Irinotecan is an intravenous antineoplastic agent. Irinotecan is one of many water-soluble derivatives of camptothecin (CPT), a cytotoxic plant alkaloid isolated from the Chinese tree Camptotheca acuminata. The activity of irinotecan is due to the parent compound and the more potent active metabolite, SN-38. Irinotecan is approved by the FDA for the treatment of metastatic colorectal cancer, both as monotherapy and in combination with 5-fluorouracil and leucovorin, along with several off-label indications. Irinotecan can cause severe myelosuppression and may necessitate interruptions of therapy or dose adjustments; complete blood counts should be monitored throughout treatment. Additionally, severe diarrhea is common with irinotecan therapy. Early diarrhea, within the first 24 hours of treatment, may be associated with cholinergic effects and should be treated with atropine. Loperamide should be initiated for the first signs of loose stool or diarrhea occurring more than 24 hours after administration of irinotecan; late diarrhea may also require an interruption of therapy or dose adjustment.
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 routine antiemetic prophylaxis prior to treatment.
Extravasation Risk
-Irritant
Route-Specific Administration
Oral Administration
Extemporaneous Compounding-Oral
-At least 30 minutes prior to oral irinotecan, administer antiemetic agents.
-Consider prophylactic or therapeutic atropine for patients experiencing cholinergic symptoms.
-Consider therapeutic loperamide for late onset irinotecan induced diarrhea.
-Consider prophylactic oral cephalosporin (e.g., cefixime, cefdinir, or cefpodoxime) starting up to 5 days before chemotherapy administration and continuing throughout irinotecan therapy for drug-induced diarrhea.
Extemporaneous compounding instructions for irinotecan solution (20 mg/mL):
NOTE: The extemporaneous preparation of irinotecan is not approved by the FDA.
-Obtain injectable formulation of irinotecan (20 mg/mL).
-Draw up appropriate volume of irinotecan solution (20 mg/mL) into plastic oral syringe.
-Oral syringes with undiluted irinotecan may be stored in refrigerator for up to 21 days.
-Mix irinotecan with cranberry based juice immediately prior to administration to mask bitter flavor.
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-At least 30 minutes prior to irinotecan infusion, administer antiemetic agents.
-Consider prophylactic or therapeutic atropine for patients experiencing cholinergic symptoms.
-Consider therapeutic loperamide for late onset irinotecan induced diarrhea.
-Consider prophylactic oral cephalosporin (e.g., cefixime, cefdinir, or cefpodoxime) starting up to 5 days before chemotherapy administration and continuing throughout the course of irinotecan for irinotecan induced diarrhea.
Dilution:
NOTE: storage and stability may depend on manufacturer and/or diluent used.
-Dilute the appropriate dose of irinotecan in 5% Dextrose Injection (preferred) or 0.9% Sodium Chloride Injection, to a final concentration of 0.12 mg/mL to 2.8 mg/mL. Discard any irinotecan remaining in the single-use vial.
-Do not add other drugs to the final admixture.
-Protect from light.
-Storage following dilution: The diluted solution (if prepared with 5% Dextrose Injection) may be refrigerated for up to 24 hours at 2 to 8 degrees Celsius if immediate administration is not possible.
Intravenous Administration:
-Administer as soon as possible after preparation.
-Infuse intravenously over 90 minutes. Some protocols may allow for infusion over 60 minutes.
Asthenia was reported in 57.9% to 76% (grade 3 or 4, 9% to 19.5%) of patients with metastatic colorectal cancer treated with irinotecan (monotherapy or in combination with fluorouracil/leucovorin) in clinical trials. Pain (unspecified) was generally reported in 22.9% to 30.7% (grade 3 or 4, 2% to 3.1%) of these patients. In one randomized clinical trial, 64.1% (grade 3 or 4, 9.7%) of patients with metastatic colorectal cancer receiving irinotecan plus infusional fluorouracil/leucovorin reported pain; however, this was similar to the incidence in patients receiving infusional fluorouracil/leucovorin without irinotecan (61.5%; grade 3 or 4, 8.4%). Grade 3 or 4 pain was also reported in 17% to 19% of patients with metastatic colorectal cancer receiving second-line irinotecan monotherapy for metastatic colorectal cancer in 2 open-label clinical trials, which was similar to the incidence in patients receiving best supportive care (22%) or fluorouracil (13%). Headache (17%; grade 3 or 4, 1%) and back pain (14%; grade 3 or 4, 2%) were additionally reported in patients receiving weekly irinotecan monotherapy as second-line therapy for metastatic colorectal cancer in an open-label, noncomparative trial. Transient dysarthria has been reported in patients treated with irinotecan in postmarketing experience; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.
Vasodilation/flushing was reported in 9% to 11% (grade 3 or 4, 0.9% or less) of patients treated with irinotecan in clinical trials while hypotension occurred in 3.4% to 5.8% (grade 3 or 4, 1.3% to 1.7%) of patients.
Dizziness (15% to 23.1%; grade 3 or 4, 1.8% or less), insomnia (grade 1 or 2, 19%), somnolence/drowsiness (9.4% to 12.4%; grade 3 or 4, 1.3% to 1.8%), and confusion (2.7% to 7.1%; grade 3 or 4, 1.8% or less) have been reported with irinotecan therapy (monotherapy or in combination with fluorouracil/leucovorin. Another clinical trial of patients with metastatic colorectal cancer reported grade 3 or 4 neurologic events such as somnolence in 9% to 12% of patients treated with irinotecan monotherapy; grade 3 or 4 syncope and vertigo were also reported in patients receiving irinotecan.
Bacterial, viral, and fungal infections have occurred in patients treated with irinotecan. In clinical trials, infection was reported in 13.9% to 35.9% (grade 3 or 4, 8% or less) of patients with metastatic colorectal cancer treated with irinotecan and fever was reported in 22.1% to 45% (grade 3 or 4, 0.4% to 2%) of patients. Severe (grade 3 or 4) infection (23.8%) was also reported in a phase 2 trial of pediatric patients receiving first-line irinotecan monotherapy for rhabdomyosarcoma followed by multimodal therapy (n = 21). In a randomized clinical trial of patients receiving first-line therapy for metastatic colorectal cancer, pneumonia occurred in 6.2% (grade 3 or 4, 2.7%) of patients receiving weekly irinotecan plus bolus fluorouracil/leucovorin and in 3.6% (grade 3 or 4, 1.3%) of patients receiving weekly irinotecan monotherapy. Chills (grade 1 or 2, 14%) and rhinitis (grade 1 or 2, 16%) were also reported in patients receiving second-line irinotecan monotherapy for metastatic colorectal cancer in an open-label, noncomparative trial.
Interstitial lung disease (ILD)-like or pneumonitis-like events, including fatalities, have occurred in patients receiving treatment with irinotecan. In Japanese studies, a reticulonodular pattern on chest x-ray was observed in a small percentage of patients. Symptoms of pneumonitis include new or progressive dyspnea, cough, or fever; if these symptoms occur, interrupt irinotecan therapy pending evaluation. Discontinue irinotecan for confirmed ILD and begin appropriate treatment. Cough has been reported in 17% to 26.7% (grade 3 or 4, 1.3% or less) and dyspnea in 9.7% to 27.6% (grade 3 or 4, 1.4% to 6.3%) with irinotecan treatment (monotherapy and in combination with chemotherapy). Grade 3 or 4 respiratory adverse reactions including dyspnea and cough were also reported in 5% to 10% of patients with metastatic colorectal cancer receiving second-line monotherapy with irinotecan every 3 weeks.
Irinotecan can cause severe bone marrow suppression; deaths due to sepsis following severe neutropenia have been reported. When administered as first-line therapy for metastatic colorectal cancer, the incidence of severe neutropenia was greater when irinotecan was administered in combination with bolus or infusional fluorouracil compared to irinotecan monotherapy (82.5% to 96.9% vs. 96.4%; grade 3 or 4, 46.2% to 53.8% vs. 31.4%). Neutropenia was less common with irinotecan monotherapy as second-line therapy for metastatic colorectal cancer (54% or less; grade 3 or 4, 14% to 26%). The risk of grade 3 or 4 neutropenia was higher in patients who treated with weekly irinotecan and had received previous pelvic/abdominal radiation therapy compared to those who had not (48% vs. 24%). Patients with baseline total bilirubin levels of 1 mg/dL or more also had an increased risk of first-cycle grade 3 or 4 neutropenia compared to patients with baseline bilirubin less than 1 mg/dL (50% vs. 18%). Patients who are homozygous for the UGT1A1*28 allele also have an increased risk of grade 4 neutropenia. In one study (n = 66), patients who received irinotecan monotherapy (350 mg/m2 every 3 weeks), grade 4 neutropenia occurred in 50% of patients homozygous for the UGT1A1*28 allele and in 12.5% of patients heterozygous for this allele (UGT1A1 6/7 genotype); no grade 4 neutropenia occurred in patients homozygous for the wild-type allele (UGT1A1 6/6 genotype). In another study (n = 250), the incidence of grade 4 neutropenia in patients treated with irinotecan (180 mg/m2) in combination with infusional fluorouracil/leucovorin who were homozygous for the UGT1A1*28 allele was 4.5%, and in patients heterozygous for this allele the incidence was 5.3%; grade 4 neutropenia occurred in 1.8% of patients homozygous for the wild-type allele. In a third study (n = 109), the incidence of grade 4 neutropenia in patients who were treated with irinotecan (100 mg/m2 to 125 mg/m2) in combination with bolus fluorouracil/leucovorin and were homozygous for the UGT1A1*28 allele was 18.2%, and in patients heterozygous for this allele the incidence was 11.1%; grade 4 neutropenia occurred in 6.8% of patients homozygous for the wild-type allele. Febrile neutropenia occurred in 2% to 7.1% of patients treated with irinotecan across clinical trials, while neutropenic infection was reported in 1% to 2.2% of patients. Severe (grade 3 or 4) neutropenia (31.8%) and febrile neutropenia (8.8%) were reported in a phase 2 trial of pediatric patients receiving irinotecan monotherapy every 3 weeks for refractory solid tumors (n = 170), which is comparable to adults.
Additional hematologic adverse reactions in patients receiving weekly irinotecan as monotherapy or in combination with bolus fluorouracil/leucovorin as first-line therapy for metastatic colorectal cancer included leukopenia (96.4% to 96.9%; grade 3 or 4, 21.5% to 37.8%), anemia (96.9%; grade 3 or 4, 4.5% to 8.4%), and thrombocytopenia (96%; grade 3 or 4, 1.7% to 2.6%). The incidence of leukopenia (81.3%; grade 3 or 4, 17.4%) and anemia (97.2%; grade 3 or 4, 2.1%) were similar for first-line treatment of colorectal cancer with irinotecan and infusional fluorouracil every 2 weeks; however, the incidence of thrombocytopenia was lower in combination with infusional fluorouracil every 2 weeks (grade 1 or 2, 32.6%). Hematologic adverse reactions were less common in general with irinotecan monotherapy as second-line therapy for metastatic colorectal cancer, including leukopenia (63% or less; grade 3 or 4, 28% or less), anemia (60% or less; grade 3 or 4, 6% to 7%), and thrombocytopenia (grade 3 or 4, 4% or less).
Grade 3 or 4 hemorrhage (bleeding) was reported in 1% to 5% of patients treated with second-line irinotecan monotherapy, administered every 3 weeks for the treatment of metastatic colorectal cancer.
Diarrhea occurs commonly with irinotecan therapy. It is proposed that the irinotecan metabolite, SN-38, is responsible for late diarrhea because of biliary elimination of SN-38 and the gastrointestinal metabolism of irinotecan by carboxylesterase. Early diarrhea is dose related and occurs during or shortly after irinotecan administration (within 24 hours). It is usually transient, is not frequently severe, and may be accompanied by cholinergic symptoms (e.g., bradycardia, rhinitis, hypersalivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping). Overall, early diarrhea or cholinergic syndrome occurred in 28.3% to 51% (grade 3 or 4, 1.4% to 8%) of patients treated with irinotecan monotherapy or in combination with fluorouracil, independent of schedule. It was reported in 43% to 51% (grade 3 or 4, 4.9% to 8%) of patients receiving weekly irinotecan as monotherapy or in combination with fluorouracil/leucovorin for metastatic colorectal cancer in 3 randomized clinical trials. Cholinergic syndrome occurring during or shortly after infusion of irinotecan including rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea was reported in 28.3% (grade 3 or 4, 1.4%) of patients receiving irinotecan in combination with fluorouracil/leucovorin every 2 weeks in another clinical trial. Consider prophylactic or therapeutic administration of atropine (0.25 mg to 1 mg IV or subcutaneously) unless clinically contraindicated. Late diarrhea, occurring more than 24 hours after irinotecan administration, can be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis and may be life-threatening. Late diarrhea was reported in 72.4% to 88% (grade 3 or 4, 14.4% to 31%) of patients receiving irinotecan monotherapy or in combination with fluorouracil/leucovorin in clinical trials, independent of schedule. Patients older than 65 years of age have a higher incidence of grade 3 or 4 late diarrhea compared to younger patients (28.6% to 40% vs. 23% to 23.9%). Grade 3 or 4 diarrhea occurred in 22% of patients receiving irinotecan monotherapy every 3 weeks for recurrent metastatic colorectal cancer; early versus late diarrhea was not specified. The median time to onset of late diarrhea was 5 days with every-3-week dosing and 11 days with weekly administration. Complications of late diarrhea include colitis, ulceration, GI bleeding, ileus, GI obstruction, and infection; cases of toxic megacolon and GI perforation have been reported. Late diarrhea can be life-threatening and should be treated promptly with loperamide. Monitor patients and give fluids and electrolytes as needed. Begin antibiotic therapy for patients with ileus, fever, or severe neutropenia. An interruption of therapy or dose reduction may be necessary for severe diarrhea.
Nausea (66.9% to 86%; grade 3 or 4, 2.1% to 17%) and vomiting (44.8% to 67%; grade 3 or 4, 3.5% to 14%) are commonly reported with irinotecan therapy in clinical trials. Anorexia (34.2% to 55%; grade 3 or 4, 2.1% to 7.2%) and constipation (30% to 41.3%; grade 3 or 4, 0.4% to 10%) were also reported across irinotecan clinical trials. Mucositis/oral ulceration was reported in 29.6% to 40% (grade 3 or 4, 2.2% to 4.1%) of patients receiving irinotecan (monotherapy or in combination with fluorouracil/leucovorin as first-line therapy for metastatic colorectal cancer; stomatitis occurred in 12% (grade 3 or 4, 1% to 2%) of patients receiving irinotecan monotherapy as second-line therapy for metastatic colorectal cancer. Abdominal pain was reported in 57% to 67.6% (grade 3 or 4, 9% to 16%) of patients with metastatic colorectal cancer receiving weekly irinotecan (monotherapy or in combination with bolus fluorouracil/leucovorin); in patients receiving irinotecan plus infusional fluorouracil/leucovorin every 2 weeks, abdominal pain was reported in 17.2% (grade 3 or 4, 2.1%) of patients with metastatic colorectal cancer. Mild flatulence (grade 1 or 2, 12%) and dyspepsia (grade 1 or 2, 10%) were also reported in patients with metastatic colorectal cancer receiving second-line therapy with weekly irinotecan monotherapy.
Symptomatic pancreatitis and asymptomatic elevations in pancreatic enzymes (e.g., hyperamylasemia, increased lipase) have been reported in postmarketing experience with irinotecan therapy.
Renal impairment and acute renal failure (unspecified) have been identified in patients treated with irinotecan, usually in patients with severe vomiting and/or diarrhea who developed hypovolemia. Dehydration was reported in 15% (grade 3 or 4, 4%) of patients with metastatic colorectal cancer treated with weekly irinotecan monotherapy in one clinical trial. Severe (grade 3 or 4) dehydration (28.6%) was also reported in a phase 2 trial of pediatric patients receiving first-line irinotecan monotherapy for rhabdomyosarcoma followed by multimodal therapy (n = 21).
Severe (grade 3 or 4) hypokalemia (23.8%) and hyponatremia (14.3%) were reported in a phase 2 trial of pediatric patients receiving first-line irinotecan monotherapy for rhabdomyosarcoma followed by multimodal therapy (n = 21). Hyponatremia has also been reported in postmarketing experience with irinotecan in adult patients, mostly in association with diarrhea and vomiting.
Thromboembolic events (thromboembolism) including angina, arterial thrombosis, cerebral infarct, cerebrovascular accident (stroke), lower extremity thromboembolism, cardiac arrest, myocardial infarction, myocardial ischemia, peripheral vascular disorder, pulmonary embolism, sudden death, thrombo-phlebitis, thrombosis, and vascular disorder were reported in 5.4% to 11.7% of patients receiving first-line therapy with irinotecan (monotherapy or in combination with fluorouracil/leucovorin) for metastatic colorectal cancer in 2 randomized clinical trials. Grade 3 or 4 cardiovascular events including dysrhythmias, ischemia, and mechanical cardiac dysfunction were also reported in 4% to 9% of patients receiving irinotecan monotherapy as second-line therapy for metastatic colorectal cancer. Myocardial ischemic events and thromboembolic events have also been reported in postmarketing experience with irinotecan.
Hyperbilirubinemia was reported in 83.9% to 87.6% (grade 3 or 4, 7.1% to 7.2%) of patients with metastatic colorectal cancer receiving first-line therapy with weekly irinotecan (monotherapy or in combination with bolus fluorouracil/leucovorin) in a randomized clinical trial; the primary tumor was in the colon in 81% to 84% (primary rectum, 15% to 17%). The incidence of hyperbilirubinemia was much lower in patients receiving first-line irinotecan in combination with infusional fluorouracil/leucovorin every 2 weeks for metastatic colorectal cancer (19.1%; grade 3 or 4, 3.5%); 55% of these patients had a primary colon tumor (primary rectum, 45%). Abdominal enlargement (grade 1 or 2, 10%), increased alkaline phosphatase (13%; grade 3 or 4, 4%), and increased SGOT (10%; grade 3 or 4, 1%) were reported with weekly irinotecan monotherapy as second-line treatment for metastatic colorectal cancer in 2 open-label, noncomparative clinical trials. Grade 3 or 4 hepatic adverse reactions including jaundice and ascites were also reported with irinotecan monotherapy administered every 3 weeks in an open-label, noncomparative clinical trial; grade 3 or 4 hepatomegaly was also reported in this trial. Elevated hepatic enzymes (i.e., AST and ALT) in the absence of progressive liver metastasis have been observed in postmarketing experience with irinotecan.
Alopecia including complete hair loss occurs commonly in patients treated with irinotecan in clinical trials (43.1% to 60%). Rash occurred in 13% to 19.1% (grade 3 or 4, 1% or less) of patients with metastatic colorectal cancer treated with irinotecan (monotherapy or in combination with fluorouracil/leucovorin) in 2 clinical trials, while "cutaneous signs" including rash were reported in 17.2% (grade 3 or 4, 0.7% to 2%) of patients who received irinotecan in 2 other clinical trials. Mild hyperhidrosis occurred in patients with metastatic colorectal cancer receiving weekly irinotecan monotherapy as second-line therapy (grade 1 or 2, 16%). Exfoliative dermatitis (0.9% vs. 3.2%; grade 3 or 4, 0% vs. 0.5%) and palmar-plantar erythrodysesthesia (hand and foot syndrome) (10.3% vs. 12.6%; grade 3 or 4, 0.7% vs. 0.7% to 5%) were each reported less frequently in patients with metastatic colorectal cancer receiving irinotecan in combination with fluorouracil/leucovorin compared with fluorouracil/leucovorin alone.
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been reported during irinotecan therapy. Discontinue irinotecan if an anaphylactic reaction occurs.
The incidence of akathisia in clinical trials of weekly irinotecan was greater when prochlorperazine was administered on the same day as irinotecan than when the drugs were administered on separate days (n = 80) (8.5% vs. 1.3%); the higher incidence, however, is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies.
Edema was reported in 10% (grade 3 or 4, 1%) of patients with metastatic colorectal cancer treated with second-line irinotecan monotherapy in an open-label, noncomparative clinical trial.
Weight loss was reported in 30% (grade 3 or 4, 1%) of patients with metastatic colorectal cancer treated with irinotecan monotherapy in an open-label, noncomparative clinical trial.
Radiation therapy is associated with an increased risk of several adverse reactions associated with irinotecan therapy. The incidence of grade 3 or 4 neutropenia is higher in patients who have received prior pelvic/abdominal irradiation; based on sparse data, concurrent administration of irinotecan with radiation therapy is not recommended. Patients with prior radiation therapy are also at increased risk of interstitial lung disease. Closely monitor patients who have received prior radiation therapy for an increase in irinotecan-related adverse reactions.
Severe bone marrow suppression has been reported with irinotecan therapy, sometimes resulting in neutropenic fever or fatal infection. Patients at increased risk include those who have received prior pelvic/abdominal irradiation, patients with baseline total bilirubin levels greater than or equal to 1 mg/dL, patients with deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome, and patients with UGT1A1*28 or *6 alleles. Monitor complete blood counts during treatment with irinotecan; an interruption of therapy or dose reduction may be necessary for grade 2 or higher anemia, leukopenia, neutropenia, and thrombocytopenia, as well as neutropenic fever. Subsequent cycles of irinotecan should not begin until the ANC has recovered to greater than 1,500/mm3 and the platelet count to greater than 100,000/mm3, and neutropenic fever is resolved. Patients with an active infection should be treated prior to receiving irinotecan. Opportunistic infections, including fungal infection, may occur in some patients due to severe myelosuppression. Patients with a history of varicella zoster, other 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.
Genetic variants of the UGT1A1 gene lead to reduced UGT1A1 enzyme expression or activity and decreased function. Consider UGT1A1 genotype testing for the *28 and *6 alleles to identify UGT1A1 poor metabolizers such as patients who are homozygous for the UGT1A1*28 or *6 alleles (*28/*28 or *6/*6) or those who are compound or double heterozygous for the UGT1A1*28 and *6 alleles (*28/*6). These patients are at increased risk for severe or life-threatening neutropenia during treatment with irinotecan due to increased exposure to an active metabolite, SN-38; homozygous patients and heterozygous patients receiving irinotecan doses greater than 125 mg/m2 may also be at an increased risk of severe diarrhea. Reduce the dose of irinotecan by at least one dose level for these patients, whether administered as monotherapy or in combination with other chemotherapy; subsequent dose modifications should be considered based on individual patient tolerance to treatment. Patients who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*28 or *1/*6) are intermediate metabolizers and may also have an increased risk of severe neutropenia. Closely monitor patients with UGT1A1*28 or *6 alleles for neutropenia during and after treatment with irinotecan. Of note, the UGT1A1*6/*6 genotype is different from the 6/6 genotype, which is sometimes used to represent the genotype of patients who are wild type for UGT1A1*28.
Interstitial lung disease-like events/pneumonitis has occurred in patients treated with irinotecan, both as monotherapy and in combination with other agents, including some fatalities. Patients with chronic lung disease (CLD), prior use of pneumotoxic drugs, prior radiation therapy, and colony stimulating factors are at an increased risk. Closely monitor patients with risk factors for respiratory symptoms before and during irinotecan therapy. Interrupt treatment for new or progressive dyspnea, cough, and fever, pending diagnostic evaluation; if interstitial lung disease is diagnosed, discontinue irinotecan and initiate appropriate therapy.
Patients with pre-existing diarrhea or dehydration should be treated prior to irinotecan therapy, as diarrhea is a common and potentially severe adverse reaction of irinotecan. In some patients, dehydration resulting from treatment-related diarrhea and/or vomiting has resulted in renal impairment and acute renal failure. Do not administer irinotecan to patients with GI obstruction. Avoid diuretics or laxatives in patients with diarrhea. Diarrhea occurring during or shortly after irinotecan administration ("early diarrhea") is often dose-related, and may be accompanied by cholinergic symptoms (e.g., rhinitis, salivation, miosis, lacrimation, diaphoresis, flushing, and hyperperistalsis with possible abdominal cramping) or bradycardia. Consider the prophylactic or therapeutic use of atropine (0.25 mg to 1 mg intravenous or subcutaneous) for early diarrhea. "Late diarrhea", which occurs more than 24 hours after the administration of irinotecan, can be life-threatening as it may be prolonged and lead to dehydration, electrolyte imbalance, or sepsis. Monitor patients for diarrhea and begin loperamide at the first episode of poorly formed or loose stools (4 mg for 1 dose, then 2 mg every 2 hours until diarrhea-free for 12 hours), or at the earliest onset of more frequent than normal bowel movements. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. Replace fluid and electrolytes as necessary. Use antibiotic support for ileus, fever, or severe neutropenia. Do not administer subsequent doses of irinotecan until the return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication; an interruption of therapy or dose reduction may be necessary.
Closely monitor patients greater than 65 years of age (geriatric patients) due to a greater risk of early and late diarrhea in this population. In patients older than 70 years of age, reduce the starting dose of irinotecan monotherapy for the every-3-week schedule to 300 mg/m2.
Irinotecan should be used with caution in patients with baseline hepatic disease or biliary tract disease. Irinotecan clearance is decreased in patients with hepatic impairment while exposure to the active metabolite SN-38 is increased; the magnitude of these effects is proportional to the degree of liver impairment. The safety of irinotecan in patients with significant hepatic impairment has not been established, as patients without liver metastases and bilirubin levels greater than 2 mg/mL or transaminases more than 3 times the upper limit of normal (ULN) were excluded from clinical trials; patients who had liver metastases and transaminases more than 5 times ULN were also excluded form clinical trials. In clinical trials of patients receiving weekly irinotecan, patients with total bilirubin levels of 1 mg/dL to 2 mg/dL had a significantly increased risk of first-cycle, grade 3 or 4 neutropenia compared to patients with bilirubin levels less than 1 mg/dL. The incidence of myelosuppression is also increased in patients with deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome.
Monitor the infusion site for signs of inflammation; avoid extravasation. If extravasation occurs, flush the site with sterile water and apply ice.
Avoid accidental exposure to irinotecan during preparation, handling and administration. The use of protective gloves is recommended. If an irinotecan solution contacts the skin, wash the skin immediately and thoroughly with soap and water; if it contacts the mucous membranes, flush thoroughly with water.
The effectiveness of irinotecan in pediatric patients (children) has not been established. In an open-label, single arm study of pediatric patients with refractory solid tumors treated with irinotecan 50 mg/m2 IV daily on days 1 to 5, repeated every 3 weeks, the adverse event profile was comparable to that observed in adults. Accrual to the single agent irinotecan phase (20 mg/m2 IV on days 1 to 5 on weeks 0, 1, 3, and 4) of an open-label, single arm trial of pediatric patients with previously untreated rhabdomyosarcoma was prematurely halted due to a high rate of progressive disease and early deaths. In this trial, the adverse event profile differed from adults, with the most significant grade 3 or 4 adverse events including dehydration (28.6%), severe hypokalemia (23.8%), hyponatremia (14.3%), and infection (23.8%).
Pregnancy should be avoided by females of reproductive potential during irinotecan treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant women, irinotecan can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Available postmarketing and published data reporting the use of irinotecan in pregnant women are insufficient and confounded by the concomitant use of other cytotoxic drugs to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Women who are pregnant or who become pregnant while receiving irinotecan should be apprised of the potential hazard to the fetus. Intravenous administration of irinotecan to rats during organogenesis increased postimplantation loss and decreased numbers of live fetuses at approximately 0.2 times the clinical exposure at a 125 mg/m2 dose in humans; at exposures of approximately 0.3 times the clinical exposure at a 125 mg/m2 dose in humans, there were increases in a variety of external, visceral, and skeletal abnormalities. When administered to rat dams following organogenesis through weaning, the offspring experienced decreased learning ability and decreased female body weights. Administration of irinotecan to pregnant rabbits at exposures of approximately half of the clinical exposure at a human dose of 125 mg/m2 resulted in similar findings to those in rats, with increased postimplantation loss, decreased live fetuses, and increased external, visceral, and skeletal abnormalities.
Counsel patients about the reproductive risk and contraception requirements during irinotecan treatment. Irinotecan can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy during treatment with irinotecan and for 6 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of irinotecan. Women who become pregnant while receiving irinotecan should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use condoms during treatment and for 3 months after the last dose of irinotecan. Irinotecan can cause both male and female infertility. Menstrual dysfunction has been reported following irinotecan administration; based on postmarketing reports, female fertility may be impaired by irinotecan treatment. Male fertility may also be impaired based on findings from animal studies. Atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at approximately the same exposure seen in humans receiving a dose of 125 mg/m2, and in dogs at exposures of approximately 1/15th seen in humans receiving a dose of 125 mg/m2.
Due to the potential for serious adverse reactions in nursing infants from irinotecan, advise women to discontinue breast-feeding during treatment and for 7 days after the last dose. It is not known whether irinotecan is present in human milk, although many drugs are excreted in human milk.
For the treatment of metastatic colorectal cancer:
NOTE: The use of irinotecan in combination with fluorouracil/leucovorin regimens administered for 4 to 5 consecutive days every 4 weeks are not recommended due to an increased risk of toxicity, including death; use of these regimens should be limited to clinical trials.
-for the treatment of metastatic colorectal cancer, in combination with leucovorin and fluorouracil (FOLFIRI):
Intravenous dosage:
Adults: 180 mg/m2 IV over 90 minutes on day 1, administered concomitantly but in separate bags with leucovorin 400 mg/m2 IV over 2 hours; when the leucovorin infusion is complete, administer fluorouracil 400 mg/m2 IV bolus, followed by fluorouracil 2,400 mg/m2 by continuous IV infusion (CIV) over 46 hours (1,200 mg/m2/day) every 14 days until disease progression or unacceptable toxicity. The dose of fluorouracil may be increased to 3,000 mg/m2 CIV over 46 hours (1,500 mg/m2/day) after the second cycle if there are no grade 1 or higher toxicities. Reduce the dose of irinotecan by at least one dose level in patients who are homozygous for the UGT1A1*28 or *6 alleles, or compound heterozygous for UGT1A1 *28 and *6. In a multicenter, randomized, phase 3 clinical trial of patients with previously untreated metastatic colorectal cancer (mCRC), treatment with FOLFIRI significantly improved progression-free survival (PFS) compared with bolus fluorouracil/leucovorin with irinotecan (mIFL) (7.6 months vs. 5.9 months); median overall survival was also improved in the FOLFIRI arm (23.1 months vs. 17.6 months). Compared with first-line treatment of mCRC with FOLFOX6, PFS was not significantly improved by FOLFIRI (8.5 months vs. 8 months); PFS was significantly improved compared with FOLFOX6 when FOLFIRI was used as second-line therapy (2.5 months vs. 4.2 months) in another clinical trial. Alternatively, FOLFIRI has been administered as irinotecan 180 mg/m2 IV over 90 minutes, followed by leucovorin 200 mg/m2 IV over 2 hours, then fluorouracil 400 mg/m2 IV bolus followed by fluorouracil 600 mg/m2 CIV over 22 hours all on day 1; repeat leucovorin and fluorouracil (bolus and CIV) on day 2. Repeat this 2-day regimen every 2 weeks until disease progression or unacceptable toxicity.
-for the second-line treatment of metastatic colorectal cancer, in combination with oxaliplatin (IROX):
Intravenous dosage:
Adults: 200 mg/m2 IV over 30 to 90 minutes on day 1, immediately preceded by oxaliplatin 85 mg/m2 IV, repeated every 3 weeks until disease progression or unacceptable toxicity (IROX). Reduce the dose of irinotecan by at least one dose level in patients who are homozygous for the UGT1A1*28 or *6 alleles, or patients who are compound heterozygous for UGT1A1 *28 and *6. In a randomized, open-label, phase 3 clinical trial, treatment with IROX significantly improved overall survival (13.4 months vs. 11.1 months) and median time to progression (5.3 months vs. 2.8 months) compared with irinotecan alone in patients with metastatic or recurrent colorectal cancer that progressed or recurred during or after first-line fluoropyrimidines (i.e., fluorouracil/leucovorin or capecitabine). Patents treated with IROX also had significant improvement in tumor-related symptoms compared with irinotecan monotherapy (32% vs. 19%).
-for the treatment of metastatic colorectal cancer in combination with fluorouracil and leucovorin (IFL):
Intravenous dosage:
Adults: 125 mg/m2 IV over 90 minutes on days 1, 8, 15, and 22, in combination with leucovorin (20 mg/m2 IV bolus) followed by fluorouracil (500 mg/m2 IV bolus) on days 1, 8, 15, and 22. Repeat every 6 weeks until disease progression or unacceptable toxicity. Reduce the dose of irinotecan by at least one dose level in patients who are homozygous for the UGT1A1*28 or *6 alleles, or who are compound heterozygous for UGT1A1 *28 or *6. In a multicenter, randomized, open-label, phase 3 clinical trial, first-line treatment with IFL significantly improved median progression free survival (7 months vs. 4.3 months) as well as the objective response rate (50% vs. 28%) compared with the Mayo Clinic bolus regimen in patients with metastatic colorectal cancer. Treatment with IFL resulted in increased mortality compared with FOLFIRI with one trial, and was inferior to FOLFOX in another.
-for the treatment of metastatic colorectal cancer that has recurred or progressed after fluorouracil-based therapy, as monotherapy:
Intravenous dosage (WEEKLY):
Adults: 125 mg/m2 IV over 90 minutes on days 1, 8, 15, and 22, repeated every 6 weeks until disease progression or unacceptable toxicity. For patients who do not experience toxicity in a given cycle, the weekly dose may be increased at the start of the next cycle by 25 mg/m2 to a maximum of 150 mg/m2. Consider reducing the dose by one dosage level for patients homozygous for the UGT1A1*28 or *6 alleles or who are compound heterozygous for UGT1A1 *28 and *6. In 3 separate open-label, single agent clinical studies of patients with metastatic colorectal cancer (mCRC) (n = 304), most of whom had progression or recurrence after previous fluorouracil-based therapy for mCRC, treatment with weekly irinotecan resulted in objective response rates of 13% to 21%, median survival of 8.1 months to 10.7 months, and 1-year survival of 31% to 46%. One of these studies included a starting dose of 150 mg/m2 in 9 patients, which was poorly tolerated due to high rates of grade 4 late diarrhea and neutropenic fever.
-for the treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) in combination with cetuximab in patients who are refractory to irinotecan-based chemotherapy*:
NOTE: Cetuximab is FDA-approved for the treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) in combination with cetuximab in patients who are refractory to irinotecan-based chemotherapy.
Intravenous dosage:
Adults: 350 mg/m2 IV every 3 weeks; 180 mg/m2 IV every 2 weeks; or 125 mg/m2 IV weekly for 4 doses every 6 weeks; the dose of irinotecan should be the same dosage that the patient had previously failed. Prior to administration of irinotecan, administer in combination with cetuximab 400 mg/m2 IV on day 1, followed by weekly infusions of cetuximab 250 mg/m2 IV until disease progression or unacceptable toxicity; complete the cetuximab infusion 1 hour prior to irinotecan. Reduce the dose of irinotecan by at least one dose level in patients who are homozygous for the UGT1A1*28 or *6 alleles, or who are compound heterozygous for UGT1A1 *28 and *6. In a randomized, open-label, phase 2 clinical trial (the BOND study), patients with metastatic colorectal cancer who were refractory to irinotecan were randomized to treatment with cetuximab monotherapy or cetuximab plus irinotecan (at the dose previously failed). The response rate in patients receiving cetuximab plus irinotecan was 22.9% compared with 10.8% in those receiving cetuximab monotherapy; the median time to progression was significantly improved in the combination therapy arm (4.1 months vs. 1.5 months). The median survival time was 8.6 months in patients receiving cetuximab plus irinotecan and 6.9 months in those who received cetuximab alone.
-for the treatment of BRAF mutation-positive, RAS wild-type, metastatic colorectal cancer, in combination with vemurafenib and cetuximab*:
Intravenous dosage:
Adults: 180 mg/m2 IV plus cetuximab (500 mg/m2 IV) on day 1, every 14 days, in combination with vemurafenib 960 mg by mouth twice daily, until disease progression or unacceptable toxicity. Reduce the dose of irinotecan by at least one dose level in patients who are homozygous for the UGT1A1*28 or *6 alleles, or who are compound heterozygous for UGT1A1 *28 and *6. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, open-label phase 2 clinical trial, treatment with vemurafenib, cetuximab and irinotecan significantly improved the median progression-free survival (PFS) over treatment with cetuximab plus irinotecan, without vemurafenib (4.4 months vs. 2 months) in patients with BRAF V600E mutation-positive, RAS wild-type, metastatic colorectal cancer (mCRC) received treatment with cetuximab and irinotecan, with or without vemurafenib (a BRAF inhibitor). Approximately 50% of patients in the control arm crossed over to receive vemurafenib after progression; the rate of disease control was also significantly improved in the vemurafenib arm (67% vs. 22%).
-for the first-line treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) in combination with fluorouracil, leucovorin, and cetuximab (FOLFIRI plus cetuximab)*:
NOTE: Cetuximab is FDA-approved for the treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) in combination with FOLFIRI.
Intravenous dosage:
Adults: 180 mg/m2 IV on day 1 followed by levoleucovorin 200 mg/m2 IV (or racemic leucovorin 400 mg/m2 IV), followed by fluorouracil 400 mg/m2 IV given as a bolus then 2,400 mg/m2 as a 46-hour continuous IV infusion, repeated every 14 days. Reduce the dose of irinotecan by at least one dose level in patients who are homozygous for the UGT1A1*28 or *6 alleles, or who are compound heterozygous for UGT1A1 *28 and *6. Administer in combination with cetuximab 400 mg/m2 IV on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV, administered 1 hour prior to chemotherapy, until disease progression or unacceptable toxicity; alternatively, cetuximab may be administered at a dose of 500 mg/m2 IV every 2 weeks. Complete cetuximab administration 1 hour prior to chemotherapy. In a multicenter, randomized, open-label, phase 3 clinical trial of patients with mCRC, unselected for KRAS mutational status, first-line treatment with cetuximab plus FOLFIRI (n = 599) significantly improved the primary endpoint of median progression-free survival (PFS) compared with FOLFIRI alone (n = 599) (8.9 months vs. 8 months); the overall response rate was 46.9% vs. 38.7%, respectively. Median overall survival was 19.9 months in the cetuximab group compared with 18.6 months in patients treated with FOLFIRI alone. In a subgroup analysis of patients with known KRAS mutational status (KRAS negative, n = 666; KRAS positive, n = 397), the addition of cetuximab to FOLFIRI therapy significantly improved the median PFS (9.9 vs. 8.4 months) and overall survival (23.5 vs. 20 months) times only in patients with KRAS wild type disease.
For the treatment of extensive small cell lung cancer (SCLC)* in combination with cisplatin:
Intravenous dosage:
Adults: 60 mg/m2 IV over 90 minutes on days 1, 8, and 15 in combination with cisplatin 60 mg/m2 IV on day 1, every 4 weeks for 4 cycles has been studied in multiple studies.
For the treatment of gastric cancer*:
-for the treatment of resectable locally advanced gastric cancer in combination with cisplatin*:
Intravenous dosage:
Adults: 65 mg/m2 IV on days 1 and 8 in combination with cisplatin 30 mg/m2 IV on days 1 and 8, for 2 cycles every 21 days. Patients then received daily radiotherapy with concurrent irinotecan 65 mg/m2 IV on days 1, 8, 15, and 22 in combination with cisplatin 30 mg/m2 IV on days 1, 8, 15, and 22. Surgical resection was performed 5 to 8 weeks after radiotherapy if feasible.
-for the treatment of previously untreated advanced gastric cancer in combination with 5-fluorouracil*:
Intravenous dosage:
Adults: 80 mg/m2 IV over 30 minutes in combination with folinic acid 500 mg/m2 IV over 2 hours and fluorouracil 2,000 mg/m2 IV over 22 hours, administered weekly for 6 weeks followed by 1 week of rest. Treatment was continued until disease progression or unacceptable toxicity.
-for the treatment of refractory advanced gastric cancer in combination with capecitabine*:
Intravenous dosage:
Adults: 250 mg/m2 IV on day 1 in combination with capecitabine 1,000 mg/m2 PO twice daily on days 1 to 14, repeated every 21 days up to a maximum of 8 cycles.
For the treatment of pancreatic cancer*:
-for the adjuvant treatment of pancreatic cancer, in combination with 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (mFOLFIRINOX)*:
Intravenous dosage:
Adults: Oxaliplatin 85 mg/m2 IV over 2 hours on day 1, immediately followed by leucovorin 400 mg/m2 IV over 2 hours; begin irinotecan 150 mg/m2 IV over 90 minutes 30 minutes after the leucovorin infusion is started, followed by 5-fluorouracil 2,400 mg/m2 IV continuously over 46 hours. Repeat every 14 days for 12 cycles. In a randomized phase 3 trial, adjuvant treatment with mFOLFIRINOX significantly increased both progression-free survival (PFS) and overall survival (OS) compared with gemcitabine monotherapy in patients with pancreatic cancer. In this trial, patients were carefully selected for treatment based on age (younger than 80 years of age), R0 or R1 resection, and a CA 19-9 level of 180 units/mL or less.
-for the first-line treatment of metastatic pancreatic cancer, in combination with oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (FOLFIRINOX)*:
Intravenous dosage:
Adults: Oxaliplatin 85 mg/m2 IV over 2 hours, immediately followed by leucovorin 400 mg/m2 IV over 2 hours, and 30 minutes after the start of the leucovorin infusion, add irinotecan 180 mg /m2 IV over 90 minutes through a Y-connector, which was immediately followed by 5-fluorouracil 400 mg/m2 IV bolus and a continuous infusion of 5-fluorouracil 2,400 mg/m2 over 46 hours (FOLFIRINOX). The regimen was repeated every 2 weeks for a period of 6 months in patients who exhibited a response.
For the monotherapy treatment of recurrent malignant glioma*:
NOTE: Concomitant use of an enzyme-inducing antiepileptic drug (EIAED) alters the metabolism and elimination of irinotecan and its active metabolite, SN-38. Irinotecan dose adjustment is needed to achieve therapeutic concentrations.
Intravenous dosage:
Adults: Multiple dosage regimens have been given with varying results. Regimens include irinotecan 125 mg/m2 IV over 90 minutes weekly for 4 weeks with 2 weeks of rest and irinotecan 350 mg/m2 IV over 90 to 120 minutes every 21 days (for patients not on EIAED) or 600 to 750 mg/m2 IV over 90 to 120 minutes every 21 days (for patients on EIAED).
For the treatment of recurrent or relapsed glioblastoma multiforme in combination with bevacizumab*:
NOTE: Concomitant use of an enzyme-inducing antiepileptic drug (EIAED) alters the metabolism and elimination of irinotecan and its active metabolite, SN-38. Irinotecan dose adjustment is needed to achieve therapeutic concentrations.
Intravenous dosage:
Adults: 125 mg/m2 (non EIAED) or 340 mg/m2 (EIAED) IV once every 14 days in combination with bevacizumab 10 mg/kg IV once every 14 days has been studied in phase II studies. Progression-free survival at 6 months ranged from 50% to 77%. In one study, toxicities of grade 3 or higher occurred in 65.8% of patients, and 17.7% had to discontinue therapy due to toxicity.
For the treatment of rhabdomyosarcoma*, in combination with chemotherapy:
-in previously untreated patients with metastatic disease*:
Intravenous dosage:
Children, Adolescents, and Adults < 50 years: 20 mg/m2/day IV over 1 hour for 5 days given in weeks 0, 1, 3, and 4 plus vincristine 1.5 mg/m2 IV (max dose: 2 mg) on day 1 of weeks 0, 1, 3, and 4 was studied as window therapy in 50 patients aged less than 50 years (median age, 14 years; range, 1 to 26 years) with previously untreated metastatic rhabdomyosarcoma (RMS) (alveolar type, n = 43) in a phase II study. Patients who responded to treatment (complete (CR) or partial response) received irinotecan plus vincristine in weeks 9, 10, 26, 27, 32, 33, 38, and 39 and VAC (vincristine 1.5 mg/m2 IV (max dose: 2 mg) on day 1, dactinomycin 1.5 mg/m2 IV (max dose: 2.5 mg) on day 1, and cyclophosphamide 2.2 grams/m2 IV on day 1 with mesna 440 mg/m2 IV over 15 minutes prior to and at 3, 6, and 9 hours after cyclophosphamide) in weeks 6, 12, 23, 29, 35, and 41. Patients also received single-agent vincristine on day 1 in weeks 7, 8, 11, 13, 15, 17, 18, 24, 25, and 34; vincristine plus cyclophosphamide on day 1 in weeks 16 and 19; and radiotherapy to primary and metastatic sites during weeks 15 to 22.
-in patients in first relapse or with disease progression following one previous chemotherapy regimen*:
Intravenous dosage:
Children, Adolescents, and Adults < 21 years: 20 mg/m2/day IV over 1 hour for 5 days given in weeks 1, 2, 4, and 5 (arm A) or irinotecan 50 mg/m2/day IV for 5 days given in weeks 1 and 4 (arm B) plus vincristine 1.5 mg/m2 IV (max dose: 2 mg) on day 1 of weeks 1, 2, 4, and 5 was studied in 92 patients (aged less than 21 years at diagnosis) with rhabdomyosarcoma (RMS) in a randomized, phase II window study. Patients who responded to treatment (complete (CR) or partial (PR) response) continued to receive chemotherapy with irinotecan 20 mg/m2/day IV for 5 days given in weeks 13, 14, 25, 26, 34, 35, 46, 47, 49, and 50 (arm A) or 50 mg/m2/day IV for 5 days given in weeks 13, 25, 34, 46, and 49 (arm B) plus vincristine (1.5 mg/m2 IV (max dose: 2 mg) on day 1 of weeks 13, 14, 25, 26, 34, 35, 46, 47, 49, and 50) and doxorubicin (75 mg/m2 IV on day 1 in weeks 7, 16, 28, 37, and 40), cyclophosphamide (1.2 grams/m2 IV on day 1 in weeks 7, 16, 28, 37, and 40), etoposide (100 mg/m2/day IV for 5 days given in weeks 10, 19, 22, 28, 31, and 37), and ifosfamide (1.8 grams/m2/day IV for 5 days given in weeks 10, 19, 22, 28, 31, and 37).
For the treatment of non-small cell lung cancer (NSCLC)* in combination with cisplatin:
Intravenous dosage:
Adults: 60 mg/m2 IV over 90 minutes on days 1, 8, and 15 in combination with cisplatin 80 mg/m2 IV on day 1, repeated every 4 weeks. Alternatively, a regimen of cisplatin 30 mg/m2 IV then irinotecan 65 mg/m2 IV over 90 minutes (50 mg/m2 IV for previously treated patients) administered weekly for 4 weeks followed by a 2-week rest has been studied. Treatment was continued for a maximum of 6 cycles. In a phase III trial, overall survival was similar for cisplatin-irinotecan compared to other platinum-based doublets.
For the treatment of neuroblastoma*:
-for the first-line treatment of relapsed or refractory neuroblastoma, in combination with temozolomide:
Intravenous dosage:
Adults 21 years and younger: 10 mg/m2 IV over 1 hour once daily on days 1 to 5 and days 8 to 12 in combination with oral temozolomide. Cycles may be repeated every 21 days. In Children's Oncology Group ANBL0421, 8 patients (15%) had objective responses with the combination of irinotecan and temozolomide. In adults, it is recommended to reduce the starting dose of irinotecan by at least one level for patients homozygous for the UGT1A1*28 allele, but there is limited data in children and adolescents. One phase II study administered monotherapy irinotecan and did not find an association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.
Infants, Children, and Adolescents: 10 mg/m2 IV over 1 hour once daily on days 1 to 5 and days 8 to 12 in combination with oral temozolomide. Cycles may be repeated every 21 days. In Children's Oncology Group ANBL0421, 8 patients (15%) had objective responses with the combination of irinotecan and temozolomide. In adults, it is recommended to reduce the starting dose of irinotecan by at least one level for patients homozygous for the UGT1A1*28 allele, but there is limited data in children and adolescents. One phase II study administered monotherapy irinotecan and did not find an association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.
-for the first-line treatment of patients with relapsed, refractory neuroblastoma, in combination with temozolomide and dinutuximab:
Intravenous dosage:
Children 2 years and older and Adolescents: 50 mg/m2 IV over 90 minutes once daily on days 1 to 5 in combination with oral temozolomide and IV dinutuximab. Cycles may be repeated every 21 days. In Children's Oncology Group trial ANBL1221, nine out of 17 patients (53%) assigned to the irinotecan, temozolomide, dinutuximab group had objective responses as compared to 1 of the 18 patients (6%) in the irinotecan, temozolomide, temsirolimus group. In adults, it is recommended to reduce the starting dose of irinotecan by at least one level for patients homozygous for the UGT1A1*28 allele, but there is limited data in children and adolescents. One phase II study administered monotherapy irinotecan and did not find an association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.
-for the treatment of patients with neuroblastoma in the relapsed, refractory, or palliative setting:
Intravenous dosage:
Children 2 years and older and Adolescents: 50 mg/m2 IV over 1 hour once daily on days 1 to 5 in combination with oral temozolomide. Cycle may be repeated every 21 to 28 days. In one clinical trial, patients with refractory or relapsed neuroblastoma (n = 49) received 1 to 15 courses (median: 5) of irinotecan and temozolomide. Of the 36 patients assessable for response, 3 patients (8%) had complete or partial response and 9 patients (25%) had objective responses. In adults, it is recommended to reduce the starting dose of irinotecan by at least one level for patients homozygous for the UGT1A1*28 allele, but there is limited data in children and adolescents. One phase II study administered monotherapy irinotecan and did not find an association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.
Therapeutic Drug Monitoring:
Dosage Adjustment for Patients Homozygous for the UGT1A1*28 or *6 Alleles (*28/*28 or *6/*6) or Compound Heterozygous for the UGT1A1*28 and *6 Alleles (*28/*6): Consider reducing the dose of irinotecan by at least one dose level. Base subsequent dose modifications on individual tolerance to treatment.
-Single agent, weekly: Reduce dose from 125 mg/m2 to 100 mg/m2, or from 100 mg/m2 to 75 mg/m2.
-Single agent, every 3 weeks: Reduce dose from 350 mg/m2 to 300 mg/m2, or from 300 mg/m2 to 250 mg/m2.
-In combination with 5-FU and leucovorin (IFL): Reduce dose from 125 mg/m2 to 100 mg/m2, or from 100 mg/m2 to 75 mg/m2.
-In combination with 5-FU and leucovorin (FOLFIRI): Reduce dose from 180 mg/m2 to 150 mg/m2, or from 150 mg/m2 to 120 mg/m2
Dosage Adjustments for Treatment-Related Toxicities (base dose adjustments on the worst preceding toxicity):
Bowel obstruction: Hold irinotecan until resolution of bowel obstruction.
Diarrhea, early onset (less than or equal to 24 hours after irinotecan administration) or cholinergic symptoms (e.g., bradycardia, rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping): Consider prophylactic or therapeutic administration of atropine (0.25 mg to 1 mg intravenous or subcutaneous).
Diarrhea, late onset (greater than 24 hours after irinotecan administration)
-Grade 1 (2 to 3 stools per day above baseline):
Single agent, weekly or every 3 weeks: No dose reduction or interruption of therapy necessary. Begin loperamide at the first episode of poorly formed or loose stools (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours). Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia.
In combination with 5-FU and leucovorin: Delay irinotecan and begin loperamide at the first episode of poorly formed or loose stools (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours). Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia. When diarrhea resolves to baseline without requiring antidiarrheal medication for greater than or equal to 24 hours, resume the current cycle of therapy at the original dose. No dose reduction is necessary for subsequent cycles of chemotherapy. Consider discontinuation of therapy if diarrhea has not resolved after a 2-week delay.
-Grade 2 (4 to 6 stools per day above baseline):
Single agent, weekly: Begin loperamide at the first episode of poorly formed or loose stools (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours) and decrease the dose of irinotecan by 25 mg/m2 for the remainder of the current cycle. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia. When diarrhea resolves to baseline without requiring antidiarrheal medication for greater than or equal to 24 hours, resume subsequent cycles of therapy at the original dose of irinotecan. Consider discontinuation of therapy if diarrhea has not resolved after a 2-week delay, or if diarrhea persists after decreasing the weekly irinotecan dose to 50 mg/m2.
Single agent, every 3 weeks: Begin loperamide at the first episode of poorly formed or loose stools (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours). Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia. When diarrhea resolves to baseline without requiring antidiarrheal medication for greater than or equal to 24 hours, resume subsequent cycles of therapy at the original dose of irinotecan. Consider discontinuation of therapy if diarrhea has not resolved after a 2-week delay, or if diarrhea persists after decreasing the dose to 200 mg/m2 every 3 weeks.
In combination with 5-FU and leucovorin: Hold irinotecan and begin loperamide at the first episode of poorly formed or loose stools (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours). Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia. When diarrhea resolves to baseline without requiring antidiarrheal medication for greater than or equal to 24 hours, reduce the dose of irinotecan by 1 dose level (IFL: 125 mg/m2 to 100 mg/m2, or 100 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 150 mg/m2, or 150 mg/m2 to 120 mg/m2) and resume the current cycle of therapy; for continued toxicity, decrease treatment in decrements of approximately 20%. At the start of the next cycle of chemotherapy, maintain the original dose of irinotecan. Consider discontinuation of therapy if diarrhea has not resolved after a 2-week delay.
-Grade 3 (7 to 9 stools per day above baseline):
Single agent, weekly: Hold irinotecan and begin loperamide (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours) at the first episode of poorly formed or loose stools. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia. When diarrhea resolves to less than or equal to grade 2, decrease the dose of irinotecan by 25 mg/m2 for the remainder of the current cycle. When diarrhea is resolved to pretreatment levels without requiring antidiarrheal medication for greater than or equal to 24 hours, begin subsequent cycles of therapy at the reduced dose of irinotecan. Consider discontinuation of therapy if diarrhea has not resolved after a 2-week delay, or if diarrhea persists after decreasing the dose to 50 mg/m2.
Single agent, every 3 weeks: Hold irinotecan and begin loperamide (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours) at the first episode of poorly formed or loose stools. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia. When diarrhea resolves to pretreatment levels without requiring antidiarrheal medication for greater than or equal to 24 hours, reduce the dose of irinotecan by 50 mg/m2 and begin subsequent cycles of therapy. Consider discontinuation of therapy if diarrhea has not resolved after a 2-week delay, or if diarrhea persists after decreasing the dose to 200 mg/m2.
In combination with 5-FU and leucovorin: Hold irinotecan and begin loperamide at the first episode of poorly formed or loose stools (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours). Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia. When diarrhea resolves to baseline without requiring antidiarrheal medication for greater than or equal to 24 hours, decrease irinotecan by one dose level (IFL: 125 mg/m2 to 100 mg/m2, or 100 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 150 mg/m2, or 150 mg/m2 to 120 mg/m2) and resume the current cycle of therapy; for continued toxicity, decrease treatment in decrements of approximately 20%. At the start of the next cycle of chemotherapy, continue the reduced dose of irinotecan. Consider discontinuation of therapy if diarrhea has not resolved after a 2-week delay.
-Grade 4 (greater than or equal to 10 stools per day above baseline):
Single agent, weekly: Hold irinotecan and begin loperamide (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours) at the first episode of poorly formed or loose stools. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia. When diarrhea resolves to less than or equal to grade 2, decrease the dose of irinotecan by 50 mg/m2 for the remainder of the current cycle. When diarrhea resolves to baseline without requiring antidiarrheal medication for greater than or equal to 24 hours, resume subsequent cycles of therapy at the reduced dose of irinotecan. Consider discontinuation of therapy if diarrhea has not resolved after a 2-week delay, or if diarrhea persists after decreasing the dose to 50 mg/m2.
Single agent, every 3 weeks: Hold irinotecan and begin loperamide (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours) at the first episode of poorly formed or loose stools. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia. When diarrhea resolves to pretreatment levels without requiring antidiarrheal medication for greater than or equal to 24 hours, reduce the dose of irinotecan by 50 mg/m2 and begin subsequent cycles of therapy. Consider discontinuation of therapy if diarrhea has not resolved after a 2-week delay, or if diarrhea persists after decreasing the dose to 200 mg/m2.
In combination with 5-FU and leucovorin: Hold irinotecan and begin loperamide at the first episode of poorly formed or loose stools (4 mg for 1 dose, followed by 2 mg every 2 hours until no diarrhea for 12 hours; during the night, the patient may take loperamide 4 mg every 4 hours). Loperamide is not recommended to be used for more than 48 consecutive hours at these doses due to the risk of paralytic ileus. Monitor and replace fluid and electrolytes; use antibiotic support for ileus, fever, or severe neutropenia. When diarrhea resolves to baseline without requiring antidiarrheal medication for greater than or equal to 24 hours, decrease irinotecan by 2 dose levels (IFL: 125 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 120 mg/m2) and resume the current cycle of therapy; for continued toxicity, decrease treatment in decrements of approximately 20%. At the start of the next cycle of chemotherapy, continue the reduced dose of irinotecan. Consider discontinuation of therapy if diarrhea has not resolved after a 2-week delay.
Hematologic
-Grade 2 neutropenia (ANC 1,000/mm3 to 1,499/mm3) or other hematologic toxicity (e.g., anemia, leukopenia, thrombocytopenia):
Single agent, weekly: Decrease the dose of irinotecan by 25 mg/m2 for the remainder of the current cycle. After adequate hematologic recovery including ANC greater than or equal to 1,500/mm3 and platelets greater than or equal to 100,000/mm3, begin the next cycle of therapy at the original dose. Consider discontinuation of therapy if the hematologic toxicity has not recovered after a 2-week delay or if it occurs after decreasing the dose to 50 mg/m2.
Single agent, every 3 weeks: After adequate hematologic recovery including ANC greater than or equal to 1,500/mm3 and platelets greater than or equal to 100,000/mm3, begin the next cycle of therapy at the original dose. Consider discontinuation of therapy if the hematologic toxicity has not recovered after a 2-week delay or if it occurs after decreasing the dose to 200 mg/m2.
In combination with 5-FU and leucovorin (NOTE: do not reduce the dose of irinotecan for mucositis/stomatitis): Decrease the dose of irinotecan by one dose level (IFL: 125 mg/m2 to 100 mg/m2, or 100 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 150 mg/m2, or 150 mg/m2 to 120 mg/m2) for the remainder of the current cycle; for continued toxicity, decrease the dose of irinotecan in decrements of approximately 20%. A 5-FU dose reduction is also necessary. After adequate hematologic recovery including ANC greater than or equal to 1,500/mm3 and platelets greater than or equal to 100,000/mm3, begin the next cycle of therapy at the original dose. Consider discontinuation of therapy if the hematologic toxicity has not recovered after a 2-week delay.
-Grade 3 neutropenia (ANC 500/mm3 to 999/mm3) or other hematologic toxicity (e.g., anemia, leukopenia, thrombocytopenia):
Single agent, weekly: Hold irinotecan. When the hematologic toxicity resolves to less than or equal to grade 2, reduce the dose of irinotecan by 25 mg/m2 and resume remainder of the current cycle. After adequate hematologic recovery including ANC greater than or equal to 1,500/mm3 and platelets greater than or equal to 100,000/mm3, begin the next cycle of therapy at the reduced dose. Consider discontinuation of therapy if the hematologic toxicity has not recovered after a 2-week delay or if it occurs after decreasing the dose to 50 mg/m2.
Single agent, every 3 weeks: After adequate hematologic recovery including ANC greater than or equal to 1,500/mm3 and platelets greater than or equal to 100,000/mm3, reduce the dose of irinotecan by 50 mg/m2 and begin the next cycle of therapy. Consider discontinuation of therapy if the hematologic toxicity has not recovered after a 2-week delay or if it occurs after decreasing the dose to 200 mg/m2.
In combination with 5-FU and leucovorin (NOTE: do not reduce the dose of irinotecan for mucositis/stomatitis): Hold irinotecan until the toxicity resolves to less than or equal to grade 2, then reduce the dose of irinotecan by one dose level (IFL: 125 mg/m2 to 100 mg/m2, or 100 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 150 mg/m2, or 150 mg/m2 to 120 mg/m2) for the remainder of the current cycle; for continued toxicity, decrease the dose of irinotecan in decrements of approximately 20%. A 5-FU dose reduction is also necessary. Begin the next cycle of therapy (after adequate recovery) at the reduced dose. If the toxicity has not recovered after a 2-week delay, consider discontinuing therapy.
-Grade 4 neutropenia (ANC less than 500/mm3) or other hematologic toxicity (e.g., anemia, leukopenia, thrombocytopenia):
Single agent, weekly: Hold irinotecan. When the hematologic toxicity resolves to less than or equal to grade 2, reduce the dose of irinotecan by 50 mg/m2 and resume remainder of the current cycle. After adequate hematologic recovery including ANC greater than or equal to 1,500/mm3 and platelets greater than or equal to 100,000/mm3, begin the next cycle of therapy at the reduced dose. Consider discontinuation of therapy if the hematologic toxicity has not recovered after a 2-week delay or if it occurs after decreasing the dose to 50 mg/m2.
Single agent, every 3 weeks: After adequate hematologic recovery including ANC greater than or equal to 1,500/mm3 and platelets greater than or equal to 100,000/mm3, reduce the dose of irinotecan by 50 mg/m2 and begin the next cycle of therapy. Consider discontinuation of therapy if the hematologic toxicity has not recovered after a 2-week delay or if it occurs after decreasing the dose to 200 mg/m2.
In combination with 5-FU and leucovorin (NOTE: do not reduce the dose of irinotecan for mucositis/stomatitis): Hold irinotecan until the toxicity resolves to less than or equal to grade 2, then reduce the dose of irinotecan by 2 dose levels (IFL: 125 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 120 mg/m2) for the remainder of the current cycle; for continued toxicity, decrease the dose of irinotecan in decrements of approximately 20%. A 5-FU dose reduction is also necessary. Begin the next cycle of therapy (after adequate recovery) at the reduced dose. If the toxicity has not recovered after a 2-week delay, consider discontinuing therapy.
Neutropenic Fever
Single agent, weekly: Hold irinotecan until neutropenic fever resolves, then reduce the dose of irinotecan by 50 mg/m2 and resume therapy. After adequate recovery including ANC greater than or equal to 1,500/mm3 and platelets greater than or equal to 100,000/mm3, begin the next cycle of therapy at the reduced dose. If neutropenic fever has not resolved after a 2-week delay or if it occurs after decreasing the dose to 50 mg/m2, consider discontinuing therapy.
Single agent, every 3 weeks: Hold irinotecan until neutropenic fever resolves, then reduce the dose of irinotecan by 50 mg/m2 and resume therapy. After adequate recovery including ANC greater than or equal to 1,500/mm3 and platelets greater than or equal to 100,000/mm3, begin the next cycle of therapy at the reduced dose. If neutropenic fever has not resolved after a 2-week delay or if it occurs after decreasing the dose to 200 mg/m2, consider discontinuing therapy.
In combination with 5-FU and leucovorin: Hold irinotecan until neutropenic fever resolves, then reduce the dose of irinotecan by 2 dose levels (IFL: 125 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 120 mg/m2) for the remainder of the current cycle; for continued toxicity, decrease the dose of irinotecan in decrements of approximately 20%. A 5-FU dose reduction is also necessary. Do not begin the next cycle until the ANC is greater than or equal to 1,500/mm3 and platelets greater than or equal to 100,000/mm3. Begin the next cycle of therapy (after adequate recovery) at the reduced dose. If the toxicity has not recovered after a 2-week delay, consider discontinuing therapy.
Pulmonary
-New or progressive dyspnea, cough, fever: Hold irinotecan pending diagnostic evaluation. Discontinue irinotecan if interstitial lung disease/pneumonitis is confirmed, and initiate appropriate treatment.
Other non-hematologic toxicities, excluding alopecia, anorexia, and asthenia
-Grade 2:
Single agent, weekly: Decrease the irinotecan dose by 25 mg/m2 for the remainder of the current cycle. After adequate recovery, begin the next cycle of therapy at the reduced dose. If the toxicity has not resolved after a 2-week delay or if it occurs after decreasing the dose to 50 mg/m2, consider discontinuing therapy.
Single agent, every 3 weeks: After adequate recovery of the toxicity, reduce the dose of irinotecan by 50 mg/m2 and begin the next cycle of therapy. If the toxicity has not resolved after a 2-week delay or if it occurs after decreasing the dose to 200 mg/m2, consider discontinuing therapy.
In combination with 5-FU and leucovorin (NOTE: do not reduce the dose of irinotecan for mucositis/stomatitis): Hold irinotecan until the toxicity resolves to less than or equal to grade 1, then decrease the dose of irinotecan by one dose level (IFL: 125 mg/m2 to 100 mg/m2, or 100 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 150 mg/m2, or 150 mg/m2 to 120 mg/m2) for the remainder of the current cycle; for continued toxicity, decrease the dose of irinotecan in decrements of approximately 20%. A 5-FU dose reduction is also necessary. After adequate recovery, begin the next cycle of therapy at the original dose. Consider discontinuation of therapy if the toxicity has not recovered after a 2-week delay.
-Grade 3:
Single agent, weekly: Hold irinotecan. When the toxicity resolves to less than or equal to grade 2, reduce the dose of irinotecan by 25 mg/m2 and resume remainder of the current cycle. After adequate recovery, begin the next cycle of therapy at the reduced dose. Consider discontinuation of therapy if the toxicity has not recovered after a 2-week delay or if it occurs after decreasing the dose to 50 mg/m2.
Single agent, every 3 weeks: After adequate recovery, reduce the dose of irinotecan by 50 mg/m2 and begin the next cycle of therapy. Consider discontinuation of therapy if the hematologic toxicity has not recovered after a 2-week delay or if it occurs after decreasing the dose to 200 mg/m2.
In combination with 5-FU and leucovorin (NOTE: do not reduce the dose of irinotecan for mucositis/stomatitis): Hold irinotecan until the toxicity resolves to less than or equal to grade 2, then decrease the dose of irinotecan by one dose level (IFL: 125 mg/m2 to 100 mg/m2, or 100 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 150 mg/m2, or 150 mg/m2 to 120 mg/m2) for the remainder of the current cycle; for continued toxicity, decrease the dose of irinotecan in decrements of approximately 20%. A 5-FU dose reduction is also necessary. After adequate recovery, begin the next cycle of therapy at the reduced dose. Consider discontinuation of therapy if the toxicity has not recovered after a 2-week delay.
-Grade 4:
Single agent, weekly: Hold irinotecan. When the toxicity resolves to less than or equal to grade 2, reduce the dose of irinotecan by 50 mg/m2 and resume remainder of the current cycle. After adequate recovery, begin the next cycle of therapy at the reduced dose. Consider discontinuation of therapy if the hematologic toxicity has not recovered after a 2-week delay or if it occurs after decreasing the dose to 50 mg/m2.
Single agent, every 3 weeks: After adequate recovery, reduce the dose of irinotecan by 50 mg/m2 and begin the next cycle of therapy. Consider discontinuation of therapy if the toxicity has not recovered after a 2-week delay or if it occurs after decreasing the dose to 200 mg/m2.
In combination with 5-FU and leucovorin (NOTE: do not reduce the dose of irinotecan for mucositis/stomatitis): Hold irinotecan until the toxicity resolves to less than or equal to grade 2, then decrease the dose of irinotecan by 2 dose levels (IFL: 125 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 120 mg/m2) for the remainder of the current cycle; for continued toxicity, decrease the dose of irinotecan in decrements of approximately 20%. A 5-FU dose reduction is also necessary. After adequate recovery, begin the next cycle of therapy at the original dose. Consider discontinuation of therapy if the toxicity has not recovered after a 2-week delay.
Maximum Dosage Limits:
-Adults
Single agent: 350 mg/m2 IV every 3 weeks or 125 mg/m2 IV weekly.
In combination with fluorouracil and leucovorin: 180 mg/m2 IV every 2 weeks or 125 mg/m2 IV weekly.
-Geriatric
Single agent: 350 mg/m2 IV (age greater than or equal to 70 years, 300 mg/m2) every 3 weeks or 125 mg/m2 IV weekly.
In combination with fluorouracil and leucovorin: 180 mg/m2 IV every 2 weeks or 125 mg/m2 IV weekly.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Increased bilirubin: Consider reducing the starting dose of irinotecan by one dose level (IFL or weekly monotherapy: 125 mg/m2 to 100 mg/m2, or 100 mg/m2 to 75 mg/m2; FOLFIRI: 180 mg/m2 to 150 mg/m2, or 150 mg/m2 to 120 mg/m2; monotherapy, every 3 weeks: 350 mg/m2 to 300 mg/m2, or 300 mg/m2 to 250 mg/m2). Dosing recommendations are not available for patients with bilirubin greater than 2 mg/dL, as irinotecan tolerability has not been assessed in these patients. In clinical trials, irinotecan was not administered to patients with serum bilirubin greater than 2 mg/dL or serum transaminases greater than 3 times the upper limit of normal (ULN) in patients without liver metastasis, or serum transaminases greater than 5 times ULN in patients with liver metastasis.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; caution is recommended if irinotecan is administered to patients with decreased renal function. Irinotecan is not recommended for use in patients on dialysis.
*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 is a camptothecin-derived topoisomerase I inhibitor. Camptothecins interact with topoisomerase I, which causes reversible single-strand breaks in the DNA, relieving torsional strain. Irinotecan and its active metabolite, SN-38, bind to the topoisomerase I/DNA complex and prevent relegation of the single-strand breaks. The cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis, when replication enzymes interact with the complex formed by topoisomerase I, DNA, and either irinotecan or SN-38, mammalian cells cannot efficiently repair these double-strand breaks.
Irinotecan is administered intravenously. Irinotecan and its active metabolite, SN-38, predominantly bind to albumin. Irinotecan exhibits moderate (30% to 68%) plasma protein binding, while SN-38 is highly protein bound (approximately 95%). After administration, plasma concentrations decline in a multi-exponential manner. After a 90-minute infusion of irinotecan 125 mg/m2, the mean terminal elimination half-life of irinotecan was 5.8 +/- 0.7 hours, and the mean terminal elimination half-life of SN-38 was 10.4 +/- 3.1 hours. The half-life increased with a higher dose (340 mg/m2), with the mean terminal elimination half-life 11.7 +/- 1 hour for irinotecan and 21 +/- 4.3 hours for SN-38. The volume of distribution of the terminal elimination phase was 110 +/- 48.5 L/m2 after the 125 mg/m2 dose and 235 +/- 69.6 L/m2 after the 340 mg/m2 dose. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form; a pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favors the hydroxy acid anion form. The half-lives of the lactone forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38. Total systemic clearance of irinotecan was 13.3 to 13.9 (+/- 4 to 6.01) L/h/m2. Urinary excretion of irinotecan is 11% to 20%; SN-38, less than 1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan in two patients ranged from 25% (100 mg/m2) to 50% (300 mg/m2).
Irinotecan is a water-soluble precursor of the lipophilic active metabolite SN-38, which is formed by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 was approximately 1,000 times as potent an inhibitor of topoisomerase I as irinotecan in human and rodent tumor cell lines; in vitro cytotoxicity assays show the potency of SN-38 relative to irinotecan varies from 2-fold to 2,000-fold. The contribution of SN-38 to the activity of irinotecan is unknown.
Affected cytochrome P-450 (CYP450) isoenzymes and drug transporters: CYP3A4, UGT1A1
Irinotecan undergoes extensive metabolism by various enzyme systems, including esterases that form an active metabolite SN-38, and UGT1A1 which mediates the glucuronidation of SN-38 to form an inactive metabolite. This metabolite, SN-38 glucuronide, had 1/50 to 1/100 the activity of SN-38. Irinotecan is also metabolized by CYP3A4 to several inactive metabolites, one of which can be hydrolyzed by carboxylesterase to release SN-38.
-Route-Specific Pharmacokinetics
Intravenous Route
The AUC of irinotecan increases linearly with dose over the recommended dose range of 50 mg/m2 to 350 mg/m2, while the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations (Cmax) of SN-38 are generally seen within 1 hour after the end of a 90-minute infusion. After a 90-minute infusion of irinotecan 125 mg/m2, the Cmax was 1,660 +/- 797 ng/mL (SN-38, 26.3 +/- 11.9 ng/mL), the AUC was 10,200 +/- 3,270 ng*h/mL (SN-38, 229 +/- 108 ng*h/mL). After a 90-minute infusion of irinotecan 340 mg/m2, the Cmax was 3,392 +/- 874 ng/mL (SN-38, 56 +/- 28.2 ng/mL), the AUC was 20,604 +/- 6,027 ng*h/mL (SN-38, 474 +/- 245 ng*h/mL).
-Special Populations
Hepatic Impairment
Irinotecan clearance is diminished in patients with hepatic impairment while exposure to the active metabolite SN-38 is increased; the magnitude of effect is proportional to the degree of liver impairment as measured by total bilirubin and transaminase concentrations.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of irinotecan has not been evaluated.
Pediatrics
Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric solid-tumor trials at dose levels of 50 mg/m2 (over 60 minutes) and 125 mg/m2 (over 90 minutes). Irinotecan mean clearance was 17.3 +/- 6.7 L/hour/m2 for the 50 mg/m2 dose and 16.2 +/- 4.6 L/hour/m2 for the 125 mg/m2 dose, which is comparable to that in adults. Dose-normalized SN-38 AUC values were comparable between adults and children. Minimal accumulation of irinotecan and SN-38 was observed in children receiving daily regimens.
Geriatric
Age did not affect the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide in a study designed to assess the effect of age on irinotecan toxicity when administered on a weekly schedule. In a separate study that was not prospectively designed to investigate the effect of age, significant differences (less than 18%) in dose-normalized irinotecan pharmacokinetic parameters in patients less than 65 years of age compared to greater than or equal to 65 years of age were observed. Dose-normalized SN-38 exposure was also higher in patients greater than or equal to 65 years of age compared to patients younger than 65, but the difference was not statistically significant.
Gender Differences
Gender does not appear to affect the pharmacokinetics of irinotecan.
Ethnic Differences
The effect of ethnicity on the pharmacokinetics of irinotecan has not been evaluated. However, approximately 20% of Black or African American patients, 10% of White patients, and 2% of East Asian patients are homozygous for the UGT1A1*28 allele; approximately 2% to 6% of East Asian patients are homozygous for the UGT1A1*6 allele, which is uncommon in Black/African American or White patients.
Other
UGT1A1 *28 or *6 Alleles
Patients who are homozygous for either the UGT1A1*28 or *6 alleles (*28/*28 or *6/*6), or who are compound or double heterozygous for these alleles (*28/*6), have a higher SN-38 AUC than patients with the wild-type UGT1A1 alleles.