Methotrexate

General characteristics. Structure:

Active ingredient: 2,5 mg, 5 mg or 10 mg of a methotrexate in 1 tablet.

Drug with an antineoplastic, cytostatic and immunodepressive effect.

Pharmacological properties:

Pharmacodynamics. Inhibits a digidrofolatreduktaza (DGF) turning dihydrofolic acid in tetrahydrofolic, being the donor of one-carbon groups in synthesis of the purine nucleotides and thymidylate necessary for synthesis for DNA. Besides, in a cell the methotrexate is exposed to a poliglutaminirovaniye with formation of the metabolites having inhibitory effect not only on DGF but also on other folatzavisimy enzymes, including a timidilatsintetaza, 5-аминоимидазоë4-карбоксамидорибонуклеотид (AIKAR) transamylase.

Suppresses synthesis and DNA repair, a cellular mitosis, to a lesser extent influences synthesis of RNA and protein. Has S-phase specificity, it is active concerning fabrics with high proliferative activity of cells, slows down growth of malignant new growths. Actively sharing cells of tumors, and also marrow, an embryo, mucous membranes of an oral cavity, intestines, a bladder are most sensitive.

Has cytotoxic effect, has teratogenic properties.

In researches on carcinogenicity it is revealed that the methotrexate causes chromosomal damages to somatic zooblasts and cells of marrow of the person, but it did not allow to draw final conclusions on carcinogenicity of drug.

Efficiency of a methotrexate at treatment of bronchial asthma is shown (steroidzavisimy), to a disease Krone, chronic ulcer colitis, fungoid mycosis (late stages), a syndrome of Reuters, a reticular erythrosis (Cesaria's syndrome), psoriasis arthritis, a juvenile pseudorheumatism, for prevention of reactions "a transplant against the owner".

Pharmacodynamics. After intake in a dose of 30 mg/sq.m and it is quickly and completely soaked up from a GIT below (bioavailability about 60%). At children with leukemia the indicator of absorption fluctuates from 23 to 95%. Absorption considerably decreases at exceeding of a dose of 80 mg/sq.m (perhaps because of effect of saturation). Cmax is reached in 1–2 h at peroral and in 30–60 min. at introduction in oil. Reception with food slows down time necessary for achievement of Cmax, approximately for 30 min., but the level of absorption and bioavailability do not change.

Later in/in introductions it is quickly distributed within the volume equivalent to the total amount of liquids of an organism. The initial volume of distribution — 0,18 l/kg (18% of body weight), the equilibrium volume of distribution makes 0,4–0,8 l/kg (40–80% of body weight).

50–60% of the methotrexate circulating in a vascular bed are connected with proteins (mainly with albumine).

Through GEB at intake or parenterally takes place only in limited degree (дозозависимо); after intrathecal introduction in significant amounts comes to a system blood stream. Cosecretes in breast milk, passes through a placenta (has teratogenic effect on a fruit).

It is metabolized in cells of a liver and other cells with formation of polyglutamates (DGF inhibitors and timidilatsintetaza) which can be converted into a methotrexate under the influence of hydrolases. It is partially metabolized by intestinal microflora (after intake). The insignificant quantity of poliglutaminirovanny derivatives keeps in fabrics a long time. Time of keeping and duration of action of these active metabolites depends on type of cells, fabric and a type of a tumor. It is slightly metabolized (at reception of usual doses) to 7 hydroxymethotrexates (solubility in water 3-5 times lower, than at a methotrexate). Accumulation of this metabolite happens at reception of the high doses of a methotrexate appointed for treatment of an osteosarcoma.

Final T1/2  dozozavisimy also makes 3–10 h at introduction of low and 8–15 h — high doses of a methotrexate. 80–90% in/in the entered dose are removed by kidneys in not changed look by glomerular filtering and active canalicular secretion during 24 h, and less than 10% — with bile. The clearance of a methotrexate varies widely, decreases at high doses.

Removal of drug at patients with the expressed ascites or an exudate in pleural liquid in a slowed-up way.

Indications to use:

Uterus choriocarcinoma, acute lymphoid leukosis, TsNS tumors (leukemoid infiltration of a meninx), breast cancer, cancer of the head and neck, lung cancer, bladder, stomach; Hodzhkin's disease, nekhodzhkinsky lymphoma, retinoblastoma, osteosarcoma, Ewing's sarcoma, sarcoma of soft tissues; refractory psoriasis (only at the established diagnosis in case of resistance to other types of therapy), a pseudorheumatism.

Route of administration and doses:

Inside, parenterally (in oil, in/in, vnutriarterialno, intratekalno), depending on indications.

The dose is individualized depending on a type of a tumor, a stage of a disease, efficiency of therapy, portability.

The applied doses according to schemes of treatment divide into usual (low) doses (a single dose lower than 100 mg/sq.m), averages (a single dose of 100-1000 mg/sq.m) and high (the single dose is higher than 1000 mg/sq.m).

Therapy by usual doses (without calcium cover folinaty): in/in 15–20 mg/sq.m 2 times a week or 30–50 mg/sq.m once in a week, or in oil, in/in 15 mg/sq.m a day 5 days with repetition in 2–3 weeks.

Therapy by average doses: in/in 50–150 mg/sq.m (without calcium cover folinaty) with repetition in 2–3 weeks or 240 mg/sq.m (in/in infusion over 24 h under cover of calcium of a folinat) with repetition in 4–7 days; or 500–1000 mg/sq.m (in/in infusion over 36-42 h under cover of calcium of a folinat) with repetition in 2–3 weeks.

Therapy by high doses (under cover of calcium of a folinat): 1000–1200 mg/sq.m (in/in infusion of 1-6 h) with repetition in 1–3 weeks (demands monitoring of level of a methotrexate in blood serum).

Intratekalno of 0,2-0,5 mg/kg of body weight or 8–12 mg/sq.m every 2-3 day. The maximum dose for intrathecal introduction — 15 mg/sq.m. After reduction of symptoms intervals between courses of therapy make week, then — month, indicators of cerebrospinal liquid are not normalized yet. Preventive intrathecal introductions are shown each 6–8 weeks.

In hard cases of generalized resistant psoriasis, including psoriasis arthritis and other autoimmune diseases, parenterally 10–50 mg of a methotrexate with a week interval. At a resistant pseudorheumatism — 5–15 mg in oil once a week, the maximum dose in a week — 25 mg.

Inside (before food). Usually initial dose — 2,5–5 mg, further gradually increase a dose to 7,5–25 mg a week, a weekly dose — 10–25 mg, the maximum total dose — 25 mg a week. Usually 2,5 mg of a methotrexate accept 3 times a week with a 12-hour interval and with a break in a week (Monday — in the morning and in the evening, Tuesday — in the morning, further — a break till next Monday).

Features of use:

Use at pregnancy and feeding by a breast. Contraindicated at pregnancy (can cause death of a fruit or to become the reason of inborn uglinesses). Category of action on a fruit on FDA — X. For the period of treatment it is necessary to stop breastfeeding.

Apply under careful medical control. For early detection of symptoms of intoxication it is necessary to control a condition of peripheral blood (quantity of leukocytes and thrombocytes: at first every other day, then each 3–5 days within the first month, further 1 time in 7-10dny, during remission — 1 time in 1–2 weeks), activity of hepatic transaminases, function of kidneys, periodically to carry out roentgenoscopy of bodies of a thorax. Therapy by a methotrexate stop if the number of lymphocytes in blood makes less than 1,5·10 9/l, quantity of neutrophils — less than 0,2·10 9/l, quantity of thrombocytes less than 75·10 9/l.

Increase in level of creatinine for 50% and more initial contents demands repeated measurement of clearance of creatinine. Increase of level of bilirubin demands intensive disintoxication care. 1 time during treatment and upon termination of a course is recommended to conduct a research of a marrowy hemopoiesis before treatment.

Methotrexate level in plasma is determined at once after the end of infusion, and also in 24, 48 and 72 h (for identification of symptoms of intoxication which is stopped administration of calcium of a folinat).

During treatment in the raised and high doses it is necessary to watch for рН urine (reaction has to be alkaline in day of introduction and in the next 2–3 days). For this purpose in/in (kapelno) enter mix from 40 ml of 4,2% of solution of Natrii hydrocarbonas and 400–800 ml of isotonic solution of sodium of chloride the day before, in day of treatment and in the next 2–3 days. Treatment by a methotrexate in the raised and high doses combine with the strengthened hydration (do2 lzhidkost in days).

It is necessary to pay special attention to the cases of decrease in the hemopoietic function of marrow caused by use of radiation therapy, chemotherapy or prolonged use of some drugs (the streptocides derivative of pyramidon, chloramphenicol, indometacin). In such cases the general state usually worsens that constitutes the greatest danger to patients of young and advanced age.

At development of diarrhea and a stomacace therapy by a methotrexate needs to be interrupted, otherwise it can lead to development of hemorrhagic enteritis.

At emergence of signs of pulmonic toxicity (especially dry cough without phlegm) treatment by a methotrexate is recommended to be stopped because of risk, perhaps, irreversible toxic action on lungs. With care appoint the patient with the broken function of a liver and/or kidneys (doses reduce).

It is necessary to avoid use of alcohol and the drugs possessing a hepatotoxic since their use at treatment by a methotrexate increases risk of damage of a liver; long stay in the sun. At the combined treatment it is necessary to accept each drug in due time; at the passed dose drug is not accepted, the dose is not doubled.

During treatment performing vaccination is not recommended by virus vaccines, it is necessary to avoid contact with the people who received a vaccine against poliomyelitis with sick bacterial infections. It is not necessary to apply live virus vaccines at patients with a leukosis in a remission stage at least within 3 months after a last year of chemotherapy. Immunization by a peroral vaccine against poliomyelitis of the people who are in close contact with such patient, especially family members should be delayed.

Emergence of signs of oppression of function of marrow, unusual bleedings or hemorrhages, black tar-like chair, blood in urine or Calais or dot red spots on skin demands immediate consultation of the doctor.

To be careful in order to avoid accidental cuts sharp objects (a safety razor, scissors), to avoid occupations contact sports or other situations at which hemorrhage or injuries are possible.

Existence of ascites, pleural exudates, exudate in the field of operational wounds promotes accumulation of a methotrexate in fabrics and strengthening of its action that can lead to organism intoxication.

Dental interventions should be completed whenever possible prior to therapy or to postpone until normalization of a picture of blood (possibly increase in risk of microbic infections, delay of processes of healing, bleeding of gums). During treatment to be careful when using toothbrushes, threads or toothpicks.

At patients with the thrombocytopenia which developed as a result of use of a methotrexate it is recommended to observe special precautionary measures (restriction of frequency of venipunctures, refusal of injections in oil, carrying out analyses of urine, a calla and secrets on the occult blood; prevention of locks, refusal of the use of acetylsalicylic acid, etc.), at a leukopenia — carefully to monitor development of infections. At patients with a neutropenia at temperature increase use of antibiotics needs to be begun empirically.

Special instructions. The methotrexate for injections in the form of the lyophilized powder in connection with presence of preservative is not suitable for intrathecal introduction.

It is necessary to avoid conception during treatment by a methotrexate and after it (to men — 3 months after treatment, to women — not less than one ovulyatsionny cycle). After carrying out a course of treatment the methotrexate recommends use of calcium of a folinat for reduction of toxic effects of high doses of drug.

It is necessary to follow necessary rules of use and destruction of drug.

Side effects:

From a nervous system and sense bodys: encephalopathy (especially at introduction of multiple doses intratekalno, and also at patients is after radiation of a brain), dizziness, a headache, a vision disorder, drowsiness, aphasia, pain in a back, muscle tension of a back part of a neck, a spasm, paralysis, a hemiparesis; in some cases — exhaustion, weakness, confusion of consciousness, an ataxy, a tremor, irritability, a coma; conjunctivitis, excess dacryagogue, a cataract, a photophobia, a cortical blindness (at high doses).

From cardiovascular system (a hemopoiesis, a hemostasis): anemia, a leukopenia, thrombocytopenia, a neutropenia, a lymphopenia (especially T lymphocytes), a hypogammaglobulinemia, a hemorrhage, a septicaemia owing to a leukopenia; seldom — a pericardis, an exudative pericardis, hypotension, thromboembolic changes (arterial thrombosis, cerebral thrombosis, a deep vein thrombosis, thrombosis of a renal vein, thrombophlebitis, a pulmonary embolism).

From respiratory system: seldom — an intersticial pneumonitis, a pneumosclerosis, an exacerbation of pulmonary infections.

From bodies of a GIT: an ulitis, pharyngitis, a stomacace, anorexia, nausea, vomiting, diarrhea, the complicated swallowing, a melena, an ulceration of a mucous membrane of a GIT, gastrointestinal bleeding, enteritis, damage of a liver, fibrosis and cirrhosis (the probability is increased at the patients receiving continuous or long therapy).

From urinogenital system: cystitis, a nephropathy, an azotemia, a hamaturia, a hyperuricemia or the expressed nephropathy, a dysmenorrhea, an unstable oligospermatism, disturbance of process of an oogenesis and a spermatogenesis, fetalis defects.

From integuments: a skin erythema, an itch, a hair loss (rarely), a photosensitization, an ecchymoma, an acneform rash, a furunculosis, a peeling, - or a skin hyperpegmentation, blistering, a folliculitis, a teleangiectasia, a toxic epidermal necrolysis, Stephens's syndrome — Johnson.

Allergic reactions: fever, fever, rash, urticaria, anaphylaxis.

Others: immunosuppression, it is rare — an opportunistic infection (bacterial, virus, fungal, protozoan), osteoporosis, a vasculitis.

Interaction with other medicines:

The strengthened and prolonged action of a methotrexate leading to intoxication is promoted by simultaneous use of NPVS, barbiturates, streptocides, corticosteroids, tetracyclines, Trimethoprimum, chloramphenicol, paraaminobenzoic and paraaminobenzaminoacetic acids, a probenetsida. Folic acid and its derivatives reduce efficiency.

Strengthens effect of indirect anticoagulants (derivatives of coumarin or an indandion) and increases risk of bleedings.

Drugs of group of penicillin reduce renal clearance of a methotrexate.

At simultaneous use of a methotrexate and asparaginase blocking of action of a methotrexate is possible.

Neomycinum (for intake) can reduce absorption of a methotrexate (for intake).

The drugs causing pathological changes of blood strengthen a leukopenia and/or thrombocytopenia if these drugs render same, as well as a methotrexate, action concerning function of marrow.

Other drugs causing oppression of function of marrow or radiation therapy exponentiate effect and is additive oppress function of marrow.

The synergy cytotoxic effect with Cytarabinum at simultaneous use is possible.

At simultaneous use of a methotrexate (intratekalno) with an acyclovir neurologic disturbances are (parenterally) possible.

In combination with live virus vaccines can cause an intensification of process of replication of a vaccinal virus, strengthening of side effect of a vaccine and decrease in development of antibodies in response to introduction both the live, and inactivated vaccines.

Contraindications:

Hypersensitivity, immunodeficiency, anemia (including hypo - and aplastic), a leukopenia, thrombocytopenia, a leukosis with a hemorrhagic syndrome, a liver or renal failure.

Restrictions to use. Infectious diseases, the ulcers of an oral cavity and GIT undergone recently operations, gout or renal concrements in the anamnesis (risk of a hyperuricemia), advanced and children's age.

Overdose:

Symptoms: specific symptoms are absent.

Treatment: immediate administration of calcium of a folinat for neutralization of myelotoxic action of a methotrexate (inside, in oil or in/in). The dose of calcium of a folinat has to be equal at least to a methotrexate dose, it needs to be entered within the first hour; the subsequent doses enter as required. Increase hydration of an organism, carry out alkalization of urine in order to avoid settling out of drug and its metabolites in uric ways.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of 2,5 mg, 5 mg and 10 mg, on 20 tablets in each blister, on one, two or three blisters together with the application instruction in cardboard packaging.