Eribulin Mesylate

Description

11 DESCRIPTION Eribulin mesylate injection contains eribulin mesylate, a microtubule dynamics inhibitor. Eribulin mesylate is a synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria okadai . The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano-12,15-methano-9 H ,15 H -furo[3,2- i ]furo[2',3':5,6]pyrano[4,3- b ][1,4]dioxacyclopentacosin-5(4 H )-one,2-[(2 S )-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-(2 R ,3 R ,3a S ,7 R ,8a S ,9 S ,10a R ,11 S ,12 R ,13a R ,13b S ,15 S ,18 S ,21 S ,24 S ,26 R ,28 R ,29a S ),methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C 40 H 59 NO 11

What Is Eribulin Mesylate Used For?

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) ].

Dosage and Administration

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 inprevious 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 whilereceiving 0.7 mg/m 2 Discontinue Eribulin Mesylate Injection ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology...

Side Effects (Adverse Reactions)

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 Gland Pharma Limited at 609-250-7990 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 1963 patients including 467 patients exposed to eribulin mesylate 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 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% 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 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...

Drug Interactions

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Eribulin Mesylate 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 was administered with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when eribulin mesylate was administered with or without rifampin (a CYP3A4 inducer) [see Clinical Pharmacology (12.3) ]. 7.2 Effects of Eribulin Mesylate 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) ].

Contraindications

4 CONTRAINDICATIONS None. None ( 4 ).

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of eribulin mesylate during pregnancy. In an animal reproduction study, eribulin mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis at doses below the recommended human dose [see Data] . Advise pregnant women of the potential risk to 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.

8.3 Females and Males of Reproductive Potential Contraception Females Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with eribulin mesylate and for at least 2 weeks following the final dose . Males Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with eribulin mesylate and for 3.5 months following the final dose. Infertility Males Based on animal data, eribulin mesylate may result in damage to male reproductive tissues leading to impaired fertility of unknown duration [see Nonclinical Toxicology (13.1) ].

Overdosage

10 OVERDOSAGE Overdosage of eribulin mesylate has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for eribulin mesylate overdose.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING NDC 68083-592-01 Eribulin Mesylate Injection : 1 mg/2 mL (0.5 mg/mL) single-dose vial. Discard unused portion. One vial per carton. Eribulin mesylate injection is a clear, colorless solution. Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86° F). Do not freeze or refrigerate. Store the vials in their original cartons. Eribulin mesylate injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹