Methotrexate

Indications

Neoplastic Diseases:
  • Treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole
  • In acute lymphoblastic leukemia
  • Used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas
  • 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.
Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis: Indicated in the management of selected adults with severe, active rheumatoid arthritis, or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs)

Psoriasis: Indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy.

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. In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This difference in proliferation rates is the basis for the use of methotrexate to control the psoriatic process.

Dosage

Neoplastic Diseases-

Choriocarcinoma and similar trophoblastic diseases: Orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. The courses are usually 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. Since hydatidiform mole may precede 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

Acute Lymphoblastic Leukemia
  • Induction dose: 3.3 mg/m2 in combination with prednisone 60 mg/m2 daily for 4 to 6 weeks
  • Maintenance dose: Orally or IM administration 2 times a week in total weekly doses of 30 mg/m2
  • Alternate maintenance dose: 2.5 mg/kg IV every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen
Lymphoma
  • Burkitt's tumor Stages I to II: 10 to 25 mg once a day for 4 to 8 days
  • Burkitt's tumor Stage III: Methotrexate is commonly given concomitantly with other antitumor agents
  • Duration of therapy: All stages usually require several courses of therapy interposed with 7 to 10 day rest periods
  • Lymphosarcoma Stage III: 0.625 to 2.5 mg/kg daily as a part of combination chemotherapy

Mycosis Fungoides: Early stage dosing: 5 to 50 mg once a week; alternatively, 15 to 37.5 mg 2 times a week may be used in patients who have responded poorly to weekly therapy

Breast Cancer: 40 mg/m 2 intravenously on the 1 st and 8 th day every 4 weeks in combination with cyclophosphamide and fluoracil for 6-12 cycles

Head and Neck Cancer: 40 mg/m2 IV weekly until disease progression or unacceptable toxicity (3 weeks equals one cycle; goal is to complete at least six cycles).

Adult Rheumatoid Arthritis: Single doses of 7.5 mg once per week, Maximum dose: 20 mg/week in adults

Polyarticular-Course Juvenile Rheumatoid Arthritis: 10 mg/m2 once weekly

Psoriasis: Single dose: 10 to 25 mg once per week, maximum dose: 30 mg/week

Administration

Should be taken on an empty stomach. Best taken on an empty stomach. May be taken with meals to reduce GI discomfort. Avoid taking with milk-rich products.

Interaction

  • NSAIDs: Should not be administered prior to or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma
  • Salicylates, Phenylbutazone, Phenytoin and Sulfonamides: Toxicity may be increased Penicillin, Theophylline, Probenecid, Azathioprine, Retinoids,
  • Sulfasalazine: Should be closely monitored for possible increased risk of hepatotoxicity
  • Cisplatin: Caution must be exercised if high-dose methotrexate is administered in combination
  • Mercaptopurine: Methotrexate increases the plasma levels of mercaptopurine
  • Tetracycline, Chloramphenicol and Nonabsorbable Broad Spectrum Antibiotics: May decrease intestinal absorption of methotrexate
  • Vitamin preparations containing folic acid or its derivatives: Decreases responses to systemically administered methotrexate
  • Trimethoprim/Sulfamethoxazole: Rarely increases bone marrow suppression

Contraindications

  • Alcoholism, alcoholic liver disease or other chronic liver disease
  • Immunodeficiency syndromes
  • Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia
  • Hypersensitivity to methotrexate
  • Pregnant women with psoriasis or rheumatoid arthritis
  • Women of childbearing potential
  • Nursing mothers
  • 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

Side Effects

  • The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress
  • Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection
  • Methotrexate has been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy

Pregnancy & Lactation

US FDA Pregnancy Category X. Methotrexate should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. It is contraindicated in nursing mothers.

Precautions & Warnings

  • Methotrexate formulations and diluents containing preservatives must not be used for intrathecal or high dose methotrexate therapy
  • It is necessary to follow patients on methotrexate closely for toxic effects
  • If adverse reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium
  • If methotrexate therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and increased alertness as to possible recurrence of toxicity
  • Persistent liver function test abnormalities, &/or depression of serum albumin may be indicators of serious liver toxicity & require evaluation
  • Folate deficiency: May increase methotrexate toxicity

Use in Special Populations

Pediatric patients: Benefits should be weighed against the potential risk before using methotrexate alone or in combination with other drugs, especially in pediatric patients or young adults.

Geriatric patients: Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity.

Overdose Effects

Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate and its administration should begin as promptly as possible.

Therapeutic Class

Antidote preparations, Immunosuppressant

Storage Conditions

Store at a temperature not exceeding 30°C in a dry place. Protect from light & moisture.

Available Brand Names