Onivyde

1 INDICATIONS AND USAGE ONIVYDE 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. [see Clinical Studies (14) ] . ONIVYDE is a topoisomerase inhibitor indicated: in combination with oxaliplatin, fluorouracil and leucovorin, for the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma, ( 1 ) in combination with fluorouracil and leucovorin, for the treatment of adult patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy. ( 1 ) Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic pancreatic adenocarcinoma. ( 1 )

2 DOSAGE AND ADMINISTRATION Do not substitute ONIVYDE for other drugs containing irinotecan HCl. ( 2.1 ) ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin: Recommended dose of ONIVYDE is 50 mg/m 2 intravenous infusion over 90 minutes every two weeks. ( 2.2 ) Recommended starting dose of ONIVYDE in patients homozygous for UGT1A1*28 is 50 mg/m 2 every two weeks. ( 2.2 ) There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. ( 2.2 ) ONIVYDE in combination with fluorouracil and leucovorin: Recommended dose of ONIVYDE is 70 mg/m 2 intravenous infusion over 90 minutes every two weeks. ( 2.2 ) Recommended starting dose of ONIVYDE in patients homozygous for UGT1A1*28 is 50 mg/m 2 every two weeks. ( 2.2 ) There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. ( 2.2 ) Premedicate with a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE. ( 2.2 ) 2.1 Important Use Information DO NOT SUBSTITUTE ONIVYDE for other drugs containing irinotecan HCl. 2.2 Recommended Dosage In combination with oxaliplatin, fluorouracil and leucovorin for the first-line treatment of patients with metastatic pancreatic adenocarcinoma Administer ONIVYDE prior to oxaliplatin, fluorouracil and leucovorin [see Clinical Studies (14) ] . The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m 2 administered by intravenous infusion over 90 minutes every 2 weeks. There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal [see Adverse Reactions (6.1) and Clinical Studies (14) ]. In combination with fluorouracil and leucovorin for the treatment of patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy Administer ONIVYDE prior to fluorouracil and leucovorin [see Clinical Studies (14) ] . The recommended dosage of ONIVYDE is 70 mg/m 2 administered by intravenous infusion over 90 minutes every 2 weeks. The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m 2 administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m 2 as tolerated in subsequent cycles. There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal [see Adverse Reactions (6.1) and Clinical Studies (14) ]. Premedication Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion. 2.3 Dosage Modifications for Adverse Reactions Recommended dosage modifications for ONIVYDE are in Table 1 and Table 2. Table 1 Recommended Dosage Modifications for ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin Toxicity Toxicity grading per NCI CTCAE v5.0. Occurrence ONIVYDE adjustment in patients receiving 50mg/m 2 Grade 3 or 4 Adverse reactions No dosage modification is necessary for asthenia, alopecia and Grade 3 anorexia. Withhold ONIVYDE Upon recovery to ≤ Grade 1 Do not resume until the absolute neutrophil count is ≥2000/mm 3 (2×10 9 /L) and the platelet count is ≥100,000/mm 3 (100×10 9 /L). , For Grade ≥3 nausea and vomiting, reduce dose only if occurs despite optimal anti-emetic therapy. , Refer to the Full Prescribing Information of fluorouracil and oxaliplatin. When ONIVYDE dose is reduced for adverse reactions, reduce fluorouracil (FU) and oxaliplatin doses: for first occurrence, reduce dose to 80% of original dose; for second occurrence, reduce dose to 65% of original dose; for third occurrence, reduce dose to 50% of original dose; discontinue therapy for fourth occurrence. 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. , resume ONIVYDE at: First 40 mg/m 2 Second 32.5 mg/m 2 Third 25 mg/m 2 Fourth Discontinue ONIVYDE Grade 3 …

5 WARNINGS AND PRECAUTIONS Interstitial lung disease (ILD): Fatal ILD has occurred in patients receiving irinotecan including ONIVYDE. Discontinue ONIVYDE if ILD is diagnosed. ( 5.3 ) Severe hypersensitivity reaction: Permanently discontinue ONIVYDE for severe hypersensitivity reactions. ( 5.4 , 4 ) Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 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 [see Adverse Reactions (6.1) ]. 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% [see Adverse Reactions (6.1) ]. 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%)] receiving ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin. Neutropenic fever was reported in 5% of Asian patients (1 of 20) compared to 2.3% of White patients (7 of 306). 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%)] receiving ONIVYDE/FU/LV. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients [see Clinical Pharmacology (12.3) ]. 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/mm 3 or if neutropenic fever occurs. Resume ONIVYDE when the ANC is 1500/mm 3 or above. Reduce ONIVYDE dose for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles [see Dosage and Administration (2.2) ] . 5.2 Severe Diarrhea ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with a bowel obstruction. Severe or life-threatening diarrhea can follow one of two patterns: late onset diarrhea (onset more than 24 hours following chemotherapy) and early onset diarrhea (onset within 24 hours of chemotherapy, sometimes occurring with other symptoms of cholinergic reaction) [see Adverse Reactions (6.1) ] . An individual patient may experience both early and late-onset diarrhea. In NAPOLI 3, Grade 3 and 4 diarrhea (early and late-onset) occurred in 20% receiving ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin (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. Of patients receiving ONIVYDE/FU/LV in NAPOLI-1, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea. 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 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. Following recovery to Grade 1 diarrhea, resume ONIVYDE at a reduced dose [see Dosage and Administration (2.3) ] . 5.3 Interstitial L…

4 CONTRAINDICATIONS ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction or anaphylaxis to ONIVYDE or irinotecan HCl. [see Warnings and Precautions (5.4) , Adverse Reactions (6.2) ]. Severe hypersensitivity reaction to ONIVYDE or irinotecan HCl. ( 4 , 5.4 )

7 DRUG INTERACTIONS Strong CYP3A4 Inducers: Avoid the use of strong CYP3A4 inducers if possible. Substitute non-enzyme inducing therapies at least 2 weeks prior to initiation of ONIVYDE. ( 7.1 ) Strong CYP3A4 Inhibitors: Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible; discontinue strong CYP3A4 inhibitors at least 1 week prior to starting therapy. ( 7.2 ) 7.1 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 [see Clinical Pharmacology (12.3) ] . 7.2 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 [see Clinical Pharmacology (12.3) ] .

8.1 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 [see Clinical Pharmacology (12.1) ] . 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 [see Data ] . 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.

12.5 Pharmacogenomics Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia from irinotecan HCl. In NAPOLI-1, patients homozygous for the UGT1A1*28 allele (N=7) initiated ONIVYDE at a reduced dose of 50 mg/m 2 in combination with FU/LV. The frequency of Grade 3 or 4 neutropenia in these patients [2 of 7 (28.6%)] was similar to the frequency in patients not homozygous for the UGT1A1*28 allele who received a starting dose of ONIVYDE of 70 mg/m 2 [30 of 110 (27.3%)]. In NAPOLI-3, patients homozygous for the UGT1A1*28 allele (N = 39) initiated ONIVYDE at the same starting dose of 50 mg/m 2 as patients not homozygous for the UGT1A1*28 allele (N = 328). The frequency of Grade 3 or 4 neutropenia was 23% in patients homozygous for the UGT1A1*28 allele and 13% in patients not homozygous for the UGT1A1*28 allele. The frequency of dose reduction of ONIVYDE due to treatment-emergent adverse effects was 59% versus 51% in patients homozygous versus non-homozygous for the UGT1A1*28 allele.

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) ] The most common adverse reactions (reported in ≥ 20% of patients) were for: ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin: 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 lymphocytes, and decreased hemoglobin. ( 6.1 ) ONIVYDE in combination with fluorouracil and leucovorin: diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common laboratory abnormalities (≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. ( 6.1 ) 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 . 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/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…