Pterin

Methotrexate.

Tablet: Each tablet contains: Methotrexate, USP 2.5 mg.
Injection: Each 2 mL vial contains: Methotrexate 50 mg.

Pharmacology: Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues.
Pharmacodynamics: Tablet: Methotrexate is a folic acid antagonist and its major site of action is the enzyme dihydrofolate reductase. Its main effect is inhibition of DNA synthesis but it also acts directly both on RNA and protein synthesis. Methotrexate is a phase specific substance, the main effect being directed during the S-phase of cell division.
The inhibition of dihydrofolate reductase can be circumvented by the use of leucovorin (folinic acid; citrovorum factor) and protection of normal tissues can be carried out by properly timed administration of leucovorin calcium.
Pharmacokinetics: When given in low doses, methotrexate is rapidly absorbed from the gastro-intestinal tract, but higher doses are less well-absorbed. It is also rapidly and completely absorbed following intramuscular administration. Peak serum concentrations are achieved in 1 to 2 hours after an oral dose, and 30 to 60 minutes after an intramuscular one. Methotrexate is distributed to tissues and extracellular fluid with a steady-state volume of distribution of 0.4 to 0.8 liters per kg bodyweight; it penetrates ascitic fluid and effusions which may act as a depot and thus enhance toxicity. Clearance from plasma is reported to be triphasic, with a terminal elimination half-life of between 3 and 10 hours after low oral doses or 8 to 15 hours after high-dose parenteral therapy. It is about 50% bound to plasma protein. Methotrexate enters the cells in part by an active transport mechanism and is bound as polyglutamate conjugates: bound drug may remain in the body for several months, particularly in the liver. It is excreted primarily in the urine, by glomerular filtration and active tubular secretion. Small amounts are excreted in bile and found in faeces; there is some evidence for enterohepatic recirculation.

Methotrexate has been used to produce regression in a wide range of neoplastic conditions including: Acute leukemias.
Trophoblastic neoplasms (choriocarcinoma, hydatidiform mole).
Non-Hodgkin's lymphoma such as Burkitt's lymphoma, mycosis fungoides.
Osteogenic sarcomas.
Solid tumors particularly breast, lungs, head and neck, bladder, cervical, ovarian and testicular carcinoma.
Methotrexate is also used in the treatment of rheumatoid arthritis and severe, uncontrolled psoriasis, which is not responsive to other therapy.

Tablet: Acute lymphoblastic leukemia: 15 to 30 mg/m² once or twice weekly.
Choriocarcinoma: 15 to 30 mg daily for 5 days at intervals of 1 to 2 weeks for 3 to 5 courses.
Burkitt's lymphoma: 10 to 25 mg daily by mouth for 4 to 8 days repeated after an interval of 7 to 10 days.
Mycosis fungoides: 2.5-10 mg daily to induce remission.
Severe psoriasis: 10-25 mg orally, once weekly, is recommended, however, intravenous or intramuscular methotrexate can also be administered. Divided oral dose schedule is 2.5 mg at 12-hour intervals for three doses. Dosage should be adjusted according to the patient's response and hematological toxicity.
Rheumatoid Arthritis: 7.5 mg by mouth once weekly.
Injection: Meningogenic leukemia for children: 12 mg/m² or 15 mg whichever is less (about 0.4-0.5 mg/kg) intrathecal once or twice weekly.
Acute lymphoblastic leukemia: 15 to 30 mg/m² once or twice weekly intramuscularly. Alternately, 2.5 mg/kg IV every 14 days.
Choriocarcinoma: 15 to 30 mg daily intramuscularly for 5 days at intervals of 1 to 2 weeks for 3 to 5 courses. Alternately, 0.25 to 1 mg/kg up to max of 60 mg IM every 48 hours for 4 doses followed by folinic acid rescue and repeated at intervals of 7 days.
Mycosis fungoides: 50 mg weekly as a single dose IM.
Osteogenic sarcoma: 12-15 g/m² IV infusion followed by folinic acid.
Severe psoriasis: 10-25 mg orally, once weekly, is recommended, however, intravenously or intramuscularly is administered. Dosage should be adjusted according to the patient's response and hematological toxicity.
Administration: Small amount administration (IV or IM).
Large amount administration (Rapid IV (bolus injection) or infusion).
Intrathecal or intraarterial administration.
It is administered through tube for infusion over 2-3 minutes. In administration of over 100 mg, IV infusion should be done within 24 hours (In initial administration, bolus administration). Dosage over 70 mg/m² (2.3 mg/kg) should be administered concomitantly with leucovorin rescue therapy, or serum methotrexate level of 24-48 hours after administration should be observed.
Methotrexate should be used alone or concomitantly with radiotherapy, surgical therapy.
Determination of dosage should be considered.

Leucovorin is indicated to neutralize and diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should be initiated as promptly as possible. A dose of leucovorin equal to or higher than the recommended dose of methotrexate should be administered by an intravenous bolus injection within one hour. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, patients should be observed cautiously and other supporting measures such as a blood transfusion, renal dialysis and reverse barrier nursing may be required.

Patients with a history of hypersensitivity to this drug.
Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease.
Patients with preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia and significant anemia.
Patients with overt or laboratory evidence of immunodeficiency syndromes.
Patients with alcoholism, alcoholic liver disease, or other chronic liver disease.

Methotrexate should be administered with caution in the following: Patients with kidney failure (elimination of this drug may be delayed), liver impairment, diarrhea or ulcerative stomatitis (splanchnic perforation may result in hemorrhagic enteritis and death), gastric ulcer or colitis ulcerativa, hematologic disorder, bone marrow depression, chickenpox (fatal systemic impairment may occur), complicated infections and mental disorder.
Since crucial adverse effects, such as bone marrow depression, hepatic impairment and renal impairment may occur, a patient's condition should be monitored and clinical tests (e.g., blood test, hepatic function test, kidney function test, urine test) should be performed frequently. If any symptoms occur, appropriate therapy such as reduction or discontinuance of the dosage should be instituted.
When elements of blood counts have increased, the administration should be discontinued, and supportive therapy such as blood transfusion or reverse barrier nursing should be instituted.
Hemopoietin depression even at low-dose may occur suddenly.
Bleeding may be a manifestation of infection.
The renal impairment by the administration of this drug is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization, and elimination by urine and measurement of serum methotrexate and creatinine levels are essential for safe administration.
Methotrexate-induced lung disease is a potentially dangerous lesion, which may occur acutely at any time during therapy and which has been reported at doses as low as 7.5 mg/week. It is not always fully reversible. When pulmonary disease is suspected, lung function test, such as baseline measurement is effective.
Since in low-dose, long-term therapy of methotrexate, liver toxicity may occur, hepatic function tests should be performed regularly. If any symptoms occur, the administration should be discontinued for at least 2 weeks.
The effects on spermiogenesis, ovogenesis by the administration of this drug may decrease reproductive function reversibly; pregnancy should be avoided at least for 6 months after therapy.
Since this drug has immunosuppressive function, it may decrease immune response to vaccine. In the concomitant administration with live vaccine, serious antigen response may occur.
Since the drug contains tartrazine as a coloring agent, administration should be cautioned in patients with hypersensitivity to the drug or a history of allergy.
Use in Children: Safety in prematures, neonates and infants (not more than 1 year) has not been established.
Use in Elderly: Clinical pharmacology in elderly has not been studied. The elderly have high reserves of folic acid and low hepatic and renal function; therefore, they should be administered with low doses of methotrexate and monitored for initial signs of toxicity.

In animal studies, methotrexate has been reported to have teratogenic effects; therefore, the drug should not be administered in pregnant women or women of childbearing potential. Because of the potential for severe adverse reactions in breast fed infants, methotrexate should not be used in nursing mothers. If the administration is necessary, breastfeeding should be discontinued.

Shock: Shock may occur, though rarely, so the patient still has to be monitored sufficiently. If necessary, the administration should be discontinued and appropriate therapy instituted.
Gastrointestinal: If gastrointestinal tract ulcer, bleeding, stomatitis, abdominal pain, diarrhea, nausea and vomiting occur, which may result in dehydration, methotrexate should be discontinued until recovery occurs. Anorexia, black vomit, enterocleisis may also occur.
Respiratory system: Death by interstitial pneumonia has been reported. Occasionally, chronic interstitial occlusive pulmonary disease, pulmonary fibrosis may occur. Pulmonary symptoms (especially a dry, non-productive cough) or nonspecific pneumonia may be the symptoms of potential impairment; therefore, it requires discontinuance of treatment and careful investigation.
Psychoneural system: Headache, dizziness, blurred vision, dysphasia, hemiplegia, paralysis, convulsion, coma, and arrhythmia, tension of neck and head and backache may occur.
Urogenital system: Aspermatism, ovarian insufficiency, catamenia insufficiency, infertility, abortion and fetal abnormality may occur.
Hematologic: Anemia, leukopenia, thrombocytopenia, bleeding, septicemia and hypogammaglobulinemia may occur. If granulocytopenia and flush occur, patient should be examined immediately and appropriate therapy, such as parenteral extensive antibiotic agents should be instituted.
Hepatic: Hepatic impairments (increases of GOT, GPT, AL-P), jaundice, fatty liver, sphacelism of liver tissue, fibrosis of liver tissue, hepatocirrhosis may occur. When crucial fibrosis of liver tissue and hepatocirrhosis occur, the administration should be discontinued.
Renal: Urethral necrobiosis, crucial nephropathy, hematuria and increases of BUN or creatinine value may occur. In high-dose administration of methotrexate for the treatment of osteosarcoma, acute renal failure may occur.
Hypersensitivity: Loss of consciousness, hypotension, tachycardia, paralysis, sneezing, and dyspnea, cold and sweating may occur. If these occur, appropriate therapy should be instituted.
Skin: Photohypersensitivity, rash, urticaria, pruritus, erythematous rash, erythema, pigmentation, depigmentation, subcutaneous ecchymosis, acne, cavities, telangiectasia and incision of wounds may occur.
Others: Malaise, parotiditis, blennophthalmia, cystitis, arthralgia, myalgia, diabetes, osteoporosis and accidental death may occur.

Concomitant administration with the following drugs decrease methotrexate-transport function which results in the delay of elimination and action of methotrexate or enhancement of its toxicity: Nonsteroidal anti-inflammatory agents like salicylates, sulfonamides, tetracycline, chloramphenicol, phenytoin, barbiturates, aminobenzoate, propionic acid, anti-inflammatory agents, probenecid and sulfinpyrazone.
This drug has wide protein-bound ability and it can be substituted by acidic agents like salicylate, phenylbutazone, phenytoin and sulfonamides. Therefore, the toxicity can be increased.
Rarely, the complex drug of sulfamethoxazole and trimethoprim can increase its action. Concomitant administration with complex drug of sulfamethoxazole and trimethoprim may increase the concentration of methotrexate.
Concomitant intraspinal administration of this drug with radiotherapeutics to central nervous system should not be recommended because it has reportedly caused leukoencephalopathy.

Tablet: Store at temperatures not exceeding 30°C.
Injection: Store at temperatures not exceeding 25°C.

Cytotoxic Chemotherapy / Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

L04AX03 - methotrexate ; Belongs to the class of other immunosuppressants.

Rx