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DOSE MODIFICATIONS AND TREATMENT TO HELP MANAGE ADVERSE REACTIONS FOR THE NALIRIFOX REGIMEN

Recommended dose modifications for ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin1

Recommended modifications from the NAPOLI 3 clinical trial of ONIVYDE® (irinotecan liposome injection) + oxaliplatin + FU/LV, including dose reduction, delay, and discontinuation. Recommended modifications from the NAPOLI 3 clinical trial of ONIVYDE® (irinotecan liposome injection) + oxaliplatin + FU/LV, including dose reduction, delay, and discontinuation.

Oxaliplatin may be discontinued if not well tolerated and treatment with ONIVYDE + FU/LV can continue. Maintain original dose level of leucovorin for first, second, and third occurrence of toxicity. Refer to the full Prescribing Information of fluorouracil and oxaliplatin1

* NCI CTCAE v5.0.

† No dosage modification is necessary for asthenia, alopecia, and Grade 3 anorexia.

‡ Do not resume until the absolute neutrophil count is ≥2000/mm3 (2x109/L) and the platelet count is ≥100,000/mm3 (100x109/L).

§ For Grade ≥3 nausea and vomiting, reduce dose only if occurs despite optimal antiemetic therapy.

Recommended dose modifications for severe neutropenia and severe diarrhea1

  Neutropenia Diarrhea
Withhold ONIVYDE 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.

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. Administer intravenous or subcutaneous atropine 0.25 mg to 1 mg (unless clinically contraindicated) for early-onset diarrhea of any severity.

Initiate loperamide for late-onset diarrhea any severity. 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.
Resume ONIVYDE Resume ONIVYDE when the ANC is 1500/mm3 or above. For Grade 2 diarrhea, upon recovery to ≤Grade 1, resume ONIVYDE at original dose.23 

For Grade 3-4 diarrhea, resume ONIVYDE at a reduced dose following recovery to Grade 1 diarrhea.
Reduce ONIVYDE For Grade 3-4 neutropenia or neutropenic fever, reduce ONIVYDE following recovery in subsequent cycles. For Grade 3-4 diarrhea, reduce ONIVYDE following recovery to Grade 1 diarrhea.
Withhold ONIVYDE
Neutropenia Diarrhea
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.

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. Administer intravenous or subcutaneous atropine 0.25 mg to 1 mg (unless clinically contraindicated) for early-onset diarrhea of any severity.

Initiate loperamide for late-onset diarrhea of any severity. 
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.
Resume ONIVYDE
Neutropenia Diarrhea
Resume ONIVYDE when the ANC is 1500/mm3 or above. For Grade 2 diarrhea, upon recovery to ≤Grade 1, resume ONIVYDE at original dose.23 

For Grade 3-4 diarrhea, resume ONIVYDE at a reduced dose following recovery to Grade 1 diarrhea.
Reduce ONIVYDE
Neutropenia Diarrhea
For Grade 3-4 neutropenia or neutropenic fever, reduce ONIVYDE following recovery in subsequent cycles. For Grade 3-4 diarrhea, reduce ONIVYDE following recovery to Grade 1 diarrhea.

ADDITIONAL DOSE MODIFICATION DATA

A post hoc analysis of NAPOLI 3 evaluated dose modifications of ONIVYDE and oxaliplatin in patients receiving NALIRIFOX for mPDAC.1,23 All patients initiated ONIVYDE at the recommended starting dose of 50 mg/m2.1

Median overall survival by lowest dose of liposomal irinotecan and oxaliplatin (safety population)24

    Overall Survival
  n Events Median (95% CI), months
Lowest dose of liposomal irinotecan
50 mg/m² (starting dose) 173 129 9.1 
(7.5–11.5)
40 mg/m² 118 74 11.8 
(10.0-14.4)
32.5 mg/m² 56 30 16.9 
(10.4–NE)
25 mg/m² 23 14 13.5 
(10.3–NE)
Lowest dose of oxaliplatin
60 mg/m² (starting dose) 150 117 7.9 
(6.3–10.2)
48 mg/m² 116 77 11.7 
(9.4–13.9)
39 mg/m² 73 36 17.1 
(11.8–NE)
30 mg/m² 30 16 14.4 
(12.2–NE)

Study limitations: This post hoc analysis was exploratory in nature and occurred after the protocol-specified final analysis. It is not powered to assess OS efficacy. There is no direct causal relationship between dose reductions and survival; therefore, no conclusions can be drawn to the impact of dose modification on overall survival.24

Cumulative dose and duration of exposure by dose reduction status in NALIRIFOX-treated mPDAC (post hoc analysis of NAPOLI 3)24

  Overall North America Rest of the world
  Dose not reduced Dose reduced Dose not reduced Dose reduced Dose not reduced Dose reduced
Liposomal Irinotecan n=176 n=194 n=49 n=63 n=127 n=131
Cumulative dose, median (IQR), mg/m² 248.9 
(100.0-760.0)		 536.0 (295.6-870.1) 403.5 
(102.1-809.4)		 460.1 
(245.9-966.9)		 200.9 
(99.7-755.0)		 544.9 
(320.0-824.4)
Duration of exposure at any dose, median (IQR), weeks 10.6 
(3.9-35.6)		 31.7 (17.1-51.7) 18.1 
(4.1-35.0)		 25.3 
(15.1-53.7)		 8.3 
(3.0-36.3)		 32.1 
(18.0-50.1)
Oxaliplatin n=153 n=217 n=40 n=72 n=113 n=145
Cumulative dose, median (IQR), mg/m² 239.9 
(119.1-595.5)		 635.6 (360.5-907.3) 327.6 
(121.6-628.5)		 653.8 
(304.9-974.8)		 238.1 
(60.3-595.4)		 635.6 
(410.7-860.3)
Duration of exposure at any dose, median (IQR), weeks 8.1 
(2.9-23.0)		 30.0 (17.3-40.1) 12.1 
(3.6-24.7)		 25.2 
(15.1-43.8)		 8.0 
(2.1-21.3)		 30.1 
(18.0-39.7)
  Overall
  Dose not reduced Dose reduced
Liposomal Irinotecan n=176 n=194
Cumulative dose, median (IQR), mg/m² 248.9 
(100.0-760.0)		 536.0 (295.6-870.1)
Duration of exposure at any dose, median (IQR), weeks 10.6 
(3.9-35.6)		 31.7 (17.1-51.7)
Oxaliplatin n=153 n=217
Cumulative dose, median (IQR), mg/m² 239.9 
(119.1-595.5)		 635.6 (360.5-907.3)
Duration of exposure at any dose, median (IQR), weeks 8.1 
(2.9-23.0)		 30.0 (17.3-40.1)
  North America
  Dose not reduced Dose reduced
Liposomal Irinotecan n=49 n=63
Cumulative dose, median (IQR), mg/m² 403.5 
(102.1-809.4)		 460.1 
(245.9-966.9)
Duration of exposure at any dose, median (IQR), weeks 18.1 
(4.1-35.0)		 25.3 
(15.1-53.7)
Oxaliplatin n=40 n=72
Cumulative dose, median (IQR), mg/m² 327.6 
(121.6-628.5)		 653.8 
(304.9-974.8)
Duration of exposure at any dose, median (IQR), weeks 12.1 
(3.6-24.7)		 25.2 
(15.1-43.8)
  Rest of the world
  Dose not reduced Dose reduced
Liposomal Irinotecan n=127 n=131
Cumulative dose, median (IQR), mg/m² 200.9 
(99.7-755.0)		 544.9 
(320.0-824.4)
Duration of exposure at any dose, median (IQR), weeks 8.3 
(3.0-36.3)		 32.1 
(18.0-50.1)
Oxaliplatin n=113 n=145
Cumulative dose, median (IQR), mg/m² 238.1 
(60.3-595.4)		 635.6 
(410.7-860.3)
Duration of exposure at any dose, median (IQR), weeks 8.0 
(2.1-21.3)		 30.1 
(18.0-39.7)

Data provided for descriptive purposes only.

Median cumulative dose and duration of exposure by dose reduction status24:

  • Patients with dose reductions had higher median cumulative doses of ONIVYDE (536.0 vs 248.9 mg/m²) and oxaliplatin (635.6 vs 239.9 mg/m²)
  • Duration of exposure was also longer with dose reductions for ONIVYDE (31.7 vs 10.6 weeks) and oxaliplatin (30.0 vs 8.1 weeks)

IQR=interquartile range; NE=not estimable.

POST-GEM SAFETY DATA

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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