2.1 Important Use Information

DO NOT SUBSTITUTE ONIVYDE for other drugs containing irinotecan HCl.

2.2 Recommended Dosage

2.3 Dosage Modifications for Adverse Reactions

Recommended dosage modifications for ONIVYDE are in Table 1 and Table 2.

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

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/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)].

5.2 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 Lung Disease

Irinotecan HCl can cause severe and fatal interstitial lung disease (ILD). Risk factors include pre-existing lung disease, use of pneumotoxic medicinal products, colony stimulating factors or having previously received radiation therapy. Patients with risk factors should be closely monitored for respiratory symptoms before and during ONIVYDE® therapy. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.

5.4 Severe Hypersensitivity Reaction

Irinotecan including ONIVYDE can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction [see Contraindications (4), Adverse reactions (6.2)].

5.5 Embryo-Fetal Toxicity

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. 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 a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONIVYDE and for seven months following the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval 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)

7.1 Strong CYP3A4 Inducers

Following administration of non-liposomal irinotecan (i.e., irinotecan HCl) substantially, 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

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness of ONIVYDE have not been established in pediatric patients.

8.5 Geriatric Use

Of the 634 patients who received ONIVYDE as a single agent, in combination with FU and leucovorin or in combination with oxaliplatin, FU and leucovorin in NAPOLI-1 and NAPOLI 3, 49% were ≥ 65 years old and 10% were ≥ 75 years old. No overall differences in safety and effectiveness were observed between these patients and younger patients.

12.1 Mechanism of Action

Irinotecan liposome injection is a topoisomerase 1 inhibitor encapsulated in a lipid bilayer vesicle or liposome. Topoisomerase 1 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 a single agent or as part of combination chemotherapy, at doses between 35 mg/m2 and 155 mg/m2 and concentration proportional to dose was observed.

The pharmacokinetic parameters of total irinotecan and total SN-38 following the administration of ONIVYDE 70 mg/m2 as a single agent or part of combination chemotherapy are presented in Table 7.

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/m2 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/m2 [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/m2 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.

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 a 91-week recovery period resulted in a 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 3 weeks at doses equal to or greater than 15 mg/kg, (approximately 3 times the clinical exposure of irinotecan following administration to ONIVYDE dosed at 70 mg/m2) for a total of 6 doses. No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan HCl in doses of up to 6 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).

Pancreatic Adenocarcinoma

In Combination with Oxaliplatin, Fluorouracil and Leucovorin for First-Line Treatment of Metastatic Pancreatic Adenocarcinoma

The efficacy of ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin (NALIRIFOX) was evaluated in NAPOLI 3 (NCT04083235), a randomized, multicenter, open-label, active-controlled trial in 770 patients with metastatic pancreatic adenocarcinoma who had not previously received chemotherapy in the metastatic setting. Randomization was stratified by region, liver metastases and ECOG performance status. Patients were randomized (1:1) to receive one of the following treatment arm:

• NALIRIFOX: ONIVYDE 50 mg/m2 as an intravenous infusion over 90 minutes, followed by oxaliplatin 60 mg/m2 as an intravenous infusion over 120 minutes, followed by leucovorin 400 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2400 mg/m2 intravenously over 46 hours, every 2 weeks.
• Gem+NabP: Nab-paclitaxel 125 mg/m2 as an intravenous infusion over 35 minutes, followed by gemcitabine 1000 mg/m2 intravenously over 30 minutes on days 1, 8 and 15 of each 28-day cycle.

Patients homozygous for the UGT1A1*28 allele initiated ONIVYDE at the same dose (50 mg/m2 ONIVYDE). Treatment continued until RECIST v1.1 defined disease progression or unacceptable toxicity. Tumor status assessments were conducted at baseline and every 8 weeks thereafter as assessed by the investigator according to RECIST v1.1.

The main efficacy outcome measure was overall survival (OS). Additional efficacy measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR).

Baseline demographic and patient characteristics were: median age of 65 years (range: 20-85); 50% age 65 or older; 56% male; 83% White, 4.9% Asian, 2.5% Black or African American, 0.4% multiple race, 0.3% American Indian or Alaska Native; 0.1% Native Hawaiian or other Pacific Islander, 1.7% other, 7% not reported; and 82% non-Hispanic, 10% Hispanic, 8% not reported. ECOG performance status was 0 or 1 in 44% and 56% of patients, respectively; 80% had liver metastases.

NAPOLI 3 demonstrated a statistically significant improvement in OS and PFS for the NALIRIFOX arm over Gem+NabP arm as summarized in Table 8 and Figure 1.

Figure 1 Kaplan-Meier Curve for Overall Survival in all randomized Patients in NAPOLI 3

Previously treated metastatic pancreatic adenocarcinoma in combination with fluorouracil and leucovorin

The efficacy of ONIVYDE was evaluated in NAPOLI-1 (NCT01494506), a 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/FU/LV), ONIVYDE, or fluorouracil/leucovorin (FU/LV). Randomization was stratified by ethnicity (White vs. East Asian vs. other), KPS (70-80 vs. 90-100), and baseline albumin level (≥ 4 g/dL vs. 3.0-3.9 g/dL). Patients randomized to ONIVYDE/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 2 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 a single agent received ONIVYDE 100 mg/m2 as an intravenous infusion over 90 minutes every 3 weeks. Patients randomized to 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 a 6-week cycle. Patients homozygous for the UGT1A1*28 allele initiated ONIVYDE at a reduced dose (50 mg/m2 ONIVYDE, if given with FU/LV or 70 mg/m2 ONIVYDE as a single agent). When ONIVYDE was withheld or discontinued for adverse reactions, FU was also withheld or discontinued. When the dose of ONIVYDE was reduced for adverse reactions, the dose of 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 FU/LV and ONIVYDE/FU/LV versus 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 6 weeks thereafter. The trial was initiated as a two-arm study and amended after initiation to include a third arm (ONIVYDE/FU/LV). The comparisons between the ONIVYDE/FU/LV and the FU/LV arms are limited to patients enrolled in the FU/LV arm after this protocol amendment.

Four hundred seventeen patients were randomized to: ONIVYDE/FU/LV (N=117), ONIVYDE (N=151), or FU/LV (N=149). Baseline demographics and tumor characteristics for the 236 patients randomized to ONIVYDE/FU/LV or FU/LV (N=119) after the addition of the third arm to the study were a 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%). A total of 13% of patients received gemcitabine in the neoadjuvant/adjuvant setting only, 55% of patients had 1 prior line of therapy for metastatic disease, and 33% of patients had 2 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.

NAPOLI-1 demonstrated a statistically significant improvement in overall survival for the ONIVYDE/FU/LV arm over the FU/LV arm as summarized in Table 9 and Figure 2.

There was no improvement in overall survival for the ONIVYDE arm over the FU/LV arm (hazard ratio=1.00, p-value=0.97 (two-sided log-rank test)).

Figure 2 Kaplan-Meier Curve for Overall Survival in all randomized Patients in NAPOLI-1

How Supplied

ONIVYDE is available in a single-dose vial containing 43 mg irinotecan free base at a concentration of 4.3 mg/mL.

NDC: 15054-0043-1

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

Severe Neutropenia

Advise 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 Diarrhea

Inform patients of the risk of severe and life-threatening diarrhea. Advise patients to stop lactose-containing products, maintain hydration, and eat frequent small meals with a low-fat diet. 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 Disease

Inform 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 ONIVYDE

Advise patients of the potential risk of severe hypersensitivity and that ONIVYDE is contraindicated in patients with a 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

Lactation

Advise women not to breastfeed during treatment with ONIVYDE and for one month after the last dose [see Use in Special Populations (8.2)].

Manufactured for:
Ipsen Biopharmaceuticals, Inc. Cambridge, MA 02142
ONIVYDE is a registered trademark of Ipsen Biopharm Ltd.