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General Information
Khapzory (levoleucovorin) is a folate analog injection.
Khapzory is specifically 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 in adult and pediatric patients.
- Treatment of adults with metastatic colorectal cancer in combination with fluorouracil
Dosage/Administration
Khapzory is supplied as an injection for intravenous administration.
Recommended Dosage for Rescue After High-Dose Methotrexate Therapy
- The recommended dosage for Khapzory is based on a methotrexate dose of 12 grams/m2 administered as intravenous infusion over 4 hours. Twenty-four hours after starting the methotrexate infusion, initiate Khapzory at a dose of 7.5 mg (approximately 5 mg/m2 ) as an intravenous infusion every 6 hours.
- Monitor serum creatinine and methotrexate levels at least once daily. Continue Khapzory, hydration, and urinary alkalinization (pH of 7 or greater) until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar).
- Please see drug label for recommended dosage for Khapzory based on Serum Methotrexate and Creatinine Levels
Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination
Start Khapzory as soon as possible after an overdosage of methotrexate or within 24 hours of methotrexate administration when methotrexate elimination is impaired. As the time interval between methotrexate administration and Khapzory increases, the effectiveness of Khapzory to diminish methotrexate toxicity may decrease.
Administer Khapzory 7.5 mg (approximately 5 mg/m2 ) as an intravenous infusion every 6 hours until the serum methotrexate level is less than 5 x 10-8 M (0.05 micromolar).
Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the dosage of Khapzory to 50 mg/m2 intravenously every 3 hours and continue Khapzory at this dosage until the methotrexate level is less than 5 x 10-8 M for the following:
- if the serum creatinine at 24-hours increases 50% or more compared to baseline
- if the methotrexate level at 24-hours is greater than 5 x 10 -6 M
- if the methotrexate level at 48-hours is greater than 9 x 10 -7 M
Continue concomitant hydration (3 L per day) and urinary alkalinization with sodium bicarbonate. Adjust the bicarbonate dose to maintain urine pH at 7 or greater.
Dosage in Combination with Fluorouracil for Metastatic Colorectal Cancer The following regimens have been used for the treatment of colorectal cancer:
- Khapzory 100 mg/m2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil 370 mg/m2 by intravenous injection once daily for 5 consecutive days
- Khapzory 10 mg/m2 by intravenous injection, followed by fluorouracil 425 mg/m2 by intravenous injection once daily for 5 consecutive days.
This five-day course may be repeated every 4 weeks for 2 courses, then every 4 to 5 weeks, if the patient has recovered from toxicity from the prior course. Do not adjust Khapzory dosage for toxicity.
Refer to fluorouracil prescribing information for information on fluorouracil dosage and dosage modifications for adverse reactions.
Mechanism of Action
Khapzory is a folate analog injection containing the active isomer of leucovorin (also called folinic acid), which is made up of a mixture of two isomers, one active, and one inactive. Folates are a group of vitamins that allow cells to reproduce. Specifically, they fuel the synthesis of purinic and pyrimidinic bases, the building blocks of DNA. Cells need to duplicate their own DNA before they can divide. Folate deficiency hinders DNA synthesis and cell division, most notably affecting rapidly proliferating tissues, such as normal bone marrow and cancer tissue. Khapzory was designed to protect against the toxic effects of methotrexate, a type of chemotherapy that prevents folates from being metabolized to the reduced active form, therefore leading to cell death.
Side Effects
Adverse events associated with the use of Khapzory may include, but are not limited to, the following:
- Stomatitis
- Vomiting
- Diarrhea
- Nausea
- Typhlitis
- Renal function abnormal
Clinical Trial Results
The safety and efficacy of Khapzory rescue following high-dose methotrexate were evaluated in 16 patients age 6-21 who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m2 IV over 4 hours was administered to 13 patients, who received Khapzory 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 g/m2 IV over 6 hours, followed by Khapzory 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of Khapzory doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of Khapzory rescue following high-dose methotrexate was based on the adverse reaction profile.
In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer comparing d,l-leucovorin 200 mg/m2 and fluorouracil 370 mg/m2 versus leucovorin 20 mg/m2 and fluorouracil 425 mg/m2 versus fluorouracil 500 mg/m2 , with all drugs administered by intravenous infusion daily for 5 days every 28 to 35 days, response rates were 26% (p=0.04 versus fluorouracil alone), 43% (p=0.001 versus fluorouracil alone), and 10%, respectively. Respective median survival times were 12.2 months, 12 months and 7.7 months. The low dose d,l-leucovorin regimen was associated with a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose d,l-leucovorin regimen was associated with a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant.
In a second randomized clinical study conducted by Mayo and NCCTG, the fluorouracil alone arm was replaced by sequentially administered methotrexate, fluorouracil, and d,l-leucovorin . Response rates with d,l-leucovorin 200 mg/m2 and fluorouracil 370 mg/m2 versus d,l-leucovorin 20 mg/m2 and fluorouracil 425 mg/m2 versus sequential methotrexate and fluorouracil and d,l-leucovorin were 31%, 42% and 14%, respectively. Respective median survival times were 12.7 months, 12.7 months and 8.4 months. There was no statistically significant difference in weight gain of more than 5% or in improvement in performance status between the treatment arms.
A randomized controlled study conducted by the NCCTG in patients with metastatic colorectal cancer failed to show superiority of a regimen of fluorouracil + levoleucovorin to fluorouracil + d,l-leucovorin in overall survival. Patients were randomized to fluorouracil 370 mg/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m2 intravenously and d,l-leucovorin 200 mg/m2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, then every 5 weeks until disease progression or unacceptable toxicity.
Approval Date: 2018-10-01
Company Name: Acrotech Biopharma