Expiration date: 09/2025

The composition and form of issue:

Solution for injection 1 ml contains:

methotrexate 10 mg

(methotrexate disodium of 10.96 mg (equivalent to 10 mg of methotrexate) 

auxiliary substances: sodium chloride sodium hydroxide water for injections 

syringes graduated from a neutral colourless glass (type I, Heb. F.) 7.5 mg/0.75 ml, 10 mg/1 ml, 15 mg/1.5 ml, 20 mg/2 ml or 25 mg/2.5 ml, closed with a rubber stopper, with a polymer tip to flange, complete with needle in blister packs of 1 set in cardboard pack 1 blister.

Description pharmaceutical form:

Transparent liquid of yellow color.

Pharmacokinetics:

Approximately 50% of methotrexate is bound to plasma proteins.

After the distribution in the tissues of the high concentration of methotrexate in the form polyglutamates found in the liver, kidney, and especially in the spleen, in which methotrexate may be held for weeks or even months.

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

T1/2 — average of 6-7 h and is characterized by high variability (3-17 h). Half-life may increase to values, 4 times exceeding average value in patients with an additional volume of distribution (the presence of pleural effusion, ascites).

About 10% of the administered dose is metabolized in the liver, the main metabolite is 7-hydroxymethotrexate, also have pharmacological activity.

It is excreted mainly unchanged by the kidneys by glomerular filtration and tubular secretion.

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

Excretion of the drug in patients with impaired renal function significantly slowed.

No data on the slow excretion of methotrexate with inadequate liver function.

Description pharmacological action:

Antagonist of folic acid, belongs to the group of immunosuppressants. Competitive inhibits the enzyme digidrofolatreduktaza involved in the restoration digidrofolieva acid tetragidrofolievu acid (carrier carbon fragments necessary for the synthesis of purine nucleotides and their derivatives).

Inhibits the synthesis, DNA repair and cell mitosis. Especially sensitive to the effects of methotrexate istropolitana cells: malignant tumor cells, bone marrow, embryonic cells, epithelial cells of the mucous membranes.

Along with the antitumor has an immunosuppressive effect.

It remains unclear what caused the effectiveness of methotrexate in the treatment of psoriasis, psoriatic arthritis and rheumatoid arthritis (including juvenile chronic arthritis): its anti-inflammatory or immunosuppressive action. Also not established to what extent the effectiveness of therapy is due to the methotrexate-induced increase in the extracellular concentration of adenosine at sites of inflammation. Psoriasis use of methotrexate can slow significantly accelerated the formation of epithelial skin cells.

Indications:

• rheumatoid arthritis in adult patients
  
• polyarthritis in patients with severe juvenile chronic arthritis in the active form
  
• severe generalized psoriasis and psoriatic arthritis in adult patients not responding to conventional therapy.
  

Contraindications:

• hypersensitivity to methotrexate or other components of the drug
  
• expressed violation of liver function (see "Method of application and dosage")
  
• alcoholism
  
• expressed kidney failure (Cl creatinine <20 ml/min, see "Method of application and dosage")
  
• violation of hematopoiesis in history, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, severe anemia
  
• severe acute or chronic infectious diseases such as tuberculosis, HIV infection
  
• pronounced immunodeficiency
  
• mouth ulcers
  
• peptic ulcer disease gastrointestinal tract in an active phase
  
• pregnancy and breast-feeding
  
• simultaneous vaccination with live vaccines.
  

Caution — dehydration, obstructive diseases of the gastrointestinal tract, pleural or peritoneal effusion, chronic renal failure, parasitic and infectious diseases virus, fungal or bacterial origin (currently or recently migrated, including the recent contact with the patient): herpes simplex, herpes zoster (vermicella phase), chickenpox, measles, amoebiasis, strongyloidiasis (established or suspected) — the risk of severe generalized disease gout (including a history) or urate nefrourolitiaz (incl. in history), infection and inflammation of the mucous membrane of the mouth, vomiting and diarrhea (fluid loss due to severe vomiting and diarrhea can lead to increased methotrexate toxicity), ulcers disease stomach and duodenal ulcers, ulcerative colitis, prior chemotherapy or radiotherapy, asthenia, old age.

Application of pregnancy and breast-feeding:

Contraindicated in pregnancy and during breastfeeding.

When applied in humans methotrexate showed teratogenic properties capable of causing fetal death or congenital deformities.

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

Patients of reproductive age of both sexes and their partners must use reliable contraceptive measures during MTX therapy and for at least for 6 months after graduation.

If a woman becomes pregnant during treatment with methotrexate, you should consider the risk of adverse effects on the fetus.

Methotrexate is excreted in breast milk in amounts dangerous for the child, so before starting treatment with methotrexate breastfeeding should cease and desist from him throughout the course of treatment.

Side effects:

The most common side effects when using Metoject are the reactions of the hematopoietic system and gastrointestinal tract.

To identify the frequency effects next, apply the following gradation: very often (&ge1/10), often (&ge1/100, <1/10), sometimes (&ge1/1000, <1/100), rare (&ge1/10000, <1/1000), very rare (<1/10000).

From the blood: very often — stomatitis, dyspepsia, nausea, loss of appetite often — ulcers in the mouth, diarrhea sometimes pharyngitis, enteritis, vomiting, rarely — erosive and ulcerative lesions of the gastrointestinal tract very rarely — vomiting blood, bleeding from the gastrointestinal tract (including melena, hematemesis).

From the liver: often — increase of transaminase level sometimes cirrhosis, fibrosis and fatty degeneration of the liver, hepatotoxicity (acute hepatitis, liver failure).

With the skin and skin appendages: often — rash, erythema, pruritus and sometimes photosensitivity, hair loss, increase of rheumatic nodes, vasculitis, Herpes zoster, herpetiformis skin rash, hives, rarely — increased pigmentation very rarely — discoloration of the nails, acute paronychia, Stevens-Johnson syndrome, epidermal necrolysis (Lyell's syndrome).

In the treatment of psoriasis: a feeling of "burning" of the skin rarely painful erosive plaques on the skin.

Common reactions: allergic reactions up to anaphylactic shock, allergic vasculitis, fever, sepsis, life-threatening opportunistic infections (including Pneumocystis pneumonia), cytomegalovirus (CMV) infection (including CMV pneumonia), sepsis (including fatal), Nocardia, histoplasmosis, cryptococcosis infection caused by Herpes simplex and Herpes zoster (including disseminated), impaired wound healing, pleural effusion, pancreatitis, diabetes, necrosis of soft tissues, epistaxis, excessive sweating, hypogammaglobulinemia.

From the side of cardiovascular system: pericarditis, pericardial effusion, pericardial tamponade, reduction of blood pressure, thromboembolism (including arterial thrombosis, thrombosis of cerebral vessels, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism).

From the nervous system: often — headache, feeling of tiredness, drowsiness and sometimes dizziness, feeling of confusion, depression very rare — pain, muscle weakness or paresthesia of the limbs, disturbance in taste (metallic taste), convulsions, meningism, paralysis.

From the side of organs of vision: conjunctivitis, rarely — visual impairment (including blindness).

From the side of respiratory system: often — interstitial alveolitis/pneumonia symptoms potentially serious interstitial pneumonia dry nonproductive cough, shortness of breath and fever, rarely pulmonary fibrosis, pulmonary Pneumocystis, pulmonary insufficiency and bronchial asthma.

With the hematopoietic system: often — leukopenia, anaemia (including aplastic), neutropenia, thrombocytopenia and sometimes pancytopenia is very rare — agranulocytosis, severe depression of bone marrow function.

Urogenital and urinary system: sometimes — inflammation and ulceration of the bladder or vagina, painful urination, hematuria, hyperuricemia, renal insufficiency is rarely severe renal failure, oliguria, anuria, azotemia, electrolyte imbalance is very rare vaginal discharge, loss of libido, impotence, oligospermia, menstrual irregularities, infertility.

From the side of musculoskeletal system: sometimes — artralgia, myalgia, osteoporosis, increased risk of fractures.

Tumors: rarely — reported sporadic cases of lymphomas. In a recent study it was found that methotrexate therapy increases the incidence of lymphomas.

The frequency and severity of side effects of MTX therapy depends on the dose and frequency of use. However, severe side effects can occur with the use of methotrexate in low doses, it is therefore imperative that patients who use methotrexate regularly at short intervals passed medical examination.

When using methotrexate/m may be a manifestation of local reactions: burning sensation at the injection site, formation of sterile abscess, destruction of fatty tissue.

Drug interactions:

Alcohol, hepatotoxic and gepatotoksicnae drugs. Regular consumption of alcohol and the use of concomitantly with methotrexate hepatotoxic drugs increase the risk of hepatotoxicity of methotrexate. For patients who use other hepatotoxic drugs (such as Leflunomide), a thorough observation. This also applies to cases of simultaneous appointment of drugs, oppressive blood that increases the risk of gematotoksichnosti methotrexate. When concomitant administration of Leflunomide and methotrexate increases the risk of pancytopenia and hepatotoxicity.

Antibiotics. Such antibiotics as the penicillins, glycopeptides, ciprofloxacin, cephalothin and sulfonamides in some cases, can reduce the excretion of methotrexate by the kidneys, which leads to an increase of its concentration in the plasma and, thus, the risk of manifestation of hematologic and gastrointestinal toxicity.

Probenecid, weak organic acids, drugs pirazolonovogo number and other NSAIDs. Probenecid, weak organic acids (such as loop diuretics), and drugs pirazolonovogo series (phenylbutazone) reduce the excretion of methotrexate and may increase its concentration in plasma and thus to an increase in hematological toxicity. The risk of increased toxicity occurs when the combination of methotrexate with NSAIDs or salicylates.

Concomitant use of salicylates, phenylbutazone, phenytoin, sulfonamides, sulfonylurea derivatives, aminobenzoic acid, pyrimethamine or trimethoprim, several antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and lipid-lowering drugs (cholestyramine) enhances the toxicity due to displacement of methotrexate from its Association with albumin and/or decrease tubular secretion, which in some cases may lead to the development of severe toxic effects, sometimes even fatal.

Medicines affecting bone marrow. In the case of the use of drugs can affect the bone marrow (including side effects) (e.g. sulfonamides, trimethoprim-sulfamethoxazole, chloramphenicol, pyrimethamine), it is necessary to consider the possibility of oppression of hematopoiesis.

Sulfasalazine. The combination of methotrexate with sulfasalazine may increase the efficacy of methotrexate and as a result, to increase the side effects associated with the inhibition of synthesis of folic acid with sulfasalazine. However, these side effects in several studies was observed only in some rare cases.

The proton pump inhibitors. When concomitant administration of proton pump inhibitors (omeprazole, pantoprazole) may change the excretion of methotrexate. Concurrent use of methotrexate and omeprazole prolongs the elimination of methotrexate. There was one reported case of reduction of excretion of metabolite of methotrexate is 7-hydroxymethotrexate, accompanied by myalgia and shivering.

Caffeine and thefilestream drinks. During treatment with methotrexate should avoid drinking large quantities of caffeine and thefilestream drinks (coffee, caffeinated beverages, tea).

Drugs that can cause folate deficiency. The simultaneous appointment of these drugs (e.g. sulfonamides, trimethoprim-sulfamethoxazole) may increase the toxicity of methotrexate. It is therefore advisable to be particularly careful in the appointment of such drugs to prevent the development of folic acid deficiency.

Voltagewise drugs (including multivitamins) to reduce the toxic effect of methotrexate on the bone marrow.

Methotrexate increases the anticoagulant activity of coumarin derivatives or indandiona and/or increases the risk of haemorrhage due to the reduction of liver synthesis of procoagulant factors and abnormalities in formation of platelets.

Increases the concentration of uric acid in the blood, so in the treatment of patients with concomitant hyperuricemia and gout may require dose adjustment protivopodagricescie drugs (allopurinol, colchicine, sulfinpirazon).

Anesthesia using dinitrogen oxide can lead to severe unpredictable myelosuppression and stomatitis.

Decreases the clearance of theophylline.

Several patients with psoriasis treated with methotrexate in combination with PUVA therapy (methoxsalen and UFO), was identified skin cancer.

Pharmaceutical incompatibility

Compatibility with other drugs administered parenterally, have not been studied. It is recommended not to mix Metoject with other drugs and solvents.

Method of application and dose:

P/to, in/m or/V.

Part of the packing needle for injection intended only for p/to the introduction of Metoject. For injection I/m and I/need to use suitable for these methods of insertion of the needle.

The drug is used 1 time in a week.

The total duration of treatment determined by the physician.

The agent should be appointed doctor, with experience in the use of methotrexate and familiar with the properties of the drug and the characteristics of his actions.

Adult patients with rheumatoid arthritis: the recommended initial dose of 7.5 mg of methotrexate once a week 1 a/m, in/in or n/a. depending on the severity of the disease and tolerability of methotrexate for patients the dose may be gradually increased (by 2.5 mg per week). The maximum dose should not exceed 25 mg in a week. Response to treatment usually occurs within 4-8 weeks after the start of treatment. After achieving the desired response should be to start reducing the dose to the lowest effective maintenance dose. In each case, the duration of therapy is determined by your 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 is recommended to introduce a parenteral test dose of 5-10 mg of methotrexate to identify the reactions of intolerance.

The recommended initial dose of 7.5 mg of methotrexate once a week 1 a/m, in/in or n/a. the Dose should be gradually increased, the maximum dose in most cases should not exceed 25 mg of methotrexate per week, but in any case should not exceed 30 mg per week. Response to treatment usually occurs within 2-6 weeks after beginning treatment. After achieving the desired response, the dose should be reduced to the lowest effective maintenance dose.

Patients with renal insufficiency: Metoject should be used with caution. The dose depending on creatinine clearance values should be adjusted in accordance with the following table:

Creatinine Cl, ml/min	Dose of methotrexate (% of normal dose)
>50	100%
20–50	50%
<20	The use of Metoject contraindicated

Patients with hepatic impairment: patients with severe liver disease currently or in history, especially caused by the intake of alcohol, Metoject should be used with great caution. When the level of bilirubin >5 mg/DL (85.5 µmol/l), methotrexate is contraindicated.

Elderly patients: use with caution, often require dose adjustment downward for age-related decline in liver function and kidney, as well as reducing the supply of folate in the body.

Children under 16 years polyarthrite form of juvenile chronic arthritis: the recommended dose of methotrexate 10-15 mg/m2 body surface per week. The lack of effectiveness of treatment, the dose may be increased up to 20 mg/m2 of body surface per week. Because of data limitations on p/to and/in the use in children the drug in juvenile arthritis should be used.

Notes

In the transition from the use of methotrexate inside to parenteral method of introduction may require a lower dose due to differences in the bioavailability of the drug with the different methods of application.

In appointing the drug should be considered simultaneous administration of folic acid in accordance with existing standards of care.

Overdose:

Symptoms: toxic effects of methotrexate is mainly manifested on the part of the hemopoietic system.

Treatment: introduction of a specific antidote — sodium folinate or folinate of calcium (preferably immediately) to neutralize the toxic effect of methotrexate.

In case of accidental overdose — in the first hour after administration of methotrexate should be injected in/in or/m dose of sodium folinate or folinate of calcium equal to or exceeding dose of methotrexate. Further, as necessary, the introduction of sodium folinate or folinate of calcium should be continued until the level of methotrexate in the serum is below 10-7 mol/L.

In case of significant overdose to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules conduct hydration and alkalinization of urine, which accelerates the excretion of methotrexate. Hemodialysis and peritoneal dialysis do not accelerate the excretion of methotrexate. It was reported about the effectiveness of intermittent (periodic) hemodialysis using high speed machine dialysis.

Special instructions:

Patients should be clearly informed that the drug should be used 1 time per week, not daily.

Methotrexate is cytotoxic, so in dealing with him be careful.

Methotrexate affects fertility function is embryo-, fetotoxic and teratogenic drug. Shows mutagenic activity in vivo and in vitro. The study of Carcinogenicity in rodents showed no increase in the frequency of tumors with use of methotrexate.

For passing the therapy Metoject patients should be proper monitoring so that signs of possible toxic effects or adverse reactions were detected and evaluated with minimal delay.

Metoject should be administered only by a physician with sufficient knowledge and experience of antimetabolites therapy.

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

Recommended examinations and safety measures

Before the start or resumption of treatment with methotrexate: must be made a full General blood analysis with determination of platelet count biochemical blood analysis with determination of the values of liver enzymes, bilirubin, serum albumin x-ray examination of chest, examination of renal function. If necessary, tests for tuberculosis and hepatitis.

During treatment (at least 1 time per month in the first 6 months of treatment, then — at least 1 time in 3 months) should be:

1. Examination of the oral mucosa and throat.

2. Full General blood analysis with determination of the platelet count. Suppression of hematopoiesis caused by methotrexate may occur abruptly, including when using the drug in small doses. In case of a significant reduction in the number of white blood cells or platelets must immediately stop treatment with methotrexate and to carry out adequate maintenance therapy. Patients should be advised to report any signs and symptoms of possible infections. Patients simultaneously applying gepatotoksicnae medications (e.g. Leflunomide) should be observed with monitoring of blood counts and platelet count.

3. The liver function tests: particular attention should be given to identify possible toxic effects on the liver. The treatment should not be started or should be aborted when detected in the course of carrying out relevant tests or biopsy of liver dysfunction, were present before treatment or developed in the course of treatment. Usually the violations that have developed in the course of treatment, come back to normal within 2 weeks after interruption of methotrexate therapy, and then at the discretion of the attending physician treatment can be resumed.

With the use of methotrexate in rheumatologic indications, there is no apparent need for liver biopsy to monitor hepatic toxicity.

Special attention should be given to patients with risk factors such as excessive alcohol consumption, steady increase in the level of liver enzymes, liver diseases in anamnesis, diabetes mellitus, obesity, use of hepatotoxic drugs or drugs acting on hemopoiesis in history.

Control of "liver" enzymes in serum: 13-20% of patients reported a transient 2-3-fold excess of normal transaminases. In the case of a steady increase in the level of "liver enzymes" should be considered for dose reduction or discontinuation of treatment.

Due to the toxic effects of the drug on the liver during treatment of patients, except in cases of obvious need, should refrain from the simultaneous use of other hepatotoxic drugs should also avoid or significantly reduce the use of alcohol.

In patients who use other hepatotoxic or hematotoxic drugs (such as Leflunomide), should carefully monitor the level of "liver" enzymes.

4. Control of renal function and urine analysis.

Because methotrexate displayed in the kidney, in case of insufficiency of kidney function should be expected to increase the level of methotrexate in the plasma, which can lead to serious unwanted side effects.

In cases of possible decrease in renal function (e.g. elderly patients) control tests should be performed more often. That also applies to cases of simultaneous appointment of drugs that affect the excretion of methotrexate, drugs that can lead to damage to the kidneys (such as NSAIDs), and medications can affect the hematopoietic system.

Dehydration can also enhance the toxicity of methotrexate.

5. Examination of the respiratory system.

Special attention should be paid to symptoms of deterioration of lung function, in case of need should be carried out relevant tests. Symptoms of the respiratory system (particularly dry nonproductive cough), nonspecific pneumonitis occurring during methotrexate therapy may indicate a potentially dangerous disease and require interruption of treatment and careful screening for diagnosis. Clinical symptoms caused by the use of methotrexate lung lesions varied, but typical symptoms are fever, cough, shortness of breath, hypoxemia. X-ray examination of the chest is mandatory to exclude the presence of infiltration or infection.

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

In the case of increasing the dose of methotrexate frequency of surveys needs to be increased!

Methotrexate affects the immune system and may impair the response to vaccination and affect the results of immunological tests. Special care is required in cases of use of the drug in patients with chronic infectious diseases outside the periods of exacerbation (Herpes zoster, tuberculosis, hepatitis b or C) due to the possibility of aggravation of the disease.

Need a waiver of immunization.

The interval between 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 immune status of the patient).

With the development of diarrhea and ulcerative stomatitis methotrexate treatment should be terminated.

Should not be exposed to unprotected skin too long sun exposure or abuse lamp UFO (possible reaction of photosensitivity).

Combination with radiotherapy may increase the risk of bone marrow suppression.

Of the patients who take low-dose methotrexate, may occur of malignant lymphoma in these cases, treatment should be discontinued. In the absence of spontaneous regression of lymphoma is necessary to conduct cytotoxic therapy.

With the use of methotrexate may develop osteonecrosis and osteoporosis (&ge1/1000, <1/100, section "Side effects"), which increases the risk of fractures.

Because methotrexate is able to exert influence on the Central nervous system (fatigue, dizziness), patients using the drug should refrain from driving and using machinery.

Storage conditions:

Do not freeze.