INDICATIONS AND USAGE Idarubicin Hydrochloride injection, USP in combination with other approved antileukemic drugs is indicated for the treatment of acute myeloid leukemia (AML) in adults.

This includes French-American-British (FAB) classifications M1 through M7.

WARNINGS 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 cardiace contractility or cardiotoxic drugs (e.g., trastuzumab, cyclophosphamide and paclitaxel).

Do not administer idarubicin with other cardiotoxic agents unless the patient’s cardiac function is monitored frequently.

Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives, may also be at an increased risk of developing cardiotoxicity.

Avoid the use of anthracycline-based therapy for at least 5 half-lives after discontinuation of the cardiotoxic agent.

If anthracyclines are used before this time, carefully monitor the cardiac function.

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 .) Pregnancy Category D - Idarubicin was embryotoxic and teratogenic in the rat at a dose of 1.2 mg/m 2 /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/m 2 /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.

If idarubicin is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential should be advised to avoid pregnancy.

ADVERSE REACTIONS 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% 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.

Myelosuppression 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.

Gastrointestinal 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.

Dermatologic 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.

Hepatic and Renal 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.

Cardiac 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.