Methotrexate-Ebeve, 1 piece, 5 ml, 10 mg/ml, solution for injection

Methotrexate

Patients should be clearly informed that the drug should not be used daily, but once a week

.

Patients receiving Methotrexate therapy should be closely monitored to ensure that signs of potential toxicity and adverse reactions are identified and assessed promptly.

Methotrexate should only be prescribed by a medical specialist with sufficient knowledge and experience in antimetabolic therapy.

Due to the possible development of severe or even fatal adverse reactions, patients should be fully informed by their physician about the possible risks and recommended safety measures.

The use of the drug in children under 3 years of age is not recommended due to insufficient data on the effectiveness and safety of treatment in this group of patients.

Recommended examinations and safety measures

Before starting or resuming treatment with methotrexate

a detailed clinical blood test must be performed with a count of blood cells, including determination of the platelet count; biochemical blood test with determination of liver enzyme activity, bilirubin concentration, serum albumin; chest x-ray, kidney function test. If necessary, diagnostic measures are taken to assess the activity of tuberculosis infection and viral hepatitis.

During treatment (at least once a month in the first six months of treatment

,
then - at least once every three months)
it is necessary to carry out the studies described below.

If the dose of methotrexate is increased, the frequency of examinations should be increased.

1. Examination of the oral mucosa and pharynx to assess the condition of the mucous membrane (stomatitis, pharyngitis).

2. Detailed clinical blood test with counting of blood cells, including determination of platelet count. Suppression of hematopoiesis caused by methotrexate can occur suddenly, including when the drug is used in small doses. In any case of a significant decrease in the number of leukocytes or platelets, it is necessary to immediately interrupt treatment with methotrexate and carry out adequate supportive therapy. Patients should be advised to report any signs and symptoms of possible infections.

Patients concomitantly using drugs that inhibit hematopoiesis (for example, leflunomide) should be carefully monitored with monitoring of blood counts, including platelet counts.

3. Liver function tests: Particular attention should be paid to identifying possible toxic effects on the liver. Treatment should not be started or should be interrupted if, during appropriate examinations or liver biopsy, abnormal liver function is detected that was present before the start of treatment or developed during treatment. Typically, disorders that develop during treatment return to normal within two weeks after interruption of methotrexate therapy, after which, at the discretion of the attending physician, treatment can be resumed.

When methotrexate is used for rheumatological indications, there is no obvious need for liver biopsy to monitor liver toxicity.

The advisability of performing a liver biopsy in patients with psoriasis is associated with the issue of the effectiveness of routine chemical analyzes of liver parameters or studies of type III collagen propeptide for identifying and assessing hepatotoxicity. Appropriate assessment should be carried out individually for each case, differentiating patients depending on the presence or absence of risk factors, such as a history of excessive alcohol consumption, persistent elevation of liver enzymes, history of liver disease, hereditary predisposition to liver disease, diabetes mellitus, obesity, history of use of hepatotoxic drugs or drugs that affect hematopoiesis, long-term previous use of methotrexate, or use of methotrexate in a cumulative dose of 1.5 g or more.

Control of “liver” enzymes in the blood serum: in 13 - 20% of patients, a transient 2-3-fold excess of normal transaminase values ​​was reported. In the case of a persistent increase in liver enzyme activity, dose reduction or discontinuation of treatment should be considered.

Due to the possible toxic effects of the drug on the liver, patients during treatment with methotrexate, unless clearly necessary, should refrain from the simultaneous use of other hepatotoxic drugs; Alcohol consumption should also be avoided or at least significantly reduced.

In patients using other hepatotoxic drugs or drugs that inhibit hematopoiesis (for example, leflunomide), the activity of liver enzymes should be carefully monitored.

4. It is necessary to monitor kidney function by performing functional tests and urine analysis.

Since methotrexate is excreted primarily by the kidneys, in the case of insufficient renal function, an increase in the plasma concentration of methotrexate should be expected, which can lead to severe unwanted side effects.

In cases of possible decline in renal function (for example, in elderly patients), control examinations should be performed more frequently. This also applies to cases of simultaneous administration of drugs that affect the elimination of methotrexate, drugs that can lead to kidney damage (for example, NSAIDs), or drugs that can affect hematopoiesis.

Dehydration may also increase the toxicity of methotrexate.

5.Examination of the respiratory system: special attention should be paid to symptoms of deterioration of lung function, if necessary, appropriate tests should be carried out. Symptoms of respiratory system damage (especially dry nonproductive cough), nonspecific pneumonitis that occur during methotrexate therapy may indicate a potentially dangerous disease and require interruption of treatment and immediate thorough examination to make a diagnosis. Acute or chronic interstitial pneumonitis may develop, often accompanied by eosinophilia; associated deaths have been reported. Clinical symptoms of methotrexate-induced lung injury are varied, but typical signs are fever, cough, difficulty breathing, and hypoxemia. An X-ray examination of the chest is necessary to exclude the presence of infiltrates or infection.

In case of lung disease, rapid diagnosis and discontinuation of treatment are necessary.

The development of respiratory diseases caused by the use of methotrexate is possible at any dose of the drug used.

If the dose of methotrexate is increased, the frequency of examinations should be increased!

Methotrexate affects the immune system and, as a result, may impair the response to vaccination and affect the results of immunological tests. Particular caution is required when using the drug in patients with chronic infectious diseases outside of periods of exacerbation ( Herpes zoster

, tuberculosis, hepatitis B or C) due to the possibility of exacerbation of the disease.

Refusal from immunization is required.

Malignant lymphomas may occur in patients using low doses of methotrexate; in these cases, treatment should be discontinued. In the absence of signs of spontaneous regression of lymphoma, cytotoxic therapy is necessary. Rare cases of acute megaloblastic pancytopenia have been reported when folic acid antagonists (such as trimethoprim/sulfamethoxazole) were co-administered with methotrexate.

The use of methotrexate increases the likelihood of developing dermatitis and skin burns under the influence of solar irradiation and UV irradiation.

In patients with psoriasis, an exacerbation of the disease may occur as a result of UV irradiation during treatment with methotrexate (photosensitivity reaction).

In patients with an additional volume of distribution (presence of pleural effusion, ascites), the elimination of methotrexate is slowed down. In such patients, particularly careful monitoring of toxicity, dose reduction, and in some cases, discontinuation of methotrexate treatment is required. Before starting therapy with Methotrexate, effusion from the pleural or abdominal cavity should be drained.

If diarrhea and ulcerative stomatitis occur, methotrexate therapy must be interrupted, since in such cases the development of hemorrhagic enteritis and death as a result of interstitial perforation are possible.

Vitamin supplements and other products containing folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate.

In patients with psoriasis, methotrexate should be used only in cases of severe, persistent, disabling forms of the disease that are difficult to treat with other treatment regimens, and only after confirmation of the diagnosis by biopsy and/or after consultation with a dermatologist.

The drug contains less than 1 mmol of sodium per dose, i.e. practically free of sodium, which is important for patients on a sodium diet.

Before prescribing the drug, women need to make sure that they are not pregnant, since methotrexate is embryotoxic and can cause abortions and fetal defects. Methotrexate affects spermatogenesis and oogenesis, which may lead to decreased fertility during treatment. These effects are reversible after discontinuation of therapy.

Patients of childbearing potential of both sexes should use reliable contraception during treatment with methotrexate and for at least 6 months after its completion.

Patients of childbearing potential and their partners should be properly informed of the possible risks to fertility and pregnancy associated with the use of methotrexate.

Methotrexate in dermatology: from theory to practice

Summary. Methotrexate has established itself as a highly effective treatment for psoriasis since 1953. The effectiveness of methotrexate is due to its cytotoxic and anti-inflammatory effects. According to the draft clinical recommendations of the Russian Society of Dermatovenerologists and Cosmetologists, the use of methotrexate is justified for many skin diseases. The long history and accumulated practical experience of use do not raise doubts about the effectiveness of methotrexate, due to its unique pharmacological properties, namely anti-inflammatory, immunomodulatory and cumulative effects, which allow the drug to occupy a leading position in the treatment of many skin diseases. The article describes in detail the metabolism of methotrexate and its pharmacodynamics. According to a review of current world literature data, the authors presented recommendations for treatment with methotrexate, its use in children, monitoring during treatment, and also drew attention to indications for special situations (infections, vaccinations, contraception, etc.).

Methotrexate (MT), formerly known as aminopterin, was originally synthesized in the 1940s. for the treatment of malignant neoplasms [1-3]. Only later did MT become used to treat rheumatoid arthritis (RA), due to its ability to inhibit inflammation and connective tissue proliferation. Over time, aminopterin was gradually replaced by less toxic MTX; the first documented clinical use of MTX for the treatment of RA was recorded in 1951 [4]. After conducting a blinded, placebo-controlled study in the 1980s. The clinical potential of the drug for the treatment of RA has been fully revealed [5]. Already in 1986, MT was approved by the US Food and Drug Administration (FDA), which for the first time approved the use of MT only for life-threatening tumor diseases or in patients with psoriasis or RA with a severe, disabling course who do not respond to other forms of therapy, but subsequently the indications were significantly expanded [6-8].

Currently, MT has become firmly established in the practice of dermatologists and is used not only in the treatment of psoriasis, but also a number of other skin diseases. The drug has received such widespread use due to its favorable cost/efficacy/toxicity ratio, although the issue of toxicity still remains relevant [9, 10].

The long history and accumulated practical experience of use do not raise doubts about the effectiveness of MT, but at the same time leave in the shadow its unique pharmacological properties, namely anti-inflammatory, immunomodulatory and cumulative effects, which allow it to occupy a leading position in the treatment of many skin diseases.

Attention should be paid to the versatile properties of MT: the anti-inflammatory effect is mediated by adenosine pathways, and inhibition of nucleic acid synthesis in activated T cells and keratinocytes explains some of the immunomodulatory effects of the drug. In addition, MT can be converted into polyglutamyl derivatives, which accumulate in cells and then, in the same way, can easily be transformed back into the active form and transported out of the cell [8].

Playing the role of a folic acid antagonist, MT competitively inhibits the activity of folate-dependent enzymes and the synthesis of purine and pyrimidine, which are necessary for the production of DNA and RNA in rapidly dividing malignant cells [11]. This is the main antitumor mechanism of MTX, which works at high doses.

Disruption of the folate cycle in the body explains the main side effect of the drug - hepatotoxicity and nephrotoxicity, which are extremely rare when low doses are prescribed in dermatology. MT undergoes metabolism after the first passage through the liver and turns into an active metabolite. A small proportion of MT is excreted in the bile, and some enterohepatic recirculation also occurs. However, the main route of elimination of the drug is renal excretion. MT is filtered by the glomeruli and additionally undergoes active tubular secretion and reabsorption [12-15].

A definitive relationship between folic acid deficiency and hepatotoxicity has not been experimentally confirmed. However, taking folic acid during MTX therapy significantly reduced the incidence of side effects from the liver [8, 16]. The administration of folic acid also eliminates other toxic phenomena, such as cytopenia, gastrointestinal intolerance and stomatitis, which mimic the manifestations of folic acid deficiency [17].

Renal dysfunction occurs much less frequently than liver damage. A decrease in glomerular filtration rate is possible, but renal failure is likely only with pre-existing, severely impaired renal function, and then only induced by high doses of MT [18, 19].

In dermatology, they practically do not resort to high doses of MT, as is customary in oncology, and they rarely even reach the high doses used in rheumatology. Therefore, dermatologists are more interested in the second mechanism of MT – anti-inflammatory, which is implemented precisely in small dosages [20].

Thus, it has been proven that low doses of MT reduce the proliferation of T lymphocytes [21]. In particular, L. Genestier, R. Paillot, S. Fournel proved that MT inhibits antigen-mediated proliferation of T cells due to the induction of apoptosis [22]. However, the impairment of T-lymphocyte proliferation was completely reversible with the administration of thymidine or folic acid. The fact that the administration of folic acid does not affect the effectiveness of MTX therapy suggests other mechanisms of action of the drug [23].

The fact is that, being intracellular, MT causes an increase in adenosine, which is released into the intercellular space and reduces the oxidative burst of neutrophils and monocytes, reduces the chemotaxis of leukocytes and suppresses the secretion of inflammatory mediators and proinflammatory cytokines [24] (TNF-α, IL-10, IL-12, IFN-γ) and the activity of monocytes, macrophages and T-lymphocytes [25, 26].

In addition, adenosine reduces the expression of adhesion molecules, thereby reducing the chemotaxis and adhesion of polymorphonuclear leukocytes [27].

Recent studies have shown that the mechanism of the anti-inflammatory effect of MT is more complex and is not limited to the adenosine-mediated effect. J. Meephansan et al. a recent study found that MT can significantly reduce the level of IL-22 cytokine, which promotes the proliferation of keratinocytes and the maintenance of inflammatory processes in the dermis in psoriasis [28].

As a result of recent research, other mechanisms of the effect of MT on inflammation have been revealed. The drug is a Jak kinase blocker [29], interrupting signal transmission from a number of pro-inflammatory cytokines and interleukins: IL-6, IL-15, IL-21, IL-23, IL-2, IFN-γ, IL-12 [30 ], playing a significant role in the pathogenesis of psoriasis [31].

Thus, MT in small doses suppresses inflammation in several directions at once: reduces the oxidative burst of neutrophils and monocytes, suppresses the secretion of inflammatory mediators, proinflammatory cytokines, the activity of monocytes, macrophages and T-lymphocytes, reduces the chemotaxis and adhesion of leukocytes, acts in a targeted manner, reducing the level of IL -22-cytokine, and breaks the chain of signaling pathways of the inflammatory process.

In recent years, another property of MT has been discovered: its inhibitory effect on the production of prostaglandin E2 (PGE2). Prostaglandins are the main mediators of joint damage. In psoriatic arthritis, PGE2 acts as a mediator of pain and inflammation and promotes bone and joint destruction [32]. High levels of PGE2 are found in the synovial fluid of RA joints. There is not much data in the clinical literature on the effect of MT on PGE2 production, but there is enough experimental work proving its inhibitory effect on PGE2 synthesis [32, 33].

The properties of MT do not end there. Intracellular accumulation of polyglutamates leads to sustained efficacy of the drug and allows it to be administered once a week, despite the relatively short half-life from plasma [14, 34].

It is also important that when taken orally, the drug is metabolized into active acid through bacterial metabolism [14]. The bioavailability of MT is relatively high – in the range of 64-90%. However, it varies widely among patients and decreases with increasing doses above 15 mg/week with a plateau effect, indicating saturation of intestinal transporters [35, 36]. In addition, the individual characteristics of the intestinal microflora should be taken into account. Therefore, a number of studies have shown higher bioavailability of the injectable form of MT [35, 36]. Injection of MT will result in a linear, dose-proportional increase in drug concentrations in the blood and no plateau effect [35], with MT concentrations in synovial fluid comparable to levels found in plasma [37].

The use of parenteral MT, especially subcutaneous, has recently attracted great interest, since several studies have proven greater clinical efficacy and better tolerability of the injectable form compared to the oral one. Complaints from the gastrointestinal tract in the form of nausea and diarrhea are observed more often with the oral form of MTX, and the transition to parenteral administration of the drug significantly reduces the frequency of these complaints [43].

There are recommendations in the literature that if the disease remains active, even at high doses or the appearance of side effects, before discontinuing the drug, consider replacing its oral administration with subcutaneous administration [44]. The subcutaneous injection dose is equivalent to the oral dose, although given differences in bioavailability between dosage forms, lower doses of subcutaneous MTX may also be effective. All this allows the doctor to vary the dosage if side effects occur [20].

Currently, the drug Methortrit (methotrexate) is especially popular among dermatologists, which has shown the effectiveness and convenience of dosing subcutaneous injections. Methortrit is available in ready-made pre-filled syringes for subcutaneous administration. The use of Methortrit in pre-filled syringes eliminates dosing violations, which reduces the risks of ineffectiveness and adverse events (AEs) for patients both in the hospital and when self-administered at home.

Specially designed syringes with wide ears are ideal for use by patients with deformed joints of the hands due to psoriatic arthritis. This allows the patient to carry out manipulations at home independently, safely and without the risk of loss of the active substance.

Recommendations for treatment of MT

The 2021 draft Clinical Guidelines of the Russian Society of Dermatovenerologists and Cosmetologists include the following nosologies, for which it is recommended to prescribe MT in a dosage of up to 25 mg per week:

1) severe bullous pemphigoid; 2) alopecia areata; 3) psoriasis, with resistance to external therapy, widespread rashes (with moderate or severe psoriasis); 4) arthropathic psoriasis; 5) as a reserve drug in the presence of resistance to antimalarial drugs in lupus erythematosus; 6) lichenoid pityriasis (acute lichenoid varioliform pityriasis); 7) pityriasis red hair pityriasis; chronic pruritus in adults, persistent; 9) pemphigus (to increase the effectiveness of glucocorticosteroid therapy and reduce their course dose); 10) localized scleroderma, juvenile localized scleroderma with ineffective phototherapy, progression, severe course of the disease and the absence of contraindications in order to stop the activity and improve the prognosis of the disease; 11) mycosis fungoides in late stages, as well as in case of ineffectiveness or insufficient response to previously performed external therapy and/or phototherapy and/or interferon-α therapy, regardless of the stage.

Considering the high effectiveness of MT and the availability of sufficient clinical observations, the indications for its use were expanded in 2020. The drug is recommended off-label:

1) in case of ineffectiveness of the therapy for lichen planus of all forms and localizations; 2) patients with extragenital lichen sclerosus when phototherapy is ineffective.

MTX is administered orally, subcutaneously or intramuscularly. According to Russian clinical guidelines, the drug is prescribed on an increasing schedule, starting with 10 mg/week and adding 5 mg every 2-4 weeks to a maximum dose of 20-25 mg/week, depending on effectiveness and tolerability [38-40].

As mentioned above, preference is given to subcutaneous administration of the drug. In daily clinical practice, there is a wide variety of MTX dosing regimens. A complete list of dosages is available for the drug Methortrit 10 mg/ml: 7.5 mg (0.75 ml), 10 mg (1 ml), 12.5 mg (1.25 ml), 15 mg (1.5 ml), 17.5 mg (1.75 ml), 20 mg (2 ml), 22.5 mg (2.25 ml), 25 mg (2.5 ml).

Patients should be warned that the therapeutic effect will appear 4–8 weeks after dose increases [41]. Once the maximum dose of 25 mg per week is reached, response to therapy should be assessed after 3 months and treatment discontinued if ineffective [42].

Once remission is achieved, the goal of therapy will be to reduce the dose of the drug to the lowest possible dose that will ensure disease control and adequate tolerability. In practice, dermatologists try to avoid MT, avoiding maintenance doses.

When treating MT, one should not forget about adjuvant therapy. Russian clinical guidelines indicate that during treatment with MT, it is recommended to prescribe folic acid in a dose of at least 5 mg, but not more than 25 mg per week 24 hours after taking MT [45, 46].

Use in children

Surprisingly, there have been no randomized clinical trials of MTX therapy in children with psoriasis, although it is often used in pediatric practice. However, in the scientific literature one can still find retrospective publications on the effectiveness of the use of MT in children, even starting from 2 years of age [47, 48].

MTX is generally well tolerated in the pediatric population. Standard recommendations: 0.2-0.4 mg/kg once a week [49]. The side effect profile is similar to adults and monitoring is generally the same.

Monitoring

According to Russian clinical recommendations, at the beginning of treatment with MT and when increasing its dose, it is necessary to monitor the levels of ALT and AST, bilirubin, creatinine, as well as a clinical blood test every 2 weeks for 2 months, and then every 3 months; Clinical assessment of AEs and/or risk factors should also be made at each patient visit.

If signs of infection appear, the next dose of the drug should be skipped until they disappear completely. The British Association of Dermatologists' recommendations for the safe use of MTX are presented in table [20].

Special cases

Alcohol

There is no evidence to indicate a safe level of alcohol consumption while taking MTX, so all patients are advised to avoid alcohol consumption [20].

Contraception

MT is a teratogen and causes specific embryopathy, therefore it is contraindicated in pregnant women. It is necessary to use a dual method of contraception during treatment and for 3 months after the last dose of the drug [50].

MT is excreted in breast milk and therefore should not be used during breastfeeding [20].

The debate about the effect of MT on spermatogenesis is still ongoing, and precise scientific data have not yet been obtained, therefore the British Association of Dermatologists recommends postponing the planned conception of a child for the period of treatment and for up to 3 months after the last dose of the drug [20].

Hepatitis B and C

If a patient has signs of active hepatitis B (high levels of hepatitis B virus DNA replication in the serum, increased alanine aminotransferase (ALT) activity and detection of hepatitis B virus e-antigen (HBeAg)), he is at risk of exacerbation of the disease. In this regard, hepatitis B is an absolute contraindication to MTX therapy.

Previous hepatitis B (suppression of viral replication, disappearance of HBeAg, disappearance of hepatitis B surface antigen (HBsAg), normalization of ALT activity) is a relative contraindication to treatment, the patient should be aware of the existing low risk (< 1%) of reactivation of the infection during treatment [51 ].

The long-term effects of MTX in patients with chronic hepatitis C are unknown, but since both hepatitis C and MTX can cause liver fibrosis, a synergistic effect leading to more rapid progression of liver fibrosis is likely. Therefore, the risks and benefits of using MT in patients with hepatitis C must be carefully weighed, and they themselves need careful monitoring for the progression of fibrosis. The involvement of a hepatologist in the management of such cases is extremely important. Therefore, MTX therapy should be avoided in patients with advanced liver fibrosis or cirrhosis [20].

HIV infection

HIV status should be checked before starting MTX treatment, as HIV-positive patients are at higher risk of leukopenia and opportunistic infections [52].

Vaccinations

Live (attenuated) vaccines may predispose immunosuppressed people to infection. Therefore, those taking MTX should avoid vaccines such as measles, mumps, rubella, chickenpox, oral polio, typhoid fever, BCG and yellow fever. Live vaccines must be administered at least 4 weeks before starting MTX therapy. When live vaccines must be administered to patients taking immunosuppressive medications, they should be discontinued for 6 months prior to administration of the vaccine [53].

Inactivated vaccines are safe to administer during treatment, but the level of immunity achieved may be lower than in non-MTX recipients [54]. Because MTX induces immunosuppression, patients should be advised to receive annual influenza vaccination.

Conclusion

MT has been used for a long time to treat a number of skin diseases; its use in pediatric practice is not excluded. MT has proven itself to be a highly effective drug, and the indications for its use are constantly expanding. The effect of MT is due not only to cytotoxic, but also anti-inflammatory mechanisms, which have been well studied and continue to be studied. In some cases, the toxicity of MT may limit its use, however, monitoring the patient's condition during therapy and the use of modern parenteral forms of the drug with flexible dosing allow one to avoid negative consequences.

CONFLICT OF INTEREST. The authors of the article have confirmed that there is no conflict of interest to disclose.

CONFLICT OF INTERESTS. Not declared.

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Yu. A. Gallyamova, Doctor of Medical Sciences, Professor A. V. Asoskova1

Federal State Budgetary Educational Institution of Further Professional Education RMANPE of the Ministry of Health of Russia, Moscow, Russia

1Contact information

Methotrexate in dermatology: from theory to practice / Yu. A. Gallyamova, A. V. Asoskova For citation: Gallyamova Yu. A., Asoskova A. V. Methotrexate in dermatology: from theory to practice // Attending Physician. 2021; 5 (24): 46-51. DOI: 10.51793/OS.2021.11.97.010 Tags: skin, psoriasis, treatment, anti-inflammatory effect, immunomodulatory and cumulative effect

Methotrexate-Ebeve, 1 piece, 5 ml, 10 mg/ml, solution for injection

The drug Methotrexate-Ebeve is a cytotoxic drug, so care must be taken when handling it. The drug should be prescribed by a doctor who has experience in the use of methotrexate and is familiar with its properties and characteristics of action. Before prescribing methotrexate, you should ensure that it is possible to determine the plasma concentration of the drug.

Taking into account the possibility of developing severe toxic reactions, including death, the doctor is obliged to 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 toxicity have been described during drug therapy. Discontinuation of methotrexate does not always lead to complete resolution of adverse events.

The safety and potential benefits of high-dose methotrexate used outside its approved indications have not been established.

During treatment with Methotrexate-Ebeve, patients should be closely monitored in order to promptly identify signs of possible toxicity and adverse effects. When using the drug for non-oncological indications, the patient should pay special attention to the fact that the drug is not taken daily, but once a week.

Before starting treatment with Methotrexate-Ebeve or when resuming therapy after a break, it is necessary to conduct a clinical blood test with counting the leukocyte formula and platelet count, assess the activity of “liver” transaminases, the concentration of bilirubin, albumin in the blood plasma, the concentration of uric acid in the blood plasma, and renal function ( blood urea nitrogen, creatinine clearance and/or plasma creatinine), as well as chest x-ray. If there are clinical indications, studies are prescribed to exclude tuberculosis and viral hepatitis.

Prescribing high doses of methotrexate is possible only if the concentration of creatinine in the blood plasma is normal. If an increase in creatinine concentration is noted, the dose of the drug should be reduced; if the creatinine concentration increases by more than 2 mg/dL, the drug should not be used.

Leukopenia and thrombocytopenia, as a rule, develop within 4 to 14 days from the moment of methotrexate administration. Sometimes the development of a second leukopenic phase is observed, developing in a period of 12 to 21 days.

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

During treatment with Methotrexate-Ebeve (monthly in the first 6 months and at least every 3 months thereafter, with increasing doses it is advisable to increase the frequency of examinations) the following studies are carried out:

1. Examination of the oral cavity and pharynx to identify changes in the mucous membranes.

2. Blood test to determine the leukocyte formula 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 leukocytes or platelets, treatment with Methotrexate-Ebeve is immediately stopped and symptomatic maintenance therapy is prescribed.

Patients should be instructed to immediately report any signs and symptoms indicating an infection to their physician. With concomitant or previous therapy with hematotoxic drugs (for example, leflunomide), radiation therapy, it is necessary to carefully monitor the number of leukocytes and platelets in the blood. If necessary, it is advisable to perform a bone marrow biopsy.

3. Functional liver tests. Long-term use of methotrexate may result in the development of acute hepatitis and chronic hepatotoxicity (liver fibrosis and cirrhosis). Particular attention should be paid to identifying signs of liver damage. Treatment with Methotrxat-Ebeve should not be started or should be suspended if abnormal liver function tests or liver biopsy are detected. During drug therapy, a 2-3-fold transient increase in the activity of “liver” transaminases is possible, usually

asymptomatic. As a rule, this is not a reason to change the treatment regimen; usually the indicators normalize within two weeks, after which treatment can be resumed according to the doctor’s decision. However, if a persistent increase in the activity of “liver” transaminases is detected, it is necessary to reduce the dose or discontinue treatment with Methotrexate-Ebeve. Since the drug Methotrexate-Ebeve has a toxic effect on the liver, during treatment with the drug you should not use other hepatotoxic drugs unless clearly necessary. Ethanol consumption should also be avoided or greatly reduced. The activity of liver enzymes should be especially carefully monitored in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, leflunomide).

In case of long-term treatment, especially severe forms of psoriasis, including psoriatic arthritis, due to the possible hepatotoxic effect of methotrexate, given that fibrotic and/or cirrhotic changes can develop against the background of normal liver tests, a liver biopsy is necessary in the following cases:

1. In patients without risk factors, liver biopsy is not indicated until the total cumulative dose of 1.0-1.5 g is reached.

2. Against the background of the presence of risk factors such as alcohol abuse, a persistent increase in the activity of “liver” transamises, chronic viral hepatitis, a family history of liver disease, as well as for patients with less significant risk factors such as diabetes mellitus, obesity, anamnestic data on exposure to hepatotoxic drugs/chemicals, a liver biopsy should be performed 2-4 months after the start of treatment. After reaching a total 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 (for example, respiratory system); in patients with contraindications to liver biopsy (for example, unstable hemodynamics, changes in coagulogram parameters); in patients with a poor prognosis for life expectancy.

If liver biopsy reveals only mild changes (grade I, II or IIIa on the Roenigk scale), continued methotrexate therapy is possible, subject to careful monitoring of the patient's condition. The drug should be discontinued if moderate or severe changes are detected (grades IIIb and IV on the Roenigk scale), or if a liver biopsy is refused in a patient who has a persistent increase in the activity of “liver” transaminases. If moderate fibrosis or cirrhosis of the liver is detected, methotrexate should be discontinued; in case of minimal fibrosis, a repeat liver biopsy is recommended after 6 months. Changes such as fatty liver or mild inflammation of the portal veins are a fairly common finding on liver biopsy in patients receiving methotrexate. Although the detection of such changes is usually not a reason to make a decision about the inappropriateness or discontinuation of methotrexate therapy, caution should be exercised when treating such patients.

4. Renal function tests and urine examination. Since Methotrexate-Ebeve is excreted primarily by the kidneys, patients with impaired renal function may experience increased 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 (for example, elderly patients). This is especially important in the case of concomitant therapy with drugs that reduce the excretion of methotrexate, have an adverse effect on the kidneys (in particular, non-steroidal anti-inflammatory drugs (NSAIDs)) or on the hematopoietic system. Cases of severe side effects have been described in patients taking NSAIDs during therapy with methotrexate (especially in high doses), including cases of severe suppression of bone marrow hematopoiesis, aplastic anemia, gastrointestinal damage and death.

5. Examination of the respiratory system. It is necessary to closely monitor symptoms of possible development of pulmonary function disorders and, if necessary, prescribe appropriate tests to monitor pulmonary function. The appearance of corresponding symptoms (especially a dry, nonproductive cough) or the development of nonspecific pneumonitis during treatment with Methotrexate-Ebeve may indicate a potential danger of lung damage. In such cases, the drug Methotrexate-Ebeve should be discontinued and the patient should be carefully examined. Although the clinical presentation may vary, typical cases of respiratory symptoms associated with Methotrexate-Ebeve include fever, cough with dyspnea, hypoxemia, and pulmonary infiltrates on x-ray. Lung damage caused by the use of methotrexate can occur regardless of how long the drug has been used or the doses used (cases of lung damage have been described when using methotrexate in low doses, including 7.5 mg/week). In differential diagnosis, the infectious nature of the disease should be excluded. During methotrexate therapy, the development of potentially dangerous (even fatal) opportunistic infections, including Pyeumocystis pneumonia, is possible. If respiratory symptoms develop in a patient receiving methotrexate, pneumonia caused by Pneumocystis carinii should be excluded.

If the dose of the drug is increased, the frequency of examinations should be increased.

Due to the immunosuppressive effect of methotrexate, it is necessary to avoid immunization (unless approved by a physician) during treatment with the drug and for 3 to 12 months after stopping the drug; Family members living with the patient should refuse immunization with oral polio vaccine (the patient should avoid contact with people who have received the polio vaccine or wear a protective mask covering the nose and mouth).

If stomatitis or diarrhea, hemoptysis, melena or the appearance of blood in the stool are observed during methotrexate therapy, the drug must be discontinued immediately due to the high risk of developing potentially fatal complications, such as hemorrhagic enteritis and perforation of the intestinal wall.

Symptoms such as fever, sore throat, flu-like symptoms, ulceration of the oral mucosa, severe general weakness, hemoptysis, hemorrhagic rash may be harbingers of the development of life-threatening complications.

If a patient is diagnosed with conditions leading to the accumulation of a significant amount of fluid in the body cavities (hydrothorax, ascites), given the prolongation of the half-life of the drug in such patients, therapy with Methotrxat-Ebeve should be carried out with caution; before starting therapy with the drug, the fluid should be evacuated by drainage, or stop using the drug.

Particular caution should be observed when treating patients with insulin-dependent diabetes mellitus, since cases of the development of liver cirrhosis without a previous increase in the activity of “liver” transaminases have been described.

Like other cytotoxic drugs, methotrexate can cause the development of tumor lysis syndrome in patients with rapidly growing malignant neoplasms. To prevent the development of this complication, it is necessary to take appropriate supportive therapy measures. The use of methotrexate in combination with radiation therapy may lead to an increased risk of developing soft tissue necrosis or osteonecrosis.

The condition of patients with previous radiation therapy, as well as impaired general condition, should be especially carefully monitored.

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

Cases of the development of leukoencephalopathy have been described in patients receiving therapy with high doses of methotrexate, including orally, in combination with calcium folinate (without previous radiation therapy to the head area). When using methotrexate for acute lymphocytic leukemia, pain in the left epigastric region may occur due to the development of an inflammatory process in the spleen capsule against the background of the breakdown of tumor cells.

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

When body temperature rises (more than 38°C), the elimination of methotrexate slows down significantly.

The drug Methotrexate-Ebeve may increase the risk of developing neoplasms (mainly lymphomas). Malignant lymphomas can also develop in patients receiving Methotrexate-Ebeve in 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 starting treatment with Methotrexate-Ebeve, pregnancy must be excluded. The drug Methotrexate-Ebeve has an embryotoxic effect, promotes termination of pregnancy and the formation of fetal development abnormalities. Therapy with Methotrexate-Ebeve is accompanied by inhibition of spermatogenesis and oogenesis, which can lead to decreased fertility. After discontinuation of drug therapy, these effects spontaneously regress. During therapy with Methotrexate-Ebeve and for six months after its completion, patients are advised to use contraception. Patients of reproductive age, as well as their partners, should be informed about the possible effect of Methotrexate-Ebeve on reproduction and fetal development. Men of reproductive age should be warned about the risks; fatherhood is not recommended during treatment and for 6 months after discontinuation of the drug. Since irreversible infertility may develop during treatment, men should consider cryopreserving sperm in a bank before starting treatment.

The use of methotrexate increases the likelihood of developing dermatitis and skin burns under the influence of solar and ultraviolet irradiation (UV). Do not expose unprotected skin to sunlight for too long or overuse a UV lamp (photosensitization reaction is possible). In patients with psoriasis, exacerbation of the disease may occur due to UV radiation during treatment with methotrexate.

During high-dose therapy, precipitation of methotrexate or its metabolites in the renal tubules may occur. In such cases, to prevent this complication, it is recommended to carry out infusion therapy and alkalization of urine until a pH of 6.5-7.0 is achieved through oral (5 tablets of 625 mg every 3 hours) or intravenous administration of sodium bicarbonate or acetazolamide (500 mg orally four times per day). During therapy with methotrexate, exacerbation of chronic viral hepatitis (reactivation of the hepatitis B or C virus) is possible. Cases of reactivation of the hepatitis B virus after discontinuation of methotrexate have also been described. 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.

The presence of pleural effusion, ascites, gastrointestinal obstruction, concomitant cisplatin therapy, dehydration, impaired liver function, or decreased urine pH slows down the elimination of methotrexate, which may result in an increase in the concentration of the drug in the blood plasma. It is extremely important to detect the accumulation of the drug in the body during the first 48 hours, since irreversible consequences of drug toxicity may develop. Particular caution should be exercised when using the drug in elderly patients; their condition should be monitored more often than in younger patients to identify early signs of therapy toxicity. When treating pediatric patients, pediatric treatment protocols should be followed.

Pediatric patients with acute lymphoblastic leukemia may develop severe neurotoxicity when using medium (1 g/m2) doses of methotrexate, which most often manifests clinically as a generalized or partial epileptic seizure. The development of leukoencephalopathy and/or microangiopathic calcifications 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 can manifest themselves, including changes in behavior, local disturbances in the sensory organs (including short-term blindness) and the motor system, and impaired reflexes. The exact reasons for the development of these adverse reactions are unknown. When using methotrexate at a dose higher than 100 mg/m2, it is necessary to use “rescue therapy” with calcium folinate 42-48 hours after administration of methotrexate. The dose of calcium folinate is determined depending on the size of the dose of methotrexate used and the duration of its infusion. Methotrexate concentrations should be determined after 24, 48 and 72 hours and, if necessary, over a long period of time, to determine the optimal duration of calcium folinate therapy. The use of methotrexate together with red blood cell infusion (within 24 hours) requires careful monitoring of the patient's condition, as the plasma concentration of the drug may increase.

Special precautions when disposing of unused drugs

Residues and all instruments and materials used to prepare Methotrexate-Ebeve infusion solutions must be disposed of in accordance with standard hospital cytotoxic waste disposal procedures, taking into account applicable hazardous waste disposal regulations.