Description
Latin name
METOJECT
Release form
Injection.
Packaging
In a syringe of colorless glass 2.5 ml. In the blister 1 syringe of colorless glass complete with a needle for and. In a cardboard bundle 1 blister.
Pharmacological action
Pharmacodynamics
Immunosuppressant, antitumor drug, antimetabolite, folic acid antagonist. Competitively inhibits the enzyme dihydrofolate reductase, involved in the reduction of dihydrofolic acid to tetrahydrofolic acid (a carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives). It inhibits the synthesis, DNA repair and cell mitosis.
Rapidly proliferating cells are especially sensitive to the action of methotrexate: cells of malignant tumors, bone marrow, embryonic cells, epithelial cells of the mucous membranes. Along with antitumor, it has an immunosuppressive effect.
It remains unclear what causes the effectiveness of methotrexate in the treatment of psoriasis, psoriatic arthritis and rheumatoid arthritis (including juvenile chronic arthritis): its anti-inflammatory or immunosuppressive effects. Also not established the extent to which the effectiveness of therapy is explained by the increase in extracellular concentration of adenosine caused by methotrexate at the sites of inflammation.
With psoriasis, the formation of skin epithelial cells is significantly accelerated compared to normal. The use of methotrexate can slow the formation of skin epithelial cells, which justifies the use of the drug for the treatment of psoriasis.
Pharmacokinetics
Distribution of
Plasma protein binding is approximately 50%.
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 retained for several weeks or even months.
When used in small doses, it penetrates into the cerebrospinal fluid only in minimal amounts.
Metabolism
About 10% of the administered dose is metabolized in the liver, the main metabolite – 7-hydroxymethotrexate, also has some pharmacological activity. About 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate are excreted in the bile (with subsequent reabsorption in the intestine).
The elimination of
T1 / 2 averages 6 7 hours and is characterized by high variability (3 17 hours).
It is excreted mainly unchanged by the kidneys by glomerular filtration and tubular secretion. About 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate are excreted in the bile (with subsequent reabsorption in the intestine).
Pharmacokinetics in special clinical cases
T1 / 2 may increase to 4 times the average values in patients with additional volume of distribution (presence of pleural effusion, ascites).
Withdrawal of the drug in patients with impaired renal function is significantly slowed down. There is no evidence of a slowdown in the excretion of methotrexate with insufficient liver function.
Indications
Rheumatoid arthritis in adults
polyarthritis in patients with severe juvenile chronic arthritis in the active form
severe generalized forms of psoriasis and psoriatic arthritis in adults with standard therapy ineffective.
Contraindications
Severe hepatic impairment
alcoholism
severe renal failure (CC less than 20 ml / min)
history of hematopoiesis such as bone marrow hypoplasia, leukopenia, severe thrombocytopenia, acute like tuberculosis, HIV infection
ulcerative lesions of the oral cavity
ulcerative lesions of the digestive tract in the active phase
severe immunodeficiency
pregnancy
lactation (breastfeeding Ia)
simultaneous vaccination with live vaccines
hypersensitivity to the drug.
Caution: the drug should be used in patients with ascites, dehydration, obstructive diseases of the gastrointestinal tract, pleural or peritoneal effusion, with chronic renal failure in case of parasitic and infectious diseases of a viral, fungal or bacterial nature (currently or recently transferred, including recent contact with the patient) – herpes simplex, herpes zoster in the viremic phase, chickenpox , measles, amoebiasis, strongyloidiasis identified or suspected (risk of developing a severe generalized disease) with gout (including a history) or urate nephrourolithiasis (including . in the anamnesis), infection and inflammation of the oral mucosa, with vomiting and diarrhea (fluid loss due to severe vomiting and diarrhea can lead to increased toxicity of methotrexate), gastric ulcer and duodenal ulcer, ulcerative colitis, with previous chemo- or radiation therapy , asthenia, in elderly patients.
Use during pregnancy and lactation
The method is contraindicated during pregnancy and during breastfeeding.
Methotrexate affects fertile function, is an embryo-fetotoxic and teratogenic drug. When used in humans, methotrexate exhibits teratogenic properties, is capable of causing fetal death, congenital malformations.
Limited use in pregnant women (42) has led to an increase in the frequency (1:14) of malformations (cranial, cardiovascular, limbs). In cases of interruption of methotrexate therapy before fertilization, a normal course of pregnancy was observed.
Patients of childbearing age of both sexes and their partners should use reliable contraceptive measures during treatment with methotrexate and for at least 6 months after its completion.
If pregnancy occurs during methotrexate therapy, the risk of adverse effects on the fetus should be assessed.
Methotrexate is excreted in breast milk in amounts that are dangerous for the baby, so before starting treatment with methotrexate, breastfeeding should be discontinued and refrain from it during the entire course of treatment.
Composition
1 ml (1 syringe) contains:
Active substances: disodium methotrexate 10.96 mg (27.4 mg), which corresponds to the content of methotrexate 10 mg (25 mg).
Excipients: sodium chloride, sodium hydroxide, water d / and.
Dosage and administration
Metodzhekt prescribed s / c, in / m or in / in.
The injection needle included in the package is intended only for the administration of the Metoject. To administer the drug IM and IV it is necessary to use needles suitable for these methods of administration.
The drug is used 1 time per week. The doctor determines the total duration of treatment individually.
The drug should be prescribed by a doctor who has experience in the use of methotrexate and knowledge of the properties of the drug and the features of its action.
For rheumatoid arthritis for adults, the recommended starting dose is 7.5 mg once / week. in / m, in / in or s / c. Depending on the severity of the disease and the tolerance of methotrexate, the dose can be gradually increased – 2.5 mg / week. The maximum dose is 25 mg / week. The therapeutic effect usually develops 4-8 weeks after the start of the drug. After achieving the optimal therapeutic effect, a dose reduction should begin to the lowest effective maintenance dose. The duration of drug therapy may exceed 10 years.
In case of psoriasis and psoriatic arthritis a week before the start of treatment, it is recommended to administer a parenteral test dose of 5-10 mg methotrexate to detect intolerance reactions. The recommended starting dose is 7.5 mg 1 time / week. in / m, in / in or s / c. The dose should be gradually increased. In most cases, a dose of 25 mg / week should not be exceeded, but in any case, the maximum dose is 30 mg / week. The therapeutic effect usually develops 2-6 weeks after the start of the drug. After reaching the desired response, the dose should be reduced to the lowest effective maintenance dose.
In patients with renal failure, Metoject should be used with caution. The dose adjustment of the drug depending on the QC value is given in the table.
QC (ml / min)
Dose (% of normal dose)
> 50
100%
20-50
50%
<20 Use of the Matoject is contraindicated in Patients with hepatic insufficiency: in patients with severe liver disease at present or in the anamnesis, especially caused by alcohol intake, the Method should be used with great care. At a bilirubin concentration> 5 mg / dl (85.5 μmol / L), methotrexate is contraindicated.
In elderly patients, Metoject should be used with caution, it is often necessary to adjust the dose downward due to an age-related decrease in liver and kidney function, as well as a decrease in the supply of folate in the body.
For children under 16 years of age with a polyarthritic form of juvenile chronic arthritis, the recommended dose of methotrexate is 10-15 mg / m2 of body surface per week. With insufficient treatment effectiveness, the dose can be increased up to 20 mg / m2 / week. Due to the limited data on SC and IV administration in children, the drug for juvenile arthritis should be used IM.
When switching from taking methotrexate orally to parenteral administration, a dose reduction may be required due to differences in the bioavailability of the drug for different uses.
During treatment with MethodJect, consideration should be given to the simultaneous administration of folic acid preparations in accordance with existing treatment standards.
Side effects
The most common side effects when using Metoject are reactions from the hematopoietic system and the digestive system.
Determination of the frequency of side effects: very often ( 1/10)
often ( 1/100, <1/10) sometimes ( 1/1000, <1/100) rarely ( 1/10 000, < 1/1000) is very rare (<1/10 000). From the digestive system: very often – stomatitis, dyspepsia, nausea, loss of appetite, increased activity of transaminases often – oral ulcers, diarrhea sometimes – enteritis, vomiting, cirrhosis, fibrosis and fatty degeneration of the liver, hepatotoxicity (acute hepatitis, liver failure ) rarely – erosive and ulcerative lesions of the gastrointestinal tract is very rare – vomiting with an admixture of blood, bleeding from the gastrointestinal tract (including melena, hematomesis) is possible – pancreatitis. From the hemopoietic system: often – leukopenia, anemia (including aplastic), neutropenia, thrombocytopenia sometimes – pancytopenia is very rare – agranulocytosis, severe inhibition of bone marrow function. Dermatological reactions: often – exanthema, erythema, dermatitis, skin itching sometimes – photosensitivity, baldness, enlargement of rheumatic nodes, vasculitis, Herpes zoster infections, herpetiform skin rashes, urticaria rarely – increased pigmentation very rarely – changes in nail pigmentation, acute paronychia, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome). In the treatment of psoriasis – a burning sensation of the skin, rarely – painful erosive plaques on the skin. Allergic reactions: various manifestations up to anaphylactic shock, allergic vasculitis, fever. From the cardiovascular system: pericarditis, pericardial effusion, pericardial tamponade, decreased blood pressure, thromboembolism (including arterial thrombosis, cerebral vascular thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism). From the side of the central nervous system and peripheral nervous system: often – headache, feeling tired, drowsiness sometimes – dizziness, feeling confused, depression very rarely – pain, muscle weakness or paresthesia of the extremities, violation of taste sensations (metallic taste), cramps, meningism, paralysis. From the endocrine system: possibly diabetes mellitus. On the part of the sensory organs: conjunctivitis is very rare – visual impairment, (including transient blindness) is possible – ringing in the ears. On the part of the respiratory system: often – interstitial alveolitis / pneumonia, symptoms of potentially serious interstitial pneumonia (dry unproductive cough, shortness of breath and fever) sometimes – pharyngitis rarely – pulmonary fibrosis, pulmonary pneumocystosis, pulmonary insufficiency and bronchial asthma possibly – pleural effusion, nosebleed . From the urinary system: sometimes – inflammation and peptic ulcer of the bladder, painful urination, hematuria, hyperuricemia, renal failure rarely – severe renal failure, oliguria, anuria, azotemia. From the reproductive system: less often – inflammation and ulcerative lesions of the vagina are very rare – vaginal discharge, loss of sex drive, impotence, oligospermia, menstrual irregularities, infertility. From the musculoskeletal system: rarely – arthralgia, myalgia, osteoporosis, osteonecrosis, an increased risk of fractures is possible – soft tissue necrosis. From the side of metabolism: excessive sweating, hypogammaglobulinemia rarely – electrolyte imbalance. Infections: possibly – life-threatening opportunistic infections (including pneumocystis pneumonia), cytomegalovirus infections (CMV) (including CMV pneumonia), sepsis (including fatal), nocardiosis, histoplasmosis, cryptococcosis, infections caused by Herpes zoster and Herpes simplex (including disseminated), worsening wound healing. Neoplasms: in some cases – the occurrence of lymphomas. A recent study did not find that methotrexate therapy increases the incidence of lymphomas. Local reactions: when using the / m introduction – a burning sensation at the injection site, the formation of an aseptic abscess, the destruction of fatty tissue. The frequency and severity of side effects of methotrexate treatment depends on the dose and frequency of use. However, severe side effects can occur with the use of methotrexate in low doses, so it is necessary that patients receiving methotrexate regularly underwent medical examination at short intervals. Drug Interaction Regular use of alcohol and the use of hepatotoxic drugs together with methotrexate increase the risk of methotrexate hepatotoxicity. Patients using other hepatotoxic agents (eg, leflunomide) should be closely monitored. This also applies to cases of simultaneous administration of drugs, suppress hematopoiesis, which increases the risk of hematotoxicity of methotrexate. The concomitant administration of leflunomide and methotrexate increases the risk of pancytopenia and hepatotoxicity. Antibiotics such as penicillins, glycopeptides, ciprofloxacin, cephalothin, as well as sulfanilamides in some cases may reduce the excretion of methotrexate by the kidneys, leading to an increase in plasma concentrations and, thus, a risk of hematologic and gastric toxicity. Probenecid, weak organic acids (such as loop diuretics) and pyrazolone series drugs (phenylbutazone) reduce the excretion of methotrexate and may increase its plasma concentration and thus increase hematologic toxicity. The risk of increased toxicity occurs with the combination of methotrexate with NSAIDs (since renal excretion of methotrexate may be reduced) or salicylates. These combinations require caution. Odnovremenn y pryem salicylates, phenylbutazone, fenytoyna, sulfonamides, proyzvodn h sulfonylmochevyn , amynobenzoynoy acid, pyrimethamine or trimethoprim, rjada antibiotics (penicillin, tetracycline, chloramphenicol) nepryam h antykoahulyantov and lipid-lowering funds (kolestyramyn) usylyvaet toxicity at the expense v tesnenyya methotrexate IZ connection with albumin and / or reduction of tubular secretion, which in some cases may lead to the development of severe toxic effects, sometimes even with death. In the case of the use of drugs capable of affecting the bone marrow (incl. as a side effect) (eg, sulfonamides, trimethoprim, sulfamethoxazole, chloramphenicol, pyrimethamine) the possibility of hematopoiesis suppression should be considered. The combination of methotrexate with sulfasalazine may increase the effectiveness of methotrexate and, as a result, enhance the side effects associated with the inhibition of folic acid synthesis by sulfasalazine. However, such side effects have been observed in rare cases in a number of studies. With the simultaneous administration of proton pump inhibitors (omeprazole, pantoprazole), methotrexate excretion may be altered. Concomitant use of methotrexate and omeprazole increases the withdrawal time of methotrexate. One case of a decrease in the excretion of methotrexate metabolite 7-hydroxymethotrexate was reported, which was accompanied by myalgia and yeast. During treatment with methotrexate, large amounts of caffeine-containing (including coffee, tea) and theophylline-containing beverages should be avoided. Methotrexate reduces the clearance of theophylline. Concurrent administration of drugs capable of inhibiting bone marrow (eg, sulfonamides, trimethoprim, sulfamethoxazole) may lead to increased toxicity of methotrexate. Therefore, it is recommended that special care be taken when prescribing such drugs to avoid the development of folic acid deficiency. Folate-containing medicines (including multivitamins) reduce the toxic effect of methotrexate on the bone marrow. Methotrexate increases the anticoagulant activity of coumarin or indandione derivatives and / or increases the risk of bleeding by reducing synthesis of procoagulant factors in the liver and impaired platelet formation. In the treatment of patients with concomitant hyperuricemia and gout, dose adjustment of antipagotric agents (allopurinol, colchicine, sulfinpyrazone) may be required. Anesthesia using dinitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis. Skin cancer has been identified in several patients with psoriasis receiving methotrexate in combination with PUVA therapy (methoxaline and ultraviolet radiation). Methotrexate may reduce the immune response to vaccination, therefore, the interval between methotrexate administration and the administration of live and inactivated viral vaccines should be at least 3 months, possibly up to 12 months (depending on the patient’s immune status). Pharmaceutical Incompatibility Compatibility with other parenteral medicinal products has not been studied. Do not mix Metodect with other medicines and solvents. Overdose Symptoms: the toxic effect of methotrexate is mainly manifested by the hematopoietic system. Treatment: administration of a specific antidote, a formulation of folinic acid (if possible immediately) to neutralize the toxic effect of methotrexate. In case of accidental overdose – within the first hour after administration of methotrexate, a specific antidote – a preparation of folinic acid – should be given in / in or in / m at a dose equal to or greater than the dose of methotrexate. Further, as necessary, the administration of folinic acid preparations should be continued until the serum methotrexate concentration is below 10-7 mol / l. In the event of a significant overdose to prevent the precipitation of methotrexate and / or its metabolites in the kidney tubules, the body hydrates and alkalizes the urine, which speeds up the excretion of methotrexate. Hemodialysis and peritoneal dialysis do not accelerate the excretion of methotrexate. The effectiveness of intermittent (periodic) hemodialysis using a high-speed dialysis apparatus has been reported. Storage conditions Keep out of the reach of children, in a dry, dark place at a temperature not exceeding 25 ° C. Do not freeze. Expiration 2 years. Dosage Form A dosage form injection Onkotek Pharma Production GmbH, Germany
