Eribulin
适应症/用法剂量/禁忌症/注意事项/不良反应/药物相互作用
【药品名称】
通用名：艾日布林
商品名：HALAVEN
英文名：eribulin mesylate
【开发与上市】
日本卫材公司(Eisai Inc.)开发，于2010年在美国首次上市。
【美FDA批准的适应症】
艾日布林是一种微管抑制剂，用于治疗至少接受过2种化疗方案的晚期转移性乳腺癌。患者既往的辅助或转移性化疗应该包括蒽环类和紫杉类药物。
【用法用量】
（1）1.4 mg/m2，静注2至5分钟，第1天和第8 天，每21天重复。
（2）肝轻度受损者（Child-Pugh A）的推荐剂量为1.1 mg/m2，静注2至5分钟，第1天和第8 天，每21天重复。
（3）肝中度受损者（Child-Pugh B）的推荐剂量为0.7 mg/m2，静注2至5分钟，第1天和第8 天，每21天重复。
（4）肾中度受损者（肌酐清除率30-50 mL/min）的推荐剂量为1.1 mg/m2，静注2至5分钟，第1天和第8 天，每21天重复。
（5）调整剂量
每次用药前评价外周神经毒性与全血细胞计数
推荐延迟给药：
 — 中性粒< 1,000/mm3
 — 血小板< 75,000/mm3
 — 3/4级非血液学毒性

第8天给药推迟最多1周：
 — 如果第15天，毒性没有消失或没有恢复至≤2级，跳过第8天用药
 — 如果第15天，毒性已消失或恢复至≤2级，本品减量给药，在至少2周后才开始下一疗程的治疗。
推荐减量给药：
如果由于毒性延迟本品给药，毒性恢复至2级或更小，按照表1减量使用本品治疗。
一旦减量使用本品，随后的治疗中不再增加本品剂量。 
表1   推荐减量用药
 

（6）不要与含葡萄糖溶液的药物使用同样的静脉通道，不要与其它药物通过同一静脉通道同时给药。
【性状】
注射剂：1 mg/2 mL(0.5 mg/mL)

【禁忌症】
无。
【注意事项】
（1）中性粒细胞减少：监测外周血细胞计数和适当调整剂量。
（2）周围神经病变：监查神经病变征象。用延迟和调整剂量处理。
（3）在妊娠中使用：当给予妊娠妇女时可能发生胎儿危害。
（4）QT延长：在有充血性心衰、心动过缓、使用已知延长QT间期药物和电解质异常的患者中监测QT间期延长。避免在先天性长QT综合征患者中使用本品。
【不良反应】
最常见不良反应(发生率≥25%)是：中性粒细胞减少，贫血，虚弱/疲劳，脱发，周围神经病变，恶心和便秘。
【药物相互作用】
临床用药浓度下，本品不会抑制CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1或CYP3A4酶，也不会诱导CYP1A2, CYP2C9, CYP2C19或CYP3A4酶。本品不会改变以上酶作用底物的血浆药物浓度。
FULL PRESCRIBING INFORMATION FROM FDA 2010:

1 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.

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.

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.
3 DOSAGE FORMS AND STRENGTHS

HALAVEN (eribulin mesylate) Injection, 1 mg/2 mL (0.5 mg/mL).

4 CONTRAINDICATIONS
None.
5 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).
6 ADVERSE REACTIONS
The most common adverse reactions (incidence ≥25%) were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation (6).
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)]