Տրեկսան

Pharmacotherapeutic groups: Other immunosuppressants, ATC code: L04AX03 Methotrexate (4-amino-10-methylfolic acid) is a folic acid antagonist which inhibits the reduction of folic acid leading to decreased cellular proliferation. Methotrexate enters the cell through an active transport mechanism of reduced folates. As a result of polyglutamylation of methotrexate caused by the folylpolyglutamate synthetase enzyme, the duration of the cytotoxic effect of the drug substance in the cell increases. Methotrexate is a phase-specific substance the main action of which is directed to the S-phase of cell mitosis. It acts generally most effectively on actively proliferating tissues, such as malignant cells, bone marrow, foetal cells, skin epithelium, oral and intestinal mucosa as well as urinary bladder cells. As the proliferation of malignant cells is faster than that of most normal cells, methotrexate can slow down the proliferation of malignant cells without causing irreversible damage to normal tissue. Calcium folinate is a folinic acid which is used to protect normal cells from the toxic effects of methotrexate. Calcium folinate enters the cell through a specific transport mechanism, is converted in the cell into active folates and reverses the inhibition of the synthesis of precursors of DNA and RNA.   Absorption The effect of orally administered methotrexate is dependent on the size of the dose. Peak concentrations in serum are reached within 1 – 2 hours. Generally a dose of methotrexate of 30 mg/m2 or less is absorbed rapidly and completely. The bioavailability of orally administered methotrexate is high (80–100%) at doses of 30 mg/m2 or less. At doses above 30 mg/m2 absorption becomes nonlinear and absorption at doses exceeding 80 mg/m2 is incomplete. Distribution Approximately 50 % of methotrexate is bound to serum proteins. Upon being distributed into body tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in particular, which can be retained for weeks or months. When administered in small doses, methotrexate passes into the liquor in minimal amounts. Biotransformation Approx. 10 % of the administered methotrexate dose is metabolised in the liver. The principle metabolite is 7-hydroxymethotrexate. Elimination Excretion takes place, mainly in unchanged form, primarily via glomerular filtration and active secretion in the proximal tubule. Approx. 5 – 20 % methotrexate and 1 – 5 % 7-hydroxymethotrexate are eliminated biliary with pronounced enterohepatic circulation The terminal half-life is on average 6 – 7 hours and demonstrates considerable variation (3 – 17 hours). The half-life can be prolonged to 4 times the normal length in patients who possess a third distribution space (pleural effusion, ascites). Special populations In the case of renal insufficiency, elimination is delayed significantly.

Each tablet contains methotrexate disodium equivalent to 10 mg methotrexate (anhydrous). Excipient with known effect: 311.2 mg lactose (as lactose monohydrate).

- Antirheumatic: Active rheumatoid arthritis in adult patients - Antipsoriatic: Severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients - Cytostatic: Maintenance treatment of acute lymphoblastic leukaemia (ALL) in adults, adolescents and children aged 3 years and over.

- Hypersensitivity - Significantly impaired hepatic function - Alcoholism - Significantly impaired renal function - Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia - Severe acute or chronic infections and immunodeficiency syndromes - Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcer disease - Breast-feeding (see section 4.6) - During methotrexate therapy concurrent vaccination with live vaccines must not be carried out. Additionally for non-oncological indications - Pregnancy

Generally the frequency and severity of adverse reactions are dependent of the size of the dose, the dosing frequency, the method of administration and the duration of exposure. In the antineoplastic treatment, myelosuppression and mucositis are the predominant dose-limiting toxic effects of methotrexate. The severity of these reactions depends on the dose, mode and duration of application of methotrexate. Mucositis generally appears about 3 to 7 days after methotrexate application, leucopenia and thrombocytopenia follow a few days later. In patients with unimpaired elimination mechanisms, myelosuppression and mucositis are generally reversible within 14 to 28 days. Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and StevensJohnson syndrome. Most frequently observed (very common) adverse reactions of methotrexate include gastrointestinal disorders (e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite) and abnormal liver function tests (e.g. increased Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), bilirubin, alkaline phosphatase). Other frequently occurring (common) adverse reactions are leukopenia, anaemia, thrombocytopenia, headache, tiredness, drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythema and pruritus. The occurrence and severity of adverse reactions depend on dosage level and frequency of administration of methotrexate. However, as severe adverse reactions may occur even at low doses, it is essential for the treating physician to monitor patients closely.

Pharmacodynamic interactions Hepatotoxic agents Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate. If concomitant administration cannot be avoided, patients should be monitored closely for signs and symptoms of liver toxicity including closer monitoring of liver enzymes. Consumption of alcohol should be avoided or minimised. Potentially hepatotoxic agents include e.g. retinoids (e.g. acitretin, etrenitate), azathioprine and leflunomide. Hematotoxic agents Hematotoxic medicinal products should not be taken during treatment with methotrexate. If concomitant administration cannot be avoided, patients should be monitored closely for signs and symptoms of hematotoxicity including close monitoring of blood count and platelets. Administration of additional haematotoxic medicinal products (e.g. metamizole) increases the probability of severe haematotoxic effects of methotrexate. Concomitant administration with leflunomide increases risk for pancytopenia. In the case of (pre-)treatment with medicinal products, which may have adverse reactions on the bone marrow (e.g. sulfonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine); attention should be paid to the possibility of pronounced impairment of blood formation. Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances. Medicinal products which affect folate levels and folic acid containing vitamin products The concomitant administration of products which cause folate deficiency (e.g. sulfonamides, trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is therefore advisable in the presence of existing folic acid deficiency. The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression and stomatitis and in case of intrathecal administration increased severe, unpredictable neurotoxicity. Whilst this effect can be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided. Although the combination of methotrexate and sulfasalazine can cause an increase in efficacy of methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis through sulfasalazine, such undesirable effects have only been observed in rare individual cases in the course of several studies Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate. Ciclosporin Ciclosporin may potentiate methotrexate efficacy and toxicity. There is a risk of excessive immunosuppression with risk of lymphoproliferation when the combination is used. Pharmacokinetic interactions Interactions which may increase methotrexate levels Frequent patient monitoring is necessary especially if high methotrexate doses are administered concomitantly with medicinal products, which reduce methotrexate protein binding, elimination of methotrexate or cause kidney damage. If concomitant use cannot be avoided, consider dose adjustment of methotrexate. Monitoring of methotrexate serum levels may be useful. Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the elimination of methotrexate and higher serum concentrations may be assumed inducing higher haematological toxicity. Methotrexate is plasma protein bound and certain drugs such as oral hypoglycaemics, thiazide diuretics, sulfonamides, phenytoin, barbiturates, tranquilisers, oral contraceptives, amidopyrine derivatives, doxorubicin, p-aminobenzoic acid, some antibiotics such as penicillin, tetracyclines, chloramphenicol decrease this binding, which can lead to increased toxicity when used concurrently. There is also a possibility of increased toxicity when low dose methotrexate and non-steroidal antiinflammatory medicinal products or salicylates are combined. NSAIDs may cause kidney damage. Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs. A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to interactions. Concomitant administration of methotrexate and omeprazole has led to delayed renal elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case. Penicillines, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate with simultaneous haematological and gastrointestinal toxicity may occur. The application of procarbazine during high-dose methotrexate therapy increases the risk of impairment of renal function. Delayed methotrexate clearance should also be considered in combination with other cytostatic medicinal products. Interactions which may reduce methotrexate levels Concomitant use of enzyme inducing anticonvulsants (carbamazepine, phenytoin, phenobarbital, primidone) may decrease the methotrexate exposure and impair its therapeutic effect. If used  concomitantly, dose adjustment of methotrexate should be considered. Monitoring of methotrexate serum levels may be useful. Cholestyramine can increase the non-renal elimination of methotrexate by interrupting the enterohepatic circulation. If cholestyramine administration cannot be avoided doses of cholestyramine and methotrexate should be separated as much as possible. Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics can interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of the bacterial metabolism. Methotrexate effects on other medicinal products Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment. One should be aware of pharmacokinetic interactions between methotrexate and 5-fluorouracil (increased t½ of 5--fluorouracil). If coadministration is necessary, patient should be monitored for 5- fluorouracil toxicity and dose adjustments should be considered if necessary. Theophylline and caffeine An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeinecontaining soft drinks, black tea) should be avoided during methotrexate therapy since the efficacy of methotrexate may be reduced due to possible interaction between methotrexate and methylxanthines at adenosine receptors. Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.  Infection risk and vaccinations Vaccination with a live vaccine in patients receiving chemotherapeutic agents may result in severe and fatal infections. On account of its possible effect on the immune system, methotrexate can falsify vaccinal and test results (immunological procedures to record the immune reaction). During methotrexate therapy concurrent vaccination with live vaccines must not be carried out. Particularly in the case of orthopaedic surgery where susceptibility to infection is high, a combination of methotrexate with immune-modulating medicinal products must be used with caution. Radiotherapy Radiotherapy during use of methotrexate can increase the risk of soft tissue or bone necrosis

Symptoms: Toxicity of methotrexate mainly affects the haematopoietic and gastrointestinal systems. Symptoms include leukopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, bone marrow depression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration and gastrointestinal bleeding. Some patients showed no signs of overdose. There are reports of death due to sepsis, septic shock, renal failure and aplastic anaemia. Cases of overdose have been reported, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate. In these cases, symptoms that have been commonly reported are haematological and gastrointestinal reactions. Treatment: Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate. In cases of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of methotrexate should be administered intravenously or intramuscularly within one hour Observation of serum methotrexate concentrations is relevant in determining the right dose of calcium folinate and the duration of the therapy. In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy. Important warning with reference to the dosing of Trexan (methotrexate): In the treatment of rheumatic diseases, psoriasis or severe psoriatic arthritis, Trexan (methotrexate) must only be taken once a week. Dosage errors in the use of Trexan (methotrexate) can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully. The prescriber should ensure that patients or their carers will be able to comply with the once weekly regimen. It must be explicitly pointed out to the patient that for the therapy of rheumatic diseases, psoriasis or severe psoriatic arthritis methotrexate is administered only once a week. The prescriber should specify the day of intake on the prescription. Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration  Rheumatoid arthritis The usual dose is 7.5 - 15 mg once weekly. The schedule may be adjusted gradually to achieve an optimal response but should not exceed a total weekly dose of 25 mg. Doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression. Thereafter the dose should be reduced to the lowest possible effective dose which in most cases is achieved within 6 weeks. Psoriasis Before starting treatment it is advisable to give the patient a test dose of 2.5–5.0 mg to exclude unexpected toxic effects. If, one week later, appropriate laboratory tests are normal, treatment may be initiated. The usual dose is 7.5–15 mg taken once weekly. As necessary, the total weekly dose can be increased up to 25 mg. Doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression. Thereafter the dose should be reduced to the lowest effective dose according to therapeutic response which in most cases is achieved within 4 to 8 weeks. The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting methotrexate treatment, and repeating these during therapy as detailed in section 4.4 under “Recommended examinations and safety measures”. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy which should be encouraged. Cytostatic Dosage in acute lymphoblastic leukaemia Low-dose methotrexate is used in the maintenance treatment of ALL in children aged 3 years and over, adolescents and adults within complex protocols in combination with other cytostatic medicinal products. Treatment should follow current therapy protocols. Common accepted single doses lie in the range of 20-40 mg/m² body surface area and are usually given once weekly  If methotrexate is administered in combination with chemotherapy regimens, the dosage should take into consideration any overlapping toxicity of the other medicinal product components. Higher dosages should be given parenterally. Paediatric population Methotrexate should be used with caution in paediatric patients. Treatment should follow currently valid therapy protocols for children. Doses are usually based on the patient’s body surface area and maintenance treatment represents a long-term treatment. The use in children below 3 years of age is not recommended as insufficient data on efficacy and safety are available for this population  Use in elderly patients Methotrexate should be used with extreme caution in elderly patients, a dose reduction should be considered due to reduced liver and kidney function as well as lower folate reserves which occur with increased age. Patients with renal impairment: Methotrexate should be used with caution in patients with impaired renal function. The dose should be adjusted as follows: Dosage recommendations Creatinine clearance (ml/min) Dose ≥ 60 100 % 30–59 50 % < 30 Methotrexate must not be used Patients with hepatic impairment: Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. Methotrexate is contraindicated in patients with significantly impaired hepatic function. Use in patient with a third distribution space (pleural effusions, ascites) As the half-life of methotrexate can be prolonged to 4 times the normal length in patients who possess a third distribution space dose reduction or, in some cases, discontinuation of methotrexate administration may be required․ Special note If changing the oral application to parenteral administration a reduction of the dose may be required due to the variable bioavailability of methotrexate after oral administration. Folic acid or folinic acid supplementation may be considered according to current treatment guidelines. Women of childbearing potential / contraception in females Women must not get pregnant during methotrexate therapy and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter. Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning. Contraception in males It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure. As precautionary measures, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 6 months after cessation of methotrexate. Men should not donate semen during therapy or for 6 months following discontinuation of methotrexate. Pregnancy Methotrexate is contraindicated during pregnancy in non-oncological indications. If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and ultrasonography examinations should be performed to confirm normal foetal development. In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester. Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related). Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy. • Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in diseasematched patients treated with drugs other than methotrexate. • Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in disease-matched patients treated with drugs other than methotrexate. Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but higher rates of spontaneous abortions and congenital malformations are expected, in particular at doses commonly used in oncologic indications. When methotrexate was discontinued prior to conception, normal pregnancies have been reported. When used in oncological indications, methotrexate should not be administered during pregnancy in particular during the first trimester of pregnancy. In each individual case the benefit of treatment must be weighed up against the possible risk to the foetus. If the drug is used during pregnancy or if the patient becomes pregnant while taking methotrexate the patient should be informed of the potential risk to the foetus. Breastfeeding As methotrexate passes into breast milk and may cause toxicity in nursing infants, treatment is contraindicated during the lactation period. Breast-feeding is therefore to be stopped prior to treatment. Fertility Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These effects appear to be reversible after discontinuation of therapy in most cases. In oncologic indications, women who are planning to become pregnant are advised to consult a genetic counselling centre, if possible, prior to therapy and men should seek advice about the possibility of sperm preservation before starting therapy as methotrexate may be genotoxic at higher doses

Store at original package in order to protect from light at temperature not above 25 °C.