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Epirubicin Hydrochloride

FDA Drug Information • Also known as: Ellence

Brand Names
Ellence
Dosage Form
POWDER
Product Type
BULK INGREDIENT

⚠ Boxed Warning (Black Box)

WARNING: CARDIAC TOXICITY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION

  • Cardiac Toxicity: Myocardial damage, including acute left ventricular failure, can occur with ELLENCE. The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 0.9% at a cumulative dose of 550 mg/m 2 , 1.6% at 700 mg/m 2 , and 3.3% at 900 mg/m 2 . 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 ELLENCE [see Warnings and Precautions (5.1) ] .
  • Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including ELLENCE [see Warnings and Precautions (5.2) ] .
  • Extravasation and Tissue Necrosis: Extravasation of ELLENCE can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. Immediately terminate the drug and apply ice to the affected area [see Warnings and Precautions (5.3) ] .
  • Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur [see Warnings and Precautions (5.4) ] . WARNING: CARDIAC TOXICITY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION See full prescribing information for complete boxed warning .
  • Cardiac Toxicity: Myocardial damage, including acute left ventricular failure, can occur with ELLENCE. The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 0.9% at a cumulative dose of 550 mg/m 2 , 1.6% at 700 mg/m 2 , and 3.3% at 900 mg/m 2 . 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 ELLENCE ( 5.1 ).
  • Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including ELLENCE ( 5.2 ).
  • Extravasation and Tissue Necrosis: Extravasation of ELLENCE can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. Immediately terminate the drug and apply ice to the affected area ( 5.3 ).
  • Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur ( 5.4 ).

    • Description

    11 DESCRIPTION ELLENCE (epirubicin hydrochloride injection) is an anthracycline topoisomerase inhibitor for intravenous administration. ELLENCE is supplied as a sterile, clear, red solution and is available in polypropylene vials containing 50 and 200 mg of epirubicin hydrochloride as a preservative-free, ready-to-use solution. Each milliliter of solution contains 2 mg of epirubicin hydrochloride. Inactive ingredients include 9 mg sodium chloride, USP, and water for injection, USP. The pH of the solution has been adjusted to 3.0 with hydrochloric acid and/or sodium hydroxide, NF. Epirubicin hydrochloride is the 4-epimer of doxorubicin and is a semi-synthetic derivative of daunorubicin. The chemical name is (8S- cis )-10-[(3-amino-2,3,6-trideoxy-α-L- arabino -hexopyranosyl)oxy]-7,8,9,10-tetrahydro6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione hydrochloride. The active ingredient is a red-orange hygroscopic powder, with the empirical formula C 27 H 29 NO 11 HCl and a molecular weight of 579.95. The structural formula is as follows: Chemical Structure

    What Is Epirubicin Hydrochloride Used For?

    1 INDICATIONS AND USAGE ELLENCE is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer [see Clinical Studies (14.1) ] . ELLENCE is an anthracycline topoisomerase inhibitor indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer ( 1 ).

    Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • The recommended starting dose of ELLENCE is 100 to 120 mg/m 2 . Dosage reductions are possible when given in certain combinations ( 2.2 ).
  • Administer intravenously in repeated 3- to 4-week cycles, either total dose on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle ( 2.2 ).
  • Consider use of antiemetics when given in conjunction with other emetigenic drugs ( 2.1 ).
  • Patients administered the 120 mg/m 2 regimen of ELLENCE should receive prophylactic antibiotic therapy ( 2.1 ).
  • Adjust dosage after the first treatment cycle based on hematologic and nonhematologic toxicities ( 2.3 ).
  • Reduce dose in patients with hepatic impairment ( 2.3 , 8.6 ).
  • Consider lower doses in patients with severe renal impairment ( 2.3 , 8.7 ). 2.1 Important Administration Instructions When possible, to reduce the risk of developing cardiotoxicity in patients receiving ELLENCE after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, delay ELLENCE-based therapy until the other agents have cleared from the circulation [see Warnings and Precautions (5.1) ]. Antiemetics may reduce nausea and vomiting; consider use of antiemetics before administration of ELLENCE or when clinically indicated, particularly when given in conjunction with other emetigenic drugs [see Adverse Reactions (6.1) ]. Patients administered the 120 mg/m 2 regimen of ELLENCE should receive prophylactic antibiotic therapy. 2.2 Recommended Dose The recommended dose of ELLENCE is 100 to 120 mg/m 2 administered as an intravenous bolus [see Dosage and Administration (2.4) ] . The following regimens are recommended: CEF-120: Cyclophosphamide 75 mg/m 2 oral on Days 1 to 14 ELLENCE 60 mg/m 2 intravenously on Days 1 and 8 5-Fluorouracil 500 mg/m 2 intravenously on Days 1 and 8 Repeat every 28 days for 6 cycles FEC-100: 5-Fluorouracil 500 mg/m 2 intravenously on Day 1 ELLENCE 100 mg/m 2 intravenously on Day 1 Cyclophosphamide 500 mg/m 2 intravenously on Day 1 Repeat every 21 days for 6 cycles Administer ELLENCE in repeated 3- to 4-week cycles. The total dose of ELLENCE may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. 2.3 Dose Modifications ELLENCE dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm 3 , absolute neutrophil counts (ANC) <250/mm 3 , neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce ELLENCE Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥100,000/mm 3 , ANC ≥1500/mm 3 , and nonhematologic toxicities have recovered to ≤ Grade 1. Cardiac Toxicity Discontinue ELLENCE in patients who develop signs or symptoms of cardiomyopathy [see Warnings and Precautions (5.1) ]. Bone Marrow Dysfunction Consider administering a...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Cardiac Toxicity [see Warnings and Precautions (5.1) ]
  • Secondary Malignancies [see Warnings and Precautions (5.2) ]
  • Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3) ]
  • Severe Myelosuppression [see Warnings and Precautions (5.4) ]
  • Tumor-Lysis Syndrome [see Warnings and Precautions (5.7) ]
  • Thrombophlebitis and Thromboembolic Events [see Warnings and Precautions (5.9) ]
  • Potentiation of Radiation Toxicity and Radiation Recall [see Warnings and Precautions (5.10) ] The most common adverse reactions (≥10%) are leukopenia, neutropenia, anemia, thrombocytopenia, amenorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local skin toxicity, and rash/itch ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ELLENCE was evaluated in two studies (Studies MA-5 and GFEA-05) evaluating combination regimens in patients with early breast cancer [see Clinical Studies (14.1) ] . Of the 1260 patients treated in these studies, 620 patients received the higher-dose ELLENCE regimen (FEC-100/CEF-120), 280 patients received the lower-dose ELLENCE regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant adverse reactions are summarized in Table 1. Table 1. Adverse Reactions in Patients with Early Breast Cancer Event % of Patients FEC-100/CEF-120 (N=620) FEC-50 (N=280) CMF (N=360) Grades 1–4 Grades 3/4 Grades 1–4 Grades 3/4 Grades 1–4 Grades 3/4 FEC & CEF = cyclophosphamide + ELLENCE + fluorouracil; CMF = cyclophosphamide + methotrexate + fluorouracil; NA = not available Grade 1 or 2 changes in transaminase levels were observed but were more frequently seen with CMF than with CEF. Hematologic Leukopenia 80 59 50 1.5 98 60 Neutropenia 80 67 54 11 96 78 Anemia 72 6 13 0 71 0.9 Thrombocytopenia 49 5 4.6 0 51 3.6 Endocrine Amenorrhea 72 0 69 0 68 0 Hot flashes 39 4 5 0 69 6 Body as a Whole Lethargy 46 1.9 1.1 0 73 0.3 Fever 5 0 1.4 0 4.5 0 Gastrointestinal Nausea/vomiting 92 25 83 22 85 6 Mucositis 59 9 9 0 53 1.9 Diarrhea 25 0.8 7 0 51 2.8 Anorexia 2.9 0 1.8 0 6 0.3 Infection Infection 22 1.6 15 0 26 0.6 Febrile neutropenia NA 6 0 0 NA 1.1 Ocular Conjunctivitis/keratitis 15 0 1.1 0 38 0 Skin Alopecia 96 57 70 19 84 7 Local toxicity 20 0.3 2.5 0.4 8 0 Rash/itch 9 0.3 1.4 0 14 0 Skin changes 4.7 0 0.7 0 7 0 Delayed Events Table 2 describes the incidence of delayed adverse reactions in patients participating in the MA-5 and GFEA-05 trials. Table 2. Long-Term Adverse Reactions in Patients with Early Breast Cancer Event % of Patients FEC-100/CEF-120 (N=620) FEC-50 (N=280) CMF (N=360) Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving ELLENCE. However, an association between anthracyclines such as ELLENCE and ALL has not been clearly established. Cardiac events Asymptomatic drops in LVEF 2.1 In study MA-5, cardiac function was not monitored after 5 years. 1.4 0.8 CHF 1.5 0.4 0.3 Leukemia AML 0.8 0 0.3 Hematologic Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with ELLENCE and represents the most common acute dose-limiting toxicity of this drug. In most cases, the white blood cell (WBC) nadir is reached 10 to 14 days from drug administration. Leukopenia/neutropenia is usually transient, with WBC and neutrophil counts generally returning to normal values by Day 21...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • Avoid using cardiotoxic agents in combination with ELLENCE ( 7.1 ).
  • Discontinue cimetidine during treatment with ELLENCE ( 7.2 ). 7.1 Cardiotoxic Agents Closely monitor cardiac function when ELLENCE is used in combination with other cardiotoxic agents. Patients receiving ELLENCE after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may be at an increased risk of developing cardiotoxicity [see Dosage and Administration (2) and Warnings and Precautions (5.1) ] . Trastuzumab may persist in the circulation for up to 7 months. Therefore, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. Monitor the patient's cardiac function closely if anthracyclines are used before this time. Concomitant use of ELLENCE with other cardioactive compounds that could cause heart failure (e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment. 7.2 Cimetidine Cimetidine increases the exposure to epirubicin [see Clinical Pharmacology (12.3) ]. Discontinue cimetidine during treatment with ELLENCE. 7.3 Other Cytotoxic Drugs ELLENCE used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects. Paclitaxel: The administration of epirubicin immediately prior to or after paclitaxel increased the systemic exposure of epirubicin, epirubicinol and 7-deoxydoxorubicin aglycone [see Clinical Pharmacology (12.3) ]. Docetaxel: The administration of epirubicin immediately prior to or after docetaxel did not have an effect on the systemic exposure of epirubicin, but increased the systemic exposure of epirubicinol and 7-deoxydoxorubicin aglycone [see Clinical Pharmacology (12.3) ]. 7.4 Radiation Therapy There are few data regarding the coadministration of radiation therapy and ELLENCE. In adjuvant trials of ELLENCE-containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received ELLENCE-based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of ELLENCE with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of ELLENCE after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.

    • Contraindications

    4 CONTRAINDICATIONS ELLENCE is contraindicated in patients with:

  • Severe myocardial insufficiency [see Warnings and Precautions (5.1) ]
  • Recent myocardial infarction or severe arrhythmias, or previous treatment with maximum cumulative dose of anthracyclines [see Warnings and Precautions (5.1) ]
  • Severe persistent drug-induced myelosuppression [see Warnings and Precautions (5.4) ]
  • Severe hepatic impairment (defined as Child-Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Warnings and Precautions (5.5) ]
  • Severe hypersensitivity to ELLENCE, other anthracyclines, or anthracenediones [see Adverse Reactions (6.1) ]
  • Severe myocardial insufficiency ( 4 ).
  • Recent myocardial infarction ( 4 ).
  • Severe persistent drug-induced myelosuppression ( 4 ).
  • Severe hepatic impairment ( 4 ).
  • Severe hypersensitivity to ELLENCE, other anthracyclines, or anthracenediones ( 4 ).

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, ELLENCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] ; avoid the use of ELLENCE during the 1 st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of epirubicin during the 2 nd and 3 rd trimesters. There are reports of fetal and/or neonatal cardiotoxicity following in utero exposure to epirubicin (see Clinical Considerations ). In animal reproduction studies in pregnant rats, epirubicin was embryo-fetal lethal and caused structural abnormalities when administered during organogenesis at doses less than the maximum recommended human dose on a body surface area basis ( see Data ). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions There have been rare reports of fetal and/or neonatal transient ventricular hypokinesia, transient elevation of cardiac enzymes, and a case of fetal demise from suspected anthracycline-induced cardiotoxicity following in utero exposure to epirubicin in 2 nd and/or 3 rd trimesters. Cardiotoxicity is a known risk of anthracycline treatment in adults [see Warnings and Precautions (5.1) ]. Monitor the fetus and/or neonate for cardiotoxicity and perform testing consistent with community standards of care. Data Animal Data Intravenous administration of 0.8 mg/kg/day epirubicin (about 0.04 times the maximum recommended single human dose on a body surface area basis) to rats during Days 5 to 15 of gestation resulted in embryofetal lethality...

    Overdosage

    10 OVERDOSAGE There is no known antidote for overdoses of ELLENCE. A 36-year-old man with non-Hodgkin's lymphoma received a daily 95 mg/m 2 dose of ELLENCE for 5 consecutive days. Five days later, he developed bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding. No signs of acute cardiac toxicity were observed. He was treated with antibiotics, colony-stimulating factors, and antifungal agents, and recovered completely. A 63-year-old woman with breast cancer and liver metastasis received a single 320 mg/m 2 dose of ELLENCE. She was hospitalized with hyperthermia and developed multiple organ failure (respiratory and renal), with lactic acidosis, increased lactate dehydrogenase, and anuria. Death occurred within 24 hours after administration of ELLENCE. Additional instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/m 2 . The observed adverse events in these patients were qualitatively similar to known toxicities of epirubicin. Most of the patients recovered with appropriate supportive care. If an overdose occurs, provide supportive treatment (including antibiotic therapy, blood and platelet transfusions, colony-stimulating factors, and intensive care as needed) until the recovery of toxicities. Delayed CHF has been observed months after anthracycline administration. Observe patients carefully over time for signs of CHF and provided with appropriate supportive therapy.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING ELLENCE is available in polypropylene single-dose CYTOSAFE ® vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use, clear, red solution in the following strengths: Unit of Sale Strength NDC 0009-5091-01 Carton of 1 Single-dose Vial 50 mg/25 mL (2 mg/mL) NDC 0009-5093-01 Carton of 1 Single-dose Vial 200 mg/100 mL (2 mg/mL) Discard unused portion. ELLENCE is available in ONCO-TAIN ® glass vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use, clear, red solution in the following strengths: Unit of Sale Strength NDC 0009-5091-25 Carton of 1 Single-dose Vial 50 mg/25 mL (2 mg/mL) NDC 0009-5093-10 Carton of 1 Single-dose Vial 200 mg/100 mL (2 mg/mL) ONCO-TAIN ® is the vial external protection system. Discard unused portion. Store refrigerated between 2°C and 8°C (36°F and 46°F). Do not freeze. Protect from light. Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15–25°C). Solution for injection should be used within 24 hours after removal from refrigeration. ELLENCE is a hazardous drug. Follow applicable special handling and disposal procedures 1 [see References (15) ].

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.