FDA Approves ONIVYDE™ (Irinotecan liposome injection) in Combination with Fluorouracil and Leucovorin, for the Treatment of Patients with Metastatic Adenocarcinoma of the Pancreas Whose Disease Has Progressed Following Gemcitabine-based Therapy

On October 22, 2015, the United States Food and Drug Administration (FDA) approved ONIVYDE™ (Irinotecan liposome injection) for intravenous use in combination with fluorouracil (5-FU) and leucovorin (LV), for the treatment of patients with metastatic adenocarcinoma of the pancreas whose disease has progressed following gemcitabine-based therapy.The approved recommended dosage of ONIVYDE following appropriate dilution is 70 mg/m2 administered by intravenous infusion over 90 minutes every two weeks. Reduce the starting dose to 50 mg/m2 every two weeks in patients homozygous for UGT1A1*28. There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. A corticosteroid and an antiemetic should be administered 30 minutes prior to the ONIVYDE infusion. ONIVYDE is not indicated as a single agent for the treatment of metastatic adenocarcinoma of the pancreas.

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of ONIVYDE

  • MOA: Topoisomerase 1 inhibitor
  • Dose proportionality: Total irinotecan exhibited dose-proportional increases in Cmax and AUC over the dose range of 50 to 155 mg/m2 (i.e., 0.71 to 2.2 times the approved recommended dosage). The Cmax of the active metabolite (i.e., total SN-38) increases proportionally with dose; however, the AUC increases less than proportionally.
  • Accumulation:Unknown
  • Plasma protein binding: Less than 0.44% of the total irinotecan in ONIVYDE
  • Terminal half-life (mean (standard deviation)): Approximately 25.8 (15.7) hours for total irinotecan and 67.8 (44.5) hours for total SN-38 in patients
  • Metabolism: The metabolism of irinotecan liposome has not been evaluated; however irinotecan is subject to extensive metabolic conversion by various enzyme systems to form the active metabolite SN-38, and UGT1A1 mediated glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan also undergoes CYP3A4-mediated oxidative metabolism.
  • Excretion: The disposition of irinotecan liposome has not been elucidated in humans; however, following administration of irinotecan HCl, 11 to 20% and less than 1% of irinotecan and SN-38 are excreted in the urine, respectively. The cumulative biliary and urinary excretion of irinotecan and its metabolites over 48 hours following administration of irinotecan HCl ranged from approximately 25% to 50% in two patients.

Drug Interaction Potential

  • Avoid the use of strong CYP3A4 inducers. Substitute non-enzyme inducing therapies at least 2 weeks prior to initiation of ONIVYDE therapy. Following administration of irinotecan HCl, exposure to irinotecan or its active metabolite, SN-38, is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsant phenytoin as well as other strong CYP3A4 inducers.
  • Avoid the use of strong CYP3A4 or UGT1A1 inhibitors if possible. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting ONIVYDE therapy. Following administration of irinotecan HCl, patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38.  

Use in Specific Populations

  • Hepatic Impairment: The pharmacokinetics of irinotecan liposome in patients with hepatic impairment is unknown; however, patients with baseline bilirubin concentrations of 1-2 mg/dL had average steady state concentrations for total SN-38 that were increased by 37% compared to patients with baseline bilirubin concentrations of less than 1 mg/dL. As stated above, a dosage recommendation for patients with serum bilirubin above the upper limit of normal cannot be determined because the clinical impact of this finding is unknown.
  • Homozygous for the UGT1A1*28 allele: There is an increased risk of neutropenia from irinotecan HCl in patients that are homozygous for the UGT1A1*28 allele; however, patients receiving ONIVYDE at the recommended lower dosage (see above) achieved similar steady state SN-38 concentrations and incidence of Grade 3 or 4 neutropenia compared to non-homozygous patients at the full dosage.
  • Ethnicity: 56% lower total irinotecan and 8% higher total SN-38 average steady state concentrations were observed in Asian patients enrolled from Taiwan and South Korea compared to Caucasians.  The clinical significance of this finding is unknown.
  • The following population or disease characteristics did not result in a clinically significant effect on the exposure (i.e., Cmax and AUC) of irinotecan and SN-38: Age (28 to 87 years), sex, and mild-to-moderate renal impairment (estimated creatinine clearance (CLcr) by Cockcroft-Gault (C-G) method: 30 to 89 mL/minute). The effect of more severe renal impairment (estimated CLcr by C-G less than 30 mL/minute) with or without hemodialysis is unknown.

Safety and Efficacy

The approval was based on the demonstration of improved overall survival (OS) in a three-arm, randomized, open-label trial in patients with metastatic pancreatic adenocarcinoma with documented disease progression, after gemcitabine or gemcitabine-based therapy. Patients were randomized to receive ONIVYDE plus 5-FU/LV, ONIVYDE, or 5-FU/LV. Patients homozygous for the UGT1A1*28 allele initiated treatment with irinotecan liposome at a reduced dose in the two irinotecan liposome-containing arms.  The primary study endpoint was OS. A 1.9 month improvement in median overall survival for the ONIVYDE/5-FU/LV arm (median (95% CI) 6.1 mo (4.8, 8.5)) over the 5-FU/LV arm (median (95% CI) 4.2 mo (3.3, 5.3)) was reported (hazard ratio (95% CI): 0.68 (0.50, 0.93), p=0.014). There was no improvement in OS for the ONIVYDE arm over the 5-FU/LV arm (hazard ratio=1.00, p-value=0.97 (two-sided log-rank test)).

The most common adverse drug reactions were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia.  The most common severe (grade 3-4) laboratory abnormalities were lymphopenia, and neutropenia.  The most frequent adverse reactions resulting in discontinuation of irinotecan liposome were diarrhea, vomiting, and sepsis.  The most frequent adverse reactions leading to dose reductions or delays were neutropenia, diarrhea, nausea/vomiting, anemia, fatigue, and thrombocytopenia. Severe hypersensitivity reactions have occurred with irinotecan hydrochloride; irinotecan liposome injection is contraindicated in patients with severe allergic reactions to irinotecan liposome or irinotecan hydrochloride.


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This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.