Instruction for use: Metoject

Dosage form: Injection for injection; Solution for subcutaneous administration

Active substance: Methotrexatum

ATX

L01BA01 Methotrexate

Pharmacological group:

Immunodepressants

The nosological classification (ICD-10)

L40 Psoriasis: Chronic plaque psoriasis with diffuse; generalized psoriasis; Psoriasis of the scalp; hairy parts of the skin; A generalized form of psoriasis; Psoriazoformny dermatitis; Psoriasis complicated with erythroderma; disabling psoriasis; Isolated psoriatic plaque; Eksfolliativny psoriasis; psoriatic erythroderma; Psoriasis with eczematization; Hyperkeratosis in psoriasis; Inverse psoriasis; Psoriasis ekzemopodobnye; dermatoses psoriazoformny; Psoriasis genitals; Psoriasis lesions with hairy areas of the skin; erythrodermic psoriasis; Chronic psoriasis of the scalp; Chronic psoriasis; ordinary psoriasis; refractory psoriasis; Koebner phenomenon; psoriasis

M06.9 Rheumatoid arthritis, unspecified: Rheumatoid arthritis; Pain syndrome in rheumatic diseases; Pain in rheumatoid arthritis; Inflammation in rheumatoid arthritis; Degenerative forms of rheumatoid arthritis; Children's rheumatoid arthritis; Exacerbation of rheumatoid arthritis; Acute articular rheumatism; Rheumatic arthritis; Rheumatic polyarthritis; Rheumatoid arthritis; Rheumatic polyarthritis; Rheumatoid arthritis; Rheumatoid arthritis; Rheumatoid arthritis of active course; Rheumatoid periarthritis; Rheumatoid polyarthritis; Acute rheumatoid arthritis; Acute rheumatism

M07.3 Other psoriatic arthropathies (L40.5 +): Psoriatic arthritis; Generalized form of psoriatic arthritis; Psoriatic arthritis

M08 Juvenile [juvenile] arthritis: Juvenile arthritis; Juvenile chronic polyarthritis; Juvenile chronic arthritis; Juvenile rheumatoid arthritis; Arthritis Juvenile chronic

M13 Other arthritis

Composition

Solution for subcutaneous administration 1 ml

active substance: Methotrexate disodium 54.84 mg

(Equivalent to 50 mg of methotrexate)

Prepared by the prescription: methotrexate - 50 mg; Sodium hydroxide 9.6 mg

Auxiliary substances: sodium chloride - 4 mg; Sodium hydroxide - q.s. (Up to pH 8.5-8.9), water for injection - up to 1 ml

Description of dosage form

Solution: transparent liquid from yellow to yellow-brown color.

Pharmachologic effect

Mode of action - Antitumor, immunosuppressive.

Pharmacodynamics

Antagonist of folic acid, cytotoxic drug - antimetabolite. Competitively inhibits the enzyme dihydrofolate reductase, 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), and thus inhibits DNA synthesis.

Along with the antitumor has an immunosuppressive effect.

It remains unclear what is the effectiveness of methotrexate in the treatment of psoriasis, psoriatic arthritis and rheumatoid arthritis (including juvenile chronic arthritis): its anti-inflammatory or immunosuppressive effect. Also, it is not established to what extent the effectiveness of therapy is explained by the increase in extracellular adenosine concentration caused by methotrexate in places of inflammation.

Pharmacokinetics

Bioavailability for SC, IM and IV the introduction has close values and is almost 100%.

About 50% of methotrexate binds to plasma proteins.

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

When used in small doses penetrates into the cerebrospinal fluid in a minimal amount.

T1 / 2 averages 6-7 hours and is characterized by high variability (3-17 hours). Half-life in patients with additional Vd (the presence of pleural effusion, ascites) may increase to values four times higher than the mean values.

About 10% of the administered dose is metabolized in the liver, the main metabolite is 7-hydroxymethotrexate, which also has pharmacological activity. It is excreted mostly unchanged in kidneys by glomerular filtration and tubular secretion.

About 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate is excreted with bile (followed by significant reabsorption in the intestine).

Removal of the drug in patients with impaired renal function is significantly slowed down. There is no evidence of a delay in excretion of methotrexate with insufficient liver function.

Indication of the drug Metoject

Rheumatoid arthritis in active form in adult patients;

Polyarthritis in patients with severe juvenile chronic arthritis in active form, not giving an adequate response to NSAID therapy;

Severe persistent disabling forms of psoriasis in adult patients not responding to conventional therapy, including phototherapy, PUVA therapy, retinoic therapy;

Severe forms of psoriatic arthritis in adult patients.

Contraindications

Hypersensitivity to methotrexate or other components of the drug;

Hepatic insufficiency (see "Method of administration and dose");

alcoholism;

Marked renal failure (Cl creatinine <20 ml / min, see "Method of administration and dose");

Haemorrhage in the anamnesis, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, severe anemia;

Severe acute or chronic infectious diseases, such as tuberculosis, HIV infection;

Severe immunodeficiency;

Oral ulcers;

Gastric ulcer in active phase;

pregnancy;

The period of breastfeeding;

Simultaneous vaccination with live vaccines.

Application in pregnancy and breastfeeding

Contraindicated in pregnancy and during breastfeeding.

When used in humans, methotrexate has shown teratogenic properties; Reported on methotrexate-induced fetal death, congenital malformations.

Limited use in pregnant women (42) led to an increase in the frequency (1:14) of malformations (cranial, cardiovascular, extremities). In cases of interruption of methotrexate therapy, the normal course of pregnancy was observed before fertilization.

Women during treatment with methotrexate should refrain from pregnancy.

In the event that a woman becomes pregnant during methotrexate therapy, an assessment should be made of the risk of adverse effects of treatment on the fetus.

Patients of childbearing age of both sexes should be provided with reliable contraceptive measures during the course of treatment with Metoject® and, at least 6 months after the end of treatment.

Prior to the initiation of therapy with the drug Metoject® in women of childbearing age, a reliable pregnancy test should be conducted to exclude the possibility of treatment in pregnant women.

Because methotrexate can have genotoxic effect, it is recommended that women planning a pregnancy be consulted by a geneticist, and, if possible, even before the start of therapy; Men are encouraged to consider the possibility of preserving sperm before starting treatment.

Methotrexate is excreted in breast milk in quantities that are dangerous to the baby, so before starting methotrexate, breastfeeding should be discontinued and refrained from it throughout the course of treatment.

Side effects

The most frequent side effects with the use of the preparation method are reactions from the hemopoietic system and the gastrointestinal tract.

To indicate the frequency of the effects, the following gradations are used: very often (≥1 / 10); Often (≥1 / 100, <1/10); Infrequently (≥1 / 1000, <1/100); Rarely (≥1 / 10000, <1/1000); Very rarely (<1/10000), the frequency is unknown (cannot be estimated based on available data).

From the gastrointestinal tract: very often - stomatitis, dyspepsia, nausea, loss of appetite; Often - ulcers in the mouth, diarrhea; Infrequently - pharyngitis, enteritis, vomiting; Rarely - erosive-ulcerative lesions of the gastrointestinal tract; Very rarely - hematemesis, bleeding from the gastrointestinal tract, toxic megacolon.

On the part of the liver: very often - an increase in the level of transaminases; Infrequently - cirrhosis, fibrosis and fatty degeneration of the liver, hepatotoxicity (acute hepatitis, hepatic insufficiency).

From the skin and skin appendages: often - exanthema, erythema, pruritus; Infrequently - photosensitization, alopecia, increased rheumatic nodes, vasculitis, herpes zoster, herpetiform rashes on the skin, urticaria; Rarely - increased pigmentation, acne, ecchymosis; Very rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), changes in pigmentation of nails, acute paronychia, furunculosis, telangiectasia ..

General reactions and reactions at the site of administration: allergic reactions up to anaphylactic shock; Allergic vasculitis, fever, development of infections, sepsis, deterioration of wound healing, hypogammaglobulinemia; Very rarely - local reactions at the site of administration: damage to the skin and surrounding tissues (sterile abscess, lipodystrophy).

Metabolic disorders: infrequent - the progression of diabetes.

From the nervous system: often - headache, fatigue, drowsiness; Infrequently - dizziness, a sense of confusion, depression; Very rarely - pain, muscle weakness or paresthesia of the extremities, a violation of taste sensations (metallic taste), visual impairment, convulsions, meningism, paralysis; Frequency is unknown - leukoencephalopathy ..

From the side of the organ of vision: rarely - conjunctivitis; Impaired vision; Very rarely - retinopathy.

From the hepatobiliary system: very often - an increase in the level of transaminases; Infrequently - cirrhosis, fibrosis and fatty degeneration of the liver, a decrease in the concentration of serum albumin; Rarely acute hepatitis; Very rarely liver failure.

From the CVS side: rarely - pericarditis, pericardial effusion, pericardial tamponade, lowering of blood pressure, thromboembolic complications.

On the part of the respiratory system: often - pneumonia, interstitial alveolitis / pneumonitis, often accompanied by eosinophilia, symptoms of potentially serious interstitial pneumonitis - dry, unproductive cough, shortness of breath and fever; Rarely - pulmonary fibrosis, pneumonia caused by Pneumocystis carinii, respiratory failure and bronchial asthma, pleural effusion.

From the hemopoietic system and lymphatic system: often - leukopenia, anemia, thrombocytopenia; Infrequently - pancytopenia; Very rarely - agranulocytosis, severe oppression of bone marrow function.

From the genitourinary and urinary systems: infrequently - inflammation and ulceration of the bladder and / or vagina, impaired renal function, impaired urination; Rarely - renal failure, oliguria, anuria, electrolyte imbalance; Very rarely - vaginal discharge, loss of sexual desire, gynecomastia, impotence, oligospermia, menstrual irregularities.

From the musculoskeletal system: infrequently - arthralgia, myalgia, osteoporosis.

Neoplasm: very rarely - individual cases of lymphomas have been reported, some of which have regressed after discontinuation of methotrexate therapy. In a recent study, it has not been established that methotrexate therapy increases the risk of lymphomas. The frequency and severity of the side effects of methotrexate treatment depends on the dose and frequency of the drug. However, severe side effects may occur with low-dose methotrexate, so patients requiring methotrexate should undergo regular medical examinations at short intervals at regular intervals.

When using sc methotrexate shows a good local tolerance: with this method of administration, only mild skin reactions were observed, the severity of which decreased during the therapy.

Interaction

Alcohol, hepatotoxic and hematotoxic drugs. Regular use of alcohol and the use of simultaneously with methotrexate hepatotoxic drugs increase the risk of manifestation of hepatotoxicity of the drug. For patients using other hepatotoxic drugs (eg leflunomide), careful monitoring is necessary. This also applies to the simultaneous administration of hematotoxic drugs (such as leflunomide, azathioprine, retinoids, sulfasalazine), which increases the risk of methotrexate hematotoxicity. With the simultaneous administration of leflunomide and methotrexate, the risk of pancytopenia and hepatotoxicity increases.

With the simultaneous use of retinoids with methotrexate (such as acitretin, etretinate), the risk of hepatotoxicity increases.

Such antibiotics as penicillins, glycopeptides, sulfonamides, ciprofloxacin, cephalothin, in some cases can reduce the excretion of methotrexate by the kidneys, which leads to an increase in its concentration in the plasma and, thus, to the risk of manifestations of hematologic and gastrointestinal toxicity.

Antibiotics used inside. When administered orally, antibiotics such as tetracyclines, chloramphenicol, nonabsorbable broad-spectrum antibiotics, can affect enterohepatic circulation of methotrexate due to oppression of the intestinal flora or suppression of bacterial metabolism.

Preparations that bind well to plasma proteins. Methotrexate binds to plasma proteins, and bound methotrexate can be replaced by other drugs that bind well to proteins (such as salicylates, hypoglycemic drugs, diuretics, sulfonamides, diphenylhydantoin (phenytoin, diphenin), tetracyclines, chloramphenicol, aminobenzoic acid, anti-inflammatory drugs) If used concomitantly, may increase the toxicity of methotrexate.

Probenecid, weak organic acids, preparations of pyrazolone series and other NSAIDs. Probenecid, weak organic acids (such as loop diuretics) and preparations of pyrazolone series (phenylbutazone) can reduce the excretion of methotrexate and, consequently, increase its concentration in the plasma, which can lead to an increase in hematological toxicity. The risk of increased toxicity occurs with the combination of even low doses of methotrexate and non-steroidal anti-inflammatory drugs or salicylates.

Drugs affecting the bone marrow. In the case of drugs that can affect the bone marrow (including as a side effect) (for example, sulfonamides, trimethoprim, sulfamethoxazole, chloramphenicol, pyrimethamine), the possibility of pronounced oppression of hematopoiesis should be considered.

Preparations that can cause folate deficiency. Simultaneous administration of such drugs (eg, sulfonamides, trimethoprim, sulfamethoxazole) may lead to an increase in the toxicity of methotrexate. Therefore, it is recommended that special care be taken when folic acid is deficient.

Folat containing drugs. Vitamin preparations and other preparations containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

Antirheumatic drugs. As a rule, with the simultaneous use of methotrexate with other antirheumatic drugs (such as gold preparations, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine), the toxic effect of methotrexate is not increased.

Sulfasalazine. The combination of methotrexate with sulfasalazine can increase the effectiveness of methotrexate and, as a result, enhance the side effects associated with the suppression of sulfasalazine synthesis of folic acid. However, such side effects were observed only in a few rare cases in several studies.

Mercaptopurine. Methotrexate increases the concentration of mercaptopurine in the plasma, therefore, simultaneous use of methotrexate and mercaptopurine may require dose adjustment.

With the simultaneous administration of proton pump inhibitors (such as omeprazole, pantoprazole), the excretion of methotrexate may change. The simultaneous use of methotrexate and omeprazole led to an increase in the time to excrete methotrexate. One case of decreasing the excretion of methotrexate metabolite, 7-hydroxymethotrexate, was reported, which was accompanied by myalgia and tremor, with simultaneous use of methotrexate and pantoprazole.

Theophylline. Methotrexate is able to reduce the clearance of theophylline. At simultaneous appointment of methotrexate and theophylline it is necessary to control the level of theophylline in plasma.

Caffeine and theophylline-containing beverages. During treatment with methotrexate, you should avoid consuming large quantities of beverages containing caffeine and theophylline (including coffee, tea, caffeine-containing soft drinks).

Dosing and Administration

SC.

The needle is integrated into the syringe and is intended only for the administration of the preparation Metoject®.

Metoject® should not be confused with other drugs.

The drug should be appointed by a doctor who has experience of use and is familiar with the properties of methotrexate and the characteristics of its action.

The drug is intended for single use only.

Methodic® is used once a week. The patient should be clearly informed about a single weekly mode of administration. It is recommended to assign a specific day of the week for the introduction.

In patients with additional Vd (the presence of ascites, pleural effusion), the rate of excretion of methotrexate from the body is reduced. In such patients, it is necessary to carefully control toxicity, reduce the dose of the drug, and in some cases, discontinue treatment.

Adult patients with rheumatoid arthritis: the recommended initial dose is 7.5 mg methotrexate once a week SC. Depending on the activity of the disease and the tolerability of methotrexate, patients may be gradually increased (2.5 mg / week). The maximum dose for the treatment of rheumatoid arthritis, as a rule, should not exceed 25 mg / week. In this case, increasing the dose of methotrexate to values above 20 mg / week may be accompanied by a significant increase in toxicity, primarily by suppression of bone marrow function. The answer to treatment usually comes in 4-8 weeks after the start of the drug. After achieving the desired response, a gradual dose reduction to the lowest effective maintenance dose should be started.

Children under 16 years of age with a polyarthritic form of juvenile chronic arthritis. The recommended dose is 10-15 mg / m 2 once a week. In case of insufficient effectiveness of treatment, the dose can be increased up to 20 mg / m2 once a week. With an increase in the administered dose, it is necessary to increase the frequency of the patient's examinations.

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

Patients with 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 identify possible intolerance reactions.

The recommended initial dose is 7.5 mg of methotrexate once a week. The dose should be gradually increased, while the maximum dose should not exceed 25 mg / week of methotrexate. The use of doses above 20 mg / week may be accompanied by a significant increase in toxicity, primarily by suppression of bone marrow function.

The answer to treatment usually comes in 2-6 weeks after the start of the drug. After achieving the desired response, the dose should be gradually reduced to the lowest effective maintenance dose.

In exceptional cases, when clinically justified, doses above 25 mg may be used, but in all cases not more than 30 mg / week due to a sharp increase in toxicity.

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

Special patient groups

Renal insufficiency. Methodic® should be used with caution. The dose, depending on the value of creatinine clearance, should be adjusted according to the following table.

Violation of the function of the liver. In patients with severe liver disease, currently or in history, especially those associated with alcohol intake, Methodject®, when appropriate, should be used with great caution. At a concentration of bilirubin> 5 mg / dl (85.5 μmol / L) methotrexate is contraindicated.

Elderly patients. The drug should be used with caution, the need to adjust the dose downwards due to the age-related decline in liver and kidney function, as well as a decrease in the folate reserve in the body, should be evaluated.

Patients with additional Vd (presence of pleural effusion, ascites). This group may increase the half-life to four times the normal values, which may require a reduction in the dose of the drug, and in some cases - the withdrawal of methotrexate (see "Special instructions" and "Pharmacokinetics").

Notes

In each case, the duration of treatment is determined by the doctor; The total duration of use of the drug may exceed 10 years.

In the transition from methotrexate administration to the parenteral route of administration, it may be advantageous to reduce the dose due to the possible difference in bioavailability of the drug when administered orally and parenterally.

When taking methotrexate therapy, the concomitant use of folic acid preparations should be considered in accordance with existing treatment standards.

The use of the preparation Metoject® is carried out under the supervision of a doctor.

By his decision, the drug can be used by patients independently. In this case, the patient must be trained by the doctor before applying the drug to the technique of performing SC injections. In any case, the first independent use of the drug by the patient should be conducted in the presence of a physician.

If the first signs of adverse events appear, the patient should inform the attending physician without delay.

Method of drug administration

When using the preparation Metoject®, it is necessary to comply with standard hygiene and aseptic requirements. Before using the drug, you should thoroughly wash your hands.

1. Make sure the correct dosage is selected. Check the shelf life of the product on the package. Open the package containing the blister with a filled syringe with the drug.

2. Open the blister containing the syringe with the drug, holding the plastic part of the blister, with one hand and separating the paper cover with the other hand.

Before use, it is necessary to inspect the solution of the drug in a syringe to ensure that there are no foreign particles in it. The preparation containing foreign particles cannot be used. Place the syringe with the drug on a clean surface.

A special polymeric color nozzle ("wings") is attached to the flange of the syringe body, which increases the convenience of holding the syringe with fingers and, thus, facilitates the injection. Do not remove these "wings" from the syringe

3. Choose a site for injection:

- on the abdomen, at a distance of at least 5 cm around the navel and not above the level of the lower rib,

- on the thigh, the width of the palm below the inguinal fold and above the knee.

Do not administer the drug to a place where there is soreness, tightness, redness, dermal damage or bruising.

4. Treat the injection site with a special disinfectant wipe or a pad moistened with 70% ethanol solution. Wait 30 seconds before the injection.

5. Remove the protective cap from the needle, pulling and simultaneously turning it. Do not touch the sterile needle.

6. Form a fold of the skin with a thumb and forefinger. Fully insert the needle under the skin at an angle of 90 °. The preparation should be administered in a sitting or lying position, but not standing up.

7. Introduce the entire volume of the drug from the syringe slowly and evenly, keeping the skin fold between the fingers. When the entire preparation is inserted, remove the needle at the same angle as when injected.

8. Apply a sterile gauze dressing or a sterile swab to the injection site. Do not rub the injection site; This can cause irritation. If necessary, apply adhesive plaster.

9. Place the used syringe and the previously removed protective cap in a waste container made of plastic or glass, with a lid.

Dispose of used materials so that children and other persons do not accidentally contact them.

During the course of therapy, do not inject in the same place. It is necessary to change places for each subsequent injection (every week).

Precautions for use

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

Patients undergoing therapy with Metoject® should be properly monitored so that signs of possible toxic effects and adverse reactions are identified and evaluated without delay.

Metoject® should be prescribed only by a specialist doctor who has sufficient knowledge and experience in antimetabolic therapy.

In view of the possible development of severe or even fatal adverse reactions, patients should be fully informed by the doctor about possible risks and safety measures.

The use of the drug in children under 3 years is not recommended because of the lack of data on the efficacy and safety of treatment of this group of patients.

Recommended examinations and safety measures

Before starting or resuming treatment with methotrexate, a detailed clinical blood count should be performed to count blood cells, including the determination of the number of platelets; Biochemical blood test with determination of liver enzymes activity, bilirubin concentration, serum albumin; X-ray examination of the chest, examination of the kidney function. If necessary, diagnostic measures to assess the activity of tuberculosis infection and viral hepatitis.

During the treatment (at least once a month in the first 6 months of treatment, then - at least 1 time in 3 months), it is necessary to carry out the studies described below. If the dose of methotrexate is increased, the frequency of the examinations should be increased.

1. Examination of the oral and pharyngeal mucosa to assess the mucosal status (stomatitis, pharyngitis).

2. A detailed clinical analysis of blood with the counting of blood elements, including the determination of the number of platelets. Suppression of hematopoiesis caused by methotrexate can occur suddenly, incl. when using the drug in small doses. In any case, a significant reduction in the number of white blood cells or platelets should immediately stop treatment with methotrexate and conduct adequate maintenance therapy. Patients should be advised to report any signs and symptoms of possible infections. Patients who simultaneously use drugs that depress hemopoiesis (eg leflunomide) should be carefully observed with control of the blood cell counts, including the number of platelets.

Liver function tests. Particular attention should be paid to identifying possible toxic effects on the liver. Treatment should not begin or should be interrupted if detected during appropriate examinations or liver biopsy, liver function abnormalities present before treatment or developed during treatment. Usually, the disorders that develop during the treatment come back to normal within 2 weeks after the interruption of methotrexate therapy, after which, at the discretion of the attending physician, the treatment can be resumed.

When methotrexate is used for rheumatological indications, there is no obvious need for a liver biopsy to monitor hepatic toxicity.

The expediency of liver biopsy in patients with psoriasis is related to the decision of the question of the effectiveness of routine chemical analyzes of liver parameters or the study of type III collagen propeptide for the detection and evaluation of hepatotoxicity. The corresponding assessment should be carried out individually for each case with differentiation of patients depending on the presence or absence of risk factors such as excessive use of alcohol in history, stable increase in the activity of liver enzymes, liver disease in the anamnesis, hereditary predisposition to liver diseases, diabetes, Obesity, the use in the history of hepatotoxic drugs or drugs that affect hematopoiesis, the long-term prior use of methotrexate, or USAGE methotrexate in a cumulative dose of 1.5 grams or more.

Control of hepatic enzymes in blood serum: 13-20% of patients reported transitory 2-3-fold excess of normal values of transaminases. In the case of a sustained increase in hepatic enzyme activity, the question of dose reduction or cessation of treatment should be considered. In view of the possible toxic effects of the drug on the liver, patients with methotrexate, except in cases of obvious need, should refrain from concurrent use of other hepatotoxic drugs; It should also be avoided or at least significantly reduce the consumption of alcohol.

In patients using other hepatotoxic drugs or drugs that depress blood (eg leflunomide), liver enzymes should be monitored closely.

4. It is necessary to carry out control of renal function by performing functional tests and urine tests.

Since methotrexate is excreted mainly by the kidneys, in the case of kidney failure, an increase in plasma methotrexate concentration should be expected, which can lead to severe undesirable side effects. In cases of possible reduction in kidney function (for example, in elderly patients), follow-up examinations should be conducted more often. This also applies to the simultaneous administration of drugs that affect the excretion of methotrexate, drugs that can lead to kidney damage (eg, NSAIDs), or drugs that can affect hematopoiesis. Dehydration can also increase the toxicity of methotrexate.

5. Examination of the respiratory system: special attention should be paid to the symptoms of impaired lung function, if necessary, appropriate tests should be carried out. Symptoms of respiratory damage (especially dry non-productive cough), nonspecific pneumonitis that occur during methotrexate therapy, may indicate a potentially dangerous disease and require interruption of treatment and immediate thorough examination for diagnosis. Possible development of acute or chronic interstitial pneumonitis, often accompanied by eosinophilia; Reported on the related lethal cases. The clinical symptoms of methotrexate-induced lung injury are diverse, but typical symptoms are fever, cough, shortness of breath, hypoxemia. An X-ray examination of the chest is necessary to prevent the presence of infiltrates or infection. In the case of lung disease, rapid diagnosis and withdrawal of treatment are necessary. The development of respiratory diseases caused by the use of methotrexate, it is possible with any applied doses of the drug. If the dose of methotrexate is increased, the frequency of the examinations should be increased.

Methotrexate affects the immune system and, as a result, may worsen the response to vaccination and affect the results of immunological tests. Particular caution is required when using the drug in patients with chronic infectious diseases outside the periods of exacerbation (Herpes zoster, tuberculosis, hepatitis B or C) because of the possibility of exacerbation of the disease. It is necessary to refuse immunization.

Patients using low doses of 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. There have been reports of rare cases of acute megaloblastic pancytopenia when combined with methotrexate folate antagonists (such as trimethoprim / sulfamethoxazole).

Against the background of the use of methotrexate, the likelihood of dermatitis and skin burns is increased under the influence of solar irradiation and UV irradiation.

In patients with psoriasis, exacerbation of the disease as a result of UV irradiation during treatment with methotrexate (photosensitivity reaction) is possible.

In patients with additional Vd (the presence of pleural effusion, ascites) excretion of methotrexate is slowed. Such patients require very careful toxicity control, a reduced dose, and in some cases - the elimination of methotrexate treatment. Before the beginning of therapy with the preparation of Metoject®, effusion from the pleural or abdominal cavity should be drained.

With the appearance of diarrhea and ulcerative stomatitis, methotrexate therapy must be interrupted, In such cases the development of hemorrhagic enteritis and death as a result of interstitial perforation are possible.

Vitamin preparations and other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate. In patients with psoriasis, methotrexate should be used only in cases of severe, persistent, invalidating forms of the disease that are not amenable to treatment with other therapies, and only after confirmation of the diagnosis by biopsy and / or after consulting a dermatologist.

The preparation contains less than 1 mmol of sodium in one dose, i.e. Practically free of sodium, which is important for patients on a sodium diet.

Before prescribing the drug, women should be convinced of the absence of pregnancy, because Methotrexate is embryotoxic and can cause abortions and fetal defects. Methotrexate affects spermatogenesis and ovogenesis, which can lead to a decrease in genital function during treatment. These effects are reversible after the abolition of therapy.

Patients of childbearing age of both sexes must apply reliable contraceptive measures during treatment with methotrexate and for at least 6 months after the end.

Patients of childbearing age and their partners should be properly informed about the possible risks to the childbearing function and pregnancy associated with the use of methotrexate.

Overdose

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

Treatment: the administration of a specific antidote - sodium folinate or calcium folinate (as soon as possible) - to neutralize the toxic effects of methotrexate.

In case of accidental overdose, a dose of sodium folinate or calcium folinate must be administered intravenously or intravenously within the first hour after methotrexate administration, equal to or greater than the dose of methotrexate. Further, if necessary, the administration of sodium folinate or calcium folinate should be continued until the level of methotrexate in the blood serum is below 10-7 mol / l.

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

Special instructions

Special precautions for handling the preparation of Metoject® and destruction of the unused preparation

Methotrexate is cytotoxic, therefore, when handling the preparation of Metoject®, care must be taken and the rules for handling cytotoxic drugs should be followed.

Avoid contact with the skin and mucous membranes except during the injection. In case of contact, the corresponding areas of the skin and mucous membranes should be immediately washed with a large amount of water, then the skin after that with water and soap.

In case of accidental spillage of the preparation, it is necessary to collect the spilled solution with a disposable absorbent cloth, then treat the surface with detergent contacted with it and wipe with a disposable wet cloth, after which you should wash your hands thoroughly with soap.

The drug is intended for single use only.

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

Use of the drug Metoject® in children. The use of the preparation Methodogue® in children under 3 years of age is not recommended because of insufficient data on the efficacy and safety of use of the drug in this group of patients.

Features of the drug in children under 16 years are given in the section "Method of administration and dose."

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

The features of use in patients with chronic diseases are described in the section "Method of administration and dose".

Influence on the ability to drive vehicles and use mechanisms. Methotrexate is able to influence the central nervous system (causing symptoms such as fatigue, drowsiness, dizziness) and thus adversely affect the ability to drive, use mechanisms, and perform other actions requiring rapidity of psychomotor reactions.

Release form

Solution for subcutaneous administration, 50 mg / ml. At 7.5 mg / 0.15 ml or 10 mg / 0.2 ml, or 12.5 mg / 0.25 ml, or 15 mg / 0.3 ml, or 17.5 mg / 0.35 ml, Or 20 mg / 0.4 ml, or 22.5 mg / 0.45 ml, or 25 mg / 0.5 ml, or 27.5 mg / 0.55 ml, or 30 mg / 0.6 ml in a syringe With a capacity of 1 ml of neutral colorless glass (type I EF) with an integrated needle for s / c introduction, closed with a rubber stopper with or without polymer coating, with a polymeric nozzle on the flange. On the syringe stick a label with a peeling edge, designed to unfold the label. One syringe with the preparation in a PVC blister / paper. 1 bl. With a filled syringe with the drug placed in a cardboard box.

Manufacturer

Manufacturer of ready-made dosage form: Oncotech Pharma Production GmbH, Germany. Am Pharmapark 06861 Dessau-Rosslau, Germany.

The manufacturer that carries out secondary packaging and issues quality control: medak GmbH. Theater Strasse 6, 22880 Wedel, Germany. Theaterstrasse 6, 22880 Wedel, Germany.

The owner of the registration certificate: medak GmbH. Theater Strasse 6, 22880 Wedel, Germany. Theaterstrasse 6, 22880 Wedel, Germany.

Claims from consumers and complaints on the quality of the drug should be sent to: Representative of the manufacturer in Russia LLC "Tirufarm". 125424, Moscow

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Metoject

In the dark place at a temperature of no higher than 25 ° C (do not freeze).

Keep out of the reach of children.

Shelf life of the drug Metoject

2 years.

Do not use after the expiry date printed on the package.