ONIVYDE

ONIVYDE is formulated with irinotecan hydrochloride trihydrate, a topoisomerase inhibitor, into a liposomal dispersion for intravenous use. The chemical name of irinotecan hydrochloride trihydrate is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1H-pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4'bipiperidine]-1'-carboxylate, monohydrochloride, trihydrate. The empirical formula is C 33 H 38 N 4 O 6 ∙HCl∙3H 2 O and the molecular weight is 677.19 g/mole. The molecular structure is: ONIVYDE is a sterile, white to slightly yellow opaque isotonic liposomal dispersion. Each 10 mL single-dose vial contains 43 mg irinotecan free base at a concentration of 4.3 mg/mL. The liposome is a unilamellar lipid bilayer vesicle, approximately 110 nm in diameter, which encapsulates an aqueous space containing irinotecan in a gelated or precipitated state as the sucrose octasulfate salt. The vesicle is composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) 6.81 mg/mL, cholesterol 2.22 mg/mL, and methoxy-terminated polyethylene glycol (MW 2000)-distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE) 0.12 mg/mL. Each mL also contains 2-[4-(2-hydroxyethyl) piperazin-1-yl]ethanesulfonic acid (HEPES) as a buffer 4.05 mg/mL and sodium chloride as an isotonicity reagent 8.42 mg/mL. Chemical Structure

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 )

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 or 4 Hand foot syndrome First Discontinue ONIVYDE Any grade neurocerebellar toxicity First Discontinue ONIVYDE Grade ≥ 2 cardiac toxicity First Discontinue ONIVYDE Interstitial lung disease First Discontinue ONIVYDE Anaphylactic reaction First Discontinue ONIVYDE Table 2 Recommended Dosage Modifications for ONIVYDE in combination with fluorouracil and leucovorin Toxicity NCI CTCAE v4.0 NCI CTCAE v 4.0=National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 Occurrence ONIVYDE adjustment in patients receiving 70 mg/m 2 Patients homozygous for UGT1A1*28 without previous increase to 70 mg/m 2 Grade 3 or 4 adverse reactions Withhold ONIVYDE. Upon recovery to ≤ Grade 1, resume ONIVYDE at: First 50 mg/m 2 43 mg/m 2 Second 43 mg/m 2 35 mg/m 2 Third Discontinue ONIVYDE Discontinue ONIVYDE Interstitial Lung Disease First Discontinue ONIVYDE Discontinue ONIVYDE Anaphylactic Reaction First Discontinue ONIVYDE Discontinue ONIVYDE For recommended dose modifications of fluorouracil (FU) or leucovorin (LV), refer to the Full Prescribing Information; refer to Clinical Studies (14) . 2.4 Preparation and Administration ONIVYDE is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Preparation Withdraw the calculated volume of ONIVYDE from the vial. Dilute ONIVYDE in 500 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP and mix diluted solution by gentle inversion. Discard vials with any unused portion. Protect diluted solution from light. Administer diluted solution within 4 hours of preparation when stored at room temperature or within 24 hours of preparation when stored under refrigerated conditions [2ºC to 8ºC (36ºF to 46ºF)]. Allow diluted solution to come to room temperature prior to administration. Do NOT freeze. Administration Infuse diluted solution intravenously over 90 minutes.

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 )

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% 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 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 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 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/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) [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 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 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)

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) ] .

Storage and Handling Store ONIVYDE at 2ºC to 8ºC (36°F to 46°F). Do NOT freeze. Protect from light. ONIVYDE is a hazardous drug. Follow applicable special handling and disposal procedures. 1