Eribulin

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 ) ].

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.

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 organogenesis at doses below the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with eribulin mesylate injection and for at least 2 weeks following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with eribulin mesylate injection and for 3.5 months following the final dose [ see Use in Specific Populations ( 8.1 ) ]. 5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating eribulin mesylate injection and monitor these electrolytes periodically during therapy. Avoid eribulin mesylate injection in patients with congenital long QT syndrome.

CONTRAINDICATIONS None. None ( 4 ).

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) ] .

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 fatigu

Mechanism of Action Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G 2 /M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. In addition, eribulin treatment of human breast cancer cells caused changes in morphology and gene expression as well as decreased migration and invasiveness in vitro . In mouse xenograft models of human breast cancer, eribulin treatment was associated with increased vascular perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype.