Mechanism of Action

Onivyde (irinotecan liposome injection) is a topoisomerase inhibitor encapsulated in a lipid bilayer vesicle or liposome. Topoisomerase 1 relieves torsional strain in DNA by inducing single-strand breaks. Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase 1-DNA complex and prevent re-ligation of the single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. In mice bearing human tumor xenografts, irinotecan liposome administered at irinotecan HCl-equivalent doses fivefold lower than irinotecan HCl achieved similar intratumoral exposure of SN-38.

Side Effects

Adverse effects associated with the use of Onivyde may include, but are not limited to, the following:

Diarrhea

Fatigue/asthenia

Vomiting

Nausea

Decreased appetite

Stomatitis

Pyrexia

Lymphopenia

Neutropenia

Onivyde comes with a black box warning of the potential for severe neutropenia and severe diarrhea with the use of Onivyde.

Dosing/Administration

Onivyde is supplied as an injection for intravenous infusion. Administer Onivyde prior to leucovorin and fluorouracil. The recommended dose of Onivyde is 70 mg/m2 administered by intravenous infusion over 90 minutes every two weeks. Increase the dose of Onivyde to 70 mg/m2 as tolerated in subsequent cycles.

Please see the drug label for dosing in specific populations and for dose modifications.

Clinical Trial Results

FDA Approval

The FDA approval of Onivyde was based on a three-arm, randomized, open-label trial in 417 patients with metastatic pancreatic adenocarcinoma with documented disease progression, after gemcitabine or gemcitabine-based therapy. Subjects were randomized to receive Onivyde plus fluorouracil/leucovorin (Onivyde/5-FU/LV), Onivyde or fluorouracil/leucovorin (5-FU/LV). Randomization was stratified by ethnicity (White vs. East Asian vs. other), KPS (70-80 vs. 90-100), and baseline albumin level (≥ 4 g/dL vs. 3.0-3.9 g/dL). Patients randomized to Onivyde/5-FU/LV received Onivyde 70 mg/m2 as an intravenous infusion over 90 minutes, followed by leucovorin 400 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2400 mg/m2 intravenously over 46 hours, every two weeks. The Onivyde dose of 70 mg/m2 is based on irinotecan free base (equivalent to 80 mg/m2 of irinotecan as the hydrochloride trihydrate). Patients randomized to Onivyde as a single agent received Onivyde 100 mg/m2 as an intravenous infusion over 90 minutes every three weeks. Patients randomized to 5-FU/LV received leucovorin 200 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2000 mg/m2 intravenously over 24 hours, administered on Days 1, 8, 15 and 22 of a six-week cycle. Patients homozygous for the UGT1A1*28 allele initiated Onivyde at a reduced dose (50 mg/m2 Onivyde if given with 5-FU/LV or 70 mg/m2 Onivyde as a single agent). The major efficacy outcome measure was overall survival (OS) with two pair-wise comparisons: Onivyde versus 5-FU/LV and Onivyde/5-FU/LV versus 5-FU/LV. The study showed a statistically significant improvement in overall survival for the Onivyde/5-FU/LV arm over the 5-FU/LV arm. There was no improvement in overall survival for the Onivyde arm over the 5-FU/LV arm.