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    Camptothecin Analogs

    BOXED WARNING

    Bone marrow suppression, herpes infection, infection, neutropenia, radiation therapy, thrombocytopenia, varicella, viral infection

    Irinotecan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Patients who have had previous myelosuppressive therapy, such as chemotherapy and/or prior pelvic or abdominal radiation therapy, may be at increased risk for irinotecan-induced bone marrow suppression, including neutropenia or thrombocytopenia. Concurrent administration of radiation therapy and irinotecan is not recommended. Prior to each dose of irinotecan monitoring of hematologic parameters is recommended; the absolute neutrophil count (ANC) should be >= 1500/mm3 and the platelet count >= 100,000/mm3. Treatment should be delayed 1—2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered within 2 weeks, consider discontinuing treatment. Treatment with irinotecan should be temporarily omitted during a course of therapy if neutropenic fever occurs or the ANC drops below 1000/mm3; dosage reduction is required in these patients (see Dosage). Routine use of colony-stimulating factors is not necessary, but some clinicians may consider use in patients with significant neutropenia during irinotecan therapy. Patients with active infection should be treated prior to receiving irinotecan. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Dehydration, diarrhea

    Irinotecan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Irinotecan can cause both early and late diarrhea. Early diarrhea (during or shortly after the infusion) is accompanied by cholinergic symptoms including rhinitis, salivation, miosis, lacrimation, diaphoresis, flushing, and hyperperistalsis with possible abdominal cramping. Atropine can be used to treat 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 severe volume depletion, electrolyte imbalance, or sepsis. Late diarrhea should be treated with loperamide. In addition, preexisting diarrhea or dehydration should be treated prior to receiving irinotecan. Irinotecan treatment may need to be delayed 1—2 weeks to allow for recovery from irinotecan-related diarrhea and dosage reduction may be necessary if severe diarrhea develops. Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated or antibiotic therapy if they develop ileus, fever, or severe neutropenia. After the first treatment, subsequent weekly treatments should be delayed in patients with active diarrhea until return of pretreatment bowel function for at least 24 hours without the need for antidiarrhea medication. If grade 2, 3, or 4 late diarrhea occurs, subsequent doses of irinotecan should be reduced within the current treatment cycle. If the patient has not recovered within 2 weeks, consider discontinuing treatment.

    DEA CLASS

    Rx

    DESCRIPTION

    Antineoplastic agent; topoisomerase I iinhibitor; camptothecin derivative; activity due to the parent compound and active metabolite SN-38; active in colorectal, lung, pancreatic, and gynecologic cancers, refractory lymphoma, and gliomas.

    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

    In the treatment of neoplastic disease the maximum tolerated dose of irinotecan varies significantly from 350 mg/m2 by IV infusion over 90 minutes, administered once every 3 weeks to 150 mg/m2 by IV infusion over 90 minutes, administered for 4 weeks, every 6 weeks.

    Elderly

    < 70 years : In the treatment of neoplastic disease the maximum tolerated dose of irinotecan varies significantly from 350 mg/m2 by IV infusion over 90 minutes, administered once every 3 weeks to 150 mg/m2 by IV infusion over 90 minutes, administered for 4 weeks, every 6 weeks.
    >= 70 years: The maximum tolerated dose of irinotecan varies significantly from 300 mg/m2 by IV infusion over 90 minutes, administered once every 3 weeks to 150 mg/m2 by IV infusion over 90 minutes, administered for 4 weeks, every 6 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    In clinical trials, irinotecan was not administered to patients with serum bilirubin > 2 mg/dl or serum transaminases > 3 times the upper limit of normal in patients without liver metastasis or serum transaminases > 5 times the upper limit of normal 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.
     
    Patients with homozygous UGT1A1*28
    A reduction in the starting dose by at least one level of irinotecan should be considered in individuals known to be homozygous for the UGT1A1*28 allele. The appropriate dose reduction in this patient population is not known.

    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

    Irinotecan is administered via intravenous infusion.
    Premedication with antiemetic agents is recommended prior to irinotecan therapy. Suggested management includes dexamethasone 10 mg plus another antiemetic agent, such as a 5-HT3 blocker, given at least 30 minutes before the administration of irinotecan.
    Prior to beginning a course of therapy, the granulocyte count should be >= 1500, the platelet count >= 100,000 and treatment-related diarrhea should be fully resolved.
     
    Dilution:
    Dilute appropriate dose in 5% Dextrose (preferred) or 0.9% Sodium Chloride injection to a final concentration of 0.12—2.8 mg/mL irinotecan. The most common diluent used during clinical trials was 250—500 mL of 5% Dextrose injection.
    The solution is physically and chemically stable for up to 24 hours at room temperature and room lighting. However, because of the possible microbial contamination during preparation, an admixture prepared with 5% Dextrose injection or 0.9% Sodium Chloride injection should be used within 4 hours of preparation if kept at room temperature. Solutions prepared with 5% Dextrose injection, stored at refrigerated temperatures and protected from light are physically and chemically stable for 48 hours. It is recommended that infusion solutions prepared with 0.9% Sodium Chloride injection not be refrigerated.
    The manufacturer recommends that irinotecan infusions be completed within 12 hours at room temperature or 24 hours if refrigerated.
     
    Intravenous infusion:
    Infuse intravenously over 90 minutes.

    STORAGE

    Camptosar:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from freezing
    - Protect from light
    - Store between 68 to 77 degrees F
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Pregnancy

    Irinotecan may cause fetal harm when administered to a pregnant women; it is not recommended for use during pregnancy and is FDA pregnancy risk category D. Irinotecan is embryotoxic in animals; however, there are no data concerning use in pregnant humans. Teratogenic effects in animals like rats and rabbits include a variety of external, visceral, and skeletal abnormalities. Females of childbearing age should avoid becoming pregnant while receiving irinotecan. If a woman becomes pregnant during therapy, she should be informed of the potential risk to the fetus.

    Breast-feeding

    Irinotecan is excreted into the breast milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants, breast-feeding should be avoided during therapy with irinotecan.

    Bone marrow suppression, herpes infection, infection, neutropenia, radiation therapy, thrombocytopenia, varicella, viral infection

    Irinotecan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Patients who have had previous myelosuppressive therapy, such as chemotherapy and/or prior pelvic or abdominal radiation therapy, may be at increased risk for irinotecan-induced bone marrow suppression, including neutropenia or thrombocytopenia. Concurrent administration of radiation therapy and irinotecan is not recommended. Prior to each dose of irinotecan monitoring of hematologic parameters is recommended; the absolute neutrophil count (ANC) should be >= 1500/mm3 and the platelet count >= 100,000/mm3. Treatment should be delayed 1—2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered within 2 weeks, consider discontinuing treatment. Treatment with irinotecan should be temporarily omitted during a course of therapy if neutropenic fever occurs or the ANC drops below 1000/mm3; dosage reduction is required in these patients (see Dosage). Routine use of colony-stimulating factors is not necessary, but some clinicians may consider use in patients with significant neutropenia during irinotecan therapy. Patients with active infection should be treated prior to receiving irinotecan. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Dehydration, diarrhea

    Irinotecan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Irinotecan can cause both early and late diarrhea. Early diarrhea (during or shortly after the infusion) is accompanied by cholinergic symptoms including rhinitis, salivation, miosis, lacrimation, diaphoresis, flushing, and hyperperistalsis with possible abdominal cramping. Atropine can be used to treat 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 severe volume depletion, electrolyte imbalance, or sepsis. Late diarrhea should be treated with loperamide. In addition, preexisting diarrhea or dehydration should be treated prior to receiving irinotecan. Irinotecan treatment may need to be delayed 1—2 weeks to allow for recovery from irinotecan-related diarrhea and dosage reduction may be necessary if severe diarrhea develops. Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated or antibiotic therapy if they develop ileus, fever, or severe neutropenia. After the first treatment, subsequent weekly treatments should be delayed in patients with active diarrhea until return of pretreatment bowel function for at least 24 hours without the need for antidiarrhea medication. If grade 2, 3, or 4 late diarrhea occurs, subsequent doses of irinotecan should be reduced within the current treatment cycle. If the patient has not recovered within 2 weeks, consider discontinuing treatment.

    Geriatric

    Use cautiously in geriatric patients; these patients are more likely to experience diarrhea after receiving irinotecan. Dosage adjustments are recommended for patients >= 70 years for the irinotecan single-agent 3-week regimen. In patients receiving either irinotecan/5-fluorouracil (5-FU)/leucovorin or 5-FU/leucovorin in clinical trials, higher rates of hospitalization, neutropenia, thromboembolism, first-cycle treatment discontinuation, and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance status of 0 or 1.

    Intramuscular injections

    Intramuscular injections should not be given to patients with a platelet count < 50,000/mm3 who are receiving irinotecan. IM injections can cause bleeding, bruising, or hematomas in patients with irinotecan-induced thrombocytopenia.

    Dental disease, dental work

    Myelosuppressive effects of irinotecan can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Biliary tract disease, hepatic disease, jaundice

    Irinotecan is primarily hepatically metabolized and should be used with caution in patients with hepatic disease, including jaundice or biliary tract disease. In clinical trials, irinotecan was not administered to patients with serum bilirubin > 2 mg/dl or serum transaminases > 3 times the upper limit of normal without liver metastasis or serum transaminases > 5 times the upper limit of normal with liver metastasis. However, during clinical trials, patients with modestly elevated baseline serum bilirubin levels (1—2 mg/dL) have had significantly greater risk of developing first-course grade 3—4 neutropenia than those patients whose serum bilirubin levels were < 1 mg/dL. Patients with abnormal glucuronidation of bilirubin, such as those with Gilbert's syndrome, may also be at greater risk for myelosuppression.

    Diabetes mellitus

    Patients with a diabetes mellitus or glucose intolerance are at risk for hyperglycemia during irinotecan therapy. It is probable that dexamethasone, given as antiemetic prophylaxis, contributes to the hyperglycemia in some patients.

    Extravasation

    Irinotecan is an irritant; avoid extravasation. Should extravasation occur, flushing the site with sterile water and application of ice packs are recommended.

    Accidental exposure, ocular exposure

    Use care to avoid accidental exposure to irinotecan during preparation, handling and administration. The use of protective gowns, gloves and goggles is recommended. Avoid ocular exposure of irinotecan solutions. If exposure occurs, the eye should be rinsed immediately and thoroughly.

    Children

    The safety and effectiveness of irinotecan in children have not been established. In one phase II trial where irinotecan 50 mg/m2/day x 5 days IV every 3 weeks was given to children with refractory solid tumors, the adverse reactions reported were similar to those reported in adults. Another phase II trial studied 21 children with previously untreated rhabdomyosarcoma treated with irinotecan 20 mg/m2day x 5 days on weeks 0, 1, 3 and 4 followed by multimodal therapy. Accrual to the single agent irinotecan phase was halted due to the high rate (28.6%) of progressive disease and the early deaths (14%). The adverse event profile was different in this study from that observed in adults; the most significant grade 3 or 4 adverse events were dehydration associated with severe hypokalemia in and hyponatremia; Grade 3—4 infection was also reported.

    Vaccination

    Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    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 (unspecified) / 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

    Acetazolamide: (Moderate) Volume depletion due to irinotecan-induced vomiting or diarrhea can be exacerbated by diuretics. Withholding diuretics during irinotecan dosing, especially during periods of active vomiting or diarrhea, may be desirable.
    Alogliptin; Pioglitazone: (Major) Pioglitazone is a mild inducer of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not aaffect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as magnesium hydroxide when used as a laxative, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as magnesium hydroxide when used as a laxative, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    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.
    Aprepitant, Fosaprepitant: (Moderate) Aprepitant, fosaprepitant is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting and may be used in combination with irinotecan. However, use caution and monitor for a possible increase in non-emetogenic irinotecan-related adverse effects for several days after administration of a multi-day aprepitant regimen. Of note, irinotecan was included in treatment regimens used in two of the multicenter, randomized, double-blind, controlled clinical trials evaluating the efficacy of aprepitant in moderately emetogenic chemotherapy (MEC). Irinotecan is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and theoretically could increase plasma concentrations of irinotecan. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold on day 1 and by 3.3-fold on day 5 when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Armodafinil: (Major) In vitro, armodafinil is a mild 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.
    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.
    Basiliximab: (Moderate) Basiliximab is a mild inhibitor of CYP3A4 and 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.
    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.
    Bevacizumab: (Minor) Bevacizumab may influence the pharmacokinetics of irinotecan. The combination may cause an increase in the cocentration of SN-38, the active metabolite of irinotecan. Patients may also experience a higher incidence of Grade 3 to 4 diarrhea and neutropenia.
    Bexarotene: (Major) Bexarotene 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.
    Bisacodyl: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as laxatives, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    Boceprevir: (Severe) Boceprevir 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. Concurrent use of boceprevir and irinotecan is contraindicated; discontinue boceprevir at least 1 week before starting irinotecan.
    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.
    Cabazitaxel: (Moderate) In vitro, cabazitaxel is a mild inhibitor of CYP3A4; 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.
    Cabozantinib: (Moderate) Monitor for an increase in irinotecan-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of irinotecan may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and irinotecan is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as magnesium hydroxide when used as a laxative, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    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).
    Carbonic anhydrase inhibitors: (Moderate) Volume depletion due to irinotecan-induced vomiting or diarrhea can be exacerbated by diuretics. Withholding diuretics during irinotecan dosing, especially during periods of active vomiting or diarrhea, may be desirable.
    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.
    Celecoxib: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Cimetidine: (Moderate) Cimetidine is a mild inhibitor of CYP3A4 and 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.
    Ciprofloxacin: (Moderate) Coadministration of ciprofloxacin and irinotecan 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. Ciprofloxacin is a moderate inhibitor of CYP3A4; irinotecan is a CYP3A4 substrate.
    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.
    Clobazam: (Major) Clobazam is a mild 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.
    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.
    Crizotinib: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with crizotinib is necessary. Irinotecan is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may increase exposure to irinotecan.
    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.
    Dabrafenib: (Major) Dabrafenib 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.
    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.
    Danazol: (Moderate) Danazol is a moderate inhibitor of CYP3A4; 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.
    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) 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.
    Dasatinib: (Moderate) Dasatinib is a mild inhibitor of CYP3A4; 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.
    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.
    Diclofenac: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diltiazem: (Moderate) Diltiazem 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.
    Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Irinotecan is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Drospirenone; Ethinyl Estradiol: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Efavirenz: (Major) Efavirenz 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.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Efavirenz 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.
    Elbasvir; Grazoprevir: (Major) Administering irinotecan with elbasvir may result in elevated irinotecan plasma concentrations. Irinotecan is a substrate of CYP3A and the drug transporter breast cancer resistance protein (BCRP). Elbasvir is an inhibitor of BCRP. If these drugs are used together, closely monitor for signs of adverse events. (Major) Administering irinotecan with grazoprevir may result in elevated irinotecan plasma concentrations. Irinotecan is a substrate of CYP3A and the drug transporter breast cancer resistance protein (BCRP). Grazoprevir is an inhibitor of BCRP and also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    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.
    Eltrombopag: (Moderate) Eltrombopag is an inhibitor of the transporters Breast Cancer Resistance Protein (BCRP) and OATP1B1. Irinotecan is a substrate for BCRP and irinotecan's active metabolite, SN-38, is a substrate for OATP1B1. Drugs that are substrates for these transporters may exhibit an increase in systemic exposure if coadministered with eltrombopag; monitor patients for adverse reactions if these drugs are coadministered. In a clinical study, administration of a single dose of rosuvastatin, another substrate of both OATP1B1 and BCRP, in combination with eltrombopag increased plasma rosuvastatin AUC by 55% and the Cmax by 103%.
    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.
    Eslicarbazepine: (Major) Eslicarbazepine 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.
    Esomeprazole; Naproxen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ethinyl Estradiol: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Desogestrel: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Etonogestrel: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Norelgestromin: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Norethindrone: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Norgestimate: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Ethinyl Estradiol; Norgestrel: (Moderate) In vitro, Ethinyl Estradiol is a mild inhibitor of CYP3A4; 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.
    Etodolac: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Famotidine; Ibuprofen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Felbamate: (Major) Felbamate is a mild inducer of CYP3A4; 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.
    Fenoprofen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fluconazole: (Moderate) Fluconazole is a moderate inhibitor of CYP3A4; 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.
    Flucytosine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    Fluoxetine: (Moderate) Fluoxetine is a mild inhibitor of CYP3A4; 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.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine is a mild inhibitor of CYP3A4; 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.
    Flurbiprofen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Flutamide: (Major) In vitro, flutamide is a moderate inducer of CYP3A4; 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.
    Fluvoxamine: (Moderate) Exposure to irinotecan and its active metabolite, SN-38, may increase during coadministration with fluvoxamine. Fluvoxamine is a moderate CYP3A4 inhibitor and irinotecan is a CYP3A4 substrate. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, and vomiting.
    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).
    Gallium Ga 68 Dotatate: (Moderate) Volume depletion due to irinotecan-induced vomiting or diarrhea can be exacerbated by diuretics. Withholding diuretics during irinotecan dosing, especially during periods of active vomiting or diarrhea, may be desirable.
    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.
    Glimepiride; Pioglitazone: (Major) Pioglitazone is a mild inducer of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not aaffect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    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.
    Griseofulvin: (Major) In vitro, griseofulvin is a moderate inducer of CYP3A4; 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.
    Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Imatinib: (Moderate) Imatinib, STI-571 is a moderate inhibitor of CYP3A4; 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.
    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.
    Indomethacin: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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: (Major) Isoniazid, INH 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 isoniazid concurrently with irinotecan unless there are no therapeutic alternatives; discontinue isoniazid at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Isoniazid, INH 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 isoniazid concurrently with irinotecan unless there are no therapeutic alternatives; discontinue isoniazid 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) 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) Isoniazid, INH 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 isoniazid concurrently with irinotecan unless there are no therapeutic alternatives; discontinue isoniazid 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) 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) Irinotecan is contraindicated for use during and for 2 weeks after discontinuation of itraconazole therapy. Irinotecan is a CYP3A4 and P-gp substrate; itraconazole is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor. Exposure to irinotecan and to the active metabolite, SN-38, is increased when the drugs are used together.
    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.
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Irinotecan is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in irinotecan concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    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.
    Ketoprofen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lactulose: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as laxatives, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    Lansoprazole; Naproxen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Loop diuretics: (Moderate) Volume depletion due to irinotecan-induced vomiting or diarrhea can be exacerbated by diuretics. Withholding diuretics during irinotecan dosing, especially during periods of active vomiting or diarrhea, may be desirable.
    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.
    Magnesium Hydroxide: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as magnesium hydroxide when used as a laxative, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    Mannitol: (Moderate) Volume depletion due to irinotecan-induced vomiting or diarrhea can be exacerbated by diuretics. Withholding diuretics during irinotecan dosing, especially during periods of active vomiting or diarrhea, may be desirable.
    Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Mestranol; Norethindrone: (Moderate) Any contraceptive or hormonal replacement combinations containing ethinyl estradiol should be used with extreme caution with irinotecan. In vitro, ethinyl estradiol (EE) is a mild inhibitor of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration of ethinyl estradiol-containing hormone replacement or birth control options 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. Mestranol, found in mestranol; norethindrone, is converted to ethinyl estradiol (EE), and similar precautions apply.
    Metformin; Pioglitazone: (Major) Pioglitazone is a mild inducer of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not aaffect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    Methazolamide: (Moderate) Volume depletion due to irinotecan-induced vomiting or diarrhea can be exacerbated by diuretics. Withholding diuretics during irinotecan dosing, especially during periods of active vomiting or diarrhea, may be desirable.
    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.
    Mineral Oil: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as laxatives, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    Mirabegron: (Moderate) Mirabegron is a mild inhibitor of CYP3A4; 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.
    Modafinil: (Major) In vitro, armodafinil is a mild 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.
    Nabumetone: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nafcillin: (Major) In vitro, nafcillin is a moderate inducer of CYP3A4; 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.
    Naproxen: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Sumatriptan: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as irinotecan. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. If coadministration is necessary, use caution and monitor for chemotherapeutic related adverse reactions, including diarrhea, nausea, vomiting, and myelosuppression.
    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.
    Nevirapine: (Major) Nevirapine is a moderate inducer of CYP3A4; 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.
    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.
    Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Octreotide: (Moderate) Octreotide is a moderate inhibitor of CYP3A4; 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.
    Ombitasvir; Paritaprevir; 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.
    Oritavancin: (Moderate) Irinotecan, SN-38 is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and exposure to the active metabolite of irinotecan, SN-38 and therefore efficacy of irinotecan, SN-38 may be reduced if these drugs are administered concurrently; however, coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not affect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    Osimertinib: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with osimertinib is necessary. Irinotecan is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Oxaprozin: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Oxcarbazepine: (Major) Oxcarbazepine is a moderate inducer of CYP3A4; 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.
    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.
    Pantoprazole: (Moderate) Pantoprazole is a moderate P-glycoprotein (P-gp) inhibitor and, in vitro, a moderate 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.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and irinotecan, a CYP3A4 substrate, may cause an increase in systemic concentrations of irinotecan. Use caution when administering these drugs concomitantly.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Perampanel: (Major) In vitro, perampanel is a mild inducer of CYP3A4; 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.
    Phenicol Derivatives: (Moderate) Chloramphenicol is a moderate inhibitor of CYP3A4 and 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.
    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).
    Pioglitazone: (Major) Pioglitazone is a mild inducer of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not aaffect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    Piroxicam: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Polycarbophil: (Minor) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving laxatives like calcium polycarbophil should be monitored carefully.
    Polyethylene Glycol: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as laxatives, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    Polyethylene Glycol; Electrolytes: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as laxatives, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    Polyethylene Glycol; Electrolytes; Bisacodyl: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as laxatives, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    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.
    Quinine: (Moderate) Quinine is a moderate inhibitor and inducer of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration may affect irinotecan exposure. Use caution if concomitant use is necessary and monitor for efficacy as well as increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    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.
    Regorafenib: (Moderate) Use caution if coadministration of regorafenib with irinotecan is necessary, and monitor for an increase in irinotecan-related adverse reactions. Irinotecan is a BCRP and UGT substrate. Regorafenib is BCRP inhibitor, while regorafenib, M-2, and M-5 all competitively inhibit UGT1A9 and 1A1 in vitro. The mean AUC of irinotecan increased by 28% and the mean AUC of SN-38 increased by 44% when administered 5 days after the last of 7 daily doses of regorafenib.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with irinotecan is necessary, as the systemic exposure of irinotecan may be increased resulting in an increase in treatment-related adverse reactions including diarrhea, nausea, vomiting, and myelosuppression. Ribociclib is a moderate CYP3A4 inhibitor and irinotecan is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with irinotecan is necessary, as the systemic exposure of irinotecan may be increased resulting in an increase in treatment-related adverse reactions including diarrhea, nausea, vomiting, and myelosuppression. Ribociclib is a moderate CYP3A4 inhibitor and irinotecan is a CYP3A4 substrate.
    Rifabutin: (Major) Rifabutin is a strong CYP3A4 inducer, and irinotecan is a CYP3A4 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 rifabutin within at least 2 weeks of starting irinotecan therapy.
    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.
    Rifaximin: (Major) In vitro, rifaximin is a moderate inducer of CYP3A4 and a mild P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp 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.
    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.
    Rofecoxib: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Safinamide: (Moderate) Safinamide at the 100 mg dose and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), which could increase plasma concentrations of BCRP substrates such as irinotecan. Monitor patients for increased pharmacologic or adverse effects of BCRP substrates during concurrent use of safinamide, particularly the 100 mg dose.
    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.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    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.
    Sorafenib: (Moderate) When sorafenib was administered with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway, there was a 67-120% increase in the SN-38 AUC and a 26-42% increase in the irinotecan AUC. Although the clinical significance of these findings is unknown, close clinical monitoring of patients receiving sorafenib with irinotecan is recommended.
    Sorbitol: (Moderate) Because diarrhea is a common adverse reaction to irinotecan therapy, patients receiving drugs known to cause diarrhea, such as laxatives, should be monitored carefully. Withholding laxatives during irinotecan dosing, especially during periods of active diarrhea, may be desirable.
    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.
    Sulindac: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tamoxifen: (Moderate) 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. Tamoxifen is a P-glycoprotein (P-gp) inhibitor; irinotecan is a P-gp substrate.
    Telaprevir: (Major) Telaprevir 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 telaprevir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue telaprevir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    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.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and irinotecan is necessary, as the systemic exposure of irinotecan may be decreased resulting in reduced efficacy. Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan therapy. If these drugs are used together, monitor patients for suboptimal efficacy of irinotecan. Irinotecan is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with irinotecan is necessary, and monitor for an increase in irinotecan-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro. Irinotecan is metabolized by CYP3A4 to an active metabolite (SN-38), which is further conjugated to form a glucuronide metabolite (SN-38G); elimination is dependent on the presence of P-gp. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to the active metabolite of irinotecan is likely to increase.
    Thiazide diuretics: (Moderate) Volume depletion due to irinotecan-induced vomiting or diarrhea can be exacerbated by diuretics. Withholding diuretics during irinotecan dosing, especially during periods of active vomiting or diarrhea, may be desirable.
    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.
    Tolmetin: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Ulipristal: (Minor) In vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as irinotecan may increase irinotecan concentrations; use caution. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
    Valdecoxib: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Valproic Acid, Divalproex Sodium: (Major) In vitro, valproic acid, divalproex sodium is a mild inducer and inhibitor of CYP3A4 as well as a mild P-glycoprotein (P-gp) inducer; irinotecan is a CYP3A4 and P-gp substrate. Coadministration could potentially affect irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not affect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy and increased irinotecan side effects, including nausea, vomiting, diarrhea, and myelosuppression.
    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 may cause fetal harm when administered to a pregnant women; it is not recommended for use during pregnancy and is FDA pregnancy risk category D. Irinotecan is embryotoxic in animals; however, there are no data concerning use in pregnant humans. Teratogenic effects in animals like rats and rabbits include a variety of external, visceral, and skeletal abnormalities. Females of childbearing age should avoid becoming pregnant while receiving irinotecan. If a woman becomes pregnant during therapy, she should be informed of the potential risk to the fetus.

    Irinotecan is excreted into the breast milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants, breast-feeding should be avoided during therapy with irinotecan.

    MECHANISM OF ACTION

    All camptothecin analogs, including irinotecan and its metabolite SN-38, work by inhibiting topoisomerase I, a cellular enzyme involved in maintaining the topographic structure of DNA during translation, transcription, and mitosis. Topoisomerase I relieves the torsional strain in the DNA helix during replication and RNA transcription by inducing single-strand breaks. By binding with the topoisomerase I—DNA complex, irinotecan or SN-38 prevents the relegation of the single-strand breaks. However, this activity is not sufficient to cause cytotoxicity because the complexes are easily reversible once the drug is removed. Ongoing DNA synthesis is required to cause lethal cellular damage. Irreversible DNA damage occurs when a DNA replication fork encounters the irinotecan or SN-38/topoisomerase I complexes resulting in double-strand DNA breaks (Fork Collision Model). Camptothecins are highly S-phase specific in their activity due the requirement of DNA synthesis. Inhibitors of DNA synthesis, such as hydroxyurea, can protect cells from camptothecin-induced cytotoxicity. As with other agents that damage DNA, camptothecins cause cycle arrest in the G2-phase; however, the actual mechanisms of cell death following camptothecin administration has not been determined. Several mechanisms including apoptosis (programmed cell death) have been suggested. Camptothecins can cause damage at the chromosomal level, however, little is known about the possible long-term toxicities of camptothecins. Other DNA-damaging agents such as alkylating agents and topoisomerase II inhibitors have been associated with mutagenicity and secondary malignancies. Mechanisms of resistance to irinotecan include decreased conversion of irinotecan to SN-38, point mutations of topoisomerase I, reduced topoisomerase I activity and decreased sensitivity of topoisomerase to topoisomerase inhibitors.
     
    Other effects of camptothecins include radiation sensitization and antiviral activity. Topoisomerase I inhibitors appear to inhibit initial DNA repairs including sealing of broken strands and repair of base damage following radiation therapy. Camptothecins have been shown to decrease HIV-1 replication but the mechanism has not been established. Irinotecan has anticholinesterase activity. Cholinergic effects including acute diarrhea appear to be due to the parent compound alone. SN-38 does not have anticholinesterase activity at physiologic concentrations.

    PHARMACOKINETICS

    Irinotecan is administered by intravenous infusion; although, an oral formulation is under investigation. In plasma, both irinotecan and its active metabolite, SN-38, exist in an active lactone form and an inactive hydroxy acid anion form. The equilibrium between the two forms is pH-dependent. An acid pH promotes the formation of the lactone form and a basic pH favors the hydroxy acid anion form. Plasma protein binding is roughly 30—68% for irinotecan whereas SN-38 is approximately 95% bound. Both compounds are primarily bound to albumin.
     
    Irinotecan is metabolized by carboxylesterase to SN-38 and via hepatic cytochrome P450 (CYP) 3A4 to aminopentane carboxylic acid (APC). SN-38 is further conjugated to form a glucuronide metabolite (SN-38G) by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1). Both SN-38G and APC are 50- to 200-times less active than SN-38 in vitro and do not appear to contribute to the cytotoxic activity of irinotecan. However, agents that induce CYP3A4 may increase metabolism of irinotecan to APC, decreasing the formation of the active metabolites. Individuals with a homozygous UGT1A1*28 allele (approximately 10% of the North American population) have a decreased ability to form the SN-38G metabolite and are, therefore, at increased risk for neutropenia. Although no recommendations are available regarding testing for the UGT1A1*28 allele, laboratory tests are available. Correlation between irinotecan or SN-38 AUC and development of diarrhea is unclear due to conflicting study results. Excretion of irinotecan and its metabolites occurs primarily in the bile and feces, and, to a lesser degree, through the kidneys. Urinary excretion of irinotecan accounts for 11—20% of the dose; SN-38, < 1%; and SN-38G, 3%. It appears SN-38 undergoes enterohepatic recirculation. The mean terminal elimination half-life is about 6—12 hours and 10—20 hours for irinotecan and SN-38, respectively.
     
    Affected cytochrome P-450 (CYP450) isoenzymes and drug transporters: CYP3A4, UGT1A1, UGT1A7, P-glycoprotein (P-gp)
    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).