Dosage & Administration
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Onivyde Prescribing Information
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 [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].
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 [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].
- 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 Clinical Studies (14)].
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 [see Clinical Studies (14)].
- The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50 mg/m2 administered 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/m2 administered 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/m2 administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m2 as 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.
Dosage Modifications for Adverse Reactions
Recommended dosage modifications for ONIVYDE are in Table 1 and Table 2.
| Toxicity * | Occurrence | ONIVYDE adjustment in patients receiving 50mg/m2 |
|---|---|---|
| ||
| Grade 3 or 4 Adverse reactions † | Withhold ONIVYDE Upon recovery to ≤ Grade 1 ‡, §, ¶, resume ONIVYDE at: | |
| First | 40 mg/m2 | |
| Second | 32.5 mg/m2 | |
| Third | 25 mg/m2 | |
| Fourth | Discontinue ONIVYDE | |
| Grade 3 or 4 Hand foot syndrome | First | Discontinue ONIVYDE |
| Any grade neurocerebellar toxicity | First | Discontinue ONIVYDE |
| Grade ≥ 2 cardiac toxicity | First | Discontinue ONIVYDE |
| Interstitial lung disease | First | Discontinue ONIVYDE |
| Anaphylactic reaction | First | Discontinue 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. 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 |
For recommended dose modifications of fluorouracil (FU) or leucovorin (LV), refer to the Full Prescribing Information; refer to Clinical Studies (14).
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 [2ºC to 8ºC (36ºF to 46ºF)]. Allow diluted solution to come to room temperature prior to administration.
- Do NOT freeze.
Administration
- Infuse diluted solution intravenously over 90 minutes.
Injection: 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, liposomal dispersion in a single-dose vial.
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 [see Clinical Pharmacology (12.1)]. 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 [see Data]. 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/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 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.
Females and Males of Reproductive Potential
Contraception
Females
ONIVYDE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ONIVYDE and for seven months after the last 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 last dose [see Nonclinical Toxicology (13.1)].
Pediatric Use
Safety and effectiveness of ONIVYDE have not been established in pediatric patients.
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.
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction or anaphylaxis to ONIVYDE or irinotecan HCl. [see Warnings and Precautions (5.4), Adverse Reactions (6.2)].