Irinotecan liposomal is a topoisomerase I inhibitor. It is FDA approved for the first-line treatment of metastatic pancreatic cancer in combination with oxaliplatin, fluorouracil, and leucovorin; it is also approved in combination with fluorouracil and leucovorin for the treatment of metastatic pancreatic cancer that has progressed after gemcitabine-based therapy. It carries a black box warning for severe neutropenia resulting in fatal neutropenic sepsis and severe diarrhea.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
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 a corticosteroid and an antiemetic 30 minutes prior to each treatment.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
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.
-Discard any unused drug remaining in the vial.
-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 C (36 to 46 degrees F). Do not freeze.
Intravenous Infusion:
-Allow diluted solution to come to room temperature prior to administration.
-Infuse diluted solution by intravenous infusion over 90 minutes.
Fatigue (including asthenia) was reported in 56% to 62% (grade 3 or 4, 15% to 21%) of patients treated with liposomal irinotecan in combination with chemotherapy in clinical trials. Fever occurred in 11% to 23% of patients treated with liposomal irinotecan (grade 3 or 4, 0.8% to 2%).
Bone marrow suppression including severe or life-threatening neutropenia and fatal neutropenic sepsis and neutropenic fever have occurred in patients receiving liposomal irinotecan. In clinical trials, patients who received liposomal irinotecan in combination with fluorouracil and leucovorin with or without oxaliplatin reported anemia (91% to 97%; grade 3 or 4, 6% to 10%), lymphopenia (64% to 81%; grade 3 or 4, 11% to 27%), neutropenia (52% to 56%; grade 3 or 4, 20% to 26%), and thrombocytopenia (41% to 55%; grade 3 or 4, 1.7% to 2%); leukopenia also occurred in 62% of patients who received liposomal irinotecan with fluorouracil, leucovorin, and oxaliplatin (grade 3 or 4, 8%). The incidence of grade 3 or 4 neutropenia was higher in patients homozygous for the UGT1A1*28 allele who received liposomal irinotecan, oxaliplatin, fluorouracil, and leucovorin compared to those not homozygous for the UGT1A1*28 allele (23% vs. 13%). The incidence of neutropenic fever and grade 3 or 4 neutropenia was higher in Asian patients (30% to 55%) compared to White patients (18% to 26%) in patients who received liposomal irinotecan plus chemotherapy in clinical trials; neutropenic fever/sepsis (6% vs. 1%) and neutropenic sepsis (3% vs. 0.8%) were also more frequently reported in Asian patients compared to White patients. Monitor complete blood cell counts on days 1 and 8 of every cycle and more frequently if clinically appropriate. Withhold therapy for an absolute neutrophil count below 1,500/mm3 or neutropenic fever; a dose reduction or discontinuation of therapy may be necessary.
Diarrhea occurred in 59% to 72% (grade 3 or 4, 13% to 22%) of patients treated with liposomal irinotecan. Early diarrhea (onset within 24 hours of chemotherapy) is accompanied by cholinergic symptoms including rhinitis, hypersalivation, miosis, lacrimation, diaphoresis, flushing, bradycardia, and hyperperistalsis with abdominal pain/cramping. Abdominal pain occurred in 35% of pancreatic cancer patients treated with liposomal irinotecan plus oxaliplatin, fluorouracil, and leucovorin compared with 25% of those who received gemcitabine plus nab-paclitaxel in a randomized clinical trial (grade 3 or 4, 4.3% vs. 4.7%). Grade 1 or 2 cholinergic symptoms other than early diarrhea occurred in 4.5% of liposomal irinotecan patients in another randomized clinical trial; if not contraindicated, administer atropine 0.25 mg to 1 mg IV or subcutaneous for early diarrhea of any grade. Late diarrhea, which occurs more than 24 hours after the administration chemotherapy and can be life-threatening as it may be prolonged and lead to severe volume depletion, electrolyte imbalance, or sepsis. In one trial, early diarrhea occurred in 30% (grade 3 or 4, 3%) and late diarrhea in 43% (grade 3 or 4, 9%) of patients. Avoid dehydration which occurred in 8% to 11% of patients treated with liposomal irinotecan (grade 3 or 4, 3.2% to 4%); eat a low-fat diet and avoid lactose-containing products during treatment to avoid severe diarrhea. Follow local institutional guidelines if diarrhea does not improve within 48 hours, including the addition of diphenoxylate plus atropine or octreotide. An interruption of therapy or dose reduction may be necessary depending on the severity of diarrhea.
Nausea (51% to 59%; grade 3 or 4, 8% to 12%), vomiting (40% to 52%; grade 3 or 4, 7% to 11%), and stomatitis including oral ulceration (28% to 32%; grade 3 or 4, 3.8% to 4%) were reported in patients who received liposomal irinotecan plus chemotherapy in clinical trials. The incidence of nausea, vomiting, and stomatitis were increased by 26% (grade 3 or 4, 8%), 17% (grade 3 or 4, 4%), and 20% (grade 3 or 4, 3%), respectively, when liposomal irinotecan was added to fluorouracil and leucovorin compared to fluorouracil plus leucovorin alone in one of these trials.
Infusion-related reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of liposomal irinotecan administration, were reported in 3% of patients treated with liposomal irinotecan alone (n = 147) or liposomal irinotecan in combination with fluorouracil and leucovorin (n = 117) in a randomized, open-label clinical trial. Rash (11%; grade 3 or 4, 0.3%) and nail disorders (0.3%) were each reported in patients treated with liposomal irinotecan in combination with oxaliplatin, fluorouracil, and leucovorin. Severe hypersensitivity reactions, including anaphylactic and anaphylactoid reactions and angioedema, have been reported in postmarketing experience with liposomal irinotecan. Permanently discontinue irinotecan liposome in patients who experience a severe hypersensitivity reaction.
Infection was reported in 38% (grade 3 or 4, 17%) of patients treated with irinotecan liposome plus fluorouracil and leucovorin compared with 15% (grade 3 or 4, 10%) of those who received fluorouracil/leucovorin alone in a randomized, open-label trial; infections in the liposomal irinotecan group included sepsis (4%; grade 3 or 4, 3%), neutropenic fever/sepsis (grade 3 or 4, 3%), gastroenteritis (grade 3 or 4, 3%), and IV catheter-related infections (grade 3 or 4, 3%). Pneumonia (2.4% vs. 6%; grade 3 or 4, 1.6% vs. 4%), sepsis (1.6% vs. 6%; grade 3 or 4, 1.1% vs. 3.4%), and serious cases of COVID-19 (14%) were reported in pancreatic cancer patients who received liposomal irinotecan plus oxaliplatin, fluorouracil, and leucovorin.
Severe, life-threatening, or fatal interstitial lung disease or pneumonitis has been reported in patients treated with irinotecan HCl. Dyspnea occurred in 8% of patients treated with liposomal irinotecan in combination with oxaliplatin, fluorouracil, and leucovorin compared with 13% of those who received gemcitabine plus nab-paclitaxel in a randomized clinical trial (grade 3 or 4, 0.5% vs. 2.1%). In the event of acute onset of new or progressive, unexplained pulmonary symptoms or respiratory insufficiency such as dyspnea, cough, and fever, irinotecan liposome therapy should be interrupted pending diagnostic evaluation. If interstitial lung disease is diagnosed, irinotecan liposome therapy should be discontinued and appropriate treatment instituted as necessary.
Alopecia occurred in 14% of pancreatic cancer patients receiving liposomal irinotecan plus fluorouracil and leucovorin, with or without oxaliplatin, in randomized clinical trials (grade 3 or 4, 1% or less).
Elevated hepatic enzymes have been reported in patients with pancreatic cancer treated with liposomal irinotecan in combination with fluorouracil and leucovorin, with or without oxaliplatin, including increased ALT (40% to 51%; grade 3 or 4, 2.6% to 6%), increased AST (38% or less; grade 3 or 4, 2% or less), and increased alkaline phosphatase (45% or less; grade 3 or 4, 2.9% or less); hypoalbuminemia occurred in 43% of patients in the liposomal irinotecan arm (grade 3 or 4, 2%) in one clinical trial.
Hypokalemia (32% to 62%; grade 3 or 4, 2% vs. 22%) and hyponatremia (11% to 27%; grade 3 or 4, 5% or less) occurred in pancreatic cancer patients treated with liposomal irinotecan, fluorouracil, and leucovorin, with or without oxaliplatin, in clinical trials. Hypomagnesemia (35% vs. 21%), hypocalcemia (32% vs. 20%; grade 3 or 4, 1% vs. 0%), hypokalemia (32% vs. 19%; grade 3 or 4, 2% vs. 2%), hypophosphatemia (29% vs. 18%; grade 3 or 4, 4% vs. 1%), and hyponatremia (27% vs. 12%; grade 3 or 4, 5% vs. 3%) occurred more often in patients receiving liposomal irinotecan plus fluorouracil and leucovorin compared with fluorouracil and leucovorin alone in a randomized, open-label clinical trial.
Grade 1 or 2 increases in creatinine were reported with a higher incidence in patients treated with irinotecan liposome plus fluorouracil and leucovorin compared with fluorouracil and leucovorin alone in a randomized, open-label clinical trial (18% vs. 13%). Additionally, acute renal failure (unspecified) occurred in 2% of patients who received irinotecan liposome or more in this trial.
Decreased appetite/anorexia (37% to 44%; grade 3 or 4, 4% to 9%) and weight loss (17% to 22%; grade 3 or 4, 2% to 3%) were reported in patients who received liposomal irinotecan in combination with chemotherapy in clinical trials.
GI obstruction or stenosis occurred in 3.5% of patients treated with liposomal irinotecan in combination with oxaliplatin, fluorouracil, and leucovorin. Do not administer liposomal irinotecan to patients with GI obstruction.
Thromboembolism occurred in 11% of pancreatic cancer patients receiving liposomal irinotecan in combination with oxaliplatin, fluorouracil, and leucovorin in a randomized clinical trial (grade 3 or 4, 7%); stroke occurred in 2.7% of patients who received liposomal irinotecan.
Bone marrow suppression including severe or life-threatening neutropenia and fatal neutropenic sepsis and neutropenic fever have occurred in patients receiving liposomal irinotecan in combination with chemotherapy. The incidence of neutropenic fever and grade 3 or 4 neutropenia was higher in Asian patients compared to White patients in clinical trials. Monitor complete blood cell counts on days 1 and 8 of every cycle and more frequently if clinically appropriate. Withhold therapy for an absolute neutrophil count below 1,500/mm3 or neutropenic fever; a dose reduction or discontinuation of therapy may be necessary.
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. Maintain hydration, eat a low-fat diet, and avoid lactose-containing products during treatment to avoid severe diarrhea. Early diarrhea (onset within 24 hours of chemotherapy) is accompanied by cholinergic symptoms including rhinitis, salivation, miosis, lacrimation, diaphoresis, flushing, bradycardia, and hyperperistalsis with abdominal cramping; if not contraindicated, administer atropine 0.25 mg to 1 mg IV or subcutaneous for early diarrhea of any grade. 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; begin treatment with loperamide for late diarrhea of any grade. Follow local institutional guidelines if diarrhea does not improve within 48 hours, including the addition of diphenoxylate plus atropine or octreotide. An interruption of therapy or dose reduction may be necessary depending on the severity of diarrhea.
Severe, life-threatening, or fatal interstitial lung disease or pneumonitis has been reported in patients treated with irinotecan HCl. Closely monitor patients with risk factors including pre-existing chronic lung disease (CLD), the use of pneumotoxic medications or colony stimulating factors, or prior chest radiation therapy. In the event of acute onset of new or progressive, unexplained pulmonary symptoms or respiratory insufficiency such as dyspnea, cough, and fever, irinotecan liposome therapy should be interrupted pending diagnostic evaluation. If interstitial lung disease is diagnosed, irinotecan liposome therapy should be discontinued and appropriate treatment instituted as necessary.
Administration of irinotecan liposome carries a risk of serious hypersensitivity reactions or anaphylaxis, including infusion-related reactions. Permanently discontinue irinotecan liposome in patients who experience a severe hypersensitivity reaction.
The irinotecan liposomal label contains a warning to ensure correct formulation selection for the patient. Practitioners must not prescribe or substitute irinotecan in place of irinotecan liposomal.
Pregnancy should be avoided by females of reproductive potential during liposomal irinotecan treatment and for 7 months after the last dose. Although there are no adequately controlled studies in pregnant women, liposomal irinotecan can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Irinotecan HCl 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 are pregnant or who become pregnant while receiving liposomal irinotecan 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.
It is not known whether irinotecan liposome is present in human milk; however, many drugs are excreted in human milk. Due to the potential for serious adverse reactions in nursing infants from liposomal irinotecan, advise women to discontinue breast-feeding during treatment and for 1 month after the final dose.
For the treatment of pancreatic cancer:
NOTE: The FDA has designated irinotecan liposome as an orphan drug for the treatment of pancreatic cancer.
-for the first-line treatment of metastatic pancreatic cancer, in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX):
Intravenous dosage:
Adults: 50 mg/m2 IV on day 1, followed by oxaliplatin 60 mg/m2 IV, leucovorin 400 mg/m2 IV and then fluorouracil 2,400 mg/m2 continuous IV infusion over 46 hours, every 2 weeks until disease progression or unacceptable toxicity (NALIRIFOX). Administer liposomal irinotecan prior to oxaliplatin, leucovorin, and fluorouracil. Do not substitute liposomal irinotecan with irinotecan HCl. Patients homozygous for UGT1A1*28 allele should initiate therapy at the same dose, without a dose reduction. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. First-line treatment with NALIRIFOX significantly improved overall survival (11.1 months vs. 9.2 months) and progression-free survival (7.4 months vs. 5.6 months) compared with gemcitabine plus nab-paclitaxel in patients with metastatic pancreatic adenocarcinoma in a multicenter, randomized, open-label phase 3 clinical trial (NAPOLI-3); the objective response rate was 41.8% vs. 36.2%.
-for the treatment of metastatic pancreatic cancer in patients with disease progression after gemcitabine-based therapy, in combination with fluorouracil and leucovorin:
Intravenous dosage:
Adults: 70 mg/m2 IV on day 1, followed by leucovorin 400 mg/m2 IV and then fluorouracil 2,400 mg/m2 continuous IV infusion over 46 hours, every 2 weeks until disease progression or unacceptable toxicity. Do not substitute liposomal irinotecan with irinotecan HCl. 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with liposomal irinotecan, leucovorin, and fluorouracil significantly improved overall survival (6.2 months vs. 4.2 months) and progression-free survival (3.1 months vs. 1.5 months) compared with leucovorin and fluorouracil alone in patients with metastatic pancreatic adenocarcinoma in a multicenter, randomized, open-label phase 3 clinical trial (NAPOLI-1); the objective response rate was 7.7% vs. 0.8%.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Anaphylaxis
-Discontinue liposomal irinotecan.
Diarrhea
-Early onset, any grade (within 24 hours of chemotherapy): Unless clinically contraindicated, administer subcutaneous or intravenous atropine 0.25 mg to 1 mg.
-Late onset, any grade (more than 24 hours after chemotherapy): Administer supportive treatment with loperamide.
-Grade 2: Hold liposomal irinotecan. Administer atropine or loperamide as appropriate. Follow local institutional guidelines if diarrhea does not improve within 48 hours, including the addition of diphenoxylate plus atropine or octreotide. When diarrhea resolves to grade 1 or less, resume therapy.
-Grade 3 or 4: Hold liposomal irinotecan. Administer atropine or loperamide as appropriate. Follow local institutional guidelines if diarrhea does not improve within 48 hours, including the addition of diphenoxylate plus atropine or octreotide. When diarrhea resolves to grade 1 or less, resume therapy at a reduced dose according to instructions for grade 3 or 4 adverse reactions.
Hematologic Toxicity
-ANC less than 1,500 cells/mm3 or neutropenic fever: Hold liposomal irinotecan therapy. Therapy may be resumed for patients receiving therapy with liposomal irinotecan, fluorouracil, and leucovorin when the ANC recovers to 1,500 cells/mm3 or greater; delay resuming therapy until the ANC recovers to 2,000 cells/mm3 or greater for patients receiving therapy with oxaliplatin, liposomal irinotecan, fluorouracil, and leucovorin.
-Grade 3 or 4 neutropenia: Hold liposomal irinotecan therapy. For patients receiving therapy with liposomal irinotecan, fluorouracil, and leucovorin, resume therapy at a reduced dose according to instructions for grade 3 or 4 adverse reactions when the ANC recovers to 1,500 cells/mm3; delay resuming therapy until the ANC recovers to 2,000 cells/mm3 or greater for patients receiving therapy with oxaliplatin, liposomal irinotecan, fluorouracil, and leucovorin.
-Grade 3 or 4 thrombocytopenia: For patients receiving therapy with oxaliplatin, liposomal irinotecan, fluorouracil, and leucovorin, hold liposomal irinotecan therapy. When the platelet count is 100,000 cells/mm3 or higher, resume treatment at a reduced dose according to instructions for grade 3 or 4 adverse reactions.
Interstitial Lung Disease
-Discontinue liposomal irinotecan.
In combination with oxaliplatin, fluorouracil, and leucovorin:
Cardiac Toxicity
-Grade 2 or higher: Discontinue liposomal irinotecan.
Nausea/Vomiting
-Grade 3 or 4: Only reduce the dose of liposomal irinotecan if grade 3 or higher nausea or vomiting occurs despite optimal antiemetic therapy. If a dose reduction is necessary, refer to instructions for grade 3 or 4 adverse reactions.
Neurocerebellar Toxicity
-Discontinue liposomal irinotecan.
Palmar-Plantar Erythrodysesthesia (Hand and Foot Syndrome)
-Grade 3 or 4: Discontinue liposomal irinotecan.
Other Adverse Reactions (excluding asthenia, alopecia, and grade 3 anorexia)
-Grade 3 or 4: Hold liposomal irinotecan therapy. When the toxicity resolves to grade 1 or less, resume treatment at a reduced dose. For the first occurrence, reduce the dose of liposomal irinotecan to 40 mg/m2 and reduce the doses of oxaliplatin and fluorouracil to 80% of the original dose. For the second occurrence, reduce the dose of liposomal irinotecan to 32.5 mg/m2 and reduce the doses of oxaliplatin and fluorouracil to 65% of the original dose. For the third occurrence, reduce the dose of liposomal irinotecan to 25 mg/m2 and reduce the doses of oxaliplatin and fluorouracil to 50% of the original dose. Do not reduce the dose of leucovorin. Oxaliplatin may be discontinued if not well-tolerated and treatment may continue with liposomal irinotecan, fluorouracil, and leucovorin. Discontinue liposomal irinotecan after the fourth occurrence of a grade 3 or 4 adverse reaction.
In combination with fluorouracil and leucovorin:
Other Adverse Reactions
-Grade 3 or 4: Hold liposomal irinotecan therapy. When the toxicity resolves to grade 1 or less, resume treatment at a reduced dose. For the first occurrence, reduce the dose of liposomal irinotecan to 50 mg/m2 for patients with a starting dose of 70 mg/m2, and to 43 mg/m2 for patients with a starting dose of 50 mg/m2. For the second occurrence, reduce the dose of liposomal irinotecan to 43 mg/m2 for patients with a starting dose of 70 mg/m2, and to 35 mg/m2 for patients with a starting dose of 50 mg/m2. Discontinue liposomal irinotecan after the third occurrence of a grade 3 or 4 adverse reaction. Refer to fluorouracil prescribing information for fluorouracil-related dose reductions.
Maximum Dosage Limits:
-Adults
70 mg/m2 IV every 2 weeks.
-Geriatric
70 mg/m2 IV every 2 weeks.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available. It appears that no dosage adjustments are needed for patients with mild hepatic impairment (based on NCI score); however, insufficient data are available in patients with moderate to severe hepatic impairment. There is no recommended dose for patients with serum bilirubin above the upper limit of normal.
Patients with Renal Impairment Dosing
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).
*non-FDA-approved indication
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.
Capivasertib: (Major) Avoid administration of capivasertib 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 UGT1A1 substrates; capivasertib is a UGT1A1 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
Encorafenib: (Major) Avoid administration of encorafenib 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 CYP3A substrates and encorafenib is a strong CYP3A inducer. Coadministration with other strong CYP3A 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 CYP3A inducers has not been defined.
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.
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.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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 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 by inducing single-strand breaks. By reversibly 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. In mice bearing human tumor xenografts, liposomal irinotecan achieved similar intratumoral exposure of SN-38 compared to irinotecan HCl at irinotecan HCl-equivalent doses 5 times lower.
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 170 hours post-dose. The geometric mean volume of distribution (Vd) for total irinotecan and total SN-38 after administration of liposomal irinotecan 50 mg/m2 was 3.63 liters (CV, 33.5%) and 3.46 liters (CV, 35.5%), respectively; after a dose of 70 mg/m2, the Vd was 4.23 liters (CV, 28.1%) and 4.06 liters (29.4%), respectively. The irinotecan half life ranges from 1.87 to 1.93 days (CV, 14% to 26.4%). 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 caboxylesterases, 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.
-Route-Specific Pharmacokinetics
Intravenous Route
Liposomal irinotecan concentrations were proportional to dose over a range of 35 mg/m2 to 155 mg/m2. The geometric mean Cmax of total irinotecan and total SN-38 were 25mg mcg/mL (CV, 18.5%) and 2.09 ng/mL (CV, 42.1%), respectively, after a liposomal irinotecan dose of 50 mg/m2; the geometric mean AUC of total irinotecan and total SN-38 were 37.5 days*mcg/mL (CV, 73%) and 12.1 days*ng/mL (CV, 46.6%), respectively. After a liposomal irinotecan dose of 70 mg/m2 the geometric mean Cmax of total irinotecan and total SN-38 were 30.8 mcg/mL (CV, 19.7%) and 2.64 ng/mL (CV, 64.5%), respectively; the geometric mean AUC was 50.4 days*mcg/mL (CV, 75.3%) and 14.7 days*ng/mL (CV, 58%), respectively.
-Special Populations
Hepatic Impairment
Patients with mild hepatic impairment (based on NCI score) had comparable irinotecan and SN-38 exposure to patients with normal hepatic function. There was insufficient data to assess the effect of moderate and severe hepatic impairment on irinotecan and SN-38 exposure. Increased AST/ALT had no effect on the clearance of irinotecan, but increased bilirubin was associated with a lower clearance of SN-38. SN-38 exposure was also 32% higher in patients with a bilirubin of 1.14 mg/dL compared to those with a median bilirubin of 0.44 mg/dL; no data are available in patients with bilirubin greater than 2.8 mg/dL.
Renal Impairment
Patients with mild to moderate renal impairment (CrCl 30 mL/min or higher) had comparable irinotecan and SN-38 exposure to patients with normal renal function after adjusting for BSA. There was insufficient data to assess the effect of severe renal impairment (CrCl less than 30 mL/min) on irinotecan and SN-38 exposure.
Geriatric
In a population pharmacokinetic analysis, age (20 to 87 years) did not have a clinically meaningful effect on irinotecan or SN-38 exposure.
Gender Differences
Exposure to irinotecan and SN-38 was 28% and 32% higher, respectively, in female patients than in male patients.
Ethnic Differences
Irinotecan exposure was 32% lower in Asian patients than in non-Asian patients.
Obesity
Body surface area (1.15 m2 to 2.88 m2) did not have a clinically meaningful effect on irinotecan or SN-38 exposure.
Other
UGT1A1*28 7/7 homozygous status had no effect on SN-38 clearance compared with patients not homozygous for UGT1A1*28 7/7.