irinotecan liposomal (Onivyde)

Dosing and uses of Onivyde (irinotecan liposomal)

• Adult
• Pediatric

 

Adult dosage forms and strengths

liposomal dispersion for injection

• 43mg/10mL single-dose vial

 

Pancreatic Cancer

Indicated, in combination with fluorouracil and leucovorin, for metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy

Administer irinotecan liposomal prior to leucovorin and fluorouraciL

70 mg/m² IV infused over 90 min q2wk

Premedicate with a corticosteroid and an antiemetic agent 30 min before irinotecan liposomal infusion (see Administration)

 

Dosage modifications

Patients known to be homozygous for the UGT1A1*28 allele: 50 mg/m² IV infused over 90 min q2wk; increase dose to 70 mg/m² as tolerated in subsequent cycles

Serum bilirubin >ULN: No recommended dose

Interstitial lung disease: Discontinue drug

Anaphylactic reaction: Discontinue drug

Grade 3 or 4 adverse reactions

• Withhold dose
• Upon recovery to ≤grade 1, resume dose at:
  • First occurrence: Resume dose at 50 mg/m² or 43 mg/m² (patients homozygous for UGT1A1*28 without previous increase to 70 mg/m²)
  • Second occurrence: Resume dose at 43 mg/m² or 35 mg/m² (patients homozygous for UGT1A1*28 without previous increase to 70 mg/m²)
  • Third occurrence: Discontinue drug
• Diarrhea
  • Withhold dose
  • Initiate loperamide for late-onset diarrhea of any severity
  • Administer IV or SC atropine 0.25-1 mg (unless clinically contraindicated) for early-onset diarrhea of any severity
  • Upon recovery to ≤grade 1, resume dose as described above

 

Dosing Considerations

Limitations of use: Not indicated as a single agent

Do not substitute irinotecan liposomal for other drugs containing irinotecan

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Onivyde (irinotecan liposomal) adverse (side) effects

>10%

Diarrhea, grades 1-4 (59%)

Fatigue/asthenia, grades 1-4 (56%)

Vomiting, grades 1-4 (52%)

Nausea, grades 1-4 (51%)

Decreased appetite, grades 1-4 (44%)

Late diarrhea, grades 1-4 (43%)

Stomatitis, grades 1-4 (32%)

Early diarrhea, grades 1-4 (30%)

Lymphopenia, grades 3-4 (27%)

Pyrexia, grades 1-4 (23%)

Fatigue/asthenia, grades 3-4 (21%)

Neutropenia, grades 3-4 (20%)

Weight loss, grades 1-4 (17%)

Alopecia, grades 1-4 (14%)

Diarrhea, grades 3-4 (13%)

Vomiting, grades 3-4 (11%)

 

1-10%

Early diarrhea, grades 3-4 (9%)

Nausea, grades 3-4 (8%)

Dehydration (4-8%)

Anemia, grades 3-4 (6%)

Increased ALT, grades 3-4 (6%)

Hyponatremia, grades 3-4 (5%)

Cholinergic reactions, other than diarrhea (4.5%)

Decreased appetite, grades 3-4 (4%)

Stomatitis, grades 3-4 (4%)

Hypophosphatemia, grades 3-4 (4%)

Late diarrhea, grades 3-4 (3%)

Sepsis (3-4%)

Neutropenic fever/neutropenic sepsis (3%)

Gastroenteritis (3%)

IV catheter-related infection (3%)

Infusion reactions (3%)

Pyrexia, grades 3-4 (2%)

Weight loss, grades 3-4 (2%)

Thrombocytopenia, grades 3-4 (2%)

Hypoalbuminemia, grades 3-4 (2%)

Hypokalemia, grades 3-4 (2%)

Hypocalcemia, grades 3-4 (1%)

Alopecia, grades 3-4 (1%)

 

Warnings

Black box warnings

Neutropenic sepsis

• Fatal neutropenic sepsis occurred in 0.8% of patients receiving irinotecan liposomal
• Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving irinotecan liposomal in combination with fluorouracil and leucovorin
• Withhold drug for absolute neutrophil count <1500/mm³ or neutropenic fever
• Monitor blood cell counts periodically during treatment

Diarrhea

• Severe diarrhea occurred in 13% of patients receiving irinotecan liposomal in combination with fluorouracil and leucovorin
• Do not administer to patients with bowel obstruction
• Withhold for diarrhea of grade 2-4 severity (see Dosage modifications)
• Administer loperamide for late-onset diarrhea of any severity
• Administer atropine, if not contraindicated, for early-onset diarrhea of any severity

 

Contraindications

Hypersensitivity

 

Cautions

Can cause severe or life-threatening neutropenia and fatal neutropenic sepsis (see Black box warnings)

Can cause severe and life-threatening diarrhea; do not administer to patients with bowel obstruction (see Black box warnings)

Can cause severe and fatal interstitial lung disease; withhold drug in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation

Severe hypersensitivity reactions may occur, including anaphylaxis; permanently discontinue if a severe hypersensitivity reaction occurs

Based on animal data with irinotecan HCl and the mechanism of action of irinotecan liposomal, can cause fetal harm when administered to a pregnant woman (see Pregnancy)

Strong CYP3A4 inducers are known to substantially decrease systemic exposure to irinotecan or its active metabolite, SN-38

Strong CYP3A4 or UGT1A1 inhibitors have shown to increase systemic exposure to irinotecan or its active metabolite, SN-38

 

Pregnancy

Pregnancy

Based on animal data with irinotecan HCl and the mechanism of action of irinotecan liposomal, can cause fetal harm when administered to a pregnant woman

Advise females of reproductive potential to use effective contraception during treatment and for 1 month after the final dose

Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with irinotecan liposomal 70 mg/m² in humans, when administered to pregnant rats and rabbits during organogenesis

Male reproductive recommendations

• Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment and for 4 months after the final dose

 

Lactation

Unknown if distributed in human breast milk

Because of the potential for serious adverse reactions in breastfed infants from irinotecan liposomal, advise a nursing woman not to breastfeed during treatment with and for 1 month after the final dose

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Onivyde (irinotecan liposomal)

Mechanism of action

Binds to topoisomerase-1

Topoisomerase-1 relieves torsional strain in DNA by inducing single-strand breaks

Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase-1 DNA complex and prevent re-ligation of the single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death

 

Absorption

Peak plasma concentration: 37.2 mcg/mL; 5.4 ng/mL (SN-38)

AUC: 1364 h·mcg/mL; 620 h·mcg/mL (SN-3

 

Distribution

Vd: 4.1 L; 95% remains encapsulated

 

Metabolism

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

 

Elimination

Half-life: 25.8 hr; 67.8 hr (SN-38)

Clearance: 0.2 L/hr

Excretion: 11-20% urine (SN-38 <1%); 25-50% cumulative biliary and urinary (parent drug and metabolites over 48 hr

 

Pharmacogenomics

Homozygous for UGT1A1*28 allele

• Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia from irinotecan HCL
• In clinical trials, patients homozygous for the UGT1A1*28 allele (N=7) were initiated on irinotecan liposomal (Onivyde) at a reduced dose of 50 mg/m² in combination with 5-fluorouracil/leucovorin
• The frequency of grade 3 or 4 neutropenia in these patients (2 of 7 [28.6%]) was similar to the frequency in patients not homozygous for the UGT1A1*28 allele who received a starting dose of irinotecan liposomal of 70 mg/m² (30 of 110 [27.3%])

 

Administration

IV Compatibilities

Dextrose 5% water

0.9% NaCL

 

IV Preparation

Withdraw the calculated volume for dose from the viaL

Dilute in 500 mL D5W or 0.9% NaCl and mix diluted solution by gentle inversion

Protect diluted solution from light

Administer diluted solution within 4 hr of preparation when stored at room temperature or within 24 hr of preparation when stored under refrigerated conditions

 

IV Administration

Allow diluted solution to come to room temperature prior to administration if stored under refrigeration

Premedicate with a corticosteroid and an antiemetic 30 minutes before administering irinotecan liposomaL

Infuse diluted solution IV over 90 minutes

Do not use in-line filters

Discard unused portion

 

Storage

Cytotoxic drug; follow applicable special handling and disposal procedures

Unopened vials

• Store vials refrigerated at 2-8ºC (36-46°F)
• Do not freeze
• Protect from light

Diluted solution

• Administer diluted solution within 4 hr of preparation when stored at room temperature or within 24 hr of preparation when stored under refrigerated conditions (2-8ºC [36-46ºF])
• Protect diluted solution from light
• Allow diluted solution to come to room temperature prior to administration
• Do not freeze