阿斯利康新型抗炎药Fasenra获美国FDA批准，治疗重度嗜酸性粒细胞哮喘

美国食品和药物管理局（FDA）已批准单抗类IL-5抑制剂类抗炎药Fasenra（benralizumab），作为一种附加（add-on）维持疗法，用于12岁及以上重度嗜酸性粒细胞性哮喘青少年患者及成人患者的治疗。Fasenra每8周一次皮下注射，将作为一种含固定剂量药物的预充式注射器销售。
fasenra是唯一一种在给药后24h内能提供直接、快速、嗜酸性粒细胞几乎完全耗尽的呼吸科生物疗法。据估计，在重度哮喘患者中，大约有一半的患者嗜酸性粒细胞水平升高，影响气道炎症和气道高反应性，导致哮喘严重程度和症状加重，肺功能下降，急性加重风险升高。

fasenra直接结合在一个嗜酸性粒细胞IL-5α受体和独特的吸引自然杀伤细胞诱导细胞凋亡(程序性细胞死亡)。Fasenra将作为一个每周固定剂量皮下注射经预灌封注射器。

批准日期：2017年11月17日 生产商：阿斯利康
FASENRA（贝那利珠单抗[benralizumab]）注射剂，用于皮下注射

一般描述
Benralizumab是一种对白介素-5受体α亚基（IL5Rα）具有选择性的人源化单克隆抗体（IgG1 /κ-类）。 Benralizumab通过重组DNA技术在中国仓鼠卵巢细胞中产生。Benralizumab的分子量约为150 kDa。
FASENRA（贝那利珠单抗）注射液是一种无菌，无防腐剂，透明至乳白色，无色至微黄色溶液，用于皮下注射。 由于FASENRA是一种蛋白质，溶液中可能存在少量半透明或白色至灰白色颗粒。 每个单剂量预充式注射器递送1mL含有30mg贝那利珠单抗，L-组氨酸（1.4mg）; L-组氨酸盐酸盐一水合物（2.3mg）; 聚山梨酯20（0.06mg）; α，α-海藻糖二水合物（95mg）; 和注射用水，USP。 单剂量预充式注射器包含1毫升玻璃注射器，带有29号½英寸不锈钢针头。

适应症
FASENRA适用于12岁及以上严重哮喘患者的附加维持治疗，并具有嗜酸性表型[见临床研究]。

使用限制
•FASENRA不适用于治疗其他嗜酸性粒细胞疾病。
•FASENRA不适用于缓解急性支气管痉挛或哮喘状态。

剂量和给药
推荐剂量
FASENRA仅用于皮下使用。
FASENRA的推荐剂量为30mg，前3次给药每4周给药一次，然后每8周给予一次皮下注射到上臂，大腿或腹部。

准备和管理
FASENRA应由医疗保健专业人员管理。根据临床实践，建议在给予生物制剂后监测患者[见警告和注意事项]。在施用之前，通过在室温下放置纸箱约30分钟来温暖FASENRA。在24小时内使用FASENRA或丢弃到锐器容器中。

带针安全警卫的预充式注射器说明
请勿触碰针头护罩启动夹，以防止针头安全护罩过早启动。
1.抓住注射器主体，而不是柱塞，从托盘中取出预充式注射器。检查注射器上的失效日期。在给药之前目视检查FASENRA是否有颗粒物质和变色。 FASENRA对乳白色透明，无色至微黄色，可能含有少量半透明或白色至灰白色颗粒。如果液体浑浊，变色或含有大颗粒或异物，请勿使用FASENRA。注射器可能含有小气泡;这个是正常的。给药前不要排出气泡。
2.在准备好注射之前不要取下针头盖。握住注射器主体，并直接拉下来取下针头盖。取下针盖时，请勿握住柱塞或柱塞头，否则柱塞可能会移动。如果预充式注射器受损或受污染（例如，没有使用针头盖而落下），请丢弃并使用新的预充式注射器。
3.轻轻捏紧皮肤，并将针头插入推荐的注射部位（即上臂，大腿或腹部）。
4.推入柱塞直至柱塞头完全位于针头护罩启动夹之间，从而注入所有药物。这是启动护针器所必需的。
5.注射后，保持柱塞头上的压力，并将针头从皮肤上取下。释放柱塞头上的压力，使针护套盖住针。不要重新盖上预充式注射器。
6.将用过的注射器丢弃到锐器容器中。

如何提供
剂型和强度
注射：FASENRA在单剂量预充式注射器中的30mg/mL溶液。 FASENRA是一种透明乳白色，无色至微黄色溶液，可能含有少量半透明或白色.

Class: Interleukin Antagonists
Brands: Fasenra

Benralizumab is an interleukin antagonist.

Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody (IgG1, kappa) indicated for the add-on maintenance treatment of severe asthma in patients 12 years of age and older, and with an eosinophilic phenotype.1

Not for treatment of other eosinophilic conditions.1

Not for relief of acute bronchospasm or status asthmaticus.1

Benralizumab is available in the following dosage form(s) and strength(s):

Injection: 30 mg/mL solution in a single-dose prefilled syringe.1

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

· Administer by subcutaneous injection.1

· Recommended dose is 30 mg every 4 weeks for the first 3 doses, followed by once every 8 weeks thereafter.1

Known hypersensitivity to benralizumab or excipients.1

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, rash) have occurred following administration of benralizumab. These reactions generally occur within hours of administration, but in some instances have a delayed onset (i.e., days). In the event of a hypersensitivity reaction, benralizumab should be discontinued.1

Benralizumab should not be used to treat acute asthma symptoms or acute exacerbations. Do not use benralizumab to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with benralizumab.1

Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with benralizumab. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.1

Eosinophils may be involved in the immunologic response to some helminth infections. Patients with known helminth infections were excluded from participation in clinical trials. It is unknown if benralizumab will influence a patient’s response against helminth infections.1

Treat patients with pre-existing helminth infections before initiating therapy with benralizumab. If patients become infected while receiving treatment with benralizumab and do not respond to anti-helminth treatment, discontinue treatment with benralizumab until infection resolves.1

Risk Summary: The data on pregnancy exposure from the clinical trials are insufficient to inform on drug-associated risk. Monoclonal antibodies such as benralizumab are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. In a prenatal and postnatal development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with IV administration of benralizumab throughout pregnancy at doses that produced exposures up to approximately 310 times the exposure at the maximum recommended human dose (MRHD) of 30 mg given by subcutaneous injection. 1 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.1

Clinical Considerations: In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.1

Animal Data: In a prenatal and postnatal development study, pregnant cynomolgus monkeys received benralizumab from beginning on gestational day 20 (GD20) to GD22 (dependent on pregnancy determination), on GD35, once every 14 days thereafter throughout the gestation period and 1-month postpartum (maximum 14 doses) at doses that produced exposures up to approximately 310 times that achieved with the MRHD (on an AUC basis with maternal IV doses up to 30 mg/kg once every 2 weeks). Benralizumab did not elicit adverse effects on fetal or neonatal growth (including immune function) up to 6.5 months after birth. There was no evidence of treatment-related external, visceral, or skeletal malformations. Benralizumab was not teratogenic in cynomolgus monkeys. Benralizumab crossed the placenta in cynomolgus monkeys. Benralizumab concentrations were approximately equal in mothers and infants on postpartum day 7, but were lower in infants at later time points. Eosinophil counts were suppressed in infant monkeys with gradual recovery by 6 months postpartum; however, recovery of eosinophil counts was not observed for one infant monkey during this period.1

There is no information regarding the presence of benralizumab in human or animal milk, and the effects of benralizumab on the breast-fed infant and on milk production are not known. However, benralizumab is a humanized monoclonal antibody (IgG1 kappa class), and immunoglobulin G (IgG) is present in human milk in small amounts. If benralizumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to benralizumab are unknown. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for benralizumab and any potential adverse effects on the breast-fed child from benralizumab or from the underlying maternal condition.1

There were 108 adolescents 12 to 17 years of age with asthma enrolled in the Phase 3 exacerbation trials (Trial 1: n=53, Trial 2: n=55). Of these, 46 received placebo, 40 received benralizumab every 4 weeks for 3 doses, followed by every 8 weeks thereafter, and 22 received benralizumab every 4 weeks. Patients were required to have a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months and reduced lung function at baseline (pre-bronchodilator FEV1 <90%) despite regular treatment with medium- or high-dose inhaled corticosteroids and long-acting β-adrenergic agonists with or without oral corticosteroids or other controller therapy. The pharmacokinetics of benralizumab in adolescents 12 to 17 years of age were consistent with adults based on population pharmacokinetic analysis, and the reduction in blood eosinophil counts was similar to that observed in adults following the same benralizumab treatment. The adverse event profile in adolescents was generally similar to the overall population in the Phase 3 studies. The safety and efficacy in patients younger than 12 years of age has not been established.1

Of the total number of patients in clinical trials of benralizumab, 13% (n = 320) were 65 years of age and over, while 0.4% (n=9) were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.1

Most common adverse reactions (incidence greater than or equal to 5%) include headache and pharyngitis.1

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

No formal drug interaction studies have been conducted.1

Benralizumab is a humanized afucosylated, monoclonal antibody (IgG1, kappa) that directly binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with a dissociation constant of 11 pM. The IL-5 receptor is expressed on the surface of eosinophils and basophils. In an in vitro setting, the absence of fucose in the Fc domain of benralizumab facilitates binding (45.5 nM) to FcγRIII receptors on immune effector cells, such as natural killer (NK) cells, leading to apoptosis of eosinophils and basophils through antibody-dependent cell-mediated cytotoxicity (ADCC).1

Inflammation is an important component in the pathogenesis of asthma. Multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in inflammation. Benralizumab, by binding to the IL-5Rα chain, reduces eosinophils through ADCC; however, the mechanism of benralizumab action in asthma has not been definitively established.1

Advise the patient to read the FDA-approved patient labeling (patient information). 1

Inform patients that hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, rash) have occurred after administration of benralizumab. These reactions generally occurred within hours of benralizumab administration, but in some instances had a delayed onset (i.e., days). Instruct patients to contact their healthcare professional if they experience symptoms of an allergic reaction.1

Inform patients that benralizumab does not treat acute asthma symptoms or acute exacerbations. Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with benralizumab.1

Inform patients to not discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.1

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

AHFS Drug Information. © Copyright 2018, Selected Revisions November 20, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.