Skip to Content

EPIrubicin

Pronunciation

(ep i ROO bi sin)

Index Terms

  • Epidoxorubicin
  • Epirubicin HCl
  • Epirubicin Hydrochloride
  • Pidorubicin
  • Pidorubicin Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

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)

Solution Reconstituted, Intravenous, as hydrochloride:

Generic: 50 mg (1 ea [DSC])

Brand Names: U.S.

  • Ellence

Pharmacologic Category

  • Antineoplastic Agent, Anthracycline
  • Antineoplastic Agent, Topoisomerase II Inhibitor

Pharmacology

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.

Distribution

Vdss: 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

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 involvement following tumor resection

Contraindications

Hypersensitivity to epirubicin, other anthracyclines, anthracenediones, or any component of the formulation; cardiomyopathy and/or heart failure, recent myocardial infarction, severe arrhythmias; previous treatment with anthracyclines up to the maximum cumulative dose

Dosing: Adult

Note: Patients receiving 120 mg/m2/cycle as part of combination therapy (CEF-120 regimen) should also receive prophylactic antibiotic therapy with sulfamethoxazole/trimethoprim or a fluoroquinolone. 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. The recommended lifetime maximum dose is 900 mg/m2. Epirubicin is associated with a moderate to high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2010).

Breast cancer, adjuvant treatment: IV: Usual dose: 100-120 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)

Dosage adjustment for toxicity (breast cancer; labeled dosing):

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 ≥1500/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 1000 to 1499/mm3; omit day 8 dose if platelets are <75,000/mm3, ANC <1000/mm3, or grade 3/4 nonhematologic toxicity

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: Renal Impairment

The manufacturer's labeling recommends lower doses (dose not specified) in patients with severe renal impairment (serum creatinine >5 mg/dL). Other sources (Aronoff 2007) suggest no dosage adjustment is needed for CrCl <50 mL/minute.

Dosing: Hepatic Impairment

The manufacturer's labeling recommends the following adjustments (based on clinical trial information):

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

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

Severe hepatic impairment: Use is not recommended (has not been studied).

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

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). 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 dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2010).

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: Adults: 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: Children and Adults: 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).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in D5W, LR, NS; incompatible with any solution of alkaline pH.

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 Antineoplastic Agents (Anthracycline, Systemic). 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

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 Antineoplastic Agents (Anthracycline, Systemic). Monitor therapy

Cardiac Glycosides: May diminish the cardiotoxic effect of Antineoplastic Agents (Anthracycline, Systemic). Antineoplastic Agents (Anthracycline, Systemic) 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

Cimetidine: May increase the serum concentration of EpiRUBicin. 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 Antineoplastic Agents (Anthracycline, Systemic). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

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. Consider therapy modification

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

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

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

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

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

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

Taxane Derivatives: May enhance the adverse/toxic effect of Antineoplastic Agents (Anthracycline, Systemic). Taxane Derivatives may increase the serum concentration of Antineoplastic Agents (Anthracycline, Systemic). Taxane Derivatives may also increase the formation of toxic anthracycline metabolites in heart tissue. Consider therapy modification

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. Avoid combination

Trastuzumab: May enhance the cardiotoxic effect of Antineoplastic Agents (Anthracycline, Systemic). 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

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. 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, nonspecific ST or T wave changes on ECG, sinus tachycardia, 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: Premature menopause

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% (Limited to important or life-threatening): Anaphylaxis, arterial embolism, burning sensation of gastrointestinal tract, chills, dehydration, erythema, 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

ALERT: U.S. Boxed Warning

Experienced physician:

Epirubicin should be administered only under the supervision of a health care provider who is experienced in the use of cancer chemotherapeutic agents.

Extravasation:

Severe local tissue necrosis will occur if there is extravasation during administration. Epirubicin must not be given by the intramuscular or subcutaneous route.

Myocardial toxicity:

Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with epirubicin or months to years after termination of therapy. The probability of developing clinically evident CHF is estimated as approximately 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. In the adjuvant treatment of breast cancer, the maximum cumulative dose used in clinical trials was 720 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with epirubicin may occur at lower cumulative doses whether or not cardiac risk factors are present.

Secondary malignancy:

Secondary acute myeloid leukemia (AML) has been reported in patients with breast cancer treated with anthracyclines, including epirubicin. The occurrence of refractory secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. The cumulative risk of developing treatment-related AML or myelodysplastic syndrome (MDS), in 7,110 patients with breast cancer who received adjuvant treatment with epirubicin-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years.

Hepatic impairment:

Dosage should be reduced in patients with impaired hepatic function.

Bone marrow suppression:

Severe myelosuppression may occur.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: May cause severe myelosuppression, including leukopenia, thrombocytopenia, and anemia. Myelosuppression is the dose-limiting toxicity. Obtain baseline and periodic blood counts. Patients should recover from myelosuppression due to prior chemotherapy treatment before beginning treatments. Severe neutropenia and severe infections may require supportive care.

• Extravasation: [US Boxed Warning]: For IV administration only. Vesicant; if extravasation occurs, severe local tissue damage and necrosis may occur. Not for IM or SubQ use. Injection into a small vein or repeated administration in the same vein may result in venous sclerosis. 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.

• Gastrointestinal toxicity: Epirubicin is associated with a moderate to high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2010).

• Myocardial toxicity: Myocardial toxicity, including fatal heart failure (HF) may occur, particularly in patients who have received prior anthracyclines (or anthracenediones), prior or concomitant radiotherapy to the mediastinal/pericardial area, who have preexisting cardiac disease (active or dormant), or with concomitant cardiotoxic medications. Cardiotoxicity may be concurrent or delayed (months to years after treatment). The risk of HF is ~0.9% at a cumulative dose of 550 mg/m2, ~1.6% at a cumulative dose of 700 mg/m2, and ~3.3% at a cumulative dose of 900 mg/m2. Cardiotoxicity may also occur at lower cumulative doses or without risk factors. The risk of delayed cardiotoxicity increases more steeply with cumulative doses >900 mg/m2, and this dose should be exceeded only with extreme caution. The maximum cumulative dose used in adjuvant studies was 720 mg/m2. Cardiotoxicity is dose-limiting. Early toxicity may consist of tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia. Electrocardiographic changes including ST-T wave changes, atrioventricular and bundle-branch block have also been reported. These effects are not necessarily predictive of subsequent delayed cardiotoxicity. Delayed toxicity is typically caused by cardiomyopathy which presents as decreased left ventricular ejection fraction (LVEF) and/or signs/symptoms of HF (eg, tachycardia, dyspnea, pulmonary edema, edema, hepatomegaly, ascites, pleural effusion, gallop rhythm). 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. Patients with active or dormant cardiovascular disease, concurrent administration of cardiotoxic drugs, prior therapy with other anthracyclines or anthracenediones, prior or concurrent chest irradiation, advanced age, and infants and children are at increased risk. Children are at increased risk for developing delayed cardiotoxicity. Regular monitoring of LVEF and discontinuation at the first sign of impairment is recommended especially in patients with cardiac risk factors or impaired cardiac function. Discontinue treatment with signs of decreased LVEF. The half-life of other cardiotoxic agents (eg, trastuzumab) must be considered in sequential therapy.

• Secondary malignancy: [US Boxed Warning]: Treatment with anthracyclines (including epirubicin) may increase the risk of secondary acute myeloid leukemia (AML). AML is more common when given in combination with other antineoplastic agents, in patients who have received multiple courses of previous chemotherapy, or with escalated anthracycline doses. In breast cancer patients, the risk for treatment-related AML or myelodysplastic syndrome (MDS) was estimated at 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years after treatment. The latency period for secondary leukemias may be short (1 to 3 years).

• Thromboembolic events: Thrombophlebitis and thromboembolic phenomena (including pulmonary embolism) have occurred.

• Tumor lysis syndrome: May cause tumor lysis syndrome (TLS). Although TLS does not generally occur in patients with breast cancer, if TLS risk is suspected, consider monitoring serum uric acid, potassium, calcium, phosphate and serum creatinine after initial administration; hydration and antihyperuricemic prophylaxis may minimize potential TLS complications.

Disease-related concerns:

• Hepatic impairment: [US Boxed Warning]: Dosage reduction is recommended in patients with mild-to-moderate hepatic impairment; use is not recommended in severe hepatic impairment. Evaluate hepatic function at baseline and during treatment. Epirubicin is predominantly hepatically eliminated; impaired hepatic function may lead to increased exposure and toxicity.

• Renal impairment: Dosage reduction is recommended in patients with serum creatinine >5 mg/dL. Evaluate renal function at baseline and during treatment. 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: Women ≥70 years of age should be closely monitored for toxicity.

• 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 have radiosensitizing activity; radiation recall (inflammatory) has also been reported.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Appropriate use: Patients should recover from acute toxicities (stomatitis, myelosuppression, infections) prior to initiating treatment. Assess baseline labs (blood counts, bilirubin, ALT, AST, serum creatinine) and cardiac function (with LVEF). Prophylactic antibiotics should be administered with the CDF-120 regimen.

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

• Immunizations: Patients should not be immunized with live viral vaccines during or shortly after treatment. Inactivated vaccines may be administered (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. Monitor injection site during infusion for possible extravasation or local reactions.

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Women of childbearing potential should be advised to use effective contraception and avoid becoming pregnant during treatment. Men undergoing treatment should use effective contraception. 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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience urine discoloration, hot flashes, lack of appetite, lip or mouth irritation, hair loss, amenorrhea, or eye irritation. Have patient report immediately to prescriber signs of heart problems (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), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea, or lack of appetite; or feel sluggish), signs of infection, angina, back pain, jaw pain, coughing up blood, severe dizziness, passing out, severe nausea, vomiting, severe diarrhea, excessive weight loss, bone pain, night sweats, bruising, bleeding, or loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Hide