winding up [50,000/mm:<250/mm 3 , 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/mm 3 , ANC ≥1,500/mm 3 , and nonhematologic toxicities have recovered to Grade 1. Bone Marrow Dysfunction Consider administering a lower starting dose (75-90 mg/m 2 ) 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/mm 3 and ANC is 1,000 to 1,499/mm 3 . If Day 8 platelet counts are> <75,000/mm 3 , ANC> <1,000/mm 3 , 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)]. . 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/m 2 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. DOSAGE FORMS & STRENGTHS Epirubicin Hydrochloride Injection is provided in single-dose vials containing 2 mg Epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use solution in the following sizes: 50 mg/25 mL and 200 mg/100 mL. 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)]. Warnings and Precautions Administer Epirubicin hydrochloride injection only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before beginning treatment with Epirubicin hydrochloride, patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment. Also, precede initial treatment with Epirubicin hydrochloride by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Carefully monitor patients during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to Epirubicin hydrochloride. . Injection-Related Reactions Epirubicin hydrochloride injection is administered by intravenous infusion. Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Extravasation of Epirubicin hydrochloride during the infusion may cause local pain, severe tissue lesions (vesication, severe cellulitis), and necrosis. Administer Epirubicin hydrochloride slowly into the tubing of a freely running intravenous infusion. Patients receiving initial therapy at the recommended starting doses of 100-120 mg/m 2 should generally have Epirubicin hydrochloride infused over 15-20 minutes. For patients who require lower Epirubicin hydrochloride starting doses due to organ dysfunction or who require modification of Epirubicin hydrochloride doses during therapy, the Epirubicin hydrochloride infusion time may be proportionally decreased, but should not be less than 3 minutes [see Dosage and Administration (2.3)]. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Immediately terminate infusion and restart in another vein if a burning or stinging sensation indicates perivenous infiltration. Perivenous infiltration may occur without causing pain. Facial flushing, as well as local erythematous streaking along the vein, may be indicative of excessively rapid administration. It may precede local phlebitis or thrombophlebitis. Give prophylactic antibiotic therapy to patients administered the 120-mg/m 2 regimen of Epirubicin hydrochloride as a component of combination chemotherapy [see Clinical Studies (14.1) and Dosage and Administration 2.1)]. . Hematologic Epirubicin hydrochloride can suppress bone marrow function as manifested by leukopenia, thrombocytopenia and anemia [see Adverse Reactions (6.1)], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [see Dosage and Administration (2.2, 2.3 )]. . Cardiac Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiac toxicity may be manifested by early (or acute) or late (delayed) events. Early cardiac toxicity of Epirubicin hydrochloride consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes, but tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not considered an indication for the suspension of Epirubicin hydrochloride treatment. Delayed cardiac toxicity results from a characteristic cardiomyopathy that is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, hepatomegaly, ascites, pleural effusion, gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy. This toxicity appears to be dependent on the cumulative dose of Epirubicin hydrochloride and represents the cumulative dose-limiting toxicity of the drug. If it occurs, delayed cardiotoxicity usually develops late in the course of therapy with Epirubicin hydrochloride or within 2 to 3 months after completion of treatment, but later events (several months to years after treatment termination) have been reported. Given the risk of cardiomyopathy, exceed a cumulative dose of 900 mg/m 2 Epirubicin hydrochloride only with extreme caution. Risk factors [active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs, especially those with long half-lives (e.g., trastuzumab)] may increase the risk of Epirubicin hydrochloride cardiotoxicity [see Drug Interaction (7.4) and Dosage and Administration (2)]. Although not formally tested, it is probable that the toxicity of Epirubicin hydrochloride and other anthracyclines or anthracenediones is additive. Cardiac toxicity with Epirubicin hydrochloride may occur at lower cumulative doses whether or not cardiac risk factors are present. Although endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy, this invasive examination is not practically performed on a routine basis. ECG changes such as dysrhythmias, a reduction of the QRS voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity. The risk of serious cardiac impairment may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of Epirubicin hydrochloride at the first sign of impaired function. The preferred method for repeated assessment of cardiac function is evaluation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Perform repeated MUGA or ECHO determinations of LVEF, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with Epirubicin hydrochloride in patients with impaired cardiac function must be carefully evaluated. Do not administer Epirubicin hydrochloride in combination with other cardiotoxic agents unless the patient s cardiac function is closely monitored. Patients receiving Epirubicin hydrochloride 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)] . . Secondary Leukemia The occurrence of secondary acute myelogenous leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines. Secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a short 1- to 3-year latency period. Epirubicin hydrochloride is mutagenic, clastogenic, and carcinogenic in animals [see Nonclinical Toxicology (13.1)]. . Hepatic The major route of elimination of Epirubicin is the hepatobiliary system [see Clinical Pharmacology (12.3)]. Evaluate serum total bilirubin and AST levels before and during treatment with Epirubicin hydrochloride. Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients [ see Dosage and Administration (2.2) ]. Patients with severe hepatic impairment have not been evaluated; therefore, do not use Epirubicin hydrochloride in this patient population. . Renal Assess serum creatinine before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL [see Dosage and Administration (2.2)]. Patients undergoing dialysis have not been studied. . Tumor-Lysis Syndrome As with other cytotoxic agents, Epirubicin hydrochloride may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of highly chemosensitive neoplastic cells (tumor-lysis syndrome). Other metabolic abnormalities may also occur. While not generally a problem in patients with breast cancer, consider the potential for tumor-lysis syndrome in potentially susceptible patients and consider monitoring serum uric acid, potassium, calcium, phosphate, and creatinine immediately after initial chemotherapy administration. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome. . Immunosuppressant Effects/Increased Susceptibility to Infections Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including Epirubicin, may result in serious or fatal infections. Avoid vaccination with a live vaccine in patients receiving Epirubicin hydrochloride. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished. . Gastrointestinal Epirubicin hydrochloride is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of Epirubicin hydrochloride, particularly when given in conjunction with other emetigenic drugs [see Adverse Reactions (6.2) ]. . Thrombophlebitis and Thromboembolic Phenomena As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of Epirubicin hydrochloride. . Coadministration with Cimetidine Cimetidine increased the AUC of Epirubicin by 50%. Stop Cimetidine treatment during treatment with Epirubicin hydrochloride [see Clinical Pharmacology (12.3)]. . Pregnancy Epirubicin hydrochloride can cause fetal harm when administered to a pregnant woman. Epirubicin was embryolethal and teratogenic in rats and rabbits. There are no adequate and well-controlled studies of Epirubicin hydrochloride in pregnant women. 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 a fetus. Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods [see Use In Specific Populations (8.1)]. . Male Fertility and Reproductive Outcomes Males with female sexual partners of childbearing potential should use contraception during and after cessation of Epirubicin hydrochloride therapy. Epirubicin hydrochloride may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain [see Nonclinical Toxicology (13.1)]. . Laboratory Testing Assess blood counts, including absolute neutrophil counts, and liver function before and during each cycle of therapy with Epirubicin hydrochloride. Perform repeated evaluations of LVEF during therapy [see Warnings and Precautions (5.5 and 5.6) ]. . Inflammation following Irradiation As with other anthracyclines, administration of Epirubicin hydrochloride after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation. Adverse Reactions . 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. . 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/m 2 , 1.6% at 700 mg/m 2 , and 3.3% at 900 mg/m 2 . The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an Epirubicin hydrochloride cumulative dose of 900 mg/m 2 [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/m 2 ) or cyclophosphamide (6,300 mg/m 2 ), 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/m 2 Cyclophosphamide Cumulative Dose >6,300 mg/m 2 Epirubicin Hydrochloride Cumulative Dose 720 mg/m 2 N=4760 Epirubicin Hydrochloride Cumulative Dose >720 mg/m 2 N=111 Epirubicin Hydrochloride Cumulative Dose 720 mg/m 2 N=890 Epirubicin Hydrochloride Cumulative Dose >720 mg/m 2 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)]. . 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) Drug Interactions . 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. . Cimetidine Cimetidine increases the exposure to Epirubicin [see Clinical Pharmacology (12.3)]. Stop Cimetidine during treatment with Epirubicin hydrochloride. . 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)]. . 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. . 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. . Drug/Laboratory Test Interactions There are no known interactions between Epirubicin hydrochloride and laboratory tests. USE IN SPECIFIC POPULATIONS 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) service provider
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