6 ADVERSE REACTIONS

The following adverse drug reactions are discussed in greater detail in other sections of the label:

Severe Neutropenia [see Warnings and Precautions (5.1)]
Severe Diarrhea [see Warnings and Precautions (5.2)]
Interstitial Lung Disease [see Warnings and Precautions (5.3)]
Severe Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of ONIVYDE cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.

Pancreatic Adenocarcinoma

In Combination with Oxaliplatin, Fluorouracil and Leucovorin for First-Line Treatment

The safety of ONIVYDE in patients with metastatic pancreatic adenocarcinoma who had not previously received chemotherapy was evaluated in NAPOLI 3 [see Clinical Studies (14)]. Patients received ONIVYDE 50 mg/m2 in combination with oxaliplatin 60 mg/m2, leucovorin 400 mg/m2 and fluorouracil 2400 mg/m2 over 46 hours every 2 weeks (NALIRIFOX; N=383) or nab-paclitaxel 125 mg/m2 over 35 minutes and gemcitabine 1000 mg/m2 over 30 minutes on Day 1, 8 and 15 of each 28-day cycle (Gem+NabP; N=387). The median duration of exposure to ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin was 24 weeks (range: 0 to 101 weeks).

Serious adverse reactions occurred in 54% of patients who received ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin. Serious adverse reactions in ≥2% of patients included infections including COVID-19 (14%), diarrhea (9%), vomiting (6%), nausea (4.9%), fatigue (3.8%), embolism (3.5%), gastrointestinal tract stenosis or obstruction (3.5%), hemorrhage (3%), abdominal pain (2.7%), cerebrovascular accident (2.7%), dehydration (2.7%), liver function test abnormalities (2.2%), and pyrexia (2.2%). Fatal adverse reactions occurred in 6% of patients who received ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin including cerebrovascular accident (1.1%), hemorrhage (0.5%), pneumonia (0.5%), sepsis (0.5%) and sudden death (0.5%).

Permanent discontinuation of ONIVYDE due to an adverse reaction occurred in 17% of patients. Adverse reactions which 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 which 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 adverse reactions (≥20% with a difference between arms of ≥ 5% for all grades or ≥ 2% for Grades 3 or 4 compared to Gem+NabP) of ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin were diarrhea, fatigue, nausea, vomiting, decreased appetite, abdominal pain, mucosal inflammation, constipation and decreased weight. The most common laboratory abnormalities (≥10% Grade 3 or 4) were decreased neutrophils, decreased potassium, decreased lymphocyte and decreased hemoglobin.

Table 3 and 4 summarize the adverse reactions and laboratory abnormalities, respectively, in the NAPOLI 3 study.

Table 3 Adverse Reactions* (≥ 20%) in Patients with Metastatic Pancreatic Adenocarcinoma who Received NALIRIFOX† with a Difference Between Arms of ≥5% for All Grades or ≥ 2% for Grades 3 and 4 versus Gem+NabP in NAPOLI 3*
Adverse Reaction	NALIRIFOX N=370		Gem+NabP N=379
Adverse Reaction	All Grades (%)	Grade 3 or4 (%)	All Grades (%)	Grade 3 or4 (%)
* NCI CTCAE v5.0 † NALIRIFOX=ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin; Gem+NabP=gemcitabine+nab-paclitaxel ‡ Includes multiple related terms
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 condition
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

Table 4 Laboratory Abnormalities in Patients with Metastatic Pancreatic Adenocarcinoma who Received NALIRIFOX* with a difference between arms of ≥ 5% versus Gem+NabP in NAPOLI 3 †
Laboratory abnormality	NALIRIFOX		Gem-NabP
Laboratory abnormality	All Grades (%)	Grade 3- or 4 (%)	All Grades (%)	Grade 3 or4 (%)
* NALIRIFOX=ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin ; Gem+NabP=gemcitabine+nab-paclitaxel † 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).
Hematology
Hemoglobin decreased	91	10	96	15
Lymphocytes decreased	64	11	76	19
Leukocytes decreased	62	8	77	28
Neutrophils decreased	56	26	65	37
Platelets decreased	55	1.7	75	7
Hepatic
Alkaline phosphatase increased	45	2.9	35	2.7
Alanine aminotransferase increased	40	2.6	56	4.6
Aspartate aminotransferase increased	38	2	49	2.4
Metabolic
Potassium decreased	62	22	29	8
Sodium increased	11	0	5	0.3
Potassium increased	8	0.6	21	3

In Combination with Fluorouracil and Leucovorin after Progresssion on Gemcitabine or Gemcitabine-based Therapy

The safety data described below are derived from patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy who received any part of protocol-specified therapy in NAPOLI-1, an international, randomized, active-controlled, open-label trial. Protocol-specified therapy consisted of ONIVYDE 70 mg/m2 with leucovorin 400 mg/m2 and fluorouracil 2400 mg/m2 over 46 hours every 2 weeks (ONIVYDE/FU/LV; N=117), ONIVYDE 100 mg/m2 every 3 weeks (N=147), or leucovorin 200 mg/m2 and fluorouracil 2000 mg/m2 over 24 hours weekly for 4 weeks followed by 2 week rest (FU/LV; N=134) [see Clinical Studies (14)]. Serum bilirubin within the institutional normal range, albumin ≥ 3 g/dL, and Karnofsky Performance Status (KPS) ≥ 70 were required for study entry. The median duration of exposure was 9 weeks in the ONIVYDE/FU/LV arm, 9 weeks in the ONIVYDE monotherapy arm, and 6 weeks in the FU/LV arm.

The most common adverse reactions (≥ 20%) of ONIVYDE were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common, severe laboratory abnormalities (≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. The most common serious adverse reactions (≥ 2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.

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.

Table 5 provides the frequency and severity of adverse reactions in NAPOLI-1 that occurred with higher incidence (≥5% difference for Grades 1-4 or ≥2% difference for Grades 3-4) in patients who received ONIVYDE/FU/LV compared to patients who received FU/LV.

Table 5 Adverse Reactions with Higher Incidence (≥5% Difference for Grades 1-4* or ≥2% Difference for Grades 3 and 4) in the ONIVYDE/FU/LV Arm
Adverse Reaction	ONIVYDE/FU/LV N=117		FU/LV N=134
	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
* NCI CTCAE v4.0 † Early diarrhea: onset within 24 hours of ONIVYDE administration ‡ Late diarrhea: onset >1 day after ONIVYDE administration § Includes stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation. ¶ Includes febrile neutropenia
Gastrointestinal disorders
Diarrhea	59	13	26	4
Early diarrhea†	30	3	15	0
Late diarrhea‡	43	9	17	4
Vomiting	52	11	26	3
Nausea	51	8	34	4
Stomatitis§	32	4	12	1
Infections and infestations	38	17	15	10
Sepsis	4	3	2	1
Neutropenic fever/neutropenic sepsis¶	3	3	1	0
Gastroenteritis	3	3	0	0
Intravenous catheter-related infection	3	3	0	0
General disorders and administration site conditions
Fatigue/asthenia	56	21	43	10
Pyrexia	23	2	11	1
Metabolism and nutrition disorders
Decreased appetite	44	4	32	2
Weight loss	17	2	7	0
Dehydration	8	4	7	2
Skin and subcutaneous tissue disorders
Alopecia	14	1	5	0

Other Adverse Reactions

Clinically relevant adverse reactions occurring in <5% of patients include:

Cholinergic Reactions: ONIVYDE can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early onset diarrhea. In NAPOLI-1, Grade 1 or 2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients. Six of these 12 patients received atropine and in 1 of the 6 patients, atropine was administered for cholinergic symptoms other than diarrhea.

Infusion Reactions: Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of ONIVYDE administration were reported in 3% of patients receiving ONIVYDE or ONIVYDE/FU/LV.

Laboratory abnormalities that occurred with higher incidence in the ONIVYDE/FU/LV arm compared to the FU/LV arm (≥5% difference) are summarized in the following table.

Table 6 Laboratory Abnormalities with Higher Incidence (≥5% Difference) in the ONIVYDE/FU/LV Arm*†
Laboratory abnormality	ONIVYDE/FU/LV N=117		FU/LV N=134
Laboratory abnormality	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
* NCI CTCAE v4.0, worst grade shown. † Percent based on number of patients with a baseline and at least one post-baseline measurement.
Hematology
Anemia	97	6	86	5
Lymphopenia	81	27	75	17
Neutropenia	52	20	6	2
Thrombocytopenia	41	2	33	0
Hepatic
Increased alanine aminotransferase (ALT)	51	6	37	1
Hypoalbuminemia	43	2	30	0
Metabolic
Hypomagnesemia	35	0	21	0
Hypokalemia	32	2	19	2
Hypocalcemia	32	1	20	0
Hypophosphatemia	29	4	18	1
Hyponatremia	27	5	12	3
Renal
Increased creatinine	18	0	13	0

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of ONIVYDE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: Hypersensitivity (including Anaphylactic reaction and Angioedema)