Metoject, 50 mg/ml 0.35 ml

Antitumor agent from the group of antimetabolites – folic acid antagonists. Acts in the S-phase of mitosis. The mechanism of action is associated with inhibition of synthesis of purine nucleotides and thymidylate as a result of irreversible binding with dihydrofolate reductase, which prevents reduction of dihydrofolate into active tetrahydrofolate. More active against rapidly growing cells. Has some immunosuppressive effect.

Indications

Acute lymph leukemia, trophoblastic disease, skin cancer, cervical and vulvar cancer, esophageal cancer, squamous cell head and neck cancer, renal pelvis and urothelial cancer, osteogenic and soft cell sarcoma, Ewing’s sarcoma, lung cancer, breast cancer, testicular and ovarian germ cell tumors, liver cancer, kidney cancer, retinoblastoma, medulloblastoma, penile cancer, and lymphogranulematosis.

Severe forms of psoriasis (in case of ineffectiveness of standard therapy).

The severe form of rheumatoid arthritis (in case of ineffectiveness of standard therapy).

Active ingredient

Composition

How to take, the dosage

The needle should be inserted vertically (not laterally) into the full length skin fold, gathered and held between the thumb and forefinger until the injection is complete. The skin fold, release only after the injection is completed. The injection site should not be massaged after the injection.

The pre-filled disposable syringe is ready for use.

The product must not be injected intramuscularly!

Prevention of venous thrombosis and embolism in surgical procedures, especially orthopedic and general surgical procedures

In patients with a moderate risk of thrombosis and embolism (general surgical procedures), the recommended dose of the drug is 20 mg once daily subcutaneously. The first injection is given 2 hours before the surgical intervention.

In patients with high risk of thrombosis and embolism (general surgical and orthopedic operations), the drug is recommended in a dose of 40 mg once daily subcutaneously; the first dose is given 12 hours before surgical intervention, or 30 mg 2 times daily with the beginning of the injection 12-24 hours after surgery.

The peculiarities of the drug administration during spinal/epidural anesthesia as well as during percutaneous coronary angioplasty are described in section “Special indications”.

Prevention of venous thrombosis and embolism in bedridden patients due to acute medical conditions

The recommended dose of enoxaparin sodium is 40 mg once daily subcutaneously for 6 to 14 days.

The treatment of deep vein thrombosis with or without pulmonary embolism

Enixum® is administered subcutaneously at a rate of 1.5 mg/kg once daily or at a dose of 1 mg/kg twice daily. In patients with complicated thromboembolic disorders the drug is recommended in a dose of 1 mg/kg twice daily.

The duration of treatment is on average 10 days. It is advisable to initiate therapy with oral anticoagulants immediately, while therapy with sodium enoxaparin should be continued until sufficient anticoagulant effect is achieved, i.e. INR should be 2.0-3.0. If necessary, control of anticoagulant effect should be assessed by anti-Xa activity.

The treatment of unstable angina and myocardial infarction without Q-wave in combination with acetylsalicylic acid

Enixum® is administered at a rate of 1 mg/kg body weight every 12 h subcutaneously, while acetylsalicylic acid is given simultaneously in an oral dose of 100-325 mg once daily.

The average duration of treatment is 2-8 days (until the patient’s clinical condition stabilizes).

Treatment of myocardial infarction with ST-segment elevation, medication or by percutaneous coronary intervention

. Treatment begins with an intravenous bolus injection of 30 mg of enoxaparin sodium and is immediately followed (within 15 minutes) by a subcutaneous dose of 1 mg/kg (with a maximum of 100 mg of enoxaparin sodium in the first two subcutaneous injections). Thereafter, all subsequent subcutaneous doses are administered every 12 hours at a rate of 1 mg/kg (i.e., if body weight exceeds 100 kg, the dose may exceed 100 mg).

For 30 mg bolus injection of enoxaparin sodium in the treatment of acute ST-segment elevation myocardial infarction, the 60 mg, 80 mg, and 100 mg glass syringes are discarded so that only 30 mg (0.3 ml) remains. The 30 mg dose can be given directly intravenously.

Pre-filled 60 mg, 80 mg and 100 mg hypodermic syringes may be used for intravenous bolus injection of enoxaparin sodium via a venous catheter. The 60 mg syringe is recommended because it reduces the amount of drug removed from the syringe. The 20 mg syringe is not used because it does not contain enough preparation for a 30 mg bolus of enoxaparin sodium. The 40 mg syringe is not used because it has no graduations and therefore cannot accurately measure the 30 mg.

In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection of sodium enoxaparin was given less than 8 hours before the balloon catheter inserted into the coronary artery constriction was inflated, no additional injection of sodium enoxaparin is required. If the last subcutaneous injection of sodium enoxaparin was given more than 8 hours before the balloon catheter was inflated, an intravenous additional bolus injection of sodium enoxaparin at a dose of 0.3 mg/kg should be given.

In order to improve the accuracy of additional bolus injection of small volumes into the venous catheter during percutaneous coronary interventions, it is recommended to dilute the drug to a concentration of 3 mg/ml. Dilution of the solution is recommended immediately prior to administration.

To obtain a 3 mg/ml solution of enoxaparin sodium using a pre-filled syringe, it is recommended to use a container with infusion solution from which a portion of the solution is extracted to the desired volume using a normal syringe. Enoxaparin sodium (the contents of the hypodermic syringe) is injected into the remaining infusion solution in the container.

The volume of the pre-filled syringe

The amount of infusion solution left in the container

0.3 ml

10 ml

0.6 ml

20 ml

The contents of the container with the diluted enoxaparin sodium solution are mixed gently. A syringe is used to extract the desired volume of diluted enoxaparin sodium solution, which is calculated according to the formula:

Volume of diluted solution = Patient body weight (kg) x 0.1 or using the table below.

Volumes to be administered intravenously after dilution

Patient body weight (kg)

Required dose (0.3 mg/kg) [mg]

45

13.5

4.5

50

15

5

55

16.5

5.5

1.5 mg subcutaneously once daily

1 mg/kg subcutaneously once daily

Treatment of acute ST-segment elevation myocardial infarction in patients <75 years old

Once: 30 mg bolus intravenous injection plus 1 mg/kg subcutaneously; followed by a subcutaneous injection of 1 mg/kg twice daily (maximum 100 mg for each of the first two subcutaneous injections)

Once: 30 mg bolus intravenous injection plus 1 mg/kg subcutaneously; followed by a subcutaneous injection of 1 mg/kg once daily (maximum

100 mg for the first subcutaneous injection)

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Treatment of acute myocardial infarction with ST-segment elevation in patients >75 years old

0.75 mg/kg subcutaneously 1 mg/kg subcutaneously twice daily without initial bolus injection (maximum 75 mg for each of the first two subcutaneous injections)

1 mg/kg subcutaneously once daily without initial bolus injection (maximum 100 mg for the first subcutaneous injection)

The following dosing adjustment is recommended when using the drug for prophylactic purposes

The usual dosing regimen

The dosing regimen for severe renal failure

40 mg subcutaneously once daily

20 mg subcutaneously once daily

20 mg subcutaneously once daily

20 mg subcutaneously once daily

The recommended dosing adjustment is not applicable for hemodialysis.

In mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal failure, no dose adjustment is required, but more careful laboratory monitoring of therapy should be performed.

Patients with hepatic impairment

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 the GI tract 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 there may be 3-4 times increased plasma concentration of methotrexate 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.

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

Special Instructions

Methotrexate should not be used in patients with ascites, pleural effusion, gastric and duodenal ulcers, ulcerative colitis, gout or nephropathy (including a history).

The use is not recommended in patients with varicella zoster (including those who have recently had it or have had exposure to it), herpes zoster and other acute infectious diseases.

Peripheral blood count, liver and kidney function and chest x-rays should be monitored before and during therapy.

When treating rheumatoid arthritis or psoriasis a detailed general blood test should be performed at least once a month, and laboratory tests of liver or kidney function at least once every 1-2 months.

When used for psoriasis, local treatment of the disease should not be interrupted. In case of overdose, the use of calcium folinate is recommended (but not later than 4 hours).

Particular caution should be exercised when concomitant use of methotrexate in high doses with drugs that have nephrotoxic effects (e.g., cisplatin) in combination antitumor therapy.

Vaccination of patients and family members is not recommended.

With caution, methotrexate should be combined (even in low doses) with acetylsalicylic acid.

The carcinogenic and mutagenic effects of methotrexate have been established in experimental studies.

Contraindications

Side effects

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.

Hematopoietic system: leukopenia, anemia, thrombocytopenia.

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

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

Urinary system disorders: hematuria, cystitis, marked renal dysfunction.

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

Dermatological reactions: skin rash, photosensitization, pigmentation disorders, telangiectasia, acne, furunculosis.

Overdose

Symptoms: hemorrhagic complications of accidental overdose during subcutaneous injection of enoxaparin sodium. In case of accidental ingestion of even large doses, absorption of the drug is unlikely.

Treatment: neutralize the effect of enoxaparin sodium by slow intravenous (IV) administration of protamine sulfate. 1 mg of protamine sulfate will neutralize the anticoagulant effect of 1 mg of enoxaparin sodium if the drug is administered no more than 8 hours before administration of protamine sulfate.

The 0.5 mg of protamine sulfate will neutralize the anticoagulant effect of 1 mg of enoxaparin sodium if administered more than 8 h before or if a second dose of protamine sulfate must be administered.

If, however, 12 hours or more have elapsed since the administration of enoxaparin sodium, administration of protamine sulfate is not necessary. However, even when large doses of protamine sulfate are administered, the anti-Xa activity of sodium enoxaparin is not completely neutralized (maximum 60%).

Similarities