Methotrexate

General characteristics. Structure:

Active agent: methotrexate of 2.5 mg

Excipients: sugar (sucrose) - 43.97 mg, potato starch - 21.82 mg, talc - 680 mkg, calcium stearate - 340 mkg, кросповидон - 340 mkg, povidone - 350 mkg.

Structure of a cover: sugar (sucrose) - 32.5865 mg, hydroxycarbonate magnesium hydrate - 20.457 mg, wheat flour - 16.144 mg, povidone - 166 mkg, gelatin - 138 mkg, dye an azoruby (E122) (carmoisin, dye acid red 2C) - 16.6 mkg, titanium dioxide - 450 mkg, wax - 27.9 mkg, talc - 14 mkg.

Pharmacological properties:

Antineoplastic, cytostatic means of group of antimetabolites, suppresses the digidrofolatreduktaza participating in recovery of dihydrofolic 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. Fast-proliferating fabrics are especially sensitive to action: cells of malignant tumors, marrow, embryonic cells, epithelial cells of a mucous membrane of intestines, bladder, oral cavity. Along with antineoplastic possesses an immunodepressive effect.

Pharmacokinetics. Absorption at oral administration depends on a dose: at reception of 30 mg/sq.m average bioavailability - 60% is soaked up well. Absorption decreases at reception in the doses exceeding 80 mg/sq.m.
At children with leukemia absorption fluctuates from 23% to 95%. Time of achievement of Cmax - of 40 min. to 4 h. Food slows down absorption and reduces Cmax. Communication with proteins of plasma - about 50%, are preferential with albumine.
After distribution in fabrics high concentration of a methotrexate in the form of polyglutamates are found in a liver, kidneys and especially in a spleen in which the methotrexate can keep within several weeks or even months.
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 (irrespective of a way of introduction) with formation pharmacological of the active polyglutaminic form which is also inhibiting a digidrofolatreduktaza and synthesis of thymidine is partially metabolized by an indestinal flora. T1/2 at the patients receiving less than 30 mg/sq.m of drug in an initial phase makes 2-4 h, and in a final phase (which is long) - 3-10 h when using small and 8-15 h - when using high doses of drug. 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 introduction collects in fabrics in the form of polyglutamates.

Indications to use:

— acute lymphoblastoid leukosis and nekhodzhkinsky lymphoma;
— trophoblastic tumors;
— fungoid mycosis in far come stages;
— severe forms of psoriasis;
— a pseudorheumatism (at inefficiency of other methods of therapy).

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 of time a week or to 2.5 mg/kg there 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 h. 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 (0.3-1 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 in the treatment of him it is necessary to be careful. Drug has to be appointed by the doctor having experience of use of a methotrexate and familiar with its properties and features of action. In view of possible development of heavy and even fatal side reactions, patients have to be completely informed by the doctor on possible risks and the recommended security measures. For the patients undergoing therapy by a methotrexate it is necessary to carry out appropriate observation signs of possible toxic influence and side reactions came to light and estimated timely.

Before the beginning or resuming of therapy by a methotrexate full general blood test with determination of level of thrombocytes, biochemical analysis of blood with definition of values of enzymes of a liver, bilirubin, seralbumin, radiological inspection of a thorax, a research of function of kidneys, if necessary - tests for tuberculosis and hepatitis has to be made.

For early detection of symptoms of intoxication it is necessary to control a condition of peripheral blood (number of leukocytes and thrombocytes: at first every other day, then each 3-5 days within the first month, then 1 time in 7-10 days, during remission - 1 time in 1-2 weeks), activity of "hepatic" transaminases, function of kidneys (an urea nitrogen, clearance of creatinine and/or creatine to them serums), concentration of uric acid in blood serum, periodically to carry out roentgenoscopy of bodies of a thorax, inspection of a mucous oral cavity and throat on existence an ulceration before each use. Control of a condition of a marrowy hemopoiesis is recommended to see to treatment, 1 times during treatment and upon termination of a course.

The methotrexate can potentially lead to development of symptoms of an acute or chronic hepatotoxic (including to fibrosis and cirrhosis). A chronic hepatotoxic usually develops after prolonged use of a methotrexate (usually within 2 or more years) or achievements of the general cumulative dose not less than 1.5 g and can lead to a failure. The hepatotoxic effect can be also caused by the burdened accompanying anamnesis (alcoholism, obesity, a diabetes mellitus) and senile age. In view of toxic impact of drug on a liver during treatment patients of other hepatotoxic drugs should abstain from appointment except for cases of obvious need. For the patients accepting other hepatotoxic drugs (for example лефлуномид) it is necessary to carry out careful observation.

For objectification of function of a liver along with biochemical parameters carrying out a biopsy of a liver before the beginning or in 2-4 months after an initiation of treatment is recommended; at the general cumulative dose of 1.5 g and after each additional 1-1.5 g. At moderate fibrosis of a liver or any degree of cirrhosis therapy by a methotrexate is cancelled; at fibrosis of an easy form usually recommend a repeated biopsy in 6 months. During initial therapy minor histologic changes of a liver are possible (insignificant a portal inflammation and fatty changes) that is not the basis for refusal or the termination of treatment, but indicates the need of respect for care at drug use

At development of diarrhea and a stomacace therapy by a methotrexate needs to be interrupted owing to high risk of development of hemorrhagic enteritis and a perforation of a wall of intestines which can lead to death of the patient.

It is not necessary to subject the unprotected skin to too long solar radiation or to abuse a lamp of Ural federal district (reaction of a photosensitization is possible). In a type of influence on immune system the methotrexate can worsen reaction to vaccination and influence results of immunoassays. The refusal of immunization (if it is not approved by the doctor) in the range from 3 up to 12 months after administration of drug is necessary; other members of the family of the patient living with him should refuse immunization by a peroral vaccine against poliomyelitis (to avoid contacts with the people receiving a vaccine against poliomyelitis or to wear the protective mask closing a nose and a mouth). Patients of childbearing age of both floors and their partners have to apply reliable measures of contraception during treatment by a methotrexate and after treatment within at least 3 months - men and not less than one ovulyatsionny cycle - women.

After carrying out a course of treatment high doses of a methotrexate for reduction of its toxicity recommend use of calcium of a folinat

As the methotrexate is capable to exert impact on the central nervous system (feeling of fatigue, dizziness), the patients accepting drug should refrain from control of vehicles or potentially dangerous mechanisms.

Side effects:

From system of a hemopoiesis: anemia (including aplastic), thrombocytopenia, leukopenia, neutropenia, agranulocytosis, eosinophilia, pancytopenia, limfoproliferativny diseases, hypogammaglobulinemia, lymphadenopathy.

From the alimentary system: anorexia, nausea, vomiting, stomatitis, an ulitis, pharyngitis, enteritis, erosive cankers and bleeding from a GIT (including a melena, a hematemesis), a hepatotoxic (an acute hepatitis, fibrosis and cirrhosis, a liver failure, a hypoalbuminemia, increase in activity of "hepatic" transaminases), pancreatitis.

From a nervous system: headache, dizziness, drowsiness, dysarthtia, aphasia, hemiparesis, paresis, spasms; when using in high doses - tranzitorny disturbance of cognitive functions, emotional lability; unusual cranial sensitivity, encephalopathy (including leukoencephalopathy).

From an organ of sight: conjunctivitis, vision disorder (including passing blindness).

From cardiovascular system: pericardis, pericardiac exudate, decrease in the ABP, thromboembolism (including arterial thrombosis, thrombosis of cerebral vessels, deep vein thrombosis, retina vein thrombosis, thrombophlebitis, pulmonary embolism).

From respiratory system: seldom - a pneumosclerosis, respiratory insufficiency, an alveolitis, an intersticial pneumonitis (including fatal), the chronic obstructive pulmonary disease (COPD), symptoms of potentially serious intersticial pneumonia - dry not productive cough, an otdyshka, fever.

From urinogenital system: heavy nephropathy or renal failure, azotemia, cystitis, hamaturia, proteinuria, disturbance spermato-and ovogenesis, tranzitorny oligospermatism, decrease libido, impotence, dysmenorrhea, vaginal allocations, gynecomastia, infertility, abortion, death of a fruit, defects of fetation.

From integuments: erythematic rash, skin itch, small tortoiseshell, photosensitivity, disturbance of a xanthopathy, alopecia, ecchymoma, telangiectasia, eels, furunculosis, multiformny erythema (including Stephens-Johnson's syndrome), toxic epidermal necrolysis, ulceration and necrosis of skin, exfoliative dermatitis. At treatment of psoriasis - a skin burning sensation, painful erosive plaques on skin.

From a musculoskeletal system: arthralgia, mialgiya, osteoporosis, osteonecrosis, changes.

New growths: lymphoma (including reversible).

General reactions: allergic reactions up to an acute anaphylaxis, an allergic vasculitis, a syndrome of a lysis of a tumor, a necrosis of soft tissues, sudden death, life-threatening opportunistic infections (including pneumocystic pneumonia), Cytomegaloviral (TsMV) infections (including TsMV-pneumonia), sepsis (including fatal), the nocardiosis, histoplasmosis, a cryptococcosis, infections caused by Herpes zosteri Herpes simplex (including the disseminated herpes), a diabetes mellitus, the increased perspiration.

Interaction with other medicines:

Increases aitikoagulyantny 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.

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 concomitant use of salicylates, phenylbutazone, Phenytoinum, streptocides, derivative sulphonylurea, aminobenzoic acid, Pyrimethaminum or Trimethoprimum, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and hypolipidemic medicines (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.

Nonsteroid protivospalitelny drugs (NPVP) against the background of high doses of a methotrexate increase concentration and slow down elimination of the last that can lead to death from heavy hematologic and gastrointestinal intoxication. It is recommended to stop reception of phenylbutazone in 7-12 days, piroxicam in 10 days, a diflunizal and indometacin for 24-48 h, ketoprofen and NPVP with short T1/2 for 12-24 h before performing infusion of a methotrexate in moderate and high doses and during at least 12 h (depending on concentration of a methotrexate in blood) after its termination. It is necessary to be careful at NPVP combination to low doses of a methotrexate (possibly decrease in removal of a methotrexate renal tubules). The medicines blocking canalicular secretion (for example пробенецид), increase toxicity of a methotrexate due to removal reduction by his kidneys.

The antibiotics which are badly soaking up in a GIT (tetracyclines, chloramphenicol) reduce absorption of a methotrexate and break his metabolism owing to suppression of normal intestinal microflora.

Retinoids, Azathioprinum, Sulfasalazinum, ethanol and other hepatotoxic medicines increase risk of development of a hepatotoxic.

L-asparaginase reduces expressiveness of antineoplastic action of a methotrexate at the expense of inhibition of replication of cells.

Carrying out anesthesia with use of a dinitrogene of oxide can lead to development of an unpredictable heavy miyelosupressiya and stomatitis.

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).

Gematotoksichesky medicines increase risk of development of a gematotoksichnost of a methotrexate.

The methotrexate reduces clearance of theophylline.

Neomycinum for intake can reduce absorption of a methotrexate. At several patients with psoriasis or fungoid mycosis receiving treatment by a methotrexate in a combination with PUVA therapy (Methoxalenum and ultra-violet radiation (Ural federal district)) the carcinoma cutaneum was revealed.

The combination to radiation therapy can increase risk of oppression of marrow. The methotrexate can reduce an immune response on vaccination by the live and inactivated virus vaccines.

Folatsoderzhashchy medicines (including polyvitamins) can reduce efficiency of therapy by a methotrexate.

Purpose of Amiodaronum to the patients receiving therapy by a methotrexate concerning psoriasis can cause expression of skin.

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 marrow hypoplasia, 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.

Use at pregnancy and feeding by a breast
Possesses teratogenic action: it is capable to cause fruit death, inborn uglinesses. If the woman became pregnant during therapy by a methotrexate, it is necessary to resolve an issue of abortion in connection with risk of collateral impact on a fruit. The methotrexate is allocated with breast milk, for all course of treatment breastfeeding should be stopped.

Use at abnormal liver functions
Use of a methotrexate is contraindicated at the expressed changes of function of a liver.

Use at renal failures
Use of a methotrexate is contraindicated at the expressed changes of function of kidneys.
Removal of drug at patients with a renal failure is considerably slowed down. At repeated introduction collects in fabrics in the form of polyglutamates.

Use for children
Use of a methotrexate is contraindicated to children up to 3 years.

Overdose:

Specific symptoms of overdose by a methotrexate are absent, is diagnosed on concentration of a methotrexate in plasma.

Treatment: Introduction of a specific antidote - calcium of a folinat whenever possible immediately, 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 alkalifying of urine that accelerates removal of a methotrexate. To minimize risk of a nephropathy as a result of formation of a deposit of drug or its metabolites in urine, it is necessary to define in addition рН urine before each introduction and each 6 h throughout the entire period of use of calcium of a folinat as an antidote until concentration of a methotrexate in plasma becomes below 0:05 µmol/l, for providing рН higher than 7.

Storage conditions:

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

Issue conditions:

According to the recipe

Packaging:

Tablets, покр. cover, 2.5 mg: 50 pieces.