Onivyde Drug Information

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.

Important Use Information DO NOT SUBSTITUTE ONIVYDE for other drugs containing irinotecan HCl.

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. There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal. 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.

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. Table 1 Recommended Dosage Modifications for ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin Table 2 Recommended Dosage Modifications for ONIVYDE in combination with fluorouracil and leucovorin For recommended dose modifications of fluorouracil (FU) or leucovorin (LV), refer to the Full Prescribing Information; refer to Clinical Studies.

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. Allow diluted solution to come to room temperature prior to administration.

Do NOT freeze. Administration Infuse diluted solution intravenously over 90 minutes.

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. 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. 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 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: 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. 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 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 s 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. 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. 0

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

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.

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.

Pregnancy Risk Summary 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. 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/m 2 in humans, administered to pregnant rats and rabbits during organogenesis.

Advise pregnant women of the potential risk to a 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 Data No 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 a dose of 6 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/m 2 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 a variety of external, visceral, and skeletal abnormalities. Irinotecan HCl administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.

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

ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction or anaphylaxis to ONIVYDE or irinotecan HCl.

There are no treatment interventions known to be effective for management of overdosage of ONIVYDE.