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  • CLASSES

    Anthracyclines

    BOXED WARNING

    Bone marrow suppression, herpes infection, infection, neutropenia, thrombocytopenia, varicella, viral infection

    Treatment with epirubicin is associated with dose-dependent bone marrow suppression; epirubicin is contraindicated in patients with baseline neutropenia < 1500/mm3. Therapy with epirubicin should not be initiated until patients recover normal hematopoiesis, including recovery of neutropenia and thrombocytopenia; patients should not be treated with epirubicin with neutropenia < 1500/mm3. Epirubicin should be used cautiously in patients who have had previous myelosuppressive therapy such as chemotherapy or radiotherapy. Consideration should be given to the administration of a lower starting dose (75—90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow suppression, or the presence of infiltrative neoplastic disease. During treatment with epirubicin, the hematologic status of the patient should be closely monitored. Patients should be treated for any infection prior to receiving epirubicin. Patients who receive epirubicin regimens containing >= 120 mg/m2 should also receive prophylactic antibiotic therapy with an appropriate regimen, which may include trimethoprim-sulfamethoxazole or a quinolone. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Extravasation, intramuscular administration, subcutaneous administration

    Epirubicin is a severe vesicant. Extravasation of epirubicin infusions should be avoided. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Administration in small vessels or repeated injections into the same vein may result in venous sclerosis. Patients should be closely monitored during IV infusions for signs and symptoms of extravasation such as poor blood return, burning, stinging, necrosis and swelling at the injection site. If extravasation occurs, stop the infusion and remove the tubing. Attempt to aspirate the drug prior to removing the needle. Elevate the affected area and treat with ice packs. As this can be a progressive injury, appropriate long-term follow-up is required. Intramuscular administration and subcutaneous administration of epirubicin are to be avoided due to severe skin and tissue necrosis.

    New primary malignancy

    The occurrence of a new primary malignancy, specifically acute myelogenous leukemia (AML) with or without a myelodysplastic syndrome (MDS), has been reported in patients treated with anthracyclines. 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 the anthracyclines have been escalated. 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).

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, cardiomyopathy, cardiotoxicity, coronary artery disease, diabetes mellitus, heart failure, hypertension, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, maximum cumulative lifetime dose, myocardial infarction, QT prolongation, thyroid disease

    Severe cardiotoxicity including fatal congestive heart failure (CHF) is dose related and may occur during epirubicin therapy or months to years after discontinuing therapy. The maximum cumulative lifetime dose of epirubicin is 900 mg/m2 IV and should only be exceeded with extreme caution. The risk of cardiotoxicity may be decreased by administration as a 48-hour infusion as opposed to bolus dosing. Epirubicin is contraindicated in patients with cardiomyopathy and/or heart failure, recent myocardial infarction, or severe cardiac arrhythmias. A history of cardiac disease, previous anthracycline or anthracenedione therapy (especially at maximum cumulative doses), prior or concomitant radiotherapy to the mediastinal/pericardial area, or concomitant use with other cardiac toxic agents (e.g., trastuzumab) may increase the risk of cardiotoxicity. Avoid starting epirubicin within 24 weeks of stopping trastuzumab therapy if possible. Evaluate cardiac function at baseline by assessing left ventricular ejection fraction (LVEF). Regular monitoring of LVEF by multi-gated radionuclide angiography (MUGA) or echocardiogram (ECHO) is recommended, particularly after higher, cumulative anthracycline doses. Discontinue epirubicin in patients who develop impaired cardiac function; a risk/benefit analysis should be performed before continuing epirubicin therapy in patients with impaired cardiac function. Use epirubicin with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Women, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

    Requires an experienced clinician

    Epirubicin therapy requires an experienced clinician knowledgeable in the use of cancer chemotherapeutic agents.

    DEA CLASS

    Rx

    DESCRIPTION

    Anthracycline chemotherapy agent; semi-synthetic derivative of daunorubicin; similar spectrum of activity and toxicity as doxorubicin; lower incidence of cardiotoxicity and myelotoxicity than doxorubicin.

    COMMON BRAND NAMES

    Ellence

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    NOTE: Epirubicin in combination with other agents is approved by the FDA for the adjuvant treatment of breast cancer with axillary node tumor involvement after resection of primary breast cancer.
    NOTE: Consideration should be given to the administration of a lower starting dose (75—90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow suppression, or the presence of infiltrative neoplastic disease.
    For the treatment of patients with breast cancer with evidence of axillary node involvement following resection of the primary tumor in combination with cyclophosphamide and fluorouracil.
    Intravenous dosage
    Adults

    100 mg/m2 IV on day 1 in combination with fluorouracil and cyclophosphamide (FEC regimen) every 21 days for 6 cycles or 60 mg/m2 IV on days 1 and 8 in combination with oral cyclophosphamide and fluorouracil every 28 days for 6 cycles. Patients with pre-existing bone marrow suppression or tumor involvement of the bone marrow may require lower starting doses (e.g., 75—90 mg/m2). Alternatively, FEC may be administered for 3 cycles, then followed by docetaxel (100 mg/m2 IV) given every 21 days for 3 cycles (FEC-D regimen). A phase III trial of 1944 patients with node-positive breast cancer compared the FEC-D regimen for 3 cycles to FEC for 6 cycles. The primary endpoint, 5-year disease-free survival, was significantly longer in the FEC-D arm (78.4% vs. 73.2 %, p = 0.012). Overall survival at 5 years was also higher in FEC-D (90.7% vs. 86.7%, p = 0.017). Grade 3/4 neutropenia and the incidence of nausea/vomiting were higher with FEC, while stomatitis, edema and nail changes were more common with FEC-D.

    For the adjuvant treatment of breast cancer in combination with cyclophosphamide.
    Intravenous dosage
    Adults

    60 mg/m2 IV day 1 in combination with cyclophosphamide (500 mg/m2 IV day 1), repeated every 21 days for 8 cycles. Alternately, a higher-dose regimen of epirubicin 100 mg/m2 IV day 1 in combination with cyclophosphamide (830 mg/m2 IV day 1), every 21 days for 8 cycles, has been given.

    For the neoadjuvant treatment of HER2-positive breast cancer with fluorouracil and cyclophosphamide (FEC regimen) in sequence, and in combination, with paclitaxel and trastuzumab†.
    Intravenous dosage
    Adults

    Epirubicin 75 mg/m2 IV given in combination with fluorouracil and cyclophosphamide (FEC regimen), plus trastuzumab, sequentially with paclitaxel and trastuzumab. Give trastuzumab 4 mg/kg IV on week 1 just prior to paclitaxel, then, starting on week 2, trastuzumab 2 mg/kg IV once weekly for 23 weeks. Trastuzumab is given concomitantly with paclitaxel (225 mg/m2 IV continuous infusion over 24 hours on day 1) every 3 weeks for 4 cycles, followed by fluorouracil (500 mg/m2 IV on day 1), epirubicin (75 mg/m2 IV on day 1), and cyclophosphamide (500 mg/m2 IV on day 1) every 3 weeks for 4 cycles. Alternately, in a retrospective trial, paclitaxel 80 mg/m2 IV weekly for 12 weeks was substituted for every 3 week dosing in the above regimen.

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

    90 mg/m2 IV on day 1, every 3 weeks; in a phase II 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 <= 60 mg/m2.

    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 III trial, progression free survival and overall survival were similar when compared to patients on epirubicin and paclitaxel.

    For the treatment of metastatic breast cancer in combination with cyclophosphamide and fluorouracil†.
    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 III clinical trial, treatment was planned for 6 cycles, but was given up to 9 cycles in patients with a partial or complete response.

    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

    The suggested maximum tolerated dose (MTD) for epirubicin is dependent on performance status, other chemotherapy agents or radiation given in combination, and disease state.
    NOTE: The correct dose of epirubicin will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.

    Adults

    150 mg/m2/dose as a single agent; in combination with other myelosuppressive chemotherapy, the maximum single dosage may be lower. The maximum cumulative dose of epirubicin is 900 mg/m2.

    Geriatric

    150 mg/m2/dose as a single agent; in combination with other myelosuppressive chemotherapy, the maximum single dosage may be lower. The maximum cumulative dose of epirubicin is 900 mg/m2. Toxicity may be increased in female patients >= 70 years of age.

    Adolescents

    The maximum cumulative dose of epirubicin is 900 mg/m2. Children are more susceptible to cardiotoxicity and require long term follow-up.

    Children

    The maximum cumulative dose of epirubicin is 900 mg/m2. Children are more susceptible to cardiotoxicity and require long term follow-up.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Patients with hepatic abnormalities were excluded in adjuvant trials of epirubicin treatment; therefore, advice for use in patients with hepatic impairment is not available beyond the below recommendations:
    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: Do not use epirubicin in this patient population.[41751]

    Renal Impairment

    No specific guidelines exist for patients with renal impairment; however, lower doses are recommended in patients with severe renal impairment (i.e., serum creatinine greater than 5 mg/dL).

    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.
    Avoid infusion into veins over joints or in extremities with compromised venous or lymphatic drainage. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.
    Rapid injection may cause facial flushing or erythema along the vein; avoid administration time of fewer than 3 minutes.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk, waste-disposal bags for incineration. Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. DO NOT abrade the skin by using a scrub brush. Seek medical attention. Always wash hands after removing gloves.[41751]

    Intravenous Administration

    Administration:
    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).
    Use epirubicin within 24 hours of the first penetration of the rubber stopper; discard any unused solution.
    Avoid concomitant administration and prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug.
    Do not mix epirubicin in the same syringe with other drugs.
    Administer into the tubing of a freely flowing intravenous infusion (0.9% Sodium Chloride Injection or 5% Dextrose Injection) over 15 to 20 minutes to minimize the risk of thrombosis or perivenous extravasation. 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. The infusion time may be proportionally decreased in patients who require lower doses, but should not be less than 3 minutes.[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 doxorubicin or other anthracycline hypersensitivity or anthracenedione hypersensitivity. Epirubicin therapy is contraindicated in patients who have reached their total cumulative doses of epirubicin, doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones.

    Bone marrow suppression, herpes infection, infection, neutropenia, thrombocytopenia, varicella, viral infection

    Treatment with epirubicin is associated with dose-dependent bone marrow suppression; epirubicin is contraindicated in patients with baseline neutropenia < 1500/mm3. Therapy with epirubicin should not be initiated until patients recover normal hematopoiesis, including recovery of neutropenia and thrombocytopenia; patients should not be treated with epirubicin with neutropenia < 1500/mm3. Epirubicin should be used cautiously in patients who have had previous myelosuppressive therapy such as chemotherapy or radiotherapy. Consideration should be given to the administration of a lower starting dose (75—90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow suppression, or the presence of infiltrative neoplastic disease. During treatment with epirubicin, the hematologic status of the patient should be closely monitored. Patients should be treated for any infection prior to receiving epirubicin. Patients who receive epirubicin regimens containing >= 120 mg/m2 should also receive prophylactic antibiotic therapy with an appropriate regimen, which may include trimethoprim-sulfamethoxazole or a quinolone. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Radiation therapy

    Patients who have had previous radiation therapy may experience radiation recall reactions during epirubicin therapy. Epirubicin is a radiation sensitizer and should be used with caution in patients receiving concurrent radiation therapy; although in some cases this may be a benefit.

    Dental disease, dental work

    Myelosuppressive effects of epirubicin can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Extravasation, intramuscular administration, subcutaneous administration

    Epirubicin is a severe vesicant. Extravasation of epirubicin infusions should be avoided. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Administration in small vessels or repeated injections into the same vein may result in venous sclerosis. Patients should be closely monitored during IV infusions for signs and symptoms of extravasation such as poor blood return, burning, stinging, necrosis and swelling at the injection site. If extravasation occurs, stop the infusion and remove the tubing. Attempt to aspirate the drug prior to removing the needle. Elevate the affected area and treat with ice packs. As this can be a progressive injury, appropriate long-term follow-up is required. Intramuscular administration and subcutaneous administration of epirubicin are to be avoided due to severe skin and tissue necrosis.

    Intramuscular injections

    Intramuscular injections should not be administered to patients with platelet counts < 50,000/mm3 who are receiving epirubicin. IM injections may cause bleeding, bruising, or hematomas due to epirubicin-induced thrombocytopenia.

    Geriatric

    The clearance of epirubicin is decreased in geriatric women. The predicted plasma clearance of epirubicin is about 35% lower for a 70 year old woman as compared to a 25 year old woman. An insufficient number of men > 50 years of age have been studied to make any conclusions regarding age-related changes in men. A dosage reduction of epirubicin is not recommended for women >= 70 years of age, however these women should be closely monitored during epirubicin treatment.

    Hepatic disease, jaundice

    Epirubicin is contraindicated for use in patients with severe hepatic disease; patients with jaundice or other types of hepatic disease should not receive epirubicin. The dose of epirubicin should be adjusted for elevations in the total bilirubin or AST because these patients will have a decreased clearance of epirubicin with an increase in overall toxicity. Serum bilirubin and AST levels should be evaluated before and during treatment with epirubicin.

    Renal failure, renal impairment

    Patients with severe renal impairment (serum creatinine > 5 mg/dL) or renal failure require dosage adjustment of epirubicin. Serum creatinine levels should be assessed before and during epirubicin treatment.

    Infertility, male-mediated teratogenicity, pregnancy

    Epirubicin is classified as FDA pregnancy risk category D. Fetal harm may occur if epirubicin is administered to a pregnant woman, based on animal studies. Women of reproductive potential should avoid becoming pregnant during epirubicin therapy and should be advised to utilize effective contraceptive methods. If a woman becomes pregnant during therapy, she should be advised of the potential risks to the fetus. Two pregnancies have been reported in women receiving epirubicin. In one case, a woman was 28 weeks pregnant at her diagnosis of breast cancer and was treated with cyclophosphamide and epirubicin every 3 weeks for 3 cycles. She received the last dose at 34 weeks of the pregnancy and delivered a healthy baby at 35 weeks. A second woman with breast cancer metastatic to the liver received fluorouracil, cyclophosphamide and epirubicin but was removed from the trial due to the pregnancy. She experienced a spontaneous abortion. Because epirubicin may induce chromosomal damage in sperm, there is potential for male-mediated teratogenicity. Men with sexual partners of reproductive potential should use effective contraceptive methods during and after epirubicin therapy. Men or women who receive epirubicin may have a risk of infertility. Women treated with epirubicin may develop irreversible amenorrhea or premature menopause following treatment with epirubicin. Additionally, epirubicin therapy may result in testicular tissue and spermatozoa damage in men.

    Breast-feeding

    Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends discontinuing breast-feeding or discontinuing epirubicin, taking into account the importance of the drug to the mother. It is not known whether epirubicin is excreted in human breast milk but has been detected in breast milk of animals.

    New primary malignancy

    The occurrence of a new primary malignancy, specifically acute myelogenous leukemia (AML) with or without a myelodysplastic syndrome (MDS), has been reported in patients treated with anthracyclines. 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 the anthracyclines have been escalated. 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).

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, tumor lysis syndrome (TLS)

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and decreased urine output may be indicative of epirubicin-induced tumor lysis syndrome (TLS). Appropriate measures (e.g. aggressive hydration and allopurinol) must be taken to prevent severe electrolyte imbalances and renal toxicity during and following chemotherapy administration in patients with large chemosensitive tumors. Generally, this is not a problem in patients with breast cancer, but clinicians should closely monitor susceptible patients (i.e., those with leukemia, lymphoma, or extensive small cell lung cancer).

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, cardiomyopathy, cardiotoxicity, coronary artery disease, diabetes mellitus, heart failure, hypertension, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, maximum cumulative lifetime dose, myocardial infarction, QT prolongation, thyroid disease

    Severe cardiotoxicity including fatal congestive heart failure (CHF) is dose related and may occur during epirubicin therapy or months to years after discontinuing therapy. The maximum cumulative lifetime dose of epirubicin is 900 mg/m2 IV and should only be exceeded with extreme caution. The risk of cardiotoxicity may be decreased by administration as a 48-hour infusion as opposed to bolus dosing. Epirubicin is contraindicated in patients with cardiomyopathy and/or heart failure, recent myocardial infarction, or severe cardiac arrhythmias. A history of cardiac disease, previous anthracycline or anthracenedione therapy (especially at maximum cumulative doses), prior or concomitant radiotherapy to the mediastinal/pericardial area, or concomitant use with other cardiac toxic agents (e.g., trastuzumab) may increase the risk of cardiotoxicity. Avoid starting epirubicin within 24 weeks of stopping trastuzumab therapy if possible. Evaluate cardiac function at baseline by assessing left ventricular ejection fraction (LVEF). Regular monitoring of LVEF by multi-gated radionuclide angiography (MUGA) or echocardiogram (ECHO) is recommended, particularly after higher, cumulative anthracycline doses. Discontinue epirubicin in patients who develop impaired cardiac function; a risk/benefit analysis should be performed before continuing epirubicin therapy in patients with impaired cardiac function. Use epirubicin with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Women, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

    Accidental exposure, ocular exposure

    Use care to avoid accidental exposure to epirubicin during preparation, handling, and administration. The use of protective gowns, gloves and goggles is recommended. Following skin or ocular exposure, skin and eyes should be thoroughly rinsed.

    Vaccination

    Vaccination during chemotherapy, such as epirubicin, or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    Requires an experienced clinician

    Epirubicin therapy requires an experienced clinician knowledgeable in the use of cancer chemotherapeutic agents.

    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.

    Females

    Females may have an increased risk of anthracycline-induced cardiotoxicity. Females had a significantly greater reduction in cardiac contractility compared with males based on echocardiogram evaluations in a study in 120 children and adults who had been treated with bolus doses of doxorubicin (cumulative doses of 244—550 mg/m2) in childhood. Due to the risk of fetal harm, women of reproductive potential should avoid becoming pregnant during epirubicin therapy and should be advised to utilize effective contraceptive methods.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 67.2-67.2
    leukopenia / Delayed / 58.6-58.6
    alopecia / Delayed / 56.6-56.6
    nausea / Early / 25.0-25.0
    vomiting / Early / 25.0-25.0
    heart failure / Delayed / 0-15.0
    keratitis / Delayed / 14.8-14.8
    stomatitis / Delayed / 0-8.9
    esophagitis / Delayed / 0-8.9
    anemia / Delayed / 5.8-5.8
    thrombocytopenia / Delayed / 5.4-5.4
    new primary malignancy / Delayed / 0-5.0
    hot flashes / Early / 4.0-4.0
    lethargy / Early / 1.9-1.9
    infection / Delayed / 1.6-1.6
    diarrhea / Early / 0.8-0.8
    rash / Early / 0.3-0.3
    pruritus / Rapid / 0.3-0.3
    injection site reaction / Rapid / 0.3-0.3
    cardiomyopathy / Delayed / Incidence not known
    AV block / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    cardiotoxicity / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    tissue necrosis / Early / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known

    Moderate

    conjunctivitis / Delayed / 14.8-14.8
    bone marrow suppression / Delayed / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    bundle-branch block / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    oral ulceration / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    erythema / Early / Incidence not known
    skin ulcer / 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
    cystitis / Delayed / Incidence not known

    Mild

    amenorrhea / Delayed / 71.8-71.8
    fever / Early / 5.2-5.2
    anorexia / Delayed / 2.9-2.9
    urine discoloration / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    nail discoloration / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    chills / Rapid / 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.
    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.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    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.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like anthracyclines. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    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.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    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.
    Flucytosine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    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.
    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 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.
    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

    Epirubicin is classified as FDA pregnancy risk category D. Fetal harm may occur if epirubicin is administered to a pregnant woman, based on animal studies. Women of reproductive potential should avoid becoming pregnant during epirubicin therapy and should be advised to utilize effective contraceptive methods. If a woman becomes pregnant during therapy, she should be advised of the potential risks to the fetus. Two pregnancies have been reported in women receiving epirubicin. In one case, a woman was 28 weeks pregnant at her diagnosis of breast cancer and was treated with cyclophosphamide and epirubicin every 3 weeks for 3 cycles. She received the last dose at 34 weeks of the pregnancy and delivered a healthy baby at 35 weeks. A second woman with breast cancer metastatic to the liver received fluorouracil, cyclophosphamide and epirubicin but was removed from the trial due to the pregnancy. She experienced a spontaneous abortion. Because epirubicin may induce chromosomal damage in sperm, there is potential for male-mediated teratogenicity. Men with sexual partners of reproductive potential should use effective contraceptive methods during and after epirubicin therapy. Men or women who receive epirubicin may have a risk of infertility. Women treated with epirubicin may develop irreversible amenorrhea or premature menopause following treatment with epirubicin. Additionally, epirubicin therapy may result in testicular tissue and spermatozoa damage in men.

    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. Epirubicin is about 77% protein bound, primarily to albumin. Epirubicin has a triphasic clearance with half-lives for the alpha, beta, and terminal phases of 3 minutes, 1 hour, and 30 hours, respectively. Epirubicin is rapidly and extensively metabolized by the liver and other tissues, including red blood cells. Metabolism of epirubicin occurs through four major routes: 1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol, 2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid, 3) loss of the amino sugar moiety through a hydrolytic process with the formation of doxorubicin and doxorubicinol aglycones, and 4) loss of the sugar moiety through a redox process with the formation of 7-deoxy-doxorubicin aglycone. Epirubicinol has the one-tenth the cytotoxic activity of epirubicin and is not likely to contribute to the overall cytotoxic activity of epirubicin. The glucuronide metabolites of epirubicin and epirubicinol are not active, but the glucuronide metabolism does divert epirubicin from free radical formation, which may reduce cardiotoxicity. No significant activity has been reported for the other metabolites. Epirubicin and its major metabolites are excreted through biliary excretion and to a lesser extent urinary excretion.

    Intravenous Route

    Following intravenous administration, epirubicin is widely distributed into tissues.