Methoject 10 mg solution for injection 50 mg/ml syringe 0.2 ml No. 1

Instructions for use: Methoject 10 mg solution for injection 50 mg/ml syringe 0.2 ml No. 1

Composition

active ingredient: methotrexate;

1 ml of solution contains methotrexate 50 mg (as methotrexate disodium 54.84 mg);

excipients: sodium hydroxide, sodium chloride, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: yellow-brown transparent solution without turbidity.

Pharmacotherapeutic group

Antineoplastic and immunomodulatory agents. Immunosuppressants. Other immunosuppressants. ATX code L04A X03.

Pharmacological properties

Pharmacodynamics.

Antirheumatic drug for the treatment of chronic inflammatory rheumatic diseases and polyarthritic forms of juvenile idiopathic arthritis. Immunomodulatory and anti-inflammatory drug for the treatment of Crohn's disease.

Mechanism of action.

Methotrexate is a folic acid antagonist belonging to a class of cytotoxic agents known as antimetabolites. It acts by competitively inhibiting the enzyme dihydrofolate reductase, thereby inhibiting DNA synthesis. It is not yet clear whether the anti-inflammatory or immunosuppressive effects of methotrexate in the treatment of psoriasis, psoriatic arthritis, chronic polyarthritis, and Crohn's disease are due to its efficacy, and to what extent the methotrexate-induced increase in extracellular adenosine concentration contributes to this effect.

International clinical protocols reflect the use of methotrexate as a second-line drug for patients with Crohn's disease who are intolerant to or have failed to respond to first-line immunomodulatory drugs such as azathioprine (AZA) or 6-mercaptopurine (6-MP).

Adverse events observed in studies conducted with methotrexate at maximum doses for the treatment of Crohn's disease did not indicate a different safety profile of methotrexate than that already known. Therefore, the same recommendations should be followed when using methotrexate for the treatment of Crohn's disease as for other rheumatic and non-rheumatic diseases for which methotrexate is indicated.

Pharmacokinetics.

Absorption: Methotrexate is absorbed from the gastrointestinal tract after oral administration. At low doses (7.5–80 mg/m2 body surface area), the mean bioavailability is approximately 70%, although there is considerable inter- and intra-subject variation (25–100%). Peak serum concentrations of methotrexate are reached after 1–2 hours.

The bioavailability of methotrexate after subcutaneous administration is approximately 100%.

Distribution: Approximately 50% of methotrexate is bound to serum proteins. Distribution to tissues results in high concentrations of polyglutamates, particularly in the liver, kidneys and spleen, which can persist for weeks or months. At low doses, methotrexate penetrates the body fluids in minimal amounts. The terminal half-life averages 6–7 hours and varies considerably (3–17 hours). The half-life in patients with a third distribution space (pleural effusion, ascites) may be prolonged by up to 4 times the normal duration.

Biotransformation: Approximately 10% of the administered dose of methotrexate is metabolized in the liver. The main metabolite is 7-hydroxymethotrexate.

Excretion: Methotrexate is excreted mainly unchanged, primarily by the kidneys by glomerular filtration and active secretion in the proximal tubules. Approximately 5–20% of methotrexate and 1–5% of 7-hydroxymethotrexate are excreted in the bile.

In case of renal failure, the elimination of methotrexate from the body is significantly slowed down. Regarding hepatic failure, there is no data on a decrease in the rate of elimination.

Preclinical safety data

Animal studies have shown that methotrexate impairs fertility, has embryotoxic and teratogenic effects on the fetus. Methotrexate exhibits mutagenicity in vivo and in vitro. Since traditional carcinogenicity studies have not been conducted, and chronic toxicity studies in rodents have yielded insufficient results for comparison, it is not possible to determine the carcinogenicity of methotrexate for humans.

Indication

Active rheumatoid arthritis in adults;

polyarthritic severe form of juvenile (idiopathic) arthritis, in case of inadequate response to nonsteroidal anti-inflammatory drugs;

severe psoriasis, especially in the form of plaques, in case of ineffectiveness of appropriate therapy, such as phototherapy, PUVA therapy and the use of retinoids, as well as in case of severe psoriatic arthritis in adults;

Mild to moderate Crohn's disease (as monotherapy or in combination with corticosteroids) in adults, in case of resistance or intolerance to thiopurines.

Contraindication

Hypersensitivity to methotrexate or to any of the components of the drug;

liver dysfunction (alcohol-induced liver disease or other chronic liver diseases);

alcohol abuse;

history of blood diseases, such as bone marrow hypoplasia, leukocytopenia, thrombocytopenia, or severe anemia;

mouth ulcers and active stomach or intestinal ulcers;

renal impairment (creatinine clearance less than 30 ml/min);

concomitant vaccination with live vaccines;

pregnancy and breastfeeding.

Special safety precautions

Special precautions for handling and disposal of the medicinal product should be in accordance with the requirements for cytotoxic drugs. Pregnant women should not handle cytotoxic drugs and/or receive Methoject®.

Precautions should be taken to avoid accidental contact of methotrexate with the skin or mucous membranes. In case of skin contact, the affected area should be thoroughly washed with plenty of water.

Any unused medicinal product or waste material should be disposed of in accordance with requirements for cytotoxic medicinal products.

Interaction with other medicinal products and other types of interactions

Animal studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs), including salicylic acid, cause a decrease in the tubular secretion of methotrexate and, accordingly, increase its toxic effects. However, in clinical studies in which NSAIDs and salicylic acid were used as concomitant therapy for the treatment of patients with rheumatoid arthritis, no increase in the frequency of adverse reactions was noted. The mentioned drugs can be continued to be used as part of the complex therapy of rheumatoid arthritis simultaneously with methotrexate, but only under careful medical supervision.

Nitric oxide: Nitric oxide potentiates the effect of methotrexate on folic acid, increasing toxicity, manifested by severe unpredictable myelosuppression and stomatitis. Although this effect can be reduced by the administration of calcium folinate, concomitant use should be avoided.

Alcohol, hepatotoxic drugs, hematotoxic drugs. The likelihood of developing the hepatotoxic effect of methotrexate increases with alcohol abuse and with the simultaneous use of other hepatotoxic drugs. Therefore, the condition of patients who take hepatotoxic drugs (e.g. leflunomide, azathioprine, sulfasalazine, retinoids) during methotrexate therapy requires close monitoring due to the possible increase in hepatotoxicity. Alcohol should be avoided during methotrexate treatment.

Similar monitoring is also necessary with concomitant use of hematotoxic drugs. When combining leflunomide with methotrexate, there may be an increased incidence of pancytopenia and hepatotoxicity.

Combined treatment with methotrexate and retinoids, such as acitretin or etretinate, increases the risk of hepatotoxicity.

Oral antibiotics: Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad-spectrum antibiotics can interfere with intestinal and hepatic blood flow by inhibiting intestinal flora or suppressing bacterial metabolism.

Antibiotics: Antibiotics such as penicillins, glycopeptides, sulfonamides, ciprofloxacin and cephalothin may, in some cases, reduce the renal clearance of methotrexate, thus increasing the serum concentration of methotrexate and its haematological and gastrointestinal toxicity.

Drugs with high plasma protein binding: Methotrexate is highly bound to plasma proteins and may be displaced by other protein-bound drugs, such as salicylates, hypoglycemic agents, diuretics, sulfonamides, diphenylhydantoins, tetracyclines, barbiturates, chloramphenicol and para-aminobenzoic acid, as well as acidic anti-inflammatory drugs, which may cause increased toxicity when used concomitantly.

Salicylates, phenylbutazone, phenytoin, barbiturates, tranquilizers, oral contraceptives, tetracycline, amidopyrine derivatives, sulfonamides and para-aminobenzoic acid displace methotrexate from plasma proteins and thus increase bioavailability (indirect dose increase).

Probenecid, weak organic acids, pyrazoles and non-steroidal anti-inflammatory drugs. Probenecid, weak organic acids such as loop diuretics and pyrazoles (phenylbutazone) may reduce the elimination of methotrexate, and higher serum concentrations are likely to cause greater hematological toxicity. There is also a possibility of increased toxicity when low-dose methotrexate is combined with non-steroidal anti-inflammatory drugs or salicylates.

Drugs that may cause bone marrow side effects. In the case of concomitant use of methotrexate and drugs that may cause bone marrow suppression (sulfonamides, trimethoprim/sulfamethoxazole, chloramphenicol, pyrimethamine), attention should be paid to the risk of severe hematopoietic disorders.

Preparations containing folic or folinic acid. Vitamin preparations or other medicines containing folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate.

Other antirheumatic drugs: An increase in the toxic effects of methotrexate is not generally expected when Methotrexate is used concomitantly with other antirheumatic drugs (e.g. gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine).

Cyclosporine. Cyclosporine may potentiate the efficacy and toxicity of methotrexate. There is an increased risk of renal impairment. In addition, there is a biological plausibility of excessive immunosuppression and associated complications.

Sulfasalazine: Although the combination of methotrexate and sulfasalazine may increase the efficacy of methotrexate and result in increased side effects due to inhibition of folic acid synthesis by sulfasalazine, such side effects have only been observed in isolated cases in several studies.

Mercaptopurine: Methotrexate increases plasma levels of mercaptopurine. Therefore, dose adjustment may be required when methotrexate is combined with mercaptopurine.

Proton pump inhibitors. Concomitant use of proton pump inhibitors (omeprazole, pantoprazole, lansoprazole) may lead to a delay or inhibition of the renal excretion of methotrexate and thus to an increase in plasma levels with clinical signs and symptoms of methotrexate toxicity. Methotrexate should be used with caution in patients with impaired renal function. There has been one case report of methotrexate in combination with pantoprazole inhibiting the renal excretion of the metabolite 7-hydroxymethotrexate, causing myalgia and tremor.

Theophylline: Methotrexate may reduce theophylline clearance; theophylline levels should be monitored when co-administered with methotrexate.

Beverages containing caffeine or theophylline: During treatment with methotrexate, excessive consumption of beverages containing caffeine or theophylline (coffee, caffeinated soft drinks, tea) should be avoided, as this may reduce the effectiveness of methotrexate due to the interaction of methotrexate and methyxanthine adenosine receptors.

During methotrexate therapy, vaccination with live vaccines should not be performed.

Application features

The patient should be clearly informed that the drug should be administered once a week, not daily. Also, doses exceeding 20 mg/week may be associated with a significant increase in toxicity, especially bone marrow suppression.

If symptoms of toxic effects on the digestive tract appear (usually stomatitis develops first), methotrexate treatment should be suspended, since if therapy is continued, hemorrhagic enteritis and intestinal perforation may develop, which pose a threat to the patient's life.

Patients undergoing treatment should be closely monitored by a physician for signs of toxic effects or adverse reactions and, if possible, for their prompt evaluation. Methotrexate should therefore only be used under the supervision of a physician who has appropriate knowledge and experience in the use of antimetabolites. Because of the possibility of severe or even fatal toxic reactions, the physician should inform the patient of all the risks associated with the use of Methotrexate® and of the recommended safety precautions.

Recommended medical monitoring and safety measures

Before starting therapy or when resuming methotrexate treatment after a break.

Complete blood count and biochemical blood tests with differential blood platelet count, liver enzymes, bilirubin, serum albumin level, chest X-ray, and renal function tests should be performed. Tuberculosis and hepatitis should be tested as clinically indicated to rule them out.

During treatment

The following tests should be performed once a week for the first 2 weeks, then every 2 weeks for the next month; then, depending on the leukocyte count and the patient's stability, at least once a month for the next 6 months and at least every 3 months thereafter.

Increased monitoring frequency should also be considered when increasing the dose. Elderly patients in particular should be monitored for early signs of toxicity at short intervals.

1. Examination of the oral cavity and throat to detect changes in the mucous membrane.

3. Liver function tests: Treatment should not be initiated or should be discontinued if persistent or significant abnormalities in liver function tests, other non-invasive tests of liver fibrosis, or liver biopsy are observed.

Transient elevations of transaminases to 2 or 3 times the upper limit of normal have been reported in patients with an incidence of 13–20%. Persistent elevations of liver enzymes and/or decreased serum albumin may indicate severe hepatotoxicity. In the event of persistent elevations of liver enzymes, dose reduction or discontinuation of treatment should be considered.

Histological changes, fibrosis and rarely cirrhosis may not be accompanied by abnormal liver function tests. Cases of cirrhosis have been reported even when transaminase levels were normal. Therefore, non-invasive diagnostic methods for monitoring liver function in addition to liver function tests should be considered. The need for liver biopsy should be considered on a case-by-case basis, taking into account the patient's comorbidities, medical history and risks associated with the biopsy. Risk factors for hepatotoxicity include: history of alcohol abuse, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disease, diabetes mellitus, obesity and previous use of hepatotoxic drugs or chemicals, as well as long-term treatment with methotrexate.

Any other hepatotoxic drugs should not be used during treatment with methotrexate unless absolutely necessary.

Alcohol consumption should be avoided (see sections “Contraindications” and “Ability to influence the reaction rate when driving vehicles or using other mechanisms”). More careful monitoring of liver enzyme levels is required in patients taking other hepatotoxic drugs.

Patients with insulin-dependent diabetes mellitus should be especially careful, since during methotrexate therapy, liver cirrhosis has developed in isolated cases without an increase in transaminase levels.

4. Renal function should be monitored by urinalysis and urine analysis (see sections “Special instructions” and “Interaction with other medicinal products and other types of interactions”).

Since methotrexate is excreted mainly by the kidneys, an increase in serum concentrations is expected in the event of renal failure, which may lead to severe side effects such as impaired renal function up to acute renal failure.

In cases where renal function may be impaired (e.g. in the elderly), monitoring should be more frequent. Such monitoring is particularly necessary in the case of concomitant use of medicinal products that affect the elimination of methotrexate (e.g. non-steroidal anti-inflammatory drugs), causing renal damage, or which may lead to haematopoietic disorders. Severe adverse reactions, including fatalities, have been reported with concomitant use of non-steroidal anti-inflammatory drugs.

During methotrexate therapy, renal function may deteriorate with increases in serum levels of certain laboratory parameters (creatinine, urea and uric acid). Dehydration may also increase the toxicity of methotrexate.

5. Respiratory assessment: Close monitoring for signs of pulmonary dysfunction and, if necessary, pulmonary function tests should be performed. Pulmonary disease requires prompt diagnosis and discontinuation of methotrexate. Symptoms of pulmonary disease (particularly dry, nonproductive cough) or nonspecific pneumonitis occurring during methotrexate therapy may indicate a potentially life-threatening condition and require discontinuation of therapy and careful evaluation. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may develop; fatalities have also been reported. Despite clinical variability, typical symptoms in patients with methotrexate-induced pulmonary disease include fever, cough, dyspnea, hypoxemia, and infiltrates on chest X-ray; infection should be ruled out. Potentially fatal opportunistic infections, including Pneumocystis jirovecii pneumonia, may occur during methotrexate treatment. Pulmonary involvement caused by methotrexate can occur at any stage of therapy, even at low doses of 7.5 mg/week. Pulmonary involvement requires prompt diagnosis and discontinuation of methotrexate. Pulmonary involvement caused by methotrexate has not always been fully reversible. This involvement can occur at any dose.

6. Due to its effect on the immune system, methotrexate may impair the response to vaccination and affect the results of immunological tests. Special care is also required in the case of inactive chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C), as accidental reactivation of the infection is possible. Concomitant vaccination with live vaccines should not be carried out during methotrexate treatment. Disseminated cowpox has been reported after smallpox vaccination in patients receiving methotrexate therapy.

Particular caution should be exercised when treating patients with insulin-dependent diabetes mellitus with methotrexate.

Methotrexate may cause reactivation of hepatitis B or exacerbation of hepatitis C, which in some cases has been fatal. Cases of reactivation of hepatitis B have been reported after discontinuation of methotrexate therapy. Therefore, clinical and laboratory examinations should be performed in patients with a history of hepatitis B or C to determine the appropriateness of methotrexate therapy.

Malignant lymphoma may occur in patients receiving low-dose methotrexate. In such cases, treatment should be discontinued. If there is no evidence of spontaneous regression of the lymphoma, cytotoxic therapy should be initiated.

There have been several reports of concomitant administration of folate antagonists, such as trimethoprim/sulfamethoxazole, causing acute megaloblastic pancytopenia.

Radiation-induced dermatitis and sunburn may recur during methotrexate treatment (anamnesis). Psoriasis may be exacerbated by ultraviolet irradiation during concomitant methotrexate administration.

Conditions leading to dehydration (vomiting, diarrhea, stomatitis) may increase the toxicity of methotrexate by increasing the drug levels in the body. In these cases, methotrexate should be discontinued until symptoms resolve.

Diarrhea and ulcerative stomatitis may be signs of toxic effects that require discontinuation of treatment to prevent the development of hemorrhagic enteritis, which can lead to fatal outcomes due to intestinal perforation.

In patients with pathological fluid accumulation in body cavities ("third space"), such as ascites or pleural effusion, the plasma half-life of methotrexate is prolonged, which may lead to unexpected increased toxicity. If pleural effusion or ascites is present, drainage should be performed before starting methotrexate treatment.

Vitamin preparations or other substances containing folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate.

Severe, sometimes fatal, allergic skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) have been reported.

In the treatment of psoriasis, the use of methotrexate should be limited to severe psoriasis when other forms of treatment are ineffective, but only when the diagnosis has been established by biopsy and/or after consultation with a dermatologist.

Cases of encephalopathy and leukoencephalopathy have been reported in cancer patients treated with methotrexate. This should be taken into account when methotrexate is used for the treatment of non-cancer diseases.

Intravenous administration of methotrexate can lead to the development of acute encephalitis (inflammation of the brain membrane) and acute encephalopathy (pathological changes in the brain) with fatal outcome.

Progressive multifocal leukoencephalopathy

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, mostly in combination with other immunosuppressive agents. PML can be fatal. This should be considered in the differential diagnosis in immunocompromised patients who present with worsening or new neurological symptoms.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium-free.

Fertility

Methotrexate has been reported to cause oligospermia, menstrual irregularities, and amenorrhea in humans during and for a short period after cessation of therapy, and to impair fertility by affecting spermatogenesis and oogenesis during the period of its administration - the effects are considered reversible after cessation of therapy.

Teratogenicity

Since methotrexate may be genotoxic, all women planning a pregnancy should consult a genetics centre before starting therapy regarding the risk of effects on reproductive function, and men should consult about the possibility of sperm conservation before starting treatment (see section “Use during pregnancy or lactation”).

Elderly patients: Since liver and kidney function decline with age, and folate reserves decrease, it may be appropriate to reduce doses in elderly patients.

Use during pregnancy or breastfeeding

Women of childbearing potential/contraception in women. During treatment with methotrexate, women should not become pregnant. Effective contraception should be used during treatment and for at least 6 months after the end of methotrexate therapy. Before starting treatment, women of childbearing potential should be informed of the risk of adverse effects of methotrexate on the fetus and pregnancy should be excluded by appropriate methods, such as a pregnancy test. During treatment, pregnancy tests should be performed when clinically necessary (e.g. after a break in contraceptive use). Women of childbearing potential should receive advice on pregnancy prevention and planning.

Contraception in men. There are no data on the content of methotrexate in semen. In animal studies, methotrexate has been shown to be genotoxic, therefore the risk of genotoxic effects on spermatozoa cannot be completely excluded. Limited clinical data do not indicate an increased risk of malformations or miscarriage after exposure to low doses of methotrexate (less than 30 mg per week) in the father. There are insufficient data to assess the risk of malformations or miscarriage after exposure to higher doses in the father.

Sexually active male patients or their female partners are advised to use reliable contraception during treatment and for at least 3 months after stopping methotrexate therapy. Men should not donate sperm during treatment or for 3 months after stopping methotrexate.

Pregnancy: Methotrexate is contraindicated during pregnancy (see section 4.3). If pregnancy occurs during treatment with methotrexate and within 6 months after the end of therapy, the woman should be informed of the risk of harmful effects on the child associated with treatment and ultrasound examinations of fetal development should be performed.

Animal studies have shown reproductive toxicity of methotrexate, especially in the first trimester. Methotrexate has been shown to be teratogenic, with fetal death, miscarriages and congenital anomalies (e.g. malformations of the facial skull, cardiovascular system, central nervous system and extremities).

Methotrexate is a potent human teratogen. When exposed during pregnancy, methotrexate increases the risk of spontaneous abortion, intrauterine growth retardation, and congenital malformations.

Spontaneous miscarriages were reported in 42.5% of pregnant women using low doses of methotrexate (less than 30 mg per week), compared with 22.5% in patients using other drugs.

Major birth defects occurred in 6.6% of live births of mothers who used low-dose methotrexate (less than 30 mg per week) during pregnancy, compared with approximately 4% of live births of mothers who used other drugs. There are insufficient data on the use of methotrexate in doses greater than 30 mg per week during pregnancy, but a higher rate of spontaneous abortions and congenital malformations is expected.

Normal pregnancies have been reported when methotrexate was discontinued prior to conception.

Breastfeeding. Methotrexate passes into breast milk in concentrations that pose a risk to the child, therefore breastfeeding should be discontinued before and during treatment.

Therefore, methotrexate is contraindicated during pregnancy or breastfeeding.

Fertility: See section "Special warnings and precautions for use".

Ability to influence reaction speed when driving vehicles or other mechanisms

During treatment with Methoject®, you should refrain from driving or operating other mechanisms, as side effects from the nervous system (fatigue and dizziness) may occur.

Method of administration and doses

General care of the patient should be provided by medical personnel. However, in certain cases, the doctor may decide that the patient is capable of injecting the drug himself. In such cases, the doctor should conduct detailed preparation of the patient for the use of the drug. The first injection of the drug Metoject® should be carried out under the direct supervision of a doctor. Metoject® should be injected subcutaneously once a week. The patient should be clearly informed that the drug should be injected once a week. It is advisable to establish a fixed day of the week as the day of injection. The duration of the course of treatment is determined by the doctor.

Methotrexate excretion is reduced in patients with pathological fluid accumulation (third space fluid), such as ascites or pleural effusion. Such patients require particularly careful monitoring for toxicity and dose reduction or, in some cases, discontinuation of methotrexate.

The contents of one pre-filled syringe are for single use only.

Note: When changing from oral to parenteral administration, a reduction in the methotrexate dose may be necessary due to the different bioavailability of the different routes of administration. It may be advisable to add folic acid to the current regimen.

Adult patients with rheumatoid arthritis.

The recommended initial dose is 7.5 mg of methotrexate, which should be administered subcutaneously once a week. Depending on the course of the disease and tolerability of the drug, the initial dose can be gradually increased by 2.5 mg each week. The maximum weekly dose of 25 mg should not be exceeded. Also, doses exceeding 20 mg/week may be accompanied by a significant increase in toxicity, especially bone marrow suppression. Usually, a response to treatment can be expected after about 4–8 weeks. After achieving the desired therapeutic effect, the dose should be gradually reduced to the lowest effective maintenance dose.

Children under 16 years of age with polyarthritic form of juvenile (idiopathic) arthritis.

The recommended dose is 10–15 mg/m2 body surface area once weekly. In case of insufficient effect, the weekly dose may be increased to 20 mg/m2 body surface area once weekly. Increased monitoring frequency may also be required when the dose is increased.

This group of patients should be treated under the supervision of a rheumatologist who has experience working with children and adolescents.

The use of the drug Methoject® for children under 3 years of age is not recommended, as there is no data on the effectiveness and safety of its use in this group of patients.

Patients with psoriasis vulgaris and psoriatic arthritis.

It is recommended to administer a parenteral test dose of 5–10 mg 1 week before starting treatment in order to detect idiosyncratic adverse reactions. The recommended initial dose is 7.5 mg methotrexate, which should be administered subcutaneously, once a week. The dose should be increased gradually, but the maximum weekly dose of methotrexate should not be exceeded by more than 25 mg. Doses exceeding 20 mg/week may be associated with a significant increase in toxicity, especially bone marrow suppression. A response to treatment can usually be expected after approximately 2–6 weeks. After achieving the desired therapeutic effect, the dose should be gradually reduced to the lowest possible effective maintenance dose.

Patients with Crohn's disease.

Induction therapy.

The recommended dose is 25 mg of the drug, administered subcutaneously once a week. A response to treatment can be expected after approximately 8–12 weeks.

Supportive therapy.

The recommended dose is 15 mg of the drug, which should be administered subcutaneously once a week.

Maximum weekly dose. The dose may be increased if necessary, but in general it should not exceed the maximum recommended weekly dose of 25 mg. In some cases, an increased dose may be clinically justified, but should not exceed a weekly dose of 30 mg of methotrexate, as toxicity is increased.

Patients with renal failure.

Methoject® should be administered with caution to patients with impaired renal function.