EPIrubicin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous, as hydrochloride [preservative free]:

Ellence: 50 mg/25 mL (25 mL); 200 mg/100 mL (100 mL)

Generic: 50 mg/25 mL (25 mL); 200 mg/100 mL (100 mL)

Pharmacology

Mechanism of Action

Epirubicin is an anthracycline antineoplastic agent; 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. Also inhibits DNA helicase, and generates cytotoxic free radicals.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 21 to 27 L/kg

Metabolism

Extensive via hepatic and extrahepatic (including RBCs) routes

Excretion

Feces (34% to 35%); urine (20% to 27%)

Half-Life Elimination

Triphasic; Mean terminal: 33 hours

Protein Binding

~77% to albumin

Use in Specific Populations

Special Populations: Renal Function Impairment

Clearance was reduced by 50% in patients with serum creatinine ≥5 mg/dL.

Special Populations: Hepatic Function Impairment

Clearance was reduced by ~30% in patients with elevated AST levels and normal bilirubin, and by ~50% in patients with elevated AST and bilirubin levels, as compared to patients with normal hepatic function.

Special Populations: Elderly

Plasma clearance of epirubicin in elderly female patients was reduced by 35% as compared to younger female patients.

Use: Labeled Indications

Breast cancer, adjuvant treatment: Adjuvant therapy component for primary breast cancer in patients with evidence of axillary node tumor involvement

Use: Off Label

Esophageal cancera

Data from a large, randomized, phase III trial supports the use of epirubicin in combination with cisplatin and fluorouracil (ECF regimen) pre- and postoperatively for the management of adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus Cunningham 2006. Another large phase III trial (REAL-2) investigated whether fluorouracil could be replaced by capecitabine, and cisplatin could be replaced by oxaliplatin, in the ECF regimen for the treatment of esophagogastric cancers. Data from the two-by-two design showed that capecitabine and oxaliplatin were as effective as fluorouracil and cisplatin, respectively (in combination with epirubicin) Cunningham 2008.

Gastric cancera

Data from two large, randomized, phase III trials supports the use of epirubicin in combination with cisplatin and fluorouracil (ECF regimen) for the management of adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus Cunningham 2006, Waters 1999. Another large phase III trial (REAL-2) investigated whether fluorouracil could be replaced by capecitabine, and cisplatin could be replaced by oxaliplatin, in the ECF regimen for the treatment of esophagogastric cancers. Data from the two-by-two design showed that capecitabine and oxaliplatin were as effective as fluorouracil and cisplatin, respectively (in combination with epirubicin) Cunningham 2008.

Osteosarcomab

Data from a small phase II trial in patients with nonmetastatic or extremity osteosarcoma supports the use of epirubicin (in combination with cisplatin, ifosfamide and mesna) for 3 cycles before and 3 cycles after surgery Basaran 2007.

Soft tissue sarcomab

Data from a phase II trial as well as from a phase III randomized trial support the use of epirubicin in combination with ifosfamide/mesna for the adjuvant treatment of soft tissue sarcoma after surgical resection Frustaci 2001, Petrioli 2002.

Contraindications

Severe hypersensitivity to epirubicin, other anthracyclines, anthracenediones, or any component of the formulation; severe myocardial insufficiency, recent myocardial infarction, or severe arrhythmias; previous treatment with anthracyclines up to the maximum cumulative dose; severe persistent drug-induced myelosuppression; severe hepatic impairment (Child-Pugh class C or serum bilirubin >5 mg/dL)

Canadian labeling: Additional contraindications (not in the US labeling): Marked persistent myelosuppression induced by prior treatment with other chemotherapy agents or by radiotherapy

Dosage and Administration

Dosing: Adult

Note: Patients receiving 120 mg/m²/cycle as part of combination therapy (CEF-120 regimen) should receive prophylactic antibiotic therapy. Lower starting doses may be necessary for heavily pretreated patients, patients with preexisting myelosuppression, or with bone marrow involvement. If clinically reasonable, delay epirubicin therapy until other cardiotoxic agents with long half-lives (eg, trastuzumab) have been cleared. A lifetime maximum cumulative dose >900 mg/m² should be avoided. Epirubicin is associated with a moderate to high emetic potential (depending on regimen); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).

Breast cancer, adjuvant treatment: IV: Usual dose: 100 to 120 mg/m² per 3- or 4-week treatment cycle as follows:

60 mg/m² on days 1 and 8 every 28 days for 6 cycles in combination with cyclophosphamide and fluorouracil (CEF-120 regimen; Levine 2005) or

100 mg/m² on day 1 every 21 days for 6 cycles in combination with cyclophosphamide and fluorouracil (FEC-100 regimen; Bonneterre 2005) or

Breast cancer (off-label regimens): IV:

EC regimen: 100 mg/m² on day 1 every 21 days for 8 cycles in combination with cyclophosphamide (Piccart 2001) or

EP or EC regimen: 75 mg/m² on day 1 every 21 days for up to 6 cycles in combination with either paclitaxel or cyclophosphamide (Langley 2005) or

FEC regimen ± paclitaxel: 90 mg/m² on day 1 every 21 days for 6 cycles in combination with fluorouracil and cyclophosphamide or for 4 cycles in combination with fluorouracil and cyclophosphamide followed by paclitaxel (Martin 2008) or

FEC regimen followed by pertuzumab + trastuzumab + docetaxel: 100 mg/m² on day 1 every 21 days for 3 cycles in combination with fluorouracil and cyclophosphamide, followed by 3 cycles of pertuzumab, trastuzumab, and docetaxel (Schneeweiss 2013) or

CEF regimen: 50 mg/m² on days 1 and 8 every 21 or 28 days for 6 to 9 cycles in combination with cyclophosphamide and fluorouracil (Ackland 2001)

Esophageal cancer (off-label use): IV:

ECF, ECX, EOF, and EOX regimens: 50 mg/m² on day 1 every 21 days for up to 8 cycles in combination with cisplatin (C), oxaliplatin (O), fluorouracil (F), and/or capecitabine (X) (Cunningham 2008) or

ECF regimen: 50 mg/m² on day 1 every 21 days for 3 preoperative and 3 postoperative cycles in combination with cisplatin and fluorouracil (Cunningham 2006)

Gastric cancer (off-label use): IV:

ECF, ECX, EOF, and EOX regimens: 50 mg/m² on day 1 every 21 days for up to 8 cycles in combination with cisplatin (C), oxaliplatin (O), fluorouracil (F), and/or capecitabine (X) (Cunningham 2008; Waters 1999) or

ECF regimen: 50 mg/m² on day 1 every 21 days for 3 preoperative and 3 postoperative cycles in combination with cisplatin and fluorouracil (Cunningham 2006)

Osteosarcoma (off-label use): IV: 90 mg/m² on day 1 every 21 days for 3 cycles before surgery and 90 mg/m² on day 1 every 28 days for 3 cycles after surgery (in combination with cisplatin, ifosfamide and mesna) (Basaran 2007)

Soft tissue sarcoma (off-label use): IV: 25 mg/m² on days 1, 2, and 3 every 28 days for 4 cycles (in combination with ifosfamide and mesna) (Petrioli 2002) or 60 mg/m² on days 1 and 2 every 21 days for 5 cycles (in combination with ifosfamide, mesna, and filgrastim) (Frustaci 2001)

Dosing: Geriatric

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 of age).

Dosing: Adjustment for Toxicity

Breast cancer (adjuvant therapy):

Hematologic toxicity: Note: Heavily treated patients, patients with preexisting bone marrow depression or neoplastic bone marrow infiltration: Lower starting doses (75 to 90 mg/m²) should be considered.

Delay day 1 dose of subsequent cycles until platelets are ≥100,000/mm³, ANC ≥1,500/mm³, and nonhematologic toxicities have recovered to ≤ grade 1.

Reduce day 1 dose in subsequent cycles to 75% of previous day 1 dose if patient experiences nadir platelet counts <50,000/mm³, ANC <250/mm³, neutropenic fever, or grade 3/4 nonhematologic toxicity during the previous cycle.

For CEF-120 regimen, reduce day 8 dose to 75% of day 1 dose if platelet counts are 75,000 to 100,000/mm³ and ANC is 1,000 to 1,499/mm³; omit day 8 dose if platelets are <75,000/mm³, ANC <1,000/mm³, or grade 3/4 nonhematologic toxicity.

Nonhematologic toxicity: Cardiac toxicity: Discontinue epirubicin if signs/symptoms of cardiomyopathy develop.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Reconstitute lyophilized powder with sterile water for injection (25 mL for the 50 mg vial) to a final concentration of 2 mg/mL. Shake vigorously; may take several minutes for dissolution. May be further diluted with sterile water for injection.

Administration

Epirubicin is associated with a moderate to high emetic potential (depending on regimen); antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

IV: Infuse over 15 to 20 minutes or slow IV push; if lower doses due to dose reduction are administered, may reduce infusion time proportionally. Do not infuse over <3 minutes. Infuse into a free-flowing IV solution (NS or D₅W). Avoid the use of veins over joints or in extremities with compromised venous or lymphatic drainage.

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Initiate antidote (dexrazoxane or dimethyl sulfate [DMSO]). Apply dry cold compresses for 20 minutes 4 times daily for 1 to 2 days (Perez Fidalgo 2012); withhold cooling beginning 15 minutes before dexrazoxane infusion; continue withholding cooling until 15 minutes after infusion is completed. Topical DMSO should not be administered in combination with dexrazoxane; may lessen dexrazoxane efficacy.

Dexrazoxane: 1,000 mg/m² (maximum dose: 2,000 mg) IV (administer in a large vein remote from site of extravasation) over 1 to 2 hours days 1 and 2, then 500 mg/m² (maximum dose: 1,000 mg) IV over 1 to 2 hours day 3; begin within 6 hours of extravasation. Day 2 and day 3 doses should be administered at approximately the same time (± 3 hours) as the dose on day 1 (Mouridsen 2007; Perez Fidalgo 2012). Note: Reduce dexrazoxane dose by 50% in patients with moderate to severe renal impairment (CrCl <40 mL/minute).

DMSO: Apply topically to a region covering twice the affected area every 8 hours for 7 days; begin within 10 minutes of extravasation; do not cover with a dressing (Perez Fidalgo 2012).

Storage

Protect from light.

Solution: Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Product may “gel” at refrigerated temperatures; will return to slightly viscous solution after 2 to 4 hours at room temperature (15°C to 25°C). Discard unused solution from single dose vials within 24 hours of entry.

Lyophilized powder: Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Reconstituted solutions are stable for 24 hours when stored at 2°C to 8°C (36°F to 46°F) or at room temperature.

Drug Interactions

Ado-Trastuzumab Emtansine: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with ado-trastuzumab emtansine should avoid anthracycline-based therapy for up to 7 months after stopping ado-trastuzumab emtansine. Monitor closely for cardiac dysfunction in patients receiving this combination. Consider therapy modification

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bevacizumab: May enhance the cardiotoxic effect of Anthracyclines. Avoid combination

Cardiac Glycosides: May diminish the cardiotoxic effect of Anthracyclines. Anthracyclines may decrease the serum concentration of Cardiac Glycosides. The effects of liposomal formulations may be unique from those of the free drug, as liposomal formulation have unique drug disposition and toxicity profiles, and liposomes themselves may alter digoxin absorption/distribution. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cimetidine: May increase the serum concentration of EpiRUBicin. Avoid combination

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Cyclophosphamide: May enhance the cardiotoxic effect of Anthracyclines. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fam-Trastuzumab Deruxtecan: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with fam-trastuzumab deruxtecan should avoid anthracycline-based therapy for up to 7 months after stopping fam-trastuzumab deruxtecan. Monitor closely for cardiac dysfunction in patients receiving this combination. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Taxane Derivatives: May enhance the adverse/toxic effect of Anthracyclines. Taxane Derivatives may increase the serum concentration of Anthracyclines. Taxane Derivatives may also increase the formation of toxic anthracycline metabolites in heart tissue. Consider therapy modification

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with trastuzumab should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. Monitor closely for cardiac dysfunction in patients receiving anthracyclines with trastuzumab. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Frequency not always defined. Percentages reported as part of combination chemotherapy regimens.

Cardiovascular: Decreased left ventricular ejection fraction (asymptomatic; delayed: 1% to 2%), cardiac failure (≤2%), atrioventricular block, bradycardia, bundle branch block, cardiac arrhythmia, cardiomyopathy, ECG abnormality, myocarditis, non-specific T wave on ECG, sinus tachycardia, ST segment changes on ECG, tachyarrhythmia, thromboembolism, ventricular premature contractions, ventricular tachycardia

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

Dermatologic: Alopecia (70% to 96%), skin rash (1% to 9%), skin changes (1% to 5%)

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

Gastrointestinal: Nausea and vomiting (83% to 92%; grades 3/4: 22% to 25%), mucositis (9% to 59%; grades 3/4: ≤9%), diarrhea (7% to 25%), anorexia (2% to 3%), abdominal pain, esophagitis, neutropenic enterocolitis, stomatitis, toxic megacolon

Genitourinary: Menopause (premature or early)

Hematologic & oncologic: Neutropenia (54% to 80%; grades 3/4: 11% to 67%; nadir: 10 to 14 days; recovery: by day 21), leukopenia (50% to 80%; grades 3/4: 2% to 59%), anemia (13% to 72%; grades 3/4: ≤6%), thrombocytopenia (5% to 49%; grades 3/4: ≤5%), febrile neutropenia (grades 3/4: ≤6%), acute lymphocytic leukemia, acute myelocytic leukemia, myelodysplastic syndrome

Hepatic: Ascites, hepatomegaly, increased serum transaminases

Hypersensitivity: Hypersensitivity reaction

Infection: Infection (15% to 22%; grades 3/4: ≤2%)

Local: Injection site reaction (3% to 20%; grades 3/4: <1%)

Ophthalmic: Conjunctivitis (1% to 15%)

Respiratory: Dyspnea, pulmonary edema

Miscellaneous: Fever (1% to 5%)

<1%, postmarketing, case reports: Anaphylaxis, arterial embolism, burning sensation of gastrointestinal tract, chills, dehydration, erythema, flushing, gastrointestinal erosion, gastrointestinal hemorrhage, gastrointestinal pain, gastrointestinal ulcer, hyperuricemia, nail hyperpigmentation, oral mucosa hyperpigmentation, phlebitis, pneumonia, pulmonary embolism, radiation recall phenomenon, red urine discoloration, sepsis, shock, skin hyperpigmentation, skin photosensitivity, thrombophlebitis, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur. Leukopenia, neutropenia, thrombocytopenia, and anemia may occur. Obtain blood counts prior to each dose and as clinically necessary. Myelosuppression may require therapy interruption and/or dose reduction (based on severity).
• Cardiac toxicity [US Boxed Warning]: Myocardial damage, including acute left ventricular failure, can occur with epirubicin. The risk of cardiomyopathy is proportional to the cumulative exposure, with incidence rates from 0.9% at a cumulative dose of 550 mg/m², 1.6% at 700 mg/m², and 3.3% at 900 mg/m². The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess left ventricular ejection fraction (LVEF) before and regularly during and after treatment with epirubicin. Early toxicity may consist of sinus tachycardia and/or ECG changes, such as nonspecific ST-T wave changes. Tachycardia, including premature ventricular contractions and ventricular tachycardia, as well as bradycardia, have occurred. Atrioventricular and bundle-branch block have also been reported. These early cardiotoxicities are not necessarily predictive of subsequent delayed cardiotoxicity and are not necessarily a reason to suspend epirubicin therapy. Delayed cardiotoxicity is typically caused by cardiomyopathy, which presents as decreased LVEF and/or signs/symptoms of heart failure. Delayed cardiotoxicity typically develops late during epirubicin therapy, or within 2 to 3 months after completion of epirubicin; cardiotoxicity has been reported several months to years after therapy termination. The recommended lifetime epirubicin cumulative dose is 900 mg/m²; avoid cumulative doses above this. Total cumulative dose should take into account prior treatment with other anthracyclines or anthracenediones, previous or concomitant treatment with other cardiotoxic agents, or irradiation of chest. Although the risk increases with cumulative dose, irreversible cardiotoxicity may occur at any dose level. Active or dormant cardiovascular disease, concurrent or recent administration of cardiotoxic drugs, prior therapy with other anthracyclines or anthracenediones, or prior or concurrent chest (mediastinal/pericardial area) irradiation may increase the risk of developing late cardiac toxicity. Children may be at increased risk for developing acute and/or delayed cardiotoxicity. The half-life of other cardiotoxic agents (eg, trastuzumab) must be considered in sequential therapy. Obtain a baseline ECG and LVEF evaluation prior to therapy initiation; monitor LVEF throughout epirubicin treatment and consider discontinuation if LVEF decreases or if signs/symptoms of heart failure develop.

ASCO has developed guidelines for prevention and monitoring of cardiac dysfunction in adult survivors of cancer (ASCO [Armenian 2017]). According to the guidelines, the risk of cardiac dysfunction is increased with the following:

- High-dose anthracycline therapy (eg, doxorubicin ≥250 mg/m², epirubicin ≥600 mg/m²)

- High-dose radiotherapy (≥30 Gy) with the heart in the treatment field

- Lower-dose anthracycline (eg, doxorubicin <250 mg/m², epirubicin <600 mg/m²) in combination with lower-dose radiotherapy (<30 Gy) with the heart in the treatment field

- Lower-dose anthracycline (eg, doxorubicin <250 mg/m², epirubicin <600 mg/m²) or trastuzumab alone AND any of the following risk factors: multiple cardiovascular risk factors (≥2 risk factors), including smoking, hypertension, diabetes, dyslipidemia, and obesity (during or after completion of therapy), or older age (≥60 years) at cancer treatment, or compromised cardiac function (eg, borderline low LVEF [50% to 55%], history of MI, moderate or higher valvular heart disease) before or during treatment

- Treatment with lower-dose anthracycline (eg, doxorubicin <250 mg/m², epirubicin <600 mg/m²) followed by trastuzumab (sequential therapy)

- Other risk factors for anthracycline-induced cardiotoxicity include age 60 and older at time of treatment and 2 or more cardiovascular risk factors (smoking, hypertension, diabetes, dyslipidemia, or obesity) during or after treatment.

The ASCO guidelines recommend a comprehensive assessment in patients with cancer that includes a history and physical examination and screening for cardiovascular disease risk factors, such as hypertension, diabetes, dyslipidemia, obesity, and smoking. An echocardiogram should be obtained prior to initiating potentially cardiotoxic therapies. Modifiable risk factors (smoking, hypertension, diabetes, dyslipidemia, obesity) should be actively managed before initiating potentially cardiotoxic therapies. Consider cardioprotectants (eg, dexrazoxane) or continuous infusions in patients who are likely to receive high-dose anthracycline therapy. In patients who develop signs/symptoms of cardiac dysfunction during therapy, an echocardiogram is recommended for diagnostic workup; if echocardiogram is not available or feasible, a cardiac MRI (preferred) or multigated acquisition (MUGA) scan may be utilized. Serum cardiac biomarkers are recommended, along with referral to a cardiologist if indicated.

• Extravasation: [US Boxed Warning]: Extravasation of epirubicin may result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. If extravasation occurs, immediately terminate administration and apply ice to the affected area. Local tissue injury may manifest as blistering, ulceration, or necrosis. Consider extravasation if burning/stinging occurs during infusion, or if other signs indicating perivenous infiltration or extravasation are present; extravasation may occur even when blood return is present on aspiration, or in patients without burning/stinging symptoms. Injection into a small vein or repeated administration in the same vein may result in venous sclerosis. Avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation. If perivenous infiltration occurs, immediately discontinue infusion and restart in another vein. If appropriate, dexrazoxane may be considered (if within 6 hours of extravasation).
• GI toxicity: Epirubicin is associated with a moderate to high emetic potential (depending on regimen); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).
• Secondary malignancy: [US Boxed Warning]: Secondary acute myelogenous leukemia and myelodysplastic syndrome occur at a higher incidence in patients treated with anthracyclines, including epirubicin. The latency period for secondary leukemias may be short (1 to 3 years).
• Thromboembolic events: Thrombophlebitis and thromboembolic phenomena (including pulmonary embolism) have occurred; some cases have been fatal. Local phlebitis or thrombophlebitis may be preceded by facial flushing and erythematous streaking along the vein (may be indicative of excessively rapid administration).
• Tumor lysis syndrome: Epirubicin may cause tumor lysis syndrome (TLS), particularly in patients with rapid tumor proliferation. If TLS risk is suspected, monitor serum uric acid, potassium, calcium, phosphate, and serum creatinine after initial dose; hydration and antihyperuricemic prophylaxis may minimize potential TLS complications.

Disease-related concerns:

• Hepatic impairment:Use is contraindicated in patients with severe hepatic impairment (Child-Pugh class C or serum bilirubin >5 mg/dL). Dose reduction is recommended for mild to moderate hepatic impairment. Evaluate serum total bilirubin and AST levels prior to and during epirubicin therapy. Epirubicin is predominantly hepatically eliminated; impaired hepatic function may lead to increased exposure and toxicity.
• Renal impairment: Dosage reduction is necessary in patients with serum creatinine >5 mg/dL. Evaluate renal function at baseline and during treatment. Epirubicin has not been studied in patients on dialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Females ≥70 years of age should be closely monitored for toxicity due to the possibility of decreased epirubicin clearance.
• Pediatric: Children may be at increased risk for developing acute and delayed cardiotoxicity; long-term periodic cardiac function monitoring is recommended.
• Radiation recipients: Epirubicin may increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver. Radiation recall, including cutaneous and pulmonary toxicity, may occur in patients who receive epirubicin after prior radiation therapy.

Other warnings/precautions:

• Immunizations: Patients should not be immunized with live or live-attenuated viral vaccines during or shortly after treatment; serious or fatal infection may result in immunocompromised patients. Inactivated vaccines may be administered; however, response may be diminished.

Monitoring Parameters

Baseline and repeated measurements of CBC with differential, liver function tests, serum creatinine, electrolytes, ECG, and LVEF. The method used for assessment of LVEF (echocardiogram or MUGA) should be consistent during routine monitoring. Evaluate pregnancy status prior to treatment initiation (in females of reproductive potential). Monitor injection site during infusion for possible extravasation or local reactions.

Cardiovascular monitoring (ASCO [Armenian 2017]): Comprehensive assessment prior to treatment, including a history and physical examination and screening for cardiovascular disease risk factors, such as hypertension, diabetes, dyslipidemia, obesity, and smoking; echocardiogram (prior to treatment). In patients who develop signs/symptoms of cardiac dysfunction during therapy, an echocardiogram is recommended for diagnostic workup; if echocardiogram is not available or feasible, a cardiac MRI (preferred) or multigated acquisition (MUGA) scan may be utilized; obtain serum cardiac biomarkers.

Pregnancy

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Pregnant women should avoid handling epirubicin. Women of reproductive potential should be advised to use effective contraception and avoid becoming pregnant during treatment. Men with female partners of reproductive potential should use effective contraception during and after treatment. Epirubicin may cause irreversible amenorrhea in premenopausal women.

Limited information is available from a retrospective study of women who received epirubicin (in combination with cyclophosphamide or weekly as a single-agent) during the second or third (prior to week 35) trimester for the treatment of pregnancy-associated breast cancer (Ring 2005) and from a study of women who received epirubicin (weekly as a single-agent) at gestational weeks 16 through 30 for the treatment of pregnancy-associated breast cancer (Peccatori 2009). Some pharmacokinetic properties of epirubicin may be altered in pregnant women (van Hasselt 2014). The European Society for Medical Oncology (ESMO) has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy (Peccatori 2013); the guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). If chemotherapy is indicated, it should not be administered in the first trimester, but may begin in the second trimester. There should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation.

A pregnancy registry is available for all cancers diagnosed during pregnancy at Cooper Health (877-635-4499).

Patient Education

What is this drug used for?

• It is used to treat breast cancer. It may be given for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Urine discoloration
• Hot flashes
• Lack of appetite
• Mouth irritation
• Mouth sores
• Hair loss
• Nausea
• Diarrhea
• Vomiting
• No menstrual periods
• Eye irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Infection
• Dizziness
• Passing out
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Severe loss of strength and energy
• Severe injection site redness, burning, pain, edema, or irritation
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.