate is increased, the frequency of examinations should be increased.

Methotrexate affects the immune system, can worsen the response to vaccination and affect the results of immunological tests. Special care is required when using the drug in patients with chronic infectious diseases outside of acute periods (Herpes zoster, tuberculosis, hepatitis B or C) due to the possibility of exacerbation of the disease. It is necessary to refuse immunization. The interval between the use of methotrexate and the use of live and inactivated viral vaccines should be at least 3 months, possibly up to 12 months (depending on the patient’s immune status).

If diarrhea and ulcerative stomatitis develop, methotrexate therapy should be discontinued.

Do not expose unprotected skin to too much sun exposure or ultraviolet radiation (photosensitization reaction is possible).

Patients receiving low-dose methotrexate may develop malignant lymphoma; in these cases, treatment should be discontinued. In the absence of signs of spontaneous regression of lymphoma, cytotoxic therapy is necessary.

When using methotrexate, osteonecrosis and osteoporosis may develop (with a frequency of ≥ 1/1000,

It exhibits mutagenic activity in vivo and in vitro. A rodent carcinogenicity study did not show an increase in the incidence of tumors when using methotrexate.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

Since methotrexate can have an effect on the central nervous system (fatigue, dizziness), the patient should refrain from driving and working with mechanisms during treatment.

Combination with radiation therapy may increase the risk of bone marrow suppression.

Patients using low-dose methotrexate may develop malignant lymphomas; in these cases, treatment should be discontinued. In the absence of signs of spontaneous regression of lymphoma, cytotoxic therapy is necessary.

When using methotrexate, osteonecrosis and osteoporosis may develop (≥1/1000,

Influence on the ability to drive a car or perform work that requires an increased rate of physical and mental reactions. Since methotrexate can have an effect on the central nervous system (fatigue, dizziness), patients using the drug should refrain from driving and using mechanisms.

Product form

solution for injection

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 25 °C

Shelf life

2 years

Active ingredient

Methotrexate

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

For adults as directed by your doctor

Indications

Rheumatoid Arthritis