Data from FDA - Curated by Marshall Pearce - Last updated 05 December 2017

Indication(s)

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

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Communicating Metastatic Breast Cancer Learning Zone

Communicating Metastatic Breast Cancer Learning Zone

This learning zone offers a short overview of the challenges faced by both healthcare professionals and patient when communicating end-stage or metastatic cancer.

Chronic Lymphocytic Leukaemia (CLL)

Chronic Lymphocytic Leukaemia (CLL)

Refine your knowledge of chronic lymphocytic leukaemia (CLL) with information on pathophysiology, diagnosis, treatment options and more

+ 1 more

Breakthrough Cancer Pain Learning Zone

Breakthrough Cancer Pain Learning Zone

Watch video highlights from the BeCOn OWN 2017 event, including expert opinion, patient experience and panel discussions in the Breakthrough Cancer Pain Learning Zone.

Load more

Related Content

Advisory information

contraindications
4 CONTRAINDICATIONS Patients should not be treated with Epirubicin Hydrochloride Injection if they have any of the following conditions: Cardiomyopathy and/or heart failure, recent myocardial infarction or severe arrhythmias [see Warnings and Precautions (5.3)] Previous treatment with maximum cumulative dose of anthracyclines [see Warnings and Precautions (5)]. Hypersensitivity to Epirubicin Hydrochloride Injection, other anthracyclines, or anthracenediones [see Adverse Reactions (6.2)]. Patients should not be treated with Epirubicin Hydrochloride Injection if they have any of the following conditions: baseline neutrophil count < 1,500 cells/mm3; cardiomyopathy and/or heart failure, recent myocardial infarction, severe arrhythmias; previous treatment with anthracyclines up to the maximum cumulative dose; hypersensitivity to epirubicin, other anthracyclines, or anthracenediones; or severe hepatic dysfunction (4).
Adverse reactions
6 ADVERSE REACTIONS In early breast cancer, acute adverse events occurring in ≥10% of patients are leukopenia, neutropenia, anemia, thrombocytopenia, amenhorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local toxicity and rash/itch (6). To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1. Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Integrated safety data are available from two studies (Studies MA-5 and GFEA-05) [see Clinical Studies (14.1)] evaluating epirubicin hydrochloride-containing combination regimens in patients with early breast cancer. Of the 1260 patients treated in these studies, 620 patients received the higher-dose epirubicin hydrochloride regimen (FEC-100/CEF-120), 280 patients received the lower-dose epirubicin hydrochloride regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant acute adverse events are summarized in Table 1. Table 1. Clinically Relevant Acute Adverse Events in Patients with Early Breast Cancer Event % of Patients FEC-100/CEF-120 (N=620) FEC-50 (N=280) CMF (N=360) Grades 1-4 Grades 3/4 Grades 1-4 Grades 3/4 Grades 1-4 Grades 3/4 Hematologic Leukopenia Neutropenia Anemia Thrombocytopenia 80.3 80.3 72.2 48.8 58.6 67.2 5.8 5.4 49.6 53.9 12.9 4.6 1.5 10.5 0 0 98.1 95.8 70.9 51.4 60.3 78.1 0.9 3.6 Endocrine Amenorrhea Hot flashes 71.8 38.9 0 4.0 69.3 5.4 0 0 67.7 69.1 0 6.4 Body as a Whole Lethargy Fever 45.8 5.2 1.9 0 1.1 1.4 0 0 72.7 4.5 0.3 0 Gastrointestinal Nausea/vomiting Mucositis Diarrhea Anorexia 92.4 58.5 24.8 2.9 25.0 8.9 0.8 0 83.2 9.3 7.1 1.8 22.1 0 0 0 85.0 52.9 50.7 5.8 6.4 1.9 2.8 0.3 Infection Infection Febrile neutropenia 21.5 NA 1.6 6.1 15.0 0 0 0 25.9 NA 0.6 1.1 Ocular Conjunctivitis/keratitis 14.8 0 1.1 0 38.4 0 Skin Alopecia Local toxicity Rash/itch Skin changes 95.5 19.5 8.9 4.7 56.6 0.3 0.3 0 69.6 2.5 1.4 0.7 19.3 0.4 0 0 84.4 8.1 14.2 7.2 6.7 0 0 0 FEC & CEF = cyclophosphamide + epirubicin hydrochloride + fluorouracil; CMF = cyclophosphamide + methotrexate + fluorouracil; NA = not available Grade 1 or 2 changes in transaminase levels were observed but were more frequently seen with CMF than with CEF. Delayed Events Table 2 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials. Table 2. Long-Term Adverse Events in Patients with Early Breast Cancer Event % of Patients FEC-100/CEF-120 (N=620) FEC-50 (N=280) FEC-50 (N=280) Cardiac events Asymptomatic drops in LVEF CHF 2.1* 1.5 1.4 0.4 0.8* 0.3 Leukemia AML 0.8 0 0.3 *In study MA-5, cardiac function was not monitored after 5 years. Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving epirubicin hydrochloride. However, an association between anthracyclines such as epirubicin hydrochloride and ALL has not been clearly established. 6.2. Overview of Acute and Delayed Toxicities Hematologic Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with epirubicin hydrochloride and represents the most common acute dose-limiting toxicity of this drug. In most cases, the white blood cell (WBC) nadir is reached 10 to 14 days from drug administration. Leukopenia/neutropenia is usually transient, with WBC and neutrophil counts generally returning to normal values by Day 21 after drug administration. As with other cytotoxic agents, epirubicin hydrochloride at the recommended dose in combination with cyclophosphamide and fluorouracil can produce severe leukopenia and neutropenia. Severe thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, septicemia, septic shock, hemorrhage, tissue hypoxia, symptomatic anemia, or death. If myelosuppressive complications occur, use appropriate supportive measures (e.g., intravenous antibiotics, colony-stimulating factors, transfusions). Myelosuppression requires careful monitoring. Assess total and differential WBC, red blood cell (RBC), and platelet counts before and during each cycle of therapy with epirubicin hydrochloride [see Warnings and Precautions (5.2)]. Gastrointestinal A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with epirubicin hydrochloride. Clinical manifestations of mucositis may include a pain or burning sensation, erythema, erosions, ulcerations, bleeding, or infections. Mucositis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations; most patients recover from this adverse event by the third week of therapy. Hyperpigmentation of the oral mucosa may also occur. Nausea, vomiting, and occasionally diarrhea and abdominal pain can also occur. Severe vomiting and diarrhea may produce dehydration. Antiemetics may reduce nausea and vomiting; consider prophylactic use of antiemetics before therapy [see Warnings and Precautions (5.10)]. Cutaneous and Hypersensitivity Reactions Alopecia occurs frequently, but is usually reversible, with hair regrowth occurring within 2 to 3 months from the termination of therapy. Flushes, skin and nail hyperpigmentation, photosensitivity, and hypersensitivity to irradiated skin (radiation-recall reaction) have been observed. Urticaria and anaphylaxis have been reported in patients treated with epirubicin hydrochloride; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock. Cardiovascular In a retrospective survey, including 9,144 patients, mostly with solid tumors in advanced stages, the probability of developing CHF increased with increasing cumulative doses of epirubicin hydrochloride (Figure 1). The estimated risk of epirubicin hydrochloride-treated patients developing clinically evident CHF was 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an epirubicin hydrochloride cumulative dose of 900 mg/m2 [see Warnings and Precautions (5.4)]. Figure 1. Risk of CHF in 9144 Patients Treated with Epirubicin Hydrochloride In another retrospective survey of 469 epirubicin hydrochloride-treated patients with metastatic or early breast cancer, the reported risk of CHF was comparable to that observed in the larger study of over 9,000 patients [see Warnings and Precautions (5.3)]. Other serious drug-related cardiovascular adverse events that occurred during clinical trials with epirubicin hydrochloride, administered in different indications, include ventricular tachycardia, AV block, bundle branch block, bradycardia and thromboembolism. Secondary Leukemia An analysis of 7,110 patients who received adjuvant treatment with epirubicin hydrochloride in controlled clinical trials as a component of poly-chemotherapy regimens for early breast cancer, showed a cumulative risk of secondary acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) of about 0.27% (approximate 95% CI, 0.14-0.40) at 3 years, 0.46% (approximate 95% CI, 0.28-0.65) at 5 years, and 0.55% (approximate 95% CI, 0.33-0.78) at 8 years. The risk of developing AML/MDS increased with increasing epirubicin hydrochloride cumulative doses as shown in Figure 2. Figure 2. Risk of AML/MDS in 7,110 Patients Treated with Epirubicin Hydrochloride 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 hydrochloride (720 mg/m2) or cyclophosphamide (6,300 mg/m2), as shown in Table 3. Table 3. Cumulative Probability of AML/MDS in Relation to Cumulative Doses of Epirubicin Hydrochloride and Cyclophosphamide Years from Treatment Start Cumulative Probability of Developing AML/MDS % (95% CI) Cyclophosphamide Cumulative Dose ≤6,300 mg/m2 Cyclophosphamide Cumulative Dose >6,300 mg/m2 Epirubicin Hydrochloride Cumulative Dose ≤720 mg/m2 N=4760 Epirubicin Hydrochloride Cumulative Dose >720 mg/m2 N=111 Epirubicin Hydrochloride Cumulative Dose ≤720 mg/m2 N=890 Epirubicin Hydrochloride Cumulative Dose >720 mg/m2 N=261 3 0.12 (0.01-0.22) 0.00 (0.00-0.00) 0.12 (0.00-0.37) 4.37 (1.69-7.05) 5 0.25 (0.08-0.42) 2.38 (0.00-6.99) 0.31 (0.00-0.75) 4.97 (2.06-7.87) 8 0.37 (0.13-0.61) 2.38 (0.00-6.99) 0.31 (0.00-0.75) 4.97 (2.06-7.87) Injection-Site Reactions [see Warnings and Precautions (5.9)]. Fig-1 Fig-2 6.3. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of epirubicin hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections and infestations: sepsis, pneumonia Immune system disorders: anaphylaxis Metabolism and nutrition disorders: dehydration, hyperuricemia Vascular disorders: shock, haemorrhage, embolism arterial, thrombophlebitis, phlebitis Respiratory, thoracic and mediastinal disorders: pulmonary embolism Gastrointestinal disorders: erosions, ulcerations, pain or burning sensation, bleeding, hyperpigmentation of the oral mucosa Skin and subcutaneous tissue disorders: erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction), urticaria Renal and urinary disorders: red coloration of urine for 1 to 2 days after administration General disorders and administration site conditions: fever, chills Injury, poisoning and procedural complications: chemical cystitis (following intravesical administration)

Usage information

Dosing and administration
2 DOSAGE & ADMINISTRATION When possible, to reduce the risk of developing cardiotoxicity in patients receiving Epirubicin Hydrochloride Injection after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, Epirubicin Hydrochloride Injection-based therapy should be delayed until the other agents have cleared from the circulation [see Warnings and Precautions (5.3)]. Administer Epirubicin Hydrochloride Injection by intravenous infusion. Give Epirubicin Hydrochloride Injection in repeated 3- to 4-week cycles. The total dose of Epirubicin Hydrochloride Injection may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. The recommended dosages of Epirubicin Hydrochloride Injection are as follows: • Administer intravenously in repeated 3- to 4-week cycles, either total dose on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle (2). • The recommended starting dose of Epirubicin Hydrochloride Injection is 100 to 120 mg/m2. Dosage reductions are possible when given in certain combinations (2.1). • Dosage adjustments after the first treatment cycle should be made based on hematologic and nonhematologic toxicities (2.2). • Reduce dose in patients with hepatic impairment (2.2, 8.6, 12.3). • Consider lower doses in patients with severe renal impairment (2.2,8.7, 12.3). 2.1. Recommended Dose The recommended dose of Epirubicin Hydrochloride Injection is 100 to 120 mg/m2. The following regimens are recommended: CEF-120: Cyclophosphamide 75 mg/m2 PO D 1-14 Epirubicin Hydrochloride Injection 60 mg/m2 IV D 1, 8 5-Fluorouracil 500 mg/m2 IV D 1, 8 Repeated every 28 days for 6 cycles FEC-100: 5-Fluorouracil 500 mg/m2 Epirubicin Hydrochloride Injection 100 mg/m2 Cyclophosphamide 500 mg/m2 All drugs administered intravenously on Day 1 and repeated every 21 days for 6 cycles Patients administered the 120-mg/m2 regimen of Epirubicin Hydrochloride Injection should receive prophylactic antibiotic therapy. 2.2. Dose Modifications Epirubicin Hydrochloride Injection dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3, absolute neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce Epirubicin Hydrochloride Injection Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥100,000/mm3, ANC ≥1,500/mm3, and nonhematologic toxicities have recovered to ≤ Grade 1. Bone Marrow Dysfunction Consider administering a lower starting dose (75-90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow depression, or in the presence of neoplastic bone marrow infiltration [see Warnings and Precautions (5)]. For patients receiving a divided dose of Epirubicin Hydrochloride Injection (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000-100,000/mm3 and ANC is 1,000 to 1,499/mm3. If Day 8 platelet counts are <75,000/mm3, ANC <1,000/mm3, or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose. Hepatic Impairment Recommendations regarding use of Epirubicin Hydrochloride Injection in patients with hepatic impairment are not available because patients with hepatic abnormalities were not included in the adjuvant trials [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions are recommended: • Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal 1/2 of recommended starting dose • Bilirubin > 3 mg/dL or AST > 4 times upper limit of normal 1/4 of recommended starting dose Renal Impairment While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. 2.3. Preparation and Administration Precautions Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15 to 25ºC). Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of anticancer drugs should be used when handling and preparing Epirubicin Hydrochloride Injection. Several guidelines on this subject have been published.1-4 [see References (15)]. Protective Measures Take the following protective measures when handling Epirubicin Hydrochloride Injection: • Train personnel in appropriate techniques for reconstitution and handling. • Exclude pregnant staff from working with this drug. • Wear protective clothing: goggles, gowns, and disposable gloves and masks when handling Epirubicin Hydrochloride Injection. • Define a designated area for syringe preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper. • Place all items used for reconstitution, administration, or cleaning (including gloves) in high-risk, waste-disposal bags for high temperature incineration. • Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk, waste-disposal bags for incineration. Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Seek medical attention. Always wash hands after removing gloves. Incompatibilities Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix Epirubicin Hydrochloride Injection with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation. Epirubicin Hydrochloride Injection can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe. Preparation of Infusion Solution Administer Epirubicin Hydrochloride Injection into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). Patients receiving initial therapy at the recommended starting doses of 100-120 mg/m2 should generally have Epirubicin Hydrochloride Injection infused over 15-20 minutes. For patients who require lower Epirubicin Hydrochloride Injection starting doses due to organ dysfunction or who require modification of Epirubicin Hydrochloride Injection doses during therapy, the Epirubicin Hydrochloride Injection infusion time may be proportionally decreased, but should not be less than 3 minutes. This technique is intended to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication, or tissue necrosis. A direct push injection is not recommended 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 [see Warnings and Precautions (5.9)]. Use Epirubicin Hydrochloride Injection within 24 hours of first penetration of the rubber stopper. Discard any unused solution.
Use in special populations
8 USE IN SPECIFIC POPULATIONS • Nursing Mothers: Discontinue nursing prior to taking epirubicin hydrochloride (8.3). • Pediatric Use: Safety and effectiveness of epirubicin hydrochloride in pediatric patients have not been established. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF (8.4). • Geriatric Use: Care should be taken in monitoring toxicity when epirubicin hydrochloride is administered to female patients ≥ 70 years of age. (8.5) 8.1 Pregnancy Pregnancy Category D. See ‘Warnings and Precautions’ section. Epirubicin hydrochloride can cause fetal harm when administered to a pregnant woman. Administration of 0.8 mg/kg/day intravenously of epirubicin to rats (about 0.04 times the maximum recommended single human dose on a body surface area basis) during Days 5 to 15 of gestation was embryotoxic (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight), but was not teratogenic up to this dose. Administration of 2 mg/kg/day intravenously of epirubicin to rats (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 9 and 10 of gestation was embryotoxic (increased late resorptions, post-implantation losses, and dead fetuses; and decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight. This dose was also teratogenic, causing numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations. Administration of intravenous epirubicin to rabbits at doses up to 0.2 mg/kg/day (about 0.02 times the maximum recommended single human dose on a body surface area basis) during Days 6 to 18 of gestation was not embryotoxic or teratogenic, but a maternally toxic dose of 0.32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 10 to 12 of gestation induced abortion, but no other signs of embryofetal toxicity or teratogenicity were observed. When doses up to 0.5 mg/kg/day epirubicin were administered to rat dams from Day 17 of gestation to Day 21 after delivery (about 0.025 times the maximum recommended single human dose on a body surface area basis), no permanent changes were observed in the development, functional activity, behavior, or reproductive performance of the offspring. There are no adequate and well-controlled studies of epirubicin hydrochloride in pregnant women. Two pregnancies have been reported in women taking epirubicin. A 34-year-old woman, 28 weeks pregnant at her diagnosis of breast cancer, was treated with cyclophosphamide and epirubicin every 3 weeks for 3 cycles. She received the last dose at 34 weeks of pregnancy and delivered a healthy baby at 35 weeks. A second 34-year-old woman with breast cancer metastatic to the liver was randomized to FEC-50 but was removed from study because of pregnancy. She experienced a spontaneous abortion. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [see Warnings and Precautions (5.12)]. 8.3 Nursing Mothers Epirubicin was excreted into the milk of rats treated with 0.50 mg/kg/day of epirubicin during peri- and postnatal periods. It is not known whether this drug is excreted in human milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from epirubicin hydrochloride, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of epirubicin hydrochloride have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF. The pharmacokinetics of epirubicin in pediatric patients have not been evaluated. 8.5 Geriatric Use Although a lower starting dose of epirubicin hydrochloride was not used in trials in elderly female patients, particular care should be taken in monitoring toxicity when epirubicin hydrochloride is administered to female patients ≥ 70 years of age [see Clinical Pharmacology (12.3)]. 8.6. Hepatic Impairment Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. Do not treat patients with severe hepatic impairment with epirubicin hydrochloride. Reduce the starting dose for patients with less severe hepatic impairment [see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]. 8.7. Renal Impairment No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine < 5 mg/dL. Consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL), as a reduction in plasma clearance was reported in these patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Patients on dialysis have not been studied.
Pregnancy and lactation
8.3 Nursing Mothers Epirubicin was excreted into the milk of rats treated with 0.50 mg/kg/day of epirubicin during peri- and postnatal periods. It is not known whether this drug is excreted in human milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from epirubicin hydrochloride, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS • Do not administer Epirubicin in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored (7.1). • Stop Cimetidine during treatment with epirubicin hydrochloride (7.2). 7.1. Cardioactive Compounds Do not administer epirubicin in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored. Patients receiving epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity [see Dosage and Administration (2)and Warnings and Precautions (5.3)]. Concomitant use of epirubicin hydrochloride with other cardioactive compounds that could cause heart failure (e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment. 7.2. Cimetidine Cimetidine increases the exposure to epirubicin [see Clinical Pharmacology (12.3)]. Stop Cimetidine during treatment with epirubicin hydrochloride. 7.3. Other Cytotoxic Drugs Epirubicin hydrochloride used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects. Paclitaxel: The administration of epirubicin immediately prior to or after paclitaxel increased the systemic exposure of epirubicin, epirubicinol and 7-deoxydoxorubicin aglycone [see Clinical Pharmacology (12.3)]. Docetaxel: The administration of epirubicin immediately prior to or after docetaxel did not have an effect on the systemic exposure of epirubicin, but increased the systemic exposure of epirubicinol and 7-deoxydoxorubicin aglycone [see Clinical Pharmacology (12.3)]. 7.4. Radiation Therapy There are few data regarding the coadministration of radiation therapy and epirubicin hydrochloride. In adjuvant trials of epirubicin hydrochloride-containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received epirubicin hydrochloride-based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of epirubicin hydrochloride with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of epirubicin hydrochloride after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation. 7.5. Concomitant Therapies-Hepatic Function Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity. 7.6. Drug/Laboratory Test Interactions There are no known interactions between epirubicin hydrochloride and laboratory tests.

More information

Category Value
Authorisation number ANDA065411
Agency product number 22966TX7J5
Orphan designation No
Product NDC 63323-151
Date Last Revised 11-08-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1732182
Marketing authorisation holder Fresenius Kabi USA, LLC
Warnings BOXED WARNING WARNING: RISK OF TISSUE NECROSIS, CARDIAC TOXICITY, SECONDARY ACUTE MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION 1. Severe local tissue necrosis will occur if there is extravasation during administration. Epirubicin hydrochloride must not be given by the intramuscular or subcutaneous route [see Warnings and Precautions (5.9)]. 2. Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with epirubicin hydrochloride or months to years after termination of therapy. The probability of developing clinically evident CHF is estimated as approximately 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. In the adjuvant treatment of breast cancer, the maximum cumulative dose used in clinical trials was 720 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin hydrochloride in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with epirubicin hydrochloride may occur at lower cumulative doses whether or not cardiac risk factors are present [see Warnings and Precautions (5.3)]. 3. Secondary acute myelogenous leukemia (AML) has been reported in patients with breast cancer treated with anthracyclines, including epirubicin. The occurrence of refractory secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. The cumulative risk of developing treatment-related AML or myelodysplastic syndrome (MDS), in 7,110 patients with breast cancer who received adjuvant treatment with epirubicin hydrochloride-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years [see Warnings and Precautions (5.4)]. 4. Severe myelosuppression may occur [see Warnings and Precautions (5.2)]. WARNING: SEVERE OR LIFE-THREATENING HEMATOLOGICAL AND OTHER ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Severe local tissue necrosis associated with extravasation during administration (5.9) • Myocardial toxicity, manifested in its most severe form by potentially fatal congestive heart failure (CHF) (5.3) • Secondary acute myelogenous leukemia (AML) (5.4) • Reduce dosage in patients with impaired hepatic function (5.5) • Severe myelosuppression (5.2) • Administer only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents (5)