Methotrit rompharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METOTREX ROMPHARM

Composition:

Active substance: methotrexate;

1 ml of solution contains 10 mg of methotrexate;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear yellow-colored solution.

Pharmacotherapeutic group.

Antineoplastic and immunomodulating agents. Immunosuppressants. Other immunosuppressants.

ATC code L04AX03.

Pharmacological Properties

Pharmacodynamics

Methotrexate is a folic acid antagonist belonging to the class of cytotoxic agents known as antimetabolites. It acts by competitively inhibiting the enzyme dihydrofolate reductase, thereby suppressing DNA synthesis. The anti-inflammatory or immunosuppressive effect responsible for methotrexate's efficacy in the treatment of psoriasis, psoriatic arthritis, and chronic polyarthritis has not yet been fully elucidated, nor has the extent to which methotrexate-induced elevation of extracellular adenosine concentration contributes to this effect.

Pharmacokinetics

Absorption

Following oral administration, methotrexate is absorbed from the gastrointestinal tract. When administered in low doses (7.5 to 80 mg/m² body surface area), methotrexate has a mean bioavailability of approximately 70%, although substantial inter- and intra-individual variations (25–100%) may occur. Peak plasma concentrations are reached within 1–2 hours. Subcutaneous, intravenous, and intramuscular administration demonstrate similar bioavailability.

Distribution

Approximately 50% of methotrexate is bound to plasma proteins. After distribution, methotrexate accumulates predominantly in the liver, kidneys, and spleen in the form of polyglutamates, which may be retained for weeks or months. When administered in low doses, minimal amounts of methotrexate penetrate into the cerebrospinal fluid; when administered in high doses (300 mg/kg body weight), minimal amounts of methotrexate (concentrations ranging from 4 to 7 µg/mL) are found in the cerebrospinal fluid. The terminal half-life of methotrexate varies widely (3–17 hours), averaging 6–7 hours. In patients with a third compartment of distribution (pleural effusion, ascites), the elimination half-life of methotrexate may be up to four times longer.

Metabolism

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

Excretion

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

In renal impairment, elimination of methotrexate from the body is significantly slowed. With regard to hepatic impairment, there are no data indicating reduced elimination rate.

Safety Preclinical Data

Animal studies have shown that methotrexate impairs fertility and exerts embryotoxic and teratogenic effects on the fetus. Methotrexate crosses the placental barrier in rats and monkeys. Methotrexate has demonstrated mutagenic activity in vivo and in vitro. Since carcinogenicity studies in rodents have not shown any evidence of carcinogenic potential, methotrexate cannot be classified with regard to carcinogenicity in humans. Chronic toxicity studies in animals have revealed toxic effects, including gastrointestinal damage, myelosuppression, and hepatotoxicity.

Clinical characteristics.

Indications.

• Treatment of active rheumatoid arthritis in adults.
• Treatment of severe polyarticular forms of active juvenile idiopathic arthritis in adolescents and children aged 3 years and older who have shown inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs).
• Treatment of severe psoriasis with loss of work capacity when conventional therapies such as phototherapy, PUVA, and retinoids are insufficiently effective, as well as treatment of severe forms of psoriatic arthritis in adult patients.

Contraindications.

• Hypersensitivity to methotrexate or to any of the excipients.
• Severe impairment of liver function (bilirubin level >5 mg/dL (85.5 µmol/L)) (see section "Dosage and administration").
• Alcohol abuse.
• Severe renal impairment (creatinine clearance <30 mL/min) (see section "Dosage and administration").
• Previously identified hematopoietic system disorders (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, or severe anemia).
• Severe, acute, or chronic infections (tuberculosis, HIV, or other immunodeficiency syndromes).
• Active stomatitis, oral ulcers, or active peptic ulcer disease of the stomach or intestine.
• Pregnancy or breastfeeding (see sections "Special precautions" and "Use during pregnancy or breastfeeding").
• Vaccination with live vaccines during methotrexate therapy.

Special precautions.

Special precautions must be observed when handling and disposing of the medicinal product, in accordance with requirements for disposal of cytotoxic agents. Pregnant women must not handle or administer the cytotoxic medicinal product Methotrex Rompharm (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Precautions (including use of protective gloves and goggles) should be taken to avoid accidental contact of methotrexate with skin or mucous membranes. In case of skin contact, the affected area should be thoroughly rinsed with large amounts of water.

Any unused medicinal product or waste material must be disposed of in accordance with requirements for disposal of cytotoxic agents.

Interaction with other medicinal products and other forms of interaction.

Animal studies have shown that NSAIDs, including salicylic acid, reduce tubular secretion of methotrexate and thereby enhance its toxic effects. However, in clinical studies where NSAIDs and salicylic acid were used as concomitant therapy in patients with rheumatoid arthritis, no increase in the frequency of adverse reactions was observed. These drugs may be continued as part of combination therapy for rheumatoid arthritis together with low-dose methotrexate, but only under close medical supervision. Serious adverse reactions, including fatal outcomes, unexpected severe bone marrow suppression, aplastic anemia, and gastrointestinal toxicity, have been reported with concomitant use of NSAIDs and high-dose methotrexate. Concomitant administration of methotrexate and NSAIDs is not recommended if risk factors are present, particularly in patients with impaired renal function.

L-asparaginase

When administered concomitantly with methotrexate, L-asparaginase antagonizes its effects.

Alcohol, hepatotoxic, and hematotoxic medicinal products

Regular alcohol consumption and use of additional hepatotoxic agents increase the risk of hepatotoxic effects of methotrexate. Therefore, patients receiving hepatotoxic medicinal products (e.g., leflunomide, azathioprine, sulfasalazine, retinoids) during methotrexate therapy should be closely monitored due to possible increased hepatotoxicity. Alcohol consumption should be avoided during treatment with Methotrex Rompharm.

Similarly, careful monitoring is required when hematotoxic medicinal products (e.g., leflunomide, metamizole) are used concomitantly. Combination of leflunomide with methotrexate may increase the incidence of pancytopenia and hepatotoxicity.

Combination therapy with methotrexate and retinoids (e.g., acitretin or etretinate) increases the risk of hepatotoxicity.

Concomitant use of additional hematotoxic medicinal products increases the likelihood of severe hematotoxic adverse reactions to methotrexate. Concurrent use of metamizole and methotrexate may enhance the hematotoxic effect of methotrexate, especially in elderly patients. Therefore, concomitant use of these agents should be avoided.

Oral antibiotics

Oral antibiotics (e.g., tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics) may affect enterohepatic recirculation by inhibiting intestinal flora or suppressing bacterial metabolism.

Antibiotics

Antibiotics such as penicillins, glycopeptides, sulfonamides, ciprofloxacin, and cephalothin may, in isolated cases, reduce renal clearance of methotrexate, leading to increased serum concentrations and enhanced toxicity to the hematopoietic system and gastrointestinal tract.

Medicinal products affecting bone marrow

When used concomitantly with agents that may cause adverse effects on bone marrow (e.g., amidopyrine derivatives, phenytoin, sulfonamides, trimethoprim/sulfamethoxazole, chloramphenicol, pyrimethamine, cytostatics), the possibility of more pronounced hematological disturbances should be considered.

Medicinal products causing folate deficiency

Concomitant therapy with agents causing folate deficiency (e.g., sulfonamides, trimethoprim/sulfamethoxazole) may enhance the toxic effects of methotrexate. Particular caution is also required in patients with pre-existing folic acid deficiency.

Products containing folic or folinic acid

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

Other antirheumatic agents

Combination with other antirheumatic agents (e.g., gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine) has been poorly studied; therefore, increased toxicity of methotrexate cannot be excluded.

Sulfasalazine

Although methotrexate effects may be potentiated when used concomitantly with sulfasalazine due to sulfasalazine-induced inhibition of folate synthesis (potentially increasing the frequency of adverse effects), such effects have been observed only rarely in several clinical studies.

Proton pump inhibitors

Interaction may occur when methotrexate is used concomitantly with proton pump inhibitors (e.g., omeprazole, pantoprazole, lansoprazole). Omeprazole may reduce renal clearance of methotrexate. One case has been reported in which methotrexate in combination with pantoprazole inhibited renal excretion of the metabolite 7-hydroxymethotrexate, resulting in myalgia and tremor. Caution is required, especially in patients with impaired renal function.

Beverages containing caffeine, theophylline

Methotrexate may reduce the clearance of theophylline; therefore, theophylline blood levels should be monitored when methotrexate is introduced into therapy.

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

Pharmacokinetic interactions between methotrexate and anticonvulsants (reduced blood levels of methotrexate) and 5-fluorouracil (prolonged half-life of 5-fluorouracil) should be considered.

Medicinal products with high plasma protein binding

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

Probenecid, weak organic acids, pyrazoles, and NSAIDs

Probenecid and weak organic acids such as loop diuretics and pyrazoles (phenylbutazone) may delay methotrexate excretion, leading to increased serum concentrations and enhanced hematological toxicity.

Merca­ptopurine

Concomitant use of mercaptopurine and methotrexate may increase mercaptopurine plasma concentrations. Thus, dose adjustment may be required when used together.

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

Use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, leading to increased toxicity, including unpredictable, severe bone marrow suppression and stomatitis. To reduce the intensity of such effects, calcium folinate should be administered. Concomitant use of methotrexate and nitrous oxide should be avoided.

Cholestyramine may enhance extra-renal elimination of methotrexate by interfering with enterohepatic recirculation.

When used concomitantly with other cytostatic agents, methotrexate clearance may be reduced.

During radiation therapy in patients receiving methotrexate, an increased risk of soft tissue and bone necrosis may occur.

Due to its potential effect on the immune system, methotrexate use may lead to inaccurate results in vaccination and laboratory tests (immunological procedures assessing immune response). Vaccination with live vaccines should not be performed during methotrexate therapy (see sections "Contraindications" and "Special warnings").

Special precautions for use

Patients must be clearly informed that the medication should be administered once weekly, not daily, and a fixed day of the week should be established for the injection. The physician must indicate the administration day on the prescription. Patients must be informed about the importance of adhering to the once-weekly dosing schedule and that accidental daily administration of the recommended dose has led to fatal toxicity (see sections "Dosage and administration" and "Overdose").

Patients undergoing treatment must remain under close medical supervision to detect signs of toxic effects or adverse reactions and, where possible, to allow their rapid assessment. Therefore, methotrexate must be used only under the supervision of a physician experienced in the use of antimetabolite therapy.

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

Patients undergoing treatment must be under close medical supervision to detect signs of toxic effects or adverse reactions (including regular laboratory testing).

After discontinuation of methotrexate, adverse effects that occurred during treatment may not always resolve completely.

Doses exceeding 20 mg per week are associated with a significant increase in toxicity, particularly bone marrow suppression.

Methotrexate has been reported to adversely affect reproductive function, causing oligospermia, menstrual disorders, and amenorrhea during therapy and for a short period after its discontinuation. Treatment with this drug may also cause impaired fertility by affecting spermatogenesis and oogenesis during the treatment period; these effects were generally reversible after discontinuation of therapy.

Teratogenicity – Reproductive risk

Methotrexate causes embryotoxicity, miscarriage, and congenital malformations. Therefore, physicians must warn patients of reproductive age (both women and men) about all potential risks associated with the use of this drug (see section "Use during pregnancy or breastfeeding"). The absence of pregnancy must be confirmed before initiating methotrexate therapy. Women and men of reproductive potential must use effective contraception during treatment and for at least six months after completion of methotrexate therapy. Since methotrexate may cause severe and irreversible sperm abnormalities, men should be informed about the possibility of sperm cryopreservation prior to starting treatment.

When handling the drug, standard precautions for cytotoxic substances must be observed. Measures must be taken to prevent contact of methotrexate solutions with skin or mucous membranes. Protective gloves and goggles should be used. If the drug does come into contact with skin or mucous membranes, the affected area must be immediately rinsed with large amounts of water.

Recommended medical monitoring and safety measures

Psoriasis

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

Before initiating therapy or reinitiating treatment after interruption

A complete blood count with differential platelet count, liver enzymes, bilirubin, serum albumin levels, chest X-ray, and kidney function tests should be performed. Tuberculosis and hepatitis screening should be conducted as clinically indicated to exclude these conditions.

During treatment with methotrexate (weekly during the first two weeks, every two weeks during the following month, then at least once monthly for the next 6 months and no less frequently than every 3 months thereafter; frequency of monitoring should be increased when doses are escalated), the following assessments should be performed. Patients, especially elderly ones, should be monitored closely for early signs of toxicity at short intervals.

1. Oral and pharyngeal examination to detect mucosal changes.
2. Complete blood count with differential platelet count.

Methotrexate may suppress hematopoiesis, causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. Early signs of these life-threatening complications may include fever, sore throat, oral mucosal ulceration, influenza-like symptoms, severe fatigue, and nasal or skin bleeding. Megaloblastic anemia has been reported, particularly during prolonged treatment in elderly patients. Hematopoietic suppression caused by methotrexate may occur suddenly even with apparently safe doses. Any significant decrease in white blood cell or platelet counts requires immediate discontinuation of the drug and appropriate supportive treatment. Patients are strongly advised to report any symptoms suggestive of infection. Careful monitoring of platelet counts is required in patients concurrently receiving hematotoxic drugs (e.g., leflunomide).

Bone marrow biopsy is necessary during long-term methotrexate therapy.

1. Liver function tests.

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

Transient elevation of transaminases two to three times above the upper limit of normal has been observed in 13–20% of patients. Persistent elevation of liver enzymes and/or decreased serum albumin may indicate severe hepatotoxicity. In case of persistent elevation of liver enzymes, dose reduction or discontinuation of therapy should be considered.

Histological changes, fibrosis, and rarely cirrhosis of the liver may occur without preceding abnormalities in liver function tests. Cases of cirrhosis have been reported despite normal transaminase levels. Therefore, non-invasive diagnostic methods for liver monitoring should be considered in addition to liver function tests. Liver biopsy should be considered on an individual basis, taking into account comorbidities, medical history, and risks associated with the procedure. Risk factors for hepatotoxicity include excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, familial history of hereditary liver disorders, diabetes, obesity, prior exposure to hepatotoxic drugs or chemicals, and prolonged methotrexate therapy.

Additional hepatotoxic drugs should not be prescribed during methotrexate treatment, except when clearly necessary. Alcohol consumption must be avoided (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Careful monitoring of liver enzyme levels is required in patients receiving other hepatotoxic drugs concurrently.

Particular caution is advised in patients with insulin-dependent diabetes mellitus, as cases of liver cirrhosis without elevated transaminases have been reported during methotrexate therapy.

1. Renal function tests and urinalysis (see sections "Contraindications" and "Dosage and administration").

If serum creatinine levels increase, the dose must be reduced. If creatinine clearance is less than 30 mL/min, further methotrexate therapy should not be administered (see sections "Contraindications" and "Dosage and administration"). Since methotrexate is primarily excreted in urine, patients with impaired renal function may experience elevated methotrexate plasma concentrations, potentially leading to severe adverse reactions. Dose reduction and careful monitoring are necessary in patients at risk of renal dysfunction (e.g., elderly patients). This is especially important when concomitant therapy includes drugs that reduce methotrexate excretion, have nephrotoxic effects (e.g., NSAIDs), or affect hematopoiesis. Concomitant use of methotrexate and NSAIDs is not recommended in patients with impaired renal function. Methotrexate treatment may worsen renal function, leading to increased laboratory markers (serum creatinine, urea, uric acid) and acute renal failure with oliguria/anuria. Dehydration may potentiate methotrexate toxicity.

1. Respiratory system examination.

Patients must be closely monitored for symptoms suggestive of pulmonary disorders, and pulmonary function tests should be performed when necessary. Acute or chronic interstitial pneumonitis, often with eosinophilia, may develop; fatal cases have been reported. Typical symptoms in patients with methotrexate-induced lung disease include dyspnea, cough (especially dry, non-productive), chest pain, fever, and pulmonary infiltrates on chest X-ray. Patients should be informed about the risk of pneumonitis and advised to seek immediate medical attention if persistent cough or dyspnea develops.

Additionally, pulmonary alveolar hemorrhage has been reported with methotrexate use in rheumatological and related indications. This hemorrhage may also be associated with vasculitis or other comorbid conditions. In suspected cases of pulmonary alveolar hemorrhage, prompt evaluation is required to confirm the diagnosis.

In such cases, methotrexate must be discontinued and the patient thoroughly evaluated to rule out infection or malignancy (including chest X-ray). Corticosteroid therapy should be initiated in cases of methotrexate-induced lung disease. Subsequent methotrexate therapy should not be resumed.

Methotrexate-induced lung disease is not always completely reversible.

Pulmonary disorders require prompt diagnosis and discontinuation of methotrexate.

Methotrexate-induced lung diseases, such as pneumonitis, may develop suddenly at any stage of therapy, are not always fully reversible, and have been observed with all therapeutic doses of methotrexate (including low doses of 7.5 mg/week).

Opportunistic infections, including Pneumocystis jirovecii pneumonia, may occur during methotrexate therapy and may be fatal. Pneumocystis jirovecii pneumonia should be considered in patients presenting with pulmonary symptoms.

Particular caution is required when treating patients with pre-existing lung function impairment.

Special caution is necessary in patients with inactive chronic infections (e.g., herpes zoster, tuberculosis, hepatitis B or C) due to the potential for reactivation.

1. Effects on the immune system.

Due to its effects on the immune system, methotrexate may reduce response to vaccination and affect immunological test results. Concomitant vaccination with live vaccines should not be administered during methotrexate therapy due to increased risk of infection.

Neoplasms

Cases of malignant lymphoma have been reported in patients receiving low-dose methotrexate. These sometimes resolved after discontinuation of methotrexate. In such cases, methotrexate therapy should first be discontinued. If spontaneous regression of lymphoma does not occur, cytotoxic therapy should be initiated.

In patients with 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 resolved before initiating methotrexate therapy.

Conditions causing dehydration, such as vomiting, diarrhea, or stomatitis, may increase methotrexate toxicity due to increased drug concentration. In such cases, further therapy should be temporarily interrupted until these symptoms resolve.

It is crucial to identify patients with potentially elevated methotrexate concentrations within 48 hours after administration, as otherwise methotrexate toxicity may become irreversible.

Diarrhea and ulcerative stomatitis may be manifestations of toxicity and require temporary discontinuation of further therapy; otherwise, hemorrhagic enteritis and fatal intestinal perforation may occur.

If vomiting with blood, black stools, or blood in stools occurs, further therapy must be discontinued.

Vitamin preparations and other products containing folic acid, folinic acid, or their derivatives may reduce the efficacy of methotrexate therapy. Folic acid supplements may mask symptoms of vitamin B12 deficiency, especially in adults aged 50 years and older. Folate deficiency may increase methotrexate toxicity (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.

Photosensitization

Photosensitization, manifesting as a sunburn-like reaction, has been observed in some patients receiving methotrexate (see section "Adverse reactions"). Exposure to intense sunlight or UV radiation should be avoided unless medically indicated. Patients should use appropriate sun protection to prevent exposure to intense sunlight.

Radiation-induced dermatitis and sunburn may recur during methotrexate therapy (so-called "memory reactions").

Psoriatic lesions may worsen under UV radiation when methotrexate is used concurrently.

Methotrexate is not recommended for use in children under 3 years of age due to insufficient data on efficacy and safety (see section "Dosage and administration").

Encephalopathy/leukoencephalopathy has been reported in oncology patients receiving methotrexate, and its occurrence cannot be excluded in non-oncology patients.

Progressive multifocal leukoencephalopathy (PML)

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, particularly when used concomitantly with other immunosuppressive agents. PML may be fatal. This should be considered in the differential diagnosis of immunocompromised patients presenting with worsening of pre-existing or new neurological symptoms.

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

Use during pregnancy or breastfeeding

Women of childbearing potential/contraception in women

Women must not become pregnant during methotrexate therapy. Effective contraceptive measures must be used during treatment with methotrexate and for at least 6 months thereafter (see section "Special precautions for use"). Before initiating therapy, women of childbearing age must be informed about the risk of congenital malformations associated with methotrexate, and pregnancy must be reliably excluded by appropriate means (e.g., pregnancy test). During treatment, pregnancy tests should be repeated as clinically indicated (e.g., after any contraceptive failure). Patients of reproductive age should be counselled regarding prevention and planning of pregnancy.

Contraception in men

It is unknown whether methotrexate is present in semen. Animal studies have shown methotrexate to be genotoxic; therefore, a genotoxic effect on spermatozoa cannot be completely ruled out. Limited clinical data do not indicate an increased risk of congenital malformations or miscarriage after paternal use of low-dose methotrexate (less than 30 mg/week). Regarding higher doses, insufficient data are available to assess the risks of congenital malformations or miscarriage.

As a precautionary measure, sexually active male patients or their partners are advised to use effective contraception during the male patient's treatment and for at least 3 months after discontinuation of methotrexate therapy. Men must not donate sperm during methotrexate therapy or for 3 months after its discontinuation.

Pregnancy

Methotrexate is contraindicated during pregnancy for non-oncological indications (see sections "Contraindications" and "Special safety measures").

If a woman becomes pregnant during methotrexate therapy or within 6 months thereafter, medical counselling regarding the potential harmful effects of treatment on the fetus should be provided, and an ultrasound examination should be performed to confirm normal fetal development.

Animal studies have shown methotrexate to have reproductive toxicity, particularly during the first trimester. Methotrexate is teratogenic in humans and may 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 to 22.5% in patients treated with other drugs.
• Major congenital malformations occurred in 6.6% of newborns whose mothers received low-dose methotrexate (less than 30 mg/week) during pregnancy, compared to approximately 4% in newborns of patients receiving other drugs.

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

Normal pregnancies have been reported provided methotrexate was discontinued before conception.

Lactation

Since methotrexate passes into breast milk and may cause toxic effects in breastfed infants, breastfeeding during methotrexate therapy is contraindicated (see section "Contraindications"). If use of the drug during this period is necessary, breastfeeding must be discontinued before starting treatment.

Fertility

Methotrexate affects spermatogenesis and oogenesis and may reduce fertility. Oligospermia, menstrual dysfunction, and amenorrhea have been reported. These effects are mostly reversible after discontinuation of therapy.

Ability to drive and use machines

Methotrexate Rompharm has a minor influence on the ability to drive and use machines. During methotrexate therapy, adverse effects on the central nervous system such as fatigue and confusion may occur.

Method of administration and dosage.

Methotrexate Rompharm can be prescribed only by physicians experienced in the use of methotrexate and who are fully aware of all the risks associated with therapy using this medicinal product.

Important dosage warnings for Methotrexate Rompharm (methotrexate): Methotrexate for the treatment of rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis, and psoriatic arthritis should be administered once weekly. Methotrexate Rompharm should be used only once a week. Mistakes in dosing of Methotrexate Rompharm may result in serious adverse effects, including fatal outcomes. Please read this section carefully before using this medicinal product.

Methotrexate Rompharm should be administered once weekly.

The patient (or caregiver) must be clearly informed that Methotrexate Rompharm must be used once a week, consistently whenever a new prescription is issued or the medication is dispensed.

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

Advise the patient (or caregiver) about the signs of methotrexate overdose and emphasize the need to seek immediate medical attention if overdose is suspected.

Overall patient management should be carried out by healthcare professionals. However, in certain cases, the physician may determine that the patient is capable of self-administering the medication. In such cases, the physician must provide thorough patient training prior to initiating treatment.

Adult patients with rheumatoid arthritis

A parenteral test dose is recommended one week prior to starting treatment to detect idiosyncratic adverse reactions.

The recommended initial dose is 7.5 mg of methotrexate administered subcutaneously once weekly. Depending on the individual course of the disease and drug tolerability, the initial dose may be gradually increased by 2.5 mg weekly. The maximum weekly dose of 25 mg must not be exceeded. Moreover, doses exceeding 20 mg weekly are associated with a significant increase in toxicity, particularly bone marrow suppression.

Therapeutic response is usually expected within approximately 4–8 weeks. After achieving the desired therapeutic effect, the dose should be gradually reduced to the lowest effective maintenance dose. After discontinuation of therapy, relapse of rheumatoid arthritis may occur. Methotrexate therapy for rheumatoid arthritis is intended as long-term treatment. The duration of treatment is determined by the physician.

Children aged 3 years and older with polyarticular juvenile (idiopathic) arthritis

The recommended dose is 10–15 mg/m² of body surface area once weekly. If the therapeutic response is inadequate, the weekly dose may be increased to 20 mg/m² of body surface area once weekly. Increased monitoring frequency should also be considered when increasing the dose.

Due to the lack of reliable data on intravenous administration of methotrexate in children and adolescents, methotrexate should be administered subcutaneously or intramuscularly.

This patient group must be treated under the supervision of a rheumatologist experienced in using the drug in children and adolescents.

Use of Methotrexate Rompharm for the treatment of children under 3 years of age is not recommended due to insufficient data on efficacy and safety in this patient population (see section "Special precautions").

Dosing for patients with psoriasis vulgaris and psoriatic arthritis

A test parenteral dose of 5–10 mg of methotrexate is recommended one week prior to starting therapy to detect idiosyncratic adverse effects.

The recommended initial dose is 7.5 mg of methotrexate once weekly, administered subcutaneously, intramuscularly, or intravenously. The dose may be gradually increased, but the weekly dose of methotrexate must not exceed 25 mg. Doses exceeding 20 mg/week may be associated with a significant increase in toxicity, particularly bone marrow suppression. Therapeutic response is usually expected within approximately 2–6 weeks. Depending on clinical symptoms and laboratory parameters, treatment is then continued or discontinued.

After achieving the desired therapeutic effect, the dose should be gradually reduced to the lowest possible effective maintenance dose. Doses above 25 mg may be clinically justified, but the maximum weekly dose of methotrexate must not exceed 30 mg due to a notable increase in drug toxicity.

Treatment of psoriasis vulgaris and psoriatic arthritis with methotrexate is intended as long-term therapy. The duration of treatment is determined by the physician.

Patients with renal impairment

Methotrexate Rompharm should be prescribed with caution in patients with impaired renal function (see sections "Contraindications" and "Adverse reactions"). The dose should be adjusted as follows:

Creatinine clearance (mL/min)	% of dose to be administered
≥ 60	100 % of dose
30-59	50 % of dose
< 30	Metotret Rompharm should not be prescribed

Patients with hepatic impairment

Methotrexate should be administered with particular caution or not administered at all to patients with existing severe liver disease or a history of liver disease, especially if such disease is associated with alcohol abuse.

If bilirubin levels exceed 5 mg/dL (85.5 µmol/L), methotrexate is contraindicated (see sections "Contraindications" and "Special precautions").

Elderly patients

Since hepatic and renal function decline with age and folate reserves are reduced, dose reduction may be appropriate for elderly patients.

Patients with a third space of fluid in the body (pleural effusion, ascites)

Since in patients with a third space of fluid the elimination half-life of Methotrexate Rompharm may be prolonged up to four times compared to normal duration, dose reduction or, in some cases, discontinuation of methotrexate administration may be required (see sections "Pharmacokinetics" and "Adverse reactions").

Administration method

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

Methotrexate Rompharm, solution for injection, can be administered intramuscularly, intravenously, or subcutaneously. For children (aged 3 years and older) and adolescents, only subcutaneous or intramuscular injections should be used. Administration to adults should be performed as an intravenous bolus injection.

The duration of treatment course is determined by the physician.

Methotrexate Rompharm, solution for injection, should be inspected visually before administration. Only clear solution free from mechanical particles is suitable for use.

Precautions (use of protective gloves and goggles) must be taken to prevent methotrexate solutions from contacting skin or mucous membranes. If the drug does come into contact with skin or mucous membranes, the affected area should be immediately flushed with large amounts of water (see section "Special safety precautions").

Attention:

When switching from oral to parenteral administration, dose reduction may be necessary due to the differing bioavailability of methotrexate after oral administration.

Supplementation with folic acid or folinic acid may be considered according to current therapeutic guidelines.

Children.

The medicinal product is used in children aged 3 years and older for polyarticular juvenile (idiopathic) arthritis.

Use of the drug for treatment of children under 3 years of age is not recommended due to lack of data on efficacy and safety in this patient group.

Overdose.

Symptoms of overdose. Toxic side effects of methotrexate are mostly related to bone marrow suppression and gastrointestinal toxicity. Symptoms include leukopenia, thrombocytopenia, anemia, pancytopenia, neutropenia, bone marrow suppression, mucosal inflammation, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration and bleeding. In some patients, symptoms of overdose were absent. Fatal cases due to sepsis, septic shock, renal failure, and aplastic anemia have been reported.

Treatment of overdose. Calcium folinate is a specific antidote to counteract the toxic side effects of methotrexate.

In case of accidental overdose, calcium folinate should be administered intravenously or intramuscularly at a dose equal to or exceeding the methotrexate dose, no later than 1 hour after methotrexate administration. Additional doses of calcium folinate should be administered until serum methotrexate concentration falls below 10⁻⁷ mol/L.

In cases of significant overdose, hydration and urinary alkalization may be necessary to prevent precipitation of methotrexate and/or its metabolites in renal tubules. Standard hemodialysis and peritoneal dialysis do not enhance methotrexate elimination. Effective clearance of methotrexate can be achieved through intensive intermittent hemodialysis using high-flux dialyzers.

In patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, or psoriasis vulgaris, administration of folic acid or folinic acid may reduce methotrexate toxicity (gastrointestinal symptoms, oral mucosal inflammation, hair loss, and elevated liver enzymes); see section "Interaction with other medicinal products and other forms of interaction".

Prior to administration of folic acid products, monitoring of vitamin B12 levels is recommended, since folic acid may mask vitamin B12 deficiency, particularly in adults aged 50 years and older.

Adverse Reactions

The frequency and severity of adverse reactions usually depend on the dose, route of administration, and duration of methotrexate therapy. Since severe adverse reactions may occur even at low doses and at any stage of treatment, continuous medical supervision is required.

Most adverse effects are reversible if detected early. However, serious adverse reactions may in individual cases lead to sudden death.

Oral mucosal ulcers are usually the first sign of toxicity.

If adverse reactions occur, depending on their severity and intensity, the dose should be reduced or therapy discontinued, and appropriate measures taken (see section "Overdose"). Resuming methotrexate therapy should be done cautiously, with careful reassessment of its necessity, as recurrence of toxicity is possible.

The most serious adverse reactions associated with the use of Metotrexat Rompharm include thrombocytopenia, leukopenia, headache, dizziness, cough, loss of appetite, diarrhea, abdominal pain, nausea, vomiting, inflammation and ulcers of the mucous membranes of the mouth and throat (especially within the first 24–48 hours after methotrexate administration), increased liver enzymes and bilirubin, alopecia, decreased creatinine clearance, exhaustion, and malaise.

The most serious adverse reactions associated with the use of the drug include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolism, anaphylactic shock, and Stevens-Johnson syndrome.

The most commonly observed adverse reactions are hematopoietic system suppression and gastrointestinal disorders.

The frequency of the adverse reactions listed below is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations:

common – herpes zoster;
uncommon – opportunistic infections (which may be fatal in some cases);
rare – sepsis (including fatal outcomes);
very rare – herpes hepatitis, cryptococcosis, histoplasmosis, cytomegalovirus infections (including pneumonia), disseminated simple herpes, nocardiosis, Pneumocystis jirovecii-induced pneumonia;
frequency not known – pneumonia, reactivation of hepatitis B infection, worsening of hepatitis C infection.

Cardiac disorders:

very rare – pericarditis, exudative pericarditis, pericardial tamponade.

Blood and lymphatic system disorders:

very common – thrombocytopenia, leukopenia;
common – anemia, pancytopenia, bone marrow suppression, agranulocytosis;
rare – megaloblastic anemia;
very rare – aplastic anemia, lymphadenopathy (partially reversible), lymphoproliferative disorders, eosinophilia, neutropenia.

Immune system disorders:

uncommon – allergic reactions, anaphylactic shock, immunosuppression;
very rare – hypogammaglobulinemia.

Metabolism and nutrition disorders:

uncommon – diabetes mellitus.

Psychiatric disorders:

uncommon – depression;
rare – mood changes, transient perception disturbances.

Nervous system disorders:

very common – headache, dizziness;
common – somnolence, paresthesia;
uncommon – hemiparesis, confusion, seizures, encephalopathy/leukoencephalopathy;
rare – paresis, speech disorders including dysarthria and aphasia;
very rare – muscle weakness and limb pain, taste alterations (metallic taste in mouth), acute aseptic meningitis with meningeal syndrome (paralysis, vomiting), cranial nerve syndrome;
frequency not known – neurotoxicity, arachnoiditis, paraplegia, stupor, ataxia, increased cerebrospinal fluid pressure, dementia.

Eye disorders:

common – conjunctivitis;
rare – visual disturbances, severe retinal venous thrombosis;
very rare – periorbital edema, blepharitis, epiphora, photophobia, temporary blindness, vision loss;
frequency not known – retinopathy.

Benign, malignant and unspecified neoplasms (including cysts and polyps):

uncommon – malignant lymphoma;
frequency not known – skin cancer (see section "Interaction with other medicinal products and other forms of interaction").

Vascular disorders:

uncommon – vasculitis, allergic vasculitis;
rare – hypotension, thromboembolic events (including arterial thrombosis, cerebral vessel thrombosis, thrombophlebitis, deep vein thrombosis).

Respiratory, thoracic and mediastinal disorders:

very common – cough;
common – pulmonary complications due to interstitial alveolitis/pneumonitis, which may be fatal (regardless of methotrexate dose and treatment duration);
uncommon – pulmonary fibrosis, pleural effusion;
rare – pharyngitis, respiratory failure, pulmonary embolism;
very rare – chronic interstitial lung disease, bronchial asthma-like reactions with cough, dyspnea, pathological findings in lung function tests;
frequency not known – pulmonary alveolar hemorrhage, hypoxia.

Gastrointestinal disorders:

very common – loss of appetite, diarrhea (especially within the first 24–48 hours after methotrexate administration), nausea, vomiting, abdominal pain, inflammation and ulcers of the oral and pharyngeal mucosa (especially within the first 24–48 hours after methotrexate administration);
uncommon – pancreatitis, gastrointestinal ulcers and hemorrhage;
rare – enteritis, gingivitis, melena;
very rare – hematemesis;
frequency not known – non-infectious peritonitis, toxic megacolon, intestinal perforation, glossitis.

Hepatobiliary disorders:

very common – increased activity of liver enzymes (ALT (GPT), AST (GOT)), alkaline phosphatase, and bilirubin;
uncommon – hepatotoxicity, fatty liver, chronic liver fibrosis and cirrhosis, decreased serum albumin;
rare – acute hepatitis;
very rare – acute liver necrosis, acute liver degeneration, liver failure (see section "Special precautions for use").

Skin and subcutaneous tissue disorders:

very common – alopecia;
common – exanthema, erythema, pruritus, skin ulcers;
uncommon – photosensitivity reactions (sunburn-like reactions due to increased skin sensitivity to sunlight); severe toxic reactions: herpes-like skin eruptions, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome); urticaria, increased skin pigmentation, nodulosis, painful psoriatic plaque lesions (psoriatic lesions may be exacerbated by UV radiation when methotrexate is used concurrently (see section "Special precautions for use")), impaired wound healing;
rare – acne, increased nail pigmentation, onycholysis, acneiform eruptions, petechiae, ecchymoses, erythema multiforme, erythematous rashes;
very rare – acute paronychia, furunculosis, telangiectasia;
frequency not known – drug reaction with eosinophilia and systemic symptoms (DRESS), dermatitis.

Musculoskeletal and connective tissue disorders:

uncommon – arthralgia, myalgia, osteoporosis;
rare – stress fractures;
frequency not known – osteonecrosis, jaw osteonecrosis (secondary to lymphoproliferative disorders).

Renal and urinary disorders:

very common – decreased creatinine clearance;
uncommon – nephropathy, renal failure, cystitis and bladder ulcers (possibly with hematuria), urinary disorders, dysuria, oliguria, anuria;
rare – hyperuricemia, increased serum urea and creatinine concentration, azotemia;
very rare – hematuria, proteinuria.

General disorders and administration site conditions:

very common – asthenia;
uncommon – pyrexia;
frequency not known – chest pain, chills, injection site necrosis.

Pregnancy, puerperium and perinatal disorders:

uncommon – fetal developmental abnormalities;
rare – abortion;
very rare – fetal death.

Reproductive system and breast disorders:

uncommon – vaginal inflammation and ulcers;
rare – transient oligospermia, transient menstrual disorders;
very rare – impaired oogenesis/spermatogenesis, menstrual cycle disturbances, loss of libido, impotence, vaginal discharge, infertility, gynecomastia;
frequency not known – genitourinary dysfunction.

Description of selected adverse reactions

Lymphoma or lymphoproliferative disorders:

Isolated cases of lymphoma and other lymphoproliferative disorders have been reported, some of which resolved after discontinuation of methotrexate therapy.

Following intramuscular administration of methotrexate, adverse effects (burning sensation, sterile abscess formation, fat tissue necrosis) at the injection site are usually observed. Subcutaneous administration of methotrexate is generally well tolerated. Only minor local skin reactions have been observed, which disappeared during treatment.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging to protect from light at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Incompatibilities.

In the absence of compatibility studies, Metotrexat Rompharm must not be mixed with other medicinal products.

Packaging.

0.75 ml, 1 ml, 1.5 ml, or 2 ml in a pre-filled syringe; 1 syringe in a blister; 1 blister with a single-use needle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer/Marketing Authorization Holder.

K.T. Rompharm Company S.R.L.

Manufacturer's address and location of operations.

Strada Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania – Rompharm 1 and Rompharm 2 buildings.