Idarubicin is an anthracycline chemotherapy agent indicated in combination with other approved antileukemic agents for the treatment of adults with acute myeloid leukemia including French-American-British classifications M1 through M7. Cardiotoxicity and severe myelosuppression have been reported with idarubicin therapy; monitoring is recommended.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Idarubicin is available as a 1 mg/mL solution vial or a lyophilized powder vial that requires reconstitution.
-Monitor the infusion site for signs or symptoms of extravasation; immediately discontinue idarubicin administration, restart in another vein, and administer appropriate treatment (e.g., intermittent icing, elevation of the extremity) if extravasation occurs.
Reconstitution of lyophilized vial:
-Use care when the needle is inserted into the vial; vial contents are under negative pressure to decrease aerosol formation during reconstitution.
-Reconstitute the lyophilized vial with Sterile Water for injection to a final concentration of 1 mg/mL; bacteriostatic diluents are not recommended.
-NOTE: the reconstituted solution is hypotonic.
-Storage: Reconstituted solutions are stable for 72 hours at room temperature (15 to 30 degrees C; 59 to 86 degrees F) and refrigerated (2 to 8 degrees C; 36 to 46 degrees F); discard unused portion of the vial.
-Inject idarubicin IV slowly over 10 to 15 minutes into the tubing of a freely running IV infusion of Sodium Chloride injection or 5% Dextrose injection.
-Attach the tubing to a butterfly needle or other suitable device and insert preferably into a large vein.
-Do not mix with other drugs; precipitation occurs with heparin and degradation may occur with prolonged contact with alkaline solutions.
Clinical pulmonary adverse events (39%) and allergic pulmonary symptoms (2%) were reported in patients with acute myelogenous leukemia who received idarubicin as induction therapy (n = 110) in a randomized, comparative study.
Renal toxicity (e.g., elevated serum creatinine (SCr) levels) has been reported with idarubicin therapy. Grade 4 changes in renal function occurred in 1% or less of patients. The initial idarubicin dosage should be reduced in patients with impaired renal function; a dosage reduction should be considered in patients with an elevated SCr level. Monitor kidney function tests prior to and during idarubicin therapy.
Severe bone marrow suppression (e.g., anemia, leukopenia, neutropenia, and thrombocytopenia) has been reported with idarubicin therapy. Infection (95%), fever (26%), and bleeding (63%) occurred in patients with acute myeloid leukemia who received idarubicin induction therapy (n = 110) in a randomized, comparative study. Some cases or infection or bleeding were life-threatening or fatal. In the clinical studies, the duration of pancytopenia (aplasia) was greater in the idarubicin arm than the daunorubicin arm, especially during consolidation therapy. Monitor complete blood counts frequently.
Idarubicin is a vesicant and may cause severe tissue necrosis if extravasated into soft tissues. Extravasation may occur with or without stinging or burning symptoms and if blood returns well on aspiration of the infusion needle. Immediately stop the idarubicin infusion if signs or symptoms of extravasation occur and restart the infusion in another vein. To treat extravasation, the manufacturer recommends elevating the affected area and applying ice packs for 30 minutes immediately, then 30 minutes 4 times per day for 3 days. Because of the progressive nature of the injury, the area should be closely monitored and plastic surgery consultation is warranted if there is any sign of local reactions such as pain, erythema, edema, or vesicle formation. If there is ulceration or severe persistent pain at the site of extravasation, early wide excision of the area should be considered. Alopecia (77%) and other dermatologic adverse events (46%) such as rash (unspecified), urticaria, and a bullous rash (erythrodermatous rash of the palms and soles) have been reported in patients with acute myelogenous leukemia who received idarubicin as induction therapy (n = 110) in a randomized, comparative study. Injection site reaction (e.g., hives) and radiation recall reaction have also occurred in idarubicin-treated patients.
Serious cardiotoxicity including fatal congestive heart failure (CHF), acute and life-threatening cardiac arrhythmias and cardiomyopathy may occur with idarubicin therapy. Clinical cardiac adverse events (16%) such as CHF (most cases attributed to fluid overload), arrhythmias including atrial fibrillation, chest pain (unspecified), myocardial infarction, and asymptomatic declines in left ventricular ejection fraction (LVEF) occurred in patients with acute myelogenous leukemia (AML) who received idarubicin as induction therapy (n = 110) in a randomized, comparative study. Myocardial insufficiency and arrhythmias were typically reversible and occurred in patients with sepsis or anemia or who were receiving aggressive IV fluid administration. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as atrial fibrillation, sinus bradycardia, ventricular tachycardia, supraventricular tachycardia (SVT), AV block, and premature ventricular contractions (PVCs) have been reported. In a retrospective study of patients with AML or myelodysplastic syndromes, cumulative doses of idarubicin 150 mg/m2 given to low risk patients (no prior/sequential exposure to anthracyclines or mitoxantrone and age < 70 years) had a probability of CHF of zero. The probability of CHF in high risk patients (prior/sequential exposure to anthracyclines or mitoxantrone, hypertension, and age > 70 years) is about 10-20%. Carefully monitor cardiac function (e.g., LVEF) during therapy. Manage congestive heart failure and/or arrhythmias as indicated.
Gastrointestinal (GI) adverse events including nausea and vomiting (82%), abdominal cramps/diarrhea (73%), and mucositis (oral ulceration) (50%) were reported in patients with acute myelogenous leukemia who received idarubicin as induction therapy (n = 110) in a randomized, comparative study; however, severe GI adverse events were reported in less than 5% of patients in this study. Severe enterocolitis with GI perforation has been reported rarely. In the clinical studies, the incidence of mucositis was greater in the idarubicin arm than the daunorubicin arm, especially during consolidation therapy. Evaluate patients who develop severe abdominal pain for perforation.
Nervous system adverse events including mental status changes (41%), headache (20%), peripheral nerve toxicity (peripheral neuropathy) (7%), seizures (4%), and cerebellar toxicity (4%) were reported in patients with acute myelogenous leukemia who received idarubicin as induction therapy (n = 110) in a randomized, comparative study.
Hepatotoxicity (e.g., elevated hepatic enzymes) has been reported with idarubicin therapy. Grade 4 changes in hepatic function occurred in less than 5% of patients. The initial idarubicin dosage should be reduced in patients with impaired hepatic function; a dosage reduction should be considered in patients with an elevated bilirubin level. Monitor liver function tests prior to and during idarubicin therapy.
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.
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.
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 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.
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.
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).
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.
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.
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.
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 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.
Idarubicin is classified as FDA pregnancy risk category D. Women of reproductive potential should avoid pregnancy during idarubicin therapy due to a risk 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. If a woman becomes pregnant during therapy, she should be advised of the potential risks to the fetus.
It is not known if idarubicin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from idarubicin, women should avoid breast-feeding during idarubicin therapy.
For the treatment of acute myelogenous leukemia (AML):
NOTE: Idarubicin has been designated an orphan drug by the FDA for the treatment of AML.
-for remission induction therapy in AML, in combination with other approved antileukemic drugs including cytarabine:
Adults: 12 mg/m2 daily for 3 days via slow IV injection over 10 to 15 minutes in combination with cytarabine as induction therapy. Cytarabine may be given as 100 mg/m2 daily by continuous IV infusion for 7 days or as cytarabine 25 mg/m2 as an IV bolus followed by cytarabine 200 mg/m2 daily for 5 days by continuous IV infusion. A second course of therapy may be administered in patients with unequivocal evidence of leukemia after the first induction course. A dose reduction or delay may be necessary in patients who develop toxicity. There is no consensus regarding optional regimens to be used for consolidation therapy.
-for induction therapy and post induction therapy in elderly patients with previously untreated AML without unfavorable cytogenetics, in combination with cytarabine and lomustine*:
Adults 60 years and older: 8 mg/m2 IV daily on days 1, 2, 3, 4, and 5 in combination with cytarabine 100 mg/m2 IV daily as a continuous IV infusion on days 1 to 7 and lomustine 200 mg/m2 orally on day 1 as induction therapy was evaluated in a randomized, phase 3 trial (the LAM-SA 2007 FILO Trial). Patients who achieved a complete remission (CR) or CR with incomplete recovery (CRi) after one induction course received consolidation therapy with idarubicin 8 mg/m2 IV daily on days 1, 2, and 3; cytarabine 50 mg/m2 subcutaneously every 12 hours on days 1, 2, 3, 4, and 5; and lomustine 80 mg orally on day 1 followed by 6 reinduction courses of idarubicin 8 mg/m2 IV on day 1; cytarabine 50 mg/m2 subcutaneously every 12 hours on days 1, 2, 3, 4, and 5; and lomustine 40 mg orally on day 1. In this study, patients also received 6 months of maintenance therapy with alternating courses of 6-mercaptopurine and methotrexate.
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*:
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:
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.
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.
For the treatment of acute promyelocytic leukemia (APL):
-for the treatment of APL, in combination with other approved antileukemic agents:
Adults: 12 mg/m2 given as a slow IV injection over 10 to 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*:
Adults 61 years old or younger: 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 to 17.9 years). Tretinoin was administered for a median of 32 days (range, 1 to 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*:
Adults 61 years old or younger: 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 initial WBC less than 10 x 109/L) received: idarubicin 5 mg/m2/dose IV on days 1, 2, 3, and 4 (course 1), mitoxantrone 10 mg/m2/dose IV on days 1, 2, 3, 4, and 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, 2, 3, and 4 and cytarabine 1,000 mg/m2/day IV on days 1, 2, 3, and 4 (course 1); mitoxantrone 10 mg/m2/dose IV on days 1, 2, 3, 4, and 5 and etoposide 100 mg/m2/dose IV on days 1, 2, 3, 4, and 5 (course 2); and idarubicin 12 mg/m2/dose IV on day 1, cytarabine 150 mg/m2 subcutaneously every 8 hours on days 1, 2, 3, 4, and 5, and 6-thioguanine 70 mg/m2 PO every 8 hours on days 1, 2, 3, 4, and 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.
Maximum Dosage Limits:
12 mg/m2 IV; maximum cumulative lifetime idarubicin dose: 150 mg/m2 IV.
12 mg/m2 IV; maximum cumulative lifetime idarubicin dose: 150 mg/m2 IV .
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.
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.
Patients with Hepatic Impairment Dosing
Total bilirubin 2.5-5 mg/dL: reduce recommended dose by 50%.
Total bilirubin > 5 mg/dL: do not administer.
Patients with Renal Impairment Dosing
Dosage adjustment is recommended in patients with a serum creatinine greater than 2.5 mg/dL, but no quantitative recommendations are available.
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.
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.
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.
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.
Trastuzumab; Hyaluronidase: (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.
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.
Idarubicin is administered intravenously. It exhibits extensive tissue binding due to a very high volume of distribution. Idarubicin (97%) and its primary active metabolite, idarubicinol (94%), are highly bound to human plasma proteins and this binding is concentration-dependent. Following idarubicin 10 to 12 mg/m2 daily for 3 to 4 days in adult patients with leukemia, the mean terminal half-life was 22 hours (range, 4 to 48 hours) when given as single agent and 20 hours (range, 7 to 38 hours) when given in combination with cytarabine. The estimated mean terminal half-life of idarubicinol exceeded 45 hours. Idarubicin has extensive extrahepatic metabolism. Elimination occurs primarily by biliary excretion and by renal excretion to a lesser extent (mostly as idarubicinol).
Peak concentration levels occur within a few minutes after the idarubicin injection. Levels of idarubicin and idarubicinol in nucleated blood and bone marrow cells are more than a hundred times the plasma levels. The terminal half-life was 15 hours for idarubicin in plasma and cells and 72 hours for idarubicinol in cells. Idarubicin plasma concentrations are best described by a 2- or 3-compartment open model. Based on the mean plasma levels and half-life values obtained after the first idarubicin dose, drug accumulation was 1.7- and 2.3-fold on days 2 and 3, respectively; however, there appeared to be no pharmacokinetic changes following a 3-day regimen.
Impaired metabolism and higher systemic idarubicin levels are expected in patients with moderate or severe hepatic impairment.
Renal impairment may impact the pharmacokinetic parameters of idarubicin.
Idarubicin exhibited dose-independent kinetics in pediatric leukemia patients following doses of 4.2 to 13.3 mg/m2 daily for 3 days. In these patients, there was no difference between the half-lives of idarubicin following daily dosing for 3 days or weekly dosing for 3 weeks. In 21 pediatric patients with leukemia who received IV idarubicin, 2 patients had detectable idarubicin levels in the cerebrospinal fluid (0.14 and 1.57 ng/mL) and 20 patients had detectable idarubicinol levels in the cerebrospinal fluid (mean, 0.51 ng/mL; range, 0.22 to 1.05 ng/mL) at 18 to 30 hours after dosing.