TRIMETREXATE

Fetal Risk Summary

Trimetrexate is a synthetic, competitive inhibitor of the enzyme dihydrofolate reductase from bacterial, protozoan, and mammalian sources. Its mechanism of action is similar to another folate antagonist, trimethoprim. Trimetrexate is indicated, in combination with leucovorin, as an alternative therapy for the treatment of Pneumocystis carinii pneumonia in immunocompromised patients, such as those with acquired immunodeficiency syndrome. Leucovorin (folinic acid), an active derivative of folic acid, must be given with trimetrexate to protect normal host cells (1). Trimetrexate is also used, as an orphan drug, for the treatment of some metastatic cancers.

Reproduction studies with trimetrexate have been conducted in rats and rabbits (1). In pregnant rats and rabbits, IV doses greater than 1.5 and 2.5 mg/kg, respectively, caused fetal and maternal toxicity. At lower, nontoxic maternal IV doses (5%–50% of the equivalent human therapeutic dose based on body surface area), retarded fetal development and teratogenicity were observed. Teratogenic effects included skeletal, visceral, ocular, and cardiovascular malformations.

It is not known if trimetrexate crosses the human placenta. The molecular weight of the free base (about 369) is low enough that transfer to the fetus should be expected.

No reports describing the use of trimetrexate during human pregnancy have been located. Structural abnormalities and fetal toxicity (e.g., bone marrow depression and hepatotoxicity) are potential risks if this drug is used during pregnancy. Women of childbearing age who are receiving this drug should be advised to avoid becoming pregnant.

Breast Feeding Summary

No reports describing the use of trimetrexate in human lactation have been located. The molecular weight of the free base (about 369) is low enough that excretion into breast milk should be expected. Because of the potential for severe toxicity (e.g., bone marrow depression and hepatotoxicity), women receiving this drug should not breast feed.

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