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

Composition:1ml of the drug contains:
Active substance: methotrexate disodium 54.84 mg (equivalent to 50 mg methotrexate)
Prepared by the words:
Methotrexate 50 mg
Sodium hydroxide 9.6 mg
Excipients: sodium chloride 4 mg, sodium hydroxide QS (up to pH 8.5-8.9), water for injection up to 1 ml.

Description:Transparent from yellow to yellow-brown liquid.

Pharmacotherapeutic group:Antitumor agent - antimetabolite

ATX: & nbsp

L.01.B.A Analogues of folic acid

L.01.B.A.01 Methotrexate

Pharmacodynamics:Antagonist of folic acid, cytotoxic drug - antimetabolite. Competitively inhibits the enzyme dihydrofolate reductase involved in the reduction of dihydrofolic acid to tetrahydrofolic acid (a carrier of carbon fragments required for the synthesis of purine nucleotides and their derivatives), and thus inhibits the synthesis of DNA.
Along with the antitumor has an immunosuppressive 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.

Pharmacokinetics:Bioavailability with subcutaneous, intramuscular and intravenous administration has similar values and is almost 100%.
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 in a minimal amount.
The half-life period averages 6-7 hours and is characterized by high variability (3-17 hours). Half-life in patients with an additional volume of distribution (the presence of pleural effusion, ascites) may increase to values 4 times higher than the mean values.
About 10% of the administered dose is metabolized in the liver, the main metabolite is 7-hydroxymethotrexate, which also has 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 significant 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, not giving an adequate response to therapy with nonsteroidal anti-inflammatory drugs (NSAIDs);
Severe persistent disabling forms of psoriasis in adult patients not responding to conventional therapy, including phototherapy, PUVA therapy, retinoid therapy,
Heavy forms of psoriatic arthritis in adult patients.

Contraindications:

Hypersensitivity to methotrexate or other components of the drug;
Hepatic insufficiency (see also section "Dosing and Administration");
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;
Significant immunodeficiency;
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.

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 Methodjekt at women of genital age shouldA 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.

Dosing and Administration:Methodic® Assign subcutaneously.
The needle inserted into the syringe is intended only for subcutaneous administration of the Methodic®
Methodic® should not be confused with other drugs.
The drug should be prescribed by a doctor who has experience with methotrexate and is familiar with the properties of methotrexate and the characteristics of its action.
The drug is intended for single use only.
Methodic® is used once a week.The patient should be clearly informed about a single weekly mode of administration. It is recommended to assign a specific day of the week for the introduction.
In patients with an additional volume of distribution (the presence of ascites, pleural effusion), the rate of excretion of methotresate 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.
Adult patients with rheumatoid arthritis:
The recommended initial dose is 7.5 mg of methotrexate once a week. Depending on the activity of the disease and the tolerability of methotrexate, patients may be gradually increased (2.5 mg per week). The maximum dose for the treatment of rheumatoid arthritis, as a rule, should not exceed 25 mg per week. In this case, increasing the dose of methotrexate to values greater than 20 mg per week may be accompanied by a significant increase in toxicity, primarily by suppression of bone marrow function. The response to treatment usually comes in 4-8 weeks after the start of the drug. After achieving the desired response, a gradual dose reduction to the lowest effective maintenance dose should be started.
Children under 16 with a polyarthritic form of juvenile chronic arthritis:
The recommended dose is 10-15 mg /m² body surface once a week. In case of insufficient effectiveness of treatment, the dose can be increased up to 20 mg /m² body surface once a week. With an increase in the administered dose, it is necessary to increase the frequency of the patient's examinations.
Patients with juvenile rheumatoid arthritis should be observed by a rheumatologist, a specialist in the treatment of children and adolescents.
The use of Methodect® in children under 3 years of age is not recommended because of insufficient data on the efficacy and safety of use of the drug in this group of patients.
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 identify possible intolerance reactions.
The recommended initial dose is 7.5 mg of methotrexate once a week. The dose should be gradually increased, while the maximum dose should not exceed 25 mg of methotrexate per week. The use of doses above 20 mg per week may be accompanied by a significant increase in toxicity, primarily by suppression of bone marrow function.
The response to treatment usually occurs 2-6 weeks after the start of the drug. After achieving the desired response, the dose should be gradually reduced to the lowest effective maintenance dose.
In exceptional cases, when clinically justified, doses above 25 mg may be used, but in all cases not more than 30 mg per week due to a sharp increase in toxicity.
Patients with renal insufficiency:
Methodic® should be used with caution. The dose, depending on the value of creatinine clearance, should be adjusted according to 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 impaired hepatic function:
In patients with severe liver disease, currently or in history, especially those associated with alcohol intake, Methodject®, if appropriate, should be used with great caution. At a concentration of bilirubin> 5 mg / dl (85.5 μM / L) methotrexate is contraindicated.
Elderly patients:
The drug should be used with caution,the need to correct the dose downwards should be evaluated because of the age-related decline in liver and kidney function, as well as a decrease in the folate reserve in the body.
Patients with an additional volume of distribution (presence of pleural effusion, ascites):
This group may increase the half-life time up to fourfold from normal values, which may require a reduction in the dose of the drug, and in some cases - the withdrawal of methotrexate (see also the sections "Special instructions" and "Pharmacokinetics"),
Notes
In each case, the duration of treatment is determined by the doctor; the total duration of use of the drug may exceed 10 years.
In the transition from methotrexate administration to the parenteral route of administration, it may be advantageous to reduce the dose due to the possible difference in bioavailability of the drug when administered orally and parenterally.
When taking methotrexate therapy, the concomitant use of folic acid preparations should be considered in accordance with existing treatment standards.
The use of Methodect® is carried out under the supervision of a physician.
According to the doctor's decision, the drug can be used by the patients independently. In this case, the patient must be trained by the doctor to perform the hypodermic injection before applying the drug. In any case, the first independent use of the drug by a patient should be conducted in the presence of a physician.
If the first signs of adverse events appear, the patient should inform the attending physician without delay.
Method of drug administration
When using the Methodic®, standard hygiene and aseptic requirements must be met. Before using the product, you should thoroughly wash your hands.
1. Make sure you have chosen the correct dosage. Check the expiration date on the package. Open the package containing the blister with a filled syringe with the drug.
2. Open the blister containing the syringe with the drug, holding the plastic part of the blister with one hand and separating the paper cover with the other hand.

Before use, it is necessary to examine the solution of the drug in a syringe for the absence of foreign particles. The drug containing foreign particles can not be used!
Place the syringe with the preparation on a clean surface.
A special polymeric color nozzle ("wings") is attached to the flange of the syringe body, which increases the convenience of holding the syringe with fingers and, thus, facilitates the injection. Do not remove these "wings" from the syringe.
3. Choose a site for injection:

- on the abdomen, at a distance of not less than 5 cm around the navel and not above the level of the lower rib,
- or on the hip, the width of the palm below the inguinal fold and above the knee.
Do not administer the drug to a place where there is soreness, tightness, redness, a cutaneous or hematoma.
4. Treat the injection site with a special disinfectant wipe or a pad moistened with a 70% ethanol solution. Wait 30 seconds before the injection.
5. Remove the protective cap from the needle, pulling and simultaneously turning it. Do not touch the sterile needle.

6. Form the fold of the skin with the thumb and forefinger. Fully insert the needle under the skin at an angle of 90 °. The drug should be administered in a sitting or lying position, but not standing up.

7. Insert the entire volume of the drug from the syringe slowly and evenly, keeping the skin fold between the fingers.When the entire preparation is inserted, remove the needle at the same angle as when injected.

8. Attach a sterile gauze dressing or sterile swab to the injection site.
Do not rub the injection site, as this may cause irritation. If necessary, apply adhesive plaster.
9. Place the used syringe and the previously removed protective cap in a waste container made of plastic or glass, with a lid.
Dispose of used materials, taking care to prevent accidental contact with children and other persons.
During the course of therapy, do not inject in the same place. Please change the injection site for each subsequent injection (every week).
Precautions for use:
Patients should be clearly informed that the drug should not be used on a daily basis, but once a week.
Patients undergoing therapy with Methodjet® should be provided with
proper monitoring so that signs of possible toxic effects and adverse reactions are identified and evaluated without delay.
Methodic® should be prescribed only by a specialist doctor who has sufficient knowledge and experience in 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 physician.
The use of the drug in children under 3 years is not recommended because of the lack of data on the efficacy and safety of treatment of this group of patients.
Recommended examinations and safety measures
Before starting or resuming treatment with methotrexate, a detailed clinical blood count should be performed to count the blood elements, including 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 the treatment (at least once a month in the first six months of treatment, then - at least once every three months), it is necessary to carry out the studies described below.
If the dose of methotrexate is increased, the frequency of the examinations should be increased.
1.Examination of the oral and pharyngeal mucosa to assess the mucosal status (stomatitis, pharyngitis).
2. An expanded 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 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 the blood counts (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 found during appropriate examinations, or liver biopsy, liver function disorders present before treatment or developed during treatment.Usually, the disorders developed during the treatment come back to normal within two weeks after the interruption of methotrexate therapy, after which, at the discretion of the attending physician, treatment can be resumed.
In the use of methotrexate for rheumatological indications, there is no obvious need for a liver biopsy to monitor hepatic toxicity.
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 in the history of hepatotoxic drugs or drugs that affect hematopoiesis, the long-term prior use of methotrexate, or the use of methotrexate in a cumulative dose of 1.5 g or more.
Control of "hepatic" enzymes in blood serum: in 13-20% of patients, transitional 2-3 times the normal values of transaminases were 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.
Due to possible toxic effects of the drug on the liver, patients with methotrexate, except in cases of obvious need, should refrain from concurrent use of other hepatotoxic drugs; should also be avoided, or at least substantially reduce the use of alcohol.
In patients using other hepatotoxic drugs, or drugs that depress blood (for example, leflunomide), the activity of "liver" enzymes should be carefully monitored.
4. It is necessary to monitor kidney function by performing functional tests 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 severe 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, NSAIDs), or drugs that can affect hematopoiesis.
Dehydration can also increase the toxicity of methotrexate.
5. Examination of the respiratory system: special attention should be paid to the symptoms of impaired lung function, if necessary, appropriate tests should be carried out. Respiratory symptoms (especially a dry non-productive cough), a non-specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous disease and require treatment interruption and immediate thorough examination to make a 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, but typical symptoms are fever, cough, shortness of breath, hypoxemia.An X-ray examination of the chest is necessary to exclude the presence of infiltrates or infection.
In the case of lung disease, rapid diagnosis and withdrawal of treatment are necessary.
The development of respiratory diseases caused by the use of methotrexate, it is possible with any applied doses of the drug.
In case of an increase in the dose of methotrexate, the frequency of examinations should be increased!
Methotrexate affects the immune system and, as a result, may 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.
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. There have been reports of rare cases of acute megaloblastic pancytopenia in a jointuse with methotrexate folate antagonists (such as trimethoprim / sulfamethoxazole).
The use of methotrexate increases the likelihood of dermatitis and skin burns caused by sun exposure and UV irradiation.
In patients with psoriasis, exacerbation of the disease as a result of UV irradiation during treatment with methotrexate (photosensitivity reaction) is possible.
In patients with an additional volume of distribution (presence of pleural effusion, ascites), excretion of methotrexate is slowed. Such patients require very careful toxicity control, a reduced dose, and in some cases - the elimination of methotrexate treatment. Before the beginning of therapy by Methodic^® drain the effusion from the pleural or abdominal cavity.
With the appearance 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.
Vitamin preparations and other products containing folic acid, folinic acid or their derivatives, may decrease the effectiveness of methotrexate.
In patients with psoriasis methotrexate should be used only in cases of severe, persistent, disabling forms of the disease, which are difficult to treat using other therapy regimens, and only after confirming the diagnosis by biopsy and / or after consulting a dermatologist.
The drug contains less than 1 mM sodium in one dose, i.e. practically free of sodium, which is important for patients on a sodium diet.
Before prescribing the drug, women should be convinced of the absence of pregnancy, since methotrexate embryotoxic, and can cause abortions and fetal defects. Methotrexate affects spermatogenesis and ovogenesis, which can lead to a decrease in genital function during treatment. These effects are reversible after the abolition of therapy.
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 properly informed about the possible risks to the childbearing function and pregnancy associated with the use of methotrexate.

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).
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: hematemesis, gastrointestinal bleeding, toxic megacolon.
From the skin and appendages of the skin
Often: exanthema, erythema, itchy skin. Infrequent: photosensitization, alopecia, increased rheumatic nodes, Herpes zoster, vasculitis, herpetiform rashes on the skin, hives.
Rarely: increased pigmentation, acne, ecchymosis.
Very rarely: Stevens-Johnson syndrome, toxic epidermal nsrolysis (Lyell's syndrome). changes in pigmentation of the nail, acute paropychi. furunculosis, telangiectasia.
General reactions and reactions at the site of administration
Rarely: allergic reactions up to anaphylactic shock; allergic vasculitis, fever, development of infections, sepsis, deterioration of wound healing, hypo-gammaglobulinemia.
Very rarely: local reactions at the site of administration: damage to the skin and surrounding tissues (sterile abscess, lipodystrophy).
Metabolic disorders
Infrequently: the progression of diabetes mellitus.
From the nervous system
Often: headache, fatigue, drowsiness.
Infrequently: dizziness, a sense of 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 organs of sight
Rare: conjunctivitis, visual impairment.
Very rarely: retinopathy.
From the hepatobiliary system
Very often: an increase in the level of traasaminases.
Infrequently: cirrhosis, fibrosis and fatty degeneration of the liver, a decrease in the concentration of serum albumin.
Rarely: acute hepatitis.
Very rarely: hepatic insufficiency.
From the side of the cardiovascular system
Rarely: pericarditis, pericardial effusion, pericardial tamponade, lowering of arterial pressure, thromboembolic complications.
On the part of the respiratory system
Often: pneumonia, interstitial alveolitis um / nnevmonitis, often accompanied by eosinophilia. Symptoms Potentially
severe interstitial pneumonitis: dry non-productive cough, shortness of breath, fever.
Rarely: pulmonary fibrosis, pneumonia caused by Pneumocystis carinii, respiratory failure and bronchial asthma, pleural effusion.
From the hemopoietic system and lymphatic system:
Often: leukopenia, anemia, thrombocytopenia.
Infrequent: pancytopenia.
Very rarely: agranulocytosis, severe oppression of bone marrow function.
From the side of urinary and reproductive systems
Infrequent: inflammation and ulceration of the bladder and / or vagina, impaired renal function, impaired urination.
Rarely: renal failure, oliguria, anuria, electrolyte imbalance. Very rarely: vaginal discharge, loss of sexual desire, gynecomastia, impotence, oligospermia. menstrual cycle disorders.
From the musculoskeletal system
Infrequently: arthralgia, myalgia, osteoporosis.
Neoplasms
Very rarely: individual cases of lymphoma have been reported, some of which have regressed after discontinuation of methotrexate therapy. In a recent study, it has not been established that methotrexate therapy increases the risk of lymphomas. The frequency and severity of the side effects of methotrexate treatment depends on the dose and frequency of the drug. However, severe side effects can also occur with low-dose methotrexate. Therefore, it is necessary that patients using methotrexate, medical examination was carried out regularly at short intervals.
When administered subcutaneously methotrexate shows a good local tolerance: with this method of administration, only mild skin reactions were observed, the severity of which decreased during the course of therapy.

Overdose:Overdose Symptoms
The toxic effect of methotrexate is mainly manifested by the hemopoietic system.
Treatment for overdose
Specific antidote, neutralizing the toxic effect of methotrexate, is folinic acid.
In case of an accidental overdose within the first hour after the administration of methotrexate (as soon as possible), the dose of a specific antidote - folinic acid (folic acid calcium) preparations, equal or exceeding the dose of methotrexate, should be administered intravenously or intramuscularly. 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. 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
Regular use of alcohol and the use of simultaneously with methotrexate hepatotoxic drugs increase the risk of manifestation of hepatotoxicity of the drug. For patients using other hepatotoxic drugs (for example, leflunomide), careful monitoring is necessary. This also applies to the simultaneous administration of hematotoxic drugs (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 used simultaneously with methotrexate retinoids (such as acitretin, etretinate) increases the risk of hepatotoxicity.
Such antibiotics as penicillins, glycopeptides, sulfonamides, ciprofloxacin, cefalotin 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 hematological and gastrointestinal toxicity.
Antibiotics used internally
When administered orally, antibiotics such as tetracyclines, chloramphenicol, nonabsorbable broad-spectrum antibiotics can influence enterohepatic circulation of methotrexate due to oppression of the intestinal flora or suppression of bacterial metabolism.
Preparations that bind well to plasma proteins
Methotrexate binds to plasma proteins, and bound methotrexate It can be replaced by other drugs with good binding proteins (such as salicylates, hypoglycemic agents, diuretics, sulfonamides, diphenylhydantoin (phenytoin, diphenine), tetracyclines, chloramphenicol, aminobenzoic acid, anti-inflammatory drugs), which in case of simultaneous use can 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 salicylates.
Drugs affecting the bone marrow
In the case of drugs that can affect the bone marrow (incl.as a side effect) (eg, 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.
Folate-containing medicines
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 preparations of gold, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, ciclosporin) there is no increase in the toxic effect of methotrexate.
Sulfasalazine
The combination of methotrexate with sulfasalazine can increase the effectiveness of methotrexate and, as a result, enhance the side effects associated with the suppression of sulfasalazine synthesis of folic acid.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, therefore, simultaneous use of methotrexate and mercaptopurine may require dose adjustment.
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 level of theophylline in the plasma.
Caffeine- and theophylline-containing beverages
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: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.
Features of use in patients with chronic diseases are described in the section "Method of administration and dose".
Special precautions for handling Methodic® and destruction of unused product
Methotrexate is cytotoxic, therefore, when handling Metodec ™, care must be taken and the rules for handling cytotoxic drugs should be followed.
Avoid contact with the skin and mucous membranes except during the injection. In case of contact, the corresponding areas of the skin and mucous membranes should be immediately washed with a large amount of water, then the skin areas after that with water and soap.
In case of accidental spillage of the preparation, it is necessary to collect the spilled solution with a disposable absorbent cloth, then treat the surface with a detergent contacting with it and wipe it with a disposable wet cloth, after which you should wash your hands thoroughly with soap.
The drug is intended for single use only.
Unused preparation and used materials must be disposed of in accordance with the rules for handling cytotoxic drugs.

Effect on the ability to drive transp. cf. and fur:Methotrexate is able to influence the central nervous system (causing such symptoms as fatigue, drowsiness, dizziness) and, thus, adversely affect the ability to drive, use mechanisms and perform other actions requiring rapidity of psychomotor reactions.

Form release / dosage:A solution for subcutaneous administration of 50 mg / ml.

Packaging:By 7.5 mg / 0.15 ml, or 10 mg / 0.2 ml, or 12.5 mg / 0.25 ml, or 15 mg / 0.3 ml, or 17.5 mg / 0.35 ml, or 20 mg / 0.4 ml, or 22.5 mg / 0.45 ml, or 25 mg / 0.5 ml, or 27.5 mg / 0.55 ml, or 30 mg / 0.6 ml in a 1 ml syringe from a neutral colorless glass (type I EF) with an integrateda hypodermic needle, a closed rubber stopper with a polymer coating or without a polymer coating, with a polymeric nozzle on the flange. On the syringe stick a label with a peeling edge, designed to unfold the label.
One syringe with the preparation in a PVC blister / paper.
One blister with a filled syringe with the drug, along with instructions for use in a cardboard bundle.

Storage conditions:In the dark 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:LP-002499

Date of registration:16.06.2014 / 02.02.2016

Expiration Date:16.06.2019

The owner of the registration certificate:medac GmbHmedac GmbH Germany

Manufacturer: & nbsp

ONCOTEC PHARMA PRODUKTION, GmbH Germany

Representation: & nbspTIRUFARM, LLCTIRUFARM, LLCRussia

Information update date: & nbsp2016-08-23

Illustrated instructions

Instructions

Methodic® (Metoject)