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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Doxorubicin

Last Update: January 15, 2018.

OVERVIEW

Introduction

Doxorubicin, epirubicin, idarubicin and valrubicin are structurally related cytotoxic antineoplastic antibiotics used in the therapy of several forms of lymphoma, leukemia, sarcoma and solid organ cancers. Doxorubicin is associated with a high rate of transient serum enzyme during therapy and to rare instances of clinically apparent acute liver injury with jaundice that can be severe and even fatal. Epirubicin and idarubicin have similar profiles of activity and adverse events as doxorubicin, but have been less commonly used and their potential for causing liver injury has been less well defined. Valrubicin is instilled directly in the bladder as treatment of refractory urinary bladder cancer, has little systemic distribution, and has not been associated with serum enzyme elevations or clinically apparent liver injury.

Background

Doxorubicin (dox” oh roo’ bi sin), epirubicin (ep” i roo’ bi sin), idarubicin (eye” da roo’ bi sin) and valrubicin (val roo' bi sin) are cytotoxic, anthracycline antibiotics which are believed to act by intercalating between DNA base pairs and uncoiling the DNA helix, which results in inhibition of DNA synthesis and the normal DNA breaking and resealing action of DNA toposiomerase II. These actions lead to apoptosis of rapidly dividing cells. These four agents are all semisynthetic derivatives of daunorubicin and share activities and toxicities. All four agents have severe adverse events particularly myelosuppression that can lead to severe neutropenia and sepsis. These agents should be administered only under the supervision of physicians who are experienced in the use of cancer chemotherapeutic agents and in managing their side effects.

The greatest clinical experience has been with doxorubicin which was previously known as adriamycin. Doxorubicin has potent activity in several forms of cancer, including acute leukemia, lymphomas, sarcomas and solid tumors. Doxorubicin was approved for use in the United States in 1974, and it remains an important agent in many cancer chemotherapeutic regimens. Current indications include treatment of bladder, breast, lung, ovarian stomach and thyroid cancers, Hodgkin disease, acute lymphocytic and non-lymphocytic leukemia, Wilm tumor, neuroblastoma and sarcomas. Doxorubicin is available as a powder for injection and in liquid solution in 10, 20, 50, 100, 150 and 200 mg vials [2 mg/mL] generically and under the brand name Adriamycin. Liposomal formulations are also available. Doxorubicin is typically given intravenously in doses of 60 to 75 mg per meter squared2 body surface area every 21 to 28 days. The dosage varies by indication, body surface area and hepatic function. Common side effects include bone marrow suppression, nausea, vomiting, mucositis, diarrhea, headache, dizziness, confusion, neuropathy, alopecia, skin rash and fever. High doses or prolonged therapy with doxorubicin can cause serious cardiac toxicity which is a major dose limiting side effect. Local extravasation of doxorubicin causes severe local tissue injury. Long term folllow up studies of treated patients suggest that secondary malignancies may arise more frequently in those who receive high, total accumulative doses of doxorubicin.

Epirubicin is an analogue of doxorubicin that has activity against many forms of cancer, but is used largely in the treatment of advanced breast cancer. Epirubicin was approved for use in the United States in 1999. Current indications are limited to use in patients with breast cancer who have evidence of lymph node involvement after primary resection of the breast tumor. Epirubicin is available as a solution generically and under the brand name Ellence in single use vials containing 50 or 200 mg [2 mg/mL]. The dose of epirubicin is typically 60 to 100 mg per meter squared given in combination with cyclophosphamide and fluorouracil. It is administered by slow intravenous infusion on days 1 and 8 of 28 day cycles. Common side effects are similar to those of doxorubicin and include cardiac toxicity and secondary malignancies.

Idarubicin is an analogue of doxorubicin that has activity against many forms of cancer, but most convincingly in acute myeloid leukemia (AML). Idarubicin was approved for use in the United States in 1990 and is still in common use in various combination chemotherapeutic regimens. Current indications are limited to use in combination with other antineoplastic agents for acute myelogenous leukemia in adults. Idarubicin is available as a solution generically and under the brand name Idamycin in vials and single dose syringes at concentrations of 1 mg/mL. The dose of idarubicin is typically 12 mg per meter squared body surface area, and the dose is adjusted based upon renal and hepatic function. It is administered by slow intravenous infusion daily for 3 days usually in combination with cytarabine, with repeat courses based on tolerance and efficacy. Common side effects are similar to those of doxorubicin and include cardiac toxicity.

Valrubicin is a synthetic analogue of doxorubicin that is used to treat refractory urinary bladder cancer. Valrubicin has been shown to induce clinical remissions in 18% to 30% of pateints. It was approved as a therapy of bladder cancer in the United States 1998, was removed in 2002 because of manufacturing issues, but reintroduced in 2009. Valrubicin is available only for intravesicular use in 5 mL single dose vials of 200 mg under the brand name Valstar. The recommended dose is 800 mg instilled in the bladder once weekly for 6 weeks. Common side effects include bladder pain and irritation, urgency and dysuria. Systemic absorption is minimal and systemic side effects are uncommon.

Hepatotoxicity

Serum aminotransferase elevations occur in up to 40% of patients on doxorubicin therapy, but elevations are generally asymptomatic and transient, resolving even with continuation of therapy. However, instances of acute liver injury with symptoms and jaundice have been reported with doxorubicin and rarely also with epirubicin and idarubicin. In most instances, multiple cancer chemotherapeutic agents were being administered and the anthracite antibiotic was believed to enhance the toxicity of the other agents (such as cyclosphosphamide, methotrexate or mercaptopurine). Combination antineoplastic regimens can cause sinusoidal obstruction syndrome, but the role of doxorubicin, epirubicin and idarubicin in this outcome is often not clear. Valrubicin is administered locally in the bladder (intravesical) and has little systemic absorption and has not been linked to serum enzyme elevations during therapy or to clinically apparent liver injury.

Likehood score (doxorubicin): B (likely cause of clinically apparent liver injury).

Likehood score (epirubicin and idarubicin): E* (unproven but suspected cause of clinically apparent liver injury).

Likehood score (valrubicin): E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

While hepatotoxicity from doxorubicin, epirubicin or idarubicin may be rare, it is likely due to direct toxic injury to the liver. Doxorubicin and its analogues are metabolized in the liver via microsomal enzymes, and production of a toxic or immunogenic intermediate may trigger liver injury.

Outcome and Management

The severity of the liver injury linked to doxorubicin, epirubicin and idarubicin therapy is usually mild and self-limited. These agents on their own have not been specifically linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no information on cross sensitivity to hepatic injury among the various cytotoxic antibiotics, but some degree of cross reactivity should be assumed.

Drug Class: Antineoplastic Agents

Other Drugs in the Subclass, Antibiotics, Cytotoxic: Bleomycin, Dactinomycin, Daunorubicin, Mitomycin, Mitoxantrone, Plicamycin

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Doxorubicin – Generic, Adriamycin®

Epirubicin – Generic, Ellence®, Epimycin®

Idarubicin – Generic, Idamycin®

Valrubicin – Valstar®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

DRUGCAS REGISTRY NO.MOLECULAR FORMULASTRUCTURE
Doxorubicin23214-92-8C27-H29-N-O11
Doxorubicin Chemical Structure
Epirubicin56420-45-2C27-H29-N-O11
Epirubicin Chemical Structure
Idarubicin58957-92-9C26-H27-N-O9
Idarubicin Chemical Structure
Valrubicin56124-62-0C34-H36-F3-N-O13
Image _56124-62-0.jpg

ANNOTATED BIBLIOGRAPHY

References updated: 15 January 2018

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