Trade name: Methobel
International non-proprietary name: Methotrexate.
Description: Porous mass or powder of from yellow, orange to yellow-brown nonhomogenous color, hygroscopic.
Composition:each ampoule/vial contains: active substance: methotrexate (in the form of methotrexate sodium) –50 mg.
Pharmaceutical form: lyophilized powder for solution for injection.
Pharmacotherapeutic group: Antineoplastic drug products. Antimetabolites.
ATC code: L01BA01.
It is an antimetabolite of a group of structural analogues of folic acid. It has antineoplastic (cytostatic), immunosuppressive action. It inhibits dihydrofolatereductase (DHFR), which transforms dihydrofolic acid into tetrahydrofolic acid, being one-carbon group donor in the synthesis of purine nucleotides and thymidylate necessary for DNA synthesis. Furthermore, methotrexate undergoespolyglutamation inside the cell with formation of metabolites having inhibitory action not only on DHFR, but also on other folate dependant enzymes, including thymidylate synthetase, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transamylase.
It suppresses DNA synthesis and repair, cell mitosis, to a lesser degree it affects RNA and protein synthesis. Having S-phase specificity, it is active in respect of tissues with high proliferative cell activity and inhibits growth of malignant neoplasms. The most sensitive are actively dividing tumor cells, as well as bone marrow, embryo, oral, intestinal, vesical mucous membrane cells.
Following intravenous administration it is promptly distributed within the volume equivalent to the overall body fluid volume. Initial volume of distribution is 0.18 l/kg (18% of body weight), equilibrium volume of distribution is 0.4 to 0.8 l/kg (40 to 80% of body volume). Plasma protein binding is approximately 50%.
When administered in therapeutic doses regardless of the route of administration it practically does not penetrate through the hematoencephalic barrier (high concentrations are achieved in the spinal fluid after intrathecal administration). It is secreted into breast milk, passes through placenta (has teratogenic action on the fetus).
It is metabolized mainly in the liver cells with formation of polyglutamates (DHFR and thymidylate synthetase inhibitors), which may be converted into methotrexate under the action of hydrolases. A slight quantity of polyglutamate derivatives is retained in tissues for a long time. Retention time and effective duration of these active metabolites depends on cell, tissue and tumor type. It is insignificantly metabolized (in case of standard dose administration) to 7-hydroxy-methotrexate (water solubility is 3 to 5 times lower than that of methotrexate). This metabolite is accumulated on administration of high doses of methotrexate prescribed for osteosarcoma therapy.
The initial phase half-life is 2 to 4 hours in patients receiving less than 30 mg/m2 of the drug. Terminal T1/2 is dose-dependent and amounts to 3 – 10 hours in case of administration of low (less than 30 mg/m2) doses of methotrexate and 8 – 15 hours – in case of high doses of methotrexate (80 mg/m2 and more). It is excreted mainly by kidneys by means of glomerular filtration and tubular secretion within 24 hours, less than 10% are excreted with bile. Methotrexate clearance rates vary widely and decreases in case of high doses.
Drug excretion is delayed in patients with evident ascites and pleural effusion. In case of repeated administration it is accumulated in tissues in the form of metabolites. In case of chronic renal failure, drug excretion may be significantly prolonged.
Methotrexate is indicated for treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole.
In case of acute lymphoblastic leukemia, methotrexate is indicated for the prophylactics of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents.
Methotrexate is also indicated for the treatment of meningeal leukemia.
Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T-cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents for treatment of advanced stage non-Hodgkin’s lymphoma.
Methotrexate in high doses followed by calcium folinate rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation of the primary tumor.
Methotrexate is indicated for the symptomatic control of severe, recalcitrant, disabling psoriasis in patients who do not have adequate response to other forms of therapy, but only when the diagnosis has been established, by biopsy and/or after dermatologic consultations. It is important to ensure that a psoriasis flare is not due to an undiagnosed disease affecting immune responses.
Rheumatoid arthritis including polyarticular-course juvenile rheumatoid arthritis
Methotrexate is indicated in the management of selected category of adult patients with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate first-line therapy including a full dose of non-steroidal anti-inflammatory agents (NSAIDs).
Aspirin, (NSAIDs), and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued.
Route of administration and doses
Methotrexate is administered orally and parenterally: it is introduced intramuscularly, intravenously, intra-arterially, intrathecally. Dose is calculated based on the patient weight or body surface area. Methotrexate is effective in case of the wide list of oncologic diseases both in the form of monotherapy and in combination with other chemotherapeutic agents. Oral administration in tablet form is often preferred when low doses are being administered. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Choriocarcinoma and similar trophoblastic diseases. Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course.
As a rule, such courses are repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is usually evaluated by 24 hour quantitative analysis of urinary human chorionic gonadotropin (hCG), which should return to normal value or less than 50 IU/24 h, as a rule, after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drug products has been reported as being useful.
Since hydatidiform mole may be preceded by choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended. Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.
Primary breast cancer with metastases in axillary lymph nodes. In combination with cyclophosphamide, methotrexate and Fluorouracil are used as adjuvant therapy with radical mastectomy. Average methotrexate dose is 40 mg/m2on the 1st and 8th days of treatment.
Leukemia. Acute lymphoblastic leukemia in children and adolescents is the most responsive to chemotherapy to the present day. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemia. Corticosteroid therapy, in combination with other antileukemic drug products or in cyclic combination with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisolone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions.
When remission is achieved and supportive therapy has produced general clinical improvement, maintenance therapy is initiated as follows: Methobel is administered 2 times weekly either orally or intramuscularly in total weekly dose of 30 mg/m2. It can also be given in doses of 2.5 mg/kg intravenously every 14 days.
A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy.
Meningeal leukemia. CNS damage is observed in many patients with leukemia. In all cases of lymphatic leukemia, methotrexate may be prescribed for prophylactics of central nervous system damages. But methotrexate hardly penetrates through the hematoencephalic barrier and for adequate therapy it is administered intrathecally. Preservative free methotrexate is diluted to a concentration of 1 mg/ml in an appropriate sterile, preservative free medium such as 0.9% sodium chloride injection solution.
The cerebrospinal fluid (CSF) volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.
Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following drug doses are recommended based on age instead of body surface area:
3 or older
In one study this dosage regimen resulted in consistent CSF methotrexate concentrations and less neurotoxicity.
According to some studies in pediatric patients with acute lymphocytic leukemia compared with the above-mentioned regimen, the drug was introduced in a dose of 12 mg/m2 regardless of the age or body surface area (maximum 15 mg), and this study demonstrated a significant reduction in the rate of CNS relapse in the observed group compared with the group whose dose was based on age.
For choice of regimen, it is advisable for the physician to consult the medical literature.
In patients below 3 years, methotrexate is prescribed included in combination therapy. It is usually used with a week interval until normalization of the cerebrospinal fluid cell count.
Because the CSF volume may decrease with age, a dose reduction may be indicated in elderly patients.
For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration of the drug at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylactics against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature.
Adverse side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions.
Methotrexate prescribed by the intrathecal route appears significantly in the systemic circulation and may cause systemic toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued. Leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and it is best to consider radiotherapy.
Lymphomas. In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dose is 10 to 25 mg orally every other day for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all these stages usually consists of several courses interposed with 7 to 10 day rest periods.
Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily. Response to methotrexate is insignificant in case of Hodgkin's disease.
Mycosis fungoides (cutaneous T-cell lymphoma). Therapy with methotrexate as a monotherapy appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once a week. Dose reduction or cessation is guided by patient response and hematologic control. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy that includes intravenous methotrexate administration at high doses with calcium folinate rescue have been utilized in advanced stages of the disease.
Osteosarcoma. Effective adjuvant chemotherapy requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with calcium folinate rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose methotrexate treatment is 12 g/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 10-3 mmole/l at the end of infusion, the dose may be escalated to 15 g/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral drug product, calcium folinate is given intravenously or intramuscularly at the same dose and schedule.
Treatment week after surgery
12 g/m2 intravenously for course of 4 hours (starting dose)
4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44
15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion
Doxorubicinas a single drug
30 mg/m2/day intravenously for 3 days
50 mg/m2 intravenously
100 mg/m2 intravenously
20, 23, 33, 36
20, 23, 33, 36
15 units/m2 intravenously for 2 days
2, 13, 26, 39, 42
600 mg/m2 intravenously for 2 days
2, 12, 26, 39, 42
0.6 mg/m2 intravenously for 2 days
2, 12, 26, 39, 42
When these high doses of methotrexate are to be administered, the following safety guidelines should be observed.
GUIDELINES FOR METHOTREXATE THERAPY WITH CALCIUM FOLINATE RESCUE
1. Administration of methotrexate should be delayed until recovery if:
· the leukocyte count is less than 1500/µl;
· the neutrophil count is less than 200/ µl;
· the platelet count is less than 75 000/µl;
· the serum bilirubin level is greater than 1.2 mg/dl;
· the serum glutamic pyruvic transaminase (SGPT) level is greater than 450 U;
· mucositis is present, until there is evidence of healing;
· persistent pleural effusion is present. This should be drained dry prior to infusion.
2. Normal renal function must be clinically proved.
a. Serum creatinine must be normal, and creatinine clearance must be greater than 60 ml/min before initiation of therapy.
b. Serum creatinine must be measured prior to each subsequent course of therapy.
3. Patients must be well hydrated and must be treated with sodium bicarbonate for urinary alkalinization.
a. Administer 1 000 ml/m2 of intravenous fluid during 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 ml/m2/hour (3 liters/m2/day) during the methotrexate infusion and for 2 days after the infusion has been completed.
b. Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and calcium folinate therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate solution for intravenous administration.
4. Serum creatinine and serum methotrexate should be evaluated repeatedly in 24 hours after starting methotrexate therapy and at least once daily until the methotrexate level is below 5x10-8 mole/l (0.05 micromole).
Patients who experience delayed methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate calcium folinate therapy, these patients require continuing hydration, urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen below 0.05 micromole and the renal failure has resolved. If necessary, acute short-term hemodialysis with a high-flux dialyzer may also be beneficial in these patients.
5. Some patients have abnormalities in methotrexate elimination or impaired renal function following methotrexate administration, which are significant. These abnormalities may or may not be associated with significant clinical toxicity. If significant toxicity is not observed, calcium folinate therapy should be extended for additional 24 hours (total 14 doses during 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other drug products which interact with methotrexate (e.g., drug products which may interfere with methotrexate binding to serum albumin) should always be reconsidered, even if no abnormalities are observed in laboratory tests.
CAUTION: DO NOT ADMINISTER CALCIUM FOLINATE INTRATHECALLY!
Psoriasis, rheumatoid arthritis, and juvenile rheumatoid arthritis.
Adults, rheumatoid arthritis - recommended starting dosage:
1. Single oral doses of 7.5 mg once a week.
2. Divided oral doses of 2.5 mg at 12 hour intervals for 3 doses given as a course once a week.
Parenteral route of administration:the recommended starting dose is 7.5 mg of methotrexate introduced subcutaneously, intramuscularly or intravenously once a week. Depending on the patient’s disease and drug tolerance, the starting dose may be gradually increased by 2.5. mg a week. The weekly dose of 25 mg may not be exceeded. Appearance of the response to the treatment may be expected in 4 to 8 weeks. After achievement of the therapeutic effect the dose should be gradually reduced until the last dose necessary to maintain the drug action.
Dosage for children below 16 years with polyarticular-course juvenile rheumatoid arthritis: the recommended starting dose is 10 to 15 mg/m2/week. In case of insufficient effect the weekly dose may be increased up to 20 mg/m2/week. The drug is administered intramuscularly to this group of patients.
For any adult patient with rheumatoid arthritis (RA) or in patients with juvenile rheumatoid arthritis (JRA), dosage may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/week in adults. Although there is experience with doses up to 30 mg/m2/week in children, there are too few published data to assess how doses over 20 mg/m2/week might result in serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/week (0.65 to 1.0 mg/kg/week) may have better absorption and fewer gastrointestinal side effects, if methotrexate is administered either intramuscularly or subcutaneously.
Therapeutic response usually begins within 3 to 6 weeks and the patient’s condition may continue to improve for another 12 weeks or more.
The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate therapy is discontinued, the arthritis usually worsens within 3 to 6 weeks.
The patient should be fully informed of the risks involved and should be under constant supervision of the physician.
Assessment of hematologic, hepatic, renal and pulmonary functions should be made through the whole course of therapy, physical examination and laboratory tests before beginning, periodically during therapy. Appropriate measures should be taken to avoid conception during methotrexate therapy.
All schedules should be continually revised and monitored subject to the individual patient specifics. An initial test dose may be given prior to the regular dosing schedule to detect any increased sensitivity to the drug. Maximal myelosuppression usually occurs in seven to ten days.
1. Weekly single intramuscular or intravenous administration: 10 to 25 mg per week until adequate response is achieved. A test dose of 5 to 10 mg is recommended to introduce by parenteral route 1 week before therapy in order to detect idiosyncratic reaction. The recommended starting dose is 7.5 mg of methotrexate introduced subcutaneously, intramuscularly or intravenously a week. The dose should be gradually increased, but the weekly dose of 30 mg of methotrexate should not be exceeded. Appearance of response to the treatment may be expected in 2 to 6 weeks. After achievement of the therapeutic effect the dose should be gradually reduced until the last dose necessary to maintain the drug action.
2. Divided oral doses of 2.5 mg at 12 hour intervals for three doses per week.
Dosage is introduced gradually until optimal clinical response is achieved; the dose of 30 mg/week should not be exceeded.
Once optimal clinical response has been achieved, the dose schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.
Methotrexate injection solution 1 g/10 ml or 5 g/50 ml is hypertonic and may not be used intrathecally. Solutions 500 mg/20 ml and 1 g/40 ml are also not intended for intrathecal administration.
Nervous system and sense organs disorders: encephalopathy (especially in patients after brain radiotherapy), dizziness, headaches, blurred vision, drowsiness, aphasia, dysarthria, notalgia, muscle stiffness in nape of the neck, convulsion, paralysis, hemiparesis, paresis, in individual cases – fatigue, weakness, transient cognitive impairment, emotional lability, unusual cranial sensations, mental confusion, ataxia, tremor, irritability, coma, conjunctivitis, over lacrimation, cataract, photophobia, cortical blindness (in case of high doses).
Cardiac disorders: rare - pericarditis, pericardial effusion, hypotension, thromboembolic changes events (arterial thrombosis, cerebral thrombosis, deep vein thrombosis, renal vein thrombosis, thrombophlebitis, pulmonary embolism).
Blood and lymphatic system disorders: anemia, leukopenia, thrombocytopenia, neutropenia, agranulocytosis, eosinophilia, lymphadenopathy, lymphoproliferative disorders, lymphopenia (especially T-lymphocytes), hypogammaglobulinemia, hemorrhage, septicemia in consequence of leukopena.
Respiratory disorders: rare - interstitial pneumonitis, pulmonary fibrosis, exacerbation of lung infections, respiratory failure, alveolitis, chronic obstructive pulmonary disease.
Gastrointestinal disorders: gingivitis, pharyngitis, ulcerative stomatitis, anorexia, nausea, vomiting, diarrhea, forced respiration, melena, hematemesis, pancreatitis, gastrointestinal mucosal ulceration, gastrointestinal bleeding, enteritis, liver injury, hepatic fibrosis and cirrhosis, hepatic failure, hypoalbuminemia, increased activity of “hepatic” transaminases (increased probability in patients receiving continuous or long-term therapy).
Urinary disorders: cystitis, nephropathy, azotemia, hematuria, proteinuria, hyperuricemy or expressed nephropathy, dysmenorrhea, transient oligospermia, defective oogenesis or spermatogenesis, decreased libido, impotence, vaginal discharge, gynecomastia, infertility, spontaneous abortion, fetal death, abnormal fetal development.
Skin and subcutaneous tissue disorders: skin erythema, pruritus, alopecia (rare), photosensitization, ecchymosis, acne, furunculosis, desquamation, de- and hyperpigmentation of skin, blistering, folliculitis, telangiectasia, toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis.
Allergic reactions: fever, chill, rash, hives, anaphylaxis.
Other: immunosuppression, rare – opportunistic infections (including pneumocystic pneumonia, CMV (including CMV-pneumonia), sepsis (including fatal), nocardiosis, histoplasmosis, cryptococcosis, infections caused by Herpes zoster and Herpes simplex (including disseminated), osteoporosis, osteonecrosis, fractures, arthralgia, myalgia, vasculitis, insular diabetes, lymphoma (including reversible), tumor lysis syndrome, soft tissue necrosis, sudden death.
In the therapy of rheumatoid arthritis: greater than 10% - increased activity of hepatic transaminases, nausea, vomiting; 3% to 10% - stomatitis, thrombocytopenia (less than 100 000/µl); 1% to 3% - rash, pruritis, dermatitis, diarrhea, alopecia, leukopenia (less than 3000/ µl), pancytopenia, dizziness, interstitial pneumonitis; other - decreased hematocrit, headache, infections (including upper respiratory infection), anorexia, arthralgia, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, increased sweating, tinnitus, vaginal discharge.
In the therapy of psoriasis: alopecia, photosensitivity, burning skin sensation, painful plaque erosions on skin.
Methotrexate is contraindicated in the following cases:
- significantly impaired liver function (bilirubin level > 85.5 µmole/l);
- alcohol abuse;
- impaired renal function (creatinine clearance < 20 ml/min);
- severe acute or chronic infections (such as tuberculosis or HIV);
- mouth cavity or gastrointestinal ulcers;
- vaccination with live vaccines during methotrexate therapy.
Methotrexate can cause fetal death or teratogenic effects when administered to pregnant women. Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Women of childbearing age should not use methotrexate until pregnancy is excluded and should be fully counseled on the serious risks to the fetus should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate, during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients. Because of the potential for serious adverse reactions from methotrexate in infants, it is contraindicated in nursing mothers.
Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate.
Patients with psoriasis or rheumatoid arthritis who have evident or laboratory signs of immunodeficiency syndromes should not receive methotrexate. Patients with psoriasis or rheumatoid arthritis who have pathological changes of blood, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia, should not receive methotrexate.
Patients with a known hypersensitivity to methotrexate should not receive the drug.
Symptoms: there are no specific symptoms. It is diagnosed by methotrexate plasma levels.
Treatment: immediate administration of calcium folinate to neutralise myelotoxic action of methotrexate (orally, IM or IV). The calcium folinate dose should be at least equal to the methotrexate dose, it must be introduced within the first hour; subsequent doses are administered as necessary. Increased hydration and urinary alkalinization are necessary to prevent the precipitation of the drug and its metabolites in the urinary tracts.
Administration during pregnancy and lactation. Studies detected teratogenic action of methotrexate, for this reason it should not be used during pregnancy. Patients of reproductive age (both women and men) and their partners should use effective contraceptives during therapy and for a minimum of six months after methotrexate therapy. Should a patient or a partner of a man treated with methotrexate become pregnant, consultation with specialist is necessary concerning the risk of negative effect of methotrexate on foetus. Methotrexate is excreted in breast milk, for this reason breast feeding should be discontinued during therapy with the drug.
Precautions for use
After a course of therapy with methotrexate it is recommended to use calcium folinate to reduce toxic effects of high doses of the drug. In addition, during high dose therapy it is necessary to determine methotrexate plasma concentration, urine pH (before each administration and every 6 hours through the whole period of administration of calcium folinate as an antidote until methotrexate plasma concentration becomes below 0.05 µmole/l, to ensure pH higher than 7 in order to minimize the risk of nephropathy resulting from precipitation of the drug or its metabolites in the urine). For timely detection of intoxication symptoms it is necessary to control peripheral blood condition (leukocyte and platelet count: initially every other day, then every 3 to 5 days during the first month, then once every 7 to 10 days, once a week or two during remission period), renal function (urea nitrogen, creatinine clearance and/or serum creatinine, uric acid serum concentration). Methotrexate can potentially cause development of acute or chronic hepatotoxicity symptoms (including hepatic fibrosis and cirrhosis). Chronic hepatotoxicity is usually developed after long-term methotrexate administration (usually for 2 or more years) or achievement of total cumulative dose of at least 1.5 g and may cause adverse outcome. Hepatotoxic effect may also be conditioned by compromised concomitant history (alcoholism, obesity, insulin diabetes) and old age. For objectivization of the hepatic function, along with biochemical parameters, it is advised to conduct liver biopsy before beginning and 2 to 4 months after beginning of the therapy; when total cumulative dose is 1.5 g and after every additional 1 – 1.5 g. In case of moderate hepatic fibrosis or any stage of cirrhosis, the methotrexate therapy is usually discontinued; in case of mild fibrosis, a repeated biopsy is usually recommended after 6 months. During initial therapy, insignificant histological changes in the liver are possible (insignificant portal inflammation and adiposis), which is not a ground for refusal of the treatment or its discontinuation, but indicates the necessity to exercise care during administration of the drug. It is necessary to perform chest fluoroscopy. Control of bone-marrow hemopoiesis condition is recommended before the therapy, 1 time during treatment and upon completion of the course. If diarrhea and ulcerative stomatitis develop, the methotrexate therapy must be discontinued due to high risk of development of hemorrhagic enteritis and intestinal wall perforation which may result in death of the patient.
Unprotected skin should not be exposed to too long solar radiation; one should not use UV-lamp excessively (photosensitization reaction is possible).
Immunization refusal is necessary (unless it is approved by the physician) in the interval of 3 to 12 months after administration of the drug, other patient family members (if they dwell with the patient) should refuse immunization with oral poliomyelitis vaccine (avoid contacts with persons who received poliomyelitis vaccine or wear protective mask covering nose and mouth).
Effects on ability to drive motor vehicles and operate other potentially dangerous mechanisms. With a view to possibility of such side reactions as dizziness, mental confusion and drowsiness, it is recommended to refrain from driving motor vehicles and work with mechanisms.
Special safety precautions
General rules of work with cytostatic agents should be observed when working with methotrexate. The workplace should be covered with disposable absorbent polyethylene-backed paper sheets. It is necessary to use protective gloves and goggles in order to prevent accidental contact of methotrexate solutions with skin or eyes. If the drug contacts skin or mucous membranes, injured area must be immediately flushed with large amount of water. Pregnant medical professionals should not work with the drug. Non-used solutions, instruments and materials which contacted methotrexate must be destroyed by burning. There are no specific recommendation about destruction temperature. In case of ambulatory use, residual drug should not be discharged in the sewerage system or throw out with other waste.
Interaction with other drug products
Concomitant administration of salicylates, phenylbutazone, phenytoin, sulfanilamides, sulphonylurea derivatives, aminobenzoic acid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and hypolipidemic agents (colestyramine) increases toxicity at the expense of methotrexate displacement in connection with albumins and/or reduce tubular secretion; in a number of cases it may determine development of severe toxic action, sometimes even with lethal outcome. NSAIDs, against the background of high doses of methotrexate, increase concentration and delay elimination of the latter, which may result in the fatal outcome from severe hematologic and gastrointestinal intoxication. It is recommended to discontinue administration of phenylbutazone in 7 – 12 days, piroxicam in 10 days, diflusinal and indometacin in 24 to 48 hours, ketoprofen and NSAIDs with short T1/2 in 12 to 24 hours before infusion of methotrexate in moderate and high doses and for at least 12 hours (depending on the methotrexate blood concentration) after it. Caution should be observed when NSAIDs are combined with low doses of methotrexate (reduced excretion of methotrexate through renal tubules is possible). Drug products blocking tubular secretion (such as probenecid) increase toxicity of methotrexate at the expense of its reduced renal excretion. Folic acid and its derivatives reduce efficiency. The drug product enhances action of indirect anticoagulants (derivatives of coumarin and indandion) and increases the risk of haemorrhage at the expense of decreased hepatic synthesis of procoagulant factor and platelet formation disorder. Drug products containing folates (including polyvitamins) reduce toxic effect of methotrexate on bone marrow.
Antibiotics, which are poorly absorbed in the gastrointestinal tract (tetracyclines, chloramphenicol) decrease absorption of methotrexate or interfere with its metabolism due to suppression of the normal intestinal microflora. The penicillin group drug products reduce the renal clearance of methotrexate. Retinoids, azathioprine, sulfasalazine, ethanol, and other hepatotoxins increase the risk of hepatotoxicity development. The drug elevates the uric acid blood concentration, for this reason, the therapy of patients with concomitant hyperuricemy and gout may require adjustment of dose of anti-gout drug products (allopurinol, colchicines, sulphinpyrazone), administration of uricosuric anti-gout drug products may increase the risk of development of nephropathy associated with increase formation of uric acid against the background of the methotrexate therapy (it is preferred to use allopurinol). Anaesthetic management using dinitrogen oxide may result in development of unpredictable severe myelosuppression and stomatitis. Acyclovir for parenteral administration against the background of intrathecal administration of methotrexate increases the risk of development of neurological disorders. Administration of cytarabine in 48 hours before or during 10 minutes after beginning of the methotrexate therapy may condition development of synergistic cytotoxic effect (dosage regiment adjustment is recommended to be conducted based on control of hematological factors). Methotrexate action may be blocked, when methotrexate and asparaginase administered concomitantly. Neomycin (for oral administration) may decrease absorption of methotrexate (for oral administration). Drug products inducing pathological changes of blood, increase leucopenia and/or thrombocytopenia, if these drug products have the same action as the methotrexate in relation to bone marrow function. Other drug products inducing suppression of the bone marrow function or radiation therapy potentiate the effect and additively suppress the bone marrow function. Synergistic cytotoxic effect with cytarabine is possible in case of concomitant administration. Skin cancer was detected in several patients with psoriasis or mycosis fungoides who received the methotrexate therapy in combination with PUVA-therapy (metoxalen and ultraviolet irradiation). Combination with radiation therapy may increase the risk of bone marrow suppression. In combination with live viral vaccines it may induce intensification of the process of vaccine virus replication, enhancement of vaccine side effect and reduced antibody response to introduction of both live and inactivated vaccines, for this reason the interval between introduction of live and inactivated viral vaccines varies from 3 to 12 months.
Store in protected from light place at a temperature below 25 °Ñ.
Keep out of reach of children.
2 years. Do not use after expiration of a shelf life indicated on the package.
50 mg in glass ampoules or vials. 5 ampoules along with an instruction and ampoule scarificator or 1 vial with an instruction are placed in a pack. Package for in-patient department: 40 vials with a corresponding number of package inserts in group boxes.
Republic of Belarus,
30, Fabritsius str.