Onivyde

• Severe and life-threatening neutropenia, including fatal neutropenic sepsis and fatal neutropenic fever, has occurred in patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin and 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

  2.2 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

  [see Clinical Studies (14)]

  .

  • The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
  • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
    [see Adverse Reactions (6.1)and Clinical Studies (14)].

  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

  [see Clinical Studies (14)]

  .

  • The recommended dosage of ONIVYDE is 70 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
  • The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m²administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m²as tolerated in subsequent cycles.
  • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
    [see Adverse Reactions (6.1)and Clinical Studies (14)].

  Premedication

  Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion.

  and

  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/mm³or if neutropenic fever occurs. Resume ONIVYDE when the ANC is 1500/mm³or above. Reduce ONIVYDE dose for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles

  [see Dosage and Administration (2.2)]

  .

  ].

• Severe and life-threatening diarrhea has occurred in patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin and 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

  2.2 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

  [see Clinical Studies (14)]

  .

  • The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
  • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
    [see Adverse Reactions (6.1)and Clinical Studies (14)].

  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

  [see Clinical Studies (14)]

  .

  • The recommended dosage of ONIVYDE is 70 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
  • The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m²administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m²as tolerated in subsequent cycles.
  • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
    [see Adverse Reactions (6.1)and Clinical Studies (14)].

  Premedication

  Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion.

  and

  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)]

  .

  ].

• 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.

[see

14 CLINICAL STUDIES

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/m²as an intravenous infusion over 90 minutes, followed by oxaliplatin 60 mg/m²as an intravenous infusion over 120 minutes, followed by leucovorin 400 mg/m²intravenously over 30 minutes, followed by fluorouracil 2400 mg/m²intravenously over 46 hours, every 2 weeks.
• Gem+NabP: Nab-paclitaxel 125 mg/m²as an intravenous infusion over 35 minutes, followed by gemcitabine 1000 mg/m²intravenously 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/m²ONIVYDE). 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.

Table 8 Efficacy Results of All Randomized Patients in NAPOLI 3

	NALIRIFOXNALIRIFOX= ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin; Gem+NabP=gemcitabine+nab-paclitaxel; CI=confidence interval (N=383)	Gem+NabP (N=387)
**Based on the stratified Cox proportional hazard model; stratified by ECOG PS (0 vs. 1), region (North America vs. East Asia vs. Rest of the world), and liver metastases (yes vs. no) per interaction web response system
Overall Survival
Number of Deaths, n (%)	259 (68)	285 (74)
Median Overall Survival (months)	11.1	9.2
(95% CI)	(10.0, 12.1)	(8.3, 10.6)
Hazard Ratio (95% CI)	0.84 (0.71, 0.99)
p-valueBased on stratified log-rank test.	0.0403
Progression-Free Survival
Death or Progression, n (%)	249 (65)	259 (67)
Median Progression-Free Survival (months)	7.4	5.6
(95% CI)	(6.0, 7.7)	(5.3, 5.8)
Hazard Ratio (95% CI)	0.70 (0.59, 0.85)
P-value	0.0001
Objective Response RateORR result was not statistically significant.
ORR (95% CI)	41.8 (36.8, 46.9)	36.2 (31.4, 41.2)
CR, n (%)	1 (0.3)	1 (0.3)
PR, n (%)	159 (41.5)	139 (35.9)

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/m²as an intravenous infusion over 90 minutes, followed by leucovorin 400 mg/m²intravenously over 30 minutes, followed by fluorouracil 2400 mg/m²intravenously over 46 hours, every 2 weeks. The ONIVYDE dose of 70 mg/m²is based on irinotecan free base (equivalent to 80 mg/m²of irinotecan as the hydrochloride trihydrate). Patients randomized to ONIVYDE as a single agent received ONIVYDE 100 mg/m²as an intravenous infusion over 90 minutes every 3 weeks. Patients randomized to FU/LV received leucovorin 200 mg/m²intravenously over 30 minutes, followed by fluorouracil 2000 mg/m²intravenously 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/m²ONIVYDE, if given with FU/LV or 70 mg/m²ONIVYDE 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)).

Table 9 Efficacy Results from NAPOLI-1FU/LV=5-fluorouracil/leucovorin; CI=confidence interval

	ONIVYDE/FU/LV (N=117)	FU/LV (N=119)
Overall Survival
Number of Deaths, n (%)	77 (66)	86 (72)
Median Overall Survival (months)	6.1	4.2
(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)	0.014
Progression-Free Survival
Death or Progression, n (%)	83 (71)	94 (79)
Median Progression-Free Survival (months)	3.1	1.5
(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 n (%)	9 (7.7%)	1 (0.8%)

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

]

• Do not substitute ONIVYDE for other drugs containing irinotecan HCl. (

  2.1 Important Use Information

  DO NOT SUBSTITUTE

  ONIVYDE for other drugs containing irinotecan HCl.

  )
• ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin:
  • Recommended dose of ONIVYDE is 50 mg/m² intravenous infusion over 90 minutes every two weeks. (
    2.2 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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE is 70 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m²administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m²as tolerated in subsequent cycles.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    Premedication

    Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion.
    )
  • Recommended starting dose of ONIVYDE in patients homozygous for UGT1A1*28 is 50 mg/m² every two weeks. (
    2.2 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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE is 70 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m²administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m²as tolerated in subsequent cycles.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    Premedication

    Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion.
    )
  • There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. (
    2.2 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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE is 70 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m²administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m²as tolerated in subsequent cycles.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    Premedication

    Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion.
    )
• ONIVYDE in combination with fluorouracil and leucovorin:
  • Recommended dose of ONIVYDE is 70 mg/m² intravenous infusion over 90 minutes every two weeks. (
    2.2 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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE is 70 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m²administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m²as tolerated in subsequent cycles.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    Premedication

    Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion.
    )
  • Recommended starting dose of ONIVYDE in patients homozygous for UGT1A1*28 is 50 mg/m² every two weeks. (
    2.2 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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE is 70 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m²administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m²as tolerated in subsequent cycles.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    Premedication

    Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion.
    )
  • There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. (
    2.2 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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    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

    [see Clinical Studies (14)]

    .

    • The recommended dosage of ONIVYDE is 70 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
    • The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m²administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m²as tolerated in subsequent cycles.
    • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
      [see Adverse Reactions (6.1)and Clinical Studies (14)].

    Premedication

    Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion.
    )
• Premedicate with a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE. (
  2.2 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

  [see Clinical Studies (14)]

  .

  • The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
  • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
    [see Adverse Reactions (6.1)and Clinical Studies (14)].

  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

  [see Clinical Studies (14)]

  .

  • The recommended dosage of ONIVYDE is 70 mg/m²administered by intravenous infusion over 90 minutes every 2 weeks.
  • The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m²administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m²as tolerated in subsequent cycles.
  • There is no recommended dosage of ONIVYDE for patients with serum bilirubin above the upper limit of normal
    [see Adverse Reactions (6.1)and Clinical Studies (14)].

  Premedication

  Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion.
  )

Injection: 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, liposomal dispersion in a single-dose vial.

• Lactation: Do not breastfeed. (
  8.2 Lactation

  Risk Summary

  There 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 a nursing woman not to breastfeed during treatment with ONIVYDE and for one month after the last dose.

  Data

  Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan HCl and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations.
  )