Epirubicin is an anthracycline antineoplastic agent whose mechanism of action appears to be related to its ability to bind to nucleic acids. It forms a complex with DNA by intercalation of the planar ring with the DNA double helix resulting in inhibition of DNA and RNA synthesis. Binding to cell membranes as well as to plasma proteins may also be involved. Epirubicin is cell cycle phase non-specific.
Rapidly and widely distributed into tissues. Also concentrates in red blood cells.
|Cross blood brain barrier?||
Rapidly and extensively metabolized in liver, other organs and cells (i.e. red blood cells).
9-10% within 48 hours
|Bile||40% of dose recovered in bile within 72 hours|
t ½ (terminal) = 30-40 hours
For the treatment of:
- Metastatic breast cancer
- Early stage breast cancer (adjuvant treatment)
- Small cell lung cancer (both limited and extensive disease)
- Advanced non-small cell lung cancer
- Lymphoma, non-Hodgkin's
- Lymphoma, Hodgkin's
- Ovarian carcinoma, stage III and IV (FIGO)
- Gastric carcinoma, metastatic and locally unresectable
- Soft tissue sarcoma
- Prostate cancer
- Primary unknown
Moderate (≤ 90 mg/ m2)
Extravasation Potential: Vesicant
The following pooled adverse effects were reported from combination therapy Phase III studies for adjuvant breast cancer. Severe, life-threatening and post-marketing adverse effects are also included.
|ORGAN SITE||SIDE EFFECT* (%)||ONSET**|
|Cardiovascular||Arterial thromboembolism (rare)||E D|
|Cardiotoxicity (3%)||I D L|
|Venous thromboembolism (rare)||E D|
|Dermatological||Alopecia (96%) (57% severe)***||E|
|Radiation recall reaction (rare)||I|
|Rash, pruritus (9%)||I E|
|Skin hyperpigmentation (including nail hyperpigmentation - rare)||I|
|GI hemorrhage (rare)||E|
|Nausea, vomiting (92%) ***||I E|
|Hematological||Myelosuppression ± infection, bleeding (80%) (67% severe)***||E|
|Injection site||Injection site reaction (20%)||I|
|Metabolic / Endocrine||Hyperuricemia (rare)||I|
|Neoplastic||Leukemia (secondary) (1%) (at 8 years)||L|
|Ophthalmic||Conjunctivitis (15%) (also keratitis)||E|
|Reproductive and breast disorders||Menopausal symptoms (72%)||E D|
|Urinary||Urine discoloration (red, for 1-2 days)||I|
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
***Incidences are lower when administered in a weekly schedule (Gasparini 1991)
The most common side effects for epirubicin include alopecia, nausea, vomiting, myelosuppression ± infection, bleeding, menopausal symptoms, mucositis, fatigue, diarrhea, injection site reaction, conjunctivitis.
Myelosuppression is the major dose-limiting toxicity and may be severe and even life-threatening.
Epirubicin is associated with cardiac toxicity. It may manifest as an initial, acute effect of tachyarrhythmias and/or ECG abnormalities. These effects are usually reversible, unrelated to total dose, not considered indications for suspension of therapy and do not predict subsequent development of delayed cardiotoxicity. The onset of cardiomyopathy may be delayed, occurring 2-3 months to years after therapy and present as decreased left ventricular ejection fraction (LVEF) and/or signs/symptoms of CHF. Serious, irreversible cardiomyopathy, often unresponsive to therapy, is possible as the cumulative dose approaches 1000 mg/m2. Cardiac monitoring is advised when cumulative dose exceeds 650 mg/m2 (see Recommended Clinical Monitoring section). The risk of cardiomyopathy is increased at a lower cumulative dose when patients are older, have received prior treatment with trastuzumab, anthracycline/ anthracenediones/ mitomycin C, have received mediastinal radiation or have pre-existing cardiac risk factors.
Hyperuricemia may result from cell lysis by epirubicin resulting in tumor lysis syndrome (TLS). Hydration and antihyperuricemic prophylaxis may minimize potential TLS complications.
Erythematous streaking (a histamine release phenomenon) along the vein proximal to the site of injection has been reported, and must be differentiated from an extravasation event. This 'epirubicin flare' reaction usually subsides within 30 minutes. The injection may be continued, more slowly in the same site or may be changed to another site. Local protocols should be followed regarding management.
The tissue necrosis that happens with extravasation may happen days to weeks after the treatment. Extravasation may be asymptomatic initially, and occur even if blood returns well on aspiration of the infusion needle. Patients must be observed for delayed reactions and prior injection sites carefully inspected. Local protocols should be followed regarding management and should include application of ice to the affected area; dexrazoxane has been studied in the treatment of anthracycline extravasation (Mouridsen et al).
Epirubicin has the potential to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of epirubicin. Recurrent injury to a previously radiated site may occur weeks to months following radiation.
Refer to protocol by which patient is being treated.
Numerous dosing schedules exist and depend on disease, toxicity, response and concomitant therapy. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy or bone marrow infiltration. Patients should have recovered from toxicity before re-treatment.
Dosage is usually calculated on the basis of body surface area.
Prophylactic treatment consisting of hydration, urine alkalinization, and allopurinol should be considered for patients at high-risk of tumor lysis syndrome.
|Cycle Length||Epirubicin Dose (mg/m2)|
|Weekly||12.5 to 25|
|4 Weeks||60 for one dose on days 1 and 8|
*Recommended single dose may be divided over 2 successive days
Maximum lifetime cumulative dose:
- 650 mg/m2 for patients with cardiac risk factors and
- 900-1000mg/m2 for patients with no cardiac risk factors
Suggested dose levels: 90, 75, 50 mg/m2
Worst Toxicity / Counts in Prior Cycle
for Next Cycle
Febrile neutropenia / Thrombocytopenic bleeding / ANC grade 4 ≥ 7 days
↓ 1 dose level*
Grade 3 related organ / non-hematologic
↓ 1 dose level*
Grade 4 related organ / non-hematologic
*Do not start new cycle until organ toxicity ≤ grade 2, platelets ≥ 100 x 109/L and ANC ≥ 1.5 x 109/L
**including any signs and symptoms of heart failure, > 10% decline in LVEF to below the lower limit of normal, > 20% decline in LVEF from any level, or LVEF ≤ 45%.
|Hepatic Impairment||% of Epirubicin recommended starting Dose|
|Bilirubin 21-51 micromol/L or AST 2-4 x ULN||50|
|Bilirubin > 51 micromol/L or AST > 4 x ULN||25|
|Severe||Use is contraindicated|
Use with caution; no adjustment required. Plasma clearance of epirubicin in female patients > 70 years of age was noted to be reduced by 35%.
Safety and effectiveness have not been established. May be at greater risk for anthracycline-induced acute or chronic cardiotoxicity.
Slow push through sidearm of free flowing IV (5% Dextrose, Normal Saline). Doses of 100-120 mg/m2 should be infused over 15-20 minutes. For lower dose volumes, the infusion time may be proportionally decreased to no less than 3-5 minutes.
Do not admix with other drugs. Incompatible with heparin.
Avoid contact with alkaline solutions since this can lead to hydrolysis of epirubicin.
Slow down injection rate if erythematous streaking or facial flushing occurs.
If any signs or symptoms of extravasation occur, the injection or infusion should be immediately terminated and restarted in another vein. Any known or suspected extravasation should be managed promptly as per local guidelines and should include application of ice to the affected area.
Keep refrigerated (2-8oC). Protect from light.
Hypersensitivity to epirubicin, any components of the product, other anthracyclines or anthracenediones
Severe myelosuppression induced by prior chemotherapy or radiotherapy
Severe hepatic impairment
Severe myocardial insufficiency
Recent myocardial infarction
History of severe cardiac disease
Previous treatment with maximum cumulative doses of anthracyclines or anthracenediones
Avoid live vaccines; use may result in serious infections in immunocompromised patients.
Patients who have received mediastinal radiotherapy, other anthracycline/ anthracenediones/ cardiotoxic drugs, pre-existing heart disease are at increased risk of cardiotoxicity
Other Drug Properties:
Epirubicin is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months (general recommendation) after the last dose.
Excretion into breast milk:
Breastfeeding is not recommended.
|Cimetidine and other drugs affecting hepatic metabolism||↑ epirubicin exposure by 50% and decreased clearance by 30%||↓ metabolism||Avoid concomitant use|
|radiation||↑ skin reaction||radiation sensitizer||Use with caution|
|Verapamil, other calcium channel blockers||↑ risk of heart failure||↓ cardiac function||Caution, monitor|
|Cytotoxic drugs||↑ hematologic and GI toxicity||Additive||Caution, monitor|
|Trastuzumab||↑ cardiotoxicity||Additive||Avoid anthracycline-based therapy for up to 28 weeks after stopping trastuzumab|
|Taxanes (i.e. paclitaxel, docetaxel)||↑ systemic exposure to epirubicin or its metabolites. May be schedule dependent.||Taxane or Cremophor EL possibly competes with epirubicin for biliary excretion||Caution if used in combination; give epirubicin first, taxane at least 24 hours later|
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
|Monitor Type||Monitor Frequency|
|Baseline and before each cycle|
Liver and renal function tests
|Baseline, before each cycle and as clinically indicated|
Cardiac function tests (Echo, RNA and/or MUGA scans) for all patients with cardiac risk factors and cumulative doses > 650mg/m2
|Baseline and as clinically indicated|
Clinical toxicity assessment of GI effects, dermatologic effects, tumor lysis syndrome, infection, bleeding, ocular effects, cardiotoxicity, local toxicity
|At each visit|
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
New Drug Funding Program (NDFP Website )
- Epirubicin - Adjuvant Treatment for Breast Cancer
- Epirubicin - Neoadjuvant Treatment for Non-Metastatic Breast Cancer
Baker AF, Dorr RT. Drug interactions with the taxanes: clinical implications. Cancer Treatment Reviews 2001;27(4):221-33.
Cancer Drug Manual (the Manual) 2006, British Columbia Cancer Agency (BCCA).
Danesi R, Innocenti F, Fogli S, et al. Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients. Br J Clin Pharmacol 2002; 53: 508–18.
Esposito M, Venturini M, Vannozzi MO, et al. Comparative effects of paclitaxel and docetaxel on the metabolism and pharmacokinetics of epirubicin in breast cancer patients. J Clin Oncol 1999; 17:1132-40.
Fogli S, Danesi R, Gennari A, et al. Gemcitabine, epirubicin and paclitaxel: pharmacokinetic and pharmacodynamic interactions in advanced breast cancer. Annals of Oncology 2002; 13: 919–27.
Gasparini G, Dal Fior S, Panizzoni GA, et al. Weekly epirubicin versus doxorubicin as second line therapy in advanced breast cancer. A randomized clinical trial. Am J Clin Oncol 1991 Feb; 14(1): 38-44.
Grasselli G, Vigano L, Capri G, et al. Clinical and pharmacologic study of the epirubicin and paclitaxel combination in women with metastatic breast cancer. J Clin Oncol 2001; 19:2222-31.
Mouridsen HT, Langer SW, Buter J, et al. Treatment of anthracycline extravasation with Savene® (dexrazoxane): results from two prospective clinical multicentre studies. Annals of Oncology 2007; 18: 546–50.
Product Monograph: Pharmorubicin® (epirubicin). Pfizer Canada Inc., July 9, 2014.
Pfizer Inc. ELLENCE® product monograph. New York, NY; May 2005.
Venturini M, Lunardi G, Del Mastro L, et al. Sequence effect of epirubicin and paclitaxel treatment on pharmacokinetics and toxicity. J Clin Oncol 2000; 18: 2116-25.
August 2019 Updated Dosing, Dosing in Hepatic Impairment, Contraindications, Precautions and Monitoring sections
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