NAPOLI 3 Safety Data | ONIVYDE® (irinotecan liposome injection)

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 3^1‡

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.

1L
RECOMMENDED DOSING

IMPORTANT SAFETY
INFORMATION AND INDICATIONS 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: See Boxed WARNING. 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: See Boxed WARNING. 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): Irinotecan HCl can cause severe and fatal ILD. 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: 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: Immune system disorders: 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 and Reproductive Potential: See WARNINGS & PRECAUTIONS. Advise males with female partners of reproductive potential to use condoms during and for 4 months after the last dose of ONIVYDE treatment.
Lactation: Advise nursing women not to breastfeed during and for 1 month after the last dose of ONIVYDE treatment.

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.

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.

Please see full Prescribing Information, including BOXED WARNING, for ONIVYDE.

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