Métrotrite - instructions for use, dose, side effects, contraindications

auxiliary components: sodium chloride - 7.00 mg; 2 M sodium hydroxide solution - 1.76 mg (22 μl); 1 M sodium hydroxide solution - to pH = 8.5 ± 0.1; water for injection - up to 1.00 ml.

Description:Transparent yellow solution.

Pharmacotherapeutic group:Antitumour agent, antimetabolite

ATX: & nbsp

L.01.B.A Analogues of folic acid

L.01.B.A.01 Methotrexate

Pharmacodynamics:

Antitumor drug from the group of antimetabolites of folic acid analogues. Along with the antitumor has an immunosuppressive effect.

It inhibits 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 (in the S phase). Especially sensitive to the action of methotrexate tissue with high cell proliferation: tumor tissue, bone marrow, epithelial cells of the mucous membranes, embryonic cells.

The mechanism of action for rheumatoid arthritis is associated with the immunomodulatory and anti-inflammatory effect of the drug and is due to the induction of apoptosis of rapidly proliferating cells (activated T-lymphocytes, fibroblasts, synoviocytes), inhibition of the synthesis of anti-inflammatory cytokines IL-1 (Interleukin 1), TNF-α (tumor necrosis factor alpha) ), increased synthesis of anti-inflammatory cytokines IL-4 (Interleukin 4), IL-10 (Interleukin 10), and inhibition of metalloproteinase activity.

In patients with rheumatoid arthritis, methotrexate reduces symptoms of inflammation (pain, swelling, stiffness), but there are a limited number of studies with long-term use of methotrexate (in relation to the ability to maintain remission in rheumatoid arthritis).

In psoriasis, the rate of growth of keratinocytes in psoriatic plaques increases in comparison with the normal proliferation of skin cells. This difference in cell proliferation is the basis for the use of methotrexate for the treatment of psoriasis.

Pharmacokinetics:

Suction and distribution

With the / m introduction of Cmax methotrexate in blood plasma is achieved within 30-60 minutes. Patients with leukemia are characterized by a wide interindividual variability ranging from 1 to 3 hours.

The relative bioavailability in patients with rheumatoid arthritis is comparable with intramuscular and subcutaneous administration of the same dose of the drug. Systemic absorption of methotrexate after administration under the skin of the abdomen and thigh is the same.

After IV introduction, the primary distribution is 0.18 l / kg (18% of body weight). The distribution of the saturation dose is about 0.4-0.8 l / kg (40% - 80% of body weight).

Binding to plasma proteins - about 50%, mainly with albumins. Perhaps competitive displacement with simultaneous use with sulfonamides, salicylates, tetracyclines, chloramphenicol, phenytoin.

When taken in therapeutic doses, methotrexate does not penetrate the blood-brain barrier.

Metabolism

Methotrexate undergoes hepatic and intracellular metabolism with the formation of a pharmacologically active polyglutamine form, also inhibiting dihydrofolate reductase and thymidine synthesis. A small amount of methotrexate polyglutamate may remain in the tissues for a long period of time. The preservation and prolongation of the action of active metabolites of the drug differ depending on the type of cells, tissues and tumors.

Approximately 10% of the injected methotrexate is metabolized in the liver. The main metabolite is 7-hydroxymethotrexate.

Excretion

The mean T1 / 2 values with methotrexate in a dose of less than 30 mg /m² are 6-7 hours. In patients receiving high doses of methotrexate, T1 / 2 is 8 to 17 hours.

From 80 to 90% of the received dose is excreted unchanged by glomerular filtration and tubular secretion within 24 hours.Approximately 5-20% of methotrexate and 1 -5% of 7-hydrometotrexate is excreted with bile, followed by reabsorption in the intestine.

Pharmacokinetics in special clinical cases

In chronic renal failure, both phases of excretion of the drug can be significantly elongated.

Renal impairment, severe ascites or pleural effusions, as well as simultaneous use of drugs such as weak organic acids, which also undergo tubular secretion, can significantly increase the serum concentration of methotrexate. In accordance with the distribution, methotrexate is cumulated in the liver, kidney and spleen in the form of polyglutamates and can stay in these organs for several weeks or months.

Indications:

- Rheumatoid arthritis in adults;

- the polyarthritic form of juvenile idiopathic arthritis in the case of an insufficient therapeutic response to therapy with nonsteroidal anti-inflammatory drugs (NSAIDs);

- severe form of psoriasis in adult patients, especially in the form of plaques, in case of ineffectiveness of standard therapy, including phototherapy, PUVA-therapy and the use of retinoids;

- severe form of psoriatic arthritis in adult patients.

Contraindications:

- Hypersensitivity to methotrexate and / or to any other component of the drug;

- marked renal failure (creatinine clearance <20 ml / min);

- severe hepatic impairment;

- Alcohol abuse;

- violations from the hemopoietic system in the history (in particular, bone marrow hypoplasia, leukopenia, thrombocytopenia or clinically significant anemia);

- immunodeficiency;

- Severe acute and chronic infectious diseases, such as tuberculosis and HIV infection;

- concomitant vaccination with live vaccines;

- oral ulcers, gastrointestinal ulcers in the active phase;

- simultaneous use of methotrexate in a dose ≥ 15 mg / wk. with acetylsalicylic acid;

- Pregnancy;

- the period of breastfeeding.

Carefully:With caution apply the drug if the patient has a violation of liver and kidney function, diabetes mellitus, obesity and previous exposure to hepatotoxic drugs, dehydration, oppression of bone marrow hematopoiesis, pleural or peritoneal effusion,parasitic and infectious diseases of viral, fungal or bacterial etiology (currently or recently transferred, including recent contact with the diseased), incl. such as herpes simplex, herpes zoster (viremic form), chicken pox, measles, amebiasis, strongyloidiasis (established or suspected) due to the risk of developing a severe generalized disease; gout (including history) or urinal nephrourolythiasis (including history), infections and inflammation of the oral mucosa, vomiting, diarrhea, peptic ulcer and duodenal ulcer, ulcerative colitis, obstructive diseases of the digestive tract, previous chemo- or radiation therapy, asthenia, aciduria (urine pH less than 7), as well as in children and elderly patients.

Pregnancy and lactation:

Pregnancy

Methotrexate is contraindicated during pregnancy.

Taking methotrexate during pregnancy can cause serious malformations of the fetus (an increase in the frequency of malformations of the skull, cardiovascular system and limbs by 14 times).

If pregnancy occurs during methotrexate treatment, you should consult with specialists about the risk of adverse effects of methotrexate on the fetus.

Fertility

Patients of reproductive age (women and men) should use effective contraception during and for at least 6 months after the end of treatment with Metotritis.

Lactation

Methotrexate penetrates into breast milk in concentrations dangerous to the baby. Therefore, during treatment with methotrexate, breastfeeding should be discontinued.

Dosing and Administration:

The drug Metorggrig is administered subcutaneously, intramuscularly or intravenously. Included in the package of the needle for injection is intended only for subcutaneous administration of the drug Metotrit. To administer the drug intramuscularly or intravenously, it is necessary to use needles suitable for these routes of administration.

Doses

Meteoritis can be prescribed only by physicians who are familiar with

various properties of the drug and its mode of action. Mertotrit is injected once a week. It should be clearly explained to the patient that for the treatment of rheumatic diseases, the drug Metotrite should be applied only once a week.

Incorrect use of methotrexate can lead to the development of adverse events, including fatal.

Adult patients with rheumatoid arthritis:

Parenteral administration of a trial dose of methotrexate is recommended one week before the start of therapy, to detect idiosyncratic adverse reactions.

The initial recommended dose is 7.5 mg of methotrexate once a week, administered either subcutaneously, either intramuscularly or intravenously. Depending on the individual manifestation of the disease and on the tolerability of therapy by the patient, the initial dose can be gradually increased by 2.5 mg per week. Do not exceed the dose of 25 mg per week. Doses in excess of 20 mg per week may be associated with a significant increase in toxicity, especially with bone marrow suppression. The response to treatment usually comes in 4-8 weeks. After achieving the desired therapeutic result, the dose should be gradually reduced to the lowest effective maintenance dose.

Children and adolescents with a polyarthritic form of juvenile idiopathic arthritis (JMA):

The recommended dose is 10-15 mg /m² body surface area (PPT) / week. With insufficient treatment effectiveness, a weekly dose can be increased to 20 mg /m² body surface / week.

If the dose is increased, an increase in the frequency of monitoring of treatment is recommended.

Due to limited data on intravenous use in children and adolescents, parenteral use is limited to subcutaneous and intramuscular administration.

Patients with JIA should always contact specialized departments with experience in treating children / adolescents.

Use in children <3 years of age is not recommended, due to insufficient data on the safety and efficacy of this group of patients.

Adult patients with severe forms of psoriasis or psoriatic arthritis:

It is recommended parenteral administration of a test dose of 5 to 10 mg one week before the start of therapy, to detect idiosyncratic adverse reactions.

The initial recommended dose is 7.5 mg of methotrexate once a week, administered either subcutaneously, either intramuscularly or intravenously. The dose should be gradually increased as needed, but do not exceed the maximum weekly dose of 30 mg of methotrexate. The response to treatment usually comes after 2-6 weeks. After achieving the desired therapeutic result, the dose should be gradually reduced to the lowest effective maintenance dose.

Patients with renal insufficiency:

Mesotritis should be used with caution in patients with renal insufficiency.

Doses should be adjusted as follows:

Clearance	Dose of the drug
creatinine	(% of usual
(ml / min)	dose)
>50	100%
20-50	50%
<20	Application
	Métortrites
	contraindicated

Patients with hepatic insufficiency:

In case of emergency, methotrexate should be used with caution in patients with liver disease in active form or in anamnesis, especially those associated with alcohol abuse. Methotrexate is contraindicated if the concentration of bilirubin exceeds 5 mg / dl (85.5 μmol / l).

Elderly patients

It is necessary to consider the possibility of lowering doses in elderly patients due to the age-related decrease in liver and kidney function and a decrease in folate stocks.

Patients who have an additional volume of distribution (pleural effusion, ascites)

Since the half-life of Métortrites can be extended 4-fold compared to normal, patients who have an additional volume of distribution may need a dose reduction or, in some cases, discontinuation of methotrexate.

Method of application and duration:

Mertotrit, an injection solution, can be administered subcutaneously, intramuscularly or intravenously.

In adults, intravenous use should be performed bolus.

Treatment of rheumatoid polyarthritis, juvenile idiopathic arthritis, severe psoriasis and psoriatic arthritis with Metotrite is usually carried out for a long period of time.

The total duration of treatment is determined by the doctor.

The prefilled syringe with the drug Méthorritis is intended for single use only.

Unused medication should be disposed of.

It is necessary to visually check the injection solution before

using. Use only a clear solution, practically free of particles.

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 medical personnel to perform the hypodermic injection before applying the drug. The first independent use of the drug by the patient must be carried out in the presence of a doctor.

Method of drug administration.

With the injection of Metotrite, standard hygiene and aseptic requirements must be met,First of all, you need to wash your hands thoroughly.

1. Make sure the package contains the dosage you need. Check the expiration date on the package. Open the cardboard box, take out the blister with the pre-filled syringe and the package with the needle.

2. Open the blister containing the syringe with the drug, holding the plastic part of the blister with one hand and separating the cover of the other. Remove the rubber cap from the syringe without touching the opened interior. Put the syringe with the drug on the blister. A special polymer colored nozzle is attached to the flange of the syringe body, which increases the convenience of holding the syringe with fingers and facilitates the injection. Do not remove this nozzle from the syringe.

3. Open the package with the needle. Without removing the plastic protective cap, attach the needle to the syringe and secure by turning.

4. Choose for injection such a place where you can grab a skin crease in 2-3 cm:

- 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,

- if someone helps you, then the injection can be done in the forearm.

Do not administer the drug to a place where there is soreness, tightness, redness, a cutaneous or hematoma.

It is recommended to avoid injections into the skin with visible on the surface of the mesh of small blood vessels to avoid the formation of a hematoma. It is recommended to alternate the sides of injections (right and left), and also choose different places on the abdomen or on the hips every week.

5. Treat the injection site with a special disinfectant wipe or a tampon moistened with a disinfectant.

6. Carefully remove the protective cap from the needle. Do not touch the sterile needle. Form the fold of the skin with the thumb and index finger. 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. If the skin becomes yellow at the injection site, do not worry, within 1-2 days the drug is absorbed and the skin color becomes normal. This may be due to improper subcutaneous injection or insufficient needle length.

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.

Any contact of methotrexate with skin or mucous membranes should be avoided! In case of contamination, the affected area should be washed with a large amount of water.

Note

When switching from oral methotrexate to parenteral administration, a dose reduction may be necessary, since the bioavailability of the oral drug is variable.

In accordance with the current guidelines for treatment, the use of folic or folic acid preparations should be considered.

Side effects:

According to the WHO classification, unwanted effects are classified according to their frequency of development as follows: very often (≥ 1/10), often (from ≥1/100 to <1/10), infrequently (from ≥1/1000 to <1/100), rarely (from ≥1/10 000 to <1/1000), very rarely (<1/10 000); frequency is unknown-it was not possible to establish the frequency of occurrence on the available data.

Disorders from the cardiovascular system.

Infrequently: vasculitis (as acute toxic symptoms).

Rare: pericarditis, pericardial effusion, cardiac tamponade, lowering blood pressure, thromboembolic events (including cerebral thrombosis and arterial thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism).

Violations from the blood and lymphatic system:

Often: leukopenia, thrombocytopenia, anemia.

Infrequent: pancytopenia, agranulocytosis, hematopoietic disorders.

Rarely: megaloblastic anemia.

Very rarely severe bone marrow depression, aplastic anemia, lymphadenopathy, lymphoproliferative disease (partially reversible), eosinophilia, neutropenia.

The first signs of these complications that are life-threatening, are fever, sore throat, mouth sores, flu-like symptoms, nosebleeds and bleeding into the skin.The use of methotrexate should be stopped immediately if the number of blood cells is significantly reduced.

Immune system disorders:

Infrequently: allergic reactions, anaphylactic shock, immunosuppression.

Infectious and parasitic diseases:

Very rarely: sepsis, opportunistic infections (in some cases can be fatal), infections caused by Cytomegalovirus.

The frequency is unknown: there have been reports of cases of nocardiosis, histoplasmosis and cryptococcal fungal infections, disseminated herpes simplex form.

Impaired nervous system:

Often: headache, fatigue, drowsiness.

Infrequently: depression, confusion, dizziness, convulsions.

Rarely: a change in mood.

Very rarely: pain, muscle weakness or paresthesia in the extremities, a violation of taste sensations (metallic taste), acute aseptic meningitis with meningism (paralysis, vomiting), insomnia.

The frequency is unknown: ringing in the ears.

Disorders from the side of the organ of vision:

Rarely: severe visual impairment.

Very rarely: conjunctivitis, retinopathy.

Benign, malignant and unspecified neoplasms:

Infrequent: isolated cases of lymphoma that

regress with the cessation of treatment with methotrexate. In a recent clinical study, it has not been established that methotrexate therapy increases the incidence of lymphomas.

Disturbances from the respiratory system, chest and mediastinal organs:

Often: pulmonary complications due to interstitial pneumonitis / alveolitis, including fatal (regardless of the dose and duration of treatment with methotrexate). Typical symptoms: malaise, dry, unproductive cough, shortness of breath. progressing to dyspnea at rest, chest pain, fever.

If such complications are suspected, the use of methotrexate stops immediately and infections (including pneumonia) are excluded.

Infrequent: pulmonary fibrosis.

Rarely: pharyngitis, apnea, bronchial asthma, shortness of breath and abnormal results of instrumental lung function tests.

Very rarely: pneumonia caused by Pneumocystis carinii and other infections of the lungs, shortness of breath, chronic obstructive pulmonary disease, pleural effusion.

Disorders from the gastrointestinal tract:

Very often: decreased appetite, nausea and vomiting (especially during the first 24-48 hours after methotrexate administration), abdominal pain, inflammation and ulcers in the mucous membrane of the mouth and throat, stomatitis,dyspepsia.

Often: diarrhea (especially in the first 24 to 48 hours after the application of methotrexate).

Infrequent: ulcers and bleeding of the gastrointestinal tract.

Rare: enteritis, melena, gingivitis, malabsorption syndrome.

Very rarely: vomiting with blood, toxic megacolon.

Disorders from the liver and bile ducts:

Very often: increased activity of "liver" enzymes (ALT, ACT), increased activity of alkaline phosphatase, increased bilirubin concentration.

Infrequently: steatosis of the liver, liver fibrosis, liver cirrhosis (can appear even in case of regular detection of normal "liver" transaminases during monitoring).

Rarely: acute hepatitis and hepatotoxicity.

Very rarely: reactivation of chronic hepatitis, acute liver dystrophy, liver failure. The most common is hepatitis caused by the herpes simplex virus and accompanied by hepatic insufficiency.

Disturbances from the skin and subcutaneous tissues:

Often: exanthema, erythema, itchy skin.

Infrequent: urticaria, photosensitivity, increased skin pigmentation, hair loss, abnormal wound healing, increased rheumatic nodules,herpes zoster, painful expression of psoriatic plaques (may exacerbation plaque psoriasis during therapy UV radiation and simultaneous application methotrexate), severe toxic reactions, vasculitis, hypersensitivity vasculitis, herpetiformis rash, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Rare: changes in pigmentation of nails, onycholysis, petechiae, ecchymosis, erythema multiforme, erythematous rash.

Very rare: acute paronychia, furunculosis, telangiectasia, hidradenitis.

Disturbances from the musculoskeletal and connective tissue:

Infrequently: arthralgia, myalgia, osteoporosis.

Rarely: stress fractures, osteonecrosis.

Disorders from the kidneys and urinary tract:

Infrequent: inflammation and ulceration of the bladder, (possibly with

hematuria), dysuria (urination disorder).

Rarely: renal failure, oliguria, anuria, azotemia.

Very rarely: proteinuria.

Violations of the genitals and breast:

Infrequently: vaginitis (inflammation of the vagina)

Rarely: oligospermia, menstrual cycle disorders.

Very rarely: decreased libido, impotence, vaginal discharge, infertility, gynecomastia.

The frequency is unknown: violation of oogenesis and spermatogenesis, teratogenic effect.

Disorders from the endocrine system:

The frequency is unknown: diabetes, metabolic disorders.

General disorders and disorders at the site of administration:

Infrequently: with intramuscular injection of methotrexate, burning or damaging tissues (the formation of sterile abscesses, the destruction of fatty deposits) at the injection site.

Very rarely: fever. Usually, with subcutaneous injection methotrexate is well tolerated, until today only mild local reactions have been noted that have decreased during treatment.

Laboratory and instrumental data:

Infrequent: Decreased serum albumin concentration, hypogammaglobulinemia. The frequency and severity of adverse reactions depend on the dose and frequency of application. Because severe adverse reactions can occur at low doses, it is extremely important that patients undergo medical examination regularly and at short intervals.

Overdose:

Symptoms: The most common symptoms are those associated with oppression of the hematopoiesis system.

Treatment: specific antidote of methotrexate is calcium folinate. It neutralizes adverse toxic effects.

In case of accidental overdose, not later than one hour after the administration of methotrexate, calcium folinate (in / in or / m) at a dose equal to or greater than the dose of methotrexate. The administration of calcium folinate is continued until the serum levels of methotrexate are lower than level 10^-7 mmol / l.

If there is a significant overdose, it may be necessary to rehydrate the organism and alkalinize urine (pH more than 7) to prevent precipitation of methotrexate and / or its metabolites in the renal tubules. Hemodialysis and peritoneal dialysis do not improve the elimination of methotrexate. Ensuring effective clearance of methotrexate allows intensive intermittent hemodialysis using high-flux dialyzers.

Interaction:

The likelihood of hepatotoxic action of methotrexate increases in the case of regular use of alcohol and concomitant use of other hepatotoxic drugs.

With combined therapy with methotrexate and leflunomide, the incidence of pancytopenia and hepatotoxic effects.

Antibiotics for oral administration (tetracyclines, chloramphenicol and nonabsorbable broad-spectrum antibiotics) can reduce absorption of methotrexate in the digestive tract and interfere with enterohepatic circulation due to inhibition of intestinal microflora or inhibition of bacterial metabolism.

Penicillins, ciprofloxation. cephalothin, glycopeptides can reduce the renal clearance of methotrexate, as a result of which its concentration in the blood serum can be increased and the toxic effect on the hematopoietic system and gastrointestinal tract is intensified.

Probenecid, weak organic acids (for example, "loop" diuretics) and pyrazoles (phenylbutazone) can slow down the elimination of methotrexate, which may increase its serum concentration and increase hematological toxicity.

The risk of toxic effects of methotrexate is increased in the case of combined use with NSAIDs or salicylates (possibly reducing the excretion of methotrexate by the renal tubules, caution should be exercised when combining non-steroidal anti-inflammatory drugs with methotrexate).

With concomitant therapy with drugs that may have adverse effects on the bone marrow (for example, sulfonamides. trimethoprim / sulfamethoxazole, chlorampheicol, pyrimetamy), one should take into account the possibility of developing more severe hematologic disorders.

With concomitant therapy drugs that cause folate deficiency (eg, trimethoprim / sulfamethoxazole), the toxic effect of methotrexate may be exacerbated.

Simultaneous application indirect anticoagulants and lipid-lowering drugs (cholestyramia) increases the toxicity of methotrexate.

With combined use antirheumatic drugs (eg, gold salts, penicillamines, hydroxychloroquines, azathioprins, cyclospores) and methotrexate, the toxic effect of the latter is not enhanced. In case of simultaneous application sulfasalazine and methotrexate, the effect of the latter can be potentiated by inhibiting the synthesis of folic acid.

When combined use of methotrexate and proton pump inhibitors (eg, omeprazole or pantoprazole) renal elimination of methotrexate may be delayed, and pantoprazole can inhibit the renal elimination of the metabolite 7-hydroxymethotrexate, which in one case was accompanied by the development of myalgia and tremor.

During treatment with methotrexate, excessive use should be avoided beverages containing caffeine and theophylline (coffee, sweet drinks, containing caffeine, Black tea). Methotrexate reduces the clearance of theophylline.

It is necessary to take into account the pharmacokinetic interaction between methotrexate and flucloxacillin and anticonvulsants (the concentration of methotrexate in the blood decreases), 5-fluorouracil (the half-life of 5-fluorouracil increases).

In the case of joint application with other cytostatics the clearance of methotrexate may decrease.

Simultaneous application vitamin preparations or iron preparations for oral administration containing folic acid, can weaken the response to therapy and reduce the toxic effect of methotrexate on bone marrow.

When mixing solutions of methotrexate with chlorpromazine hydrochloride, droperidol, idarubicin, metoclopramide hydrochloride, heparin, prednisolone sodium phosphate and promethazine hydrochloride possibly precipitation or clouding of the solution.

The use of drugs with an additional hematotoxic effect (eg, metamizole) increases the likelihood of serious hematotoxic effects of methotrexate.

Due to competitive binding to serum albumin with simultaneous use of methotrexate with salicylates, fairylbutazone, phenytoin, barbiturates, tranquilizers, oral contraceptives, tetracycline in and, amidopyrine derivatives, sulfonamides and p-aminobenzoic acid, the toxicity of methotrexate can be increased.

Several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (metoksalen and ultraviolet irradiation), skin cancer was detected.

Caution should be exercised with the simultaneous administration of erythrocyte mass and methotrexate.

The combination with radiotherapy can increase the risk of soft tissue necrosis. Methotrexate may reduce the immunological response to vaccination. With simultaneous administration with a live vaccine, severe antigenic reactions can develop.

L-asparaginase is a methotrexate antagonist.

Anesthesia using dinitrogen oxide can lead to unpredictable severe myelosuppression and stomatitis. Amiodarone can promote ulceration of the skin.

Pharmaceutical incompatibility

Do not mix Mettritrit with other medicines and solvents.

Special instructions:

If a patient has a significant amount of fluid in the pleural cavity or ascites, evacuate the fluid by draining before starting methotrexate therapy, or stop using methotrexate.

The appearance of symptoms of toxic damage to the digestive system, the earliest of which are stomatitis and diarrhea, requires the temporary cessation of methotrexate therapy in view of the high risk of hemorrhagic enteritis and perforation of the intestine with lethal outcome in the case of continuation of therapy. In the course of treatment with methotrexate

patients should be carefully monitored in order to identify signs of possible toxic effects and adverse effects in a timely manner. Given the risk of severe or even fatal toxic reactions, patients should be informed in detail about possible complications and recommended precautions.

Before the start of methotrexate treatment or with the resumption of therapy after a break, it is necessary to conduct a clinical blood test with counting the leukocyte formula and the number of platelets, assess the activity of "liver" enzymes, the concentration of bilirubin, serum albumin, and chest radiography and functional kidney tests. In the presence of clinical indications, studies are being conducted to exclude tuberculosis and hepatitis.

In the process of treatment with methotrexate (monthly in the first 6 months and at least every 3 months in the future, and with increasing doses it is advisable to increase the frequency of examinations), the following studies are carried out:

1. Inspection of the oral cavity and throat to detect changes in the mucous membranes.

2. A blood test with the definition of the leukocyte formula and the number of platelets.

Even when used in conventional therapeutic doses methotrexate can suddenly cause oppression of the hematopoiesis system. In the case of a significant decrease in the number of white blood cells or platelets, methotrexate treatment is immediately stopped and symptomatic maintenance therapy is prescribed.Patients should be instructed to immediately inform the doctor of any signs and symptoms that indicate the development of the infection. With concomitant therapy with hematotoxic drugs (eg leflunomide), you need to closely monitor the number of leukocytes and platelets in the blood.

During long-term treatment with methotrexate, bone marrow biopsy is useful, if necessary.

3. Functional "liver" tests.

Particular attention should be given to identifying signs of liver damage. Methotrexate treatment should not be initiated or should be stopped if any abnormalities in the results of functional liver tests or a liver biopsy are detected. Usually, the indices are normalized within two weeks, after which the treatment can be resumed by the doctor's decision.

In 13-20% of patients, a short-term increase in activity of "hepatic" enzymes was observed 2-3 times. A persistent increase in the activity of "hepatic" enzymes and / or a decrease in the serum albumin concentration may be indicative of severe hepatotoxicity.Enzyme diagnostics does not in all cases provide adequate prognosis for the development of hepatotoxicity, detectable morphologically, even in the case of normal activity of "hepatic" enzymes, liver fibrosis, or, much less rarely, cirrhosis, can be histopathologically detected.

When methotrexate is used for rheumatological indications, there is no reason to conduct a liver biopsy to monitor the hepatotoxic effect of the drug.

When treating patients with psoriasis, it is necessary to evaluate the advisability of conducting a liver biopsy before or during treatment with methotrexate, based on current scientific recommendations. If additional signs of hepatotoxicity are not detected with the help of biochemical indicators of hepatic function or determination of the concentration of type III collagen propeptide, further studies may be needed. In such an assessment, patients without risk factors and at-risk patients should be differentiated (for example, alcohol abusers who were previously abused, with persistent activity of "hepatic" enzymes, liver diseases in history, hereditary liver diseases in a family anamnesis,patients with diabetes mellitus, obese patients, as well as those who had previously received hepatotoxic drugs or who had been in contact with hepatotoxic chemicals and received long-term treatment with methotrexate in total doses of 1.5 g or more). In the case of a persistent increase in the activity of "hepatic" enzymes, it is necessary to reduce doses or stop treatment with methotrexate.

Because the methotrexate has a toxic effect on the liver, during the treatment with the drug should not without the obvious need to prescribe other hepatotoxic drugs.

Also, alcohol consumption should be avoided or greatly reduced. Particularly closely monitor the activity of "hepatic" enzymes followed in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, leflunomide). Particular care should be taken in the treatment of patients with insulin-dependent diabetes mellitus, since cases of the development of liver cirrhosis are described with the previous periodic increase in the activity of "hepatic" enzymes.

4. Functional renal tests and urinalysis.

When the concentration of serum creatinine increases, the dose of methotrexate should be reduced. When the concentration of creatinine. exceeding 2 mg / dl, the use of methotrexate is contraindicated.

Because the methotrexate excreted mainly by the kidneys, in patients with impaired renal function, there may be an increase in the concentration of methotrexate in the blood, which can lead to serious adverse reactions. It is necessary to carefully monitor the condition of patients who may have impaired renal function (eg, elderly patients). This is especially important in the case of concomitant therapy with drugs that reduce the excretion of methotrexate, have an adverse effect on the kidneys (in particular, NSAIDs) or on the hematopoiesis system. In the presence of risk factors, such as renal failure. simultaneous administration of non-steroidal anti-inflammatory drugs is not recommended. Dehydration can also potentiate the toxic effect of methotrexate.

5. Investigation of respiratory function

system. It is necessary to closely monitor the symptoms of possible development of pulmonary function disorders and, if necessary, prescribe an examination of lung function.

Pulmonary diseases require rapid diagnosis and cancellation of methotrexate. The appearance of appropriate symptoms during treatment with methotrexate (especially dry, unproductive cough) or the development of nonspecific pneumonitis may indicate a potential lung injury. In such cases methotrexate abolish and carefully examine the patient. Although the clinical picture may vary, a typical patient with pulmonary disease caused by methotrexate use has a rise in body temperature, cough with shortness of breath, hypoxemia, and pulmonary infiltrates on X-rays. Differential diagnostics should exclude infectious diseases. Lung inflammation can occur with methotrexate in any dose.

During treatment with methotrexate, it is possible to develop opportunistic infections, including pneumonia caused by Pneumocystis carinii, which can be fatal. If a patient exhibits symptoms of lung damage, pneumonia caused by Pneumocystis carinii should be excluded.

It is advisable to use caution in the treatment of patients with pulmonary insufficiency.

6. Since methotrexate has an effect on the immune system, it can change the response to vaccination and influence the results of immunological tests. Particular care is needed in the treatment of patients with inactive, chronic infections (such as herpes zoster, tuberculosis, hepatitis B or C) because of their possible activation. During the treatment with methotrexate, vaccination should not be carried out with live vaccines.

It is recommended to interrupt MTX treatment one week before surgery and resume one or two weeks after surgery.

With an increase in body temperature (more than 38 ° C), the elimination of methotrexate significantly slows down.

Methotrexate may increase the risk of developing neoplasms (mainly lymphomas). Malignant lymphomas can also develop in patients receiving methotrexate in low doses. In such cases, the drug is canceled. If spontaneous regression of lymphoma is not observed, cytotoxic therapy is prescribed.

Prior to treatment, you must exclude pregnancy. Methotrexate has embryotoxic effect, promotes abortion and fetal development abnormalities.Therapy with methotrexate is accompanied by depression of spermatogenesis and oogenesis, which can lead to a decrease in fertility. After the abolition of methotrexate therapy, these effects spontaneously regress. During the period of methotrexate therapy and for 6 months after its completion, patients are advised to use contraceptive measures.

Inform patients of reproductive age, as well as their partners, about the possible effects of methotrexate on reproductive and fetal development.

With high-dose therapy, precipitation may occur

methotrexate or its metabolites in the renal tubules. In such cases, as the prophylaxis of this complication, it is recommended to perform infusion therapy and alkalinization of urine until pH 6.5-7.0 is achieved by oral or intravenous sodium bicarbonate (5 tab to 625 mg every 3 hours) or acetazolamide (500 mg orally 4 times / day) .

Methotrexate should not be mixed with other medications in one infusion bag or vial.

When handling the solution of methotrexate, the rules for handling cytotoxic substances must be observed. Pregnant health workers should not work with the drug.

Take measures to prevent solution

methotrexate on the skin and mucous membranes. If the drug still gets on the skin or mucous membranes, the affected area is immediately washed with a large amount of water.

Effect on the ability to drive transp. cf. and fur:During treatment, Metertritem should refrain from driving vehicles or working with other mechanisms, since there may be side effects from the nervous system (fatigue and dizziness).

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

Packaging:

By 2.0 ml or 1.5 ml of the preparation into a syringe of 2.25 ml or 1.0 ml or 0.75 ml of the preparation in a 1.0 ml syringe, from a colorless glass of type I, equipped with a piston, piston rod and flange for control (pre-filled syringe). For each pre-filled syringe paste a graduated label.

1 pre-filled syringe is placed in a contour mesh box made of PVC sealed with an unmarked transparent foil made of PET / PE. 1 needle for subcutaneous injection in the blister. 1 contour pack with pre-filled syringe and 1 blister with a hypodermic needle along with instructions for useplaced in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C, in the original packaging.

Keep out of the reach of children!

Do not freeze!

Shelf life:

2 years.

The drug should be used immediately after opening.

Terms of leave from pharmacies:On prescription

Registration number:LP-002919

Date of registration:17.03.2015

Expiration Date:17.03.2020

The owner of the registration certificate:K.O. Ромфарм Компани С.Р.Л.K.O. Ромфарм Компани С.Р.Л. Romania