There are no treatment interventions known to be effective for management of overdosage of ONIVYDE.
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl.
The following adverse drug reactions are discussed in greater detail in other sections of the label:
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 2 weeks (ONIVYDE/5-FU/LV; N=117), ONIVYDE 100 mg/m² every 3 weeks (N=147), or leucovorin 200 mg/m² and fluorouracil 2000 mg/m² over 24 hours weekly for 4 weeks followed by 2 week rest (5-FU/LV; N=134). 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/5-FU/LV arm, 9 weeks in the ONIVYDE monotherapy arm, and 6 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 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/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 2 provides the frequency and severity of adverse reactions in Study 1 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.7
Table 2: Adverse Reactions with Higher Incidence
( ≥ 5% Difference for Grades 1-4* or ≥ 2% Difference for Grades 3 and
4) in the ONIVYDE/5-FU/LV Arm
| Adverse Reaction | ONIVYDE/5-FU/LV N=117 |
5-FU/LV N=134 |
||
| Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
| Gastrointestinal disorders | ||||
| Diarrhea | 59 | 13 | 26 | 4 |
| Early diarrhea† | 30 | 3 | 15 | 0 |
| Late diarrhea‡ | 43 | 9 | 17 | 4 |
| Vomiting | 52 | 11 | 26 | 3 |
| Nausea | 51 | 8 | 34 | 4 |
| Stomatitis§ | 32 | 4 | 12 | 1 |
| Infections and infestations | 38 | 17 | 15 | 10 |
| Sepsis | 4 | 3 | 2 | 1 |
| Neutropenic fever/neutropenic sepsis♠ | 3 | 3 | 1 | 0 |
| Gastroenteritis | 3 | 3 | 0 | 0 |
| Intravenous catheter-related infection | 3 | 3 | 0 | 0 |
| General disorders and administration site conditions | ||||
| Fatigue/asthenia | 56 | 21 | 43 | 10 |
| Pyrexia | 23 | 2 | 11 | 1 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 44 | 4 | 32 | 2 |
| Weight loss | 17 | 2 | 7 | 0 |
| Dehydration | 8 | 4 | 7 | 2 |
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 14 | 1 | 5 | 0 |
| * NCI CTCAE v4.0 † Early diarrhea: onset within 24 hours of ONIVYDE administration ‡ Late diarrhea: onset > 1 day after ONIVYDE administration § Includes stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation. ♠ Includes febrile neutropenia |
||||
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 1 or 2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients. Six of these 12 patients received atropine and in 1 of the 6 patients, atropine was administered for cholinergic symptoms other than diarrhea.
Infusion ReactionsInfusion 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 Arm*#
| Laboratory abnormality | ONIVYDE/5-FU/LV N=117 |
5-FU/LV N=134 |
||
| Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
| Hematology | ||||
| Anemia | 97 | 6 | 86 | 5 |
| Lymphopenia | 81 | 27 | 75 | 17 |
| Neutropenia | 52 | 20 | 6 | 2 |
| Thrombocytopenia | 41 | 2 | 33 | 0 |
| Hepatic | ||||
| Increased alanine aminotransferase (ALT) | 51 | 6 | 37 | 1 |
| Hypoalbuminemia | 43 | 2 | 30 | 0 |
| Metabolic | ||||
| Hypomagnesemia | 35 | 0 | 21 | 0 |
| Hypokalemia | 32 | 2 | 19 | 2 |
| Hypocalcemia | 32 | 1 | 20 | 0 |
| Hypophosphatemia | 29 | 4 | 18 | 1 |
| Hyponatremia | 27 | 5 | 12 | 3 |
| Renal | ||||
| Increased creatinine | 18 | 0 | 13 | 0 |
| * NCI CTCAE v4.0, worst grade shown. # Percent based on number of patients with a baseline and at least one post-baseline measurement. |
||||
ONIVYDE™ is indicated, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.
Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.
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 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 a single agent or part of combination chemotherapy are presented in Table 4.
Table 4: Summary of Mean (±Standard Deviation) Total
Irinotecan and Total SN-38
| Dose (mg/m²) | Total Irinotecan | Total SN-38 | ||||||
| Cmax
[μg/mL] (n=25) |
AUC0-∞
[h•μg/mL] (n=23) |
t½ [h] (n=23) |
CL
[L/h] (n=23) |
Vd
[L] (n=23) |
Cmax
[ng/mL] (n=25) |
AUC0-∞
[h•ng/mL] (n=13) |
t½
[h] (n=13) |
|
| 70 | 37.2 (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) |
| Cmax: Maximum plasma concentration AUC0-∞: Area under the plasma concentration curve extrapolated to time infinity t½: Terminal elimination half-life CL: Clearance Vd: Volume of distribution 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. |
Direct 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 0 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.
EliminationMetabolism
The 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 a subset with UGT1A1*28 genotypic testing, in which the analysis adjusted for the lower dose administered to patients homozygous for the UGT1A1*28 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.
Excretion
The 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 a period of 48 hours following administration of irinotecan HCl in two patients, ranged from approximately 25% (100 mg/m²) to 50% (300 mg/m²).
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/m² 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.
DataAnimal 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/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 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.
Injection: 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, liposomal dispersion in a single-dose vial.
ONIVYDE is available in a single-dose vial containing 43 mg irinotecan free base at a concentration of 4.3 mg/mL
NDC: 69171-398-01
Storage And HandlingStore ONIVYDE at 2°C to 8°C (36°F to 46°F). Do NOT freeze. Protect from light.
ONIVYDE is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
Manufactured for: Merrimack Pharmaceuticals, Inc., Cambridge, MA 02139. Revised: Oct 2015
REFERENCES
1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
Included as part of the PRECAUTIONS section.
PRECAUTIONS Severe NeutropeniaONIVYDE 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 a 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 3 or 4 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 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 DiarrheaONIVYDE 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). An individual patient may experience both early and late-onset diarrhea.
In Study 1, Grade 3 or 4 diarrhea occurred in 13% receiving ONIVYDE/5-FU/LV compared to 4% receiving 5-FU/LV. The incidence of Grade 3 or 4 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 3 or 4 early onset diarrhea was 3% in patients receiving ONIVYDE/5-FU/LV, compared to no Grade 3 or 4 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 1 mg (unless clinically contraindicated) for early onset diarrhea of any severity. Following recovery to Grade 1 diarrhea, resume ONIVYDE at a reduced dose.
Interstitial Lung DiseaseIrinotecan 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 a confirmed diagnosis of ILD.
Severe Hypersensitivity ReactionIrinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.
Embryo-Fetal ToxicityBased 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 one month following the final dose.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityNo 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).
Use In Specific Populations Pregnancy Risk SummaryBased 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/m² 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.
DataAnimal 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/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 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.
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.
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 final dose.
DataRadioactivity 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.
Females And Males Of Reproductive Potential ContraceptionFemales
ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ONIVYDE and for one month after the final dose.
Males
Because 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.
Pediatric UseSafety and effectiveness of ONIVYDE have not been established in pediatric patients.
Geriatric UseOf the 264 patients who received ONIVYDE as a 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.
DO NOT SUBSTITUTE ONIVYDE for other drugs containing irinotecan HCl.
Recommended DoseAdminister ONIVYDE prior to leucovorin and fluorouracil.
There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal.
PremedicationAdminister a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE infusion.
Dose Modifications For Adverse ReactionsTable 1: Recommended Dose Modifications for ONIVYDE
| Toxicity NCI CTCAE v4.0† | Occurrence | ONIVYDE adjustment in patients receiving 70 mg/m² | Patients homozygous for UGT1A1*28 without previous increase to 70 mg/m² |
| Grade 3 or 4 adverse reactions | Withhold ONIVYDE. Initiate loperamide for late onset diarrhea of any severity. Administer intravenous or subcutaneous atropine 0.25 to 1 mg (unless clinically contraindicated) for early onset diarrhea of any severity. Upon recovery to ≤ Grade 1, resume ONIVYDE at: |
||
| First | 50 mg/m² | 43 mg/m² | |
| Second | 43 mg/m² | 35 mg/m² | |
| Third | Discontinue ONIVYDE | Discontinue ONIVYDE | |
| Interstitial Lung Disease | First | Discontinue ONIVYDE | Discontinue ONIVYDE |
| Anaphylactic Reaction | First | Discontinue ONIVYDE | Discontinue ONIVYDE |
| † NCI CTCAE v 4.0=National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 | |||
For recommended dose modifications of fluorouracil (5-FU) or leucovorin (LV), refer to the Full Prescribing Information; refer to Clinical Studies (14).
Preparation And AdministrationONIVYDE is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
PreparationInfuse diluted solution intravenously over 90 minutes. Do not use in-line filters. Discard unused portion.
In a 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, a 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.
