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/m² regimen of ELLENCE should receive prophylactic antibiotic therapy.

The recommended dose of ELLENCE is 100 to 120 mg/m² administered as an intravenous bolus [see Dosage and Administration (2.4)].

The following regimens are recommended:

CEF-120:	Cyclophosphamide	75 mg/m2 oral on Days 1 to 14
	ELLENCE	60 mg/m2 intravenously on Days 1 and 8
	5-Fluorouracil	500 mg/m2 intravenously on Days 1 and 8
	Repeat every 28 days for 6 cycles
FEC-100:	5-Fluorouracil	500 mg/m2 intravenously on Day 1
	ELLENCE	100 mg/m2 intravenously on Day 1
	Cyclophosphamide	500 mg/m2 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.

ELLENCE 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 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/mm³, ANC ≥1500/mm³, and nonhematologic toxicities have recovered to ≤ Grade 1.

ELLENCE and other anthracycline drugs can result in either early (or acute) or late (delayed) cardiac toxicity.

The principal manifestations of early cardiac toxicity are sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. However, tachycardia (including premature ventricular contractions and ventricular tachycardia), bradycardia, as well as atrioventricular and bundle-branch block have been reported. Early cardiac toxicity does not usually predict the subsequent occurrence of delayed cardiotoxicity and generally should not be considered a reason for suspending treatment with ELLENCE.

Delayed cardiac toxicity is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF). If it occurs, late cardiotoxicity usually develops late during therapy with ELLENCE or within 2 to 3 months after completion of treatment, but there are reports of it occurring several months to years after treatment termination. In a retrospective survey, including 9144 patients, mostly with solid tumors in advanced stages, the probability of developing CHF increased with increasing cumulative doses of ELLENCE (Figure 1). In another retrospective survey of 469 ELLENCE-treated patients with metastatic or early breast cancer, the reported risk of CHF was comparable to that observed in the larger study of over 9000 patients.

Given the risk of cardiac toxicity, cumulative doses of 900 mg/m² ELLENCE should generally be avoided.

•   Figure 1. Risk of CHF in 9144 Patients Treated with ELLENCE

Prior history of cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, and concomitant use of other cardiotoxic drugs, increase the risk of developing late cardiac toxicity. Avoid administration of ELLENCE in combination with other cardiotoxic drugs. Although not formally tested, it is probable that the toxicity of ELLENCE and other anthracyclines or anthracenediones is additive. Cardiac toxicity with ELLENCE may occur at lower cumulative doses whether or not cardiac risk factors are present. Patients receiving ELLENCE after stopping treatment with other cardiotoxic drugs, especially those with long half-lives such as trastuzumab, may be at increased risk of developing cardiotoxicity [see Dosage and Administration (2) and Drug Interaction (7.1)].

Perform a baseline ECG and evaluation of LVEF prior to initiating treatment with ELLENCE. Monitor LVEF during the course of treatment and consider discontinuation of ELLENCE if LVEF decrease and/or signs or symptoms of CHF develop. Closely monitor patients with other risk factors for cardiac toxicity, particularly prior administration of anthracycline or anthracenedione.

The risk of developing secondary acute myelogenous leukemia and myelodysplastic syndrome (MDS), is increased following treatment with ELLENCE and other anthracyclines. Cumulative risk of secondary acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) of about 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years. These leukemias generally occur within 1 to 3 years of treatment [see Adverse Reactions (6.1)].

Extravasation of ELLENCE can result in severe local tissue injury manifesting as blistering, ulceration, and necrosis requiring wide excision of the affected area and skin grafting. Extravasation should be considered if a patient experiences a burning or stinging sensation or shows other evidence indicating peri-venous infiltration or extravasation; however, extravasation may be present in patients who do not experience a stinging or burning sensation or when blood return is present on aspiration of the infusion needle.

Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Administer ELLENCE slowly into the tubing of a freely running intravenous infusion. Patients receiving initial therapy at the recommended starting doses of 100–120 mg/m² should 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 [see Dosage and Administration (2.3)]. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. 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.

Immediately terminate infusion and restart in another vein if a burning or stinging sensation indicates perivenous infiltration. Perivenous infiltration may occur without causing pain. If extravasation is suspected, immediately discontinue the intravenous injection or continuous intravenous infusion [see Dosage and Administration (2.3)]. Apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. If appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation.

ELLENCE can cause severe myelosuppression [see Adverse Reactions (6.1) . Obtain complete blood counts prior to each treatment and carefully monitor patients during treatment for possible clinical complications due to myelosuppression. Delay the next dose of ELLENCE if severe myelosuppression has not improved. Consider dose reduction for patients with prolonged myelosuppression based on the severity of reaction [see Dosage and Administration (2.3)].

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 ELLENCE. 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 ELLENCE in this patient population [see Contraindications (4)].

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) and Clinical Pharmacology (12.3)]. Patients undergoing dialysis have not been studied.

ELLENCE can induce tumor lysis syndrome in patients with rapidly growing tumors. Evaluate blood uric acid levels, potassium, calcium, phosphate, and creatinine after initial treatment. Consider hydration, urine alkalinization, and prophylaxis with allopurinol to minimize hyperuricemia and potential complications of tumor lysis syndrome.

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 ELLENCE. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Thrombophlebitis and thromboembolic events, including pulmonary embolism (in some cases fatal) have been reported with the use of ELLENCE.

ELLENCE can increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver. Radiation recall, including but not limited to cutaneous and pulmonary toxicity, can occur in patients who receive ELLENCE after prior radiation therapy.

•  Based on findings from animals and its mechanism of action, ELLENCE can cause fetal harm when administered to a pregnant woman; avoid the use of ELLENCE during the 1^st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of epirubicin during the 2^nd and 3^rd trimesters. In animal reproduction studies, epirubicin was embryo-fetal lethal and caused structural abnormalities in rats and rabbits at doses less than the maximum recommended human dose on a body surface area basis. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of ELLENCE. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ELLENCE. Advise male patients with pregnant partners to use condoms during treatment and for at least 7 days after the last dose of ELLENCE [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1), and Nonclinical Toxicology (13.1)].

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

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)

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.

Cimetidine increases the exposure to epirubicin [see Clinical Pharmacology (12.3)]. Discontinue cimetidine during treatment with ELLENCE.

ELLENCE used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects.

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.

Safety and effectiveness of ELLENCE have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity or late cardiovascular dysfunction. The pharmacokinetics of epirubicin in pediatric patients have not been evaluated.

Clinical experience in patients who were 65 years of age and older who received ELLENCE chemotherapy regimens for primary breast cancer showed no overall differences in safety and effectiveness compared with younger patients.

In elderly female patients, closely monitor for increased toxicity due to the risk of decreased clearance of epirubicin [see Clinical Pharmacology (12.3)].

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 ELLENCE [see Contraindications (4)]. Reduce the starting dose for patients with less severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

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 (2.3) and Clinical Pharmacology (12.3)]. Patients on dialysis have not been studied.

Epirubicin is an anthracycline cytotoxic agent. Although it is known that anthracyclines can interfere with a number of biochemical and biological functions within eukaryotic cells, the precise mechanisms of epirubicin's cytotoxic and/or antiproliferative properties have not been completely elucidated.

Epirubicin forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs, with consequent inhibition of nucleic acid (DNA and RNA) and protein synthesis.

Such intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase activity, preventing the enzymatic separation of double-stranded DNA and interfering with replication and transcription. Epirubicin is also involved in oxidation/reduction reactions by generating cytotoxic free radicals. The antiproliferative and cytotoxic activity of epirubicin is thought to result from these or other possible mechanisms.

Epirubicin is cytotoxic in vitro to a variety of established murine and human cell lines and primary cultures of human tumors. It is also active in vivo against a variety of murine tumors and human xenografts in athymic mice, including breast tumors.

Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m² and plasma clearance is not affected by the duration of infusion or administration schedule. Pharmacokinetic parameters for epirubicin following 6- to 10-minute, single-dose intravenous infusions of ELLENCE at doses of 60 to 150 mg/m² in patients with solid tumors are shown in Table 4. The plasma concentration declined in a triphasic manner with mean half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours, and 33 hours, respectively.

Table 4. Summary of Mean (±SD) Pharmacokinetic Parameters in Patients Advanced solid tumor cancers, primarily of the lung with Solid Tumors Receiving Intravenous ELLENCE 60 to 150 mg/m²

Dose N=6 patients per dose level (mg/m2 )	Cmax Plasma concentration at the end of 6 to 10 minutes infusion (µg/mL)	AUC Area under the plasma concentration curve (µg∙h/mL)	t1/2 Half-life of terminal phase (hours)	CL Plasma clearance (L/hour)	Vss Steady state volume of distribution (L/kg)
60	5.7 ± 1.6	1.6 ± 0.2	35.3 ± 9	65 ± 8	21 ± 2
75	5.3 ± 1.5	1.7 ± 0.3	32.1 ± 5	83 ± 14	27 ± 11
120	9.0 ± 3.5	3.4 ± 0.7	33.7 ± 4	65 ± 13	23 ± 7
150	9.3 ± 2.9	4.2 ± 0.8	31.1 ± 6	69 ± 13	21 ± 7

Conventional long-term animal studies to evaluate the carcinogenic potential of epirubicin have not been conducted, but intravenous administration of a single 3.6 mg/kg epirubicin dose to female rats (about 0.2 times the maximum recommended human dose on a body surface area basis) approximately doubled the incidence of mammary tumors (primarily fibroadenomas) observed at 1 year. Administration of 0.5 mg/kg epirubicin intravenously to rats (about 0.025 times the maximum recommended human dose on a body surface area basis) every 3 weeks for ten doses increased the incidence of subcutaneous fibromas in males over an 18-month observation period. In addition, subcutaneous administration of 0.75 or 1.0 mg/kg/day (about 0.015 times the maximum recommended human dose on a body surface area basis) to newborn rats for 4 days on both the first and tenth day after birth for a total of eight doses increased the incidence of animals with tumors compared to controls during a 24-month observation period.

Epirubicin was mutagenic in vitro to bacteria (Ames test) either in the presence or absence of metabolic activation and to mammalian cells (HGPRT assay in V79 Chinese hamster lung fibroblasts) in the absence but not in the presence of metabolic activation. Epirubicin was clastogenic in vitro (chromosome aberrations in human lymphocytes) both in the presence and absence of metabolic activation and was also clastogenic in vivo (chromosome aberration in mouse bone marrow).

In fertility studies in rats, males were given epirubicin daily for 9 weeks and mated with females that were given epirubicin daily for 2 weeks prior to mating and through Day 7 of gestation. When 0.3 mg/kg/day (about 0.015 times the maximum recommended human single dose on a body surface area basis) was administered to both sexes, no pregnancies resulted. No effects on mating behavior or fertility were observed at 0.1 mg/kg/day, but male rats had atrophy of the testes and epididymis, and reduced spermatogenesis. The 0.1 mg/kg/day dose also caused embryolethality. An increased incidence of fetal growth retardation was observed in these studies at 0.03 mg/kg/day (about 0.0015 times the maximum recommended human single dose on a body surface area basis). Multiple daily doses of epirubicin to rabbits and dogs also caused atrophy of male reproductive organs. Single 20.5 and 12 mg/kg doses of intravenous epirubicin caused testicular atrophy in mice and rats, respectively (both approximately 0.5 times the maximum recommended human dose on a body surface area basis). A single dose of 16.7 mg/kg epirubicin caused uterine atrophy in rats.

Two randomized, open-label, multicenter studies evaluated the use of ELLENCE 100 to 120 mg/m² in combination with cyclophosphamide and fluorouracil for the adjuvant treatment of patients with axillary-node positive breast cancer and no evidence of distant metastatic disease (Stage II or III). Study MA-5 evaluated 120 mg/m² of ELLENCE per course in combination with cyclophosphamide and fluorouracil (CEF-120 regimen). This study randomized premenopausal and perimenopausal women with one or more positive lymph nodes to an ELLENCE-containing CEF-120 regimen or to a CMF regimen. Study GFEA-05 evaluated the use of 100 mg/m² of ELLENCE per course in combination with fluorouracil and cyclophosphamide (FEC-100). This study randomized pre- and postmenopausal women to the FEC-100 regimen or to a lower-dose FEC-50 regimen. In the GFEA-05 study, eligible patients were either required to have ≥ 4 nodes involved with tumor or, if only 1 to 3 nodes were positive, to have negative estrogen- and progesterone-receptors and a histologic tumor grade of 2 or 3. A total of 1281 women participated in these studies. Patients with T4 tumors were not eligible for either study. Table 5 shows the treatment regimens that the patients received. Relapse-free survival was defined as time to occurrence of a local, regional, or distant recurrence, or disease-related death. Patients with contralateral breast cancer, second primary malignancy, or death from causes other than breast cancer were censored at the time of the last visit prior to these events.

Table 5. Treatment Regimens Used in Phase 3 Studies of Patients with Early Breast Cancer

	Treatment Groups	Agent	Regimen
MA-5In women who underwent lumpectomy, breast irradiation was to be administered after completion of study chemotherapy. N=716	CEF-120 (total, 6 cycles)Patients also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole or fluoroquinolone for the duration of their chemotherapy. N=356 CMF (total, 6 cycles) N=360	Cyclophosphamide ELLENCE Fluorouracil Cyclophosphamide Methotrexate Fluorouracil	75 mg/m2 PO, d 1–14, q 28 days 60 mg/m2 IV, d 1 & 8, q 28 days 500 mg/m2 IV, d 1 & 8, q 28 days 100 mg/m2 PO, d 1–14, q 28 days 40 mg/m2 IV, d 1 & 8, q 28 days 600 mg/m2 IV, d 1 & 8, q 28 days
GFEA-05All women were to receive breast irradiation after the completion of chemotherapy. N=565	FEC-100 (total, 6 cycles) N=276 FEC-50 (total, 6 cycles) N=289 Tamoxifen 30 mg daily × 3 years, postmenopausal women, any receptor status	Fluorouracil ELLENCE Cyclophosphamide Fluorouracil ELLENCE Cyclophosphamide	500 mg/m2 IV, d 1, q 21 days 100 mg/m2 IV, d 1, q 21 days 500 mg/m2 IV, d 1, q 21 days 500 mg/m2 IV, d 1, q 21 days 50 mg/m2 IV, d 1, q 21 days 500 mg/m2 IV, d 1, q 21 days

In the MA-5 trial, the median age of the study population was 45 years. Approximately 60% of patients had 1 to 3 involved nodes and approximately 40% had ≥ 4 nodes involved with tumor. In the GFEA-05 study, the median age was 51 years and approximately half of the patients were postmenopausal. About 17% of the study population had 1 to 3 positive nodes and 80% of patients had ≥ 4 involved lymph nodes. Demographic and tumor characteristics were well-balanced between treatment arms in each study.

Relapse-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods in the intent-to-treat (ITT) patient populations in each study. Results were initially analyzed after up to 5 years of follow-up and these results are presented in the text below and in Table 6. Results after up to 10 years of follow-up are presented in Table 6. In Study MA-5, ELLENCE-containing combination therapy (CEF-120) showed significantly longer RFS than CMF (5-year estimates were 62% versus 53%, stratified logrank for the overall RFS p=0.013). The estimated reduction in the risk of relapse was 24% at 5 years. The OS was also greater for the ELLENCE-containing CEF-120 regimen than for the CMF regimen (5-year estimate 77% versus 70%; stratified logrank for overall survival p=0.043; non-stratified logrank p=0.13). The estimated reduction in the risk of death was 29% at 5 years.

In Study GFEA-05, patients treated with the higher-dose ELLENCE regimen (FEC-100) had a significantly longer 5-year RFS (estimated 65% versus 52%, logrank for the overall RFS p=0.007) and OS (estimated 76% versus 65%, logrank for the overall survival p=0.007) than patients given the lower dose regimen (FEC-50). The estimated reduction in risk of relapse was 32% at 5 years. The estimated reduction in the risk of death was 31% at 5 years. Results of follow-up up to 10 years (median follow-up = 8.8 years and 8.3 years, respectively, for Study MA-5 and Study GFEA-05) are presented in Table 6.

Although the trials were not powered for subgroup analyses, in the MA-5 study, improvements in favor of CEF-120 vs. CMF were observed, in RFS and OS both in patients with 1–3 node positive and in those with ≥4 node positive tumor involvement. In the GFEA-05 study, improvements in RFS and OS were observed in both pre-and postmenopausal women treated with FEC-100 compared to FEC-50.

Table 6. Efficacy Results from Phase 3 Studies of Patients with Early Breast CancerBased on Kaplan-Meier estimates

	MA-5 Study		GFEA-05 Study
	CEF-120 N=356	CMF N=360	FEC-100 N=276	FEC-50 N=289
RFS at 5 yrs (%)	62	53	65	52
Hazard ratioHazard ratio: CMF:CEF-120 in MA-5, FEC-50:FEC-100 in GFEA-05	0.76		0.68
2-sided 95% CI	(0.60, 0.96)		(0.52, 0.89)
Logrank Test stratifiedPatients in MA-5 were stratified by nodal status (1–3, 4–10, and >10 positive nodes), type of initial surgery (lumpectomy versus mastectomy), and by hormone receptor status (ER or PR positive (≥10 fmol), both negative (<10 fmol), or unknown status). Patients in GFEA-05 were stratified by nodal status (1–3, 4–10, and >10 positive nodes).	(p = 0.013)		(p = 0.007)
OS at 5 yrs (%)	77	70	76	65
Hazard ratio	0.71		0.69
2-sided 95% CI	(0.52, 0.98)		(0.51, 0.92)
Logrank Test stratified	(p = 0.043)		(p = 0.007)
	(unstratified p = 0.13)
RFS at 10 yrs (%)	51	44	49	43
Hazard ratio	0.78		0.78
2-sided 95% CI	(0.63, 0.95)		(0.62, 0.99)
Logrank Test stratified	(p = 0.017)		(p = 0.040)
	(unstratified p = 0.023)		(unstratified p = 0.09)
OS at 10 yrs (%)	61	57	56	50
Hazard ratio	0.82		0.75
2-sided 95% CI	(0.65, 1.04)		(0.58, 0.96)
Logrank Test stratified	(p = 0.100)		(p = 0.023)
	(unstratified p = 0.18)		(unstratified p = 0.039)

The Kaplan-Meier curves for RFS and OS from Study MA-5 are shown in Figures 3 and 4 and those for Study GFEA-05 are shown in Figures 5 and 6.

•   Figure 3. Relapse-Free Survival in Study MA-5

•   Figure 4. Overall Survival in Study MA-5

•   Figure 5. Relapse-Free Survival in Study GFEA-05

•   Figure 6. Overall Survival in Study GFEA-05

Discard unused portion.

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 cytotoxic drug. Follow applicable special handling and disposal procedures¹ [see References (15)].

Cardiac Toxicity

Inform patients that there is a risk of irreversible myocardial damage associated with treatment with ELLENCE. Advise patients to immediately contact their healthcare provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions (5.1)].

Secondary Malignancies

Inform patients that there is an increased risk of treatment-related leukemia from ELLENCE [see Warnings and Precautions (5.2)].

Extravasation and Tissue Necrosis

Inform patients that ELLENCE can cause severe injection site reactions. Advise patients to contact a healthcare provider if injection site pain occurs after receiving ELLENCE [see Warnings and Precautions (5.3)].

Severe Myelosuppression

Inform patients that ELLENCE can cause leukopenia, thrombocytopenia, or anemia. Advise patients to contact a healthcare provider for new onset fever or symptoms of infection [see Warnings and Precautions (5.4)].

Nausea and Vomiting

Inform patients that ELLENCE can cause nausea or vomiting. Advise patients to contact a healthcare provider should they develop any severe symptoms [see Adverse Reactions (6.1)].

Common Adverse Reactions

Inform patients of the expected adverse effects of ELLENCE, including diarrhea, stomatitis, and alopecia [see Adverse Reactions (6.1)].

Red Coloration of Urine

Advise patients that their urine may appear red for 1 to 2 days after administration of ELLENCE and that they should not be alarmed [see Adverse Reactions (6.2)].

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus, and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].
• Advise female patients of reproductive potential to use effective contraception during treatment with ELLENCE and for 6 months after the last dose [see Warnings and Precautions (5.11) and Use in Specific Populations (8.3)].
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ELLENCE. Advise male patients with pregnant partners to use condoms during treatment and for at least 7 days after the last dose of ELLENCE [see Use in Specific Populations (8.3)].

Lactation

Advise female patients not to breastfeed during treatment with ELLENCE and for at least 7 days after the last dose [see Use in Specific Populations (8.2)].

Infertility

Women treated with ELLENCE may develop irreversible amenorrhea, or premature menopause. Advise patients that ELLENCE may impair female and male fertility [see Use in Specific Populations (8.3)].