Remidject

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Remiject (Remiject)

Composition:

Active substance: methotrexate;

1 ml of solution contains methotrexate 25 mg;

Excipients: sodium chloride, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment), water for injections, nitrogen gas.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear yellow solution, free from visible particles.

Pharmacotherapeutic group.

Antimetabolites. Structural analogues of folic acid. ATC code L01BA01.

Pharmacological properties.

Pharmacodynamics.

Methotrexate is a folic acid antagonist belonging to the class of cytotoxic agents known as antimetabolites. It partially enters the cell via active transport to reduce intracellular levels of reduced folic acid and binds tightly within. Methotrexate acts by competitively inhibiting the enzyme dihydrofolate reductase, thereby suppressing DNA and RNA synthesis. The mechanism of action—whether anti-inflammatory or immunosuppressive—responsible for methotrexate's efficacy in treating rheumatoid arthritis, psoriasis, psoriatic arthritis, chronic polyarthritis, and Crohn’s disease has not yet been fully elucidated. Dihydrofolate reductase must convert dihydrofolate into tetrahydrofolate before it can act as a carrier for C1 groups in the synthesis of purine nucleotides and thymidylates. By inhibiting dihydrofolate reductase, methotrexate causes intracellular folate accumulation and suppresses DNA synthesis, repair, and replication. Thymidylate synthesis is inhibited at extracellular concentrations of free methotrexate starting from 10⁻⁸ mol/L, and purine synthesis from 10⁻⁷ mol/L. The affinity of dihydrofolate reductase for methotrexate is significantly higher than its affinity for folic acid or dihydrofolate; therefore, even simultaneous addition of large amounts of folic acid does not alter methotrexate's effects. Additionally, methotrexate increases intracellular levels of deoxyadenosine triphosphate, which normally inhibits ribonucleotide and polynucleotide ligases—enzymes involved in DNA synthesis and repair. Rapidly proliferating tissues, such as malignant tumor cells, bone marrow, fetal cells, oral and intestinal mucosa, spermatogonia, and bladder cells, are generally more sensitive to methotrexate.

In psoriasis, the replication rate of skin epithelial cells is significantly higher than normal. This difference in proliferation rate forms the basis for using methotrexate to control the psoriatic process.

International clinical guidelines recognize methotrexate as a second-line agent for patients with Crohn’s disease who are intolerant of or unresponsive to first-line immunomodulators such as azathioprine (AZA) or 6-mercaptopurine (6-MP).

Adverse reactions observed in studies using methotrexate in Crohn’s disease at cumulative doses showed no difference in the safety profile compared to the already known profile. Therefore, similar precautions should be taken when using methotrexate for Crohn’s disease as for other rheumatic and non-rheumatic indications (see sections "Special precautions" and "Use during pregnancy or breastfeeding").

Pharmacokinetics.

Absorption

Following oral administration, methotrexate is absorbed from the gastrointestinal tract. With low-dose administration (7.5–80 mg/m² body surface area (BSA)), mean bioavailability is approximately 70%, although considerable inter- and intra-individual variations (25–100%) may occur. Maximum serum concentration (Cmax) is reached within 1–2 hours. Bioavailability after subcutaneous, intravenous, and intramuscular administration is equivalent and approximately 100%.

After intramuscular administration, methotrexate is rapidly and completely absorbed. Cmax is achieved within 0.25–2 hours.

Distribution

Following intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight), followed by a later volume of approximately 0.4–0.8 L/kg (40–80% of body weight). Methotrexate competes with reduced folates for carrier-mediated active transport across cell membranes. At serum concentrations above 100 µmol/L, passive diffusion becomes the primary transport pathway, enabling effective intracellular concentrations. Approximately 50% of methotrexate is protein-bound in plasma.

Methotrexate reaches the highest concentrations in the liver, kidneys, gallbladder, spleen, small and large intestine, and skin. Methotrexate slowly enters and subsequently re-enters from the so-called "third space" (pleural effusion and ascites) after a delay, potentially increasing toxicity. At low doses, methotrexate penetrates into internal fluids in minimal amounts; at high doses (300 mg/kg body weight), methotrexate concentration in cerebrospinal fluid was 4–7 µg/mL.

Small amounts of methotrexate have been detected in saliva and breast milk, and it crosses the placenta.

Biotransformation

At low doses, methotrexate undergoes minimal biotransformation. After high-dose administration, methotrexate is metabolized in the liver to 7-hydroxymethotrexate and 2,4-diamino-10-methylpteroic acid, and intracellularly to polyglutamated forms, which can be reconverted to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthase. Small amounts of methotrexate polyglutamates may persist in tissues for prolonged periods. The retention and prolonged effect of these active metabolites vary among different cells, tissues, and tumors.

The elimination half-life of methotrexate during low-dose therapy (≤ 30 mg/m² BSA) is approximately 3–10 hours. In patients receiving high-dose methotrexate, the elimination half-life is 8–15 hours.

In children receiving methotrexate for juvenile idiopathic arthritis (JIA) (3.75–26.2 mg/m² BSA), the elimination half-life is 0.9–2.3 hours.

Elimination

Methotrexate is primarily excreted unchanged by the kidneys via glomerular filtration and active secretion in the proximal tubules, and depends on dosage and route of administration. Approximately 5–20% of methotrexate and 1–5% of 7-hydroxymethotrexate are excreted in bile. Methotrexate undergoes significant enterohepatic recirculation. The average elimination half-life is 6–7 hours, with considerable variability (3–17 hours). The half-life may increase up to fourfold from normal in patients with impaired fluid drainage (pleural effusion, ascites).

After intravenous administration, methotrexate is eliminated following an initial distribution phase lasting several minutes, then during a second 12–24-hour phase with a plasma half-life of 2–3 hours, and during a third phase with a plasma half-life of 12–24 hours. Impaired renal function may delay elimination, potentially leading to serious adverse effects. A significant correlation has been observed between methotrexate and endogenous creatinine clearance. Total methotrexate clearance averages 12 L/hour but varies widely and generally decreases at higher doses. Delayed elimination is one of the main causes of methotrexate toxicity. Impaired elimination due to liver dysfunction is not well documented.

Preclinical safety data.

Chronic toxicity

Chronic toxicity studies in mice, rats, and dogs revealed toxic effects including gastrointestinal lesions, myelosuppression, and hepatotoxicity.

Mutagenic and carcinogenic potential

Long-term studies in rats, mice, and hamsters on mutagenicity and carcinogenicity showed no evidence of increased oncogenic potential of methotrexate. Methotrexate induces gene and chromosomal mutations both in vitro and in vivo, indicating a potential mutagenic effect in humans.

Reproductive toxicity

Teratogenic effects were observed in four animal species (rats, mice, rabbits, cats). No abnormalities were observed in rhesus macaques compared to those seen in humans.

Clinical characteristics.

Indications.

• Active form of rheumatoid arthritis in adult patients.
• Severe polyarticular form of juvenile (idiopathic) arthritis in children aged 3 years and older, in cases of inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs).
• Severe generalized disabling psoriasis, particularly plaque-type, and psoriatic arthritis, when conventional therapy has been ineffective.
• Mild to moderate Crohn’s disease (as monotherapy or in combination with corticosteroids) in adults, in cases of resistance or intolerance to thiopurines.

Contraindications.

• Hypersensitivity to methotrexate or to any of the excipients of the medicinal product.
• Severe and/or existing active infections (e.g., stomatitis, gastrointestinal ulcers).
• Severe renal impairment (creatinine clearance less than 30 mL/min).
• Marked hepatic dysfunction.
• Existing or pre-existing hematopoietic disorders such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or severe anemia.
• Alcohol abuse (alcohol-induced liver disease or other chronic liver diseases).
• Immunodeficiency.
• Concomitant vaccination with live vaccines.
• Pregnancy and breastfeeding.

Special safety precautions.

Special precautions during handling and disposal of the medicinal product must comply with requirements established for cytotoxic agents.

Pregnant women must not handle or administer the cytotoxic medicinal product Remidject.

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

Interaction with other medicinal products and other forms of interaction.

The use of nitrous oxide (laughing gas) enhances the effect of methotrexate on folate metabolism and may lead to increased toxicity, e.g., unpredictable severe bone marrow suppression and stomatitis. Although adverse effects can be reduced by administration of calcium folinate, concomitant use of nitrous oxide and methotrexate should be avoided.

L-asparaginase has an antagonistic effect on methotrexate when used concomitantly.

In animal experiments, NSAIDs, including salicylic acid, caused reduced tubular secretion of methotrexate and, consequently, increased its toxic effects. Therefore, concomitant use of NSAIDs with low-dose methotrexate should be performed with caution. Serious adverse effects, including fatal outcomes, sudden severe bone marrow suppression, aplastic anemia, and gastrointestinal toxicity, have been reported with concomitant use of NSAIDs and high-dose methotrexate. Concurrent use is not recommended in patients with existing risk factors, such as borderline renal function.

Concomitant use of Remidject and other antirheumatic agents (e.g., gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine) has not been studied; therefore, increased toxicity of methotrexate cannot be excluded.

Concomitant use of proton pump inhibitors (PPIs), such as omeprazole, pantoprazole, and lansoprazole, may slow down or inhibit renal excretion of methotrexate, leading to elevated plasma levels of methotrexate and clinical signs and symptoms of methotrexate toxicity. Particular caution is required in patients with impaired renal function.

The risk of hepatotoxic effects of methotrexate is increased in patients with alcohol abuse and when used concomitantly with other hepatotoxic medicinal products, such as azathioprine, leflunomide, retinoids, sulfasalazine. Therefore, close monitoring is required for patients receiving hepatotoxic agents during methotrexate therapy. Alcohol consumption should be avoided during treatment with Remidject.

The following medicinal products may displace plasma protein-bound methotrexate, thereby increasing its bioavailability (indirect dose increase) and enhancing its toxicity: amidopyrine derivatives, para-aminobenzoic acid, barbiturates, doxorubicin, oral contraceptives, phenylbutazone, phenytoin, probenecid, salicylates, sulfonamides, tetracycline, tranquilizers, sulfonylureas, penicillins, pristinamycin, and chloramphenicol. Therefore, concomitant use of methotrexate with these agents should be closely monitored.

Reduced tubular secretion and, consequently, increased methotrexate toxicity due to indirect elevation of its blood levels (especially at low doses) may be caused by the following agents: para-aminobenzoic acid, NSAIDs, probenecid, salicylates, sulfonamides, and other weak organic acids; therefore, concomitant use of methotrexate should be carefully monitored.

Penicillins and sulfonamides may, in rare cases, reduce renal clearance of methotrexate, resulting in increased serum concentrations and enhanced toxicity to the hematopoietic system and gastrointestinal tract.

Ciprofloxacin reduces tubular secretion in the kidneys; therefore, methotrexate should be administered with this medicinal product under close supervision.

Oral antibiotics, such as tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics, may reduce methotrexate absorption, interfere with enterohepatic circulation due to inhibition of intestinal microflora, or suppress bacterial metabolism.

When treating with (prior) medicinal products that may have adverse effects on the bone marrow (e.g., amidopyrine derivatives, chloramphenicol, phenytoin, pyrimethamine, sulfonamides, trimethoprim/sulfamethoxazole, cytostatics), the possibility of severe hematological disorders due to methotrexate therapy should be considered. Concomitant use of methotrexate and metamizole may increase hematotoxicity, particularly in elderly patients.

Concomitant use of folate antagonists (e.g., sulfonamides, trimethoprim/sulfamethoxazole) may increase methotrexate toxicity. Therefore, particular caution is required in patients with existing folate deficiency. Conversely, concomitant use of medicinal products and vitamin preparations containing folic acid or its derivatives may reduce the efficacy of methotrexate.

Although the combination of methotrexate and sulfasalazine may enhance the efficacy of methotrexate due to sulfasalazine-induced inhibition of folic acid synthesis, thereby increasing the risk of adverse effects, such effects have been observed only in individual patients in a few studies.

Methotrexate may reduce the clearance of theophylline; therefore, theophylline plasma levels should be monitored when used concomitantly with methotrexate.

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

Combined use of methotrexate and leflunomide may increase the risk of pancytopenia.

Methotrexate increases plasma levels of mercaptopurines. Therefore, such combination may require dose adjustment.

Bone marrow suppression and reduced folate concentrations have been reported with concomitant use of triamterene and methotrexate.

Amiodarone has caused ulcerative skin lesions in patients receiving methotrexate for psoriasis treatment.

There have been reports of skin cancer development in some psoriasis patients undergoing concomitant treatment with methotrexate and PUVA therapy.

Concomitant use of the medicinal product with radiation therapy may increase the risk of soft tissue necrosis and osteonecrosis.

Phototoxicity may occur during methotrexate treatment; therefore, patients should be advised to limit exposure to sunlight and UV radiation.

During therapy with Remidject, vaccination with live vaccines should not be performed (see section "Special precautions for use").

Special precautions

Special warnings

The physician must specify the day of the week for administration of the drug in the prescription. The physician must also ensure that patients understand and remember that Remidject should be administered only once weekly, not daily. Patients must be clearly informed that the drug must be administered once a week, and incorrect (daily) use of the recommended dose may lead to fatal poisoning (see sections "Method of administration and dosage" and "Overdose"). In particular, fatal cases have been reported in elderly patients due to accidental daily administration of the weekly dose. Therefore, methotrexate must be prescribed and administered only by a physician with appropriate knowledge and experience in antimetabolite therapy, or under such physician's supervision. Due to the risk of severe or even fatal toxic reactions, the physician must inform the patient about all associated risks and necessary safety measures.

Fertility and reproductive capacity

Fertility

Oligospermia, menstrual cycle disturbances, and amenorrhea have been reported in patients during and shortly after therapy with methotrexate, leading to impaired fertility by affecting spermatogenesis and oogenesis during the period of use; however, these effects were reversible after discontinuation of therapy.

Teratogenicity – reproductive risk

Methotrexate causes embryotoxicity, miscarriage, and fetal developmental abnormalities. Therefore, potential effects on fertility, pregnancy loss, and congenital fetal malformations should be discussed with women of reproductive potential (see section "Use during pregnancy or breastfeeding"). Absence of pregnancy must be confirmed in women of reproductive age prior to administration of Remidject. Sexually active women must use effective contraception during treatment and for at least 6 months after completion of methotrexate therapy.

For recommendations on contraception for men, see section "Use during pregnancy or breastfeeding".

Toxicity

Psoriasis: Due to the risk of severe toxic reactions (which may be fatal), methotrexate should be used only in patients with severe, recalcitrant psoriasis who have not responded adequately to other therapies.

Patients undergoing treatment must be under close medical supervision to detect signs of toxic effects or adverse reactions and to assess them promptly. Patients must be informed about the potential benefits and risks (including early signs and symptoms of toxicity) of methotrexate therapy. Furthermore, they must be informed about the necessity of immediate medical consultation if symptoms of intoxication occur, and about ongoing monitoring of these symptoms (including regular laboratory tests).

Discontinuation of methotrexate does not always result in complete resolution of adverse effects that have occurred.

Methotrexate is slowly eliminated from *pathological fluid accumulations in body cavities* (so-called "third space"), such as ascites or pleural effusion, leading to a prolonged plasma half-life and unpredictable toxicity. These fluid accumulations should be removed by puncture prior to initiation of methotrexate therapy, if possible.

Hematopoietic system

Methotrexate may suppress hematopoiesis, causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. Initial signs of these life-threatening complications may include fever, sore throat, oral mucosal ulcers, flu-like symptoms, severe fatigue, and nasal or skin bleeding.

Megaloblastic anemia has been observed in elderly patients, particularly during prolonged therapy.

Liver function

Since methotrexate has hepatotoxic effects, additional hepatotoxic or potentially hepatotoxic drugs should not be used during treatment. Alcohol consumption should also be avoided or significantly limited.

Methotrexate may cause acute hepatitis and chronic, potentially fatal, hepatotoxicity (fibrosis and cirrhosis), although usually only after prolonged use. Persistent elevation of liver enzymes is frequently observed, which is typically transient and asymptomatic and not a precursor of subsequent liver disease.

Chronic toxicity usually occurs after prolonged use (over two years) and cumulative doses of at least 1.5 g. Studies in psoriatic patients have shown that hepatotoxicity depends on total cumulative dose, with increased risk due to alcohol abuse, obesity, diabetes, and in elderly patients. Liver biopsy after prolonged methotrexate therapy often reveals histological changes; fibrosis and cirrhosis of the liver have also been reported.

Methotrexate may cause reactivation of hepatitis B infection or exacerbation of hepatitis C, sometimes with fatal outcome. Some cases of hepatitis B reactivation occurred after discontinuation of methotrexate. Therefore, clinical and laboratory evaluations should be performed in patients with a history of hepatitis B or C to determine the appropriateness of methotrexate therapy. As a result, methotrexate treatment may be unsuitable for some patients.

Particular caution is required when treating patients with inactive chronic infections, such as herpes zoster or tuberculosis, due to possible reactivation.

Special caution is needed when treating patients with insulin-dependent diabetes mellitus, as isolated cases of cirrhosis have been reported during methotrexate therapy without prior elevation of transaminase activity.

Renal function

Since methotrexate is primarily excreted by the kidneys, impaired renal function may lead to increased serum concentration and prolonged elimination, potentially resulting in serious adverse effects.

Methotrexate therapy should be administered with particular caution and at lower doses in patients with impaired renal function (e.g., elderly patients) due to delayed methotrexate elimination in these patients (see section "Method of administration and dosage"). Concomitant use of methotrexate with NSAIDs is not recommended if risk factors such as renal dysfunction, including mild renal impairment, are present.

Renal function may deteriorate during methotrexate therapy, accompanied by increased levels of certain laboratory parameters (serum creatinine, urea, and uric acid), potentially leading to acute renal failure with oliguria/anuria. This is likely due to precipitation of methotrexate and its metabolites in renal tubules.

Conditions leading to dehydration, such as vomiting, diarrhea, or stomatitis, may increase methotrexate toxicity due to elevated drug levels. In such cases, supportive therapy should be initiated, and discontinuation of methotrexate should be considered until symptoms resolve.

Gastrointestinal disorders

If ulcerative stomatitis or diarrhea, hematemesis, melena, or blood in stools occurs, further therapy should be discontinued, otherwise hemorrhagic enteritis and death due to intestinal perforation may occur.

Immune system

Since methotrexate affects the immune system, it may alter response to vaccination and affect results of immunological tests (immunological methods for determining immunoreactivity). Vaccinations administered during methotrexate therapy may be ineffective. Due to increased risk of infection, live vaccines should not be administered during methotrexate therapy.

Lung function

Particular caution is recommended for patients with impaired lung function.

Pulmonary complications, pleural effusion, alveolitis, or pneumonitis with symptoms such as dry non-productive cough, fever, malaise, cough, chest pain, dyspnea, hypoxemia, and radiologically detected infiltrate or nonspecific pneumonia occurring during methotrexate therapy may indicate potentially dangerous and possibly fatal lung injury. Lung biopsies have yielded various results (e.g., interstitial edema, presence of mononuclear infiltrates, or caseous granuloma). If such complications are suspected, methotrexate therapy should be immediately discontinued and a thorough evaluation performed to exclude infection or tumor. Methotrexate-induced lung disease may begin suddenly at any stage of therapy, may not resolve completely, and has been observed even with low doses – 7.5 mg/week.

Pulmonary alveolar hemorrhage has been reported during methotrexate therapy for rheumatological and similar indications. This phenomenon may also be associated with vasculitis and other concomitant diseases. Rapid tests should be considered to confirm diagnosis in suspected cases of pulmonary alveolar hemorrhage.

Potentially fatal opportunistic infections, including Pneumocystis jirovecii pneumonia, may occur during methotrexate therapy. In patients with symptoms of impaired lung function, Pneumocystis jirovecii pneumonia should be considered.

Skin and subcutaneous tissue disorders

Severe, sometimes fatal, skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) have been reported after single or prolonged administration of methotrexate.

Psoriatic lesions may worsen after UV exposure during concomitant methotrexate therapy. Photosensitization may occur with methotrexate use. After methotrexate administration, there is a risk of recurrence of dermatitis and radiation-induced sunburns (so-called "anamnestic" reactions).

Neoplasms

Cases of malignant lymphoma have been reported in patients receiving low-dose methotrexate, which in some cases resolved after discontinuation of methotrexate therapy. If lymphoma develops, methotrexate therapy should be discontinued first, and specific treatment initiated only if the lymphoma does not regress.

Recent studies have not shown increased incidence of lymphoma during methotrexate therapy.

Nervous system

Intravenous administration of methotrexate may lead to acute encephalitis and acute fatal encephalopathy. Cases of leukoencephalopathy have been reported in patients taking methotrexate.

Folic acid preparations

Folate deficiency may increase methotrexate toxicity (see section "Interaction with other medicinal products and other forms of interaction").

Administration of folates or folic acid may reduce methotrexate toxicity (gastrointestinal symptoms, stomatitis, alopecia, and elevated liver enzymes).

Before taking folic acid preparations, vitamin B12 levels should be checked, as folate intake may mask vitamin B12 deficiency, especially in patients aged 50 years and older.

Recommended medical monitoring and safety measures

Careful monitoring of patients is required during methotrexate therapy, using adequate hydration, urine alkalinization, measurement of methotrexate concentration in serum and kidneys, for prompt detection of intoxication symptoms.

Before starting therapy, the following should be performed: complete blood count with differential platelet count, liver enzyme tests (ALT, AST), bilirubin, serum albumin, hepatitis screening (A, B, C), renal function tests (if necessary, creatinine clearance), and, if needed, chest X-ray, lung function tests, and tests to exclude tuberculosis.

During therapy (weekly for the first 2 weeks, every 2 weeks for the next month, then at least once a month depending on leukocyte count and patient stability); frequency of monitoring should be increased when dosage is changed or drug levels in blood are elevated (e.g., due to dehydration) due to increased toxicity:

1. Examination of the oral cavity and throat to detect *mucosal changes*.
2. *Complete blood count with differential platelet count*. Methotrexate administration should be immediately discontinued if significant reduction in blood cell counts is observed. Hematopoiesis suppression caused by methotrexate may occur suddenly even with apparently safe doses. Any significant reduction in leukocyte or platelet counts requires immediate discontinuation of the drug and appropriate supportive treatment. Patients should be strongly advised to report all symptoms indicating infection. Platelet count should be carefully monitored in patients concomitantly taking hematotoxic drugs (e.g., leflunomide).
3. *Liver enzyme tests in serum*. Particular attention should be paid to the development of hepatotoxicity. Treatment should not be initiated or should be discontinued if any abnormalities in liver function tests or liver biopsy occur or develop during therapy. Such disorders should normalize within 2 weeks, after which therapy may be resumed if the physician deems it necessary. However, there is no evidence supporting the necessity of liver biopsy for monitoring hepatotoxicity in rheumatological indications.

For psoriasis patients, the need for liver biopsy before or during treatment remains uncertain. Further studies are needed to determine whether serial liver chemical tests or measurement of type III collagen precursor levels are sufficient to detect hepatotoxicity. Such assessment is necessary to differentiate between patients without risk factors and those with risk factors such as prior alcohol abuse, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver diseases, diabetes, obesity, marked reaction to hepatotoxic drugs or chemicals, prolonged methotrexate therapy, or cumulative doses of 1.5 g or more. Transient elevation of transaminases 2–3 times above the upper limit of normal has been reported in 13–20% of patients during methotrexate use. Usually, this is not a reason to change the treatment regimen. However, persistent liver test abnormalities and/or decreased serum albumin levels may indicate severe hepatotoxicity.

Enzyme level determination does not reliably predict morphologically detectable liver damage; even with normal transaminase levels, liver fibrosis may be detected only histologically, and cirrhosis may rarely develop.

If persistent elevation of liver enzymes occurs, dose reduction or discontinuation of therapy should be considered. Methotrexate should be discontinued in patients with prolonged liver dysfunction. For severe forms of psoriasis, see also section 4 "Liver biopsy". Due to potential hepatotoxic effects, additional hepatotoxic drugs should not be taken during methotrexate therapy unless absolutely necessary, and alcohol consumption should be avoided or significantly reduced (see section "Interaction with other medicinal products and other forms of interaction"). More careful monitoring of liver enzyme levels is required in patients concomitantly taking other hepatotoxic drugs. Similar monitoring is also necessary when hematotoxic drugs (e.g., leflunomide) are used concomitantly.

1. *Liver biopsy*. When deciding on liver biopsy, current national guidelines and individual patient circumstances should always be considered, and alternative methods (e.g., type III collagen propeptide measurement) should be evaluated.

For longer-term treatment of severe psoriasis with Remidject, due to the risk of hepatotoxicity, liver biopsy should be performed. Patients with normal and increased risk of hepatotoxicity should be differentiated.

Patients without risk factors. According to current medical knowledge, liver biopsy is not necessary after reaching a cumulative dose of 1.0–1.5 g.

Patients with risk factors. Risk factors primarily include:

• history of alcohol abuse;
• persistent elevation of liver enzymes;
• history of hepatopathy, including chronic hepatitis B or C;
• hereditary hepatopathy in family history.

Also (with possible lower significance):

• diabetes;
• obesity;
• treatment with hepatotoxic drugs or chemotherapeutic agents.

Liver biopsy is recommended for such patients during or immediately after initiation of Remidject therapy. Since a small percentage of patients discontinue treatment for various reasons within 2–4 months, the first biopsy may be performed after the initial phase. Biopsy should be performed when long-term therapy is anticipated. Repeat liver biopsies are recommended after reaching a cumulative dose of 1.0–1.5 g.

For severe forms of rheumatoid arthritis and psoriatic arthritis, risk factors for hepatotoxicity may include patient age at first use and duration of treatment. In patients with rheumatoid arthritis, prolonged deviation from normal liver function test results may be a precursor of liver fibrosis or cirrhosis. Liver biopsy should be performed before therapy initiation in patients with suspected pre-existing liver disease. Liver biopsy is recommended during methotrexate therapy in patients with abnormal liver function test results that persist during and after methotrexate therapy. In cases of moderate liver fibrosis or cirrhosis, drug use should be discontinued; in cases of mild fibrosis, repeat biopsy is recommended after 6 months.

Liver biopsy is not necessary for the following patients:

• elderly patients;
• patients with acute illnesses;
• patients in whom liver biopsy is contraindicated (e.g., cardiac disorders, coagulation parameter abnormalities);
• patients with short life expectancy.

Appropriate physician monitoring according to national guidelines for methotrexate therapy is important for making therapeutic decisions.

1. *Monitoring of renal function/serum creatinine levels*. Renal function should be monitored by functional tests and urine analysis.

If serum creatinine levels increase, the dose should be reduced. Methotrexate therapy should not be used if serum creatinine exceeds 2 mg/dL or creatinine clearance is less than 30 mL/min (see sections "Contraindications" and "Method of administration and dosage").

Since methotrexate is primarily excreted by the kidneys, increased drug concentration in serum may occur in renal insufficiency, potentially leading to severe adverse effects such as renal dysfunction up to acute renal failure.

Patients with possible renal function impairment (e.g., elderly patients) should be monitored more frequently. This is particularly important during concomitant therapy with drugs that reduce methotrexate excretion, have adverse effects on kidneys (e.g., NSAIDs), or may cause hematopoietic system disorders.

1. Patient questioning regarding any symptoms of *pulmonary function impairment*, and, if necessary, pulmonary function testing if lung disease is suspected (e.g., interstitial pneumonia), especially if such indicators are present at initial examination.

More frequent checks may be necessary:

• during the initial treatment phase;
• when dosage is changed;
• during episodes of higher risk of increased methotrexate blood levels (e.g., dehydration, renal dysfunction, additional or increased doses of concomitantly administered drugs such as NSAIDs).

Lung injury requires prompt diagnosis and discontinuation of methotrexate therapy. Symptoms of lung injury (especially dry non-productive cough) or nonspecific pneumonia occurring during methotrexate therapy may indicate potentially dangerous injury and require discontinuation of therapy and full medical evaluation. Acute or chronic interstitial pneumonitis may develop, often with eosinophilia, and fatal cases have been reported. Despite clinical variability, typical symptoms in patients with methotrexate-induced lung disease include fever, cough, dyspnea, hypoxemia, and presence of infiltrate on chest X-ray; infection must be excluded. Lung effects require prompt diagnosis and discontinuation of methotrexate therapy. These injuries may occur with any dose of the drug.

Progressive multifocal leukoencephalopathy

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients using methotrexate, primarily in combination with other immunosuppressive drugs. PML may have fatal outcomes. This should be considered in differential diagnosis in immunocompromised patients with worsening or new neurological symptoms.

Elderly patients

Elderly patients should be examined at short intervals for early signs of toxicity. Dose adjustment should be considered due to age-related decline in liver and kidney function (see section "Method of administration and dosage").

Children and adolescents

Methotrexate therapy in children and adolescents should be prescribed and monitored only by specialists with sufficient experience in diagnosis and treatment of the relevant disease.

Information on excipients

Remidject contains sodium, but less than 1 mmol (23 mg) of sodium per pre-filled syringe.

Use during pregnancy or breastfeeding.

Women of reproductive age

Women should not become pregnant during methotrexate therapy, and must use effective contraception during treatment and for at least 6 months after completion of methotrexate therapy (see section "Special precautions"). Before starting therapy, women of reproductive age must be informed about the risk of fetal malformations. Furthermore, current pregnancy must be excluded by appropriate methods, such as pregnancy test. During therapy, pregnancy tests should be performed as clinically indicated (e.g., if contraception was not used). Women of reproductive age should receive counseling on pregnancy prevention and planning.

Contraception recommendations for men

There are no data on methotrexate accumulation in sperm. Genotoxicity of methotrexate has been observed in animal studies; therefore, genotoxic effects on spermatozoa cannot be completely excluded. Limited clinical data do not indicate increased risk of developmental abnormalities or miscarriage after paternal exposure to low doses of methotrexate (less than 30 mg per week). Insufficient data are available to assess the risk of developmental abnormalities or miscarriage after paternal exposure to higher doses.

As a precautionary measure, sexually active male patients or their partners are recommended to use reliable contraception during male patient's therapy and for at least 3 months after completion of methotrexate therapy. Men should not be sperm donors during this period.

Pregnancy

Use of Remidject for non-oncological indications during pregnancy is contraindicated (see section "Contraindications"). If a patient becomes pregnant during methotrexate therapy or within 6 months after completion of therapy, she must be informed about the risk of negative effects of methotrexate on the fetus. Ultrasound examinations should also be performed to confirm normal fetal development.

Reproductive toxicity of methotrexate has been observed in animal studies, particularly in the first trimester. Teratogenic effects of methotrexate have been reported; fetal death, miscarriage, and/or congenital abnormalities (e.g., craniofacial, cardiovascular, central nervous system, and limb developmental defects) have been reported.

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 occurred in 42.5% of pregnant women who used low-dose methotrexate (less than 30 mg per week), compared to 22.5% in patients who used other drugs.
• Significant congenital defects occurred in 6.6% of live-born children whose mothers used low-dose methotrexate (less than 30 mg per week) during pregnancy, compared to approximately 4% of live-born children whose mothers used other drugs.

Insufficient data are available on methotrexate use during pregnancy at doses exceeding 30 mg per week, but a higher frequency of spontaneous abortions and congenital malformations is expected. Normal pregnancy outcomes have been reported after discontinuation of methotrexate before conception.

Period of breastfeeding

Since methotrexate is excreted in breast milk and may cause toxic effects on breastfed infants, the drug is contraindicated during breastfeeding (see section "Contraindications"). Breastfeeding must therefore be discontinued before and during therapy.

Fertility

Methotrexate affects oogenesis and spermatogenesis and may reduce fertility. Oligospermia, menstrual cycle disturbances, and amenorrhea have been reported in humans. These effects are usually reversible after discontinuation of therapy. Since methotrexate may have genotoxic effects, women who wish to become pregnant are recommended to consult a genetic counseling center, if possible, before starting therapy, and men are recommended to consider sperm cryopreservation before starting treatment.

Ability to affect reaction speed when driving or operating machinery.

During Remidject therapy, patients should refrain from driving or operating machinery, as adverse effects on the central nervous system such as fatigue and dizziness may occur (see section "Adverse reactions"). These effects usually occur in combination with alcohol.

Method of administration and dosage.

Remidject should only be prescribed by physicians experienced in the use of the drug and who are fully aware of all the risks associated with methotrexate therapy.

Dosing

Remidject is administered once a week! The patient must be clearly informed about the necessity of using the drug once a week! It is advisable to establish a fixed day of the week as the injection day.

Adult patients with rheumatoid arthritis

The recommended initial dose is 7.5 mg of methotrexate once a week. The physician must specify the day of the week for administration in the prescription.

Depending on the course of the disease and the patient's tolerance of the drug, the initial dose may be gradually increased by 2.5 mg. Additionally, treatment may be initiated with a higher dose. The average weekly dose is 15–20 mg of methotrexate. The weekly dose of methotrexate should not exceed 20 mg. After achieving the desired therapeutic effect, the dose should be gradually reduced to the lowest effective maintenance dose. A response to treatment can usually be expected within approximately 4–8 weeks. After discontinuation of treatment, symptoms may return.

Children (from 3 years of age) and adolescents with polyarticular juvenile (idiopathic) arthritis

The recommended dose is 10–15 mg/m² BSA once a week. The physician must indicate the day of the week for administration in the prescription. If the response is inadequate, the weekly dose may be increased to 20–30 mg/m² BSA per week. However, with dose escalation, monitoring should be performed more frequently.

Due to the lack of available information on use in children and adolescents, intravenous administration should be replaced with subcutaneous or intramuscular administration.

Severe forms of psoriasis and psoriatic arthritis

Recommended initial dose (based on an average adult with a body weight of 70 kg): a single dose of 2.5 mg prior to starting treatment to detect toxicity. The physician must specify the day of the week for administration in the prescription.

If laboratory parameters remain unchanged, treatment should be continued at a dose of approximately 7.5 mg of methotrexate once a week. The dose should be gradually increased (in increments of 5–7.5 mg per week), with monitoring of laboratory parameters, until the optimal therapeutic response is achieved. Usually, the maximum weekly dose of methotrexate should not exceed 25 mg. From the moment the desired therapeutic effect is achieved, the dose should be gradually reduced to the lowest effective maintenance dose, as far as possible. A response to treatment can be expected within approximately 4–8 weeks. After this, therapy should be continued or discontinued according to the clinical picture and changes in laboratory parameters.

Duration of treatment

The physician decides on the duration of treatment. Treatment with Remidject for severe forms of rheumatoid arthritis, juvenile (idiopathic) arthritis, psoriasis, and psoriatic arthritis is long-term.

Elderly patients

Methotrexate should be used with particular caution in elderly patients. Dose adjustment should be considered in elderly patients due to reduced liver and kidney function, as well as decreased folate stores.

Maximum weekly dose

The dose should be increased as needed, but it generally should not exceed the maximum recommended weekly dose of 25 mg. In some cases, a higher dose may be clinically justified, but it should not exceed a maximum weekly dose of 30 mg of methotrexate, as toxicity increases significantly.

Patients with Crohn's disease

• Induction therapy.

25 mg once a week – should be administered subcutaneously, intramuscularly, or intravenously.

• Maintenance therapy.

15 mg once a week – should be administered subcutaneously, intramuscularly, or intravenously.

Methotrexate is not recommended for the treatment of Crohn's disease in children due to insufficient experience with its use in this patient population.

Patients with renal impairment

Remidject should be prescribed with caution to patients with impaired kidney function (see sections "Contraindications" and "Special precautions"). The dose should be adjusted as follows:

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.

Methotrexate is contraindicated if bilirubin levels exceed 5 mg/dL (85.5 µmol/L).

Route of administration

Remidject can be administered subcutaneously, intramuscularly, or intravenously. In children (aged 3 years and older) and adolescents, it should be administered only subcutaneously or intramuscularly.

Intravenous administration in adult patients should be performed as a bolus injection. Contact of methotrexate with skin and mucous membranes must be avoided. In case of contact with skin, affected areas should be immediately washed thoroughly with large amounts of water.

Children.

The medicinal product is used in children aged 3 to 16 years for polyarticular juvenile (idiopathic) arthritis. The use of the drug in 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

Post-marketing experience with the drug indicates cases of overdose following oral, intravenous, or intramuscular administration. Reports of oral overdose describe weekly doses accidentally taken daily (either as a single dose or divided into multiple doses).

Symptoms observed in such cases typically involved hematological and gastrointestinal reactions, including leukopenia, thrombocytopenia, anemia, pancytopenia, neutropenia, bone marrow suppression, mucositis, stomatitis, oral ulcers, nausea, vomiting, gastrointestinal ulceration and bleeding. In some cases, no symptoms of intoxication were observed. There have also been reports of fatal outcomes due to overdose. In such cases, sepsis, septic shock, renal failure, and aplastic anemia were also reported.

Treatment

The specific antidote for methotrexate is calcium folinate, which neutralizes the adverse toxic effects of methotrexate. In cases of decreased leukocyte counts following low-dose methotrexate (e.g., 6–12 mg), intravenous or intramuscular calcium folinate therapy should be initiated as soon as possible, followed by multiple administrations (at least 4 times) of the same dose at 3–6 hour intervals.

The effectiveness of calcium folinate decreases with increasing time interval between methotrexate and calcium folinate administration. To determine the optimal dose and duration of calcium folinate administration, serum methotrexate levels should be monitored.

In cases of significant overdose, hydration and urinary alkalinization are required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. If intoxication is caused by markedly delayed elimination (monitor serum methotrexate levels), for example due to acute renal failure, hemodialysis and/or hemoperfusion should be performed. Effective methotrexate clearance can be achieved through intensive intermittent hemodialysis using high-permeability dialyzers. Neither standard hemodialysis nor peritoneal dialysis significantly enhance methotrexate elimination.

Adverse Reactions

The frequency and severity of adverse reactions usually depend on the dose and duration of methotrexate use. Since severe adverse reactions may occur even at low doses and at any time during therapy, regular physician monitoring at short intervals is required. Most adverse reactions are reversible if detected early. However, some severe adverse reactions may, in very rare cases, lead to fatal outcomes.

If adverse reactions occur, depending on their severity and intensity, the dose of the drug should be reduced or therapy discontinued, and appropriate measures taken (see section "Overdose"). Resumption of methotrexate treatment should be done cautiously, with careful assessment of the necessity of therapy and increased vigilance for possible recurrence of toxic effects.

The most common adverse reactions include thrombocytopenia, leukopenia, headache, dizziness, cough, loss of appetite, diarrhea, abdominal pain, nausea, vomiting, inflammation and ulceration of the mucous membranes of the oral cavity and throat (especially within the first 24–48 hours after methotrexate administration), increased levels of liver enzymes and bilirubin, alopecia, decreased creatinine clearance, exhaustion, and malaise.

Ulceration of the oral mucosa is usually the first clinical sign of toxicity.

When assessing adverse effects, their frequency 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, sometimes with fatal outcome.

Rare: Sepsis (in some cases may be fatal).

Very rare: Herpes simplex encephalitis, cryptococcosis, histoplasmosis, cytomegalovirus infections (including pneumonitis), disseminated herpes simplex virus, nocardiosis, Pneumocystis jirovecii-induced pneumonia.

Frequency not known: Pneumonia, reactivation of hepatitis B, exacerbation of hepatitis C.

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

Uncommon: Malignant lymphomas*.

Frequency not known: Skin cancer (see section "Interaction with other medicinal products and other forms of interaction").

Blood and lymphatic system disorders*

Very common: Thrombocytopenia, leukopenia.

Common: Anemia, pancytopenia, bone marrow suppression, agranulocytosis.

Rare: Megaloblastic anemia.

Very rare: Aplastic anemia, eosinophilia, neutropenia, lymphadenopathy (partially reversible), lymphoproliferative disorders1.

Immune system disorders

Uncommon: Allergic reactions up to anaphylactic shock, immunosuppression.

Very rare: Hypogammaglobulinemia.

Metabolism and nutrition disorders

Uncommon: Diabetes mellitus.

Psychiatric disorders

Uncommon: Depression.

Rare: Mood swings, transient cognitive disorders.

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: Muscular asthenia and limb pain, taste alterations (metallic taste in the mouth), meningeal signs (paralysis, vomiting), acute aseptic meningitis, cranial nerve syndrome.

Frequency not known: Neurotoxicity, arachnoiditis, paraplegia, stupor, ataxia, dementia, increased cerebrospinal fluid pressure.

Eye disorders

Common: Conjunctivitis.

Rare: Visual disturbances such as severe retinal venous thrombosis.

Very rare: Periorbital edema, blepharitis, epiphora, photophobia, temporary blindness, loss of vision.

Frequency not known: Retinopathy.

Cardiac disorders

Very rare: Pericarditis, pericardial effusion, cardiac tamponade.

Vascular disorders

Uncommon: Vasculitis, allergic vasculitis.

Rare: Arterial hypotension, thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, thrombophlebitis).

Respiratory, thoracic and mediastinal disorders*

Very common: Cough.

Common: Lung disorders associated with interstitial alveolitis or pneumonitis, sometimes with fatal outcome (regardless of dose and duration of methotrexate treatment).

Uncommon: Pulmonary fibrosis, pleural effusion.

Rare: Pharyngitis, apnea, pulmonary embolism.

Very rare: Chronic obstructive pulmonary disease, bronchial asthma with cough, dyspnea, abnormal lung function tests.

Frequency not known: Hypoxia, pulmonary alveolar hemorrhage.

Gastrointestinal disorders*

Very common: Loss of appetite, diarrhea (especially within the first 24–48 hours after methotrexate administration), nausea, vomiting, abdominal pain, inflammation and ulceration of the oral and pharyngeal mucosa (especially within the first 24–48 hours after methotrexate administration).

Uncommon: Gastrointestinal ulcers and bleeding, pancreatitis.

Rare: Enteritis, melena, gingivitis.

Very rare: Hematemesis.

Frequency not known: Non-infectious peritonitis, toxic megacolon, intestinal perforation, glossitis.

Hepatobiliary disorders*

Very common: Increased levels of liver enzymes (ALT, AST, alkaline phosphatase) and bilirubin.

Uncommon: Hepatotoxicity, hepatic steatosis, chronic cirrhosis and liver fibrosis, decreased serum albumin levels.

Rare: Acute hepatitis.

Very rare: Liver failure, acute liver necrosis, acute liver disintegration (for information on liver biopsy, see section "Special warnings and precautions for use").

Skin and subcutaneous tissue disorders*

Very common: Alopecia.

Common: Exanthema, erythema, pruritus, photosensitization, skin ulcers.

Uncommon: Severe toxic skin reactions such as herpes-like skin eruptions, Stevens-Johnson syndrome*, toxic epidermal necrolysis (Lyell's syndrome)*; urticaria, increased skin pigmentation, rheumatoid nodules, painful erosions of psoriatic plaques, impaired wound healing, photosensitization.

Rare: Increased nail pigmentation, acne, skin hemorrhages, erythema multiforme, ecchymosis, erythematous rashes, onycholysis.

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, ulcerative cystitis (possibly with hematuria), dysuria, oliguria, anuria, impaired urination.

Rare: Hyperuricemia, increased serum urea and creatinine concentrations, azotemia.

Very rare: Hematuria, proteinuria.

Pregnancy, puerperium and perinatal disorders

Uncommon: Congenital malformations of the fetus.

Rare: Spontaneous abortion.

Very rare: Intrauterine fetal death.

Reproductive system disorders

Uncommon: Vaginal ulcers and inflammation.

Rare: Temporary oligospermia, temporary menstrual cycle disturbances.

Very rare: Impaired oogenesis and spermatogenesis*, infertility*, menstrual cycle disturbances, loss of libido, impotence, vaginal discharge, gynecomastia.

Frequency not known: Urogenital dysfunction.

General disorders and administration site conditions

Very common: Asthenia.

Uncommon: Pyrexia.

Frequency not known: Chest pain, chills, injection site necrosis.

1Lymphoma/lymphoproliferative disorders: Isolated cases of lymphoma and other lymphoproliferative disorders have been reported, which sometimes resolved after discontinuation of methotrexate.

*See section "Special warnings and precautions for use" for detailed description of serious adverse reactions.

With intramuscular administration, local adverse reactions (burning sensation) or tissue damage (formation of sterile abscess, destruction of fatty tissue) may occasionally occur at the injection site.

Subcutaneous administration of methotrexate is well tolerated. Only minor local skin reactions, which resolve during treatment, have been observed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the drug. If any adverse reactions occur, healthcare professionals should be informed.

Shelf life.

24 months.

Storage conditions.

Store in the original packaging in a light-protected, child-resistant place at a temperature not exceeding 25 °C. Do not freeze.

Incompatibilities.

Do not mix with other medicinal products or solvents due to lack of comparative study data.

Packaging.

0.4 ml (10 mg), 0.6 ml (15 mg), 0.8 ml (20 mg), 1 ml (25 mg) in a pre-filled syringe, 1 syringe with integrated injection needle in a blister pack; 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Onko Ilac Sanayi ve Ticaret A.S./Onko Ilac Sanayi ve Ticaret A.S.

Manufacturer's address and place of business.

GOSB 1700. Sokak No: 1703, Cayirova, Kocaeli, Turkey/GOSB 1700. Sokak No: 1703, Cayirova, Kocaeli, Turkey.

Marketing authorization holder.

Amaxa Ltd/Amaxa Ltd.

Address of marketing authorization holder.

31 John Islip Street, London SW1P 4FE, United Kingdom/31 John Islip Street, London SW1P 4FE, United Kingdom.