Epirubicin is an anthracycline chemotherapy agent and is the 4'-epimer of doxorubicin. It is indicated for the adjuvant treatment of node-positive early breast cancer. Epirubicin has a similar spectrum of activity and toxicity as doxorubicin. In two European phase 3 trials comparing epirubicin (FEC) and doxorubicin (CAF) in combination with cyclophosphamide and fluorouracil for the treatment of breast cancer, the patients treated with epirubicin had similar response and survival rates as patients treated with doxorubicin. Epirubicin has similar response rates to doxorubicin in early breast cancer, non-small cell and small cell lung cancer, non-Hodgkin lymphoma, ovarian cancer, gastric cancer, and nonresectable primary hepatocellular carcinoma. While the spectrum of toxicities for epirubicin and doxorubicin are similar, the incidence of toxicity differs. At equimolar doses, epirubicin is less myelotoxic than doxorubicin. Epirubicin is contraindicated in patients with severe persistent drug-induced myelosuppression. In addition, epirubicin has a lower incidence of cardiotoxicity; the maximum cumulative dose is almost twice that of doxorubicin. However, similar to other anthracyclines, cardiac monitoring is required; epirubicin is contraindicated in patients with severe myocardial insufficiency and in patients with a recent myocardial infarction or severe arrhythmias. Epirubicin primarily undergoes biliary elimination and therefore is also contraindicated in patients with severe hepatic impairment (Child-Pugh C or serum bilirubin greater than 5 mg/dL).
General Administration Information
For storage information, see the specific product information within the How Supplied section.
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.
Route-Specific Administration
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.
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.
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. Refer to guidelines for intravesical administration of medications for further recommendations.
Treatment with epirubicin can result in either early (i.e., acute) or late (i.e., delayed) cardiotoxicity. Early cardiotoxicity is primarily manifested as sinus tachycardia and/or ECG changes including nonspecific ST-T wave changes, but premature ventricular contractions (PVCs), ventricular tachycardia, bradycardia, AV block, and bundle-branch block have also been reported. The occurrence of early cardiac toxicity does not usually predict subsequently delayed cardiotoxicity and generally should not be considered a reason for suspending treatment with epirubicin. Delayed cardiotoxicity includes reduced left ventricular ejection fraction (LVEF) and signs/symptoms of congestive heart failure (CHF) that may develop either during therapy or within 2 to 3 months after completion of therapy; however, there are case reports of cardiotoxicity occurring several months to years after the last dose of epirubicin. Overall, 2.1% of patients with early breast cancer treated with FEC-100/CEF-120 (n = 620) experienced an asymptomatic decrease in LVEF compared to 1.4% of those treated with FEC-50 (n = 280) in separate clinical trials; congestive heart failure occurred in 1.5% and 0.4% of patients, respectively. In a retrospective survey (n = 9,144), the probability of developing congestive heart failure or cardiomyopathy increased with increasing cumulative dose of epirubicin (550 mg/m2, 0.9%; 700 mg/m2, 1.6%; 900 mg/m2, 3.3%). Consider discontinuation of epirubicin therapy if LVEF decreases or the patient has signs/symptoms of congestive heart failure. There are also reports of fetal and/or neonatal cardiotoxicity following in utero exposure to epirubicin, including rare reports of transient ventricular hypokinesia, transient elevation of cardiac enzymes, and a case of fetal demise from suspected anthracycline-induced cardiotoxicity following in utero exposure in the second and/or third trimesters.
Severe bone marrow suppression has been reported with epirubicin therapy. Dose-dependent, reversible leukopenia and/or neutropenia occurs most often, and is the most common dose-limiting toxicity of epirubicin. In most cases, the white blood cell nadir is reached 10 to 14 days after epirubicin administration and returns to normal values by day 21. In clinical trials, hematologic adverse reactions were more common in patients with early breast cancer who received higher doses of epirubicin (FEC-100/CEF-120; n = 620) compared to those who have received lower doses of epirubicin (FEC-50; n = 280), including leukopenia (80% vs. 50%; grade 3 or 4, 59% vs. 1.5%), neutropenia (80% vs. 54%; grade 3 or 4, 67% vs. 11%), anemia (72% vs. 13%; grade 3 or 4, 6% vs. 0%), and thrombocytopenia (49% vs. 4.6%; grade 3 or 4, 5% vs. 0%). Complete blood counts with differential should be assessed prior to each cycle and during therapy; an interruption of therapy or dose reduction may be necessary. Do not start a new cycle of therapy until platelet counts are 100,000 cells/mm3 or more and absolute neutrophil counts are 1,500 cells/mm3 or more.
Hemorrhage (bleeding) and shock have been reported in postmarketing experience with epirubicin.
Gastrointestinal (GI) erosions, GI ulcerations, and GI bleeding have been reported in postmarketing experience with epirubicin.
Infection was reported in 15% to 22% (grade 3 or 4, 1.6% or less) of patients with early breast cancer treated with epirubicin (FEC-50, FEC-100, or CEF-120; n = 900) in clinical trials. Febrile neutropenia was not reported in patients treated with FEC-50 (n = 280), but occurred in 6% of patients who received FEC-100 or CEF-120 (n = 620). Additionally, pneumonia and sepsis have been reported in postmarketing experience with epirubicin.
Fever occurred in 1.4% to 5% of patients treated with early breast cancer who received epirubicin (FEC-50, FEC-100, or CEF-120; n = 900) in clinical trials. Chills were also reported in postmarketing experience with epirubicin.
Dose-dependent mucositis, primarily manifested as oral stomatitis and less often esophagitis, may occur in patients treated with epirubicin. It generally appears early after drug administration and if severe, may progress over a few days to oral ulceration; recovery usually occurs by the third week of therapy. In clinical trials, mucositis was reported in 9% of patients with early breast cancer treated with lower doses of epirubicin (FEC-50; n = 280) and in 59% (grade 3 or 4, 9%) of patients who received higher doses (FEC-100 or CEF-120; n = 620). Symptoms of mucositis may include oral pain or burning, oral erythema, mucosal erosions, oral ulceration, bleeding, or infections. Hyperpigmentation of the oral mucosa has also been reported in postmarketing experience with epirubicin.
An injection site reaction resulting in severe local tissue injury including skin ulcer, blistering, and tissue necrosis can be caused by extravasation of epirubicin; wide excision of the affected area and skin grafting may be required. Local skin toxicity was reported in 20% (grade 3 or 4, 0.3%) of patients with early breast cancer treated with FEC-100/CEF-120 (n = 620), and in 2.5% (grade 3 or 4, 0.4%) of patients treated with the lower-dose epirubicin regimen FEC-50. Immediately stop the epirubicin infusion if a patient experiences burning or stinging during administration or shows other evidence of perivenous infiltration; the infusion may be restarted in another vein. 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. If extravasation occurs, apply ice 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. Topical cooling does not reduce anthracycline skin concentrations but decreases cellular uptake of anthracyclines, thereby decreasing the cytotoxic effect. Local erythematous streaking along the vein may be indicative of excessively rapid administration. Venous sclerosis may result from administration into a small vessel or from repeated injections into the same vein.
Alopecia occurs frequently with epirubicin treatment. In patients with early breast cancer, 96% (grade 3 or 4, 57%) of patients treated with FEC-100/CEF-120 (n = 620) reported alopecia; the overall incidence was slightly lower (70%; grade 3 or 4, 19%) in patients receiving the lower-dose epirubicin regimen FEC-50 (n = 280). Epirubicin-associated alopecia is usually reversible, with hair regrowth occurring within 2 to 3 months from termination of therapy.
Rash/pruritus occurred in 9% (grade 3 or 4, 0.3%) of epirubicin-treated patients with early breast cancer treated who received FEC-100/CEF-120 (n = 620) and in 1.4% of those who received the lower-dose epirubicin regimen FEC-50 (n = 280). More generally, skin changes were reported in 0.7% to 4.7% of patients treated with epirubicin. Erythema, flushing, nail discoloration, skin hyperpigmentation, and photosensitivity have additionally been reported in postmarketing experience with epirubicin. Facial flushing may be indicative of excessively rapid administration.
Red urine discoloration has been reported for 1 to 2 days after administration of epirubicin in postmarketing experience.
Chemical cystitis was reported in postmarketing experience following intravesical administration of epirubicin.
A radiation recall reaction has been reported with epirubicin treatment in postmarketing experience. There are few data regarding coadministration of radiation therapy with epirubicin. In adjuvant trials of patients treated with FEC-100 or CEF-120, breast irradiation was delayed until after chemotherapy was completed. A small number of patients received epirubicin-based chemotherapy concomitantly with radiation but had to have chemotherapy interrupted to avoid potential overlapping toxicities. It is likely that the use of epirubicin with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation.
Hyperuricemia was reported in postmarketing experience with epirubicin treatment.
A new primary malignancy, specifically acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), has been reported with epirubicin therapy; the latency period may be as short as 1 to 3 years. In clinical trials, AML occurred in 0.8% of patients with early breast cancer treated with FEC-100/CEF-120 (n = 620), and was not reported in patients who received the lower-dose epirubicin regimen FEC-50 (n = 280). Two cases of acute lymphocytic leukemia (ALL) were also observed in patients who received epirubicin, but an association between anthracyclines and ALL has not been clearly established. In an analysis of patients with early breast cancer who received adjuvant epirubicin in combination with other chemotherapy in controlled clinical trials (n = 7,110), the cumulative risk of secondary AML or MDS was approximately 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years; the risk increased with increasing cumulative doses of epirubicin. In patients with early breast cancer who received a cumulative cyclophosphamide dose of 6,300 mg/m2 or less, those with a cumulative epirubicin dose greater than 720 mg/m2 (n = 111) had a higher incidence of AML/MDS compared to those with a cumulative epirubicin dose of 720 mg/m2 or less (n = 4,760) at 5 years (2.38% vs. 0.25%) and 8 years (2.38% vs. 0.37%); the incidence at 3 years was similar in both groups of patients (0% vs. 0.12%). In patients with early breast cancer who received a cumulative cyclophosphamide dose of more than 6,300 mg/m2, the incidence of AML/MDS was higher in both patients with a cumulative epirubicin dose greater than 720 mg/m2 (n = 261) and in those with a cumulative epirubicin dose of 720 mg/m2 or less (n = 890) at 3 years (4.37% vs. 0.12%), 5 years (4.97% vs. 0.31%) and 8 years (4.97% vs. 0.31%).
Hot flashes occurred in 39% (grade 3 or 4, 4%) of patients treated with early breast cancer who received higher doses of epirubicin (FEC-100 or CEF-120; n = 620) and in 5% of those who received lower doses of epirubicin (FEC-50; n = 280) in clinical trials.
Urticaria and anaphylaxis/anaphylactoid reactions have been reported in patients treated with epirubicin; symptoms may vary and include rash, pruritus, fever, chills, and anaphylactic shock.
Thromboembolism, including pulmonary embolism (PE), has been reported in patients who received epirubicin; some cases of PE were fatal. Arterial embolism, phlebitis, and thrombophlebitis were reported postmarketing surveillance in patients who received epirubicin.
Nausea and vomiting (83% to 92%; grade 3 or 4, 22% to 25%) have commonly occurred in patients with early breast cancer treated with epirubicin (FEC-100, CEF-120, or FEC-50; n = 900) in clinical trials. Diarrhea has also been reported in 7% of patients receiving lower doses of epirubicin (FEC-50; n = 280) and in 25% (grade 3 or 4, 0.8%) of patients receiving higher doses (FEC-100 or CEF-120; n = 620). Severe vomiting and diarrhea may cause dehydration, which has been reported in postmarketing experience with epirubicin.
Lethargy occurred in 46% (grade 3 or 4, 1.9%) of patients treated with early breast cancer who received higher doses of epirubicin (FEC-100 or CEF-120; n = 620) and in 1.1% of those who received lower doses of epirubicin (FEC-50; n = 280) in clinical trials.
Conjunctivitis/keratitis was reported in 1.1% of patients with early breast cancer treated with lower doses of epirubicin (FEC-50; n = 280) and in 15% in patients receiving higher doses (FEC-100 or CEF-120; n = 620) in clinical trials.
Epirubicin may cause male and female infertility. In females, premature menopause can occur; recovery of menses and ovulation is related to age at treatment. Amenorrhea was reported in 69% to 72% of patients with early breast cancer treated with epirubicin (FEC-50, FEC-100, or CEF-120; n = 900) in clinical trials. In males, epirubicin may cause oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men, although this may occur several years after the end of therapy.
Anorexia was reported in 1.8% to 2.9% of patients with early breast cancer treated with epirubicin (FEC-50, FEC-100, or FEC-120; n = 900) in clinical trials.
Epirubicin is contraindicated in patients with known idarubicin or other severe anthracycline hypersensitivity or anthracenedione hypersensitivity.
Treatment with epirubicin can be associated with severe bone marrow suppression and is contraindicated in patients with severe persistent drug-induced bone marrow suppression. Dose-dependent, reversible leukopenia and/or neutropenia is usually the dose-limiting toxicity of epirubicin therapy. Consideration should be given to the administration of a lower starting dose (75 mg/m2 to 90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow suppression, or the presence of infiltrative neoplastic disease. Carefully monitor complete blood counts (CBC) at baseline and during treatment; an interruption of therapy or dose reduction may be necessary. Monitor for possible clinical complications due to myelosuppression; supportive care may be necessary for severe neutropenia and severe infection. Patients who receive epirubicin regimens containing 120 mg/m2 or more per cycle should also receive prophylactic antibiotic therapy with an appropriate regimen.
Use epirubicin with caution in patients receiving concurrent radiation therapy and in patients who have received prior radiation therapy. Patients may experience an inflammatory radiation recall reaction at the site of irradiation (e.g., cutaneous toxicity and pulmonary toxicity) during epirubicin therapy including the myocardium, mucosa, skin, and liver.
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).
Use epirubicin with caution in patients with pre-existing hepatic disease; epirubicin is contraindicated in patients with severe hepatic impairment (Child-Pugh C or serum bilirubin greater than 5 mg/dL). Because the hepatobiliary system is the major route of elimination for epirubicin, a dose reduction may be necessary for patients with hyperbilirubinemia or transaminitis; these patients may experience slower drug clearance and an increase in overall toxicity. Monitor liver function tests at baseline and during treatment with epirubicin.
Use epirubicin with caution in patients with renal impairment. A dosage adjustment may be necessary for patients with renal failure (SCr greater than 5 mg/dL), as reduced plasma clearance was reported in these patients; patients undergoing dialysis have not been studied. Assess serum creatinine at baseline and during epirubicin therapy.
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).
Epirubicin may induce tumor lysis syndrome (TLS) as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of highly chemosensitive neoplastic cells. Generally, this is not a problem in patients with breast cancer, but clinicians should closely monitor susceptible patients. Evaluate serum uric acid, potassium, calcium, phosphate, and creatinine after initial treatment. Consider hydration, urine alkalinization, and prophylaxis with allopurinol to minimize hyperuricemia and potential complications.
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.
Avoid vaccination with live or live-attenuated vaccines in patients receiving epirubicin, as this may result in serious or fatal infections due to immunosuppression. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
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.
Closely monitor for a possible increase in epirubicin-related adverse reactions in geriatric patients, and particularly in elderly female patients, due to the risk of decreased epirubicin clearance.
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.
Counsel patients about the reproductive risk and contraception requirements during epirubicin treatment. Epirubicin can be embryolethal and teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during treatment with epirubicin and for 6 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of epirubicin. Women who become pregnant while receiving epirubicin should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use contraception during treatment with epirubicin and for 3 months after the last dose; men with pregnant partners should use condoms during treatment and for at least 7 days after the last dose of epirubicin. Based on clinical findings and animal studies, male and female infertility may occur. In females, amenorrhea can occur, resulting in premature menopause; recovery of menses and ovulation is related to age at treatment. In males, epirubicin may cause oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men, which may occur several years after the end of therapy.
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.
For the treatment of breast cancer:
NOTE: The FDA has designated epirubicin as an orphan drug for the treatment of breast cancer.
-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.
-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 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 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 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.
-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.
-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.
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.
For the treatment of gastric cancer*:
-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.
-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 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.
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%). 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. 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, 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. 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: 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.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities
Cardiomyopathy
-Discontinue epirubicin.
Neutropenia
-Nadir absolute neutrophil count (ANC) less than 250 cells/mm3: Hold Day 1 epirubicin until the ANC is greater than or equal to 1,500 cells/mm3. When counts have recovered, reduce the Day 1 dose of epirubicin to 75% of the dose administered in the previous cycle.
-ANC less than 1,000 cells/mm3 on day 8: For patients receiving a divided dose of epirubicin (on day 1 and day 8), omit the day 8 dose if the ANC is less than 1,000 cells/mm3.
-ANC 1,000 to 1,499 cells/mm3 on day 8 (and platelets are 75,000 to 100,000 cells/mm3): For patients receiving a divided dose of epirubicin (on day 1 and day 8), reduce the dose of Day 8 epirubicin to 75% of the Day 1 dose.
Neutropenic Fever
-When the fever has resolved, reduce the Day 1 dose of epirubicin of the subsequent cycle to 75% of the dose administered in the previous cycle.
Non-Hematologic Toxicity
-Grade 3 or 4: Hold epirubicin. When the toxicity resolves to grade 1 or less, reduce the Day 1 dose of epirubicin to 75% of the dose administered in the previous cycle. For patients receiving a divided dose of epirubicin (on day 1 and day 8), omit the Day 8 dose if grade 3 or 4 toxicity has occurred.
Thrombocytopenia
-Nadir platelet counts less than 50,000 cells/mm3: Hold Day 1 epirubicin until platelet counts are greater than or equal to 100,000 cells/mm3. When counts have recovered, reduce the Day 1 dose of epirubicin to 75% of the dose administered in the previous cycle.
-Platelet counts less than 75,000 cells/mm3 on day 8: For patients receiving a divided dose of epirubicin (on day 1 and day 8), omit the day 8 dose if platelets are less than 75,000 cells/mm3.
-Platelet counts 75,000 to 100,000 cells/mm3 on day 8 (and ANC is 1,000 to 1,499 cells/mm3): For patients receiving a divided dose of epirubicin (on day 1 and day 8), reduce the dose of Day 8 epirubicin to 75% of the Day 1 dose.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
-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.
Patients with Renal Impairment Dosing
-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.
*non-FDA-approved indication
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
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.
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.
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).
Affected cytochrome P450 isoenzymes and drug transporters: None.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
Epirubicin is eliminated by both hepatic metabolism and biliary excretion, therefore clearance is reduced in patients with hepatic dysfunction. The median plasma clearance of epirubicin was decreased by about 30% in patients with solid tumors who had AST greater than the upper limit of normal (ULN) (median, 93 units/L) and normal bilirubin compared to patients with normal hepatic function. Median epirubicin clearance was decreased by 50% in solid tumor patients with a median AST of 175 units/L and elevated bilirubin (median, 2.7 mg/dL) compared to patients with normal hepatic function. The pharmacokinetics of epirubicin have not been evaluated in patients with more severe hepatic impairment.
Renal Impairment
No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine less than 5 mg/dL. A 50% reduction in plasma clearance was reported in four patients with serum creatinine of 5 mg/dL or more. The pharmacokinetics of epirubicin have not been studied in patients on dialysis.
Pediatrics
The pharmacokinetics of epirubicin have not been evaluated in pediatric patients.
Geriatric
The mean clearance of epirubicin was similar in adult male and female patients age 50 years or less. However, the clearance of epirubicin is decreased in elderly women.
Gender Differences
In a population analysis (n = 36), the predicted plasma clearance of epirubicin for a female cancer patient of 70 years of age was about 35% less than that for a female cancer patient of 25 years of age. There were an insufficient number of males greater than 50 years of age to evaluate age-related changes in epirubicin clearance in males.
Ethnic Differences
The impact of race on the pharmacokinetics of epirubicin has not been evaluated.