Methotrexate-Ebeve, 10 mg/ml 1 ml

Pharmacodynamics

Antitumor, cytostatic agent of the group of antimetabolites – analogues of folic acid with immunosuppressive and anti-inflammatory effect.

Inhibits dihydrofolate reductase, participating in the reduction of dihydrofolic acid to tetrahydrofolic acid (carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives). Inhibits synthesis, DNA repair and cellular mitosis (in the synthesis phase). Tissues with high cell proliferation are especially sensitive to the action of methotrexate: tumor tissue, bone marrow, mucosal epithelial cells, embryonic cells. When the cell proliferation of malignant tissue is greater than in most normal tissue, methotrexate can lead to disruption of malignant growth without irreversible damage to normal tissue.

. The mechanism of action in rheumatoid arthritis is associated with the immunomodulatory and anti-inflammatory effects of the drug and is due to the induction of apoptosis of rapidly proliferating cells (activated T-lymphocytes, fibroblasts, synoviocytes), inhibition of anti-inflammatory cytokine synthesis (interleukin (IL)-1, tumor necrosis factor alpha), enhancement of anti-inflammatory cytokine synthesis IL-4, IL-10 and suppression of metalloproteinases activity.

In patients with rheumatoid arthritis, methotrexate reduces symptoms of inflammation (pain, swelling, stiffness), but there are limited studies on the long-term use of methotrexate (regarding the ability to maintain remission in rheumatoid arthritis). The growth rate of keratinocytes in psoriatic plaques is increased in psoriasis compared to normal skin cell proliferation. This difference in cell proliferation is the basis for the use of methotrexate to treat psoriasis.

Pharmacokinetics

In intramuscular administration, the maximum plasma concentration of methotrexate is reached within 30-60 minutes. A wide interindividual variability ranging from 1 to 3 hours is characteristic of leukemic patients. Relative bioavailability in patients with rheumatoid arthritis is comparable after intramuscular or subcutaneous injection when using the same doses of the drug. Systemic absorption of methotrexate after injection under the skin of the abdomen and thigh is the same.

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

About 50% of methotrexate is bound to plasma proteins, mainly to albumin. Competitive displacement is possible in concomitant use with sulfonamides, salicylates, tetracyclines, chloramphenicol, phenytoin.

Methotrexate does not penetrate the blood-brain barrier when used in therapeutic doses. High concentration of methotrexate in the central nervous system can be achieved by intrathecal administration.

Methotrexate undergoes hepatic and intracellular metabolism to form the pharmacologically active polyglutamine form, which also inhibits dihydrofolate reductase and thymidine synthesis. A small amount of polyglutamate methotrexate can remain in tissues for a long period of time. Retention and prolongation of the action of active metabolites of the drug vary depending on the type of cells, tissues and tumors.

The average half-life of methotrexate at doses less than 30 mg/m2 is 6-7 hours. In patients receiving high doses of methotrexate, the half-life is 8 to 17 h. In chronic renal failure both phases of methotrexate excretion may be significantly prolonged.

80 to 90% of the dose taken is eliminated unchanged by glomerular filtration and tubular secretion within 24 hours. With the bile not more than 10% or less of the administered dose is excreted with subsequent reabsorption in the intestine.

Disordered renal function, marked ascites or transudate, as well as concomitant use of drugs such as weak organic acids, which also undergo tubular secretion, can significantly increase the serum concentration of methotrexate. According to the distribution, methotrexate cumulates in the liver, kidney and spleen as polyglutamates and can be retained in these organs for weeks or months.

In children In children treated with methotrexate for acute lympholeukemia (6.3 to 30 mg/m²) or juvenile idiopathic arthritis (3.75 to 26.2 mg/m²), the final half-life was 0.7 to 5.8 hours and 0.9 to 2.3 hours, respectively.

Indications

Active ingredient

Composition

active ingredient:

Methotrexate – 10,000 mg;

excipients:

Sodium hydroxide – 1.783 mg,

Sodium chloride – 6.900 mg,

Injection water – 988.317 mg.

How to take, the dosage

Methotrexate is part of many chemotherapy regimens, and therefore the route of administration, regimen, and dosage should be guided by the literature in each individual case.

Methotrexate-Ebeve in the dosage form of solution for injection can be administered intramuscularly, subcutaneously, intravenously, intra-arterially, or intrathecally.
Doses of the drug over 100 mg/m2 are administered only by intravenous drip! The solution is pre-diluted with 5% dextrose solution. When using high doses of the drug (more than 100 mg/m2), subsequent administration of calcium folinate is obligatory.

Methotrexate for therapy of rheumatic diseases or skin diseases should be used only once a week!
Improper use of methotrexate can lead to serious adverse effects, including death.

The following dosing regimens are used:

Trophoblastic tumors:
15-30 mg intramuscularly, daily for 5 days at one or more weekly intervals (depending on signs of toxicity). Or 50 mg once every 5 days at intervals of at least 1 month. Treatment courses are usually repeated 3 to 5 times up to a total dose of 300-400 mg. Solid tumors: in combination with other antitumor drugs, 30-40 mg/m2 intravenously by IV stream once a week.

Leukemia and lymphoma: 200-500 mg/m2 by intravenous infusion once every 2-4 weeks.

Neuroleukemia: 12 mg/m2 intrathecally for 15-30 seconds once or twice a week.

When treating children, the dose is adjusted according to the age of the child: children under 1 year of age are prescribed 6 mg, children 1 year of age 8 mg, children 2 years of age 10 mg, children 3 years and older 12 mg. Before administration, the cerebrospinal fluid should be removed in an amount approximately equal to the volume of the drug to be injected. For intrathecal administration methotrexate is diluted to a concentration of 1 mg/ml in 0.9% isotonic sodium chloride solution. Intrathecal administration should be administered with caution.

Exceeding the recommended dose when administered intrathecally greatly increases the risk of marked toxicity.
Caution: calcium folinate must not be administered intrathecally!

Fungal mycosis: intramuscularly 50 mg once weekly or 25 mg twice weekly for several weeks or months. Dose reduction or discontinuation of the drug is determined by the patient’s response and hematologic parameters.

Dermatomyositis: adults 7.5-15 mg weekly; children 2.5-7.5 mg weekly. Subsequently, the dose is reduced until the lowest effective dose is achieved and is used for a long time, for months, in combination with a maintenance dose of glucocorticosteroids.

Systemic lupus erythematosus: adults 15 mg weekly; children 7.5-10 mg/m2. The course of treatment is 6-8 weeks, then a maintenance dose is used for many months.

Psoriasis and psoriatic arthritis: one week before treatment, a parenteral test dose of 5-10 mg of methotrexate is recommended to detect intolerance reactions.
The recommended initial dose is 7.5 mg of methotrexate once a week intramuscularly, intravenously or subcutaneously. The dose should be gradually increased, with the maximum dose not exceeding 30 mg of methotrexate per week. Response to treatment usually occurs 2-6 weeks after the start of the drug. When optimal clinical effect is achieved, dose reduction is started until the lowest effective dose is achieved.

Rheumatoid arthritis: The starting dose is usually 7.5 mg once a week, administered once daily intravenously, intramuscularly, or subcutaneously. For optimal effect, the weekly dose may be gradually increased (2.5 mg per week) and should not exceed 20 mg. When optimal clinical effect is achieved (usually 4-8 weeks after the start of therapy), dose reduction should be initiated until the lowest effective maintenance dose is achieved.
The optimal duration of therapy has not been established; in each individual case, the duration of therapy is determined by the physician.

Juvenile chronic arthritis: in children under 16 years of age at a dose of 10-20 mg/m2 once a week. Usually an effective dose is 10-15 mg/m2 per week. Initially, the drug is used in a half dose. If tolerated well, a full dose is administered after one week. In children and adolescents, if parenteral administration of the drug is necessary, subcutaneous or intramuscular route of administration should be used due to the fact that available data on safety of intravenous administration are limited. Due to the limited data on efficacy and safety of methotrexate administration in children younger than 3 years, it is not recommended to use the drug in this group of patients. When using methotrexate in children as immunosuppressive therapy (in psoriasis, rheumatoid arthritis, juvenile chronic arthritis, dermatomyositis and systemic lupus erythematosus) the benefit/risk ratio of use should be carefully considered.

Method of administration by syringe (prefilled)
Subcutaneously.
The injection needle included in the package is for subcutaneous administration of Methotrexate-Ebeve only.
The pre-filled syringe is equipped with a special automatic needle protection system.

Choose where to inject the medication. When applying subcutaneously, choose a place where you can grab a 2-3 cm fold of skin, usually in the abdomen or thighs as shown. If you have someone to help you, it is possible to inject in the forearm. If the intended place of injection is the abdominal area, you need to step back at least 3 finger widths from the navel. It is recommended to alternate sides (left, right) of the injection, as well as to choose different locations on the hips or abdomen.
Do not inject subcutaneously near scars, bruises, red or swollen areas, or close to the groin.
In order to minimize bruising, it is recommended to avoid injecting into skin with a net of small blood vessels visible on the surface. Remove the inner pack containing the pre-filled syringe and needle. Open the inner package by pulling the notched corner. Remove the syringe.

Remove the gray rubber cap from the syringe without touching the exposed inner part of the syringe. Place the syringe back into the inner pack without fear that the yellow solution might leak.

Make sure the protective label is intact.
Remove the cap, attach the needle without removing the protective cover, and secure the needle to the syringe.
Before using the syringe, the intended injection site should be disinfected in advance.

Pull on the cap (at a right angle) to remove it. Do not touch the protective sheath of the needle. Using two fingers to form a skin fold, quickly insert the needle fully into the skin (at about a 90-degree angle) until the safety mechanism is completely retracted inside. Slowly inject the contents of the syringe under the skin. Gently pull the needle out, after which it will automatically retract inside the syringe.

If you notice blood at the injection site after removing the needle, place a cotton swab over the injection site until the blood or medicine has absorbed. A small amount of bleeding or bleeding medication will stop shortly. If necessary, apply a bandage. Do not rub the injection site.

If the skin at the injection site turns yellow, don’t worry, within a day or two the drug will be absorbed and the skin color will return to normal. This could be due to an improperly performed subcutaneous injection or an insufficient length of the needle.

Patients with impaired renal function need to have the dose adjusted depending on creatinine clearance (if creatinine clearance is 30-50 ml/min, the dose is reduced by 50%; if creatinine clearance is less than 30 ml/min, methotrexate is contraindicated).

In patients with impaired liver function, Methotrexate-Ebeve is used with caution. Methotrexate should not be used with plasma bilirubin concentrations greater than 5 mg/dL (85.5 µmol/L).

Elderly patients (over 65 years of age) may need lower doses of methotrexate because liver and kidney function worsens with age, and folate levels decrease.

Interaction

The likelihood of hepatotoxic effects of methotrexate increases in case of regular use of ethanol and concomitant use of other hepatotoxic drugs (e.g., azathioprine, leflunomide, sulfasalazine, retinoids). When combined therapy with methotrexate and leflunomide, the incidence of pancytopenia and hepatotoxic effects increases.

Penicillins, ciprofloxacin, cephalothin, glycopeptides may decrease renal clearance of methotrexate and therefore its concentration in plasma may increase and toxic effect on hematopoiesis and gastrointestinal system may be increased.

Probenecid, weak organic acids (e.g., loop diuretics) and pyrazoles (phenylbutazone) may delay elimination of methotrexate, which may increase its plasma concentration and hematological toxicity.

The risk of toxic effects of methotrexate increases in case of combined use with nonsteroidal anti-inflammatory drugs or salicylates, especially in patients with impaired renal function. If concomitant use is necessary, peripheral blood count (count of blood cells) and renal function should be monitored.

When concomitant therapy with drugs that may have adverse effects on bone marrow (e.g., sulfonamides, trimethoprim/sulfamethoxazole, chloramphenicol, pyrimethamine), the possibility of more pronounced hematological disorders should be considered. The development of pancytopenia has been described when using methotrexate in combination with co-trimoxazole or pyrimethamine.

When 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 (colestyramine) increases the toxicity of methotrexate.

Increases the concentration of uric acid in the blood, so when treating patients with concomitant hyperuricemia and gout it may be necessary to adjust the dose of antipodagric agents (allopurinol, colchicine, sulfinpyrazone); use of uricosuric antipodagric drugs may increase the risk of nephropathy associated with increased uric acid formation with methotrexate treatment (allopurinol is preferable if concomitant use is necessary).

In combined use of antirheumatic drugs (e.g., gold salts, penicillamine, hydroxychloroquine, azathioprine, cyclosporine) 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 concomitantly, renal elimination of methotrexate may be delayed, and pantoprazole may inhibit renal elimination of the 7-hydroxymethotrexate metabolite, which in one case was followed by 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 antiepileptic drugs must be taken into account (decreases methotrexate concentration in blood), fluorouracil (increases fluorouracil elimination half-life).

In case of combined use with other cytostatics methotrexate clearance may decrease.

Drugs and other products containing folic acid or folinic acid (including multivitamins) may decrease the effectiveness of therapy with the drug (while reducing the toxic effects of methotrexate).

Due to competitive binding to plasma proteins during concomitant use of methotrexate toxicity of methotrexate may be increased with the use of amidopyrine derivatives, para-aminobenzoic acid, barbiturates, doxorubicin, oral contraceptives, phenylbutazone, phenytoin, probenecid, salicylates, sulfonamides, tetracyclines and tranquilizers.

A few patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (methoxalen and ultraviolet irradiation) have been diagnosed with skin cancer.

Combination with radiation therapy may increase the risk of soft tissue necrosis.

Methotrexate may decrease the immunological response to vaccination. Severe antigenic reactions may develop if used concomitantly with live vaccine. Asparaginase reduces the anti-tumor effect of methotrexate by inhibiting cell replication.

The administration of anesthesia with dinitrogen oxide may lead to the development of unpredictable severe myelosuppression and stomatitis.

Amiodarone may contribute to skin ulceration.

The concomitant use of mercaptopurine and methotrexate increases the plasma concentration and bioavailability of the former, probably due to inhibition of its metabolism. Dose adjustment of mercaptopurine may be required with concomitant therapy.

Outerine neomycin may decrease the absorption of methotrexate for oral administration.

The use of colestyramine may interfere with hepatic-intestinal recirculation of methotrexate, increasing the elimination of the drug.

Drugs that can cause folate deficiency (sulfonamides, trimethoprim/sulfamethoxazole) in the body or decrease tubular secretion (ciprofloxacin, paraminobenzoic acid, non-steroidal anti-inflammatory drugs, probenecid, salicylates, sulfonamides, weak organic acids) may increase the myelosuppressive effect of methotrexate.

The combined use of methotrexate and glucocorticosteroids may provoke disseminated herpetic infection and development of post-herpetic neuralgia.

With coadministration of cytarabine there is an increased risk of adverse events in the nervous system, including headache, paralysis, coma, stroke-like episodes.

Prescribing procarbazine while using high doses of methotrexate increases the risk of impaired renal function.

Special Instructions

The drug Methotrexate-Ebeve is a cytotoxic drug, so care must be taken when handling it. The drug should be prescribed by a physician experienced in the use of methotrexate and familiar with its properties and characteristics of action. Before prescribing methotrexate, make sure that the plasma concentration of the drug can be determined.

With consideration of the possibility of severe toxic reactions, including death, the physician must inform the patient in detail about the possible risk and the necessary precautions. Methotrexate, especially in medium and high doses, should be used only in patients with potentially life-threatening malignancies. Cases of fatal manifestations of toxicity against the background of therapy with the drug have been described. Withdrawal of methotrexate does not always lead to complete resolution of adverse events.

The safety and potential benefits of high doses of methotrexate outside of the approved indications have not been established.

Patients should be closely monitored during treatment with Methotrexate-Ebeve to detect signs of possible toxicity and adverse effects in a timely manner. When using the drug for non-oncologic indications, special attention should be given to the patient that the drug is not taken daily, but once a week.

Before initiating treatment with Methotrexate-Ebeve or during resumption of therapy after a pause, it is necessary to perform a clinical blood test with leukocyte count and platelet count, assess liver transaminase activity, bilirubin and plasma albumin concentration, plasma uric acid concentration, renal function (urea nitrogen, creatinine clearance and/or plasma creatinine) as well as chest X-ray examination. If clinically indicated, studies to rule out tuberculosis and viral hepatitis are prescribed.

The administration of high doses of methotrexate is possible only if creatinine plasma concentrations are normal. If elevated creatinine concentration is noted, the dose of the drug should be decreased; if creatinine concentration is more than 2 mg/dL, the drug should not be used.

Leukopenia and thrombocytopenia usually develop within 4 to 14 days after methotrexate administration. Sometimes a second leukopenic phase developing within 12 to 21 days is noted.

In elderly patients, development of megaloblastic anemia on prolonged therapy with methotrexate has been described.

In the course of treatment with Methotrexate-Ebeve (monthly in the first 6 months and at least every 3 months thereafter, it is reasonable to increase the frequency of tests when increasing the doses) the following tests are performed:

1. Oral and pharyngeal exams to detect mucosal changes.

2. blood tests with determination of the white blood cell count and platelet count.Even when used in normal therapeutic doses, methotrexate can suddenly cause suppression of hematopoiesis. In case of a significant decrease in the number of white blood cells or platelets, treatment with Methotrexate-Ebeve is stopped immediately and symptomatic supportive therapy is prescribed. Patients should be instructed to immediately inform the physician of any signs and symptoms suggestive of an infection. If concomitant or previous therapy with hematotoxic drugs (e.g., leflunomide) or radiation therapy has been performed, the number of leukocytes and platelets in the blood should be monitored closely. If necessary, a bone marrow biopsy may be appropriate.

3. functional liver function tests. Against the background of prolonged use of methotrexate it is possible to develop acute hepatitis and phenomena of chronic hepatotoxicity (liver fibrosis and cirrhosis). Particular attention should be paid to detection of signs of liver damage. Methotrexate-Ebeve treatment should not be started or should be suspended in case of detection of abnormal results of liver function tests or liver biopsy. During the drug therapy, a 2-3-fold transient increase in liver transaminase activity is possible, which is usually asymptomatic. As a rule, this is not a reason to change the treatment regimen, usually the values are normalized within two weeks, after which the treatment can be resumed by the doctor’s decision. However, in case of detection of persistent increase in liver transaminases it is necessary to decrease the dose or cancel treatment with Methotrexate-Ebeve. Since Methotrexate-Ebeve has toxic effect on liver, other hepatotoxic preparations should not be used during treatment with this medicine without a clear necessity. Ethanol consumption should also be avoided or greatly reduced. The activity of “liver” enzymes should be monitored particularly carefully in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, with leflunomide).

In case of prolonged treatment, especially severe forms of psoriasis, including psoriatic arthritis, due to possible hepatotoxic effects of methotrexate, given that fibrotic and/or cirrhotic changes may develop against normal liver samples, liver biopsy is necessary in the following cases:
1. In patients without risk factors before reaching a cumulative cumulative dose of 1.0-1.5 g, liver biopsy is not indicated.
2. against the background of the presence of risk factors such as alcohol abuse, persistent increase in “liver” transaminase activity, chronic viral hepatitis, family history of liver disease, and for patients with less significant risk factors such as diabetes, obesity, history of exposure to hepatotoxic drugs/chemicals, liver biopsy should be performed 2-4 months after starting treatment. After reaching a cumulative cumulative dose of 1.0-1.5 g, a repeat liver biopsy is recommended.

Liver biopsy is not indicated in elderly patients; in patients with active acute diseases (e.g., respiratory system); in patients with contraindications to liver biopsy (e.g., unstable hemodynamics, changed coagulogram parameters); in patients with unfavorable prognosis with respect to longevity. If the liver biopsy shows only mild changes (grade I, II, or IIIa on Roenigk scale), continuation of methotrexate therapy is possible with close monitoring of the patient.

The medication should be withdrawn if moderate to severe changes are present (Roenigk grade IIIb and IV), or if a liver biopsy is refused if there is a persistent elevation of hepatic transaminases. Methotrexate should be withdrawn if moderate fibrosis or cirrhosis is detected, and a repeat liver biopsy is recommended after 6 months if fibrosis is minimal. Changes such as fatty liver dystrophy or mild portal vein inflammation are common findings in liver biopsies in patients receiving methotrexate. Although the finding of these changes is generally not a reason to decide whether methotrexate therapy is inappropriate or to withdraw it, caution should be exercised when treating these patients.

4. renal function tests and urinalysis. Since Methotrexate-Ebeve is mainly excreted by the kidneys, patients with impaired renal function may experience elevated plasma concentrations of methotrexate, which may result in severe adverse reactions. It is necessary to carefully monitor the condition of patients who may have impaired renal function (e.g., elderly patients). This is especially important in case of concomitant therapy with drugs that reduce methotrexate excretion, have an adverse effect on the kidneys (in particular, nonsteroidal anti-inflammatory drugs (NSAIDs)) or on the hematopoietic system. There have been described cases of severe adverse effects in patients treated with NSAIDs with methotrexate (especially high doses), including severe suppression of medullary hematopoiesis, aplastic anemia, gastrointestinal damage and death.

5. examination of the respiratory system. The symptoms of possible pulmonary dysfunction should be closely monitored and, if necessary, appropriate investigations should be ordered to monitor pulmonary function. The occurrence of relevant symptoms during treatment with Methotrexate-Ebeve (especially dry, non-productive cough) or the development of nonspecific pneumonitis may indicate the potential danger of lung damage. In such cases, Methotrexate-Ebeve should be discontinued and the patient should be carefully evaluated.

While the clinical picture may vary, typical cases of respiratory symptoms caused by Methotrexate-Ebeve use include elevated body temperature, cough with shortness of breath, hypoxemia, and pulmonary infiltrates on x-rays. Lung damage caused by the use of methotrexate may occur regardless of the duration of use of the drug, the doses used (there are cases of lung damage when methotrexate is used in low doses, including 7.5 mg/week). Differential diagnosis should exclude the infectious nature of the disease. Against the background of methotrexate therapy potentially dangerous (up to fatal) opportunistic infections may develop, including pneumocystis pneumonia. In case of respiratory system symptoms in a patient receiving methotrexate, pneumonia caused by Pneumocystis carinii should be excluded.

In case of increasing the dose of the drug, the frequency of examinations should be increased.Because of the immunosuppressive effect of methotrexate, immunizations should be withheld (unless approved by a physician) during treatment with the drug and for 3 to 12 months after completion of therapy; family members living with the patient should refuse immunizations with oral polio vaccine (patients should avoid contact with people who have received polio vaccine, or wear a protective mask covering their nose and mouth).

If stomatitis or diarrhea, hemoptysis, melena, or blood in stools occur during methotrexate therapy, the drug should be stopped immediately because of the high risk of potentially fatal complications, such as hemorrhagic enteritis and perforation of the intestinal wall.

Symptoms such as fever, sore throat, flu-like symptoms, oral mucosal ulceration, marked generalized weakness, hemoptysis, and a hemorrhagic rash may be precursors to life-threatening complications.

If a patient is found to have conditions leading to significant fluid accumulation in the body cavities (hydrothorax, ascites), given the prolonged elimination half-life of the drug in such patients, therapy with Methotrexate-Ebeve should be performed with caution and the fluid should be evacuated by drainage before starting therapy with the drug or discontinue use.

Particular caution should be exercised when treating patients with insulin-dependent diabetes mellitus, as cases of cirrhosis without a previous increase in “hepatic” transaminase activity have been described.

Like other cytotoxic drugs, methotrexate can cause tumor lysis syndrome in patients with rapidly growing malignancies. Appropriate measures of supportive therapy should be taken to prevent the development of this complication. Methotrexate use in combination with radiation therapy may increase the risk of soft tissue necrosis or osteonecrosis.

Patients with prior radiation therapy as well as impaired general condition should be monitored particularly closely.

Dehydration may also potentiate the toxic effects of Methotrexate-Ebeve, so if conditions develop that may lead to dehydration (severe vomiting, diarrhea), therapy with methotrexate should be interrupted until these conditions resolve.

There have been cases of leukoencephalopathy in patients treated with high doses of methotrexate, including oral therapy in combination with calcium folinate (without prior radiation therapy to the head area).

When using methotrexate for acute lymph leukemia, pain may be noted in the left epigastric region due to inflammation of the spleen capsule with decay of tumor cells.

It is recommended that treatment with Methotrexate-Ebeve be interrupted one week before surgery and restarted one or two weeks after surgery. Special caution should be exercised when using methotrexate in patients with active infections. The use of methotrexate in patients with immunodeficiency syndrome is contraindicated.

The elimination of methotrexate is significantly delayed with elevated body temperature (over 38 °C). The drug Methotrexate-Ebeve may increase the risk of neoplasms (mainly lymphoma). Malignant lymphomas may also develop in patients receiving Methotrexate-Ebeve at low doses. In such cases the drug should be discontinued. If spontaneous regression of lymphoma is not observed, therapy with other cytotoxic drugs is prescribed.

Before treatment with Methotrexate-Ebeve, pregnancy should be excluded. The drug Methotrexate-Ebeve has embryotoxic effect and promotes pregnancy termination and formation of fetal abnormalities. Methotrexate-Ebeve therapy is accompanied by inhibition of spermatogenesis and ovogenesis, which may lead to reduced fertility. These effects spontaneously regress after cancellation of therapy. During the treatment with Methotrexate-Ebeve and for 6 months after its completion, patients are recommended to use contraceptive measures. Patients of reproductive age as well as their partners should be informed about the possible effect of Methotrexate-Ebeve on fertility and fetal development. Men of reproductive age should be warned of the risks involved, and parenthood is not recommended during treatment and for 6 months after discontinuation of the drug.

As irreversible infertility may develop during treatment, men should consider cryopreservation of sperm in a jar before starting treatment.

Methotrexate can increase the chance of dermatitis and skin burns from sunlight and ultraviolet (UV) exposure. Unprotected skin should not be exposed to prolonged exposure to sunlight or UV light (photosensitization may occur). Psoriasis patients may worsen with UV radiation during treatment with methotrexate.

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

An exacerbation of chronic viral hepatitis (reactivation of hepatitis B or C virus) is possible during therapy with methotrexate. There have also been described cases of hepatitis B virus reactivation after methotrexate withdrawal. If it is necessary to prescribe the drug to a patient with a history of viral hepatitis, a thorough clinical and laboratory examination should be performed. Presence of pleural effusion, ascites, GI disturbances, concomitant cisplatin therapy, dehydration, hepatic dysfunction or urine pH decrease slows down excretion of methotrexate, and as a result, increased plasma concentration of the drug may occur. It is extremely important to detect cumulation of the drug in the body during the first 48 hours, since irreversible effects of the drug toxicity may develop.

Particular caution should be exercised when using the drug in elderly patients, their condition should be monitored more frequently than in younger patients for early signs of therapy toxicity. Pediatric treatment protocols should be followed when treating pediatric patients.

Pediatric patients with acute lymphoblastic leukemia may develop severe neurotoxicity with medium (1 g/m2) doses of methotrexate, most commonly manifested clinically as a generalized or partial epileptic seizure. The development of leukoencephalopathy and/or microangiopathic calcinates during instrumental studies in such patients has been described.

When using high doses of methotrexate, the development of transient acute neurological symptoms has been described, which may be manifested, including behavioral changes, local sensory disturbances (including short-term blindness) and motor system, impaired reflexes. The exact causes of these adverse reactions are unknown.

When using methotrexate at a dose above 100 mg/m2, the use of calcium folinate “rescue therapy” 42-48 hours after methotrexate administration is mandatory.

The dose of calcium folinate is determined depending on the size of the applied dose of methotrexate and the duration of its infusion. Concentration of methotrexate should be determined after 24, 48 and 72 hours and, if necessary, for a long time to determine the optimal duration of calcium folinate therapy. Administration of methotrexate together with an infusion of red blood cell mass (for 24 h) requires close monitoring of the patient’s condition, because increased plasma concentration of the drug is possible.

Impact on driving, operating machinery

Because of the possibility of side effects such as drowsiness, headache and mental confusion, caution should be exercised when engaging in potentially dangerous activities requiring increased concentration and rapid psychomotor reactions. In case of occurrence of the described adverse effects, the above-mentioned activities should be avoided.

Special Precautions for Disposal of Unused Medications

Metotrexate-Ebeve drug residues, all instruments and materials used to prepare solutions for infusion must be disposed of in accordance with standard hospital procedures for disposal of cytotoxic waste, subject to current hazardous waste disposal regulations.

Contraindications

Side effects

According to the World Health Organization (WHO) adverse events are classified according to the frequency of their development as follows: very common (≥1/10), common (from ≥1/100 to Infectious and parasitic diseases
common: herpes zoster;
infrequent: opportunistic infections, including pneumonia (including fatal);
rare: sepsis (including, very rarely, fatal);
very rare: nocardiasis, histoplasmosis, cryptococcosis, hepatitis and disseminated infections caused by herpes simplex virus, infections caused by cytomegalovirus (including pneumonia);
frequency unknown: reactivation of hepatitis B virus, hepatitis C.

Benign, malignant and unspecified neoplasms (including cysts and polyps)
infrequent: lymphoma;
very rare: tumor lysis syndrome.

Disorders of the blood and lymphatic system
very common: leukopenia, thrombocytopenia;
frequent: anemia, pancytopenia, agranulocytosis;
rare: megaloblastic anemia;
very rare: aplastic anemia, lymphadenopathy and lymphoproliferative disease, eosinophilia, neutropenia, severe progressive suppression of bone marrow function.

Immune system disorders
infrequent: allergic reactions, anaphylactic shock, allergic vasculitis, increased body temperature, immunosuppression;
very rare: hypogammaglobulinemia.

Metabolic and nutritional disorders
infrequent: diabetes mellitus.

Psychiatric disorders
infrequent: depression;
rare: transient cognitive impairment, emotional lability. Nervous system disorders
often: headache, increased fatigue, somnolence, paresthesia;
infrequently: seizures, development of hemiparesis, vertigo (dizziness), confusion, encephalopathy/leukoencephalopathy (including fatal cases);
rare: paresis, speech disorders, including dysarthria and aphasia, myelopathy (with intrathecal administration);
very rare: discomfort in the head, myasthenia, pain in the extremities, perversion of taste (metallic taste in the mouth), acute aseptic meningitis with meningeal phenomena (paralysis, vomiting), insomnia;
frequency unknown: increased pressure in the spinal canal (after intrathecal administration), development of spinal hernia (after intrathecal administration for periventricular lymphoma).

Visual disorders
rare: visual disturbances (blurred vision, including severe visual disturbances of unclear etiology);
very rare: periorbital edema, blepharitis, lacrimation, photophobia, conjunctivitis, transient blindness, vision loss.

Cardiac disorders
rarely: arterial hypotension (decreased blood pressure);
very rarely: pericarditis, effusion into the pericardial cavity (including cardiac tamponade).

Vascular disorders
infrequent: vasculitis;
rare: thromboembolic complications (including arterial thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism).

Respiratory, thoracic and mediastinal disorders
often: interstitial pneumonitis/alveolitis (including fatal, regardless of the dose and duration of methotrexate therapy). Symptoms suggestive of potentially serious lung damage in interstitial pneumonitis: dry, unproductive cough, dyspnea progressing to dyspnea at rest, chest pain, and elevated body temperature.
If these symptoms occur, treatment with methotrexate should be stopped immediately, and lower respiratory tract infections should also be excluded.
infrequent: pulmonary fibrosis, pleural effusion;
rare: pharyngitis, apnea, nasal bleeding;
very rare: Chronic obstructive pulmonary disease (COPD), bronchial asthma-like reactions (accompanied by cough, shortness of breath, abnormalities in functional pulmonary tests), pneumonia caused by Pneumocystis carinii, acute pulmonary edema;
frequency unknown: respiratory paralysis.

Gastrointestinal tract disorders
very common: stomatitis, abdominal pain, loss of appetite, nausea and vomiting (especially during the first 24-48 hours after the start of treatment), dyspepsia;
frequent: diarrhea;
infrequent: Gastrointestinal tract (GIT) mucosal ulceration, GIT bleeding, pancreatitis;
rare: enteritis, gingivitis, melena, malabsorption syndrome;
very rare: hematemesis (bloody vomiting), toxic megacolon;
frequency unknown: noninfectious peritonitis.

Liver and biliary tract disorders
very often: increased activity of “hepatic” transaminases, alkaline phosphatase, increased concentration of bilirubin in blood plasma;
often: development of steatosis, fibrosis or cirrhosis of the liver, hypoalbuminemia;
rare: acute hepatitis and other manifestations of hepatotoxicity;
very rare: exacerbation of chronic hepatitis, acute liver dystrophy (including.acute hepatitis), acute liver failure, liver necrosis.

Skin and subcutaneous tissue disorders
often: exanthema, erythematous rash, itching of skin;
infrequently: alopecia, erythema multiforme (including malignant exudative erythema [Stevens-Johnson syndrome]), toxic epidermal necrolysis (Lyell syndrome), herpetiform skin rashes, photosensitivity, urticaria, increased skin pigmentation, delayed wound healing;
rare: acne, skin ulcers, ecchymoses, appearance of nodules on the skin, painful erosions, psoriatic plaques, nail pigmentation, onycholysis, increased size of rheumatoid nodules;
very rare: furunculosis, telangiectasia, acute paronychia, hydradenitis; frequency unknown: skin necrosis (in place of injection).
Against the background of methotrexate therapy it is possible to develop complications of psoriatic nodules due to exposure to ultraviolet radiation.

Skeletal-muscular system and connective tissue
infrequent: arthralgia, myalgia, osteoporosis;
rarely: march (fatigue) fracture.

Renal and urinary tract disorders
very common: decreased creatinine clearance;
infrequent: severe nephropathy, renal failure, cystitis with ulceration of bladder mucosa, dysuria (urinary disorders), oliguria, anuria;
rare: hyperuricemia, increased plasma urea concentration, increased plasma creatinine concentration;
very rare: azotemia, hematuria, proteinuria.

Influence on the course of pregnancy, postpartum and perinatal conditions
infrequent: abnormal fetal development;
rare: premature termination of pregnancy;
very rare: fetal death.

Genital and mammary disorders
infrequent: vaginitis and ulceration of the vaginal mucosa;
rare: menstrual disorders;
very rare: disorders of spermatogenesis or oocyte maturation, impotence, infertility, loss of libido, transient oligospermia, abnormal vaginal discharge, menstrual disorders, gynecomastia.

Indesirable reactions occurring during intrathecal administration of methotrexate:
acute chemical arachnoiditis (clinical manifestations include headache, dorsalgia, numbness in the neck and fever), subacute myelopathy (paresis or paraplegia in the innervation area of one or more affected spinal cord roots), chronic leukoencephalopathy, whose manifestations include confusion, increased irritability, somnolence, ataxia, dementia, seizures and development of coma. If progressive, these toxicities can lead to death.

The combined use of intrathecal injection of methotrexate and brain irradiation increases the risk of leukoencephalopathy. After intrathecal administration of the drug the patient’s condition should be closely monitored for possible signs of neurotoxicity (meningism, paralysis, encephalopathy).

Overdose

Symptoms: mainly symptoms associated with depression of the hematopoietic system are observed.
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 (intravenously or intramuscularly) 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, hydration of the body and alkalization of the 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-flux” dialyzers can provide effective clearance of methotrexate.

In case of overdose with intrathecal administration, repeated lumbar punctures should be performed immediately after an overdose is detected to ensure rapid drainage of cerebrospinal fluid, possibly neurosurgical intervention with ventriculolumbar perfusion. All these procedures should be performed against a background of intensive supportive therapy and systemic administration of high doses of calcium folinate.

Similarities