Name:

Methotrexate (Methotrexatum)

Pharmacological
action:

Antitumor agent from the group of antimetabolites - folic acid antagonists.
Acts in the S-phase of mitosis.
The mechanism of action is associated with inhibition of the synthesis of purine nucleotides and thymidylate as a result of irreversible binding to dihydrofolate reductase, which prevents the reduction of dihydrofolate to active tetrahydrofolate.
More active against rapidly growing cells. Has some immunosuppressive effects.

Pharmacokinetics
Penetrates the BBB to a small extent (depending on the dose used).
When administered intrathecally, a significant amount enters the systemic circulation. Plasma protein binding (mainly albumin) is about 50%. Biotransformed in the liver.
Excreted by the kidneys(unchanged) and with bile (less than 10%). T1/2 depends on the dose used and has significant individual differences.
Upon repeated administration, it accumulates in tissues in the form of metabolites.

Indications for
application:

Acute lymphocytic leukemia;
- trophoblastic disease;
- skin cancer;
- cancer of the cervix and vulva;
- esophageal cancer;
- squamous cell carcinoma of the head and neck;
- cancer of the renal pelvis and ureters;
- osteogenic and soft cell sarcoma;
- Ewing's sarcoma;
- lung cancer;
- breast cancer;
- germ cell tumors of the testicle and ovaries;
- liver cancer;
- kidney cancer;
- retinoblastoma;
- medulloblastoma;
- cancer of the penis;
- lymphogranulomatosis;
- severe forms of psoriasis (in case of ineffectiveness of adequate therapy);
- severe form of rheumatoid arthritis (in case of ineffectiveness of adequate therapy).

Directions for use:

Taken orally, administered intravenously, intramuscularly, intralumbarally. They are set individually, depending on the indications and stage of the disease, the state of the hematopoietic system, and the antitumor therapy regimen.

Methotrexate injection can be administered intramuscularly, intravenously, intraarterially or intrathecally.

The use of Methotrexate in high doses can be very dangerous, therefore high-dose therapy should be carried out only by experienced chemotherapists who can control the concentration of methotrexate in the blood plasma in hospital conditions under the cover of calcium folinate.

During the treatment period, once a week it is necessary to examine the blood picture.

Trophoblastic tumors: 15-30 mg intramuscularly, daily for 5 days at intervals of one or more weeks (depending on signs of toxicity). Courses of treatment are usually repeated 3 to 5 times.

Solid tumors: 30-40 mg/m2 intravenously 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 1 or 2 times a week.
When treating children, the dose is selected depending on the age of the child: children under the age of 1 year are prescribed 6 mg, children under the age of 1 year - 8 mg, children under the age of 2 years - 10 mg, children aged 3 years and older - 12 mg.
Before administration, cerebrospinal fluid should be removed in a volume approximately equal to the volume of the drug that is intended to be administered.

High-dose therapy: from 2 to 15 g/m2 in the form of a 4-6 hour intravenous infusion with an interval of 1-5 weeks with mandatory subsequent administration of calcium folinate, which usually begins 24 hours after the start of the methotrexate infusion and is administered every 6 hours at a dose of 3- 40 mg/m2 (usually 15 mg/m2) and higher depending on the concentration of methotrexate in the blood serum for 48-72 hours (see instructions for use of calcium folinate).

Rheumatoid arthritis: The initial dose is usually 7.5 mg once a week, which is administered simultaneously or divided into three doses with an interval of 12 hours.
To achieve optimal effect, the weekly dose can be increased, but it should not exceed 20 mg.
When optimal clinical effect is achieved, dose reduction should begin until the lowest effective dose is achieved.
The optimal duration of therapy is unknown.

Psoriasis: Methotrexate therapy is carried out in doses of 10 to 25 mg per week. The dose is usually increased gradually; when the optimal clinical effect is achieved, the dose is reduced until the lowest effective dose is achieved.

Mycosis fungoides: intramuscularly 50 mg once a week or 25 mg 2 times a week. Reducing the dose or discontinuing the drug is determined by the patient’s response and hematological parameters.

Side effects:

Hematopoietic system: leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia.
Gastrointestinal tract and liver: anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, enteritis, diarrhea, erosive and ulcerative lesions of the gastrointestinal tract, liver dysfunction, fibrosis and cirrhosis of the liver (their likelihood is increased in patients receiving long-term continuous or daily therapy with methotrexate).

Nervous system: encephalopathy, especially when multiple doses are administered intrathecally, as well as in patients who received radiation therapy to the cranial area. There are also reports of fatigue, weakness, confusion, ataxia, tremor, irritability, seizures and coma.
Acute side effects caused by intrathecal administration of methotrexate may include dizziness, blurred vision, headache, back pain, stiffness of the back of the neck, convulsions, paralysis, hemiparesis.
Urinary system: Renal dysfunction is dose dependent. The risk of impairment is increased in patients with reduced renal function or dehydration, as well as in patients taking other nephrotoxic drugs. Renal failure is manifested by elevated creatinine levels and hematuria. Cystitis may occur.

Reproductive system: disruption of the process of oogenesis, spermatogenesis, changes in fertility, teratogenic effects.
Dermatological phenomena: skin erythema and/or rash, urticaria, alopecia (rare), photosensitivity, furunculosis, depigmentation or hyperpigmentation, acne, skin peeling, blistering, folliculitis.
Allergic reactions: fever, chills, rash, urticaria, anaphylaxis.
Organs of vision: conjunctivitis, excessive lacrimation, cataracts, photophobia, cortical blindness (at high doses).
Immune status: immunosuppression, decreased resistance to injection diseases.
Other: Malaise, osteoporosis, hyperuricemia, vasculitis. Rarely - pneumonitis, pulmonary fibrosis.

Contraindications:

Severe liver and/or kidney dysfunction;
- leukopenia;
- thrombocytopenia;
- pregnancy;
- should not be used in immunodeficiency states.

Should not be used methotrexate for ascites, pleural effusion, gastric and duodenal ulcers, ulcerative colitis, gout or nephropathy (including a history).
Not recommended for use in patients with chickenpox (including recent or after contact with sick people), herpes zoster and other acute infectious diseases.
Before starting therapy and during treatment peripheral blood picture should be monitored, liver and kidney function, chest x-ray.
When treating rheumatoid arthritis or psoriasis, a detailed general blood test should be done at least once a month, and laboratory tests of liver or kidney function at least once every 1-2 months.

When used for psoriasis Local treatment of the disease should not be interrupted. In case of overdose, it is recommended to use calcium folinate (but no later than after 4 hours).
During combination antitumor therapy Particular caution should be exercised when concomitantly using high doses of methotrexate with drugs that have nephrotoxic effects (for example, cisplatin).
It is not recommended to vaccinate patients and their families.
Caution should be used when combining b methotrexate (even in low doses) with acetylsalicylic acid.
Experimental studies have established the carcinogenic and mutagenic effects of methotrexate.

Interaction with
other medicinal
by other means:

When used simultaneously with vitamin preparations containing folic acid or its derivatives may reduce the effectiveness of methotrexate.
The simultaneous use of NSAIDs in high doses can lead to an increase in the concentration of methotrexate in plasma and to a prolongation of its elimination period, as well as an increase in the concentration of methotrexate not bound to plasma albumin, which in turn increases the toxic effects of methotrexate (primarily on the gastrointestinal tract and hematopoietic system ).
When used simultaneously with penicillins methotrexate (even in low doses) may increase its toxic effects.
When used simultaneously with sulfonamides, especially with co-trimoxazole, there is a risk of increased myelosuppressive effects.

When using nitrous oxide in patients receiving methotrexate, severe unpredictable myelodepression and stomatitis may develop.
When used simultaneously with methotrexate valproic acid a decrease in its concentration in blood plasma is possible.
Cholestyramine binds methotrexate, reduces its enterohepatic recirculation, which leads to a decrease in its concentration in the blood plasma.
When used simultaneously with mercaptopurine, it is possible to increase its bioavailability due to impaired metabolism during the “first pass” through the liver.
Neomycin and paromomycin reduce the absorption of methotrexate from the gastrointestinal tract.

In patients receiving omeprazole, it is possible increased concentration of methotrexate in blood plasma.
When used simultaneously with probenecid, a 3-4 fold increase in the concentration of methotrexate in the blood plasma is possible due to a decrease in its renal excretion.
With simultaneous use of methotrexate with retinoids, the risk of hepatotoxicity may increase.
Salicylates potentiate the effect of methotrexate due to a decrease in its renal excretion.

After a course of treatment with tetracycline, methotrexate, used even in low doses, can have a toxic effect.
With sequential administration of methotrexate and fluorouracil, synergistic action is possible; fluorouracil administered before methotrexate may reduce its toxicity.
Cisplatin has a nephrotoxic effect and therefore may reduce the renal excretion of methotrexate, which leads to increased toxicity.
Increased toxicity is possible when using cyclosporine in patients receiving methotrexate.

Pregnancy:

Methotrexate contraindicated for use during pregnancy.
If necessary, use during lactation should stop breastfeeding.
Women of childbearing potential should use reliable methods of contraception while using methotrexate.
Experimental studies have established the embryotoxic and teratogenic effects of methotrexate.

Overdose:

Symptoms: There are no specific symptoms.
Treatment: immediate administration of calcium folinate to neutralize the myelotoxic effect of methotrexate (orally, intramuscularly or intravenously).
The dose of calcium folinate should be at least equal to the dose of methotrexate and should be administered within the first hour; subsequent doses are administered as needed. Increase body hydration and alkalize urine to avoid precipitation of the drug and its metabolites in the urinary tract.

Release form:

Methotrexate tablets, coated, 0.0025 g (2.5 mg) in a package of 10-500 pieces; in ampoules (for injection) 0.005; 0.05 and 0.1 g.
Solution for injection Vero-Methotrexate 5 mg/1 ml, 10 mg/2 ml, 50 mg/5 ml in bottles of 1-5 pieces.
Lyophilisate for the preparation of solution for injection Vero-Methotrexate 5 mg, 10 mg, 50 mg, 100 mg, 500 mg and 1 g in bottles of 1-5 pieces.

If translated literally from Greek, it means a state of inflammation. The question of what factors provoke the development of this disease still remains unclear. Indirect information that the number of leukocytes in the blood increases and increases makes it possible to conclude that the process of development of the disease is of an infectious nature. It is believed that the impetus for the development of the disease is an infection that provokes disturbances in the functioning of the immune system. However, not everyone is susceptible to this, but only those with a hereditary predisposition. The result of the introduction of this infection into the human body is the formation of immune complexes (from viruses, antibodies, etc.), which accumulate in tissues and lead to joint damage.

In most cases, the treatment of this formidable disease consists of relieving pain, slowing down the progression of the disease and restoring damage (to the extent possible in each case) using surgical methods.

Currently there are a great variety. One of these is Methotrexate. For rheumatoid arthritis (reviews from health workers and patients confirm this information), the medication mentioned is quite effective, the results of its influence will be felt for quite a long time.

Composition and principle of action

The main active ingredient of the drug is methotrexate. It is a nitostatic, an antagonist. Currently, to slow down the development of rheumatoid arthritis, treatment with Methotrexate is used more often than other methods. In essence, this medication is an antitumor, cytostatic agent, inhibits mitosis (indirect cell division), slows down the growth of actively proliferating tissues, and inhibits the development of tumors.

According to statistics, the effectiveness of the medication is observed in 80% of patients, positive dynamics become noticeable 2-6 weeks after the start of the course of therapy. After a long period of treatment (up to 5 years), Methotraxate therapy is discontinued much less frequently than any other medications used to slow the development of rheumatoid arthritis.

Forms of release of the drug

The medication itself is a Russian analogue of the Austrian “Methotrexate Ebewe”. The manufacturer offers the original drug to its customers in several release forms. Tablets go on sale in three dosages: 2.5 mg, 5 mg and 10 mg of the main active ingredient. All of them are packaged in polypropylene bottles of 50 pieces each. In addition, Methotrexate (Austria - manufacturer) can be purchased in the form of an injection solution in a dosage of 50 mg/5 ml. The ampoules are made of dark glass and packed in a cardboard box.

It is also possible to buy the medicine in the form of a concentrate for preparing infusions (droppers). Dosage - 100 mg/1 ml. In this form, Methotrexate is sold in bottles of 5, 10, 50 ml. One bottle is packed in a cardboard box.

Indications for taking Methotrexate

Indications for the use of the drug are quite specific, since its main purpose is to fight tumors. It is recommended to take Methotrexate in cases where the patient suffers from acute lymphoblastic leukemia and non-Hodgin lymphomas. It is also prescribed for trophoblastic tumors, mycosis fungoides and psoriasis (in severe stages).

Also, if other treatment methods and medications do not have a noticeable effect, Methotrexate is used for rheumatoid arthritis. Reviews from rheumatology specialists about the medication are quite positive.

The indications for taking Methotrexate Ebeve are somewhat more extensive. Experts prescribe it if the patient has malignant neoplasms of a variety of systems and organs: lung and breast cancer, osteosarcoma and soft tissue sarcoma, ovarian and testicular tumors, Young's sarcoma, retinoblastoma and autoimmune diseases.

Who should not take the medication?

The drug should not be taken by people with hypersensitivity to the main active ingredient. Methotrexate is contraindicated for pregnant women and nursing mothers. The drug is not prescribed for existing abnormalities in the functioning of the liver and kidneys, or for hematological disorders (anemia, thrombocytopenia, leukopenia). Patients who are in the acute stage of any infectious diseases or those suffering from immunodeficiency syndrome should not be started on medication. Both the Russian analogue and the original Methotrexate (Austria) should not be given to children under three years of age.

For a number of diseases, the drug is prescribed with great caution. Such problems include the duodenum and ulcerative colitis. In case of viral, fungal and bacterial infections, you also need to act very carefully. This group of problems also includes previous radiation or chemotherapy.

Possible side effects

Methotrexate in ampoules, tablets, or infusions can cause a number of side effects. Quite serious problems can arise from the hematopoietic system (leukopenia, thrombocytopenia, etc.) and the gastrointestinal tract (dyspepsia, anorexia, hepatotoxicity, pancreatitis). The nervous system may react with headaches, drowsiness, paresis, and convulsions. High doses of medication can provoke the development of encephalopathy. Deviations from the organs of vision and the cardiovascular system are possible (hypotension, pericarditis, thromboembolism).

Respiratory failure, shortness of breath, dry nonproductive cough, and fever may develop. From the genitourinary system, there is a possibility of severe forms of nephropathy or renal failure. Possible disturbance of spermatogenesis and oogenesis, decreased libido, development of infertility, impotence.

If a woman is pregnant, Methotrexate (injections, tablets, droppers) can cause miscarriage, developmental defects or fetal death.

Tablet dosage regimen

In the treatment of malignant neoplasms, the tablet dosage regimen is developed individually and depends on the regimen of chemotherapy sessions. If we are talking about the use of the drug “Methotrexate” for rheumatoid arthritis (patient reviews are positive), then the initial dose is usually 7.5 mg once a week. You can take the entire dose at once, or you can divide it into 3 doses at 12-hour intervals.

In some cases (to achieve optimal effect), the weekly dose may be increased. However, it should not exceed 20 mg. When the required clinical effect is achieved, the dosage should be gradually reduced to the minimum. The optimal period for the course of therapy has not been clinically identified.

Methotrexate injections

How are injections made with the drug “Methotrexate”? Injections for rheumatoid arthritis begin with a dosage of 7.5 mg per week. This can be done subcutaneously, intramuscularly or intravenously. If the drug is well tolerated by the patient, the dose can be gradually increased weekly by 2.5 mg, but not more than 25 mg. When the therapeutic effect is achieved (usually 1-2 months after the start of treatment), the dose should be gradually reduced to the minimum required. For any patient with rheumatoid arthritis, the dosage may be gradually adjusted to maintain optimal treatment effect. Clinical studies have shown that Methotrexate is better absorbed and produces minimal side effects if injections are given subcutaneously or intramuscularly.

With continuous use of Methotrexate, the initial positive therapeutic effect persists for two years. When the medication is discontinued, rheumatoid arthritis makes itself felt within 3-6 weeks.

Exceeding the permissible dose

Exceeding the permissible dose of the Russian medicine or the medicine “Methotrexate Ebeve” (tablets, injections, infusions) does not manifest itself in any specific symptoms. The fact of overdose can be determined by the level of methotrexate concentration in the blood plasma.

Treatment consists of immediate (optimally in the first hour) use of an antidote, which is calcium folinate. The volume of the administered substance must be equal to or exceed the dose of Methotrexate taken. Additionally, doses of calcium folinate can be prescribed by your doctor as needed. Before administering each subsequent dose, and then every 6 hours throughout the entire process of eliminating the symptoms of an overdose using an antidote, the pH of the urine must be determined. Such measures will minimize the likelihood of developing nephropathy.

Also, the necessary set of measures to eliminate the consequences of a drug overdose includes hydration of the body and alkalization of urine. These procedures will speed up the elimination of methotrexate.

Interaction with other substances and drugs

If a patient has gout and is prescribed Methotrexate or Methotrexate Ebewe, the dose of anti-gout drugs must be adjusted. Concurrent use of salicylates, phenylbutazone, phenytoion, sulfonamides, a number of certain antibiotics (tetracycline, penicillin, chloramphenicol), indirect anticoagulants and lipid-lowering medications can lead to severe intoxication, even death.

Large volumes of Methotrexate in parallel with NSAIDs can cause death from severe hematological and gastrointestinal intoxication. The combination of NSAIDs and low doses of the drug we are considering can reduce the excretion of the latter by the renal tubules.

Hepatotoxic medications (based on sulfasalazine, azathioprine, ethanol) increase the risk of developing hepatotoxicity, hematotoxic ones - the hematotoxicity of Methotrexate. Concurrent use of the drug and radiation therapy procedures may cause bone marrow suppression.

Special instructions

Before starting treatment with the drug “Methotrexate” (injections, whether tablets are used - it doesn’t matter), it is necessary to conduct a general blood test (find out the level of platelets), biochemistry (determine the values ​​of liver enzymes, albumin, bilirubin), and take a chest x-ray. In addition, it is necessary to examine the functioning of the kidneys; in some cases, tests for hepatitis and tuberculosis will not be superfluous.

In order not to miss the moment of development of intoxication, it is necessary to monitor the composition of peripheral blood (the number of platelets and leukocytes), kidney function, the activity of liver transaminases, and the level of uric acid in the blood serum. Before each use of Methotrexate, the mucous membranes of the oral cavity and pharynx should be checked for the presence of ulcers. The process of bone marrow hematopoiesis should be monitored at the beginning of therapy, once during the course of treatment and after its completion.

Price range

The release form (tablets, injections) and dosage are the main factors influencing the cost of the drug "Methotrexate".

The price of a package of tablets (50 pieces) with a dosage of 2.5 mg can range from 240 to 250 rubles. The same number of tablets with a dose of 5 mg can be purchased for an amount from 390 to 420 rubles. A package of the drug with the highest dosage (10 mg) will cost the buyer 530-550 rubles.

The injection solution is much more expensive, and the price range is much wider. For example, 5 ampoules of a medication with a dosage of 50 mg/5 ml in some pharmacies can cost about 1200-1300 rubles, in others - 4900 rubles.

Consumer Opinion

There are both positive and negative opinions of patients about the drug Methotrexate. In rheumatoid arthritis, reviews were mostly positive (about 80% of patients felt effectiveness in the first 1-1.5 months from the start of treatment). However, you can often hear about the negative impact of the medication on the patient’s body, about the development of side effects of varying severity and from different systems and organs.

To minimize the negative impact, Methotrexate should be prescribed exclusively by the attending physician, and he must also develop a treatment regimen and select an effective dose.

An antitumor drug that is used more often than other drugs of the same pharmacological group due to its low hematological toxicity. It was first synthesized about 80 years ago, therefore it has a sufficient clinical base of research and therapeutic results.

Dosage form

The drug is available in the form of oral tablets, 50 pieces per package. The tablets are coated and have a pinkish color.

Description and composition

The drug contains one active ingredient called methotrexate. Its dosage in one tablet is 2.5 mg. The shell contains sucrose, which should be taken into account in patients with intolerance to this component or a disorder of its metabolism.

The action of the drug is based on inhibition of reactions necessary for DNA synthesis and cell division. Methotrexate is especially active against tissues with high cell proliferation, therefore it is successfully used for the treatment of malignant neoplasms. High sensitivity to the active substance is demonstrated by tumor cells, growing embryos, bone marrow, intestines, bladder and oral mucosa. This leads to the fact that during treatment, undesirable reactions can occur in places where tissues are highly susceptible to the drug.

Methotrexate exhibits cytotoxic and immunosuppressive activity. In the fetus, the drug provokes teratogenic disorders.

Methotrexate has also shown positive results in the treatment of other diseases, including bronchial asthma, Crohn's disease, arthritis, and mycosis.

The active substance penetrates the blood-brain barrier, the placenta and into breast milk.

Pharmacological group

Refers to antimetabolites and antitumor agents.

Indications for use

for adults

Methotrexate is prescribed for the treatment of:

1. Leukemia.
2. Lymphomas.
3. Central nervous system tumors, breast, neck, lung, stomach cancer.
4. Mycosis fungoides.
5. Severe psoriasis.
6. Rheumatoid arthritis.

for children

Used for children from the age of three, in accordance with the main indications for use.

for pregnant women and during lactation

Methotrexate is strictly prohibited to be taken during pregnancy and lactation. The drug can cause fetal death or congenital deformities. If an unexpected pregnancy occurs during treatment, the woman should decide to terminate the pregnancy. Therapy in nursing women begins after cessation of lactation.

Contraindications

The medicine should not be prescribed for the following conditions:

1. Acute infectious process.
2. Hypersensitivity to methotrexate.
3. Age under 3 years.
4. Pregnancy and lactation period.
5. Pathologies of the liver and kidneys.
6. Diseases in the field of hematology.

Relative contraindications that require a more thorough examination of the patient are peptic ulcers, dehydration, gout, ascites, and infectious processes caused by various pathogens.

Applications and dosages

for adults

Eating only changes the rate of absorption of the drug, but not its bioavailability, so Methotrexate can be used at any time of the day.

The tablets are taken orally with water. The exact dosage and duration of the course are determined by the doctor individually, taking into account the nature of the disease and the patient’s medical history.

Treatment of tumors is carried out in courses. One course lasts 5 days and is repeated up to 5 times at weekly intervals. The daily dose of Methotrexate is 15-30 mg. Another scheme is possible, in which the drug is taken once every five days at a dose of 50 mg.

For leukemia, Methotrexate is one of the drugs in complex therapy. The required dosage is calculated taking into account body weight or area.

For rheumatoid arthritis, the initial dose is 7.5 mg. It is taken once a week and in severe cases can be increased at the discretion of the doctor. After achieving positive dynamics, the dose of the hormone must be reduced to the minimum effective.

Therapy for psoriasis involves gradually increasing the dose until the desired result is achieved. As a rule, it is 10-25 mg per week.

Side effects

The disadvantage of Methotrexate's wide spectrum of activity is the large number of side effects that affect almost all organs and systems.

1. Hematopoiesis: anemia, changes in blood counts, lymph diseases.
2. Digestion: nausea, inflammatory diseases of the oral cavity, liver disorders, pancreatitis, bleeding, enteritis.
3. Nervous system: dizziness, drowsiness, convulsions, changes in emotional state, encephalopathy.
4. Vision: inflammatory processes and visual impairment.
5. Heart and blood vessels: inflammation of the pericardium, venous thrombosis, inflammatory vascular diseases, decreased blood pressure.
6. Breathing: respiratory failure, obstructive disease, shortness of breath.
7. Genitourinary system: kidney damage and functional failure, decreased libido and germ cell production, impotence, infertility, gynecomastia, fetal death, cycle disorders, bleeding.
8. Skin: rash, itching, infectious and inflammatory processes, psoriasis, necrosis, dermatitis.

Side effects can be minimized by prescribing the lowest dose that leads to the desired treatment result and effectiveness.

Interaction with other drugs

Methotrexate increases the activity of anticoagulants, resulting in an increased risk of bleeding.

The drug increases the amount of uric acid in the blood, which is dangerous for patients with gout.

The toxicity of methotrexate increases significantly when taken simultaneously with salicylates, sulfonamides, trimethoprim, some antibiotics, lipid-lowering agents, and anticoagulants. The patient must inform the attending physician about all drugs he is taking, except Methotrexate, to avoid unexpected interactions and complications.

The release of Methotrexate slows down when taken simultaneously with non-steroidal anti-inflammatory drugs. This can lead to severe intoxication and death due to damage to the gastrointestinal tract and blood system.

And chloramphenicol reduce the absorption of Methotrexate.

When taking retinoids and ethanol-containing substances, the hepatotoxicity of the drug significantly increases.

Other interactions are also possible and should be taken into account by your healthcare professional.

Special instructions

Methotrexate is a fairly serious drug and therefore requires caution when used. The treatment regimen, dosage and duration of the course should be prescribed by a specialist who has experience working with cytostatic drugs. The patient must fully understand the treatment mechanism and its complexity, and also be aware of the likelihood of severe complications that can lead to death.

Before starting therapy, the patient must undergo a complete examination of the affected organ and undergo a detailed blood test.

After starting treatment, tests and analyzes should be carried out periodically to help identify intoxication in a timely manner. In particular, the doctor should pay attention to the condition of the oral mucosa and conduct a chest x-ray.

You should always remember about the high hepatotoxicity of the drug, monitor biochemical blood parameters and, if necessary, perform a biopsy.

If Methotrexate provokes diarrhea or ulcers, treatment with the drug must be interrupted due to the high likelihood of perforation of the intestinal wall and death.

During treatment with Methotrexate, the patient must use reliable methods of contraception and continue to use them for another 3 months after the end of the course.

Overdose

There are no specific symptoms that can be used to determine an overdose of Methotrexate. The condition is diagnosed based on test results that show an increased concentration of the active substance in the blood plasma.

In case of overdose, immediate administration of an antidote, calcium folinate, is indicated.

Storage conditions

Methotrexate should be stored out of the reach of children, at a temperature not exceeding 25 degrees.

Analogues

Methotrexane is produced by different pharmaceutical companies under the same name with the addition of the manufacturer. Analogs are also:

1. Methodject. Antimetabolic drug based on methotrexate for systemic use. It is a solution for subcutaneous administration. Manufacturer – Germany.
2. Trexan. Analogue of Methotrexate. Available in oral form.
3. Evetrex. Antitumor drug for oral administration. Available in 5 and 10 mg dosages.
4. Zeksat. Injection solution for the treatment of various malignant neoplasms.

Price

The cost of Methotrexate is on average 630 rubles. Prices range from 92 to 3143 rubles.

Methotrexate is an antimetabolite. It is used in the treatment of non-oncological diseases.

Photo of the drug Methotrexate

• Active ingredient: methotrexate sodium.
• Excipients: lactose anhydrous, magnesium stearate, pregelatinized starch, sodium hydroxide and sodium starch glycolate.
• Pharmacotherapeutic group: Antineoplastic agents. Antimetabolites. Structural analogues of folic acid.
• Release form: tablets, solution for injection, lyophilisate for solution for injection.
• Storage conditions: The medicine is stored at room temperature away from moisture and heat.
• Terms of sale: according to the recipe.
• Manufacturer: VINUS REMEDIES LIMITED, INDIA.

Indications for use

Methotrexate is used to treat:

• certain types of cancer, head and neck, and;
• tumors and;
• severe psoriasis;
• rheumatoid arthritis;
• anaplastic anemia.

This drug is usually given when no other medications help relieve the symptoms of the disease.

Contraindications

Methotrexate is contraindicated in people with:

• liver diseases (especially if they are caused by alcoholism);
• disorders of bone marrow function;
• blood system disorders such as anemia or leukopenia;
• pneumonia;
• stomach ulcer;
• immunodeficiency;
• any infectious disease.

Do not use methotrexate if you have previously had an allergic reaction to it.

Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis, and should only be used as chemotherapy to treat cancer and other neoplastic diseases when the potential benefit outweighs the risk to the fetus.

Patients with impaired renal function, ascites, or pleural effusion require particularly careful monitoring of toxicity and dose reduction or, in some cases, discontinuation of the drug.

Use during pregnancy and lactation

Do not use Methotrexate if you are pregnant or breastfeeding. This substance can cause birth defects in a child.

Both women and men who are being treated with Methotrexate must use contraception to prevent pregnancy. Use of this drug by one of the parents may cause teratogenic effects in the fetus.

Children

The safety and effectiveness of Methotrexate in children has only been established for chemotherapy of cancer and polyarticular juvenile rheumatoid arthritis.

Pharmacological action

Methotrexate inhibits dihydrofolic acid reductase, thereby interfering with DNA synthesis and cellular replication. The specificity of its action is observed in the S-phase of the cell cycle. Actively proliferating tissues, such as malignant cells, bone marrow, intestinal mucosa, and bladder cells, are more sensitive to its effect. When cell proliferation in malignant tumors is significantly higher than in most normal tissues, methotrexate can suppress the growth of cancer cells without irreversibly damaging healthy tissue.

In psoriasis, the rate of production of epithelial cells in the skin increases significantly. This is the basis for the use of methotrexate in the treatment of this disease.

The effect of the drug on immune activity and its connection with rheumatoid immunopathogenesis awaits further research. In patients with rheumatoid arthritis, the effect of methotrexate is observed within 3-6 weeks. Although this medication clearly improves symptoms of inflammation (pain, swelling), there is no evidence that it causes remission of rheumatoid arthritis.

Pharmacokinetics

Peak serum levels of methotrexate after oral administration in adults are achieved within 1-2 hours. At doses of 30 mg/m2 or less, the drug is usually well absorbed with an average bioavailability of about 60%. In children, oral absorption of methotrexate is dose dependent and has a wide range in time to peak concentration and bioavailability (23% - 95%). The half-life of the drug ranges from 0.7 to 5.8 hours.

When given intravenously, Methotrexate is usually completely absorbed. After absorption, the drug undergoes hepatic and intracellular metabolism. Methotrexate is also partially metabolized by intestinal flora after oral administration. Small amounts of methotrexate in polyglutated forms may remain in tissues for a long time.

The terminal half-life of the drug is approximately 3-10 hours when administered at a dose of less than 30 mg/m2. For patients receiving high doses of methotrexate, the half-life ranges from 8-15 hours.

Methotrexate does not penetrate the blood-brain barrier.

Renal excretion is the main route of elimination of drug metabolites. When administered intravenously, 80 to 90% of the administered dose is excreted unchanged in the urine within 24 hours, another 10% is excreted in the bile.

Impaired renal function, as well as the simultaneous use of drugs that also undergo tubular secretion in the kidneys, can markedly increase the level of methotrexate in the blood serum.

Instructions for use of Methotrexate

Methotrexate can be administered orally, intravenously, intramuscularly, intraarterially, intrathecally. Oral administration in tablet form is often preferred when low doses are administered because absorption from the GI tract is faster.

The method of administration, dosage schedule and dose of the drug depend on the diagnosis, age and condition of the patient. Below are examples of the use of Methotrexate for various malignant tumors.

1. Choriocarcinoma and similar trophoblastic diseases. Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg per day for 5 days. Such courses are usually repeated 3-5 times as needed. Between them they take a break of 1-2 weeks until any manifestations of toxic side effects disappear.
2. Leukemia. Methotrexate is used to induce remission in acute lymphoblastic leukemia alone or in combination with steroids. The combination of Methotrexate in doses of 3.3 mg/m2 with Prednisone (60 mg/m2) led to remission in 50% of patients over a period of 4 to 6 weeks. Upon the onset of remission, maintenance therapy is prescribed: methotrexate is administered 2 times a week either orally or intramuscularly in total weekly doses of 30 mg/m2.
3. For patients with stage I-II Burkitt tumor, Methotrexate is administered at a dose of 10-25 mg/day orally for 4-8 days. Stage III lymphosarcoma may respond to combination chemotherapy with methotrexate in doses ranging from 0.625 to 2.5 mg/kg per day.
4. Cutaneous T-cell lymphoma. The dosage in the early stages is usually 50 mg/1 time per week. Methotrexate was also administered twice weekly in doses ranging from 15 to 37.5 mg in patients who responded poorly to weekly therapy.

Side effects

Methotrexate has serious toxicity. Toxic side effects may be related to the dose or frequency of administration, but are observed in all cases. Since they can occur at any time during treatment with Methotrexate, it is necessary to regularly monitor the patient's condition.

Common methotrexate side effects may include:

• changes in menstruation;
• nausea, vomiting, upset stomach;
• headache, dizziness;
• malaise, excessive fatigue;
• hair loss;
• blurred vision.

Methotrexate can suppress hematopoiesis and cause anemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia.

After long-term use, Methotrexate causes hepatotoxicity, including liver fibrosis and cirrhosis. An increase in liver enzymes is very common. Such changes are usually temporary and asymptomatic, but there is a possibility of subsequent liver failure and death. In order to timely detect histological changes in the liver, patients treated with Methotrexate are advised to undergo a biopsy. Like other cytotoxic drugs, methotrexate can induce tumor lysis syndrome. Appropriate supportive and pharmacological measures can prevent or alleviate this complication.

Methotrexate can cause serious or life-threatening changes in the liver, lungs, or kidneys. Tell your doctor if you experience any of the following: symptoms:

• stomach pain, dark urine, clay-colored stools, jaundice, loss of appetite (a combination of these signs may indicate liver problems);
• dry cough, shortness of breath;
• blood in urine;
• convulsions, hemiparesis;
• white spots or sores in the mouth or lips;
• fever, along with other symptoms of infection;
• severe skin reaction (swelling of the face or tongue, burning eyes, red or purple skin rash that spreads and causes peeling);
• problems with urination.

Diarrhea and ulcerative stomatitis require interruption of therapy, otherwise hemorrhagic enteritis and intestinal perforation may develop, leading to death.

Before starting treatment, the patient should be informed that Methotrexate may affect fertility (the ability to have children).

Overdose

In cases of taking too large a dose of methotrexate and overdose, it is recommended to use Leucovorin as quickly as possible. Hydration and alkalinization of the urine help prevent sedimentation of methotrexate and its metabolites in the renal tubules.

Neither hemodialysis nor peritoneal dialysis improves the elimination of this drug from the body.

Symptoms that are usually observed after oral overdose include those presented in side effects, especially hematological and gastrointestinal reactions: leukopenia, thrombocytopenia, anemia, mucositis, stomatitis, nausea, vomiting, gastric ulcers, gastrointestinal bleeding. There have been reports of deaths preceded by sepsis or septic shock, renal failure and aplastic anemia.

Special instructions

Methotrexate can be found in urine, feces and vomit. Caregivers should wear rubber gloves when cleaning up such organic liquids or changing clothes or diapers. Contaminated clothing and bedding should be washed separately from other items.

Avoid exposure to bright sunlight or artificial ultraviolet rays, especially if you are being treated for psoriasis. Methotrexate can make the skin more sensitive to sunlight, and the disease may worsen.

Avoid drinking alcohol while taking methotrexate.

Interaction

The following drugs or substances may interact with methotrexate:

• azathioprine;
• leucovorin;
• phenytoin;
• probenecid;
• theophylline;
• antibiotics or sulfa drugs;
• isotretinoin, retinol, tretinoin;
• non-steroidal anti-inflammatory drugs (Ibuprofen, Naproxen, Celecoxib, Diclofenac and others);
• salicylates (aspirin, Pepto-Bismol, trilisate and others).

Chemotherapy with Methotrexate in combination with radiation therapy increases the risk of soft tissue necrosis.

Immunization with live viral vaccines during chemotherapy is usually not recommended.

Antitumor drug. It is used in the treatment of benign and malignant tumors.

Instructions for use:

Methotrexate is a cytostatic drug from the group of antimetabolites, folic acid antagonists. It has a pronounced immunosuppressive effect even in relatively low doses without noticeable hematological toxicity. Due to this, methotrexate is used more widely than other cytostatics with immunosuppressive activity as an immunosuppressive drug.

Description of the drug Methotrexate is not intended for prescribing treatment without the participation of a physician.

Release form and composition

Pills

Solution for injection

Pharmacological properties

Has antitumor and immunosuppressive effects. Actively dividing cells of malignant tumors, as well as bone marrow, embryo, mucous membranes of the oral cavity, intestines, and bladder are especially sensitive to the action of methotrexate.

After intravenous administration, it is quickly distributed within a volume equivalent to the total volume of body fluids. The initial volume of distribution is 0.18 l/kg (18% of body weight), the equilibrium volume of distribution is 0.4-0.8 l/kg (40-80% of body weight). The binding to plasma proteins is about 50%.

When taken in therapeutic doses, regardless of the route of administration, it practically does not penetrate the blood-brain barrier (after intrathecal administration, high concentrations are reached in the cerebrospinal fluid). Secreted into breast milk, passes through the placenta (has a teratogenic effect on the fetus).

Metabolized predominantly in liver cells to form polyglutamates (DHF and thymidylate synthetase inhibitors), which can be converted into methotrexate under the action of hydrolases.

A small amount of polyglutaminated derivatives is retained in tissues for a long time. The retention time and duration of action of these active metabolites depends on the cell type, tissue, and tumor type.

Slightly metabolized (when administered in normal doses) to 7-hydroxymethotrexate (solubility in water is 3-5 times lower than that of methotrexate). Accumulation of this metabolite occurs with the administration of high doses of methotrexate prescribed for the treatment of osteosarcoma.

The half-life in patients receiving less than 30 mg/m2 of the drug in the initial phase is 2-4 hours. The final half-life is dose-dependent and is 3-10 hours with the introduction of low (less than 30 mg/m2) and 8-15 hours with high doses of methotrexate (80 mg/m2 or more).

It is excreted primarily by the kidneys by glomerular filtration and tubular secretion within 24 hours, less than 10% is excreted in bile. Clearance of methotrexate varies widely and decreases at high doses.

The elimination of the drug in patients with severe ascites or effusion into the pleural fluid is slow. Upon repeated administration, it accumulates in tissues in the form of metabolites. In chronic renal failure, the elimination of the drug can be significantly prolonged.

Indications for use of Methotrexate

• lympho- and myeloblastic leukemia;
• neuroleukemia;
• multiple myeloma;
• trophoblastic tumors;
• esophageal cancer;
• squamous cell carcinoma of the head and neck;
• bladder cancer;
• lung cancer;
• liver cancer;
• breast cancer;
• kidney cancer;
• ureteral cancer;
• prostate cancer;
• cervical cancer;
• vulvar cancer;
• ovarian cancer;
• testicular cancer;
• penile cancer;
• Hodgkin and non-Hodgkin lymphomas (including Burkitt lymphoma);
• mycosis fungoides (local treatment);
• non-metastatic osteosarcoma.

Besides:

• rheumatoid arthritis (including Felty's syndrome);
• steroid-dependent bronchial asthma;
• Crohn's disease;
• chronic nonspecific ulcerative colitis;
• lichen planus;
• psoriasis;
• psoriatic arthritis;
• Reiter's syndrome;
• Sézary syndrome;
• multiple sclerosis.

Directions for use and doses

Doses and timing of treatment are set individually, depending on the chemotherapy regimen, indications, treatment regimen, patient response and tolerability. Doses are calculated based on body surface area or patient weight.

The doses used in accordance with the treatment regimens are divided:

• usual (low) doses (single dose below 100 mg/m2);
• medium (single dose 100-1000 mg/m2);
• high (single dose above 1000 mg/m2).

Doses above 100 mg/m2 are administered only intravenously and under the protection of calcium folinate. For intravenous administration, the drug is diluted in a 5% dextrose solution to a concentration of 10 mg/ml.

The following dosage regimens are used:

Features of application

Conception should be avoided during treatment with methotrexate and after it (men - 3 months after treatment, women - at least one ovulation cycle). After a course of treatment with methotrexate, the use of calcium folinate is recommended to reduce the toxic effects of high doses of the drug. If diarrhea and ulcerative stomatitis develop, methotrexate therapy should be interrupted and consult a doctor immediately.

Side effects

From the nervous system and sensory organs:

• encephalopathy;
• dizziness;
• headache;
• visual impairment;
• drowsiness;
• aphasia;
• back pain;
• stiffness of the muscles in the back of the neck;
• convulsions;
• paralysis;
• hemiparesis.

In some cases:

• fatigue;
• weakness;
• confusion;
• ataxia;
• tremor;
• irritability;
• coma;
• conjunctivitis;
• excessive tearing;
• cataract;
• photophobia;
• cortical blindness (at high doses).

From the cardiovascular system:

• pericarditis;
• exudative pericarditis;
• hypotension.

Thromboembolic changes:

• arterial thrombosis;
• cerebral thrombosis;
• deep vein thrombosis;
• renal vein thrombosis;
• thrombophlebitis;
• pulmonary embolism.

From the hematopoietic organs and hemostasis system:

• anemia;
• leukopenia;
• thrombocytopenia;
• neutropenia;
• lymphopenia (especially T lymphocytes);
• hypogamma globulinemia;
• hemorrhage;
• septicemia due to leukopenia.

From the respiratory system:

• interstitial pneumonitis;
• pulmonary fibrosis;
• exacerbation of pulmonary infections.

From the gastrointestinal tract:

• gingivitis;
• pharyngitis;
• ulcerative stomatitis;
• anorexia;
• nausea;
• vomit;
• diarrhea;
• difficulty swallowing;
• melena;
• ulceration of the gastrointestinal mucosa;
• gastrointestinal bleeding;
• enteritis;
• liver damage;
• fibrosis and cirrhosis of the liver.

From the genitourinary system:

• cystitis;
• nephropathy;
• azotemia;
• hematuria;
• hyperuricemia or severe nephropathy;
• dysmenorrhea;
• unstable oligospermia;
• disruption of the process of oogenesis and spermatogenesis;
• abnormalities of fetal development.

From the skin:

• skin erythema;
• hair loss (rare);
• photosensitivity;
• ecchymosis;
• acne-like rash;
• furunculosis;
• peeling;
• de- or hyperpigmentation of the skin;
• blistering;
• folliculitis;
• telangiectasia;
• toxic epidermal necrolysis;
• Stevens-Johnson syndrome.

Allergic reactions:

• fever;
• chills;
• rash;
• hives;
• anaphylaxis.

Others:

• immunosuppression;
• opportunistic infection;
• osteoporosis;
• vasculitis

Interaction with other drugs

Contraindications

• hypersensitivity;
• immunodeficiency;
• anemia (including hypo- and aplastic);
• leukopenia;
• thrombocytopenia;
• leukemia with hemorrhagic syndrome;
• liver or kidney failure;
• effusion into the pleural cavity;
• ascites;
• suppression of bone marrow function;
• chicken pox (including recently suffered);
• stomatitis;
• ulcerative colitis.

Contraindicated during pregnancy (can cause fetal death or cause congenital deformities). During treatment should be stopped breast-feeding.

Overdose

There are no specific symptoms of overdose. In case of intentional or accidental intake of doses exceeding the recommended ones, as well as in the event of obvious symptoms of side effects, you should immediately consult a doctor.

Storage conditions and periods

Conditions for dispensing from pharmacies

Dispensed by prescription.

Methotrexate analogues

The following drugs are analogues:

• Vero-Methotrexate;
• Methotrexate Teva;
• Methotab;
• Methodject;
• Zeksat.

Methotrexate price

You can buy Methotrexate tablets and solution for injections in pharmacies for 169–597 rubles.