Prescribing Information
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Adverse Event Management

Icon for downloading the Guide to Chemotherapy-Induced Adverse Events.
Guide to
Chemotherapy-Induced
Adverse Events
Guide to Chemotherapy-Induced Adverse Events

A helpful overview on identifying and
managing certain adverse events in patients
who are receiving ONIVYDE.

A helpful overview on identifying
and managing certain adverse
events in patients who are
receiving ONIVYDE.

Icon for downloading the Guide to Chemotherapy-Induced Diarrhea.
Guide to
Chemotherapy-Induced
Diarrhea
Guide to Chemotherapy-Induced Diarrhea

Information on assessing
and managing diarrhea in patients
receiving ONIVYDE who may require
dose modifications.

Information on assessing
and managing diarrhea in patients
receiving ONIVYDE who may
require dose modifications.

Office Resources

Icon for downloading the ONIVYDE® (irinotecan liposome injection) Patient Brochure.
Electronic Health Record 
(EHR) Instructions
Electronic Health Record (EHR) Instructions

Instructions for the Epic® EHR system to create
or update order sets with ONIVYDE, as part of
the NALIRIFOX regimen.

Instructions for the Epic® EHR
system to create or update order
sets with ONIVYDE, as part of
the NALIRIFOX regimen.

Patient Resources

Icon for downloading the ONIVYDE® (irinotecan liposome injection) Patient Brochure.
ONIVYDE 
Patient Brochure
ONIVYDE Patient Brochure

Easy-to-understand information to
help patients take an active role in
their own treatment.

Easy-to-understand information
to help patients take an active
role in their own treatment.

VIDEOS

ONIVYDE Mode of 
Delivery Video

Watch how the ONIVYDE 
liposome addresses the 
challenges of the dense stroma 
surrounding mPDAC tumors.

    Read the transcript

    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.

    Please stay tuned for additional Important Safety Information at the end of this video, and please see full Prescribing Information, including BOXED WARNING, at ONIVYDE.com/USPI.

    Metastatic pancreatic cancer is considered to be one of the most challenging types of cancer to treat.

    The tumors have dense stroma, which can hinder the delivery of some therapeutic agents.

    ONIVYDE represents a technological advance in drug delivery. It is a liposomal formulation of irinotecan that was designed to address the challenge of the dense stroma.

    This design is different from conventional irinotecan and helps ONIVYDE stay in the fight.

    The ONIVYDE liposome is a lipid bilayer vesicle that shelters an aqueous space containing approximately 80,000 irinotecan molecules. This liposomal encapsulation helps protect irinotecan from early conversion to a more active metabolite, SN-38.

    The ONIVYDE liposome is stabilized through the addition of a hydrophilic polymer coating, polyethylene glycol, or PEG.

    PEGylation helps protect the ONIVYDE liposome from being rapidly cleared from the body, so it can stay in circulation longer.

    Following administration of ONIVYDE by intravenous infusion, the half-life of total irinotecan in the body is 1.93 days for the 50 mg/m2 dose and 1.87 days for the 70 mg/m2 dose.

    In addition, direct measurement of the ONIVYDE liposome showed that 95% of irinotecan remained liposome-encapsulated in circulation and the ratio between total and encapsulated forms did not change from 0 to 170 hours postdose.

    Protection of irinotecan and prolonged circulation time allow ONIVYDE to deliver its cytotoxic payload to the tumor.

    Tumors often have leaky vasculature and defective lymphatic drainage allowing larger particles, such as macromolecules and liposomes, to gain access and be retained.

    This effect is known as the enhanced permeability and retention—or EPR effect. The EPR effect is believed to enable the ONIVYDE liposome to exit circulation and reach the tumor.

    The tumor environment contains a high concentration of macrophages.

    These tumor-associated macrophages engulf the ONIVYDE liposomes through phagocytosis and unpack the liposomes, facilitating the release of irinotecan.

    The irinotecan is then converted by carboxylesterases into SN-38, its active metabolite.

    Both irinotecan and SN-38 are topoisomerase inhibitors, which work by overwhelming the DNA repair mechanisms in cells.

    However, SN-38 is more potent than irinotecan.

    In a preclinical study in equivalent doses, ONIVYDE showed higher and sustained intratumoral levels of irinotecan and SN-38 relative to conventional irinotecan.

    ONIVYDE is a liposomal formulation of irinotecan specifically designed to protect its payload while in circulation, so it can reach the pancreatic tumor and help stay in the fight.

    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 at ONIVYDE.com/USPI.

    Discover the 
    NAPOLI-3 Story

    Explore pivotal clinical endpoints,
    OS, PFS, and ORR, along
    with safety and dose modification
    information.

      Read the transcript

      Hello, I’m Dr Raji Shameem, a hematologist oncologist at Orlando health cancer institute. I've been caring for patients with pancreatic cancer for the better part of my career. With recent advancements, I see more hope for the future of treatment than ever before. In this video, I'd like to focus on NALIRIFOX, the first FDA-approved option for the first-line treatment of patients with metastatic pancreatic cancer in over a decade. I’ll do this by taking a deep dive into NAPOLI 3, a clinical trial that studied this regimen.

      Before we begin, let’s review the indications, limitations of use, and black box warning for ONIVYDE. ONIVYDE is indicated, in combination with oxaliplatin, fluorouracil, and leucovorin, for the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma. ONIVYDE is also indicated, in combination with fluorouracil and leucovorin, for the treatment of adult patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy. Importantly, ONIVYDE has limitations of use and a boxed warning for severe neutropenia and severe diarrhea. For additional safety information, please visit Onivyde.com.

      Let's take a moment to appreciate how we got here. We saw the first major advancement since fluorouracil (5-FU) with the approval of gemcitabine in 1996. Then, in 2011, use of FOLFIRINOX, an irinotecan-containing regimen, became widespread.

      In 2013, Abraxane was FDA-approved in combination with gemcitabine as an additional treatment option. Over a decade later, the triplet regimen, NALIRIFOX, which contains ONIVYDE (irinotecan liposome injection), was FDA-approved for the first line use in metastatic pancreatic adenocarcinoma.

      This liposomal formulation encapsulates irinotecan in a lipid bilayer vesicle, which allows irinotecan to remain in circulation for longer than unencapsulated irinotecan before conversion to its active metabolite.

      NCCN Clinical Practice Guidelines in Oncology or the (NCCN Guidelines®) recommend the NALIRIFOX regimen as first-line therapy in metastatic disease for patients with a good Eastern Cooperative Oncology Group performance status (or ECOG PS) of 0 to 1.

      Additionally, liposomal irinotecan is recommended as a subsequent therapy for locally advanced, metastatic (category 1), or recurrent disease in patients with prior gemcitabine-based therapy and a good-to-intermediate ECOG performance status of 0 to 2.

      So, how did NAPOLI 3 evaluate the efficacy and safety of NALIRIFOX? Let’s take a closer look. NAPOLI 3 was the first phase 3 global trial to compare 2 combination chemotherapy regimens head-to-head in patients with metastatic pancreatic ductal adenocarcinoma who have not previously received treatment for metastatic disease.

      The primary endpoint was overall survival, and the secondary endpoints included progression free survival, objective response rate, and safety.

      A total of 770 patients were enrolled and randomized 1:1, with 383 receiving NALIRIFOX and 387 receiving gem-nab. The baseline characteristics between the 2 groups were well balanced. Unlike most phase 3 pancreatic cancer trials, NAPOLI 3 had no upper age restrictions and did not exclude patients with clinical ascites. 6.9% of patients were 75 years or older.

      NAPOLI 3 is the only study to demonstrate superiority of triplet therapy over double therapy with gem-nab. Median overall survival in the NALIRIFOX arm was 11.1 months vs 9.2 months with gem-nab, an improvement in median survival of approximately 2 months. Overall survival hazard ratio was 0.84, with 95% confidence interval of 0.71 to 0.99, and a P value of 0.0403.

      The NALIRIFOX PFS data demonstrated in NAPOLI 3 are particularly remarkable among the triplet therapy options. The median PFS was 7.4 months with NALIRIFOX vs 5.6 months with gem-nab, which is an improvement of approximately 2 months. PFS hazard ratio was 0.7, with 95% confidence interval of 0.59 to 0.85, and a P value of 0.0001.

      The objective response rate with NALIRIFOX was 41.8% vs 36.2% with gem-nab, that’s a relative difference of 15%.

      Common adverse events of clinical interest include peripheral neuropathy and peripheral sensory neuropathy. Grade 3 and 4 peripheral neuropathy occurred in 3.2% of patients who received NALIRIFOX and in 5.8% of patients receiving nab-paclitaxel and gemcitabine. Grade 3 and 4 peripheral sensory neuropathy occurred in 3.5% of patients who received NALIRIFOX and 2.9% of patients receiving nab-paclitaxel and gemcitabine.

      Adverse reactions associated with NALIRIFOX included hematologic events such as decreased hemoglobin, neutrophils, and platelets. Gastrointestinal events were also reported, including diarrhea, nausea, vomiting, fatigue, decreased appetite, and abdominal pain. The discontinuation rate due to adverse events was 17%. Adverse reactions that resulted in permanent discontinuation of ONIVYDE in ≥1% of patients included neutropenia, thrombocytopenia, diarrhea, fatigue, infections, and cerebrovascular accident.

      Please take a moment to review the full adverse events table on screen. For additional safety information, please visit ONIVYDE.com.

      In NAPOLI 3, dose modifications were sometimes needed to manage adverse reactions. 1.9% of patients required dose interruptions, 17% of patients discontinued therapy, and 52% of patients received a reduced dose to help manage an adverse reaction.

      A post hoc analysis of NAPOLI 3 evaluated FDA-approved dose modifications of ONIVYDE and oxaliplatin in patients receiving NALIRIFOX for metastatic pancreatic ductal adenocarcinoma (or mPDAC). It is worth noting that as a study limitation, this retrospective, post hoc analysis was not preplanned, and there is no direct causal relationship between dose reductions and survival. Of the 370 patients who received NALIRIFOX, over 50% received a dose adjustment. Patients who received a liposomal irinotecan starting dose of 50 mg/m2 had a median overall survival of 9.1 months. Those who received a dose reduction to 40 mg/m2 had a median survival of 11.8 months. The 32.5 mg/m2 dose had a median survival of 16.9 months, and the 25 mg/m2 dose had a median survival of 13.5 months.

      The median cumulative dose for patients who did not receive a reduced dose of liposomal irinotecan or oxaliplatin was 248.9 mg/m2 and 239.9 mg/m2, respectively. Patients who did receive a dose reduction had higher median cumulative doses of 536.0 mg/m2 and 635.6 mg/m2, respectively.

      Based on the evidence presented, I encourage you to consider NALIRIFOX as an option in your treatment decisions for patients. Thank you for watching.

      Please continue for Important Safety Information and see full Prescribing Information.

      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 at ONIVYDE.com/USPI.

      CONTACT AN IPSEN REP
      callout-image

      Contact an IPSEN Rep
      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 V2.2025. ©National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed December 4, 2025. 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.

      ©2025 Ipsen Biopharmaceuticals, Inc. All rights reserved. October 2025 ONV-US-004559

      ©2025 Ipsen Biopharmaceuticals, Inc.
      All rights reserved.
      October 2025
      ONV-US-004559