Methotrex, 10 mg/ml 3 ml

.

Indications

Rheumatoid arthritis in adults;

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

The severe form of psoriasis in adult patients, especially as plaques, when standard therapy, including phototherapy, PUVA therapy and retinoid use, has failed;

the severe form of psoriatic arthritis in adult patients.

Active ingredient

Composition

For 1 ml of the drug:

the active ingredient: methotrexate dinatrium 10.97 mg in terms of methotrexate 10.00 mg;

auxiliary components:

Sodium chloride, 7.00 mg;

2 M sodium hydroxide solution, 1.76 mg (22 µl);

/p>

1 M sodium hydroxide solution – to pH = 8.5 ± 0.1;

water for injection – up to 1.00 ml.

How to take, the dosage

Medtorgrig is administered subcutaneously, intramuscularly or intravenously. The injection needle included in the package is intended only for subcutaneous administration of Medtorgrig. To administer the drug intramuscularly or intravenously, needles suitable for these routes of administration must be used.

Dosages

Methotrex should only be prescribed by physicians who are familiar with the various properties of the drug and its mode of action. Metotrite is given as an injection once a week. It needs to be clearly explained to the patient that for the treatment of rheumatic diseases, Medortritis should only be used once a week.

Inappropriate use of methotrexate can lead to adverse events, including death.

Adult patients with rheumatoid arthritis:

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

The initial recommended dose is 7.5 mg of methotrexate once weekly, given either subcutaneously or intramuscularly or intravenously. Depending on the individual manifestation of the disease and the patient’s tolerance to therapy, the initial dose may be gradually increased by 2.5 mg per week. The dose of 25 mg per week should not be exceeded.

Doses in excess of 20 mg per week may be associated with a significant increase in toxicity, particularly bone marrow suppression. Response to treatment usually occurs in 4-8 weeks.

After achieving the desired therapeutic response, the dose should be gradually reduced to the lowest effective maintenance dose.

Children and adolescents with the polyarthritic form of juvenile idiopathic arthritis (JIA):

The recommended dose is 10-15 mg/m2 body surface area (BSA)/week. If treatment is not effective enough, the weekly dose may be increased to 20 mg/m2 body surface area/week.

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

Because of limited data regarding intravenous use in children and adolescents, parenteral use is limited to subcutaneous and intramuscular administration.

Patients with JIA should always go to specialized departments experienced in treating children/adolescents.

The use in children aged < 3 years is not recommended due to insufficient data regarding safety and effectiveness in this patient group.

Adult patients with severe forms of psoriasis or psoriatic arthritis:

Parenteral administration of a trial dose of 5 to 10 mg one week before therapy is recommended to detect idiosyncratic adverse reactions.

The initial recommended dose is 7.5 mg of methotrexate once a week, given either subcutaneously, intramuscularly, or intravenously. The dose should be gradually increased as needed, but the maximum weekly dose of 30 mg of methotrexate should not be exceeded.

The response to treatment usually occurs 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:

Methodritis should be used with caution in patients with renal impairment.

Doses should be adjusted as follows:

Clearance

Drug dose

creatinine

(% of normal

(ml/min)

doses)

<20

Application

Metarthritis

contraindicated

Patients with liver failure:

When absolutely necessary, methotrexate should be used with caution in patients with active or history of liver disease, particularly those associated with alcohol abuse. Methotrexate is contraindicated if bilirubin concentrations are greater than 5 mg/dL (85.5 µmol/L).

Elderly patients

We should consider reducing doses in elderly patients due to age-related decline in liver and kidney function and decrease in folate reserves.

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

Since the half-life of Methotrexate can be prolonged by 4 times the normal value, patients who have additional volume of distribution may need to reduce the dose or, in some cases, discontinue methotrexate.

Method of administration and duration:

Methotrexate, a solution for injection, can be given subcutaneously, intramuscularly, or intravenously.

In adults, intravenous administration should be done bolus.

The treatment of rheumatoid polyarthritis, juvenile idiopathic arthritis, severe psoriasis, and psoriatic arthritis with Medtortrin is usually long-term.

The total duration of treatment is determined by the physician.

The pre-filled syringe of Métortritis is for single use only.

Unused medication must be disposed of.

The injection solution must be visually checked before

use. Only a clear solution, almost particle-free, should be used.

The drug may be administered independently by the physician’s decision. In this case, the patient must be trained by medical personnel in the technique of subcutaneous injections before using the drug. The first self-administration of the drug by the patient must be done in the presence of a physician.

Interaction

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

In combination therapy with methotrexate and leflunomide, the incidence of pancytopenia and hepatotoxic effects increases.

The oral antibiotics (tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics) may decrease gastrointestinal absorption of methotrexate and interfere with enterohepatic circulation due to inhibition of gut microflora or inhibition of bacterial metabolism.

Penicillins, ciprofloxacin. cephalothin, glycopeptides may decrease renal clearance of methotrexate, which may increase its serum concentrations and increase toxic effects on the hematopoietic system and the GI tract.

Probenecid, weak organic acids (e.g., “loop” diuretics) and pyrazoles (phenylbutazone) may delay elimination of methotrexate, which may increase its serum concentrations and hematologic toxicity.

The risk of toxic effects of methotrexate increases in case of combined use with NSAIDs or salicylates (renal tubular excretion of methotrexate may decrease, caution should be exercised when combining nonsteroidal anti-inflammatory drugs with methotrexate).

When concomitant therapy with drugs that may have adverse effects on bone marrow (e.g., sulfonamides. trimethoprim/sulfamethoxazole, chlorampheicol, pyrimethamide), the possibility of more pronounced hematologic disorders must be considered.

In concomitant therapy with drugs that cause folate deficiency (e.g., trimethoprim/sulfamethoxazole), the toxic effects of methotrexate may be increased.

The concomitant use of indirect anticoagulants and hypolipidemic drugs (cholestyramine) increases the toxicity of methotrexate.

In combined use of antirheumatic drugs (e.g., gold salts, penicillamine, hydroxychloroquine, azathioprine, cyclosporime) and methotrexate the toxic effect of the latter is not increased. In case of concomitant use of sulfasalazine and methotrexate the effect of the latter may be potentiated due to inhibition of folic acid synthesis.

When methotrexate and proton pump inhibitors (e.g., omeprazole or pantoprazole) are used together, renal elimination of methotrexate may be delayed, and pantoprazole may inhibit renal elimination of the 7-hydroxymethotrexate metabolite, which in one case was accompanied by development of myalgia and tremor.

An excessive consumption of beverages containing caffeine and theophylline (coffee, sweet beverages containing caffeine, black tea) should be avoided during treatment with methotrexate. Methotrexate decreases theophylline clearance.

The pharmacokinetic interaction between methotrexate and flucloxacillin and anticonvulsants must be taken into account (decreases methotrexate concentration in blood), 5-fluorouracil (increases half-life of 5-fluorouracil).

In case of co-administration with other cytostatics methotrexate clearance may decrease.

The concomitant use of vitamin preparations or oral iron preparations containing folic acid may weaken the response to therapy and reduce the toxic effects of methotrexate on bone marrow.

Mixed solutions of methotrexate with chlorpromazine hydrochloride, droperidol, idarubicin, metoclopramide hydrochloride, heparin, prednisolone sodium phosphate and promethazine hydrochloride may precipitate or cloud the solution.

The use of drugs with additional hematotoxic effects (e.g., methamisole) increases the likelihood of serious hematotoxic effects of methotrexate.

Special Instructions

If a patient presents with significant pleural fluid or ascites, the fluid should be evacuated by drainage before starting methotrexate therapy, or methotrexate should be discontinued.

The onset of toxic digestive symptoms, the earliest of which are stomatitis and diarrhea, requires temporary discontinuation of methotrexate therapy due to the high risk of hemorrhagic enteritis and fatal intestinal perforation if therapy is continued. Patients should be closely monitored during treatment with methotrexate to detect signs of possible toxicity and adverse effects. Given the risk of severe or even fatal toxic reactions, patients should be informed in detail about possible complications and recommended precautions.

Before starting treatment with methotrexate or when resuming therapy after a break, a clinical blood count with leukocyte count and platelet count, assessment of liver enzymes activity, bilirubin concentration, serum albumin concentration, as well as chest radiography and functional renal tests should be performed.

In case of clinical indications, studies are prescribed in order to exclude tuberculosis and hepatitis.

In the course of treatment with methotrexate (monthly for the first 6 months and at least every 3 months thereafter, and with increasing doses it is reasonable to increase the frequency of examinations) the following examinations are performed:

1. Oral and throat examinations to detect mucosal changes.

2. blood tests with determination of the white blood cell count and platelet count.

Even when used at normal therapeutic doses, methotrexate can suddenly cause suppression of the hematopoietic system. If the number of white blood cells or platelets decreases significantly, treatment with methotrexate is stopped immediately and symptomatic supportive therapy is indicated.

Patients should be instructed to immediately inform the physician of any signs and symptoms suggestive of infection. If concomitant therapy with hematotoxic drugs (e.g., leflunomide), the number of white blood cells and platelets in the blood should be monitored closely.

A bone marrow biopsy may be appropriate during long-term treatment with methotrexate, if necessary.

3. Functional “liver” tests.

Particular attention should be paid to detect signs of liver damage. Treatment with methotrexate should not be started or should be suspended if any abnormal results of liver function tests or liver biopsies are found.

The values usually normalize within two weeks, after which treatment may be resumed at the discretion of the physician.

In 13 to 20% of patients, a transient 2 to 3-fold increase in “hepatic” enzyme activity has been seen. A persistent increase in the activity of “liver” enzymes and/or a decrease in serum albumin concentrations may be indicative of severe hepatotoxicity.

The enzyme diagnosis does not in all cases provide adequate prediction of the development of hepatotoxicity detected morphologically, even in cases of normal values of activity of “hepatic” enzymes histopathologically may reveal liver fibrosis, or, much less frequently, liver cirrhosis.

When methotrexate is used for rheumatologic indications, there is no reason to perform a liver biopsy to monitor the hepatotoxic effects of the drug.

When treating psoriasis patients, the appropriateness of performing a liver biopsy before or during methotrexate treatment should be evaluated based on current scientific guidelines. If no evidence of hepatotoxicity is found with biochemical measures of liver function or type III collagen propeptide concentration, additional studies may be necessary.

. This evaluation should differentiate between patients without risk factors and those at risk (e.g., those with a history of alcohol abuse, persistent elevated liver enzymes, a history of liver disease, a family history of hereditary liver disease, diabetics, obese patients, and those previously taking hepatotoxic medications or exposed to hepatotoxic chemicals and receiving long-term methotrexate treatment at total doses of 1.5 g or greater).

In case of persistent increase in the activity of “liver” enzymes it is necessary to reduce doses or discontinue treatment with methotrexate.

Because methotrexate has toxic effects on the liver, other hepatotoxic drugs should not be prescribed without a clear need during treatment with the drug.

Alcohol consumption should also be avoided or greatly reduced. Particular care should be taken to monitor the activity of “liver” enzymes in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, with leflunomide).

Particular caution should be exercised when treating patients with insulin-dependent diabetes mellitus, since cases of cirrhosis have been described with prior periodic elevation of “liver” enzyme activity.

4. functional renal tests and urinalysis.

If serum creatinine concentration increases, the dose of methotrexate should be reduced. If creatinine concentration exceeds 2 mg/dL, use of methotrexate is contraindicated.

Since methotrexate is mainly excreted by the kidneys, patients with impaired renal function may experience elevated blood concentrations of methotrexate, which may lead to serious adverse reactions. The condition of patients with possible renal dysfunction (e.g., elderly patients) should be monitored closely.

This is particularly important in case of concomitant therapy with drugs which decrease methotrexate excretion, have adverse effects on the kidneys (particularly NSAIDs) or on the hematopoietic system. Concomitant administration of non-steroidal anti-inflammatory drugs is not recommended if there are risk factors, such as renal insufficiency.

Dehydration may also potentiate the toxic effects of methotrexate.

5. Investigation of respiratory function

. Symptoms of possible pulmonary dysfunction should be closely monitored and pulmonary function studies should be ordered if necessary.

Pulmonary disease requires prompt diagnosis and withdrawal of methotrexate. If symptoms occur during treatment with methotrexate (particularly a dry, non-productive cough) or nonspecific pneumonitis may indicate a potential risk of lung disease. In such cases, methotrexate should be withdrawn and the patient should be carefully evaluated.

While the clinical picture may vary, the typical patient with methotrexate-induced lung disease presents with elevated body temperature, cough with shortness of breath, hypoxemia, and pulmonary infiltrates on x-rays. In the differential diagnosis, infectious diseases should be excluded. Pulmonary involvement may occur with treatment with methotrexate in any dose.

When treated with methotrexate, opportunistic infections may develop, including pneumonia caused by Pneumocystis carinii, which can be fatal. If the patient has symptoms of lung damage, pneumonia caused by Pneumocystis carinii should be excluded.

We recommend caution when treating patients with pulmonary insufficiency.

6 Because methotrexate affects the immune system, it may alter the response to vaccination and affect immunological test results.

Particular caution is needed when treating patients with inactive, chronic infections (such as shingles, tuberculosis, hepatitis B or C) because of their possible activation. Vaccination with live vaccines should not be performed during treatment with methotrexate.

It is recommended that treatment with methotrexate be stopped one week before surgery and restarted one or two weeks after surgery.

The elimination of methotrexate is significantly delayed if body temperature increases (over 38°C).

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

Pregnancy should be excluded before treatment with Methotrexate. Methotrexate has embryotoxic effects, it promotes abortion and formation of fetal abnormalities.

Methotrexate therapy is accompanied by inhibition of spermatogenesis and ovogenesis, which may lead to decreased fertility. These effects spontaneously regress after discontinuation of methotrexate therapy. During the treatment with methotrexate and for 6 months after its termination the patients are recommended to use contraceptive measures.

Patients of reproductive age as well as their partners should be informed about the possible effects of methotrexate on fertility and fetal development.

In high-dose therapy, precipitation of methotrexate or its metabolites in the renal tubules is possible. In these cases, to prevent this complication, infusion therapy and alkalinization of urine to pH 6.5-7.0 by oral or intravenous administration of sodium bicarbonate (5 tablets of 625 mg every 3 hours) or acetazolamide (500 mg orally 4 times daily) is recommended.

Methotrexate must not be mixed with other medications in the same infusion bag or bottle.

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

A precautions should be taken to prevent contact of methotrexate solution with the skin and mucous membranes. If the drug does come into contact with the skin or mucous membranes, the affected area should be immediately rinsed with copious amounts of water.

Contraindications

Hypersensitivity to methotrexate and/or any other drug component;

Side effects

According to the WHO classification, adverse effects are classified according to their frequency of occurrence as follows: Very common (≥1/10), common (≥1/100 to <1/10), infrequent (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000); frequency unknown-no data were available to determine the incidence.

Disorders of the cardiovascular system.

Infrequent: vasculitis (as acute toxic symptoms).

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

Disorders of the blood and lymphatic system:

Often: leukopenia, thrombocytopenia, anemia.

Infrequent: pancytopenia, agranulocytosis, hematopoietic disorders.

Rare: megaloblastic anemia.

Very rare: severe suppression of bone marrow function, aplastic anemia, enlarged lymph nodes, lymphoproliferative disorders (partially reversible), eosinophilia, neutropenia.

The first signs of these complications, which are life-threatening, are fever, sore throat, mouth ulcers, flu-like symptoms, nosebleeds, and skin hemorrhages. Use of methotrexate should be stopped immediately if blood cell counts decrease significantly.

Disorders of the immune system:

Infrequent: allergic reactions, anaphylactic shock, immunosuppression.

Infectious and parasitic diseases:

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

Frequency unknown: cases of nocardiasis, histoplasmosis and cryptococcal fungal infections, disseminated form of herpes simplex have been reported.

Nervous system disorders:

Often: headache, increased fatigue, drowsiness.

Infrequently: depression, confusion, dizziness, seizures.

Rare: change in mood.

Very rare: pain, muscle weakness or paresthesia in the extremities, taste disturbance (metallic taste), acute aseptic meningitis with meningism (paralysis, vomiting), insomnia.

Prevalence unknown: ringing in the ears.

Visual disorders:

Rarely: severe visual disturbances.

Very rare: conjunctivitis, retinopathy.

Benign, malignant and unspecified neoplasms:

Infrequent: isolated cases of lymphoma, which

regress when treatment with methotrexate is discontinued. In a recent clinical trial, methotrexate therapy was not found to increase the incidence of lymphoma.

Disorders of the respiratory system, thorax and mediastinum:

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

If these complications are suspected, methotrexate is stopped immediately and infections (including pneumonia) are ruled out.

Infrequent: pulmonary fibrosis.

Rare: pharyngitis, apnea, bronchial asthma, dyspnea and abnormal results of instrumental pulmonary function tests.

Very rare: pneumonia caused by Pneumocystis carinii and other lung infections, difficulty in breathing, chronic obstructive pulmonary disease, pleural effusion.

Gastrointestinal disorders:

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

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

Infrequent: ulcers and bleeding of the gastrointestinal tract.

Rare: enteritis, melena, gingivitis, malabsorption syndrome.

very rarely: vomiting with blood, toxic megacolon.

Liver and biliary tract disorders:

very often: increased activity of “liver” enzymes (ALT, ACT), increased activity of alkaline phosphatase, increased concentration of bilirubin.

Infrequent: hepatic steatosis, hepatic fibrosis, cirrhosis (can occur even if normal values of “hepatic” transaminases are regularly monitored).

Rare: acute hepatitis and hepatotoxicity.

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

Skin and subcutaneous tissue disorders:

Often: exanthema, erythema, skin itching.

Infrequent: Urticaria, photosensitization, increased skin pigmentation, hair loss, abnormal wound healing, enlarged rheumatic nodules, shingles, painful psoriatic plaque eruptions (exacerbation of plaque psoriasis may occur with UV therapy and concurrent use of methotrexate), severe toxic reactions, vasculitis, allergic vasculitis, herpetiform skin rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

Rarely: changes in nail pigmentation, onycholisis, petechiae, ecchymosis, erythema multiforme, erythematous skin rash.

very rarely: acute paronychia, furunculosis, telangiectasia, hydradenitis.

Muscular and connective tissue disorders:

Infrequent: arthralgia, myalgia, osteoporosis.

Rarely: stress fractures, osteonecrosis.

Rare: Renal and urinary tract disorders:

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

hematuria), dysuria (urinary disorders).

Rarely: renal failure, oliguria, anuria, azotemia.

very rarely: proteinuria.

Rarely: vaginitis (vaginal inflammation)

Rarely: oligospermia, menstrual disorders.

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

Frequency unknown: disruption of oogenesis and spermatogenesis, teratogenic effects.

Disorders of the endocrine system:

Frequency unknown: diabetes mellitus, metabolic disorders.

General disorders and disorders at the site of administration:

Infrequent: with intramuscular injection of methotrexate, burning or tissue damage (formation of sterile abscesses, destruction of fatty deposits) at the injection site.

Very rare: fever. Usually, when injected subcutaneously, methotrexate is well tolerated; only mild local reactions have been reported so far, which decreased during treatment.

Laboratory and instrumental findings:

Infrequent: Decreased serum albumin concentration, hypogammaglobulinemia. Frequency and severity of adverse reactions depend on the dose and frequency of administration.

Because serious adverse reactions can also occur at low doses, it is extremely important that patients be evaluated by a physician regularly and at short intervals.

Overdose

Symptoms: the most common symptoms are associated with depression of the hematopoietic system.

Treatment: a specific antidote to methotrexate is calcium folinate. It neutralizes the adverse toxic effects.

In case of accidental overdose no later than one hour after methotrexate administration, calcium folinate is administered (IV or IV/m) in a dose equal to or greater than the dose of methotrexate. Calcium folinate administration is continued until methotrexate serum concentrations fall below 10-7 mmol/L.

In case of significant overdose, rehydration of the body and alkalization of urine (pH greater than 7) may be required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Hemodialysis and peritoneal dialysis do not improve methotrexate elimination.

Intensive intermittent hemodialysis using high-permeability (“high-flux”) dialyzers can provide effective clearance of methotrexate.

Pregnancy use

Pregnancy

Methotrexate is contraindicated during pregnancy.

Methotrexate administration during pregnancy can cause serious fetal malformations (14-fold increase in the incidence of malformations of the skull, cardiovascular system and limbs).

If you become pregnant while being treated with methotrexate, you should consult 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 treatment with Methotrexate.

Breastfeeding

Methotrexate penetrates into breast milk in concentrations that are harmful to the infant. Therefore, breastfeeding should be stopped during treatment with methotrexate.

Similarities