Camptosar

Camptothecin Analogs

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

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.

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

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.

neutropenia / Delayed / 14.0-53.8
leukopenia / Delayed / 14.0-37.8
diarrhea / Early / 1.4-31.0
asthenia / Delayed / 9.0-19.5
nausea / Early / 2.1-17.0
abdominal pain / Early / 9.0-16.0
vomiting / Early / 3.5-14.0
drowsiness / Early / 0-12.0
thromboembolism / Delayed / 0-11.7
cough / Delayed / 0-10.0
dyspnea / Early / 1.4-10.0
constipation / Delayed / 0.4-10.0
anemia / Delayed / 2.1-8.4
infection / Delayed / 0-8.0
anorexia / Delayed / 2.1-7.2
hyperbilirubinemia / Delayed / 0-7.2
thrombocytopenia / Delayed / 1.7-4.0
dehydration / Delayed / 4.0-4.0
back pain / Delayed / 0-2.0
fever / Early / 0.4-2.0
stomatitis / Delayed / 0-2.0
confusion / Early / 0-1.8
dizziness / Early / 0-1.8
hypotension / Rapid / 1.3-1.7
headache / Early / 0-1.0
elevated hepatic enzymes / Delayed / 0-1.0
edema / Delayed / 0-1.0
weight loss / Delayed / 0-1.0
flushing / Rapid / 0-0.9
exfoliative dermatitis / Delayed / 0.9-0.9
bradycardia / Rapid / Incidence not known
GI bleeding / Delayed / Incidence not known
GI obstruction / Delayed / Incidence not known
toxic megacolon / Delayed / Incidence not known
ileus / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
cardiac arrest / Early / Incidence not known
pulmonary embolism / Delayed / Incidence not known
stroke / Early / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known

hypokalemia / Delayed / 0-23.8
hyponatremia / Delayed / 0-14.3
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 10.3-10.3
bleeding / Early / 1.0-5.0
dysarthria / Delayed / Incidence not known
pneumonitis / Delayed / Incidence not known
interstitial lung disease / Delayed / Incidence not known
bone marrow suppression / Delayed / Incidence not known
colitis / Delayed / Incidence not known
oral ulceration / Delayed / Incidence not known
hyperamylasemia / Delayed / Incidence not known
hypovolemia / Early / Incidence not known
phlebitis / Rapid / Incidence not known
angina / Early / Incidence not known
jaundice / Delayed / Incidence not known
ascites / Delayed / Incidence not known
hepatomegaly / Delayed / Incidence not known
akathisia / Delayed / Incidence not known

alopecia / Delayed / 46.1-72.0
insomnia / Early / 0-19.0
rhinitis / Early / 0-16.0
rash / Early / 13.0-14.3
chills / Rapid / 0-14.0
flatulence / Early / 0-12.0
dyspepsia / Early / 0-10.0
vertigo / Early / Incidence not known
syncope / Early / Incidence not known
miosis / Early / Incidence not known
diaphoresis / Early / Incidence not known
lacrimation / Early / Incidence not known
hypersalivation / Early / Incidence not known

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.[30469]

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.

Camptosar

Rx

Camptothecin-derived topoisomerase I inhibitor
Used for the treatment of metastatic colorectal cancer, as well as several off-label indications
Severe myelosuppression and diarrhea are common; monitor and treat appropriately

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.

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.

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.

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.

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%).

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%).

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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).

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.]

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.  

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.

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.

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.

†Indicates off-label use

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.

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.

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

Camptosar/Irinotecan/Irinotecan Hydrochloride Intravenous Inj Sol: 1mL, 20mg

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.

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.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.

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).

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.

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.