Methotrexate (Amethopterin; MTX)

A to Z Drug Facts

 Action Competitively inhibits dihydrofolic acid reductase and thereby inhibits DNA synthesis and cellular replication. In rheumatoid arthritis, believed to reduce immune function.

 Indications Antineoplastic chemotherapy for treatment of gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole; treatment and prophylaxis of acute meningeal) lymphocytic leukemia; treatment of breast cancer, epidermoid cancers of head and neck, advanced mycosis fungoides and lung cancer; in combination therapy in advanced-stage non-Hodgkin's lymphoma; as adjunct in high doses followed by leucovorin rescue in nonmetastatic osteosarcoma (postsurgically); ymptomatic control of severe psoriasis and severe rheumatoid arthritis. Unlabeled use(s): Reduction of corticosteroid requirements in patients with severe corticosteroid-dependent asthma.

 Contraindications Use in nursing mothers. In patients with psoriasis or rheumatoid arthritis, methotrexate is contraindicated in pregnancy, alcoholism, alcoholic liver disease, chronic liver disease, overt or laboratory evidence of immunodeficiency syndrome and preexisting blood dyscrasias (eg, leukopenia, thrombocytopenia).

 Route/Dosage

Choriocarcinoma and Thromboblastic Diseases

ADULTS: PO/IM 15–30 mg for 5 days. Repeat courses 3–5 times as required, with rest periods of > 1 wk between courses.

Leukemia

ADULTS & CHILDREN: INDUCTION: 3.3 mg/m²/day in combination with prednisone 60 mg/m²/day usually for 4 to 6 wk. Postremission maintenance therapy (usually in combination with other drugs): PO/IM 2 times weekly in total weekly doses of 30 mg/m² or IV 2.5 mg/kg q 14 days.

Meningeal Leukemia

ADULTS: Intrathecal 12 mg/m² or empirical dose of 15 mg. Administer q 2–5 days until cell count of CSF returns to normal; then give one additional dose. Dose reduction may be required in elderly patients because of differences in CSF volume. CHILDREN ³ 3 YR: 12 mg. Administer q 2–5 days until CSF cell count returns to normal. CHILDREN 2 YR: 10 mg. CHILDREN 1 YR: 8 mg. CHILDREN < 1 YR: 6 mg.

Lymphoma: Burkitt's Lymphoma, Stages 1 & 2

ADULTS: PO 10–25 mg/day for 4–8 days. Provide 7-to 10-day rest period between courses.

Stage 3 Lymphosarcoma as Part of Combination Therapy

ADULTS: PO 0.625–2.5 mg/kg/day.

Mycosis Fungoides

ADULTS: PO 2.5–10 mg/day for weeks to months (based on clinical response or hematologic function). IM 25 mg twice weekly or 50 mg weekly.

Osteosarcoma

Complex high dose with leucovorin rescue and other chemotherapeutic agents. Starting dose for high-dose methotrexate is 12 gm/m².

Rheumatoid Arthritis

ADULTS: INITIAL THERAPY: PO 7.5 mg/week in single dose or 2.5 mg q 12 hr for 3 doses each wk. Gradually adjust dosage to maximal response; do not exceed 20 mg/wk.

Psoriasis

Individualize dosage. Administer 5–10 mg parenteral test dose 1 wk prior to therapy. ADULTS: IM/IV 10–25 mg/wk (maximum 50 mg/wk). ADULTS: PO 2.5 mg q 12 hr for 3 doses or at 8 hr intervals for 4 doses q wk (maximum 30 mg/wk). ALTERNATIVE SCHEDULE: PO 2.5 mg qd for 5 days followed by 2-day rest period (maximum 6.25 mg qd). This schedule may pose increased risk of liver toxicity.

 Interactions

Charcoal, folic acid: May reduce methotrexate efficacy. Digoxin: May reduce serum digoxin levels and actions. Hydantoins: May reduce plasma levels. Etretinate, NSAIDs, penicillins, probenecid, salicylates, sulfonamides: May increase methotrexate blood levels and toxicity.

 Lab Test Interferences None well documented.

 Adverse Reactions

CNS: Dizziness; fatigue; headache; aphasia; hemiparesis; paresis; convulsions; eukoencephalopathy (IV after craniospinal irradiation); chemical arachnoiditis; ransient paresis; neurotoxicity. DERM: Erythematous rashes; pruritus; urticaria; photosensitivity; igmentary changes; alopecia; ecchymosis; telangiectasia; acne; furunculosis; ggravation of psoriasis by ultraviolet light. EENT: Blurred vision; ulcerative stomatitis; gingivitis; pharyngitis. GI: Nausea; abdominal distress (common); anorexia; vomiting; diarrhea; hematemesis; elena; GI ulceration and bleeding; enteritis. GU: Renal failure; azotemia; cystitis; hematuria; severe nephropathy; reproductive disorders; infertility; abortion; fetal defects. HEMA: Leukopenia; bone marrow depression; thrombocytopenia; anemia; ypogammaglobulinemia; hemorrhage; septicemia. HEPA: Hepatotoxicity; hepatic cirrhosis and fibrosis. RESP: Deaths from interstitial pneumonitis; chronic interstitial obstructive pulmonary disease. OTHER: Malaise; chills; fever; lower resistance to infections; arthralgia; yalgia; diabetes; osteoporosis; anaphylactoid reaction; sudden death.

 Precautions

Pregnancy: Category X (for rheumatoid arthritis and psoriasis); Category D (other uses). Lactation: Contraindicated in nursing mothers. Children: Safety and efficacy not established other than for cancer treatment. Elderly patients: Closely monitor for early signs of toxicity. May require dose reduction. Infection: Severe reactions may occur if live vaccines are administered. Intrathecal therapy: Large doses may cause convulsions and systemic toxicity. Dosage regimens based on age may be more effective and associated with fewer neurotoxic side effects. Do not use formulations or diluents containing preservatives. Renal impairment: Use drug with extreme caution. Determine renal status before and during therapy. Severe effects: Use of high-dose methotrexate regimens (ie, to treat osteosarcoma) require meticulous care. Deaths have occurred after use of methotrexate for any condition. Potential toxicities include bone marrow depression; hepatotoxicity; lung disease (suggested by symptoms of dry, nonproductive cough); nephrotoxicity and GI toxicity.

 Administration/Storage

• Ensure that leucovorin is available from pharmacy before beginning high-dose administration of methotrexate. Leucovorin diminishes methotrexate toxicity.
• Oral administration is often preferred. Give medication 1–2 hr before meals.
• Preservative-free methotrexate may be given IM, IV, intra-arterially or intrathecally.
• For intrathecal use, reconstitute immediately prior to use with preservative-free medium such as 0.9% Sodium Chloride for Injection.
• Follow procedures for proper handling and disposal of anticancer drugs. Wear gloves and avoid skin exposure and inhalation of fumes.
• Store medication in tightly closed, light-resistant container.

 Assessment/Interventions

• Obtain patient history, including drug history and any known allergies.
• Before beginning therapy, check that serum creatinine is normal and creatinine clearance is > 60 ml/min.
• Assess for alcoholism, alcoholic liver disease or other chronic liver disease.
• Determine whether patient has any evidence of immunodeficiency syndromes, active infection, preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia).
• Assess pulmonary function; note especially presence of any pulmonary effusion. Establish baseline pulmonary function measurements.
• Maintain adequate hydration and urine alkalinization during therapy. Monitor I&O.
• Avoid IM injections and taking temperatures rectally during methotrexate therapy; apply pressure to venipuncture sites for at least 10 min.
• Determine renal status before therapy and monitor during therapy.
• During therapy monitor periodically for toxicity. Mandatory monitoring includes CBC with differential and platelet counts and liver and renal function tests. Periodic liver biopsies may be indicated in some situations.
• Assess frequently for pulmonary symptoms, especially dry, nonproductive cough or nonspecific pneumonitis.
• Monitor closely for any symptoms of diarrhea and ulcerative stomatitis.
• Inspect patient's mouth daily. Report any patchy necrotic areas, bleeding and discomfort or black/“furry” tongue.
• Inform physician if diarrhea or ulcerative stomatitis occur during treatment; therapy must be interrupted.
• Inform physician of development of pulmonary symptoms (dry, nonproductive cough, fever, shortness of breath, hypoxemia or presence of infiltrate on chest x-ray film) during therapy. Methotrexate must be discontinued and symptoms investigated and treated.

 Patient/Family Education

• Advise patient to contact physician if vomiting occurs after medication is taken.
• Inform patient that pregnancy should be avoided during therapy if either partner is receiving methotrexate and for minimum of 3 mo after therapy for men and during and for at least one ovulatory cycle after therapy for women.
• Advise patient and parents that immunization with live virus vaccines is generally not recommended during methotrexate therapy.
• Instruct patient to avoid crowds and persons with known infections.
• Emphasize importance of lab tests during therapy and encourage patient to keep all scheduled appointments.
• Stress importance of strict oral hygiene to prevent infection.
• Inform patient of possibility of hair loss and reassure patient that hair will regrow following discontinuation of therapy.
• Instruct patient to report these symptoms to physician immediately: ny symptoms of pulmonary infection (cough, shortness of breath, fever) or GI complications (diarrhea, abdominal pain, black tarry stools) occur. Instruct patient to report these symptoms to physician: presence of chills and fever, unusual bleeding or bruising, jaundice, dark or bloody urine, swelling of feet or legs and joint pain.
• Advise patient to avoid intake of alcoholic beverages, salicylates and NSAIDs.
• Caution patient to avoid exposure to sunlight or sunlamps and to wear protective clothing to avoid photosensitivity reaction.
• Instruct patient not to take otc preparations (including vitamins) ithout notifying physician. Folic acid, an ingredient in some otc products, reduces methotrexate efficacy.

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Copyright © 2003 Facts and Comparisons
David S. Tatro
A to Z Drug Facts