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Idarubicin Hydrochloride

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
Brands: Idamycin PFS

Warning(s)

  • Severe local tissue necrosis if extravasation occurs.1 Do not administer IM or sub-Q.1 Administer slowly into the tubing of a freely flowing IV infusion.1 (See Administration under Dosage and Administration.)

  • Possible cardiotoxicity and potentially fatal CHF.1 Risk of cardiotoxicity is greater in patients who have preexisting cardiac disease or who have received prior therapy with anthracyclines or other cardiotoxic agents.1 (See Cardiac Effects under Cautions.)

  • Severe myelosuppression may occur.1 (See Hematologic Effects under Cautions.)

  • Administer only under supervision of qualified clinicians experienced in use of cytotoxic therapy.1 Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.1 (See Adequate Patient Evaluation and Monitoring under Cautions.)

  • Dosage reduction should be considered in patients with hepatic or renal impairment. (See Special Populations under Dosage and Administration.)

Introduction

Antineoplastic agent;1 semisynthetic anthracycline; structurally and pharmacologically related to daunorubicin.1

Uses for Idarubicin Hydrochloride

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 M7.1 7 10 16 21

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Regimen consisting of cytarabine with either daunorubicin or idarubicin is a regimen of choice for remission induction in AML.7 10

Used in combination with cytarabine for the treatment of recurrent or refractory AML.7 13 14

Idarubicin Hydrochloride 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.1

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.1 Attach tubing to a butterfly needle or other suitable device and preferably insert into a large vein.1

Must not administer IM or sub-Q.1

Avoid extravasation.1 Extremely irritating to tissues.1 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.1 If signs or symptoms of extravasation occur (i.e., pain, erythema, edema, vesication), immediately discontinue administration and restart in another vein;1 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.1 Examine affected area frequently and promptly consult specialist in plastic surgery.1 In case of ulceration or severe persistent pain at the site of extravasation, consider early wide excision of the affected area.1 (See Local Effects under Cautions.)

Prepare and handle cautiously to avoid skin reactions.1 Use of goggles, gloves, and protective gowns recommended during preparation and administration.1 If skin contact occurs, thoroughly wash affected areas with soap and water; if eye contact occurs, standard irrigation techniques should be used immediately.1

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.1

Dosage

Available as idarubicin hydrochloride; dosage expressed in terms of the salt.1

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.1

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.1 3

A second induction course may be administered in the event of an incomplete antileukemic response after the first course.1

Consolidation Therapy
IV

Patients who have complete remission of disease following 1 or 2 courses of induction therapy generally receive consolidation chemotherapy.7 21 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.1 7

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%.1 22

Special Populations

Hepatic Impairment

Consider dosage reduction; monitor hepatic function.1 Administration not recommended in patients with serum bilirubin concentration >5 mg/dL.1 (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.1

Renal Impairment

Consider dosage reduction; monitor renal function.1 (See Renal Impairment under Cautions.)

Cautions for Idarubicin Hydrochloride

Contraindications

Serum bilirubin concentration >5 mg/dL.1

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.1 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.1

Prior to and during therapy, assess hepatic and renal function; carefully assess hematopoietic and cardiac function during therapy.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenic and embryotoxic in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Major Toxicities

Hematologic Effects

Severe and potentially fatal myelosuppression occurs following adminstration of therapeutic dosages.1 Careful hematologic monitoring required; perform CBCs at frequent intervals during therapy.1

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.1

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.1

Cardiac insufficiency and arrhythmias generally reversible; usually occur in setting of sepsis, anemia, and aggressive IV fluid administration.1

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.1 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.1

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.2

Monitor cardiac function carefully, particularly in those patients at increased risk for cardiotoxicity.1 Anthracyline-induced cardiomyopathy usually is associated with a decrease in left ventricular ejection fraction from pretreatment baseline values.1 Institute appropriate therapeutic measures for the management of CHF and/or arrhythmias as clinically indicated.1

General Precautions

Hyperuricemia

Hyperuricemia may result from the rapid lysis of leukemic cells.1 Appropriate measures should be taken to prevent the occurrence of hyperuricemia.1

GI Effects

Nausea and/or vomiting, abdominal pain and/or diarrhea, and mucositis reported frequently, but were severe in <5% of patients.1 Delay subsequent administration and reduce dosage if severe mucositis occurs.1 (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.1

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.1

Local Effects

Extravasation produces severe tissue necrosis.1 If signs or symptoms of extravasation occur (i.e., pain, erythema, edema, vesication), immediately discontinue administration and restart in another vein.1 (See Administration under Dosage and Administration.)

Urticaria, hives, and erythematous streaking reported.1

Specific Populations

Pregnancy

Category D.1

Lactation

Not known whether idarubicin is distributed into milk.1 Discontinue nursing because of potential risk to nursing infants.1

Pediatric Use

Safety and efficacy not established.1

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.1

Hepatic Impairment

Pharmacokinetics have not been fully evaluated.1 However, possible decreased metabolism and increased systemic exposure in patients with moderate or severe hepatic dysfunction.1 Consider dosage adjustment.1 Use not recommended in patients with serum bilirubin concentration >5 mg/dL.1 (See Contraindications under Cautions.)

Renal Impairment

Pharmacokinetics have not been fully evaluated.1 However, disposition of idarubicin may be altered; consider dosage adjustment.1

Common Adverse Effects

Infection, nausea, vomiting, hair loss, abdominal cramps/diarrhea, hemorrhage, mucositis, mental status changes, fever, headache.1

Interactions for Idarubicin Hydrochloride

No formal drug interaction studies to date.1

Specific Drugs

Drug

Interaction

Comments

Antifungals

Concurrent therapy may result in decreased hepatic and/or renal function1

Usually transient and occurring in patients with sepsis1

Hepatotoxic agents

Concurrent therapy may result in decreased hepatic function1

Usually transient and occurring in patients with sepsis1

Nephrotoxic agents

Concurrent therapy may result in decreased renal function1

Usually transient and occurring in patients with sepsis1

Idarubicin Hydrochloride Pharmacokinetics

Distribution

Extent

Rapidly and widely distributed into tissues following IV administration.1 Concentrations in nucleated blood and bone marrow cells exceed plasma concentrations by more than 100 times.1

Following IV administration in pediatric patients, idarubicin and idarubicinol were detected in CSF.1 20

Not known whether idarubicin is distributed into milk.1

Plasma Protein Binding

Idarubicin: Approximately 97%.1

Idarubicinol: Approximately 94%.1

Elimination

Metabolism

Metabolized principally to an active metabolite, idarubicinol, via aldoketoreductase.1 Undergoes extensive extrahepatic metabolism.1

Elimination Route

Excreted principally in feces via biliary excretion and to a lesser extent in urine.1

Half-life

Idarubicin: Terminal half-life is approximately 15 hours.1

Idarubicinol: Terminal half-life is approximately 72 hours.1

Stability

Storage

Parenteral

Injection

2–8°C; protect from light.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Do not mix with other drugs (unless specific compatibility data are available).1 Precipitation occurs when mixed with heparin; prolonged contact with any alkaline solution will cause degradation of idrarubicin.1

Compatible

Dextrose 3.3% in sodium chloride 0.3%

Dextrose 5% in sodium chloride 0.9%

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Amifostine

Amikacin sulfate

Aztreonam

Cimetidine HCl

Cladribine

Cyclophosphamide

Cytarabine

Diphenhydramine HCl

Droperidol

Erythromycin lactobionate

Etoposide phosphate

Filgrastim

Gemcitabine HCl

Granisetron HCl

Imipenem–cilastatin sodium

Magnesium sulfate

Mannitol

Melphalan HCl

Metoclopramide HCl

Potassium chloride

Ranitidine HCl

Sargramostim

Thiotepa

Vinorelbine tartrate

Incompatible

Acyclovir sodium

Allopurinol sodium

Ampicillin sodium–sulbactam sodium

Cefazolin sodium

Cefepime HCl

Ceftazidime

Clindamycin phosphate

Dexamethasone sodium phosphate

Etoposide

Furosemide

Gentamicin sulfate

Heparin sodium

Hydrocortisone sodium succinate

Lorazepam

Meperidine HCl

Methotrexate sodium

Piperacillin sodium–tazobactam sodium

Sodium bicarbonate

Teniposide

Vancomycin HCl

Vincristine sulfate

Actions

  • A DNA-reactive agent, although the exact mechanism(s) of action has not been fully elucidated.1

  • Intercalates into DNA and/or inhibits topoisomerase II, resulting in disruption of nucleic acid synthesis.1 2

  • Compared with other anthracyclines, is more lipophilic, and consequently undergoes more rapid cellular uptake.1

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.1

  • Risk of myocardial toxicity.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • 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.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Idarubicin Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV infusion

1 mg/mL

Idamycin PFS

Pfizer

Idarubicin Hydrochloride Injection

Sicor

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

1. Pharmacia. Idamycin PFS (idarubicin hydrochloride) injection prescribing information. Kalamazoo, MI; 2003 May.

2. Hollingshead LM, Faulds D. Idarubicin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs. 1991; 42:690-719. [PubMed 1723369]

3. Berman E, Heller G, Santorsa J et al. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood. 1991; 77:1666-74. [IDIS 280706] [PubMed 2015395]

4. Vogler WR, Velez-Garcia E, Weiner RS et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group study. J Clin Oncol. 1992; 10:1103-11. [PubMed 1607916]

5. Wiernik PH, Banks PLC, Case Jr DC et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992; 79:313-9. [IDIS 290353] [PubMed 1730080]

6. Berman E, Wiernik P, Vogler R et al. Long-term follow-up of three randomized trials comparing idarubicin and daunorubicin as induction therapies for patients with untreated acute myeloid leukemia. Cancer. 1997; 80(Suppl 11):2181-5. [IDIS 397676] [PubMed 9395031]

7. Adult acute myeloid leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Jun 5.

8. Scheinberg DA, Maslak P, Weiss M. Acute leukemias. In: DeVita VT Jr, Hellman S, Rosenberg SA eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:2404-33.

9. Mandelli F, Petti MC, Ardia A et al. A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia: a multicentric study from the Italian Co-operative Group GIMEMA. Eur J Cancer. 1991; 27:750-5. [PubMed 1829918]

10. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]

11. AML Collaborative Group. A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukemia. Br J Haematol. 1998; 103:100-9. [PubMed 9792296]

12. Rowe JM, Neuberg D, Friedenberg W, et al. A phase III study of daunorubicin vs idarubicin vs mitoxantrone for older adult patients (>55 yrs) with acute myelogenous leukemia (AML): a study of the Eastern Cooperative Oncology Group (E3993). Blood 1998; 92(Suppl 1):313a. Abstract 1284.

13. Lambertenghi-Deliliers G, Maiolo AT, Annaloro C et al. Idarubicin in sequential combination with cytosine arabinoside in the treatment of relapsed and refractory patients with acute non-lymphoblastic leukemia. Eur J Cancer Clin Oncol. 1987; 23:1041-5. [PubMed 3478198]

14. Harousseau JL, Reiffers J, Hurteloup P et al. Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose cytarabine. J Clin Oncol. 1989; 7:45-9. [PubMed 2642539]

15. Anderlini P, Benjamin RS, Wong FC et al. Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myelodysplasia. J Clin Oncol. 1995; 13:2827-34. [IDIS 355450] [PubMed 7595745]

16. Anon. Idarubicin. Med Lett Drugs Ther. 1991; 33:84-5. [PubMed 1875860]

17. Childhood acute myeloid leukemia/other myeloid malignancies. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Jun 18.

18. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist. 1979; 44:7434-67.

19. Department of Health and Human Services, Food and Drug Administration. Subpart B--Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.

20. Reid JM, Pendergrass TW, Krailo MD et al. Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Childrens Cancer Study Group report. Cancer Res. 1990; 50:6525-8. [IDIS 272658] [PubMed 2208112]

21. Reviewers’ comments (personal observations).

22. Pfizer. Kalamazoo, MI: Personal communication.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:919-22.

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