Each tablet contains: Methotrexate 2.5 mg.
Pharmacology: Methotrexate is a folic acid antagonist with cytotoxic activity belonging to the group of antimetabolites. Methotrexate acts mainly in the S phase of the cell division. It inhibits competitively dihydrofolate reductase and the reduction of the dihydrofolic acid (FH2) to tetrahydrofolic acid (FH4). Activated reduced folate derivatives are necessary for the transmission of C1 units and the synthesis of pyrimidine, purine and amino acids. Therefore methotrexate induces an inhibition of the DNA, RNA and protein synthesis through the intracellular decrease of FH4 and activated reduced folate derivatives. The cytotoxic activity of methotrexate correlates in vitro with the inhibition of the DNA synthesis. Rapidly proliferating tissues like malignant cells, bone marrow, fetal cells, skin epithelium and mucosa are generally more sensitive to methotrexate. The cell proliferation is mainly more intensive in malignomas than in normal tissues, and therefore methotrexate can influence persistently the malignant growth without causing irreversible damages to the normal tissues.
In psoriasis the cell proliferation of the epithelium compared to normal skin is increased. This difference in the cell proliferation rate is the reason for the use of methotrexate in severe recalcitrant disabling psoriasis and arthritis psoriatica.
The activity of methotrexate can be neutralised with the administration of folinic acid (as calcium folinate). Folinic acid is metabolised intracellularly through N5 methyl tetrahydrofolic acid in tetrahydrofolic acid and N5,10 methylen tetrahydrofolic acid and causes a filling of the intracellular pool of reduced folate derivatives avoiding the inhibition of the dihydrofolate reductase by methotrexate.
Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destrients and hydatidiform mole. In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with ether chemotherapeutic agent, methotrexate is also indicated in the treatment of meningeal leukemia. Methotrexate is used alone or in combination with other anticancer agent in the treatment of breast cancer, epidermoid cancers of the head and neck, advance mycosis fungicides and lung cancer, particularly squamous cell and small cell type. Methotrexate is also used in combination with other chemotherapeutic agent in the treatment of advanced stage non-hodgkins lymphomas.
Only indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy but only when the diagnosis has been established and the need for therapy has been confirmed by dermatologic consultation.
Choriocarcinoma and similar throphoblastic disease: 15-30 mg daily intramuscularly or orally for a five days course. Such courses are usually repeated for 3-5 times are required, with rest periods of one or more weeks interpaused between courses until any manifesting toxic symptom subside. The effectiveness of therapy can be evaluated by 24 hours quantitative analysis or urinary chorionic gonadothropin hormone (nCG).
Hydatiform mole may precede or be followed by choriocarcinoma and methotrexate has been used in similar dosage for the treatment of hydatiform mole and chorioadenoma destruents.
Breast carcinoma: Prolonged cyclic combination with cyclophosphamide, methotrexate and fluorouracil has given good results when used as adjuvant treatment with radical mastectomy in primary breast cancer with positive axilary lymph nodes, methotrexate dosage was 40 mg/m2 intravenously on the first and eight days.
Leukemia: Acute lymphoblastic leukemia in children and young is the most responsive to present-day chemotherapy. In young adults and other patients, clinical remission is more difficult to obtain and early relapse is more common.
Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias.
More recently corticosteroid therapy, in combination with other antileukemia drug or in cyclic combination with methotrexate included, has appeared to produce rapid and effective remissions.
When used for induction, methotrexate in dosage of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone given daily, produce remissions of 50% of patients treated, usually within a period of 4 to 6 weeks.
Methotrexate in combination with other agent appeared to be the drug of choice for securing maintenance of drug induced remissions.
When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: methotrexate is administered two times weekly either by mouth or intravenously every 14 days.
If and when relapse dose occurred reinduction of remission can again usually be obtained by repeating the initial induction regimen.
A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia.
The physician should be familiar with the new advances in antileukemic therapy.
Meningeal leukemia: Some patients with leukemia are subject to leukemia invasions of the central nervous system and the CSF should be examined in all leukemia patients. Passage of methotrexate from blood to the cerebrospinal fluid is minimal and for adequate therapy the drug should be administered intrathecally.
Methotrexate is administered by intrathecal injection in doses 200 to 500 micrograms/kg body weight.
The administration is at intervals of 2 to 5 days and is usually repeated until the cell cone of cerebrospinal fluid returns to normal.
At this point one additional close is advised. Alternatively, methotrexate 12 mg/m2 can be given once weekly for 2 weeks, and then once monthly large doses may cause convulsions and untoward side effects may occur as with any intrathecal injection and are commonly neurological in character.
Psoriasis chemotherapy: Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, have responded to weekly single, i.m. or i.v. doses of 10-25 mg per week and adjusted according to the patient's response.
And initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy.
A suggested dose range is 5-10 mg parenterally.
Hypersensitivity to one of the components of the drug.
Severe liver and renal impairments (serum creatinine >2 mg%, serum creatinine 1.5-2 mg% dose reduction to 25%).
Abuse of alcohol.
Disease of the haematopoietic system (bone marrow hypoplasia, leucopenia, thrombocytopenia, anemia).
Ulcera of the oral cavity and the gastro-intestinal tract.
Fresh operation wounds.
Particular care is to be taken in impaired activity of the bone marrow after an intensive radiotherapy, chemotherapy and/or longer pretreatment with drugs causing bone marrow impairment (e.g. sulphonamide, chloramphenicol, pyrazole derivatives, indomethacin, diphenylhydantoin); further in impaired general condition of the patient as well as in children and aged patients.
In the therapy of rheumatoid arthritis or psoriasis vulgaris methotrexate should not be administered in case of previous severe lungs diseases.
If a "third space" is present as a reserve compartment in which methotrexate can accumulate (e.g. ascites, pleural effusion, seroma in the region of operation wounds) an intensified and prolonged action or toxicity of methotrexate is to be reckoned with. Pregnancy and lactation period are a strict contraindication. A strict contraception must be guaranteed before, during and after a methotrexate therapy, for male and female patients as well.
Therapy with methotrexate should only be carried out by qualified physicians experienced in the field of (antineoplastic) chemotherapy and only in hospital departments. Particular care is to be taken in simultaneous administration of methotrexate and non-steroidal antiphlogistics. Severe side effects and also deaths (after high methotrexate doses) have been reported.
Alcohol is to be avoided, also in low doses. The patient should be informed about possible risks (side effects). Contraindications and precautions for use must be strictly observed because of possible severe, under particular circumstances lethal toxic reactions. Plasma concentrations of methotrexate: Higher than 1-2 times 10-5 mol/L (24 hours after beginning of methotrexate administration);
Twice 10-6 mol/L (48 hours after beginning of methotrexate administration);
10-7 mol/L (72 hours after beginning of methotrexate administration).
Show an increased intoxication risk (myelosuppression, mucositis) and require a long-lasting and high dose calcium folinate rescue therapy. In impaired renal functions methotrexate dosage has to be reduced correspondingly. In high dose methotrexate therapy the creatinine clearance should be at least 75% of the normal value (50 mL/min/m2 resp. 90 mL/min).
A medium dose methotrexate therapy (>100 mg/m2) should not be carried out if the creatinine clearance is reduced below 50% of the normal value (<35 mL/min/m2 resp. <60 mL/min), unless in daily determination of serum creatinine, methotrexate concentration and calcium folinate rescue until the methotrexate serum concentration decrease below 10-7 mol/L during conventional methotrexate therapy a dose reduction of 50% is recommended if the serum creatinine values are 1.2-2 mg/dL, and stopping of therapy is recommended if the serum creatinine values are over 2 mg/dL. Prerequisites for a medium or high dose methotrexate therapy: Adequate availability of calcium folinate for subsequent rescue therapy;
Opportunity for rapid determination of methotrexate serum levels;
Opportunities for haemodialysis;
Supply of autologous bone marrow conserves, blood conserves, leucocyte and thrombocyte concentrates.
Check up and safety measures: Exclusion of renal and liver function disturbances, disturbances of the haematopoietic system (renal and liver function tests, complete blood count).
Before treatment of rheumatoid arthritis with methotrexate in hepatic diseases a liver biopsy should be carried out.
A gravidity must be excluded.
For prevention of intrarenal precipitation of methotrexate resp. its metabolites and for prophylaxis and therapy of a cell nucleus dependent disintegration of hyperuricaemia a forced hydratation and alkalinisation of the urine (e.g. by infusion of a NaHCO3 solution, 20-25 mmol/L in an amount of 3 L/m2/24 hours) 24 hours before up to 24 hours after methotrexate administration is required.
If necessary 150-220 mg/m2/day acetazolamide resp. 8 mg/kg/day allopurinol can be used.
A medium and high dose methotrexate therapy must not be started when urinary pH values are below 7.0. Urinary alkalinisation must be controlled at least during the first 24 hours after beginning of methotrexate administration by repeated controls of the pH-value (≥6.8).
Methotrexate serum level must be determined immediately after therapy stopping as well as after 24, 48 and 72 hours. Signs of toxicity and the adjustment of calcium folinate therapy can be determined according to the serum values.
During intrathecal administration systemic side effects may also appear.
A careful clinical examination of the patients particularly inspection of the oral cavity, pharynx and larynx for changes of the mucosa, regular control of the leucocytes and thrombocytes (daily up to 3 times weekly), complete blood count (once weekly), renal and liver functions should be made. During long term or high dosage therapy bone marrow biopsies may be necessary.
In severe leucopenia the risk of an infection should be borne in mind. In case of infections a therapy stop and a corresponding antibiotic therapy is required. In severe cases of myelosuppression the transfusion of blood, leucocyte and thrombocyte concentrates may be necessary.
During methotrexate therapy pregnancy is to avoid strictly because of possible embryotoxic, faetotoxic and teratogenic activities. If a pregnancy is desired after therapy end, a genetic consultation is required. Methotrexate may impair concentration capacity and ability to drive and handle with machines.
Methotrexate intoxications and neutralisation of toxic side effects are carried out with the specific antidote calcium folinate.
Like all other cytostatic drugs care is to be taken in handling methotrexate. Pregnant women must avoid contact with methotrexate.
Because of the possibility of serious toxic reaction the patients should be informed by the physician of the risks involved and should be under a physician constant supervision.
Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis and rheumatoid arthritis.
In the treatment of psoriasis or rheumatoid arthritis methotrexate use should be restricted to patients with severe, recalcitrant, disabling disease, which is not adequately responsive to other forms of therapy and only when the diagnosis has been established and after appropriate consultation.
Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen, these are usually transient and asymptomatic and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes and fibrosis.
Methotrexate-induced lung diseases is a potentially dangerous lesion, which may occur acutely at any time during therapy and which has been reported at doses as low as 7.5 mg/week.
It is not always fully reversible. Pulmonary symptoms (especially a dry, non productive cough) may require interruption of treatment and careful investigation. Methotrexate may produce marked bone marrow depression with resultant anemia and/or thrombocytopenia.
Diarrhea and ulcerative stomatitis require interruption of therapy, otherwise hemorrhagic enteritis and death from intestinal perforation may occur.
Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution and at reduced dosage, because renal dysfunction will prolong methotrexate elimination.
Unexpectedly severe (sometimes fatal) marrow suppression and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) alone with some nonsteroidal antiinflamatory drug.
Pregnancy and lactation period are a strict contraindication. A strict contraception must be guaranteed before, during and after a methotrexate therapy, for male and female patients as well.
During methotrexate therapy pregnancy is to avoid strictly because of possible embryotoxic, faetotoxic and teratogenic activities. If a pregnancy is desired after therapy end, a genetic consultation is required.
Pregnant women must avoid contact with methotrexate.
Even if the therapeutic plan is correctly carried out, side effects are to be expected, especially in tissues with a high proliferation rate. Frequency and severity of side effects are generally dose dependent and clearly correlate with the lowering of the urinary pH-value. Since methotrexate is mainly excreted renally, if signs of disturbed renal excretion are present, severe signs of toxicity are to be reckoned with due to raised serum levels of methotrexate. The most frequent side effects are nausea and vomiting, difficulty in swallowing, stomatitis, pharyngitis, leucopenia and thrombocytopenia.
Haematopoietic system: Primary bone marrow depression (with a maximum 7-10 days after i.v. short term infusion or bolus, regeneration approx. after one week). A severe haematotoxicity leads to a transient hypo-up to aplastic condition with leucopenia, thrombocytopenia, anemia and hypogammaglobulinaemia (rarely in intermittent massive-dose treatment). Bleedings and septicaemia can appear.
Gastro-intestinal tract: Changes in the gastro-intestinal tract appear approx. 2-7 days after a high-dose methotrexate therapy with symptoms of enthema and/or ulcerations of the oral cavity, the pharynx and the gastro-intestinal tract (mucositis). Furthermore anorexia, nausea and vomiting can appear. Gastro-intestinal ulcerations can lead to bleedings, perforations and toxic megacolon.
Urogenital tract: A nephrotoxic activity like oliguria, anuria, electrolyte disturbances due to a precipitation of methotrexate resp. its metabolites or metabolic disturbances of the tubuli cells may appear. An increase of serum creatinine and a decrease of the creatinine clearance, cystitis, mucosa of the bladder with haematuria are first signs of nephrotoxicity. Disturbances of oogenesis and spermatogenesis, temporary oligospermia, loss of libido, impotence, menstrual disturbance, abortion and teratogenesis were described.
Liver: In high dose methotrexate therapy a transient increase of serum transaminase, alkaline phosphatase and rarely hyperbilirubinaemia may appear. During a long term therapy an acute liver dystrophy, periportal fibrosis, liver metamorphosis and cirrhosis were observed. During intermittent massive-dose treatment with subsequent calciumfolinate rescue the mentioned side effects do not appear anymore.
Lungs: A methotrexate pneumonitis (granuloma and infiltrations) and lung fibrosis are rare. First symptoms are cough, tachypnoea and dyspnoea.
Central nervous system: High dose i.v. methotrexate therapy: Acute neurotoxicity (within 24 hours) with dizziness, lethargy, confusion, somnolence, coma which can lead to death and rarely spasms. The symptoms are transient and appear probably due to a cerebral oedema which disappears quickly after systemic administration of cortisone. Subacute neurotoxicity (after 9-13 days) with stroke-like signs as aphasia, haemiparesis, paraplegia and spasms in few patients (mostly after several therapy cycles, but reversible). Retarded neurotoxicity (months to years after methotrexate administration) manifesting in an encephalopathy (spasms, quadriplegia, ataxia and dementia).
Intrathecal methotrexate therapy: Acute neurotoxicity (within 12 hours) caused by an acute arachnoiditis (chemical meningitis, toxic syndrome) with headache, nausea, vomiting and meningism. The symptoms usually disappear after 1-2 days but may also disappear after 1 week or later. Subacute neurotoxicity (within some days to weeks after starting methotrexate therapy) due to a myelopathy or an encephalopathy with mainly myokinetic disturbances (paraplegia) which are mostly reversible after stopping methotrexate therapy. Retarded neurotoxicity is manifested in a leucencephalopathy.
Skin: Erythema, exanthema, pruritus, photosensitization, alopecias, telangiectasias, dyschromia; ecchymoses, acne, furunculosis. Severe toxic manifestations like vasculitis, severe herpetiform skin eruptions and Lyell syndrome may appear. Psoriatic lesions can increase by simultaneous UV radiation therapy.
Other side effects: Allergic reactions (up to anaphylactic shock), fever, chills, impaired resistance to infections, immunosuppression, osteoporosis, metabolic disorders (diabetes mellitus, hyperuricaemia). During treatment with methotrexate in acute lymphatic leucaemia complaints in the left epigastrium can appear (episplenitis by destruction of the leucaemic cells).
Several drugs may cause interactions (mainly pharmacokinetic) during simultaneous administration of methotrexate.
The activity of methotrexate is increased by: Inhibition of the renal elimination (secretion) of methotrexate, e.g. non-steroidal antiphlogistic agents, salicylates, sulphonamides, probenecid, cephalothin, penicillin, carbenicillin, ticarcillin, para-amminohippuric acid.
Usually drugs which are involved in the active tubular secretion impair the elimination of methotrexate and therefore cause an increased plasma concentration.
The displacement of the methotrexate which is bound to plasma proteins leads to a higher free concentration in the plasma, e.g. salicylates, sulfisoxazole, sulfurazole, doxorubicin, bleomycin, cyclophosphamide, phenytoin, barbiturates, tranquilizers, tetracyclines, chloramphenicol, p-amminobenzoic acid, oral antidiabetics (e.g. chlorpropamide, amidopyrine derivatives).
Increase of the intracellular accumulation of methotrexate and methotrexate polyglutamates, e.g. vincaalkaloids, epipodophyllotoxines, probenecid.
The activity of methotrexate is decreased by: Inhibition of the intracellular uptake of methotrexate (corticosteroids, L-asparaginase, bleomycin, penicillin); increase of the dihydrofolate reductase concentration (triamteren) or increase of the intracellular purine concentration (allopurinol); vitamin preparations which contain folic acid or its derivatives (especially folinic acid).
Because of an increased hepatotoxic risk drugs with known hepatotoxicity should not be administered simultaneously. Drugs with folic acid antagonist activity (e.g. trimetoprim) can increase the toxicity of methotrexate.
The myelosuppressive activity can increase due to long-lasting pretreatment with myelosuppressive substances (e.g. sulphonamide, chloramphenicol, pyrazole derivatives, indomethacin, diphenylhydantoin).
Methotrexate can improve the activity of coumarin-like oral anticoagulants (the prothrombin time is prolonged due to a reduced decomposition of coumarin derivatives). During simultaneous parenteral administration of acyclovir and intrathecal administration of methotrexate neurologic disturbances cannot be excluded.
Methotrexate may impair the immunologic reaction to vaccinations and may lead to severe complications. Therefore vaccinations should not be carried out during methotrexate therapy.
According to the type and intensity of the immunosuppressive therapy of the disease and other factors the restoration of the normal reaction ability to vaccine administration can last 3-12 months. Patient with leukaemia should receive life vaccines after remission at least 3 months after the last methotrexate administration.
L04AX03 - methotrexate ; Belongs to the class of other immunosuppressants.