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  • CLASSES

    Anthracyclines

    BOXED WARNING

    Extravasation, intramuscular administration, subcutaneous administration

    Extravasation of epirubicin can cause severe local tissue injury (e.g., blistering, ulceration) and necrosis, requiring wide excision of the affected area and skin grafting. Avoid intramuscular administration or subcutaneous administration of epirubicin. If a patient experiences burning or stinging during the administration of epirubicin or shows other evidence of perivenous infiltration, consider the possibility of extravasation and immediately terminate the infusion; it may be restarted in another vein. Apply ice to the affected area intermittently for 15 minutes, 4 times daily for 3 days; if appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation. Perivenous infiltration may occur despite the presence of blood return on aspiration of the infusion needle, and may also occur without causing pain, stinging, or burning. Venous sclerosis may result from administration into a small vessel or from repeated injections into the same vein. If possible, avoid administration into veins over joints or in extremities with compromised venous or lymphatic drainage. To decrease the risk of extravasation, epirubicin should be administered slowly into the tubing of a freely running IV infusion over 15 to 20 minutes; the infusion may be proportionally decreased with lower doses (minimum infusion time, 3 minutes).[41751]

    New primary malignancy

    The occurrence of a new primary malignancy, specifically acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), has been reported in patients treated with epirubicin and other anthracyclines; these leukemias can have a short latency period of 1 to 3 years. The cumulative probability of developing AML/MDS was found to be particularly increased in patients who received more than the maximum recommended cumulative dose of epirubicin (720 mg/m2) and cyclophosphamide (6,300 mg/m2).[41751]

    Cardiac arrhythmias, cardiac disease, cardiomyopathy, cardiotoxicity, heart failure, maximum cumulative lifetime dose, myocardial infarction

    Epirubicin has been associated with both early and late cardiotoxicity and should be used with caution in patients with a history of cardiac disease. It is contraindicated in patients with severe myocardial insufficiency (heart failure), recent myocardial infarction, or severe cardiac arrhythmias. It is also contraindicated in patients who have previously received the maximum cumulative lifetime dose of anthracyclines, as the risk of cardiomyopathy is proportional to cumulative exposure; although not formally tested, it is probable that the cardiac toxicity of epirubicin and other anthracyclines or anthracenediones is additive. The maximum recommended cumulative dose is 720 mg/m2; cumulative epirubicin doses of 900 mg/m2 should generally be avoided. Cardiotoxicity may occur at lower cumulative doses, whether or not cardiac risk factors are present. Closely monitor patients with a history of prior anthracycline or anthracenedione exposure. Additional risk factors for epirubicin-related cardiac toxicity include concomitant cardiotoxic chemotherapy and a history of prior or concomitant mediastinal/pericardial radiotherapy. Avoid administration of epirubicin in combination with other cardiotoxic drugs; the increased risk associated with these drugs may persist after discontinuation of therapy, especially for those with long half-lives. Assess a baseline ECG and evaluate left ventricular ejection fraction (LVEF) prior to initiation of therapy with epirubicin. Continue to monitor LVEF during treatment and consider discontinuation of therapy if the LVEF decreases or if the patient develops signs or symptoms of congestive heart failure.[41751]

    DEA CLASS

    Rx

    DESCRIPTION

    Anthracycline topoisomerase inhibitor
    Used for node-positive early breast cancer
    Contraindicated in patients with severe drug-induced myelosuppression, severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias, and severe hepatic impairment

    COMMON BRAND NAMES

    Ellence

    HOW SUPPLIED

    Ellence/Epirubicin/Epirubicin Hydrochloride Intravenous Inj Sol: 1mL, 2mg

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    NOTE: The total dose of epirubicin may be given on day 1 of each cycle or divided equally and given on days 1 and 8.
    For the adjuvant treatment of patients with breast cancer with evidence of axillary node involvement following resection of the primary tumor, in combination with 5-fluorouracil (5-FU) and cyclophosphamide (FEC-100).
    Intravenous dosage
    Adults

    100 mg/m2 IV in combination with 5-FU (500 mg/m2 IV) and cyclophosphamide (500 mg/m2 IV) on day 1 (FEC-100), every 21 days for 6 cycles. Dose adjustments for subsequent cycles are recommended by the manufacturer based on nadir platelet counts, ANC, or grade 3 to 4 toxicity. In a randomized clinical trial, relapse-free survival (RFS; 65% vs. 52%) and overall survival (OS; 76% vs. 65%) at 5 years as well as RFS (49% vs. 43%) and OS (56% vs. 50%) at 10 years were significantly improved in patients receiving adjuvant breast cancer treatment with FEC-100 compared with FEC-50 (epirubicin 50 mg/m2 IV instead of 100 mg/m2).

    For the neoadjuvant treatment of HER2-positive breast cancer in combination with 5-fluorouracil (5-FU) and cyclophosphamide (FEC-75), followed by paclitaxel and trastuzumab†.
    Intravenous dosage
    Adults

    75 mg/m2 IV in combination with 5-FU (500 mg/m2 IV) and cyclophosphamide (500 mg/m2 IV) on day 1, every 21 days for 4 cycles (FEC-75).  Epirubicin dose adjustments for subsequent cycles are recommended by the manufacturer based on nadir platelet counts, ANC, or grade 3 to 4 toxicity. After completion of 4 cycles of FEC-75, administer paclitaxel 80 mg/m2 IV once weekly in combination with trastuzumab (4 mg/kg IV over 90 minutes on week 1, then 2 mg/kg IV over 30 minutes once weekly), every 21 days for 4 cycles (12 weeks). Surgery should be performed after completion of paclitaxel plus trastuzumab therapy, followed by trastuzumab 6 mg/kg IV every 3 weeks for a total of 52 weeks from the first preoperative dose. In a randomized, phase 3 clinical trial, neoadjuvant treatment with FEC-75 followed by paclitaxel plus trastuzumab (sequential therapy) resulted in similar rates of pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) compared with paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab (concurrent therapy). Sequential therapy was better tolerated and had a lower incidence of cardiac adverse reactions.[63560] [63561]

    For the treatment of metastatic breast cancer, as monotherapy†.
    Intravenous dosage
    Adults

    90 mg/m2 IV on day 1, every 3 weeks; in a phase 2 dose-range study, the overall response rate (ORR) was 37.5% and time to progression (TTP) was 8.4 months. Differences in ORR and TTP were not statistically different when using doses of 60 mg/m2 or less. Dose adjustments for subsequent cycles are recommended by the manufacturer based on nadir platelet counts, ANC, or grade 3 to 4 toxicity.

    For the treatment of metastatic breast cancer, in combination with cyclophosphamide†.
    Intravenous dosage
    Adults

    75 mg/m2 IV on day 1 in combination with cyclophosphamide 600 mg/m2 IV on day 1, every 3 weeks for 6 cycles. In a phase 3 trial, progression free survival and overall survival were similar when compared to patients on epirubicin and paclitaxel. Dose adjustments for subsequent cycles are recommended by the manufacturer based on nadir platelet counts, ANC, or grade 3 to 4 toxicity.

    For the treatment of metastatic breast cancer, in combination with cyclophosphamide and 5-fluorouracil (5-FU)†.
    Intravenous dosage
    Adults

    50 mg/m2 IV on days 1 and 8 in combination with cyclophosphamide 500 mg/m2 IV on days 1 and 8, plus fluorouracil 400 mg/m2 IV on days 1 and 8, every 3 to 4 weeks depending on patient recovery. In a phase 3 clinical trial, treatment was planned for 6 cycles, but was given up to 9 cycles in patients with a partial or complete response.[49142] Dose adjustments for subsequent cycles are recommended by the manufacturer based on nadir platelet counts, ANC, or grade 3 to 4 toxicity.

    For the adjuvant treatment of patients with breast cancer with evidence of axillary node involvement following resection of the primary tumor, in combination with 5-fluorouracil (5-FU) and cyclophosphamide (CEF-120).
    Intravenous dosage
    Adults

    60 mg/m2 IV in combination with 5-FU (500 mg/m2 IV) on days 1 and 8, with cyclophosphamide 75 mg/m2 PO on days 1 through 14, every 28 days for 6 cycles (CEF-120); patients should receive prophylactic antibiotic therapy during treatment. Dose adjustments for subsequent cycles are recommended by the manufacturer based on nadir platelet counts, ANC, or grade 3 to 4 toxicity. In a randomized, phase 3 clinical trial, relapse-free survival (RFS; 62% vs. 53%) and overall survival (OS; 77% vs. 70%) at 5 years as well as RFS (51% vs. 44%) at 10 years were significantly improved in patients receiving adjuvant breast cancer treatment with CEF-120 compared with cyclophosphamide, methotrexate, and 5-FU (CMF); 10-year OS was not significantly different between groups (61% vs. 57%).

    For the treatment soft-tissue sarcoma†, in combination with ifosfamide.
    As first-line treatment for advanced disease†.
    Intravenous dosage
    Adolescents >= 17 years and Adults

    45 mg/m2/day as a continuous IV infusion over 24 hours (CIV) on days 2 and 3 plus ifosfamide 2.5 g/m2/day CIV on days 1—5 (with hydration and mesna 1.5 g/m2/day CIV) administered every 3 weeks (median of 5 cycles; range, 2—6 cycles) with growth-factor support with filgrastim (5 mcg/kg/day subcutaneously on days 6—15 or until leukocyte recovery) OR epirubicin 75 mg/m2 IV on day 1 plus ifosfamide 1.8 g/m2/day IV over 1 hour on days 1—5 (with mesna at 20% of ifosfamide dose given every 4 hours for 3 daily doses on days 1—5) repeated every 3—4 weeks for at least 3 cycles have been evaluated in patients with previously untreated, advanced soft-tissue sarcoma (STS) in phase II studies.

    As adjuvant therapy†.
    Intravenous dosage
    Adults < 65 years

    60 mg/m2/day IV on day 1 and 2 plus ifosfamide 1.8 g/m2/day IV over 1 hour on days 1—5 with mesna (20% of ifosfamide dose given prior to and 4 and 8 hours after ifosfamide on days 1—5) administered every 3 weeks for 5 cycles following local treatment with surgery with or without radiation therapy was evaluated in 104 patients with high-risk soft-tissue sarcoma in a randomized study. All patients received hydration, antiemetics, and filgrastim 300 mcg subcutaneously daily on days 8—15.

    For the treatment of relapsed or refractory multiple myeloma†, in combination with other chemotherapy agents.
    Intravenous dosage
    Adults

    Multiple regimens have been evaluated in patients with relapsed or refractory multiple myeloma, including epirubicin 70 mg/m2 IV on day 1 plus prednisone 2 mg/kg PO daily on days 1—4 and 11—15 and interferon alfa-2b 3 million units 3 times weekly repeated every 3 weeks for 3 cycles (or until a maximum monoclonal component reduction was reached and maintained for 6 months in responding patients; followed by maintenance therapy with interferon alfa-2b). Additionally, epirubicin 20 mg/m2 IV bolus on days 2 and 3 plus vincristine (1.5 mg IV bolus on day 1), cyclophosphamide (200 mg/m2 IV over 1 hour daily on days 1—3), and dexamethasone (20 mg/m2 PO daily on days 1—5) repeated every 3 weeks for 1 or 2 cycles past maximum monoclonal component reduction (median of 4 cycles; range, 1—9 cycles) has been studied.

    For the first-line treatment of advanced ovarian cancer† in combination with carboplatin and paclitaxel.
    Intravenous dosage
    Adults

    At the time of this review, evidence does not support using epirubicin with paclitaxel and carboplatin for this indication. A dose of 60 mg/m2 IV on day 1 in combination with paclitaxel (175 mg/m2 IV over 3 hours on day 1) and carboplatin (AUC 5 on day 1), every 3 weeks has been studied. In a phase III clinical trial, overall survival was not significantly improved with the addition of epirubicin to paclitaxel and carboplatin. Additionally, quality of life scores were significantly worse in the epirubicin-containing arm.

    For the treatment of gastric cancer†.
    For the treatment of advanced gastric cancer in combination with capecitabine and cisplatin or oxaliplatin†.
    Intravenous dosage
    Adults

    50 mg/m2 IV on day 1 in combination with capecitabine (625 mg/m2 PO twice daily on days 1—21) and oxaliplatin (130 mg/m2 IV on day 1) or cisplatin (60 mg/m2 IV on day 1); repeated every 3 weeks up to a maximum of 8 cycles. In a phase III trial, 1002 patients with locally advanced or metastatic esophagogastric cancer were randomized in a 2:2 trial design to receive epirubicin and oxaliplatin with either capecitabine (EOX) or 5-FU (EOF), or epirubicin and cisplatin with either capecitabine (ECX) or 5-FU (ECF). The trial was designed to show non-inferiority in overall survival for the treatment arms containing capecitabine as compared to the treatment arms containing 5-FU. Non-inferiority was met with a median overall survival of 10.9 months for capecitabine-containing arms vs. 9.6 months 5-FU-containing arms (HR 0.86, 95% CI 0.80—0.99 with a noninferiority margin of 1.23); toxicity was similar between the capecitabine and 5-FU treatment arms.

    For the adjuvant treatment of gastric cancer in combination with cisplatin and 5-fluorouracil given sequentially with chemoradiation therapy†.
    Intravenous dosage
    Adults

    50 mg/m2 IV on day 1 in combination with cisplatin 60 mg/m2 IV on day 1 and 5-fluorouracil (5-FU) 200 mg/m2/day CIVI on days 1—21, repeated every 3 weeks (ECF regimen). One cycle of ECF chemotherapy was given, followed by 5 weeks of concomitant 5-FU continuous IV infusion and radiation therapy, with 2 additional cycles of ECF starting 4 weeks after the completion of chemoradiotherapy. In a phase II study, 54 patients with adenocarcinoma of the stomach or gastroesophageal junction received multimodality treatment with ECF and 5-FU chemoradiotherapy. Patients had negative margins following complete R0 resection.

    For the perioperative treatment of gastric cancer in combination with cisplatin and 5-fluorouracil†.
    Intravenous dosage
    Adults

    50 mg/m2 IV on day 1 in combination with cisplatin 60 mg/m2 IV on day 1 and 5-fluorouracil (5-FU) 200 mg/m2/day CIVI on days 1—21, repeated every 3 weeks (ECF regimen). Treatment should be given for 3 cycles before and 3 cycles after surgical resection. In a phase III clinical trial, surgery was performed 3—6 weeks after the third cycle of preoperative chemotherapy; postoperative chemotherapy was initiated 6—12 weeks after surgery. Overall survival and progression free survival were significantly improved in the ECF arm.

    For the treatment of hepatocellular cancer†.
    For the treatment of hepatocellular cancer ineligible for surgical or locoregional therapy in combination with etoposide†.
    Intravenous dosage
    Adults

    Epirubicin 40 mg/m2 IV on day 1 in combination with etoposide (120 mg/m2 IV on days 1, 3, and 5) every 28 days has been studied in a phase II trial. An objective response of 39% in 36 patients who were not candidates for surgical or locoregional procedures was reported. Significant hematological toxicity occurred, and was more prevalent in patients who received higher cumulative doses of chemotherapy, however, neither treatment interruption or dose reduction was required.

    For the locoregional treatment of inoperable hepatocellular cancer†.
    Hepatic arterial chemoembolization† dosage
    Adults

    10 mg epirubicin and 2 mL Lipiodol per centimeter of tumor diameter (tumor size of multinodular disease calculated by the sum of the diameters of all tumor nodes) intra-arterially as part of the transarterial chemoembolization procedure (TACE). Maximum epirubicin dose is 80 mg. Patients underwent 1—6 treatments at 2-month intervals. In a phase II trial of 56 patients with compensated cirrhosis and inoperable hepatocellular carcinoma, epirubicin was dissolved in a solution of nonionic water-soluble contrast medium and saline solution and mixed with Lipiodol. Epirubicin 30—80 mg and Lipiodol 4—16 mL were injected. If blood flow was maintained, the full dose of epirubicin was injected; if blood flow stopped, the injection was stopped. At the end of the injection, gelfoam particles were injected as an embolizing agent. The overall survival rate at 3 years (3-year OS) was 32%. Patients who received > 1 course of treatment had a better 3-year OS than did patients who received only one treatment (39% vs. 13%, p = 0.003).

    For prophylaxis of primary or recurrent stage Ta or T1 transitional-cell bladder cancer† following transurethral resection.
    Intravesical dosage†
    Adults

    50 mg or 80 mg in 50 mL of saline administered intravesically following transurethral resection (TUR) as prophylaxis of superficial transitional-cell carcinoma (TCC) of the bladder has been studied in randomized clinical trials; however, the dosage schedule and duration of therapy has varied. A single 80-mg dose of intravesical epirubicin following TUR resulted in a significantly improved recurrence-free survival (RFS) rate (p = 0.016) and time to first recurrence (adjusted hazard ratio (HR) = 0.56; 95% CI, 0.39—0.8; p < 0.002) compared with TUR alone at a median follow-up time of 3.9 years in 219 patients with primary (53%) or low- or intermediate-risk recurrent (47%), superficial bladder cancer in a multicenter, randomized trial. Overall, the recurrence rate was 62% in the epirubicin arm compared with 77% in the no adjuvant therapy arm; however, a significant difference was only observed with epirubicin therapy in patients with a primary tumor (40% vs. 67%; p = 0.008) and not recurrent tumors (87% vs. 88%). Treatment with intravesical epirubicin or doxorubicin after TUR and then weekly for 8 weeks and then monthly for up to 1 year led to significantly improved recurrence rates (p = 0.0002) and time to first recurrence (p < 0.001) compared with TUR alone in 253 patients with primary (58.1%) or recurrent (41.9%), superficial TCC of the bladder a randomized, 4-arm trial (mean follow-time of 30.1 months). In the 50-mg dose epirubicin arm, 80-mg dose epirubicin arm, 50-mg dose doxorubicin arm, and no therapy arm, the recurrence rates were 25%, 17.6%, 36.7%, and 65.6%, respectively, and the mean times to first recurrence were 16, 15.4, 18.9, and 6.3 months, respectively. When pooled results from both epirubicin arms were compared with the doxorubicin arm, the recurrence rate (p = 0.02) was significantly better with epirubicin therapy; there was no significant difference between the 3 treatment arms for time to first recurrence. Additionally, time to progression and progression rates did not significantly differ among any of the 4 study arms. Significantly less toxicity was reported with intravesical epirubicin compared with doxorubicin therapy (p < 0.0001). Six weekly doses of either intravesical epirubicin 50 mg, intravesical Bacillus Calmette-guerin (BCG), or intravesical BCG plus isoniazid following TUR and continued for a total of 27 installations over a 3-year period was studied in 837 patients with intermediate- or high- risk primary (44%) or recurrent (54%), completely resectable, superficial TCC of the bladder in a multicenter, randomized, phase III trial. At a median follow-up of 9.2 years, the risk of recurrence (HR = 0.62; 95% CI, 0.5—0.76; p < 0.001), development of distant metastases (HR = 0.55; 95% CI, 0.32—0.94; p = 0.046), death (HR = 0.76; 95% CI, 0.59—0.96; p = 0.023), and death due to bladder cancer (HR = 0.47; 95% CI, 0.25—0.89; p = 0.026) were significantly lower with BCG when pooled results from both BCG-containing arms were compared with epirubicin; however, time to progression was not significantly different (p = 0.55). Chemical cystitis, urinary frequency, and macroscopic hematuria occurred less often with intravesical epirubicin compared with BCG, and there was one case of BCG induced lung infection.

    For peripheral blood stem cell (PBSC) mobilization† in multiple myeloma, in combination with ifosfamide, and etoposide, and filgrastim.
    Intravenous dosage
    Adults and Geriatric patients <= 70 years

    Multiple dosage regimens have been studied. Epirubicin 50 mg/m2 IV on day 1 plus ifosfamide (3 g/m2 continuous IV infusion over 24 hours on days 1—3), etoposide (200 mg/m2 IV on days 1—3), and filgrastim 10 mcg/kg/day subcutaneously daily starting on day 5 until apheresis completed (chemotherapy doses reduced to 75% of full dose in patients > 60 years of age); and, epirubicin 100 mg/m2 IV on day 1 plus ifosfamide (2500 mg/m2 IV over 3 hours daily on days 1—3) with mesna and hydration, etoposide (150 mg/m2 IV daily on days 1—3), and filgrastim 10 mcg/kg subcutaneously daily starting 48—96 hours after chemotherapy until apheresis completed have been evaluated for peripheral blood stem cell mobilization in patients with multiple myeloma.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    120 mg/m2 per dose as a single agent. The maximum cumulative dose of epirubicin is 900 mg/m2.

    Geriatric

    120 mg/m2 per dose as a single agent. The maximum cumulative dose of epirubicin is 900 mg/m2.

    Adolescents

    Safety and effectiveness have not been established.

    Children

    Safety and effectiveness have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Total bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times the upper limit of normal (ULN): Reduce the starting dose of epirubicin to 50% of the recommended starting dose.
    Total bilirubin greater than 3 mg/dL or AST greater than 4 times ULN: Reduce the starting dose of epirubicin to 25% of the recommended starting dose.
    Severe hepatic impairment (Child-Pugh C or serum bilirubin greater than 5 mg/dL): The use of epirubicin is contraindicated.[41751]

    Renal Impairment

    Mild to moderate renal impairment (SCr less than 5 mg/dL): No dosage adjustments are necessary.
    Severe renal impairment (SCr greater than 5 mg/dL): Consider lower doses of epirubicin. Specific dosage recommendations are not available, but plasma clearance was reduced by 50% in four patients with a SCr of 5 mg/dL or more. Patients undergoing dialysis have not been studied.

    ADMINISTRATION

     
     
    CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.

    Injectable Administration

    Epirubicin is administered intravenously. For off-label indications, it may also be given by intravesical or intraarterial administration.
    Because epirubicin is vesicant, it should not be administered intramuscularly or subcutaneously. If evidence of extravasation occurs during administration, immediately stop infusion and restart in another vein, preferably in another limb.
    When possible, delay epirubicin-based therapy until other cardiotoxic agents have cleared from the circulation to reduce the risk of epirubicin-related cardiotoxicity.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Preparation:
    Storage of epirubicin solution for injection at refrigerated conditions can result in the formation of a gelled product. This will return to a slightly viscous to mobile solution after 2 to 4 hours equilibration at controlled room temperature (15 to 25 degrees Celsius).
    Do not mix epirubicin in the same syringe with other drugs.
    Do not mix epirubicin with heparin or fluorouracil due to chemical incompatibilities that may lead to precipitation.
    Use epirubicin within 24 hours of first penetration of the rubber stopper; discard any unused solution.
     
    Administration:
    Avoid concomitant administration and prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug.
    Administer into the tubing of a freely flowing IV infusion (0.9% Sodium Chloride, Injection or 5% Dextrose, Injection).
    Patients receiving initial therapy at the recommended starting doses (100 mg/m2 to 120 mg/m2) should generally have epirubicin infused over 15 to 20 minutes to minimize the risk of thrombosis or perivenous extravasation.
    The infusion time may be proportionally decreased in patients who require lower doses but should not be less than 3 minutes.
    Do not administer by direct IV push due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.
    Avoid infusion into veins over joints or in extremities with compromised venous or lymphatic drainage if possible. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.[41751]

    Other Injectable Administration

    Intraarterial administration
    NOTE: Epirubicin is not approved by the FDA for intraarterial administration.
    Hepatic artery chemoembolization as part of TACE procedure:
    Hepatic artery chemoembolization is done with angiography. Patients with contraindications to angiography should be excluded.
    Other contraindications to hepatic chemoembolization include greater than 50% of liver volume replaced by tumor, LDH greater than 425 IU/L, AST greater than 100 IU/L, bilirubin greater than 2 mg/dL, biliary obstruction, hepatic encephalopathy, jaundice, patent portal vein or insufficient hepatopetal collateral flow.
    In the randomized clinical trial, epirubicin was dissolved in a solution of nonionic water-soluble contrast medium and saline, and mixed with Lipiodol. The epirubicin/Lipiodol ratio was calculated according to tumor size. Doses of epirubicin 30 mg to 80 mg and Lipiodol 4 mL to 16 mL were injected. If blood flow was maintained, the full dose was administered. If blood flow stopped, the injection was stopped. At the end of the procedure, gelfoam particles were injected as an embolizing agent.[48355]
     
    Intravesical administration
    NOTE: Epirubicin is not approved by the FDA for intravesical administration.
    The appropriate dose of epirubicin should be diluted in 50 ml of sterile 0.9% Sodium Chloride Injection. Length of instillation may differ between regimens; refer to individual protocols.[47223] [47224] [47225] [47226] Refer to guidelines for intravesical administration of medications for further recommendations.

    STORAGE

    Generic:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Reconstituted product is stable for 24 hours under refrigeration (36-46 degrees F) and protected from light, or 77 degrees under normal lighting conditions
    - Store unreconstituted product at room temperature (77 degrees F), excursions of 59 to 86 degrees F permitted
    - Store upright
    Ellence:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Anthracycline hypersensitivity

    Epirubicin is contraindicated in patients with known idarubicin or other severe anthracycline hypersensitivity or anthracenedione hypersensitivity.[41751]

    Bone marrow suppression, leukopenia, neutropenia

    Treatment with epirubicin can be associated with severe bone marrow suppression and is contraindicated in patients with severe persistent drug-induced bone marrow suppression. Dose-dependent, reversible leukopenia and/or neutropenia is usually the dose-limiting toxicity of epirubicin therapy. Consideration should be given to the administration of a lower starting dose (75 mg/m2 to 90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow suppression, or the presence of infiltrative neoplastic disease. Carefully monitor complete blood counts (CBC) at baseline and during treatment; an interruption of therapy or dose reduction may be necessary. Monitor for possible clinical complications due to myelosuppression; supportive care may be necessary for severe neutropenia and severe infection. Patients who receive epirubicin regimens containing 120 mg/m2 or more per cycle should also receive prophylactic antibiotic therapy with an appropriate regimen.[41751]

    Radiation therapy

    Use epirubicin with caution in patients receiving concurrent radiation therapy and in patients who have received prior radiation therapy. Patients may experience an inflammatory radiation recall reaction at the site of irradiation (e.g., cutaneous toxicity and pulmonary toxicity) during epirubicin therapy including the myocardium, mucosa, skin, and liver.[41751]

    Extravasation, intramuscular administration, subcutaneous administration

    Extravasation of epirubicin can cause severe local tissue injury (e.g., blistering, ulceration) and necrosis, requiring wide excision of the affected area and skin grafting. Avoid intramuscular administration or subcutaneous administration of epirubicin. If a patient experiences burning or stinging during the administration of epirubicin or shows other evidence of perivenous infiltration, consider the possibility of extravasation and immediately terminate the infusion; it may be restarted in another vein. Apply ice to the affected area intermittently for 15 minutes, 4 times daily for 3 days; if appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation. Perivenous infiltration may occur despite the presence of blood return on aspiration of the infusion needle, and may also occur without causing pain, stinging, or burning. Venous sclerosis may result from administration into a small vessel or from repeated injections into the same vein. If possible, avoid administration into veins over joints or in extremities with compromised venous or lymphatic drainage. To decrease the risk of extravasation, epirubicin should be administered slowly into the tubing of a freely running IV infusion over 15 to 20 minutes; the infusion may be proportionally decreased with lower doses (minimum infusion time, 3 minutes).[41751]

    Hepatic disease

    Use epirubicin with caution in patients with pre-existing hepatic disease; epirubicin is contraindicated in patients with severe hepatic impairment (Child-Pugh C or serum bilirubin greater than 5 mg/dL). Because the hepatobiliary system is the major route of elimination for epirubicin, a dose reduction may be necessary for patients with hyperbilirubinemia or transaminitis; these patients may experience slower drug clearance and an increase in overall toxicity. Monitor liver function tests at baseline and during treatment with epirubicin.[41751]

    Renal failure, renal impairment

    Use epirubicin with caution in patients with renal impairment. A dosage adjustment may be necessary for patients with renal failure (SCr greater than 5 mg/dL), as reduced plasma clearance was reported in these patients; patients undergoing dialysis have not been studied. Assess serum creatinine at baseline and during epirubicin therapy.[41751]

    New primary malignancy

    The occurrence of a new primary malignancy, specifically acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), has been reported in patients treated with epirubicin and other anthracyclines; these leukemias can have a short latency period of 1 to 3 years. The cumulative probability of developing AML/MDS was found to be particularly increased in patients who received more than the maximum recommended cumulative dose of epirubicin (720 mg/m2) and cyclophosphamide (6,300 mg/m2).[41751]

    Tumor lysis syndrome (TLS)

    Epirubicin may induce tumor lysis syndrome (TLS) as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of highly chemosensitive neoplastic cells. Generally, this is not a problem in patients with breast cancer, but clinicians should closely monitor susceptible patients. Evaluate serum uric acid, potassium, calcium, phosphate, and creatinine after initial treatment. Consider hydration, urine alkalinization, and prophylaxis with allopurinol to minimize hyperuricemia and potential complications.[41751]

    Cardiac arrhythmias, cardiac disease, cardiomyopathy, cardiotoxicity, heart failure, maximum cumulative lifetime dose, myocardial infarction

    Epirubicin has been associated with both early and late cardiotoxicity and should be used with caution in patients with a history of cardiac disease. It is contraindicated in patients with severe myocardial insufficiency (heart failure), recent myocardial infarction, or severe cardiac arrhythmias. It is also contraindicated in patients who have previously received the maximum cumulative lifetime dose of anthracyclines, as the risk of cardiomyopathy is proportional to cumulative exposure; although not formally tested, it is probable that the cardiac toxicity of epirubicin and other anthracyclines or anthracenediones is additive. The maximum recommended cumulative dose is 720 mg/m2; cumulative epirubicin doses of 900 mg/m2 should generally be avoided. Cardiotoxicity may occur at lower cumulative doses, whether or not cardiac risk factors are present. Closely monitor patients with a history of prior anthracycline or anthracenedione exposure. Additional risk factors for epirubicin-related cardiac toxicity include concomitant cardiotoxic chemotherapy and a history of prior or concomitant mediastinal/pericardial radiotherapy. Avoid administration of epirubicin in combination with other cardiotoxic drugs; the increased risk associated with these drugs may persist after discontinuation of therapy, especially for those with long half-lives. Assess a baseline ECG and evaluate left ventricular ejection fraction (LVEF) prior to initiation of therapy with epirubicin. Continue to monitor LVEF during treatment and consider discontinuation of therapy if the LVEF decreases or if the patient develops signs or symptoms of congestive heart failure.[41751]

    Vaccination

    Avoid vaccination with live or live-attenuated vaccines in patients receiving epirubicin, as this may result in serious or fatal infections due to immunosuppression. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.[41751]

    Children, infants, neonates

    The safety and efficacy of epirubicin have not been established in adolescents, children, infants, and neonates. Pediatric patients may be at increased risk for acute anthracycline-induced cardiotoxicity and chronic heart failure. Due to the risk of long-term cardiotoxicity, it has been recommended that patients treated with anthracyclines should undergo screening with electrocardiograms (ECGs) and echocardiograms every 2 years and 24-hour continuous electrocardiograms and radionuclide angiograms every 5 years.

    Geriatric

    Closely monitor for a possible increase in epirubicin-related adverse reactions in geriatric patients, and particularly in elderly female patients, due to the risk of decreased epirubicin clearance.[41751]

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during epirubicin treatment and for at least 6 months after the last dose. In women already pregnant, avoid the use of epirubicin during the first trimester. Epirubicin may be administered in the second and third trimesters if absolutely necessary; monitor the fetus and/or neonate for cardiotoxicity and perform testing consistent with community standards of care. Women who are pregnant or who become pregnant while receiving epirubicin should be apprised of the potential hazard to the fetus. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of epirubicin in the second and third trimesters. 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 the second and/or third trimesters. In animal reproduction studies in pregnant rats, epirubicin caused embryofetal lethality (e.g., increased resorptions, postimplantation loss, fetal death, decreased live fetuses), fetal growth retardation (decreased body weight), and numerous external (e.g., anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily GI, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations when administered during organogenesis at doses less than the maximum recommended human dose based on body surface area.[41751]

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during epirubicin treatment. Epirubicin can be embryolethal and teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during treatment with epirubicin and for 6 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of epirubicin. Women who become pregnant while receiving epirubicin should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use contraception during treatment with epirubicin and for 3 months after the last dose; men with pregnant partners should use condoms during treatment and for at least 7 days after the last dose of epirubicin. Based on clinical findings and animal studies, male and female infertility may occur. In females, amenorrhea can occur, resulting in premature menopause; recovery of menses and ovulation is related to age at treatment. In males, epirubicin may cause oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men, which may occur several years after the end of therapy.[41751]

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from epirubicin, advise women to discontinue breast-feeding during treatment and for at least 7 days after the final dose. It is not known whether epirubicin is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 11.0-67.0
    leukopenia / Delayed / 1.5-59.0
    alopecia / Delayed / 19.0-57.0
    keratitis / Delayed / 1.1-15.0
    stomatitis / Delayed / 0-9.0
    anemia / Delayed / 0-6.0
    thrombocytopenia / Delayed / 0-5.4
    new primary malignancy / Delayed / 0-5.0
    hot flashes / Early / 0-4.0
    heart failure / Delayed / 0.4-3.3
    lethargy / Early / 0-1.9
    infection / Delayed / 0-1.6
    nausea / Early / 0-0.8
    vomiting / Early / 0-0.8
    injection site reaction / Rapid / 0.3-0.4
    rash / Early / 0-0.3
    AV block / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    cardiotoxicity / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    leukemia / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known

    Moderate

    conjunctivitis / Delayed / 1.1-15.0
    bundle-branch block / Early / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    bone marrow suppression / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known
    erythema / Early / Incidence not known
    cystitis / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    dehydration / Delayed / Incidence not known
    infertility / Delayed / Incidence not known

    Mild

    amenorrhea / Delayed / 69.0-72.0
    fever / Early / 1.4-5.2
    anorexia / Delayed / 1.8-2.9
    chills / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    nail discoloration / Delayed / Incidence not known
    urine discoloration / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    oligospermia / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Aliskiren; Amlodipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Amlodipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Amlodipine; Atorvastatin: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Amlodipine; Benazepril: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Amlodipine; Olmesartan: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Amlodipine; Telmisartan: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Amlodipine; Valsartan: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Calcium-channel blockers: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Cimetidine: (Major) Discontinue cimetidine during treatment with epirubicin due to the risk of increased epirubicin exposure which may result in an increase of epirubicin-related adverse reactions. Coadministration of cimetidine increased the mean AUC of epirubicin by 50% and decreased its plasma clearance by 30%.
    Clevidipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Cyclophosphamide: (Major) Use caution if cyclophosphamide is used concomitantly with anthracyclines, as there may be an increased risk of cardiotoxicity. Concurrent administration of cyclophosphamide and doxorubicin has resulted in an increase in exposure to doxorubicinol, a more cardiotoxic metabolite of doxorubicin. Additionally, concurrent treatment with doxorubicin (including doxorubicin liposomal) has been reported to exacerbate cyclophosphamide-induced hemorrhagic cystitis.
    Diltiazem: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Docetaxel: (Moderate) Monitor for an increase in epirubicin-related adverse reactions, including hematologic and gastrointestinal toxicities, if coadministration with docetaxel is necessary. Coadministration of docetaxel immediately before or after epirubicin had no effect on the systemic exposure of epirubicin. However, the mean AUC of epirubicinol and 7-deoxy-aglycone (inactive metabolites) increased by 22.5% and 95%, respectively, when docetaxel was administered immediately after epirubicin. Epirubicin had no effect on the exposure of docetaxel.
    Enalapril; Felodipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Felodipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as anthracyclines, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Isradipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Nicardipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Nifedipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Nimodipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Nisoldipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Paclitaxel: (Moderate) Monitor for an increase in epirubicin-related adverse reactions, including hematologic and gastrointestinal toxicities, if coadministration with paclitaxel is necessary. Coadministration of paclitaxel immediately before or after epirubicin increased the mean AUC of epirubicin by 5% to 109%; the mean AUC of epirubicinol and 7-deoxy-aglycone (inactive metabolites) increased by 120% and 70%, respectively, when paclitaxel was administered immediately after epirubicin. Epirubicin had no effect on the exposure of paclitaxel.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Perindopril; Amlodipine: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Trandolapril; Verapamil: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Trastuzumab: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Trastuzumab; Hyaluronidase: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Verapamil: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during epirubicin treatment and for at least 6 months after the last dose. In women already pregnant, avoid the use of epirubicin during the first trimester. Epirubicin may be administered in the second and third trimesters if absolutely necessary; monitor the fetus and/or neonate for cardiotoxicity and perform testing consistent with community standards of care. Women who are pregnant or who become pregnant while receiving epirubicin should be apprised of the potential hazard to the fetus. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of epirubicin in the second and third trimesters. 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 the second and/or third trimesters. In animal reproduction studies in pregnant rats, epirubicin caused embryofetal lethality (e.g., increased resorptions, postimplantation loss, fetal death, decreased live fetuses), fetal growth retardation (decreased body weight), and numerous external (e.g., anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily GI, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations when administered during organogenesis at doses less than the maximum recommended human dose based on body surface area.[41751]

    Due to the potential for serious adverse reactions in nursing infants from epirubicin, advise women to discontinue breast-feeding during treatment and for at least 7 days after the final dose. It is not known whether epirubicin is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Epirubicin is an anthracycline. Although it is known that anthracyclines can interfere with several biochemical and biological functions within eukaryotic cells, the precise mechanisms of the cytotoxic and/or antiproliferative properties of epirubicin are not clear. Epirubicin forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs, with consequent inhibition of nucleic acid (DNA and RNA) and protein synthesis. This intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase activity, preventing the enzymatic separation of double-stranded DNA and interfering with replication and transcription. Epirubicin is also involved in oxidation/reduction reactions by generating cytotoxic free radicals. The antiproliferative and cytotoxic activity of epirubicin is thought to result from these or other possible mechanisms. Epirubicin is cytotoxic in vitro to a variety of established murine and human cell lines and primary cultures of human tumors. It is also active in vivo against a variety of murine tumors and human xenografts in athymic mice, including breast tumors.[41751]
     
    Anthracycline-induced cardiotoxicity is related to free radical formation caused by metabolism of the anthracycline. The reactive oxygen species produced by anthracycline metabolism in cardiomyocytes subsequently cause cell death through apoptotic pathways by causing caspase 9 and caspase 3 activation, opening the mitochondrial permeability transition pore and releasing cytochrome C into the cytosol. Binding directly to the mitochondrial phospholipid, cardiolipin, also disrupts the association of inner mitochondrial membrane proteins with cardiolipin, which could enhance cytochrome C release in response to oxidant stress.[63572]

    PHARMACOKINETICS

    Epirubicin is administered intravenously (IV). It is approximately 77% protein-bound, primarily to albumin; protein binding is not affected by drug concentration. Following IV administration, epirubicin is rapidly and widely distributed into tissues and also appears to concentrate in red blood cells. It is extensively and rapidly metabolized by the liver and is also metabolized by other organs and cells, including red blood cells, with a mean volume of distribution (Vd) at steady-state of 21 to 27 L/kg. There are four main metabolic routes: reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; conjugation of both the unchanged drug and epirubicinol with glucuronic acid; loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. The metabolite epirubicinol has one-tenth of the cytotoxic activity of epirubicin and is unlikely to reach in vivo plasma concentrations sufficient for cytotoxicity. The pharmacokinetics of epirubicin are linear over a range of 60 mg/m2 to 150 mg/m2; plasma clearance is not affected by the duration of infusion or administration schedule. After a single dose of epirubicin, plasma concentrations in patients with solid tumors declined in a triphasic manner with mean half-lives for the alpha, beta, and gamma phases of approximately 3 minutes, 2.5 hours, and 33 hours, respectively. The mean clearance of epirubicin ranged from 65 to 83 L/hour. Epirubicin and its major metabolites are primarily eliminated through biliary excretion and, to a lesser extent, by urinary excretion. Mass-balance data from 1 patient found 34% of a radioactive dose in the feces and 27% in the urine, which was consistent with data in the 4 days after treatment from 3 patients with extrahepatic obstruction and percutaneous drainage (35% feces, 20% urine).[41751]
     
    Affected cytochrome P450 isoenzymes and drug transporters: None.[41751]

    Intravenous Route

    The mean Cmax of epirubicin was 5.3 to 5.7 mcg/mL (+/- 1.5 to 1.6 mcg/mL) after a single dose (60 mg/m2 to 75 mg/m2) administered to cancer patients over 6 to 10 minutes; the mean AUC was 1.6 to 1.7 mcg x hour/mL (+/- 0.2 to 0.3 mcg x hour/mL). As expected, concentrations were higher over the dose range of 120 mg/m2 to 150 mg/m2, with a mean Cmax of 9 to 9.3 mcg/mL (+/- 2.9 to 3.5 mcg/mL) and a mean AUC of 3.4 to 4.2 mcg x hour/mL (+/- 0.7 to 0.8 mcg x hour/mL). As epirubicin appears to concentrate in red blood cells as well as tissues, whole blood concentrations are approximately twice those of plasma.