FDA label 98fb65ae-54db-d288-e053-2a95a90a6779

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/m 2 , 1.6% at 700 mg/m 2 , and 3.3% at 900 mg/m 2 . In the adjuvant treatment of breast cancer, the maximum cumulative dose used in clinical trials was 720 mg/m 2 . The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin hydrochloride in excess of 900 mg/m 2 ; 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 )

5 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. • A 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 ( 5.2 ). • Cardiotoxicity is a known risk of anthracycline treatment and may be manifested by early (or acute) or late (delayed) events ( 5.3 ). • The occurrence of secondary acute myelogenous leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines ( 5.4 ). • Serum total bilirubin and AST levels should be evaluated 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. Patients with severe hepatic impairment have not been evaluated ( 5.5 ). • Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL. Patients undergoing dialysis have not been studied ( 5.6 ). • 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) ( 5.7 ). • Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin hydrochloride, may result in serious or fatal infections ( 5.8 ). • 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. 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. Patients administered the 120-mg/m 2 regimen of epirubicin hydrochloride as a component of combination chemotherapy should also receive prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole (e.g., Septra®, Bactrim®) or a fluoroquinolone ( 5.9 ). • 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 ( 5.10 ). • Administration of epirubicin hydrochloride after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation ( 5.11 ) • Thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of epirubicin hydrochloride ( 5.12 ). • Epirubicin hydrochloride can cause fetal harm when administered to a pregnant woman. Advise women of potential risk to the fetus ( 5.12 ). 5.1. 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)]. 5.2. 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 )]. 5.3. 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)] . 5.4. 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)]. 5.5. 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. 5.6. 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. 5.7. 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. 5.8. 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. 5.9. 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) ]. 5.10. 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. 5.11. Coadministration with Cimetidine Cimetidine increased the AUC of epirubicin by 50%. Stop Cimetidine treatment during treatment with epirubicin hydrochloride [see Clinical Pharmacology (12.3)]. 5.12. 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)]. 5.13. 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)]. 5.14. 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) ]. 5.15. 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.

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/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)]. 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)

<table cellspacing="0" cellpadding="0" border="0" width="672"> <col width="25.3298938386745%"/> <col width="12.0845321956543%"/> <col width="13.0766941164798%"/> <col width="13.0667724972716%"/> <col width="10.864173033039%"/> <col width="12.9973211628138%"/> <col width="12.5806131560671%"/> <tbody> <tr styleCode="Botrule"> <td rowspan="3" styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Event</content> </td> <td colspan="6" styleCode="Rrule" valign="top"> <content styleCode="bold">% of Patients</content> </td> </tr> <tr styleCode="Botrule"> <td colspan="2" styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">FEC-100/CEF-120</content> <content styleCode="bold"> </content> <content styleCode="bold">(N=620)</content> </td> <td colspan="2" styleCode="Rrule" valign="top"> <content styleCode="bold">FEC-50</content> <content styleCode="bold"> </content> <content styleCode="bold">(N=280)</content> </td> <td colspan="2" styleCode="Rrule" valign="top"> <content styleCode="bold">CMF</content> <content styleCode="bold"> </content> <content styleCode="bold">(N=360)</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Grades 1-4</content> </td> <td styleCode="Rrule" valign="top"> <content styleCode="bold">Grades 3/4</content> </td> <td styleCode="Rrule" valign="top"> <content styleCode="bold">Grades 1-4</content> </td> <td styleCode="Rrule" valign="top"> <content styleCode="bold">Grades 3/4</content> </td> <td styleCode="Rrule" valign="top"> <content styleCode="bold">Grades 1-4</content> </td> <td styleCode="Rrule" valign="top"> <content styleCode="bold">Grades 3/4</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Hematologic</content> Leukopenia Neutropenia Anemia Thrombocytopenia </td> <td styleCode="Rrule" valign="top"> 80.3 80.3 72.2 48.8 </td> <td styleCode="Rrule" valign="top"> 58.6 67.2 5.8 5.4 </td> <td styleCode="Rrule" valign="top"> 49.6 53.9 12.9 4.6 </td> <td styleCode="Rrule" valign="top"> 1.5 10.5 0 0 </td> <td styleCode="Rrule" valign="top"> 98.1 95.8 70.9 51.4 </td> <td styleCode="Rrule" valign="top"> 60.3 78.1 0.9 3.6 </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Endocrine</content> Amenorrhea Hot flashes </td> <td styleCode="Rrule" valign="top"> 71.8 38.9 </td> <td styleCode="Rrule" valign="top"> 0 4.0 </td> <td styleCode="Rrule" valign="top"> 69.3 5.4 </td> <td styleCode="Rrule" valign="top"> 0 0 </td> <td styleCode="Rrule" valign="top"> 67.7 69.1 </td> <td styleCode="Rrule" valign="top"> 0 6.4 </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Body as a Whole</content> Lethargy Fever </td> <td styleCode="Rrule" valign="top"> 45.8 5.2 </td> <td styleCode="Rrule" valign="top"> 1.9 0 </td> <td styleCode="Rrule" valign="top"> 1.1 1.4 </td> <td styleCode="Rrule" valign="top"> 0 0 </td> <td styleCode="Rrule" valign="top"> 72.7 4.5 </td> <td styleCode="Rrule" valign="top"> 0.3 0 </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Gastrointestinal</content> Nausea/vomiting Mucositis Diarrhea Anorexia </td> <td styleCode="Rrule" valign="top"> 92.4 58.5 24.8 2.9 </td> <td styleCode="Rrule" valign="top"> 25.0 8.9 0.8 0 </td> <td styleCode="Rrule" valign="top"> 83.2 9.3 7.1 1.8 </td> <td styleCode="Rrule" valign="top"> 22.1 0 0 0 </td> <td styleCode="Rrule" valign="top"> 85.0 52.9 50.7 5.8 </td> <td styleCode="Rrule" valign="top"> 6.4 1.9 2.8 0.3 </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Infection</content> Infection Febrile neutropenia </td> <td styleCode="Rrule" valign="top"> 21.5 NA </td> <td styleCode="Rrule" valign="top"> 1.6 6.1 </td> <td styleCode="Rrule" valign="top"> 15.0 0 </td> <td styleCode="Rrule" valign="top"> 0 0 </td> <td styleCode="Rrule" valign="top"> 25.9 NA </td> <td styleCode="Rrule" valign="top"> 0.6 1.1 </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Ocular</content> Conjunctivitis/keratitis </td> <td styleCode="Rrule" valign="top"> 14.8 </td> <td styleCode="Rrule" valign="top"> 0 </td> <td styleCode="Rrule" valign="top"> 1.1 </td> <td styleCode="Rrule" valign="top"> 0 </td> <td styleCode="Rrule" valign="top"> 38.4 </td> <td styleCode="Rrule" valign="top"> 0 </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Skin</content> Alopecia Local toxicity Rash/itch Skin changes </td> <td styleCode="Rrule" valign="top"> 95.5 19.5 8.9 4.7 </td> <td styleCode="Rrule" valign="top"> 56.6 0.3 0.3 0 </td> <td styleCode="Rrule" valign="top"> 69.6 2.5 1.4 0.7 </td> <td styleCode="Rrule" valign="top"> 19.3 0.4 0 0 </td> <td styleCode="Rrule" valign="top"> 84.4 8.1 14.2 7.2 </td> <td styleCode="Rrule" valign="top"> 6.7 0 0 0 </td> </tr> </tbody> </table>

<table cellspacing="0" cellpadding="0" border="0"> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="middle"> <content styleCode="bold">Event</content> </td> <td styleCode="Rrule" valign="middle"> <content styleCode="bold">% of Patients</content> </td> <td styleCode="Rrule" valign="middle"> </td> <td styleCode="Rrule" valign="middle"> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="middle"> </td> <td styleCode="Rrule" valign="middle"> <content styleCode="bold">FEC-100/CEF-120 (N=620)</content> </td> <td styleCode="Rrule" valign="middle"> <content styleCode="bold">FEC-50 (N=280) </content> </td> <td styleCode="Rrule" valign="middle"> <content styleCode="bold">FEC-50 (N=280)</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="middle"> <content styleCode="bold">Cardiac events </content>Asymptomatic drops in LVEF CHF </td> <td styleCode="Rrule" valign="middle"> 2.1* 1.5 </td> <td styleCode="Rrule" valign="middle"> 1.4 0.4 </td> <td styleCode="Rrule" valign="middle"> 0.8* 0.3 </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="middle"> <content styleCode="bold">Leukemia</content> AML </td> <td styleCode="Rrule" valign="middle"> 0.8 </td> <td styleCode="Rrule" valign="middle"> 0 </td> <td styleCode="Rrule" valign="middle"> 0.3 </td> </tr> </tbody> </table>

<table cellspacing="0" cellpadding="0" border="0"> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="middle">Years from Treatment Start </td> <td styleCode="Rrule" valign="middle">Cumulative Probability of Developing AML/MDS % (95% CI) </td> <td styleCode="Rrule" valign="middle"> </td> <td styleCode="Rrule" valign="middle"> </td> <td styleCode="Rrule" valign="middle"> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="middle"> </td> <td styleCode="Rrule" valign="middle"> Cyclophosphamide Cumulative Dose &#x2264;6,300 mg/m ² </td> <td styleCode="Rrule" valign="middle"> </td> <td styleCode="Rrule" valign="middle">Cyclophosphamide Cumulative Dose &gt;6,300 mg/m ² </td> <td styleCode="Rrule" valign="middle"> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="middle"> </td> <td styleCode="Rrule" valign="middle"> Epirubicin Hydrochloride Cumulative Dose &#x2264;720 mg/m ² N=4760 </td> <td styleCode="Rrule" valign="middle">Epirubicin Hydrochloride Cumulative Dose &gt;720 mg/m ² N=111 </td> <td styleCode="Rrule" valign="middle">Epirubicin Hydrochloride Cumulative Dose &#x2264;720 mg/m ² N=890 </td> <td styleCode="Rrule" valign="middle">Epirubicin Hydrochloride Cumulative Dose &gt;720 mg/m ² N=261 </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="middle"> 3</td> <td styleCode="Rrule" valign="middle">0.12 (0.01-0.22) </td> <td styleCode="Rrule" valign="middle"> 0.00 (0.00-0.00)</td> <td styleCode="Rrule" valign="middle"> 0.12 (0.00-0.37)</td> <td styleCode="Rrule" valign="middle"> 4.37 (1.69-7.05)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="middle"> 5</td> <td styleCode="Rrule" valign="middle"> 0.25 (0.08-0.42)</td> <td styleCode="Rrule" valign="middle"> 2.38 (0.00-6.99)</td> <td styleCode="Rrule" valign="middle"> 0.31 (0.00-0.75)</td> <td styleCode="Rrule" valign="middle"> 4.97 (2.06-7.87)</td> </tr> <tr> <td styleCode="Lrule Rrule" valign="middle"> 8</td> <td styleCode="Rrule" valign="middle"> 0.37 (0.13-0.61)</td> <td styleCode="Rrule" valign="middle"> 2.38 (0.00-6.99)</td> <td styleCode="Rrule" valign="middle"> 0.31 (0.00-0.75)</td> <td styleCode="Rrule" valign="middle"> 4.97 (2.06-7.87)</td> </tr> </tbody> </table>