PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Camptothecin Analogs

    BOXED WARNING

    Anemia, bone marrow suppression, neutropenia, thrombocytopenia

    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 homozygous for the UGT1A1*28 allele. 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.

    Dehydration, diarrhea, GI obstruction

    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.

    DEA CLASS

    Rx

    DESCRIPTION

    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

    COMMON BRAND NAMES

    Camptosar

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of metastatic colorectal cancer.
    NOTE: The use of irinotecan in combination with 5-FU/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 5-fluorouracil (5-FU) 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 5-FU (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 (125 mg/m2 to 100 mg/m2; 100 mg/m2 to 75 mg/m2) in patients who are homozygous for the UGT1A1*28 allele. Also consider reducing the dose by one dosage level for patients with prior pelvic/abdominal radiotherapy, performance status of 2, or bilirubin levels greater than 1 mg/dL. 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 5-fluorouracil (5-FU) 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 (i.e., 125 mg/m2 to 100 mg/m2; 100 mg/m2 to 75 mg/m2; minimum dose, 50 mg/m2) for patients homozygous for the UGT1A1*28 allele, patients with prior pelvic/abdominal radiotherapy, performance status of 2, or bilirubin levels greater than 1 mg/dL. 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 5-FU 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 previously treated KRAS wild-type, EGFR-expressing, metastatic colorectal cancer in combination with cetuximab†.
    NOTE: In combination with irinotecan, cetuximab is FDA-approved for the treatment of ironetacn-refractory, EGFR-expressing metastatic colorectal cancer.
    Intravenous dosage
    Adults

    Multiple irinotecan dosage regimens have been studied in combination with cetuximab; irinotecan should be administered 1 hour after completion of the cetuximab infusion. Irinotecan 350 mg/m2 IV over 90 minutes on day 1, every 3 weeks until disease progression or unacceptable toxicity, in combination with cetuximab (400 mg/m2 IV over 120 minutes on day 1, then 250 mg/m2 IV over 60 minutes, once weekly thereafter), has been administered to irinotecan naive patients; the maximum infusion rate for cetuximab is 10 mg/minute. In patients who are refractory to irinotecan-based therapy, cetuximab (400 mg/m2 IV over 120 minutes on day 1, then 250 mg/m2 IV over 60 minutes, once weekly thereafter) has been added to the dose of irinotecan that the patient had previously failed (i.e., 350 mg/m2 IV every 3 weeks; 180 mg/m2 every 2 weeks; or 125 mg/m2 IV on days 1, 8, 15, and 22, repeated 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 allele. In an open-label, randomized, phase 3 study, second-line treatment with irinotecan plus cetuximab significantly improved progression-free survival (PFS) (4 months vs. 2.6 months) compared with irinotecan alone in irinotecan-naive patients with EGFR mutation-positive metastatic colorectal cancer. Overall survival, the primary endpoint, was comparable between arm; however, almost half of the patients on the irinotecan arm received irinotecan plus cetuximab after progression. In a multicenter trial of EGFR mutation-positive metastatic colorectal cancer, recurrent on irinotecan therapy, the addition of cetuximab to the previous dose of irinotecan improved the objective response rate, median duration of response, and median time to progression compared with cetuximab monotherapy.

    For the treatment of metastatic colorectal cancer, in combination with leucovorin and 5-fluorouracil (5-FU) (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 5-FU 400 mg/m2 IV bolus, followed by 5-FU 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 5-FU 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 (180 mg/m2 to 150 mg/m2; 150 mg/m2 to 120 mg/m2) in patients who are homozygous for the UGT1A1*28 allele. Also consider reducing the dose by one dosage level for patients with prior pelvic/abdominal radiotherapy, performance status of 2, or bilirubin levels greater than 1 mg/dL. 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 5-FU/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 5-FU 400 mg/m2 IV bolus followed by 5-FU 600 mg/m2 CIV over 22 hours all on day 1; repeat leucovorin and 5-FU (bolus and CIV) on day 2. Repeat this 2-day regimen every 2 weeks until disease progression or unacceptable toxicity.

    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 allele. 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 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 over 120 minutes, 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 allele. Also consider reducing the dose by one dosage level for patients with prior pelvic/abdominal radiotherapy, performance status of 2, or bilirubin levels greater than 1 mg/dL. 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., 5-FU/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 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 first-line treatment of metastatic pancreatic cancer† in combination with oxaliplatin, fluorouracil, 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 fluorouracil 400 mg/m2 IV bolus and a continuous infusion of 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.]

    †Indicates off-label use

    MAXIMUM DOSAGE

    NOTE: The suggested maximum tolerated dose (MTD) for irinotecan is dependent on the disease state, performance status, and other chemotherapy agents or radiation given in combination.
    NOTE: The correct dose of irinotecan in the treatment of neoplastic disease will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.

    Adults

    Single agent: 350 mg/m2 IV every 3 weeks or 125 mg/m2 IV weekly.
    In combination with 5-FU 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 5-FU 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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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.

    ADMINISTRATION

     
    CAUTION: Observe and exercise usual precautions for handling, preparing, and administering solutions of cytotoxic drugs.

    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 (e.g., dexamethasone 10 mg plus another antiemetic agent, such as a 5-HT3 blocker).
    Consider prophylactic or therapeutic atropine (0.25 mg to 1 mg, intravenous or subcutaneous) for patients experiencing cholinergic symptoms.
     
    Dilution:
    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.
     
    Storage after dilution:
    Administer diluted irinotecan within 4 hours (including infusion time) when stored at room temperature, as it contains no preservatives; if reconstitution and dilution are performed under strict aseptic conditions, irinotecan may be used within 12 hours. Solutions prepared with 5% Dextrose Injection may be stored for up to 24 hours (including infusion time) if refrigerated (2 to 8 degrees C; 36 to 46 degrees F).
    Do not refrigerate irinotecan diluted in 0.9% Sodium Chloride Injection due to a low and sporadic incidence of visible particles. Do not freeze, regardless of diluent.
     
    Intravenous Administration:
    Infuse intravenously over 90 minutes.

    STORAGE

    Camptosar:
    - Do not freeze
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Radiation therapy

    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/pneumonitis. Closely monitor patients who have received prior radiation therapy for an increase in irinotecan-related adverse reactions.

    Anemia, bone marrow suppression, neutropenia, thrombocytopenia

    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 homozygous for the UGT1A1*28 allele. 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.

    Poor metabolizers

    Patients who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are poor metabolizers and are at increased risk for neutropenia during treatment with irinotecan. Reduce the dose of irinotecan by at least one dose level for patients known to be homozygous for the UGT1A1*28 allele, whether administered as monotherapy or in combination with other chemotherapy; however, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment.

    Chronic lung disease (CLD), pneumonitis

    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.

    Dehydration, diarrhea, GI obstruction

    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.

    Geriatric

    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.

    Biliary tract disease, hepatic disease

    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.

    Extravasation

    Monitor the infusion site for signs of inflammation; avoid extravasation. If extravasation occurs, flush the site with sterile water and apply ice.

    Accidental exposure

    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.

    Children

    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

    Irinotecan is FDA pregnancy risk category D. Pregnancy should be avoided by females of reproductive potential during irinotecan treatment. 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. Women who are pregnant or who become pregnant while receiving irinotecan should be apprised of the potential hazard to the fetus. Administration to rats and rabbits at a dose of 6 mg/kg/day during the period of organogenesis increased post-implantation loss and decreased numbers of live fetuses. In separate rat studies, this dose produced an irinotecan AUC of approximately 0.2 times that achieved at a dose of 125 mg/m2 in humans. In rabbits, the embryotoxic dose was about one-half the recommended human weekly starting dose on a mg/m2 basis. Teratogenic effects include a variety of external, visceral, and skeletal abnormalities. When administered to rats during the period following organogenesis through weaning at doses of 6 mg/kg/day, irinotecan administration decreased learning ability and decreased female body weights in the offspring.

    Infertility, reproductive risk

    Counsel patients about the reproductive risk during irinotecan treatment. Irinotecan can be teratogenic if taken by the mother during pregnancy. Females and males with female partners of reproductive potential should avoid pregnancy during treatment with irinotecan. 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. The effects of irinotecan on infertility in animal studies are conflicting. No significant effects on fertility and general reproductive performance were observed when administered at doses up to 6 mg/kg/day IV to rats and rabbits. However, 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.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from irinotecan, advise women to discontinue breast-feeding during treatment. It is not known whether irinotecan is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 14.0-31.4
    diarrhea / Early / 6.7-31.0
    anemia / Delayed / 4.5-7.0
    thromboembolism / Delayed / 5.4-5.4
    exfoliative dermatitis / Delayed / 0.9-0.9
    renal failure (unspecified) / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    typhlitis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    stroke / Early / Incidence not known
    thrombosis / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    leukopenia / Delayed / 63.0-96.4
    thrombocytopenia / Delayed / 96.0-96.0
    hyperbilirubinemia / Delayed / 83.9-83.9
    constipation / Delayed / 30.0-32.3
    stomatitis / Delayed / 12.0-29.6
    dyspnea / Early / 22.0-22.0
    dehydration / Delayed / 15.0-15.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 10.3-10.3
    edema / Delayed / 10.0-10.0
    elevated hepatic enzymes / Delayed / 10.0-10.0
    hypotension / Rapid / 5.8-5.8
    bleeding / Early / 1.0-5.0
    confusion / Early / 2.7-2.7
    dysarthria / Delayed / Incidence not known
    bone marrow suppression / Delayed / Incidence not known
    hypovolemia / Early / Incidence not known
    colitis / Delayed / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    angina / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    ascites / Delayed / Incidence not known

    Mild

    nausea / Early / 70.0-86.0
    asthenia / Delayed / 69.1-76.0
    alopecia / Delayed / 46.1-72.0
    abdominal pain / Early / 57.0-67.7
    vomiting / Early / 62.0-67.0
    anorexia / Delayed / 43.9-55.0
    fever / Early / 43.5-45.0
    weight loss / Delayed / 30.0-30.0
    dizziness / Early / 15.0-21.1
    cough / Delayed / 17.0-20.2
    insomnia / Early / 19.0-19.0
    headache / Early / 17.0-17.0
    rhinitis / Early / 16.0-16.0
    rash / Early / 13.0-14.3
    back pain / Delayed / 14.0-14.0
    chills / Rapid / 14.0-14.0
    infection / Delayed / 1.0-14.0
    flatulence / Early / 12.0-12.0
    flushing / Rapid / 9.0-11.0
    dyspepsia / Early / 10.0-10.0
    drowsiness / Early / 9.4-9.4
    hypersalivation / Early / Incidence not known
    diaphoresis / Early / Incidence not known
    miosis / Early / Incidence not known
    lacrimation / Early / Incidence not known
    syncope / Early / Incidence not known
    vertigo / Early / Incidence not known
    hiccups / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acalabrutinib: (Moderate) Coadministration of acalabrutinib and irinotecan may increase irinotecan exposure and increase the risk of irinotecan toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Irinotecan is a BCRP subtrate.
    Amoxicillin; Clarithromycin; Lansoprazole: (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 is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    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 is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Apalutamide: (Major) Avoid coadministration of irinotecan with apalutamide unless there are no therapeutic alternatives, due to decreased plasma concentrations of irinotecan; consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan therapy. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Apalutamide is a strong CYP3A4 inducer as well as a UGT inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or its active metabolite SN-38 in both adult and pediatric patients.
    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: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together. (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.
    Atracurium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Atropine; Hyoscyamine; Phenobarbital; 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 is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with phenobarbital and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Belladonna Alkaloids; Ergotamine; 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 is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with phenobarbital and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Bosentan: (Major) Bosentan is a moderate CYP3A4 inducer; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not affect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    Cabozantinib: (Minor) Monitor for an increase in irinotecan-related adverse reactions if coadministration with cabozantinib is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    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 is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with carbamazepine and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Carvedilol: (Moderate) Increased concentrations of irinotecan may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and irinotecan is a P-gp substrate. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Ceritinib: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with ceritinib is necessary. Ceritinib is a CYP3A4 inhibitor and irinotecan is metabolized by CYP3A4. Patients treated with a strong CYP3A4 inhibitor had increased exposure to irinotecan. The manufacturer of irinotecan recommends avoiding strong CYP3A4 inhibitors for at least 1 week prior to starting therapy unless there are no therapeutic alternatives; the degree of CYP3A4 inhibition by ceritinib is unknown.
    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 is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Cisatracurium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    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 is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Cobicistat: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together.
    Conivaptan: (Major) Avoid administration of conivaptan 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 conivaptan is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38; concomitant use of other strong CYP3A4 inhibitors may also increase systemic exposure.
    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 is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Darunavir; Cobicistat: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together. (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 is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together. (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 is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid administration of dasabuvir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; dasabuvir is a UGT1A1 inhibitor. Concomitant use of UGT1A1 inhibitors may increase systemic exposure to SN-38. (Major) Avoid administration of ombitasvir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; ombitasvir is a UGT1A1 inhibitor. Concomitant use may increase systemic exposure to SN-38 (Major) Avoid administration of paritaprevir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; paritaprevir is a UGT1A1 inhibitor. Concomitant use with UGT1A1 inhibitors may increase systemic exposure to SN-38. (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 is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    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 is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with quinidine is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Doxacurium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    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 is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Flibanserin: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with flibanserin is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and flibanserin is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    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 is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    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 is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with phenytoin and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Fostamatinib: (Moderate) Monitor for irinotecan toxicities that may require irinotecan dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP or P-gp substrate may increase the concentration of the BCRP or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a BCRP inhibitor; irinotecan is a substrate for BCRP and P-gp. Coadministration of fostamatinib with another BCRP substrate increased the substrate AUC by 95% and Cmax by 88%. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%.
    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.
    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 is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    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 is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. 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 is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Itraconazole: (Severe) 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 is a CYP3A4 substrate and its active metabolite, SN-38, is a UGT1A1 substrate. Ketoconazole is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased exposure to both 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.
    Lomitapide: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with lomitapide is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and lomitapide is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Lopinavir; Ritonavir: (Major) Avoid administration of lopinavir; ritonavir 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 lopinavir; ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan. (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 is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    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 is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Mefloquine: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with mefloquine is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and mefloquine is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Mephobarbital: (Major) Avoid administration of mephobarbital during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Mifepristone: (Major) Avoid administration of chronic mifepristone therapy 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 mifepristone is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan. 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 is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Mivacurium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    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 is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    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 is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Neratinib: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with neratinib is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Neuromuscular blockers: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid administration of ombitasvir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; ombitasvir is a UGT1A1 inhibitor. Concomitant use may increase systemic exposure to SN-38 (Major) Avoid administration of paritaprevir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; paritaprevir is a UGT1A1 inhibitor. Concomitant use with UGT1A1 inhibitors may increase systemic exposure to SN-38. (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 is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Osimertinib: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with osimertinib is necessary. Irinotecan is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pancuronium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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 is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with phenobarbital and other strong CYP3A4 inducers. 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 is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with phenytoin and other strong CYP3A4 inducers. 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 is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38; concomitant use of other strong CYP3A4 inhibitors may also increase systemic exposure.
    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 is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. 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.
    Propafenone: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with propafenone is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Quinidine: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with quinidine is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Rapacuronium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Ribociclib: (Major) Discontinue ribociclib at least 1 week prior to starting irinotecan therapy; do not administer ribociclib with irinotecan unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to both irinotecan and SN-38.
    Ribociclib; Letrozole: (Major) Discontinue ribociclib at least 1 week prior to starting irinotecan therapy; do not administer ribociclib with irinotecan unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased 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 is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. 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 is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Rocuronium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    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 is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Sofosbuvir; Velpatasvir: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with velpatasvir is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with velpatasvir is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    St. John's Wort, Hypericum perforatum: (Major) Avoid administration of St. John's Wort during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with St. John's Wort and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Streptogramins: (Major) Avoid administration of dalfopristin; quinupristin 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 quinupristin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Succinylcholine: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Telithromycin: (Major) Avoid administration of telithromycin 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 telithromycin is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38; concomitant use of other strong CYP3A4 inhibitors may also increase systemic exposure.
    Temsirolimus: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with temsirolimus is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of irinotecan.
    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 is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    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.
    Tubocurarine: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Vecuronium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    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 is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.

    PREGNANCY AND LACTATION

    Pregnancy

    Irinotecan is FDA pregnancy risk category D. Pregnancy should be avoided by females of reproductive potential during irinotecan treatment. 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. Women who are pregnant or who become pregnant while receiving irinotecan should be apprised of the potential hazard to the fetus. Administration to rats and rabbits at a dose of 6 mg/kg/day during the period of organogenesis increased post-implantation loss and decreased numbers of live fetuses. In separate rat studies, this dose produced an irinotecan AUC of approximately 0.2 times that achieved at a dose of 125 mg/m2 in humans. In rabbits, the embryotoxic dose was about one-half the recommended human weekly starting dose on a mg/m2 basis. Teratogenic effects include a variety of external, visceral, and skeletal abnormalities. When administered to rats during the period following organogenesis through weaning at doses of 6 mg/kg/day, irinotecan administration decreased learning ability and decreased female body weights in the offspring.

    Due to the potential for serious adverse reactions in nursing infants from irinotecan, advise women to discontinue breast-feeding during treatment. It is not known whether irinotecan is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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 multiexponential 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 extensively metabolized by various enzyme systems. It 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, P-glycoprotein (P-gp)
    Irinotecan is a CYP3A4 substrate, undergoing oxidative metabolism to several inactive products, one of which can be hydrolyzed by carboxylesterase to release SN-38. UGT1A1 mediates the glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G; SN-38 glucuronide has 1/50 to 1/100 the activity of SN-38. Patients with certain genetic polymorphisms, such as UGT1A1*28 polymorphism, have reduced UGT1A1 activity; these patients have had higher exposure to SN-38 than patients with wild-type UGT1A1 allele (UGT1A1 6/6 genotype). Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype). Elimination is dependent on the presence of P-glycoprotein (P-gp). In vitro, neither irinotecan, SN-38, nor aminopentane carboxylic acid (APC) inhibit CYP450 isoenzymes.

    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).