Methotrexat Ebewe

Methotrexate.

1 tablet contains 2.5mg methotrexate as active ingredient.
Excipients/Inactive Ingredients: Lactose monohydrate, maize starch, microcrystalline cellulose, magnesium stearate and colloidal silicon dioxide.

ATC Code: L 01 BA 01.
Pharmacology: Pharmacodynamics: Methotrexate, a derivative of folic acid, belongs to the class of cytotoxic agents known as antimetabolites. It acts principally during the 'S' phase of cell division, by the competitive inhibition of the enzyme dihydrofolate reductase, thus preventing the reduction of dihydrofolate to tetrahydrofolate, a necessary step in the process of DNA synthesis and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, foetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are generally more sensitive to the effects of methotrexate. When cellular proliferation in malignant tissues is greater than in more normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues.
The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Clarification of the effect of methotrexate on immune activity and its relation to rheumatoid immunopathogenesis await further investigation.
In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process.
Pharmacokinetics: Following oral administration of Methotrexat "Ebewe", 2 x 2.5mg tablets, methotrexate is rapidly absorbed achieving T_max at 0.83h. The mean maximum serum concentration was 170 ng/mL.
Methotrexate is generally completely absorbed from parenteral routes of administration. Peak serum concentrations following intramuscular administration are achieved in 30 to 60 minutes. After intravenous administration the initial volume of distribution is approximately 0.18L/kg (18% of body weight) and steady-state volume of distribution if approximately 0.4 to 0.8L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound.
Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration.
Methotrexate is reversibly bound in pleural exudates and ascites, for which reason the elimination from the body may be considerably delayed (see also Precautions).
Methotrexate is metabolised predominantly to three forms: 7-hydroxy-methotrexate is produced by hepatic aldehyde oxidase, especially after high-dose infusions, although it has a 200 fold lower affinity to dihydrofolate reductase it may play a role in the cellular uptake of methotrexate, polyglutamylation and inhibition of DNA-synthesis. 2,4-diamino-N-methylpteroic acid (DAMPA) is produced by an enteral bacterial carboxypeptidase. Following intravenous administration of methotrexate, DAMPA represented only 6% of the metabolites recovered from the urine.
Methotrexate polyglutymation results in intracellular accumulation of drug which is not at steady state with extracellular methotrexate concentration. As methotrexate and natural folates compete for the enzyme polyglutamyl synthetase, a high level of intracellular methotrexate will result in increased methotrexate polyglutymate synthesis, augmenting the cytotoxic effect of the drug.
The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis or rheumatoid arthritis or low-dose anti-neoplastic therapy (less than 30mg/m²). For patients receiving high doses of methotrexate, the terminal half-life is 8 to 15 hours. Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.
Toxicology: Preclinical safety data: Methotrexate acts mainly on proliferating tissues. This effect is common in all mammalian species studied including humans.
Reproductive toxicity: Methotrexate is capable of inducing teratogenic and embryolethal effects in several species at dose levels non-toxic to the mother.
Animal carcinogenicity studies have demonstrated methotrexate to be free of carcinogenic potential. Although methotrexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with methotrexate, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.
Mutagenicity: methotrexate is genotoxic in a number of in vitro and in vivo mammalian test systems.

Antirheumatic: Active rheumatoid arthritis in adults.
Antipsoriatic: Disseminated chronic psoriasis, especially in elderly and handicapped patients when other therapy has failed.
Cytostatic: Maintenance therapy in acute lymphatic leukaemia.

Posology: The tablets should be taken 1 hour before or 1.5-2 hours after a meal.
Rheumatoid arthritis and psoriasis: The product should be used by specialists in dermatology, rheumatology and internal medicine.
Psoriasis: The recommended initial dose is 2.5mg 3 times per week with 12 hours interval alternatively one single dose of 7.5mg once a week.
Rheumatoid arthritis: Initial dose of 7.5mg per week given as a single dose.
For both dose regimens, the therapeutic effect is obtained usually within 6 weeks with the condition of the patient improving after another 12 weeks or more. If no response has been achieved after 6-8 weeks and no toxic symptoms are observed the dose can be increased stepwise by 2.5mg/week.
Usually the optimum dose per week is between 7.5-16mg and the dose should not exceed 20mg/week. If no response is obtained after 8 weeks with the maximum dose, methotrexate should be withdrawn. When response to the treatment effect has been achieved the maintenance dose should be reduced to the lowest possible. The optimal therapy duration is so far unknown but preliminary data indicates that the initially achieved effect may remain for at least 2 years with continued maintenance dose. When the treatment is withdrawn the symptoms may return within 3-6 weeks.
Cytostatic: Oral administration of methotrexate in doses up to 30mg/m² is possible while higher doses should be given parenterally. Oral treatment with doses up to 20mg/m² per week should be used together with intravenous administration and intrathecal CNS-prophylaxis as maintenance treatment in acute lymphatic leukaemia (ALL) in children.

Calcium leucovorin is the antidote for neutralising the immediate toxic effects of methotrexate on the haemopoietic system. It may be administered orally, intramuscularly or by an intravenous bolus injection or infusion. In cases of accidental overdosage, a dose of calcium leucovorin equal to or higher than the offending dose of methotrexate should be administered within one hour and dosing continued until the serum levels of methotrexate are below 10^-7M. Other supporting therapy such as a blood transfusion and renal dialysis may be required.

Pregnancy and lactation.
Significant hepatic dysfunction including, fibrosis, cirrhosis, or hepatitis.
Significant renal dysfunction.
Blood dyscrasias including hypoplasia of the bone marrow, leukopenia, thrombocytopenia, anaemia.
Active infectious disease, evidence of immuno-deficiency syndrome.
Known hypersensitivity of methotrexate.
General poor condition.

Methotrexate may only be administered under the supervision of a physician qualified in oncology with experience in the use of antineoplastic chemotherapy.
Methotrexate should be used with extreme caution in patients with haematological depression, renal impairment, peptic ulcer, ulcerative colitis, ulcerative stomatitis, diarrhoea debility and in young children and the elderly.
Patients with pleural effusions or ascites should have these drained if appropriate before treatment or treatment should be withdrawn.
Symptoms of gastro-intestinal toxicity, usually first manifested by stomatitis, indicate interruption of therapy otherwise haemorrhagic enteritis and death from intestinal perforation may occur if the treatment is continued.
Methotrexate may cause decreased fertility, oligospermia, menstrual dysfunction and amenorrhoea. This effect appears to be reversible on discontinuing therapy. Beyond this methotrexate causes embryo toxicity and foetal defects and may cause abortion. If one of the partners is being treated with methotrexate, conception should be avoided during treatment and at least three months after cessation of treatment.
Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests. Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay.
It is essential that the following laboratory tests are included regularly in the clinical evaluation and monitoring of patients receiving methotrexate: complete haematological analysis, urinalysis, renal function tests, liver function tests and when high doses are administered, determination of plasma levels of methotrexate.
Particular attention should be given to the appearance of liver toxicity which may occur without correlative changes in liver function tests. Treatment should not be instituted or should be discontinued if any abnormality in liver function tests or liver biopsy is present or develops during therapy. Such abnormalities should return to normal within two weeks after which treatment may be recommenced at the discretion of the physician.
When to perform a liver biopsy in rheumatoid arthritis patients has not been established either in terms of a cumulative methotrexate dose or duration of therapy.
Pleuropulmonary manifestation of rheumatoid arthritis have been reported in the literature. In patients with rheumatoid arthritis, the physician should be specifically alerted to the potential for methotrexate induced adverse effects in the pulmonary system. Patients should be advised to contact their physicians immediately should they develop a cough or dyspnoea.
Haemopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Any profound drop in white-cell or platelet counts indicate immediate withdrawal of the drug and appropriate supportive therapy.
High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5-7.0 by oral or intravenous administration of sodium bicarbonate (5 x 625mg tablets every three hours) or acetazolamide (500mg orally four times a day) is recommended as a preventive measure.
The Rules of the National Working Environment Authority concerning handling of cytostatics should be followed.
Effects on ability to drive and use machines: Depending on individual susceptibility, the patient's ability to drive a vehicle or operate machinery may be impaired.

Methotrexate has been shown to be teratogenic. Therefore, it is not recommended in women of childbearing potential unless the benefits can be expected to outweigh the considered risks. If methotrexate is used during pregnancy for antineoplastic indications, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus.
Methotrexate is excreted in breast milk for which reason breast feeding is contraindicated during therapy.

The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are eye irritation, malaise, undue fatigue, chills and fever, dizziness, loss of libido/impotence and decreased resistance to infection. In general, the incidence and severity of side effects are considered to be dose-related.
The incidence of the more frequent adverse reactions is as follows: See table.

Click on icon to see table/diagram/image

Integument: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration has been reported in psoriatic patients. The recall phenomenon has been reported in both radiation and solar damaged skin.
Single cases of Stevens-Johnson-Syndrome and epidermal necrolysis have been reported.
Hematopoietic: Bone marrow depression is most frequently manifested by leukopenia, but thrombocytopenia, anaemia or any combination may occur. Infection or septicemia and haemorrhage from various sites may result. Hypogammaglobulinaemia has been reported.
Alimentary system: Mucositis (most frequently stomatitis, although gingivitis, pharyngitis and even enteritis, intestinal ulceration and bleeding) may occur. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon. Nausea, anorexia and vomiting and/or diarrhoea may also occur.
Hepatic: Reversible increase in transaminases occurs frequently. Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.
Urogenital system: Renal failure and uraemia may follow methotrexate administration, usually in high doses. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported.
Pulmonary system: Infrequently an acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.
In the treatment of rheumatoid arthritis: Methotrexate induced lung disease is a potentially serious adverse drug reaction which may occur acutely at any time during therapy. It is not always fully reversible. Pulmonary symptoms (especially a dry, non productive cough) may require interruption of treatment and careful investigation.
Central nervous system: Headaches, drowsiness and blurred vision have occurred. Following low doses of methotrexate, transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations have been reported occasionally. Aphasia, paresis, hemiparesis, and convulsions have also occurred following administration of higher doses.
Adverse reactions particularly following intrathecal administration: Acute: chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever.
Subacute: may include paresis (usually transient), paraplegia, nerve palsies and cerebellar dysfunction.
Chronic: leucoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely death. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leucoencephalopathy.
Additional reactions related to or attributed to the use of methotrexate such as osteoporosis, abnormal (usually 'megaloblastic') red cell morphology, precipitation of diabetes, other metabolic changes and sudden death have been reported.
Carcinogenesis, mutagenesis, and impairment of fertility: Methotrexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with methotrexate, this may cause an increased risk of neoplasia (Lymphoma, usually reversible), but evidence is insufficient to permit conclusive evaluation. Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation.
In addition, methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible risks of effects on reproduction should be discussed with patients of child-bearing potential.

Methotrexate has some immunosuppressive activity and therefore the immunological response to concurrent vaccination may be decreased. In addition, concomitant use of a live vaccine could cause a severe antigenic reaction.
Protein bound methotrexate may be displaced by salicylates, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol, sulfazole, doxorubicin, cyclophosphamide and barbiturates. The higher plasma levels of unbound methotrexate may lead to increased toxicity.
Methotrexate is subject to active renal secretion. It interferes in general with other drugs subject to the same excretion-mode and this causes increased Methotrexate plasma-levels.
The dose of methotrexate should be reduced when given concomitantly with probenecid.
Vinca alkaloids may increase intracellular methotrexate and methotrexate polyglutamates.
Concomitant use of drugs with nephrotoxic or hepatotoxic potential (including alcohol) should be avoided.
Vitamin preparations or oral iron preparations containing folic acid may alter the response to methotrexate.
Non-steroidal anti-inflammatory drugs may impair the renal clearance of methotrexate and lead to severe toxicity.
Serum levels of methotrexate may be increased by etretinate and severe hepatitis has been reported following concurrent use.
Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole is reported to cause acute pancytopenia in rare cases.

Instruction for use/handling: No special requirements.
Incompatibilities: None.

Do not store above 25°C.
Shelf life: 36 months.

Cytotoxic Chemotherapy

L04AX03 - methotrexate ; Belongs to the class of other immunosuppressants.

POM

Tab 2.5 mg x 50's.