Methotrexate Rompharm solution for injection 10mg/ml syringe 2ml No. 1

Instructions for use Methotrexate Rompharm solution for injection 10mg/ml syringe 2ml No. 1

Composition

active ingredient: methotrexate;

1 ml of solution contains 10 mg of methotrexate;

Excipients: sodium chloride, 2 M sodium hydroxide solution, 1 M sodium hydroxide solution, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: clear yellow solution.

Pharmacotherapeutic group

Antineoplastic agents. Antimetabolites. Structural analogues of folic acid.

ATX code L01B A01.

Pharmacological properties

Pharmacodynamics.

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, and chronic polyarthritis are due to its efficacy, and to what extent the methotrexate-induced increase in extracellular adenosine concentration contributes to this effect.

Pharmacokinetics.

Absorption

After oral administration, methotrexate is absorbed from the gastrointestinal tract. At low doses (7.5 to 80 mg/m² body surface area), methotrexate has a mean bioavailability of approximately 70%, although significant inter- and intra-subject variations (25-100%) are possible. Peak plasma concentrations are reached within 1-2 hours. Subcutaneous, intravenous and intramuscular administration have shown similar bioavailability.

Distribution

Approximately 50% of methotrexate is bound to plasma proteins. After distribution, methotrexate accumulates mainly in the liver, kidneys and spleen in the form of polyglutamates, which can persist for weeks or months. When used in low doses, minimal amounts of methotrexate penetrate into the cerebrospinal fluid; when used in high doses (300 mg/kg body weight), minimal amounts of methotrexate penetrate into the cerebrospinal fluid (concentration in the range of 4 to 7 μg/ml). The terminal half-life of methotrexate varies widely (3-17 hours) and averages 6-7 hours. In patients with a third distribution chamber (pleural effusion, ascites), the half-life of methotrexate can be up to 4 times longer.

Metabolism

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

Breeding

Methotrexate is excreted mainly unchanged, primarily by the kidneys, by glomerular filtration and active secretion in the proximal tubule. Approximately 5–20% of methotrexate and 1–5% of 7-hydroxymethotrexate are excreted in the bile. There is significant enterohepatic recirculation of methotrexate.

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 and is embryotoxic and teratogenic to the fetus. Methotrexate crosses the placental barrier in rats and monkeys. Methotrexate is mutagenic in vivo and in vitro. Since studies in rodents have shown no evidence of carcinogenicity, methotrexate cannot be classified as carcinogenic to humans. Chronic toxicity studies in animals have shown toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity.

Indication

Treatment of active rheumatoid arthritis in adults.

· Treatment of polyarthritic forms of active juvenile idiopathic arthritis in severe form in adolescents and children aged 3 years and older in case of inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs).

· Treatment of severe forms of psoriasis with loss of work capacity in case of insufficient effectiveness of traditional therapies, such as phototherapy, PUVA and the use of retinoids, as well as the treatment of severe forms of psoriatic arthritis in adult patients.

Contraindication

Hypersensitivity to methotrexate or to any of the other ingredients of the drug.

Severe liver dysfunction (bilirubin level >5 mg/dL (85.5 μmol/L) (see section "Method of administration and dosage").

· Alcohol abuse.

Severe renal impairment (creatinine clearance < 30 ml/min) (see section "Method of administration and dosage").

· Previously identified disorders of the hematopoietic system (in particular, bone marrow hypoplasia, leukopenia, thrombocytopenia or severe anemia).

Severe, acute or chronic infections (tuberculosis, HIV or other immunodeficiency syndromes).

Stomatitis, mouth ulcers and active stomach or intestinal ulcers.

· Pregnancy or breastfeeding (see sections “Special precautions” and “Use during pregnancy or breastfeeding”).

· Vaccination with live vaccines during treatment with methotrexate.

Special precautions for handling and disposal of the medicinal product should comply with the requirements for the disposal of cytotoxic medicinal products. Pregnant women should not handle and/or take the cytotoxic medicinal product Metortrit Rompharm (see sections “Contraindications” and “Use during pregnancy or breastfeeding”).

Precautions should be taken (use protective gloves and goggles) 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 used material should be disposed of in accordance with the requirements for the disposal of cytotoxic drugs.

Interaction with other medicinal products and other types of interactions

Animal studies have shown that 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 continue to be used as part of the complex therapy of rheumatoid arthritis simultaneously with methotrexate at low doses, but only under close medical supervision. Serious adverse reactions, including fatal outcomes, unexpected severe bone marrow depression, aplastic anemia and gastrointestinal toxicity, have been reported with the simultaneous use of NSAIDs and high doses of methotrexate. If such risk factors exist, especially in case of impaired renal function, the simultaneous use of methotrexate and NSAIDs is not recommended.

L-asparginase

When used simultaneously with methotrexate, it antagonizes its effects.

Alcohol, hepatotoxic and hematotoxic drugs

Regular alcohol consumption and concomitant use of hepatotoxic drugs increase the likelihood of hepatotoxic effects of methotrexate. Therefore, patients receiving hepatotoxic drugs (e.g. leflunomide, azathioprine, sulfasalazine, retinoids) during methotrexate therapy should be closely monitored due to the possible increase in hepatotoxicity. Alcohol consumption should be avoided during treatment with Methotrexate.

Similar monitoring of patients is also necessary with concomitant use of hematotoxic drugs (e.g. leflunomide, metamizole). When leflunomide is combined with methotrexate, an increased incidence of pancytopenia and hepatotoxicity is possible.

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

Oral antibiotics

Oral antibiotics (including tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics) may affect enterohepatic circulation by inhibiting the intestinal microflora or suppressing bacterial metabolism.

Antibiotics

Antibiotics such as penicillins, glycopeptides, sulfonamides, ciprofloxacin and cephalothin may, in isolated cases, reduce the renal clearance of methotrexate, which may result in an increase in its serum concentration and an increase in toxic effects on the hematopoietic system and the digestive tract.

Drugs that adversely affect the bone marrow

With concomitant therapy with drugs that may have side effects on the bone marrow (such as amidopyrine derivatives, phenytoin, sulfonamides, trimethoprim/sulfamethoxazole, chloramphenicol, pyrimethamine, cytostatics), the possibility of developing more pronounced hematological disorders should be taken into account.

Drugs that cause folate deficiency

Concomitant treatment with drugs that cause folate deficiency (e.g. sulfonamides, trimethoprim/sulfamethoxazole) may increase the toxicity of methotrexate. Special caution is also required when treating patients with pre-existing folic acid deficiency.

Preparations containing folic or folinic acid

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

Other antirheumatic drugs

Combined use with other antirheumatic drugs (e.g., gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine) has not been studied much, so an increase in the toxic effects of methotrexate cannot be ruled out.

Sulfasalazine

Although the effect of methotrexate may be potentiated when used in combination with sulfasalazine due to inhibition of folic acid synthesis by sulfasalazine (which may result in an increased incidence of side effects), such effects were observed only in isolated cases in several clinical studies.

An interaction may occur when methotrexate is used concomitantly with proton pump inhibitors (e.g. omeprazole, pantoprazole, lansoprazole). Omeprazole may reduce the renal clearance of methotrexate. There has been one case report where methotrexate in combination with pantoprazole inhibited the renal excretion of the metabolite 7-hydroxymethotrexate, causing myalgia and tremor. Caution is advised, especially in patients with impaired renal function.

Beverages containing caffeine, theophylline

Methotrexate may reduce theophylline clearance, so theophylline blood levels should be monitored when methotrexate is added to therapy.

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

It is necessary to consider the pharmacokinetic interaction between methotrexate, anticonvulsants (decreases methotrexate blood levels) and 5-fluorouracil (increases the half-life of 5-fluorouracil).

Drugs with high levels of plasma protein binding

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 NSAIDs

Probenecid and weak organic acids, such as loop diuretics and pyrazoles (phenylbutazole), may slow the elimination of methotrexate, which may result in increased serum concentrations and increased hematological toxicity.

Mercaptopurine

Concomitant use of mercaptopurine and methotrexate may increase the plasma concentration of mercaptopurine. Therefore, concomitant use may require dose adjustment.

Methotrexate should be used with caution in combination with immunomodulators during orthopedic surgery, when susceptibility to infection is increased.

The use of nitric oxide potentiates the effect of methotrexate on folate metabolism and leads to increased toxicity, resulting in unpredictable, severe bone marrow depression and stomatitis. Calcium folinate should be administered to reduce the intensity of these effects. Concomitant use of methotrexate and nitric oxide should be avoided.

Cholestyramine may enhance the extrarenal excretion of methotrexate by interfering with the enterohepatic circulation process.

In case of simultaneous use with other cytostatic drugs, the clearance of methotrexate may decrease.

When undergoing radiotherapy while the patient is receiving methotrexate, the risk of soft tissue and bone necrosis may increase.

Due to the possible effect on the immune system, the use of methotrexate may lead to incorrect results of vaccination and laboratory tests (immunological procedures for recording the immune response). During treatment with methotrexate, vaccination with live vaccines should not be carried out (see sections "Contraindications" and "Special instructions").

Application features

The patient should be clearly informed that the drug should be administered once a week, not daily, and a fixed day of the week should be established as the day of injection. The physician should indicate the day of administration on the prescription. Patients should be informed of the importance of adhering to the once-weekly regimen and that failure to administer the recommended dose daily has resulted in fatal toxicity (see sections 4.2 and 4.4).

Patients undergoing treatment should be closely monitored for signs of toxic effects or adverse reactions and, if possible, for prompt evaluation. Methotrexate should therefore only be used under the supervision of a physician with appropriate knowledge and experience in the use of antimetabolites.

Due to the possibility of severe or even fatal toxic reactions, the physician should inform the patient of all risks (including early signs and symptoms of toxicity) associated with the use of Methotrexate Rompharm and of recommended safety measures.

Patients undergoing treatment should be closely monitored by a physician for signs of toxic effects or adverse reactions (including regular laboratory tests).

After discontinuation of methotrexate, side effects that occurred after its use do not always completely disappear.

Administration at doses exceeding 20 mg per week is associated with a significant increase in toxic effects, especially bone marrow suppression.

Methotrexate has been reported to have adverse effects on reproductive function, causing oligospermia, menstrual irregularities and amenorrhea during therapy and for a short period after its discontinuation. Treatment with the drug may also cause impaired fertility by affecting spermatogenesis and oogenesis during the period of its administration, these effects being reversible after discontinuation of treatment.

Methotrexate causes embryotoxicity, miscarriages and fetal malformations. Accordingly, the physician should warn patients (women and men) of reproductive age about all possible risks associated with taking the drug (see section "Use during pregnancy or breastfeeding"). The absence of pregnancy should be confirmed before using methotrexate. Women and men of reproductive age should use effective contraceptive methods during treatment and for six months after the end of methotrexate therapy. Since methotrexate can cause severe and irreversible pathological changes in sperm formation, men should learn about the possibilities of sperm conservation before starting treatment.

When handling the drug, it is necessary to follow the rules for handling cytotoxic substances. It is necessary to take measures to prevent methotrexate solutions from getting on the skin and mucous membranes. Protective gloves and glasses should be used. If the drug does get on the skin or mucous membranes, the affected area should be washed immediately with plenty of water.

Recommended medical monitoring and safety measures

With psoriasis

Due to the risk of serious toxic reactions (which can be fatal), methotrexate should only be used in patients who have severe, refractory psoriasis and have not responded adequately to other therapies.

Before starting therapy or when resuming methotrexate treatment after a break

Complete blood count and biochemical blood test 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 for as clinically indicated to exclude them.

During methotrexate treatment (once a week for the first two weeks, every two weeks for the next month, then, depending on the leukocyte count and the stability of the patient's condition, at least once a month for the next 6 months and no less than every 3 months thereafter; with increasing doses, it is advisable to increase the frequency of examinations) the following examinations should be performed. Patients, especially the elderly, should be examined for early signs of toxicity at short intervals.

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

2. A complete blood count with differential analysis of platelet content in the blood.

Methotrexate may suppress haematopoiesis, causing anaemia, aplastic anaemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia. The first signs of these life-threatening complications may be: fever, sore throat, oral ulceration, flu-like symptoms, severe exhaustion, epistaxis and skin bleeding. Megaloblastic anaemia has been reported, especially during long-term treatment in elderly patients. Haematopoietic suppression caused by methotrexate may occur suddenly at apparently safe doses. Any significant decrease in leukocyte or platelet counts requires immediate discontinuation of the medicinal product and appropriate supportive treatment. Patients are strongly advised to report any symptoms suggestive of infection. Patients taking concomitant hematotoxic drugs (e.g. leflunomide) should have their platelet counts closely monitored.

During long-term therapy with methotrexate, a bone marrow biopsy is necessary.

3. Liver function tests.

Particular attention should be paid to the development of hepatic toxicity. Treatment should not be initiated or should be discontinued if any liver function abnormality is present or develops during treatment. Liver function should return to normal within 2 weeks, after which treatment may be resumed if the physician deems it appropriate.

Transient elevations of transaminases to 2 or 3 times the upper limit of normal have been reported in patients with a frequency of 13–20%. Persistent elevations of liver enzymes and/or decreases in serum albumin may indicate significant hepatotoxicity.

There is no evidence to support the use of liver biopsies for monitoring hepatotoxicity in rheumatologic indications. The need for liver biopsy before and during therapy in patients with psoriasis is controversial. Further studies are needed to determine whether serial liver chemistry tests or propeptide of collagen type III can adequately detect hepatotoxicity. This assessment should differentiate between patients without any risk factors and those with risk factors, such as previous excessive alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity, and previous exposure to hepatotoxic drugs or chemicals, and long-term treatment with methotrexate or cumulative doses of 1.5 g or more.

In case of persistent elevation of liver-related enzymes, dose reduction or discontinuation of therapy should be considered.

Due to the potential for liver toxicity, additional hepatotoxic drugs should not be taken during methotrexate treatment unless absolutely necessary.

and alcohol should be avoided (see section "Interaction with other medicinal products and other forms of interaction"). More careful monitoring of liver enzymes is required in patients taking other hepatotoxic medicinal products (e.g. leflunomide). Similar monitoring of patients is also necessary when concomitantly using haematotoxic medicinal products. When leflunomide is combined with methotrexate, an increased incidence of pancytopenia and hepatotoxicity may occur.

Particular caution is required when treating patients with insulin-dependent diabetes mellitus, as there are reports of isolated cases of liver cirrhosis during methotrexate therapy without a prior increase in transaminase activity.

Methotrexate use can cause the development of acute or chronic hepatitis, fibrosis, cirrhosis, but most often only after prolonged use. Elevated liver enzymes are usually observed. Most often this is temporary and asymptomatic and is not a sign of developing liver disease.

Methotrexate may cause reactivation of hepatitis B or exacerbation of hepatitis C infection, which has been fatal in some cases. Some cases of hepatitis B reactivation have occurred after discontinuation of methotrexate therapy. Clinical and laboratory investigations should be performed to evaluate for pre-existing liver disease in patients with a history of hepatitis B or C virus infection. As a result, the use of methotrexate in such patients may be contraindicated.

4. Renal function tests and urine tests (see sections “Contraindications” and “Method of administration and dosage”).

In case of an increase in serum creatinine, the dose of the drug should be reduced. If the creatinine clearance is less than 30 ml/min, further treatment with methotrexate should not be carried out (see sections "Contraindications" and "Dosage and Administration"). Since methotrexate is excreted mainly in the urine, patients with impaired renal function may experience an increase in the concentration of methotrexate in the blood, which may result in severe adverse reactions. The dose should be reduced and the condition of patients with possible impaired renal function (e.g. elderly patients) should be carefully monitored. This is especially important in the case of concomitant therapy with drugs that reduce the excretion of methotrexate, have an adverse effect on the kidneys (in particular NSAIDs) or on the hematopoietic system. The simultaneous use of methotrexate with NSAIDs is not recommended in patients with impaired renal function. Treatment with methotrexate may lead to deterioration of renal function with increases in certain laboratory parameters (serum creatinine, urea and uric acid) and acute renal failure with oliguria/anuria. Dehydration may also potentiate the toxic effects of methotrexate.

5. Study of the respiratory system.

Patients should be monitored closely for signs of pulmonary dysfunction and pulmonary function tests should be performed as necessary. Acute or chronic interstitial pneumonitis, often with eosinophilia, may develop, and fatalities have been reported. Typical symptoms in patients with methotrexate-induced pulmonary disease include dyspnea, cough (especially dry, nonproductive cough), chest pain, fever, and infiltrates on chest X-ray. Patients should be informed of the risk of pneumonitis and advised to seek immediate medical attention if persistent cough or dyspnea occurs.

In addition, pulmonary alveolar hemorrhage has been reported with methotrexate in rheumatologic and related indications. This bleeding may also be associated with vasculitis and other comorbid conditions. If pulmonary alveolar hemorrhage is suspected, prompt evaluation is necessary to confirm the diagnosis.

Lung disease caused by methotrexate is not always completely reversible.

Pulmonary diseases require rapid diagnosis and discontinuation of methotrexate.

Pulmonary diseases caused by methotrexate, such as pneumonitis, can begin suddenly and at any stage of therapy, do not always resolve completely and have been observed with methotrexate at all therapeutic doses (including the low dose of 7.5 mg/week).

Opportunistic infections, including plasma cell pneumonia, which can be fatal, may occur during methotrexate therapy. Plasma cell pneumonia should be considered in patients presenting with symptoms of pulmonary dysfunction.

Patients with impaired pulmonary function should be especially careful when using methotrexate.

Particular caution is required when treating patients with inactive chronic infections (such as herpes zoster, tuberculosis, hepatitis B or C) due to their possible activation.

6. Effect on the immune system.

Due to its effect on the immune system, methotrexate may reduce the response to vaccination and affect the results of immunological studies. Concomitant vaccination with live vaccines should not be carried out during treatment with methotrexate due to the increased risk of infection.

Neoplasm

Cases of malignant lymphomas have been reported in patients receiving low doses of methotrexate. Sometimes they have resolved after methotrexate withdrawal. In such cases, methotrexate should be discontinued first. If the lymphoma does not regress spontaneously, cytotoxic therapy should be considered.

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. Pleural effusion or ascites should be eliminated before starting methotrexate therapy.

Dehydration disorders such as vomiting, diarrhoea, stomatitis may increase the toxic effects of methotrexate due to increased concentrations. In such cases, further therapy should be temporarily interrupted until such symptoms resolve.

It is very important to identify patients with possible increased methotrexate concentrations within 48 hours after administration, as otherwise the toxic effects of methotrexate may be irreversible.

Diarrhea and ulcerative stomatitis may be manifestations of toxic effects and require temporary discontinuation of further therapy, otherwise hemorrhagic enteritis and death due to perforation of the intestinal wall are possible.

In case of vomiting blood, black stools, or blood in the stools, further therapy should be discontinued.

Vitamin preparations and other products containing folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate therapy. Taking supplements containing folic acid may mask the symptoms of vitamin B12 deficiency, especially in adults over 50 years of age. Folate deficiency may increase the toxicity of methotrexate (see section "Interaction with other medicinal products and other forms of interaction").

Serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) have been reported after single or repeated use of methotrexate. Radiation-induced dermatitis and sunburn may recur during use of methotrexate (so-called memory reactions). Psoriatic lesions may be exacerbated by UV radiation during concomitant use of methotrexate.

Methotrexate is not recommended for use in children under 3 years of age due to the lack of sufficient information on the efficacy and safety of its use (see section "Method of administration and dosage").

Encephalopathy/leukoencephalopathy has been reported with methotrexate in cancer patients and cannot be excluded with methotrexate in non-cancer patients.

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

Use during pregnancy or breastfeeding

Women of reproductive age/contraception in women and men

Women should not become pregnant during treatment with methotrexate. Patients of reproductive age (both women and men) and their partners should use effective contraception during treatment and for at least 6 months after stopping Methotrexate therapy (see section "Special warnings and precautions for use").

It is not known whether methotrexate is present in semen. Animal studies have shown that methotrexate is genotoxic, so the risk of genotoxic effects on sperm cannot be completely excluded. Limited clinical data do not indicate an increased risk of malformations or miscarriage after low-dose (less than 30 mg per week) methotrexate administered by the father. For higher doses, there are insufficient data to assess the risks of malformations or miscarriage.

Men should not donate sperm during therapy or for 6 months after the end of therapy with Methotrexate Rompharm.

The use of methotrexate is contraindicated during pregnancy for non-oncological indications (see sections “Contraindications” and “Special precautions”).

If a woman becomes pregnant during treatment with methotrexate or within 6 months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and an ultrasound examination should be performed to confirm normal fetal development.

In animal studies, methotrexate has shown reproductive toxicity, particularly during the first trimester of pregnancy. Methotrexate is teratogenic in humans; it has been reported to cause fetal death and/or congenital malformations (e.g., craniofacial, cardiovascular, central nervous system, and limb malformations).

Methotrexate is a potent human teratogen that increases the risk of spontaneous abortion, intrauterine growth retardation, and congenital malformations when used during pregnancy.

• Spontaneous abortions were reported in 42.5% of pregnant women treated with low-dose methotrexate (less than 30 mg/week) compared with 22.5% of patients treated with other drugs.

• Major birth defects occurred in 6.6% of newborns whose mothers were treated with low-dose methotrexate (less than 30 mg/week) during pregnancy, compared with approximately 4% of newborns in patients who took other drugs.

There is insufficient data on the effects of methotrexate during pregnancy at doses above 30 mg/week, but higher rates of spontaneous abortion and congenital malformations are expected.

Normal pregnancy has been reported, provided that methotrexate is discontinued before conception.

Breastfeeding period

Since methotrexate passes into breast milk and may cause toxic effects in nursing infants, breastfeeding is contraindicated during treatment with methotrexate.

(see section "Contraindications"). If use of the drug during this period is necessary, breastfeeding should be discontinued before starting treatment with the drug.

Fertility

Methotrexate affects spermatogenesis and oogenesis and may reduce fertility. Methotrexate has been reported to cause oligospermia, menstrual dysfunction, and amenorrhea. These effects are reversible in most cases after discontinuation of therapy.

Ability to influence reaction speed when driving vehicles or other mechanisms

Methotrexate has a minor influence on the ability to drive or use machines. During treatment with methotrexate, side effects from the central nervous system such as fatigue and confusion may occur.

Method of administration and doses

Methotrexate Rompharm can only be prescribed by doctors who have experience in the use of methotrexate and who are aware of all the risks of therapy with this drug.

Methotrexate Rompharm should be administered once a week.

The patient (caregiver) should be clearly informed that Metortrit Rompharm should be used once a week, and this should be done each time a new prescription is issued or the medicine is dispensed.

Set a fixed day of the week as the injection day.

Advise the patient (caregiver) on the signs of methotrexate overdose and emphasize immediate medical attention if overdose is suspected.

General patient care should be provided by medical staff. However, in certain cases, the doctor may decide that the patient is capable of self-injecting the drug. In this case, the doctor should conduct detailed patient training before administering the drug.

Adult patients with rheumatoid arthritis

It is recommended to administer a parenteral test dose 1 week before the start of treatment in order to detect idiosyncratic adverse reactions.

The recommended starting dose is 7.5 mg of methotrexate, which should be administered subcutaneously.