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General Information
Onivyde (irinotecan liposome injection) is a topoisomerase inhibitor.
Onivyde is specifically indicated:
in combination with oxaliplatin, fluorouracil and leucovorin, for the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma,
in combination with fluorouracil and leucovorin, for the treatment of adult patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy.
Dosing/Administration
Onivyde is supplied as an injection for intravenous infusion. Premedicate with a corticosteroid and an anti-emetic 30 minutes prior to Onivyde.
Onivyde in combination with oxaliplatin, fluorouracil and leucovorin:
- Recommended dose of Onivyde is 50 mg/m² intravenous infusion over 90 minutes every two weeks.
- Recommended starting dose of Onivyde in patients homozygous for UGT1A1*28 is 50 mg/m2 every two weeks.
- There is no recommended dose of Onivyde for patients with serum bilirubin above the upper limit of normal.
Onivyde in combination with fluorouracil and leucovorin:
- Recommended dose of Onivyde is 70 mg/m2 intravenous infusion over 90 minutes every two weeks.
- Recommended starting dose of Onivyde in patients homozygous for UGT1A1*28 is 50 mg/m2 every two weeks.
- There is no recommended dose of Onivyde for patients with serum bilirubin above the upper limit of normal.
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.
Clinical Trial Results
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.
The FDA approval was also based on efficacy and safety data from NAPOLI 3, a randomized, open-label, Phase III pivotal trial that enrolled 770 people living with mPDAC between the ages of 20 and 85 without prior treatment across 187 trial site locations in 18 countries. The study demonstrated NALIRIFOX (n=383) provided a statistically significant improvement in median overall survival (mOS) of 11.1 months compared to 9.2 months in nab-paclitaxel and gemcitabine treated patients (n=387). NALIRIFOX regimen also demonstrated a statistically significant improvement in median progression-free survival (mPFS) of 7.4 months versus 5.6 months for nab-paclitaxel and gemcitabine treated patients. The objective response rate was 41.8% for patients treated with the NALIRIFOX regimen versus 36.2% for patients treated with nab-paclitaxel and gemcitabine.