USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Do not breastfeed. (8.2) Hepatic Impairment: 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: lower starting dose is recommended for patients with moderate (CLcr 30-49 mL/min) or severe (CLcr 15-29 mL/min) renal impairment. (8.7) Lactation: Do not breastfeed. (8.2) Hepatic Impairment: 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: lower starting dose is recommended for patients with moderate (CLcr 30-49 mL/min) or severe (CLcr 15-29 mL/min) renal impairment. (8.7) 8.1 Pregnancy Risk Summary Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to 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 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 lower jaw and tongue, or stomach and spleen, were observed at doses 0.64 times the recommended human dose of 1.4 mg/m2 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 maternally toxic dose of approximately 0.43 times the recommended human dose.. 8.2 Lactation 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 weeks after the final dose.. 8.3 Females and Males of Reproductive Potential Contraception FemalesBased on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to 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 weeks following the final dose. MalesBased 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.InfertilityMalesBased 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) ]. 8.4 Pediatric Use. 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 Incs HALAVEN(R) (eribulin mesylate) injection. However, due to Eisai Incs marketing exclusivity rights, this drug product is not labeled with that information.. 8.5 Geriatric Use. Study 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 sufficient number of subjects in Study aged 65 years and older to determine whether they respond differently from younger subjects.. 8.6 Hepatic Impairment. Administration of eribulin mesylate at dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 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) . 8.7 Renal Impairment. For patients with moderate or severe renal impairment (CLcr 15-49 mL/min), reduce the starting dose to 1.1 mg/m2 [see Dosage and Administration (2.1) Clinical Pharmacology (12.3).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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). 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). 5.1 Neutropenia In Study 1, severe neutropenia (ANC 500/mm3) 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 >=38.5C with Grade or 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 higher incidence of Grade neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin 1.5 ULN also had higher incidence of Grade neutropenia and febrile neutropenia.In Study 2, severe neutropenia (ANC 500/mm3) 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 or cytopenias. Delay administration of eribulin mesylate and reduce subsequent doses in patients who experience febrile neutropenia or Grade neutropenia lasting longer than days see Dosage and Administration (2.2) ]. Clinical studies of eribulin mesylate did not include patients with baseline neutrophil counts below 1,500/mm3.. 5.2 Peripheral Neuropathy In Study 1, Grade peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 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 new or worsening neuropathy that had not recovered within median follow-up duration of 269 days (range 25-662 days).In Study 2, Grade 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 months (range: 3.5 months to months). Neuropathy lasting more than 60 days occurred in 58% (38/65) of patients. Sixty three percent (41/65) had not recovered within 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 or peripheral neuropathy, until resolution to Grade or less see Dosage and Administration (2.2) ].. 5.3 Embryo-Fetal Toxicity. Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to 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 fetus. Advise females of reproductive potential to use effective contraception during treatment with eribulin mesylate and for at least 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) ].. 5.4 QT Prolongation. 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.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions (>=25%) in metastatic breast cancer were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. (6.1)The most common adverse reactions (>=25%) in liposarcoma and leiomyosarcoma were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common (>=5%) Grade 3-4 laboratory abnormalities in liposarcoma and leiomyosarcoma were neutropenia, hypokalemia, and hypocalcemia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact the WhiteOak Group, LLC at 1-202-316-0138 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, the adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.The following adverse reactions are discussed in detail in other sections of the labeling:Neutropenia see Warnings and Precautions (5.1) Peripheral neuropathy [see Warnings and Precautions (5.2)] QT prolongation [see Warnings and Precautions (5.4) In clinical trials, eribulin mesylate has been administered to 1963 patients including 467 patients exposed to eribulin mesylate for months or longer. The majority of the 1963 patients were women (92%) with median age of 55 years (range: 17 to 85 years). The racial and ethnic distribution was White (72%), Black (4%), Asian (9%), and other (3%).Metastatic Breast CancerThe most common adverse reactions (>=25%) reported in patients receiving eribulin mesylate were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving eribulin mesylate were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of eribulin mesylate was peripheral neuropathy (5%).The adverse reactions described in Table were identified in 750 patients treated in Study [ see Clinical Studies (14.1) ]. In Study 1, patients were randomized (2:1) to receive either eribulin mesylate (1.4 mg/m2on Days and of 21-day cycle) or single agent treatment chosen by their physician (control group). total of 503 patients received eribulin mesylate and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving eribulin mesylate and 63 days for patients receiving control therapy. Table reports the most common adverse reactions occurring in at least 10% of patients in either group.Table 2: Adverse Reactionsa with Per-Patient Incidence of at Least 10% in Study 1Adverse ReactionsEribulin Mesylaten=503Control Groupn=247All Grades>= Grade 3All Grades>= Grade 3Blood and lymphatic system disordersb Neutropenia82%57%53%23% Anemia58%2%55%4%Nervous system disorders Peripheral neuropathyc 35%8%16%2% Headache19%<1%12%<1%General disorders Asthenia/Fatigue54%10%40%11% Pyrexia21%<1%13%<1% Mucosal inflammation9%1%10%2%Gastrointestinal disorders Nausea35%1%28%3% Constipation25%1%21%1% Vomiting18%1%18%1% Diarrhea18%018%0Musculoskeletal and connective tissue disorders Arthralgia/Myalgia22%<1%12%1% Back pain16%1%7%2% Bone pain12%2%9%2% Pain in extremity11%1%10%1%Metabolism and nutrition disorders Decreased weight21%1%14%<1% Anorexia20%1%13%1%Respiratory, thoracic, and mediastinal disorders Dyspnea16%4%13%4% Cough14%09%0Skin and subcutaneous tissue disorders Alopecia45%NAd 10%NAd Infections Urinary Tract Infection10%1%5%0aadverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.0. bbased upon laboratory data. cincludes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. dnot applicable; (grading system does not specify Grade for alopecia).Cytopenias: Grade neutropenia occurred in 28% (143/503) of patients who received eribulin mesylate in Study 1, and 29% (144/503) of patients experienced Grade neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was days. Grade or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor) was used in 19% of patients who received eribulin mesylate. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade peripheral neuropathy and 3% of patients had Grade peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received eribulin mesylate. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade peripheral motor neuropathy.Liver Function Test Abnormalities: Among patients with Grade or ALT levels at baseline, 18% of eribulin mesylate-treated patients experienced Grade or greater ALT elevation. One eribulin mesylate-treated patient without documented liver metastases had concomitant Grade elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to eribulin mesylate.Less Common Adverse Reactions: The following additional adverse reactions were reported in >=5% to <10% of the eribulin mesylate-treated group:Eye Disorders: increased lacrimationGastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouthGeneral Disorders and Administration Site Conditions: peripheral edemaInfections and Infestations: upper respiratory tract infectionMetabolism and Nutrition Disorders: hypokalemiaMusculoskeletal and Connective Tissue Disorders:muscle spasms, muscular weaknessNervous System Disorders: dysgeusia, dizzinessPsychiatric Disorders: insomnia, depressionSkin and Subcutaneous Tissue Disorders: rashLiposarcomaThe safety of eribulin mesylate was evaluated in Study 2, an open-label, randomized, multicenter, active-controlled trial, in which patients were randomized (1:1) to receive either eribulin mesylate 1.4 mg/m2 on Days and of 21-day cycle or dacarbazine at doses of 850 mg/m2 (20%), 1000 mg/m2 (64%), or 1200 mg/m2 (16%) every weeks. total of 223 patients received eribulin mesylate and 221 patients received dacarbazine. Patients were required to have received at least two prior systemic chemotherapy regimens. The trial excluded patients with pre-existing >= Grade peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, history of myocardial infarction within months, history of New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment. The median age of the safety population in Study was 56 years (range: 24 to 83 years); 67% female; 73% White, 3% Black or African American, 8% Asian/Pacific Islander, and 15% unknown; 99% received prior anthracycline-containing regimen; and 99% received >= prior regimens. The median duration of exposure was 2.3 months (range: 21 days to 26 months) for patients receiving eribulin mesylate see Clinical Studies (14.2) ].The most common adverse reactions (>=25%) reported in patients receiving eribulin mesylate were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common (>=5%) Grade 3-4 laboratory abnormalities reported in patients receiving eribulin mesylate were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions reported in patients receiving eribulin mesylate were neutropenia (4.9%) and pyrexia (4.5%). Permanent discontinuation of eribulin mesylate for adverse reactions occurred in 8% of patients. The most common adverse reactions resulting in discontinuation of eribulin mesylate were fatigue and thrombocytopenia (0.9% each). Twenty-six percent of patients required at least one dose reduction. The most frequent adverse reactions that led to dose reduction were neutropenia (18%) and peripheral neuropathy (4.0%).Table summarizes the incidence of adverse reactions occurring in at least 10% of patients in the eribulin mesylate-treated arm in Study 2.Table 3: Adverse Reactionsa Occurring in >=10% (all Grades) of Patients Treated on the Eribulin Mesylate arm and at Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of >=5% for All Grades or >=2% for Grades and 4) (Study 2)b Adverse ReactionEribulin Mesylaten=223Dacarbazinen=221All GradesGrades 3-4All GradesGrades 3-4Nervous system disordersPeripheral Neuropathyc 29%3.1%8%0.5%Headache18%0%10%0%General disorders Pyrexia28%0.9%14%0.5%GastrointestinaldisordersConstipation32%0.9%26%0.5%Abdominal paind 29%1.8%23%4.1%Stomatitis14%0.9%5%0.5%Skin and subcutaneous tissue disordersAlopecia35%NAe 2.7%NAe InfectionsUrinary tract infection11%2.2%5%0.5%a Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03). Safety data from one study site enrolling six patients were excluded. cIncludes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort. Not applicable; (grading system does not specify Grade for alopecia).Other clinically important adverse reactions occurring in >=10% of the eribulin mesylate-treated patients were:Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%)General Disorders: asthenia/fatigue (62%); peripheral edema (12%)Metabolism and Nutrition Disorders: decreased appetite (19%)Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); back pain (16%)Respiratory Disorders: cough (18%)Less Common Adverse Reactions: The following additional clinically important adverse reactions were reported in >=5% to <10% of the eribulin mesylate-treated group:Blood and Lymphatic System Disorders: thrombocytopeniaEye Disorders: increased lacrimationGastrointestinal Disorders: dyspepsiaMetabolism and Nutrition Disorders: hyperglycemiaMusculoskeletal and Connective Tissue Disorders: muscle spasms, musculoskeletal painNervous System Disorders: dizziness, dysgeusiaPsychiatric Disorders: insomnia, anxietyRespiratory, Thoracic, and Mediastinal Disorders: oropharyngeal painVascular Disorders: hypotensionTable 4: Laboratory Abnormalities Occurring in >=10% (all Grades) of Patients Treated on the Eribulin Mesylate arm and at Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of >=5% for All Grades or >=2% for Grades and 4)a (Study 2)+ Laboratory AbnormalityEribulin MesylateDacarbazineAll GradesGrades - 4All GradesGrades - 4HematologyAnemia70%4.1%52%6%Neutropenia63%32%30%8.9%ChemistryIncreased alanine aminotransferase (ALT)43%2.3%28%2.3%Increased aspartate aminotransferase (AST)36%0.9%16%0.5%Hypokalemia30%5.4%14%2.8%Hypocalcemia28%5%18%1.4%Hypophosphatemia20%3.2%11%1.4%aEach test incidence is based on the number of patients who had both baseline and at least one on-study measurement and at least grade increase from baseline. Eribulin Mesylate group (range 221-222) and dacarbazine group (range 214-215). +Laboratory results were graded per NCI CTCAE v4.03.. Neutropenia see Warnings and Precautions (5.1) . Peripheral neuropathy [see Warnings and Precautions (5.2)] QT prolongation [see Warnings and Precautions (5.4) . Eye Disorders: increased lacrimation. Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth. General Disorders and Administration Site Conditions: peripheral edema. Infections and Infestations: upper respiratory tract infection. Metabolism and Nutrition Disorders: hypokalemia. Musculoskeletal and Connective Tissue Disorders:muscle spasms, muscular weakness. Nervous System Disorders: dysgeusia, dizziness. Psychiatric Disorders: insomnia, depression. Skin and Subcutaneous Tissue Disorders: rash. Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%). General Disorders: asthenia/fatigue (62%); peripheral edema (12%). Metabolism and Nutrition Disorders: decreased appetite (19%). Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); back pain (16%). Respiratory Disorders: cough (18%). Blood and Lymphatic System Disorders: thrombocytopenia. Eye Disorders: increased lacrimation. Gastrointestinal Disorders: dyspepsia. Metabolism and Nutrition Disorders: hyperglycemia. Musculoskeletal and Connective Tissue Disorders: muscle spasms, musculoskeletal pain. Nervous System Disorders: dizziness, dysgeusia. Psychiatric Disorders: insomnia, anxiety. Respiratory, Thoracic, and Mediastinal Disorders: oropharyngeal pain. Vascular Disorders: hypotension. 6.2 Postmarketing Experience. The following adverse drug reactions have been identified during post-approval of eribulin mesylate. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and Lymphatic System Disorders: lymphopeniaGastrointestinal Disorders: pancreatitisHepatobiliary Disorders: hepatotoxicityImmune System Disorders: drug hypersensitivityInfections and Infestations: pneumonia, sepsis/neutropenic sepsisMetabolism and Nutrition Disorders: hypomagnesemia, dehydrationRespiratory, thoracic and mediastinal disorders: interstitial lung diseaseSkin and Subcutaneous Tissue Disorders: pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis. Blood and Lymphatic System Disorders: lymphopenia. Gastrointestinal Disorders: pancreatitis. Hepatobiliary Disorders: hepatotoxicity. Immune System Disorders: drug hypersensitivity. Infections and Infestations: pneumonia, sepsis/neutropenic sepsis. Metabolism and Nutrition Disorders: hypomagnesemia, dehydration. Respiratory, thoracic and mediastinal disorders: interstitial lung disease. Skin and Subcutaneous Tissue Disorders: pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via tubulin-based antimitotic mechanism leading to G2/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 change in phenotype.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of eribulin mesylate on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. total of 26 patients with solid tumors received 1.4 mg/m2 of eribulin mesylate on Days and of 21-day cycle. 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.. 12.3 Pharmacokinetics. The pharmacokinetics (PK) of eribulin is linear with mean elimination half-life of approximately 40 hours, mean volume of distribution of 43 L/m2 to 114 L/m2 and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 mg/m2. 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 single dose. No accumulation of eribulin is observed with weekly administration.EliminationMetabolismUnchanged eribulin was the major circulating species in plasma following administration of 14C-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.ExcretionEribulin is eliminated primarily in feces unchanged. After administration of 14C-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 PopulationsAge, Sex, and Race/Ethnicity: Based on population pharmacokinetic analysis, no clinically meaningful differences in the pharmacokinetics of eribulin were observed based on age, sex, or race.Hepatic ImpairmentIn 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 dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin at dose of 1.4 mg/m2 to patients with normal hepatic function [see Dosage and Administration (2.1) Use in Specific Populations (8.6) . Renal ImpairmentIn study evaluating the effect of renal impairment on the PK of eribulin, patients with moderate (CLcr 30-49 mL/min; n=7) and severe renal impairment (CLcr 15-29 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 50-79 mL/min; n=27) [see Dosage and Administration (2.1) Use in Specific Populations (8.7) . Drug Interaction StudiesEffect of Strong Inhibitors or Inducers of CYP3A4 on Eribulin: The effect of strong CYP3A4 inhibitor and P-gp inhibitor, ketoconazole, on the PK of eribulin was studied in 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 CYP3A4 inducer, rifampin, on the PK of eribulin was studied in 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 uM 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 substrate of P-gp, but is not 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 (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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Metastatic Breast Cancer. Study 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 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 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 dose of 1.4 mg/m2 on Days and of 21-day cycle. Eribulin mesylate-treated patients received median of cycles (range: 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 baseline ECOG performance status of 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 median of four prior chemotherapy regimens in both arms.In Study 1, 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 1Overall SurvivalEribulin Mesylate(n=508)Control Arm(n=254)Primary survival analysis Number of deaths274148 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 valueb 0.041Updated survival analysis Number of deaths386203 Median, months (95% CI)13.2 (12.1, 14.4)10.6 (9.2, 12.0)CI confidence interval Based on Cox proportional hazards model stratified by geographic region, HER2 status, and prior capecitabine therapy. Based on log-rank test stratified by geographic region, HER2 status, and prior capecitabine therapy.Figure 1: Updated Overall Survival Analysis for Study 1. Figure 1. 14.2 Liposarcoma 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 months of the most recent chemotherapy regimen. Patients were randomized to eribulin mesylate 1.4 mg/m2 administered intravenously on Days and of 21-day cycle or to dacarbazine at dose of 850 mg/m2, 1000 mg/m2, or 1200 mg/m2 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) 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 and 53% had ECOG PS of 1; 35% were enrolled in Region 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 demonstrated 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 and and Figure 2). There was no evidence of efficacy of eribulin mesylate in patients with advanced or metastatic leiomyosarcoma in Study (see Table 7).Table 6: Efficacy Results for the Liposarcoma Stratum and All Patients in Study 2a LiposarcomaStratumAll PatientsEribulin Mesylate(n=71)Dacarbazine(n=72)Eribulin Mesylate(n=225)Dacarbazine(n=221)Overall survival Deaths, (%)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 valueN/A+ 0.011Progression-free survival Events, (%)57 (80)59 (82)194 (86)185 (84) Disease progression5352180170 Death471415 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 applicableFigure 2: Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2Table 7: Efficacy Results for the Leiomyosarcoma Stratum in Study 2a LeiomyosarcomaStratumEribulin Mesylate(n=154)Dacarbazine(n=149)Overall survival Deaths, (%)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, (%)137 (89)126 (85) Disease progression127118 Death108 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.. Figure 2.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.The following adverse reactions are discussed in detail in other sections of the labeling:Neutropenia see Warnings and Precautions (5.1) Peripheral neuropathy [see Warnings and Precautions (5.2)] QT prolongation [see Warnings and Precautions (5.4) In clinical trials, eribulin mesylate has been administered to 1963 patients including 467 patients exposed to eribulin mesylate for months or longer. The majority of the 1963 patients were women (92%) with median age of 55 years (range: 17 to 85 years). The racial and ethnic distribution was White (72%), Black (4%), Asian (9%), and other (3%).Metastatic Breast CancerThe most common adverse reactions (>=25%) reported in patients receiving eribulin mesylate were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving eribulin mesylate were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of eribulin mesylate was peripheral neuropathy (5%).The adverse reactions described in Table were identified in 750 patients treated in Study [ see Clinical Studies (14.1) ]. In Study 1, patients were randomized (2:1) to receive either eribulin mesylate (1.4 mg/m2on Days and of 21-day cycle) or single agent treatment chosen by their physician (control group). total of 503 patients received eribulin mesylate and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving eribulin mesylate and 63 days for patients receiving control therapy. Table reports the most common adverse reactions occurring in at least 10% of patients in either group.Table 2: Adverse Reactionsa with Per-Patient Incidence of at Least 10% in Study 1Adverse ReactionsEribulin Mesylaten=503Control Groupn=247All Grades>= Grade 3All Grades>= Grade 3Blood and lymphatic system disordersb Neutropenia82%57%53%23% Anemia58%2%55%4%Nervous system disorders Peripheral neuropathyc 35%8%16%2% Headache19%<1%12%<1%General disorders Asthenia/Fatigue54%10%40%11% Pyrexia21%<1%13%<1% Mucosal inflammation9%1%10%2%Gastrointestinal disorders Nausea35%1%28%3% Constipation25%1%21%1% Vomiting18%1%18%1% Diarrhea18%018%0Musculoskeletal and connective tissue disorders Arthralgia/Myalgia22%<1%12%1% Back pain16%1%7%2% Bone pain12%2%9%2% Pain in extremity11%1%10%1%Metabolism and nutrition disorders Decreased weight21%1%14%<1% Anorexia20%1%13%1%Respiratory, thoracic, and mediastinal disorders Dyspnea16%4%13%4% Cough14%09%0Skin and subcutaneous tissue disorders Alopecia45%NAd 10%NAd Infections Urinary Tract Infection10%1%5%0aadverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.0. bbased upon laboratory data. cincludes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. dnot applicable; (grading system does not specify Grade for alopecia).Cytopenias: Grade neutropenia occurred in 28% (143/503) of patients who received eribulin mesylate in Study 1, and 29% (144/503) of patients experienced Grade neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was days. Grade or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor) was used in 19% of patients who received eribulin mesylate. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade peripheral neuropathy and 3% of patients had Grade peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received eribulin mesylate. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade peripheral motor neuropathy.Liver Function Test Abnormalities: Among patients with Grade or ALT levels at baseline, 18% of eribulin mesylate-treated patients experienced Grade or greater ALT elevation. One eribulin mesylate-treated patient without documented liver metastases had concomitant Grade elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to eribulin mesylate.Less Common Adverse Reactions: The following additional adverse reactions were reported in >=5% to <10% of the eribulin mesylate-treated group:Eye Disorders: increased lacrimationGastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouthGeneral Disorders and Administration Site Conditions: peripheral edemaInfections and Infestations: upper respiratory tract infectionMetabolism and Nutrition Disorders: hypokalemiaMusculoskeletal and Connective Tissue Disorders:muscle spasms, muscular weaknessNervous System Disorders: dysgeusia, dizzinessPsychiatric Disorders: insomnia, depressionSkin and Subcutaneous Tissue Disorders: rashLiposarcomaThe safety of eribulin mesylate was evaluated in Study 2, an open-label, randomized, multicenter, active-controlled trial, in which patients were randomized (1:1) to receive either eribulin mesylate 1.4 mg/m2 on Days and of 21-day cycle or dacarbazine at doses of 850 mg/m2 (20%), 1000 mg/m2 (64%), or 1200 mg/m2 (16%) every weeks. total of 223 patients received eribulin mesylate and 221 patients received dacarbazine. Patients were required to have received at least two prior systemic chemotherapy regimens. The trial excluded patients with pre-existing >= Grade peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, history of myocardial infarction within months, history of New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment. The median age of the safety population in Study was 56 years (range: 24 to 83 years); 67% female; 73% White, 3% Black or African American, 8% Asian/Pacific Islander, and 15% unknown; 99% received prior anthracycline-containing regimen; and 99% received >= prior regimens. The median duration of exposure was 2.3 months (range: 21 days to 26 months) for patients receiving eribulin mesylate see Clinical Studies (14.2) ].The most common adverse reactions (>=25%) reported in patients receiving eribulin mesylate were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common (>=5%) Grade 3-4 laboratory abnormalities reported in patients receiving eribulin mesylate were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions reported in patients receiving eribulin mesylate were neutropenia (4.9%) and pyrexia (4.5%). Permanent discontinuation of eribulin mesylate for adverse reactions occurred in 8% of patients. The most common adverse reactions resulting in discontinuation of eribulin mesylate were fatigue and thrombocytopenia (0.9% each). Twenty-six percent of patients required at least one dose reduction. The most frequent adverse reactions that led to dose reduction were neutropenia (18%) and peripheral neuropathy (4.0%).Table summarizes the incidence of adverse reactions occurring in at least 10% of patients in the eribulin mesylate-treated arm in Study 2.Table 3: Adverse Reactionsa Occurring in >=10% (all Grades) of Patients Treated on the Eribulin Mesylate arm and at Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of >=5% for All Grades or >=2% for Grades and 4) (Study 2)b Adverse ReactionEribulin Mesylaten=223Dacarbazinen=221All GradesGrades 3-4All GradesGrades 3-4Nervous system disordersPeripheral Neuropathyc 29%3.1%8%0.5%Headache18%0%10%0%General disorders Pyrexia28%0.9%14%0.5%GastrointestinaldisordersConstipation32%0.9%26%0.5%Abdominal paind 29%1.8%23%4.1%Stomatitis14%0.9%5%0.5%Skin and subcutaneous tissue disordersAlopecia35%NAe 2.7%NAe InfectionsUrinary tract infection11%2.2%5%0.5%a Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03). Safety data from one study site enrolling six patients were excluded. cIncludes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort. Not applicable; (grading system does not specify Grade for alopecia).Other clinically important adverse reactions occurring in >=10% of the eribulin mesylate-treated patients were:Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%)General Disorders: asthenia/fatigue (62%); peripheral edema (12%)Metabolism and Nutrition Disorders: decreased appetite (19%)Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); back pain (16%)Respiratory Disorders: cough (18%)Less Common Adverse Reactions: The following additional clinically important adverse reactions were reported in >=5% to <10% of the eribulin mesylate-treated group:Blood and Lymphatic System Disorders: thrombocytopeniaEye Disorders: increased lacrimationGastrointestinal Disorders: dyspepsiaMetabolism and Nutrition Disorders: hyperglycemiaMusculoskeletal and Connective Tissue Disorders: muscle spasms, musculoskeletal painNervous System Disorders: dizziness, dysgeusiaPsychiatric Disorders: insomnia, anxietyRespiratory, Thoracic, and Mediastinal Disorders: oropharyngeal painVascular Disorders: hypotensionTable 4: Laboratory Abnormalities Occurring in >=10% (all Grades) of Patients Treated on the Eribulin Mesylate arm and at Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of >=5% for All Grades or >=2% for Grades and 4)a (Study 2)+ Laboratory AbnormalityEribulin MesylateDacarbazineAll GradesGrades - 4All GradesGrades - 4HematologyAnemia70%4.1%52%6%Neutropenia63%32%30%8.9%ChemistryIncreased alanine aminotransferase (ALT)43%2.3%28%2.3%Increased aspartate aminotransferase (AST)36%0.9%16%0.5%Hypokalemia30%5.4%14%2.8%Hypocalcemia28%5%18%1.4%Hypophosphatemia20%3.2%11%1.4%aEach test incidence is based on the number of patients who had both baseline and at least one on-study measurement and at least grade increase from baseline. Eribulin Mesylate group (range 221-222) and dacarbazine group (range 214-215). +Laboratory results were graded per NCI CTCAE v4.03.. Neutropenia see Warnings and Precautions (5.1) . Peripheral neuropathy [see Warnings and Precautions (5.2)] QT prolongation [see Warnings and Precautions (5.4) . Eye Disorders: increased lacrimation. Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth. General Disorders and Administration Site Conditions: peripheral edema. Infections and Infestations: upper respiratory tract infection. Metabolism and Nutrition Disorders: hypokalemia. Musculoskeletal and Connective Tissue Disorders:muscle spasms, muscular weakness. Nervous System Disorders: dysgeusia, dizziness. Psychiatric Disorders: insomnia, depression. Skin and Subcutaneous Tissue Disorders: rash. Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%). General Disorders: asthenia/fatigue (62%); peripheral edema (12%). Metabolism and Nutrition Disorders: decreased appetite (19%). Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); back pain (16%). Respiratory Disorders: cough (18%). Blood and Lymphatic System Disorders: thrombocytopenia. Eye Disorders: increased lacrimation. Gastrointestinal Disorders: dyspepsia. Metabolism and Nutrition Disorders: hyperglycemia. Musculoskeletal and Connective Tissue Disorders: muscle spasms, musculoskeletal pain. Nervous System Disorders: dizziness, dysgeusia. Psychiatric Disorders: insomnia, anxiety. Respiratory, Thoracic, and Mediastinal Disorders: oropharyngeal pain. Vascular Disorders: hypotension.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer 1.4 mg/m2 intravenously over to minutes on Days and of 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). Administer 1.4 mg/m2 intravenously over to minutes on Days and of 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). 2.1 Recommended Dose. The recommended dose of eribulin mesylate injection is 1.4 mg/m2 administered intravenously over to minutes on Days and of 21-day cycle.The recommended dose of eribulin mesylate injection in patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m2 administered intravenously over to minutes on Days and of 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/m2 administered intravenously over to minutes on Days and of 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) 15-49 mL/min) is 1.1 mg/m2 administered intravenously over to minutes on Days and of 21-day cycle see Use in Specific Populations (8.7) ].. 2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.Recommended dose delaysDo not administer eribulin mesylate injection on Day or Day for any of the following:- ANC 1,000/mm3 Platelets 75,000/mm3 Grade or non-hematological toxicities.The Day dose may be delayed for maximum of week.- If toxicities do not resolve or improve to <= Grade severity by Day 15, omit the dose. If toxicities resolve or improve to <= Grade severity by Day 15, administer eribulin mesylate injection at reduced dose and initiate the next cycle no sooner than weeks later.Recommended dose reductionsIf dose has been delayed for toxicity and toxicities have recovered to Grade severity or less, resume eribulin mesylate injection at 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 ReductionsEvent DescriptionRecommended Eribulin Mesylate Injection DosePermanently reduce the 1.4 mg/m2 eribulin mesylate injection dose for any of the following:1.1 mg/m2 ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade or toxicities Omission or delay of Day eribulin mesylate injection dose in previous cycle for toxicityOccurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue eribulin mesylate injectionANC absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.. Do not administer eribulin mesylate injection on Day or Day for any of the following:- ANC 1,000/mm3 Platelets 75,000/mm3 Grade or non-hematological toxicities.. The Day dose may be delayed for maximum of week.- If toxicities do not resolve or improve to <= Grade severity by Day 15, omit the dose. If toxicities resolve or improve to <= Grade severity by Day 15, administer eribulin mesylate injection at reduced dose and initiate the next cycle no sooner than weeks later.. If dose has been delayed for toxicity and toxicities have recovered to Grade severity or less, resume eribulin mesylate injection at reduced dose as set out in Table 1.. Do not re-escalate eribulin mesylate injection dose after it has been reduced.. 2.3 Instructions for Preparation and Administration 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 hours at room temperature or for up to 24 hours under refrigeration at 4C (40F). Store diluted solutions of eribulin mesylate injection for up to hours at room temperature or up to 24 hours under refrigeration at 4C (40F).Discard unused portions of the vial.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics (PK) of eribulin is linear with mean elimination half-life of approximately 40 hours, mean volume of distribution of 43 L/m2 to 114 L/m2 and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 mg/m2. 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 single dose. No accumulation of eribulin is observed with weekly administration.EliminationMetabolismUnchanged eribulin was the major circulating species in plasma following administration of 14C-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.ExcretionEribulin is eliminated primarily in feces unchanged. After administration of 14C-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 PopulationsAge, Sex, and Race/Ethnicity: Based on population pharmacokinetic analysis, no clinically meaningful differences in the pharmacokinetics of eribulin were observed based on age, sex, or race.Hepatic ImpairmentIn 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 dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin at dose of 1.4 mg/m2 to patients with normal hepatic function [see Dosage and Administration (2.1) Use in Specific Populations (8.6) . Renal ImpairmentIn study evaluating the effect of renal impairment on the PK of eribulin, patients with moderate (CLcr 30-49 mL/min; n=7) and severe renal impairment (CLcr 15-29 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 50-79 mL/min; n=27) [see Dosage and Administration (2.1) Use in Specific Populations (8.7) . Drug Interaction StudiesEffect of Strong Inhibitors or Inducers of CYP3A4 on Eribulin: The effect of strong CYP3A4 inhibitor and P-gp inhibitor, ketoconazole, on the PK of eribulin was studied in 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 CYP3A4 inducer, rifampin, on the PK of eribulin was studied in 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 uM 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 substrate of P-gp, but is not 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 (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.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION eribulin mesylate injectionfor intravenous useWhat is the most important information should know about eribulin mesylate injectionEribulin mesylate can cause serious side effects, including:Low white blood cell count (neutropenia). This can lead to serious infections that could lead to death. Your healthcare provider will check your blood cell counts before you receive each dose of eribulin mesylate injection and during treatment. Call your healthcare provider right away if you develop any of these symptoms of infection: fever (temperature above 100.5F) chills cough burning or pain when you urinateNumbness, tingling, or painin your hands or feet (peripheral neuropathy). Peripheral neuropathy is common with eribulin mesylate injection and sometimes can be severe. Tell your healthcare provider if you have new or worsening symptoms of peripheral neuropathy.Your healthcare provider may delay, decrease your dose, or stop treatment with eribulin mesylate injection if you have side effects.See What are possible side effects of eribulin mesylate injection for more information about side effects. What is eribulin mesylate injection Eribulin Mesylate Injection is prescription medicine used to treat people with: Breast cancer that has spread to other parts of the body, and who have already received certain types of anticancer medicines after the cancer has spreadLiposarcoma that cannot be treated with surgery or has spread to other parts of the body, and who have received treatment with certain type of anticancer medicineIt is not known if Eribulin Mesylate Injection is safe and effective in children under 18 years of age.Before you receive eribulin mesylate injection, tell your healthcare provider about all of your medical conditions, including if you:have liver or kidney problemshave heart problems, including problem called congenital long QT syndromehave low potassium or low magnesium in your bloodare pregnant or plan to become pregnant. Eribulin mesylate injection can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with eribulin mesylate injection. Females who are able to become pregnant should use an effective birth control during treatment with eribulin mesylate injection and for at least weeks after the final dose of eribulin mesylate injection. Males should use an effective form of birth control when having sex with female partners who are able to become pregnant during treatment with eribulin mesylate injection and for 1/2 months (14 weeks) after the final dose of eribulin mesylate injection.are breastfeeding or plan to breastfeed. It is not known if eribulin mesylate passes into your breast milk. Do not breastfeed during treatment with eribulin mesylate injection and for weeks after the final dose of eribulin mesylate injection.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive eribulin mesylate injectioneribulin mesylate injection is given by intravenous (IV) injection in your vein.eribulin mesylate injection is given in cycles of treatment, with each cycle lasting 21 days.eribulin mesylate injection is usually given on day and day of treatment cycle.What are the possible side effects of eribulin mesylate injectioneribulin mesylate injection may cause serious side effects, including: See What is the most important information should know about eribulin mesylate injection eribulin mesylate injection can cause changes in your heartbeat (called QT prolongation). This can cause irregular heartbeats. Your healthcare provider may do heart monitoring (electrocardiogram or ECG) or blood tests during your treatment with eribulin mesylate injection to check for heart problems.The most common side effects of eribulin mesylate injection in people with breast cancer include: low white blood cell count (neutropenia)low red blood cell count (anemia)weakness or tirednesshair loss (alopecia)nauseaconstipationThe most common side effects of eribulin mesylate injection in people with liposarcoma include: tirednessnauseahair loss (alopecia)constipationstomach painfeverYour healthcare provider will do blood tests before and during treatment while you are taking eribulin mesylate injection. The most common changes to blood tests in people with liposarcoma include:low white blood cell count (neutropenia)decreased blood levels of potassium or calciumTell your healthcare provider about any side effect that bothers you or that does not go away.These are not all the possible side effects of eribulin mesylate injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about eribulin mesylate injectionMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about eribulin mesylate injection that is written for health professionals.What are the ingredients in eribulin mesylate injectionActive Ingredient: eribulin mesylateInactive Ingredients: dehydrated alcohol, water for injection, and sodium hydroxide or hydrochloric acid may be used for pH adjustment. Manufactured for:The WhiteOak Group, LLCWashington DC, 20006Made in ChinaThis Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 12/2023. Low white blood cell count (neutropenia). This can lead to serious infections that could lead to death. Your healthcare provider will check your blood cell counts before you receive each dose of eribulin mesylate injection and during treatment. Call your healthcare provider right away if you develop any of these symptoms of infection: fever (temperature above 100.5F) chills cough burning or pain when you urinate. Numbness, tingling, or painin your hands or feet (peripheral neuropathy). Peripheral neuropathy is common with eribulin mesylate injection and sometimes can be severe. Tell your healthcare provider if you have new or worsening symptoms of peripheral neuropathy.. Your healthcare provider may delay, decrease your dose, or stop treatment with eribulin mesylate injection if you have side effects.. Breast cancer that has spread to other parts of the body, and who have already received certain types of anticancer medicines after the cancer has spread. Liposarcoma that cannot be treated with surgery or has spread to other parts of the body, and who have received treatment with certain type of anticancer medicine. have liver or kidney problems. have heart problems, including problem called congenital long QT syndrome. have low potassium or low magnesium in your blood. are pregnant or plan to become pregnant. Eribulin mesylate injection can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with eribulin mesylate injection. Females who are able to become pregnant should use an effective birth control during treatment with eribulin mesylate injection and for at least weeks after the final dose of eribulin mesylate injection. Males should use an effective form of birth control when having sex with female partners who are able to become pregnant during treatment with eribulin mesylate injection and for 1/2 months (14 weeks) after the final dose of eribulin mesylate injection.. are breastfeeding or plan to breastfeed. It is not known if eribulin mesylate passes into your breast milk. Do not breastfeed during treatment with eribulin mesylate injection and for weeks after the final dose of eribulin mesylate injection.. eribulin mesylate injection is given by intravenous (IV) injection in your vein.. eribulin mesylate injection is given in cycles of treatment, with each cycle lasting 21 days.. eribulin mesylate injection is usually given on day and day of treatment cycle.. See What is the most important information should know about eribulin mesylate injection eribulin mesylate injection can cause changes in your heartbeat (called QT prolongation). This can cause irregular heartbeats. Your healthcare provider may do heart monitoring (electrocardiogram or ECG) or blood tests during your treatment with eribulin mesylate injection to check for heart problems.. low white blood cell count (neutropenia). low red blood cell count (anemia). weakness or tiredness. hair loss (alopecia). nausea. constipation. tiredness. nausea. hair loss (alopecia). constipation. stomach pain. fever. low white blood cell count (neutropenia). decreased blood levels of potassium or calcium.