ELLENCE

ELLENCE (epirubicin hydrochloride injection) is an anthracycline topoisomerase inhibitor for intravenous administration. ELLENCE is supplied as a sterile, clear, red solution and is available in polypropylene vials containing 50 and 200 mg of epirubicin hydrochloride as a preservative-free, ready-to-use solution. Each milliliter of solution contains 2 mg of epirubicin hydrochloride. Inactive ingredients include 9 mg sodium chloride, USP, and water for injection, USP. The pH of the solution has been adjusted to 3.0 with hydrochloric acid and/or sodium hydroxide, NF. Epirubicin hydrochloride is the 4-epimer of doxorubicin and is a semi-synthetic derivative of daunorubicin. The chemical name is (8S- cis )-10-[(3-amino-2,3,6-trideoxy-α-L- arabino -hexopyranosyl)oxy]-7,8,9,10-tetrahydro6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione hydrochloride. The active ingredient is a red-orange hygroscopic powder, with the empirical formula C 27 H 29 NO 11 HCl and a molecular weight of 579.95. The structural formula is as follows: Chemical Structure

ELLENCE 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) ] . ELLENCE is an anthracycline topoisomerase inhibitor indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer ( 1 ).

• The recommended starting dose of ELLENCE is 100 to 120 mg/m 2 . Dosage reductions are possible when given in certain combinations ( 2.2 ). • 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 ( 2.2 ). • Consider use of antiemetics when given in conjunction with other emetigenic drugs ( 2.1 ). • Patients administered the 120 mg/m 2 regimen of ELLENCE should receive prophylactic antibiotic therapy ( 2.1 ). • Adjust dosage after the first treatment cycle based on hematologic and nonhematologic toxicities ( 2.3 ). • Reduce dose in patients with hepatic impairment ( 2.3 , 8.6 ). • Consider lower doses in patients with severe renal impairment ( 2.3 , 8.7 ). 2.1 Important Administration Instructions When possible, to reduce the risk of developing cardiotoxicity in patients receiving ELLENCE after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, delay ELLENCE-based therapy until the other agents have cleared from the circulation [see Warnings and Precautions (5.1) ]. Antiemetics may reduce nausea and vomiting; consider use of antiemetics before administration of ELLENCE or when clinically indicated, particularly when given in conjunction with other emetigenic drugs [see Adverse Reactions (6.1) ]. Patients administered the 120 mg/m 2 regimen of ELLENCE should receive prophylactic antibiotic therapy. 2.2 Recommended Dose The recommended dose of ELLENCE is 100 to 120 mg/m 2 administered as an intravenous bolus [see Dosage and Administration (2.4) ] . The following regimens are recommended: CEF-120: Cyclophosphamide 75 mg/m 2 oral on Days 1 to 14 ELLENCE 60 mg/m 2 intravenously on Days 1 and 8 5-Fluorouracil 500 mg/m 2 intravenously on Days 1 and 8 Repeat every 28 days for 6 cycles FEC-100: 5-Fluorouracil 500 mg/m 2 intravenously on Day 1 ELLENCE 100 mg/m 2 intravenously on Day 1 Cyclophosphamide 500 mg/m 2 intravenously on Day 1 Repeat every 21 days for 6 cycles Administer ELLENCE in repeated 3- to 4-week cycles. The total dose of ELLENCE may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. 2.3 Dose Modifications ELLENCE dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm 3 , absolute neutrophil counts (ANC) <250/mm 3 , neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce ELLENCE 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 ≥1500/mm 3 , and nonhematologic toxicities have recovered to ≤ Grade 1. Cardiac Toxicity Discontinue ELLENCE in patients who develop signs or symptoms of cardiomyopathy [see Warnings and Precautions (5.1) ]. 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 (5.4) ]. For patients receiving a divided dose of ELLENCE (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 1000 to 1499/mm 3 . If Day 8 platelet counts are <75,000/mm 3 , ANC <1000/mm 3 , or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose. Hepatic Impairment In patients with elevated serum AST or serum total bilirubin concentrations [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ] , reduce dosage as follows: • 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 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) ] . 2.4 Preparation and Administration Precautions Preparation 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 (15–25°C). Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ELLENCE is a cytotoxic drug. Follow applicable special handling and disposable procedures 1 [see References (15) ]. Incompatibilities Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix ELLENCE with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation. ELLENCE can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe. Administration Administer ELLENCE 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 ELLENCE infused over 15–20 minutes. For patients who require lower ELLENCE starting doses due to organ dysfunction or who require modification of ELLENCE doses during therapy, the ELLENCE 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 (5.3) ]. Storage Use ELLENCE within 24 hours of first penetration of the rubber stopper. Discard any unused solution.

ELLENCE is contraindicated in patients with: • Severe myocardial insufficiency [see Warnings and Precautions (5.1) ] • Recent myocardial infarction or severe arrhythmias, or previous treatment with maximum cumulative dose of anthracyclines [see Warnings and Precautions (5.1) ] • Severe persistent drug-induced myelosuppression [see Warnings and Precautions (5.4) ] • Severe hepatic impairment (defined as Child-Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Warnings and Precautions (5.5) ] • Severe hypersensitivity to ELLENCE, other anthracyclines, or anthracenediones [see Adverse Reactions (6.1) ] • Severe myocardial insufficiency ( 4 ). • Recent myocardial infarction ( 4 ). • Severe persistent drug-induced myelosuppression ( 4 ). • Severe hepatic impairment ( 4 ). • Severe hypersensitivity to ELLENCE, other anthracyclines, or anthracenediones ( 4 ).

The following clinically significant adverse reactions are described elsewhere in the labeling: • Cardiac Toxicity [see Warnings and Precautions (5.1) ] • Secondary Malignancies [see Warnings and Precautions (5.2) ] • Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3) ] • Severe Myelosuppression [see Warnings and Precautions (5.4) ] • Tumor-Lysis Syndrome [see Warnings and Precautions (5.7) ] • Thrombophlebitis and Thromboembolic Events [see Warnings and Precautions (5.9) ] • Potentiation of Radiation Toxicity and Radiation Recall [see Warnings and Precautions (5.10) ] The most common adverse reactions (≥10%) are leukopenia, neutropenia, anemia, thrombocytopenia, amenorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local skin toxicity, and rash/itch ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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. The safety of ELLENCE was evaluated in two studies (Studies MA-5 and GFEA-05) evaluating combination regimens in patients with early breast cancer [see Clinical Studies (14.1) ] . Of the 1260 patients treated in these studies, 620 patients received the higher-dose ELLENCE regimen (FEC-100/CEF-120), 280 patients received the lower-dose ELLENCE regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant adverse reactions are summarized in Table 1. Table 1. Adverse Reactions 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 FEC & CEF = cyclophosphamide + ELLENCE + 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. Hematologic Leukopenia 80 59 50 1.5 98 60 Neutropenia 80 67 54 11 96 78 Anemia 72 6 13 0 71 0.9 Thrombocytopenia 49 5 4.6 0 51 3.6 Endocrine Amenorrhea 72 0 69 0 68 0 Hot flashes 39 4 5 0 69 6 Body as a Whole Lethargy 46 1.9 1.1 0 73 0.3 Fever 5 0 1.4 0 4.5 0 Gastrointestinal Nausea/vomiting 92 25 83 22 85 6 Mucositis 59 9 9 0 53 1.9 Diarrhea 25 0.8 7 0 51 2.8 Anorexia 2.9 0 1.8 0 6 0.3 Infection Infection 22 1.6 15 0 26 0.6 Febrile neutropenia NA 6 0 0 NA 1.1 Ocular Conjunctivitis/keratitis 15 0 1.1 0 38 0 Skin Alopecia 96 57 70 19 84 7 Local toxicity 20 0.3 2.5 0.4 8 0 Rash/itch 9 0.3 1.4 0 14 0 Skin changes 4.7 0 0.7 0 7 0 Delayed Events Table 2 describes the incidence of delayed adverse reactions in patients participating in the MA-5 and GFEA-05 trials. Table 2. Long-Term Adverse Reactions in Patients with Early Breast Cancer Event % of Patients FEC-100/CEF-120 (N=620) FEC-50 (N=280) CMF (N=360) Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving ELLENCE. However, an association between anthracyclines such as ELLENCE and ALL has not been clearly established. Cardiac events Asymptomatic drops in LVEF 2.1 In study MA-5, cardiac function was not monitored after 5 years. 1.4 0.8 CHF 1.5 0.4 0.3 Leukemia AML 0.8 0 0.3 Hematologic Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with ELLENCE 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, ELLENCE 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 ELLENCE [see Warnings and Precautions (5.4) ]. Gastrointestinal A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with ELLENCE. 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 Dosage and Administration (2.1) ] . 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 ELLENCE; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock. Cardiovascular Serious drug-related cardiovascular adverse events that occurred during clinical trials with ELLENCE, administered in different indications, include ventricular tachycardia, AV block, bundle branch block, bradycardia and thromboembolism. Secondary Leukemia An analysis of 7110 patients who received adjuvant treatment with ELLENCE 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 ELLENCE cumulative doses as shown in Figure 2. Figure 2. Risk of AML/MDS in 7110 Patients Treated with ELLENCE 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 ELLENCE (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 ELLENCE 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 ELLENCE Cumulative Dose ≤720 mg/m 2 N=4760 ELLENCE Cumulative Dose >720 mg/m 2 N=111 ELLENCE Cumulative Dose ≤720 mg/m 2 N=890 ELLENCE 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) Figure 2 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ELLENCE. 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, hemorrhage, 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)

• Avoid using cardiotoxic agents in combination with ELLENCE ( 7.1 ). • Discontinue cimetidine during treatment with ELLENCE ( 7.2 ). 7.1 Cardiotoxic Agents Closely monitor cardiac function when ELLENCE is used in combination with other cardiotoxic agents. Patients receiving ELLENCE after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may be at an increased risk of developing cardiotoxicity [see Dosage and Administration (2) and Warnings and Precautions (5.1) ] . Trastuzumab may persist in the circulation for up to 7 months. Therefore, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. Monitor the patient's cardiac function closely if anthracyclines are used before this time. Concomitant use of ELLENCE 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) ]. Discontinue cimetidine during treatment with ELLENCE. 7.3 Other Cytotoxic Drugs ELLENCE 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 ELLENCE. In adjuvant trials of ELLENCE-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 ELLENCE-based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of ELLENCE with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of ELLENCE after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.

Store refrigerated between 2°C and 8°C (36°F and 46°F). Do not freeze. Protect from light. 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 (15–25°C). Solution for injection should be used within 24 hours after removal from refrigeration. ELLENCE is a hazardous drug. Follow applicable special handling and disposal procedures 1 [see References (15) ].