USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Do not breastfeed. (8.2). Lactation: Do not breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to 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/m2 in humans, administered to pregnant rats and rabbits during organogenesis [see Data]. Advise pregnant women of the potential risk to 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 DataNo 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 dose of 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/m2 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 variety of external, visceral, and skeletal abnormalities. Irinotecan HCl administered to rat dams for the period following organogenesis through weaning at doses of mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of irinotecan liposome, irinotecan, or SN-38 (an active metabolite of irinotecan) in human milk, or the effects on the breastfed infant or on milk production. Irinotecan is present in rat milk [see Data]. Because of the potential for serious adverse reactions in breastfed infants from ONIVYDE, advise nursing woman not to breastfeed during treatment with ONIVYDE and for one month after the final dose.. DataRadioactivity appeared in rat milk within minutes of intravenous administration of radiolabeled irinotecan HCl and was concentrated up to 65-fold at hours after administration relative to plasma concentrations.. 8.3 Females and Males of Reproductive Potential. Contraception. FemalesONIVYDE can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ONIVYDE and for one month after the final dose. MalesBecause of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with ONIVYDE and for four months after the final dose [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. Safety and effectiveness of ONIVYDE have not been established in pediatric patients.. 8.5 Geriatric Use. Of the 264 patients who received ONIVYDE as single agent or in combination with 5-FU and leucovorin in Study 1, 49% were >= 65 years old and 13% were >= 75 years old. No overall differences in safety and effectiveness were observed between these patients and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Interstitial lung disease (ILD): Fatal ILD has occurred in patients receiving irinotecan HCl. 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 fetus and to use effective contraception. (5.5, 8.1, 8.3). Interstitial lung disease (ILD): Fatal ILD has occurred in patients receiving irinotecan HCl. 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 fetus and to use effective contraception. (5.5, 8.1, 8.3). 5.1Severe Neutropenia. ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In Study 1, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE, occurring in one of 117 patients in the ONIVYDE plus fluorouracil/leucovorin (ONIVYDE/5-FU/LV) arm and one of 147 patients receiving ONIVYDE as single agent. Severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LV compared to 2% of patients receiving fluorouracil/leucovorin alone (5-FU/LV). Grade or neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not occur in patients receiving 5-FU/LV.In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade or neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. 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 and of every cycle and more frequently if clinically indicated. Withhold ONIVYDE if the absolute neutrophil count (ANC) is below 1500/mm3 or if neutropenic fever occurs. Resume ONIVYDE when the ANC is 1500/mm3 or above. Reduce ONIVYDE dose for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles [see Dosage and Administration (2.2)].. 5.2Severe Diarrhea. ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with bowel obstruction.Severe or life-threatening diarrhea followed 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 Cholinergic Reactions (6.1)]. An individual patient may experience both early and late-onset diarrhea.In Study 1, Grade or diarrhea occurred in 13% receiving ONIVYDE/5-FU/LV compared to 4% receiving 5-FU/LV. The incidence of Grade or late onset diarrhea was 9% in patients receiving ONIVYDE/5-FU/LV, compared to 4% in patients receiving 5-FU/LV. The incidence of Grade or early onset diarrhea was 3% in patients receiving ONIVYDE/5-FU/LV, compared to no Grade or early onset diarrhea in patients receiving 5-FU/LV. Of patients receiving ONIVYDE/5-FU/LV in Study 1, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea. Withhold ONIVYDE for Grade 2-4 diarrhea. Initiate loperamide for late onset diarrhea of any severity. Administer intravenous or subcutaneous atropine 0.25 to mg (unless clinically contraindicated) for early onset diarrhea of any severity. Following recovery to Grade diarrhea, resume ONIVYDE at reduced dose [see Dosage and Administration (2.2)].. 5.3Interstitial Lung Disease. Irinotecan HCl can cause severe and fatal interstitial lung disease (ILD). Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with confirmed diagnosis of ILD.. 5.4Severe Hypersensitivity Reaction. Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience severe hypersensitivity reaction.. 5.5Embryo-Fetal Toxicity. Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to pregnant woman. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with ONIVYDE 70 mg/m2 in humans, administered to pregnant rats and rabbits during organogenesis. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with ONIVYDE and for one month following the final dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

ADVERSE REACTIONS SECTION.

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) and Boxed Warning] Severe Diarrhea [see Warnings and Precautions (5.2) and Boxed Warning] Interstitial Lung Disease [see Warnings and Precautions (5.3)] Severe Hypersensitivity Reactions [see Warnings and Precautions (5.4)] Severe Neutropenia [see Warnings and Precautions (5.1) and Boxed Warning] Severe Diarrhea [see Warnings and Precautions (5.2) and Boxed Warning] Interstitial Lung Disease [see Warnings and Precautions (5.3)] Severe Hypersensitivity Reactions [see Warnings and Precautions (5.4)] The most common adverse reactions (>= 20%) of ONIVYDE: diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common laboratory abnormalities (>= 10% Grade or 4) were lymphopenia and neutropenia. (6)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. 6.1Clinical 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.The safety data described below are derived from patients with 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-label trial. Protocol-specified therapy consisted of ONIVYDE 70 mg/m2 with leucovorin 400 mg/m2 and fluorouracil 2400 mg/m2 over 46 hours every weeks (ONIVYDE/5-FU/LV; N=117), ONIVYDE 100 mg/m2 every weeks (N=147), or leucovorin 200 mg/m2 and fluorouracil 2000 mg/m2 over 24 hours weekly for weeks followed by week rest (5-FU/LV; N=134) [see Clinical Studies (14)]. Serum bilirubin within the institutional normal range, albumin >= g/dL, and Karnofsky Performance Status (KPS) >= 70 were required for study entry. The median duration of exposure was weeks in the ONIVYDE/5-FU/LV arm, weeks in the ONIVYDE monotherapy arm, and weeks in the 5-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 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/5-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/5-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/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.Table provides the frequency and severity of adverse reactions in Study that occurred with higher incidence (>=5% difference for Grades 1-4 or >=2% difference for Grades 3-4) in patients who received ONIVYDE/5-FU/LV compared to patients who received 5-FU/LV. Table 2: Adverse Reactions with Higher Incidence (>=5% Difference for Grades 1-4NCI CTCAE v4.0 or >=2% Difference for Grades and 4) in the ONIVYDE/5-FU/LV Arm Adverse ReactionONIVYDE/5-FU/LVN=1175-FU/LVN=134Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4 (%)Gastrointestinal disorders Diarrhea5913264 Early diarrheaEarly diarrhea: onset within 24 hours of ONIVYDE administration 303150 Late diarrheaLate diarrhea: onset >1 day after ONIVYDE administration 439174 Vomiting5211263 Nausea518344 StomatitisIncludes stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation. 324121Infections and infestations38171510 Sepsis4321 Neutropenic fever/neutropenic sepsisIncludes febrile neutropenia 3310 Gastroenteritis3300 Intravenous catheter-related infection3300General disorders and administration site conditions Fatigue/asthenia56214310 Pyrexia232111Metabolism and nutrition disorders Decreased appetite444322 Weight loss17270 Dehydration8472Skin and subcutaneous tissue disorders Alopecia14150. 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 Study 1, Grade or cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients. Six of these 12 patients received atropine and in of the 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/5-FU/LV.Laboratory abnormalities that occurred with higher incidence in the ONIVYDE/5-FU/LV arm compared to the 5-FU/LV arm (>=5% difference) are summarized in the following table.Table 3: Laboratory Abnormalities with Higher Incidence (>=5% Difference) in the ONIVYDE/5-FU/LV ArmNCI CTCAE v4.0, worst grade shown. Percent based on number of patients with baseline and at least one post-baseline measurement. Laboratory abnormalityONIVYDE/5-FU/LVN=1175-FU/LVN=134Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4 (%)Hematology Anemia976865 Lymphopenia 81277517 Neutropenia522062 Thrombocytopenia412330Hepatic Increased alanine aminotransferase (ALT)516371 Hypoalbuminemia432300Metabolic Hypomagnesemia350210 Hypokalemia322192 Hypocalcemia321200 Hypophosphatemia294181 Hyponatremia275123Renal Increased creatinine180130.

BOXED WARNING SECTION.

WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin. Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)]. WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEASee full prescribing information for complete boxed warning Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin. Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment (2.2), (5.1). Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity (2.2), (5.2).. Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin. Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment (2.2), (5.1). Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity (2.2), (5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No studies have been performed to assess the potential of irinotecan liposome for carcinogenicity, genotoxicity or impairment of fertility. Intravenous administration of irinotecan hydrochloride to rats once weekly for 13 weeks followed by 91-week recovery period resulted in significant linear trend between irinotecan HCl dosage and the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan HCl was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan nor its active metabolite, SN-38, was mutagenic in the in vitro Ames assay.Dedicated fertility studies have not been performed with irinotecan liposome injection. Atrophy of male and female reproductive organs was observed in dogs receiving irinotecan liposome injection every weeks at doses equal to or greater than 15 mg/kg, (approximately times the clinical exposure of irinotecan following administration to ONIVYDE dosed at 70 mg/m2 for total of doses. No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan HCl in doses of up to mg/kg/day to rats; however, atrophy of male reproductive organs was observed after multiple daily irinotecan HCl doses both in rodents at 20 mg/kg (approximately 0.007 times the clinical irinotecan exposure following ONIVYDE administration at 70 mg/m2) and in dogs at 0.4 mg/kg (0.0007 times the clinical exposure to irinotecan following administration of ONIVYDE).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Irinotecan liposome injection is topoisomerase inhibitor encapsulated in lipid bilayer vesicle or liposome. Topoisomerase relieves torsional strain in DNA by inducing single-strand breaks. Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase 1-DNA complex and prevent re-ligation of the single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. In mice bearing human tumor xenografts, irinotecan liposome administered at irinotecan HCl-equivalent doses 5-fold lower than irinotecan HCl achieved similar intratumoral exposure of SN-38.. 12.3 Pharmacokinetics. The plasma pharmacokinetics of total irinotecan and total SN-38 were evaluated in patients with cancer who received ONIVYDE, as single agent or as part of combination chemotherapy, at doses between 50 and 155 mg/m2 and 353 patients with cancer using population pharmacokinetic analysis. The pharmacokinetic parameters of total irinotecan and total SN-38 following the administration of ONIVYDE 70 mg/m2 as single agent or part of combination chemotherapy are presented in Table 4.Table 4: Summary of Mean (+-Standard Deviation) Total Irinotecan and Total SN-38Dose (mg/m2)Total IrinotecanTotal SN-38Cmax [ug/mL] (n=25)AUC0- [hug/mL] (n=23)t1/2 [h] (n=23)CL [L/h] (n=23)Vd [L] (n=23)Cmax [ng/mL] (n=25)AUC0- [hng/mL] (n=13)t1/2 [h] (n=13)Cmax: Maximum plasma concentrationAUC0-: Area under the plasma concentration curve extrapolated to time infinityt 1/2 Terminal elimination half-lifeCL: ClearanceVd: Volume of distribution7037.2(8.8)1364(1048)25.8(15.7)0.20(0.17)4.1(1.5)5.4(3.4)620(329)67.8(44.5)Over the dose range of 50 to 155 mg/m2, the Cmax and AUC of total irinotecan increases with dose. Additionally, the Cmax of total SN-38 increases proportionally with dose; however, the AUC of total SN-38 increases less than proportionally with dose. DistributionDirect measurement of irinotecan liposome showed that 95% of irinotecan remains liposome-encapsulated, and the ratios between total and encapsulated forms did not change with time from to 169.5 hours post-dose. The mean volume of distribution is summarized in Table 4. Plasma protein binding is <0.44% of the total irinotecan in ONIVYDE. Elimination. MetabolismThe metabolism of irinotecan liposome has not been evaluated. Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including esterases to form the active metabolite SN-38, and UGT1A1 mediating glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive oxidation products, one of which can be hydrolyzed by carboxylesterase to release SN-38. In the population pharmacokinetic analysis using the results of subset with UGT1A128 genotypic testing, in which the analysis adjusted for the lower dose administered to patients homozygous for the UGT1A128 allele, patients homozygous (N=14) and non-homozygous (N=244) for this allele had total SN-38 average steady-state concentrations of 1.06 and 0.95 ng/mL, respectively. ExcretionThe disposition of ONIVYDE has not been elucidated in humans. Following administration of irinotecan HCl the urinary excretion of irinotecan is 11 to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide), over period of 48 hours following administration of irinotecan HCl in two patients, ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).. Specific Populations. Age, Gender, and Renal Impairment: The population pharmacokinetic analysis suggests that age (28 to 87 years) had no clinically meaningful effect on the exposure of irinotecan and SN-38. The population pharmacokinetic analysis suggests that gender (196 males and 157 females) had no clinically meaningful effect on the exposure of irinotecan and SN-38 after adjusting for body surface area (BSA).In population pharmacokinetic analysis, mild-to-moderate renal impairment had no effect on the exposure of total SN-38 after adjusting for BSA. The analysis included 68 patients with moderate (CLcr 30 59 mL/min) renal impairment, 147 patients with mild (CLcr 60 89 mL/min) renal impairment, and 135 patients with normal renal function (CLcr 90 mL/min). There was insufficient data in patients with severe renal impairment (CLcr 30 mL/min) to assess its effect on pharmacokinetics. Ethnicity: The population pharmacokinetic analysis suggests that Asians (East Asians, N=150) have 56% lower total irinotecan average steady state concentration and 8% higher total SN-38 average steady state concentration than Whites (N=182).. Hepatic Impairment: The pharmacokinetics of irinotecan liposome have not been studied in patients with hepatic impairment. In population pharmacokinetic analysis, patients with baseline bilirubin concentrations of 1-2 mg/dL (N=19) had average steady state concentrations for total SN-38 that were increased by 37% compared to patients with baseline bilirubin concentrations of <1 mg/dL (N=329); however, there was no effect of elevated ALT/AST concentrations on total SN-38 concentrations. No data are available in patients with bilirubin >2 mg/dL.. Drug InteractionsIn population pharmacokinetic analysis, the pharmacokinetics of total irinotecan and total SN-38 were not altered by the co-administration of fluorouracil/leucovorin.Following administration of irinotecan HCl, dexamethasone, moderate CYP3A4 inducer, does not alter the pharmacokinetics of irinotecan.In vitro studies indicate that irinotecan, SN-38 and another metabolite, aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 isozymes.. 12.5Pharmacogenomics. Individuals who are homozygous for the UGT1A128 allele are at increased risk for neutropenia from irinotecan HCl. In Study 1, patients homozygous for the UGT1A128 allele (N=7) initiated ONIVYDE at reduced dose of 50 mg/m2 in combination with 5-FU/LV. The frequency of Grade or neutropenia in these patients [2 of (28.6% )] was similar to the frequency in patients not homozygous for the UGT1A128 allele who received starting dose of ONIVYDE of 70 mg/m2 [30 of 110 (27.3%)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of ONIVYDE was evaluated in Study 1, three-arm, randomized, open-label trial in patients with metastatic pancreatic adenocarcinoma with documented disease progression, after gemcitabine or gemcitabine-based therapy. Key eligibility criteria included Karnofsky Performance Status (KPS) >=70, serum bilirubin within institution limits of normal, and albumin >=3.0 g/dL. Patients were randomized to receive ONIVYDE plus fluorouracil/leucovorin (ONIVYDE/5-FU/LV), ONIVYDE, or fluorouracil/leucovorin (5-FU/LV). Randomization was stratified by ethnicity (White vs. East Asian vs. other), KPS (70-80 vs. 90-100), and baseline albumin level (>= g/dL vs. 3.0-3.9 g/dL). Patients randomized to ONIVYDE/5-FU/LV received ONIVYDE 70 mg/m2 as an intravenous infusion over 90 minutes, followed by leucovorin 400 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2400 mg/m2 intravenously over 46 hours, every weeks. The ONIVYDE dose of 70 mg/m2 is based on irinotecan free base (equivalent to 80 mg/m2 of irinotecan as the hydrochloride trihydrate). Patients randomized to ONIVYDE as single agent received ONIVYDE 100 mg/m2 as an intravenous infusion over 90 minutes every weeks. Patients randomized to 5-FU/LV received leucovorin 200 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2000 mg/m2 intravenously over 24 hours, administered on Days 1, 8, 15 and 22 of 6-week cycle. Patients homozygous for the UGT1A128 allele initiated ONIVYDE at reduced dose (50 mg/m2 ONIVYDE, if given with 5-FU/LV or 70 mg/m2 ONIVYDE as single agent). When ONIVYDE was withheld or discontinued for adverse reactions, 5-FU was also withheld or discontinued. When the dose of ONIVYDE was reduced for adverse reactions, the dose of 5-FU was reduced by 25%. Treatment continued until disease progression or unacceptable toxicity.The major efficacy outcome measure was overall survival (OS) with two pair-wise comparisons: ONIVYDE versus 5-FU/LV and ONIVYDE/5-FU/LV versus 5-FU/LV. Additional efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). Tumor status assessments were conducted at baseline and every weeks thereafter. The trial was initiated as two-arm study and amended after initiation to include third arm (ONIVYDE/5-FU/LV). The comparisons between the ONIVYDE/5-FU/LV and the 5-FU/LV arms are limited to patients enrolled in the 5-FU/LV arm after this protocol amendment. Four hundred seventeen patients were randomized to: ONIVYDE/5-FU/LV (N=117), ONIVYDE (N=151), or 5-FU/LV (N=149). Baseline demographics and tumor characteristics for the 236 patients randomized to ONIVYDE/5-FU/LV or 5-FU/LV (N=119) after the addition of the third arm to the study were median age of 63 years (range 34-81 years) and with 41% >= 65 years of age; 58% were men; 63% were White, 30% were Asian, 3% were Black or African American, and 5% were other. Mean baseline albumin level was 3.97 g/dL, and baseline KPS was 90-100 in 53% of patients. Disease characteristics included liver metastasis (67%) and lung metastasis (31%). total of 13% of patients received gemcitabine in the neoadjuvant/adjuvant setting only, 55% of patients had prior line of therapy for metastatic disease, and 33% of patients had or more prior lines of therapy for metastatic disease. All patients received prior gemcitabine (alone or in combination with another agent), 54% received prior gemcitabine in combination with another agent, and 13% received prior gemcitabine in combination with nab-paclitaxel. Study demonstrated statistically significant improvement in overall survival for the ONIVYDE/5-FU/LV arm over the 5-FU/LV arm as summarized in Table and Figure 1.There was no improvement in overall survival for the ONIVYDE arm over the 5-FU/LV arm (hazard ratio=1.00, p-value=0.97 (two-sided log-rank test)).Table 5: Efficacy Results from Study 15-FU/LV=5-fluorouracil/leucovorin; CI=confidence interval ONIVYDE/5-FU/LV(N=117)5-FU/LV(N=119)Overall Survival Number of Deaths, (%)77 (66)86 (72) Median Overall Survival (months)6.14.2 (95% CI)(4.8, 8.5)(3.3, 5.3) Hazard Ratio (95% CI)0.68 (0.50, 0.93) p-value (log-rank test)0.014Progression-Free Survival Death or Progression, (%)83 (71)94 (79) Median Progression-Free Survival (months)3.11.5 (95% CI)(2.7, 4.2)(1.4, 1.8) Hazard Ratio (95% CI) 0.55 (0.41, 0.75)Objective Response Rate Confirmed Complete or Partial Response (%) (7.7%)1 (0.8%) Figure 1: Overall Survival Chemical Structure.

DESCRIPTION SECTION.

11 DESCRIPTION. ONIVYDE is formulated with irinotecan hydrochloride trihydrate, topoisomerase inhibitor, into 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-[1,4bipiperidine]-1-carboxylate, monohydrochloride, trihydrate. The empirical formula is C33H38N4O6HCl3H2O and the molecular weight is 677.19 g/mole. The molecular structure is:ONIVYDE is sterile, white to slightly yellow opaque isotonic liposomal dispersion. Each 10 mL single-dose vial contains 43 mg irinotecan free base at concentration of 4.3 mg/mL. The liposome is unilamellar lipid bilayer vesicle, approximately 110 nm in diameter, which encapsulates an aqueous space containing irinotecan in 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 buffer 4.05 mg/mL and sodium chloride as an isotonicity reagent 8.42 mg/mL.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Do not substitute ONIVYDE for other drugs containing irinotecan HCl. (2.1)Recommended dose of ONIVYDE is 70 mg/m2 intravenous infusion over 90 minutes every two weeks. (2.2)Recommended starting dose of ONIVYDE in patients homozygous for UGT1A128 is 50 mg/m2 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 corticosteroid and an anti-emetic. 30 minutes prior to ONIVYDE. (2.2). Do not substitute ONIVYDE for other drugs containing irinotecan HCl. (2.1). Recommended dose of ONIVYDE is 70 mg/m2 intravenous infusion over 90 minutes every two weeks. (2.2). Recommended starting dose of ONIVYDE in patients homozygous for UGT1A128 is 50 mg/m2 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 corticosteroid and an anti-emetic. 30 minutes prior to ONIVYDE. (2.2). 2.1Important Use Information. DO NOT SUBSTITUTE ONIVYDE for other drugs containing irinotecan HCl.. 2.2Recommended Dose. Administer ONIVYDE prior to leucovorin and fluorouracil [see Clinical Studies (14)].The recommended dose of ONIVYDE is 70 mg/m2 administered by intravenous infusion over 90 minutes every weeks.The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A128 allele is 50 mg/m2 administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m2 as tolerated in subsequent cycles.There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal [see Adverse Reactions (6.1) and Clinical Studies (14)]. The recommended dose of ONIVYDE is 70 mg/m2 administered by intravenous infusion over 90 minutes every weeks.. The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A128 allele is 50 mg/m2 administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m2 as tolerated in subsequent cycles.. There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal [see Adverse Reactions (6.1) and Clinical Studies (14)]. PremedicationAdminister corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE infusion.. 2.3Dose Modifications for Adverse Reactions. Table 1: Recommended Dose Modifications for ONIVYDEToxicity NCI CTCAE v4.0NCI CTCAE 4.0=National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 OccurrenceONIVYDE adjustment in patients receiving 70 mg/m2 Patients homozygous for UGT1A128 without previous increase to 70 mg/m2 Grade or adverse reactions Withhold ONIVYDE. Initiate loperamide for late onset diarrhea of any severity. Administer intravenous or subcutaneous atropine 0.25 to mg (unless clinically contraindicated) for early onset diarrhea of any severity. Upon recovery to <= Grade 1, resume ONIVYDE at:First50 mg/m2 43 mg/m2 Second43 mg/m2 35 mg/m2 ThirdDiscontinue ONIVYDEDiscontinue ONIVYDEInterstitial Lung DiseaseFirstDiscontinue ONIVYDEDiscontinue ONIVYDEAnaphylactic ReactionFirstDiscontinue ONIVYDEDiscontinue ONIVYDEFor recommended dose modifications of fluorouracil (5-FU) or leucovorin (LV), refer to the Full Prescribing Information; refer to Clinical Studies (14).. 2.4Preparation and Administration. ONIVYDE is cytotoxic drug. Follow applicable special handling and disposal procedures.1 PreparationWithdraw 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.Protect diluted solution from light. Administer diluted solution within hours of preparation when stored at room temperature or within 24 hours of preparation when stored under refrigerated conditions [2C to 8C (36F to 46F)]. Allow diluted solution to come to room temperature prior to administration. Do NOT freeze.. 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.. Protect diluted solution from light. Administer diluted solution within hours of preparation when stored at room temperature or within 24 hours of preparation when stored under refrigerated conditions [2C to 8C (36F to 46F)]. Allow diluted solution to come to room temperature prior to administration. Do NOT freeze.. AdministrationInfuse diluted solution intravenously over 90 minutes. Do not use in-line filters. Discard unused portion.. Infuse diluted solution intravenously over 90 minutes. Do not use in-line filters. Discard unused portion.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong CYP3A4 Inducers: Avoid the use of strong CYP3A4 inducers if possible. Substitute non-enzyme inducing therapies at least 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 week prior to starting therapy. (7.2). Strong CYP3A4 Inducers: Avoid the use of strong CYP3A4 inducers if possible. Substitute non-enzyme inducing therapies at least 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 week prior to starting therapy. (7.2). 7.1Strong 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. Johns wort if possible. Substitute non-enzyme inducing therapies at least weeks prior to initiation of ONIVYDE therapy [see Clinical Pharmacology (12.3)].. 7.2Strong CYP3A4 or UGT1A1 Inhibitors. Following administration of non-liposomal irinotecan (i.e., irinotecan HCl), patients receiving concomitant ketoconazole, 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 week prior to starting ONIVYDE therapy [see Clinical Pharmacology (12.3)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients of the following:. Severe NeutropeniaAdvise patients of the risk of neutropenia leading to severe and life-threatening infections and the need for monitoring of blood counts. Instruct patients to contact their healthcare provider immediately if experiencing signs of infection, such as fever, chills, dizziness, or shortness of breath [see Warnings and Precautions (5.1)].. Severe DiarrheaInform patients of the risk of severe diarrhea. Advise patients to contact their healthcare provider if they experience persistent vomiting or diarrhea; black or bloody stools; or symptoms of dehydration such as lightheadedness, dizziness, or faintness [see Warnings and Precautions (5.2)].. Interstitial Lung DiseaseInform patients of the potential risk of ILD. Advise patients to contact their healthcare provider as soon as possible for new onset cough or dyspnea [see Interstitial Lung Disease (5.3)]. Hypersensitivity to irinotecan HCl or ONIVYDEAdvise patients of the potential risk of severe hypersensitivity and that ONIVYDE is contraindicated in patients with history of severe allergic reactions with irinotecan HCl or ONIVYDE. Instruct patients to seek immediate medical attention for signs of severe hypersensitivity reaction such as chest tightness; shortness of breath; wheezing; dizziness or faintness; or swelling of the face, eyelids, or lips [see Contraindications (4) and Warnings and Precautions (5.4)]. Females and males of reproductive potential. Embryo-fetal toxicity: Inform females of reproductive potential of the potential risk to fetus, to use effective contraception during treatment and for one month after the final dose, and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].. Contraception: Advise male patients with female partners of reproductive potential to use condoms during treatment with ONIVYDE and for four months after the final dose [see Females and Males of Reproductive Potential (8.3)].. LactationAdvise women not to breastfeed during treatment with ONIVYDE and for one month after the final dose [see Use in Special Populations (8.2)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No studies have been performed to assess the potential of irinotecan liposome for carcinogenicity, genotoxicity or impairment of fertility. Intravenous administration of irinotecan hydrochloride to rats once weekly for 13 weeks followed by 91-week recovery period resulted in significant linear trend between irinotecan HCl dosage and the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan HCl was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan nor its active metabolite, SN-38, was mutagenic in the in vitro Ames assay.Dedicated fertility studies have not been performed with irinotecan liposome injection. Atrophy of male and female reproductive organs was observed in dogs receiving irinotecan liposome injection every weeks at doses equal to or greater than 15 mg/kg, (approximately times the clinical exposure of irinotecan following administration to ONIVYDE dosed at 70 mg/m2 for total of doses. No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan HCl in doses of up to mg/kg/day to rats; however, atrophy of male reproductive organs was observed after multiple daily irinotecan HCl doses both in rodents at 20 mg/kg (approximately 0.007 times the clinical irinotecan exposure following ONIVYDE administration at 70 mg/m2) and in dogs at 0.4 mg/kg (0.0007 times the clinical exposure to irinotecan following administration of ONIVYDE).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The plasma pharmacokinetics of total irinotecan and total SN-38 were evaluated in patients with cancer who received ONIVYDE, as single agent or as part of combination chemotherapy, at doses between 50 and 155 mg/m2 and 353 patients with cancer using population pharmacokinetic analysis. The pharmacokinetic parameters of total irinotecan and total SN-38 following the administration of ONIVYDE 70 mg/m2 as single agent or part of combination chemotherapy are presented in Table 4.Table 4: Summary of Mean (+-Standard Deviation) Total Irinotecan and Total SN-38Dose (mg/m2)Total IrinotecanTotal SN-38Cmax [ug/mL] (n=25)AUC0- [hug/mL] (n=23)t1/2 [h] (n=23)CL [L/h] (n=23)Vd [L] (n=23)Cmax [ng/mL] (n=25)AUC0- [hng/mL] (n=13)t1/2 [h] (n=13)Cmax: Maximum plasma concentrationAUC0-: Area under the plasma concentration curve extrapolated to time infinityt 1/2 Terminal elimination half-lifeCL: ClearanceVd: Volume of distribution7037.2(8.8)1364(1048)25.8(15.7)0.20(0.17)4.1(1.5)5.4(3.4)620(329)67.8(44.5)Over the dose range of 50 to 155 mg/m2, the Cmax and AUC of total irinotecan increases with dose. Additionally, the Cmax of total SN-38 increases proportionally with dose; however, the AUC of total SN-38 increases less than proportionally with dose. DistributionDirect measurement of irinotecan liposome showed that 95% of irinotecan remains liposome-encapsulated, and the ratios between total and encapsulated forms did not change with time from to 169.5 hours post-dose. The mean volume of distribution is summarized in Table 4. Plasma protein binding is <0.44% of the total irinotecan in ONIVYDE. Elimination. MetabolismThe metabolism of irinotecan liposome has not been evaluated. Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including esterases to form the active metabolite SN-38, and UGT1A1 mediating glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive oxidation products, one of which can be hydrolyzed by carboxylesterase to release SN-38. In the population pharmacokinetic analysis using the results of subset with UGT1A128 genotypic testing, in which the analysis adjusted for the lower dose administered to patients homozygous for the UGT1A128 allele, patients homozygous (N=14) and non-homozygous (N=244) for this allele had total SN-38 average steady-state concentrations of 1.06 and 0.95 ng/mL, respectively. ExcretionThe disposition of ONIVYDE has not been elucidated in humans. Following administration of irinotecan HCl the urinary excretion of irinotecan is 11 to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide), over period of 48 hours following administration of irinotecan HCl in two patients, ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).. Specific Populations. Age, Gender, and Renal Impairment: The population pharmacokinetic analysis suggests that age (28 to 87 years) had no clinically meaningful effect on the exposure of irinotecan and SN-38. The population pharmacokinetic analysis suggests that gender (196 males and 157 females) had no clinically meaningful effect on the exposure of irinotecan and SN-38 after adjusting for body surface area (BSA).In population pharmacokinetic analysis, mild-to-moderate renal impairment had no effect on the exposure of total SN-38 after adjusting for BSA. The analysis included 68 patients with moderate (CLcr 30 59 mL/min) renal impairment, 147 patients with mild (CLcr 60 89 mL/min) renal impairment, and 135 patients with normal renal function (CLcr 90 mL/min). There was insufficient data in patients with severe renal impairment (CLcr 30 mL/min) to assess its effect on pharmacokinetics. Ethnicity: The population pharmacokinetic analysis suggests that Asians (East Asians, N=150) have 56% lower total irinotecan average steady state concentration and 8% higher total SN-38 average steady state concentration than Whites (N=182).. Hepatic Impairment: The pharmacokinetics of irinotecan liposome have not been studied in patients with hepatic impairment. In population pharmacokinetic analysis, patients with baseline bilirubin concentrations of 1-2 mg/dL (N=19) had average steady state concentrations for total SN-38 that were increased by 37% compared to patients with baseline bilirubin concentrations of <1 mg/dL (N=329); however, there was no effect of elevated ALT/AST concentrations on total SN-38 concentrations. No data are available in patients with bilirubin >2 mg/dL.. Drug InteractionsIn population pharmacokinetic analysis, the pharmacokinetics of total irinotecan and total SN-38 were not altered by the co-administration of fluorouracil/leucovorin.Following administration of irinotecan HCl, dexamethasone, moderate CYP3A4 inducer, does not alter the pharmacokinetics of irinotecan.In vitro studies indicate that irinotecan, SN-38 and another metabolite, aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 isozymes.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to 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/m2 in humans, administered to pregnant rats and rabbits during organogenesis [see Data]. Advise pregnant women of the potential risk to 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 DataNo 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 dose of 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/m2 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 variety of external, visceral, and skeletal abnormalities. Irinotecan HCl administered to rat dams for the period following organogenesis through weaning at doses of mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.