Source: FDA, National Drug Code (US) Revision Year: 2022
Idarubicin is intended for administration under the supervision of a physician who is experienced in leukemia chemotherapy.
Idarubicin is a potent bone marrow suppressant. Idarubicin should not be given to patients with pre-existing bone marrow suppression induced by previous drug therapy or radiotherapy unless the benefit warrants the risk.
Severe myelosuppression will occur in all patients given a therapeutic dose of this agent for induction, consolidation or maintenance. Careful hematologic monitoring is required. Deaths due to infection and/or bleeding have been reported during the period of severe myelosuppression. Facilities with laboratory and supportive resources adequate to monitor drug tolerability and protect and maintain a patient compromised by drug toxicity should be available. It must be possible to treat rapidly and completely a severe hemorrhagic condition and/or a severe infection.
Pre-existing heart disease and previous therapy with anthracyclines at high cumulative doses or other potentially cardiotoxic agents are co-factors for increased risk of idarubicin-induced cardiac toxicity and the benefit to risk ratio of idarubicin therapy in such patients should be weighed before starting treatment with idarubicin.
Myocardial toxicity as manifested by potentially fatal congestive heart failure, acute life-threatening arrhythmias or other cardiomyopathies may occur following therapy with idarubicin. Appropriate therapeutic measures for the management of congestive heart failure and/or arrhythmias are indicated.
Cardiac function should be carefully monitored during treatment in order to minimize the risk of cardiac toxicity of the type described for other anthracycline compounds. The risk of such myocardial toxicity may be higher following concomitant or previous radiation to the mediastinal-pericardial area or in patients with anemia, bone marrow depression, infections, leukemic pericarditis and/or myocarditis, active or dormant cardiovascular disease, previous therapy with other anthracyclines or anthracenediones, and concomitant use of drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab, cyclophosphamide and paclitaxel). Due to the increased risk of cardiotoxicity, avoid concomitant use of IDAMYCIN PFS until the cardiotoxic agent has been discontinued for at least 5 half-lives, and specifically avoid IDAMYCIN PFS for up to 7 months after stopping trastuzumab.
While there are no reliable means for predicting congestive heart failure, cardiomyopathy induced by anthracyclines is usually associated with a decrease of the left ventricular ejection fraction (LVEF) from pretreatment baseline values.
Since hepatic and/or renal function impairment can affect the disposition of idarubicin, liver and kidney function should be evaluated with conventional clinical laboratory tests (using serum bilirubin and serum creatinine as indicators) prior to and during treatment. In a number of Phase III clinical trials, treatment was not given if bilirubin and/or creatinine 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 and/or creatinine levels are above the normal range. (See DOSAGE AND ADMINISTRATION.)
Idarubicin was embryotoxic and teratogenic in the rat at a dose of 1.2 mg/m²/day or one tenth the human dose, which was nontoxic to dams. Idarubicin was embryotoxic but not teratogenic in the rabbit even at a dose of 2.4 mg/m²/day or two tenths the human dose, which was toxic to dams. There is no conclusive information about idarubicin adversely affecting human fertility or causing teratogenesis. There has been one report of a fetal fatality after maternal exposure to idarubicin during the second trimester.
There are no adequate and well-controlled studies in pregnant women. IDAMYCIN PFS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If IDAMYCIN PFS is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised and informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid pregnancy. Women of childbearing potential should be advised to use effective contraception during treatment with IDAMYCIN PFS and for 6.5 months after the last dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment with IDAMYCIN PFS and for 3.5 months after the last dose. Both men and women should seek advice for fertility preservation before treatment and/or seek genetic counselling after treatment.
Approximately 550 patients with AML have received idarubicin in combination with cytarabine in controlled clinical trials worldwide. In addition, over 550 patients with acute leukemia have been treated in uncontrolled trials utilizing idarubicin as a single agent or in combination. The table below lists the adverse experiences reported in U.S. Study 2 (see CLINICAL STUDIES) and is representative of the experiences in other studies. These adverse experiences constitute all reported or observed experiences, including those not considered to be drug related. Patients undergoing induction therapy for AML are seriously ill due to their disease, are receiving multiple transfusions, and concomitant medications including potentially toxic antibiotics and antifungal agents. The contribution of the study drug to the adverse experience profile is difficult to establish.
| Induction Phase | Percentage of Patients | |
|---|---|---|
| IDR | DNR | |
| Adverse Experiences | (N=110) | (N=118) |
| Infection | 95% | 97% |
| Nausea & Vomiting | 82% | 80% |
| Hair Loss | 77% | 72% |
| Abdominal Cramps/Diarrhea | 73% | 68% |
| Hemorrhage | 63% | 65% |
| Mucositis | 50% | 55% |
| Dermatologic | 46% | 40% |
| Mental Status | 41% | 34% |
| Pulmonary-Clinical | 39% | 39% |
| Fever (not elsewhere classified) | 26% | 28% |
| Headache | 20% | 24% |
| Cardiac-Clinical | 16% | 24% |
| Neurologic-Peripheral Nerves | 7% | 9% |
| Pulmonary Allergy | 2% | 4% |
| Seizure | 4% | 5% |
| Cerebellar | 4% | 4% |
Abbreviations: IDR=Idarubicin; DNR=Daunorubicin
The duration of aplasia and incidence of mucositis were greater on the IDR arm than the DNR arm, especially during consolidation in some U.S. controlled trials (see CLINICAL STUDIES).
The following information reflects experience based on U.S. controlled clinical trials.
Severe myelosuppression is the major toxicity associated with idarubicin therapy, but this effect of the drug is required in order to eradicate the leukemic clone. During the period of myelosuppression, patients are at risk of developing infection and bleeding which may be life-threatening or fatal.
Nausea and/or vomiting, mucositis, abdominal pain and diarrhea were reported frequently, but were severe (equivalent to WHO Grade 4) in less than 5% of patients. Severe enterocolitis with perforation has been reported rarely. The risk of perforation may be increased by instrumental intervention. The possibility of perforation should be considered in patients who develop severe abdominal pain and appropriate steps for diagnosis and management should be taken.
Alopecia was reported frequently and dermatologic reactions including generalized rash, urticaria and a bullous erythrodermatous rash of the palms and soles have occurred. The dermatologic reactions were usually attributed to concomitant antibiotic therapy. Local reactions including hives at the injection site have been reported. Recall of skin reaction due to prior radiotherapy has occurred with idarubicin administration.
Changes in hepatic and renal function tests have been observed. These changes were usually transient and occurred in the setting of sepsis and while patients were receiving potentially hepatotoxic and nephrotoxic antibiotics and antifungal agents. Severe changes in renal function (equivalent to WHO Grade 4) occurred in no more than 1% of patients, while severe changes in hepatic function (equivalent to WHO Grade 4) occurred in less than 5% of patients.
Congestive heart failure (frequently attributed to fluid overload), serious arrhythmias including atrial fibrillation, chest pain, myocardial infarction and asymptomatic declines in LVEF have been reported in patients undergoing induction therapy for AML. Myocardial insufficiency and arrhythmias were usually reversible and occurred in the setting of sepsis, anemia and aggressive intravenous fluid administration. The events were reported more frequently in patients over age 60 years and in those with pre-existing cardiac disease.
Therapy with idarubicin requires close observation of the patient and careful laboratory monitoring. Hyperuricemia secondary to rapid lysis of leukemic cells may be induced. Appropriate measures must be taken to prevent hyperuricemia and to control any systemic infection before beginning therapy.
Extravasation of idarubicin can cause severe local tissue necrosis. Extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If signs or symptoms of extravasation occur the injection or infusion should be terminated immediately and restarted in another vein. (See DOSAGE AND ADMINISTRATION.)
Frequent complete blood counts and monitoring of hepatic and renal function tests are recommended.
(See WARNINGS.)
It is not known whether this drug 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, mothers should discontinue nursing prior to taking this drug and do not breastfeed during treatment and for 14 days after last dose.
Safety and effectiveness in children have not been established.
Patients over 60 years of age who were undergoing induction therapy experienced congestive heart failure, serious arrhythmias, chest pain, myocardial infarction, and asymptomatic declines in LVEF more frequently than younger patients (see ADVERSE REACTIONS).
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