Levoleucovorin

KHAPZORY is indicated for: rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma. diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination adult and pediatric patients. The treatment of adults with metastatic colorectal cancer in combination with fluorouracil. Limitations of Use KHAPZORY is not indicated for pernicious anemia and megaloblastic anemia secondary to lack the of vitamin B 12 because of the risk of progression of neurologic manifestations despite hematologic remission. KHAPZORY is a folate analog indicated for: Rescue after high-dose methotrexate therapy in adults and pediatric patients with osteosarcoma. Diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients.

High-Dose Methotrexate Therapy Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by dihydrofolate reductase to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of levoleucovorin counteracts the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Combination with Fluorouracil in Colorectal Cancer Levoleucovorin enhances the therapeutic and toxic effects of fluorouracil. Fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication).

For intravenous administration only. Do not administer intrathecally. Rescue After High-Dose Methotrexate Therapy Rescue recommendations are based on a methotrexate dose of 12 grams/ m 2 administered by intravenous infusion over 4 hours. Initiate rescue at a dose of 7.5 mg (approximately 5 mg/m 2 ) every 6 hours, 24 hours after the beginning of the methotrexate infusion. Continue until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). Adjust dose if necessary, based on methotrexate elimination, refer to Full Prescribing Information. Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start as soon as possible after methotrexate overdosage or within 24 hours of delayed methotrexate elimination. Administer KHAPZORY 7.5 mg (approximately 5 mg/m 2 ) intravenously every 6 hours until methotrexate level is less than 5 x 10 -8 M (0.05 micromolar).

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

Increased Gastrointestinal Toxicities with Fluorouracil: Do not initiate or continue therapy with KHAPZORY and fluorouracil in patients with symptoms of gastrointestinal toxicity until symptoms have resolved. Monitor patients with diarrhea until it has resolved as rapid deterioration leading to death can occur. Drug Interaction with Trimethoprim-Sulfamethoxazole: Increased rates of treatment failure and morbidity with concomitant use of d, l -leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia in patients with HIV.

The following clinical significant adverse reactions are described elsewhere in the labeling: • Increased gastrointestinal toxicities with fluorouracil The most common adverse reactions (≥ 20%) in patients receiving high-dose methotrexate therapy with levoleucovorin rescue are stomatitis and vomiting. The most common adverse reactions (>50%) in patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer are stomatitis, diarrhea, and nausea.

Effects of Leucovorin Products on Other Drugs Antiepileptic Drugs Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects, however, both folic and folinic acids share some common metabolic pathways. Monitor patients taking folinic acid in combination with antiepileptic drugs. Fluorouracil Leucovorin products increase the toxicity of 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 the diarrhea has resolved, as rapid deterioration leading to death can occur.

Store at 20°C to 25°C (68°F to 77°F) in original carton until contents are used. Excursions permitted between 15°C and 30°C (59°F and 86°F).