Methodical - instructions for use, doses, side effects, contraindications

Antagonist of folic acid, belongs to the group of immunosuppressants. Competitively inhibits the enzyme dihydrofolate reductase involved in the reduction of dihydrofolic acid into tetrahydrofolic acid (a carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives). It inhibits synthesis, DNA repair and cellular mitosis. Especially sensitive to the action of methotrexate are rapidly proliferating cells: cells of malignant tumors, bone marrow, embryonic cells, mucosal epithelial cells. Along with the antitumor has an immunodepressant effect.

It remains unclear what is the effectiveness of methotrexate in the treatment of psoriasis, psoriatic arthritis and rheumatoid arthritis (including juvenile chronic arthritis): its anti-inflammatory or immunosuppressive effect.Also, it is not established to what extent the effectiveness of therapy is explained by the increase in extracellular adenosine concentration caused by methotrexate in places of inflammation.

With psoriasis, the formation of skin epithelial cells is significantly accelerated compared with the norm. The use of methotrexate can slow the formation of skin epithelial cells, which justifies the use of the drug in the treatment of psoriasis.

Pharmacokinetics:

About 50% of methotrexate binds to plasma proteins.

After distribution in tissues, high concentrations of methotrexate in the form of polyglutamates are found in the liver, kidneys and especially in the spleen, in which methotrexate can be held for several weeks or even months.

When used in small doses penetrates into the cerebrospinal fluid only in minimal amounts.

The half-life period averages 6-7 hours and is characterized by high variability (3-17 hours). Elimination half-life may increase to 4 times the average values in patients with an additional volume of distribution (presence of pleural effusion, ascites).

About 10% of the administered dose is metabolized in the liver, the main metabolite is 7-hydro xitometrexate, which also has some pharmacological activity. It is excreted mainly unchanged in kidneys by glomerular filtration and tubular secretion.

About 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate is excreted with bile (followed by reabsorption in the intestine).

Removal of the drug in patients with impaired renal function is significantly slowed down.

There is no evidence of a delay in excretion of methotrexate with insufficient liver function.

Indications:

Rheumatoid arthritis in active form in adult patients;
Polyarthritis in patients with severe juvenile chronic arthritis in active form;
Heavy generalized forms of psoriasis and psoriatic arthritis in adult patients not responding to conventional therapy.

Contraindications:

Hypersensitivity to methotrexate or other components of the drug;
Severe dysfunction of the liver (see also section "Method of administration and dose");
Alcoholism;
Severe renal insufficiency (creatinine clearance less than 20 ml / min, see also section "Method of administration and dose");
Hemorrhage disorders in the anamnesis, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, severe anemia;
Severe acute or chronic infectious diseases, such as tuberculosis, HIV infection;
Ulcers of the oral cavity, peptic ulcer of the gastrointestinal tract in the active phase;
Pregnancy and the period of breastfeeding;
Simultaneous vaccination with live vaccines;
Pronounced immunodeficiency.

Carefully:Ascites, dehydration, obstructive diseases of the gastrointestinal tract, pleural or peritoneal effusion, chronic renal failure, parasitic and infectious diseases of viral, fungal or bacterial nature (currently or recently transferred, including recent contact with the patient): herpes simplex surrounding herpes (viremic phase), chickenpox, measles, amebiasis, strongyloidiasis (established or suspected) - the risk of developing a severe generalized disease; gout (including history) or urate nephrourolythiasis (including history), infections and inflammation of the oral mucosa, vomiting and diarrhea (loss of fluid due to severe vomiting and diarrhea can lead to increased toxicity of methotrexate), stomach ulcer and duodenal ulcer, ulcerative colitis,previous chemo-or radiation therapy, asthenia, elderly age.

Pregnancy and lactation:

Methodic® is contraindicated during pregnancy and during lactation.

When used in humans methotrexate exhibited teratogenic properties; reports of methotrexate-induced fetal death, congenital malformations.

Limited use in pregnant women (42) led to an increase in the frequency (1:14) of malformations (cranial, cardiovascular, extremities). In cases of interruption of methotrexate therapy, normal pregnancy was observed before fertilization.

Women during treatment with methotrexate should refrain from pregnancy.

In the event that a woman becomes pregnant during methotrexate therapy, an assessment should be made of the risk of adverse effects of treatment on the fetus.

Patients of childbearing age of both sexes should be provided with reliable contraceptive measures during treatment with Metaecect® and, at least, within 6 months after its termination.

Before the beginning of therapy by Methodgette in women of childbearing age, a reliable pregnancy test should be conducted to exclude the possibility of treatment in pregnant women.

Because the methotrexate can have genotoxic effect, women planning pregnancy, it is recommended to consult with a geneticist, and, if possible, even before the start of therapy; Men should be advised to consider the possibility of preserving sperm before starting treatment. Methotrexate is excreted in breast milk in quantities that are dangerous to the baby, so you should stop breastfeeding before starting methotrexate treatment and abstain from it throughout the course of treatment.

Application of the Method® in children

Use of the Method® in children under 3 years is not recommended because of insufficient data on the efficacy and safety of use of the drug in this group of patients.

Features of the drug in children under 16 years are given in the section "Method of administration and dose."

Patients with juvenile rheumatoid arthritis should be observed by a rheumatologist, a specialist in the treatment of children and adolescents.

Dosing and Administration:

Methodic designate subcutaneously, intramuscularly or intravenously.

The injection needle included in the package is intended only for subcutaneous administration of the Methodic.To administer the drug intramuscularly and intravenously, it is necessary to use needles suitable for these methods of administration.

The drug is used once a week.

The total duration of treatment is determined by the doctor.

The drug should be prescribed by a doctor who has experience with methotrexate and is familiar with the properties of the drug and the characteristics of its action.

Adult patients with rheumatoid arthritis:

The recommended initial dose is 7.5 mg of methotrexate once a week intramuscularly, intravenously or subcutaneously. Depending on the severity of the disease and the tolerability of methotrexate, patients may be gradually increased (2.5 mg per week). The maximum dose for treating rheumatoid arthritis should not exceed 25 mg per week. The response to treatment usually comes in 4-8 weeks after the start of the drug. After the desired response is achieved, the dose should be reduced to the lowest effective maintenance dose. In each case, the duration of therapy is determined by the doctor, the duration of use of the drug may exceed 10 years.

Patients with psoriasis and psoriatic arthritis:

A week before the start of treatment, it is recommended to enter a parenteral test dose of 5-10 mg of methotrexate to detect intolerance reactions.

The recommended initial dose is 7.5 mg of methotrexate once a week intramuscularly, intravenously or subcutaneously. The dose should be gradually increased, while the maximum

The dose should not exceed in most cases 25 mg of methotrexate per week, but in any case should not exceed 30 mg per week. The response to treatment usually occurs 2-6 weeks after the start of the drug. After achieving the desired response, the dose should be reduced to the lowest effective maintenance dose.

Patients with renal insufficiency:

The method must be applied with caution. The dose, depending on the value of creatinine clearance, should be adjusted in accordance with the following table.

Creatinine clearance, ml / min	The dose of methotrexate (% of the usual dose)
>50	100%
20-50	50%
<20	The use of Methodect® is contraindicated

Patients with hepatic insufficiency:

In patients with severe liver disease, currently or in history, especially caused by alcohol intake, the Method should be used with great care.At a concentration of bilirubin> 5 mg / dl (85.5 μM / L) methotrexate is contraindicated.

Elderly patients:

It should be used with caution, it is often necessary to adjust the dose downwards due to the age-related decline in liver and kidney function, as well as a decrease in the folate reserve in the body.

Children under 16 with polyarthritic form of juvenile chronic arthritis:

The recommended dose of methotrexate is 10-15 mg /m² body surface in a week. With insufficient effectiveness of treatment, the dose can be increased up to 20 mg /m² body surface in a week. Due to the limited data on subcutaneous and intravenous use in children, the drug should be administered intramuscularly with juvenile arthritis.

Notes.

In the transition from methotrexate administration to the parenteral route of administration, a dose reduction may be required due to the difference in bioavailability of the preparation for different routes of administration.

When prescribing the drug should consider the simultaneous administration of folic acid preparations in accordance with existing standards of treatment.

Side effects:

The most common side effects when applying the Method^® are suppression of the hematopoiesis system and disorders of the gastrointestinal tract.

To indicate the frequency of effects, the following gradations are applied: very often (≥ 1/10), often (≥ 1/100, <1/10), infrequently (≥ 1/1000, <1/100). rarely (≥ 1/10000, <1/1000). very rarely (<1/10000), the frequency is unknown (can not be estimated based on available data).

Disorders from the gastrointestinal tract

Very often: stomatitis, dyspepsia, nausea, loss of appetite.

Often: oral ulcers, diarrhea.

Infrequently: pharyngitis, enteritis, vomiting.

Rarely: erosive and ulcerative lesions of the gastrointestinal tract.

Very rarely: vomiting with an admixture of blood, bleeding from the gastrointestinal tract (including melena, hematemesis), toxic megacolon.

Disturbances from the liver and bile ducts

Very often: increased activity of transaminases.

Infrequently: cirrhosis, fibrosis and fatty degeneration of the liver, a decrease in the concentration of serum albumin.

Rarely: acute hepatitis.

Very rarely: hepatic insufficiency.

Disturbances from the skin and subcutaneous tissues

Often: exanthema, erythema, itchy skin.

Infrequently: photosensitization, hair loss, increased rheumatic nodes, vasculitis, Herpes zoster, herpetiform rashes on the skin, urticaria.

Rarely: increased pigmentation, acne, ecchymosis.

Very rarely: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), changes in the pigmentation of the nails, acute paronychia, furunculosis, telangiectasia.

Disorders from the metabolism and nutrition

Infrequently: the progression of diabetes.

Disorders from the cardiovascular system

Rarely, pericarditis, pericardial effusion, pericardial tamponade, lowering of arterial pressure, thromboembolic complications (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism).

Disturbances from the nervous system

Often: headache, fatigue, snotty.

Infrequently: dizziness, confusion, depression.

Very rarely: pain, muscle weakness or paresthesia of the extremities. a violation of taste sensations (metallic taste), visual impairment, convulsions, meningism, paralysis.

Frequency unknown: leukoencephalopathy.

From the side of the organ of vision

Rarely: visual impairment, conjunctivitis.

Very rarely: retinopathy.

General disorders and disorders at the site of administration

Rarely: allergic reactions up to anaphylactic shock, allergic vasculitis, fever, development of infections, sepsis, deterioration of wound healing, hypogammaglobulinemia.

Very rarely: reactions at the injection site: damage to the skin and surrounding tissue (sterile abscess, lipodystrophy).

Disturbances from the respiratory system, chest and mediastinal organs

Often: pneumonia, interstitial alveolitis / pneumonitis, often in combination with eosionophilia. Symptoms of a potentially serious interstitial pneumonitis: dry, unproductive cough, shortness of breath and fever.

Rarely: pulmonary fibrosis, pneumocystis pneumonia, dyspnea and bronchial asthma, pleural effusion.

On the part of the hematopoiesis system

Often: leukopenia, anemia, thrombocytopenia.

Infrequent: pancytopenia.

Very rarely: agranulocytosis, severe oppression of bone marrow function.

From the genitourinary and urinary systems

Infrequent: inflammation and ulceration of the bladder and / or vagina, impaired urination, impaired renal function.

Rarely: renal failure, oliguria, anuria, electrolyte imbalance.

Very rarely: vaginal discharge, loss of libido, impotence, gynecomastia, oligospermia, menstrual irregularities.

Disturbances from the musculoskeletal system and connective tissue

Infrequently: arthralgia, myalgia, osteoporosis.

Neoplasms benign, malignant and unspecified nature (including cysts and polyps)

Very rarely: single cases of lymphoma have been reported, which in some cases have regressed after discontinuation of methotrexate therapy. In a recent study, it has not been established that methotrexate therapy increases the risk of developing lymphomas.

The frequency and severity of side effects depend on the dose and frequency of methotrexate. Since severe side effects can occur even with the use of low doses of the drug, it is necessary to conduct regular medical examination of patients at short intervals.

With intramuscular introduction of methotrexate, local reactions can occur: a burning sensation at the injection site, the formation of a sterile abscess, the destruction of fatty tissue. When administered subcutaneously methotrexate well tolerated: only moderate local skin reactions were observed, the severity of which decreased during the therapy.

Overdose:

Signs of an overdose: The toxic effect of methotrexate is mainly manifested by the hematopoietic system.

Treatment for overdose: the introduction of a specific antidote - preparations of folinic acid (as soon as possible) to neutralize the toxic effects of methotrexate.

In case of an accidental overdose, a dose of a specific antidote-folic acid preparation, equal to or greater than the dose of methotrexate, should be administered intravenously or intramuscularly within the first hour after the administration of methotrexate. Further, as necessary, the administration of folic acid preparations should be continued until the serum levels of methotrexate are lower 10^-⁷ mol / l.

In case of a significant overdose to prevent precipitation of methotrexate and / or its metabolites in the renal tubules, the body is hydrated and alkalinized urine, which accelerates the excretion of methotrexate. Hemodialysis and peritoneal dialysis do not accelerate the excretion of methotrexate.The effectiveness of intermittent (periodic) hemodialysis with the use of a high-speed dialysis machine has been reported.

Interaction:

Alcohol, hepatotoxic and hematotoxic drugs

The combined use of methotrexate and hepatotoxic drugs, as well as regular use of alcohol, increase the risk of methotrexate hepatotoxicity. For patients using methotrexate other hepatotoxic drugs (for example, leflunomide), careful monitoring is necessary. This also applies to the simultaneous prescription of drugs that depress hemopoiesis (such as leflunomide, azathioprine, retinoids, sulfasalazine), which increases the risk of hematotoxicity of methotrexate. With the simultaneous administration of leflunomide and methotrexate, the risk of pancytopenia and hepatotoxicity increases. When combined therapy with methotrexate and retinoids (such as acitretin, etretinate) increases the risk of hepatotoxicity.

Antibacterial drugs

Such antibiotics as penicillins, glycopeptides, ciprofloxacin, cephalothin, as well as sulphopamides in some cases can reduce the excretion of methotrexate by the kidneys, which leads to an increase in its concentration in the plasma and, thus, to the risk of manifestations of hematologic and gastrointestinal toxicity. Antibiotics for internal use When administered orally, antibiotics such as tetracyclines, chloramphenicol, nonabsorbable broad-spectrum antibiotics can affect enterohepatic circulation of methotrexate due to oppression of the intestinal flora or suppression of bacterial metabolism.

Medications that bind well to plasma proteins

Methotrexate binds to plasma proteins, and bound methotrexate can be replaced by other drugs that bind well to proteins (such as salicylates, hypoglycemic drugs, diuretics, sulfonamides, diphenylhydantoins (phenytoin, diphenine), tetracyclines, chloramfinekol, iara-amino-benzoic acid, anti-inflammatory drugs. The simultaneous use of methotrexate with such drugs may lead to increased toxicity of methotrexate.

Probenecid, weak organic acids, pyrazolone series preparations and other non-steroidal anti-inflammatory drugs

Probenecid, weak organic acids (such as loop diuretics) and preparations of pyrazolone series (phenylbutazone) can reduce the excretion of methotrexate and, consequently, increase its concentration in the plasma, which can lead to an increase in hematological toxicity. The risk of increased toxicity occurs with the combination of even low doses of methotrexate and non-steroidal anti-inflammatory drugs or salicylagues.

Drugs affecting the bone marrow

In the case of drugs that can affect the bone marrow (including as a side effect) (for example, sulfonamides, trimethoprim, sulfamethoxazole, chloramphenicol, pyrimethamine) it is necessary to take into account the possibility of pronounced oppression of hematopoiesis.

Preparations that can cause folate deficiency

The simultaneous administration of such drugs (eg, sulfonamides, trimethoprim, sulfamethoxazole) may lead to an increase in the toxicity of methotrexate.Therefore, it is recommended that you take special care when folic acid is deficient.

Medicines containing folic and folinic acids

Vitamin preparations and other preparations containing folic acid, folinic acid or their derivatives, may reduce the effectiveness of methotrexate.

Anti-rheumatic drugs

As a rule, with simultaneous use of methotrexate with other antirheumatic drugs (such as gold preparations, penicillin-lamin, hydroxychloroquine, sulfasalazine, azathioprine, ciclosporin) there is no increase in the toxic effect of methotrexate.

Sulfasalazine

The combination of methotrexate with sulfasalazine may increase the effectiveness of methotrexate and. as a result, to increase the side effects associated with the suppression of folic acid synthesis by sulfasalazine. However, such side effects have been observed only in a few rare cases in several studies.

Mercaptopurine

Methotrexate increases the concentration of mercaptopurine in the plasma, so when using methotrexate and mercaptopurine, a dose adjustment of mercaptopurine may be required.

Proton pump inhibitors

With simultaneous administration of proton pump inhibitors (such as omeprazole, pantoprazole) the excretion of methotrexate may change. Simultaneous use of methotrexate and omeprazole led to an increase in the time to excrete methotrexate.

One case of decreasing the excretion of methotrexate metabolite, 7-hydroxymethotrexate, was reported, which was accompanied by myalgia and tremor, with simultaneous use of methotrexate and pantoprazole.

Theophylline

Methotrexate is able to reduce the clearance of theophylline. With the simultaneous administration of methotrexate and theophylline, it is necessary to control the concentration of theophylline in the blood plasma.

Caffeine- and theophylline-containing drinks

During treatment with methotrexate, use should be made in large quantities of drinks containing caffeine and theophylline (including coffee, tea, containing caffeine soft drinks).

Special instructions:

Patients should be clearly informed that the drug should be used once a week, not daily. It is recommended to fix a certain day of the week for weekly administration of the drug.

Methotrexate is cytotoxic, so care must be taken when handling it.

For patients undergoing therapy with Methodic, patients should be properly monitored so that signs of possible toxic effects and adverse reactions are detected and evaluated with minimal delay.

The method must be appointed only by a specialist doctor who has sufficient knowledge and experience in conducting antimetabolic therapy.

In view of the possible development of severe, or even fatal, adverse reactions, patients should be fully informed of the possible risks and recommended safety measures by the doctor.

Recommended examinations and safety measures

Before starting or resuming treatment with methotrexate, a detailed clinical blood test should be performed to determine the number of platelets; biochemical blood test with determination of liver enzymes activity, bilirubin concentration, serum albumin; X-ray examination of the chest, examination of the kidney function. If necessary, diagnostic measures to assess the activity of tuberculosis infection and viral hepatitis.

During treatment (at least once a month in the first six months of treatment, then - at least once every two months) it is necessary to conduct:

1. Examination of the oral and pharyngeal mucosa.

2. A detailed clinical analysis of blood counting blood cells, including the determination of the number of platelets. Suppression of hemopoiesis caused by methotrexate, can occur suddenly, including when using the drug in small doses. In any case, a significant reduction in the number of white blood cells or platelets should immediately stop the treatment with methotrexate and conduct adequate maintenance therapy. Patients should be advised to report any signs and symptoms of possible infections. Patients who simultaneously use drugs that depress hemopoiesis (for example, leflunomide), should be carefully observed with the control of blood indices (shaped elements), including the number of platelets.

3. Investigation of liver function:

special attention should be paid to identifying possible toxic effects on the liver. Treatment should not begin, or should be interrupted if detected during appropriate surveysliver function abnormalities that were present before treatment or developed during treatment. Usually, the disorders that develop during the treatment come back to normal within two weeks after the interruption of methotrexate therapy, after which the treatment can be resumed at the discretion of the attending physician.

When methotrexate is used for rheumatological indications, there is no obvious need for a liver biopsy to control hepatotoxicity.

The feasibility of liver biopsy in patients with psoriasis is related to the decision of the question of the effectiveness of routine chemical analyzes of liver parameters or the study of type III collagen propeptide for the detection and evaluation of hepatotoxicity. The appropriate assessment should be carried out individually for each case with differentiation of patients depending on the presence or absence of risk factors such as excessive use of alcohol in history, stable increase in the activity of liver enzymes, liver disease in the anamnesis, hereditary predisposition to liver diseases, diabetes, obesity, the use of a history of hepatotoxic drugs or drugs,affecting long-term use of methotrexate, or the use of methotrexate in a cumulative dose of 1.5 g or more.

Control of "hepatic" enzymes in the blood serum: in 13-20% of patients, a transitory 2-3 times excess of the normal values of transaminases was reported. In the case of a sustained increase in the activity of "hepatic" enzymes, the question of dose reduction or cessation of treatment should be considered. In view of the possible toxic effects of the drug on the liver during treatment, patients, with the exception of cases of obvious necessity, should refrain from the simultaneous use of other hepatotoxic drugs; alcohol should also be avoided.

In patients using other hepatotoxic drugs or drugs that depress hemopoiesis (for example, leflunomide), the activity of "hepatic" enzymes and the parameters of the general blood test should be carefully monitored and the amount of platelets measured.

4. Control of kidney function and urinalysis.

As methotrexate is excreted mainly by the kidneys, in the case of insufficient kidney function, an increase in plasma methotrexate concentration should be expected, which can lead to serious undesirable side effects.

In cases of possible reduction in kidney function (for example, in elderly patients), follow-up examinations should be conducted more often. This also applies to the simultaneous administration of drugs that affect the excretion of methotrexate, drugs that can lead to kidney damage (eg, IPVP), as well as drugs that can affect the hematopoiesis system. Dehydration can also increase the toxicity of methotrexate.

5. Examination of the respiratory system. Particular attention should be paid to the symptoms of worsening lung function, if necessary, appropriate tests should be carried out. Symptoms of respiratory damage (especially dry non-productive cough), pesnotsificheskiy pneumonitis, arising during methotrexate therapy, can indicate a potentially dangerous disease and require interruption of treatment and immediate thorough examination for diagnosis. Possible development of acute or chronic interstitial pneumonitis, often accompanied by eosinophilia; reported on the related lethal cases. The clinical symptoms of methotrexate-induced lung injury are diverse,however, typical signs are fever, cough, shortness of breath, hypoxemia. X-ray examination of the chest is mandatory to exclude the presence of infiltrates or infection.

The possibility of a respiratory disease caused by the use of methotrexate does not depend on the applied doses of the drug.

If the dose of methotrexate is increased, the frequency of the examinations should be increased!

Methotrexate affects the immune system, can worsen the response to vaccination and affect the results of immunological tests. Particular caution is required when using the drug in patients with chronic infectious diseases outside the periods of exacerbation (Herpes zoster, tuberculosis, hepatitis B or C) because of the possibility of exacerbation of the disease. It is necessary to refuse immunization.

The interval between the use of methotrexate and the introduction of live and inactivated viral vaccines should be at least 3 months, possibly up to 12 months (depending on the patient's immune status).

With the development of diarrhea and ulcerative stomatitis, methotrexate therapy must be discontinued, since in such cases hemorrhagic enteritis development and death as a result of interstitial perforation are possible.

Patients using low doses of methotrexate may develop malignant lymphomas; in these cases treatment should be discontinued. In the absence of signs of spontaneous regression of lymphoma, cytotoxic therapy is necessary.

With the use of methotrexate, the development of osteonecrosis and osteoporosis is possible, which increases the risk of fractures.

There have been reports of rare cases of development of acute megaloblastic pancytopenia in combination with folic acid antagonists (such as trimethoprim / sulfamethoxazole) with methotrexate.

The use of methotrexate increases the likelihood of dermatitis and skin burns caused by sun exposure and UV irradiation. In patients with psoriasis, the disease may be exacerbated by UV irradiation during treatment with methotrexate (photosensitivity reaction).

In patients with an additional volume of distribution (the presence of ascites, pleural effusion), the rate of excretion of methotrexate from the body is reduced. In such patients, it is necessary to carefully control toxicity, reduce the dose of the drug, and in some cases, if necessary, discontinue treatment.Before the start of therapy, Methodic should drain the effusion from the pleural or abdominal cavity.

For the treatment of psoriasis methotrexate It should be used only in case of severe, persistent, invalidating forms of the disease, which can not be treated with other therapies, but only after confirming the diagnosis by biopsy and / or after consulting a dermatologist. The drug contains less than 1 mMol (23 mg) of sodium in a single dose, i.e. practically free of sodium.

Methotrexate affects fertility, is embryo, fetotoxic and teratogenic. It shows mutagenic activity in vivo and in vitro. Methotrexate genotoxichep, affects spermatogenesis and ovogenesis, which can lead to a decrease in genital function during treatment. These effects are reversible after the abolition of therapy. Nevertheless, before the start of therapy, men are encouraged to save the sperm. Patients of childbearing age of both sexes must apply reliable contraceptive measures during treatment with methotrexate and for at least 6 months after the end.

Patients of childbearing age and their partners should be duly informed of the possible risks to the childbearing function andpregnancy associated with the use of methotrexate.

Effect on the ability to drive transp. cf. and fur:

Methotrexate is able to influence the central nervous system (causing symptoms such as fatigue, drowsiness, dizziness) and, thus, adversely affect the ability to drive and use mechanisms.

In the event of the above symptoms, one should refrain from driving vehicles and practicing other potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Solution for injection 10 mg / ml.

Packaging:

For 7.5mg / 0.75ml, 10mg / 1ml, 15mg / 1.5ml, 20mg / 2ml or 25mg / 2.5ml in a graduated syringe from a neutral colorless glass (type I EF), closed with a rubber stopper, with a polymer nozzle on the flange, in a PVC blister / paper.

Needle for injection in PE blister / paper.

One filled syringe with the preparation and one needle in the blister together with instructions for use in a cardboard bundle.

Storage conditions:

List B.

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Do not freeze!

Keep out of the reach of children!

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-006731/09

Date of registration:21.08.2009 / 22.11.2017

Expiration Date:Unlimited

The owner of the registration certificate:medac GmbHmedac GmbH Germany

Manufacturer: & nbsp

ONCOTEC PHARMA PRODUKTION, GmbH Germany

Representation: & nbspKorPharma, Open CompanyKorPharma, Open CompanyRussia

Information update date: & nbsp09.05.2018

Illustrated instructions

Instructions

Methodic® (Metoject)