METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS WHOSE KNOWLEDGE AND EXPERIENCE INCLUDE THE USE OF ANTIMETABOLITE THERAPY. BECAUSE OF THE POSSIBILITY OF SERIOUS TOXIC REACTIONS (WHICH CAN BE FATAL):
METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING NEOPLASTIC DISEASES, OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS WITH SEVERE, RECALCITRANT, DISABLING DISEASE WHICH IS NOT ADEQUATELY RESPONSIVE TO OTHER FORMS OF THERAPY.
DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS.
PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND KIDNEY TOXICITIES. (See PRECAUTIONS.)
PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY.
THE USE OF METHOTREXATE HIGH DOSE REGIMENS RECOMMENDED FOR OSTEOSARCOMA REQUIRES METICULOUS CARE. (See DOSAGE AND ADMINISTRATION.) HIGH DOSE REGIMENS FOR OTHER NEOPLASTIC DISEASES ARE INVESTIGATIONAL AND A THERAPEUTIC ADVANTAGE HAS NOT BEEN ESTABLISHED.
METHOTREXATE FORMULATIONS AND DILUENTS CONTAINING PRESERVATIVES MUST NOT BE USED FOR INTRATHECAL OR HIGH DOSE METHOTREXATE THERAPY.
1. Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate (See CONTRAINDICATIONS).
2. Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration.
3. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs). (See PRECAUTIONS, Drug Interactions.)
4. Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. (See PRECAUTIONS, Organ System Toxicity, Hepatic.)
5. Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
6. Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
7. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.
8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
9. Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. (See PRECAUTIONS, Organ System Toxicity, Skin.)
10. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy.
11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Methotrexate is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Chemically methotrexate is L-(+)- N -[ p -[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]-benzoyl]glutamic acid. The structural formula is:
Methotrexate for injection and Methotrexate injection (Preservative Free) products are sterile and non-pyrogenic and may be given by the intramuscular, intravenous, intra-arterial or intrathecal route. (See DOSAGE AND ADMINISTRATION.)
Methotrexate Injection, USP, isotonic liquid, preservative free, for single use only, is available in 25 mg/mL, 2 mL (50 mg), 4 mL (100 mg), 8 mL (200 mg), and 10 mL (250 mg) vials.
Each 25 mg/mL, 2 mL, 4 mL, 8 mL, and 10 mL vial contains methotrexate sodium equivalent to 50 mg, 100 mg, 200 mg, and 250 mg methotrexate respectively, and the following inactive ingredients: sodium chloride 0.490% w/v and water for injection qs ad 100% v. Sodium hydroxide and, if necessary, hydrochloric acid are added to adjust the pH to approximately 8.5. The 2 mL, 4 mL, 8 mL, and 10 mL solutions contain approximately 0.43 mEq, 0.86 mEq, 1.72 mEq, and 2.15 mEq of sodium per vial, respectively, and are isotonic solutions.
Methotrexate for Injection, USP, lyophilized, preservative free, for single use only, is available in 1 gram vials.
Each 1 gram vial of lyophilized powder contains methotrexate sodium equivalent to 1 gram methotrexate. Contains no preservative. Sodium hydroxide and, if necessary, hydrochloric acid are added during manufacture to adjust the pH. The 1 gram vial contains approximately 7 mEq sodium.