ONIVYDE

Camptothecin Analogs

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Moderate
Administer routine antiemetic prophylaxis prior to treatment.

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Preparation:
Withdraw calculated volume of irinotecan liposome from the vial and dilute in 500 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Mix by gentle inversion.
Storage of Diluted Solution: Protect from light. Administer within 4 hours of preparation if stored at room temperature, or within 24 hours if refrigerated at 2 to 8 degrees Celsius (36 to 46 degrees Farenheit). Do not freeze.
 
Administration:
Allow diluted solution to come to room temperature prior to administration.
Infuse diluted solution by intravenous infusion over 90 minutes.
Do not use in-line filters.

neutropenia / Delayed / 20.0-55.0
lymphopenia / Delayed / 27.0-27.0
fatigue / Early / 21.0-21.0
asthenia / Delayed / 21.0-21.0
infection / Delayed / 17.0-17.0
diarrhea / Early / 3.0-13.0
vomiting / Early / 11.0-11.0
nausea / Early / 8.0-8.0
anemia / Delayed / 6.0-6.0
elevated hepatic enzymes / Delayed / 6.0-6.0
hyponatremia / Delayed / 5.0-5.0
dehydration / Delayed / 4.0-4.0
anorexia / Delayed / 4.0-4.0
stomatitis / Delayed / 4.0-4.0
hypophosphatemia / Delayed / 4.0-4.0
fever / Early / 2.0-2.0
thrombocytopenia / Delayed / 2.0-2.0
weight loss / Delayed / 2.0-2.0
hypoalbuminemia / Delayed / 2.0-2.0
hypokalemia / Delayed / 2.0-2.0
alopecia / Delayed / 1.0-1.0
hypocalcemia / Delayed / 1.0-1.0
renal failure (unspecified) / Delayed / 2.0
bradycardia / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
pneumonitis / Delayed / Incidence not known

hypomagnesemia / Delayed / 35.0-35.0
infusion-related reactions / Rapid / 3.0-3.0
oral ulceration / Delayed / Incidence not known
edema / Delayed / Incidence not known
dyspnea / Early / Incidence not known

lacrimation / Early / Incidence not known
diaphoresis / Early / Incidence not known
hypersalivation / Early / Incidence not known
miosis / Early / Incidence not known
rhinitis / Early / Incidence not known
flushing / Rapid / Incidence not known
pruritus / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
rash / Early / Incidence not known
cough / Delayed / Incidence not known

Bone marrow suppression, including neutropenia, can occur with irinotecan liposome therapy. Severe or life-threatening neutropenic fever and fatal neutropenic sepsis have occurred in patients receiving irinotecan liposome in combination with 5-fluorouracil and leucovorin; the incidence of grade 3 or 4 neutropenia was higher in Asian patients (55%) compared to White patients (18%). Monitor complete blood cell counts on days 1 and 8 of every cycle and more frequently if clinically appropriate. Withhold therapy for absolute neutrophil count below 1,500/mm3 or neutropenic fever; a dose reduction or discontinuation of therapy may be necessary. Patients who have had previous myelosuppressive therapy such as chemotherapy or pelvic radiation therapy may be at risk of increased bone marrow suppression; therefore, this drug should be used only by clinicians experienced in chemotherapy. Patients with an active infection should be treated prior to receiving irinotecan liposome. Opportunistic infections, including fungal infection, may occur in some patients due to severe myelosuppression. Patients with a history of varicella-zoster, herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding.

Irinotecan liposome can cause severe and life-threatening diarrhea; do not administer irinotecan liposome to patients with GI obstruction. Similar to irinotecan HCl, irinotecan liposome can cause both early and late diarrhea. Early diarrhea (onset within 24 hours of chemotherapy) is accompanied by cholinergic symptoms including rhinitis, salivation, miosis, lacrimation, diaphoresis, flushing, and hyperperistalsis with possible abdominal cramping; atropine can be used to treat early diarrhea. Late diarrhea, which occurs more than 24 hours after the administration chemotherapy, can be life-threatening as it may be prolonged and lead to severe volume depletion, electrolyte imbalance, or sepsis; late diarrhea should be treated with loperamide. A patient may experience both acute and late onset diarrhea. Preexisting diarrhea or dehydration should be treated prior to receiving irinotecan liposome. A treatment delay may be necessary to allow for recovery from irinotecan-related diarrhea, and dosage reduction or discontinuation of therapy may be necessary if severe diarrhea develops. Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated or antibiotic therapy if they develop ileus, fever, or severe neutropenia.

ONIVYDE

Rx

Topoisomerase I inhibitor
Indicated, in combination with 5-FU and leucovorin, for metastatic pancreatic adenocarcinoma that has progressed after gemcitabine-based therapy
Black box warning for fatal neutropenic sepsis and severe diarrhea; most common adverse effects include diarrhea, fatigue/asthenia, vomiting, nausea, anorexia, stomatitis, fever, lymphopenia, and neutropenia

70 mg/m2 IV over 90 minutes, followed by leucovorin (LV) 400 mg/m2 IV over 30 minutes, followed by 5-FU 2,400 mg/m2 IV over 46 hours, every 2 weeks until disease progression or unacceptable toxicity. For patients homozygous for UGT1A1*28 allele, decrease the starting dose for irinotecan liposome to 50 mg/m2, and increase to 70 mg/m2 as tolerated in subsequent cycles. Patients with metastatic pancreatic adenocarcinoma and disease progression after gemcitabine-based therapy were randomized to receive irinotecan liposome plus 5-FU/LV (n = 117), irinotecan liposome monotherapy (100 mg/m2 IV every 3 weeks; n = 151), or 5-FU/LV alone (LV 200 mg/m2 IV, followed by 5-FU 2,000 mg/m2 IV over 24 hours weekly for 4 weeks, repeated every 6 weeks; n = 119) in an open-label clinical trial. The addition of irinotecan liposome to 5-FU/LV significantly improved overall survival (OS) compared with 5-FU/LV alone (6.1 vs. 4.2 months; HR 0.68; p = 0.014); an improvement in OS compared with 5-FU/LV was not evident with irinotecan liposome monotherapy (HR 1; p = 0.97). Progression-free survival (PFS) was 3.1 months in patients receiving irinotecan liposome plus 5-FU/LV compared with 1.5 months in those treated with 5-FU/LV alone (HR 0.55; 95% CI, 0.41 to 0.75), and the objective response rate was 7.7% vs. 0.8%.

Specific guidelines for dosage adjustments in hepatic impairment are not available as the pharmacokinetics of irinotecan liposome have not been studied in patients with hepatic impairment; however, irinotecan is subject to hepatic metabolism. There is no recommended dose for patients with serum bilirubin above the upper limit of normal.

Specific guidelines for dosage adjustments in renal impairment are not available. It appears that no dosage adjustments are needed for patients with mild to moderate renal impairment; however, insufficient data are available in patients with severe renal impairment (CrCl less than 30 mL/min).

Adagrasib: (Major) Avoid administration of adagrasib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A substrates. Adagrasib is a strong CYP3A inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Apalutamide: (Major) Avoid administration of apalutamide during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Atazanavir: (Major) Avoid administration of atazanavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if atazanavir is boosted with cobicistat. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Atazanavir is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38.
Atazanavir; Cobicistat: (Major) Avoid administration of atazanavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if atazanavir is boosted with cobicistat. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Atazanavir is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38. (Major) Avoid administration of cobicistat during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if cobicistat is boosted with atazanavir. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Cobicistat is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38.
Atracurium: (Moderate) Irinotecan may antagonize the neuromuscular blocking effects of atracurium due to anticholinesterase activity.
Carbamazepine: (Major) Avoid administration of carbamazepine during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Carbamazepine is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Ceritinib: (Major) Discontinue ceritinib at least 1 week prior to starting irinotecan therapy; do not administer ceritinib with irinotecan unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to both irinotecan and SN-38.
Chloramphenicol: (Major) Avoid administration of chloramphenicol during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; chloramphenicol is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cisatracurium: (Moderate) Irinotecan may antagonize the neuromuscular blocking effects of cisatracurium due to anticholinesterase activity.
Clarithromycin: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Cobicistat: (Major) Avoid administration of cobicistat during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if cobicistat is boosted with atazanavir. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Cobicistat is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38.
Darunavir: (Major) Avoid administration of darunavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Darunavir; Cobicistat: (Major) Avoid administration of cobicistat during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if cobicistat is boosted with atazanavir. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Cobicistat is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38. (Major) Avoid administration of darunavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid administration of cobicistat during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if cobicistat is boosted with atazanavir. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Cobicistat is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38. (Major) Avoid administration of darunavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Delavirdine: (Major) Avoid administration of delavirdine during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; delavirdine is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid administration of cobicistat during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if cobicistat is boosted with atazanavir. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Cobicistat is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid administration of cobicistat during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if cobicistat is boosted with atazanavir. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Cobicistat is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38.
Enzalutamide: (Major) Avoid administration of enzalutamide during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Enzalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Fosamprenavir: (Major) Avoid administration of fosamprenavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; fosamprenavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Fosphenytoin: (Major) Avoid administration of fosphenytoin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Fosphenytoin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Gemfibrozil: (Major) Avoid administration of gemfibrozil during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; gemfibrozil is a UGT1A1 inhibitor. Concomitant use of UGT1A1 inhibitors may increase systemic exposure to SN-38.
Glecaprevir; Pibrentasvir: (Major) Avoid administration of glecaprevir during treatment with irinotecan unless there are no therapeutic alternatives. Irinotecan is a P-glycoprotein (P-gp) substrate and its active metabolite, SN-38, is a UGT1A1 substrate. Glecaprevir is a P-gp and UGT1A1 inhibitor. Concomitant use may increase systemic exposure to irinotecan and SN-38. (Major) Avoid administration of pibrentasvir during treatment with irinotecan unless there are no therapeutic alternatives. Irinotecan is a P-glycoprotein (P-gp) substrate and its active metabolite, SN-38, is a UGT1A1 substrate. Pibrentasvir is a P-gp and UGT1A1 inhibitor. Concomitant use may increase systemic exposure to irinotecan and SN-38.
Grapefruit juice: (Major) Advise patients to avoid regular consumption of grapefruit or grapefruit juice during treatment with irinotecan and for at least 1 week prior to starting therapy. Irinotecan is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and its active metabolite, SN-38.
Idelalisib: (Major) Avoid administration of idelalisib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Idelalisib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Indinavir: (Major) Avoid administration of indinavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a UGT1A1 substrate. Indinavir is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and SN-38.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid administration of rifampin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Rifampin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Isoniazid, INH; Rifampin: (Major) Avoid administration of rifampin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Rifampin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Itraconazole: (Contraindicated) According to the manufacturer of itraconazole, the use of irinotecan is contraindicated for use during and for 2 weeks after discontinuation of itraconazole therapy. The manufacturer of irinotecan recommends that any strong CYP3A4 inhibitor be discontinued at least 1 week prior to starting irinotecan liposomal therapy. Itraconazole is a strong CYP3A4 inhibitor; irinotecan is metabolized extensively by CYP3A4 and UGT1A1. Exposure to irinotecan and to the active metabolite, SN-38, is increased when the drugs are used together, which can cause severe toxicity, including neutropenia and severe and life-threatening diarrhea.
Ketoconazole: (Major) Avoid administration of ketoconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ketoconazole is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Letermovir: (Moderate) An increase in the plasma concentration of irinotecan or its active metabolite, SN-38, may occur if given with letermovir. Do not administer this combination unless there are no alternative treatment options if the patient is also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. If possible, discontinue letermovir, cyclosporine, or both drugs at least 1 week prior to starting irinotecan. Irinotecan is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Levoketoconazole: (Major) Avoid administration of ketoconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ketoconazole is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Lonafarnib: (Major) Avoid administration of lonafarnib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; lonafarnib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Lopinavir; Ritonavir: (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Lumacaftor; Ivacaftor: (Major) Avoid administration of lumacaftor; ivacaftor during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Lumacaftor is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Mifepristone: (Major) Avoid administration of mifepristone during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Mifepristone is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Mitotane: (Major) Avoid administration of mitotane during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Mitotane is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Mivacurium: (Moderate) Irinotecan may antagonize the neuromuscular blocking effects of mivacurium due to anticholinesterase activity.
Nefazodone: (Major) Avoid administration of nefazodone during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Nefazodone is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Nelfinavir: (Major) Avoid administration of nelfinavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Nelfinavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Nirmatrelvir; Ritonavir: (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Pancuronium: (Moderate) Irinotecan may antagonize the neuromuscular blocking effects of pancuronium due to anticholinesterase activity.
Phenobarbital: (Major) Avoid administration of phenobarbital during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Phenobarbital is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid administration of phenobarbital during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Phenobarbital is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Phenytoin: (Major) Avoid administration of phenytoin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Phenytoin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Posaconazole: (Major) Avoid administration of posaconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Posaconazole is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Primidone: (Major) Avoid administration of primidone during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Primidone is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Prochlorperazine: (Minor) Monitor for an increased incidence of akathisia if prochlorperazine is administered with irinotecan. In clinical trials of patients receiving weekly irinotecan, 8.5% of patients who received prochlorperazine on the same day as irinotecan reported akathisia, compared with 1.3% of patients who received the drugs on separate days; however, this incidence is within the range reported when prochlorperazine is given as a premedication for other chemotherapies.
Ribociclib: (Major) Avoid administration of ribociclib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ribociclib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Ribociclib; Letrozole: (Major) Avoid administration of ribociclib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ribociclib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Rifampin: (Major) Avoid administration of rifampin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Rifampin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Rifapentine: (Major) Avoid administration of rifapentine during treatment with irinotecan and for at least two weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates and rifapentine is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Ritonavir: (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Rocuronium: (Moderate) Irinotecan may antagonize the neuromuscular blocking effects of rocuronium due to anticholinesterase activity.
Saquinavir: (Major) Avoid administration of saquinavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Saquinavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sorafenib: (Major) Avoid administration of sorafenib during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate. Sorafenib inhibits UGT1A1 in vitro and may increase the concentrations of concomitantly administered drugs that are UGT1A1 substrates.
St. John's Wort, Hypericum perforatum: (Major) Avoid administration of St. Johns Wort during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. St. Johns Wort is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Succinylcholine: (Moderate) Concomitant use of succinylcholine and irinotecan may prolong neuromuscular blockade. Irinotecan has anticholinesterase activity.
Tipranavir: (Major) Avoid administration of tipranavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Tipranavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Tucatinib: (Major) Avoid administration of tucatinib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Tucatinib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Vecuronium: (Moderate) Irinotecan may antagonize the neuromuscular blocking effects of vecuronium due to anticholinesterase activity.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Voriconazole: (Major) Avoid administration of voriconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Voriconazole is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.

Irinotecan, Liposomal/ONIVYDE Intravenous Inj Lipos: 1mL, 4.3mg

70 mg/m2 IV every 2 weeks.

70 mg/m2 IV every 2 weeks.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Irinotecan liposome is a topoisomerase I inhibitor, encapsulated in a lipid bilayer vesical (liposome). Topoisomerase I is a cellular enzyme involved in maintaining the topographic structure of DNA during translation, transcription, and mitosis; it relieves the torsional strain in the DNA helix during replication and RNA transcription by inducing single-strand breaks. By binding with the topoisomerase I / DNA complex, irinotecan and its active metabolite, SN-38, prevent the re-ligation of these single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. Mechanisms of resistance to irinotecan include decreased conversion of irinotecan to SN-38, point mutations of topoisomerase I, reduced topoisomerase I activity and decreased sensitivity of topoisomerase to topoisomerase inhibitors.

Irinotecan liposome is administered by intravenous infusion. Total irinotecan plasma protein binding is less than 0.44%. Direct measurement of irinotecan liposome showed that 95% of irinotecan remains liposome-encapsulated after administration, and the ratios between total and encapsulated forms did not change with time, up to 169.5 hours post-dose. The mean volume of distribution (Vd) for total irinotecan after administration of 70 mg/m2 to cancer patients (n = 23) was 4.1 +/- 1.5 liters, and the clearance was 0.2 +/- 0.17 L/h. The half-life  was 25.8 +/- 15.7 hours for total irinotecan and 67.8 +/- 44.5 hours for SN-38 (n = 13). The metabolism of irinotecan liposome has not been established in humans. However, after administration of irinotecan HCl, urinary excretion of irinotecan is 11 to 20%, SN-38 (active) is less than 1%, and SN-38 glucuronide (inactive) is 3%. The cumulative biliary and urinary excretion of irinotecan HCl in 2 patients was 25% (100 mg/m2) and 50% (300 mg/m2).
 
Affected cytochrome P450 (CYP) isoenzymes and other metabolic enzymes: CYP3A4 and UGT1A1
The metabolism of irinotecan liposome has not been evaluated. However, irinotecan is subject to extensive metabolic conversion; the active metabolite SN-38 is formed via esterases, while UGT1A1 mediates the glucuronidation of SN-38 to the inactive metabolite, SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive metabolites, one of which can be hydrolyzed by carboxylesterase to release SN-38. In vitro studies indicate that neither irinotecan, SN-38, nor another metabolite, aminopentane carboxylic acid (APC) inhibit CYP450 isoenzymes. In a population pharmacokinetic analysis adjusted for the lower dose of irinotecan administered to patients homozygous for the UGT1A1*28 allele, patients homozygous for this allele (n = 14) had a total SN-38 average steady-state concentration of 1.06 ng/mL, non-homozygous patients (n = 244) had a concentration of 0.95 ng/mL.

In a population pharmacokinetic analysis of cancer patients who received liposomal irinotecan 70 mg/m2, either as a single agent or as part of combination chemotherapy, the mean irinotecan Cmax was 37.2 +/- 8.8 mcg/mL (n = 25), while the mean Cmax of SN-38 was 5.4 +/- 3.4 ng/mL (n = 25); the mean AUC was 1,364 +/- 1,048 h x mcg/mL (n = 23) and 620 +/- 329 h x ng/mL (n = 13), respectively. Over the dose range of 50 to 155 mg/m2, the Cmax and AUC of total irinotecan, as well as the Cmax of total SN-38, increased with dose. However, the AUC of total SN-38 increased less than proportionally with dose. In mice bearing human tumor xenografts, irinotecan liposome administered at irinotecan HCl-equivalent doses 5-fold lower than irinotecan HCl achieved similar intratumoral exposure of SN-38.

Based on animal data with irinotecan HCl and its mechanism of action, irinotecan liposome can cause fetal harm when administered during pregnancy. There are no available data in pregnant women; however, irinotecan crosses the placenta of rats after intravenous administration. When administered to pregnant rats and rabbits during organogenesis, embryotoxicity and teratogenicity were observed at irinotecan HCl exposures lower than those achieved with liposomal irinotecan at the recommended dosing (0.002 to 0.0002 times the clinical exposure at the recommended dosing based on AUC). Fetal abnormalities included increased post-implantation loss, structural abnormalities, growth delays, and a variety of external, visceral, and skeletal abnormalities. Women who become pregnant while receiving irinotecan liposome should be apprised of the potential hazard to the fetus.

Counsel patients about the reproductive risk and contraception requirements during irinotecan liposome treatment. Irinotecan liposome can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for 7 months after the last dose of liposomal irinotecan. Because of the potential for male-mediated teratogenicity, males with female partners of reproductive potential should use condoms during treatment and for 4 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of treatment. Women who become pregnant while receiving liposomal irinotecan should be apprised of the potential hazard to the fetus. In addition, based on animal data, irinotecan liposome may cause atrophy of both male and female reproductive organs, resulting in impaired fertility or infertility.