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EPIrubicin

( e-pee-ROO-bi-sin )
Funding:
New Drug Funding Program
  • Epirubicin - Adjuvant Treatment for Breast Cancer
  • Epirubicin - Neoadjuvant Treatment for Non-Metastatic Breast Cancer
Other Name(s): Pharmorubicin PFS®
Appearance: Red solution ; may be mixed into larger bags of fluids
A - Drug Name

EPIrubicin

COMMON TRADE NAME(S):   Pharmorubicin PFS®

 
B - Mechanism of Action and Pharmacokinetics

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.



Distribution

Rapidly and widely distributed into tissues. Also concentrates in red blood cells.

Cross blood brain barrier?

No

PPB 77%
Metabolism

Rapidly and extensively metabolized in liver, other organs and cells (i.e. red blood cells).

Active metabolites

Yes

Inactive metabolites

Yes

Elimination
Urine

9-10% within 48 hours

Bile 40% of dose recovered in bile within 72 hours
Half-life

t ½ (terminal) = 30-40 hours

 
C - Indications and Status
Health Canada Approvals:

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


Other Uses:

  • Soft tissue sarcoma
  • Prostate cancer
  • Primary unknown 
 
D - Adverse Effects

Emetogenic Potential:  

High (> 90 mg/ m2)
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
Photosensitivity (rare) I
Radiation recall reaction (rare) I
Rash, pruritus (9%) I  E
Skin hyperpigmentation (including nail hyperpigmentation - rare) I
Gastrointestinal Anorexia (3%) E
Diarrhea (25%) E
GI hemorrhage (rare) E
Mucositis (59%) E
Nausea, vomiting (92%) *** I  E
General Fatigue (46%) E
Fever (5%) E
Hematological Myelosuppression ± infection, bleeding (80%) (67% severe)*** E
Hypersensitivity Anaphylaxis (rare) I
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
Respiratory Pneumonitis (rare) E
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.

 
E - Dosing

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.



Adults:

Cycle Length Epirubicin Dose (mg/m2)
Weekly 12.5 to 25
2 Weeks 35
3-4 Weeks 50-150*
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

Dosage with Toxicity:

Suggested dose levels:  90, 75, 50 mg/m2

Worst Toxicity / Counts in Prior Cycle

Epirubicin Dose

for Next Cycle

Febrile neutropenia / Thrombocytopenic bleeding / ANC grade 4 ≥ 7 days

 ↓ 1 dose level*

Cardiotoxicity**

Discontinue

Grade 3 related organ / non-hematologic

↓ 1 dose level*

Grade 4 related organ / non-hematologic

Discontinue

*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%.



Dosage with Hepatic Impairment:

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

 



Dosage with Renal Impairment:

Adjust dose with severe renal impairment (creatinine > 442 micromol/L).


Dosage in the elderly:

Use with caution; no adjustment required. Plasma clearance of epirubicin in female patients > 70 years of age was noted to be reduced by 35%.



Children:

Safety and effectiveness have not been established. May be at greater risk for anthracycline-induced acute or chronic cardiotoxicity.



 
F - Administration Guidelines

  • 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.



 
G - Special Precautions
Contraindications:

  • 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

  • Severe arrhythmias

  • History of severe cardiac disease

  • Previous treatment with maximum cumulative doses of anthracyclines or anthracenediones

Other Warnings/Precautions:

  • 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:

  • Carcinogenicity: Yes

Pregnancy and Lactation:
  • Mutagenicity: Yes
  • Embryotoxicity: Yes
  • Fetotoxicity: Yes

    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: Probable

    Breastfeeding is not recommended.

  • Fertility effects: Probable
 
H - Interactions

AGENT EFFECT MECHANISM MANAGEMENT
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
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

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



 
J - Supplementary Public Funding

New Drug Funding Program (NDFP Website )

  • Epirubicin - Adjuvant Treatment for Breast Cancer
  • Epirubicin - Neoadjuvant Treatment for Non-Metastatic Breast Cancer

 
K - References

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

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.