Idarubicin hydrochloride, a semisynthetic anthracycline, is an antineoplastic agent.1
Idarubicin is used in combination with other antineoplastic agents for the treatment of acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL), including French-American-British classifications M1 through M7, in adults, particularly younger adults.1, 7, 10, 16, 21 Cytarabine with either daunorubicin or idarubicin is a regimen of choice for remission induction in acute myeloid leukemia.7, 10 Induction regimens are used to rapidly reduce the tumor burden in order to achieve complete remission, which generally is defined as less than 5% leukemic blast cells in the bone marrow, normalization of peripheral blood counts, and absence of any evidence of extramedullary disease.7 Optimal postremission therapy has not been established, but current approaches include consolidation chemotherapy with cytarabine-based regimens similar to standard induction regimens, consolidation chemotherapy with high-dose cytarabine-based regimens (for younger adults), high-dose chemotherapy or chemoradiotherapy with bone marrow infusion, or high-dose marrow-ablative therapy with stem cell transplantation.7, 10, 21 There is no evidence of benefit from prolonged administration of chemotherapy in the treatment of most types of AML, and most current treatment regimens in the US no longer employ maintenance therapy.7 An exception is type M3 AML (acute promyelocytic leukemia), for which improvement in overall survival and/or disease-free survival has been demonstrated with the use of maintenance therapy.7
The current indication for idarubicin is based principally on the results of 4 randomized trials, 3 US studies (studies 1 through 3) and an Italian study (study 4), showing that combined therapy with idarubicin and cytarabine is at least as effective as with daunorubicin and cytarabine for induction therapy in patients with previously untreated AML.1, 3, 4, 5, 7, 9 Patients with prior myelodysplastic syndrome, an indicator of poor prognosis,7 were excluded in study 1,3 but eligible for enrollment in studies 2-4.4, 5, 9 Both a higher rate of complete remission and prolonged overall survival in patients receiving idarubicin were reported in only one of the studies (study 1).1 Higher rates of complete remission (studies 1 and 2) and longer median survival (studies 1 and 3) associated with the idarubicin regimen each were reported in 2 of the 3 US studies.1 Long-term follow-up shows that, at 5 years, longer median survival in patients receiving idarubicin was maintained for only one of these 2 studies (study 1).6 Some clinicians have questioned the equivalence of the doses of daunorubicin and idarubicin used in these randomized trials, suggesting that the doses used may have contributed to any differences in patient outcome.7, 8, 11, 21 No randomized trials comparing idarubicin versus higher dosages of daunorubicin in induction regimens for AML have been conducted to date, and the optimal dosage for daunorubicin in AML has not been established.8, 11, 21
Analysis of pooled data for individual patients from 5 randomized studies (including the 4 randomized trials described in this discussion) indicates higher rates of complete remission (62 versus 53%) and survival at 5 years (13 versus 9%) in patients receiving idarubicin compared with those receiving daunorubicin.11 However, the difference in the rate of complete remission between idarubicin and daunorubicin appears to decrease with increasing age.11 Subgroup analysis of the data suggests a tendency toward a higher rate of early death (during the first 40 days of induction therapy) in patients aged 60 years and older receiving idarubicin compared with patients in the same age group receiving daunorubicin.11 Although the rate of later death (after 40 days of induction therapy) is lower for patients in all age groups receiving idarubicin compared with those receiving daunorubicin, there is a trend toward a lesser reduction in older patients compared with younger patients.11 The combined effect of these trends results in a difference in the rate of complete remission among older and younger patients receiving idarubicin.11 In addition, interim analysis of a phase 3 trial involving 363 patients aged 55 years and older with previously untreated AML shows no difference in response rate for patients receiving cytarabine, with idarubicin, daunorubicin, or mitoxantrone.12
In study 1, a total of 130 patients 16-60 years of age (median age: approximately 40 years) with previously untreated AML received either idarubicin 12 mg/m2 or daunorubicin 50 mg/m2 IV daily for 3 days; both groups received cytarabine 25 mg/m2 by rapid IV (“bolus”) infusion followed by cytarabine 200 mg/m2 continuous IV infusion daily for 5 days.1, 3 Patients with a complete remission following 1 or 2 courses of induction therapy received 2 courses of consolidation therapy using the same doses as used in the induction regimen but for shorter periods (anthracycline for 2 days and cytarabine rapid IV loading dose followed by continuous IV infusion for 4 days).1, 3 A rest period of 4-6 weeks is recommended before initiation of consolidation therapy and between the courses.1, 3 Patients receiving idarubicin and cytarabine had a higher rate of complete remissions (78 versus 58%) and longer median survival (508 versus 435 days at a median follow-up of 2.5 years) than those receiving daunorubicin and cytarabine.1 Long-term follow-up shows that median survival at 5 years was longer in patients receiving the idarubicin regimen.6
In study 2, a total of 230 patients aged 15 years to 60 years or older (median age about 60 years) with previously untreated AML received either idarubicin 12 mg/m2 or daunorubicin 45 mg/m2 IV daily for 3 days; both groups received cytarabine 100 mg/m2 daily for 7 days by continuous IV infusion.1, 4 Patients with complete remission following 1 or 2 courses of induction therapy received 3 courses of consolidation therapy at 21-day intervals or upon hematologic recovery using the same anthracycline (idarubicin 15 mg/m2 or daunorubicin 50 mg/m2), cytarabine 100 mg/m2 by rapid IV infusion every 12 hours for 10 doses, and thioguanine 100 mg/m2 orally every 12 hours for 10 doses.1, 4 If severe myelosuppression occurred, treatment was delayed then resumed upon hematologic recovery, and subsequent courses were given with a 25% reduction in the dosage of all drugs.1, 4 The study plan also included 4 courses of maintenance therapy to be given at 13-week intervals (2 days of the same anthracycline as used in induction and 5 days of cytarabine); however, this practice was discontinued following substantial toxicity, including 6 deaths from aplasia, among the first 47 patients enrolled in the trial.1, 4 In this study, patients receiving idarubicin and cytarabine had a higher rate of complete remissions (69 versus 55%) than those receiving daunorubicin and cytarabine; similar median survival (328 versus 277 days) was observed between the groups.1
In study 3, a total of 214 patients aged 18 years to 60 years or older (median age about 55 years) with previously untreated AML received either idarubicin 13 mg/m2 or daunorubicin 45 mg/m2 IV daily for 3 days; both groups received cytarabine 100 mg/m2 daily for 7 days by continuous IV infusion.1, 5 Patients with a complete remission following 1 or 2 courses of induction therapy received 2 courses of consolidation therapy using the same doses as used in the induction regimen but for shorter periods (anthracycline for 2 days and cytarabine for 5 days).1, 5 Patients receiving idarubicin and cytarabine had a similar rate of complete remissions (67 versus 58%) but longer median survival (393 versus 281 days) than those receiving daunorubicin and cytarabine.1 However, an update of the study data shows no difference in survival at 5 years.6
Patients with AML who have complete remission of disease following induction therapy generally receive consolidation chemotherapy.7, 21 The optimal regimen has not been established, but consolidation chemotherapy typically consists of a cytarabine-based regimen similar to that used in induction therapy administered over a short-term period.7 In the 3 US studies comparing cytarabine regimens using either idarubicin or daunorubicin for AML, patients with complete remission of disease following 1 or 2 courses of induction therapy received consolidation chemotherapy including the same anthracycline.1 Maintenance therapy for AML generally is not recommended.7 In study 2, substantial hematologic toxicity, including 6 deaths from aplasia (5 of which were in those receiving idarubicin), occurred in patients receiving maintenance therapy;4 as for other anthracyclines, intensive maintenance therapy with idarubicin for AML is not recommended.1
In addition to the 3 US studies, a multicenter, randomized study similar in design was conducted in Italy.1, 9 In study 4, a total of 255 patients aged 55-78 years (median age about 62 years) with previously untreated AML received either idarubicin 12 mg/m2 or daunorubicin 45 mg/m2 IV daily for 3 days; both groups received cytarabine 100 mg/m2 daily for 7 days by continuous IV infusion.1, 9 Patients with a complete remission following 1 or 2 courses of induction therapy received consolidation therapy using the same dose of anthracycline as used in the induction regimen, cytarabine, and thioguanine; consolidation therapy was followed by a maintenance regimen with cytarabine and thioguanine.9 No difference was found in the rate of complete remissions (40 versus 39%) or median survival (87 versus 169 days) for patients receiving the idarubicin regimen compared with those receiving the daunorubicin regimen.1, 9 A higher death rate during induction therapy was observed in patients receiving the idarubicin regimen; because this finding was not observed in patients of a similar age in the US studies, a difference in the level of supportive care has been suggested as a possible cause.1
Idarubicin has been used in combination with cytarabine for the treatment of recurrent or refractory AML.7, 13, 14 Various agents are continually being evaluated for the treatment of recurrent AML.7
Idarubicin is being investigated as a component of combination regimens for the treatment of acute lymphocytic leukemia†.2
Idarubicin is administered by IV injection.1 The drug is extremely irritating to tissues and, therefore, must not be given IM or subcutaneously.1 Care should be taken to avoid extravasation of the drug. 1
Idarubicin should be administered slowly (i.e., over 10-15 minutes) into a freely flowing IV infusion of 0.9% sodium chloride or 5% dextrose injection.1 The tubing for the IV infusion should be attached to a butterfly needle or other suitable device and preferably inserted into a large vein.1
Although a stinging or burning sensation may be a symptom of extravasation during IV administration of idarubicin, extravasation may occur without these symptoms and even when blood returns well during initial aspiration of the infusion needle.1 If signs or symptoms of extravasation occur, administration of the drug should be discontinued immediately and the infusion restarted in another vein.1 In cases of known or suspected subcutaneous extravasation, intermittent ice packs (immediately for 30 minutes, then 30 minutes 4 times daily for 3 days) should be applied over the affected area and the involved extremity should be elevated.1 The involved extremity should be examined frequently, and plastic surgery consultation should be obtained promptly upon any sign of a local reaction (i.e., pain, erythema, edema, or vesication).1 In case of ulceration or severe persistent pain at the site of extravasation, early wide excision of the affected area should be considered.1
Caution should be exercised in handling and preparing solutions of idarubicin.1 Because skin reactions may occur with accidental exposure to the drug, the manufacturer recommends the use of goggles, gloves, and protective gowns during preparation and administration of idarubicin.1 Skin accidentally exposed to the drug should be washed thoroughly with soap and water, and standard irrigation techniques should be used immediately in the event of eye involvement.1
Parenteral idarubicin solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1 The manufacturer states that idarubicin should not be mixed with other drugs (unless specific compatibility data are available).1 Precipitation occurs when the drug is mixed with heparin, and prolonged contact with any alkaline solution will cause degradation of idarubicin.1
For remission induction therapy in patients with acute myeloid leukemia (AML), the recommended dosage of idarubicin is 12 mg/m2 daily for 3 days by slow IV injection (over 10-15 minutes) in combination with cytarabine.1 Cytarabine may be administered as 100 mg/m2 daily by continuous IV infusion for 7 days;1 this is the cytarabine schedule used in 3 of the 4 randomized trials on which the current indication is based.4, 5, 9 Cytarabine also has been administered as a 25-mg/m2 IV loading dose followed by 200 mg/m2 daily by continuous IV infusion for 5 days.1, 3 A second induction course may be administered in the event of an incomplete antileukemic response after the first course.1
Consolidation chemotherapy was administered to patients in the 3 US studies and the Italian study comparing the use of idarubicin and daunorubicin in the treatment of AML. (See Uses: Acute Myeloid Leukemia.)1
Dosage Modification for Toxicity
In patients who experience severe mucositis with the first course of induction therapy with idarubicin, administration of a second course should be delayed until the mucositis resolves, and the dosage of idarubicin should be reduced by 25%.1, 22
Dosage in Renal and Hepatic Impairment
Hepatic or renal impairment may affect the disposition of idarubicin.1 The patient's hepatic and renal function should be evaluated prior to administration of idarubicin, and a dosage reduction should be considered if serum bilirubin and/or creatinine concentrations exceed the normal range.1 In several phase 3 clinical trials, idarubicin therapy was withheld in patients with serum bilirubin or creatinine concentrations exceeding 2 mg/dL.1 In one trial, patients with serum bilirubin concentrations of 2.6-5 mg/dL received idarubicin with a 50% reduction in dose.1, 4 Idarubicin should not be given to patients who have a serum bilirubin concentration exceeding 5 mg/dL.1
Unless otherwise stated, the incidence of adverse effects reported is derived from data for 110 patients receiving the drug in combination with cytarabine during induction therapy for AML in one randomized clinical trial; these data are representative of the observations in other studies.1, 4 Because patients receiving induction therapy for AML are seriously ill and are receiving multiple transfusions and concomitant medications, including potentially toxic anti-infective agents, it is difficult to determine the contribution of the study drug to adverse effects.1 Unless otherwise noted, these adverse effects occurred at a similar rate in patients receiving the daunorubicin regimen as induction therapy for AML.1
During induction therapy in 3 US studies, hematologic toxicity, including duration of aplasia, and nonhematologic toxicity, including cardiac toxicity, were similar for the idarubicin and daunorubicin regimens in all 3 studies except for an increase in mucositis in patients receiving idarubicin in one study.1 During consolidation therapy, a longer duration of aplasia (in all 3 studies) and a higher incidence of mucositis (in 2 studies) were reported in patients receiving the idarubicin regimen.1 In addition, patients receiving the idarubicin regimen required more transfusions (in 2 studies reporting such data) and a greater number of days of IV anti-infective treatment (in study 3, which used a higher dose of idarubicin).1
Hematologic Effects and Infectious Complications
The major dose-limiting adverse effect of idarubicin, bone marrow suppression, occurs in all patients receiving therapeutic doses of the drug for the treatment of AML; myelosuppression also represents the therapeutic effect of the drug that is necessary to eradicate the leukemic clone.1 Deaths secondary to infection and/or bleeding have occurred in patients receiving idarubicin.1 Hemorrhage occurred in 63% of patients receiving idarubicin.1 In all 3 US studies comparing the idarubicin and daunorubicin regimens for AML, a longer duration of aplasia was reported during consolidation therapy in patients receiving idarubicin.1
Infections occurred in 95% of patients receiving idarubicin.1 During consolidation therapy, the incidence and severity of infection was greater in patients receiving idarubicin compared with daunorubicin.4
The incidence of adverse cardiac effects did not differ significantly for patients receiving idarubicin versus daunorubicin.4 Adverse cardiac effects were reported in 16% of patients receiving idarubicin versus 24% of patients receiving daunorubicin as a component of induction therapy for AML; such clinical myocardial toxicity was severe or life-threatening in 11% of those receiving idarubicin and in 21% of those receiving daunorubicin.1, 4 Although data from animal studies suggest that idarubicin has reduced cardiotoxicity compared with daunorubicin and doxorubicin, no difference in cardiotoxicity was observed between idarubicin and daunorubicin during induction therapy for AML in the 3 US studies.2, 15
Myocardial toxicity associated with idarubicin was manifested by potentially fatal congestive heart failure (often attributed to fluid overload), acute life-threatening arrhythmias including atrial fibrillation, myocardial infarction, chest pain, asymptomatic decreases in left ventricular ejection fraction, or other cardiomyopathies.1 Cardiac insufficiency and arrhythmias generally were reversible and usually occurred in the setting of sepsis, anemia, and aggressive IV fluid administration.1 Adverse cardiac effects occurred more frequently in patients older than 60 years and in those with preexisting cardiac disease.1 Appropriate therapeutic measures for the management of congestive heart failure and/or arrhythmias should be used as clinically indicated.1 As with other anthracyclines, cardiac function should be monitored carefully in patients receiving idarubicin, particularly those at increased risk for myocardial toxicity.1
For information on risk factors and monitoring for cardiotoxicity associated with idarubicin, see Precautions and Contraindications: Cardiac Toxicity. For additional information on the cardiotoxicity of anthracyclines, see Cautions: Cardiac Effects in Doxorubicin Hydrochloride 10:00.
Adverse GI effects, including nausea and/or vomiting (82%), abdominal pain and/or diarrhea (73%), and mucositis (50%), have been reported frequently but were severe (equivalent to WHO grade 4 toxicity) in less than 5% of patients receiving idarubicin.1 The incidence of mucositis was higher in patients receiving the idarubicin regimen than in those receiving the daunorubicin regimen, especially during the consolidation treatment phase, in some US controlled trials.1
Severe enterocolitis with perforation has been reported rarely in patients receiving the drug. (See Precautions and Contraindications: Other Precautions and Contraindications.).1
Alopecia occurs in about 77% of patients receiving idarubicin.1 Skin reactions, including generalized rash, urticaria, and a bullous erythematous rash of the palms and soles, occur in 46% of patients receiving the drug.1 Dermatologic reactions occurring in patients receiving idarubicin usually have been attributed to concomitant anti-infective therapy.1 Radiation recall reactions at the site of prior radiation therapy also have been reported in patients receiving idarubicin.1
Changes in liver function test results have been reported in patients treated with idarubicin; these changes usually were transient and tended to occur in patients with sepsis who were receiving potentially hepatotoxic anti-infective agents.1 Severe changes in hepatic function (equivalent to WHO grade 4 toxicity) occurred in less than 5% of patients receiving idarubicin.1
Alterations in renal function test results have been reported in patients treated with idarubicin; these changes usually were transient and tended to occur in patients with sepsis who were receiving potentially nephrotoxic anti-infective agents.1 Severe changes in renal function (equivalent to WHO grade 4 toxicity) occurred in 1% or less of patients receiving idarubicin.1
Extravasation of idarubicin can cause severe tissue necrosis.1 Other adverse local effects, including urticaria, hives, and erythematous streaking, also have been reported with idarubicin.1 For information on the management of extravasation of idarubicin, see Dosage and Administration: Administration.
Mental status changes, headache, peripheral neuropathy, seizures, and cerebellar abnormalities were reported in 41, 20, 7, 4, and 4%, respectively, of patients receiving idarubicin.1
Adverse pulmonary effects have been reported in 39% of patients receiving idarubicin.1 Allergy-related pulmonary symptoms occurred in 2% of patients.1
Fever (not classified elsewhere) was reported in 26% of patients receiving idarubicin.1
Precautions and Contraindications
Idarubicin is a toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without evidence of toxicity.1 The drug must be used only under the supervision of clinicians experienced in the use of cytotoxic agents for leukemia therapy and only when the potential benefits of idarubicin therapy are thought to outweigh the possible risks.1 Close observation of the patient and careful laboratory monitoring are required; in addition, appropriate diagnostic and treatment facilities must be readily available in case the patient develops severe hemorrhagic conditions, infection, or other drug toxicity.1
Idarubicin causes severe and sometimes fatal hematologic toxicity and generally should not be used in patients with preexisting bone marrow suppression caused by previous drug or radiation therapy unless the potential benefit outweighs the risk.1 Because idarubicin therapy causes severe myelosuppression which can lead to potentially fatal infection and/or bleeding (see Cautions: Hematologic Effects and Infectious Complications), complete blood cell counts should be monitored regularly during idarubicin therapy.1
The potential benefit of idarubicin therapy must be weighed carefully against the risk of anthracycline-associated cardiotoxicity.1 The risk of idarubicin-induced cardiovascular toxicity is greater in patients who are older than 60 years of age, who have preexisting cardiac disease, or who have received prior therapy with anthracyclines or other cardiotoxic agents; the risk of cardiac toxicity also may be increased in patients with concomitant or previous radiation therapy to the mediastinal-pericardial area or in patients with anemia, bone marrow suppression, infections, or leukemic pericarditis and/or myocarditis.1
The risk of anthracycline-induced cardiotoxicity increases with increasing dose; a cumulative dose of idarubicin beyond which the incidence of cardiotoxicity rapidly increases has not been determined.2 However, retrospective analysis of data from 115 evaluable patients (median age: 40 years, range: 13-82 years) receiving a median cumulative dose of idarubicin 96 mg/m2 with a median follow-up of 225 days following the last dose of idarubicin suggests that the risk of congestive heart failure is low for cumulative idarubicin doses up to 150 mg/m2 in patients with no risk factors for cardiac toxicity.15
Cardiac function should be monitored carefully during idarubicin therapy.1 While there are no reliable methods for predicting which patients will develop congestive heart failure, anthracyline-induced cardiomyopathy usually is associated with a decrease in left ventricular ejection fraction from pretreatment baseline values.1
For additional information on the cardiotoxicity of anthracyclines, see Cardiac Effects and also Precautions and Contraindications, under Cautions in Doxorubicin Hydrochloride 10.00.
Other Precautions and Contraindications
Appropriate measures should be taken to prevent the occurrence of hyperuricemia related to the rapid lysis of leukemic cells.1 Any systemic infections should be treated before the initiation of idarubicin therapy.1
Instrumental intervention may increase the risk of perforation in patients experiencing severe enterocolitis associated with idarubicin, and patients developing severe abdominal pain should be evaluated for the possibility of perforation.1
Because hepatic or renal impairment may affect the disposition of idarubicin, hepatic and renal function should be evaluated before initiation of idarubicin therapy, and a dosage reduction should be considered if serum bilirubin and/or creatinine concentrations are elevated.1 Idarubicin is contraindicated in patients who have a serum bilirubin concentration exceeding 5 mg/dL; in some clinical trials, idarubicin therapy was not initiated if serum bilirubin and/or creatinine concentration exceeded 2 mg/dL.1 Changes in renal and hepatic function test results have been observed in patients receiving idarubicin, and frequent monitoring of these tests is recommended.1
Safety and efficacy of idarubicin in children have not been established.1 Although the drug has been used in induction therapy for children with acute myeloid leukemia, the efficacy and safety of idarubicin compared with the commonly used anthracycline daunorubicin have not been established.17
The risk of cardiovascular toxicity associated with idarubicin is greater in geriatric patients.1 Patients 60 years of age or older receiving induction therapy containing idarubicin experienced adverse cardiac effects, including congestive heart failure, serious arrhythmias, chest pain, myocardial infarction, and asymptomatic declines in left ventricular ejection fraction, more frequently than younger patients.1
The difference in the rate of complete remission between idarubicin and daunorubicin appears to decrease with increasing age.11 (See Uses: Acute Myeloid Leukemia.)
Mutagenicity and Carcinogenicity
Formal long-term studies to evaluate the carcinogenicity of idarubicin have not been performed to date.1 Mutagenic and carcinogenic properties of idarubicin and related compounds have been demonstrated in tests conducted in experimental models (including bacterial systems, mammalian cells in culture, and rats).1
Pregnancy, Fertility, and Lactation
Idarubicin can cause fetal toxicity when administered to pregnant women, but potential benefits may be acceptable in certain conditions despite possible risks to the fetus.1, 18, 19 A case of a human fetal death following maternal exposure to idarubicin during the second trimester of pregnancy has been reported.1 When administered to rats at a dosage of 1.2 mg/m2 daily (equivalent to one-tenth the recommended human dosage), the drug was embryotoxic and teratogenic; this dosage was not toxic to dams.1 The drug was embryotoxic but not teratogenic in rabbits receiving 2.4 mg/m2 daily (equivalent to one-fifth the recommended human dosage), a dosage which was toxic to dams.1
Adequate, well-controlled studies in pregnant women have not been conducted.1 Idarubicin should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.18 When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1 Women of childbearing potential who are treated with idarubicin should be advised to avoid pregnancy.1 Men receiving idarubicin should be advised to use barrier contraception.21
Studies have not been conducted to date to determine whether idarubicin affects fertility in males or females.1 When administered in male dogs at a dosage of 1.8 mg/m2 daily 3 times per week (approximately one-seventh the recommended human dosage on a mg/m2 basis) for 13 weeks (3 times the total human dose), idarubicin caused testicular atrophy and inhibition of spermatogenesis and sperm maturation resulting in few or no mature sperm; these effects were not readily reversible following an 8-week recovery period.1
It is not known whether idarubicin or its metabolites are distributed into milk.1 Because of the potential for serious adverse reactions to idarubicin in nursing infants, nursing should be discontinued prior to idarubicin therapy.1
Two cases of fatal overdosage of idarubicin have been reported to date in patients receiving idarubicin 135 mg/m2 over 3 days, or idarubicin 45 mg/m2 and daunorubicin 90 mg/m2 over 3 days.1 Manifestations of idarubicin overdosage may include severe, prolonged myelosuppression, acute cardiac toxicity or delayed cardiac failure, and possibly increased severity of GI toxicity.1 Severe arrhythmia was reported in one of the cases of fatal idarubicin overdose.1 In case of idarubicin overdose, appropriate supportive care, including platelet tranfusions, anti-infectives, and symptomatic treatment of mucositis, should be instituted.1 There is no known antidote to idarubicin, and it is considered unlikely that the drug is removed by conventional peritoneal dialysis or hemodialysis.1
Although the exact mechanism(s) of action has not been fully elucidated, idarubicin is a DNA-reactive agent.1 Idarubicin is thought to cause cytotoxicity by intercalation of the drug into DNA and/or inhibition of the enzyme topoisomerase II, resulting in disruption of nucleic acid synthesis.1, 2
Although an oral dosage form is not commercially available, idarubicin is known to be rapidly absorbed from the GI tract following oral administration; in contrast, other anthracyclines (i.e., doxorubicin, daunorubicin) are not absorbed to any appreciable extent following oral administration.2 Bioavailability varies widely in patients receiving oral idarubicin.2
When administered by IV injection, idarubicin hydrochloride is rapidly and widely distributed in tissues and has a large volume of distribution.1 Measurement of idarubicin concentrations in nucleated blood and bone marrow cells in patients with leukemia has demonstrated that peak cellular idarubicin concentrations occur within a few minutes following IV injection.1 Concentrations of idarubicin and idarubicinol (the principal active metabolite of idarubicin) in nucleated blood and bone marrow cells exceed plasma concentrations by more than 100 times.1 The rate of disappearance of idarubicin was similar in plasma and cells, with a terminal half-life of approximately 15 hours.1 The terminal half-life of idarubicinol in cells was about 72 hours.1 The expected extent of drug and metabolite accumulation on days 2 and 3 of dosing is 1.7- and 2.3-fold, respectively, and no change is expected in the disposition of idarubicin during a 3-day dosing regimen.1
At concentrations similar to the maximum plasma concentrations measured in pharmacokinetic studies, the extent of protein binding averaged 97 and 94% for idarubicin and idarubicinol, respectively.1 Protein binding of idarubicin and idarubicinol is not concentration dependent.1
The distribution of idarubicin and idarubicinol into CSF has been studied in pediatric patients with leukemia receiving idarubicin on a schedule of once weekly for 3 weeks or once daily for 3 days every 3 weeks.1, 20 Idarubicin (concentration 0.14 and 1.57 ng/mL) was detected in 2 of 21 CSF samples and idarubicinol (mean concentration 0.51 ng/mL; range, 0.22-1.05 ng/mL) was detected in 20 of the 21 samples;1, 20 the clinical importance of these findings is unclear.1
It is not known whether idarubicin or its metabolites are distributed into milk.1
The pharmacokinetics of idarubicin have been evaluated in adult patients with leukemia and normal renal and hepatic function following IV administration of 10-12 mg/m2 idarubicin daily for 3-4 days alone or in combination with cytarabine.1 The decline in plasma concentrations of idarubicin is best described by a 2- or 3-compartment open pharmacokinetic model.1 Elimination of idarubicin is slow, with an estimated mean terminal half-life of 22 hours (range: 4-48 hours) when given as a single agent and 20 hours (range: 7-38 hours) when administered in combination with cytarabine.1
Idarubicin is metabolized by the enzyme aldoketoreductase to idarubicinol, the principal active metabolite, which has in vitro antitumor activity similar to idarubicin.2 The plasma clearance of idarubicin is about twice the expected hepatic blood flow, indicating extensive extrahepatic metabolism.1 Idarubicinol is eliminated more slowly than the parent drug, with an estimated mean elimination half-life exceeding 45 hours.1 Detectable plasma concentrations of idarubicinol are present for more than 8 days following IV administration of idarubicin.1 Idarubicin is excreted principally in bile; renal excretion (mostly as the metabolite idarubicinol) also plays a role.1
The pharmacokinetics of idarubicin have been studied in pediatric patients with leukemia and appear to be linear.1 When idarubicin was administered IV at doses of 4.2-13.3 mg/m2 per day, no difference in half-life was observed between daily and weekly administration (with 3 repeated doses for both regimens).1
The pharmacokinetics of idarubicin in patients with hepatic and/or renal impairment have not been fully evaluated.1 The metabolism of idarubicin may be impaired in patients with moderate or severe hepatic dysfunction.1 Renal impairment also may affect the disposition of idarubicin.1
Idarubicin hydrochloride, a semisynthetic anthracycline, is an antineoplastic agent.1 The drug is structurally and pharmacologically related to the anthracycline daunorubicin.1 Idarubicin differs from daunorubicin in that idarubicin contains a hydrogen atom instead of a methoxy group at the 4-position of the D ring of the aglycone.2 Idarubicin has greater lipophilicity and consequently undergoes more rapid cellular uptake compared with other anthracyclines; these properties may result from the absence of the methoxy group.1
Commercially available idarubicin hydrochloride injection occurs as a sterile, red-orange, isotonic, preservative-free solution.1 Hydrochloric acid is used to adjust the pH to 3.5.1
Idarubicin hydrochloride injection should be refrigerated at 2-8°C and protected from light.1 Vials of the injection should remain in the original package until immediately prior to use.1
The manufacturer recommends that idarubicin generally not be mixed with other drugs; specialized references should be consulted for specific compatibility information.1 Precipitation occurs when the drug is mixed with heparin, and prolonged contact with any alkaline solution will cause degradation of the drug.1
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion | 1 mg/mL* | ||
Idarubicin Hydrochloride Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Pharmacia. Idamycin PFS® (idarubicin hydrochloride) injection prescribing information. Kalamazoo, MI; 2003 May.
2. Hollingshead LM, Faulds D. Idarubicin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs . 1991; 42:690-719. [PubMed 1723369]
3. Berman E, Heller G, Santorsa J et al. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood . 1991; 77:1666-74. [PubMed 2015395]
4. Vogler WR, Velez-Garcia E, Weiner RS et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group study. J Clin Oncol . 1992; 10:1103-11. [PubMed 1607916]
5. Wiernik PH, Banks PLC, Case Jr DC et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood . 1992; 79:313-9. [PubMed 1730080]
6. Berman E, Wiernik P, Vogler R et al. Long-term follow-up of three randomized trials comparing idarubicin and daunorubicin as induction therapies for patients with untreated acute myeloid leukemia. Cancer . 1997; 80(Suppl 11):2181-5. [PubMed 9395031]
7. Adult acute myeloid leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Jun 5.
8. Scheinberg DA, Maslak P, Weiss M. Acute leukemias. In: DeVita VT Jr, Hellman S, Rosenberg SA eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:2404-33.
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