Methotrexate 50s 2.5 mg coated tablets
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The instruction
for medical use of medicine
the Methotrexate
the Trade name
the Methotrexate
the International unlicensed
name Methotrexate Dosage Form
of the Tablet, coated, 2.5 mg
Structure
One tablet contains
active agent: a methotrexate (in terms of 100% substance) - 2.5 mg,
excipients: sucrose (sugar), potato starch, talc, calcium stearate, krospovidon, povidone
structure of an internal cover: sucrose (sugar), magnesium carbonate easy, wheat flour
structure of an outer sheath: sucrose (sugar), magnesium carbonate easy, wheat flour, povidone, gelatin, dye azoruby E 122, titan E 171 dioxide, wax, talc.
The description
Round biconvex tablets, coated from pink till dark pink color, on cross section are visible two layers of a cover and a kernel. A cover layer from pink till dark pink color and a layer of white color. A kernel from yellow till orange-yellow color.
Pharmacotherapeutic group
Antineoplastic drugs. Antimetabolites. Folic acid analogs. Methotrexate.
The ATX L01BA01 code
the Pharmacological
Pharmacokinetics Absorption properties at oral administration depends on a dose: at reception of 30 mg/sq.m the average bioavailability - 60% is soaked up well. Absorption decreases at reception in the doses exceeding 80 mg/sq.m.
At children with leukemia the absorption fluctuates from 23% to 95%. Time of achievement of the maximum concentration (TCmax) – of 40 min. to 4 h. Food slows down absorption and reduces Cmax. Communication with proteins of blood plasma about 50%, mainly with albumine.
After distribution in fabrics high concentrations 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 oral introduction the main part is partially metabolized by indestinal flora, - in a liver (irrespective of a way of introduction) with formation pharmacological of the active polyglutamic form which is also inhibiting a digidrofolatreduktaza and synthesis of thymidine.
Elimination half-life (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. In chronic kidney disease both phases of removal of drug can be considerably prolonged.
It is removed mainly by kidneys in not changed look by glomerular filtration and canalicular secretion, with bile it is removed up to 10% (with the subsequent reabsorption in intestines). Removal of drug at patients with a renal failure, the profound ascites or transudate is considerably slowed down. At repeated introduction collects in fabrics in the form of polyglutamates.
A pharmacodynamics
Antineoplastic, cytostatic means of group of antimetabolites - analogs of folic acid. Inhibits the digidrofolatreduktaza participating in restoration of dihydrofolic acid in tetrahydrofolic acid (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 immunodepressive effect.
Indications
– an active course of a pseudorheumatism at adult patients
– the severe forms of simple (blyashkovidny) psoriasis which are not responding to treatment by retinoids, to phototherapy and PUVA therapy
– heavy psoriasis arthritis
the Route of administration and doses
apply the Methotrexate inside, once a week.
A pseudorheumatism
the Usual dose of a methotrexate makes 7.5 - 15 mg once a week, the maximum dose – 20 mg once a week. The planned weekly dose can be entered in three steps with an interval of not less than 36 hours. For the purpose of achievement of the optimum answer the selection of the individual scheme of reception of a methotrexate with use of the total dose which is not exceeding 20 mg a week is possible. After achievement of the optimum answer (which can be in most cases reached within 6 weeks of therapy) the dose has to be reduced to a minimal effective dose.
Psoriasis
to exclude unexpected toxic effects, treatment it is necessary to begin after single dose of a methotrexate in a dose 2.5-5.0 mg with control of laboratory indicators of function of a liver in one week. The usual dose of a methotrexate makes 7.5 - 15 mg once a week, the maximum dose – 25 mg once a week. The planned weekly dose can be entered in three steps with an interval not less than 24 hours. After achievement of the optimum answer (which can be in most cases reached within 4 - 8 weeks of therapy) the dose has to be reduced to a minimal effective dose.
The purpose of therapy has to consist in achievement of a minimal effective dose, maximum break between therapy courses a methotrexate and, whenever possible, to return to usual therapy.
Use for patients of advanced age
For patients of advanced age the methotrexate has to be used with care. In case of depression of function of a liver and kidneys, deficiency of folic acid which can be observed at advanced age it is necessary to consider the possibility of reduction of a dose of drug.
The feature of use for patients with an abnormal liver function
to Patients with liver diseases, including in the anamnesis, especially in case of the diseases caused by alcohol intake should appoint a methotrexate with extra care and if the expected advantage exceeds potential risk.
Side effects
Classification of frequency of development of side effects: very often (≥1/10), it is frequent (≥1/100, but & lt, 1/10), infrequently (≥1/1000, & lt, 1/100), is rare (≥1/10,000, & lt, 1/1000), is very rare (& lt, 1/10,000), frequency is not known.
Often
- a leukopenia,
- anorexia, nausea, vomiting, stomatitis, diarrhea,
- increase in activity of 'hepatic' transaminases,
- a headache, dizziness, fatigue,
- infections,
- erythematic rash, an alopecia.
Not often
- anemia (including aplastic), thrombocytopenia, a neutropenia, an agranulocytosis, a pancytopenia,
- nasal bleeding,
- a pneumosclerosis, an interstitial pneumonitis (including fatal),
- opportunistic infections,
- a heavy nephropathy or a renal failure,
- vagina ulcers,
- a lymphoma (including reversible),
- an itching of skin, Stephens-Johnson's syndrome, a toxic epidermal necrolysis,
- allergic reactions up to an acute anaphylaxis,
is rare
- an ulitis, pharyngitis, enteritis, erosive cankers and bleeding from the digestive tract (DT),
- a hemiparesis,
- a depression, confusion of consciousness,
- a lowering of arterial pressure, a thrombembolia (including arterial thrombosis, thrombosis of cerebral vessels, a deep vein thrombosis, a retina vein thrombosis, thrombophlebitis, a pulmonary embolism),
- an asthma,
- Herpes zoster and sepsis (including fatal),
- decrease a libido, impotence, a dysmenorrhea,
- an arthralgia, myalgia, osteoporosis, increase in quantity of rheumatoid small knots,
- diabetes,
- photosensitivity, eels, xanthopathy disturbance, a small tortoiseshell, a multiformny erythema, an ulceration and necrosis of skin,
- at treatment of psoriasis – burning sensation of skin, painful erosive plaques on skin.
Very seldom
- a hypogammaglobulinemia,
- a hematemesis,
- hepatotoxicity (acute hepatitis, fibrosis and cirrhosis),
- a dysarthtia, aphasia, irritability, a lethargy,
- conjunctivitis, a disorder of vision (including a passing blindness),
- a pericarditis, a pericardiac exudate,
- a vasculitis,
- pneumocystic pneumonia, a chronic obstructive pulmonary disease, dry unproductive cough, pleurisy,
- a dysuria, an azotemia, cystitis, a hamaturia,
- disturbance spermato- and an ovogenesis, a tranzitorny oligospermatism, infertility, vaginal discharges, a gynecomastia,
- a telangiectasia, a furunculosis, an ecchymoma.
Frequency is not known
- an eosinophilia, limfoproliferativny diseases, a lymphadenopathy,
- a melena,
- a hypoalbuminemia,
- pancreatitis,
- drowsiness, spasms, when using in high doses - tranzitorny disturbance of cognitive functions, emotional lability, unusual cranial sensitivity, encephalopathy (including a leukoencephalopathy),
- respiratory insufficiency, an alveolitis,
- Herpes simplex (including disseminate herpes),
- a proteinuria,
- an abortion, death of a fruit, defects of fetation,
- exfoliative dermatitis,
- an osteonecrosis, fractures,
- a syndrome of lysis of a tumor,
- necrosis of soft tissues,
- sudden death,
- Cytomegaloviral (CMV) infections (including CMV-pneumonia), a nocardiosis, histoplasmosis, a cryptococcosis,
- the increased perspiration.
Contraindications
– hypersensitivity to a methotrexate or other components of drug
– the significant disturbances of functions of kidneys and a liver
– hematologic disorders (marrow hypoplasia, a leukopenia, thrombocytopenia, anemia)
– heavy acute or persistent infections
– alcoholism
– an immunodeficiency syndrome
– pregnancy and the period of a lactation
– children's and teenage age up to 18 years
– vaccination by live vaccines during therapy by a methotrexate
Medicinal interactions
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.
Increases concentration of uric acid in blood therefore at treatment of patients with the accompanying hyperuricemia and gout the 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) enhances 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.
At the solution of a question of joint prescribing of Phenytoinum and a methotrexate it is necessary to consider that the risk of strengthening of spasms owing to reduction of absorption of Phenytoinum at reception with cytotoxic drugs or risk of toxicity exceeds possible efficiency of a methotrexate.
The concomitant use of a methotrexate in combination with leflunomidy can increase risk of a pancytopenia.
Cisplatinum can break removal through kidneys of a methotrexate and enhance its toxicity.
It is necessary to be careful at a combination of non-steroidal anti-inflammatory drugs (NPVP) to low doses of a methotrexate (possibly decrease in removal of a methotrexate renal tubules). Treatment of a pseudorheumatism a methotrexate in combination with NPVP usually is not followed by toxic effects. However, it is necessary to consider that the methotrexate doses used for treatment of a pseudorheumatism (7.5 - 15 mg a week), below, than used for treatment of psoriasis and that higher doses can result in unexpected toxicity.
The medicines blocking canalicular secretion (for example, probenetsid), 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, leflunomid, ethanol and other hepatotoxic medicines increase risk of development of hepatotoxicity.
Simultaneous use of a methotrexate and omeprazolum increases time of removal of a methotrexate. At the combined use of a methotrexate and inhibitors of a proton pomp (omeprazolum or a pantoprazol) the development undesirable to interactions is possible.
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 unpredictable heavy myelosuppression 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. At simultaneous use with a methotrexate it is necessary to control theophylline level in blood plasma.
At simultaneous use with a methotrexate the increase in concentration of Mercaptopurinum in blood plasma is observed (combined use can demand correction of doses).
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 the immune response on vaccination by the live and inactivated virus vaccines. Vaccination by live vaccine can lead to heavy and fatal infections. The accompanying use of a methotrexate with live vaccine is not recommended.
Cyclosporine can enhance efficiency and toxicity of a methotrexate. In case of use of this combination there is a risk of an excess immunosuppression with risk of a limfoproliferation.
Prescribing of Amiodaronum to the patients receiving therapy by a methotrexate concerning psoriasis can cause expression of skin.
Folatsoderzhashchy medicines (including polyvitamins) can reduce efficiency of therapy by a methotrexate.
The special
instructions Methotrexate is cytotoxic drug therefore in 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 potential toxic impact and side reactions came to light and estimated in due time.
There are messages about fatal cases at treatment of psoriasis with use of a methotrexate. At treatment of psoriasis the methotrexate has to be appointed only in case of its persistent course, with emergence of disability, lack of the response to other types of therapy when the diagnosis is established on the basis of a biopsy and/or consultation of the dermatologist.
The patient needs to report that at treatment of psoriasis and pseudorheumatism the administration of drug is in most cases carried out once a week. Patients have to be informed that disturbance of the mode of dosing is connected with risk of emergence of toxic effects.
Observation of the patients accepting a methotrexate has to be organized so that signs of possible toxic effects or side reactions were found and estimated with the minimum delay.
It was reported about fatal cases at reception of a methotrexate owing to an acute and chronic pneumonitis which was often connected with an eosinophilia. Symptoms of a pneumonitis as a rule include short wind, cough (especially dry cough) and fever. Patients need to report about risk of a pneumonitis and need to report about ultimate cough or an asthma. Existence of these symptoms needs to be controlled at each visit of the patient (in case of their existence the methotrexate needs to be cancelled to a pneumonitis exception). In case of confirmation of communication of a disease with reception of a methotrexate it is necessary to carry out treatment of a pneumonitis with use of corticosteroids and to exclude repeated purpose of a methotrexate in the future.
Before the beginning or resuming of therapy by a methotrexate and also during therapy and after its end the full general blood test with definition of a hematocrit, level of leukocytes and thrombocytes, biochemical analysis of blood with determination of values of enzymes of a liver, bilirubin, seralbumin, a research of function of kidneys (urea nitrogen, clearance of creatinine and/or creatinine of serum), concentration of uric acid in blood serum has to be made). Prior to therapy the methotrexate also recommends to perform radiological examination of a thorax.
In case of clinically significant decrease in quantity of leukocytes or thrombocytes the methotrexate has to be immediately cancelled. Patients have to be informed on need to report about any signs of developing of infectious diseases.
The methotrexate can potentially lead to development of symptoms of sharp or chronic hepatotoxicity (including to an atrophy, fibrosis and cirrhosis), especially in high doses or at long therapy.
Patients have to be informed concerning risk of toxic effects from a liver.
The course of treatment should not be begun or has to be stopped in case of a deviation in laboratory indicators of function of a liver. Such deviations have to return to normal values within two weeks then treatment can be resumed to the discretion of the doctor.
Frequency of a deviation of laboratory indicators in two or three times at biochemical analysis of blood with determination of values of enzymes of a liver is 13-20%. In case of continuous increase in such indicators it is necessary to resolve an issue of a dose decline or the termination of therapy.
Chronic hepatotoxicity 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, diabetes) 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 taking other hepatotoxic drugs (for example, leflunomid), 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. In moderate fibrosis of a liver or any degree of cirrhosis the therapy by a methotrexate is cancelled, in fibrosis of an easy form usually recommend a repeated biopsy in 6 months. During initial therapy, minor histologic changes of a liver (insignificant portal inflammation and fat changes) are possible that is not the basis for refusal or the termination of treatment, but indicates the need of respect for care at drug use.
The biopsy of a liver is not carried out in the following cases:
- elderly patients
- patients with acute diseases
- patients with a contraindication for a liver biopsy (for example, heart failure, fibrillation disturbance)
- patients with the low forecast of survival
of Data on need and expediency of carrying out a biopsy of a liver at treatment by a methotrexate of a pseudorheumatism is not enough.
More frequent biopsies of a liver can be necessary in the following cases:
- during an initial phase of treatment
- in case of increase in a dose of a methotrexate
- in case of risk of increase in level of a methotrexate in blood plasma (for example, in dehydration, risk of depression of function of kidneys owing to addition or increase in a dose of the accompanying drugs, for example NPVP).
The methotrexate is applied with care in 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 and also at patients of young and advanced age.
The methotrexate is allocated generally with kidneys. Its use in case of a renal failure can result in toxic effects or even to additional injury of kidneys. High doses can cause accumulation of a methotrexate or its metabolites in renal tubules. At patients with diseases of kidneys the dose of a methotrexate has to be reduced. For the purpose of prevention (diuretic effect and alkalifying of urine to rn 6.5 - 7.0) it is recommended, oral administration (on 5 tablets on 625 mg each three hours) or intravenous administration of sodium bicarbonate or acetazoleamide (on 500 mg four times a day).
There are messages about serious side reactions including fatal cases at combined use of a methotrexate and NPVP.
At treatment by a methotrexate of a pseudorheumatism use of acetylsalicylic acid, NPVP and also steroid drugs in a small dose is possible. Nevertheless, it is necessary to consider that combined use of NPVP and methotrexate is connected with the increased risk of toxicity. The dose of steroid drugs at patients with affirmative answer by a methotrexate can be reduced by therapy.
Interaction between a methotrexate and such antirheumatic medicines as Penicillaminum, hydroxychloroquine, Sulfasalazinum, gold drugs - is not studied. It is necessary to consider that their joint reception with a methotrexate can increase the frequency of side reactions.
There are data on development in rare instances of a sharp megaloblastny pancytopenia at combined use of a methotrexate and antagonists of folic acid, such as Trimethoprimum-sulfamethoxazole.
After absorption the methotrexate partially communicates albumine and its toxicity can increase due to replacement from this communication at intake of salicylates, sulphamides, Phenytoinum and some antibiotics, such as tetracycline, chloramphenicol and para-aminobenzoic acid. These medicines, especially salicylates and sulphamides, have to be appointed together with a methotrexate only if the potential advantage of their use exceeds possible risk.
It is necessary to consider that the gematotoksichesky effect of a methotrexate can suddenly be shown when the patient accepts presumably safe dose of drug therefore any considerable decrease in blood cells demands the termination of reception of a methotrexate. Serious decrease in gematopoetichesky activity of marrow can demand transfusion of blood or platelet concentrate.
At development of diarrhea and stomacace the therapy by a methotrexate needs to be interrupted owing to high risk of developing 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 view of influence on the 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 it should refuse immunization by the oral vaccine against poliomyelitis (to avoid contacts with the people receiving the vaccine against poliomyelitis or to wear the protective mask closing a nose and a mouth). Special attention has to be paid on inactive persistent infections at patients (for example, shingles, tuberculosis, hepatitis B and C) because of their potential activation.
Malignant lymphoma can be diagnosed for the patients receiving low doses of a methotrexate. Therapy by a methotrexate in this case has to be stopped. The lack of signs of spontaneous regress of a lymphoma demands performing therapy by cytotoxic drugs.
There are data that the methotrexate can cause an oligospermatism, disturbances of a menstrual cycle (including an amenorrhea) in time and during the short period after the therapy termination.
Patients of childbearing age of both sexes and their partners have to take 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.
Intake of the vitamin drugs containing folic acid or its derivatives can change the response to therapy by a methotrexate.
Prescribing of folic acid can be required in case of acute toxicity of a methotrexate.
After carrying out a course of treatment the high doses of a methotrexate for reduction of its toxicity recommend folinat calcium use.
Pregnancy and the period of a lactation
Possesses teratogenic action: it is capable to cause fruit death, congenital malformations.
If the woman became pregnant during therapy by a methotrexate, it is necessary to resolve an issue of termination of pregnancy in connection with risk of collateral impact on a fruit.
The methotrexate is allocated with breast milk, for all course of treatment the breastfeeding should be stopped.
Features of influence of medicine on ability to run
the vehicle or potentially dangerous mechanisms
As the methotrexate is capable to influence the central nervous system (feeling of fatigue, dizziness), the patients taking the drug should refrain from control of vehicles or potentially dangerous mechanisms.
Overdose
Specific symptoms of overdose by a methotrexate are absent, is diagnosed on concentration of a methotrexate in plasma.
Treatment: Administration of specific antidote - folinat calcium 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 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 urine pH before each introduction and each 6 h throughout the entire period of use of calcium of the folinat as antidote until concentration of a methotrexate in plasma becomes lower than 0.05 µmol/l, for providing pH higher than 7.
Form of release and packing
of the Tablet, coated, 2.5 mg.
On 50 tablets in banks polymeric complete with covers. After 1 bank together with the instruction for medical use in the state and Russian languages place in a pack from cardboard.
To Store storage conditions in the place protected from light at a temperature not above 25 °C.
To store out of children's reach!
3 years
not to use a period of storage after expiry date.
Prescription status
According to the prescription of the doctor
Valenta Pharmatsevtika Open Joint Stock Company Russian Federation Producer 141101, Shchyolkovo, Moscow Region, Fabrichnaya St., 2
the Owner of the registration certificate
Valenta Pharmatsevtika Open joint stock company Russian Federation 141101, Shchyolkovo, Moscow Region, Fabrichnaya St., 2
the Address of the organization accepting in the territory of the Republic of Kazakhstan claims from consumers on quality of products (goods) Representative office of JSC Valenta Pharmatsevtika in RK Republic of Kazakhstan, 050009, Almaty, the ave. of Abay, ug. Radostovts St., 151/115, business center "Ala Tau", office No. 1102telefon/fax 8 (727) 334-15-52Электронный address:
To Develop asia@valentapharm.com
for medical use of medicine
the Methotrexate
the Trade name
the Methotrexate
the International unlicensed
name Methotrexate Dosage Form
of the Tablet, coated, 2.5 mg
Structure
One tablet contains
active agent: a methotrexate (in terms of 100% substance) - 2.5 mg,
excipients: sucrose (sugar), potato starch, talc, calcium stearate, krospovidon, povidone
structure of an internal cover: sucrose (sugar), magnesium carbonate easy, wheat flour
structure of an outer sheath: sucrose (sugar), magnesium carbonate easy, wheat flour, povidone, gelatin, dye azoruby E 122, titan E 171 dioxide, wax, talc.
The description
Round biconvex tablets, coated from pink till dark pink color, on cross section are visible two layers of a cover and a kernel. A cover layer from pink till dark pink color and a layer of white color. A kernel from yellow till orange-yellow color.
Pharmacotherapeutic group
Antineoplastic drugs. Antimetabolites. Folic acid analogs. Methotrexate.
The ATX L01BA01 code
the Pharmacological
Pharmacokinetics Absorption properties at oral administration depends on a dose: at reception of 30 mg/sq.m the average bioavailability - 60% is soaked up well. Absorption decreases at reception in the doses exceeding 80 mg/sq.m.
At children with leukemia the absorption fluctuates from 23% to 95%. Time of achievement of the maximum concentration (TCmax) – of 40 min. to 4 h. Food slows down absorption and reduces Cmax. Communication with proteins of blood plasma about 50%, mainly with albumine.
After distribution in fabrics high concentrations 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 oral introduction the main part is partially metabolized by indestinal flora, - in a liver (irrespective of a way of introduction) with formation pharmacological of the active polyglutamic form which is also inhibiting a digidrofolatreduktaza and synthesis of thymidine.
Elimination half-life (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. In chronic kidney disease both phases of removal of drug can be considerably prolonged.
It is removed mainly by kidneys in not changed look by glomerular filtration and canalicular secretion, with bile it is removed up to 10% (with the subsequent reabsorption in intestines). Removal of drug at patients with a renal failure, the profound ascites or transudate is considerably slowed down. At repeated introduction collects in fabrics in the form of polyglutamates.
A pharmacodynamics
Antineoplastic, cytostatic means of group of antimetabolites - analogs of folic acid. Inhibits the digidrofolatreduktaza participating in restoration of dihydrofolic acid in tetrahydrofolic acid (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 immunodepressive effect.
Indications
– an active course of a pseudorheumatism at adult patients
– the severe forms of simple (blyashkovidny) psoriasis which are not responding to treatment by retinoids, to phototherapy and PUVA therapy
– heavy psoriasis arthritis
the Route of administration and doses
apply the Methotrexate inside, once a week.
A pseudorheumatism
the Usual dose of a methotrexate makes 7.5 - 15 mg once a week, the maximum dose – 20 mg once a week. The planned weekly dose can be entered in three steps with an interval of not less than 36 hours. For the purpose of achievement of the optimum answer the selection of the individual scheme of reception of a methotrexate with use of the total dose which is not exceeding 20 mg a week is possible. After achievement of the optimum answer (which can be in most cases reached within 6 weeks of therapy) the dose has to be reduced to a minimal effective dose.
Psoriasis
to exclude unexpected toxic effects, treatment it is necessary to begin after single dose of a methotrexate in a dose 2.5-5.0 mg with control of laboratory indicators of function of a liver in one week. The usual dose of a methotrexate makes 7.5 - 15 mg once a week, the maximum dose – 25 mg once a week. The planned weekly dose can be entered in three steps with an interval not less than 24 hours. After achievement of the optimum answer (which can be in most cases reached within 4 - 8 weeks of therapy) the dose has to be reduced to a minimal effective dose.
The purpose of therapy has to consist in achievement of a minimal effective dose, maximum break between therapy courses a methotrexate and, whenever possible, to return to usual therapy.
Use for patients of advanced age
For patients of advanced age the methotrexate has to be used with care. In case of depression of function of a liver and kidneys, deficiency of folic acid which can be observed at advanced age it is necessary to consider the possibility of reduction of a dose of drug.
The feature of use for patients with an abnormal liver function
to Patients with liver diseases, including in the anamnesis, especially in case of the diseases caused by alcohol intake should appoint a methotrexate with extra care and if the expected advantage exceeds potential risk.
Side effects
Classification of frequency of development of side effects: very often (≥1/10), it is frequent (≥1/100, but & lt, 1/10), infrequently (≥1/1000, & lt, 1/100), is rare (≥1/10,000, & lt, 1/1000), is very rare (& lt, 1/10,000), frequency is not known.
Often
- a leukopenia,
- anorexia, nausea, vomiting, stomatitis, diarrhea,
- increase in activity of 'hepatic' transaminases,
- a headache, dizziness, fatigue,
- infections,
- erythematic rash, an alopecia.
Not often
- anemia (including aplastic), thrombocytopenia, a neutropenia, an agranulocytosis, a pancytopenia,
- nasal bleeding,
- a pneumosclerosis, an interstitial pneumonitis (including fatal),
- opportunistic infections,
- a heavy nephropathy or a renal failure,
- vagina ulcers,
- a lymphoma (including reversible),
- an itching of skin, Stephens-Johnson's syndrome, a toxic epidermal necrolysis,
- allergic reactions up to an acute anaphylaxis,
is rare
- an ulitis, pharyngitis, enteritis, erosive cankers and bleeding from the digestive tract (DT),
- a hemiparesis,
- a depression, confusion of consciousness,
- a lowering of arterial pressure, a thrombembolia (including arterial thrombosis, thrombosis of cerebral vessels, a deep vein thrombosis, a retina vein thrombosis, thrombophlebitis, a pulmonary embolism),
- an asthma,
- Herpes zoster and sepsis (including fatal),
- decrease a libido, impotence, a dysmenorrhea,
- an arthralgia, myalgia, osteoporosis, increase in quantity of rheumatoid small knots,
- diabetes,
- photosensitivity, eels, xanthopathy disturbance, a small tortoiseshell, a multiformny erythema, an ulceration and necrosis of skin,
- at treatment of psoriasis – burning sensation of skin, painful erosive plaques on skin.
Very seldom
- a hypogammaglobulinemia,
- a hematemesis,
- hepatotoxicity (acute hepatitis, fibrosis and cirrhosis),
- a dysarthtia, aphasia, irritability, a lethargy,
- conjunctivitis, a disorder of vision (including a passing blindness),
- a pericarditis, a pericardiac exudate,
- a vasculitis,
- pneumocystic pneumonia, a chronic obstructive pulmonary disease, dry unproductive cough, pleurisy,
- a dysuria, an azotemia, cystitis, a hamaturia,
- disturbance spermato- and an ovogenesis, a tranzitorny oligospermatism, infertility, vaginal discharges, a gynecomastia,
- a telangiectasia, a furunculosis, an ecchymoma.
Frequency is not known
- an eosinophilia, limfoproliferativny diseases, a lymphadenopathy,
- a melena,
- a hypoalbuminemia,
- pancreatitis,
- drowsiness, spasms, when using in high doses - tranzitorny disturbance of cognitive functions, emotional lability, unusual cranial sensitivity, encephalopathy (including a leukoencephalopathy),
- respiratory insufficiency, an alveolitis,
- Herpes simplex (including disseminate herpes),
- a proteinuria,
- an abortion, death of a fruit, defects of fetation,
- exfoliative dermatitis,
- an osteonecrosis, fractures,
- a syndrome of lysis of a tumor,
- necrosis of soft tissues,
- sudden death,
- Cytomegaloviral (CMV) infections (including CMV-pneumonia), a nocardiosis, histoplasmosis, a cryptococcosis,
- the increased perspiration.
Contraindications
– hypersensitivity to a methotrexate or other components of drug
– the significant disturbances of functions of kidneys and a liver
– hematologic disorders (marrow hypoplasia, a leukopenia, thrombocytopenia, anemia)
– heavy acute or persistent infections
– alcoholism
– an immunodeficiency syndrome
– pregnancy and the period of a lactation
– children's and teenage age up to 18 years
– vaccination by live vaccines during therapy by a methotrexate
Medicinal interactions
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.
Increases concentration of uric acid in blood therefore at treatment of patients with the accompanying hyperuricemia and gout the 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) enhances 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.
At the solution of a question of joint prescribing of Phenytoinum and a methotrexate it is necessary to consider that the risk of strengthening of spasms owing to reduction of absorption of Phenytoinum at reception with cytotoxic drugs or risk of toxicity exceeds possible efficiency of a methotrexate.
The concomitant use of a methotrexate in combination with leflunomidy can increase risk of a pancytopenia.
Cisplatinum can break removal through kidneys of a methotrexate and enhance its toxicity.
It is necessary to be careful at a combination of non-steroidal anti-inflammatory drugs (NPVP) to low doses of a methotrexate (possibly decrease in removal of a methotrexate renal tubules). Treatment of a pseudorheumatism a methotrexate in combination with NPVP usually is not followed by toxic effects. However, it is necessary to consider that the methotrexate doses used for treatment of a pseudorheumatism (7.5 - 15 mg a week), below, than used for treatment of psoriasis and that higher doses can result in unexpected toxicity.
The medicines blocking canalicular secretion (for example, probenetsid), 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, leflunomid, ethanol and other hepatotoxic medicines increase risk of development of hepatotoxicity.
Simultaneous use of a methotrexate and omeprazolum increases time of removal of a methotrexate. At the combined use of a methotrexate and inhibitors of a proton pomp (omeprazolum or a pantoprazol) the development undesirable to interactions is possible.
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 unpredictable heavy myelosuppression 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. At simultaneous use with a methotrexate it is necessary to control theophylline level in blood plasma.
At simultaneous use with a methotrexate the increase in concentration of Mercaptopurinum in blood plasma is observed (combined use can demand correction of doses).
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 the immune response on vaccination by the live and inactivated virus vaccines. Vaccination by live vaccine can lead to heavy and fatal infections. The accompanying use of a methotrexate with live vaccine is not recommended.
Cyclosporine can enhance efficiency and toxicity of a methotrexate. In case of use of this combination there is a risk of an excess immunosuppression with risk of a limfoproliferation.
Prescribing of Amiodaronum to the patients receiving therapy by a methotrexate concerning psoriasis can cause expression of skin.
Folatsoderzhashchy medicines (including polyvitamins) can reduce efficiency of therapy by a methotrexate.
The special
instructions Methotrexate is cytotoxic drug therefore in 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 potential toxic impact and side reactions came to light and estimated in due time.
There are messages about fatal cases at treatment of psoriasis with use of a methotrexate. At treatment of psoriasis the methotrexate has to be appointed only in case of its persistent course, with emergence of disability, lack of the response to other types of therapy when the diagnosis is established on the basis of a biopsy and/or consultation of the dermatologist.
The patient needs to report that at treatment of psoriasis and pseudorheumatism the administration of drug is in most cases carried out once a week. Patients have to be informed that disturbance of the mode of dosing is connected with risk of emergence of toxic effects.
Observation of the patients accepting a methotrexate has to be organized so that signs of possible toxic effects or side reactions were found and estimated with the minimum delay.
It was reported about fatal cases at reception of a methotrexate owing to an acute and chronic pneumonitis which was often connected with an eosinophilia. Symptoms of a pneumonitis as a rule include short wind, cough (especially dry cough) and fever. Patients need to report about risk of a pneumonitis and need to report about ultimate cough or an asthma. Existence of these symptoms needs to be controlled at each visit of the patient (in case of their existence the methotrexate needs to be cancelled to a pneumonitis exception). In case of confirmation of communication of a disease with reception of a methotrexate it is necessary to carry out treatment of a pneumonitis with use of corticosteroids and to exclude repeated purpose of a methotrexate in the future.
Before the beginning or resuming of therapy by a methotrexate and also during therapy and after its end the full general blood test with definition of a hematocrit, level of leukocytes and thrombocytes, biochemical analysis of blood with determination of values of enzymes of a liver, bilirubin, seralbumin, a research of function of kidneys (urea nitrogen, clearance of creatinine and/or creatinine of serum), concentration of uric acid in blood serum has to be made). Prior to therapy the methotrexate also recommends to perform radiological examination of a thorax.
In case of clinically significant decrease in quantity of leukocytes or thrombocytes the methotrexate has to be immediately cancelled. Patients have to be informed on need to report about any signs of developing of infectious diseases.
The methotrexate can potentially lead to development of symptoms of sharp or chronic hepatotoxicity (including to an atrophy, fibrosis and cirrhosis), especially in high doses or at long therapy.
Patients have to be informed concerning risk of toxic effects from a liver.
The course of treatment should not be begun or has to be stopped in case of a deviation in laboratory indicators of function of a liver. Such deviations have to return to normal values within two weeks then treatment can be resumed to the discretion of the doctor.
Frequency of a deviation of laboratory indicators in two or three times at biochemical analysis of blood with determination of values of enzymes of a liver is 13-20%. In case of continuous increase in such indicators it is necessary to resolve an issue of a dose decline or the termination of therapy.
Chronic hepatotoxicity 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, diabetes) 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 taking other hepatotoxic drugs (for example, leflunomid), 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. In moderate fibrosis of a liver or any degree of cirrhosis the therapy by a methotrexate is cancelled, in fibrosis of an easy form usually recommend a repeated biopsy in 6 months. During initial therapy, minor histologic changes of a liver (insignificant portal inflammation and fat changes) are possible that is not the basis for refusal or the termination of treatment, but indicates the need of respect for care at drug use.
The biopsy of a liver is not carried out in the following cases:
- elderly patients
- patients with acute diseases
- patients with a contraindication for a liver biopsy (for example, heart failure, fibrillation disturbance)
- patients with the low forecast of survival
of Data on need and expediency of carrying out a biopsy of a liver at treatment by a methotrexate of a pseudorheumatism is not enough.
More frequent biopsies of a liver can be necessary in the following cases:
- during an initial phase of treatment
- in case of increase in a dose of a methotrexate
- in case of risk of increase in level of a methotrexate in blood plasma (for example, in dehydration, risk of depression of function of kidneys owing to addition or increase in a dose of the accompanying drugs, for example NPVP).
The methotrexate is applied with care in 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 and also at patients of young and advanced age.
The methotrexate is allocated generally with kidneys. Its use in case of a renal failure can result in toxic effects or even to additional injury of kidneys. High doses can cause accumulation of a methotrexate or its metabolites in renal tubules. At patients with diseases of kidneys the dose of a methotrexate has to be reduced. For the purpose of prevention (diuretic effect and alkalifying of urine to rn 6.5 - 7.0) it is recommended, oral administration (on 5 tablets on 625 mg each three hours) or intravenous administration of sodium bicarbonate or acetazoleamide (on 500 mg four times a day).
There are messages about serious side reactions including fatal cases at combined use of a methotrexate and NPVP.
At treatment by a methotrexate of a pseudorheumatism use of acetylsalicylic acid, NPVP and also steroid drugs in a small dose is possible. Nevertheless, it is necessary to consider that combined use of NPVP and methotrexate is connected with the increased risk of toxicity. The dose of steroid drugs at patients with affirmative answer by a methotrexate can be reduced by therapy.
Interaction between a methotrexate and such antirheumatic medicines as Penicillaminum, hydroxychloroquine, Sulfasalazinum, gold drugs - is not studied. It is necessary to consider that their joint reception with a methotrexate can increase the frequency of side reactions.
There are data on development in rare instances of a sharp megaloblastny pancytopenia at combined use of a methotrexate and antagonists of folic acid, such as Trimethoprimum-sulfamethoxazole.
After absorption the methotrexate partially communicates albumine and its toxicity can increase due to replacement from this communication at intake of salicylates, sulphamides, Phenytoinum and some antibiotics, such as tetracycline, chloramphenicol and para-aminobenzoic acid. These medicines, especially salicylates and sulphamides, have to be appointed together with a methotrexate only if the potential advantage of their use exceeds possible risk.
It is necessary to consider that the gematotoksichesky effect of a methotrexate can suddenly be shown when the patient accepts presumably safe dose of drug therefore any considerable decrease in blood cells demands the termination of reception of a methotrexate. Serious decrease in gematopoetichesky activity of marrow can demand transfusion of blood or platelet concentrate.
At development of diarrhea and stomacace the therapy by a methotrexate needs to be interrupted owing to high risk of developing 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 view of influence on the 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 it should refuse immunization by the oral vaccine against poliomyelitis (to avoid contacts with the people receiving the vaccine against poliomyelitis or to wear the protective mask closing a nose and a mouth). Special attention has to be paid on inactive persistent infections at patients (for example, shingles, tuberculosis, hepatitis B and C) because of their potential activation.
Malignant lymphoma can be diagnosed for the patients receiving low doses of a methotrexate. Therapy by a methotrexate in this case has to be stopped. The lack of signs of spontaneous regress of a lymphoma demands performing therapy by cytotoxic drugs.
There are data that the methotrexate can cause an oligospermatism, disturbances of a menstrual cycle (including an amenorrhea) in time and during the short period after the therapy termination.
Patients of childbearing age of both sexes and their partners have to take 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.
Intake of the vitamin drugs containing folic acid or its derivatives can change the response to therapy by a methotrexate.
Prescribing of folic acid can be required in case of acute toxicity of a methotrexate.
After carrying out a course of treatment the high doses of a methotrexate for reduction of its toxicity recommend folinat calcium use.
Pregnancy and the period of a lactation
Possesses teratogenic action: it is capable to cause fruit death, congenital malformations.
If the woman became pregnant during therapy by a methotrexate, it is necessary to resolve an issue of termination of pregnancy in connection with risk of collateral impact on a fruit.
The methotrexate is allocated with breast milk, for all course of treatment the breastfeeding should be stopped.
Features of influence of medicine on ability to run
the vehicle or potentially dangerous mechanisms
As the methotrexate is capable to influence the central nervous system (feeling of fatigue, dizziness), the patients taking the drug should refrain from control of vehicles or potentially dangerous mechanisms.
Overdose
Specific symptoms of overdose by a methotrexate are absent, is diagnosed on concentration of a methotrexate in plasma.
Treatment: Administration of specific antidote - folinat calcium 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 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 urine pH before each introduction and each 6 h throughout the entire period of use of calcium of the folinat as antidote until concentration of a methotrexate in plasma becomes lower than 0.05 µmol/l, for providing pH higher than 7.
Form of release and packing
of the Tablet, coated, 2.5 mg.
On 50 tablets in banks polymeric complete with covers. After 1 bank together with the instruction for medical use in the state and Russian languages place in a pack from cardboard.
To Store storage conditions in the place protected from light at a temperature not above 25 °C.
To store out of children's reach!
3 years
not to use a period of storage after expiry date.
Prescription status
According to the prescription of the doctor
Valenta Pharmatsevtika Open Joint Stock Company Russian Federation Producer 141101, Shchyolkovo, Moscow Region, Fabrichnaya St., 2
the Owner of the registration certificate
Valenta Pharmatsevtika Open joint stock company Russian Federation 141101, Shchyolkovo, Moscow Region, Fabrichnaya St., 2
the Address of the organization accepting in the territory of the Republic of Kazakhstan claims from consumers on quality of products (goods) Representative office of JSC Valenta Pharmatsevtika in RK Republic of Kazakhstan, 050009, Almaty, the ave. of Abay, ug. Radostovts St., 151/115, business center "Ala Tau", office No. 1102telefon/fax 8 (727) 334-15-52Электронный address:
To Develop asia@valentapharm.com
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