Onivyde Drug Information

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 . Patients received ONIVYDE 50 mg/m 2 in combination with oxaliplatin 60 mg/m 2, leucovorin 400 mg/m 2 and fluorouracil 2400 mg/m 2 over 46 hours every 2 weeks (NALIRIFOX; N=383) or nab-paclitaxel 125 mg/m 2 over 35 minutes and gemcitabine 1000 mg/m 2 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 NCI CTCAE v5.0 (≥ 20%) in Patients with Metastatic Pancreatic Adenocarcinoma who Received NALIRIFOX NALIRIFOX=ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin; Gem+NabP=gemcitabine+nab-paclitaxel 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 All Grades (%) Grade 3 or4 (%) All Grades (%) Grade 3 or4 (%) Gastrointestinal disorders Diarrhea Includes multiple related terms 72 22 37 5 Nausea 59 12 43

Vomiting 40 7 27 2.1 Abdominal pain 35 4.3 25 4.7 Constipation

25 0.8 30

General disorders and administration site condition Fatigue 62 15 63 10 Mucosal

inflammation 28 3.8 17

Peripheral edema 16 0.3 34 2.4 Pyrexia 11 0.8 24 1.6 Investigations

Weight decreased 22 3 9

Metabolism and nutrition disorders Decreased appetite 37 9 28 2.6 Dehydration 11

3.2 9

Skin and subcutaneous tissue disorders Alopecia 14 0 31 0.5 Rash 11

0.3 22

Embolism 11 7 11 5 Respiratory, thoracic and mediastinal disorders Dyspnea 8

0.5 13

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

Table 4 Laboratory Abnormalities in Patients with Metastatic Pancreatic Adenocarcinoma who Received

NALIRIFOX NALIRIFOX=ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin ; Gem+NabP=gemcitabine+nab-paclitaxel with a difference between arms of ≥ 5% versus Gem+NabP in NAPOLI 3 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). Laboratory abnormality NALIRIFOX Gem-NabP All Grades (%) Grade 3- or 4 (%) All Grades (%) Grade 3 or4 (%) 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

Alanine aminotransferase increased 40 2.6 56 4.6 Aspartate aminotransferase increased 38 2

49

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/m 2 with leucovorin 400 mg/m 2 and fluorouracil 2400 mg/m 2 over 46 hours every 2 weeks (ONIVYDE/FU/LV; N=117), ONIVYDE 100 mg/m 2 every 3 weeks (N=147), or leucovorin 200 mg/m 2 and fluorouracil 2000 mg/m 2 over 24 hours weekly for 4 weeks followed by 2 week rest (FU/LV; N=134) . 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 NCI CTCAE v4.0 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 (%) Gastrointestinal disorders Diarrhea 59 13 26 4 Early diarrhea Early diarrhea: onset within 24 hours of ONIVYDE administration 30 3 15 0 Late diarrhea Late diarrhea: onset >1 day after ONIVYDE administration 43 9 17 4 Vomiting 52 11 26 3 Nausea 51 8 34 4 Stomatitis Includes stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation. 32 4 12 1 Infections and infestations 38 17 15 10 Sepsis 4 3 2 1 Neutropenic fever/neutropenic sepsis Includes febrile neutropenia 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 NCI CTCAE v4.0, worst grade shown. Percent based on number of patients with a baseline and at least one post-baseline measurement.

Laboratory abnormality ONIVYDE/FU/LV N=117 FU/LV N=134 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) 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

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)

Strong

CYP3A4 Inducers Following administration of non-liposomal irinotecan (i.e., irinotecan HCl), exposure to irinotecan or its active metabolite, SN-38, is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin and strong CYP3A4 inducers. Avoid the use of strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, St. John's wort) if possible.

Substitute non-enzyme inducing therapies at least 2 weeks prior to initiation of ONIVYDE therapy .

Strong

CYP3A4 or UGT1A1 Inhibitors Following administration of non-liposomal irinotecan (i.e., irinotecan HCl), patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Co-administration of ONIVYDE with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38. Avoid the use of strong CYP3A4 or UGT1A1 inhibitors if possible. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting ONIVYDE therapy .

Pregnancy Risk Summary 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. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with ONIVYDE 70 mg/m 2 in humans, administered to pregnant rats and rabbits during organogenesis . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Animal Data No animal studies have been conducted to evaluate the effect of irinotecan liposome on reproduction and fetal development; however, studies have been conducted with irinotecan HCl. Irinotecan crosses the placenta of rats following intravenous administration. Intravenous administration of irinotecan at a dose of 6 mg/kg/day to rats and rabbits during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses.

In separate studies in rats, this dose resulted in an irinotecan exposure of approximately 0.002 times the exposure of irinotecan based on area under the curve (AUC) in patients administered ONIVYDE at the 70 mg/m 2 dose. Administration of irinotecan HCl resulted in structural abnormalities and growth delays in rats at doses greater than 1.2 mg/kg/day (approximately 0.0002 times the clinical exposure to irinotecan in ONIVYDE based on AUC). Teratogenic effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan HCl administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.

Pediatric Use Safety and effectiveness of ONIVYDE have not been established in pediatric patients.

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

There are no treatment interventions known to be effective for management of overdosage of ONIVYDE.