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SAFETY PROFILE OF ONIVYDE (AS PART OF THE NALIRIFOX REGIMEN)

Adverse reactions (≥20%) in patients with mPDAC who received NALIRIFOX with a difference between arms of ≥5% for all Grades or ≥2% for Grades 3 and 4 vs Gem+NabP in NAPOLI 31*

 
ONIVYDE + oxaliplatin 
+ FU/LV 
(N=370)
ONIVYDE +
oxaliplatin + FU/LV
(N=370)
 Gem+NabP
(N=379)
Adverse reaction All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Gastrointestinal disorders
Diarrhea† 72 22 37 5
Nausea 59 12 43 2.6
Vomiting† 40 7 27 2.1
Abdominal pain† 35 4.3 25 4.7
Constipation 25 0.8 30 2.1
General disorders and administration site conditions
Fatigue† 62 15 63 10
Mucosal inflammation† 28 3.8 17 0.8
Peripheral edema† 16 0.3 34 2.4
Pyrexia† 11 0.8 24 1.6
Investigations
Weight decreased 22 3 9 0.3
Metabolism and nutrition disorders
Decreased appetite 37 9 28 2.6
Dehydration 11 3.2 9 1.1
Skin and subcutaneous tissue disorders
Alopecia 14 0 31 0.5
Rash† 11 0.3 22 1.6
Nail disorder 0.3 0 7 0.3
Vascular disorders
Hemorrhage† 11 2.4 18 3.4
Embolism† 11 7 11 5
Respiratory, thoracic, and mediastinal disorders
Dyspnea† 8 0.5 13 2.1
Musculoskeletal and 
connective tissue disorders
Musculoskeletal pain† 18 1.6 27 1.1
Infections and infestations
Pneumonia 2.4 1.6 6 4
Sepsis† 1.6 1.1 6 3.4

 

Laboratory abnormalities in patients with mPDAC who received NALIRIFOX with a difference between arms of ≥5% for all vs Gem+NabP in NAPOLI 31‡

Laboratory abnormalities with ONIVYDE® (irinotecan liposome injection) + oxaliplatin + FU/LV in the NAPOLI 3 clinical trial. Laboratory abnormalities with ONIVYDE® (irinotecan liposome injection) + oxaliplatin + FU/LV in the NAPOLI 3 clinical trial.

Discontinuation rate due to adverse events was 17%1

  • The incidence of all grade and severe neutrophils decreased, platelets decreased, lymphocytes decreased, leukocytes decreased, and hemoglobin decreased were lower in the NALIRIFOX treatment arm

Median duration of treatment2

  • ONIVYDE (as part of the NALIRIFOX regimen): 24.3 weeks
  • Gem+NabP: 17.6 weeks

*NCI CTCAE v5.0.1

†Includes multiple related terms.

‡Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: NALIRIFOX (range: 294 to 351 patients) and Gem+NabP (range: 303 to 373 patients).1

AEs=adverse events; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

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ADDITIONAL SAFETY DATA BY UGT1A1*28 STATUS IN NAPOLI 321

UGT1A1 encodes for an enzyme critical for metabolizing irinotecan. Variations in the UGT1A1 gene, specifically the *28 allele, may influence how patients process and tolerate irinotecan.22 A preplanned exploratory analysis from NAPOLI 3 evaluated the impact of UGT1A1*28 status on treatment tolerability in patients receiving NALIRIFOX.21

Post hoc analysis exploratory endpoint: Safety by UGT1A1*28 status21*

UGT1A1*28 status was evaluated to understand whether genotype influenced tolerability in NAPOLI 3

  • UGT1A1*28 status was determined for all patients prior to enrollment
  • Regardless of genotype, all patients received the full starting dose of ONIVYDE (50 mg/m2) and followed the same dose reduction guidance
  • In NAPOLI 3, 83 patients (~11%) were homozygous for UGT1A1*28 (NALIRIFOX, n=39/83; Gem+NabP, n=44/83)

*Homozygous [TA77] or nonhomozygous [other genotypes].

Study limitations: Analyses were descriptive in nature. The conclusions are limited due to the small number of patients with homozygous UGT1A1*28 status (n=83).21

Safety was evaluated by UGT1A1 status to explore potential differences in tolerability between genotypes in NAPOLI 3.21

TEAEs by UGT1A1*28 status (safety population)21*

TEAE, % (n) UGT1A1*28 homozygous UGT1A1*28 nonhomozygous
NALIRIFOX
(n=39)		 Gem+NabP (n=44) NALIRIFOX (n=328) Gem+NabP (n=331)
Any 100.0% (39) 100.0% (44) 99.7% (327) 99.1% (328)
Related to any drug 100.0% (39) 93.2% (41) 94.5% (310) 93.1% (308)
Grade ≥3 79.5% (31) 77.3% (34) 87.8% (288) 87.0% (288)
Related to any drug 69.2% (27) 68.2% (30) 70.7% (232) 68.3% (226)
Serious 61.5% (24) 54.5% (24) 53.7% (176) 50.8% (168)
Leading to death 5.1% (2) 9.1% (4) 6.1% (20) 5.7% (19)

*UGT1A1*28 status was unknown for three patients who received NALIRIFOX and four patients who received Gem+NabP.

TEAE, % (n) UGT1A1*28 homozygous
NALIRIFOX (n=39) Gem+NabP (n=44)
Any 100.0% (39) 100.0% (44)
Related to any drug 100.0% (39) 93.2% (41)
Grade ≥3 79.5% (31) 77.3% (34)
Related to any drug 69.2% (27) 68.2% (30)
Serious 61.5% (24) 54.5% (24)
Leading to death 5.1% (2) 9.1% (4)
TEAE, % (n) UGT1A1*28 nonhomozygous
NALIRIFOX (n=328) Gem+NabP (n=331)
Any 99.7% (327) 99.1% (328)
Related to any drug 94.5% (310) 93.1% (308)
Grade ≥3 87.8% (288) 87.0% (288)
Related to any drug 70.7% (232) 68.3% (226)
Serious 53.7% (176) 50.8% (168)
Leading to death 6.1% (20) 5.7% (19)

*UGT1A1*28 status was unknown for three patients who received NALIRIFOX and four patients who received Gem+NabP.

Study limitations: This post hoc analysis was exploratory and descriptive in nature. This study describes the impact of UGT1A1*28 status on the management of all components of NALIRIFOX. Per the ONIVYDE USPI, in NAPOLI 3 patients homozygous (N=39) and nonhomozygous (N=328) for the UGT1A1*28 allele initiated ONIVYDE at the same starting dose of 50 mg/m². Grade 3 or 4 neutropenia occurred in 23% vs 13% of homozygous and nonhomozygous patients, and dose reductions of ONIVYDE due to TEAEs occurred in 59% vs 51%.21

TEAEs leading to treatment discontinuation, dose reduction, or dose interruption† by UGT1A1*28 allele status21‡

 
Patients on NALIRIFOX experienced higher rates of dose reduction and treatment discontinuation compared to those on Gem+NabP.
Patients on NALIRIFOX experienced higher rates of dose reduction and treatment discontinuation compared to those on Gem+NabP. Patients on NALIRIFOX experienced higher rates of dose reduction and treatment discontinuation compared to those on Gem+NabP. Patients on NALIRIFOX experienced higher rates of dose reduction and treatment discontinuation compared to those on Gem+NabP.

†Reflects modifications to any component of the NALIRIFOX regimen.

‡The homozygous group includes 39 patients who received NALIRIFOX and 44 patients who received Gem+NabP.

The nonhomozygous group includes 328 patients who received NALIRIFOX and 331 patients who received Gem+NabP.

Most frequently reported TEAEs (≥40%) in homozygous group vs the overall NAPOLI 3 population21:

TEAE In the NALIRIFOX arm
Diarrhea 59.0% (vs 70.5%)
Nausea 56.4% (vs 59.5%)
Vomiting 46.2% (vs 39.7%)
Anemia 41.0% (vs 26.2%)
Most frequently reported adverse reactions for NAPOLI 3 was diarrhea, nausea, vomiting, and anemia. While most frequent adverse reactions for NALIRIFOX were diarrhea, nausea, vomiting, and anemia.
TEAE In the Gem+NabP arm
Diarrhea 45.5% (vs 36.7%)
Nausea 45.5% (vs 42.7%)
Anemia 40.9% (vs 40.4%)
Fatigue 45.5% (vs 37.7%)
Most frequently reported adverse reactions for NAPOLI 3 was diarrhea, nausea, vomiting, and anemia. While most frequent adverse reactions for Gem+NabP were diarrhea, nausea, anemia, and fatigue.

USPI=United States Prescribing Information.

1L 
RECOMMENDED DOSING
INDICATIONS
  • ONIVYDE® (irinotecan liposome injection) is indicated, in combination with oxaliplatin, fluorouracil, and leucovorin, for the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma.
  • ONIVYDE is indicated, in combination with fluorouracil and leucovorin, for the treatment of adult patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy.

Limitations of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic pancreatic adenocarcinoma.

IMPORTANT SAFETY INFORMATION

WARNING: SEVERE NEUTROPENIA AND SEVERE DIARRHEA

Neutropenia

  • Severe and life-threatening neutropenia, including fatal neutropenic sepsis and fatal neutropenic fever, has occurred in patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin and in combination with fluorouracil and leucovorin. Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment.

Diarrhea

  • Severe and life-threatening diarrhea has occurred in patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin and in combination with fluorouracil and leucovorin. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity.
CONTRAINDICATIONS

ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction or anaphylaxis to ONIVYDE or irinotecan HCl.

WARNINGS AND PRECAUTIONS

Severe Neutropenia: ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In NAPOLI 3, Grade 3 and 4 neutropenia occurred in 26% of patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) and fatal neutropenic fever in 0.3% of patients. In NAPOLI 3, the incidence of Grade 3 or 4 neutropenia was similar among Asian patients [6 of 20 (30%)] compared to White patients [76 of 289 (26%)]. Neutropenic fever/neutropenic sepsis was reported in 5% of Asian patients (1 of 20) compared to 2.3% of White patients (7 of 306). In NAPOLI-1, Grade 3 and 4 neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin (ONIVYDE/FU/LV). Neutropenic sepsis occurred in 3% and fatal neutropenic sepsis in 0.8%. In NAPOLI-1, the incidence of Grade 3 or 4 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients.

Monitor complete blood cell counts on Days 1 and 8 of every cycle and more frequently if clinically indicated. Withhold ONIVYDE if the absolute neutrophil count (ANC) is below 1500/mm3 or if neutropenic fever occurs. Resume ONIVYDE when the ANC is 1500/mm3 or above. Reduce ONIVYDE dose for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles.

Severe Diarrhea: In NAPOLI 3, Grade 3 and 4 diarrhea (early-onset [within 24 hours of chemotherapy] and late-onset [more than 
24 hours following chemotherapy]) occurred in 20% receiving NALIRIFOX. In NAPOLI-1, Grade 3 or 4 diarrhea occurred in 13% receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 late-onset diarrhea was 9% in patients receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 early-onset diarrhea was 3% in patients receiving ONIVYDE/FU/LV.

To reduce the risk of severe diarrhea, patients should stop lactose-containing products, eat a low-fat diet, and maintain hydration during treatment with ONIVYDE. Withhold ONIVYDE for Grade 2-4 diarrhea. Local institutional guidelines should be followed for the treatment of diarrhea that does not improve within 48 hours and may include the addition of diphenoxylate hydrochloride plus atropine sulfate or octreotide. Following recovery to Grade 1 diarrhea, resume ONIVYDE at a reduced dose.

Interstitial Lung Disease (ILD): ONIVYDE can cause severe and fatal ILD. Postmarketing cases of severe and fatal ILD have been reported with ONIVYDE. Risk factors include pre-existing lung disease, use of pneumotoxic medicinal products, colony stimulating factors or having previously received radiation therapy. Patients with risk factors should be closely monitored for respiratory symptoms before and during ONIVYDE therapy. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.

Severe Hypersensitivity Reaction: Irinotecan, including ONIVYDE, can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.

Embryo-Fetal Toxicity: Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 7 months after the last dose of ONIVYDE treatment.

ADVERSE REACTIONS FOR NALIRIFOX
  • The most common adverse reactions (≥20%) of NALIRIFOX were diarrhea (72%), fatigue (62%), nausea (59%), vomiting (40%), decreased appetite (37%), abdominal pain (35%), mucosal inflammation (28%), constipation (25%), and weight decreased (22%).
  • Permanent discontinuation of ONIVYDE due to an adverse reaction occurred in 17% of patients. Adverse reactions that resulted in permanent discontinuation of ONIVYDE in ≥1% of patients included neutropenia, thrombocytopenia, diarrhea, fatigue, infections, and cerebrovascular accident.
  • Dosage reduction of ONIVYDE due to an adverse reaction occurred in 52% of patients. Adverse reactions that required dosage reduction in ≥1% of patients included anemia, decreased appetite, diarrhea, fatigue, febrile neutropenia, hypokalemia, liver function test abnormalities, nausea, mucosal inflammation, neutropenia, peripheral neuropathy, vomiting, thrombocytopenia, and weight decreased.
  • Dosage interruptions of ONIVYDE due to an adverse reaction occurred in 1.9% of patients. Adverse reactions which required dosage interruption in ≥0.5% of patients included hypersensitivity and infusion-related reaction.
  • The most common laboratory abnormalities (≥10% Grade 3 or 4) were decreased neutrophils (26%), decreased potassium (22%), decreased lymphocytes (11%), and decreased hemoglobin (10%).
ADVERSE REACTIONS FOR ONIVYDE/FU/LV
  • The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%).
  • Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis.
  • Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia.
  • ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.
  • The most common severe laboratory abnormalities (≥10% Grade 3 or 4) were lymphopenia and neutropenia.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of ONIVYDE:

  • Hypersensitivity (including anaphylactic reaction and angioedema).
DRUG INTERACTIONS
  • Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme inducing therapies ≥2 weeks prior to initiation of ONIVYDE.
  • Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy.
USE IN SPECIFIC POPULATIONS
  • Pregnancy: Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women. Advise pregnant women of the potential risk to a fetus.
  • Lactation: Advise nursing women not to breastfeed during and for 1 month after the last dose of ONIVYDE.
To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 or FDA at 
1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full Prescribing Information, including BOXED WARNING, for ONIVYDE.

References: 1. ONIVYDE® [package insert]. Cambridge, MA. Ipsen Biopharmaceuticals, Inc.; 2024. 2. Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet. 2023;402(10409):1272-1281. 3. Zhang H. Onivyde for the therapy of multiple solid tumors. Onco Targets Ther. 2016;9:3001-3007. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma V2.2026. ©National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed April 30, 2026. To view the most recent and complete version of the guideline, go online to NCCN.org. 5. Dimou A, Syrigos KN, Saif MW. Overcoming the stromal barrier: technologies to optimize drug delivery in pancreatic cancer. Ther Adv Med Oncol. 2012;4(5):271-279. 6. Drummond DC, Noble CO, Guo Z, Hong K, Park JW, Kirpotin DB. Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Cancer Res. 2006;66(6):3271-3277. 7. CAMPTOSAR® [package insert]. New York, NY. Pfizer, Inc.; 2022. 8. Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and challenges of liposome assisted drug delivery. Front Pharmacol. 2015;6:286. 9. Hsueh C-T, Selim JH, Tsai JY, Hsueh C-T. Nanovectors for anti-cancer drug delivery in the treatment of advanced pancreatic adenocarcinoma. World J Gastroenterol. 2016;22(31):7080-7090. 10. Kelly C, Jefferies C, Cryan S-A. Targeted liposomal drug delivery to monocytes and macrophages. J Drug Deliv. 2011;2011:727241. 11. National Cancer Institute. Drugs approved for pancreatic cancer. https://www.cancer.gov/about-cancer/treatment/drugs/pancreatic. Accessed June 27, 2024. 12. Data on file. Cambridge, MA. Ipsen Biopharmaceuticals, Inc. 2023. 13. Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. 14. Ipsen data on file: ASCO advisory board roundtable. 2023. 15. Wang-Gillam A, Li C-P, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557. 16. Data on file #1. Basking Ridge, NJ. Ipsen Biopharmaceuticals, Inc.; 2015. 17. Wang-Gillam A, Hubner RA, Siveke JT, et al. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019;108:78-87. 18. Ipsen data on file: IQVIA medical claims post-gemcitabine usage analysis, Q4 2017–Q1 2023. 19. Department of Health and Human Services. U.S. Food and Drug Administration. ONIVYDE (irinotecan liposome injection) Approval Letter. NDA 207793. October 22, 2015. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207793Orig1s000Approv.pdf. Accessed June 27, 2024. 20. Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J Oncol. 2019;10(1):10-27. doi:10.14740/wjon1166 21. Abdelrahim M, Khan G, Hatoum H, et al. Presented at the American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2025; Chicago, IL, USA: #H5. 22. Dean L. Irinotecan therapy and UGT1A1 genotype. In: Pratt VM, Scott SA, Pirmohamed M, et al., eds. Medical Genetics Summaries [Internet]. National Center for Biotechnology Information (US); 2012. 23. Data on file_NON-US-004598. Basking Ridge, NJ. Ipsen Biopharmaceuticals, Inc. 3-31-2026. 24. Patel A, Laursen A, Cockrum P, et al. Effect of dose adjustments on overall survival in patients with metastatic pancreatic ductal adenocarcinoma treated with NALIRIFOX: a post hoc analysis of NAPOLI 3. Presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 23-25, 2025; San Francisco, CA, USA: #71.

©2026 Ipsen Biopharmaceuticals, Inc. All rights reserved. May 2026 ONV-US-004559

©2026 Ipsen Biopharmaceuticals, Inc.
All rights reserved.
May 2026
ONV-US-004559