HALAVEN - eribulin mesylate injection  Eisai Inc. Halaven(甲磺酸艾日布林)新型化疗药获准用于晚期乳腺癌 2010年11月15日，美国食品药品管理局(FDA)宣布，Halaven(甲磺酸艾日布林)已获准用于治疗曾接受至少2种以前的晚期化疗方案治疗的转移性乳腺癌患者。 Halaven是一种从黑色软海绵(Halichondria okadai)中提取的一种有化疗活性化合物的合成制剂。该注射药是一种微管抑制剂，能抑制癌细胞生长。在接受Halaven治疗之前，患者应先接受以前的以蒽环类为基础和以紫杉烷为基础的化疗方案治疗早期或晚期乳腺癌。 Halaven的安全性与疗效在一项涉及762例转移性乳腺癌女性患者的单项研究中得到证实，这些患者曾采用至少2种以前的化疗方案治疗晚期疾病，她们被随机分配至接受Halaven治疗组或接受由其肿瘤医生选择的不同种单药治疗组。 该研究旨在测定总生存时间。Halaven治疗组的中位总生存时间为13.1个月，而单药治疗组为10.6个月。使用Halaven最常见的不良反应包括中性粒细胞减少症、贫血、白细胞减少症、脱发、疲乏、恶心、无力、便秘和周围神经病变。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use HALAVEN™ safely and effectively. See full prescribing information for HALAVEN. HALAVEN™ (eribulin mesylate) Injection For intravenous administration only. Eisai Inc. Initial U.S. Approval: 2010 INDICATIONS AND USAGE HALAVEN 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). DOSAGE AND ADMINISTRATION Administer 1.4 mg/m2 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 and moderate renal impairment (2.1). Do not mix with other drugs or administer with dextrose-containing solutions (2.3). DOSAGE FORMS AND STRENGTHS Intravenous administration. Eribulin mesylate injection, 1 mg per 2 mL (0.5 mg per mL) (3). CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Neutropenia: Monitor peripheral blood cell counts and adjust dose as appropriate (2.2, 5.1, 6). Peripheral Neuropathy: Monitor for signs of neuropathy. Manage with dose delay and adjustment (2.2, 5.2, 6). Use in Pregnancy: Fetal harm can occur when administered to a pregnant woman (5.3) (8.1). 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). ADVERSE REACTIONS The most common adverse reactions (incidence ≥25%) were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation (6). To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at (1-877-873-4724) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch USE IN SPECIFIC POPULATIONS Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of the drug to the mother (8.3). Hepatic Impairment: A lower starting dose is recommended for patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh C) were not studied (8.6). Renal Impairment: A lower starting dose is recommended for patients with moderate (CrCl 30-50 mL/min) renal impairment. Patients with severe (CrCl < 30 mL/min) renal impairment were not studied (8.7). See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling  Revised: 11/2010 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE HALAVEN 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. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended dose of HALAVEN 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 HALAVEN 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 HALAVEN 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 HALAVEN in patients with moderate renal impairment (creatinine clearance of 30-50 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)] 2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. Recommended dose delays Do not administer HALAVEN on Day 1 or Day 8 for any of the following: - ANC < 1,000/mm3 - Platelets < 75,000/mm3 - 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 HALAVEN 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 HALAVEN at a reduced dose as set out in Table 1. Do not re-escalate HALAVEN dose after it has been reduced. Table 1 Recommended Dose Reductions Event Description Recommended HALAVEN Dose ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Permanently reduce the 1.4 mg/m2 HALAVEN 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 HALAVEN 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 HALAVEN 2.3 Instructions for Preparation and Administration Aseptically withdraw the required amount of HALAVEN from the single-use 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 HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration (40°F or/ 4°C). Store diluted solutions of HALAVEN for up to 4 hours at room temperature or up to 24 hours under refrigeration. Discard unused portions of the vial. 3 DOSAGE FORMS AND STRENGTHS HALAVEN (eribulin mesylate) Injection, 1 mg/2 mL (0.5 mg/mL). 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in < 1% of patients [see Adverse Reactions (6)]. Patients with alanine aminotransferase or aspartate aminotransferase > 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. 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 HALAVEN 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 HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3. 5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). 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). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN 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 There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus [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 HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome. 6 ADVERSE REACTIONS 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 interval prolongation [see Warnings and Precautions (5.4)]. The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). 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. In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%). The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 [see Clinical Studies (14)]. In Study 1, patients were randomized (2:1) to receive either HALAVEN (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 HALAVEN, 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 HALAVEN 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 with a Per-Patient Incidence of at Least 10% in Study 1 MedDRA ver 10.0 HALAVEN n=503 Control Group n=247 All Grades ≥ Grade 3 All Grades ≥ Grade 3 a based upon laboratory data. b includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c not applicable; (grading system does not specify > Grade 2 for alopecia). Blood and Lymphatic System Disordersa    Neutropenia 82% 57% 53% 23%    Anemia 58% 2% 55% 4% Nervous system disorders    Peripheral neuropathyb 35% 8% 16% 2%    Headache 19% <1% 12% <1% General disorders and administrative site conditions    Asthenia/Fatigue 54% 10% 40% 11%    Mucosal inflammation 9% 1% 10% 2%    Pyrexia 21% <1% 13% <1% Gastrointestinal disorders    Constipation 25% 1% 21% 1%    Diarrhea 18% 0 18% 0    Nausea 35% 1% 28% 3%    Vomiting 18% 1% 18% 1% 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% Investigations    Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders    Anorexia 20% 1% 13% 1% Respiratory, thoracic, and mediastinal disorders    Cough 14% 0 9% 0    Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders    Alopecia 45% NAc 10% NAc Infections and Infestations    Urinary Tract Infection 10% 1% 5% 0 Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN 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 HALAVEN. 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 HALAVEN. 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 HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-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 HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥ 5% to < 10% of the HALAVEN-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 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on HALAVEN No drug-drug interactions are expected with CYP3A4 inhibitors or P-gp inhibitors. The effect of ketoconazole, a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and a P-gp inhibitor, on the pharmacokinetics (PK) of eribulin was studied in an open-label, two-treatment, two-sequence, two-way crossover trial in 12 patients with advanced solid tumors. The mean dose-normalized AUC values were similar when eribulin was administered with or without ketoconazole (ratio of the mean AUC: 0.97; 90% CI: 0.83, 1.12). 7.2 Effect of HALAVEN on Other Drugs Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D [see Warnings and Precautions (5.3)] There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor, therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In a 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 (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose. Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m2), and included enlarged spleen, reduced maternal weight gain and decreased food consumption. 8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established. 8.5 Geriatric Use Study 1 did not include sufficient numbers of subjects 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 HALAVEN in clinical studies, 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. 8.6 Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN 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. 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). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). [see Dosage and Administration (2.1)] 8.7 Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that no dose adjustment is necessary for patients with mild renal impairment (CrCl 50-80 mL/min). However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl < 30 mL/min). [see Dosage and Administration (2.1)] 10 OVERDOSAGE Overdosage of HALAVEN 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 HALAVEN overdose. 11 DESCRIPTION HALAVEN (eribulin mesylate) Injection is a non-taxane 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: HALAVEN is a clear colorless, sterile solution for intravenous administration. Each vial contains 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95). 12 CLINICAL PHARMACOLOGY 12.1 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 G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of HALAVEN 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 HALAVEN 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. 12.3 Pharmacokinetics The pharmacokinetics 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. 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. Eribulin inhibits CYP3A4 activity in human liver microsomes, but it is unlikely that eribulin will substantially increase the plasma levels of CYP3A4 substrates. Eribulin shows no induction potential for CYP1A, CYP2C9, CYP2C19, and CYP3A in primary human hepatocytes. 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. Eribulin is a substrate and a weak inhibitor of the drug efflux transporter P-gp in vitro. Elimination 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 the dose in feces and urine, respectively. Effects of Age, Gender, and Race Based on a population pharmacokinetic analysis with data collected from 340 patients, gender, race, and age do not have a clinically meaningful effect on the PK of eribulin. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility 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. The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-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 (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) 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 (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles. 14 CLINICAL STUDIES 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 HALAVEN (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. HALAVEN was administered at a dose of 1.4 mg/m2 on Days 1 and 8 of a 21-day cycle. HALAVEN-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 HALAVEN 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 HALAVEN arm compared to the control arm (see Table 3). 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 HALAVEN, 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). Table 3 Comparison of Overall Survival in HALAVEN and Control Arm - Study 1 Overall Survival HALAVEN (n=508) Control Arm (n=254) CI = confidence interval a Based on Cox proportional hazards model stratified by geographic region, HER2 status, and prior capecitabine therapy. b Based on a log-rank test stratified by geographic region, HER2 status, and prior capecitabine therapy. 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)a 0.81 (0.66, 0.99)    P valueb 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) Figure 1 Updated Overall Survival Analysis for Study 1 16 HOW SUPPLIED/STORAGE AND HANDLING NDC 62856-389-01 Eribulin mesylate injection, 1 mg/2 mL, in a single-use vial. One vial per carton. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Do not freeze. Store the vials in their original cartons. 乳腺癌治疗药-甲磺酸艾日布林 Eisai公司研发的非紫衫烷类微管抑制剂甲磺酸艾日布林注射剂(商品名: Halven) 于2010年11月获美国FDA 批准用于治疗曾接受至少2种抗癌药物,包括蒽环类和紫衫烷类药物治疗的转移性乳腺癌患者。其可基于微管蛋白的抗有丝分裂机制,使细胞周期停滞于G2 /M 期, 破坏有丝分裂纺锤体,最终诱导肿瘤细胞凋亡。2011年上半年, 本品已陆续在新加坡、欧盟和日本上市, 其在日本的适应证为不可手术治疗及复发性乳腺癌。目前,Eisai公司正进行考察本品单独治疗其他类型的癌症,包括未经治疗的乳腺癌、非小细胞肺癌、肉瘤和前列腺癌的疗效的后期临床研究。 本品为海绵Halichondria  okadai中的halichondrin B的合成类似物, 其合成工艺相当复杂, 全合成路线共有62步。其结构中含19个手性碳原子, 理论上有52.4万个立体异构体, 故给立体控制带来极大的困难, 然而,以Eisai公司的技术能力, Halaven全合成过程中的立体选择性控制的难题已得到解决, 并实现了工业化生产。 药动学  艾日布林在0.25～4.0 mg﹒m-2剂量范围内, 平均消除半衰期约为40 h,平均分布容积为43～114 L﹒m-2,平均清除率为1.16～2.42 L﹒h-1﹒m-2在100～ 1000 g﹒L- 1质量浓度范围内, 艾日布林的人血浆蛋白结合率介于49%～65% 。其多剂量给药时的AUC与单剂量给药时相似, 每周1次给药未见有药物蓄积现象。给乳腺癌患者静脉注射14C标记的艾日布林后发现, 其血浆中代谢物浓度不到原药的0.6% , 证实艾日布林在人体中很少有代谢产物; 同时, 粪便和尿液中药物的回收量分别为给药剂量的82%和9%。 临床研究  一项名为EMBRACE 的开标记、随机、多中心Ⅲ期临床试验考察了H alaven 对曾使用至少两种化疗药物(蒽环类、紫杉烷类)的转移性乳腺癌和在使用最后一种化疗药物治疗后6个月内疾病进展的患者的疗效。根据患者的地理分布、体内HER2/neu的表达状态及入组前卡培他滨的使用量, 将患者按2:1的比例随机分为Halaven 治疗组( n = 508)和对照组( n = 254), 两组患者在试验开始前平均接受过4个疗程的化疗。Halaven治疗组患者在第1 和第8天静脉注射H alaven( 1.4 mg﹒m-2 ),21天为1疗程,持续1～23个疗程不等(平均5个疗程);对照组则有97% 的患者接受过化疗(长春瑞滨26%,吉西他滨18%,卡培他滨18% ,紫杉烷16% ,蒽环类药物9% ,其他10%),3%的患者接受过激素治疗。主要考察指标为总生存期。结果显示, 与对照组相比, Halaven治疗组患者的总生存期明显延长( 13.1 vs 10.6 个月, P = 0.041) ;根据实体瘤疗效评价标准( REC IST) , Halaven治疗组患者的客观应答率为11% , 持续应答时间中位数为4.2个月。 除了上述EMBRACE 研究结果外, H alaven在日本的上市还基于一项在日本进行的多中心、开标记的Ⅱ期临床研究的阳性结果, 在该研究中, 患者同样在接受本品治疗前经蒽环类药物和紫杉烷类药物治疗, 结果显示,本品治疗组患者的应答率达21.3%,且患者对其的耐受性良好。 药物不良反应 EMBRACE 研究剔除了入组前中性粒细胞计数低于1 500个﹒mm-3的患者, 该研究显示, Halaven治疗组分别有28%和29%的患者出现3级和4级中性粒细胞减少;5%的患者出现发热性中性粒细胞减少,并有0.4% 的患者死于其并发症; 12%的患者持续1 周以上出现严重的中性粒细胞减少(绝对中性粒细胞计数少于500 个﹒mm- 3 ), 1% 的患者因此而退出研究。3级以上的血小板减少症发生率为1%。谷丙转氨酶(或谷草转氨酶)水平以及胆红素水平分别为正常值上限的3倍以上和1.5倍以上的患者, 其4级中性粒细胞减少和发热性中性粒细胞减少的发生率明显高于转氨酶水平和胆红素水平正常的患者。该研究中Halaven治疗组有19% 的患者使用了粒细胞集落刺激因子( G-CSF)或粒细胞-巨噬细胞集落刺激因子( GM-CSF) 以升高体内中性粒细胞水平。因此,在每次给予Halaven前均应监测血细胞计数,对出现3级或4级血细胞减少的患者则应增加监测频次;出现发热性中性粒细胞减少或持续7天以上出现4 级中性粒细胞减少的患者应推迟给药。 在EMBRACE 研究中, Ha laven 治疗组分别有8% 和0.4% 的患者出现3级和4级外周神经病症状, 结果有5%的患者停药, 该症状持续1年以上的患者占5% 。此外, Halaven治疗组有22%的患者出现新的神经病症状或症状加剧, 在平均为期269天(25～662天)的随访期内也未能恢复。因此, 在接受本品治疗时应密切监测患者的外周运动和感觉神经病征象, 出现3级或4 级外周神经病症状的患者应停药, 直至症状降至2级或更低水平。 一项有26名乳腺癌患者参加的开标记单组研究考察了H alaven对患者的心脏功能的影响。结果显示,给药第1天,患者均未出现QT 间期延长,但在给药第8天, 无论给药剂量如何, 均会导致QT间期延长。因此, 对于充血性心衰患者、心动过缓患者、电解质异常的患者以及同时使用可延长QT 间期的药物, 包括Ⅰa类或Ⅲ类抗心律失常药物的患者而言, 建议在其接受本品治疗时应监测心电图; 对于电解质异常的患者,在使用本品前应纠正低钾血症或低镁血症, 并在整个治疗期间定期监测电解质水平。此外, 先天性长QT 综合征患者也应避免使用本品。 本品的其他不良反应还包括流泪增加、消化不良、上腹痛、口腔炎、嘴干、上呼吸道感染、低血钾症、肌肉痉挛、肌力下降、味觉障碍、眩晕、失眠、抑郁等,发生率介于5%～10%之间。