Idarubicin Hydrochloride

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.

DOSAGE AND ADMINISTRATION (See WARNINGS ) For induction therapy in adult patients with AML the following dose schedule is recommended: Idarubicin Hydrochloride Injection 12 mg/m 2 daily for 3 days by slow (10 to 15 min) intravenous injection in combination with cytarabine. The cytarabine may be given as 100 mg/m 2 daily by continuous infusion for 7 days or as cytarabine 25 mg/m 2 intravenous bolus followed by cytarabine 200 mg/m 2 daily for 5 days continuous infusion. In patients with unequivocal evidence of leukemia after the first induction course, a second course may be administered. Administration of the second course should be delayed in patients who experience severe mucositis, until recovery from this toxicity has occurred, and a dose reduction of 25% is recommended. In patients with hepatic and/or renal impairment, a dose reduction of Idarubicin Hydrochloride Injection should be considered. Idarubicin Hydrochloride Injection should not be administered if the bilirubin level exceeds 5 mg% (see WARNINGS ). The benefit of consolidation in prolonging the duration of remissions and survival is not proven. There is no consensus regarding optional regimens to be used for consolidation (see CLINICAL STUDIES for doses used in U.S. Clinical studies). Preparation and Administration Precautions Caution in handling the solution must be exercised as skin reactions associated with Idarubicin Hydrochloride Injection may occur. Skin accidentally exposed to Idarubicin Hydrochloride Injection should be washed thoroughly with soap and water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug. Care in the administration of Idarubicin Hydrochloride Injection will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions such as urticaria and erythematous streaking. During intravenous administration of Idarubicin Hydrochloride Injection extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs (1/2 hour immediately, then 1/2 hour 4 times per day for 3 days) be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and plastic surgery consultation obtained early if there is any sign of a local reaction such as pain, erythema, edema or vesication. If ulceration begins or there is severe persistent pain at the site of extravasation, early wide excision of the involved area should be considered. Idarubicin Hydrochloride Injection should be administered slowly (over 10 to 15 minutes) into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP (0.9%) or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. Idarubicin Hydrochloride Injection is provided in single dose vials. Discard unused portion. Incompatibility Unless specific compatibility data are available, Idarubicin Hydrochloride Injection should not be mixed with other drugs. Precipitation occurs with heparin. Prolonged contact with any solution of an alkaline pH will result in degradation of the drug. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and containers permit. Handling and Disposal Procedures for handling and disposal of anticancer drugs should be considered. Several guidelines on this sub …

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 Adverse Experiences IDR (N=110) DNR (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. 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. To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals, …

Mechanism of Action Idarubicin hydrochloride is a DNA-intercalating analog of daunorubicin which has an inhibitory effect on nucleic acid synthesis and interacts with the enzyme topoisomerase II. The absence of a methoxy group at position 4 of the anthracycline structure gives the compound a high lipophilicity which results in an increased rate of cellular uptake compared with other anthracyclines.

DESCRIPTION Idarubicin Hydrochloride Injection, USP contains idarubicin hydrochloride, USP and is a sterile, semi-synthetic, preservative-free solution (PFS) antineoplastic anthracycline for intravenous use. Chemically, idarubicin hydrochloride, USP is 5, 12-Naphthacenedione, 9-acetyl-7-[(3-amino-2,3,6-trideoxy-α-L- lyxo -hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxyhydrochloride, (7S- cis ). The structural formula is as follows: C 26 H 27 NO 9 •HCl M.W. 533.95 Idarubicin Hydrochloride Injection, USP is a sterile, clear, orange-red, isotonic parenteral preservative-free solution, available in 5 mL (5 mg), 10 mL (10 mg) and 20 mL (20 mg) single-dose-only vials. Each mL contains idarubicin hydrochloride USP, 1 mg (equivalent to 0.93 mg idarubicin free base) and the following inactive ingredients: glycerin USP, 25 mg and q.s. water for injection, USP. Hydrochloric acid and/or sodium hydroxide is used to adjust pH to a target of 3.5. Structural Formula

OVERDOSAGE There is no known antidote to idarubicin. Two cases of fatal overdosage in patients receiving therapy for AML have been reported. The doses were 135 mg/m 2 over 3 days and 45 mg/m 2 of idarubicin and 90 mg/m 2 of daunorubicin over a three day period. It is anticipated that overdosage with idarubicin will result in severe and prolonged myelosuppression and possibly in increased severity of gastrointestinal toxicity. Adequate supportive care including platelet transfusions, antibiotics and symptomatic treatment of mucositis is required. The effect of acute overdose on cardiac function is not fully known, but severe arrhythmia occurred in 1 of the 2 patients exposed. It is anticipated that very high doses of idarubicin may cause acute cardiac toxicity and may be associated with a higher incidence of delayed cardiac failure. Disposition studies with idarubicin in patients undergoing dialysis have not been carried out. The profound multicompartment behavior, extensive extravascular distribution and tissue binding, coupled with the low unbound fraction available in the plasma pool make it unlikely that therapeutic efficacy or toxicity would be altered by conventional peritoneal or hemodialysis.

HOW SUPPLIED Idarubicin Hydrochloride Injection, USP is a clear, orange-red, isotonic parenteral solution, free from visible particles for intravenous use only and is available as below: NDC Idarubicin Hydrochloride Injection, USP (1 mg per mL) Package Factor 71288- 184 -05 5 mg per 5 mL Single-Dose Vial 1 vial per carton 71288- 185 -10 10 mg per 10 mL Single-Dose Vial 1 vial per carton 71288- 186 -20 20 mg per 20 mL Single-Dose Vial 1 vial per carton Contains no preservative. Discard unused portion. Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex. Store under refrigeration 2° to 8°C (36° to 46°F). Protect from light. Retain in carton until time of use.