Methotrexate of Lakhem

General characteristics. Structure:

METHOTREXATE Lakhema of 5 mg, solution for injections
Contains in 1 bottle: A methotrexate of 5 mg, chloride sodium of 16,5 mg, a sodium hydroxide in the quantity necessary for adjustment рН, water for injections of 2 ml.

METHOTREXATE Lakhema of 20 mg, solution for injections
Contains in 1 bottle: A methotrexate of 20 mg, chloride sodium of 14 mg, a sodium hydroxide in the quantity necessary for adjustment рН, water for injections of 2 ml.

METHOTREXATE Lakhema of 50 mg, solution for injections
Contains in 1 bottle: A methotrexate of 50 mg, chloride sodium of 35 mg, a sodium hydroxide in the quantity necessary for adjustment рН, water for injections of 5 ml.

METHOTREXATE Lakhema of 1000 mg, solution for injections
Contains in 1 bottle: A methotrexate of 1000 mg, chloride sodium of 50 mg, a sodium hydroxide in the quantity necessary for adjustment рН, water for injections of 20 ml.

Pharmacological properties:

Pharmacodynamics. The methotrexate represents itself the antimetabolite relating to group of analogs of folic acid.

Activity of a methotrexate is caused by inhibition of synthesis of DNA, RNA, thymidylate and protein in result of rather irreversible binding with digidrofolatreduktazoy that interferes with recovery of dihydrofolate in active tetrahydrofolate.

So as the methotrexate renders action in S-faze of a cellular cycle, it is most active concerning fabrics with high proliferation of cells, such as tumoral fabric, marrow, epithelium cells. Besides, the methotrexate has immunosuppressive properties.

Pharmacokinetics. After intravenous administration the methotrexate is quickly distributed in limits of the volume equivalent to the total amount of liquids of an organism. The drug elimination half-life in an early phase of distribution makes 0,75±0,11 hours. The methotrexate disappears from blood plasma in the two-phase way. In an initial phase the period of its semi-removal makes 2-4 hours, an in a final phase (which is long) the period of its semi-removal makes 8-10 hours. At renal insufficiency both phases of removal of drug can be considerably prolonged. 50-80% of the entered dose of a methotrexate are found in an invariable look in urine within the first twelve hours after drug infusion. For use of normal doses of drug the clearance of creatinine has to be not less than 40 ml/min. For schemes in which higher doses are applied the clearance of creatinine has to be not less than 60 ml/min. If these values provided below, a methotrexate it is impossible to enter. The methotrexate badly diffuses in cerebrospinal fluid therefore at system therapy achievement of cytotoxic concentration of drug in cerebrospinal fluid requires purpose of high doses for a long time. Removal of drug at patients with the expressed ascites or exudates considerably in a slowed-up way.

Indications to use:

• trophoblastic tumors,
• acute leukoses (especially lymphoblastoid and miyeloblastny options),
• neuroleukaemias,
• nekhodzhkinsky lymphoma, including lymphosarcomas,
• cancer of a mammary gland, planocellular cancer of the head and neck, lung cancer, skin cancer, cancer of a neck of a uterus and vulva, gullet cancer, cancer of kidneys, bladder cancer, germinogenny tumors of a small egg and ovaries, cancer of the sexual member, retinoblastoma, medulloblastoma,
• osteogennaya sarcoma and sarcoma of soft fabrics, Ewing's sarcoma,
• severe forms of psoriasis,
• fungoid mycosis (far come stages),
• rhematoid arthritis (at inefficiency of standard therapy).

Route of administration and doses:

The methotrexate enters into structure of many schemes of chemotherapeutic treatment in this connection at the choice of a way of introduction, the mode and doses in each individual case it is necessary to be guided by data of specialized literature.

METHOTREXATE Lakhema for injections can be entered intramusculary, intravenously, vnutriarterialno or intratekalno.

Use of the Methotrexate in high doses can be very dangerous therefore high-dose therapy has to be carried out only experienced himioterapevtami which can control concentration of a methotrexate in blood plasma in stationary conditions under calcium cover folinata.

During treatment of times a week it is necessary to investigate a blood picture.

Trophoblastic tumors: 15-30 mg inside or intramusculary, daily within 5 days with an interval in one or more weeks (in dependence on toxicity signs). Courses of treatment usually repeat from 3 to 5 times.

Solid tumors: 30-40 mg/sq.m intravenously 1 time a week.

Leukoses and lymphoma: 200-500 mg/sq.m by intravenous infusion of 1 times in 2-4 weeks.

Neuroleukaemia: 12 mg/sq.m intratekalno within 15-30 seconds 1 or 2 times a week. At treatment of children the dose is selected in dependence on age of the child: to children at age till 1 year appoint 6 mg, to children at age of 1 year - 8 mg, to children at age of 2 years - 10 mg, to children at age of 3 years and is more senior - 12 mg. Before introduction it is necessary to make removal of cerebrospinal fluid in the volume approximately equal to the volume of medicinal means which is supposed to be entered.

High-dose therapy: from 2 to 15-ú/sq.m in the form of 4-6 hour intravenous infusions with an interval of 1-5 weeks with obligatory subsequent administration of calcium folinata which is usually begun in 24 hours after the beginning of infusion of a methotrexate and enter each 6 hours in a dose of 3-40 mg/sq.m (usually 15 mg/sq.m) and above into dependences on concentration of a methotrexate in blood serum within 48-72 hours (see the Application instruction of calcium folinata).

Rhematoid arthritis: the initial dose usually makes 7,5 mg one time a week which is entered in one step or is divided into three receptions with an interval at 12 o'clock. 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 unknown.

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: intramusculary on 50 mg of 1 times a week or 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.

Side effects:

System of a hemopoiesis: Leukopenia, neutropenia, lymphopenia (especially T lymphocytes), thrombocytopenia, anemia.

Gastrointestinal path and liver: Anorexia, nausea, vomiting, stomatitis, an ulitis, a glossitis, enteritis, diarrhea, erosive and ulcer defeats of a gastrointestinal path, disturbance of function of a liver, fibrosis and cirrhosis (their probability is increased at the patients receiving long continuous or daily therapy by a methotrexate).

Nervous system: Encephalopathy, especially at introduction of repeated doses intratekalno, an also at patients who received beam therapy on area of a skull. Also there are messages on exhaustion, weakness, confusion to consciousness, an ataxy, a tremor, annoyance, spasms and a coma. The acute by-effects caused by intrathecal introduction of a methotrexate can include dizziness, a sight ambiguity, a headache, pains in areas of a back, rigidity of a back part of a neck, a spasm, paralysis, a hemiparesis.

Mochevyvoditelnaya system: Disturbance of function of kidneys depends on a dose. The risk of disturbance is increased at patients with the lowered renal function or with dehydration, an also at the patients accepting other nephrotoxic drugs. Renal insufficiency is shown by the increased level of creatinine and a hamaturia. Emergence of cystitis is possible.

Reproductive system: disturbance of process of an oogenesis, spermatogenesis, fertility change, teratogenic effects.

Dermatological phenomena: Skin erythema and/or rash, small tortoiseshell, alopecia (seldom), photosensitivity, furunculosis, depigmentation or hyperpegmentation, eels, skin peeling, formation of blisters, folliculitis.

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

Bodies of sight: Konjyuktivit, excess dacryagogue, a cataract, a photophobia, a cortical blindness (at high doses).

Immune status: Immunosuppression, decrease in resistance to injection diseases.

Others: Indisposition, osteoporosis, hyperuricemia, vasculitis. Seldom - a pneumonitis, a pneumosclerosis.

Prevention and precautionary measures:

The methotrexate is cytotoxic drug therefore it is necessary to observe care in the treatment of him.

The medicinal forms containing preservatives in a particular benzyl alcohol, it is forbidden to use for intrathecal introduction and at high-dose therapy.

At introduction of high doses of the Methotrexate careful control of the patient is necessary for early identification of the first signs of toxic reactions.

During therapy by the Methotrexate in the raised and high doses it is necessary to watch for рН urine: in day of introduction and in the next 2-3 days reaction of urine has to be alkaline. It is reached by intravenous drop administration of the mix consisting of 40 ml of 4,2% of solution gidrokarbonata sodium and 400-800 ml of isotonic solution of chloride of sodium the day before in day of treatment and in the next 2-3 days.

Methotrexate in the raised and high doses it is necessary to combine treatment with the strengthened hydration to 2 l of liquid a day. Introduction of the Methotrexate in a dose of 2 g/m2 and is carried out under control of its concentration in blood serum above. Decrease in maintenance of a methotrexate in blood serum in 22 hours after introduction to 2 times in comparison with initial level is considered normal. Increase in level of creatinine for 50% and more initial contents and/or increase of level of bilirubin demand intensive disintoxication care.

For treatment of psoriasis the Methotrexate is appointed only the patient with a severe form of a disease, not poddayushchiyeysya to treatment by other types of therapy.

The periodic analysis of blood, 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 the Methotrexate.

At development of diarrhea and ulcer stomatitis therapy by the Methotrexate needs to be interrupted, in an opposite case 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 identification of the Methotrexate is increased therefore, at such patients therapy should be carried out with extra care, using reduced doses.

Interaction with other medicines:

Simultaneous use of high doses of the Methotrexate with various nonsteroid antiinflammatory drugs (NPVP), including aspirin and other salicylates, azapropazon, diclofenac, indometacin and ketoprofen, toxicity of a methotrexate can amplify, and in a number of cases perhaps heavy toxic action, sometimes even with a lethal outcome. At observance of special precautionary measures and a provedeeniye of the corresponding monitoring use of a methotrexate in low doses (7,5-15 mg a week), in a particular at treatment of rhematoid arthritis, in a combination with NPVP is not contraindicated.

Simultaneous use of streptocides, derivative sulphonylurea, Phenytoinum, phenylbutazone, aminobenzoic acid, probenitsida, Pyrimethaminum or Trimethoprimum, a number of antibiotics (penicillin, tetracycline, chloramphenicol), anticoagulants and hypolipidemic drugs (holestiramin) increases risk of toxicity of a methotrexate.

The patients receiving the accompanying therapy etretinatom or other retinoids, have to be under constant observation because of the increased risk of a hepatotoxic.

The polyvitaminic drugs containing folic acid or its derivatives can reduce efficiency of therapy by a methotrexate.

L-aspariganaza is an antagonist of a methotrexate.

Carrying out anesthesia with use of protoxide of nitrogen can lead to development of an unpredictable heavy miyelosupressiya and stomatitis.

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

At several patients with psoriasis or fungoid mycosis receiving treatment by a methotrexate in a combination with PUVA-terapiya (Methoxalenum and ultra-violet radiation) skin cancer was revealed.

It is necessary to observe care at simultaneous introduction of erythrocyte weight and a methotrexate.

The methotrexate is an immunosuppressant and can reduce the immunological response to vaccination if it is carried out along with therapy by a methotrexate. At simultaneous introduction with a live vaccine heavy antigenic reactions can develop.

Contraindications:

The methotrexate has teratogenic properties and can cause death of a fruit owing to what it is contraindicated to pregnant women.

The methotrexate is excreted in breast milk therefore women cannot appoint it during feeding a breast.

The methotrexate is contraindicated to patients with heavy anemia, a leukopenia, thrombocytopenia, renal or hepatic failure, the patient with chicken pox in the present time or recently postponed, the patient with the surrounding herpes or other infections.

The methotrexate cannot be appointed by the patient with hypersensitivity to this drug.

Overdose:

At accidental overdose of the Methotrexate for decrease in toxicity and for rendering counteraction it is recommended to use Calcium folinat (calcic salt of folinovy acid). Administration of Calcium folinata 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 in process of need for dependence on concentration of a methotrexate for 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. In a case when sredny doses of a methotrexate render undesirable action, it is possible to enter an equivalent of 6-12 mg of folinovy acid intramusculary each 6 hours (4 doses).

At accidental overdose at intrathecal introduction, at once how the overdose is revealed, it is necessary to make repeated lumbar punctures for providing a bystry drainage of cerebrospinal fluid, perhaps neurosurgical intervention with ventrikulolyumbalnoy perfusion. All these procedures should be performed on a background of the intensive supporting care and system introduction of high doses of Calcium folinata.

Storage conditions:

To store in the place, unavailable to children, at a temperature not above 10 °C. To protect from effect of light. Period of validity: 2 years. Drug should not be used after the expiration of the term of the validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

METHOTREXATE Lakhema for injections in the form of solution in bottles on 5 mg / 2 ml, 20 mg / 2 ml, 50 mg / 5 ml and 1000 mg / 20 ml on 1 or 10 bottles in packaging.