Methotrexate

General characteristics. Structure:

Active agent: a methotrexate (in terms of active agent at the expense of sucrose) 2,5 mg;

Excipients: a kernel - sucrose - 60,0 mg, potato starch - 6,45 mg, calcium stearate - 0,7 mg, talc (a matiya hydrosilicate) - 0,35 mg; a cover - sucrose - 62,248 mg, dye an azoruby - 0,011 mg, polysorbate 80 (twin-80) - 0,165 mg, povidone of 30 - 0,408 mg, gelatin - 0,063 mg, titanium dioxide of-1,778 mg, croscarmellose sodium - 0,499 mg, silicon dioxide colloid (aerosil) - 0,549 mg, talc (magnesium hydrosilicate) - 4,195 mg, опаглос 6000 (wax, white wax a Brazilian wax palm, shellac) - 0,084 mg.

Pharmacological properties:

Pharmacodynamics. Antineoplastic, cytostatic means of group of antimetabolites — analogs of folic acid. Inhibits the digidrofolatreduktaza participating in recovery of di hydrofolic acid in tetrahydrofolic acid (a carrier of the carbon fragments necessary for synthesis of purine nucleotides and their derivatives). Slows down synthesis, DNA repair and a cellular mitosis (in a S-phase). Are especially sensitive to action of a methotrexate of fabric with high proliferation of cells: tumoral tissue, marrow, cells of an epithelium of mucous membranes, embryonic cells. Along with antineoplastic possesses immunosuppressive action.

Pharmacokinetics. Absorption at oral administration depends on a dose: at reception of 30 mg/sq.m average bioavailability — 50% is soaked up well. Absorption decreases at reception in the doses exceeding 80 mg/sq.m (believe, owing to saturation). At children absorption fluctuates from 23 to 95%. Time of achievement of the maximum concentration (CU) — 1-2 h. Food slows down absorption and reduces (TC^J. Communication with proteins of a blood plasma — about 50%. At reception in therapeutic doses practically does not get through a blood-brain barrier. Gets into breast milk.
After peroral introduction the main part — in a liver with formation pharmacological of the active poliglyutaminovy form inhibiting a digidrofolatreduktaza and synthesis of thymidine is partially metabolized by an indestinal flora. The elimination half-life (T1/2) in an initial phase makes 2-4 h, and in a final phase — 3-10 h. At a chronic renal failure both phases of removal of drug can be considerably prolonged. It is removed preferential by kidneys in not changed look by glomerular filtering and canalicular secretion, with bile it is removed to 10% (with the subsequent reabsorption in intestines). Removal of drug at patients with the renal failure expressed by ascites or transudate is considerably slowed down. At repeated introductions collects in fabrics in the form of metabolites.

Indications to use:

The methotrexate in tablets is applied when using low doses to treatment of trophoblastic tumors, an acute lymphoblastoid leukosis and nekhodzhkinsky lymphoma and far come stages of fungoid mycosis, severe forms of psoriasis, and also at a pseudorheumatism when other methods of therapy are inefficient.

Route of administration and doses:

 The methotrexate in tablets is applied inside. Doses and terms of treatment establish individually depending on the scheme of chemotherapy. Trophoblastic tumors:
— 15-30 mg inside, daily within 5 days at an interval of one or more weeks (depending on toxicity signs). Courses of treatment usually repeat from 3 to 5 times — on 50 mg of 1 times in 5 days with an interval not less than 1 month. On a course of treatment 300-400 mg are required.
Acute lymphoblastoid leukosis (as a part of complex therapy): — on 3,3 mg/sq.m in a combination with Prednisolonum before achievement of remission, then on 15 mg/sq.m 2 times a week or to 2,5 mg/kg are each 14 days.
Nekhodzhkinsky lymphoma (as a part of complex therapy): — on 15-20 mg/sq.m for 1 reception 2 times a week;
— on 7,5 mg/sq.m daily within 5 days. Pseudorheumatism:
The initial dose usually makes 7,5 mg once a week which is accepted in one step or is divided into three receptions at an interval of 12 hours. For achievement of optimum effect the week dose can be raised, at the same time it should not exceed 20 mg. When the optimum clinical effect is reached, it is necessary to begin a dose decline before achievement of the lowest effective dose. The optimum duration of therapy is not known. At juvenile chronic arthritis for children doses of 10-30 mg/sq.m/week (03-1 mg/kg) are effective.
Psoriasis: Therapy by a methotrexate is carried out in doses from 10 to 25 mg a week. The dose is usually increased gradually, at achievement of optimum clinical effect begin a dose decline before achievement of the lowest effective dose.
Fungoid mycosis:
— on 25 mg 2 times a week. The dose decline or cancellation of administration of drug is defined by reaction of the patient and hematologic indicators.

Features of use:

The methotrexate is cytotoxic drug therefore it is necessary to be careful in the treatment of him. Periodic blood test (once a week), determination of content of leukocytes and thrombocytes, carrying out hepatic and renal functional tests is necessary for prevention of toxicity in the course of treatment by a methotrexate. At development of diarrhea and a stomacace therapy by a methotrexate needs to be interrupted, otherwise, it can lead to development of hemorrhagic enteritis and to death of the patient owing to an intestines perforation. At patients with the broken function of a liver the period of removal of a methotrexate is increased therefore, at such patients therapy should be carried out with extra care, using reduced doses.
The renal failure depends on a dose. The risk of disturbance is increased at patients with the lowered renal function or with dehydration, and also at the patients accepting other nephrotoxic drugs.
Special attention should be paid to manifestations of toxic action of a methotrexate on a liver which not always find reflection in results of functional trials. Treatment should not be begun or it has to be stopped at detection of any functional frustration or deviations at a biopsy research of hepatic fabric which are present or develop during therapy. These disturbances take place for two weeks then resuming of therapy at the discretion of the attending physician is possible. Now there are no recommendations concerning terms of carrying out a biopsy of a liver at patients with a pseudorheumatism: or depending on a cumulative dose of a methotrexate, or therapy duration.
Men and women of childbearing age during treatment by a methotrexate and at least within 3 months later should apply reliable methods of contraception. Some side effects of drug can negatively influence ability of driving and performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

- From system of a hemopoiesis: pancytopenia, leukopenia, neutropenia, lymphopenia (especially T lymphocytes), thrombocytopenia, anemia, agranulocytosis, zozinofiliya.
- From cardiovascular system: a pericardis, an exudative pericardis, the thromboembolic phenomena (including thrombosis of arteries, cerebral thrombosis, a deep vein thrombosis, an eye retina vein thrombosis, thrombophlebitis, an embolism of lungs).
- From an urinary system: cystitis, renal failure, nephropathy, azotemia, hamaturia.
- From a respiratory organs: chronic intersticial pneumonitis, fluid lungs, pulmonary fibrosis of consciousness, ataxy, tremor, irritability, spasms and coma., pneumonitis, alveolitis, bronchial asthma, pleural exudate.
- From the alimentary system: anorexia, nausea, vomiting, stomatitis, an ulitis, a glossitis, pharyngitis, it is rare — enteritis, diarrhea, erosive cankers and bleedings from digestive tract, in some cases (at prolonged daily use) — an abnormal liver function, increase in activity of "hepatic" transaminases, periportal fibrosis and cirrhosis, a liver necrosis, fatty dystrophy of a liver, pancreatitis.
- From a nervous system: encephalopathy (at patients who received radiation therapy on area of a skull), increased fatigue, dizziness, a headache, aphasia, paresis, a hemiparesis, weakness, confusion.
- From reproductive system: disturbance of process of an oogenesis, spermatogenesis, decrease libido/impotence, fertility change, teratogenic effects.
- From skin and skin appendages: a skin erythema and/or rash, a skin itch, a small tortoiseshell, telangiectasias, a furunculosis, a depigmentation or a hyperpegmentation, eels, a skin peeling, a folliculitis, an alopecia (seldom), the increased photosensitivity, an exacerbation of radiation dermatitis.
- From sense bodys: conjunctivitis, excess dacryagogue, a cataract, a photophobia, a cortical blindness (at high doses), a vision disorder.
- Allergic reactions: fever, fever, rash, urticaria, anaphylaxis, malignant exudative erythema (Stephens-Johnson's syndrome), toxic epidermalyiy necrolysis (Lyell's disease).
- Other: immunosuppression (decrease in resistance to infectious diseases), indisposition, osteoporosis, hyperuricemia, hemorrhagic syndrome, vasculitis, arthralgia / миалгия, pericardiac exudate.

Interaction with other medicines:

Simultaneous use of high doses of a methotrexate with various non-steroidal anti-inflammatory drugs (NPVP), including acetylsalicylic acid and other salicylates, азапропазон, diclofenac, indometacin and ketoprofen toxicity of a methotrexate can amplify, and in some cases perhaps heavy toxic action, sometimes even with a lethal outcome. At observance of special precautionary measures and carrying out the corresponding monitoring use of a methotrexate in low doses (7,5-15 mg a week), in particular at treatment of a pseudorheumatism, in a combination with NPVP is not contraindicated. The methotrexate increases anticoagulating activity of derivatives of coumarin or an indandion and/or increases risk of bleedings due to decrease in synthesis in a liver of a procoagulant factor and disturbance of formation of thrombocytes. Simultaneous use of streptocides, derivative sulphonylurea, Phenytoinum, phenylbutazone, aminobenzoic acid, Pyrimethaminum or Trimethoprimum, number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and hypolipidemic drugs (Colestyraminum) increases toxicity due to replacement of a methotrexate from communication with albumine and/or decrease in canalicular secretion that in some cases can cause development of heavy toxic action, sometimes even with a lethal outcome. The methotrexate increases concentration of uric acid in blood therefore at treatment of patients with the accompanying hyperuricemia and gout dose adjustment of antigouty medicines (Allopyrinolum, colchicine, Sulfinpyrazonum) can be required; use of uricosuric antigouty medicines can increase risk of development of the nephropathy connected with the increased formation of uric acid against the background of treatment by a methotrexate (it is preferable to use Allopyrinolum). The antibiotics which are badly soaking up in digestive tract (tetracyclines, chloramphenicol) reduce absorption of a methotrexate and break his metabolism owing to suppression of normal intestinal microflora. Retinoids, Azathioprinum, Sulfasalazinum increase risk of development of a hepatotoxic.
The polyvitaminic drugs containing folic acid or its derivatives can reduce efficiency of therapy by a methotrexate.
Use of Cytarabinum for 48 h to or within 10 min. after the beginning of therapy by a methotrexate can cause development of sinergidny cytotoxic effect (correction of the mode of dosing is recommended to be carried out on the basis of control of hematologic indicators).
Neomycinum for intake can reduce absorption of a methotrexate for intake.
Gematotoksichesky medicines increase risk of development of a gematotoksichnost of a methotrexate. L-asparaginase is an antagonist of a methotrexate. Carrying out anesthesia with use of a dinitrogene of oxide can lead to development of unpredictable heavy miyelo-suppression and stomatitis.
Purpose of Amiodaronum to the patients receiving therapy by a methotrexate concerning psoriasis can cause a skin ulceration.
The methotrexate reduces clearance of theophylline. At several patients with psoriasis or fungoid mycosis receiving treatment by a methotrexate in a combination with PUVA therapy (Methoxalenum and ultra-violet radiation) the carcinoma cutaneum was revealed.
It is necessary to be careful at simultaneous introduction of a packed red cells and methotrexate. The combination to radiotheraphy can increase risk of a necrosis of soft tissues. The methotrexate can reduce the immunological response to vaccination. At simultaneous introduction with a live vaccine heavy antigenic reactions can develop.

Contraindications:

Use of a methotrexate is contraindicated at pregnancy and during feeding by a breast, at the expressed changes of function of kidneys and a liver, at hematologic frustration, such as a marrow hypoplasia, a leukopenia, thrombocytopenia, anemia, at an acute stage of infectious diseases, an immunodeficiency syndrome, at hypersensitivity to a methotrexate or other components of a tablet, children up to 3 years.
With CARE: at ascites, an exudate in a pleural cavity, a peptic ulcer of a stomach and a duodenum, ulcer colitis, dehydration, gout or a nephrolithiasis in the anamnesis, earlier carried out radiation therapy or chemotherapy, infectious diseases of the virus, fungal or bacterial nature.

Overdose:

Specific symptoms are absent. At accidental overdose of a methotrexate it is recommended to use a specific antidote — calcium фолинат. Administration of calcium of a folinat should be begun whenever possible immediately, it is desirable within the first hour, in the dose equal or exceeding a methotrexate dose; the subsequent doses enter as required depending on concentration of a methotrexate in blood serum. For the prevention of precipitation of a methotrexate and/or its metabolites in renal tubules carry out hydration of an organism and alkalization of urine.

Storage conditions:

List B. To store in the dry, protected from light place, at a temperature not above 25 °C.
To store in the place, unavailable to children!

Issue conditions:

According to the recipe

Packaging:

Tablets, coated 2,5 mg.
On 10, 50 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.
On 10, 20, 30, 40, 50 or 100 tablets in a container polymeric for medicines.
One container or 1, 2, 3, 4, 5, 6, 8 or 10 blister strip packagings together with the application instruction in a pack from a cardboard.