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 to 49 mL/min) is 1.1 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations ( 8.7 )]. 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.

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 to 4 laboratory abnormalities in liposarcoma and leiomyosarcoma were neutropenia, hypokalemia, and hypocalcemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc., at 1-888-375-3784 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 has been administered to 1,963 patients including 467 patients exposed to eribulin mesylate for 6 months or longer. The majority of the 1,963 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 were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving eribulin mesylate were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of eribulin mesylate was peripheral neuropathy (5%). The adverse reactions described in Table 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 (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 and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving eribulin mesylate and 63 days for patients receiving control therapy. Table 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 Adverse Reactions Eribulin Mesylate 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% Mucosalinflammation 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 Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Metabolism and nutrition disorders Decreased weight 21% 1% 14% <1% Anorexia 20% 1% 13% 1% Respiratory, thoracic, and mediastinal disorders Dyspnea 16% 4% 13% 4% Cough 14% 0 9% 0 Skin and subcutaneous tissue disorders Alopecia 45% NA d 10% NA d Infections Urinary Tract Infection 10% 1% 5% 0 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 motorneuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. d not applicable; (grading system does not specify > Grade 2 for alopecia). Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received eribulin mesylate in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm 3 ) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received eribulin mesylate. Peripheral Neuropathy : In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received eribulin mesylate. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy. Liver Function Test Abnormalities : Among patients with Grade 0 or 1 ALT levels at baseline, 18% of eribulin mesylate-treated patients experienced Grade 2 or greater ALT elevation. One eribulin mesylate-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to eribulin mesylate. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the eribulin mesylate-treated group: Eye Disorders: increased lacrimation Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth General Disorders and Administration Site Conditions: peripheral edema Infections and Infestations: upper respiratory tract infection Metabolism and Nutrition Disorders: hypokalemia Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness Nervous System Disorders: dysgeusia, dizziness Psychiatric Disorders: insomnia, depression· Skin and Subcutaneous Tissue Disorders: rash Liposarcoma The safety of eribulin mesylate was evaluated in Study 2, an open-label, randomized, multicenter, active-controlled trial, in which patients were randomized (1:1) to receive either eribulin mesylate 1.4 mg/m 2 on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 850 mg/m 2 (20%), 1,000 mg/m 2 (64%), or 1,200 mg/m 2 (16%) every 3 weeks. A total of 223 patients received eribulin mesylate and 221 patients received dacarbazine. Patients were required to have received at least two prior systemic chemotherapy regimens. The trial excluded patients with pre-existing ≥ Grade 3 peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, history of myocardial infarction within 6 months, history of New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment. The median age of the safety population in Study 2 was 56 years (range: 24 to 83 years); 67% female; 73% White, 3% Black or African American, 8% Asian/Pacific Islander, and 15% unknown; 99% received prior anthracycline-containing regimen; and 99% received ≥ 2 prior regimens. The median duration of exposure was 2.3 months (range: 21 days to 26 months) for patients receiving eribulin mesylate [see Clinical Studies ( 14.2 )]. The most common adverse reactions (≥25%) reported in patients receiving eribulin mesylate were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common (≥5%) Grade 3 to 4 laboratory abnormalities reported in patients receiving eribulin mesylate were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions reported in patients receiving eribulin mesylate were neutropenia (4.9%) and pyrexia (4.5%). Permanent discontinuation of eribulin mesylate for adverse reactions occurred in 8% of patients. The most common adverse reactions resulting in discontinuation of eribulin mesylate were fatigue and thrombocytopenia (0.9% each). Twenty-six percent of patients required at least one dose reduction. The most frequent adverse reactions that led to dose reduction were neutropenia (18%) and peripheral neuropathy (4.0%). Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients in the eribulin mesylate-treated arm in Study 2. Table 3: Adverse Reactions a Occurring in ≥10% (all Grades) of Patients Treated on the Eribulin Mesylate 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) (Study 2) b Adverse Reaction Eribulin Mesylate n=223 Dacarbazine n=221 All Grades Grades 3 to 4 All Grades Grades 3 to 4 Nervous system disorders Peripheral Neuropathy c 29% 3.1% 8% 0.5% Headache 18% 0% 10% 0% General disorders Pyrexia 28% 0.9% 14% 0.5% Gastrointestinal disorders Constipation 32% 0.9% 26% 0.5% Abdominal pain d 29% 1.8% 23% 4.1% Stomatitis 14% 0.9% 5% 0.5% Skin and subcutaneous tissue disorders Alopecia 35% NA e 2.7% NA e Infections Urinary tract infection 11% 2.2% 5% 0.5% a Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03). b Safety data from one study site enrolling six patients were excluded. c Includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. d Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort. e Not applicable; (grading system does not specify > Grade 2 for alopecia). Other clinically important adverse reactions occurring in ≥10% of the eribulin mesylate-treated patients were: Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%) General Disorders: asthenia/fatigue (62%); peripheral edema (12%) Metabolism and Nutrition Disorders: decreased appetite (19%) Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); back pain (16%) Respiratory Disorders: cough (18%) Less Common Adverse Reactions: The following additional clinically important adverse reactions were reported in ≥5% to <10% of the eribulin mesylate-treated group: Blood and Lymphatic System Disorders: thrombocytopenia Eye Disorders: increased lacrimation Gastrointestinal Disorders: dyspepsia Metabolism and Nutrition Disorders: hyperglycemia Musculoskeletal and Connective Tissue Disorders: muscle spasms, musculoskeletal pain Nervous System Disorders: dizziness, dysgeusia Psychiatric Disorders: insomnia, anxiety Respiratory, Thoracic, and Mediastinal Disorders: oropharyngeal pain Vascular Disorders: hypotension Table 4: Laboratory Abnormalities Occurring in ≥10% (all Grades) of Patients Treated on the Eribulin Mesylate 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) a (Study 2) † Laboratory Abnormality Eribulin Mesylate Dacarbazine All Grades Grades 3 to 4 All Grades Grades 3 to 4 Hematology Anemia 70% 4.1% 52% 6% Neutropenia 63% 32% 30% 8.9% Chemistry Increased alanine aminotransferase (ALT) 43% 2.3% 28% 2.3% Increased aspartate aminotransferase (AST) 36% 0.9% 16% 0.5% Hypokalemia 30% 5.4% 14% 2.8% Hypocalcemia 28% 5% 18% 1.4% Hypophosphatemia 20% 3.2% 11% 1.4% a Each test incidence is based on the number of patients who had both baseline and at least one on-study measurement and at least 1 grade increase from baseline. Eribulin mesylate group (range221 to 222) and dacarbazine group (range 214 to 215). † Laboratory results were graded per NCI CTCAE v4.03. 6.2 Postmarketing Experience The following adverse drug reactions have been identified during post-approval use of eribulin mesylate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: lymphopenia Gastrointestinal Disorders: pancreatitis Hepatobiliary Disorders: hepatotoxicity Immune System Disorders: drug hypersensitivity Infections and Infestations: pneumonia, sepsis/neutropenic sepsis Metabolism and Nutrition Disorders: hypomagnesemia, dehydration Respiratory, thoracic and mediastinal disorders: interstitial lung disease Skin and Subcutaneous Tissue Disorders: pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis

12.3 Pharmacokinetics The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m 2 to 114 L/m 2 and mean clearance of 1.16 L/hr/m 2 to 2.42 L/hr/m 2 over the dose range of 0.25 mg/m 2 to 4.0 mg/m 2 . The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65%. Eribulin exposure after multiple dosing is comparable to that following a single dose. No accumulation of eribulin is observed with weekly administration. Elimination Metabolism Unchanged eribulin was the major circulating species in plasma following administration of 14 C‑eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin. Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro . Excretion Eribulin is eliminated primarily in feces unchanged. After administration of 14 C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin accounted for approximately 88% and 91% of total eribulin in feces and urine, respectively. Specific Populations Age, Sex, and Race/Ethnicity: Based on a population pharmacokinetic analysis, no clinically meaningful differences in the pharmacokinetics of eribulin were observed based on age, sex, or race. Hepatic Impairment In a study evaluating the effect of hepatic impairment on the PK of eribulin, eribulin exposures increased by 1.8-fold in patients with mild hepatic impairment (Child-Pugh A; n=7) and by 2.5‑fold in patients with moderate (Child-Pugh B; n=5) hepatic impairment as compared to patients with normal hepatic function (n=6). Administration of eribulin mesylate at a dose of 1.1 mg/m 2 to patients with mild hepatic impairment and 0.7 mg/m 2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin at a dose of 1.4 mg/m 2 to patients with normal hepatic function [see Dosage and Administration ( 2.1 ), Use in Specific Populations ( 8.6 )]. Renal Impairment In a study evaluating the effect of renal impairment on the PK of eribulin, patients with moderate (CLcr 30 to 49 mL/min; n=7) and severe renal impairment (CLcr 15 to 29 mL/min; n=6) had 1.5-fold higher eribulin dose-normalized exposures compared to that in patients with normal renal function (CLcr ≥ 80 mL/min; n=6). There were no clinically meaningful changes in patients with mild renal impairment (CLcr 50 to 79 mL/min; n=27) [see Dosage and Administration ( 2.1 ), Use in Specific Populations ( 8.7) ]. Drug Interaction Studies Effect of Strong Inhibitors or Inducers of CYP3A4 on Eribulin: The effect of a strong CYP3A4 inhibitor and a P-gp inhibitor, ketoconazole, on the PK of eribulin was studied in a crossover trial of 12 patients with advanced solid tumors. No clinically relevant PK interaction was observed when eribulin mesylate was administered with or without ketoconazole (the geometric mean ratio of the AUC: 0.97; 90% CI: 0.83, 1.12). The effect of a CYP3A4 inducer, rifampin, on the PK of eribulin was studied in a crossover trial of 14 patients with advanced solid tumors. No clinically relevant PK interaction was observed when eribulin mesylate was administered with or without rifampin (the geometric mean ratio of the AUC: 1.10; 90 CI%: 0.91, 1.34). Effect of Eribulin on CYP Substrates : Eribulin shows no induction potential for CYP1A, CYP2B6, CYP2C9, CYP2C19, and CYP3A in primary human hepatocytes. Eribulin inhibits CYP3A4 activity in human liver microsomes, but it is unlikely that eribulin will substantially increase the plasma levels of CYP3A4 substrates. No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 was detected with eribulin concentrations up to 5 μM in pooled human liver microsomes. In vitro drug interaction studies indicate that eribulin does not inhibit drugs that are substrates of these enzymes and it is unlikely that eribulin will affect plasma levels of drugs that are substrates of CYP enzymes. Effect of Transporters on Eribulin: In vitro data suggest that eribulin at clinically relevant concentrations is a substrate of P-gp, but is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance proteins (MRP2, MRP4), bile salt extrusion pump (BSEP), organic anion transporting polypeptides (OATP1B1, OATP1B3), organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1, OCT2), or multidrug and toxin extrusion 1 (MATE1). Effect of Eribulin on Transporters: In vitro data suggest that eribulin at clinically relevant concentrations may inhibit P-gp, but does not inhibit BCRP, OATP1B1, OCT1, OAT1, OAT3, or MATE1.