No

Antineoplastic Agent, Miscellaneous

Alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to, co-trimoxazole therapy or for whom co-trimoxazole and pentamidine are contraindicated. Concurrent folinic acid (leucovorin) must always be administered.

D

Previous hypersensitivity to trimetrexate or methotrexate, severe existing myelosuppression

Must be administered with concurrent leucovorin to avoid potentially serious or life-threatening toxicities; leucovorin therapy must extend for 72 hours past the last dose of trimetrexate; use with caution in patients with mild myelosuppression, severe hepatic or renal dysfunction, hypoproteinemia, hypoalbuminemia, or previous extensive myelosuppressive therapies

1% to 10%:

Dermatologic: Rash

Gastrointestinal: Stomatitis, nausea, vomiting

Hematologic: Neutropenia, thrombocytopenia, anemia

Hepatic: Elevated LFTs

Neuromuscular & skeletal: Peripheral neuropathy

Renal: Increased serum creatinine

Miscellaneous: Flu-like illness, hypersensitivity reactions

Decreased effect of pneumococcal vaccine

Increased toxicity (infection rates) of yellow fever vaccine

Reconstituted I.V. solution is stable for 24 hours at room temperature or 7 days when refrigerated; intact vials should be refrigerated at 2°C to 8°C

Exerts an antimicrobial effect through potent inhibition of the enzyme dihydrofolate reductase (DHFR)

Distribution: V_d: 0.62 L/kg

Metabolism: Extensive in the liver

Half-life: 15-17 hours

Adults: I.V.: 45 mg/m² once daily over 60 minutes for 21 days; it is necessary to reduce the dose in patients with liver dysfunction, although no specific recommendations exist; concurrent folinic acid 20 mg/m² every 6 hours orally or I.V. for 24 days

Check and record patient's temperature daily; absolute neutrophil counts (ANC), platelet count, renal function tests (serum creatinine, BUN), hepatic function tests (ALT, AST, alkaline phosphatase)

None reported

May cause neutropenia; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

This medication can only be administered I.V. Frequent blood tests will be required to assess effectiveness of therapy. Avoid aspirin, and aspirin-containing medication unless approved by prescriber. Report persistent fever, chills, joint pain, numbness or tingling of extremities, vomiting or nausea, acute abdominal pain, mouth sores, increased bruising or bleeding, blood in urine or stool, changes in sensorium (eg, confusion, hallucinations, seizures), increased difficulty breathing, or acute persistent malaise or weakness. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication - both male and female should use appropriate barrier contraceptive measures. Do not give blood during this therapy or for 1 month following discontinuation of therapy. Do not breast-feed.

Notify primary physician if there is fever greater than or equal to 103°F, generalized rash, seizures, bleeding from any site, uncontrolled nausea/vomiting; laboratory abnormalities which warrant dose modification; any other clinical adverse event or laboratory abnormality occurring in therapy which is judged as serious for that patient or which causes unexplained effects or concern; initiate "Bleeding Precautions" for platelet counts less than or equal to 50,000/mm³; initiate "Infection Control Measures" for absolute neutrophil counts (ANC) less than or equal to 1000/mm³

Powder for injection: 25 mg

Amsden GW, Kowalsky SF, and Morse GD, "Trimetrexate for Pneumocystis carinii Pneumonia in Patients With AIDS," Ann Pharmacother, 1992, 26(2):218-26.

Bertino JR, "Folate Antagonists: Toward Improving the Therapeutic Index and Development of New Analogs," J Clin Pharmacol, 1990, 30(4):291-5.

Bertino JR, "Trimetrexate: Overall Clinical Results," Semin Oncol, 1988, 15(2 Suppl 2):50-1.

Donehower RC, "Understanding Trimetrexate Toxicity," J Natl Cancer Inst, 1988, 80(16):1268-9.

Fulton B, Wagstaff AJ, and McTavish D, "Trimetrexate. A Review of Its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Pneumocystis carinii Pneumonia," Drugs, 1995, 49(4):563-76.

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Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Levien TL and Baker DE, "Reviews of Trimetrexate and Oxadrolone," Hosp Pharm, 1994, 29:696-708.

Marshall JL and De Lap RJ, "Clinical Pharmacokinetics and Pharmacology of Trimetrexate," Clin Pharmacokinet, 1994, 26(3):190-200.

Masur H, "Prevention and Treatment of Pneumocystis Pneumonia," N Engl J Med, 1992, 327(26):1853-60.

Rogers P, Allegra CJ, Murphy RF, et al, "Bioavailability of Oral Trimetrexate in Patients With Acquired Immunodeficiency Syndrome," Antimicrob Agents Chemother, 1988, 32(3):324-6.