b'ONIVYDE (irinotecan liposome injection) for intravenous use loperamide for late-onset diarrhea of any severity. Administer IV or Initial U.S. Approval: 1996subcutaneous atropine 0.251 mg (unless clinically contraindicated) for early-onset diarrhea of any severity. Following recovery to Grade 1 BRIEF SUMMARY: refer to full Prescribing Information fordiarrhea, resume ONIVYDE at a reduced dose. complete product information.Interstitial Lung Disease (ILD): Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE in patients with new or progressive dyspnea, INDICATIONS AND USAGEcough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in ONIVYDE is indicated, in combination with fluorouracil (5-FU) andpatients with a confirmed diagnosis of ILD. leucovorin (LV), for the treatment of patients with metastaticSevere Hypersensitivity Reaction: Irinotecan HCl can cause severe adenocarcinoma of the pancreas after disease progression followinghypersensitivity reactions, including anaphylactic reactions. Permanently gemcitabine-based therapy.discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction. Limitation of Use: ONIVYDE is not indicated as a single agent for theEmbryo-Fetal Toxicity: Based on animal data with irinotecan HCl and the treatment of patients with metastatic adenocarcinoma of the pancreas.mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. Embryotoxicity and teratogenicity WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEAwere observed following treatment with irinotecan HCl, at doses resulting Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE.in irinotecan exposures lower than those achieved with ONIVYDE 70 Severe or life-threatening neutropenic fever or sepsis occurred in 3%mg/m2 in humans, administered to pregnant rats and rabbits during and severe or life-threatening neutropenia occurred in 20% of patientsorganogenesis. Advise pregnant women of the potential risk to a fetus. receiving ONIVYDE in combination with 5-FU/LV. Withhold ONIVYDE forAdvise females of reproductive potential to use effective contraception absolute neutrophil count below 1500/mm 3or neutropenic fever.during treatment with ONIVYDE and for 1 month following the final dose. Monitor blood cell counts periodically during treatment.Severe diarrhea occurred in 13% of patients receiving ONIVYDE/5- ADVERSE REACTIONS FU/LV. Do not administer ONIVYDE to patients with bowel obstruction.The following adverse drug reactions are discussed in greater detail in Withhold ONIVYDE for diarrhea of Grade 24 severity. Administerother sections of the label: loperamide for late diarrhea of any severity. Administer atropine, if notSevere Neutropenia contraindicated, for early diarrhea of any severity.Severe DiarrheaInterstitial Lung DiseaseSevere Hypersensitivity Reactions CONTRAINDICATIONSClinical Trials Experience ONIVYDE is contraindicated in patients who have experienced a severeThe safety data described below are derived from patients with hypersensitivity reaction to ONIVYDE or irinotecan HCl.metastatic adenocarcinoma of the pancreas previously treated with gemcitabine-based therapy who received any part of protocol-specified therapy in Study 1, an international, randomized, active-controlled, open-WARNINGS AND PRECAUTIONSlabel trial. Protocol-specified therapy consisted of ONIVYDE 70 mg/m2 Severe Neutropenia: ONIVYDE can cause severe or life-threateningwith LV 400 mg/m2 and 5-FU 2400 mg/m2 over 46 hours every 2 weeks neutropenia and fatal neutropenic sepsis. In Study 1, the incidence of(ONIVYDE/5-FU/LV; n=117), ONIVYDE 100 mg/m2 every 3 weeks (n=147), fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE,or LV 200 mg/m2 and 5-FU 2000 mg/m2 over 24 hours weekly for 4 weeks occurring in 1/117 patients in the ONIVYDE/5-FU/LV arm and 1/147followed by a 2 week rest (5-FU/LV; n=134). Serum bilirubin within the patients receiving single-agent ONIVYDE. Severe or life-threateninginstitutional normal range, albumin 3 g/dL, and Karnofsky Performance neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LVStatus (KPS) 70 were required for study entry. The median duration of compared to 2% of patients receiving fluorouracil/leucovorin alone (5- exposure was 9 weeks in the ONIVYDE/5-FU/LV arm, 9 weeks in the FU/LV). Grade 3/4 neutropenic fever/neutropenic sepsis occurred in 3%ONIVYDE monotherapy arm and 6 weeks in the 5-FU/LV arm. of patients receiving ONIVYDE/5-FU/LV, and did not occur in patientsThe most common adverse reactions (20%) of ONIVYDE were diarrhea, receiving 5-FU/LV.fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4pyrexia. The most common, severe laboratory abnormalities (10%, neutropenia was higher among Asian patients (18/33 [55%]) vs WhiteGrade 3 or 4) were lymphopenia and neutropenia. The most common patients (13/73 [18%]). Neutropenic fever/neutropenic sepsis wasserious adverse reactions (2%) of ONIVYDE were diarrhea, vomiting, reported in 6% of Asian patients vs 1% of White patients.neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, Monitor complete blood cell counts on Days 1 and 8 of every cycle anddehydration, septic shock, pneumonia, acute renal failure, and more frequently if clinically indicated. Withhold ONIVYDE if the absolutethrombocytopenia. neutrophil count (ANC) is below 1500/mm3 or if neutropenic fever occurs.Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of Resume ONIVYDE when the ANC is 1500/mm3 or above. Reduce ONIVYDEpatients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions dose for Grade 34 neutropenia or neutropenic fever following recoveryresulting in discontinuation of ONIVYDE were diarrhea, vomiting, and in subsequent cycles.sepsis. Dose reductions of ONIVYDE for adverse reactions occurred in 33% Severe Diarrhea: ONIVYDE can cause severe and life-threateningof patients receiving ONIVYDE/5-FU/LV; the most frequent adverse diarrhea. Do not administer ONIVYDE to patients with bowel obstruction.reactions requiring dose reductions were neutropenia, diarrhea, nausea, Severe or life-threatening diarrhea followed one of two patterns: late- and anemia. ONIVYDE was withheld or delayed for adverse reactions in onset diarrhea (onset 24 hours following chemotherapy) and early-onset62% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse diarrhea (onset 24 hours of chemotherapy, sometimes occurring withreactions requiring interruption or delays were neutropenia, diarrhea, other symptoms of cholinergic reaction). An individual patient mayfatigue, vomiting, and thrombocytopenia. experience both early- and late-onset diarrhea. In Study 1, Grade 3 or 4 diarrhea occurred in 13% receiving ONIVYDE/5-FU/LV vs 4% receiving 5-FU/LV. The incidence of Grade 3 or 4 late-onset diarrhea was 9% in patients receiving ONIVYDE/5-FU/LV vs 4% in patients receiving 5-FU/LV. The incidence of Grade 3 or 4 early-onset diarrhea was 3% in patients receiving ONIVYDE/5-FU/LV vs none in patients receiving 5-FU/LV. Of patients receiving ONIVYDE/5-FU/LV in Study 1, 34% receivedContinued next page loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea. Withhold ONIVYDE for Grade 24 diarrhea. Initiate'