The following Structured Product Label (SPL) was submitted to the FDA by Sandoz Inc for the product Eribulin Mesylate (NDC 0781-3391). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1.1 metastatic breast cancer, 1.2 liposarcoma, 2.1 recommended dose, 2.2 dose modification, 2.3 instructions for preparation and administration, 3 dosage forms and strengths, 4 contraindications, 5.1 neutropenia, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
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)].
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)].
The recommended dose of eribulin mesylate injection is 1.4 mg/m2 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/m2 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/m2 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/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations (8.7)].
Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.
Recommended dose delays
Recommended dose reductions
Event Description | Recommended Eribulin Mesylate Injection |
Permanently reduce the 1.4 mg/m2 eribulin mesylate injection dose for any of the following: | 1.1 mg/m2 |
ANC <500/mm3 for >7 days | |
ANC <1,000 /mm3 with fever or infection | |
Platelets <25,000/mm3 | |
Platelets <50,000/mm3 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/m2 | 0.7 mg/m2 |
Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 | Discontinue eribulin mesylate injection |
ANC = absolute neutrophil count. | |
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.
Injection: 1 mg/2 mL (0.5 mg/mL) eribulin mesylate is a clear, colorless, sterile solution in a single-dose vial.
None.
In Study 1, severe neutropenia (ANC <500/mm3) 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/mm3) 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 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 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 did not include patients with baseline neutrophil counts below 1,500/mm3.
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 (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-treated patients. Peripheral neuropathy led to discontinuation of eribulin mesylate 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 in patients who experience Grade 3 or 4 peripheral neuropathy, until resolution to Grade 2 or less [see Dosage and Administration (2.2)].
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. There are no adequate and well-controlled studies of eribulin mesylate 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 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 and for 3.5 months following the final dose [see Use in Specific Populations (8.1)].
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 and monitor these electrolytes periodically during therapy. Avoid eribulin mesylate in patients with congenital long QT syndrome.
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:
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/m2 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.
| Eribulin Mesylate | Control Group | ||
All Grades | ≥Grade 3 | All Grades | ≥Grade 3 | |
Blood and lymphatic system disorders† | ||||
Neutropenia | 82% | 57% | 53% | 23% |
Anemia | 58% | 2% | 55% | 4% |
Nervous system disorders | ||||
Peripheral neuropathy‡ | 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§ | 10% | NA§ |
Infections | ||||
Urinary Tract Infection | 10% | 1% | 5% | 0 |
* Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.0.
† Based upon laboratory data.
‡ Includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia.
§ 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/mm3) 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:
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/m2 on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 850 mg/m2 (20%), 1000 mg/m2 (64%), or 1200 mg/m2 (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 3-4 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.
| Eribulin Mesylate | Dacarbazine | ||
All Grades | Grades 3-4 | All Grades | Grades 3-4 | |
Nervous system disorders | ||||
Peripheral Neuropathy‡ | 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§ | 29% | 1.8% | 23% | 4.1% |
Stomatitis | 14% | 0.9% | 5% | 0.5% |
Skin and subcutaneous tissue disorders | ||||
Alopecia | 35% | NA¶ | 2.7% | NA¶ |
Infections | ||||
Urinary tract infection | 11% | 2.2% | 5% | 0.5% |
* Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03).
† Safety data from one study site enrolling six patients were excluded.
‡ Includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia.
§ Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort.
¶ 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:
Less Common Adverse Reactions
The following additional clinically important adverse reactions were reported in ≥5% to <10% of the eribulin mesylate-treated group:
Laboratory Abnormality | Eribulin Mesylate | Dacarbazine | ||
All Grades | Grades 3 - 4 | All Grades | Grades 3 – 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% |
* 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 (range 221-222) and dacarbazine group (range 214-215).
† Laboratory results were graded per NCI CTCAE v4.03.
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.
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)].
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)].
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/m2 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.
Risk Summary
There is no information regarding the presence of eribulin mesylate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. No lactation studies in animals were conducted. Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with eribulin mesylate and for 2 weeks after the final dose.
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)].
The safety and effectiveness of eribulin mesylate in pediatric patients have not been established.
Pediatric use information describing clinical studies in which efficacy was not demonstrated is approved for Eisai Inc’s
HALAVEN® (eribulin mesylate) injection. However, due to Eisai Inc’s marketing exclusivity rights, this drug product is not labeled with that information.
Study 1 did not include sufficient numbers of subjects with metastatic breast cancer aged 65 years and older to determine whether they respond differently from younger subjects. Of the 827 subjects who received the recommended dose and schedule of eribulin mesylate in clinical studies with advanced breast cancer, 15% (121/827) were 65 and older, and 2% (17/827) patients were 75 and older. No overall differences in safety were observed between these subjects and younger subjects.
Clinical studies of eribulin mesylate did not include a sufficient number of subjects in Study 2 aged 65 years and older to determine whether they respond differently from younger subjects.
Administration of eribulin mesylate at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). Eribulin mesylate was not studied in patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].
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.
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-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 2-[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C40H59NO11•CH4O3S. Eribulin mesylate has the following structural formula:
Chemical_structure (Eribulin 01)
Eribulin mesylate injection is a clear, colorless, sterile solution for intravenous administration. Each single-dose vial contains 1 mg of eribulin mesylate in 2 mL of solution. Each mL of solution contains 0.5 mg of eribulin mesylate (equivalent to 0.44 mg eribulin) in dehydrated alcohol (5% v/v) and water for injection (95% v/v). Sodium hydroxide or hydrochloric acid may be used for pH adjustment.
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 G2/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.
Cardiac Electrophysiology
The effect of eribulin mesylate on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of eribulin mesylate on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.
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/m2 to 114 L/m2 and mean 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. 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 14C-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 14C-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/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin at a dose of 1.4 mg/m2 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 30-49 mL/min; n=7) and severe renal impairment (CLcr 15-29 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 50-79 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.
Carcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.
Fertility studies have not been conducted with eribulin mesylate in humans or animals; however, nonclinical findings in repeat-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (based on body surface area) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (based on body surface area) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (based on body surface area) weekly for 3 out of 5 weeks, repeated for 6 cycles.
Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast cancer who received at least two chemotherapeutic regimens for the treatment of metastatic disease and experienced disease progression within 6 months of their last chemotherapeutic regimen. Patients were required to receive prior anthracycline- and taxane- based chemotherapy for adjuvant or metastatic disease. Patients were randomized (2:1) to receive eribulin mesylate (n=508) or a single agent therapy selected prior to randomization (control arm, n=254). Randomization was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. Eribulin mesylate was administered at a dose of 1.4 mg/m2 on Days 1 and 8 of a 21-day cycle. Eribulin mesylate-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal therapy. The main efficacy outcome was overall survival.
Patient demographic and baseline characteristics were comparable between the treatment arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients had a baseline ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative status (ER-, PR-, HER2/neu-: 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in the eribulin mesylate and control arms. Patients received a median of four prior chemotherapy regimens in both arms.
In Study 1, a statistically significant improvement in overall survival was observed in patients randomized to the eribulin mesylate arm compared to the control arm (see Table 5). An updated, unplanned survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent with the primary analysis. In patients randomized to eribulin mesylate, the objective response rate by the RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months (95% CI: 3.8, 5.0 months).
Overall Survival | Eribulin Mesylate | Control Arm |
Primary survival analysis | ||
Number of deaths | 274 | 148 |
Median, months (95% CI) | 13.1 (11.8, 14.3) | 10.6 (9.3, 12.5) |
Hazard Ratio (95% CI)* | 0.81 (0.66, 0.99) | |
P value† | 0.041 | |
Updated survival analysis | ||
Number of deaths | 386 | 203 |
Median, months (95% CI) | 13.2 (12.1, 14.4) | 10.6 (9.2, 12.0) |
CI = confidence interval | ||
* Based on Cox proportional hazards model stratified by geographic region, HER2 status, and prior capecitabine therapy.
† Based on a log-rank test stratified by geographic region, HER2 status, and prior capecitabine therapy.
Figure 1: Updated Overall Survival Analysis for Study 1
Figure-1 (Eribulin 02)
The efficacy and safety of eribulin mesylate were evaluated in Study 2, 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 two 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 eribulin mesylate 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, 1000 mg/m2, or 1200 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 (U.S. and Canada vs. Western Europe, Australia, and Israel vs. Eastern Europe, Latin America, and Asia). The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were progression-free survival (PFS) and confirmed objective response rate (ORR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Patients in the dacarbazine arm were not offered eribulin mesylate at the time of disease progression.
A total of 446 patients were randomized, 225 to the eribulin mesylate arm and 221 to the dacarbazine arm. The median age was 56 years (range: 24 to 83); 33% were male; 73% were White; 44% had ECOG performance status (PS) 0 and 53% had ECOG PS 1; 68% had leiomyosarcoma and 32% had liposarcoma; 39% were enrolled in U.S. and Canada (Region 1) and 46% were enrolled in Western Europe, Australia, and Israel (Region 2); and 47% received more than two prior systemic chemotherapies. The most common (>40%) prior systemic chemotherapies were doxorubicin (90%), ifosfamide (62%), gemcitabine (59%), trabectedin (50%), and docetaxel (48%).
Of the 143 patients with liposarcoma, the median age was 55 years (range: 32 to 83); 62% were male, 72% were White; 41% had ECOG PS of 0 and 53% had ECOG PS of 1; 35% were enrolled in Region 1 and 51% were enrolled in Region 2; and 44% received more than two prior systemic chemotherapies. The distribution of subtypes of liposarcoma, based on local histologic assessment, were 45% dedifferentiated, 37% myxoid/round cell, and 18% pleomorphic.
Study 2 demonstrated a statistically significant improvement in OS in patients randomized to eribulin mesylate compared with dacarbazine (see Table 6). There was no significant difference in progression-free survival in the overall population. Treatment effects of eribulin mesylate were limited to patients with liposarcoma based on pre-planned, exploratory subgroup analyses of OS and PFS (see Tables 6 and 7 and Figure 2). There was no evidence of efficacy of eribulin mesylate in patients with advanced or metastatic leiomyosarcoma in Study 2 (see Table 7).
Liposarcoma | All Patients† | |||
Eribulin Mesylate | Dacarbazine | Eribulin Mesylate | Dacarbazine | |
Overall survival | ||||
Deaths, n (%) | 52 (73) | 63 (88) | 173 (77) | 179 (81) |
Median, months | 15.6 | 8.4 | 13.5 | 11.3 |
Hazard ratio (HR) | 0.51 | 0.75 | ||
Stratified log-rank p value | N/A‡ | 0.011 | ||
Progression-free survival | ||||
Events, n (%) | 57 (80) | 59 (82) | 194 (86) | 185 (84) |
Disease progression | 53 | 52 | 180 | 170 |
Death | 4 | 7 | 14 | 15 |
Median, months | 2.9 | 1.7 | 2.6 | 2.6 |
HR | 0.52 | 0.86 | ||
Objective response rate | ||||
Objective response rate (%) | 1.4 | 0 | 4.0 | 5.0 |
* Efficacy data from one study site enrolling six patients were excluded.
† All patients = liposarcoma and leiomyosarcoma.
‡ N/A = not applicable
Figure 2: Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2
Figure-2 (Eribulin 03)
Leiomyosarcoma | ||
Eribulin Mesylate | Dacarbazine | |
Overall survival | ||
Deaths, n (%) | 121 (79) | 116 (78) |
Median, months | 12.8 | 12.3 |
HR (95% CI) | 0.90 (0.69, 1.18) | |
Progression-free survival | ||
Events, n (%) | 137 (89) | 126 (85) |
Disease progression | 127 | 118 |
Death | 10 | 8 |
Median, months | 2.2 | 2.6 |
HR (95% CI) | 1.05 (0.81, 1.35) | |
Objective response rate (%) | 5.2 | 7.4 |
* Efficacy data from one study site enrolling six patients were excluded.
1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
Eribulin mesylate injection 1 mg/2 mL (0.5 mg/mL) is a clear, colorless sterile solution free of particles for intravenous administration is supplied as follows:
NDC 0781-3391-94, in a single-dose vial. One vial per carton.
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. 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
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Neutropenia
Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination [see Warnings and Precautions (5.1)].
Peripheral Neuropathy
Advise patients to inform their healthcare providers of new or worsening numbness, tingling and pain in their extremities [see Warnings and Precautions (5.2)].
Embryo-Fetal Toxicity
Lactation
Advise women not to breastfeed during treatment with eribulin mesylate and for 2 weeks after the final dose [see Use in Specific Populations (8.2)].
Manufactured by Kindos Pharmaceuticals Co., Ltd. for
Sandoz Inc., Princeton, NJ 08540
PATIENT INFORMATION |
What is the most important information I should know about eribulin mesylate injection? Eribulin mesylate injection can cause serious side effects, including:
See “What are possible side effects of eribulin mesylate injection?” for more information about side effects. |
What is eribulin mesylate injection? Eribulin mesylate injection is a prescription medicine used to treat people with:
It is not known if eribulin mesylate injection is safe and effective in children under 18 years of age. |
Before you receive eribulin mesylate injection, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. |
How will I receive eribulin mesylate injection?
|
What are the possible side effects of eribulin mesylate injection? Eribulin mesylate injection may cause serious side effects, including:
The most common side effects of eribulin mesylate injection in people with breast cancer include: The most common side effects of eribulin mesylate injection in people with liposarcoma include: Your healthcare provider will do blood tests before and during treatment while you are taking eribulin mesylate injection. The most common changes to blood tests in people with liposarcoma include: Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of eribulin mesylate injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
General information about eribulin mesylate injection |
What are the ingredients in eribulin mesylate injection? Active Ingredient:eribulin mesylate Manufactured by Kindos Pharmaceuticals Co., Ltd. for Sandoz Inc., Princeton, NJ 08540 |
NDC 0781-3391-94
Eribulin Mesylate Injection
1 mg/2 mL
(0.5 mg/mL)
For Intravenous Use Only
Sterile Solution
Rx Only
CAUTION: Cytotoxic Agent
1 x 2 mL Single-Dose Vial
Discard Unused Portion.
SANDOZ
Carton (Eribulin 04)
* Please review the disclaimer below.
