Idamycin

Pregnancy Category: D

Lactation: not known if excreted in breast milk; do not nurse

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

IDAMYCIN® (idarubicin hydrochloride for injection, USP) is a sterile, semi-synthetic antineoplastic anthracycline for intravenous use. Chemically, idarubicin hydrochloride 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:

IDAMYCIN, a sterile lyophilized powder for reconstitution and intravenous administration, is available in a 20 mg single use only vial.

Each 20 mg vial contains 20 mg Idarubicin Hydrochloride, USP and 200 mg of Lactose NF (hydrous) as an orange-red, lyophilized powder.

Four prospective randomized studies, three U.S. and one Italian, have been conducted to compare the efficacy and safety of idarubicin (IDR) to that of daunorubicin (DNR), each in combination with cytarabine as induction therapy in previously untreated adult patients with acute myeloid leukemia (AML). These data are summarized in the following table and demonstrate significantly greater complete remission rates for the IDR regimen in two of the three U.S. studies and significantly longer overall survival for the IDR regimen in two of the three U.S. studies.

There is no consensus regarding optional regimens to be used for consolidation; however, the following consolidation regimens were used in U.S. controlled trials. Patients received the same anthracycline for consolidation as was used for induction.

Studies 1 and 3 utilized 2 courses of consolidation therapy consisting of idarubicin 12 or 13 mg/m2 daily for 2 days, respectively (or DNR 50 or 45 mg/m2 daily for 2 days), and cytarabine, either 25 mg/m2 by IV bolus followed by 200 mg/m2 daily by continuous infusion for 4 days (Study 1), or 100 mg/m2 daily for 5 days by continuous infusion (Study 3). A rest period of 4 to 6 weeks was recommended prior to initiation of consolidation and between the courses. Hematologic recovery was mandatory prior to initiation of each consolidation course.

Study 2 utilized 3 consolidation courses, administered at intervals of 21 days or upon hematologic recovery. Each course consisted of idarubicin 15 mg/m2 IV for 1 dose (or DNR 50 mg/m2 IV for 1 dose), cytarabine 100 mg/m2 every 12 hours for 10 doses and 6-thioguanine 100 mg/m2 orally for 10 doses. If severe myelosuppression occurred, subsequent courses were given with 25% reduction in the doses of all drugs. In addition, this study included 4 courses of maintenance therapy (2 days of the same anthracycline as was used in induction and 5 days of cytarabine).

Toxicities and duration of aplasia were similar during induction on the 2 arms in the U.S. studies except for an increase in mucositis on the IDR arm in one study. During consolidation, duration of aplasia on the IDR arm was longer in all three studies and mucositis was more frequent in two studies. During consolidation, transfusion requirements were higher on the IDR arm in the two studies in which they were tabulated, and patients on the IDR arm in Study 3 spent more days on IV antibiotics (Study 3 used a higher dose of idarubicin).

The benefit of consolidation and maintenance therapy in prolonging the duration of remission and survival is not proven.

Intensive maintenance with Idamycin (idarubicin hydrochloride for injection, USP) is not recommended in view of the considerable toxicity (including deaths in remission) experienced by patients during the maintenance phase of Study 2.

A higher induction death rate was noted in patients on the IDR arm in the Italian trial. Since this was not noted in patients of similar age in the U.S. trials, one may speculate that it was due to a difference in the level of supportive care.

Idamycin (idarubicin hydrochloride for injection, USP) is intended for administration under the supervision of a physician who is experienced in leukemia chemotherapy.

Idamycin is a potent bone marrow suppressant. Idamycin 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 IDAMYCIN.

Myocardial toxicity as manifested by potentially fatal congestive heart failure, acute life-threatening arrhythmias or other cardiomyopathies may occur following therapy with IDAMYCIN. 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. 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 IDAMYCIN, 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 Idamycin 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/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. If Idamycin 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.

(See WARNINGS)

For induction therapy in adult patients with AML the following dose schedule is recommended:

Idamycin (idarubicin hydrochloride for injection, USP) 12 mg/m2 daily for 3 days by slow (10 to 15 min) intravenous injection in combination with cytarabine. The cytarabine may be given as 100 mg/m2 daily by continuous infusion for 7 days or as cytarabine 25 mg/m2 intravenous bolus followed by cytarabine 200 mg/m2 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 Idamycin should be considered. Idamycin 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 of Solution

Caution in handling of the powder and preparation of the solution must be exercised as skin reactions associated with Idamycin may occur. Skin accidently exposed to Idamycin 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.

Idamycin 20 mg vials should be reconstituted with 20 mL of Water for Injection, USP, to give a final concentration of 1 mg/mL of idarubicin hydrochloride. Bacteriostatic diluents are not recommended. The reconstituted solution is hypotonic, and the recommended administration procedure via a freely flowing intravenous infusion must be followed.

The vial contents are under a negative pressure to minimize aerosol formation during reconstitution; therefore, particular care should be taken when the needle is inserted. Inhalation of any aerosol produced during reconstitution must be avoided.

Reconstituted solutions are physically and chemically stable for 72 hours (3 days) under refrigeration (2° to 8°C, 36° to 46°F) and at controlled room temperature, (15° to 30°C, 59° to 86°F). Discard unused solutions in an appropriate manner (see Handling and Disposal).

Care in the administration of Idamycin 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 Idamycin 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.

Idamycin 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.

Incompatibility

Unless specific compatibility data are available, Idamycin 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 subject have been published.1–8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Idamycin (idarubicin hydrochloride for injection, USP)
NDC 0013-2526-86                20 mg single dose vial.                Available in single vials.

Store at controlled room temperature, 15° to 30°C (59° to 86°F), and protect from light.

1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society. 1999:32–41.
2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Washington, DC; Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health; 1992. US Department of Health and Human Services, Public Health Service Publication NIH 92-2621.
3. AMA Council on Scientific Affairs. Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985;253:1590–1591.
4. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. 1987. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.
5. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426–428.
6. Jones RB, Frank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA Cancer J Clin. 1983;33:258–263.
7. American Society of Hospital Pharmacists. ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033–1049.
8. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health-Syst Pharm. 1996;53:1669–1685.

LAB-0130-2.0
January 2006

Applies to idarubicin: intravenous powder for solution, intravenous solution

Along with its needed effects, idarubicin (the active ingredient contained in Idamycin) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking idarubicin:

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• coughing up blood
• cough or hoarseness
• difficulty with breathing or swallowing
• dizziness
• fever or chills
• increased menstrual flow or vaginal bleeding
• lower back or side pain
• nosebleeds
• painful or difficult urination
• paralysis
• pinpoint red spots on the skin
• prolonged bleeding from cuts
• red or dark brown urine
• red or black, tarry stools
• sores in the mouth and on the lips
• unusual bleeding or bruising

• Fast or irregular heartbeat
• joint pain
• pain at the injection site
• swelling of the feet and lower legs

• Skin rash or hives
• stomach pain (severe)

Some side effects of idarubicin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach cramps
• diarrhea
• headache
• nausea and vomiting

• Darkening or redness of the skin (after x-ray treatment)
• numbness or tingling of the fingers, toes, or face

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

• Fast or irregular heartbeat
• shortness of breath
• swelling of the feet and lower legs

Applies to idarubicin: intravenous powder for injection, intravenous solution

Hematologic

Very common (10% or more): Hemorrhage (up to 63%), anemia, severe leukopenia, severe neutropenia, thrombocytopenia
Frequency not reported: Bone marrow depression (dose dependent), pancytopenia[Ref]

For induction therapy for AML, a median WBC nadir of < 500/mm3 (ANC) usually occurs at 10 to 12 days, with recovery at around 15 to 20 days. Idarubicin monotherapy typically induces an absolute neutrophil count of 3000/mm3. Thrombocytopenia is less commonly encountered, with platelet nadirs occurring on days 10 to 15 over a median duration of approximately 25 days. Anemia is rare. Although prolonged myelosuppression is rarely observed, full hematologic recovery is typically observed in all cases.[Ref]

Gastrointestinal

Very common (10% or more): Nausea/vomiting (up to 82%), abdominal cramps/diarrhea (up to 73%), burning sensation, mucositis/stomatitis, anorexia
Common (1% to 10%): GI tract bleeding
Uncommon (0.1% to 1%): Dehydration, esophagitis, colitis (including severe enterocolitis/neutropenic enterocolitis with perforation)
Very rare (less than 0.01%): Gastric erosions or ulcerations[Ref]

-Idarubicin-induced nausea and vomiting can be seen as early as 15 to 30 minutes after IV dosing, and can be easily controlled with appropriate antiemetic therapy.
-Mucositis can be severe, especially in patients receiving multiple leukemia induction courses.
-Gastrointestinal perforation should be suspected in patients with severe abdominal pain.[Ref]

Dermatologic

Very common (10% or more): Alopecia (up to 77%)
Common (1% to 10%): Rash, itch, hypersensitivity of irradiated skin (radiation recall reaction)
Uncommon (0.1% to 1%): Skin and nail hyperpigmentation, urticaria, cellulitis (can be severe), tissue necrosis
Very rare (less than 0.01%): Acral erythema (bullous erythrodermatous rash of the palms and soles)
Frequency not reported: Hives, local toxicity[Ref]

Nervous system

Very common (10% or more): Headache (up to 20%)
Common (1% to 10%): Seizure[Ref]

Cardiovascular

Common (1% to 10%): Bradycardia, sinus tachycardia, tachyarrhythmias, asymptomatic reduction of left ventricular ejection fraction, congestive heart failure, cardiomyopathies, local phlebitis, thrombophlebitis
Uncommon (0.1% to 1%): ECG abnormalities (e.g., nonspecific ST segment changes), myocardial infarction, shock
Rare (0.01% to 0.1%): Cerebral hemorrhage

Very rare (less than 0.01%): Pericarditis, myocarditis, atrioventricular and bundle branch block
Frequency not reported: Serious arrhythmias including atrial fibrillation, chest pain, myocardial infarction, myocardial insufficiency, asymptomatic declines in LVEF, ECG changes, hot flushes, phlebitis, thrombophlebitis, thromboembolism[Ref]

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 acute myeloid leukemia (AML). Myocardial insufficiency and arrhythmias were usually reversible and occurred in the setting of sepsis, anemia, and aggressive IV fluid administration. The events were reported more frequently in patients over age 60 years and in those with preexisting cardiac disease.[Ref]

Local

Frequency not reported: Local skin irritation, extravasation (resulting in inflammation, thrombophlebitis, and/or tissue necrosis)[Ref]

In cases of extravasation most experts recommend topical ice packs to the affected area. Topical DMSO has been shown to be useful in cases of extravasation involving other anthracyclines; its usefulness in cases of idarubicin extravasation is unknown.[Ref]

Hepatic

Changes in hepatic function tests have been observed. These changes were usually transient and occurred in the setting of sepsis and while patients were receiving potentially hepatotoxic antibiotics and antifungal agents. Severe changes in hepatic function (equivalent to WHO Grade 4) occurred in less than 5% of patients.[Ref]

Very common (10% or more): Bilirubin and serum transaminase elevations (20% to 40%)[Ref]

Renal

Renal side effects including new or worsened renal insufficiency (perhaps associated with hyperuricemia), concomitant potentially nephrotoxic antimicrobial therapy, and/or dehydration has been reported in less than 5% of patients in large clinical trials. The nephrotic syndrome has been associated with the use of other anthracyclines in patients with acute myelogenous leukemias.[Ref]

Hypersensitivity

Very rare (less than 0.01%): Anaphylaxis[Ref]

Genitourinary

Very common (10% or more): Red coloration of the urine for 1 to 2 days after treatment[Ref]

Immunologic

Very common (10% or more): Infection (up to 95%)
Uncommon (0.1% to 1%): Sepsis/septicemia[Ref]

Metabolic

Uncommon (0.1% to 1%): Hyperuricamia
Frequency not reported: Tumor lysis syndrome[Ref]

Oncologic

Uncommon (0.1% to 1%): Secondary leukemia (acute myeloid leukemia and myelodysplastic syndrome)[Ref]

Other

Very common (10% or more): Fever (up to 26%), chills[Ref]

Respiratory

Common (1% to 10%): Pulmonary allergy[Ref]

Some side effects of Idamycin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.