Ellence

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Ellence

Classes

Anthracyclines

Administration

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Moderate
Administer routine antiemetic prophylaxis prior to treatment.
Extravasation Risk
Vesicant
Administer drug through a central venous line.

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.

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

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]

Common Brand Names

Ellence

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

Dosage And Indications
For the treatment of breast cancer.
NOTE: The FDA has designated epirubicin as an orphan drug for the treatment of breast cancer.
For the adjuvant treatment of patients with breast cancer with evidence of axillary node involvement following resection of the primary tumor, in combination with fluorouracil and cyclophosphamide (FEC-100). Intravenous dosage Adults

100 mg/m2 IV on day 1 in combination with fluorouracil (500 mg/m2 IV on day 1) and cyclophosphamide (500 mg/m2 IV on day 1) on day 1 (FEC-100), every 21 days for 6 cycles. The total dose of epirubicin may also be divided equally and administered on days 1 and 8 of each cycle. 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 fluorouracil and cyclophosphamide (FEC-75), followed by paclitaxel and trastuzumab†. Intravenous dosage Adults

75 mg/m2 IV on day 1 in combination with fluorouracil (500 mg/m2 IV on day 1) and cyclophosphamide (500 mg/m2 IV on day 1), every 21 days for 4 cycles (FEC-75). 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.[49141]

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.[49168]

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 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]

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

60 mg/m2 IV on days 1 and 8 in combination with fluorouracil (500 mg/m2 IV on days 1 and 8), with cyclophosphamide (75 mg/m2 PO on days 1 to 14), every 28 days for 6 cycles (CEF-120); patients should receive prophylactic antibiotic therapy during treatment. 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 neoadjuvant treatment of high-risk, early-stage hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with cyclophosphamide and pembrolizumab, after completion of neoadjuvant paclitaxel/carboplatin/pembrolizumab†.
NOTE: Pembrolizumab is FDA-approved in combination with sequential paclitaxel/carboplatin followed by cyclophosphamide/epirubicin for this indication.
Intravenous dosage Adults

90 mg/m2 IV every 3 weeks in combination with cyclophosphamide (600 mg/m2 IV every 3 weeks) for 4 cycles, followed by surgery; administer epirubicin/cyclophosphamide in combination with pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks). Begin epirubicin/cyclophosphamide/pembrolizumab after the completion of 12 weeks of neoadjuvant carboplatin (AUC 5 IV on day 1 every 3 weeks), paclitaxel (80 mg/m2 IV once weekly), and pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks); alternatively, carboplatin may be dosed once weekly at an AUC of 1.5 IV for 12 weeks. Administer pembrolizumab prior to chemotherapy when given on the same day. After surgery, administer pembrolizumab 200 mg IV every 3 weeks for up to 9 doses OR 400 mg IV repeated every 6 weeks for up to 5 doses or until disease progression or unacceptable toxicity. Do not administer adjuvant pembrolizumab monotherapy to patients with disease progression or unacceptable toxicity related to neoadjuvant treatment with pembrolizumab plus chemotherapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with high-risk (tumor size more than 1 cm but up to and including 2 cm in diameter with nodal involvement; or tumor size more than 2 cm in diameter regardless of nodal involvement), early stage triple-negative breast cancer were randomized to neoadjuvant treatment with pembrolizumab or placebo in combination with carboplatin and paclitaxel, followed by anthracycline and cyclophosphamide in a phase 3 clinical trial (KEYNOTE-522); after definitive surgery, patients received adjuvant pembrolizumab or placebo. Treatment with pembrolizumab plus chemotherapy significantly improved the rate of pathologic complete response (pCR) (63% vs. 55.6%) compared with placebo plus chemotherapy. The median event-free survival (EFS) was not reached in either arm, although EFS at 18 months was 91.3% in patients who received pembrolizumab compared with 85.3% in those who received placebo (HR 0.63; 95% CI, 0.43 to 0.93); overall survival results are immature.

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 to 4 and 11 to 15) and interferon alfa-2b (3 million units 3 times weekly), 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 to 3), and dexamethasone (20 mg/m2 PO daily on days 1 to 5) repeated every 3 weeks for 1 or 2 cycles past maximum monoclonal component reduction 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, the evidence does not support using epirubicin with paclitaxel and carboplatin for this indication. In a phase 3 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.[48205]

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 to 21) and either 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 3 trial, 1,002 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 fluorouracil (EOF), or epirubicin and cisplatin with either capecitabine (ECX) or fluorouracil (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 fluorouracil. Non-inferiority was met with a median overall survival of 10.9 months for capecitabine-containing arms compared with 9.6 months fluorouracil-containing arms; toxicity was similar between the capecitabine and fluorouracil treatment arms.[40571]

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 fluorouracil (200 mg/m2 per day CIVI on days 1 to 21), repeated every 3 weeks (ECF regimen). One cycle of ECF chemotherapy was given, followed by 5 weeks of concomitant fluorouracil continuous IV infusion and radiation therapy, with 2 additional cycles of ECF starting 4 weeks after the completion of chemoradiotherapy. In a phase 2 study, 54 patients with adenocarcinoma of the stomach or gastroesophageal junction received multimodality treatment with ECF and fluorouracil 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 fluorouracil (200 mg/m2 per day CIVI on days 1 to 21), repeated every 3 weeks (ECF regimen). Treatment should be given for 3 cycles before and 3 cycles after surgical resection. In a phase 3 clinical trial, surgery was performed 3 to 6 weeks after the third cycle of preoperative chemotherapy; postoperative chemotherapy was initiated 6 to 12 weeks after surgery. Overall survival and progression free survival were significantly improved in the ECF arm.[34867]

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 2 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 to 6 treatments at 2-month intervals. In a phase 2 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 to 80 mg and Lipiodol 4 to 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 more than 1 course of treatment had significantly better 3-year OS than did patients who received only one treatment.[48355]

For prophylaxis of primary or recurrent stage Ta or T1 transitional-cell bladder cancer† following transurethral resection. Intravenous 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 have varied. A single 80-mg dose of intravesical epirubicin following TUR significantly improved recurrence-free survival (RFS) and time to first recurrence compared with TUR alone in patients with primary or low- or intermediate-risk recurrent, 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 and not recurrent tumors (87% vs. 88%).[47223] Treatment with intravesical epirubicin or doxorubicin after TUR and then weekly for 8 weeks and then monthly for up to 1 year significantly improved recurrence rates and time to first recurrence compared with TUR alone in patients with primary or recurrent, superficial TCC of the bladder a randomized, 4-arm trial. 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 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.[47224] 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.[47225] At a median follow-up of 9.2 years, the risk of recurrence, development of distant metastases, death, and death due to bladder cancer 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.[47226] 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.[47225]

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

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 to 3), etoposide (200 mg/m2 IV on days 1 to 3), and filgrastim 10 mcg/kg per day subcutaneously daily starting on day 5 until apheresis completed (chemotherapy doses reduced to 75% of full dose in patients more than 60 years of age); and, epirubicin 100 mg/m2 IV on day 1 plus ifosfamide (2,500 mg/m2 IV over 3 hours daily on days 1 to 3) with mesna and hydration, etoposide (150 mg/m2 IV daily on days 1 to 3), and filgrastim 10 mcg/kg subcutaneously daily starting 48 to 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

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.

Drug Interactions

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; Celecoxib: (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; 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; Valsartan; 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.
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.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
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: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy.
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.
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.
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.
Levamlodipine: (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.
Margetuximab: (Major) Avoid administration of anthracyclines during margetuximab therapy and for up to 4 months after the last dose of margetuximab due to the risk of increased cardiac dysfunction. If concomitant use is unavoidable, closely monitor cardiac function. This interaction has not been studied with margetuximab; however, clinical data from other HER2-directed antibodies warrants consideration.
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.
Olmesartan; 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.
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.
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.
Pertuzumab; 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.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Telmisartan; 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.
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.
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.

How Supplied

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

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.

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.

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.