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  • 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 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:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from freezing
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 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
    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

    Amiodarone: (Moderate) Amiodarone is an inhibitor of CYP3A4 and P-glycoprotein (P-gp); irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Clarithromycin is a strong CYP3A4 and moderate 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 the drugs are used together. Do not administer clarithromycin concurrently with irinotecan unless there are no therapeutic alternatives; discontinue clarithromycin at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Clarithromycin is a strong CYP3A4 and moderate 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 the drugs are used together. Do not administer clarithromycin concurrently with irinotecan unless there are no therapeutic alternatives; discontinue clarithromycin at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Atazanavir: (Major) Do not administer atazanavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue atazanavir at least 1 week before starting irinotecan. Atazanavir; cobicistat is contraindicated in combination with irinotecan. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Atazanavir is a strong CYP3A4 inhibitor and a UGT1A1 inhibitor; irinotecan is a CYP3A4 and UGT1A1 substrate.
    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) Do not administer atazanavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue atazanavir at least 1 week before starting irinotecan. Atazanavir; cobicistat is contraindicated in combination with irinotecan. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Atazanavir is a strong CYP3A4 inhibitor and a UGT1A1 inhibitor; irinotecan is a CYP3A4 and UGT1A1 substrate.
    Atracurium: (Moderate) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Substantial reduction in the exposure of irinotecan and SN-38, the active metabolite, occurs in children and adults who concomitantly receive CYP3A4-inducing drugs such as phenobarbital. As the appropriate starting dose of irinotecan for patients taking a CYP3A4-inducing anticonvulsant has not been formally defined, substitution of a non-enzyme inducing drug at least 2 weeks before irinotecan initiation should be considered. Do not administer strong CYP3A4 inducers such as phenobarbital unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for decreased irinotecan effects. Pharmacokinetic interactions resulting in decreased irinotecan toxicity were noted during a clinical study in patients with malignant gliomas. During this study, 29 of 32 patients (91%) were receiving concurrent enzyme-inducing anticonvulsant therapy (i.e., carbamazepine, phenobarbital, or phenytoin). In this study, irinotecan clearance was approximately 2-fold higher than usually reported and resulted in a mean AUC that was 40% of previously reported values. The Cmax of the metabolites of irinotecan, SN-38 and SN-38G, were 47% and 71% of previously reported values, respectively, resulting in AUC values that were 25% of those previously observed. The low ratio of SN-38 and SN-38G AUC suggests increased rates of glucuronidation of SN-38. The increased clearance of irinotecan is consistent with induction of cytochrome P450 3A4 by the enzyme-inducing anticonvulsants, leading to increased conversion of irinotecan to aminopentane carboxylic acid (APC). Since mephobarbital and primidone are barbiturates metabolized to phenobarbital, similar interactions may be anticipated. This interaction may be relevant to combination products containing these drugs, such as combinations of atropine; hyoscyamine; phenobarbital; scopolamine and combinations of belladonna alkaloids; ergotamine; phenobarbital.
    Azithromycin: (Major) Irinotecan is a substrate of P-glycoprotein (P-gp) and azithromycin is a P-gp inhibitor; therefore, irinotecan concentrations could be increased with coadministration. Monitor patients for increased side effects if these drugs are given together.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Substantial reduction in the exposure of irinotecan and SN-38, the active metabolite, occurs in children and adults who concomitantly receive CYP3A4-inducing drugs such as phenobarbital. As the appropriate starting dose of irinotecan for patients taking a CYP3A4-inducing anticonvulsant has not been formally defined, substitution of a non-enzyme inducing drug at least 2 weeks before irinotecan initiation should be considered. Do not administer strong CYP3A4 inducers such as phenobarbital unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for decreased irinotecan effects. Pharmacokinetic interactions resulting in decreased irinotecan toxicity were noted during a clinical study in patients with malignant gliomas. During this study, 29 of 32 patients (91%) were receiving concurrent enzyme-inducing anticonvulsant therapy (i.e., carbamazepine, phenobarbital, or phenytoin). In this study, irinotecan clearance was approximately 2-fold higher than usually reported and resulted in a mean AUC that was 40% of previously reported values. The Cmax of the metabolites of irinotecan, SN-38 and SN-38G, were 47% and 71% of previously reported values, respectively, resulting in AUC values that were 25% of those previously observed. The low ratio of SN-38 and SN-38G AUC suggests increased rates of glucuronidation of SN-38. The increased clearance of irinotecan is consistent with induction of cytochrome P450 3A4 by the enzyme-inducing anticonvulsants, leading to increased conversion of irinotecan to aminopentane carboxylic acid (APC). Since mephobarbital and primidone are barbiturates metabolized to phenobarbital, similar interactions may be anticipated. This interaction may be relevant to combination products containing these drugs, such as combinations of atropine; hyoscyamine; phenobarbital; scopolamine and combinations of belladonna alkaloids; ergotamine; phenobarbital.
    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.
    Brigatinib: (Moderate) Monitor for decreased efficacy of irinotecan if coadministration with brigatinib is necessary. Irinotecan is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of irinotecan may decrease.
    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) Substantial reduction in the exposure of irinotecan and SN-38, the active metabolite, occurs in children and adults who concomitantly receive CYP3A4-inducing drugs such as carbamazepine. As the appropriate starting dose of irinotecan for patients taking a CYP3A4-inducing anticonvulsant has not been formally defined, substitution of a non-enzyme inducing drug at least 2 weeks before irinotecan initiation should be considered. Do not administer strong CYP3A4 inducers such as carbamazepine unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for decreased irinotecan effects. Pharmacokinetic interactions resulting in decreased irinotecan toxicity were noted during a clinical study in patients with malignant gliomas. During this study, 29 of 32 patients (91%) were receiving concurrent enzyme-inducing anticonvulsant therapy such as carbamazepine, In this study, irinotecan clearance was approximately 2-fold higher than usually reported and resulted in a mean AUC that was 40% of previously reported values. The Cmax of the metabolites of irinotecan, SN-38 and SN-38G, were 47% and 71% of previously reported values, respectively, resulting in AUC values that were 25% of those previously observed. The low ratio of SN-38 and SN-38G AUC suggests increased rates of glucuronidation of SN-38. The increased clearance of irinotecan is consistent with induction of cytochrome P450 3A4 by the enzyme-inducing anticonvulsants, leading to increased conversion of irinotecan to aminopentane carboxylic acid (APC).
    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) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Clarithromycin: (Major) Clarithromycin is a strong CYP3A4 and moderate 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 the drugs are used together. Do not administer clarithromycin concurrently with irinotecan unless there are no therapeutic alternatives; discontinue clarithromycin at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    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 coadministration of conivaptan, a strong CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and irinotecan, a CYPA4/P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Cyclosporine: (Moderate) Cyclosporine is a moderate inhibitor of both CYP3A4 and P-glycoprotein (P-gp); irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Daclatasvir: (Moderate) Systemic exposure of irinotecan, a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a P-gp and BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of irinotecan; monitor patients for potential adverse effects.
    Darunavir: (Major) Darunavir is a strong CYP3A4 and moderate 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 the drugs are used together. Do not administer darunavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue darunavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    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) Darunavir is a strong CYP3A4 and moderate 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 the drugs are used together. Do not administer darunavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue darunavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Dasabuvir; 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) Ritonavir is a strong CYP3A4 inhibitor, moderate P-glycoprotein inhibitor, and moderate CYP3A4 inducer. Irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer ritonavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue ritonavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Delavirdine: (Major) Delavirdine is a strong CYP3A4 inhibitor; irinotecan is a CYP3A4 substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer delavirdine concurrently with irinotecan unless there are no therapeutic alternatives; discontinue delavirdine at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    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) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Eliglustat: (Major) Coadministration of irinotecan and eliglustat may result in increased plasma concentrations of irinotecan. If coadministration is necessary, use caution and monitor closely. Irinotecan is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
    Enzalutamide: (Major) Avoid coadministration of irinotecan with enzalutamide 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 enzalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or its active metabolite SN-38 in both adult and pediatric patients.
    Erythromycin: (Moderate) Erythromycin is an inhibitor of CYP3A4 and P-glycoprotein (P-gp); irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Erythromycin; Sulfisoxazole: (Moderate) Erythromycin is an inhibitor of CYP3A4 and P-glycoprotein (P-gp); irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Etravirine: (Moderate) Etravirine is a CYP3A4 inducer/substrate and a P-glycoprotein (PGP) inhibitor and irinotecan is a CYP3A4 and PGP substrate. Caution is warranted if these drugs are coadministered.
    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) Fosamprenavir is a strong inhibitor of CYP3A4; irinotecan is a CYP3A4 substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer fosamprenavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue fosamprenavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Fosphenytoin: (Major) Substantial reduction in the exposure of irinotecan and SN-38, the active metabolite, occurs in children and adults who concomitantly receive CYP3A4-inducing drugs such as phenytoin or fosphenytoin. As the appropriate starting dose of irinotecan for patients taking a CYP3A4-inducing anticonvulsant has not been formally defined, substitution of a non-enzyme inducing drug at least 2 weeks before irinotecan initiation should be considered. Do not administer strong CYP3A4 inducers unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for decreased irinotecan effects. Pharmacokinetic interactions resulting in decreased irinotecan toxicity were noted during a clinical study in patients with malignant gliomas. During this study, 29 of 32 patients (91%) were receiving concurrent enzyme-inducing anticonvulsant therapy (e.g., phenytoin and others). In this study, irinotecan clearance was approximately 2-fold higher than usually reported and resulted in a mean AUC that was 40% of previously reported values. The Cmax of the metabolites of irinotecan, SN-38 and SN-38G, were 47% and 71% of previously reported values, respectively, resulting in AUC values that were 25% of those previously observed. The low ratio of SN-38 and SN-38G AUC suggests increased rates of glucuronidation of SN-38. The increased clearance of irinotecan is consistent with induction of cytochrome P450 3A4 by the enzyme-inducing anticonvulsants, leading to increased conversion of irinotecan to aminopentane carboxylic acid (APC).
    Gemfibrozil: (Major) Gemfibrozil is a UGT1A1 inhibitor and irinotecan is a UGT1A1 substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer gemfibrozil concurrently with irinotecan unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. A dose reduction of irinotecan may be required if used concomitantly with gemfibrozil.
    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) Grapefruit juice is a strong CYP3A4 inhibitor; irinotecan is a CYP3A4 substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer grapefruit juice concurrently with irinotecan unless there are no therapeutic alternatives; discontinue grapefruit juice at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Idelalisib: (Major) Idelalisib is a strong CYP3A4 inhibitor; irinotecan is a CYP3A4 substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer idelalisib concurrently with irinotecan unless there are no therapeutic alternatives; discontinue idelalisib at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Indinavir: (Major) Indinavir is a strong CYP3A4 inhibitor; irinotecan is a CYP3A4 substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer indinavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue indinavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with irinotecan may result in increased serum concentrations of irinotecan. Irinotecan is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin is a strong CYP3A4 inducer and moderate P-glycoprotein (P-gp) inducer; irinotecan is a CYP3A4 and P-gp substrate. In patients treated with other strong CYP3A4 inducers, exposure to irinotecan and its active metabolite, SN-38, were substantially reduced in both adult and pediatric patients. The appropriate starting dose for patients taking strong CYP3A4 inducers is not known; do not administer strong CYP3A4 inducers such as rifampin unless there are no therapeutic alternatives.
    Isoniazid, INH; Rifampin: (Major) Rifampin is a strong CYP3A4 inducer and moderate P-glycoprotein (P-gp) inducer; irinotecan is a CYP3A4 and P-gp substrate. In patients treated with other strong CYP3A4 inducers, exposure to irinotecan and its active metabolite, SN-38, were substantially reduced in both adult and pediatric patients. The appropriate starting dose for patients taking strong CYP3A4 inducers is not known; do not administer strong CYP3A4 inducers such as rifampin unless there are no therapeutic alternatives.
    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.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and irinotecan concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as irinotecan, can increase irinotecan exposure leading to increased or prolonged therapeutic effects and adverse events. If concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Ketoconazole: (Major) Ketoconazole is a strong CYP3A4 inhibitor and an inhibitor of UGT1A1; irinotecan is a CYP3A4 and UGT1A1 substrate. Exposure to irinotecan and to the active metabolite, SN-38, is increased when the drugs are used together. Discontinue ketoconazole at least 1 week before starting irinotecan. Do not administer ketoconazole concurrently with irinotecan unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Lapatinib: (Moderate) Irinotecan is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Coadministration of lapatinib and irinotecan may lead to increased serum concentrations of irinotecan. Cautious coadministration is recommended, and consider a dose reduction of irinotecan.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of irinotecan-associated adverse reactions is advised with concomitant administration of ledipasvir. Irinotecan is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase irinotecan plasma concentrations.
    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) Lopinavir; ritonavir is a strong CYP3A4 inhibitor, moderate P-glycoprotein (P-gp) inhibitor, and moderate CYP3A4 inducer. Irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer ritonavir or lopinavir; ritonavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue lopinavir; ritonavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. (Major) Ritonavir is a strong CYP3A4 inhibitor, moderate P-glycoprotein inhibitor, and moderate CYP3A4 inducer. Irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer ritonavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue ritonavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Lumacaftor; Ivacaftor: (Major) Concomitant use of lumacaftor; ivacaftor and irinotecan should be avoided unless there are no therapeutic alternatives. If used together, monitor patients closely for loss of irinotecan efficacy; a irinotecan dosage adjustment may be required to obtain the desired therapeutic effect. Irinotecan is a CYP3A4 and P-gp substrate. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. In patients treated with other strong CYP3A4 inducers, exposure to irinotecan and its active metabolite, SN-38, were substantially reduced in both adult and pediatric patients. The appropriate starting dose for patients taking strong CYP3A4 inducers is not known.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and irinotecan concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as irinotecan, can increase irinotecan exposure leading to increased or prolonged therapeutic effects and adverse events. If concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    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) Substantial reduction in the exposure of irinotecan and SN-38, the active metabolite, occurs in children and adults who concomitantly receive CYP3A4-inducing drugs such as phenobarbital. As the appropriate starting dose of irinotecan for patients taking a CYP3A4-inducing anticonvulsant has not been formally defined, substitution of a non-enzyme inducing drug at least 2 weeks before irinotecan initiation should be considered. Do not administer strong CYP3A4 inducers such as phenobarbital unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for decreased irinotecan effects. Pharmacokinetic interactions resulting in decreased irinotecan toxicity were noted during a clinical study in patients with malignant gliomas. During this study, 29 of 32 patients (91%) were receiving concurrent enzyme-inducing anticonvulsant therapy (i.e., carbamazepine, phenobarbital, or phenytoin). In this study, irinotecan clearance was approximately 2-fold higher than usually reported and resulted in a mean AUC that was 40% of previously reported values. The Cmax of the metabolites of irinotecan, SN-38 and SN-38G, were 47% and 71% of previously reported values, respectively, resulting in AUC values that were 25% of those previously observed. The low ratio of SN-38 and SN-38G AUC suggests increased rates of glucuronidation of SN-38. The increased clearance of irinotecan is consistent with induction of cytochrome P450 3A4 by the enzyme-inducing anticonvulsants, leading to increased conversion of irinotecan to aminopentane carboxylic acid (APC). Since mephobarbital and primidone are barbiturates metabolized to phenobarbital, similar interactions may be anticipated. This interaction may be relevant to combination products containing these drugs, such as combinations of atropine; hyoscyamine; phenobarbital; scopolamine and combinations of belladonna alkaloids; ergotamine; phenobarbital.
    Mifepristone, RU-486: (Moderate) Mifepristone, RU-486 is a moderate inhibitor of P-glycoprotein (P-gp) and, in vitro, a moderate CYP3A4 inhibitor; irinotecan is a CYP3A4 substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Mitotane: (Major) The appropriate starting dose for irinotecan in patients taking mitotane is unknown; do not administer strong CYP3A4 inducers such as mitotane with irinotecan, a CYP3A substrate, unless there are no therapeutic alternatives. If coadministration is necessary, consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan therapy. In patients treated with other strong CYP3A4 inducers, exposure to irinotecan and its active metabolite, SN-38, were substantially reduced in both adult and pediatric patients.
    Mivacurium: (Moderate) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Nefazodone: (Major) Nefazodone is a strong CYP3A4 inhibitor; irinotecan is a CYP3A4 substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer nefazodone concurrently with irinotecan unless there are no therapeutic alternatives; discontinue nefazodone at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Nelfinavir: (Major) Nelfinavir is a strong CYP3A4 and moderate 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 the drugs are used together. Do not administer nelfinavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue nelfinavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    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) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Nicardipine: (Moderate) Nicardipine is a strong P-glycoprotein (P-gp) inhibitor and, in vitro, a moderate inhibitor of CYP3A4; irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Nilotinib: (Major) Concomitant use of nilotinib, a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and irinotecan, a CYP3A4 and P-gp substrate with a narrow therapeutic range, may result in increased irinotecan levels. An irinotecan dose reduction may be necessary if these drugs are used together.
    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) Ritonavir is a strong CYP3A4 inhibitor, moderate P-glycoprotein inhibitor, and moderate CYP3A4 inducer. Irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer ritonavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue ritonavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    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) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenobarbital: (Major) Substantial reduction in the exposure of irinotecan and SN-38, the active metabolite, occurs in children and adults who concomitantly receive CYP3A4-inducing drugs such as phenobarbital. As the appropriate starting dose of irinotecan for patients taking a CYP3A4-inducing anticonvulsant has not been formally defined, substitution of a non-enzyme inducing drug at least 2 weeks before irinotecan initiation should be considered. Do not administer strong CYP3A4 inducers such as phenobarbital unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for decreased irinotecan effects. Pharmacokinetic interactions resulting in decreased irinotecan toxicity were noted during a clinical study in patients with malignant gliomas. During this study, 29 of 32 patients (91%) were receiving concurrent enzyme-inducing anticonvulsant therapy (i.e., carbamazepine, phenobarbital, or phenytoin). In this study, irinotecan clearance was approximately 2-fold higher than usually reported and resulted in a mean AUC that was 40% of previously reported values. The Cmax of the metabolites of irinotecan, SN-38 and SN-38G, were 47% and 71% of previously reported values, respectively, resulting in AUC values that were 25% of those previously observed. The low ratio of SN-38 and SN-38G AUC suggests increased rates of glucuronidation of SN-38. The increased clearance of irinotecan is consistent with induction of cytochrome P450 3A4 by the enzyme-inducing anticonvulsants, leading to increased conversion of irinotecan to aminopentane carboxylic acid (APC). Since mephobarbital and primidone are barbiturates metabolized to phenobarbital, similar interactions may be anticipated. This interaction may be relevant to combination products containing these drugs, such as combinations of atropine; hyoscyamine; phenobarbital; scopolamine and combinations of belladonna alkaloids; ergotamine; phenobarbital.
    Phenytoin: (Major) Substantial reduction in the exposure of irinotecan and SN-38, the active metabolite, occurs in children and adults who concomitantly receive CYP3A4-inducing drugs such as phenytoin or fosphenytoin. As the appropriate starting dose of irinotecan for patients taking a CYP3A4-inducing anticonvulsant has not been formally defined, substitution of a non-enzyme inducing drug at least 2 weeks before irinotecan initiation should be considered. Do not administer strong CYP3A4 inducers unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for decreased irinotecan effects. Pharmacokinetic interactions resulting in decreased irinotecan toxicity were noted during a clinical study in patients with malignant gliomas. During this study, 29 of 32 patients (91%) were receiving concurrent enzyme-inducing anticonvulsant therapy (e.g., phenytoin and others). In this study, irinotecan clearance was approximately 2-fold higher than usually reported and resulted in a mean AUC that was 40% of previously reported values. The Cmax of the metabolites of irinotecan, SN-38 and SN-38G, were 47% and 71% of previously reported values, respectively, resulting in AUC values that were 25% of those previously observed. The low ratio of SN-38 and SN-38G AUC suggests increased rates of glucuronidation of SN-38. The increased clearance of irinotecan is consistent with induction of cytochrome P450 3A4 by the enzyme-inducing anticonvulsants, leading to increased conversion of irinotecan to aminopentane carboxylic acid (APC).
    Ponatinib: (Moderate) Concomitant use of ponatinib, an ABCG2 (BCRP) inhibitor, and irinotecan, an ABCG2 (BCRP) substrate, may increase the exposure of irinotecan.
    Posaconazole: (Major) Posaconazole is a strong CYP3A4 and moderate 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 the drugs are used together. Do not administer posaconazole concurrently with irinotecan unless there are no therapeutic alternatives; discontinue posaconazole at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Primidone: (Severe) Substantial reduction in the exposure of irinotecan and SN-38, the active metabolite, occurs in children and adults who concomitantly receive the CYP3A4-inducing drugs phenytoin, fosphenytoin, phenobarbital, and carbamazepine. As the appropriate starting dose of irinotecan for patients taking a CYP3A4-inducing anticonvulsant has not been formally defined, substitution of a non-enzyme inducing drug at least 2 weeks before irinotecan initiation should be considered. Do not administer strong CYP3A4 inducers such as phenytoin, fosphenytoin, phenobarbital, or carbamazepine within at least 2 weeks of starting irinotecan therapy. Pharmacokinetic interactions resulting in decreased irinotecan toxicity were noted during a clinical study in patients with malignant gliomas. During this study, 29 of 32 patients (91%) were receiving concurrent enzyme-inducing anticonvulsant therapy (i.e., carbamazepine, phenobarbital, or phenytoin). In this study, irinotecan clearance was approximately 2-fold higher than usually reported and resulted in a mean AUC that was 40% of previously reported values. The Cmax of the metabolites of irinotecan, SN-38 and SN-38G, were 47% and 71% of previously reported values, respectively, resulting in AUC values that were 25% of those previously observed. The low ratio of SN-38 and SN-38G AUC suggests increased rates of glucuronidation of SN-38. The increased clearance of irinotecan is consistent with induction of cytochrome P450 3A4 by the enzyme-inducing anticonvulsants, leading to increased conversion of irinotecan to aminopentane carboxylic acid (APC). Since mephobarbital and primidone are barbiturates metabolized to phenobarbital, similar interactions may be anticipated.
    Prochlorperazine: (Minor) Of 47 patients who received prochlorperazine on the same day as irinotecan, 4 had akathisia as compared with 1 of 80 patients who received the drugs on different days. Patients received the weekly irinotecan dosage schedule. Of note, the 8.5% incidence of akathisia (4 of 47 patients) is within the normal range reported for use of prochlorperazine when 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.
    Ranolazine: (Moderate) In vitro, ranolazine is a moderate inhibitor of P-glycoprotein (P-gp) and a mild CYP3A4 inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Rapacuronium: (Moderate) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Rifampin: (Major) Rifampin is a strong CYP3A4 inducer and moderate P-glycoprotein (P-gp) inducer; irinotecan is a CYP3A4 and P-gp substrate. In patients treated with other strong CYP3A4 inducers, exposure to irinotecan and its active metabolite, SN-38, were substantially reduced in both adult and pediatric patients. The appropriate starting dose for patients taking strong CYP3A4 inducers is not known; do not administer strong CYP3A4 inducers such as rifampin unless there are no therapeutic alternatives.
    Ritonavir: (Major) Ritonavir is a strong CYP3A4 inhibitor, moderate P-glycoprotein inhibitor, and moderate CYP3A4 inducer. Irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer ritonavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue ritonavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Rocuronium: (Moderate) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Rolapitant: (Moderate) Avoid the concurrent use of irinotecan and rolapitant if possible; if coadministration is necessary, monitor for irinotecan-related adverse effects. Irinotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and irinotecan as coadministration may result in increased systemic exposure of irinotecan. Irinotecan is a substrate for the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); in vitro data show that sapropterin may inhibit these transporters. If these drugs are used together, closely monitor for increased side effects of irinotecan.
    Saquinavir: (Major) Saquinavir is a strong CYP3A4 and moderate 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 the drugs are used together. Do not administer saquinavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue saquinavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Simeprevir: (Moderate) Simeprevir, a breast cancer resistance protein (BCRP) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of irinotecan, which is a BCRP and CYP3A4 substrate. Monitor patients for adverse effects of irinotecan, such as hematologic and GI events.
    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: (Major) Avoid concurrent administration of voxilaprevir with irinotecan. Taking these medications together may increase the plasma concentrations of irinotecan. Irinotecan is a substrate for the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Voxilaprevir is a P-gp and BCRP inhibitor. (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) St. John's wort, Hypericum perforatum is a strong CYP3A4 inducer, and exposure to irinotecan and its active metabolite, SN-38, is reduced when the drugs are used together. In one study, the concomitant administration of St. John's wort with irinotecan resulted in substantially decreased irinotecan blood levels (by roughly 40%). As the appropriate starting dose of irinotecan for patients taking strong CYP3A4 inducers has not been formally defined, substitution of a non-enzyme inducing drug at least 2 weeks before irinotecan initiation should be considered. Do not administer strong CYP3A4 inducers unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for decreased irinotecan effects.
    Streptogramins: (Major) Quinupristin is a strong CYP3A4 inhibitor; irinotecan is a CYP3A4 substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer dalfopristin; quinupristin concurrently with irinotecan unless there are no therapeutic alternatives; discontinue dalfopristin; quinupristin at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Succinylcholine: (Moderate) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Telithromycin: (Major) Telithromycin is a strong CYP3A4 and mild 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 the drugs are used together. Do not administer telithromycin concurrently with irinotecan unless there are no therapeutic alternatives; discontinue telithromycin at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and irinotecan concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as irinotecan, can increase irinotecan exposure leading to increased or prolonged therapeutic effects and adverse events. If concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Tipranavir: (Major) Tipranavir is a strong CYP3A4 inhibitor and strong P-glycoprotein (P-gp) inducer; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer tipranavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue tipranavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Trandolapril; Verapamil: (Moderate) Verapamil is a moderate inhibitor of both CYP3A4 and P-glycoprotein (P-gp); irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    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) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with irinotecan is necessary, due to a possible increase in irinotecan-related adverse reactions. Irinotecan is metabolized by carboxylesterase to an active metabolite (SN-38) and via hepatic cytochrome P450 (CYP) 3A4 to aminopentane carboxylic acid (APC). The active metabolite (SN-38) is further conjugated to form a glucuronide metabolite (SN-38G) by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) and 1A7 (UGT1A7); elimination is dependent on the presence of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    Vecuronium: (Moderate) Irinotecan has anticholinesterase activity, which may antagonize the neuromuscular blockade of non-depolarizing drugs such as atracurium. Although an interaction has not been proven, use caution if these drugs are used concomitantly.
    Vemurafenib: (Major) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as irinotecan, could be expected with concurrent use. The manufacturer of irinotecan suggests that CYP3A4 inducers should be stopped 2 weeks prior to the initiation of irinotecan.
    Verapamil: (Moderate) Verapamil is a moderate inhibitor of both CYP3A4 and P-glycoprotein (P-gp); irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Voriconazole: (Major) Voriconazole is an inhibitor of CYP3A4; irinotecan is a CYP3A4 substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer voriconazole concurrently with irinotecan unless there are no therapeutic alternatives; discontinue voriconazole at least 1 week before starting irinotecan. If concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and irinotecan is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    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).