Ellence

Generic Name: Epirubicin Hydrochloride
Class: Antineoplastic Agents
VA Class: AN200
Chemical Name: (8S - cis) - 10 - [(3 - Amino - 2,3,6 - trideoxy - α - l - arabino - hexopyranosyl)oxy] - 7,8,9,10 - tetrahydro - 6,8,11 - trihydroxy - 8 - (hydroxyacetyl) - 1 - methoxy-5,12-naphthacenedione hydrochloride
Molecular Formula: C₂₇H₂₉NO₁₁•HCl
CAS Number: 56390-09-1

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  Severe local tissue necrosis if extravasation occurs.¹ Do not administer IM or sub-Q.¹

  
  


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  Possible cardiotoxicity and potentially fatal CHF during or after therapy.¹ Increased risk of CHF with cumulative doses >900 mg/m²; exceed this cumulative dose with extreme caution.¹ Toxicity may occur at lower cumulative doses, regardless of whether cardiac risk factors are present.¹ Cardiac effects of epirubicin and other anthracyclines or anthracenediones may be additive.¹

  
  


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  Possible secondary acute myelogenous leukemia (AML); risk of refractory AML increases when epirubicin is combined with other DNA-damaging antineoplastics, after extensive exposure to cytotoxic drugs, or when anthracycline doses have been escalated.¹

  
  


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  Reduce dosage in patients with hepatic impairment.¹ (See Hepatic Impairment under Dosage and Administration.)

  
  


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  Severe myelosuppression may occur.¹

  
  


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  Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.¹

  
  

Introduction

Anthracycline glycoside antineoplastic antibiotic; the 4′-epimer of doxorubicin; a semisynthetic derivative of daunorubicin.^{1 2 3 4 5}

Uses for Ellence

Breast Cancer

A component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast carcinoma; efficacy was established in combination with cyclophosphamide and fluorouracil.^{1 2 3 4 5}

Ellence Dosage and Administration

General

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  Optimize results and minimize adverse effects by basing dose on clinical, cardiac, hepatic, renal, and hematologic response; patient tolerance; and other chemotherapy or irradiation being used.¹

  
  


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

  
  

Administration

Extremely irritating to tissues.¹ Administer IV only; do not administer IM or sub-Q.¹

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer slowly into tubing of a freely running IV infusion of 0.9% sodium chloride or 5% dextrose injection.¹ Do not use veins over joints or in extremities with compromised venous or lymphatic drainage.¹

Avoid extravasation.¹ If signs or symptoms of extravasation occur, immediately stop the injection or infusion and restart at another site.¹

Handle cautiously (by trained nonpregnant personnel); use protective equipment (e.g., latex gloves) and wash hands after removal of the latex gloves.¹

Immediately treat accidental contact with the skin, mucous membranes, or eyes by copious lavage with water, soap and water, or sodium bicarbonate solution, but avoid abrasion of skin by use of a scrub brush; seek prompt medical attention.¹

Rate of Administration

Usually administered over 3–20 minutes, depending on the volume of the infusion solution and the dosage.¹

Rapid administration may cause local erythematous streaking along the vein and/or facial flushing;¹ local phlebitis or thrombophlebitis may follow.¹

Dosage

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

Adults

Breast Cancer

IV

100–120 mg/m² in repeated 3- to 4-week cycles; give total dose for each cycle 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/m² epirubicin hydrochloride regimen 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/m² epirubicin hydrochloride regimen 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.¹

Adjust dosage after first treatment cycle based on hematologic and nonhematologic toxicities.¹

In patients with nadir platelet counts <50,000/mm³, absolute neutrophil counts (ANCs) <250/mm³, neutropenic fevers, or grade 3 or 4 nonhematologic toxicity, reduce day-1 dose of each antineoplastic agent in subsequent cycles to 75% of the day-1 dose given in current cycle.¹

Delay day-1 chemotherapy in subsequent cycles until platelet counts are ≥100,000/mm³, ANCs are ≥1500/mm³, and nonhematologic toxicities have recovered to grade 1 or better.¹

If epirubicin hydrochloride dose is divided between days 1 and 8, reduce the day-8 dose of each drug to 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 <75,000 or 1000/mm³, respectively, or grade 3 or 4 nonhematologic toxicity has occurred, omit day-8 dose of each drug.¹

Special Populations

Hepatic Impairment

In clinical studies, patients with serum bilirubin concentration of 1.2–3 mg/dL or AST concentration 2–4 times the upper limit of normal (ULN) received 50% of recommended initial dosage of epirubicin hydrochloride.¹

In clinical studies, patients with serum bilirubin concentration of >3 mg/dL or AST >4 times the ULN received 25% of initial recommended dosage of epirubicin hydrochloride.¹

Epirubicin is not recommended in patients with severe hepatic impairment.¹

Renal Impairment

Consider dosage reduction if S_cr is >5 mg/dL; not studied in those undergoing dialysis.¹

Bone Marrow Impairment

Consider decreasing dosage for the initial cycle to 75–90 mg/m² in patients with bone marrow impairment (e.g., extensive pretreatment, preexisting myelosuppression, neoplastic bone marrow infiltration).¹

Cautions for Ellence

Contraindications

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  Known hypersensitivity to epirubicin, other anthracyclines, anthracenediones, or any ingredient in the formulation.¹

  
  


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  Baseline neutrophil count <1500/mm³.¹

  
  


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  Severe myocardial or hepatic impairment or recent myocardial infarction.¹

  
  


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  Previous anthracycline therapy up to the maximum cumulative dose.¹

  
  

Warnings/Precautions

Warnings

Adequate Patient Evaluation and Monitoring

Administer 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, assess hematopoietic, hepatic, renal, and cardiac function; monitor for clinical complications associated with myelosuppression (e.g., granulocytopenia, infections) and potential cardiotoxicity (e.g., CHF), especially with increasing cumulative exposure to anthracyclines.¹

Provide supportive care for the treatment of toxicity (e.g., severe neutropenia, severe infectious complications, cardiotoxicity).¹

Carcinogenicity

Possible secondary AML; risk of refractory AML increases with concomitant DNA-damaging antineoplastics, extensive exposure to cytotoxic drugs, or escalation of anthracycline doses.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

Fertility

Possible chromosomal damage in human spermatozoa; males should utilize effective contraceptive methods.¹

Possible irreversible amenorrhea in premenopausal women.¹

Local Effects

Local pain, severe tissue lesions, and severe local necrosis if extravasation occurs.¹ Must not be given IM or sub-Q (see IV Administration under Dosage and Administration).¹

Possible venous sclerosis if injected into a small vessel or injected repeatedly into the same vein.¹

Tumor Lysis Syndrome

Tumor lysis syndrome may result from extensive purine catabolism accompanying rapid cellular destruction; monitor serum uric acid concentration.¹

Minimize or prevent by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.¹

Major Toxicities

Hematologic Effects

Possible dose-dependent, reversible leukopenia and/or granulocytopenia (most common acute dose-limiting toxicity).¹

Leukocyte nadir at day 10–14, with return to baseline by day 21.¹

Possible severe myelosuppression.¹

Cardiac Effects

Early (acute) cardiotoxicity (e.g, sinus tachycardia, ECG abnormalities such as nonspecific ST-T wave changes, AV block, ventricular tachycardia) does not predict subsequent development of delayed cardiotoxicity, is rarely of clinical importance, and generally is not an indication for suspension of therapy.¹

Delayed cardiotoxicity (cardiomyopathy), manifested by reduced left ventricular ejection fraction (LVEF) and CHF, may be life-threatening.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 risk.¹

Monitor LVEF during therapy and discontinue epirubicin at the first sign of impaired cardiac function.¹

Strictly monitor cardiac function in patients with risk factors for cardiotoxicity; evaluate risk versus benefit of continued therapy in those with impaired cardiac function.¹

Cardiotoxicity is a cumulative dose-limiting toxicity of the drug.¹ Probability of developing CHF estimated as 0.9, 1.6, and 3.3% at cumulative epirubicin hydrochloride dosages of 550, 700, and 900 mg/m², respectively.¹ Risk of CHF increases rapidly with total cumulative dose >900 mg/m²; exceed this dose with extreme caution.¹ Possible toxicity at lower cumulative doses, regardless of whether cardiac risk factors are present.¹

Cardiac effects of epirubicin and other anthracyclines or anthracenediones may be additive.¹

Cardiovascular Effects

Thrombophlebitis and thromboembolic phenomena, including pulmonary embolism, sometimes fatal, have been reported.¹

GI Effects

Possible nausea and vomiting; consider prophylaxis with antiemetics.¹

Possible dose-dependent mucositis (e.g., oral stomatitis, esophagitis); may be severe.¹

Irradiation

Possible additive cytotoxicity with combined epirubicin and radiation therapy; in clinical studies with epirubicin, radiation therapy was delayed until after completion of the chemotherapy.¹

Possible inflammatory recall reaction at the site of prior irradiation.¹

Prophylactic Anti-infective Therapy

In clinical studies, prophylactic anti-infective therapy with co-trimoxazole or a fluoroquinolone was used with the 120-mg/m² regimen (see Dosage under Dosage and Administration).¹

Specific Populations

Pregnancy

Category D.¹

Lactation

Discontinue nursing because of potential risk to nursing infants.¹

Pediatric Use

Safety and efficacy not established.¹

Possible increased risk of acute or delayed cardiotoxicity.¹

Geriatric Use

Careful monitoring for toxicity is recommended.¹

Hepatic Impairment

Use not recommended in severe impairment.¹ Dosage adjustment for mild to moderate impairment (see Hepatic Impairment under Dosage and Administration).¹

Common Adverse Effects

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 changes, fever, anorexia.¹

Interactions for Ellence

Antineoplastic Agents

Potential pharmacodynamic interaction (additive pharmacologic and toxic effects).¹

Cardioactive Agents

Potential pharmacodynamic interaction (potentiation of cardiotoxicity); monitor cardiac function closely with concurrent use of cardioactive drugs that may precipitate CHF (e.g., verapamil).¹

Cimetidine

Potential pharmacokinetic interaction (increased epirubicin concentrations); discontinue during epirubicin therapy.¹

Hepatoactive Drugs

Potential pharmacologic or pharmacokinetic interaction.¹

Ellence Pharmacokinetics

Distribution

Extent

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

Plasma Protein Binding

Approximately 77% bound to plasma proteins, principally albumin.¹

Elimination

Metabolism

Extensively and rapidly metabolized in the liver; also is metabolized in other organs and cells, including erythrocytes.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

Elimination Route

Epirubicin and its major metabolites are eliminated in feces via biliary excretion and to a lesser extent in urine.¹

Half-life

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

Special Populations

Clearance is reduced in geriatric women and in patients with hepatic impairment.¹

Stability

Storage

Parenteral

Injection, for IV Use

2–8^° C.¹ Do not freeze; protect from light.¹ Discard unused solution within 24 hours after initial entry into vial.^{1 HID}

Compatibility

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

Parenteral

Incompatible with any alkaline pH solution (hydrolysis of drug).¹

Solution Compatibility^HID

Compatible
Dextrose 3.3% in sodium chloride 0.3%
Dextrose 5% in water
Ringer’s injection, lactated
Sodium chloride 0.9%

Drug Compatibility

Admixture Compatibility

Compatible
Ifosfamide
Incompatible
Fluorouracil

Y-Site CompatibilityHID

Compatible
Oxaliplatin

Manufacturer states that epirubicin hydrochloride should not be mixed with other drugs in the same syringe.¹

Compatibility in Syringe1HID

Compatible
Ifosfamide
Incompatible
Fluorouracil
Heparin sodium
Ifosfamide with mesna

ActionsActions

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  Pharmacologic actions similar to those of daunorubicin and doxorubicin.^{1 2 3 4}

  
  


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  Intercalates between base pairs causing template disordering and steric obstruction; thereby inhibits DNA synthesis, DNA-dependent RNA synthesis, and protein synthesis ^{1 2 4} and triggers DNA cleavage by topoisomerase II.^{1 2 3 4} Also inhibits DNA helicase and generates cytotoxic free radicals.^{1 2 3 4}

  
  


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  Compared with doxorubicin, is more lipophilic, may have improved therapeutic index, ^{3 4} and is less toxic;^{2 3} similar spectrum of activity against a wide variety of solid tumors and hematologic malignancies, and complete cross-resistance.^{2 3 4}

  
  

Advice to Patients

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  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

  
  


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  Risk of irreversible myocardial toxicity and leukemia.¹

  
  


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  Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy, advise pregnant women of risk to the fetus, and advise males to utilize effective contraception during therapy.¹ Inform women of risk of irreversible amenorrhea or premature menopause.¹

  
  


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

  
  


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  Probable alopecia; reddish appearance of urine for 1–2 days (harmless).¹

  
  


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  Importance of informing 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.

Epirubicin Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV use only	2 mg/mL (50 and 200 mg)	Ellence (preservative-free)	Pharmacia

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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. 19997; 53:453-82.

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]

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2007:626-8.

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