Mechanism of Action

Fluorouracil inhibits DNA synthesis, but can be reversed1,2

Treatment with fluorouracil alone








Thymidylate synthase (TS) is a key enzyme in the creation of thymine, a building block of DNA. fluorouracil competes with the natural substrate to bind the TS active site. When bound to TS, fluorouracil inhibits its activity, arresting DNA synthesis.








However, fluorouracil alone can be displaced, enabling DNA synthesis in cancer cells to continue.

5-MTHF stabilizes fluorouracil metabolite to block DNA synthesis1,2,3

Treatment with fluorouracil +KHAPZORY








Levoleucovorin is readily converted to 5-MTHF, which stabilizes the bond between the fluorouracil metabolite and thymidylate synthase, enhancing the inhibition of this enzyme.

Note: Mechanism of action pathway has been simplified for illustrative purposes.

Selected Safety Information

KHAPZORY enhances the therapeutic and toxic effects of fluorouracil in mCRC combination treatment.

Indications and Usage

KHAPZORYTM is a folate analog indicated for:

  • Rescue after high-dose methotrexate therapy in patients with osteosarcoma.
  • Diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination.
  • Treatment of patients with metastatic colorectal cancer in combination with fluorouracil.

Limitations of Use

KHAPZORY is not indicated for the treatment of pernicious anemia and megaloblastic anemia secondary to lack of vitamin B12 because of the risk of progression of neurologic manifestations despite hematologic remission.

Important Safety Information


  • KHAPZORY is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid, or folinic acid.

Warnings and Precautions

  • Increased gastrointestinal toxicities with fluorouracil: Gastrointestinal toxicities, including stomatitis and diarrhea, occur more commonly and may be of greater severity and of prolonged duration. Deaths from severe enterocolitis, diarrhea, and dehydration have occurred in elderly patients receiving weekly d,l-leucovorin and fluorouracil. Do not initiate or continue therapy with KHAPZORY and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until it has resolved as rapid deterioration leading to death can occur.
  • Drug interaction with trimethoprim-sulfamethoxazole: Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection increased treatment failure and morbidity.

Adverse Reactions

  • The most common adverse reactions (≥20%) in patients receiving high-dose methotrexate therapy with levoleucovorin rescue were stomatitis (38%) and vomiting (38%).
  • The most common adverse reactions (>50%) in patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer were stomatitis (72%), diarrhea (70%), and nausea (62%).

Drug Interactions

Leucovorin products increase the toxicity of fluorouracil.

Use in Specific Populations

Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm. Refer to methotrexate and fluorouracil prescribing information for additional information.

Please click here to see full Prescribing Information for KHAPZORY.


Reporting of Suspected Adverse Reactions

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800-FDA-1088.


  1. Zittoun J. Pharmacokinetics and in vitro studies of l-leucovorin. Comparison with the d and d,l-leucovorin. Ann Oncol. 1993;4(suppl 2):S1-S5.
  2. Peters GJ, van der Wilt CL, van Triest B, et al. Thymidylate synthase and drug resistance. Eur J Cancer. 1995;31A(7/8):1299-1305.
  3. Santi DV, McHenry CS, Sommer H. Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochem. 1974;13(3):471-481.

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