Index of drugs

Active rheumatoid arthritis in adult patients. Polyarticular forms of severe active juvenile idiopathic arthritis if treatment with non-steroidal anti-inflammatory drugs (NSAIDs) has failed. Severe, refractory, leading to disability of psoriasis, in adult patients with an inadequate response to other treatments, such as phototherapy, photochemotherapy (PUVA) and retinoids, and severe psoriatic arthritis (psoriatic arthritis).

1 ml of solution contains 20 mg of Methotrexate (as a disodium salt).

A cytostatic of the anti-metabolite group, a folic acid antagonist. The action of methotrexate is based on the competitive inhibition of dihydrofolate reductase and consequently leads to inhibition of DNA synthesis. It also works immunosuppressively. After subcutaneous, intramuscular and intravenous administration, methotrexate bioavailability is similar. Methotrexate is approximately 50% bound to plasma proteins. In the distribution phase, it is accumulated mainly in the liver, kidneys and spleen in the form of polyglutamates that have been deposited in these organs for several weeks or months. Administered in small doses, it penetrates into body fluids in minimal amounts. In about 10% it is metabolized in the liver, the major metabolite is 7-hydroxymetrexate. It is excreted by the kidneys, mainly unchanged. About 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate are excreted in bile. Methotrexate is present in the enterohepatic circulation in significant quantities. The average final T_0,5 is 6-7 h and shows significant variability (3-17 h); T_0,5 It is prolonged in patients with impaired renal function, as well as in patients with pleural effusion or ascites.

Hypersensitivity to methotrexate or to any of the excipients. Severe hepatic impairment - serum bilirubin> 5 mg / dl (85.5 μmol / l). Alcohol abuse. Severe renal impairment - Creatinine clearance <20 ml / min or serum creatinine> 2 mg / dl. A history of a hematopoietic system such as: bone marrow hypoplasia, leukopenia, thrombocytopenia or clinically significant anemia. Immunity deficiency. Severe, acute or chronic infections such as tuberculosis and HIV infection. Inflammation and / or ulceration of the oral mucosa. Active gastric and / or duodenal ulcer disease. Simultaneous vaccination with live vaccines. Pregnancy and breastfeeding.

Methotrexate should only be administered by or under the supervision of physicians with knowledge and experience including the use of cytotoxic drugs from the antimetabolite group. During treatment with Methotrexate, regular monitoring of the patient's condition is required at short intervals to detect the toxicity of the drug and to evaluate it as soon as possible. Before commencing treatment with methotrexate or re-use after a break, complete blood count with a smear and platelet count, determine liver enzymes, bilirubin and serum albumin, take a chest x-ray and check for renal function and exclude pregnancy; if clinically indicated, tuberculosis and hepatitis should be excluded. During treatment - every week for the first 2 weeks of treatment, then every 2 weeks for the Next month, then at least once a month for the next 6 months of treatment, and then at least once every 3 months, perform the following tests: examination of the oral cavity and throat to rule out mucosal lesions, complete blood count with smear and platelet count, liver function tests, renal function tests (including urinalysis), test for possible pulmonary dysfunction and if necessary to test the function spit. More frequent check-ups should be considered in elderly patients and when increasing the dose. Any significant reduction in the number of leukocytes or platelets requires immediate discontinuation of therapy and the implementation of appropriate supportive care.Patients should be advised to report all symptoms indicative of developing infection. Particular monitoring of blood counts and platelet counts requires patients being treated concomitantly with other medicines that have blood-forming toxicity (eg leflunomide). During long-term treatment with methotrexate, a bone marrow biopsy should be performed. Particular attention should be paid to early symptoms of hepatic toxicity. Treatment should not be started or stopped immediately if abnormal liver function tests or abnormalities in the biopsy material are found before or during methotrexate therapy (such disorders should resolve within 2 weeks, then re-initiation may be considered). There is no evidence for the usefulness of liver biopsies in the monitoring of hepatotoxicity during treatment of rheumatic diseases. In patients with psoriasis, the need for liver biopsies before and during treatment is controversial. Further studies are needed to determine if repeated liver function tests or type III collagen propeptide tests are sufficiently effective to establish hepatotoxic effects. An individual assessment of patients should be carried out taking into account the differences between the presence or absence of risk factors such as: previous excessive alcohol consumption, persistent elevation of liver enzymes, a history of liver disease, family history of hereditary liver disorders, diabetes, obesity, previous exposure to hepatotoxic drugs or substances and long-term treatment with methotrexate or cumulative doses ≥1.5 g. If persistence of high hepatic enzymes persists, consideration should be given to reducing the dose of methotrexate or discontinuing treatment. During treatment with methotrexate, other hepatotoxic drugs should not be used unless strictly necessary (discontinue or significantly reduce alcohol consumption and strictly control liver enzymes); this also applies to the concomitant use of drugs with toxic effects on the hematopoietic system. The dose of methotrexate should be reduced if there is renal dysfunction. Suspicion of renal dysfunction (eg in elderly patients) requires more frequent testing, especially when other drugs are used concomitantly with methotrexate, which affect its excretion, cause kidney damage (eg NSAIDs) or may have a detrimental effect on the hematopoietic system. . In the presence of risk factors, such as renal dysfunction (even borderline), concomitant use of NSAIDs is not recommended. Patients should be advised to report any distressing respiratory symptoms such as persistent cough or shortness of breath. Patients with pulmonary signs should discontinue methotrexate and perform thorough examinations (including chest X-ray) to exclude infection and tumors. If the symptoms of lung disease are suspected to be related to methotrexate, corticosteroid therapy should be initiated and methotrexate should not be restarted. Patients with pulmonary symptoms should also consider the diagnosis of opportunistic infections, including pneumocystosis. Special care should be taken: in patients with impaired lung function; in the case of latent, chronic infections (e.g. shingles, tuberculosis, hepatitis B or C), due to the possibility of making the disease sick; in patients with pathological accumulation of fluid in the body cavities (eg with ascites or pleural effusion), due to the prolonged elimination of methotrexate (in the case of exudate to the pleura and peritoneum it is necessary to drain before methotrexate therapy). Conditions leading to dehydration, such as vomiting, diarrhea, and oral mucositis, may increase the concentration and increase the toxicity of methotrexate; in such cases, methotrexate should be discontinued until symptoms resolve. Diarrhea and ulcerative stomatitis can be signs of methotrexate toxicity and require discontinuation of treatment. Treatment should be discontinued if there is bloody vomiting, black stool or blood in the stool.Patients receiving low-dose methotrexate may show malignant lymphomas; in this case, the treatment should be discontinued; if the lymphoma does not show signs of spontaneous regression, it is necessary to implement treatment with cytotoxic drugs. Methotrexate may relapse of dermatitis caused by radiotherapy and sunburn (so-called "reaction from a reminder"). Skin changes in psoriasis may be intensified during UV irradiation and methotrexate concomitant administration. Methotrexate may weaken the response to vaccination and interfere with the results of immunological tests. Folic acid or folin supplementation may be considered during treatment in accordance with current treatment guidelines. It should be remembered that Vitamins or other preparations containing folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate. Avoid contact of methotrexate with the skin and mucous membranes. Methotrexate is not recommended for children <3 years of age.

Methotrexate is teratogenic, causes birth defects in the fetus and / or miscarriage. The use of methotrexate in pregnancy is contraindicated. Before beginning treatment, pregnancy should be ruled out using reliable methods, eg a pregnancy test. Patients (women and men) should use effective contraception during and up to 6 months after treatment with methotrexate. Because methotrexate can be genotoxic, all women who plan to become pregnant should benefit from genetic counseling before starting treatment. Men should seek advice on how to store semen before starting treatment. Methotrexate is excreted in human milk and may harm the fed baby, therefore its use during breast-feeding is contraindicated.

The occurrence and severity of side effects depends on the dose of the drug and the frequency of administration, however, serious side effects may occur even after low doses of methotrexate. Very common: loss of appetite, nausea, vomiting, abdominal pain, inflammation and ulceration of the oral mucosa and pharynx (especially in the first 24-48 h after administration), oral mucositis, indigestion, increased liver enzymes (ALAT, AST) , alkaline phosphatase) and bilirubin. Common: leukopenia, thrombocytopenia, anemia, headache, fatigue, pulmonary complications due to interstitial pneumonitis or exudative pneumonia and death associated with these complications (regardless of the dose and duration of methotrexate therapy; the most common symptoms are: general malaise, dry, irritating cough, shortness of breath that changes into dyspnoea, chest pain, fever), diarrhea (especially in the first 24-48 h after administration), rash, erythema, pruritus. Uncommon: pancytopenia, agranulocytosis, hematopoietic disorders, allergic reactions, anaphylactic shock, diabetes, depression, labyrinthine dizziness, confusion, convulsions, vasculitis, pulmonary fibrosis, ulceration and gastrointestinal bleeding, development of steatosis, fibrosis and cirrhosis liver (often occurs despite regular monitoring and normal liver enzymes), decrease in serum albumin, urticaria, allergy to light, increased skin pigmentation, hair loss, wound healing disorders, enlargement of rheumatic nodules, shingles, painful psoriatic changes (psoriatic lesions) can be exacerbated by UV irradiation during treatment with methotrexate), vasculitis, herpes-like epidermis on the skin, Stevens-Johnson syndrome, toxic epidermal necrolysis, joint pain, muscle pain, osteoarthritis porosis, inflammation and ulceration of the bladder mucosa (may be with haematuria), painful urination, inflammation and ulceration of the vaginal mucosa, reactions at the site of administration - after intramuscular administration (burning sensation or tissue damage, formation of a sterile abscess, loss of body fat) . Rare: pericarditis, pericardial effusion, pericardial tamponade, megaloblastic anemia, mood swings, severe visual disturbances, hypotension, thromboembolic events (including arterial and cerebrovascular thrombosis, thrombophlebitis, deep vein thrombosis, retinal vascular thrombosis,pulmonary embolism), pharyngitis, apnea, bronchial asthma-like reactions with cough and pathological changes in lung function tests, intestinal inflammation, tarry stools, gingivitis, malabsorption syndrome, acute hepatitis and hepatotoxicity, exacerbation of pigmentation changes in the nails, acne, ecchymosis, bloody stroke, erythema multiforme, erythematous skin rashes, fractures from overload, kidney failure, oliguria, anuria, azotemia, oligospermia, menstrual disorders. Very rare: septicemia, opportunistic infections (may be fatal), cytomegalovirus infections, nocturnal carcinoma, histoplasty and cryptococcosis and disseminated herpes simplex infection, severe myelosuppression, aplastic anemia, lymphadenopathy, lymphoproliferative diseases (partly reversible), eosinophilia and neutropenia (the first symptoms of life-threatening complications may be: fever, sore throat, mouth ulcer, flu-like symptoms, severe exhaustion, nosebleeds and skin hemorrhage), immunosuppression, γ-globulin deficiency in the blood, allergic vasculitis, insomnia, pain , muscle weakness or paresthesia in the extremities, taste disorders (metallic taste), acute juvenile meningitis with tire reaction (paralysis, vomiting), conjunctivitis, retinopathy, pneumonia caused byPneumocystis carinii and other lung infections, chronic obstructive pulmonary disease, pleural effusion, bloody vomiting, toxic colitis with widening of its light, reactivation of chronic hepatitis, acute degeneration of the liver, liver failure, hepatitis induced byHerpes simplex with hepatic failure, acute erysipelia, hyperactivity, telangiectasia, nocturnalism, histopathism and cryptococcosis and diffuse herpes simplex infection, allergic vasculitis, sweat gland inflammation, proteinuria, fever, slight skin reactions after subcutaneous administration, atrophy of sexual desire, impotence, vaginal discharge , infertility, gynecomastia. Isolated cases of malignant lymphoma which persisted in many patients after discontinuation of methotrexate; however, no relationship was established between methotrexate treatment and an increased incidence of lymphomas.

Rheumatoid arthritis (adults). Administer subcutaneously, intramuscularly or intravenously (bolus). The recommended starting dose is 7.5 mg once a week. Depending on the individual's disease severity and tolerability, the starting dose may be increased. Generally, a dose of more than 25 mg / week should not be used. The response to treatment can be expected after about 4-8 weeks. Once the desired effect has been achieved, the dose should be gradually reduced to the lowest possible effective maintenance dose.Polyarticular forms of juvenile idiopathic arthritis (children and adolescents <16 years of age). Administer subcutaneously or intramuscularly. The recommended dose is 10-15 mg / m² pc./tydz. In non-treatment cases, the weekly dose may be increased to 20 mg / m² pc./tydz. Use in children under <3 years is not recommended.Severe forms of psoriasis and psoriatic arthritis (adults). Administer subcutaneously, intramuscularly or intravenously (bolus). It is recommended to give a 5 to 10 mg parenteral dose of methotrexate to evaluate idiosyncratic side effects prior to initiation of therapy. The recommended initial dose is 7.5 mg once per week. The dose should be increased gradually. Generally, a dose of more than 25 mg / week should not be used. In exceptional cases, a higher dose may be clinically warranted, but the maximum dose of 30 mg / week should not be exceeded. Treatment reactions can be expected after approximately 2-6 weeks. Once the desired effect has been achieved, the dose should be gradually reduced to the lowest possible effective maintenance dose.Special groups of patients. Patients with impaired renal function: creatinine clearance (CCr)> 50 ml / min: use 100% of the dose due; CCr 20-50 ml / min: use 50% of the dose due; CCr <20 ml / min: do not use. In elderly patients, a dose reduction should be considered, due to decreased liver and kidney function with age and a reduction in systemic folic acid resources. In patients with fluid accumulation in the third space (pleural effusion, ascites) T_0,5 Methotrexate may be prolonged up to 4 times, therefore in some cases a reduction in dose or discontinuation of methotrexate may be necessary.