Eribulin Mesylate

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

2 DOSAGE AND ADMINISTRATION Administer 1.4 mg/m 2 intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. ( 2.1 ) Reduce dose in patients with hepatic impairment or with moderate or severe renal impairment. ( 2.1 ) Do not mix with other drugs or administer with dextrose-containing solutions. ( 2.3 ) 2.1 Recommended Dose The recommended dose of eribulin mesylate injection is 1.4 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. The recommended dose of eribulin mesylate injection in patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations ( 8.6 )] . The recommended dose of eribulin mesylate injection in patients with moderate hepatic impairment (Child-Pugh B) is 0.7 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations ( 8.6 )] . The recommended dose of eribulin mesylate injection in patients with moderate or severe renal impairment (creatinine clearance (CLcr) 15-49 mL/min) is 1.1 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations (8.7 ) ] . 2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. Recommended dose delays Do not administer eribulin mesylate injection on Day 1 or Day 8 for any of the following ANC < 1,000/mm 3 Platelets < 75,000/mm 3 Grade 3 or 4 non-hematological toxicities. The Day 8 dose may be delayed for a maximum of 1 week. If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer eribulin mesylate injection at a reduced dose and initiate the next cycle no sooner than 2 weeks later. Recommended dose reductions If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume eribulin mesylate injection at a reduced dose as set out in Table 1 . Do not re-escalate eribulin mesylate injection dose after it has been reduced. Table 1: Recommended Dose Reductions Event Description Recommended Eribulin Mesylate Injection Dose Permanently reduce the 1.4 mg/m 2 eribulin mesylate injection dose for any of the following: 1.1 mg/m 2 ANC <500/mm 3 for >7 days ANC <1,000 /mm 3 with fever or infection Platelets <25,000/mm 3 Platelets <50,000/mm 3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 eribulin mesylate injection dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m 2 0.7 mg/m 2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m 2 Discontinue Eribulin Mesylate Injection ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. 2.3 Instructions for Preparation and Administration Aseptically withdraw the required amount of eribulin mesylate injection from the single-dose vial and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. Do not dilute in or administer through an intravenous line containing solutions with dextrose. Do not administer in the same intravenous line concurrent with the other medicinal products. Store undiluted eribulin mesylate injection in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration at 4°C (40°F). Store diluted solutions of eribulin mesylate injection for up to 4 hours at room temperature or up to 24 hours under refrigeration at 4°C (40°F). Discard unused portions of the vial.

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

4 CONTRAINDICATIONS None. None ( 4 )

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Eribulin Mesylate Injection No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not observed in patients with advanced solid tumors when eribulin mesylate injection was administered with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when eribulin mesylate injection was administered with or without rifampin (a CYP3A4 inducer) [see Clinical Pharmacology ( 12.3 )]. 7.2 Effects of Eribulin Mesylate Injection on Other Drugs Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes [see Clinical Pharmacology ( 12.3 )].

8.1 Pregnancy Risk Summary Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on the use of eribulin mesylate injection during pregnancy. In an animal reproduction study, eribulin mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis at doses below the recommended human dose [see Data ] . Advise pregnant women of the potential risk to a fetus. The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area. Increased abortion and severe fetal external or soft tissue malformations, including the absence of a lower jaw and tongue, or stomach and spleen, were observed at doses 0.64 times the recommended human dose of 1.4 mg/m 2 based on body surface area. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at doses at or above a maternally toxic dose of approximately 0.43 times the recommended human dose.

6 ADVERSE REACTIONS The most common adverse reactions (≥25%) in metastatic breast cancer were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. ( 6.1 ) The most common adverse reactions (≥25%) in liposarcoma and leiomyosarcoma were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common (≥5%) Grade 3-4 laboratory abnormalities in liposarcoma and leiomyosarcoma were neutropenia, hypokalemia, and hypocalcemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Long Grove Pharmaceuticals, LLC at 1-855-642-2594 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. The following adverse reactions are discussed in detail in other sections of the labeling: Neutropenia [see Warnings and Precautions ( 5.1 )] Peripheral neuropathy [see Warnings and Precautions ( 5.2 )] QT prolongation [see Warnings and Precautions ( 5.4 )] In clinical trials, eribulin mesylate injection has been administered to 1963 patients including 467 patients exposed to eribulin mesylate injection for 6 months or longer. The majority of the 1963 patients were women (92%) with a median age of 55 years (range: 17 to 85 years). The racial and ethnic distribution was White (72%), Black (4%), Asian (9%), and other (3%). Metastatic Breast Cancer The most common adverse reactions (≥25%) reported in patients receiving eribulin mesylate injection were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving eribulin mesylate injection were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of eribulin mesylate injection was peripheral neuropathy (5%). The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 [see Clinical Studies ( 14.1 )] . In Study 1, patients were randomized (2:1) to receive either eribulin mesylate injection (1.4 mg/m 2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received eribulin mesylate injection and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving eribulin mesylate injection and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group. Table 2: Adverse Reactions a with a Per-Patient Incidence of at Least 10% in Study 1 a adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.0. b based upon laboratory data. c includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. d not applicable; (grading system does not specify > Grade 2 for alopecia). Adverse Reactions Eribulin Mesylate Injection n=503 Control Group n=247 All Grades ≥ Grade 3 All Grades ≥ Grade 3 Blood and lymphatic system disorders b Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders Peripheral neuropathy c 35% 8% 16% 2% Headache 19% <1% 12% <1% General disorders Asthenia/Fatigue 54% 10% 40% 11% Pyrexia 21% <1% 13% <1% Mucosal inflammation 9% 1% 10% 2% Gastrointestinal disorders Nausea 35% 1% 28% 3% Constipation 25% 1% 21% 1% Vomiting 18% 1% 18% 1% Diarrhea 18% 0 18% 0 Musculoskeletal and connective tissue disorders A…