b"Table 2: Adverse Reactions with Higher Incidence (5% Difference forGrades 14* or 2% Difference for Grades 3 and 4) in the ONIVYDE/5- DRUG INTERACTIONS FU/LV ArmStrong CYP3A4 Inducers: Following administration of non-liposomal ONIVYDE/5- 5-FU/LVirinotecan (i.e., irinotecan HCl), exposure to irinotecan or its active Adverse ReactionFU/LV n=117n=134metabolite, SN-38, is substantially reduced in adult and pediatric patients GradesGradesGradesGrades concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants 14 (%)34 (%) 14 (%) 34 (%)phenytoin and strong CYP3A4 inducers. Avoid the use of strong CYP3A4 Gastrointestinal disordersinducers (e.g., rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, Diarrhea59n=11713264phenobarbital, St. John's wort) if possible. Substitute non-enzyme Early diarrhea303150inducing therapies 2 weeks prior to initiation of ONIVYDE therapy. Late diarrhea439174Strong CYP3A4 or UGT1A1 Inhibitors: Following administration of non-Vomiting5211263liposomal irinotecan (i.e., irinotecan HCl), patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure Nausea518344to irinotecan and its active metabolite SN-38. Co-administration of Stomatitis324121ONIVYDE with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, Infections and infestations38171510itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, Sepsis4321telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, Neutropenic fever/neutropenic3310indinavir) may increase systemic exposure to irinotecan or SN-38. Avoid the use of strong CYP3A4 or UGT1A1 inhibitors if possible. Discontinue sepsis strong CYP3A4 inhibitors 1 week prior to starting ONIVYDE therapy. Gastroenteritis3300 Intravenous catheter-related infection3300USE IN SPECIFIC POPULATIONS General disorders and administration site conditionsPregnancy, Risk Summary: Based on animal data with irinotecan HCl and Fatigue/asthenia56214310the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm Pyrexia232111when administered to a pregnant woman. There are no available data in Metabolism and nutrition disorderspregnant women. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan Decreased appetite444322exposures lower than those achieved with ONIVYDE 70 mg/m 2in humans, Weight loss17270administered to pregnant rats and rabbits during organogenesis (see Data Dehydration8472in the full Prescribing Information). Advise pregnant women of the Skin and subcutaneous tissue disorderspotential risk to a fetus. Alopecia14150Lactation, Risk Summary: There is no information regarding the presence *NCI CTCAE v4.0.of irinotecan liposome, irinotecan, or SN-38 (an active metabolite of Early diarrhea: onset 24 hours of ONIVYDE administration.irinotecan) in human milk, or the effects on the breastfed infant or on Late diarrhea: onset 1 day after ONIVYDE administration.milk production. Irinotecan is present in rat milk (see Data in the full Includes stomatitis, aphthous stomatitis, mouth ulceration, mucosalPrescribing Information). inflammation.Because of the potential for serious adverse reactions in breastfed infantsIncludes febrile neutropenia.from ONIVYDE, advise a nursing woman not to breastfeed during Cholinergic Reactions: ONIVYDE can cause cholinergic reactionstreatment with ONIVYDE and for 1 month after the final dose.manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis,Females and Males of Reproductive Potential, Contraception, Females: lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominalONIVYDE can cause fetal harm when administered to a pregnant woman. cramping and early-onset diarrhea. In Study 1, Grade 1 or 2 cholinergicAdvise females of reproductive potential to use effective contraception symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE- during treatment with ONIVYDE and for 1 month after the final dose. treated patients. Six of these 12 patients received atropine and in 1 of theMales: Because of the potential for genotoxicity, advise males with 6 patients, atropine was administered for cholinergic symptoms otherfemale partners of reproductive potential to use condoms during than diarrhea.treatment with ONIVYDE and for 4 months after the final dose. Infusion Reactions: Infusion reactions, consisting of rash, urticaria,Pediatric Use: Safety and effectiveness of ONIVYDE have not been periorbital edema, or pruritus, occurring on the day of ONIVYDEestablished in pediatric patients. administration, were reported in 3% of patients receiving ONIVYDE orGeriatric Use: Of the 264 patients who received single-agent ONIVYDE or ONIVYDE/5-FU/LV.ONIVYDE/5-FU/LV in Study 1, 49% were 65 years old and 13% were 75 years old. No overall differences in safety and effectiveness were The following laboratory abnormalities were reported (NCI CTCAE v4.0,observed between these patients and younger patients. worst grade shown) with higher incidence (5% difference Grades 14 [any] or 5% difference Grades 34 [severe] according to NCI CTCAEOVERDOSAGE v4.0) for patients receiving ONIVYDE/5-FU/LV (n=117) vs 5-FU/LVThere are no treatment interventions known to be effective for (n=134). Percentages were based on the number of patients with amanagement of overdosage of ONIVYDE. baseline and at least 1 post-baseline measurement. Hematology: anemia (any 97%, 86%; severe 6%, 5%), lymphopenia (any 81%, 75%; severe 27%, 17%), neutropenia (any 52%, 6%; severe 20%, 2%), thrombocytopenia (any 41%, 33%; severe 2%, 0%). Hepatic: increased alanine aminotransferase (any 51%, 37%; severe 6%, 1%), hypoalbuminemia (any 43%, 30%; severe 2%, 0%). Metabolic: hypomagnesemia (any 35%, 21%;Distributed by Ipsen Biopharmaceuticals, Inc. Basking Ridge, NJ 07920 severe 0%, 0%), hypokalemia (any 32%, 19%; severe 2%, 2%),2021 Ipsen Biopharmaceuticals, Inc. All rights reserved.ONIVYDE is a registered trademark of Ipsen Biopharm Limited hypocalcemia (any 32%, 20%; severe 1%, 0%), hypophosphatemia (anyONIVYDE is a registered trademark of Ipsen Biopharm Ltd.29%, 18%; severe 4%, 1%), hyponatremia (any 27%, 12%; severe 5%, 3%).2019 Ipsen Biopharmaceuticals, Inc.August 2019All other trademarks are the property of their respective owners.Renal: increased creatinine (any 18%, 13%; severe 0%, 0%).ONV-US-002028April 2021 ONV-US-003068"