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    Anthracyclines

    BOXED WARNING

    Bone marrow suppression, herpes infection, infection, neutropenia, requires a specialized care setting, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Severe bone marrow suppression is a relative contraindication to idarubicin depending upon the etiology of the suppression. Patients with acute leukemia may require treatment with idarubicin despite severe bone marrow suppression. Idarubicin should be used cautiously in patients with bone marrow suppression, coagulopathy, or in those who have received previous myelosuppressive therapy such as chemotherapy or radiotherapy. Therefore, this drug requires an experienced clinician knowledgeable in the use of cancer chemotherapy. Administration of idarubicin requires a specialized care setting such as a hospital or treatment facility. Patients with preexisting marrow suppression, including neutropenia and/or thrombocytopenia, should be allowed to recover their counts prior to idarubicin administration. Patients should be treated for any active infection prior to receiving idarubicin. 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.

    Extravasation, intramuscular administration, subcutaneous administration

    Idarubicin is a vesicant. Extravasations of idarubicin infusions should be avoided. Patients should be closely monitored during IV infusions for signs and symptoms of extravasation such as poor blood return, pain and swelling. If extravasation occurs, stop the infusion and remove the tubing. Attempt to aspirate the drug prior to removing the needle. Elevate the affected area and treat with ice packs. As this can be a progressive injury, appropriate long-term follow-up is required. Intramuscular administration and subcutaneous administration of idarubicin should be avoided due to severe skin and tissue necrosis which may occur.

    Hepatic disease, jaundice

    Idarubicin should be used cautiously in patients with hepatic disease and/or jaundice. Since hepatic impairment can affect the disposition of idarubicin, liver function should be evaluated using serum bilirubin as an indicator prior to and during treatment. In a number of Phase III clinical trials, treatment was not given if bilirubin serum levels exceeded 2 mg%. However, in one Phase III trial, patients with bilirubin levels between 2.6 and 5 mg% received the anthracycline with a 50% reduction in dose. Dose reduction of idarubicin should be considered if the bilirubin levels are above the normal range (see Dosage).

    Renal impairment

    Doses of idarubicin should be adjusted for severe renal impairment or renal failure, although specific guidelines are not available and < 5% of the dose is eliminated renally. Kidney function should be evaluated with serum creatinine as an indicator prior to and during treatment. In a number of Phase III clinical trials, treatment was not given if creatinine serum levels exceeded 2 mg%. Dose reduction of idarubicin should be considered if the creatinine levels are above the normal range.

    Acute myocardial infarction, angina, cardiac arrhythmias, cardiac disease, cardiotoxicity, children, heart failure, maximum cumulative lifetime dose, radiation therapy, ventricular dysfunction

    Idarubicin is a cardiotoxin and can cause congestive heart failure due to its effects on cardiac myofibrils. Patients with preexisting cardiac disease including heart failure, angina, left ventricular dysfunction (i.e., ejection fraction less than 50%), recent or acute myocardial infarction, or cardiac arrhythmias are not good candidates to receive idarubicin. Angina and arrhythmias are relative contraindications to idarubicin therapy, depending on the degree of clinical impairment. Although it is suggested that idarubicin causes less cardiotoxicity than other agents in its class, patients should be observed closely for signs of cardiotoxicity if idarubicin is given. The risk of cardiac toxicity may be higher in children less than 2 years or geriatric patients 60 years of age or greater, patients who have received prior anthracycline therapy, and those who are receiving or have received radiation therapy to the mediastinal-pericardial area. Patients 60 years of age or more undergoing induction therapy with idarubicin experienced an increased incidence of cardiac effects vs. younger patients. Females and children may be more sensitive to the cardiotoxic effects of anthracyclines. Children treated with anthracyclines may develop late cardiotoxicity. Due to the risk of long-term cardiotoxicity, it has been recommended that children treated with anthracyclines should undergo screening with ECGs and echocardiograms every 2 years and 24-hour continuous ECGs and radionuclide angiograms every 5 years. Generally, patients with a left ventricular ejection fraction less than 50% are not considered candidates for anthracycline therapy; the risks vs. benefits of anthracycline therapy must be carefully considered in these patients. Patients should be observed closely for signs of idarubicin-induced cardiotoxicity; early recognition is essential for successful treatment. Establishment of baseline left ventricular function and periodic monitoring are recommended. Patients currently receiving idarubicin should wait at least 4 weeks following the last dose before undergoing periodic cardiac evaluation to allow cardiac function to return to baseline. Although the most definitive technique for assessing anthracycline-induced cardiotoxicity is endomyocardial biopsy, echocardiograms or serial gated cardiography (MUGA) scans may also indicate if a patient is developing cardiotoxicity. A left ventricular ejection fraction less than 50% or an absolute decrease of 10% to 20% in left ventricular heart function are indications to discontinue anthracycline therapy. Cardiotoxicity is dose related; although there is little data, the maximum cumulative lifetime dose of idarubicin is suggested to be 150 mg/m2 IV, and should only be exceeded with extreme caution.

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic anthracycline; analog of daunorubicin; less cardiotoxicity and may produce more aplasia and mucositis with repeated use than other anthracyclines; oral form under investigation.

    COMMON BRAND NAMES

    Idamycin PFS

    HOW SUPPLIED

    Idamycin PFS/Idarubicin/Idarubicin Hydrochloride Intravenous Inj Sol: 1mg, 1mL

    DOSAGE & INDICATIONS

    For induction therapy or post-remission therapy in adults with acute myelogenous leukemia (AML) in combination with cytarabine, Ara-C.
    NOTE: Idarubicin has been designated an orphan drug by the FDA for this indication.
    Intravenous dosage
    Adults

    8—12 mg/m2 IV (over 10—15 minutes) once daily for 3 days in combination with cytarabine. If severe mucositis occurred following a course of therapy, allow mucositis to resolve and reduce the dose of the next course by 25%.

    Adolescents† and Children†

    10—12 mg/m2 IV (over 10—30 minutes) once daily for 3 days; repeat every 3 weeks. NOTE: These are general guidelines. Refer to individual protocols for exact dosage.

    For the treatment of acute promyelocytic leukemia (APL).
    For the treatment of APL, in combination with other approved antileukemic agents.
    Intravenous dosage
    Adults

    12 mg/m2 given as a slow IV injection over 10—15 minutes daily for 3 days in combination with cytarabine. A second course may be administered in patients who have evidence of leukemia after the first induction course. If severe mucositis occurred following the first course of therapy, allow mucositis to resolve and reduce the dose of the next course by 25%. Induction therapy may be followed by consolidation therapy; however, there is no consensus regarding the optimal regimen to be used for consolidation.

    For remission induction treatment in patients with newly diagnosed APL, in combination with tretinoin†.
    Intravenous dosage
    Adults <= 61 years

    12 mg/m2/dose IV on days 2, 4, 6, and 8 plus tretinoin 45 mg/m2/day PO in 2 divided doses until complete remission (CR) to a maximum of 45 or 90 days has been evaluated in 2 clinical trials (AIDA 0493 study; AIDA 2000 study). Adults less than 20 years of age received tretinoin 25 mg/m2/day PO in the AIDA 0493 study. Patients who achieved a hematologic CR received 3 anthracycline-containing consolidation therapy courses. Additionally, most patients in these studies who achieved a molecular CR after consolidation received up to 2 years of tretinoin-containing maintenance therapy. Prophylactic use of corticosteroids was recommended during induction therapy to help prevent differentiation (retinoic acid) syndrome.

    Children and Adolescents

    12 mg/m2/dose IV on days 2, 4, 6, and 8 plus tretinoin 25 mg/m2/day PO in 2 divided doses until complete remission (CR) or a maximum of 90 days has been evaluated in a clinical trial (AIDA 0493 study). Patients who achieved a hematologic CR received 3 multi-agent chemotherapy consolidation courses containing anthracyclines and cytarabine. Additionally, most patients who achieved a molecular CR after consolidation received up to 2 years of tretinoin-containing maintenance therapy. In a subgroup analysis of the AIDA 0493 study, induction therapy with tretinoin plus idarubicin resulted in a post-induction hematologic CR rate of 96% in 107 evaluable pediatric patients (median age, 11.6 years; range, 1.4—17.9 years). Tretinoin was administered for a median of 32 days (range, 1—56 days) during induction therapy. The 10-year event-free survival and overall survival rates were 76% and 89%, respectively. Retinoic acid syndrome was reported in 8 patients (definitely present, n = 2; indeterminate, n = 6) and pseudotumor cerebri developed in 10 patients. There were 4 deaths during induction therapy.

    For consolidation treatment following tretinoin and idarubicin induction therapy in patients with newly diagnosed APL, in combination with tretinoin-containing chemotherapy†.
    Intravenous dosage
    Adults <= 61 years

    Following induction therapy with tretinoin (45 mg/m2/day PO in 2 divided daily doses until complete remission (CR) or a maximum of 45 days) plus idarubicin (12 mg/m2/dose IV on days 2, 4, 6, and 8), patients who achieved a hematologic CR received 3 risk-adapted tretinoin- and anthracycline-based consolidation therapy courses in a clinical study (AIDA 2000 study). All patients in this study received tretinoin 45 mg/m2/day PO for 15 days starting on day 1 of each consolidation cycle. Patients with low- or intermediate–risk APL (defined as an initial white blood cell count < 10 X 109/L) received: idarubicin 5 mg/m2/dose IV on days 1—4 (course 1), mitoxantrone 10 mg/m2/dose IV on days 1—5 (course 2); and idarubicin 12 mg/m2/dose IV on day 1 (course 3). Patients with high–risk APL received: idarubicin 5 mg/m2/dose IV on days 1—4 and cytarabine 1000 mg/m2/day IV on days 1—4 (course 1); mitoxantrone 10 mg/m2/dose IV on days 1—5 and etoposide 100 mg/m2/dose IV on days 1—5 (course 2); and idarubicin 12 mg/m2/dose IV on day 1, cytarabine 150 mg/m2 subcutaneously every 8 hours on days 1—5, and 6-thioguanine 70 mg/m2 PO every 8 hours on days 1—5 (course 3). Intrathecal methotrexate 12 mg and methylprednisone 40 mg were administered prior to each consolidation course in patients with high-risk disease. Additionally, patients who achieved a molecular CR after consolidation received up to 2 years of tretinoin-containing maintenance therapy.

    For the treatment of acute lymphocytic leukemia (ALL)†.
     NOTE: Idarubicin has been designated an orphan drug by the FDA for ALL in pediatric patients.
    For the treatment of relapsed or refractory ALL, in combination with cytarabine†.
    Intravenous dosage
    Adults

    40 mg/m2 IV once on day 3 plus cytarabine 3 grams/m2 daily IV over 3 hours on days 1 to 5 (with granulocyte colony-stimulating factor starting on day 7 until neutrophil recovery) and idarubicin 5 mg/m2 daily IV for 6 days, cytarabine 1 gram/m2 daily IV over 6 hours for 6 days, and prednisone 40 mg/m2 daily for 21 days have been studied as induction therapy in patients with relapsed or refractory acute lymphocytic leukemia (ALL) in nonrandomized trials. In some responding patients, induction therapy was followed by multi-agent consolidation therapy and bone marrow transplantation (BMT) (in patients less than 55 years of age).

    Adolescents and Children

    40 mg/m2 IV once on day 3 and cytarabine 3 grams/m2 daily IV over 3 hours on days 1 to 5 plus prophylactic intrathecal methotrexate (dosed for age) on days 1 and 5 (with prednisone 0.5 mg/kg daily and glucocorticoid eye drops during therapy plus granulocyte colony-stimulating factor starting on day 7 until granulocyte recovery) and idarubicin 5 mg/m2 IV daily for 6 days, cytarabine 1 gram/m2 daily IV over 6 hours for 6 days, and prednisone 40 mg/m2 daily PO for 21 days have been studied as induction therapy in patients with relapsed or refractory acute lymphocytic leukemia (ALL) in nonrandomized trials. In some responding patients, induction therapy was followed by multiagent consolidation therapy and bone marrow transplantation (BMT).

    For the treatment of relapsed or refractory non-Hodgkin's lymphoma (NHL)†, in combination with chemotherapy.
    Intravenous dosage
    Adults

    10 to 12 mg/m2 IV in combination with other chemotherapies has been studied in nonrandomized trials. In a multicenter, phase II trial of 54 previously treated NHL patients (prior anthracycline therapy, 89%), idarubicin 12 mg/m2 IV bolus over 15 minutes on day 1 plus etoposide 100 mg/m2/day IV on days 1-3 and ifosfamide 1500 mg/m2/day IV (with mesna 1:1) on days 1-3 repeated every 3 to 4 weeks (mean number of 4.33 cycles; range, 1-6 cycles) led to an overall response rate (ORR) of 72% (complete response (CR), 46%). All patients received oral hydration starting 24 hours prior to chemotherapy, allopurinol 300 mg/m2 PO, and oral bicarbonate solution (to keep urine pH > 7). The median overall survival (OS) time was 17.5 months and the 2-year OS rate was 41%. In another multicenter, phase II study in 38 patients with relapsed or primary resistant high-grade NHL, idarubicin 10 mg/m2 IV on days 1 and 2 (or days 1 and 8) plus etoposide 150 mg/m2/day IV on days 1-3 and ifosfamide 1000 mg/m2/day IV on days 1-5 repeated every 21 days resulted in an ORR of 47.4% (CR, 21.1%) and a median OS time of 6.9 months. All patients in this study received filgrastim until granulocyte recovery. Additionally, idarubicin 12 mg/m2 IV once on day 1 plus etoposide 60 mg/m2 IV every 12 hours for 3 days and cytarabine 1 g/m2 IV over 3 hours every 12 hours for 3 days repeated every 21 days for up to 4 cycles (mean number of 2.6 cycles) led to an ORR of 60% (CR, 20%) and 3-year relapse-free and OS rates of 20% and 15%, respectively, in 30 patients with intermediate- or high-grade NHL who had prior anthracycline exposure in another clinical study. Serious treatment-related toxicity with idarubicin-containing regimens in clinical trials included grade 3 or 4 neutropenia/granulocytopenia, thrombocytopenia, febrile neutropenia; additionally, death attributed to septic shock during severe neutropenia has been reported.

    For the treatment of myeloid blast crisis chronic myelogenous leukemia (CML)†, in combination with cytarabine or imatinib and cytarabine.
    NOTE: Idarubicin has been designated an orphan drug by the FDA for this indication.
    Intravenous dosage
    Adults

    12 mg/m2 IV with cytarabine and with or without imatinib has been studied in small, nonrandomized studies. Idarubicin 12 mg/m2 IV repeated every 14 days plus imatinib 600 mg/day PO and cytarabine 10 mg/day SC until patients returned to chronic phase (CP) followed by maintenance therapy with idarubicin 8 mg/m2 IV repeated every 4 weeks plus imatinib 600 mg orally and cytarabine 10 mg SC once daily until disease progression (median duration of therapy, 11 weeks; range, 4-124 weeks) resulted in a hematologic response rate of 74% (complete hematologic response rate (CHR), 47%) in 19 patients with CML in myeloid blast crisis in a pilot study; additionally, 26% of patients returned to CP. Most patients (n=17) had previously failed treatment with single-agent imatinib. Six patients received an allogeneic stem-cell transplant, including one patient still in myeloid blast phase. The median overall survival time was 23 weeks and the 1-year OS rate was 26%. All patients experienced at least 1 episode of grade 3 or 4 hematologic toxicity and 16 patients (84%) required hospitalization for febrile neutropenia, hemorrhage, pneumonia, cellulitis, and/or central nervous system leukemic infiltration. In a small phase II study in 16 patients with Philadelphia chromosome-positive CML in myeloid blast crisis who received idarubicin 12 mg/m2/day IV for 3 days and cytarabine 600 mg/m2 IV twice daily for 5 days, no patient achieved a CHR but 4 patients (25%) had a second CP. Three patients in second CP received maintenance therapy with interferon alfa-2b 5 million international units/day SQ and cytarabine 20 mg/day SQ for 14 days per month until disease progression. The median OS time was 16 weeks for all patients; however, the median OS time for the 4 patients in second CP was 31.1 weeks (range, 16.1 to 111 weeks). All patients became pancytopenic and transfusion dependent following induction therapy with idarubicin and cytarabine and 3 patients died due to septic complications during bone marrow aplasia.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    12 mg/m2 IV; maximum cumulative lifetime idarubicin dose: 150 mg/m2 IV.

    Geriatric

    12 mg/m2 IV; maximum cumulative lifetime idarubicin dose: 150 mg/m2 IV  .

    Adolescents

    Safety and efficacy have not been established. Doses up to 12 mg/m2 IV have been given off-label for AML; maximum cumulative lifetime idarubicin dose: 150 mg/m2 IV.

    Children

    Safety and efficacy have not been established. Doses up to 12 mg/m2 IV have been given off-label for AML; maximum cumulative lifetime dosage limits should be considered.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Total bilirubin 2.5—5 mg/dL: reduce recommended dose by 50%.
    Total bilirubin > 5 mg/dL: do not administer.

    Renal Impairment

    Dosage adjustment is recommended in patients with a serum creatinine greater than 2.5 mg/dL, but no quantitative recommendations are available.

    ADMINISTRATION

     
    CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.

    Injectable Administration

    Idarubicin is a vesicant and should not be administered intramuscularly or subcutaneously. If evidence of extravasation occurs during administration, the infusion should be stopped and completed via another vein, preferably in another limb. The affected area should be elevated and treated with cold compresses. Appropriate long-term follow-up of the area is recommended.
    Idarubicin is intended for administration under the supervision of a physician who is experienced in leukemia chemotherapy.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Idarubicin is administered intravenously as a rapid infusion over 10—15 minutes via Y-site or 3-way stopcock into a free-flowing IV infusion of 0.9% Sodium Chloride injection or 5% Dextrose injection. A Butterfly needle inserted into a large vein may be used. Idarubicin has been given as prolonged (4-hour) infusions as well.
     
    Reconstitution:
    Do not use diluents containing bacteriostatic agents to reconstitute idarubicin powder for injection.
    Reconstitute 5, 10, or 20 mg of idarubicin with 5 mL, 10 mL, or 20 mL, respectively, of nonbacteriostatic water for injection to give an IV solution containing 1 mg of idarubicin per ml. Insert needle into vial carefully because the vial contents are under pressure. The reconstituted solution is hypotonic and is stable for 72 hours at room temperature or 1 week under refrigeration.
    Vial contents are under negative pressure to decrease aerosol formation during reconstitution. Care should be taken when the needle is inserted into the vial.

    STORAGE

    Idamycin PFS:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Anthracycline hypersensitivity

    Idarubicin is should be avoided in patients with known idarubicin or other anthracycline hypersensitivity or anthracenedione hypersensitivity. Idarubicin therapy is not recommended in patients who have reached their total cumulative doses of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones.

    Bone marrow suppression, herpes infection, infection, neutropenia, requires a specialized care setting, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Severe bone marrow suppression is a relative contraindication to idarubicin depending upon the etiology of the suppression. Patients with acute leukemia may require treatment with idarubicin despite severe bone marrow suppression. Idarubicin should be used cautiously in patients with bone marrow suppression, coagulopathy, or in those who have received previous myelosuppressive therapy such as chemotherapy or radiotherapy. Therefore, this drug requires an experienced clinician knowledgeable in the use of cancer chemotherapy. Administration of idarubicin requires a specialized care setting such as a hospital or treatment facility. Patients with preexisting marrow suppression, including neutropenia and/or thrombocytopenia, should be allowed to recover their counts prior to idarubicin administration. Patients should be treated for any active infection prior to receiving idarubicin. 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.

    Dental disease, dental work

    Myelosuppressive effects of idarubicin 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.

    Intramuscular injections

    Intramuscular injections should not be administered to patients with platelet counts < 50,000/mm3 who are receiving idarubicin. IM injections may cause bleeding, bruising, or hematomas due to idarubicin-induced thrombocytopenia.

    Extravasation, intramuscular administration, subcutaneous administration

    Idarubicin is a vesicant. Extravasations of idarubicin infusions should be avoided. Patients should be closely monitored during IV infusions for signs and symptoms of extravasation such as poor blood return, pain and swelling. If extravasation occurs, stop the infusion and remove the tubing. Attempt to aspirate the drug prior to removing the needle. Elevate the affected area and treat with ice packs. As this can be a progressive injury, appropriate long-term follow-up is required. Intramuscular administration and subcutaneous administration of idarubicin should be avoided due to severe skin and tissue necrosis which may occur.

    Hepatic disease, jaundice

    Idarubicin should be used cautiously in patients with hepatic disease and/or jaundice. Since hepatic impairment can affect the disposition of idarubicin, liver function should be evaluated using serum bilirubin as an indicator prior to and during treatment. In a number of Phase III clinical trials, treatment was not given if bilirubin serum levels exceeded 2 mg%. However, in one Phase III trial, patients with bilirubin levels between 2.6 and 5 mg% received the anthracycline with a 50% reduction in dose. Dose reduction of idarubicin should be considered if the bilirubin levels are above the normal range (see Dosage).

    Renal impairment

    Doses of idarubicin should be adjusted for severe renal impairment or renal failure, although specific guidelines are not available and < 5% of the dose is eliminated renally. Kidney function should be evaluated with serum creatinine as an indicator prior to and during treatment. In a number of Phase III clinical trials, treatment was not given if creatinine serum levels exceeded 2 mg%. Dose reduction of idarubicin should be considered if the creatinine levels are above the normal range.

    Pregnancy

    Idarubicin is classified as FDA pregnancy risk category D and should not be administered during pregnancy because of the possibility of teratogenic effects. Idarubicin was teratogenic and embryotoxic in animals at doses less than the recommended human dose on a body surface area basis. There have been no adequate and well-controlled studies of idarubicin in pregnant women. There has been a report of a fetal fatality after maternal exposure in the second trimester. Women of childbearing potential should be cautioned to avoid getting pregnant. If a woman becomes pregnant during therapy, she should be advised of the potential risks to the fetus.

    Breast-feeding

    It is unknown whether idarubicin is excreted in breast milk. Breast-feeding should be discontinued during idarubicin therapy because of the possibility of severe adverse reactions to the infant.

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, tumor lysis syndrome (TLS)

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and decreased urine output may be indicative of idarubicin-induced tumor lysis syndrome (TLS). Appropriate measures (e.g. aggressive hydration and allopurinol) must be taken to prevent severe electrolyte imbalances and renal toxicity during and following chemotherapy administration in patients with large chemosensitive tumors.

    Acute myocardial infarction, angina, cardiac arrhythmias, cardiac disease, cardiotoxicity, children, heart failure, maximum cumulative lifetime dose, radiation therapy, ventricular dysfunction

    Idarubicin is a cardiotoxin and can cause congestive heart failure due to its effects on cardiac myofibrils. Patients with preexisting cardiac disease including heart failure, angina, left ventricular dysfunction (i.e., ejection fraction less than 50%), recent or acute myocardial infarction, or cardiac arrhythmias are not good candidates to receive idarubicin. Angina and arrhythmias are relative contraindications to idarubicin therapy, depending on the degree of clinical impairment. Although it is suggested that idarubicin causes less cardiotoxicity than other agents in its class, patients should be observed closely for signs of cardiotoxicity if idarubicin is given. The risk of cardiac toxicity may be higher in children less than 2 years or geriatric patients 60 years of age or greater, patients who have received prior anthracycline therapy, and those who are receiving or have received radiation therapy to the mediastinal-pericardial area. Patients 60 years of age or more undergoing induction therapy with idarubicin experienced an increased incidence of cardiac effects vs. younger patients. Females and children may be more sensitive to the cardiotoxic effects of anthracyclines. Children treated with anthracyclines may develop late cardiotoxicity. Due to the risk of long-term cardiotoxicity, it has been recommended that children treated with anthracyclines should undergo screening with ECGs and echocardiograms every 2 years and 24-hour continuous ECGs and radionuclide angiograms every 5 years. Generally, patients with a left ventricular ejection fraction less than 50% are not considered candidates for anthracycline therapy; the risks vs. benefits of anthracycline therapy must be carefully considered in these patients. Patients should be observed closely for signs of idarubicin-induced cardiotoxicity; early recognition is essential for successful treatment. Establishment of baseline left ventricular function and periodic monitoring are recommended. Patients currently receiving idarubicin should wait at least 4 weeks following the last dose before undergoing periodic cardiac evaluation to allow cardiac function to return to baseline. Although the most definitive technique for assessing anthracycline-induced cardiotoxicity is endomyocardial biopsy, echocardiograms or serial gated cardiography (MUGA) scans may also indicate if a patient is developing cardiotoxicity. A left ventricular ejection fraction less than 50% or an absolute decrease of 10% to 20% in left ventricular heart function are indications to discontinue anthracycline therapy. Cardiotoxicity is dose related; although there is little data, the maximum cumulative lifetime dose of idarubicin is suggested to be 150 mg/m2 IV, and should only be exceeded with extreme caution.

    Accidental exposure, ocular exposure

    Use care to avoid accidental exposure to idarubicin during preparation, handling, and administration. The use of protective gowns, gloves and goggles is recommended. Following skin or ocular exposure, skin and eyes should be thoroughly rinsed.

    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

    atrial fibrillation / Early / 0-16.0
    myocardial infarction / Delayed / 0-16.0
    vomiting / Early / 0-5.0
    oral ulceration / Delayed / 0-5.0
    nausea / Early / 0-5.0
    seizures / Delayed / 4.0-4.0
    pancytopenia / Delayed / 10.0
    tissue necrosis / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    AV block / Early / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    cardiotoxicity / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known

    Moderate

    bleeding / Early / 63.0-63.0
    bullous rash / Early / 0-46.0
    chest pain (unspecified) / Early / 0-16.0
    peripheral neuropathy / Delayed / 7.0-7.0
    elevated hepatic enzymes / Delayed / 0-5.0
    neutropenia / Delayed / 10.0
    anemia / Delayed / 10.0
    thrombocytopenia / Delayed / 10.0
    leukopenia / Delayed / 10.0
    bone marrow suppression / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    QT prolongation / Rapid / Incidence not known

    Mild

    infection / Delayed / 95.0-95.0
    alopecia / Delayed / 77.0-77.0
    abdominal pain / Early / 73.0-73.0
    diarrhea / Early / 73.0-73.0
    urticaria / Rapid / 0-46.0
    rash / Early / 0-46.0
    fever / Early / 26.0-26.0
    headache / Early / 20.0-20.0
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Cyclophosphamide: (Major) Use caution if cyclophosphamide is used concomitantly with anthracyclines, as there may be an increased risk of cardiotoxicity. Concurrent administration of cyclophosphamide and doxorubicin has resulted in an increase in exposure to doxorubicinol, a more cardiotoxic metabolite of doxorubicin. Additionally, concurrent treatment with doxorubicin (including doxorubicin liposomal) has been reported to exacerbate cyclophosphamide-induced hemorrhagic cystitis.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like anthracyclines. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    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.
    Flucytosine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as anthracyclines, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Trastuzumab: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    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.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Idarubicin is classified as FDA pregnancy risk category D and should not be administered during pregnancy because of the possibility of teratogenic effects. Idarubicin was teratogenic and embryotoxic in animals at doses less than the recommended human dose on a body surface area basis. There have been no adequate and well-controlled studies of idarubicin in pregnant women. There has been a report of a fetal fatality after maternal exposure in the second trimester. Women of childbearing potential should be cautioned to avoid getting pregnant. If a woman becomes pregnant during therapy, she should be advised of the potential risks to the fetus.

    It is unknown whether idarubicin is excreted in breast milk. Breast-feeding should be discontinued during idarubicin therapy because of the possibility of severe adverse reactions to the infant.

    MECHANISM OF ACTION

    The mechanism of action of idarubicin is similar to that of other anthracycline antineoplastics. Idarubicin complexes with DNA by intercalating between DNA base pairs, causing the helix to change shape. Idarubicin has a higher affinity for DNA intercalation than daunorubicin and is more readily taken up into cells. This simple act of changing the conformation of DNA can interfere with strand elongation by inhibiting DNA polymerase and inhibit protein synthesis due to effects on RNA polymerase. Idarubicin inhibits the uptake of thymidine into cancer cells and normal fibroblasts at lower concentrations than other anthracyclines. As with other anthracylines, idarubicin inbibits topoisomerase II, an enzyme responsible for repairing faulty sections of DNA, causing double-strand DNA breaks. This occurs most commonly in the G2-phase of the cell cycle, although, in general, idarubicin is considered non-cell cycle specific. Idarubicin does not form free radicals to the same extent as doxorubicin or daunorubicin. This may account for the decrease in clinical cardiotoxicity seen with idarubicin. The alcohol metabolite of idarubicin is as active as the parent compound and plays an important role in the activity of the drug. Idarubicin and its metabolite seem to be less susceptible to multiple drug resistance (MDR, P-gp) than daunorubicin and its metabolites. Studies have shown that cyclosporine and other modulators of MDR may increase the cytotoxicity of the alcohol metabolite of idarubicin. Idarubicin may offer an advantage over other anthracyclines in the treatment of leukemia and other diseases which may overexpress MDR. Resistance to idarubicin may also be mediated by changes in topoisomerase II activity.

    PHARMACOKINETICS

    Idarubicin is currently administered by slow IV injection (over 10—15 minutes).  Idarubicin is converted to an active metabolite, idarubicinol, via ketoreductase transformation. This metabolite is equally active as the parent compound and 16—122 times more potent in antileukemic activity than other anthracycline metabolites. Following administration of idarubicin to adult or pediatric patients, systemic exposure to idarubicinol is greater than that of idarubicin. Idarubicin and idarubicinol concentrate in nucleated blood cells. Both idarubicin and idarubicinol are 97% bound to plasma proteins. Idarubicin metabolism occurs primarily in the liver, however, plasma clearance values almost twice that of hepatic blood flow suggest extensive extrahepatic metabolism. The plasma half-life of idarubicin as a single agent averages 22 hours. The elimination half-life of idarubicinol is >45 hours. This rapidly leads to plasma concentrations of the metabolite 2—4 times the parent compound. Elimination is primarily biliary and to a lesser extent renal (<5%). Biliary elimination involves conjugates with sulfate or glucuronide. Dosage reduction in patients with elevated bilirubin concentrations is recommended (see Dosage). Total elimination from the body may happen very slowly because of distribution to blood cells with slow release from this site. The small amount of renal elimination may cause red or orange discoloration of the urine.

    Oral Route

    An oral dosage form has been investigated and demonstrates a bioavailability of 24—39%. Peak concentrations are not achieved for 3 hours after oral administration.