VA Class:AN200
Epirubicin, the 4'-epimer of doxorubicin, is an anthracycline glycoside antineoplastic antibiotic.1, 2, 3, 4
Epirubicin is used as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast carcinoma.1, 2, 3, 4, 5 Efficacy as adjuvant therapy in the treatment of breast cancer (axillary node-positive with no evidence of distant metastatic disease [stage II or II]) was established in 2 randomized phase III clinical studies; one a comparative study and the other a dose-ranging study.1, 2, 4 Patients in one arm of the comparative study received cyclophosphamide, fluorouracil, and epirubicin hydrochloride (120 mg/m2 per cycle [60 mg/m2 on days 1 and 8 of each cycle] for 6 cycles); patients in the second arm received cyclophosphamide, fluorouracil, and methotrexate.1, 2, 4 Patients studied were premenopausal and perimenopausal women. Relapse-free (RFS) and overall (OS) survival were the clinical end points.1, 4 The epirubicin-containing regimen was statistically superior to the methotrexate-containing regimen with respect to 5-year RFS (62 versus 53%) and OS (77 versus 70%).1, 4 The dose-ranging study randomized premenopausal and postmenopausal women, with both groups receiving cyclophosphamide and fluorouracil, along with either 50 or 100 mg/m2 of epirubicin hydrochloride on day 1 of each cycle for 6 cycles.1, 4 The 100-mg/m2 dose of epirubicin hydrochloride was more effective than the 50-mg/m2 dose with respect to 5-year RFS (65 versus 52%) and OS (76 versus 65%).1, 4 Similar improvements in RFS and OS were observed in both premenopausal and postmenopausal women treated with the 100-mg/m2 epirubicin hydrochloride dose.1, 4
Epirubicin hydrochloride is administered IV.1 The drug is extremely irritating to tissues and, therefore, must not be given IM or subcutaneously.1 Care should be taken to avoid extravasation of the drug. 1 It is recommended that solutions of the drug be administered slowly into the tubing of a freely running IV infusion of 0.9 % sodium chloride or 5% dextrose injection.1 Direct IV injection of epirubicin hydrochloride is not recommended because of the risk of extravasation even in the presence of adequate blood return upon needle aspiration.1 When possible, veins over joints or in extremities with compromised venous or lymphatic drainage should not be used.1 The rate of injection depends on the volume of the infusion solution and the dosage, but usually ranges from 3-20 minutes.1 Local erythematous streaking along the vein and/or facial flushing may be indicative of too rapid an administration rate, and may be followed by local phlebitis or thrombophlebitis.1
Although a stinging or burning sensation may be a symptom of extravasation during IV administration of epirubicin hydrochloride, extravasation may occur without these symptoms and even when blood returns well during initial aspiration of the infusion needle.1 If any signs or symptoms of extravasation occur, the injection or infusion should be immediately stopped and restarted at another site.1 For information on the management of extravasation, see Dosage and Administration: Reconstitution and Administration, in Doxorubicin 10:00.
Epirubicin hydrochloride is incompatible with any alkaline pH solution; hydrolysis of the drug will occur with prolonged contact.1 The drug also is incompatible with heparin or fluorouracil; precipitation may occur.1 The manufacturer recommends that epirubicin hydrochloride not be mixed with other drugs in the same syringe.1
Epirubicin hydrochloride injection and solutions of the drug must be prepared and handled cautiously by trained nonpregnant personnel, and the use of protective equipment (e.g., latex gloves) is recommended.1 Hands must be washed after removal of the latex gloves.1 Accidental contact with the skin, mucous membranes, or eyes should be treated immediately by copious lavage with water, soap and water, or sodium bicarbonate solution; abrasion of the skin by use of a scrub brush should be avoided, and prompt medical attention is necessary.1 Parenteral epirubicin hydrochloride solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1
To obtain optimum therapeutic results with minimum adverse effects, dosage of epirubicin hydrochloride must be based on the clinical, cardiac, hepatic, renal, and hematologic response and tolerance of the patient and on other chemotherapy or irradiation being used.1
The recommended initial dosage of epirubicin hydrochloride as a component of adjuvant therapy for axillary node-positive breast cancer is 100-120 mg/m2.1, 4 Doses of the anthracycline are given in repeated 3- to 4-week cycles, with the total dose for each cycle given as a single dose on day 1 or as 2 equally divided doses on days 1 and 8.1, 4 In clinical trials, the 100-mg epirubicin hydrochloride regimen (FEC-100) included fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2, with all drugs administered IV on day 1 of a 21-day cycle and repeated for 6 cycles.1, 4 In clinical trials, the 120-mg epirubicin hydrochloride regimen (CEF-120) was given IV as 60 mg/m2 of the anthracycline and fluorouracil 500 mg/m2 on days 1 and 8 of each cycle combined with oral cyclophosphamide 75 mg/m2 on days 1-14 of each cycle, with the cycles being repeated at 28-day intervals; for 6 cycles. Prophylactic anti-infective therapy with co-trimoxazole or a fluoroquinolone was used concomitantly for the duration of chemotherapy.1, 4
Dose Modification for Toxicity
Dosage adjustments after the first treatment cycle should be made based on hematologic and nonhematologic toxicities.1 Patients experiencing (during the current treatment cycle) nadir platelet counts less than 50,000/mm3, absolute neutrophil counts (ANC) less than 250/mm3, neutropenic fevers, or grade 3 or 4 nonhematologic toxicity should have the day-1 dose of each antineoplastic agent in subsequent cycles reduced to 75% of the day-1 dose given in the current cycle.1 Day-1 chemotherapy in subsequent cycles should be delayed until platelet counts are at least 100,000/mm3, ANCs are at least 1500/mm3, and nonhematologic toxicities have recovered to grade 1 or better.1 For patients receiving a divided dose of epirubicin hydrochloride (days 1 and 8), the day-8 dose of the anthracycline, fluorouracil, and cyclophosphamide should be 75% of the day-1 dose if platelet counts and ANCs are 75,000-100,000 and 1000-1499/mm3, respectively.1 If day-8 platelet counts or ANCs are less than 75,000 or 1000/mm3, respectively, or grade 3 or 4 nonhematologic toxicity has occurred, the day-8 dose of each drug should be omitted.1
Radiation therapy in combination with epirubicin may result in additive cytotoxicity, and generally is not administered concurrently with antineoplastic agents.1 In adjuvant trials with the drug, radiation was delayed until after completion of chemotherapy; such delay did not appear to result in any appreciable increase in local breast cancer recurrence.1 In the limited number of patients who received concomitant radiation, chemotherapy was interrupted to avoid overlapping toxicities.1 Epirubicin is likely to sensitize tissues to the cytotoxic effects of radiation, and administration of the drug after radiation may induce an inflammatory recall reaction at the site of irradiation.1
For patients with bone marrow impairment (e.g., those extensively pretreated or with preexisting myelosuppression or neoplastic bone marrow infiltration), decreasing the epirubicin hydrochloride dosage for the initial cycle to 75-90 mg/m2 should be considered.1
Although the manufacturer does not provide definitive recommendations for dosage adjustment in patients with hepatic or renal impairment, reduced dosage should be given to those with hepatic impairment and considered for those with renal impairment.1 In clinical trials, patients with a serum bilirubin concentration of 1.2-3 mg/dL or AST concentration 2-4 times the upper limit of normal (ULN) received 50% of the recommended initial epirubicin hydrochloride dosage, and patients with bilirubin exceeding 3 mg/dL or AST exceeding 4 times the ULN received 25% of the initial dosage.1 Patients with severe hepatic impairment have not been evaluated; therefore, epirubicin should not be used in this population.1 Patients with severe renal impairment (serum creatinine concentration exceeding 5 mg/dL) may require dosage reductions; the drug has not been studied in those undergoing dialysis1
Known hypersensitivity to epirubicin, other anthracyclines, anthracenediones, or any ingredient in the formulation.1
Baseline neutrophil count less than 1500/mm3; severe myocardial or hepatic impairment or recent myocardial infarction; previous anthracycline therapy up to the maximum cumulative dose.1
Adequate Patient Evaluation and Monitoring
Epirubicin should be administered only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.1 Patients must have recovered from acute toxicities (e.g., stomatitis, neutropenia, thrombocytopenia, generalized infections) of prior cytotoxic therapy before starting treatment with epirubicin.1 Prior to and during therapy, determination of hematopoietic, hepatic, renal, and cardiac (left ventricular ejection fraction [LVEF]) function should be performed.1 Monitor for clinical complications associated with myelosuppression (e.g., granulocytopenia and infections) and potential cardiotoxicity (e.g., congestive heart failure [CHF]), especially with increasing cumulative exposure to anthracyclines.1 Supportive care may be necessary for the treatment of toxicity (e.g., severe neutropenia, severe infectious complications, cardiotoxicity).1
Dose-dependent, reversible leukopenia and/or granulocytopenia is the principal manifestation of hematologic toxicity and is the most common acute dose-limiting toxicity.1 Leukocyte nadir at day 10-14; return to baseline by day 21.1 Severe myelosuppression may occur.1
Cardiotoxicity is a known risk of anthracycline therapy; toxicity may be manifested by early (acute) or late (delayed) events.1
Early cardiotoxicity of epirubicin consists of sinus tachycardia and/or ECG abnormalities such as nonspecific ST-T wave changes, but more serious signs (e.g., AV block, ventricular tachycardia) also have been reported.1 Early effects generally do not predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and generally are not an indication for suspension of epirubicin therapy.1
Delayed cardiotoxicity (cardiomyopathy) is manifested by reduced LVEF and CHF, which may be life-threatening in its most severe form.1 Active or occult cardiovascular disease, prior or concomitant irradiation to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiotoxicity.1
Risk of serious cardiotoxicity may be decreased by regular monitoring of LVEF during therapy, and prompt discontinuance of epirubicin at the first sign of impaired cardiac function.1 In patients with risk factors for cardiotoxicity, monitoring of cardiac function must be particularly strict; risk versus benefit of continued therapy with impaired cardiac function must be carefully evaluated.1
Cardiotoxicity depends on the cumulative dose of epirubicin and represents the cumulative dose-limiting toxicity of the drug.1 Probability of developing clinically evident CHF is estimated as: 0.9, 1.6, and 3.3% at cumulative epirubicin hydrochloride dosages of 550, 700, and 900 mg/m2, respectively.1 The risk of developing CHF increases rapidly with increasing total cumulative doses exceeding 900 mg/m2; this cumulative dosage should only be exceeded with extreme caution.1 Toxicity may occur at lower cumulative doses, regardless of whether cardiac risk factors are present.1 It is probable that the cardiac effects of epirubicin and other anthracyclines or anthracenediones are additive.1
Thrombophlebitis and thromboembolic phenomena, including pulmonary embolism, sometimes fatal, also have been reported in patients receiving epirubicin.1
For a more complete discussion of the cardiotoxic effects of anthracyclines, see Cautions: Cardiac Effects, in Doxorubicin 10:00.
Secondary acute myelogenous leukemia (AML) has been reported in patients treated with anthracyclines; risk of refractory AML increases when epirubicin is combined with other DNA-damaging antineoplastics, when patients have had extensive exposure to cytotoxic drugs, or when anthracycline doses have been escalated.1 The cumulative risk for adjuvant epirubicin therapy-related leukemia is estimated as 0.2 and 0.8% at 3 and 5 years, respectively.1
Epirubicin is mutagenic, clastogenic, and carcinogenic in animals.1 Although experimental data are not available, epirubicin could induce chromosomal damage in human spermatozoa.1 Males should utilize effective contraceptive methods.1 Epirubicin may induce irreversible amenorrhea in premenopausal women.1
See Dosage and Administration: Special Populations, and Cautions: Specific Populations. Contraindicated in patients with severe hepatic impairment.1
Severe local necrosis if extravasation during administration occurs.1 Must not be given by IM or subcutaneous injection.1 (See Cautions: General Precautions, and Dosage and Administration: Administration.)
As a result of extensive purine catabolism accompanying rapid cellular destruction, hyperuricemia, including tumor lysis syndrome, may occur in patients receiving epirubicin; serum uric acid concentrations should be monitored.1 Hyperuricemia and its potential adverse effects may be minimized or prevented by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.1
Venous sclerosis may result from injection into a small vessel or repeated injections into the same vein.1 Extravasation during infusion may cause local pain, severe tissue lesions, and necrosis.1 (See Cautions: Warnings/Precautions, and Dosage and Administration: Administration.)
Epirubicin is emetogenic; prophylaxis with antiemetics should be considered prior to administration.1
Epirubicin, like other anthracyclines, may induce an inflammatory recall reaction at the site of prior irradiation.1 (See Dosage and Administration: Dosage.)
Category D.1 (See Users' Guide.)
It is unknown whether epirubicin is distributed in milk.1 Because other anthracyclines are distributed in milk, and because of the potential for serious adverse reactions in nursing infants from epirubicin, nursing should be discontinued prior to therapy.1
Safety and efficacy have not been established in children; children may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF.1
Although a reduced initial dosage was not used in clinical trials in women 70 years of age and older, careful monitoring for toxicity should be employed in this age group.1
Use is not recommended in severe impairment.1 Dosage adjustment for mild-to-moderate impairment.1
Dosage reductions should be considered for severe impairment.1 (See Dosage and Administration: Special Populations.)
Dosage reductions should be considered.1 (See Dosage and Administration: Special Populations.)
Epirubicin hydrochloride is a toxic drug with a low therapeutic index.1 A therapeutic response is not likely to occur without some evidence of toxicity.1 The major toxic effects of the drug are on the normal, rapidly proliferating tissues, particularly those of the bone marrow, GI and oral mucosa, and hair follicles.1 Alopecia, nausea/vomiting, myelosuppression (leukopenia, neutropenia, anemia, thrombocytopenia), amenorrhea, mucositis, lethargy, hot flushes (flashes), diarrhea, infection, local effects (e.g., venous irritation), conjunctivitis/keratitis, rash/pruritus, skin and nail changes (e.g., hyperpigmentation) , fever, and anorexia occur commonly.1 Urticaria, photosensitivity, and anaphylaxis (including shock) also have occurred.1
Potential pharmacodynamic interaction; additive pharmacologic and toxic effects.1
Cardioactive drugs that may precipitate CHF (e.g., calcium-channel blocking agents such as verapamil); close cardiac function monitoring required.1
Potential additive toxicities and inflammatory recall reactions at the site of irradiation.1 (See Dosage and Administration: Dosage.)
Potential pharmacokinetic interaction (increased epirubicin concentrations); discontinue during epirubicin therapy.1
Because of epirubicin's extensive hepatic metabolism, changes in hepatic function induced by concomitant therapy may affect metabolism, pharmacokinetics, efficacy, and/or toxicity.1
Rapidly and widely distributed into body tissues following IV administration.1 Appears to concentrate in red blood cells; concentrations in whole blood are approximately twice those in plasma.1 Distributed into milk in rats; not known whether the drug is distributed into milk in humans.1
Approximately 77% bound to plasma proteins, principally albumin.1
Extensively and rapidly metabolized in the liver; also is metabolized in other organs and cells, including red blood cells.1 Four main metabolic pathways have been identified.1 Only the metabolite epirubicinol appears to have cytotoxic activity; however, epirubicinol is unlikely to reach in vivo concentrations sufficient to produce cytotoxic effects.1
Epirubicin and its major metabolites are eliminated in feces via biliary excretion and to a lesser extent in urine.1
Plasma concentrations of epirubicin decline in a triphasic manner, with mean half-lives for the α, β, and γ phases of about 3 minutes, 2.5 hours, and 33 hours, respectively.1
Clearance is reduced in geriatric women and in patients with hepatic impairment.1
Epirubicin, the 4'-epimer of doxorubicin, is an anthracycline glycoside antineoplastic antibiotic that is a semisynthetic derivative of daunorubicin.1, 2, 3, 4 The spacial orientation of the hydroxyl group at carbon 4' of the sugar moiety results in epirubicin being a weaker base and more lipophilic than doxorubicin, which may result in an improved therapeutic index for epirubicin;3, 4 however, substantial differences in the types of biochemical interactions involved in the mechanism(s) of action and toxicity of the epimeric analogs do not appear to exist.3 As a result, the spectrum of pharmacologic, antineoplastic, and toxic effects of the drugs are qualitatively identical,1, 2, 3, 4 but at equimolar doses, epirubicin appears to be less toxic with regard to both general toxicity and cardiotoxicity.2, 3 The spacial orientation of the hydroxyl group also allows glucuronide conjugation of epirubicin, which is unique among currently available anthracyclines, and may be responsible for the relatively high plasma clearance and faster elimination of the drug.2, 3, 4
Epirubicin exhibits pharmacologic actions similar to those of daunorubicin and doxorubicin.1, 2, 3, 4 The precise and/or principal mechanism(s) of antineoplastic action of anthracyclines is not fully understood.1, 2, 4 Experimental evidence indicates that epirubicin, like other anthracyclines, forms a complex with DNA by intercalation between base pairs, causing inhibition of DNA synthesis and DNA-dependent RNA synthesis by the resulting template disordering and steric obstruction.1, 2, 4 Protein synthesis also is inhibited.1 Such intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity.1, 2, 3, 4 DNA helicase also is inhibited, resulting in interference with replication and transcription; epirubicin also generates cytotoxic free radicals.1, 2, 3, 4 For additional information, see Pharmacology in Doxorubicin 10:00. Because of the shared mechanisms between doxorubicin and epirubicin, the drugs appear to exhibit a similar spectrum of activity against a wide variety of solid tumors and hematologic malignancies, and complete cross-resistance between the 2 anthracyclines has been documented in vitro.2, 3, 4
Epirubicin undergoes extensive hepatic metabolism, and is eliminated principally by metabolism and biliary excretion; urinary excretion is only a minor elimination pathway.1, 2, 3, 4
Importance of recognizing and reporting adverse effects of epirubicin, including GI and myelosuppressive effects (and related precautions), infectious complications, CHF symptoms, and injection site pain.1
Risk of irreversible myocardial toxicity and leukemia.1
Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.1 Males must utilize effective contraception during therapy.1 (See Carcinogenicity in Cautions: Warnings.) Inform women of risk of irreversible amenorrhea or premature menopause.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1
Advise patients on alopecia, and reddish appearance of urine for 1-2 days (harmless).1
Additional Information
Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions January 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Pharmacia. Ellence® (epirubicin hydrochloride) injection prescribing information. Kalamazoo, MI; 2002 Jan.
2. Coukell AJ, Faulds D. Epirubicin: an updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of breast cancer. Drugs . 1997; 53:453-82. [PubMed 9074845]
3. Bonadonna G, Giannia L, Santoro A et al. Drugs ten years later: epirubicin. Ann Oncol . 1993; 4:359-69. [PubMed 8353070]
4. Pharmacia & Upjohn Co. Oncologic Drugs Advisory Committee (ODAC) brochure: NDA 21-010, epirubicin hydrochloride injection, amendment 019. Kalamazoo, MI; 1999 Jun 7.
5. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther . 2000; 42:83-92. [PubMed 10994034]