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5-FU inhibits DNA synthesis, but can
be reversed1,2

Treatment with 5-FU alone

Mechanism of action of 5-FU alone.
 

Watch the video below to see how FUSILEV works:
FUSILEV Mechanism of Action vide

 

Thymidylate synthase (TS) is a key enzyme in the creation of thymine, a building block of DNA. 5-FU competes with the natural substrate to bind the TS active site. When bound to TS, 5-FU inhibits its activity, arresting DNA synthesis.

Mechanism of action of 5-FU alone.

However, 5-FU alone can be displaced, enabling DNA synthesis in cancer cells to continue.

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

Treatment with 5-FU + FUSILEV

Mechanism of action of 5-FU + FUSILEV.

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

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

Selected Safety Information

Drug Interactions

FUSILEV may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients.

FUSILEV enhances the therapeutic and toxic effects of 5-FU in mCRC combination treatment.

Indications and Usage

FUSILEV is a folate analog indicated for:

  • Rescue after high-dose methotrexate therapy in osteosarcoma.
  • Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.
  • Use in combination chemotherapy with 5-FU in the palliative treatment of patients with advanced metastatic colorectal cancer.

Limitations of Use

FUSILEV is not approved for pernicious anemia and megaloblastic anemias. Improper use may cause a hematologic remission while neurologic manifestations continue to progress.

Important Safety Information

Contraindications

FUSILEV is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid.

Warnings and Precautions

  • Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute.
  • FUSILEV enhances the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. When these drugs are administered concurrently in the palliative treatment of advanced colorectal cancer, the dosage of 5-FU must be lower than usually administered. Although the toxicities observed in patients treated with the combination of FUSILEV and 5-FU are qualitatively similar to those observed with 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration in patients treated with the combination.
  • Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study.

Adverse Reactions

  • Allergic reactions were reported in patients receiving FUSILEV.
  • The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving FUSILEV in combination with 5-FU were diarrhea, nausea and stomatitis.
  • Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving FUSILEV as rescue after high dose methotrexate therapy.

Drug Interactions

FUSILEV may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients.

FUSILEV adverse event profile

Adverse reactions (≥10% in either arm) in patients with advanced metastatic colorectal cancer

Adverse Reaction Levoleucovorin/5FU
n=318
d,l-Leucovorin/5FU
n=307
Adverse Event N (%) Grade 1–4 Grade 3–4 Grade 1–4 Grade 3–4
Gastrointestinal Disorders
Stomatitis 229 (72%) 37 (12%) 221 (72%) 44 (14%)
Diarrhea 222 (70%) 61 (19%) 201 (65%) 51 (17%)
Nausea 197 (62%) 25 (8%) 186 (61%) 26 (8%)
Vomiting 128 (40%) 17 (5%) 114 (37%) 18 (6%)
Abdominal Pain* 45 (14%) 10 (3%) 57 (19%) 10 (3%)
General Disorders
Asthenia/Fatigue/Malaise 91 (29%) 15 (5%) 99 (32%) 34 (11%)
Metabolism and Nutrition
Anorexia/Decreased Appetite 76 (24%) 13 (4%) 77 (25%) 5 (2%)
Skin Disorders
Dermatitis 91 (29%) 3 (1%) 86 (28%) 4 (1%)
Alopecia 83 (26%) 1 (0.3%) 87 (28%) 3 (1%)

* Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness

ISI-0154-079600

Please click here to see full Prescribing Information for FUSILEV.

Reporting of Suspected Adverse Reactions

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

References:

  • 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.
  • 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.
  • 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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