PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Camptothecin Analogs

    BOXED WARNING

    Asian patients, bone marrow suppression, chemotherapy, fungal infection, herpes infection, infection, neutropenia, radiation therapy

    Bone marrow suppression, including neutropenia, can occur with irinotecan liposome therapy. Severe or life-threatening neutropenic fever and fatal neutropenic sepsis have occurred in patients receiving irinotecan liposome in combination with 5-fluorouracil and leucovorin; the incidence of grade 3 or 4 neutropenia was higher in Asian patients (55%) compared to Caucasian patients (18%). Monitor complete blood cell counts on days 1 and 8 of every cycle and more frequently if clinically appropriate. Withhold therapy for absolute neutrophil count below 1,500/mm3 or neutropenic fever; a dose reduction or discontinuation of therapy may be necessary. Patients who have had previous myelosuppressive therapy such as chemotherapy or pelvic radiation therapy may be at risk of increased bone marrow suppression; therefore, this drug should be used only by clinicians experienced in chemotherapy. Patients with an active infection should be treated prior to receiving irinotecan liposome. Opportunistic infections, including fungal infection, may occur in some patients due to severe myelosuppression. Patients with a history of varicella zoster, herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding.

    Dehydration, diarrhea, GI obstruction

    Irinotecan liposome can cause severe and life-threatening diarrhea; do not administer irinotecan liposome to patients with GI obstruction. Similar to irinotecan HCl, irinotecan liposome can cause both early and late diarrhea. Early diarrhea (onset within 24 hours of chemotherapy) 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 chemotherapy, 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. A patient may experience both acute and late onset diarrhea. Preexisting diarrhea or dehydration should be treated prior to receiving irinotecan liposome. A treatment delay may be necessary to allow for recovery from irinotecan-related diarrhea, and dosage reduction or discontinuation of therapy 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.

    DEA CLASS

    Rx

    DESCRIPTION

    Topoisomerase I inhibitor
    Indicated, in combination with 5-FU and leucovorin, for metastatic pancreatic adenocarcinoma that has progressed after gemcitabine-based therapy
    Black box warning for fatal neutropenic sepsis and severe diarrhea; most common adverse effects include diarrhea, fatigue/asthenia, vomiting, nausea, anorexia, stomatitis, fever, lymphopenia, and neutropenia

    COMMON BRAND NAMES

    ONIVYDE

    HOW SUPPLIED

    Irinotecan, Liposomal/ONIVYDE Intravenous Inj Lipos: 1mL, 4.3mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic pancreatic cancer, in combination with 5-fluorouracil (5-FU) and leucovorin, in patients with disease progression after gemcitabine-based therapy.
    NOTE: Do not substitute irinotecan liposome for other drugs containing irinotecan HCl.
    NOTE: The FDA has designated irinotecan liposome as an orphan drug for pancreatic cancer.
    Intravenous dosage
    Adults

    70 mg/m2 IV over 90 minutes, followed by leucovorin (LV) 400 mg/m2 IV over 30 minutes, followed by 5-FU 2,400 mg/m2 IV over 46 hours, every 2 weeks until disease progression or unacceptable toxicity. For patients homozygous for UGT1A1*28 allele, decrease the starting dose for irinotecan liposome to 50 mg/m2, and increase to 70 mg/m2 as tolerated in subsequent cycles. Patients with metastatic pancreatic adenocarcinoma and disease progression after gemcitabine-based therapy were randomized to receive irinotecan liposome plus 5-FU/LV (n = 117), irinotecan liposome monotherapy (100 mg/m2 IV every 3 weeks; n = 151), or 5-FU/LV alone (LV 200 mg/m2 IV, followed by 5-FU 2,000 mg/m2 IV over 24 hours weekly for 4 weeks, repeated every 6 weeks; n = 119) in an open-label clinical trial. The addition of irinotecan liposome to 5-FU/LV significantly improved overall survival (OS) compared with 5-FU/LV alone (6.1 vs. 4.2 months; HR 0.68; p = 0.014); an improvement in OS compared with 5-FU/LV was not evident with irinotecan liposome monotherapy (HR 1; p = 0.97). Progression-free survival (PFS) was 3.1 months in patients receiving irinotecan liposome plus 5-FU/LV compared with 1.5 months in those treated with 5-FU/LV alone (HR 0.55; 95% CI, 0.41 to 0.75), and the objective response rate was 7.7% vs. 0.8%.

    MAXIMUM DOSAGE

    Adults

    70 mg/m2 IV every 2 weeks.

    Geriatric

    70 mg/m2 IV every 2 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available as the pharmacokinetics of irinotecan liposome have not been studied in patients with hepatic impairment; however, irinotecan is subject to hepatic metabolism. There is no recommended dose for patients with serum bilirubin above the upper limit of normal.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. It appears that no dosage adjustments are needed for patients with mild to moderate renal impairment; however, insufficient data are available in patients with severe renal impairment (CrCl less than 30 mL/min).

    ADMINISTRATION

     
    CAUTION: Observe and exercise usual cautions for handling, preparing, and administering cytotoxic drugs.
    Premedicate with a corticosteroid and anti-emetic 30 minutes prior to irinotecan liposome administration.

    Injectable Administration

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

    Intravenous Administration

    Preparation:
    Withdraw calculated volume of irinotecan liposome from the vial and dilute in 500 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Mix by gentle inversion.
    Storage of Diluted Solution: Protect from light. Administer within 4 hours of preparation if stored at room temperature, or within 24 hours if refrigerated at 2 to 8 degrees Celsius (36 to 46 degrees Farenheit). Do not freeze.
     
    Administration:
    Allow diluted solution to come to room temperature prior to administration.
    Infuse diluted solution by intravenous infusion over 90 minutes.
    Do not use in-line filters.

    STORAGE

    ONIVYDE:
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Asian patients, bone marrow suppression, chemotherapy, fungal infection, herpes infection, infection, neutropenia, radiation therapy

    Bone marrow suppression, including neutropenia, can occur with irinotecan liposome therapy. Severe or life-threatening neutropenic fever and fatal neutropenic sepsis have occurred in patients receiving irinotecan liposome in combination with 5-fluorouracil and leucovorin; the incidence of grade 3 or 4 neutropenia was higher in Asian patients (55%) compared to Caucasian patients (18%). Monitor complete blood cell counts on days 1 and 8 of every cycle and more frequently if clinically appropriate. Withhold therapy for absolute neutrophil count below 1,500/mm3 or neutropenic fever; a dose reduction or discontinuation of therapy may be necessary. Patients who have had previous myelosuppressive therapy such as chemotherapy or pelvic radiation therapy may be at risk of increased bone marrow suppression; therefore, this drug should be used only by clinicians experienced in chemotherapy. Patients with an active infection should be treated prior to receiving irinotecan liposome. Opportunistic infections, including fungal infection, may occur in some patients due to severe myelosuppression. Patients with a history of varicella zoster, herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding.

    Dehydration, diarrhea, GI obstruction

    Irinotecan liposome can cause severe and life-threatening diarrhea; do not administer irinotecan liposome to patients with GI obstruction. Similar to irinotecan HCl, irinotecan liposome can cause both early and late diarrhea. Early diarrhea (onset within 24 hours of chemotherapy) 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 chemotherapy, 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. A patient may experience both acute and late onset diarrhea. Preexisting diarrhea or dehydration should be treated prior to receiving irinotecan liposome. A treatment delay may be necessary to allow for recovery from irinotecan-related diarrhea, and dosage reduction or discontinuation of therapy 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.

    Pneumonitis

    Severe, life-threatening, or fatal interstitial lung disease or pneumonitis has been reported in patients treated with irinotecan HCl. In the event of acute onset of new or progressive, unexplained pulmonary symptoms or respiratory insufficiency such as dyspnea, cough, and fever, irinotecan liposome therapy should be interrupted pending diagnostic evaluation. If interstitial lung disease is diagnosed, irinotecan liposome therapy should be discontinued and appropriate treatment instituted as necessary.

    Infusion-related reactions

    Administration of irinotecan liposome carries a risk of serious hypersensitivity reactions or anaphylaxis, including infusion-related reactions. Permanently discontinue irinotecan liposome in patients who experience a severe hypersensitivity reaction.

    Pregnancy

    Based on animal data with irinotecan HCl and its mechanism of action, irinotecan liposome can cause fetal harm when administered during pregnancy. There are no available data in pregnant women; however, irinotecan crosses the placenta of rats after intravenous administration. When administered to pregnant rats and rabbits during organogenesis, embryotoxicity and teratogenicity were observed at irinotecan HCl exposures lower than those achieved with liposomal irinotecan at the recommended dosing (0.002 to 0.0002 times the clinical exposure at the recommended dosing based on AUC). Fetal abnormalities included increased post-implantation loss, structural abnormalities, growth delays, and a variety of external, visceral, and skeletal abnormalities. Women who become pregnant while receiving irinotecan liposome should be apprised of the potential hazard to the fetus.

    Ensure correct formulation selection

    The irinotecan liposomal label contains a warning to ensure correct formulation selection for the patient. Practitioners must not prescribe or substitute irinotecan in place of irinotecan liposomal.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during irinotecan liposome treatment. Irinotecan liposome can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 1 months after treatment with liposomal irinotecan. Because of the potential for male-mediated teratogenicity, males with female partners of reproductive potential should use condoms during treatment and for 4 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of treatment. Women who become pregnant while receiving liposomal irinotecan should be apprised of the potential hazard to the fetus. In addition, based on animal data, irinotecan liposome may cause atrophy of both male and female reproductive organs, resulting in impaired fertility or infertility.

    Breast-feeding

    It is not known whether irinotecan liposome is present in human milk; however, many drugs are excreted in human milk. Due to the potential for serious adverse reactions in nursing infants from liposomal irinotecan, advise women to discontinue breast-feeding during treatment and for 1 month after the final dose.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 20.0-55.0
    lymphopenia / Delayed / 27.0-27.0
    fatigue / Early / 21.0-21.0
    asthenia / Delayed / 21.0-21.0
    infection / Delayed / 17.0-17.0
    diarrhea / Early / 3.0-13.0
    vomiting / Early / 11.0-11.0
    nausea / Early / 8.0-8.0
    anemia / Delayed / 6.0-6.0
    elevated hepatic enzymes / Delayed / 6.0-6.0
    hyponatremia / Delayed / 5.0-5.0
    dehydration / Delayed / 4.0-4.0
    anorexia / Delayed / 4.0-4.0
    stomatitis / Delayed / 4.0-4.0
    hypophosphatemia / Delayed / 4.0-4.0
    fever / Early / 2.0-2.0
    thrombocytopenia / Delayed / 2.0-2.0
    weight loss / Delayed / 2.0-2.0
    hypoalbuminemia / Delayed / 2.0-2.0
    hypokalemia / Delayed / 2.0-2.0
    alopecia / Delayed / 1.0-1.0
    hypocalcemia / Delayed / 1.0-1.0
    renal failure (unspecified) / Delayed / 2.0
    bradycardia / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Moderate

    hypomagnesemia / Delayed / 35.0-35.0
    infusion-related reactions / Rapid / 3.0-3.0
    oral ulceration / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    dyspnea / Early / Incidence not known

    Mild

    lacrimation / Early / Incidence not known
    diaphoresis / Early / Incidence not known
    hypersalivation / Early / Incidence not known
    miosis / Early / Incidence not known
    rhinitis / Early / Incidence not known
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known
    cough / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acalabrutinib: (Moderate) Coadministration of acalabrutinib and irinotecan may increase irinotecan exposure and increase the risk of irinotecan toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Irinotecan is a BCRP subtrate.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Apalutamide: (Major) Avoid coadministration of irinotecan with apalutamide unless there are no therapeutic alternatives, due to decreased plasma concentrations of irinotecan; consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan therapy. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Apalutamide is a strong CYP3A4 inducer as well as a UGT inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or its active metabolite SN-38 in both adult and pediatric patients.
    Atazanavir: (Major) Avoid administration of atazanavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if atazanavir is boosted with cobicistat. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Atazanavir is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38.
    Atazanavir; Cobicistat: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together. (Major) Avoid administration of atazanavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if atazanavir is boosted with cobicistat. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Atazanavir is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38.
    Atracurium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid administration of phenobarbital during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with phenobarbital and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid administration of phenobarbital during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with phenobarbital and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Bosentan: (Major) Bosentan is a moderate CYP3A4 inducer; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not affect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    Brigatinib: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with brigatinib is necessary. Irinotecan is a substrate of BCRP. Brigatinib inhibits BCRP in vitro and may have the potential to increase concentrations of BCRP substrates.
    Cabozantinib: (Minor) Monitor for an increase in irinotecan-related adverse reactions if coadministration with cabozantinib is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Carbamazepine: (Major) Avoid administration of carbamazepine during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with carbamazepine and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Carvedilol: (Moderate) Increased concentrations of irinotecan may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and irinotecan is a P-gp substrate. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Ceritinib: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with ceritinib is necessary. Ceritinib is a CYP3A4 inhibitor and irinotecan is metabolized by CYP3A4. Patients treated with a strong CYP3A4 inhibitor had increased exposure to irinotecan. The manufacturer of irinotecan recommends avoiding strong CYP3A4 inhibitors for at least 1 week prior to starting therapy unless there are no therapeutic alternatives; the degree of CYP3A4 inhibition by ceritinib is unknown.
    Chloramphenicol: (Major) Avoid administration of chloramphenicol during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Cisatracurium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Clarithromycin: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Cobicistat: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together.
    Conivaptan: (Major) Avoid administration of conivaptan during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38; concomitant use of other strong CYP3A4 inhibitors may also increase systemic exposure.
    Darunavir: (Major) Avoid administration of darunavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Darunavir; Cobicistat: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together. (Major) Avoid administration of darunavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Severe) Discontinue use of antiretroviral regimens containing cobicistat at least 1 week prior to starting irinotecan. Concurrent use of irinotecan with cobicistat 'boosted' atazanavir is contraindicated; however, irinotecan may be used with other cobicistat-containing regimens if no other therapeutic alternatives are available. If these drugs are administered concurrently, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Cobicistat is a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when these drugs are used together. (Major) Avoid administration of darunavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid administration of dasabuvir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; dasabuvir is a UGT1A1 inhibitor. Concomitant use of UGT1A1 inhibitors may increase systemic exposure to SN-38. (Major) Avoid administration of ombitasvir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; ombitasvir is a UGT1A1 inhibitor. Concomitant use may increase systemic exposure to SN-38 (Major) Avoid administration of paritaprevir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; paritaprevir is a UGT1A1 inhibitor. Concomitant use with UGT1A1 inhibitors may increase systemic exposure to SN-38. (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Delavirdine: (Major) Avoid administration of delavirdine during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with quinidine is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Doxacurium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Enzalutamide: (Major) Avoid administration of enzalutamide during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Flibanserin: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with flibanserin is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and flibanserin is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Fosamprenavir: (Major) Avoid administration of fosamprenavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Fosphenytoin: (Major) Avoid administration of fosphenytoin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with phenytoin and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Fostamatinib: (Moderate) Monitor for irinotecan toxicities that may require irinotecan dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP or P-gp substrate may increase the concentration of the BCRP or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a BCRP inhibitor; irinotecan is a substrate for BCRP and P-gp. Coadministration of fostamatinib with another BCRP substrate increased the substrate AUC by 95% and Cmax by 88%. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%.
    Gemfibrozil: (Major) Avoid administration of gemfibrozil during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; gemfibrozil is a UGT1A1 inhibitor. Concomitant use of UGT1A1 inhibitors may increase systemic exposure to SN-38.
    Glecaprevir; Pibrentasvir: (Major) Avoid administration of glecaprevir during treatment with irinotecan unless there are no therapeutic alternatives. Irinotecan is a P-glycoprotein (P-gp) substrate and its active metabolite, SN-38, is a UGT1A1 substrate. Glecaprevir is a P-gp and UGT1A1 inhibitor. Concomitant use may increase systemic exposure to irinotecan and SN-38. (Major) Avoid administration of pibrentasvir during treatment with irinotecan unless there are no therapeutic alternatives. Irinotecan is a P-glycoprotein (P-gp) substrate and its active metabolite, SN-38, is a UGT1A1 substrate. Pibrentasvir is a P-gp and UGT1A1 inhibitor. Concomitant use may increase systemic exposure to irinotecan and SN-38.
    Grapefruit juice: (Major) Advise patients to avoid regular consumption of grapefruit or grapefruit juice during treatment with irinotecan and for at least 1 week prior to starting therapy. Irinotecan is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Idelalisib: (Major) Avoid administration of idelalisib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Indinavir: (Major) Avoid administration of indinavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a UGT1A1 substrate. Indinavir is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and SN-38.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid administration of rifampin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Isoniazid, INH; Rifampin: (Major) Avoid administration of rifampin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Itraconazole: (Severe) According to the manufacturer of itraconazole, the use of irinotecan is contraindicated for use during and for 2 weeks after discontinuation of itraconazole therapy. The manufacturer of irinotecan recommends that any strong CYP3A4 inhibitor be discontinued at least 1 week prior to starting irinotecan liposomal therapy. Itraconazole is a strong CYP3A4 inhibitor; irinotecan is metabolized extensively by CYP3A4 and UGT1A1. Exposure to irinotecan and to the active metabolite, SN-38, is increased when the drugs are used together, which can cause severe toxicity, including neutropenia and severe and life-threatening diarrhea.
    Ketoconazole: (Major) Avoid administration of ketoconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a UGT1A1 substrate. Ketoconazole is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased exposure to both irinotecan and SN-38.
    Letermovir: (Moderate) An increase in the plasma concentration of irinotecan or its active metabolite, SN-38, may occur if given with letermovir. Do not administer this combination unless there are no alternative treatment options if the patient is also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. If possible, discontinue letermovir, cyclosporine, or both drugs at least 1 week prior to starting irinotecan. Irinotecan is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Lomitapide: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with lomitapide is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and lomitapide is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Lopinavir; Ritonavir: (Major) Avoid administration of lopinavir; ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and lopinavir; ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan. (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Lumacaftor; Ivacaftor: (Major) Avoid administration of lumacaftor; ivacaftor during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Mefloquine: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with mefloquine is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and mefloquine is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Mephobarbital: (Major) Avoid administration of mephobarbital during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Mifepristone: (Major) Avoid administration of chronic mifepristone therapy during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Major) Avoid administration of mitotane during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Mivacurium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Nefazodone: (Major) Avoid administration of nefazodone during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Nelfinavir: (Major) Avoid administration of nelfinavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Neratinib: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with neratinib is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Neuromuscular blockers: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid administration of ombitasvir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; ombitasvir is a UGT1A1 inhibitor. Concomitant use may increase systemic exposure to SN-38 (Major) Avoid administration of paritaprevir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; paritaprevir is a UGT1A1 inhibitor. Concomitant use with UGT1A1 inhibitors may increase systemic exposure to SN-38. (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Osimertinib: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with osimertinib is necessary. Irinotecan is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Pancuronium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Phenobarbital: (Major) Avoid administration of phenobarbital during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with phenobarbital and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Phenytoin: (Major) Avoid administration of phenytoin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with phenytoin and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Posaconazole: (Major) Avoid administration of posaconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38; concomitant use of other strong CYP3A4 inhibitors may also increase systemic exposure.
    Primidone: (Major) Avoid administration of primidone during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Prochlorperazine: (Minor) Monitor for an increased incidence of akathisia if prochlorperazine is administered with irinotecan. In clinical trials of patients receiving weekly irinotecan, 8.5% of patients who received prochlorperazine on the same day as irinotecan reported akathisia, compared with 1.3% of patients who received the drugs on separate days; however, this incidence is within the range reported when prochlorperazine is given as a premedication for other chemotherapies.
    Propafenone: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with propafenone is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Quinidine: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with quinidine is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Rapacuronium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Ribociclib: (Major) Discontinue ribociclib at least 1 week prior to starting irinotecan therapy; do not administer ribociclib with irinotecan unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to both irinotecan and SN-38.
    Ribociclib; Letrozole: (Major) Discontinue ribociclib at least 1 week prior to starting irinotecan therapy; do not administer ribociclib with irinotecan unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to both irinotecan and SN-38.
    Rifampin: (Major) Avoid administration of rifampin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Ritonavir: (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Rocuronium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Saquinavir: (Major) Avoid administration of saquinavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Sofosbuvir; Velpatasvir: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with velpatasvir is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with velpatasvir is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    St. John's Wort, Hypericum perforatum: (Major) Avoid administration of St. John's Wort during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with St. John's Wort and other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Succinylcholine: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Telithromycin: (Major) Avoid administration of telithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38; concomitant use of other strong CYP3A4 inhibitors may also increase systemic exposure.
    Temsirolimus: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with temsirolimus is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of irinotecan.
    Tipranavir: (Major) Avoid administration of tipranavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Tubocurarine: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Vecuronium: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Voriconazole: (Major) Avoid administration of voriconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.

    PREGNANCY AND LACTATION

    Pregnancy

    Based on animal data with irinotecan HCl and its mechanism of action, irinotecan liposome can cause fetal harm when administered during pregnancy. There are no available data in pregnant women; however, irinotecan crosses the placenta of rats after intravenous administration. When administered to pregnant rats and rabbits during organogenesis, embryotoxicity and teratogenicity were observed at irinotecan HCl exposures lower than those achieved with liposomal irinotecan at the recommended dosing (0.002 to 0.0002 times the clinical exposure at the recommended dosing based on AUC). Fetal abnormalities included increased post-implantation loss, structural abnormalities, growth delays, and a variety of external, visceral, and skeletal abnormalities. Women who become pregnant while receiving irinotecan liposome should be apprised of the potential hazard to the fetus.

    It is not known whether irinotecan liposome is present in human milk; however, many drugs are excreted in human milk. Due to the potential for serious adverse reactions in nursing infants from liposomal irinotecan, advise women to discontinue breast-feeding during treatment and for 1 month after the final dose.

    MECHANISM OF ACTION

    Irinotecan liposome is a topoisomerase I inhibitor, encapsulated in a lipid bilayer vesical (liposome). Topoisomerase I is a cellular enzyme involved in maintaining the topographic structure of DNA during translation, transcription, and mitosis; it 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 and its active metabolite, SN-38, prevent the re-ligation of these single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. 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.

    PHARMACOKINETICS

    Irinotecan liposome is administered by intravenous infusion. Total irinotecan plasma protein binding is less than 0.44%. Direct measurement of irinotecan liposome showed that 95% of irinotecan remains liposome-encapsulated after administration, and the ratios between total and encapsulated forms did not change with time, up to 169.5 hours post-dose. The mean volume of distribution (Vd) for total irinotecan after administration of 70 mg/m2 to cancer patients (n = 23) was 4.1 +/- 1.5 liters, and the clearance was 0.2 +/- 0.17 L/h. The half-life  was 25.8 +/- 15.7 hours for total irinotecan and 67.8 +/- 44.5 hours for SN-38 (n = 13). The metabolism of irinotecan liposome has not been established in humans. However, after administration of irinotecan HCl, urinary excretion of irinotecan is 11 to 20%, SN-38 (active) is less than 1%, and SN-38 glucuronide (inactive) is 3%. The cumulative biliary and urinary excretion of irinotecan HCl in 2 patients was 25% (100 mg/m2) and 50% (300 mg/m2).
     
    Affected cytochrome P450 (CYP) isoenzymes and other metabolic enzymes: CYP3A4 and UGT1A1
    The metabolism of irinotecan liposome has not been evaluated. However, irinotecan is subject to extensive metabolic conversion; the active metabolite SN-38 is formed via esterases, while UGT1A1 mediates the glucuronidation of SN-38 to the inactive metabolite, SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive metabolites, one of which can be hydrolyzed by carboxylesterase to release SN-38. In vitro studies indicate that neither irinotecan, SN-38, nor another metabolite, aminopentane carboxylic acid (APC) inhibit CYP450 isoenzymes. In a population pharmacokinetic analysis adjusted for the lower dose of irinotecan administered to patients homozygous for the UGT1A1*28 allele, patients homozygous for this allele (n = 14) had a total SN-38 average steady-state concentration of 1.06 ng/mL, non-homozygous patients (n = 244) had a concentration of 0.95 ng/mL.

    Intravenous Route

    In a population pharmacokinetic analysis of cancer patients who received liposomal irinotecan 70 mg/m2, either as a single agent or as part of combination chemotherapy, the mean irinotecan Cmax was 37.2 +/- 8.8 mcg/mL (n = 25), while the mean Cmax of SN-38 was 5.4 +/- 3.4 ng/mL (n = 25); the mean AUC was 1,364 +/- 1,048 h x mcg/mL (n = 23) and 620 +/- 329 h x ng/mL (n = 13), respectively. Over the dose range of 50 to 155 mg/m2, the Cmax and AUC of total irinotecan, as well as the Cmax of total SN-38, increased with dose. However, the AUC of total SN-38 increased less than proportionally with dose. In mice bearing human tumor xenografts, irinotecan liposome administered at irinotecan HCl-equivalent doses 5-fold lower than irinotecan HCl achieved similar intratumoral exposure of SN-38.