DailyMed Label: eribulin mesylate

DailyMed Label: eribulin mesylate

2024

DailyMed Prescription

eribulin mesylate

eribulin mesylate

Apotex Corp.

NDC: 60505-6289

NDC: 60505-6289

NDC: 60505-6289

NDC: 60505-6289

Eribulin mesylate injection contains eribulin mesylate, a microtubule dynamics inhibitor. Eribulin mesylate is a synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria okadai . The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano-12,15-methano-9 H ,15 H -furo[3,2- i ]furo[2',3':5,6]pyrano[4,3- b ][1,4]dioxacyclopentacosin-5(4 H )-one,2-[(2 S )-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-(2 R ,3 R ,3a S ,7 R ,8a S ,9 S ,10a R ,11 S ,12 R ,13a R ,13b S ,15 S ,18 S ,21 S ,24 S ,26 R ,28 R ,29a S ),methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C 40 H 59 NO 11 •CH 4 O 3 S. Eribulin mesylate has the following structural formula: Eribulin mesylate injection is a clear, colorless, sterile solution for intravenous administration. Each single-dose vial contains 1 mg of eribulin mesylate in 2 mL of solution. Each mL of solution contains 0.5 mg of eribulin mesylate (equivalent to 0.44 mg eribulin) in dehydrated alcohol (5% v/v) and water for injection (95% v/v). Sodium hydroxide or hydrochloric acid may be used for pH adjustment. eribulin-spl-structure

Eribulin mesylate injection is a microtubule inhibitor indicated for the treatment of patients with: Metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. ( 1.1 ) Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen. ( 1.2 ) Eribulin mesylate injection is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting [see Clinical Studies ( 14.1 )] . Eribulin mesylate injection is indicated for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen [see Clinical Studies ( 14.2 )].

Administer 1.4 mg/m 2 intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. ( 2.1 ) Reduce dose in patients with hepatic impairment or with moderate or severe renal impairment. ( 2.1 ) Do not mix with other drugs or administer with dextrose-containing solutions. ( 2.3 ) The recommended dose of eribulin mesylate injection is 1.4 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. The recommended dose of eribulin mesylate injection in patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations ( 8.6 )] . The recommended dose of eribulin mesylate injection in patients with moderate hepatic impairment (Child-Pugh B) is 0.7 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations ( 8.6 )]. The recommended dose of eribulin mesylate injection in patients with moderate or severe renal impairment (creatinine clearance (CLcr) 15 to 49 mL/min) is 1.1 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations ( 8.7 )]. Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. Recommended dose delays Do not administer eribulin mesylate injection on Day 1 or Day 8 for any of the following: ANC < 1,000/mm 3 Platelets < 75,000/mm 3 Grade 3 or 4 non-hematological toxicities.   The Day 8 dose may be delayed for a maximum of 1 week. If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer eribulin mesylate injection at a reduced dose and initiate the next cycle no sooner than 2 weeks later.     Recommended dose reductions If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume eribulin mesylate injection at a reduced dose as set out in Table 1. Do not re-escalate eribulin mesylate injection dose after it has been reduced. Table 1: Recommended Dose Reductions Event Description Recommended Eribulin Mesylate Injection Dose Permanently reduce the 1.4 mg/m 2 Eribulin Mesylate Injection dose for any of the following:         1.1 mg/m 2     ANC <500/mm 3  for >7 days     ANC <1,000 /mm 3 with fever or infection     Platelets <25,000/mm 3     Platelets <50,000/mm 3 requiring transfusion     Non-hematologic Grade 3 or 4 toxicities   Omission or delay of Day 8 eribulin mesylate injection dose inprevious cycle for toxicity Occurrence  of any event requiring permanent dose reduction while  receiving 1.1 mg/m 2 0.7 mg/m 2 Occurrence  of any event requiring permanent dose reduction whilereceiving 0.7 mg/m 2 Discontinue Eribulin Mesylate Injection ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)  version 3.0. Aseptically withdraw the required amount of eribulin mesylate injection from the single-dose vial and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP.   Do not dilute in or administer through an intravenous line containing solutions with dextrose. Do not administer in the same intravenous line concurrent with the other medicinal products. Store undiluted eribulin mesylate injection in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration at 4°C (40°F). Store diluted solutions of eribulin mesylate injection for up to 4 hours at room temperature or up to 24 hours under refrigeration at 4°C (40°F). Discard unused portions of the vial.

Injection: 1 mg/2 mL (0.5 mg/mL) eribulin mesylate is a clear, colorless, sterile solution in a single-dose vial. Injection: 1 mg per 2 mL (0.5 mg per mL) eribulin mesylate in a single-dose vial ( 3 )

None. None ( 4 ).

Neutropenia : Monitor peripheral blood cell counts and adjust dose as appropriate. ( 5.1 ) Peripheral Neuropathy : Monitor for signs of neuropathy. Manage with dose delay and adjustment. ( 5.2 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) QT Prolongation : Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid in patients with congenital long QT syndrome. ( 5.4 ) In Study 1, severe neutropenia (ANC < 500/mm 3 ) lasting more than one week occurred in 12% (62/503) of patients with metastatic breast cancer, leading to discontinuation in <1% of patients. Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia [see Adverse Reactions ( 6.1 )] . In Study 1, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia. In Study 2, severe neutropenia (ANC < 500/mm 3 ) lasting more than one week occurred in 12% (26/222) of patients with liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 0.9% of patients treated with eribulin mesylate and fatal neutropenic sepsis in 0.9% [see Adverse Reactions ( 6.1 )] . Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of eribulin mesylate and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days [see Dosage and Administration ( 2.2 )] . Clinical studies of eribulin mesylate did not include patients with baseline neutrophil counts below 1,500/mm 3 . In Study 1, Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients with metastatic breast cancer (MBC). Peripheral neuropathy was the most common toxicity leading to discontinuation of eribulin mesylate (5% of patients; 24/503) in Study 1. Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25 to 662 days). In Study 2, Grade 3 peripheral neuropathy occurred in 3.1% (7/223) of eribulin mesylate -treated patients. Peripheral neuropathy led to discontinuation of eribulin mesylate in 0.9% of patients. The median time to first occurrence of peripheral neuropathy of any severity was 5 months (range: 3.5 months to 9 months). Neuropathy lasting more than 60 days occurred in 58% (38/65) of patients. Sixty three percent (41/65) had not recovered within a median follow-up duration of 6.4 months (range: 27 days to 29 months). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold eribulin mesylate in patients who experience Grade 3 or 4 peripheral neuropathy, until resolution to Grade 2 or less [see Dosage and Administration ( 2.2 )] . Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of eribulin mesylate in pregnant women. In animal reproduction studies, eribulin mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis at doses below the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with eribulin mesylate and for at least 2 weeks following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with eribulin mesylate and for 3.5 months following the final dose [see Use in Specific Populations ( 8.1 )] . In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating eribulin mesylate and monitor these electrolytes periodically during therapy. Avoid eribulin mesylate in patients with congenital long QT syndrome.

The most common adverse reactions (≥25%) in metastatic breast cancer were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. (

No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not observed in patients with advanced solid tumors when eribulin mesylate was administered with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when eribulin mesylate was administered with or without rifampin (a CYP3A4 inducer) [see Clinical Pharmacology ( 12.3 )]. Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes [see Clinical Pharmacology ( 12.3 )].

Lactation: Do not breastfeed. ( 8.2 ) Hepatic Impairment: A lower starting dose is recommended for patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh C) were not studied. ( 8.6 ) Renal Impairment: A lower starting dose is recommended for patients with moderate (CLcr 30 to 49 mL/min) or severe (CLcr 15 to 29 mL/min) renal impairment. ( 8.7 ) Risk Summary Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on the use of eribulin mesylate during pregnancy. In an animal reproduction study, eribulin mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis at doses below the recommended human dose [see Data] . Advise pregnant women of the potential risk to a fetus. The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area. Increased abortion and severe fetal external or soft tissue malformations, including the absence of a lower jaw and tongue, or stomach and spleen, were observed at doses 0.64 times the recommended human dose of 1.4 mg/m 2  based on body surface area. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at doses at or above a maternally toxic dose of approximately 0.43 times the recommended human dose. Risk Summary There is no information regarding the presence of eribulin mesylate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. No lactation studies in animals were conducted. Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with eribulin mesylate and for 2 weeks after the final dose. Contraception   Females Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with eribulin mesylate and for at least 2 weeks following the final dose . Males Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with eribulin mesylate and for 3.5 months following the final dose. Infertility   Males Based on animal data, eribulin mesylate may result in damage to male reproductive tissues leading to impaired fertility of unknown duration [see Nonclinical Toxicology ( 13.1 )]. The safety and effectiveness of eribulin mesylate in pediatric patients have not been established. Pediatric use information describing clinical studies in which efficacy was not demonstrated is approved for Eisai Inc’s HALAVEN ® (eribulin mesylate) injection. However, due to Eisai Inc’s marketing exclusivity rights, this drug product is not labeled with that information. Study 1 did not include sufficient numbers of subjects with metastatic breast cancer aged 65 years and older to determine whether they respond differently from younger subjects. Of the 827 subjects who received the recommended dose and schedule of eribulin mesylate in clinical studies with advanced breast cancer, 15% (121/827) were 65 and older, and 2% (17/827) patients were 75 and older. No overall differences in safety were observed between these subjects and younger subjects. Clinical studies of eribulin mesylate did not include a sufficient number of subjects in Study 2 aged 65 years and older to determine whether they respond differently from younger subjects. Administration of eribulin mesylate at a dose of 1.1 mg/m 2 to patients with mild hepatic impairment and 0.7 mg/m 2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m 2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m 2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m 2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). Eribulin mesylate was not studied in patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration ( 2.1 ), Clinical Pharmacology (12.3)]. For patients with moderate or severe renal impairment (CLcr 15 to 49 mL/min), reduce the starting dose to 1.1 mg/m 2 [see Dosage and Administration ( 2.1 ), Clinical Pharmacology (12.3)].

NDC 60505-6289-0 Eribulin Mesylate Injection : 1 mg/2 mL (0.5 mg/mL) single-dose vial. Discard unused portion. One vial per carton. Eribulin mesylate injection is a clear, colorless solution. Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86° F). Do not freeze or refrigerate. Store the vials in their original cartons. Eribulin mesylate injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G 2 /M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. In addition, eribulin treatment of human breast cancer cells caused changes in morphology and gene expression as well as decreased migration and invasiveness in vitro . In mouse xenograft models of human breast cancer, eribulin treatment was associated with increased vascular perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype. Cardiac Electrophysiology The effect of eribulin mesylate on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m 2 of eribulin mesylate on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms. The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m 2 to 114 L/m 2 and mean clearance of 1.16 L/hr/m 2 to 2.42 L/hr/m 2 over the dose range of 0.25 mg/m 2 to 4.0 mg/m 2 . The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65%. Eribulin exposure after multiple dosing is comparable to that following a single dose. No accumulation of eribulin is observed with weekly administration. Elimination   Metabolism Unchanged eribulin was the major circulating species in plasma following administration of 14 C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin. Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro .   Excretion   Eribulin is eliminated primarily in feces unchanged. After administration of 14 C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin accounted for approximately 88% and 91% of total eribulin in feces and urine, respectively.   Specific Populations   Age, Sex, and Race/Ethnicity: Based on a population pharmacokinetic analysis, no clinically meaningful differences in the pharmacokinetics of eribulin were observed based on age, sex, or race. Hepatic Impairment In a study evaluating the effect of hepatic impairment on the PK of eribulin, eribulin exposures increased by 1.8-fold in patients with mild hepatic impairment (Child-Pugh A; n=7) and by 2.5-fold in patients with moderate (Child-Pugh B; n=5) hepatic impairment as compared to patients with normal hepatic function (n=6). Administration of eribulin mesylate at a dose of 1.1 mg/m 2 to patients with mild hepatic impairment and 0.7 mg/m 2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin at a dose of 1.4 mg/m 2 to patients with normal hepatic function [see Dosage and Administration ( 2.1 ), Use in Specific Populations (8.6)].   Renal Impairment In a study evaluating the effect of renal impairment on the PK of eribulin, patients with moderate (CLcr 30 to 49 mL/min; n=7) and severe renal impairment (CLcr 15 to 29 mL/min; n=6) had 1.5-fold higher eribulin dose-normalized exposures compared to that in patients with normal renal function (CLcr ≥ 80 mL/min; n=6). There were no clinically meaningful changes in patients with mild renal impairment (CLcr 50 to 79 mL/min; n=27) [see Dosage and Administration ( 2.1 ), Use in Specific Populations (8.7)].   Drug Interaction Studies   Effect of Strong Inhibitors or Inducers of CYP3A4 on Eribulin: The effect of a strong CYP3A4 inhibitor and a P-gp inhibitor, ketoconazole, on the PK of eribulin was studied in a crossover trial of 12 patients with advanced solid tumors. No clinically relevant PK interaction was observed when eribulin mesylate was administered with or without ketoconazole (the geometric mean ratio of the AUC: 0.97; 90% CI: 0.83, 1.12). The effect of a CYP3A4 inducer, rifampin, on the PK of eribulin was studied in a crossover trial of 14 patients with advanced solid tumors. No clinically relevant PK interaction was observed when eribulin mesylate was administered with or without rifampin (the geometric mean ratio of the AUC: 1.10; 90 CI%: 0.91, 1.34). Effect of Eribulin on CYP Substrates: Eribulin shows no induction potential for CYP1A, CYP2B6, CYP2C9, CYP2C19, and CYP3A in primary human hepatocytes. Eribulin inhibits CYP3A4 activity in human liver microsomes, but it is unlikely that eribulin will substantially increase the plasma levels of CYP3A4 substrates. No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 was detected with eribulin concentrations up to 5 μM in pooled human liver microsomes. In vitro drug interaction studies indicate that eribulin does not inhibit drugs that are substrates of these enzymes and it is unlikely that eribulin will affect plasma levels of drugs that are substrates of CYP enzymes. Effect of Transporters on Eribulin : In vitro data suggest that eribulin at clinically relevant concentrations is a substrate of P-gp, but is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance proteins (MRP2, MRP4), bile salt extrusion pump (BSEP), organic anion transporting polypeptides (OATP1B1, OATP1B3), organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1, OCT2), or multidrug and toxin extrusion 1 (MATE1). Effect of Eribulin on Transporters: In vitro data suggest that eribulin at clinically relevant concentrations may inhibit P-gp, but does not inhibit BCRP, OATP1B1, OCT1, OAT1, OAT3, or MATE1.

Carcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay. Fertility studies have not been conducted with eribulin mesylate in humans or animals; however, nonclinical findings in repeat-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (based on body surface area) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (based on body surface area) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (based on body surface area) weekly for 3 out of 5 weeks, repeated for 6 cycles.

Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast cancer who received at least two chemotherapeutic regimens for the treatment of metastatic disease and experienced disease progression within 6 months of their last chemotherapeutic regimen. Patients were required to receive prior anthracycline- and taxane-based chemotherapy for adjuvant or metastatic disease. Patients were randomized (2:1) to receive eribulin mesylate (n=508) or a single agent therapy selected prior to randomization (control arm, n=254). Randomization was stratified by geographic region, HER2/ neu status, and prior capecitabine exposure. Eribulin mesylate was administered at a dose of 1.4 mg/m 2 on Days 1 and 8 of a 21-day cycle. Eribulin mesylate -treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal therapy. The main efficacy outcome was overall survival. Patient demographic and baseline characteristics were comparable between the treatment arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients had a baseline ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: 39%), HER2/ neu receptor status (positive: 16%, negative: 74%), triple negative status (ER-,PR-, HER2/ neu - : 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in the eribulin mesylate and control arms. Patients received a median of four prior chemotherapy regimens in both arms. In Study 1, a statistically significant improvement in overall survival was observed in patients randomized to the eribulin mesylate arm compared to the control arm (see Table 5). An updated, unplanned survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent with the primary analysis. In patients randomized to eribulin mesylate , the objective response rate by the RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months (95% CI: 3.8, 5.0 months). Table 5: Comparison of Overall Survival in Eribulin Mesylate and Control Arm – Study 1   Overall Survival Eribulin Mesylate (n=508) Control Arm (n=254) Primary survival analysis Number of deaths 274 148 Median, months (95% CI) 13.1 (11.8, 14.3) 10.6 (9.3, 12.5) Hazard Ratio (95% CI) a 0.81 (0.66, 0.99) P value b 0.041 Updated survival analysis Number of deaths 386 203 Median, months (95% CI) 13.2 (12.1, 14.4) 10.6 (9.2, 12.0) CI = confidence interval a Based on Cox proportional hazards model stratified by geographic region, HER2 status, and prior capecitabine therapy. b Based on a log-rank test stratified by geographic region, HER2 status, and prior capecitabine therapy. Figure 1: Updated Overall Survival Analysis for Study 1 eribulin-spl-fig-1 The efficacy and safety of eribulin mesylate were evaluated in Study 2, an open-label, randomized (1:1), multicenter, active-controlled trial. Eligible patients were required to have unresectable, locally advanced or metastatic liposarcoma or leiomyosarcoma, at least two prior systemic chemotherapies (one of which must have included an anthracycline), and disease progression within 6 months of the most recent chemotherapy regimen. Patients were randomized to eribulin mesylate 1.4 mg/m 2 administered intravenously on Days 1 and 8 of a 21-day cycle or to dacarbazine at a dose of 850 mg/m 2 , 1000 mg/m 2, or 1200 mg/m 2 administered intravenously every 21 days (dacarbazine dose was selected by the investigator prior to randomization). Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified by histology (liposarcoma or leiomyosarcoma), number of prior therapies (2 vs. > 2), and geographic region (U.S. and Canada vs. Western Europe, Australia, and Israel vs. Eastern Europe, Latin America, and Asia). The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were progression-free survival (PFS) and confirmed objective response rate (ORR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Patients in the dacarbazine arm were not offered eribulin mesylate at the time of disease progression. A total of 446 patients were randomized, 225 to the eribulin mesylate arm and 221 to the dacarbazine arm. The median age was 56 years (range: 24 to 83); 33% were male; 73% were White; 44% had ECOG performance status (PS) 0 and 53% had ECOG PS 1; 68% had leiomyosarcoma and 32% had liposarcoma; 39% were enrolled in U.S. and Canada (Region 1) and 46% were enrolled in Western Europe, Australia, and Israel (Region 2); and 47% received more than two prior systemic chemotherapies. The most common (>40%) prior systemic chemotherapies were doxorubicin (90%), ifosfamide (62%), gemcitabine (59%), trabectedin (50%), and docetaxel (48%). Of the 143 patients with liposarcoma, the median age was 55 years (range: 32 to 83); 62% were male, 72% were White; 41% had ECOG PS of 0 and 53% had ECOG PS of 1; 35% were enrolled in Region 1 and 51% were enrolled in Region 2; and 44% received more than two prior systemic chemotherapies. The distribution of subtypes of liposarcoma, based on local histologic assessment, were 45% dedifferentiated, 37% myxoid/round cell, and 18% pleomorphic. Study 2 demonstrated a statistically significant improvement in OS in patients randomized to eribulin mesylate compared with dacarbazine (see Table 6). There was no significant difference in progression-free survival in the overall population. Treatment effects of eribulin mesylate were limited to patients with liposarcoma based on pre-planned, exploratory subgroup analyses of OS and PFS (see Tables 6 and 7 and Figure 2). There was no evidence of efficacy of eribulin mesylate in patients with advanced or metastatic leiomyosarcoma in Study 2 (see Table 7). Table 6: Efficacy Results for the Liposarcoma Stratum and All Patients* in Study 2 a   Liposarcoma Stratum All Patients* Eribulin Mesylate (n=71) Dacarbazine (n=72) Eribulin Mesylate (n=225) Dacarbazine (n=221) Overall survival Deaths, n (%) 52 (73) 63 (88) 173 (77) 179 (81) Median, months (95% CI) 15.6 (10.2, 18.6) 8.4 (5.2, 10.1) 13.5 (11.1, 16.5) 11.3 (9.5, 12.6) Hazard ratio (HR) (95% CI) 0.51 (0.35, 0.75) 0.75 (0.61, 0.94) Stratified log-rank p value N/A † 0.011 Progression-free survival Events, n (%) 57 (80) 59 (82) 194 (86) 185 (84) Disease progression 53 52 180 170 Death 4 7 14 15 Median, months (95% CI) 2.9 (2.6, 4.8) 1.7 (1.4, 2.6) 2.6 (2.0, 2.8) 2.6 (1.7, 2.7) HR (95% CI) 0.52 (0.35, 0.78) 0.86 (0.69, 1.06) Objective response rate Objective response rate (%) (95% CI) 1.4 (0, 7.6) 0 (0, 4.2) 4.0 (1.8, 7.5) 5.0 (2.5, 8.7) a Efficacy data from one study site enrolling six patients were excluded. * All patients = liposarcoma and leiomyosarcoma. † N/A = not applicable Figure 2: Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2     Table 7: Efficacy Results for the Leiomyosarcoma Stratum in Study 2 a   Leiomyosarcoma Stratum Eribulin Mesylate (n=154) Dacarbazine (n=149) Overall survival Deaths, n (%) 121 (79) 116 (78) Median, months (95% CI) 12.8 (10.3, 14.8) 12.3 (11.0, 15.1) HR (95% CI) 0.90 (0.69, 1.18) Progression-free survival Events, n (%) 137 (89) 126 (85) Disease progression 127 118 Death 10 8 Median, months (95% CI) 2.2 (1.5, 2.7) 2.6 (2.2, 2.9) HR (95% CI) 1.05 (0.81, 1.35) Objective response rate (%) (95% CI) 5.2 (2.3, 10) 7.4 (3.7, 12.8) a Efficacy data from one study site enrolling six patients were excluded. eribulin-spl-fig-2

Carton Label : NDC 60505-6289-0             Rx only Eribulin Mesylate Injection 1 mg/2 mL (0.5 mg/mL) For Intravenous Use STERILE SOLUTION CAUTION: Cytotoxic Agent SINGLE-DOSE VIAL- discard unused portion. DOSAGE AND USE See accompanying prescribing information. 1 x 2 mL Single-Dose Vial Vial Label : NDC 68083-592-01             Rx only Eribulin Mesylate Injection 1 mg/2 mL (0.5 mg/mL) For Intravenous Use SINGLE DOSE VIAL-Discard unused portion eribulin-spl-carton-label eribulin-spl-vial-label