For patients who stand up to their cancer For health care teams that stand up for their patients

The first and only single agent with a significant overall survival benefit in advanced liposarcoma and following 2 prior chemotherapies for metastatic breast cancer1-5

HALAVEN improved median overall survival in advanced liposarcoma vs dacarbazine (15.6 months vs 8.4 months) and in mBC vs Treatment of Physician’s Choice (13.2 months vs 10.6 months) when following 2 prior mBC therapies4

Indications Metastatic Breast Cancer HALAVEN (eribulin mesylate) Injection is indicated for the treatment of patients with metastatic breast cancer (mBC) who have previously received at least 2 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. Liposarcoma HALAVEN is indicated for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen. Important Safety Information Warnings and Precautions Neutropenia: Severe neutropenia (ANC <500/mm3) lasting >1 week occurred in 12% of patients with mBC and liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 5% of patients with mBC and 2 patients (0.4%) died from complications. Febrile neutropenia occurred in 0.9% of patients with liposarcoma or leiomyosarcoma, and fatal neutropenic sepsis occurred in 0.9% of patients. Patients with mBC with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels. Monitor complete blood cell counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting >7 days. Please see additional Important Safety Information throughout and accompanying HALAVEN full Prescribing Information. HALAVEN—the Preclinical studies have demonstrated the ability of HALAVEN® to first agent in the halichondrin class6 Induce tumor cell death With its distinct binding profile, HALAVEN causes irreversible mitotic blockage resulting in apoptosis, leading to the destruction of many tumor cells4,7-9

HALAVEN binds with high affinity to the growing plus ends of microtubules.10 Microtubule growth occurs primarily at these plus ends7

HALAVEN sequesters tubulin into nonproductive aggregates, preventing participation in microtubule assembly.4,9 Microtubules are a key part of the cell-division process, allowing tumor growth11

HALAVEN inhibits microtubule growth and prevents normal mitotic spindle formation.4,7 Disruption of microtubule function results in mitotic blockage, leading to tumor cell death by apoptosis7

HALAVEN induces apoptosis and may impact the residual tumor cells4,12

Important Safety Information (continued) Peripheral Neuropathy: Grade 3 peripheral neuropathy occurred in 8% of patients with mBC (Grade 4=0.4%) and 22% developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Neuropathy lasting >1 year occurred in 5% of patients with mBC.

Please see additional Important Safety Information throughout 2 and accompanying HALAVEN full Prescribing Information. MECHANISM OF ACTION MECHANISM

Alter the tumor microenvironment* By promoting the epithelial phenotype, HALAVEN reduces the migration and invasive capacity of tumor cells4,12,13

HALAVEN induces vascular remodeling, increasing oxygen flow to the tumor.4,13 Abnormal vasculature causes irregular blood flow throughout the tumor, resulting in hypoxic regions14

HALAVEN reduces the hypoxic conditions associated with an abnormal tumor microenvironment.4,13 Hypoxic conditions lead to phenotypic changes that cause increased migration and invasive capacity of the tumor cells14,15

Mesenchymal cell HALAVEN opposes the mesenchymal phenotype and promotes the epithelial phenotype.4,12 The mesenchymal phenotype correlates with increased 12 Epithelial migration and invasiveness of tumor cells cell

HALAVEN makes the residual tumor cells into ones that are less prone to migrate and invade4

Preclinical evidence does not imply clinical efficacy. *Based on preclinical studies of human breast cancer models (in vitro/in vivo). Important Safety Information (continued) Grade 3 peripheral neuropathy occurred in 3.1% of patients with liposarcoma and leiomyosarcoma receiving HALAVEN and neuropathy lasting more than 60 days occurred in 58% (38/65) of patients who had neuropathy at the last treatment visit. Patients should be monitored for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

3

The treatment landscape in mBC is changing Although mBC treatment can potentially extend to 6 lines and beyond, not all patients will be alive to benefit from subsequent lines of therapy16

ESTIMATED REDUCTION IN PATIENTS ALIVE BY THE END OF EACH LINE OF THERAPY17 BREAST CANCER METASTATIC First line

Second line

Third line

Fourth line

mBC=metastatic breast cancer.

It’s important to choose an option following 2 prior mBC therapies that gives more patients an opportunity for an OS benefit17

OS=overall survival.

Important Safety Information (continued) Embryo-Fetal Toxicity: HALAVEN can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with HALAVEN 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 HALAVEN and for 3.5 months following the final dose.

Please see additional Important Safety Information throughout and accompanying HALAVEN full Prescribing Information. 5 ERIBULIN (HALAVEN) IS LISTED AS A PREFERRED The first and only single SINGLE AGENT IN THE NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY agent that significantly extended (NCCN GUIDELINES®)18 overall survival following 2 prior mBC therapies1-3

UPDATED OS ANALYSIS (UNPLANNED): MEDIAN OS, MONTHS (95% CI)1,4,a

1.0 0.9 0.8 HALAVEN 0.7 (n=508) 0.6 13.2 0.5 Treatment of months 0.4 Physician’s Choice (12.1, 14.4) (n=254) Deaths=386 0.3 10.6 0.2 months 0.1 (9.2, 12.0)

PROPORTION OF PATIENTS ALIVE Deaths=203 0.0 0 6 12 18 24 30 36 TIME (MONTHS)

Number of 508 406 274 142 54 11 0 HALAVEN patients at risk 254 178 106 61 26 5 0 TPC

Results from an updated, unplanned survival analysis of the Phase III, randomized (2:1), open-label, multicenter, multinational Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus E7389 (Eribulin) (EMBRACE) trial of HALAVEN versus Treatment of Physician’s Choice (TPC) (Control arm) in patients with mBC (N=762), conducted when 77% of events (deaths) had been observed.1,4 NCCN®=National Comprehensive Cancer Network®; CI=confidence interval. aConducted in the intent-to-treat population.

Patients in the HALAVEN arm had a 19% reduction in relative risk of death vs control group4,19

Results of the updated analysis were consistent with the primary analysis, which was conducted when ~50% of events (deaths) had been observed. HALAVEN demonstrated median overall survival of 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months with the TPC arm (95% CI: 9.3, 12.5), hazard ratio=0.81 (95% CI: 0.66, 0.99) (P=0.041)1,4

Please see additional Important Safety Information throughout 6 and accompanying HALAVEN full Prescribing Information. Evaluated against real-world, single-agent treatment options used by physicians

THE PHASE III EMBRACE TRIAL: RANDOMIZED, OPEN-LABEL, MULTICENTER, MULTINATIONAL1,4

Patients with metastatic HALAVEN breast cancer (N=762) (n=508) 1.4 mg/m2 IV for • ≥2 chemotherapeutic 2 to 5 minutes Days 1 and 8 regimens for (21-day cycle) metastatic disease PRIMARY RANDOMIZATION (2:1)b • Prior anthracycline- ENDPOINT: and taxane-based TPC chemotherapy, unless (Control arm, n=254)c OS contraindicated Any single-agent therapy, selected prior • Progression within 6 months to randomization of last chemotherapeutic regimen

IV=intravenous. bRandomization was stratified by geographic region, human epidermal growth factor receptor 2 (HER2/neu) status, and prior capecitabine exposure. cTherapies included in the TPC arm were determined prior to randomization to eliminate bias and had to be approved for the treatment of cancer, administered according to local practice, and available at time of study.

The FDA recognizes overall survival as the most reliable and preferred clinical endpoint in cancer trials20

Important Safety Information (continued) QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome.

7 Patients in the Treatment of Physician's Choice (TPC) arm primarily received chemotherapy

THERAPIES IN THE TPC ARM4

Vinorelbine 26% Gemcitabine 18% Capecitabine 18% Taxanesa 16% Other chemotherapyb 10% Anthracyclines 9% Hormone therapy 3%

aIncluded paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone.1 bIncluded cisplatin, carboplatin, cyclophosphamide, etoposide, mitomycin, fluorouracil, and methotrexate.1

97% of patients in the TPC arm received chemotherapy4

Please see Important Safety Information throughout 8 and accompanying HALAVEN full Prescribing Information. Studied in patients regardless of receptor status

BASELINE PATIENT CHARACTERISTICS21 HALAVEN TPC SELECTED PATIENT FACTORS (n=508) (n=254) Median age (range) 55 years (28 to 85) 56 years (27 to 81) 0 43% 41% ECOG PS 1 48% 50% 2 8% 9% Positive 18% 17% HER2/neu status Negative 81% 83% Unknown 1% 0% Positive 70% 70% ER status Negative 30% 30% Unknown <1% 0% Positive 56% 55% PR status Negative 44% 45% Unknown <1% 0% Triple negative HER2/neu-, ER-, PR- 18% 21% Liver 58% 63% Sites of involvement Lung 39% 37% Bone 60% 62% 2 34% 32% Metastatic sites 3 29% 30% 4 14% 15% 2 43% 36% Number of prior mBC  3 32% 33% chemotherapy regimens 4 18% 22%

ECOG PS=Eastern Cooperative Oncology Group performance status; ER=estrogen receptor; PR=progesterone receptor.

Evaluated in patients with pre-existing peripheral neuropathy: at baseline, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% had Grade 24

More patients (43%) received HALAVEN following 2 prior mBC therapies than in later settings21

9 Choose HALAVEN® when your goal is extending life following 2 prior mBC therapies

A treatment option for patients with mBC4

Who are still active (ECOG PS 0 or 1)4

Who are ready for chemotherapy after 2 prior chemotherapy regimens for mBC, which should have included an anthracycline and a taxane in the adjuvant or Regardless of 4,21 metastatic setting4 receptor status • ER/PR +/- • HER2 +/- • Triple negative

A growing body of real-world experience HALAVEN has been prescribed to approximately 40,000 patients with mBC in the United States21

Important Safety Information (continued) Adverse Reactions In patients with mBC receiving HALAVEN, the most common adverse reactions (≥25%) were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%). Febrile neutropenia (4%) and neutropenia (2%) were the most common serious adverse reactions. The most common adverse reaction resulting in discontinuation was peripheral neuropathy (5%).

Please see additional Important Safety Information throughout 10 and accompanying HALAVEN full Prescribing Information. Safety profile demonstrated in the Phase III EMBRACE trial

ADVERSE REACTIONS4,a HALAVEN TPC (n=503) (n=247) INCIDENCE ≥10% BY GRADE All ≥3 All ≥3

Blood and lymphatic Neutropenia 82% 57% 53% 23% b system disorders Anemia 58% 2% 55% 4% Peripheral neuropathyc 35% 8% 16% 2% Nervous system disorders Headache 19% <1% 12% <1% Asthenia/Fatigue 54% 10% 40% 11% General disorders Pyrexia 21% <1% 13% <1% Mucosal inflammation 9% 1% 10% 2% Nausea 35% 1% 28% 3% Constipation 25% 1% 21% 1% Gastrointestinal disorders Vomiting 18% 1% 18% 1% Diarrhea 18% 0% 18% 0% Arthralgia/Myalgia 22% <1% 12% 1%

Musculoskeletal and Back pain 16% 1% 7% 2% connective tissue disorders Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1%

Metabolism and Decreased weight 21% 1% 14% <1% nutrition disorders Anorexia 20% 1% 13% 1%

Respiratory, thoracic, Dyspnea 16% 4% 13% 4% and mediastinal disorders Cough 14% 0% 9% 0%

Skin and subcutaneous Alopecia 45% NAd 10% NAd tissue disorders

Infections Urinary tract infection 10% 1% 5% 0%

aAdverse reactions were graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.4 bBased upon laboratory data.4 cIncludes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy (in the HALAVEN arm: all Grades=4%, Grade 3=2%), polyneuropathy, peripheral sensory neuropathy, and paresthesia.4 dNot applicable; grading system does not specify greater than Grade 2 for alopecia. Rate of alopecia in the HALAVEN arm: Grade 1=26%, Grade 2=17%. Rate of alopecia in the TPC arm: Grade 1=5%, Grade 2=5%.4,21

The median duration of exposure was 118 days in the HALAVEN arm and 63 days in the TPC arm4

11

Increasing overall survival has been challenging in patients with soft tissue sarcomas22

An expected median survival of 8 to 13 months is estimated from the start of a first-line anthracycline in advanced soft tissue sarcoma22

In patients with liposarcoma for whom surgical resection is not an option, the mortality rate is high across subtypes (well and dedifferentiated, myxoid/round cell, and pleomorphic)22 LIPOSARCOMA ADVANCED

Both dedifferentiated and pleomorphic subtypes have shown low responsiveness to typical regimens22

There is an opportunity to extend overall survival for patients with advanced liposarcoma4,5

Important Safety Information (continued) Adverse Reactions (continued) In patients with liposarcoma and leiomyosarcoma receiving HALAVEN, the most common adverse reactions (≥25%) reported in patients receiving HALAVEN were fatigue (62%), nausea (41%), alopecia (35%), constipation (32%), peripheral neuropathy (29%), abdominal pain (29%), and pyrexia (28%). The most common (≥5%) Grade 3-4 laboratory abnormalities reported in patients receiving HALAVEN were neutropenia (32%), hypokalemia (5.4%), and hypocalcemia (5%). Neutropenia (4.9%) and pyrexia (4.5%) were the most common serious adverse reactions. The most common adverse reactions resulting in discontinuation were fatigue and thrombocytopenia (0.9% each).

Please see additional Important Safety Information throughout and accompanying HALAVEN full Prescribing Information. 13 ERIBULIN (HALAVEN) IS LISTED AS A SINGLE AGENT FOR PALLIATIVE The first and only single agent to THERAPY IN THE NCCN CLINICAL PRACTICE GUIDELINES show a significant survival advantage IN ONCOLOGY in a Phase III study of patients with (NCCN GUIDELINES®)23 advanced liposarcoma5

OVERALL SURVIVAL ANALYSIS (LIPOSARCOMA STRATUM): MEDIAN OS, MONTHS (95% CI)4

1.0

0.8 HALAVEN (n=71) 0.6 15.6 months 0.4 (10.2, 18.6) Dacarbazine Deaths=52 (n=72) SURVIVAL PROBABILITY 0.2 8.4 months (5.2, 10.1) 0.0 Deaths=63

30 6 9 12 15 18 21 24 27 30 33 36 39 42 45 TIME (MONTHS)

Number of HALAVEN patients 71 63 51 43 39 34 30 20 15 12 7 4 2 0 0 0 at risk 72 59 42 33 22 17 12 11 6 3 2 0 0 0 0 0 Dacarbazine

The efficacy and safety of HALAVEN were evaluated in 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 2 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 HALAVEN 1.4 mg/m2 administered intravenously on Days 1 and 8 of a 21-day cycle or to dacarbazine at a dose of 850 mg/m2, 1,000 mg/m2, or 1,200 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. The most common (>40%) prior systemic chemotherapies were doxorubicin (90%), ifosfamide (62%), gemcitabine (59%), trabectedin (50%), and docetaxel (48%).4 NCCN®=National Comprehensive Cancer Network®; OS=overall survival; CI=confidence interval.

Patients in the HALAVEN arm with liposarcoma had a 49% reduction in relative risk of death vs control group4,19

Please see additional Important Safety Information throughout 14 and accompanying HALAVEN full Prescribing Information. Treatment effects of HALAVEN® were demonstrated in patients with advanced liposarcoma based on the preplanned, exploratory subgroup analysis of OS and PFS4

MEDIAN OS FOR HALAVEN AND DACARBAZINE: LIPOSARCOMA STRATUM AND ALL PATIENTS4,a,b

18 15.6 (10.2, 18.6) 16 n=71 13.5 (11.1, 16.5) 14 n=225 11.3 (9.5, 12.6) 12 n=221 8.4 10 (5.2, 10.1) n=72

8

6

4 MEDIAN OS, MONTHS (95% CI)

2 HALAVEN Dacarbazine 0 LIPOSARCOMA ALL PATIENTSb HR=0.51 (95% CI: 0.35, 0.75) HR=0.75 (95% CI: 0.61, 0.94), P=0.011

PFS=progression-free survival; HR=hazard ratio. aEfficacy data from 1 study site enrolling 6 patients were excluded. bAll patients=liposarcoma and leiomyosarcoma.

There was no evidence of efficacy of HALAVEN in patients with advanced or metastatic leiomyosarcoma in this trial4 Secondary endpoint: PFS4 Median PFS in the liposarcoma stratum was 2.9 months (95% CI: 2.6, 4.8) for patients receiving HALAVEN vs 1.7 months (95% CI: 1.4, 2.6) for patients receiving dacarbazine, HR=0.52 (95% CI: 0.35, 0.78) Median PFS in all patients was 2.6 months (95% CI: 2.0, 2.8) for patients receiving HALAVEN vs 2.6 months (95% CI: 1.7, 2.7) for patients receiving dacarbazine, HR=0.86 (95% CI: 0.69, 1.06) Important Safety Information (continued) Use in Specific Populations Lactation: Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final dose.

15 Evaluated against dacarbazine A Phase III, open-label, randomized, multicenter, active-controlled trial to compare the efficacy and safety of HALAVEN® in patients with advanced liposarcoma or leiomyosarcoma4,5

THE PHASE III STUDY 309: MULTICENTER, RANDOMIZED, OPEN-LABEL4,5

Patients with unresectable, HALAVEN locally advanced or metastatic liposarcoma (n=225) 1.4 mg/m2 IV for or leiomyosarcoma (N=446) 2 to 5 minutes PRIMARY Days 1 and 8 ENDPOINT: • ≥2 prior chemotherapy (21-day cycle) regimens, 1 of which OS RANDOMIZATION (1:1)a must have been DACARBAZINE an anthracycline (Control arm, n=221)b 850 mg/m2, Selected • Disease progression within 1,000 mg/m2, Secondary Endpoint 6 months of the most recent or 1,200 mg/m2 PFS chemotherapy regimen every 21 days

IV=intravenous. aRandomization was stratified by histology (liposarcoma or leiomyosarcoma), number of prior therapies, and geographic region. bDose determined by the investigator prior to randomization.

The FDA recognizes overall survival as the most reliable and preferred clinical endpoint in cancer trials20

BASELINE CHARACTERISTICS4 LIPOSARCOMA STRATUM SELECTED PATIENT FACTORS (n=143) Median age 55 years Sex Female 38% 0 41% ECOG PS 1 53% Prior systemic chemotherapies >2 44% Dedifferentiated 45% Liposarcoma Myxoid/round cell 37% histological subtype Pleomorphic 18%

ECOG PS=Eastern Cooperative Oncology Group performance status.

Please see Important Safety Information throughout 16 and accompanying HALAVEN full Prescribing Information. HALAVEN was studied in patients with advanced liposarcoma or leiomyosarcoma and with intermediate-to-high tumor grades5

BASELINE PATIENT CHARACTERISTICS5,21 HALAVEN DACARBAZINE SELECTED PATIENT FACTORS (n=228) (n=224) <65 years 78% 79% Age ≥65 years 22% 21% Sex Female 71% 63% 0 49% 40% ECOG PS 1 50% 54% 2 1% 6% Liposarcoma 33% 35% Histology Leiomyosarcoma 67% 65% Dedifferentiated 14% 17% Liposarcoma Myxoid/round cell 13% 12% histological subtype Pleomorphic 6% 7% Uterine 30% 28% Leiomyosarcoma Nonuterine 36% 37% primary site Unknown <1% 0% High 66% 68% Tumor grade Intermediate 34% 31% Not known <1% 1% 1 7% 6% Number of prior regimens for 2 51% 44% advanced disease >2 42% 50%

A treatment option for patients with advanced liposarcoma4,5

Who have received a prior anthracycline-containing regimen With intermediate-to-high tumor grades regardless of liposarcoma subtype

17 Safety profile demonstrated in the pivotal Phase III trial in advanced liposarcoma and leiomyosarcoma

ADVERSE REACTIONS4,a Occurring in ≥10% (all Grades) of patients treated in the HALAVEN arm and at a higher incidence than in the dacarbazine arm (between-arm difference of ≥5% for all Grades or ≥2% for Grades 3 and 4)b

HALAVEN DACARBAZINE (n=223) (n=221) ADVERSE REACTION BY GRADE All 3-4 All 3-4 Peripheral neuropathyc 29% 3.1% 8% 0.5% Nervous system disorders Headache 18% 0% 10% 0% General disorders Pyrexia 28% 0.9% 14% 0.5% Constipation 32% 0.9% 26% 0.5% Gastrointestinal disorders Abdominal paind 29% 1.8% 23% 4.1% Stomatitis 14% 0.9% 5% 0.5% Skin and subcutaneous Alopecia 35% NAe 2.7% NAe tissue disorders

Infections Urinary tract infection 11% 2.2% 5% 0.5%

aAdverse reactions were graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. bSafety data from 1 study site enrolling 6 patients were excluded. cIncludes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paresthesia. dIncludes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal discomfort. eNot applicable; grading system does not specify greater than Grade 2 for alopecia.

Other clinically important adverse reactions occurring in ≥10% of the HALAVEN-treated patients were nausea (41%), vomiting (19%), diarrhea (17%), asthenia/fatigue (62%), peripheral edema (12%), decreased appetite (19%), arthralgia/myalgia (16%), back pain (16%), and cough (18%)4 The median duration of exposure was 2.3 months (range: 21 days to 26 months) for patients receiving HALAVEN4

Please see additional Important Safety Information throughout 18 and accompanying HALAVEN full Prescribing Information. Laboratory abnormalities in the Phase III trial

LABORATORY ABNORMALITIES4,f,g Occurring in ≥10% (all Grades) of patients treated in the HALAVEN arm and at a higher incidence than in the dacarbazine arm (between-arm difference of ≥5% for all Grades or ≥2% for Grades 3 and 4)

HALAVEN DACARBAZINE LABORATORY ABNORMALITY BY GRADE All 3-4 All 3-4 Anemia 70% 4.1% 52% 6% Hematology Neutropenia 63% 32% 30% 8.9% Increased alanine 43% 2.3% 28% 2.3% aminotransferase Increased aspartate 36% 0.9% 16% 0.5% aminotransferase Chemistry Hypokalemia 30% 5.4% 14% 2.8% Hypocalcemia 28% 5% 18% 1.4% Hypophosphatemia 20% 3.2% 11% 1.4%

fEach test incidence is based on the number of patients who had both baseline and at least 1 on-study measurement and at least 1 grade increase from baseline. HALAVEN group (range 221-222) and dacarbazine group (range 214-215). gLaboratory results were graded per NCI CTCAE version 4.03.

19 One consistent dose and schedule for mBC and advanced liposarcoma Quick 2- to 5-minute IV infusion4

RECOMMENDED HALAVEN ADMINISTRATION4 DOSE INFUSION TIME SCHEDULE

Recommended dose 1.4 mg/m2 In patients with 1.1 mg/m2 • Mild hepatic impairmenta 2 to 5 Days 1 and 8 minutes (21-day cycle) • Moderate hepatic impairmentb 0.7 mg/m2

• Moderate or severe renal impairmentc 1.1 mg/m2

aMild hepatic impairment=Child-Pugh A. bModerate hepatic impairment=Child-Pugh B. cCreatinine clearance (CLcr) of 15-49 mL/min.

Patients with severe hepatic impairment (Child-Pugh C) were not studied4 Straightforward preparation Administer undiluted or diluted HALAVEN may be diluted in 100 mL of 0.9% Sodium Chloride Injection, USP4 Do not dilute in or administer through an intravenous line containing solutions with dextrose. Do not administer in the same intravenous line with other medicinal products4 HALAVEN is not formulated in solvents such as Cremophor® or polysorbate 8021

No known drug-drug interactions4 No premedication required21 No premixing required4

Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose4 Cremophor® EL Castor Oil is a registered trademark of BASF Corporation or BASF SE.

Please see Important Safety Information throughout 20 and accompanying HALAVEN full Prescribing Information. Recommended dose modifications Recommended dose delays4* Do not administer HALAVEN on Day 1 or Day 8 in patients with ≥Grade 3 neutropenia,† ≥Grade 2 thrombocytopenia,‡ or Grade 3/4 nonhematologic toxicities

The Day 8 dose may be delayed for up to 1 week in patients with toxicities — If toxicities resolve or improve to Grade 2 or less by Day 15, administer at a reduced dose and initiate the next cycle no sooner than 2 weeks later — If toxicities do not resolve or improve to Grade 2 or less by Day 15, omit the dose

If a dose has been delayed for toxicities that have recovered to a severity of Grade 2 or less, resume at the recommended reduced dose

If a dose has been reduced due to toxicities, do not re-escalate

RECOMMENDED DOSE REDUCTIONS4* RECOMMENDED EVENTS REQUIRING PERMANENT DOSE REDUCTION CURRENT DOSE DOSE REDUCTION Hematologic toxicities • ANC <500/mm3 for >7 days or ANC <1,000/mm3 with fever or infection • Platelets <25,000/mm3 or platelets <50,000/mm3 1.4 mg/m2 1.1 mg/m2 requiring transfusion Grade 3/4 nonhematologic toxicities Omission or delay of Day 8 dose in previous cycle for toxicity

Any event requiring permanent dose reduction while 1.1 mg/m2 0.7 mg/m2 receiving 1.1 mg/m2

Any event requiring permanent dose reduction while 2 Discontinue 2 0.7 mg/m receiving 0.7 mg/m HALAVEN ADMINISTRATION DOSING AND

ANC=absolute neutrophil count. *Toxicities graded in accordance with NCI CTCAE version 3.0.4 † Greater than or equal to Grade 3 neutropenia=ANC <1,000/mm3.24 ‡ Greater than or equal to Grade 2 thrombocytopenia=platelets <75,000/mm3.24

21 HALAVEN® $0 Co-Pay Program Simplified paperwork—no income requirements The HALAVEN $0 Co-Pay Program assists eligible patients with the out-of-pocket costs of HALAVEN (up to $18,000 per year).

To qualify,* patients must Be covered by commercial insurance Not be enrolled in state or federal health care programs, including Medicare, Medicaid, Medigap, VA, DoD, or TRICARE *Other eligibility requirements may apply.

HALAVEN® $0 Co-Pay Program HALAVEN $0 Co-Pay Program • Phone: 1-866-61-EISAI (1-866-613-4724) • Fax: 1-844-745-2350 2250 Perimeter Park Drive, Suite 300 • Morrisville, North Carolina 27560

Your Patient Information Card

HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. ©2016 Eisai Inc. All rights reserved. Printed in USA May 2016 HALA-US0403(1)

Welcome to the HALAVEN® (eribulin mesylate) injection $0 Co-Pay Program. To the Patient: Present this HALAVEN $0 Co-Pay Card to your healthcare provider to participate in this program. Commercially insured patients will pay no more than $0. Maximum bene t paid by Eisai Inc. will be $18,000 per year. Depending on your insurance plan, you could have additional nancial responsibility for any amounts over Eisai's maximum liability. For questions, please call 1-866-61-EISAI (1-866-613-4724). To the Health Care Provider: In order for the patient to receive a rebate, you or the patient must submit an Explanation of Bene ts (EOB) from the primary insurance provider (as well as any secondary insurance provider) or the Specialty Pharmacy Provider receipt after every infusion, either by mail to the address at the top of this card or by fax to 1-844-745-2350. Once we receive and process the patient’s EOB or Specialty Pharmacy receipt, we will fax your site a virtual debit card loaded with the patient’s savings. If you Learn moreindicated onabout the patient’s enrollment theform that your siteHALAVEN does not accept Debit Card Payment or$0 if the patient Co-Pay uses a specialty Program pharmacy to purchase HALAVEN, we will instead provide a rebate check to the patient. For questions, please call 1-866-61-EISAI (1-866-613-4724). and theEligibility Eisai Criteria: Good towardAssistance the purchase of HALAVEN prescriptions. Program No substitutions permitted. Not available for to patients HALAVEN enrolled in state and federal healthcare programs, including Medicare, Medicaid, Medigap, VA, DoD or TRICARE. Offer available to MA residents through June 30, 2017. Offer only available to patients with private, commercial insurance. May not be combined with any other coupon, discount, prescription savings card, free trial or other offer. Federal law prohibits the selling, purchasing, trading, by visitingor counterfeiting www.eisaireimbursement.com/hcp/halaven of this card. Such activities may result in imprisonment of 10 years, nes up to $25,000, or both. Void outside the USA and where prohibited by law. Eisai Inc. reserves the right to rescind, revoke, or amend this offer at any time without notice. Patients and pharmacies are responsible for disclosing to insurance carriers the redemption and value of the card and complying orwith calling any other conditions imposed 1.866.61.EISAI by insurance carriers on third-party payers. The value (1.866.613.4724) of this card is not contingent on any prior or future purchases. The card is solely intended to provide savings on any purchase of HALAVEN. Use of the card for any one purchase does not obligate the patient to make future purchases of HALAVEN. This offer will expire November 20, 2019. Monday-Friday, 8 am to 8 pm, ET HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. ©2016 Eisai Inc. All rights reserved. Printed in USA May 2016 HALA-US0403(1)

Please see Important Safety Information throughout 22 and accompanying HALAVEN full Prescribing Information. REIMBURSEMENT/ REFERENCES 23

Kuznetsov G, Towle MJ, Cheng H, et MJ, al. G, Towle Kuznetsov Funahashi Y, Okamoto K, Adachi Y, et al. Y, K, Adachi Okamoto Funahashi Y, 13. U.S. Department of Health and Human Services, Food and Drug Food Department of Health and Human Services, U.S. NCI dictionary of cancer terms. National Cancer Institute Web site. http://www.cancer.gov/ http://www.cancer.gov/ site. Web Institute Cancer National terms. NCI dictionary of cancer † , complete with details on coding, including utilizing utilizing on coding, including with details mation, complete about HALAVEN billing and the appeal process ers about HALAVEN

Cortes J, O’Shaughnessy J, Loesch D, et al. EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389) E7389) Versus Choice Physician’s Assessing Study Cancer Breast (Eisai Metastatic et al. EMBRACE D, Loesch J, O’Shaughnessy J, 1. Cortes

in evaluating denials Claims assistance Educating pay P the HALAVEN J-code, J9179 the HALAVEN options with an approximate coverage and verification Insurance for all queries 24- to 48-hour turnaround options and advising on coverage alternate in evaluating Support application requirements and individual requirements assistance with researching authorization Prior payer instructions Reimbursement infor Reimbursement   atient assistance and free product to eligible patients     CancerMPact®. Kantar Health. Treatment Architecture: Western Europe Breast Cancer, v1.2. Available from www.cancermpact.com. Published January 2015. Published January 2015. www.cancermpact.com. from v1.2. Available Cancer, Breast Europe Western Architecture: Health. Treatment Kantar CancerMPact®.

Reimbursement services Reimbursement The Eisai Assistance Program for HALAVEN for Program Assistance Eisai The their payers for all relevant coding, reimbursement, and coverage requirements. It is the sole responsibility of the provider to select the proper code and ensure the and ensure code the proper select to of the provider It is the sole responsibility requirements. and coverage reimbursement, coding, all relevant for their payers coverage and reimbursement decisions are made by individual payers following the receipt of claims. For additional information, customers should consult with should consult customers additional information, of claims. For the receipt following individual payers made by decisions are and reimbursement coverage medical record. in the patient supported and properly be medically appropriate must All services used in seeking reimbursement. of all claims accuracy Eisai cannot guarantee payment of any claim. Coding, coverage, and reimbursement may vary significantly by payer, plan, patient, and setting of care. Actual Actual of care. and setting plan, patient,  payer, significantly by vary may and reimbursement coverage, claim. Coding, of any payment Eisai cannot guarantee . 2011;20(6):574-578. . 2011;20(6):574-578. Breast practice? in current cancer breast in metastatic benefit survival lines of treatment E, et al. Late E, Abrial C, Thivat 16. Planchat 17. V.2.2016. Cancer Breast Guidelines®) for (NCCN Guidelines in Oncology Practice Clinical the NCCN from with permission 18. Referenced 2015. May Updated of the version and complete recent the most view To 2016. 24, August Accessed Inc. All rights reserved. Network, Cancer Comprehensive National © 2016 trademarks are Content GUIDELINES®, and all other NCCN NCCN NCCN®, CANCER NETWORK®, COMPREHENSIVE NATIONAL NCCN.org. go online to guideline, Inc. 19. Network, Cancer Comprehensive the National by owned 20. 2016. 24, August Accessed publications/dictionaries/cancer-terms?CdrID=618612. Drugs and Biologics. http://www.fda.gov/downloads/Drugs/ of Cancer the Approval Endpoints for Clinical Trial Industry: for Guidance Administration. Eisai Inc. on file, 21. Data 2016. 24, August Accessed 2007. Published May guidancecomplianceregulatoryinformation/guidances/ucm071590.pdf. Cancers clinical trial results. of recent a review liposarcoma: in advanced therapies systemic RE. Novel DC, Pollock Lev Lazar AJ, Somaiah N, WW, 22. Tseng Soft Tissue Guidelines®) for (NCCN Guidelines in Oncology Clinical Practice the NCCN from with permission 23. Referenced (Basel). 2013;5(2):529-549. and complete recent the most view To 2016. 24, August Accessed Inc. All rights reserved. Network, Cancer Comprehensive National © 2016 V.2.2016. Sarcoma Content GUIDELINES®, and all other NCCN NCCN NCCN®, CANCER NETWORK®, COMPREHENSIVE NATIONAL NCCN.org. go online to guideline, of the version Common Program, Evaluation Therapy Cancer Institute. Cancer National Inc. 24. Network, Cancer Comprehensive the National by owned trademarks are http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. # 03-5410. NIH Publication v3.0. Events Adverse for Criteria Terminology 2016. 24, August 2006. Accessed 9, August Updated 31, 2003. Published March Cancer Sci . models. Cancer cancer human breast in preclinical remodeling vascular abnormality by tumor microenvironment reduces Eribulin mesylate agent. mechanism of action of a unique microtubule-targeting Risinger AL, Mooberry SL. Eribulin mesylate: NF, 14. Dybdal-Hargreaves 2014;105(10):1334-1342. 2011;11(8):714-723. Biol Ther. Cancer progression. cancer promoting vision of hypoxia a new YL, Liang XH. EMT: Tang 15. Jiang J, Res. 2015;21(11):2445-2452. Clin Cancer References: investigators. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label a phase (EMBRACE): cancer breast with metastatic in patients choice of physician’s treatment versus monotherapy Eribulin investigators. cancer: breast in advanced survival and post-progression survival M. Overall A, Buyse Katz 2. Saad ED, . 2011;377(9769):914-923. Lancet study. randomised phase III trial of et al. Randomized O, E, Rixe Vrdoljak JA, 3. Sparano . 2010;28(11):1958-1962. clinical trials. J Clin Oncol randomized of recent a review . J Clin Oncol and a taxane. with an anthracycline treated previously cancer breast with metastatic capecitabine in patients plus capecitabine versus ixabepilone dacarbazine et al. Eribulin versus S, Maki RG, Chawla 5. Schöffski NJ: Eisai Inc; 2016. P, Lake, insert]. Woodcliff [package 4. HALAVEN 2010;28(20):3256-3263. . 2016;387(10028):1629-1637. phase 3 trial. Lancet open-label, multicentre, a randomised, or leiomyosarcoma: liposarcoma with advanced patients in treated previously Res . of halichondrin B. Cancer analogues ketone macrocyclic activities of synthetic anticancer and in vivo et al. In vitro J, Budrow KA, Salvato MJ, 6. Towle of is suppression halichondrin E7389 mechanism of action of the synthetic primary antimitotic et al. The 7. K, Manna T, 2001;61(3):1013-1021. Kamath MA, Jordan of implications blockade: mitotic irreversible et al. Eribulin induces BF, Wels KA, Salvato MJ, 8. Towle . 2005;4(7):1086-1095. Ther Mol Cancer growth. microtubule 9. Res . 2011;71(2):496-505. conditions. Cancer dosing efficacy under intermittent in vivo for pharmacodynamics cell-based Res . Cancer analog E7389. ketone halichondrin B macrocyclic by blockage mitotic prolonged following Induction of morphological and biochemical apoptosis instability. dynamic suppress on tubulin to site a single ends to microtubule et al. Eribulin binds at O, L, Azarenko Wilson Smith JA, 10. 2004;64(16):5760-5766. 2004;4(4):253-265. Cancer. Rev drugs. Nat anticancer for as a target L. Microtubules Wilson MA, 11. Jordan . 2010;49(6):1331-1337. Biochemistry epithelial– phenotype from reversing by cells cancer of breast metastasis experimental suppresses et al. Eribulin mesilate T, Kimura Y, Ozawa T, 12. Yoshida 2014;110(6):1497-1505. Br J Cancer. (MET) states. transition mesenchymal–epithelial (EMT) to transition mesenchymal † Significant overall survival benefit TWICE PROVEN: and consistent safety profile4

MEDIAN OS4 HALAVEN CONTROL ARM HAZARD RATIO (95% CI) (95% CI) (95% CI)

mBC: following 2 (n=508) (TPC, n=254) 0.81 prior mBC therapies 13.1 months 10.6 months (0.66, 0.99) (primary analysis) (11.8, 14.3) (9.3, 12.5)

(n=71) (dacarbazine, n=72) 0.51 Advanced liposarcoma 15.6 months 8.4 months (0.35, 0.75) (10.2, 18.6) (5.2, 10.1)

Tumor types4 Consistent dose mBC: following 2 prior mBC and schedule4 therapies  Quick 2- to 5-minute IV infusion: Advanced liposarcoma administered on Days 1 and 8 of a 21-day cycle Established dose modification schedule

Proven clinical-trial and real-world experience4,21 Prescribed to approximately 40,000 patients with mBC in the United States

The first agent in the halichondrin class6 Based on preclinical studies, HALAVEN exerts its effects through its distinct binding profile4,7 HALAVEN showed biological effects on tumor vascularization and microenvironment in human cancer models in vivo. HALAVEN also showed decreased migration and invasiveness of cancer cells in vitro4,5

For more information, please visit www.halaven.com

OS=overall survival; CI=confidence interval; mBC=metastatic breast cancer; TPC=Treatment of Physician’s Choice; IV=intravenous.

Important Safety Information (continued) Hepatic and Renal Impairment: A reduction in starting dose is recommended for patients with mild or moderate hepatic impairment and/or moderate or severe renal impairment.

Please see additional Important Safety Information throughout and accompanying HALAVEN full Prescribing Information.

HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2016 Eisai Inc. All rights reserved. Printed in USA/September 2016 HALA-US0218(2)a HIGHLIGHTS OF PRESCRIBING INFORMATION WARNINGS AND PRECAUTIONS Store undiluted HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were These highlights do not include all the information needed to use HALAVEN safely and • Neutropenia: Monitor peripheral blood cell counts and adjust dose as appropriate. (5.1) hours under refrigeration (40°F or 4°C). Store diluted solutions of HALAVEN for up to 4 hours at common adverse reactions occurring in at least 10% of patients in either group. fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The PATIENT INFORMATION ® effectively. See full prescribing information for HALAVEN. • Peripheral Neuropathy: Monitor for signs of neuropathy. Manage with dose delay and room temperature or up to 24 hours under refrigeration. Table 2: Adverse Reactionsa with a Per-Patient Incidence of at Least 10% in Study 1 most common (≥5%) Grade 3-4 laboratory abnormalities reported in patients receiving HALAVEN HALAVEN (HAL-ih-ven) Discard unused portions of the vial. were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions ® adjustment. (5.2) (eribulin mesylate) HALAVEN (eribulin mesylate) injection, for intravenous use 3 DOSAGE FORMS AND STRENGTHS HALAVEN Control Group reported in patients receiving HALAVEN were neutropenia (4.9%) and pyrexia (4.5%). Permanent • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the Adverse Reactions n=503 n=247 injection, for intravenous use Initial U.S. Approval: 2010 potential risk to the fetus and to use effective contraception. (5.3, 8.1, 8.3) Injection: 1 mg/2 mL (0.5 mg/mL). discontinuation of HALAVEN for adverse reactions occurred in 8% of patients. The most common 4 CONTRAINDICATIONS All Grades ≥ Grade 3 All Grades ≥ Grade 3 adverse reactions resulting in discontinuation of HALAVEN were fatigue and thrombocytopenia • QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, b What is the most important information I should know about HALAVEN? RECENT MAJOR CHANGES None. Blood and lymphatic system disorders (0.9% each). Twenty-six percent of patients required at least one dose reduction. The most Indications and Usage (1.2) 01/2016 bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid Neutropenia 82% 57% 53% 23% 5 WARNINGS AND PRECAUTIONS frequent adverse reactions that led to dose reduction were neutropenia (18%) and peripheral HALAVEN can cause serious side effects, including: in patients with congenital long QT syndrome. (5.4) Anemia 58% 2% 55% 4% neuropathy (4.0%). Warnings and Precautions (5.1, 5.2, 5.3) 01/2016 5.1 Neutropenia ADVERSE REACTIONS Nervous system disorders In Study 1, severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients in • Low white blood cell count (neutropenia). This can lead to INDICATIONS AND USAGE The most common adverse reactions (≥25%) in metastatic breast cancer were neutropenia, anemia, Peripheral neuropathyc 35% 8% 16% 2% the HALAVEN-treated arm in Study 2. HALAVEN is a microtubule inhibitor indicated for the treatment of patients with: (62/503) of patients with metastatic breast cancer, leading to discontinuation in <1% of patients. asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. (6.1) Headache 19% <1% 12% <1% a serious infections that could lead to death. Your healthcare provider • Metastatic breast cancer who have previously received at least two chemotherapeutic regimens Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 5% (23/503) Table 3: Adverse Reactions Occurring in ≥10% (all Grades) of Patients Treated on The most common adverse reactions (≥25%) in liposarcoma and leiomyosarcoma were fatigue, General disorders the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm will check your blood cell counts before you receive each dose of for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a of patients; two patients (0.4%) died from complications of febrile neutropenia [see Adverse nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most Reactions (6.1)]. Asthenia/Fatigue 54% 10% 40% 11% (Between Arm Difference of ≥5% for All Grades or ≥2% for Grades 3 and 4) HALAVEN and during treatment. Call your healthcare provider right taxane in either the adjuvant or metastatic setting. (1.1) common (≥5%) Grade 3-4 laboratory abnormalities in liposarcoma and leiomyosarcoma were Pyrexia 21% <1% 13% <1% (Study 2)b • Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing neutropenia, hypokalemia, and hypocalcemia. (6.1) In Study 1, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) away if you develop any of these symptoms of infection: > 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia Mucosal inflammation 9% 1% 10% 2% regimen. (1.2) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at (1-877-873-4724) or FDA Gastrointestinal disorders HALAVEN Dacarbazine and febrile neutropenia than patients with normal aminotransferase levels. Patients with Adverse Reaction n=223 n=221 –fever (temperature above 100.5°F) at 1-800-FDA-1088 or www.fda.gov/medwatch Nausea 35% 1% 28% 3% DOSAGE AND ADMINISTRATION bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia. All Grades Grades 3-4 All Grades Grades 3-4 –chills • Administer 1.4 mg/m2 intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. (2.1) USE IN SPECIFIC POPULATIONS In Study 2, severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% Constipation 25% 1% 21% 1% Vomiting 18% 1% 18% 1% Nervous system disorders –cough • Reduce dose in patients with hepatic impairment or with moderate or severe renal impairment. (2.1) • Lactation: Do not breastfeed. (8.2) (26/222) of patients with liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 0.9% of Peripheral Neuropathyc 29% 3.1% 8% 0.5% • Hepatic Impairment: A lower starting dose is recommended for patients with mild patients treated with HALAVEN and fatal neutropenic sepsis in 0.9% [see Adverse Reactions (6.1)]. Diarrhea 18% 0 18% 0 –burning or pain when you urinate • Do not mix with other drugs or administer with dextrose-containing solutions. (2.3) Musculoskeletal and connective tissue disorders Headache 18% 0% 10% 0% (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. Patients with severe Monitor complete blood counts prior to each dose; increase the frequency of monitoring in General disorders DOSAGE FORMS AND STRENGTHS hepatic impairment (Child-Pugh C) were not studied. (8.6) patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce Arthralgia/Myalgia 22% <1% 12% 1% • Numbness, tingling, or pain in your hands or feet (peripheral Back pain 16% 1% 7% 2% Pyrexia 28% 0.9% 14% 0.5% Injection: 1 mg per 2 mL (0.5 mg per mL) (3) • Renal Impairment: A lower starting dose is recommended for patients with moderate subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting Bone pain 12% 2% 9% 2% Gastrointestinal disorders neuropathy). Peripheral neuropathy is common with HALAVEN and (CLcr 30-49 mL/min) or severe (CLcr 15-29 mL/min) renal impairment. (8.7) longer than 7 days [see Dosage and Administration (2.2)]. Clinical studies of HALAVEN did not Constipation 32% 0.9% 26% 0.5% CONTRAINDICATIONS 3 Pain in extremity 11% 1% 10% 1% sometimes can be severe. Tell your healthcare provider if you have See 17 for PATIENT COUNSELING INFORMATION and FDA-approved Patient Labeling include patients with baseline neutrophil counts below 1,500/mm . d None (4) Metabolism and nutrition disorders Abdominal pain 29% 1.8% 23% 4.1% (Patient Information). 5.2 Peripheral Neuropathy new or worsening symptoms of peripheral neuropathy. Decreased weight 21% 1% 14% <1% Stomatitis 14% 0.9% 5% 0.5% Revised: October 2016 In Study 1, Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in Anorexia 20% 1% 13% 1% Skin and subcutaneous tissue disorders • Your healthcare provider may delay, decrease your dose, or stop 0.4% (2/503) of patients with metastatic breast cancer (MBC). Peripheral neuropathy was the Alopecia 35% NAe 2.7% NAe treatment with HALAVEN if you have side effects. FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503) in Study 1. Respiratory, thoracic, and mediastinal disorders Dyspnea 16% 4% 13% 4% Infections 8.1 Pregnancy Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent Urinary tract infection 11% 2.2% 5% 0.5% 1 INDICATIONS AND USAGE (109/503) of patients developed a new or worsening neuropathy that had not recovered within a Cough 14% 0 9% 0 See “What are possible side effects of HALAVEN?” for more 8.2 Lactation a 1.1 Metastatic Breast Cancer median follow-up duration of 269 days (range 25-662 days). Skin and subcutaneous tissue disorders Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events information about side effects. 8.3 Females and Males of Reproductive Potential d d 1.2 Liposarcoma In Study 2, Grade 3 peripheral neuropathy occurred in 3.1% (7/223) of HALAVEN-treated Alopecia 45% NA 10% NA version 4.03 (NCI CTCAE v4.03). 2 DOSAGE AND ADMINISTRATION 8.4 Pediatric Use Infections b Safety data from one study site enrolling six patients were excluded. What is HALAVEN? patients. Peripheral neuropathy led to discontinuation of HALAVEN in 0.9% of patients. The c 2.1 Recommended Dose 8.5 Geriatric Use median time to first occurrence of peripheral neuropathy of any severity was 5 months (range: Urinary Tract Infection 10% 1% 5% 0 Includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor 8.6 Hepatic Impairment a neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. 2.2 Dose Modification 3.5 months to 9 months). Neuropathy lasting more than 60 days occurred in 58% (38/65) of adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.0. d HALAVEN is a prescription medicine used to treat people with: 8.7 Renal Impairment patients. Sixty three percent (41/65) had not recovered within a median follow-up duration of b Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort. 2.3 Instructions for Preparation and Administration based upon laboratory data. e Not applicable; (grading system does not specify > Grade 2 for alopecia). 3 DOSAGE FORMS AND STRENGTHS 10 OVERDOSAGE 6.4 months (range: 27 days to 29 months). c includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor • Breast cancer 4 CONTRAINDICATIONS 11 DESCRIPTION Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. Other clinically important adverse reactions occurring in ≥10% of the HALAVEN-treated – that has spread to other parts of the body, and 5 WARNINGS AND PRECAUTIONS 12 CLINICAL PHARMACOLOGY HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy, until resolution to d not applicable; (grading system does not specify > Grade 2 for alopecia). patients were: Grade 2 or less [see Dosage and Administration (2.2)]. – who have already received certain types of anticancer medicines 5.1 Neutropenia 12.1 Mechanism of Action Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN • Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%) 5.3 Embryo-Fetal Toxicity 5.2 Peripheral Neuropathy 12.2 Pharmacodynamics in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia • General Disorders: asthenia/fatigue (62%); peripheral edema (12%) after the cancer has spread Based on findings from an animal reproduction study and its mechanism of action, HALAVEN 5.3 Embryo-Fetal Toxicity 12.3 Pharmacokinetics occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile • Metabolism and Nutrition Disorders: decreased appetite (19%) • Liposarcoma 13 NONCLINICAL TOXICOLOGY can cause fetal harm when administered to a pregnant woman. There are no adequate and neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and • Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); 5.4 QT Prolongation well-controlled studies of HALAVEN in pregnant women. In animal reproduction studies, eribulin – that cannot be treated with surgery or has spread to other parts 6 ADVERSE REACTIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the back pain (16%) mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis 3 of the body, and 6.1 Clinical Trials Experience 14 CLINICAL STUDIES mean time to recovery from severe neutropenia (<500/mm ) was 8 days. Grade 3 or greater • Respiratory Disorders: cough (18%) at doses below the recommended human dose. Advise pregnant women of the potential risk to thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating 6.2 Postmarketing Experience 14.1 Metastatic Breast Cancer a fetus. Advise females of reproductive potential to use effective contraception during treatment Less Common Adverse Reactions: The following additional clinically important adverse reactions – who have received treatment with a certain type of 14.2 Liposarcoma factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of were reported in ≥5% to <10% of the HALAVEN-treated group: 7 DRUG INTERACTIONS with HALAVEN and for at least 2 weeks following the final dose. Advise males with female patients who received HALAVEN. anticancer medicine 16 HOW SUPPLIED/STORAGE AND HANDLING partners of reproductive potential to use effective contraception during treatment with HALAVEN • Blood and Lymphatic System Disorders: thrombocytopenia 7.1 Effects of Other Drugs on HALAVEN Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy 17 PATIENT COUNSELING INFORMATION and for 3.5 months following the final dose[see Use in Specific Populations (8.1)]. • Eye Disorders: increased lacrimation 7.2 Effects of HALAVEN on Other Drugs and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to It is not known if HALAVEN is safe and effective in children under 18 years *Sections or subsections omitted from the full prescribing information are not listed. • Gastrointestinal Disorders: dyspepsia 5.4 QT Prolongation peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four of age. In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% • Metabolism and Nutrition Disorders: hyperglycemia FULL PRESCRIBING INFORMATION – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. (8/503) of patients developed Grade 3 peripheral motor neuropathy. • Musculoskeletal and Connective Tissue Disorders: muscle spasms, Before you receive HALAVEN, tell your healthcare provider about 1 INDICATIONS AND USAGE reduced dose and initiate the next cycle no sooner than 2 weeks later. ECG monitoring is recommended if therapy is initiated in patients with congestive heart Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, musculoskeletal pain all of your medical conditions, including if you: 1.1 Metastatic Breast Cancer Recommended dose reductions failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN- • Nervous System Disorders: dizziness, dysgeusia HALAVEN is indicated for the treatment of patients with metastatic breast cancer who have • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia treated patient without documented liver metastases had concomitant Grade 2 elevations in • Psychiatric Disorders: insomnia, anxiety • have liver or kidney problems previously received at least two chemotherapeutic regimens for the treatment of metastatic less, resume HALAVEN at a reduced dose as set out in Table 1. prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. • Respiratory, Thoracic, and Mediastinal Disorders: oropharyngeal pain disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant Avoid HALAVEN in patients with congenital long QT syndrome. • Do not re-escalate HALAVEN dose after it has been reduced. Less Common Adverse Reactions: The following additional adverse reactions were reported in • Vascular Disorders: hypotension • have heart problems, including a problem called congenital long or metastatic setting [see Clinical Studies (14.1)]. 6 ADVERSE REACTIONS Table 1: Recommended Dose Reductions ≥5% to <10% of the HALAVEN-treated group: QT syndrome 1.2 Liposarcoma 6.1 Clinical Trials Experience Table 4: Laboratory Abnormalities Occurring in ≥10% (all Grades) of Patients Treated Recommended • Eye Disorders: increased lacrimation • have low potassium or low magnesium in your blood HALAVEN is indicated for the treatment of patients with unresectable or metastatic liposarcoma Event Description Because clinical trials are conducted under widely varying conditions, the adverse reaction rates on the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm who have received a prior anthracycline-containing regimen [see Clinical Studies (14.2)]. HALAVEN Dose observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth (Between Arm Difference of ≥5% for All Grades or ≥2% for Grades 3 and 4)a • are pregnant or plan to become pregnant. HALAVEN can harm your 2 DOSAGE AND ADMINISTRATION Permanently reduce the 1.4 mg/m2 HALAVEN dose and may not reflect the rates observed in clinical practice. • General Disorders and Administration Site Conditions: peripheral edema (Study 2)† for any of the following: • Infections and Infestations: upper respiratory tract infection unborn baby. Tell your healthcare provider right away if you become 2.1 Recommended Dose The following adverse reactions are discussed in detail in other sections of the labeling: Laboratory Abnormality Halaven Dacarbazine The recommended dose of HALAVEN is 1.4 mg/m2 administered intravenously over 2 to 5 ANC <500/mm3 for >7 days • Neutropenia [see Warnings and Precautions (5.1)] • Metabolism and Nutrition Disorders: hypokalemia pregnant or think you are pregnant during treatment with HALAVEN. 3 All Grades Grades 3-4 All Grades Grades 3-4 minutes on Days 1 and 8 of a 21-day cycle. ANC <1,000 /mm with fever or infection • Peripheral neuropathy [see Warnings and Precautions (5.2)] • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness – Females who are able to become pregnant should use an 3 2 Hematology The recommended dose of HALAVEN in patients with mild hepatic impairment (Child-Pugh A) is Platelets <25,000/mm 1.1 mg/m • QT prolongation [see Warnings and Precautions (5.4)] • Nervous System Disorders: dysgeusia, dizziness Anemia 70% 4.1% 52% 6% effective birth control during treatment with HALAVEN and for at 2 Platelets <50,000/mm3 requiring transfusion 1.1 mg/m administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle In clinical trials, HALAVEN has been administered to 1963 patients including 467 patients • Psychiatric Disorders: insomnia, depression Neutropenia 63% 32% 30% 8.9% least 2 weeks after the final dose of HALAVEN. [see Use in Specific Populations (8.6)]. Non-hematologic Grade 3 or 4 toxicities exposed to HALAVEN for 6 months or longer. The majority of the 1963 patients were women • Skin and Subcutaneous Tissue Disorders: rash Chemistry The recommended dose of HALAVEN in patients with moderate hepatic impairment (Child-Pugh B) Omission or delay of Day 8 HALAVEN dose in previous (92%) with a median age of 55 years (range: 17 to 85 years). The racial and ethnic distribution Liposarcoma Increased alanine aminotransferase – Males should use an effective form of birth control when 2 43% 2.3% 28% 2.3% is 0.7 mg/m administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle cycle for toxicity was White (72%), Black (4%), Asian (9%), and other (3%). The safety of HALAVEN was evaluated in Study 2, an open-label, randomized, multicenter, (ALT) having sex with female partners who are able to become [see Use in Specific Populations (8.6)]. Occurrence of any event requiring permanent dose reduction 0.7 mg/m2 Metastatic Breast Cancer active-controlled trial, in which patients were randomized (1:1) to receive either HALAVEN Increased aspartate 2 2 2 36% 0.9% 16% 0.5% pregnant during treatment with HALAVEN and for 3 1/2 months The recommended dose of HALAVEN in patients with moderate or severe renal impairment while receiving 1.1 mg/m The most common adverse reactions (≥25%) reported in patients receiving HALAVEN 1.4 mg/m on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 850 mg/m (20%), aminotransferase (AST) 2 2 2 (creatinine clearance (CLcr) 15-49 mL/min) is 1.1 mg/m administered intravenously over Occurrence of any event requiring permanent dose reduction were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and 1000 mg/m (64%), or 1200 mg/m (16%) every 3 weeks. A total of 223 patients received HALAVEN Hypokalemia 30% 5.4% 14% 2.8% (14 weeks) after the final dose of HALAVEN. 2 to 5 minutes on Days 1 and 8 of a 21-day cycle . 2 Discontinue HALAVEN [see Use in Specific Populations (8.7)] while receiving 0.7 mg/m constipation. The most common serious adverse reactions reported in patients receiving and 221 patients received dacarbazine. Patients were required to have received at least two Hypocalcemia 28% 5% 18% 1.4% • are breastfeeding or plan to breastfeed. It is not known if HALAVEN 2.2 Dose Modification ANC = absolute neutrophil count. HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse prior systemic chemotherapy regimens. The trial excluded patients with pre-existing ≥ Grade 3 Hypophosphatemia 20% 3.2% 11% 1.4% Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or passes into your breast milk. Do not breastfeed during treatment with Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). a Recommended dose delays Criteria for Adverse Events (CTCAE) version 3.0. The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 significant chronic liver disease, history of myocardial infarction within 6 months, history of Each test incidence is based on the number of patients who had both baseline and at least one HALAVEN and for 2 weeks after the final dose of HALAVEN. [see Clinical Studies (14.1)]. In Study 1, patients were randomized (2:1) to receive either New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment. on-study measurement and at least 1 grade increase from baseline. Halaven group (range • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: 2.3 Instructions for Preparation and Administration 221-222) and dacarbazine group (range 214-215) 3 HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by The median age of the safety population in Study 2 was 56 years (range: 24 to 83 years); Tell your healthcare provider about all the medicines you take, – ANC < 1,000/mm Aseptically withdraw the required amount of HALAVEN from the single-use vial and † Laboratory results were graded per NCI CTCAE v4.03. – Platelets < 75,000/mm3 administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. their physician (control group). A total of 503 patients received HALAVEN and 247 patients in 67% female; 73% White, 3% Black or African American, 8% Asian/Pacific Islander, and including prescription and over-the-counter medicines, vitamins, and – Grade 3 or 4 non-hematological toxicities. Do not dilute in or administer through an intravenous line containing solutions the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, 15% unknown; 99% received prior anthracycline-containing regimen; and 99% received ≥ 2 prior herbal supplements. with dextrose. Do not administer in the same intravenous line concurrent with the other capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies regimens. The median duration of exposure was 2.3 months (range: 21 days to 26 months) for • The Day 8 dose may be delayed for a maximum of 1 week. patients receiving HALAVEN [see Clinical Studies (14.2)]. – If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. medicinal products. 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients ✃ HIGHLIGHTS OF PRESCRIBING INFORMATION WARNINGS AND PRECAUTIONS Store undiluted HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were These highlights do not include all the information needed to use HALAVEN safely and • Neutropenia: Monitor peripheral blood cell counts and adjust dose as appropriate. (5.1) hours under refrigeration (40°F or 4°C). Store diluted solutions of HALAVEN for up to 4 hours at common adverse reactions occurring in at least 10% of patients in either group. fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The PATIENT INFORMATION ® effectively. See full prescribing information for HALAVEN. • Peripheral Neuropathy: Monitor for signs of neuropathy. Manage with dose delay and room temperature or up to 24 hours under refrigeration. Table 2: Adverse Reactionsa with a Per-Patient Incidence of at Least 10% in Study 1 most common (≥5%) Grade 3-4 laboratory abnormalities reported in patients receiving HALAVEN HALAVEN (HAL-ih-ven) Discard unused portions of the vial. were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions ® adjustment. (5.2) (eribulin mesylate) HALAVEN (eribulin mesylate) injection, for intravenous use 3 DOSAGE FORMS AND STRENGTHS HALAVEN Control Group reported in patients receiving HALAVEN were neutropenia (4.9%) and pyrexia (4.5%). Permanent • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the Adverse Reactions n=503 n=247 injection, for intravenous use Initial U.S. Approval: 2010 potential risk to the fetus and to use effective contraception. (5.3, 8.1, 8.3) Injection: 1 mg/2 mL (0.5 mg/mL). discontinuation of HALAVEN for adverse reactions occurred in 8% of patients. The most common 4 CONTRAINDICATIONS All Grades ≥ Grade 3 All Grades ≥ Grade 3 adverse reactions resulting in discontinuation of HALAVEN were fatigue and thrombocytopenia • QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, b What is the most important information I should know about HALAVEN? RECENT MAJOR CHANGES None. Blood and lymphatic system disorders (0.9% each). Twenty-six percent of patients required at least one dose reduction. The most Indications and Usage (1.2) 01/2016 bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid Neutropenia 82% 57% 53% 23% 5 WARNINGS AND PRECAUTIONS frequent adverse reactions that led to dose reduction were neutropenia (18%) and peripheral HALAVEN can cause serious side effects, including: in patients with congenital long QT syndrome. (5.4) Anemia 58% 2% 55% 4% neuropathy (4.0%). Warnings and Precautions (5.1, 5.2, 5.3) 01/2016 5.1 Neutropenia ADVERSE REACTIONS Nervous system disorders In Study 1, severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients in • Low white blood cell count (neutropenia). This can lead to INDICATIONS AND USAGE The most common adverse reactions (≥25%) in metastatic breast cancer were neutropenia, anemia, Peripheral neuropathyc 35% 8% 16% 2% the HALAVEN-treated arm in Study 2. HALAVEN is a microtubule inhibitor indicated for the treatment of patients with: (62/503) of patients with metastatic breast cancer, leading to discontinuation in <1% of patients. asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. (6.1) Headache 19% <1% 12% <1% a serious infections that could lead to death. Your healthcare provider • Metastatic breast cancer who have previously received at least two chemotherapeutic regimens Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 5% (23/503) Table 3: Adverse Reactions Occurring in ≥10% (all Grades) of Patients Treated on The most common adverse reactions (≥25%) in liposarcoma and leiomyosarcoma were fatigue, General disorders the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm will check your blood cell counts before you receive each dose of for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a of patients; two patients (0.4%) died from complications of febrile neutropenia [see Adverse nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most Reactions (6.1)]. Asthenia/Fatigue 54% 10% 40% 11% (Between Arm Difference of ≥5% for All Grades or ≥2% for Grades 3 and 4) HALAVEN and during treatment. Call your healthcare provider right taxane in either the adjuvant or metastatic setting. (1.1) common (≥5%) Grade 3-4 laboratory abnormalities in liposarcoma and leiomyosarcoma were Pyrexia 21% <1% 13% <1% (Study 2)b • Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing neutropenia, hypokalemia, and hypocalcemia. (6.1) In Study 1, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) away if you develop any of these symptoms of infection: > 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia Mucosal inflammation 9% 1% 10% 2% regimen. (1.2) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at (1-877-873-4724) or FDA Gastrointestinal disorders HALAVEN Dacarbazine and febrile neutropenia than patients with normal aminotransferase levels. Patients with Adverse Reaction n=223 n=221 –fever (temperature above 100.5°F) at 1-800-FDA-1088 or www.fda.gov/medwatch Nausea 35% 1% 28% 3% DOSAGE AND ADMINISTRATION bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia. All Grades Grades 3-4 All Grades Grades 3-4 –chills • Administer 1.4 mg/m2 intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. (2.1) USE IN SPECIFIC POPULATIONS In Study 2, severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% Constipation 25% 1% 21% 1% Vomiting 18% 1% 18% 1% Nervous system disorders –cough • Reduce dose in patients with hepatic impairment or with moderate or severe renal impairment. (2.1) • Lactation: Do not breastfeed. (8.2) (26/222) of patients with liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 0.9% of Peripheral Neuropathyc 29% 3.1% 8% 0.5% • Hepatic Impairment: A lower starting dose is recommended for patients with mild patients treated with HALAVEN and fatal neutropenic sepsis in 0.9% [see Adverse Reactions (6.1)]. Diarrhea 18% 0 18% 0 –burning or pain when you urinate • Do not mix with other drugs or administer with dextrose-containing solutions. (2.3) Musculoskeletal and connective tissue disorders Headache 18% 0% 10% 0% (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. Patients with severe Monitor complete blood counts prior to each dose; increase the frequency of monitoring in General disorders DOSAGE FORMS AND STRENGTHS hepatic impairment (Child-Pugh C) were not studied. (8.6) patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce Arthralgia/Myalgia 22% <1% 12% 1% • Numbness, tingling, or pain in your hands or feet (peripheral Back pain 16% 1% 7% 2% Pyrexia 28% 0.9% 14% 0.5% Injection: 1 mg per 2 mL (0.5 mg per mL) (3) • Renal Impairment: A lower starting dose is recommended for patients with moderate subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting Bone pain 12% 2% 9% 2% Gastrointestinal disorders neuropathy). Peripheral neuropathy is common with HALAVEN and (CLcr 30-49 mL/min) or severe (CLcr 15-29 mL/min) renal impairment. (8.7) longer than 7 days [see Dosage and Administration (2.2)]. Clinical studies of HALAVEN did not Constipation 32% 0.9% 26% 0.5% CONTRAINDICATIONS 3 Pain in extremity 11% 1% 10% 1% sometimes can be severe. Tell your healthcare provider if you have See 17 for PATIENT COUNSELING INFORMATION and FDA-approved Patient Labeling include patients with baseline neutrophil counts below 1,500/mm . d None (4) Metabolism and nutrition disorders Abdominal pain 29% 1.8% 23% 4.1% (Patient Information). 5.2 Peripheral Neuropathy new or worsening symptoms of peripheral neuropathy. Decreased weight 21% 1% 14% <1% Stomatitis 14% 0.9% 5% 0.5% Revised: October 2016 In Study 1, Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in Anorexia 20% 1% 13% 1% Skin and subcutaneous tissue disorders • Your healthcare provider may delay, decrease your dose, or stop 0.4% (2/503) of patients with metastatic breast cancer (MBC). Peripheral neuropathy was the Alopecia 35% NAe 2.7% NAe treatment with HALAVEN if you have side effects. FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503) in Study 1. Respiratory, thoracic, and mediastinal disorders Dyspnea 16% 4% 13% 4% Infections 8.1 Pregnancy Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent Urinary tract infection 11% 2.2% 5% 0.5% 1 INDICATIONS AND USAGE (109/503) of patients developed a new or worsening neuropathy that had not recovered within a Cough 14% 0 9% 0 See “What are possible side effects of HALAVEN?” for more 8.2 Lactation a 1.1 Metastatic Breast Cancer median follow-up duration of 269 days (range 25-662 days). Skin and subcutaneous tissue disorders Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events information about side effects. 8.3 Females and Males of Reproductive Potential d d 1.2 Liposarcoma In Study 2, Grade 3 peripheral neuropathy occurred in 3.1% (7/223) of HALAVEN-treated Alopecia 45% NA 10% NA version 4.03 (NCI CTCAE v4.03). 2 DOSAGE AND ADMINISTRATION 8.4 Pediatric Use Infections b Safety data from one study site enrolling six patients were excluded. What is HALAVEN? patients. Peripheral neuropathy led to discontinuation of HALAVEN in 0.9% of patients. The c 2.1 Recommended Dose 8.5 Geriatric Use median time to first occurrence of peripheral neuropathy of any severity was 5 months (range: Urinary Tract Infection 10% 1% 5% 0 Includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor 8.6 Hepatic Impairment a neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. 2.2 Dose Modification 3.5 months to 9 months). Neuropathy lasting more than 60 days occurred in 58% (38/65) of adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.0. d HALAVEN is a prescription medicine used to treat people with: 8.7 Renal Impairment patients. Sixty three percent (41/65) had not recovered within a median follow-up duration of b Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort. 2.3 Instructions for Preparation and Administration based upon laboratory data. e Not applicable; (grading system does not specify > Grade 2 for alopecia). 3 DOSAGE FORMS AND STRENGTHS 10 OVERDOSAGE 6.4 months (range: 27 days to 29 months). c includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor • Breast cancer 4 CONTRAINDICATIONS 11 DESCRIPTION Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. Other clinically important adverse reactions occurring in ≥10% of the HALAVEN-treated –that has spread to other parts of the body, and 5 WARNINGS AND PRECAUTIONS 12 CLINICAL PHARMACOLOGY HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy, until resolution to d not applicable; (grading system does not specify > Grade 2 for alopecia). patients were: Grade 2 or less [see Dosage and Administration (2.2)]. – who have already received certain types of anticancer medicines 5.1 Neutropenia 12.1 Mechanism of Action Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN • Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%) 5.3 Embryo-Fetal Toxicity 5.2 Peripheral Neuropathy 12.2 Pharmacodynamics in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia • General Disorders: asthenia/fatigue (62%); peripheral edema (12%) after the cancer has spread Based on findings from an animal reproduction study and its mechanism of action, HALAVEN 5.3 Embryo-Fetal Toxicity 12.3 Pharmacokinetics occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile • Metabolism and Nutrition Disorders: decreased appetite (19%) • Liposarcoma 13 NONCLINICAL TOXICOLOGY can cause fetal harm when administered to a pregnant woman. There are no adequate and neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and • Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); 5.4 QT Prolongation well-controlled studies of HALAVEN in pregnant women. In animal reproduction studies, eribulin – that cannot be treated with surgery or has spread to other parts 6 ADVERSE REACTIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the back pain (16%) mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis 3 of the body, and 6.1 Clinical Trials Experience 14 CLINICAL STUDIES mean time to recovery from severe neutropenia (<500/mm ) was 8 days. Grade 3 or greater • Respiratory Disorders: cough (18%) at doses below the recommended human dose. Advise pregnant women of the potential risk to thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating 6.2 Postmarketing Experience 14.1 Metastatic Breast Cancer a fetus. Advise females of reproductive potential to use effective contraception during treatment Less Common Adverse Reactions: The following additional clinically important adverse reactions – who have received treatment with a certain type of 14.2 Liposarcoma factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of were reported in ≥5% to <10% of the HALAVEN-treated group: 7 DRUG INTERACTIONS with HALAVEN and for at least 2 weeks following the final dose. Advise males with female patients who received HALAVEN. anticancer medicine 16 HOW SUPPLIED/STORAGE AND HANDLING partners of reproductive potential to use effective contraception during treatment with HALAVEN • Blood and Lymphatic System Disorders: thrombocytopenia 7.1 Effects of Other Drugs on HALAVEN Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy 17 PATIENT COUNSELING INFORMATION and for 3.5 months following the final dose[see Use in Specific Populations (8.1)]. • Eye Disorders: increased lacrimation 7.2 Effects of HALAVEN on Other Drugs and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to It is not known if HALAVEN is safe and effective in children under 18 years *Sections or subsections omitted from the full prescribing information are not listed. • Gastrointestinal Disorders: dyspepsia 5.4 QT Prolongation peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four of age. In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% • Metabolism and Nutrition Disorders: hyperglycemia FULL PRESCRIBING INFORMATION – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. (8/503) of patients developed Grade 3 peripheral motor neuropathy. • Musculoskeletal and Connective Tissue Disorders: muscle spasms, Before you receive HALAVEN, tell your healthcare provider about 1 INDICATIONS AND USAGE reduced dose and initiate the next cycle no sooner than 2 weeks later. ECG monitoring is recommended if therapy is initiated in patients with congestive heart Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, musculoskeletal pain all of your medical conditions, including if you: 1.1 Metastatic Breast Cancer Recommended dose reductions failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN- • Nervous System Disorders: dizziness, dysgeusia HALAVEN is indicated for the treatment of patients with metastatic breast cancer who have • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia treated patient without documented liver metastases had concomitant Grade 2 elevations in • Psychiatric Disorders: insomnia, anxiety • have liver or kidney problems previously received at least two chemotherapeutic regimens for the treatment of metastatic less, resume HALAVEN at a reduced dose as set out in Table 1. prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. • Respiratory, Thoracic, and Mediastinal Disorders: oropharyngeal pain disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant Avoid HALAVEN in patients with congenital long QT syndrome. • Do not re-escalate HALAVEN dose after it has been reduced. Less Common Adverse Reactions: The following additional adverse reactions were reported in • Vascular Disorders: hypotension • have heart problems, including a problem called congenital long or metastatic setting [see Clinical Studies (14.1)]. 6 ADVERSE REACTIONS Table 1: Recommended Dose Reductions ≥5% to <10% of the HALAVEN-treated group: QT syndrome 1.2 Liposarcoma 6.1 Clinical Trials Experience Table 4: Laboratory Abnormalities Occurring in ≥10% (all Grades) of Patients Treated Recommended • Eye Disorders: increased lacrimation • have low potassium or low magnesium in your blood HALAVEN is indicated for the treatment of patients with unresectable or metastatic liposarcoma Event Description Because clinical trials are conducted under widely varying conditions, the adverse reaction rates on the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm who have received a prior anthracycline-containing regimen [see Clinical Studies (14.2)]. HALAVEN Dose observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth (Between Arm Difference of ≥5% for All Grades or ≥2% for Grades 3 and 4)a • are pregnant or plan to become pregnant. HALAVEN can harm your 2 DOSAGE AND ADMINISTRATION Permanently reduce the 1.4 mg/m2 HALAVEN dose and may not reflect the rates observed in clinical practice. • General Disorders and Administration Site Conditions: peripheral edema (Study 2)† for any of the following: • Infections and Infestations: upper respiratory tract infection unborn baby. Tell your healthcare provider right away if you become 2.1 Recommended Dose The following adverse reactions are discussed in detail in other sections of the labeling: Laboratory Abnormality Halaven Dacarbazine The recommended dose of HALAVEN is 1.4 mg/m2 administered intravenously over 2 to 5 ANC <500/mm3 for >7 days • Neutropenia [see Warnings and Precautions (5.1)] • Metabolism and Nutrition Disorders: hypokalemia pregnant or think you are pregnant during treatment with HALAVEN. 3 All Grades Grades 3-4 All Grades Grades 3-4 minutes on Days 1 and 8 of a 21-day cycle. ANC <1,000 /mm with fever or infection • Peripheral neuropathy [see Warnings and Precautions (5.2)] • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness – Females who are able to become pregnant should use an 3 2 Hematology The recommended dose of HALAVEN in patients with mild hepatic impairment (Child-Pugh A) is Platelets <25,000/mm 1.1 mg/m • QT prolongation [see Warnings and Precautions (5.4)] • Nervous System Disorders: dysgeusia, dizziness Anemia 70% 4.1% 52% 6% effective birth control during treatment with HALAVEN and for at 2 Platelets <50,000/mm3 requiring transfusion 1.1 mg/m administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle In clinical trials, HALAVEN has been administered to 1963 patients including 467 patients • Psychiatric Disorders: insomnia, depression Neutropenia 63% 32% 30% 8.9% least 2 weeks after the final dose of HALAVEN. [see Use in Specific Populations (8.6)]. Non-hematologic Grade 3 or 4 toxicities exposed to HALAVEN for 6 months or longer. The majority of the 1963 patients were women • Skin and Subcutaneous Tissue Disorders: rash Chemistry The recommended dose of HALAVEN in patients with moderate hepatic impairment (Child-Pugh B) Omission or delay of Day 8 HALAVEN dose in previous (92%) with a median age of 55 years (range: 17 to 85 years). The racial and ethnic distribution Liposarcoma Increased alanine aminotransferase – Males should use an effective form of birth control when 2 43% 2.3% 28% 2.3% is 0.7 mg/m administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle cycle for toxicity was White (72%), Black (4%), Asian (9%), and other (3%). The safety of HALAVEN was evaluated in Study 2, an open-label, randomized, multicenter, (ALT) having sex with female partners who are able to become [see Use in Specific Populations (8.6)]. Occurrence of any event requiring permanent dose reduction 0.7 mg/m2 Metastatic Breast Cancer active-controlled trial, in which patients were randomized (1:1) to receive either HALAVEN Increased aspartate 2 2 2 36% 0.9% 16% 0.5% pregnant during treatment with HALAVEN and for 3 1/2 months The recommended dose of HALAVEN in patients with moderate or severe renal impairment while receiving 1.1 mg/m The most common adverse reactions (≥25%) reported in patients receiving HALAVEN 1.4 mg/m on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 850 mg/m (20%), aminotransferase (AST) 2 2 2 (creatinine clearance (CLcr) 15-49 mL/min) is 1.1 mg/m administered intravenously over Occurrence of any event requiring permanent dose reduction were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and 1000 mg/m (64%), or 1200 mg/m (16%) every 3 weeks. A total of 223 patients received HALAVEN Hypokalemia 30% 5.4% 14% 2.8% (14 weeks) after the final dose of HALAVEN. 2 to 5 minutes on Days 1 and 8 of a 21-day cycle . 2 Discontinue HALAVEN [see Use in Specific Populations (8.7)] while receiving 0.7 mg/m constipation. The most common serious adverse reactions reported in patients receiving and 221 patients received dacarbazine. Patients were required to have received at least two Hypocalcemia 28% 5% 18% 1.4% • are breastfeeding or plan to breastfeed. It is not known if HALAVEN 2.2 Dose Modification ANC = absolute neutrophil count. HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse prior systemic chemotherapy regimens. The trial excluded patients with pre-existing ≥ Grade 3 Hypophosphatemia 20% 3.2% 11% 1.4% Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or passes into your breast milk. Do not breastfeed during treatment with Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). a Recommended dose delays Criteria for Adverse Events (CTCAE) version 3.0. The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 significant chronic liver disease, history of myocardial infarction within 6 months, history of Each test incidence is based on the number of patients who had both baseline and at least one HALAVEN and for 2 weeks after the final dose of HALAVEN. [see Clinical Studies (14.1)]. In Study 1, patients were randomized (2:1) to receive either New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment. on-study measurement and at least 1 grade increase from baseline. Halaven group (range • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: 2.3 Instructions for Preparation and Administration 221-222) and dacarbazine group (range 214-215) 3 HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by The median age of the safety population in Study 2 was 56 years (range: 24 to 83 years); Tell your healthcare provider about all the medicines you take, – ANC < 1,000/mm Aseptically withdraw the required amount of HALAVEN from the single-use vial and † Laboratory results were graded per NCI CTCAE v4.03. – Platelets < 75,000/mm3 administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. their physician (control group). A total of 503 patients received HALAVEN and 247 patients in 67% female; 73% White, 3% Black or African American, 8% Asian/Pacific Islander, and including prescription and over-the-counter medicines, vitamins, and – Grade 3 or 4 non-hematological toxicities. Do not dilute in or administer through an intravenous line containing solutions the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, 15% unknown; 99% received prior anthracycline-containing regimen; and 99% received ≥ 2 prior herbal supplements. with dextrose. Do not administer in the same intravenous line concurrent with the other capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies regimens. The median duration of exposure was 2.3 months (range: 21 days to 26 months) for • The Day 8 dose may be delayed for a maximum of 1 week. patients receiving HALAVEN [see Clinical Studies (14.2)]. – If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. medicinal products. 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients ✃ HIGHLIGHTS OF PRESCRIBING INFORMATION WARNINGS AND PRECAUTIONS Store undiluted HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were 6.2 Postmarketing Experience impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic Drug Interaction Studies Figure 1: Updated Overall Survival Analysis for Study 1 Figure 2: Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2 • Neutropenia: Monitor peripheral blood cell counts and adjust dose as appropriate. (5.1) hours under refrigeration (40°F or 4°C). Store diluted solutions of HALAVEN for up to 4 hours at common adverse reactions occurring in at least 10% of patients in either group. Howfatigue, will nausea, I receive alopecia, HALAVEN? constipation, peripheral neuropathy, abdominal pain, and pyrexia. The The following adverse drug reactionsPATIENT have been INFORMATION identified during post-approval of HALAVEN. impairment (Child-Pugh C) [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. Effect of Strong Inhibitors or Inducers of CYP3A4 on Eribulin: The effect of a strong CYP3A4 These highlights do not include all the information needed to use HALAVEN safely and 1.0 a ® • Peripheral Neuropathy: Monitor for signs of neuropathy. Manage with dose delay and room temperature or up to 24 hours under refrigeration. most common (≥5%) Grade 3-4 laboratory abnormalities reported in patients receiving HALAVEN Because these reactions are reportedHALAVEN voluntarily (HAL-ih-ven)from a population of uncertain size, it is not always 8.7 Renal Impairment inhibitor and a P-gp inhibitor, ketoconazole, on the PK of eribulin was studied in a crossover trial 1.0 effectively. See full prescribing information for HALAVEN. Table 2: Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 • HALAVEN is given by intravenous (IV) injection in your vein. HALAVEN Discard unused portions of the vial. were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions possible to reliably estimate their frequency or establish a causal relationship to drug exposure. of 12 patients with advanced solid tumors. No clinically relevant PK interaction was observed Dacarbazine ® adjustment. (5.2) For patients with moderate or severe renal impairment (CLcr 15-49 mL/min), reduce the starting 0.9 HALAVEN Control Group (eribulin mesylate) 2 HALAVEN (eribulin mesylate) injection, for intravenous use • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the 3 DOSAGE FORMS AND STRENGTHS Adverse Reactions • HALAVENreported in patients is given receiving in “cycles” HALAVEN of were treatment, neutropenia with (4.9%) each and pyrexia cycle (4.5%). lasting Permanent • Blood and Lymphatic System Disorders: lymphopenia dose to 1.1 mg/m [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. when HALAVEN was administered with or without ketoconazole (the geometric mean ratio of the n=503 n=247 discontinuation of HALAVEN for adverse reactions occurred in 8% of patients. The most common injection, for intravenous use 0.8 Initial U.S. Approval: 2010 potential risk to the fetus and to use effective contraception. (5.3, 8.1, 8.3) Injection: 1 mg/2 mL (0.5 mg/mL). 21 days. • Gastrointestinal Disorders: pancreatitis 10 OVERDOSAGE AUC: 0.97; 90% CI: 0.83, 1.12). 0.8 4 CONTRAINDICATIONS All Grades ≥ Grade 3 All Grades ≥ Grade 3 adverse reactions resulting in discontinuation of HALAVEN were fatigue and thrombocytopenia • Hepatobiliary Disorders: hepatotoxicity Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, The effect of a CYP3A4 inducer, rifampin, on the PK of eribulin was studied in a crossover trial of RECENT MAJOR CHANGES • QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, Blood and lymphatic system disordersb • HALAVEN is usually given on day 1 and day 8 of a treatment cycle. What is the most important information I should know about HALAVEN? None. (0.9% each). Twenty-six percent of patients required at least one dose reduction. The most • Immune System Disorders: drug hypersensitivity which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction 14 patients with advanced solid tumors. No clinically relevant PK interaction was observed when 0.7 Indications and Usage (1.2) 01/2016 bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid Neutropenia 82% 57% 53% 23% frequent adverse reactions that led to dose reduction were neutropenia (18%) and peripheral 0.6 in patients with congenital long QT syndrome. (5.4) 5 WARNINGS AND PRECAUTIONS HALAVEN• Infections can and cause Infestations: serious pneumonia, side effects, sepsis/neutropenic including: sepsis lasting one day. HALAVEN was administered with or without rifampin (the geometric mean ratio of the AUC: HALAVEN (N=508) Warnings and Precautions (5.1, 5.2, 5.3) 01/2016 Anemia 58% 2% 55% 4% Whatneuropathy are the (4.0%). possible side effects of HALAVEN? 0.6 5.1 Neutropenia • Metabolism and Nutrition Disorders: hypomagnesemia, dehydration There is no known antidote for HALAVEN overdose. 1.10; 90 CI%: 0.91, 1.34). ADVERSE REACTIONS 3 Nervous system disorders Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients in Effect of Eribulin on CYP Substrates: Eribulin shows no induction potential for CYP1A, CYP2B6, In Study 1, severe neutropenia (ANC < 500/mm ) lasting more than one week occurred in 12% c • Low white blood cell count (neutropenia). This can lead to 11 DESCRIPTION 0.4 INDICATIONS AND USAGE The most common adverse reactions (≥25%) in metastatic breast cancer were neutropenia, anemia, Peripheral neuropathy 35% 8% 16% 2% the HALAVEN-treated arm in Study 2. • Respiratory, thoracic and mediastinal disorders: interstitial lung disease 0.5 Survival Probability HALAVEN is a microtubule inhibitor indicated for the treatment of patients with: (62/503) of patients with metastatic breast cancer, leading to discontinuation in <1% of patients. HALAVEN may cause serious side effects, including: • Skinserious and Subcutaneousinfections that Tissue could Disorders: lead to death.pruritus, YourStevens-Johnson healthcare syndrome, provider HALAVEN contains eribulin mesylate, a microtubule dynamics inhibitor. Eribulin mesylate is a CYP2C9, CYP2C19, and CYP3A in primary human hepatocytes. Eribulin inhibits CYP3A4 activity asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. (6.1) Headache 19% <1% 12% <1% Table 3: Adverse Reactionsa Occurring in ≥10% (all Grades) of Patients Treated on in human liver microsomes, but it is unlikely that eribulin will substantially increase the plasma • Metastatic breast cancer who have previously received at least two chemotherapeutic regimens Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 5% (23/503) toxic epidermal necrolysis synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria 0.4 The most common adverse reactions (≥25%) in liposarcoma and leiomyosarcoma were fatigue, of patients; two patients (0.4%) died from complications of febrile neutropenia [see Adverse General disorders • See “Whatthe HALAVEN is the arm most and atimportant a Higher Incidence information than in I the should Dacarbazine know Arm will check your blood cell counts before you receive each dose of okadai. The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano- levels of CYP3A4 substrates. No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, 0.2 for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most Asthenia/Fatigue 54% 10% 40% 11% 7 DRUG INTERACTIONS Reactions (6.1)]. about(Between HALAVEN?” Arm Difference of ≥5% for All Grades or ≥2% for Grades 3 and 4) HALAVEN and during treatment. Call your healthcare provider right 12,15-methano-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, or CYP2E1 was detected with eribulin concentrations up to 5 μM in pooled human liver 0.3 taxane in either the adjuvant or metastatic setting. (1.1) common (≥5%) Grade 3-4 laboratory abnormalities in liposarcoma and leiomyosarcoma were b 7.1 Effects of Other Drugs on HALAVEN In Study 1, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) Pyrexia 21% <1% 13% <1% (Study 2) 2-[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, microsomes. In vitro drug interaction studies indicate that eribulin does not inhibit drugs that are Proportion of Patients Alive • Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing neutropenia, hypokalemia, and hypocalcemia. (6.1) Mucosal inflammation 9% 1% 10% 2% • HALAVEN can cause changes in your heartbeat (called QT No drug-drugaway if interactionsyou develop are expected any of withthese CYP3A4 symptoms inhibitors, of CYP3A4 infection: inducers or substrates of these enzymes and it is unlikely that eribulin will affect plasma levels of drugs that 0.0 > 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia HALAVEN Dacarbazine P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, 0.2 regimen. (1.2) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at (1-877-873-4724) or FDA Gastrointestinal disorders Adverseprolongation). Reaction This can cause irregular heartbeats. Your healthcare –fever (temperature above 100.5°F) are substrates of CYP enzymes. 063 9121518212427303336394245 and febrile neutropenia than patients with normal aminotransferase levels. Patients with n=223 n=221 observed in patients with advanced solid tumors when HALAVEN was administered with or methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free base). The empirical CONTROL (N=254) at 1-800-FDA-1088 or www.fda.gov/medwatch Nausea 35% 1% 28% 3% formula is C H NO •CH O S. Eribulin mesylate has the following structural formula: Effect of Transporters on Eribulin: In vitro data suggest that eribulin at clinically relevant 0.1 Survival Time (months) DOSAGE AND ADMINISTRATION bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia. provider may do heart monitoringAll Grades (electrocardiogram Grades 3-4 All or Grades ECG) or Gradesblood 3-4 without ketoconazole–chills (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when HALAVEN 40 59 11 4 3 Subjects at Risk: 2 3 Constipation 25% 1% 21% 1% concentrations is a substrate of P-gp, but is not a substrate of breast cancer resistance protein HALAVEN • Administer 1.4 mg/m intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. (2.1) USE IN SPECIFIC POPULATIONS In Study 2, severe neutropenia (ANC < 500/mm ) lasting more than one week occurred in 12% Nervous system disorders was administered with or without rifampin (a CYP3A4 inducer) . H3C 71 63 51 43 39 34 30 20 15 12 7 4 2 0 0 0 tests during your treatment with HALAVEN to check for –cough [see Clinical Pharmacology (12.3)] O H 0.0 Dacarbazine 72 59 42 33 22 17 12 11 6 3 2 0 0 0 0 0 • Lactation: Do not breastfeed. (8.2) (26/222) of patients with liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 0.9% of Vomiting 18% 1% 18% 1% c (BCRP), multidrug resistance proteins (MRP2, MRP4), bile salt extrusion pump (BSEP), organic • Reduce dose in patients with hepatic impairment or with moderate or severe renal impairment. (2.1) Peripheralheart problems. Neuropathy 29% 3.1% 8% 0.5% 7.2 Effect of HALAVEN on Other Drugs H • Hepatic Impairment: A lower starting dose is recommended for patients with mild patients treated with HALAVEN and fatal neutropenic sepsis in 0.9% [see Adverse Reactions (6.1)]. Diarrhea 18% 0 18% 0 –burning or pain when you urinate anion transporting polypeptides (OATP1B1, OATP1B3), organic anion transporters (OAT1, OAT3), • Do not mix with other drugs or administer with dextrose-containing solutions. (2.3) Musculoskeletal and connective tissue disorders Headache 18% 0% 10% 0% Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes H H H H organic cation transporters (OCT1, OCT2), or multidrug and toxin extrusion 1 (MATE1). Table 7: Efficacy Results for the Leiomyosarcoma Stratum in Study a2 (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. Patients with severe Monitor complete blood counts prior to each dose; increase the frequency of monitoring in General disorders or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. H2N O O DOSAGE FORMS AND STRENGTHS Arthralgia/Myalgia 22% <1% 12% 1% The most common side effects of HALAVEN in people with breast HO H O O Effect of Eribulin on Transporters: In vitro data suggest that eribulin at clinically relevant 0612 18 24 30 36 hepatic impairment (Child-Pugh C) were not studied. (8.6) patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce Pyrexia 28% 0.9% 14% 0.5% Eribulin• Numbness, is not expected tingling, to alter the or plasma pain concentrations in your hands of drugs or that feet are substrates(peripheral of these H H H H H Leiomyosarcoma Stratum Injection: 1 mg per 2 mL (0.5 mg per mL) (3) Back pain 16% 1% 7% 2% cancer include: CH concentrations may inhibit P-gp, but does not inhibit BCRP, OATP1B1, OCT1, OAT1, OAT3, or MATE1. Time (months) Halaven (n=154) Dacarbazine (n=149) • Renal Impairment: A lower starting dose is recommended for patients with moderate subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting Gastrointestinal disorders enzymesneuropathy). [see Clinical Pharmacology Peripheral (12.3)]neuropathy. is common with HALAVEN and 2 H3CSO3H Bone pain 12% 2% 9% 2% O O 13 NONCLINICAL TOXICOLOGY Number of 508 406 274 142 54 11 0 Overall survival (CLcr 30-49 mL/min) or severe (CLcr 15-29 mL/min) renal impairment. (8.7) longer than 7 days [see Dosage and Administration (2.2)]. Clinical studies of HALAVEN did not Constipation 32% 0.9% 26% 0.5% 8 USE IN SPECIFIC POPULATIONS H O H Patients at Risk 254 178 106 61 26 5 0 CONTRAINDICATIONS 3 Pain in extremity 11% 1% 10% 1% • low white blood cell count (neutropenia) • hair loss (alopecia) sometimes can be severe. Tell your healthcare provider if you have 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Deaths, n (%) 121 (79) 116 (78) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved Patient Labeling include patients with baseline neutrophil counts below 1,500/mm . Abdominal paind 29% 1.8% 23% 4.1% 8.1 Pregnancy O None (4) Metabolism and nutrition disorders CH Carcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was Median, months (95% CI) 12.8 (10.3, 14.8) 12.3 (11.0, 15.1) (Patient Information). 5.2 Peripheral Neuropathy •Stomatitis low red blood cell count (anemia)14% 0.9%• nausea 5% 0.5% new or worsening symptoms of peripheral neuropathy. H 3 H 14.2 Liposarcoma Decreased weight 21% 1% 14% <1% Risk Summary O not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was HR (95% CI) 0.90 (0.69, 1.18) Revised: October 2016 In Study 1, Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in •Skin weakness and subcutaneous or tiredness tissue disorders • constipation Based• Your on findingshealthcare from anprovider animal reproduction may delay, study decrease and its mechanism your dose, of action, or stop HALAVEN The efficacy and safety of HALAVEN were evaluated in Study 2, an open-label, randomized Progression-free survival 0.4% (2/503) of patients with metastatic breast cancer (MBC). Peripheral neuropathy was the Anorexia 20% 1% 13% 1% e e H H positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone (1:1), multicenter, active-controlled trial. Eligible patients were required to have unresectable, Respiratory, thoracic, and mediastinal disorders Alopecia 35% NA 2.7% NA can treatmentcause fetal harm with when HALAVEN administered if you to a pregnanthave side woman effects. [see Clinical Pharmacology marrow micronucleus assay. Events, n (%) 137 (89) 126 (85) FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503) in Study 1. Infections (12.1)]. There are no available data on the use of HALAVEN during pregnancy. In an animal locally advanced or metastatic liposarcoma or leiomyosarcoma, at least two prior systemic Disease progression 127 118 Dyspnea 16% 4% 13% 4% The most common side effects of HALAVEN in people with H2C Fertility studies have not been conducted with eribulin mesylate in humans or animals; however, 8.1 Pregnancy Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent Urinary tract infection 11% 2.2% 5% 0.5% reproduction study, eribulin mesylate caused embryo-fetal toxicity when administered to chemotherapies (one of which must have included an anthracycline), and disease progression Death 10 8 1 INDICATIONS AND USAGE (109/503) of patients developed a new or worsening neuropathy that had not recovered within a Cough 14% 0 9% 0 liposarcoma include: See “What are possible side effects of HALAVEN?” for more HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each vial contains nonclinical findings in repeat-dose dog and rat toxicology studies suggest that male fertility a pregnant rats during organogenesis at doses below the recommended human dose [see Data]. within 6 months of the most recent chemotherapy regimen. Patients were randomized to Median, months (95% CI) 2.2 (1.5, 2.7) 2.6 (2.2, 2.9) 8.2 Lactation Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events 2 1.1 Metastatic Breast Cancer median follow-up duration of 269 days (range 25-662 days). Skin and subcutaneous tissue disorders information about side effects. 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95). may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity HALAVEN 1.4 mg/m administered intravenously on Days 1 and 8 of a 21-day cycle or to HR (95% CI) 1.05 (0.81, 1.35) 8.3 Females and Males of Reproductive Potential d d Advise pregnant women of the potential risk to a fetus. 1.2 Liposarcoma In Study 2, Grade 3 peripheral neuropathy occurred in 3.1% (7/223) of HALAVEN-treated Alopecia 45% NA 10% NA •version tiredness 4.03 (NCI CTCAE v4.03). • constipation 12 CLINICAL PHARMACOLOGY (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with dacarbazine at a dose of 850 mg/m2, 1000 mg/m2, or 1200 mg/m2 administered intravenously Objective response rate (%) (95% CI) 5.2 (2.3, 10) 7.4 (3.7, 12.8) 8.4 Pediatric Use b Safety data from one study site enrolling six patients were excluded. The estimated background risks of major birth defects and miscarriage for the indicated populations 2 DOSAGE AND ADMINISTRATION Infections What is HALAVEN? 12.1 Mechanism of Action eribulin mesylate at or above 0.43 times the recommended human dose (based on body surface every 21 days (dacarbazine dose was selected by the investigator prior to randomization). a patients. Peripheral neuropathy led to discontinuation of HALAVEN in 0.9% of patients. The •c nausea • stomach pain are unknown. In the U.S. general population, the estimated background risk of major birth defects Efficacy data from one study site enrolling six patients were excluded. 2.1 Recommended Dose 8.5 Geriatric Use median time to first occurrence of peripheral neuropathy of any severity was 5 months (range: Urinary Tract Infection 10% 1% 5% 0 Includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and area) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose Treatment continued until disease progression or unacceptable toxicity. Randomization was •neuropathy, hair loss polyneuropathy, (alopecia) peripheral sensory neuropathy, and• paraesthesia.fever and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 2.2 Dose Modification 8.6 Hepatic Impairment 3.5 months to 9 months). Neuropathy lasting more than 60 days occurred in 58% (38/65) of a sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based (based on body surface area) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. stratified by histology (liposarcoma or leiomyosarcoma), number of prior therapies (2 vs. > 2), 16 HOW SUPPLIED/STORAGE AND HANDLING adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.0. d Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort. HALAVENData is a prescription medicine used to treat people with: 8.7 Renal Impairment patients. Sixty three percent (41/65) had not recovered within a median follow-up duration of b antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose and geographic region (U.S. and Canada vs. Western Europe, Australia, and Israel vs. Eastern NDC 62856-389-01 2.3 Instructions for Preparation and Administration based upon laboratory data. Youre Not healthcare applicable; (grading provider system will does do not blood specify tests > Grade before 2 for alopecia).and during treatment Animal Data 10 OVERDOSAGE 6.4 months (range: 27 days to 29 months). c • Breast cancer ultimately, apoptotic cell death after prolonged mitotic blockage. (based on body surface area) weekly for 3 out of 5 weeks, repeated for 6 cycles. Europe, Latin America, and Asia). The major efficacy outcome measure was overall survival 3 DOSAGE FORMS AND STRENGTHS includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor In an embryo-fetal developmental toxicity study, pregnant rats received intravenous infusion of Injection: 1 mg/2 mL, in a single-use vial. One vial per carton. 11 DESCRIPTION whileOther you clinically are taking important HALAVEN. adverse reactions The most occurring common in ≥10% changes of the HALAVEN-treated to blood tests In addition, eribulin treatment of human breast cancer cells caused changes in morphology and 14 CLINICAL STUDIES (OS). Additional efficacy outcome measures were progression-free survival (PFS) and confirmed 4 CONTRAINDICATIONS Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. eribulin mesylate–that duringhas spread organogenesis to other (Gestation parts Days of the 8, 10, body, and 12) and at doses approximately Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° – 86° F). Do not freeze. Store the 12 CLINICAL PHARMACOLOGY d patients were: gene expression as well as decreased migration and invasiveness in vitro. In mouse xenograft 14.1 Metastatic Breast Cancer objective response rate (ORR) as assessed by the investigator according to Response Evaluation 5 WARNINGS AND PRECAUTIONS HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy, until resolution to not applicable; (grading system does not specify > Grade 2 for alopecia). in people with liposarcoma include: 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area. vials in their original cartons. 12.1 Mechanism of Action Grade 2 or less [see Dosage and Administration (2.2)]. • Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%) – who have already received certain types of anticancer medicines models of human breast cancer, eribulin treatment was associated with increased vascular Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast Criteria in Solid Tumors (RECIST v1.1). Patients in the dacarbazine arm were not offered 17 PATIENT COUNSELING INFORMATION 5.1 Neutropenia Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN Increased abortion and severe fetal external or soft tissue malformations, including the cancer who received at least two chemotherapeutic regimens for the treatment of metastatic 12.2 Pharmacodynamics 5.3 Embryo-Fetal Toxicity • low• General white Disorders: blood cell asthenia/fatigue count (neutropenia) (62%); peripheral edema (12%) after the cancer has spread perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes HALAVEN at the time of disease progression. Advise the patient to read the FDA-approved patient labeling (Patient Information). 5.2 Peripheral Neuropathy in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia absence of a lower jaw and tongue, or stomach and spleen, were observed at doses 0.64 in the expression of genes in tumor specimens associated with a change in phenotype. disease and experienced disease progression within 6 months of their last chemotherapeutic A total of 446 patients were randomized, 225 to the HALAVEN arm and 221 to the dacarbazine 12.3 Pharmacokinetics Based on findings from an animal reproduction study and its mechanism of action, HALAVEN • Metabolism and Nutrition Disorders: decreased appetite (19%) 2 Neutropenia 5.3 Embryo-Fetal Toxicity occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile • decreased blood levels of potassium or calcium times• Liposarcoma the recommended human dose of 1.4 mg/m based on body surface area. Increased 12.2 Pharmacodynamics regimen. Patients were required to receive prior anthracycline- and taxane-based chemotherapy arm. The median age was 56 years (range: 24 to 83); 33% were male; 73% were White; 44% 13 NONCLINICAL TOXICOLOGY can cause fetal harm when administered to a pregnant woman. There are no adequate and Advise patients to contact their health care provider for a fever of 100.5°F or greater or other 5.4 QT Prolongation neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and • Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent Cardiac Electrophysiology for adjuvant or metastatic disease. Patients were randomized (2:1) to receive HALAVEN (n=508) had ECOG performance status (PS) 0 and 53% had ECOG PS 1; 68% had leiomyosarcoma 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility well-controlled studies of HALAVEN in pregnant women. In animal reproduction studies, eribulin discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the Tell yourback healthcare pain (16%) provider about any side effect that bothers you or that with developmental– that cannot delay were be treatedalso reported with at dosessurgery at or or above has a spreadmaternally to toxic other dose parts of signs or symptoms of infection such as chills, cough, or burning or pain on urination [see 6 ADVERSE REACTIONS mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, or a single agent therapy selected prior to randomization (control arm, n=254). Randomization and 32% had liposarcoma; 39% were enrolled in U.S. and Canada (Region 1) and 46% were 14 CLINICAL STUDIES mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater • Respiratory Disorders: cough (18%) approximatelyof 0.43the times body, the and recommended human dose. Warnings and Precautions (5.1)]. 6.1 Clinical Trials Experience at doses below the recommended human dose. Advise pregnant women of the potential risk to does not go away. multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. enrolled in Western Europe, Australia, and Israel (Region 2); and 47% received more than two thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating 8.2 Lactation 2 Peripheral Neuropathy 6.2 Postmarketing Experience 14.1 Metastatic Breast Cancer a fetus. Advise females of reproductive potential to use effective contraception during treatment Less Common Adverse Reactions: The following additional clinically important adverse reactions – who have received treatment with a certain type of 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was HALAVEN was administered at a dose of 1.4 mg/m on Days 1 and 8 of a 21-day cycle. prior systemic chemotherapies. The most common (>40%) prior systemic chemotherapies were factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of Risk Summary Advise patients to inform their healthcare providers of new or worsening numbness, tingling and 7 DRUG INTERACTIONS 14.2 Liposarcoma with HALAVEN and for at least 2 weeks following the final dose. Advise males with female were reported in ≥5% to <10% of the HALAVEN-treated group: observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change HALAVEN-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. doxorubicin (90%), ifosfamide (62%), gemcitabine (59%), trabectedin (50%), and docetaxel (48%). patients who received HALAVEN. These are not all the possible side effects of HALAVEN. Call your doctor anticancer medicine pain in their extremities [see Warnings and Precautions (5.2)]. 16 HOW SUPPLIED/STORAGE AND HANDLING partners of reproductive potential to use effective contraception during treatment with HALAVEN • Blood and Lymphatic System Disorders: thrombocytopenia There is no information regarding the presence of eribulin mesylate or its metabolites in human from baseline (95% upper confidence interval) was 11.4 (19.5) ms. Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% Of the 143 patients with liposarcoma, the median age was 55 years (range: 32 to 83); 62% 7.1 Effects of Other Drugs on HALAVEN Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy for medical advice about side effects. You may report side effects to FDA 17 PATIENT COUNSELING INFORMATION and for 3.5 months following the final dose[see Use in Specific Populations (8.1)]. • Eye Disorders: increased lacrimation milk, the effects on the breastfed infant, or the effects on milk production. No lactation studies 12.3 Pharmacokinetics capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal were male, 72% were White; 41% had ECOG PS of 0 and 53% had ECOG PS of 1; 35% were Embryo-Fetal Toxicity 7.2 Effects of HALAVEN on Other Drugs and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to It is not known if HALAVEN is safe and effective in children under 18 years *Sections or subsections omitted from the full prescribing information are not listed. at 1-800-FDA-1088.• Gastrointestinal Disorders: dyspepsia in animals were conducted. Because of the potential for serious adverse reactions in breastfed therapy. The main efficacy outcome was overall survival. enrolled in Region 1 and 51% were enrolled in Region 2; and 44% received more than two prior • Advise females of reproductive potential of the potential risk to a fetus and to inform their 5.4 QT Prolongation peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four of age. The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of • Metabolism and Nutrition Disorders: hyperglycemia infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean Patient demographic and baseline characteristics were comparable between the treatment systemic chemotherapies. The distribution of subtypes of liposarcoma, based on local histologic healthcare provider of a known or suspected pregnancy [see Warnings and Precautions In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% and for 2 weeks after the final dose. FULL PRESCRIBING INFORMATION – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. General• Musculoskeletal information and about Connective HALAVEN Tissue Disorders: muscle spasms, 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. arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent assessment, were 45% dedifferentiated, 37% myxoid/round cell, and 18% pleomorphic. (5.3), Use in Specific Populations (8.1)]. (8/503) of patients developed Grade 3 peripheral motor neuropathy. Before8.3 Females you andreceive Males HALAVEN,of Reproductive tell Potential your healthcare provider about of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/ 1 INDICATIONS AND USAGE reduced dose and initiate the next cycle no sooner than 2 weeks later. ECG monitoring is recommended if therapy is initiated in patients with congestive heart musculoskeletal pain The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL Study 2 demonstrated a statistically significant improvement in OS in patients randomized to • Advise females of reproductive potential to use effective contraception during treatment Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, allContraception of your medical conditions, including if you: ranges from 49% to 65%. Eribulin exposure after multiple dosing is comparable to that following Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients had a baseline HALAVEN compared with dacarbazine (see Table 6). There was no significant difference in with HALAVEN and for at least 2 weeks after the final dose[see Use in Specific 1.1 Metastatic Breast Cancer Recommended dose reductions failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN- Medicines• Nervous are Systemsometimes Disorders: prescribed dizziness, for purposesdysgeusia other than those listed in a HALAVEN is indicated for the treatment of patients with metastatic breast cancer who have antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia Females a single dose. No accumulation of eribulin is observed with weekly administration. ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor progression-free survival in the overall population. Treatment effects of HALAVEN were limited Populations (8.3)]. • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or treated patient without documented liver metastases had concomitant Grade 2 elevations in Patient• Psychiatric Information Disorders: leaflet. insomnia,You can anxietyask your pharmacist or healthcare provider • have liver or kidney problems status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: previously received at least two chemotherapeutic regimens for the treatment of metastatic prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Based on findings from an animal reproduction study and its mechanism of action, HALAVEN Elimination - - to patients with liposarcoma based on pre-planned, exploratory subgroup analyses of OS and • Advise males with female partners of reproductive potential to use effective contraception less, resume HALAVEN at a reduced dose as set out in Table 1. bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. for information• Respiratory, about Thoracic, HALAVEN and Mediastinal that is written Disorders: for health oropharyngeal professionals. pain 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative status (ER , PR , disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant Avoid HALAVEN in patients with congenital long QT syndrome. can cause fetal harm when administered to a pregnant woman [see Use in Specific - PFS (see Tables 6 and 7 and Figure 2). There was no evidence of efficacy of HALAVEN in patients during treatment with HALAVEN and for 3.5 months following the final dose[see Use in • Do not re-escalate HALAVEN dose after it has been reduced. Less Common Adverse Reactions: The following additional adverse reactions were reported in • Vascular Disorders: hypotension • have heart problems, including a problem called congenital long Metabolism HER2/ : 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone or metastatic setting [see Clinical Studies (14.1)]. 6 ADVERSE REACTIONS Populations (8.1)]. Advise females of reproductive potential to use effective contraception neu with advanced or metastatic leiomyosarcoma in Study 2 (see Table 7). Specific Populations (8.3)]. Table 1: Recommended Dose Reductions ≥5% to <10% of the HALAVEN-treated group: QT syndrome Unchanged eribulin was the major circulating species in plasma following administration of disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in What are the ingredients in HALAVEN? during treatment with HALAVEN and for at least 2 weeks following the final dose. 14 a Lactation 1.2 Liposarcoma 6.1 Clinical Trials Experience Table 4: Laboratory Abnormalities Occurring in ≥10% (all Grades) of Patients Treated C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, the HALAVEN and control arms. Patients received a median of four prior chemotherapy regimens in Table 6: Efficacy Results for the Liposarcoma Stratum and All Patients* in Study 2 HALAVEN is indicated for the treatment of patients with unresectable or metastatic liposarcoma Recommended Because clinical trials are conducted under widely varying conditions, the adverse reaction rates • Eye Disorders: increased lacrimation Males• have low potassium or low magnesium in your blood confirming that there are no major human metabolites of eribulin. Cytochrome P450 3A4 Advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final Event Description on the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm both arms. Liposarcoma who have received a prior anthracycline-containing regimen [see Clinical Studies (14.2)]. HALAVEN Dose observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth Active Ingredient:(Between Arm eribulin Difference mesylate of ≥5% for All Grades or ≥2% for Grades 3 and 4)a Based• are on pregnantits mechanism or of plan action, to advise become males withpregnant. female partners HALAVEN of reproductive can harm potential your to use (CYP3A4) negligibly metabolizes eribulin in vitro. All Patients* dose [see Use in Specific Populations (8.2)]. 2 In Study 1, a statistically significant improvement in overall survival was observed in patients Stratum 2 DOSAGE AND ADMINISTRATION Permanently reduce the 1.4 mg/m HALAVEN dose and may not reflect the rates observed in clinical practice. • General Disorders and Administration Site Conditions: peripheral edema (Study 2)† effective contraception during treatment with HALAVEN and for 3.5 months following the final dose. Excretion unborn baby. Tell your healthcare provider right away if you become randomized to the HALAVEN arm compared to the control arm (see Table 5). An updated, unplanned Halaven Dacarbazine Halaven Dacarbazine 2.1 Recommended Dose for any of the following: The following adverse reactions are discussed in detail in other sections of the labeling: • Infections and Infestations: upper respiratory tract infection Inactive Ingredients: ethanol, water Infertility Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to patients, Distributed by: 3 Laboratory Abnormality Halaven Dacarbazine survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent (n=71) (n=72) (n=225) (n=221) The recommended dose of HALAVEN is 1.4 mg/m2 administered intravenously over 2 to 5 ANC <500/mm for >7 days • Neutropenia [see Warnings and Precautions (5.1)] • Metabolism and Nutrition Disorders: hypokalemia Malespregnant or think you are pregnant during treatment with HALAVEN. approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin Eisai Inc. 3 All Grades Grades 3-4 All Grades Grades 3-4 with the primary analysis. In patients randomized to HALAVEN, the objective response rate by the Overall Survival minutes on Days 1 and 8 of a 21-day cycle. ANC <1,000 /mm with fever or infection • Peripheral neuropathy [see Warnings and Precautions (5.2)] • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness ® Based on– animal Females data, HALAVEN who are may able result to in becomedamage to pregnantmale reproductive should tissues use leading an to accounted for approximately 88% and 91% of total eribulin in feces and urine, respectively. Woodcliff Lake, NJ 07677 3 2 HALAVENHematology is a registered trademark used by Eisai Inc. under license from RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months Deaths, n (%) 52 (73) 63 (88) 173 (77) 179 (81) The recommended dose of HALAVEN in patients with mild hepatic impairment (Child-Pugh A) is Platelets <25,000/mm 1.1 mg/m • Nervous System Disorders: dysgeusia, dizziness impaired fertility of unknown duration [see Nonclinical Toxicology (13.1)]. Specific Populations 3 • QT prolongation [see Warnings and Precautions (5.4)] Anemia 70% 4.1% 52% 6% effective birth control during treatment with HALAVEN and for at (95% CI: 3.8, 5.0 months). 15.6 8.4 13.5 11.3 2 Platelets <50,000/mm requiring transfusion Eisai R&D Management Co., Ltd. 8.4 Pediatric Use Median, months (95% CI) 1.1 mg/m administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle In clinical trials, HALAVEN has been administered to 1963 patients including 467 patients • Psychiatric Disorders: insomnia, depression Neutropenia 63% 32% 30% 8.9% Age, Sex, and Race/Ethnicity: Based on a population pharmacokinetic analysis with data (10.2, 18.6) (5.2, 10.1) (11.1, 16.5) (9.5, 12.6) [see Use in Specific Populations (8.6)]. Non-hematologic Grade 3 or 4 toxicities The safety andleast effectiveness 2 weeks of after HALAVEN the infinal pediatric dose patients of HALAVEN. below the age of 18 years have Table 5: Comparison of Overall Survival in HALAVEN and Control Arm - Study 1 exposed to HALAVEN for 6 months or longer. The majority of the 1963 patients were women • Skin and Subcutaneous Tissue Disorders: rash DistributedChemistry by: collected from 340 patients, sex, race, and age do not have a clinically meaningful effect on the Hazard ratio (HR) (95% CI) 0.51 (0.35, 0.75) 0.75 (0.61, 0.94) The recommended dose of HALAVEN in patients with moderate hepatic impairment (Child-Pugh B) Omission or delay of Day 8 HALAVEN dose in previous not been established. exposure of eribulin. HALAVEN Control Arm (92%) with a median age of 55 years (range: 17 to 85 years). The racial and ethnic distribution Liposarcoma Increased alanine aminotransferase – Males should use an effective form of birth control when Overall Survival Stratified log-rank p value N/A† 0.011 is 0.7 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle cycle for toxicity Eisai Inc. 43% 2.3% 28% 2.3% 8.5 Geriatric Use (n=508) (n=254) was White (72%), Black (4%), Asian (9%), and other (3%). The safety of HALAVEN was evaluated in Study 2, an open-label, randomized, multicenter, (ALT) having sex with female partners who are able to become Hepatic Impairment Progression-free survival [see Use in Specific Populations (8.6)]. Occurrence of any event requiring permanent dose reduction Study 1 did not include sufficient numbers of subjects with metastatic breast cancer aged 65 0.7 mg/m2 Metastatic Breast Cancer active-controlled trial, in which patients were randomized (1:1) to receive either HALAVEN WoodcliffIncreased Lake, aspartate NJ 07677 In a study evaluating the effect of hepatic impairment on the PK of eribulin, eribulin exposures Primary survival analysis Events, n (%) 57 (80) 59 (82) 194 (86) 185 (84) 2 2 2 36% 0.9% 16% 0.5% years and olderpregnant to determine during whether treatment they respond with differently HALAVEN from youngerand for subjects. 3 1/2 Ofmonths the The recommended dose of HALAVEN in patients with moderate or severe renal impairment while receiving 1.1 mg/m The most common adverse reactions (≥25%) reported in patients receiving HALAVEN 1.4 mg/m on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 850 mg/m (20%), aminotransferase (AST) increased by 1.8-fold in patients with mild hepatic impairment (Child-Pugh A; n=7) and by 2.5-fold Number of deaths 274 148 2 2 2 827 subjects who received the recommended dose and schedule of HALAVEN in clinical studies Disease progression 53 52 180 170 (creatinine clearance (CLcr) 15-49 mL/min) is 1.1 mg/m administered intravenously over Occurrence of any event requiring permanent dose reduction were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and 1000 mg/m (64%), or 1200 mg/m (16%) every 3 weeks. A total of 223 patients received HALAVEN (14 weeks) after the final dose of HALAVEN. in patients with moderate (Child-Pugh B; n=5) hepatic impairment as compared to patients with Median, months (95% CI) 13.1 (11.8, 14.3) 10.6 (9.3, 12.5) 2 Discontinue HALAVEN For moreHypokalemia information, go to www.HALAVEN.com30% 5.4%or call Eisai 14% Inc. 2.8% with advanced breast cancer, 15% (121/827) were 65 and older, and 2% (17/827) patients 2 a Death 4 7 14 15 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations (8.7)]. while receiving 0.7 mg/m constipation. The most common serious adverse reactions reported in patients receiving and 221 patients received dacarbazine. Patients were required to have received at least two normal hepatic function (n=6). Administration of HALAVEN at a dose of 1.1 mg/m to patients Hazard Ratio (95% CI) 0.81 (0.66, 0.99) Hypocalcemia 28% 5% 18% 1.4% were• are 75 andbreastfeeding older. No overall or differences plan to breastfeed.in safety were observedIt is not between known these if HALAVEN subjects 2 b 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) 2.2 Dose Modification ANC = absolute neutrophil count. HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse prior systemic chemotherapy regimens. The trial excluded patients with pre-existing ≥ Grade 3 at 1-877-873-4724. If you would like a leaflet with larger printing, with mild hepatic impairment and 0.7 mg/m to patients with moderate hepatic impairment P value 0.041 Hypophosphatemia 20% 3.2% 11% 1.4% and younger subjects. 2 HR (95% CI) 0.52 (0.35, 0.78) 0.86 (0.69, 1.06) Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or passes into your breast milk. Do not breastfeed during treatment with resulted in similar exposure to eribulin at a dose of 1.4 mg/m to patients with normal hepatic Updated survival analysis Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology pleasea contact Eisai Inc. at 1-877-873-4724. Objective response rate significant chronic liver disease, history of myocardial infarction within 6 months, history of Each test incidence is based on the number of patients who had both baseline and at least one ClinicalHALAVEN studies of and HALAVEN for 2 did weeks not include after a sufficientthe final number dose of ofsubjects HALAVEN. in Study 2 aged 65 function [see Dosage and Administration (2.1), Use in Specific Populations (8.6)]. Number of deaths 386 203 Recommended dose delays Criteria for Adverse Events (CTCAE) version 3.0. The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 Objective response rate New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment. on-study measurement and at least 1 grade increase from baseline. Halaven group (range years and older to determine whether they respond differently from younger subjects. Renal Impairment Median, months (95% CI) 13.2 (12.1, 14.4) 10.6 (9.2, 12.0) 1.4 (0, 7.6) 0 (0, 4.2) 4.0 (1.8, 7.5) 5.0 (2.5, 8.7) • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: 2.3 Instructions for Preparation and Administration [see Clinical Studies (14.1)]. In Study 1, patients were randomized (2:1) to receive either This Patient Information has been approved by the (%) (95% CI) 3 2 The median age of the safety population in Study 2 was 56 years (range: 24 to 83 years); 221-222) and dacarbazine group (range 214-215) Tell8.6 Hepaticyour healthcare Impairment provider about all the medicines you take, – ANC < 1,000/mm Aseptically withdraw the required amount of HALAVEN from the single-use vial and HALAVEN (1.4 mg/m on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by † 2 In a study evaluating the effect of renal impairment on the PK of eribulin, patients with moderate CI = confidence interval U.S. Laboratory Food and results Drug were Administration. graded per NCI CTCAE Revised: v4.03. 01/2016 Administration of HALAVEN at a dose of 1.1 mg/m to patients with mild hepatic impairment a 3 their physician (control group). A total of 503 patients received HALAVEN and 247 patients in 67% female; 73% White, 3% Black or African American, 8% Asian/Pacific Islander, and (CLcr 30-49 mL/min; n=7) and severe renal impairment (CLcr 15-29 mL/min; n=6) had 1.5-fold a Efficacy data from one study site enrolling six patients were excluded. ® – Platelets < 75,000/mm administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. including prescription2 and over-the-counter medicines, vitamins, and Based on Cox proportional hazards model stratified by geographic region, HER2 status, and HALAVEN is a registered trademark used by Eisai Inc. under license from the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, 15% unknown; 99% received prior anthracycline-containing regimen; and 99% received ≥ 2 prior and 0.7 mg/m to patients with moderate hepatic impairment resulted in similar exposure to higher eribulin dose-normalized exposures compared to that in patients with normal renal * All patients = liposarcoma and leiomyosarcoma. – Grade 3 or 4 non-hematological toxicities. Do not dilute in or administer through an intravenous line containing solutions herbal supplements. 2 prior capecitabine therapy. † Eisai R&D Management Co., Ltd. capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies regimens. The median duration of exposure was 2.3 months (range: 21 days to 26 months) for eribulin as a dose of 1.4 mg/m to patients with normal hepatic function. Therefore, a lower function (CLcr ≥ 80 mL/min; n=6). There were no clinically meaningful changes in patients with b N/A = not applicable • The Day 8 dose may be delayed for a maximum of 1 week. with dextrose. Do not administer in the same intravenous line concurrent with the other starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment Based on a log-rank test stratified by geographic region, HER2 status, and prior capecitabine 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients patients receiving HALAVEN [see Clinical Studies (14.2)]. mild renal impairment (CLcr 50-79 mL/min; n=27) [see Dosage and Administration (2.1), Use in © 2016 Eisai Inc. All rights reserved. HALA-US0277(1) – If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. medicinal products. © 2016 Eisai Inc. All rights reserved. HALA-US0277(1) (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic therapy. Printed in USA / October 2016 Specific Populations (8.7)]. Printed in USA / October 2016 ✃ ✁ 6.2 Postmarketing Experience impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic Drug Interaction Studies Figure 1: Updated Overall Survival Analysis for Study 1 Figure 2: Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2 How will I receive HALAVEN? The following adverse drug reactions have been identified during post-approval of HALAVEN. impairment (Child-Pugh C) [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. Effect of Strong Inhibitors or Inducers of CYP3A4 on Eribulin: The effect of a strong CYP3A4 Because these reactions are reported voluntarily from a population of uncertain size, it is not always 8.7 Renal Impairment inhibitor and a P-gp inhibitor, ketoconazole, on the PK of eribulin was studied in a crossover trial 1.0 • HALAVEN is given by intravenous (IV) injection in your vein. 1.0 HALAVEN possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dacarbazine For patients with moderate or severe renal impairment (CLcr 15-49 mL/min), reduce the starting of 12 patients with advanced solid tumors. No clinically relevant PK interaction was observed 0.9 • HALAVEN is given in “cycles” of treatment, with each cycle lasting • Blood and Lymphatic System Disorders: lymphopenia dose to 1.1 mg/m2 [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. when HALAVEN was administered with or without ketoconazole (the geometric mean ratio of the 21 days. • Gastrointestinal Disorders: pancreatitis 10 OVERDOSAGE AUC: 0.97; 90% CI: 0.83, 1.12). 0.8 0.8 • Hepatobiliary Disorders: hepatotoxicity Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, The effect of a CYP3A4 inducer, rifampin, on the PK of eribulin was studied in a crossover trial of • HALAVEN is usually given on day 1 and day 8 of a treatment cycle. which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction 14 patients with advanced solid tumors. No clinically relevant PK interaction was observed when 0.7 • Immune System Disorders: drug hypersensitivity 0.6 HALAVEN was administered with or without rifampin (the geometric mean ratio of the AUC: HALAVEN (N=508) What are the possible side effects of HALAVEN? • Infections and Infestations: pneumonia, sepsis/neutropenic sepsis lasting one day. • Metabolism and Nutrition Disorders: hypomagnesemia, dehydration There is no known antidote for HALAVEN overdose. 1.10; 90 CI%: 0.91, 1.34). 0.6 11 DESCRIPTION Effect of Eribulin on CYP Substrates: Eribulin shows no induction potential for CYP1A, CYP2B6, 0.4 • Respiratory, thoracic and mediastinal disorders: interstitial lung disease 0.5 Survival Probability HALAVEN may cause serious side effects, including: • Skin and Subcutaneous Tissue Disorders: pruritus, Stevens-Johnson syndrome, HALAVEN contains eribulin mesylate, a microtubule dynamics inhibitor. Eribulin mesylate is a 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 toxic epidermal necrolysis synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria 0.4 • See “What is the most important information I should know okadai. The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano- levels of CYP3A4 substrates. No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, 0.2 7 DRUG INTERACTIONS or CYP2E1 was detected with eribulin concentrations up to 5 μM in pooled human liver about HALAVEN?” 7.1 Effects of Other Drugs on HALAVEN 12,15-methano-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 0.3 2-[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, microsomes. In vitro drug interaction studies indicate that eribulin does not inhibit drugs that are Proportion of Patients Alive • HALAVEN can cause changes in your heartbeat (called QT No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or substrates of these enzymes and it is unlikely that eribulin will affect plasma levels of drugs that 0.0 P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, 0.2 prolongation). This can cause irregular heartbeats. Your healthcare are substrates of CYP enzymes. 063 9121518212427303336394245 observed in patients with advanced solid tumors when HALAVEN was administered with or methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free base). The empirical CONTROL (N=254) formula is C H NO •CH O S. Eribulin mesylate has the following structural formula: Effect of Transporters on Eribulin: In vitro data suggest that eribulin at clinically relevant 0.1 Survival Time (months) provider may do heart monitoring (electrocardiogram or ECG) or blood without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when HALAVEN 40 59 11 4 3 Subjects at Risk: concentrations is a substrate of P-gp, but is not a substrate of breast cancer resistance protein HALAVEN was administered with or without rifampin (a CYP3A4 inducer) [see Clinical Pharmacology (12.3)]. H3C 71 63 51 43 39 34 30 20 15 12 7 4 2 0 0 0 tests during your treatment with HALAVEN to check for O H (BCRP), multidrug resistance proteins (MRP2, MRP4), bile salt extrusion pump (BSEP), organic 0.0 Dacarbazine 72 59 42 33 22 17 12 11 6 3 2 0 0 0 0 0 heart problems. 7.2 Effect of HALAVEN on Other Drugs H anion transporting polypeptides (OATP1B1, OATP1B3), organic anion transporters (OAT1, OAT3), Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes H H H H organic cation transporters (OCT1, OCT2), or multidrug and toxin extrusion 1 (MATE1). Table 7: Efficacy Results for the Leiomyosarcoma Stratum in Study a2 or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. H2N O O The most common side effects of HALAVEN in people with breast O O Effect of Eribulin on Transporters: In vitro data suggest that eribulin at clinically relevant 0612 18 24 30 36 Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these HO H H H H H Leiomyosarcoma Stratum H concentrations may inhibit P-gp, but does not inhibit BCRP, OATP1B1, OCT1, OAT1, OAT3, or MATE1. Time (months) cancer include: CH2 H CSO H Halaven (n=154) Dacarbazine (n=149) enzymes [see Clinical Pharmacology (12.3)]. O 3 3 Number of 508 406 274 142 54 11 0 O H 13 NONCLINICAL TOXICOLOGY Overall survival • low white blood cell count (neutropenia) • hair loss (alopecia) 8 USE IN SPECIFIC POPULATIONS H O 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Patients at Risk 254 178 106 61 26 5 0 Deaths, n (%) 121 (79) 116 (78) 8.1 Pregnancy O Median, months (95% CI) 12.8 (10.3, 14.8) 12.3 (11.0, 15.1) • low red blood cell count (anemia) • nausea H CH3 H Carcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was 14.2 Liposarcoma Risk Summary O not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was HR (95% CI) 0.90 (0.69, 1.18) • weakness or tiredness • constipation Based on findings from an animal reproduction study and its mechanism of action, HALAVEN The efficacy and safety of HALAVEN were evaluated in Study 2, an open-label, randomized Progression-free survival H H positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone (1:1), multicenter, active-controlled trial. Eligible patients were required to have unresectable, can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology marrow micronucleus assay. Events, n (%) 137 (89) 126 (85) The most common side effects of HALAVEN in people with (12.1)]. There are no available data on the use of HALAVEN during pregnancy. In an animal locally advanced or metastatic liposarcoma or leiomyosarcoma, at least two prior systemic Disease progression 127 118 H2C Fertility studies have not been conducted with eribulin mesylate in humans or animals; however, chemotherapies (one of which must have included an anthracycline), and disease progression liposarcoma include: reproduction study, eribulin mesylate caused embryo-fetal toxicity when administered to HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each vial contains nonclinical findings in repeat-dose dog and rat toxicology studies suggest that male fertility Death 10 8 pregnant rats during organogenesis at doses below the recommended human dose [see Data]. within 6 months of the most recent chemotherapy regimen. Patients were randomized to Median, months (95% CI) 2.2 (1.5, 2.7) 2.6 (2.2, 2.9) 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95). may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity 2 Advise pregnant women of the potential risk to a fetus. HALAVEN 1.4 mg/m administered intravenously on Days 1 and 8 of a 21-day cycle or to HR (95% CI) 1.05 (0.81, 1.35) • tiredness • constipation 12 CLINICAL PHARMACOLOGY (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with dacarbazine at a dose of 850 mg/m2, 1000 mg/m2, or 1200 mg/m2 administered intravenously Objective response rate (%) (95% CI) 5.2 (2.3, 10) 7.4 (3.7, 12.8) The estimated background risks of major birth defects and miscarriage for the indicated populations eribulin mesylate at or above 0.43 times the recommended human dose (based on body surface • nausea • stomach pain 12.1 Mechanism of Action every 21 days (dacarbazine dose was selected by the investigator prior to randomization). a are unknown. In the U.S. general population, the estimated background risk of major birth defects Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and area) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose Efficacy data from one study site enrolling six patients were excluded. and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Treatment continued until disease progression or unacceptable toxicity. Randomization was • hair loss (alopecia) • fever sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based (based on body surface area) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. stratified by histology (liposarcoma or leiomyosarcoma), number of prior therapies (2 vs. > 2), Data 16 HOW SUPPLIED/STORAGE AND HANDLING antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose and geographic region (U.S. and Canada vs. Western Europe, Australia, and Israel vs. Eastern NDC 62856-389-01 Your healthcare provider will do blood tests before and during treatment Animal Data ultimately, apoptotic cell death after prolonged mitotic blockage. (based on body surface area) weekly for 3 out of 5 weeks, repeated for 6 cycles. Europe, Latin America, and Asia). The major efficacy outcome measure was overall survival In an embryo-fetal developmental toxicity study, pregnant rats received intravenous infusion of Injection: 1 mg/2 mL, in a single-use vial. One vial per carton. while you are taking HALAVEN. The most common changes to blood tests In addition, eribulin treatment of human breast cancer cells caused changes in morphology and 14 CLINICAL STUDIES (OS). Additional efficacy outcome measures were progression-free survival (PFS) and confirmed Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° – 86° F). Do not freeze. Store the eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately gene expression as well as decreased migration and invasiveness in vitro. In mouse xenograft 14.1 Metastatic Breast Cancer objective response rate (ORR) as assessed by the investigator according to Response Evaluation in people with liposarcoma include: 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area. vials in their original cartons. models of human breast cancer, eribulin treatment was associated with increased vascular Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast Criteria in Solid Tumors (RECIST v1.1). Patients in the dacarbazine arm were not offered 17 PATIENT COUNSELING INFORMATION Increased abortion and severe fetal external or soft tissue malformations, including the cancer who received at least two chemotherapeutic regimens for the treatment of metastatic • low white blood cell count (neutropenia) perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes HALAVEN at the time of disease progression. Advise the patient to read the FDA-approved patient labeling (Patient Information). absence of a lower jaw and tongue, or stomach and spleen, were observed at doses 0.64 in the expression of genes in tumor specimens associated with a change in phenotype. disease and experienced disease progression within 6 months of their last chemotherapeutic 2 A total of 446 patients were randomized, 225 to the HALAVEN arm and 221 to the dacarbazine Neutropenia • decreased blood levels of potassium or calcium times the recommended human dose of 1.4 mg/m based on body surface area. Increased 12.2 Pharmacodynamics regimen. Patients were required to receive prior anthracycline- and taxane-based chemotherapy arm. The median age was 56 years (range: 24 to 83); 33% were male; 73% were White; 44% Advise patients to contact their health care provider for a fever of 100.5°F or greater or other embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent Cardiac Electrophysiology for adjuvant or metastatic disease. Patients were randomized (2:1) to receive HALAVEN (n=508) had ECOG performance status (PS) 0 and 53% had ECOG PS 1; 68% had leiomyosarcoma signs or symptoms of infection such as chills, cough, or burning or pain on urination [see Tell your healthcare provider about any side effect that bothers you or that with developmental delay were also reported at doses at or above a maternally toxic dose of or a single agent therapy selected prior to randomization (control arm, n=254). Randomization and 32% had liposarcoma; 39% were enrolled in U.S. and Canada (Region 1) and 46% were approximately 0.43 times the recommended human dose. The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, Warnings and Precautions (5.1)]. does not go away. multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. enrolled in Western Europe, Australia, and Israel (Region 2); and 47% received more than two 2 Peripheral Neuropathy 8.2 Lactation 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was HALAVEN was administered at a dose of 1.4 mg/m on Days 1 and 8 of a 21-day cycle. prior systemic chemotherapies. The most common (>40%) prior systemic chemotherapies were These are not all the possible side effects of HALAVEN. Call your doctor Risk Summary observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change HALAVEN-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. doxorubicin (90%), ifosfamide (62%), gemcitabine (59%), trabectedin (50%), and docetaxel (48%). Advise patients to inform their healthcare providers of new or worsening numbness, tingling and There is no information regarding the presence of eribulin mesylate or its metabolites in human Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% pain in their extremities [see Warnings and Precautions (5.2)]. for medical advice about side effects. You may report side effects to FDA from baseline (95% upper confidence interval) was 11.4 (19.5) ms. Of the 143 patients with liposarcoma, the median age was 55 years (range: 32 to 83); 62% milk, the effects on the breastfed infant, or the effects on milk production. No lactation studies 12.3 Pharmacokinetics capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal were male, 72% were White; 41% had ECOG PS of 0 and 53% had ECOG PS of 1; 35% were Embryo-Fetal Toxicity at 1-800-FDA-1088. in animals were conducted. Because of the potential for serious adverse reactions in breastfed The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of therapy. The main efficacy outcome was overall survival. enrolled in Region 1 and 51% were enrolled in Region 2; and 44% received more than two prior • Advise females of reproductive potential of the potential risk to a fetus and to inform their infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean Patient demographic and baseline characteristics were comparable between the treatment systemic chemotherapies. The distribution of subtypes of liposarcoma, based on local histologic healthcare provider of a known or suspected pregnancy [see Warnings and Precautions General information about HALAVEN and for 2 weeks after the final dose. 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. arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent assessment, were 45% dedifferentiated, 37% myxoid/round cell, and 18% pleomorphic. (5.3), Use in Specific Populations (8.1)]. 8.3 Females and Males of Reproductive Potential The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/ Study 2 demonstrated a statistically significant improvement in OS in patients randomized to • Advise females of reproductive potential to use effective contraception during treatment Medicines are sometimes prescribed for purposes other than those listed in a Contraception ranges from 49% to 65%. Eribulin exposure after multiple dosing is comparable to that following Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients had a baseline HALAVEN compared with dacarbazine (see Table 6). There was no significant difference in with HALAVEN and for at least 2 weeks after the final dose[see Use in Specific Females a single dose. No accumulation of eribulin is observed with weekly administration. ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor progression-free survival in the overall population. Treatment effects of HALAVEN were limited Populations (8.3)]. Patient Information leaflet. You can ask your pharmacist or healthcare provider status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: Based on findings from an animal reproduction study and its mechanism of action, HALAVEN Elimination - - to patients with liposarcoma based on pre-planned, exploratory subgroup analyses of OS and • Advise males with female partners of reproductive potential to use effective contraception for information about HALAVEN that is written for health professionals. can cause fetal harm when administered to a pregnant woman 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative status (ER , PR , [see Use in Specific Metabolism - PFS (see Tables 6 and 7 and Figure 2). There was no evidence of efficacy of HALAVEN in patients during treatment with HALAVEN and for 3.5 months following the final dose[see Use in Populations (8.1)]. Advise females of reproductive potential to use effective contraception HER2/neu : 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone with advanced or metastatic leiomyosarcoma in Study 2 (see Table 7). Specific Populations (8.3)]. Unchanged eribulin was the major circulating species in plasma following administration of disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in What are the ingredients in HALAVEN? during treatment with HALAVEN and for at least 2 weeks following the final dose. 14 a Lactation C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, the HALAVEN and control arms. Patients received a median of four prior chemotherapy regimens in Table 6: Efficacy Results for the Liposarcoma Stratum and All Patients* in Study 2 Males confirming that there are no major human metabolites of eribulin. Cytochrome P450 3A4 Advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final both arms. Liposarcoma Active Ingredient: eribulin mesylate Based on its mechanism of action, advise males with female partners of reproductive potential to use (CYP3A4) negligibly metabolizes eribulin in vitro. All Patients* dose [see Use in Specific Populations (8.2)]. In Study 1, a statistically significant improvement in overall survival was observed in patients Stratum effective contraception during treatment with HALAVEN and for 3.5 months following the final dose. Excretion randomized to the HALAVEN arm compared to the control arm (see Table 5). An updated, unplanned Halaven Dacarbazine Halaven Dacarbazine Inactive Ingredients: ethanol, water Infertility Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to patients, Distributed by: Males survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent (n=71) (n=72) (n=225) (n=221) approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin with the primary analysis. In patients randomized to HALAVEN, the objective response rate by the Eisai Inc. HALAVEN® is a registered trademark used by Eisai Inc. under license from Based on animal data, HALAVEN may result in damage to male reproductive tissues leading to accounted for approximately 88% and 91% of total eribulin in feces and urine, respectively. Overall Survival Woodcliff Lake, NJ 07677 impaired fertility of unknown duration [see Nonclinical Toxicology (13.1)]. RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months Deaths, n (%) 52 (73) 63 (88) 173 (77) 179 (81) Eisai R&D Management Co., Ltd. Specific Populations (95% CI: 3.8, 5.0 months). 15.6 8.4 13.5 11.3 8.4 Pediatric Use Age, Sex, and Race/Ethnicity: Based on a population pharmacokinetic analysis with data Median, months (95% CI) The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have Table 5: Comparison of Overall Survival in HALAVEN and Control Arm - Study 1 (10.2, 18.6) (5.2, 10.1) (11.1, 16.5) (9.5, 12.6) Distributed by: collected from 340 patients, sex, race, and age do not have a clinically meaningful effect on the Hazard ratio (HR) (95% CI) 0.51 (0.35, 0.75) 0.75 (0.61, 0.94) not been established. exposure of eribulin. HALAVEN Control Arm Overall Survival Stratified log-rank p value N/A† 0.011 Eisai Inc. 8.5 Geriatric Use (n=508) (n=254) Hepatic Impairment Progression-free survival Study 1 did not include sufficient numbers of subjects with metastatic breast cancer aged 65 In a study evaluating the effect of hepatic impairment on the PK of eribulin, eribulin exposures Primary survival analysis Woodcliff Lake, NJ 07677 years and older to determine whether they respond differently from younger subjects. Of the Events, n (%) 57 (80) 59 (82) 194 (86) 185 (84) increased by 1.8-fold in patients with mild hepatic impairment (Child-Pugh A; n=7) and by 2.5-fold Number of deaths 274 148 Disease progression 53 52 180 170 827 subjects who received the recommended dose and schedule of HALAVEN in clinical studies in patients with moderate (Child-Pugh B; n=5) hepatic impairment as compared to patients with Median, months (95% CI) 13.1 (11.8, 14.3) 10.6 (9.3, 12.5) For more information, go to www.HALAVEN.com or call Eisai Inc. with advanced breast cancer, 15% (121/827) were 65 and older, and 2% (17/827) patients 2 a Death 4 7 14 15 normal hepatic function (n=6). Administration of HALAVEN at a dose of 1.1 mg/m to patients Hazard Ratio (95% CI) 0.81 (0.66, 0.99) 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) at 1-877-873-4724. If you would like a leaflet with larger printing, were 75 and older. No overall differences in safety were observed between these subjects with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment b P value 0.041 HR (95% CI) 0.52 (0.35, 0.78) 0.86 (0.69, 1.06) and younger subjects. resulted in similar exposure to eribulin at a dose of 1.4 mg/m2 to patients with normal hepatic please contact Eisai Inc. at 1-877-873-4724. Updated survival analysis Objective response rate Clinical studies of HALAVEN did not include a sufficient number of subjects in Study 2 aged 65 function [see Dosage and Administration (2.1), Use in Specific Populations (8.6)]. Number of deaths 386 203 Objective response rate years and older to determine whether they respond differently from younger subjects. Renal Impairment Median, months (95% CI) 13.2 (12.1, 14.4) 10.6 (9.2, 12.0) 1.4 (0, 7.6) 0 (0, 4.2) 4.0 (1.8, 7.5) 5.0 (2.5, 8.7) This Patient Information has been approved by the (%) (95% CI) 8.6 Hepatic Impairment In a study evaluating the effect of renal impairment on the PK of eribulin, patients with moderate 2 CI = confidence interval a U.S. Food and Drug Administration. Revised: 01/2016 Administration of HALAVEN at a dose of 1.1 mg/m to patients with mild hepatic impairment (CLcr 30-49 mL/min; n=7) and severe renal impairment (CLcr 15-29 mL/min; n=6) had 1.5-fold a Efficacy data from one study site enrolling six patients were excluded. 2 Based on Cox proportional hazards model stratified by geographic region, HER2 status, and HALAVEN® is a registered trademark used by Eisai Inc. under license from and 0.7 mg/m to patients with moderate hepatic impairment resulted in similar exposure to higher eribulin dose-normalized exposures compared to that in patients with normal renal * All patients = liposarcoma and leiomyosarcoma. 2 prior capecitabine therapy. † Eisai R&D Management Co., Ltd. eribulin as a dose of 1.4 mg/m to patients with normal hepatic function. Therefore, a lower function (CLcr ≥ 80 mL/min; n=6). There were no clinically meaningful changes in patients with b N/A = not applicable starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment Based on a log-rank test stratified by geographic region, HER2 status, and prior capecitabine mild renal impairment (CLcr 50-79 mL/min; n=27) [see Dosage and Administration (2.1), Use in © 2016 Eisai Inc. All rights reserved. HALA-US0277(1) © 2016 Eisai Inc. All rights reserved. HALA-US0277(1) (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic therapy. Printed in USA / October 2016 Specific Populations (8.7)]. Printed in USA / October 2016 ✁ 6.2 Postmarketing Experience impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic Drug Interaction Studies Figure 1: Updated Overall Survival Analysis for Study 1 Figure 2: Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2 How will I receive HALAVEN? The following adverse drug reactions have been identified during post-approval of HALAVEN. impairment (Child-Pugh C) [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. Effect of Strong Inhibitors or Inducers of CYP3A4 on Eribulin: The effect of a strong CYP3A4 Because these reactions are reported voluntarily from a population of uncertain size, it is not always 8.7 Renal Impairment inhibitor and a P-gp inhibitor, ketoconazole, on the PK of eribulin was studied in a crossover trial 1.0 • HALAVEN is given by intravenous (IV) injection in your vein. 1.0 HALAVEN possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dacarbazine For patients with moderate or severe renal impairment (CLcr 15-49 mL/min), reduce the starting of 12 patients with advanced solid tumors. No clinically relevant PK interaction was observed 0.9 • HALAVEN is given in “cycles” of treatment, with each cycle lasting • Blood and Lymphatic System Disorders: lymphopenia dose to 1.1 mg/m2 [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. when HALAVEN was administered with or without ketoconazole (the geometric mean ratio of the 21 days. • Gastrointestinal Disorders: pancreatitis 10 OVERDOSAGE AUC: 0.97; 90% CI: 0.83, 1.12). 0.8 0.8 • Hepatobiliary Disorders: hepatotoxicity Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, The effect of a CYP3A4 inducer, rifampin, on the PK of eribulin was studied in a crossover trial of • HALAVEN is usually given on day 1 and day 8 of a treatment cycle. which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction 14 patients with advanced solid tumors. No clinically relevant PK interaction was observed when 0.7 • Immune System Disorders: drug hypersensitivity 0.6 HALAVEN was administered with or without rifampin (the geometric mean ratio of the AUC: HALAVEN (N=508) What are the possible side effects of HALAVEN? • Infections and Infestations: pneumonia, sepsis/neutropenic sepsis lasting one day. • Metabolism and Nutrition Disorders: hypomagnesemia, dehydration There is no known antidote for HALAVEN overdose. 1.10; 90 CI%: 0.91, 1.34). 0.6 11 DESCRIPTION Effect of Eribulin on CYP Substrates: Eribulin shows no induction potential for CYP1A, CYP2B6, 0.4 • Respiratory, thoracic and mediastinal disorders: interstitial lung disease 0.5 Survival Probability HALAVEN may cause serious side effects, including: • Skin and Subcutaneous Tissue Disorders: pruritus, Stevens-Johnson syndrome, HALAVEN contains eribulin mesylate, a microtubule dynamics inhibitor. Eribulin mesylate is a 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 toxic epidermal necrolysis synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria 0.4 • See “What is the most important information I should know okadai. The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano- levels of CYP3A4 substrates. No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, 0.2 7 DRUG INTERACTIONS or CYP2E1 was detected with eribulin concentrations up to 5 μM in pooled human liver about HALAVEN?” 7.1 Effects of Other Drugs on HALAVEN 12,15-methano-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 0.3 2-[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, microsomes. In vitro drug interaction studies indicate that eribulin does not inhibit drugs that are Proportion of Patients Alive • HALAVEN can cause changes in your heartbeat (called QT No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or substrates of these enzymes and it is unlikely that eribulin will affect plasma levels of drugs that 0.0 P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, 0.2 prolongation). This can cause irregular heartbeats. Your healthcare are substrates of CYP enzymes. 063 9121518212427303336394245 observed in patients with advanced solid tumors when HALAVEN was administered with or methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free base). The empirical CONTROL (N=254) formula is C H NO •CH O S. Eribulin mesylate has the following structural formula: Effect of Transporters on Eribulin: In vitro data suggest that eribulin at clinically relevant 0.1 Survival Time (months) provider may do heart monitoring (electrocardiogram or ECG) or blood without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when HALAVEN 40 59 11 4 3 Subjects at Risk: concentrations is a substrate of P-gp, but is not a substrate of breast cancer resistance protein HALAVEN was administered with or without rifampin (a CYP3A4 inducer) [see Clinical Pharmacology (12.3)]. H3C 71 63 51 43 39 34 30 20 15 12 7 4 2 0 0 0 tests during your treatment with HALAVEN to check for O H (BCRP), multidrug resistance proteins (MRP2, MRP4), bile salt extrusion pump (BSEP), organic 0.0 Dacarbazine 72 59 42 33 22 17 12 11 6 3 2 0 0 0 0 0 heart problems. 7.2 Effect of HALAVEN on Other Drugs H anion transporting polypeptides (OATP1B1, OATP1B3), organic anion transporters (OAT1, OAT3), Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes H H H H organic cation transporters (OCT1, OCT2), or multidrug and toxin extrusion 1 (MATE1). Table 7: Efficacy Results for the Leiomyosarcoma Stratum in Study a2 or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. H2N O O The most common side effects of HALAVEN in people with breast O O Effect of Eribulin on Transporters: In vitro data suggest that eribulin at clinically relevant 0612 18 24 30 36 Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these HO H H H H H Leiomyosarcoma Stratum H concentrations may inhibit P-gp, but does not inhibit BCRP, OATP1B1, OCT1, OAT1, OAT3, or MATE1. Time (months) cancer include: CH2 H CSO H Halaven (n=154) Dacarbazine (n=149) enzymes [see Clinical Pharmacology (12.3)]. O 3 3 Number of 508 406 274 142 54 11 0 O H 13 NONCLINICAL TOXICOLOGY Overall survival • low white blood cell count (neutropenia) • hair loss (alopecia) 8 USE IN SPECIFIC POPULATIONS H O 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Patients at Risk 254 178 106 61 26 5 0 Deaths, n (%) 121 (79) 116 (78) 8.1 Pregnancy O Median, months (95% CI) 12.8 (10.3, 14.8) 12.3 (11.0, 15.1) • low red blood cell count (anemia) • nausea H CH3 H Carcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was 14.2 Liposarcoma Risk Summary O not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was HR (95% CI) 0.90 (0.69, 1.18) • weakness or tiredness • constipation Based on findings from an animal reproduction study and its mechanism of action, HALAVEN The efficacy and safety of HALAVEN were evaluated in Study 2, an open-label, randomized Progression-free survival H H positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone (1:1), multicenter, active-controlled trial. Eligible patients were required to have unresectable, can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology marrow micronucleus assay. Events, n (%) 137 (89) 126 (85) The most common side effects of HALAVEN in people with (12.1)]. There are no available data on the use of HALAVEN during pregnancy. In an animal locally advanced or metastatic liposarcoma or leiomyosarcoma, at least two prior systemic Disease progression 127 118 H2C Fertility studies have not been conducted with eribulin mesylate in humans or animals; however, chemotherapies (one of which must have included an anthracycline), and disease progression liposarcoma include: reproduction study, eribulin mesylate caused embryo-fetal toxicity when administered to HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each vial contains nonclinical findings in repeat-dose dog and rat toxicology studies suggest that male fertility Death 10 8 pregnant rats during organogenesis at doses below the recommended human dose [see Data]. within 6 months of the most recent chemotherapy regimen. Patients were randomized to Median, months (95% CI) 2.2 (1.5, 2.7) 2.6 (2.2, 2.9) 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95). may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity 2 Advise pregnant women of the potential risk to a fetus. HALAVEN 1.4 mg/m administered intravenously on Days 1 and 8 of a 21-day cycle or to HR (95% CI) 1.05 (0.81, 1.35) • tiredness • constipation 12 CLINICAL PHARMACOLOGY (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with dacarbazine at a dose of 850 mg/m2, 1000 mg/m2, or 1200 mg/m2 administered intravenously Objective response rate (%) (95% CI) 5.2 (2.3, 10) 7.4 (3.7, 12.8) The estimated background risks of major birth defects and miscarriage for the indicated populations eribulin mesylate at or above 0.43 times the recommended human dose (based on body surface • nausea • stomach pain 12.1 Mechanism of Action every 21 days (dacarbazine dose was selected by the investigator prior to randomization). a are unknown. In the U.S. general population, the estimated background risk of major birth defects Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and area) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose Efficacy data from one study site enrolling six patients were excluded. and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Treatment continued until disease progression or unacceptable toxicity. Randomization was • hair loss (alopecia) • fever sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based (based on body surface area) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. stratified by histology (liposarcoma or leiomyosarcoma), number of prior therapies (2 vs. > 2), Data 16 HOW SUPPLIED/STORAGE AND HANDLING antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose and geographic region (U.S. and Canada vs. Western Europe, Australia, and Israel vs. Eastern NDC 62856-389-01 Your healthcare provider will do blood tests before and during treatment Animal Data ultimately, apoptotic cell death after prolonged mitotic blockage. (based on body surface area) weekly for 3 out of 5 weeks, repeated for 6 cycles. Europe, Latin America, and Asia). The major efficacy outcome measure was overall survival In an embryo-fetal developmental toxicity study, pregnant rats received intravenous infusion of Injection: 1 mg/2 mL, in a single-use vial. One vial per carton. while you are taking HALAVEN. The most common changes to blood tests In addition, eribulin treatment of human breast cancer cells caused changes in morphology and 14 CLINICAL STUDIES (OS). Additional efficacy outcome measures were progression-free survival (PFS) and confirmed Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° – 86° F). Do not freeze. Store the eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately gene expression as well as decreased migration and invasiveness in vitro. In mouse xenograft 14.1 Metastatic Breast Cancer objective response rate (ORR) as assessed by the investigator according to Response Evaluation in people with liposarcoma include: 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area. vials in their original cartons. models of human breast cancer, eribulin treatment was associated with increased vascular Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast Criteria in Solid Tumors (RECIST v1.1). Patients in the dacarbazine arm were not offered 17 PATIENT COUNSELING INFORMATION Increased abortion and severe fetal external or soft tissue malformations, including the cancer who received at least two chemotherapeutic regimens for the treatment of metastatic • low white blood cell count (neutropenia) perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes HALAVEN at the time of disease progression. Advise the patient to read the FDA-approved patient labeling (Patient Information). absence of a lower jaw and tongue, or stomach and spleen, were observed at doses 0.64 in the expression of genes in tumor specimens associated with a change in phenotype. disease and experienced disease progression within 6 months of their last chemotherapeutic 2 A total of 446 patients were randomized, 225 to the HALAVEN arm and 221 to the dacarbazine Neutropenia • decreased blood levels of potassium or calcium times the recommended human dose of 1.4 mg/m based on body surface area. Increased 12.2 Pharmacodynamics regimen. Patients were required to receive prior anthracycline- and taxane-based chemotherapy arm. The median age was 56 years (range: 24 to 83); 33% were male; 73% were White; 44% Advise patients to contact their health care provider for a fever of 100.5°F or greater or other embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent Cardiac Electrophysiology for adjuvant or metastatic disease. Patients were randomized (2:1) to receive HALAVEN (n=508) had ECOG performance status (PS) 0 and 53% had ECOG PS 1; 68% had leiomyosarcoma signs or symptoms of infection such as chills, cough, or burning or pain on urination [see Tell your healthcare provider about any side effect that bothers you or that with developmental delay were also reported at doses at or above a maternally toxic dose of or a single agent therapy selected prior to randomization (control arm, n=254). Randomization and 32% had liposarcoma; 39% were enrolled in U.S. and Canada (Region 1) and 46% were approximately 0.43 times the recommended human dose. The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, Warnings and Precautions (5.1)]. does not go away. multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. enrolled in Western Europe, Australia, and Israel (Region 2); and 47% received more than two 2 Peripheral Neuropathy 8.2 Lactation 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was HALAVEN was administered at a dose of 1.4 mg/m on Days 1 and 8 of a 21-day cycle. prior systemic chemotherapies. The most common (>40%) prior systemic chemotherapies were These are not all the possible side effects of HALAVEN. Call your doctor Risk Summary observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change HALAVEN-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. doxorubicin (90%), ifosfamide (62%), gemcitabine (59%), trabectedin (50%), and docetaxel (48%). Advise patients to inform their healthcare providers of new or worsening numbness, tingling and There is no information regarding the presence of eribulin mesylate or its metabolites in human Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% pain in their extremities [see Warnings and Precautions (5.2)]. for medical advice about side effects. You may report side effects to FDA from baseline (95% upper confidence interval) was 11.4 (19.5) ms. Of the 143 patients with liposarcoma, the median age was 55 years (range: 32 to 83); 62% milk, the effects on the breastfed infant, or the effects on milk production. No lactation studies 12.3 Pharmacokinetics capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal were male, 72% were White; 41% had ECOG PS of 0 and 53% had ECOG PS of 1; 35% were Embryo-Fetal Toxicity at 1-800-FDA-1088. in animals were conducted. Because of the potential for serious adverse reactions in breastfed The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of therapy. The main efficacy outcome was overall survival. enrolled in Region 1 and 51% were enrolled in Region 2; and 44% received more than two prior • Advise females of reproductive potential of the potential risk to a fetus and to inform their infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean Patient demographic and baseline characteristics were comparable between the treatment systemic chemotherapies. The distribution of subtypes of liposarcoma, based on local histologic healthcare provider of a known or suspected pregnancy [see Warnings and Precautions General information about HALAVEN and for 2 weeks after the final dose. 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. arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent assessment, were 45% dedifferentiated, 37% myxoid/round cell, and 18% pleomorphic. (5.3), Use in Specific Populations (8.1)]. 8.3 Females and Males of Reproductive Potential The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/ Study 2 demonstrated a statistically significant improvement in OS in patients randomized to • Advise females of reproductive potential to use effective contraception during treatment Medicines are sometimes prescribed for purposes other than those listed in a Contraception ranges from 49% to 65%. Eribulin exposure after multiple dosing is comparable to that following Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients had a baseline HALAVEN compared with dacarbazine (see Table 6). There was no significant difference in with HALAVEN and for at least 2 weeks after the final dose[see Use in Specific Females a single dose. No accumulation of eribulin is observed with weekly administration. ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor progression-free survival in the overall population. Treatment effects of HALAVEN were limited Populations (8.3)]. Patient Information leaflet. You can ask your pharmacist or healthcare provider status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: Based on findings from an animal reproduction study and its mechanism of action, HALAVEN Elimination - - to patients with liposarcoma based on pre-planned, exploratory subgroup analyses of OS and • Advise males with female partners of reproductive potential to use effective contraception for information about HALAVEN that is written for health professionals. can cause fetal harm when administered to a pregnant woman 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative status (ER , PR , [see Use in Specific Metabolism - PFS (see Tables 6 and 7 and Figure 2). There was no evidence of efficacy of HALAVEN in patients during treatment with HALAVEN and for 3.5 months following the final dose[see Use in Populations (8.1)]. Advise females of reproductive potential to use effective contraception HER2/neu : 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone with advanced or metastatic leiomyosarcoma in Study 2 (see Table 7). Specific Populations (8.3)]. Unchanged eribulin was the major circulating species in plasma following administration of disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in What are the ingredients in HALAVEN? during treatment with HALAVEN and for at least 2 weeks following the final dose. 14 a Lactation C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, the HALAVEN and control arms. Patients received a median of four prior chemotherapy regimens in Table 6: Efficacy Results for the Liposarcoma Stratum and All Patients* in Study 2 Males confirming that there are no major human metabolites of eribulin. Cytochrome P450 3A4 Advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final both arms. Liposarcoma Active Ingredient: eribulin mesylate Based on its mechanism of action, advise males with female partners of reproductive potential to use (CYP3A4) negligibly metabolizes eribulin in vitro. All Patients* dose [see Use in Specific Populations (8.2)]. In Study 1, a statistically significant improvement in overall survival was observed in patients Stratum effective contraception during treatment with HALAVEN and for 3.5 months following the final dose. Excretion randomized to the HALAVEN arm compared to the control arm (see Table 5). An updated, unplanned Halaven Dacarbazine Halaven Dacarbazine Inactive Ingredients: ethanol, water Infertility Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to patients, Distributed by: Males survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent (n=71) (n=72) (n=225) (n=221) approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin with the primary analysis. In patients randomized to HALAVEN, the objective response rate by the Eisai Inc. HALAVEN® is a registered trademark used by Eisai Inc. under license from Based on animal data, HALAVEN may result in damage to male reproductive tissues leading to accounted for approximately 88% and 91% of total eribulin in feces and urine, respectively. Overall Survival Woodcliff Lake, NJ 07677 impaired fertility of unknown duration [see Nonclinical Toxicology (13.1)]. RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months Deaths, n (%) 52 (73) 63 (88) 173 (77) 179 (81) Eisai R&D Management Co., Ltd. Specific Populations (95% CI: 3.8, 5.0 months). 15.6 8.4 13.5 11.3 8.4 Pediatric Use Age, Sex, and Race/Ethnicity: Based on a population pharmacokinetic analysis with data Median, months (95% CI) The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have Table 5: Comparison of Overall Survival in HALAVEN and Control Arm - Study 1 (10.2, 18.6) (5.2, 10.1) (11.1, 16.5) (9.5, 12.6) Distributed by: collected from 340 patients, sex, race, and age do not have a clinically meaningful effect on the Hazard ratio (HR) (95% CI) 0.51 (0.35, 0.75) 0.75 (0.61, 0.94) not been established. exposure of eribulin. HALAVEN Control Arm Overall Survival Stratified log-rank p value N/A† 0.011 Eisai Inc. 8.5 Geriatric Use (n=508) (n=254) Hepatic Impairment Progression-free survival Study 1 did not include sufficient numbers of subjects with metastatic breast cancer aged 65 In a study evaluating the effect of hepatic impairment on the PK of eribulin, eribulin exposures Primary survival analysis Woodcliff Lake, NJ 07677 years and older to determine whether they respond differently from younger subjects. Of the Events, n (%) 57 (80) 59 (82) 194 (86) 185 (84) increased by 1.8-fold in patients with mild hepatic impairment (Child-Pugh A; n=7) and by 2.5-fold Number of deaths 274 148 Disease progression 53 52 180 170 827 subjects who received the recommended dose and schedule of HALAVEN in clinical studies in patients with moderate (Child-Pugh B; n=5) hepatic impairment as compared to patients with Median, months (95% CI) 13.1 (11.8, 14.3) 10.6 (9.3, 12.5) For more information, go to www.HALAVEN.com or call Eisai Inc. with advanced breast cancer, 15% (121/827) were 65 and older, and 2% (17/827) patients 2 a Death 4 7 14 15 normal hepatic function (n=6). Administration of HALAVEN at a dose of 1.1 mg/m to patients Hazard Ratio (95% CI) 0.81 (0.66, 0.99) 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) at 1-877-873-4724. If you would like a leaflet with larger printing, were 75 and older. No overall differences in safety were observed between these subjects with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment b P value 0.041 HR (95% CI) 0.52 (0.35, 0.78) 0.86 (0.69, 1.06) and younger subjects. resulted in similar exposure to eribulin at a dose of 1.4 mg/m2 to patients with normal hepatic please contact Eisai Inc. at 1-877-873-4724. Updated survival analysis Objective response rate Clinical studies of HALAVEN did not include a sufficient number of subjects in Study 2 aged 65 function [see Dosage and Administration (2.1), Use in Specific Populations (8.6)]. Number of deaths 386 203 Objective response rate years and older to determine whether they respond differently from younger subjects. Renal Impairment Median, months (95% CI) 13.2 (12.1, 14.4) 10.6 (9.2, 12.0) 1.4 (0, 7.6) 0 (0, 4.2) 4.0 (1.8, 7.5) 5.0 (2.5, 8.7) This Patient Information has been approved by the (%) (95% CI) 8.6 Hepatic Impairment In a study evaluating the effect of renal impairment on the PK of eribulin, patients with moderate 2 CI = confidence interval a U.S. Food and Drug Administration. Revised: 01/2016 Administration of HALAVEN at a dose of 1.1 mg/m to patients with mild hepatic impairment (CLcr 30-49 mL/min; n=7) and severe renal impairment (CLcr 15-29 mL/min; n=6) had 1.5-fold a Efficacy data from one study site enrolling six patients were excluded. 2 Based on Cox proportional hazards model stratified by geographic region, HER2 status, and HALAVEN® is a registered trademark used by Eisai Inc. under license from and 0.7 mg/m to patients with moderate hepatic impairment resulted in similar exposure to higher eribulin dose-normalized exposures compared to that in patients with normal renal * All patients = liposarcoma and leiomyosarcoma. 2 prior capecitabine therapy. † Eisai R&D Management Co., Ltd. eribulin as a dose of 1.4 mg/m to patients with normal hepatic function. Therefore, a lower function (CLcr ≥ 80 mL/min; n=6). There were no clinically meaningful changes in patients with b N/A = not applicable starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment Based on a log-rank test stratified by geographic region, HER2 status, and prior capecitabine mild renal impairment (CLcr 50-79 mL/min; n=27) [see Dosage and Administration (2.1), Use in © 2016 Eisai Inc. All rights reserved. HALA-US0277(1) © 2016 Eisai Inc. All rights reserved. HALA-US0277(1) (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic therapy. Printed in USA / October 2016 Specific Populations (8.7)]. Printed in USA / October 2016 ✁ HIGHLIGHTS OF PRESCRIBING INFORMATION WARNINGS AND PRECAUTIONS Store undiluted HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were 6.2 Postmarketing Experience impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic Drug Interaction Studies Figure 1: Updated Overall Survival Analysis for Study 1 Figure 2: Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2 • Neutropenia: Monitor peripheral blood cell counts and adjust dose as appropriate. (5.1) hours under refrigeration (40°F or 4°C). Store diluted solutions of HALAVEN for up to 4 hours at common adverse reactions occurring in at least 10% of patients in either group. fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The PATIENT INFORMATION How will I receive HALAVEN? The following adverse drug reactions have been identified during post-approval of HALAVEN. impairment (Child-Pugh C) [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. Effect of Strong Inhibitors or Inducers of CYP3A4 on Eribulin: The effect of a strong CYP3A4 These highlights do not include all the information needed to use HALAVEN safely and 1.0 a ® • Peripheral Neuropathy: Monitor for signs of neuropathy. Manage with dose delay and room temperature or up to 24 hours under refrigeration. most common (≥5%) Grade 3-4 laboratory abnormalities reported in patients receiving HALAVEN HALAVEN (HAL-ih-ven) Because these reactions are reported voluntarily from a population of uncertain size, it is not always 8.7 Renal Impairment inhibitor and a P-gp inhibitor, ketoconazole, on the PK of eribulin was studied in a crossover trial 1.0 effectively. See full prescribing information for HALAVEN. Table 2: Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 • HALAVEN is given by intravenous (IV) injection in your vein. HALAVEN Discard unused portions of the vial. were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions possible to reliably estimate their frequency or establish a causal relationship to drug exposure. of 12 patients with advanced solid tumors. No clinically relevant PK interaction was observed Dacarbazine ® adjustment. (5.2) For patients with moderate or severe renal impairment (CLcr 15-49 mL/min), reduce the starting 0.9 HALAVEN Control Group (eribulin mesylate) 2 HALAVEN (eribulin mesylate) injection, for intravenous use • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the 3 DOSAGE FORMS AND STRENGTHS Adverse Reactions reported in patients receiving HALAVEN were neutropenia (4.9%) and pyrexia (4.5%). Permanent • HALAVEN is given in “cycles” of treatment, with each cycle lasting • Blood and Lymphatic System Disorders: lymphopenia dose to 1.1 mg/m [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. when HALAVEN was administered with or without ketoconazole (the geometric mean ratio of the n=503 n=247 discontinuation of HALAVEN for adverse reactions occurred in 8% of patients. The most common injection, for intravenous use 0.8 Initial U.S. Approval: 2010 potential risk to the fetus and to use effective contraception. (5.3, 8.1, 8.3) Injection: 1 mg/2 mL (0.5 mg/mL). 21 days. • Gastrointestinal Disorders: pancreatitis 10 OVERDOSAGE AUC: 0.97; 90% CI: 0.83, 1.12). 0.8 4 CONTRAINDICATIONS All Grades ≥ Grade 3 All Grades ≥ Grade 3 adverse reactions resulting in discontinuation of HALAVEN were fatigue and thrombocytopenia • Hepatobiliary Disorders: hepatotoxicity Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, The effect of a CYP3A4 inducer, rifampin, on the PK of eribulin was studied in a crossover trial of RECENT MAJOR CHANGES • QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, Blood and lymphatic system disordersb What is the most important information I should know about HALAVEN? • HALAVEN is usually given on day 1 and day 8 of a treatment cycle. None. (0.9% each). Twenty-six percent of patients required at least one dose reduction. The most • Immune System Disorders: drug hypersensitivity which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction 14 patients with advanced solid tumors. No clinically relevant PK interaction was observed when 0.7 Indications and Usage (1.2) 01/2016 bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid Neutropenia 82% 57% 53% 23% frequent adverse reactions that led to dose reduction were neutropenia (18%) and peripheral 0.6 in patients with congenital long QT syndrome. (5.4) 5 WARNINGS AND PRECAUTIONS HALAVEN can cause serious side effects, including: • Infections and Infestations: pneumonia, sepsis/neutropenic sepsis lasting one day. HALAVEN was administered with or without rifampin (the geometric mean ratio of the AUC: HALAVEN (N=508) Warnings and Precautions (5.1, 5.2, 5.3) 01/2016 Anemia 58% 2% 55% 4% neuropathy (4.0%). What are the possible side effects of HALAVEN? 0.6 5.1 Neutropenia • Metabolism and Nutrition Disorders: hypomagnesemia, dehydration There is no known antidote for HALAVEN overdose. 1.10; 90 CI%: 0.91, 1.34). ADVERSE REACTIONS 3 Nervous system disorders Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients in Effect of Eribulin on CYP Substrates: Eribulin shows no induction potential for CYP1A, CYP2B6, In Study 1, severe neutropenia (ANC < 500/mm ) lasting more than one week occurred in 12% c • Low white blood cell count (neutropenia). This can lead to 11 DESCRIPTION 0.4 INDICATIONS AND USAGE The most common adverse reactions (≥25%) in metastatic breast cancer were neutropenia, anemia, Peripheral neuropathy 35% 8% 16% 2% the HALAVEN-treated arm in Study 2. • Respiratory, thoracic and mediastinal disorders: interstitial lung disease 0.5 Survival Probability HALAVEN is a microtubule inhibitor indicated for the treatment of patients with: (62/503) of patients with metastatic breast cancer, leading to discontinuation in <1% of patients. serious infections that could lead to death. Your healthcare provider HALAVEN may cause serious side effects, including: • Skin and Subcutaneous Tissue Disorders: pruritus, Stevens-Johnson syndrome, HALAVEN contains eribulin mesylate, a microtubule dynamics inhibitor. Eribulin mesylate is a CYP2C9, CYP2C19, and CYP3A in primary human hepatocytes. Eribulin inhibits CYP3A4 activity asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. (6.1) Headache 19% <1% 12% <1% Table 3: Adverse Reactionsa Occurring in ≥10% (all Grades) of Patients Treated on in human liver microsomes, but it is unlikely that eribulin will substantially increase the plasma • Metastatic breast cancer who have previously received at least two chemotherapeutic regimens Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 5% (23/503) toxic epidermal necrolysis synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria 0.4 The most common adverse reactions (≥25%) in liposarcoma and leiomyosarcoma were fatigue, of patients; two patients (0.4%) died from complications of febrile neutropenia [see Adverse General disorders the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm will check your blood cell counts before you receive each dose of • See “What is the most important information I should know okadai. The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano- levels of CYP3A4 substrates. No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, 0.2 for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most Asthenia/Fatigue 54% 10% 40% 11% 7 DRUG INTERACTIONS Reactions (6.1)]. (Between Arm Difference of ≥5% for All Grades or ≥2% for Grades 3 and 4) HALAVEN and during treatment. Call your healthcare provider right about HALAVEN?” 12,15-methano-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, or CYP2E1 was detected with eribulin concentrations up to 5 μM in pooled human liver 0.3 taxane in either the adjuvant or metastatic setting. (1.1) common (≥5%) Grade 3-4 laboratory abnormalities in liposarcoma and leiomyosarcoma were b 7.1 Effects of Other Drugs on HALAVEN In Study 1, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) Pyrexia 21% <1% 13% <1% (Study 2) 2-[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, microsomes. In vitro drug interaction studies indicate that eribulin does not inhibit drugs that are Proportion of Patients Alive • Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing neutropenia, hypokalemia, and hypocalcemia. (6.1) Mucosal inflammation 9% 1% 10% 2% away if you develop any of these symptoms of infection: • HALAVEN can cause changes in your heartbeat (called QT No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or substrates of these enzymes and it is unlikely that eribulin will affect plasma levels of drugs that 0.0 > 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia HALAVEN Dacarbazine P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, 0.2 regimen. (1.2) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at (1-877-873-4724) or FDA Gastrointestinal disorders Adverse Reaction –fever (temperature above 100.5°F) prolongation). This can cause irregular heartbeats. Your healthcare are substrates of CYP enzymes. 063 9121518212427303336394245 and febrile neutropenia than patients with normal aminotransferase levels. Patients with n=223 n=221 observed in patients with advanced solid tumors when HALAVEN was administered with or methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free base). The empirical CONTROL (N=254) at 1-800-FDA-1088 or www.fda.gov/medwatch Nausea 35% 1% 28% 3% formula is C H NO •CH O S. Eribulin mesylate has the following structural formula: Effect of Transporters on Eribulin: In vitro data suggest that eribulin at clinically relevant 0.1 Survival Time (months) DOSAGE AND ADMINISTRATION bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia. All Grades Grades 3-4 All Grades Grades 3-4 –chills provider may do heart monitoring (electrocardiogram or ECG) or blood without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when HALAVEN 40 59 11 4 3 Subjects at Risk: 2 3 Constipation 25% 1% 21% 1% concentrations is a substrate of P-gp, but is not a substrate of breast cancer resistance protein HALAVEN • Administer 1.4 mg/m intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. (2.1) USE IN SPECIFIC POPULATIONS In Study 2, severe neutropenia (ANC < 500/mm ) lasting more than one week occurred in 12% Nervous system disorders was administered with or without rifampin (a CYP3A4 inducer) . H3C 71 63 51 43 39 34 30 20 15 12 7 4 2 0 0 0 –cough tests during your treatment with HALAVEN to check for [see Clinical Pharmacology (12.3)] O H 0.0 Dacarbazine 72 59 42 33 22 17 12 11 6 3 2 0 0 0 0 0 • Lactation: Do not breastfeed. (8.2) (26/222) of patients with liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 0.9% of Vomiting 18% 1% 18% 1% c (BCRP), multidrug resistance proteins (MRP2, MRP4), bile salt extrusion pump (BSEP), organic • Reduce dose in patients with hepatic impairment or with moderate or severe renal impairment. (2.1) Peripheral Neuropathy 29% 3.1% 8% 0.5% heart problems. 7.2 Effect of HALAVEN on Other Drugs H • Hepatic Impairment: A lower starting dose is recommended for patients with mild patients treated with HALAVEN and fatal neutropenic sepsis in 0.9% [see Adverse Reactions (6.1)]. Diarrhea 18% 0 18% 0 –burning or pain when you urinate anion transporting polypeptides (OATP1B1, OATP1B3), organic anion transporters (OAT1, OAT3), • Do not mix with other drugs or administer with dextrose-containing solutions. (2.3) Musculoskeletal and connective tissue disorders Headache 18% 0% 10% 0% Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes H H H H organic cation transporters (OCT1, OCT2), or multidrug and toxin extrusion 1 (MATE1). Table 7: Efficacy Results for the Leiomyosarcoma Stratum in Study a2 (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. Patients with severe Monitor complete blood counts prior to each dose; increase the frequency of monitoring in General disorders or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. H2N O O DOSAGE FORMS AND STRENGTHS Arthralgia/Myalgia 22% <1% 12% 1% The most common side effects of HALAVEN in people with breast HO H O O Effect of Eribulin on Transporters: In vitro data suggest that eribulin at clinically relevant 0612 18 24 30 36 hepatic impairment (Child-Pugh C) were not studied. (8.6) patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce Pyrexia 28% 0.9% 14% 0.5% • Numbness, tingling, or pain in your hands or feet (peripheral Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these H H H H H Leiomyosarcoma Stratum Injection: 1 mg per 2 mL (0.5 mg per mL) (3) Back pain 16% 1% 7% 2% cancer include: CH concentrations may inhibit P-gp, but does not inhibit BCRP, OATP1B1, OCT1, OAT1, OAT3, or MATE1. Time (months) Halaven (n=154) Dacarbazine (n=149) • Renal Impairment: A lower starting dose is recommended for patients with moderate subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting Gastrointestinal disorders neuropathy). Peripheral neuropathy is common with HALAVEN and enzymes [see Clinical Pharmacology (12.3)]. 2 H3CSO3H Bone pain 12% 2% 9% 2% O O 13 NONCLINICAL TOXICOLOGY Number of 508 406 274 142 54 11 0 Overall survival (CLcr 30-49 mL/min) or severe (CLcr 15-29 mL/min) renal impairment. (8.7) longer than 7 days [see Dosage and Administration (2.2)]. Clinical studies of HALAVEN did not Constipation 32% 0.9% 26% 0.5% 8 USE IN SPECIFIC POPULATIONS H O H Patients at Risk 254 178 106 61 26 5 0 CONTRAINDICATIONS 3 Pain in extremity 11% 1% 10% 1% sometimes can be severe. Tell your healthcare provider if you have • low white blood cell count (neutropenia) • hair loss (alopecia) 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Deaths, n (%) 121 (79) 116 (78) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved Patient Labeling include patients with baseline neutrophil counts below 1,500/mm . Abdominal paind 29% 1.8% 23% 4.1% 8.1 Pregnancy O None (4) Metabolism and nutrition disorders CH Carcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was Median, months (95% CI) 12.8 (10.3, 14.8) 12.3 (11.0, 15.1) (Patient Information). 5.2 Peripheral Neuropathy Stomatitis 14% 0.9% 5% 0.5% new or worsening symptoms of peripheral neuropathy. • low red blood cell count (anemia) • nausea H 3 H 14.2 Liposarcoma Decreased weight 21% 1% 14% <1% Risk Summary O not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was HR (95% CI) 0.90 (0.69, 1.18) Revised: October 2016 In Study 1, Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in Skin and subcutaneous tissue disorders • Your healthcare provider may delay, decrease your dose, or stop • weakness or tiredness • constipation Based on findings from an animal reproduction study and its mechanism of action, HALAVEN The efficacy and safety of HALAVEN were evaluated in Study 2, an open-label, randomized Progression-free survival 0.4% (2/503) of patients with metastatic breast cancer (MBC). Peripheral neuropathy was the Anorexia 20% 1% 13% 1% e e H H positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone (1:1), multicenter, active-controlled trial. Eligible patients were required to have unresectable, Respiratory, thoracic, and mediastinal disorders Alopecia 35% NA 2.7% NA treatment with HALAVEN if you have side effects. can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology marrow micronucleus assay. Events, n (%) 137 (89) 126 (85) FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503) in Study 1. Infections (12.1)]. There are no available data on the use of HALAVEN during pregnancy. In an animal locally advanced or metastatic liposarcoma or leiomyosarcoma, at least two prior systemic Disease progression 127 118 Dyspnea 16% 4% 13% 4% The most common side effects of HALAVEN in people with H2C Fertility studies have not been conducted with eribulin mesylate in humans or animals; however, 8.1 Pregnancy Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent Urinary tract infection 11% 2.2% 5% 0.5% reproduction study, eribulin mesylate caused embryo-fetal toxicity when administered to chemotherapies (one of which must have included an anthracycline), and disease progression Death 10 8 1 INDICATIONS AND USAGE (109/503) of patients developed a new or worsening neuropathy that had not recovered within a Cough 14% 0 9% 0 See “What are possible side effects of HALAVEN?” for more liposarcoma include: HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each vial contains nonclinical findings in repeat-dose dog and rat toxicology studies suggest that male fertility a pregnant rats during organogenesis at doses below the recommended human dose [see Data]. within 6 months of the most recent chemotherapy regimen. Patients were randomized to Median, months (95% CI) 2.2 (1.5, 2.7) 2.6 (2.2, 2.9) 8.2 Lactation Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events 2 1.1 Metastatic Breast Cancer median follow-up duration of 269 days (range 25-662 days). Skin and subcutaneous tissue disorders information about side effects. 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95). may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity HALAVEN 1.4 mg/m administered intravenously on Days 1 and 8 of a 21-day cycle or to HR (95% CI) 1.05 (0.81, 1.35) 8.3 Females and Males of Reproductive Potential d d Advise pregnant women of the potential risk to a fetus. 1.2 Liposarcoma In Study 2, Grade 3 peripheral neuropathy occurred in 3.1% (7/223) of HALAVEN-treated Alopecia 45% NA 10% NA version 4.03 (NCI CTCAE v4.03). • tiredness • constipation 12 CLINICAL PHARMACOLOGY (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with dacarbazine at a dose of 850 mg/m2, 1000 mg/m2, or 1200 mg/m2 administered intravenously Objective response rate (%) (95% CI) 5.2 (2.3, 10) 7.4 (3.7, 12.8) 8.4 Pediatric Use b Safety data from one study site enrolling six patients were excluded. The estimated background risks of major birth defects and miscarriage for the indicated populations 2 DOSAGE AND ADMINISTRATION Infections What is HALAVEN? 12.1 Mechanism of Action eribulin mesylate at or above 0.43 times the recommended human dose (based on body surface every 21 days (dacarbazine dose was selected by the investigator prior to randomization). a patients. Peripheral neuropathy led to discontinuation of HALAVEN in 0.9% of patients. The c • nausea • stomach pain are unknown. In the U.S. general population, the estimated background risk of major birth defects Efficacy data from one study site enrolling six patients were excluded. 2.1 Recommended Dose 8.5 Geriatric Use median time to first occurrence of peripheral neuropathy of any severity was 5 months (range: Urinary Tract Infection 10% 1% 5% 0 Includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and area) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose Treatment continued until disease progression or unacceptable toxicity. Randomization was neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. • hair loss (alopecia) • fever and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 2.2 Dose Modification 8.6 Hepatic Impairment 3.5 months to 9 months). Neuropathy lasting more than 60 days occurred in 58% (38/65) of a sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based (based on body surface area) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. stratified by histology (liposarcoma or leiomyosarcoma), number of prior therapies (2 vs. > 2), 16 HOW SUPPLIED/STORAGE AND HANDLING adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.0. d Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort. HALAVEN is a prescription medicine used to treat people with: Data 8.7 Renal Impairment patients. Sixty three percent (41/65) had not recovered within a median follow-up duration of b antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose and geographic region (U.S. and Canada vs. Western Europe, Australia, and Israel vs. Eastern NDC 62856-389-01 2.3 Instructions for Preparation and Administration based upon laboratory data. e Not applicable; (grading system does not specify > Grade 2 for alopecia). Your healthcare provider will do blood tests before and during treatment Animal Data 10 OVERDOSAGE 6.4 months (range: 27 days to 29 months). c • Breast cancer ultimately, apoptotic cell death after prolonged mitotic blockage. (based on body surface area) weekly for 3 out of 5 weeks, repeated for 6 cycles. Europe, Latin America, and Asia). The major efficacy outcome measure was overall survival 3 DOSAGE FORMS AND STRENGTHS includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor In an embryo-fetal developmental toxicity study, pregnant rats received intravenous infusion of Injection: 1 mg/2 mL, in a single-use vial. One vial per carton. 11 DESCRIPTION Other clinically important adverse reactions occurring in ≥10% of the HALAVEN-treated while you are taking HALAVEN. The most common changes to blood tests In addition, eribulin treatment of human breast cancer cells caused changes in morphology and 14 CLINICAL STUDIES (OS). Additional efficacy outcome measures were progression-free survival (PFS) and confirmed 4 CONTRAINDICATIONS Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. –that has spread to other parts of the body, and eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° – 86° F). Do not freeze. Store the 12 CLINICAL PHARMACOLOGY d patients were: gene expression as well as decreased migration and invasiveness in vitro. In mouse xenograft 14.1 Metastatic Breast Cancer objective response rate (ORR) as assessed by the investigator according to Response Evaluation 5 WARNINGS AND PRECAUTIONS HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy, until resolution to not applicable; (grading system does not specify > Grade 2 for alopecia). in people with liposarcoma include: 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area. vials in their original cartons. 12.1 Mechanism of Action Grade 2 or less [see Dosage and Administration (2.2)]. • Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%) – who have already received certain types of anticancer medicines models of human breast cancer, eribulin treatment was associated with increased vascular Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast Criteria in Solid Tumors (RECIST v1.1). Patients in the dacarbazine arm were not offered 17 PATIENT COUNSELING INFORMATION 5.1 Neutropenia Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN Increased abortion and severe fetal external or soft tissue malformations, including the cancer who received at least two chemotherapeutic regimens for the treatment of metastatic 12.2 Pharmacodynamics 5.3 Embryo-Fetal Toxicity • General Disorders: asthenia/fatigue (62%); peripheral edema (12%) after the cancer has spread • low white blood cell count (neutropenia) perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes HALAVEN at the time of disease progression. Advise the patient to read the FDA-approved patient labeling (Patient Information). 5.2 Peripheral Neuropathy in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia absence of a lower jaw and tongue, or stomach and spleen, were observed at doses 0.64 in the expression of genes in tumor specimens associated with a change in phenotype. disease and experienced disease progression within 6 months of their last chemotherapeutic A total of 446 patients were randomized, 225 to the HALAVEN arm and 221 to the dacarbazine 12.3 Pharmacokinetics Based on findings from an animal reproduction study and its mechanism of action, HALAVEN • Metabolism and Nutrition Disorders: decreased appetite (19%) 2 Neutropenia 5.3 Embryo-Fetal Toxicity occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile • Liposarcoma • decreased blood levels of potassium or calcium times the recommended human dose of 1.4 mg/m based on body surface area. Increased 12.2 Pharmacodynamics regimen. Patients were required to receive prior anthracycline- and taxane-based chemotherapy arm. The median age was 56 years (range: 24 to 83); 33% were male; 73% were White; 44% 13 NONCLINICAL TOXICOLOGY can cause fetal harm when administered to a pregnant woman. There are no adequate and Advise patients to contact their health care provider for a fever of 100.5°F or greater or other 5.4 QT Prolongation neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and • Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent Cardiac Electrophysiology for adjuvant or metastatic disease. Patients were randomized (2:1) to receive HALAVEN (n=508) had ECOG performance status (PS) 0 and 53% had ECOG PS 1; 68% had leiomyosarcoma 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility well-controlled studies of HALAVEN in pregnant women. In animal reproduction studies, eribulin discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the back pain (16%) – that cannot be treated with surgery or has spread to other parts Tell your healthcare provider about any side effect that bothers you or that with developmental delay were also reported at doses at or above a maternally toxic dose of signs or symptoms of infection such as chills, cough, or burning or pain on urination [see 6 ADVERSE REACTIONS mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, or a single agent therapy selected prior to randomization (control arm, n=254). Randomization and 32% had liposarcoma; 39% were enrolled in U.S. and Canada (Region 1) and 46% were 14 CLINICAL STUDIES mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater • Respiratory Disorders: cough (18%) of the body, and approximately 0.43 times the recommended human dose. Warnings and Precautions (5.1)]. 6.1 Clinical Trials Experience at doses below the recommended human dose. Advise pregnant women of the potential risk to does not go away. multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. enrolled in Western Europe, Australia, and Israel (Region 2); and 47% received more than two thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating 8.2 Lactation 2 Peripheral Neuropathy 6.2 Postmarketing Experience 14.1 Metastatic Breast Cancer a fetus. Advise females of reproductive potential to use effective contraception during treatment Less Common Adverse Reactions: The following additional clinically important adverse reactions – who have received treatment with a certain type of 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was HALAVEN was administered at a dose of 1.4 mg/m on Days 1 and 8 of a 21-day cycle. prior systemic chemotherapies. The most common (>40%) prior systemic chemotherapies were factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of Risk Summary Advise patients to inform their healthcare providers of new or worsening numbness, tingling and 7 DRUG INTERACTIONS 14.2 Liposarcoma with HALAVEN and for at least 2 weeks following the final dose. Advise males with female were reported in ≥5% to <10% of the HALAVEN-treated group: observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change HALAVEN-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. doxorubicin (90%), ifosfamide (62%), gemcitabine (59%), trabectedin (50%), and docetaxel (48%). patients who received HALAVEN. anticancer medicine These are not all the possible side effects of HALAVEN. Call your doctor pain in their extremities [see Warnings and Precautions (5.2)]. 16 HOW SUPPLIED/STORAGE AND HANDLING partners of reproductive potential to use effective contraception during treatment with HALAVEN • Blood and Lymphatic System Disorders: thrombocytopenia There is no information regarding the presence of eribulin mesylate or its metabolites in human from baseline (95% upper confidence interval) was 11.4 (19.5) ms. Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% Of the 143 patients with liposarcoma, the median age was 55 years (range: 32 to 83); 62% 7.1 Effects of Other Drugs on HALAVEN Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy for medical advice about side effects. You may report side effects to FDA 17 PATIENT COUNSELING INFORMATION and for 3.5 months following the final dose[see Use in Specific Populations (8.1)]. • Eye Disorders: increased lacrimation milk, the effects on the breastfed infant, or the effects on milk production. No lactation studies 12.3 Pharmacokinetics capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal were male, 72% were White; 41% had ECOG PS of 0 and 53% had ECOG PS of 1; 35% were Embryo-Fetal Toxicity 7.2 Effects of HALAVEN on Other Drugs and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to It is not known if HALAVEN is safe and effective in children under 18 years *Sections or subsections omitted from the full prescribing information are not listed. • Gastrointestinal Disorders: dyspepsia at 1-800-FDA-1088. in animals were conducted. Because of the potential for serious adverse reactions in breastfed therapy. The main efficacy outcome was overall survival. enrolled in Region 1 and 51% were enrolled in Region 2; and 44% received more than two prior • Advise females of reproductive potential of the potential risk to a fetus and to inform their 5.4 QT Prolongation peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four of age. The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of • Metabolism and Nutrition Disorders: hyperglycemia infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean Patient demographic and baseline characteristics were comparable between the treatment systemic chemotherapies. The distribution of subtypes of liposarcoma, based on local histologic healthcare provider of a known or suspected pregnancy [see Warnings and Precautions In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% and for 2 weeks after the final dose. FULL PRESCRIBING INFORMATION – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. • Musculoskeletal and Connective Tissue Disorders: muscle spasms, General information about HALAVEN 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. arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent assessment, were 45% dedifferentiated, 37% myxoid/round cell, and 18% pleomorphic. (5.3), Use in Specific Populations (8.1)]. (8/503) of patients developed Grade 3 peripheral motor neuropathy. Before you receive HALAVEN, tell your healthcare provider about 8.3 Females and Males of Reproductive Potential of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/ 1 INDICATIONS AND USAGE reduced dose and initiate the next cycle no sooner than 2 weeks later. ECG monitoring is recommended if therapy is initiated in patients with congestive heart musculoskeletal pain The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL Study 2 demonstrated a statistically significant improvement in OS in patients randomized to • Advise females of reproductive potential to use effective contraception during treatment Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, all of your medical conditions, including if you: Contraception ranges from 49% to 65%. Eribulin exposure after multiple dosing is comparable to that following Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients had a baseline HALAVEN compared with dacarbazine (see Table 6). There was no significant difference in with HALAVEN and for at least 2 weeks after the final dose[see Use in Specific 1.1 Metastatic Breast Cancer Recommended dose reductions failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN- • Nervous System Disorders: dizziness, dysgeusia Medicines are sometimes prescribed for purposes other than those listed in a HALAVEN is indicated for the treatment of patients with metastatic breast cancer who have antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia Females a single dose. No accumulation of eribulin is observed with weekly administration. ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor progression-free survival in the overall population. Treatment effects of HALAVEN were limited Populations (8.3)]. • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or treated patient without documented liver metastases had concomitant Grade 2 elevations in • Psychiatric Disorders: insomnia, anxiety • have liver or kidney problems Patient Information leaflet. You can ask your pharmacist or healthcare provider status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: previously received at least two chemotherapeutic regimens for the treatment of metastatic prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Based on findings from an animal reproduction study and its mechanism of action, HALAVEN Elimination - - to patients with liposarcoma based on pre-planned, exploratory subgroup analyses of OS and • Advise males with female partners of reproductive potential to use effective contraception less, resume HALAVEN at a reduced dose as set out in Table 1. bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. • Respiratory, Thoracic, and Mediastinal Disorders: oropharyngeal pain for information about HALAVEN that is written for health professionals. 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative status (ER , PR , disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant Avoid HALAVEN in patients with congenital long QT syndrome. can cause fetal harm when administered to a pregnant woman [see Use in Specific - PFS (see Tables 6 and 7 and Figure 2). There was no evidence of efficacy of HALAVEN in patients during treatment with HALAVEN and for 3.5 months following the final dose[see Use in • Do not re-escalate HALAVEN dose after it has been reduced. Less Common Adverse Reactions: The following additional adverse reactions were reported in • Vascular Disorders: hypotension • have heart problems, including a problem called congenital long Metabolism HER2/ : 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone or metastatic setting [see Clinical Studies (14.1)]. 6 ADVERSE REACTIONS Populations (8.1)]. Advise females of reproductive potential to use effective contraception neu with advanced or metastatic leiomyosarcoma in Study 2 (see Table 7). Specific Populations (8.3)]. Table 1: Recommended Dose Reductions ≥5% to <10% of the HALAVEN-treated group: QT syndrome Unchanged eribulin was the major circulating species in plasma following administration of disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in What are the ingredients in HALAVEN? during treatment with HALAVEN and for at least 2 weeks following the final dose. 14 a Lactation 1.2 Liposarcoma 6.1 Clinical Trials Experience Table 4: Laboratory Abnormalities Occurring in ≥10% (all Grades) of Patients Treated C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, the HALAVEN and control arms. Patients received a median of four prior chemotherapy regimens in Table 6: Efficacy Results for the Liposarcoma Stratum and All Patients* in Study 2 HALAVEN is indicated for the treatment of patients with unresectable or metastatic liposarcoma Recommended Because clinical trials are conducted under widely varying conditions, the adverse reaction rates • Eye Disorders: increased lacrimation • have low potassium or low magnesium in your blood Males confirming that there are no major human metabolites of eribulin. Cytochrome P450 3A4 Advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final Event Description on the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm both arms. Liposarcoma who have received a prior anthracycline-containing regimen [see Clinical Studies (14.2)]. HALAVEN Dose observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth (Between Arm Difference of ≥5% for All Grades or ≥2% for Grades 3 and 4)a • are pregnant or plan to become pregnant. HALAVEN can harm your Active Ingredient: eribulin mesylate Based on its mechanism of action, advise males with female partners of reproductive potential to use (CYP3A4) negligibly metabolizes eribulin in vitro. All Patients* dose [see Use in Specific Populations (8.2)]. 2 In Study 1, a statistically significant improvement in overall survival was observed in patients Stratum 2 DOSAGE AND ADMINISTRATION Permanently reduce the 1.4 mg/m HALAVEN dose and may not reflect the rates observed in clinical practice. • General Disorders and Administration Site Conditions: peripheral edema (Study 2)† effective contraception during treatment with HALAVEN and for 3.5 months following the final dose. Excretion unborn baby. Tell your healthcare provider right away if you become randomized to the HALAVEN arm compared to the control arm (see Table 5). An updated, unplanned Halaven Dacarbazine Halaven Dacarbazine 2.1 Recommended Dose for any of the following: The following adverse reactions are discussed in detail in other sections of the labeling: • Infections and Infestations: upper respiratory tract infection Inactive Ingredients: ethanol, water Infertility Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to patients, Distributed by: 3 Laboratory Abnormality Halaven Dacarbazine survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent (n=71) (n=72) (n=225) (n=221) The recommended dose of HALAVEN is 1.4 mg/m2 administered intravenously over 2 to 5 ANC <500/mm for >7 days • Neutropenia [see Warnings and Precautions (5.1)] • Metabolism and Nutrition Disorders: hypokalemia pregnant or think you are pregnant during treatment with HALAVEN. Males approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin Eisai Inc. 3 All Grades Grades 3-4 All Grades Grades 3-4 with the primary analysis. In patients randomized to HALAVEN, the objective response rate by the Overall Survival minutes on Days 1 and 8 of a 21-day cycle. ANC <1,000 /mm with fever or infection • Peripheral neuropathy [see Warnings and Precautions (5.2)] • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness – Females who are able to become pregnant should use an ® Based on animal data, HALAVEN may result in damage to male reproductive tissues leading to accounted for approximately 88% and 91% of total eribulin in feces and urine, respectively. Woodcliff Lake, NJ 07677 3 2 Hematology HALAVEN is a registered trademark used by Eisai Inc. under license from RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months Deaths, n (%) 52 (73) 63 (88) 173 (77) 179 (81) The recommended dose of HALAVEN in patients with mild hepatic impairment (Child-Pugh A) is Platelets <25,000/mm 1.1 mg/m • Nervous System Disorders: dysgeusia, dizziness impaired fertility of unknown duration [see Nonclinical Toxicology (13.1)]. Specific Populations 3 • QT prolongation [see Warnings and Precautions (5.4)] Anemia 70% 4.1% 52% 6% effective birth control during treatment with HALAVEN and for at (95% CI: 3.8, 5.0 months). 15.6 8.4 13.5 11.3 2 Platelets <50,000/mm requiring transfusion Eisai R&D Management Co., Ltd. 8.4 Pediatric Use Median, months (95% CI) 1.1 mg/m administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle In clinical trials, HALAVEN has been administered to 1963 patients including 467 patients • Psychiatric Disorders: insomnia, depression Neutropenia 63% 32% 30% 8.9% Age, Sex, and Race/Ethnicity: Based on a population pharmacokinetic analysis with data (10.2, 18.6) (5.2, 10.1) (11.1, 16.5) (9.5, 12.6) [see Use in Specific Populations (8.6)]. Non-hematologic Grade 3 or 4 toxicities least 2 weeks after the final dose of HALAVEN. The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have Table 5: Comparison of Overall Survival in HALAVEN and Control Arm - Study 1 exposed to HALAVEN for 6 months or longer. The majority of the 1963 patients were women • Skin and Subcutaneous Tissue Disorders: rash Chemistry Distributed by: collected from 340 patients, sex, race, and age do not have a clinically meaningful effect on the Hazard ratio (HR) (95% CI) 0.51 (0.35, 0.75) 0.75 (0.61, 0.94) The recommended dose of HALAVEN in patients with moderate hepatic impairment (Child-Pugh B) Omission or delay of Day 8 HALAVEN dose in previous not been established. exposure of eribulin. HALAVEN Control Arm (92%) with a median age of 55 years (range: 17 to 85 years). The racial and ethnic distribution Liposarcoma Increased alanine aminotransferase – Males should use an effective form of birth control when Overall Survival Stratified log-rank p value N/A† 0.011 is 0.7 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle cycle for toxicity 43% 2.3% 28% 2.3% Eisai Inc. 8.5 Geriatric Use (n=508) (n=254) was White (72%), Black (4%), Asian (9%), and other (3%). The safety of HALAVEN was evaluated in Study 2, an open-label, randomized, multicenter, (ALT) having sex with female partners who are able to become Hepatic Impairment Progression-free survival [see Use in Specific Populations (8.6)]. Occurrence of any event requiring permanent dose reduction Study 1 did not include sufficient numbers of subjects with metastatic breast cancer aged 65 0.7 mg/m2 Metastatic Breast Cancer active-controlled trial, in which patients were randomized (1:1) to receive either HALAVEN Increased aspartate Woodcliff Lake, NJ 07677 In a study evaluating the effect of hepatic impairment on the PK of eribulin, eribulin exposures Primary survival analysis Events, n (%) 57 (80) 59 (82) 194 (86) 185 (84) 2 2 2 36% 0.9% 16% 0.5% pregnant during treatment with HALAVEN and for 3 1/2 months years and older to determine whether they respond differently from younger subjects. Of the The recommended dose of HALAVEN in patients with moderate or severe renal impairment while receiving 1.1 mg/m The most common adverse reactions (≥25%) reported in patients receiving HALAVEN 1.4 mg/m on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 850 mg/m (20%), aminotransferase (AST) increased by 1.8-fold in patients with mild hepatic impairment (Child-Pugh A; n=7) and by 2.5-fold Number of deaths 274 148 2 2 2 827 subjects who received the recommended dose and schedule of HALAVEN in clinical studies Disease progression 53 52 180 170 (creatinine clearance (CLcr) 15-49 mL/min) is 1.1 mg/m administered intravenously over Occurrence of any event requiring permanent dose reduction were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and 1000 mg/m (64%), or 1200 mg/m (16%) every 3 weeks. A total of 223 patients received HALAVEN (14 weeks) after the final dose of HALAVEN. in patients with moderate (Child-Pugh B; n=5) hepatic impairment as compared to patients with Median, months (95% CI) 13.1 (11.8, 14.3) 10.6 (9.3, 12.5) 2 Discontinue HALAVEN Hypokalemia 30% 5.4% 14% 2.8% For more information, go to www.HALAVEN.com or call Eisai Inc. with advanced breast cancer, 15% (121/827) were 65 and older, and 2% (17/827) patients 2 a Death 4 7 14 15 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations (8.7)]. while receiving 0.7 mg/m constipation. The most common serious adverse reactions reported in patients receiving and 221 patients received dacarbazine. Patients were required to have received at least two normal hepatic function (n=6). Administration of HALAVEN at a dose of 1.1 mg/m to patients Hazard Ratio (95% CI) 0.81 (0.66, 0.99) Hypocalcemia 28% 5% 18% 1.4% • are breastfeeding or plan to breastfeed. It is not known if HALAVEN were 75 and older. No overall differences in safety were observed between these subjects 2 b 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) 2.2 Dose Modification ANC = absolute neutrophil count. HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse prior systemic chemotherapy regimens. The trial excluded patients with pre-existing ≥ Grade 3 at 1-877-873-4724. If you would like a leaflet with larger printing, with mild hepatic impairment and 0.7 mg/m to patients with moderate hepatic impairment P value 0.041 Hypophosphatemia 20% 3.2% 11% 1.4% and younger subjects. 2 HR (95% CI) 0.52 (0.35, 0.78) 0.86 (0.69, 1.06) Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or passes into your breast milk. Do not breastfeed during treatment with resulted in similar exposure to eribulin at a dose of 1.4 mg/m to patients with normal hepatic Updated survival analysis Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology a please contact Eisai Inc. at 1-877-873-4724. Objective response rate significant chronic liver disease, history of myocardial infarction within 6 months, history of Each test incidence is based on the number of patients who had both baseline and at least one HALAVEN and for 2 weeks after the final dose of HALAVEN. Clinical studies of HALAVEN did not include a sufficient number of subjects in Study 2 aged 65 function [see Dosage and Administration (2.1), Use in Specific Populations (8.6)]. Number of deaths 386 203 Recommended dose delays Criteria for Adverse Events (CTCAE) version 3.0. The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 Objective response rate New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment. on-study measurement and at least 1 grade increase from baseline. Halaven group (range years and older to determine whether they respond differently from younger subjects. Renal Impairment Median, months (95% CI) 13.2 (12.1, 14.4) 10.6 (9.2, 12.0) 1.4 (0, 7.6) 0 (0, 4.2) 4.0 (1.8, 7.5) 5.0 (2.5, 8.7) • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: 2.3 Instructions for Preparation and Administration [see Clinical Studies (14.1)]. In Study 1, patients were randomized (2:1) to receive either This Patient Information has been approved by the (%) (95% CI) 3 2 The median age of the safety population in Study 2 was 56 years (range: 24 to 83 years); 221-222) and dacarbazine group (range 214-215) Tell your healthcare provider about all the medicines you take, 8.6 Hepatic Impairment – ANC < 1,000/mm Aseptically withdraw the required amount of HALAVEN from the single-use vial and HALAVEN (1.4 mg/m on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by † 2 In a study evaluating the effect of renal impairment on the PK of eribulin, patients with moderate CI = confidence interval Laboratory results were graded per NCI CTCAE v4.03. U.S. Food and Drug Administration. Revised: 01/2016 Administration of HALAVEN at a dose of 1.1 mg/m to patients with mild hepatic impairment a 3 their physician (control group). A total of 503 patients received HALAVEN and 247 patients in 67% female; 73% White, 3% Black or African American, 8% Asian/Pacific Islander, and (CLcr 30-49 mL/min; n=7) and severe renal impairment (CLcr 15-29 mL/min; n=6) had 1.5-fold a Efficacy data from one study site enrolling six patients were excluded. ® – Platelets < 75,000/mm administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. including prescription and over-the-counter medicines, vitamins, and 2 Based on Cox proportional hazards model stratified by geographic region, HER2 status, and HALAVEN is a registered trademark used by Eisai Inc. under license from the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, 15% unknown; 99% received prior anthracycline-containing regimen; and 99% received ≥ 2 prior and 0.7 mg/m to patients with moderate hepatic impairment resulted in similar exposure to higher eribulin dose-normalized exposures compared to that in patients with normal renal * All patients = liposarcoma and leiomyosarcoma. – Grade 3 or 4 non-hematological toxicities. Do not dilute in or administer through an intravenous line containing solutions herbal supplements. 2 prior capecitabine therapy. † Eisai R&D Management Co., Ltd. capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies regimens. The median duration of exposure was 2.3 months (range: 21 days to 26 months) for eribulin as a dose of 1.4 mg/m to patients with normal hepatic function. Therefore, a lower function (CLcr ≥ 80 mL/min; n=6). There were no clinically meaningful changes in patients with b N/A = not applicable • The Day 8 dose may be delayed for a maximum of 1 week. with dextrose. Do not administer in the same intravenous line concurrent with the other starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment Based on a log-rank test stratified by geographic region, HER2 status, and prior capecitabine 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients patients receiving HALAVEN [see Clinical Studies (14.2)]. mild renal impairment (CLcr 50-79 mL/min; n=27) [see Dosage and Administration (2.1), Use in © 2016 Eisai Inc. All rights reserved. HALA-US0277(1) – If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. medicinal products. © 2016 Eisai Inc. All rights reserved. HALA-US0277(1) (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic therapy. Printed in USA / October 2016 Specific Populations (8.7)]. Printed in USA / October 2016 ✃ ✁