NAPOLI 3 Dose Modifications | ONIVYDE® (irinotecan liposome injection)

DOSE MODIFICATIONS AND TREATMENT TO HELP MANAGE ADVERSE REACTIONS FOR THE NALIRIFOX REGIMEN

Recommended modifications from the NAPOLI 3 clinical trial of ONIVYDE® (irinotecan liposome injection) + oxaliplatin + FU/LV, including dose reduction, delay, and discontinuation.

Oxaliplatin may be discontinued if not well tolerated and treatment with ONIVYDE + FU/LV can continue. Maintain original dose level of leucovorin for first, second, and third occurrence of toxicity. Refer to the full Prescribing Information of fluorouracil and oxaliplatin¹

* NCI CTCAE v5.0.

† No dosage modification is necessary for asthenia, alopecia, and Grade 3 anorexia.

‡ Do not resume until the absolute neutrophil count is ≥2000/mm³ (2x10⁹/L) and the platelet count is ≥100,000/mm³ (100x10⁹/L).

§ For Grade ≥3 nausea and vomiting, reduce dose only if occurs despite optimal antiemetic therapy.

Recommended dose modifications for neutropenia and diarrhea¹

	Neutropenia	Diarrhea
Withhold ONIVYDE	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.	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 mg to 1 mg (unless clinically contraindicated) for early-onset diarrhea of any severity. Initiate loperamide for late-onset diarrhea 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.
Resume ONIVYDE	Resume ONIVYDE when the ANC is 1500/mm³ or above.	Resume ONIVYDE at a reduced dose following recovery to Grade 1 diarrhea.
Reduce ONIVYDE	Reduce ONIVYDE for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles.	Reduce ONIVYDE following recovery to Grade 1 diarrhea.

Neutropenia

Diarrhea

Withhold ONIVYDE

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 mg to 1 mg (unless clinically contraindicated) for early-onset diarrhea of any severity.

Initiate loperamide for late-onset diarrhea
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.

Resume ONIVYDE

Resume ONIVYDE when the ANC is 1500/mm³ or above.

Resume ONIVYDE at a reduced dose
following recovery to Grade 1 diarrhea.

Reduce ONIVYDE

Reduce ONIVYDE for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles.

Reduce ONIVYDE following recovery
to Grade 1 diarrhea.

Withhold ONIVYDE
Neutropenia	Diarrhea
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.	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 mg 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.
Resume ONIVYDE
Neutropenia	Diarrhea
Resume ONIVYDE when the ANC is 1500/mm³ or above.	Resume ONIVYDE at a reduced dose following recovery to Grade 1 diarrhea.
Reduce ONIVYDE
Neutropenia	Diarrhea
Reduce ONIVYDE for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles.	Reduce ONIVYDE following recovery to Grade 1 diarrhea.

POST-GEM SAFETY DATA

INDICATIONS

ONIVYDE® (irinotecan liposome injection) 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 SAFETY INFORMATION

WARNING: SEVERE NEUTROPENIA AND SEVERE DIARRHEA

Neutropenia

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.

Diarrhea

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.

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

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. 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%)]. Neutropenic fever/neutropenic sepsis was reported in 5% of Asian patients (1 of 20) compared to 2.3% of White patients (7 of 306). 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%. 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%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients.

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.

Severe Diarrhea: In NAPOLI 3, Grade 3 and 4 diarrhea (early-onset [within 24 hours of chemotherapy] and late-onset [more than 24 hours following chemotherapy]) occurred in 20% receiving 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.

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. 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.

Interstitial Lung Disease (ILD): ONIVYDE can cause severe and fatal ILD. Postmarketing cases of severe and fatal ILD have been reported with ONIVYDE. 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.

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.

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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 7 months after the last dose of ONIVYDE treatment.

ADVERSE REACTIONS FOR NALIRIFOX

The most common adverse reactions (≥20%) of NALIRIFOX were diarrhea (72%), fatigue (62%), nausea (59%), vomiting (40%), decreased appetite (37%), abdominal pain (35%), mucosal inflammation (28%), constipation (25%), and weight decreased (22%).
Permanent discontinuation of ONIVYDE due to an adverse reaction occurred in 17% of patients. Adverse reactions that 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 that 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 laboratory abnormalities (≥10% Grade 3 or 4) were decreased neutrophils (26%), decreased potassium (22%), decreased lymphocytes (11%), and decreased hemoglobin (10%).

ADVERSE REACTIONS FOR ONIVYDE/FU/LV

The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%).
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.
The most common severe laboratory abnormalities (≥10% Grade 3 or 4) were lymphopenia and neutropenia.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of ONIVYDE:

Hypersensitivity (including anaphylactic reaction and angioedema).

DRUG INTERACTIONS

Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme inducing therapies ≥2 weeks prior to initiation of ONIVYDE.
Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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. Advise pregnant women of the potential risk to a fetus.
Lactation: Advise nursing women not to breastfeed during and for 1 month after the last dose of ONIVYDE.

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.

Please see full Prescribing Information, including BOXED WARNING, for ONIVYDE.

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