Khapzory™ – Spectrum Pharmaceuticals, Inc. FDA approval for three indications

New Drug Overview – levoleucovorin (Khapzory)

On October 19, 2018, the U.S. Food and Drug Administration (FDA) approved levoleucovorin (Khapzory) for three indications.

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

It is noted in the package insert that Khapzory is not indicated for the treatment of pernicious anemia and megaloblastic anemia secondary to lack of vitamin B12, due to a risk of progression of neurologic manifestations despite hematologic remission.  Khapzory is a folate analog and the pharmacologically active levo-isomer of d,l-leucovorin. It is a sodium salt verses a calcium salt, available as Fusilev ® (FDA approved in 2008 from the same manufacturer) and as generics, therefore it does not have the same administration rate restrictions due to the calcium content. It is anticipated that Khapzory may have less drug interactions than the calcium salt versions of levoleucovorin. In the past recommendations for the use of levoleucovorin over leucovorin was for instances when leucovorin was not available.

Generic Name Brand Name Manufacturer Approval Date Anticipated Availability Accelerated Review
levoleucovorin Khapzory Spectrum Pharmaceuticals, Inc.. October 19, 2018 January 2019 n/a
Labeled Indications:
Rescue after high-dose methotrexate therapy in patients with osteosarcoma.
Diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination.
The treatment of patients with metastatic colorectal cancer in combination with fluorouracil.
Drug Class Comparative Drugs in Class Route of Administration Dosing Schedule
folate analog Fusilev ®, levoleucovorin, leucovorin intravenous Indication and response dependant
Mechanism of Action:
Levoleucovorin counteracts the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.
Enhances the therapeutic and toxic effects of fluorouracil acting to stabilize the binding of the active metabolite of fluorouracil to thymidylate synthase increasing its inhibition.  Thymidylate synthase is an enzyme important in DNA repair and replication.
Clinical Trial Summary (Efficacy):
Rescue after High-Dose Methotrexate Therapy in Patients with Osteosarcoma

Study: Evaluated in 16 patients, ages 6-21 years, who received 58 courses of chemotherapy for osteogenic sarcoma

Study Dose: 13 patients: 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate 12 g/m2 IV over 4 hours, three patients: 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate 12.5 g/m2 IV over 6 hours.

Primary Outcome Measurements:

·         The efficacy of levoleucovorin rescue following high-dose methotrexate was based on adverse reaction profile

Metastatic Colorectal Cancer

Study 1: randomized clinical study in patients with metastatic colorectal cancer

Study Dose: d,l-leucovorin (LV) 200 mg/m2 and fluorouracil 370 mg/m2 versus LV 20 mg/m2 and fluorouracil 425 mg/m2 versus fluorouracil 500 mg/m2 administered by intravenous infusion daily for 5 days every 28 to 35 days

Outcome Measurements:

·         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 (p=0.037), 12 months (p=0.050), and 7.7 months.

Study 2: randomized clinical study in patients with metastatic colorectal cancer

Study Dose: d,l-leucovorin (LV) 200 mg/m2 and fluorouracil 370 mg/m2 versus LV 20 mg/m2 and fluorouracil 425 mg/m2 versus sequentially administered methotrexate (MTX), fluorouracil, and LV

Outcome Measurements:

·         Response rates were 31% (p≤0.01), 42% (p≤0.01), and 14%, respectively.

·         Respective median survival times were 12.7 months (p≤0.04), 12.7 months (p≤0.01), and 8.4 months.

Study 3: randomized clinical study in patients with metastatic colorectal cancer

Study Dose: fluorouracil 370 mg/m2 and levoleucovorin 100 mg/m2 or fluorouracil 370 mg/m2 intravenously and d,l-leucovorin 200 mg/m2

Outcome Measurement:

·         Failed to show superiority of a regimen of fluorouracil + levoleucovorin to fluorouracil + d,l-leucovorin in overall survival.

Warnings and Adverse Effects (AE):
Warning(s):

·         Increased gastrointestinal toxicities with fluorouracil. 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 for Pneumocystis jiroveci pneumonia in patients with HIV.

AE(s):

·         The most common adverse reactions (≥ 20%) in patients receiving highdose methotrexate therapy with levoleucovorin rescue were stomatitis and vomiting.

·         The most common adverse reactions (>50%) in patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer were stomatitis, diarrhea, and nausea.

NDC Strength Volume Presentation Storage
68152-0112-01 175 mg lyophilized powder Single dose vial Room Temperature
68152-0114-01 300 mg lyophilized powder Single dose vial Room Temperature
Drug Sales Forecast (in millions):
2018(F) 2019(F) 2020(F) 2021(F) 2022(F) 2023(F) 2024(F)
Fusilev ® 2 1 1 1 1 1 n/a


References:

Business Wire A Berkshire Hathaway Company Press Release, “Spectrum Pharmaceuticals Receives FDA Approval of KHAPZORY™ (levoleucovorin) for injection” https://www.businesswire.com/news/home/20181023005463/en/Spectrum-Pharmaceuticals-Receives-FDA-Approval-KHAPZORY%E2%84%A2-levoleucovorin  Accessed October 24, 2018

Global Data Pharma Intelligence Center https://pharma.globaldata.com Accessed October 24, 2018.

RJ Health Systems Inc Reimbursement Codes https://www.reimbursementcodes.com Accessed October 24, 2018.

U.S. Food and Drug Administration Drugs@FDA: FDA Approved Drug Products Product Labeling https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211226s000lbl.pdf  Accessed October 24, 2018.

 

Additional 2018 Pipeline Reviews are available in our pipeline library.

Please see the October 2018 FDA Actions Newsletter for additional information on recent FDA approvals.