Pronunciation:
(ep i ROO bi sin)(ep i ROO bi sin)

U.S. Brand Names: Ellence�(r)

Synonyms: Pidorubicin; Pidorubicin Hydrochloride

Generic Available: No

Canadian Brand Names: Ellence�(r); Pharmorubicin�(r)

Use: Adjuvant therapy for primary breast cancer

Pregnancy Risk Factor: D

Pregnancy Implications: Epirubicin is mutagenic and carcinogenic. If a pregnant woman is treated with epirubicin, or if a woman becomes pregnant while receiving this drug, she should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Lactation: Excretion in breast milk unknown/contraindicated

Contraindications: Hypersensitivity to epirubicin, other anthracyclines, or anthracenediones; severe myocardial insufficiency, severe arrhythmias; recent myocardial infarction; severe hepatic dysfunction; baseline neutrophil count 1500 cells/mm³; previous anthracycline treatment up to maximum cumulative dose; pregnancy

Warnings/Precautions: The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. The primary toxicity is myelosuppression, especially of the granulocytic series, with less marked effects on platelets and erythroid series.

Potential cardiotoxicity, particularly in patients who have received prior anthracyclines or who have pre-existing cardiac disease, may occur. Acute toxicity (primarily arrhythmias) and delayed toxicity (CHF) have been described. Delayed toxicity usually develops late in the course of therapy or within 2-3 months after completion, however, events with an onset of several months to years after termination of treatment have been described. The risk of delayed cardiotoxicity increases more steeply at dosages above 900 mg/m², and this dose should be exceeded only with extreme caution. Toxicity may be additive with other anthracyclines or anthracenediones.

Reduce dosage and use with caution in mild to moderate hepatic impairment or in severe renal dysfunction (serum creatinine >5 mg/dL). May cause tumor lysis syndrome or radiation recall. Treatment with anthracyclines may increase the risk of secondary leukemias. For I.V. administration only, severe local tissue necrosis will result if extravasation occurs. Epirubicin is emetogenic.

Adverse Reactions:

>10%:

Central nervous system: Lethargy (1% to 46%)

Dermatologic: Alopecia (69% to 95%)

Endocrine & metabolic: Amenorrhea (69% to 72%), hot flashes (5% to 39%)

Gastrointestinal: Nausea, vomiting (83% to 92%), mucositis (9% to 59%), diarrhea (7% to 25%)

Hematologic: Leukopenia (49% to 80%; Grade 3 and 4: 1.5% to 58.6%), neutropenia (54% to 80%), anemia (13% to 72%), thrombocytopenia (5% to 49%)

Local: Injection site reactions (3% to 20%)

Ocular: Conjunctivitis (1% to 15%)

Miscellaneous: Infection (15% to 21%)

1% to 10%:

Cardiovascular: CHF (0.4% to 1.5%), decreased LVEF (asymptomatic) (1.4% to 1.8%); recommended maximum cumulative dose: 900 mg/m²

Central nervous system: Fever (1% to 5%)

Dermatologic: Rash (1% to 9%), skin changes (0.7% to 5%)

Gastrointestinal: Anorexia (2% to 3%)

Other reactions (percentage not specified): Acute lymphoid leukemia, acute myelogenous leukemia (0.2% at 3 years), anaphylaxis, hypersensitivity, photosensitivity reaction, premature menopause in women, radiation recall, skin and nail hyperpigmentation, transaminases increased, urticaria

Overdosage/Toxicology: Symptoms of overdose are generally extensions of known cytotoxic effects, including myelosuppression, mucositis, gastrointestinal bleeding, lactic acidosis, multiple organ failure, and death. Treatment is supportive.

Drug Interactions: Cimetidine increased the AUC of epirubicin by 50%.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (due to GI irritation).

Herb/Nutraceutical: St John's wort may decrease doxorubicin levels. Avoid black cohosh, dong quai in estrogen-dependent tumors.

Stability: Store refrigerated (2°C to 8°C/36°F to 46°F). Protect from light. Solution should be used within 24 hours of penetrating the rubber stopper. Incompatible with heparin, fluorouracil, or any solution of alkaline pH.

Compatibility: Stable in D5W, LR, NS; incompatible with heparin, fluorouracil, or any solution of alkaline pH

Compatibility in syringe: Compatible: Ifosfamide. Incompatible: Fluorouracil, ifosfamide with mesna, any solution of alkaline pH

Mechanism of Action: Epirubicin is an anthracycline antibiotic. Epirubicin is known to inhibit DNA and RNA synthesis by steric obstruction after intercalating between DNA base pairs; active throughout entire cell cycle. Intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase, and generates cytotoxic free radicals.

Pharmacodynamics/Kinetics:

Distribution: Vss 21-27 L/kg

Protein binding: 77% to albumin

Metabolism: Extensively via hepatic and extrahepatic (including RBCs) routes

Half-life elimination: Triphasic; Mean terminal: 33 hours

Excretion: Feces; urine (lesser extent)

Dosage: Adults: I.V.: 100-120 mg/m² once weekly every 3-4 weeks or 50-60 mg/m² days 1 and 8 every 3-4 weeks

Breast cancer:

CEF-120: 60 mg/m² on days 1 and 8 every 28 days for 6 cycles

FEC-100: 100 mg/m² on day 1 every 21 days for 6 cycles

Dosage adjustment in renal impairment: Severe renal impairment (serum creatinine >5 mg/dL): Lower doses should be considered

Dosage adjustment in hepatic impairment:

Bilirubin 1.2-3 mg/dL or AST 2-4 times the upper limit of normal: 50% of recommended starting dose

Bilirubin >3 mg/dL or AST >4 times the upper limit of normal: 25% of recommended starting dose

Elderly: Plasma clearance of epirubicin in elderly female patients was noted to be reduced by 35%. Although no initial dosage reduction is specifically recommended, particular care should be exercised in monitoring toxicity and adjusting subsequent dosage in elderly patients (particularly females >70 years).

Administration: Administer I.V. into the tubing of a freely-flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution) over 3-5 minutes.

Monitoring Parameters: Monitor injection site during infusion for possible extravasation or local reactions; CBC with differential and platelet count, liver function tests, renal function, ECG, and left ventricular ejection fraction

Patient Education: Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This medication can only be administered by infusion. Report immediately any swelling, pain, burning, or redness at infusion site. Avoid alcohol. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake, and adequate nutrition (small, frequent meals may help). You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); diarrhea (buttermilk, boiled milk, or yogurt may help); loss of hair (reversible); hyperpigmentation of skin or nails; mouth sores (frequent mouth care, soft toothbrush may help); or changes in menstrual cycle (consult prescriber). Report chest pain, swelling of extremities, palpitations, or rapid heartbeat; respiratory difficulty or unusual cough; unresolved nausea, vomiting, or diarrhea; alterations in urinary pattern (increased or decreased); opportunistic infection (fever, chills, unusual bruising or bleeding, fatigue, purulent vaginal discharge, unhealed mouth sores); skin rash; abdominal pain; blood in urine or stool; or other unresolved reactions. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication and for 1 month following therapy. Consult prescriber for appropriate barrier contraceptives. Do not breast-feed.

Dental Health: Effects on Dental Treatment: Key adverse event(s) related to dental treatment: Mucositis.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions: No information available to require special precautions

Mental Health: Effects on Mental Status: Lethargy is common

Mental Health: Effects on Psychiatric Treatment: Leukopenia is common; use caution with clozapine and carbamazepine

Oncology: Vesicant: Yes

Dosage Forms: Injection, solution [preservative free]: 2 mg/mL (25 mL, 100 mL)

References:

Coukell AJ and Faulds D, "Epirubicin. An Updated Review of Its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Efficacy in the Management of Breast Cancer,"Drugs, 1997, 53(3):453-82.

Gluck S, "The Expanding Role of Epirubicin in the Treatment of Breast Cancer,"Cancer Control, 2002, 9(2 Suppl):16-27.

Onrust SV, Wiseman LR, and Goa KL, "Epirubicin: A Review of Its Intravesical Use in Superficial Bladder Cancer,"Drugs Aging, 1999, 15(4):307-33.

Trudeau M and Pagani O, "Epirubicin in Combination With the Taxanes,"Semin Oncol, 2001, 28(4 Suppl 12):41-50.

International Brand Names: Bioepicyna�(r) (PL); Crisabon�(r) (AR); Ellence�(r) (CA); EPI-cell�(r) (DE); Epidoxo�(r) (AR); Epifil�(r) (AR); Epikebir�(r) (AR); Epilem�(r) [inj.] (MX, RU, TH); Epirubicina Delta Farma�(r) (AR); Epirubicin�(r) (AT); Epirubicin Ebewe�(r) (AT, CH, CZ, DK, HU, SI); Epirubicin Hexal�(r) (DE); Epirubicin Pharmalink�(r) (SE); Episindan�(r) (RO); Farmorrubicina RTU�(r) (CL); Farmorubicina�(r) (BR, CO, CR, ES, GT, HN, IT, PA, PT, SV); Farmorubicin�(r) (AR, AT, BE, BG, CH, CZ, DE, DK, FI, HR, HU, ID, IL, LU, MX, NO, PL, RO, RU, SE, SI, TH, TR, YU); Farmorubicine�(r) (BE, FR, NL); Pharmorubicin�(r) (AU, CA, GB, HK, NZ, SG); Riboepi�(r) (DE); Robanul�(r) (AR); Rubifarm�(r) (AR)