IDArubicin (Monograph)

Brand name: Idamycin PFS
Drug class: Antineoplastic Agents
VA class: AN200
Chemical name: (7S-cis)-9-Acetyl-7-[(3-amino-2,3,6-trideoxy-α-l-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxyhydrochloride-5,12-naphthacenedione
Molecular formula: C₂₆H₂₇NO₉HCl
CAS number: 57852-57-0

Introduction

Antineoplastic agent; semisynthetic anthracycline; structurally and pharmacologically related to daunorubicin.

Uses for IDArubicin

Acute Myeloid Leukemia

Used in combination with other antineoplastic agents for the treatment of acute myeloid (myelogenous, nonlymphocytic) leukemia (AML), including French-American-British classifications M1 through M7.

Regimen consisting of cytarabine with either daunorubicin or idarubicin is a regimen of choice for remission induction in AML.

Used in combination with cytarabine for the treatment of recurrent or refractory AML.

IDArubicin Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

• Monitor serum creatinine and bilirubin concentrations prior to initiating and during idarubicin therapy.

Administration

IV Administration

Administer by slow IV injection into the tubing of a freely flowing IV infusion of 0.9% sodium chloride or 5% dextrose injection. Attach tubing to a butterfly needle or other suitable device and preferably insert into a large vein.

Must not administer IM or sub-Q.

Avoid extravasation. Extremely irritating to tissues. Stinging or burning sensation during IV administration may be a symptom, but extravasation may occur without these symptoms and even when blood returns well during initial aspiration of the infusion needle. If signs or symptoms of extravasation occur (i.e., pain, erythema, edema, vesication), immediately discontinue administration and restart in another vein; apply intermittent ice packs (immediately for 30 minutes, then 30 minutes 4 times daily for 3 days) over the affected area and elevate the involved extremity. Examine affected area frequently and promptly consult specialist in plastic surgery. In case of ulceration or severe persistent pain at the site of extravasation, consider early wide excision of the affected area. (See Local Effects under Cautions.)

Prepare and handle cautiously to avoid skin reactions. Use of goggles, gloves, and protective gowns recommended during preparation and administration. If skin contact occurs, thoroughly wash affected areas with soap and water; if eye contact occurs, standard irrigation techniques should be used immediately.

Rate of Administration

Administer slowly (i.e., over 10–15 minutes) into a freely flowing IV infusion of 0.9% sodium chloride or 5% dextrose injection.

Dosage

Available as idarubicin hydrochloride; dosage expressed in terms of the salt.

Adults

Acute Myeloid Leukemia

Induction Therapy

IV

12 mg/m² daily for 3 days in combination with cytarabine 100 mg/m² daily by continuous IV infusion for 7 days.

Alternatively, 12 mg/m² daily for 3 days in combination with cytarabine (25-mg/m² IV loading dose followed by 200 mg/m² daily) by continuous IV infusion for 5 days.

A second induction course may be administered in the event of an incomplete antileukemic response after the first course.

Consolidation Therapy

IV

Patients who have complete remission of disease following 1 or 2 courses of induction therapy generally receive consolidation chemotherapy. The optimal regimen has not been established, but in clinical studies, consolidation chemotherapy typically consists of a cytarabine-based regimen similar to that used in induction therapy administered over a short-term period.

Dosage Modification for Toxicity

IV

In patients who experience severe mucositis with the first course of induction therapy, delay administration of a second course until the mucositis resolves and reduce dosage by 25%.

Special Populations

Hepatic Impairment

Consider dosage reduction; monitor hepatic function. Administration not recommended in patients with serum bilirubin concentration >5 mg/dL. (See Hepatic Impairment under Cautions.)

In one clinical study, patients with serum bilirubin concentration of 2.6–5 mg/dL received 50% of the recommended dosage.

Renal Impairment

Consider dosage reduction; monitor renal function. (See Renal Impairment under Cautions.)

Cautions for IDArubicin

Contraindications

Serum bilirubin concentration >5 mg/dL.

Warnings/Precautions

Warnings

Adequate Patient Evaluation and Monitoring

Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic agents for leukemia therapy. Close observation of the patient and careful laboratory monitoring are required; appropriate diagnostic and treatment facilities must be readily available in case the patient develops severe hemorrhagic conditions, infection, or other drug toxicity.

Prior to and during therapy, assess hepatic and renal function; carefully assess hematopoietic and cardiac function during therapy.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenic and embryotoxic in animals. Avoid pregnancy during therapy. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Major Toxicities

Hematologic Effects

Severe and potentially fatal myelosuppression occurs following adminstration of therapeutic dosages. Careful hematologic monitoring required; perform CBCs at frequent intervals during therapy.

Use generally not recommended in patients with preexisting bone marrow suppression caused by previous drug or radiation therapy unless the potential benefit outweighs the risk.

Cardiac Effects

Risk of anthracycline-associated cardiotoxicity manifested by potentially fatal CHF, acute life-threatening arrhythmias (e.g., atrial fibrillation), MI, chest pain, asymptomatic decreases in left ventricular ejection fraction, or other cardiomyopathies.

Cardiac insufficiency and arrhythmias generally reversible; usually occur in setting of sepsis, anemia, and aggressive IV fluid administration.

Increased risk of cardiotoxicity in patients >60 years of age, patients with preexisting cardiac disease, or those who have received prior therapy with anthracyclines or other cardiotoxic agents. Possible increased risk 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.

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.

Monitor cardiac function carefully, particularly in those patients at increased risk for cardiotoxicity. Anthracyline-induced cardiomyopathy usually is associated with a decrease in left ventricular ejection fraction from pretreatment baseline values. Institute appropriate therapeutic measures for the management of CHF and/or arrhythmias as clinically indicated.

General Precautions

Hyperuricemia

Hyperuricemia may result from the rapid lysis of leukemic cells. Appropriate measures should be taken to prevent the occurrence of hyperuricemia.

GI Effects

Nausea and/or vomiting, abdominal pain and/or diarrhea, and mucositis reported frequently, but were severe in <5% of patients. Delay subsequent administration and reduce dosage if severe mucositis occurs. (See Dosage Modification for Toxicity under Dosage and Administration.)

Hepatic Effects

Changes in liver function test results reported; usually transient and tended to occur in patients with sepsis who were receiving potentially hepatotoxic anti-infective agents.

Renal Effects

Changes in renal function test results reported; usually transient and tended to occur in patients with sepsis who were receiving potentially nephrotoxic anti-infective agents.

Local Effects

Extravasation produces severe tissue necrosis. If signs or symptoms of extravasation occur (i.e., pain, erythema, edema, vesication), immediately discontinue administration and restart in another vein. (See Administration under Dosage and Administration.)

Urticaria, hives, and erythematous streaking reported.

Specific Populations

Pregnancy

Category D.

Lactation

Not known whether idarubicin is distributed into milk. Discontinue nursing because of potential risk to nursing infants.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Increased risk of cardiovascular toxicity including CHF, serious arrhythmias, chest pain, MI, and asymptomatic declines in left ventricular ejection fraction in patients >60 years of age.

Hepatic Impairment

Pharmacokinetics have not been fully evaluated. However, possible decreased metabolism and increased systemic exposure in patients with moderate or severe hepatic dysfunction. Consider dosage adjustment. Use not recommended in patients with serum bilirubin concentration >5 mg/dL. (See Contraindications under Cautions.)

Renal Impairment

Pharmacokinetics have not been fully evaluated. However, disposition of idarubicin may be altered; consider dosage adjustment.

Common Adverse Effects

Infection, nausea, vomiting, hair loss, abdominal cramps/diarrhea, hemorrhage, mucositis, mental status changes, fever, headache.

No formal drug interaction studies to date.

Specific Drugs

IDArubicin Pharmacokinetics

Distribution

Extent

Rapidly and widely distributed into tissues following IV administration. Concentrations in nucleated blood and bone marrow cells exceed plasma concentrations by more than 100 times.

Following IV administration in pediatric patients, idarubicin and idarubicinol were detected in CSF.

Not known whether idarubicin is distributed into milk.

Plasma Protein Binding

Idarubicin: Approximately 97%.

Idarubicinol: Approximately 94%.

Elimination

Metabolism

Metabolized principally to an active metabolite, idarubicinol, via aldoketoreductase. Undergoes extensive extrahepatic metabolism.

Elimination Route

Excreted principally in feces via biliary excretion and to a lesser extent in urine.

Half-life

Idarubicin: Terminal half-life is approximately 15 hours.

Idarubicinol: Terminal half-life is approximately 72 hours.

Stability

Storage

Parenteral

Injection

2–8°C; protect from light.

Compatibility

Parenteral

Solution CompatibilityHID

Do not mix with other drugs (unless specific compatibility data are available). Precipitation occurs when mixed with heparin; prolonged contact with any alkaline solution will cause degradation of idrarubicin.

Drug Compatibility

Actions

• A DNA-reactive agent, although the exact mechanism(s) of action has not been fully elucidated.

• Intercalates into DNA and/or inhibits topoisomerase II, resulting in disruption of nucleic acid synthesis.

• Compared with other anthracyclines, is more lipophilic, and consequently undergoes more rapid cellular uptake.

Advice to Patients

• Importance of recognizing and reporting adverse effects, including GI, and myelosuppresive (and related precautions), infectious complications, CHF symptoms, and injection site pain.

• Risk of myocardial toxicity.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

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.

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