2018年4月18日，Shire公司宣布美国FDA已批准Vonvendi（重组血管假性血友病因子，rVWF），用于血管性血友病（VWD）成人患者（18岁及以上）的围手术期出血管理。在美国，Vonvendi于2015年12月首次获批，用于VWD成人患者按需治疗和出血事件控制。截至目前，该药仍是FDA批准的首个也是唯一一个治疗VWD成人患者的rVWF药物。

此次批准是基于一项前瞻性、无对照、开放标签、非随机、多中心III期临床研究的数据。该研究在15例确诊为重度先天性VWD并进行择期手术的成人患者中开展，评估了Vonvendi联用或不联用重组凝血因子VIII（rFVIII）用于手术前、手术期间或手术后的止血效果和安全性。

数据显示，该研究达到了主要终点，最后一次围手术期Vonvendi输注后24h评估或研究完成时考察评估的结果表明，在全部15例患者中的总体止血效果被评为“优秀”或“良好”。总体的每天一次中位给药频率被证明在恰当的患者中可使止血正常化。研究中，有1例患者在接受髋关节置换术期间输注Vonvendi治疗后的3天内发生深静脉血栓，1例患者体内VWF结合抗体检测结果呈阳性。Vonvendi治疗后，所有患者均没有检测到针对潜在杂质（例如rFurin，CHO-蛋白、小鼠IgG）的结合抗体。

该药的处方信息也进行了更新，包括关于药代动力学和存储的新信息。Vonvendi可储存在冷藏温度2℃-8℃或不超过30℃的室内温度，不能冷冻储存，应储存在原包装盒内，避免受到光的极端暴露。

VWD是一种常见的遗传性出血性疾病，由于VWF缺乏或功能障碍引起，患者由于VWF不足或有缺陷，血液无法有效凝结，可能导致鼻部、牙龈、肠道以及肌肉和关节内发生严重出血。女性患者可能有严重的超常持续的月经，并且在分娩后可能出现过多出血。

Vonvendi由Baxalta研制，在2016年1月，Shire以320亿美元将Baxalta收购，一举成为全球罕见病药物研发领域的领导者。目前，Shire也正在开发Vonvendi作为预防性用药以及儿科适应症。

Generic Name: Von Willebrand Factor (recombinant)
Class: Hemostatics

Von Willebrand factor (recombinant) is a hemostatic.

Von Willebrand factor (recombinant) is a recombinant von Willebrand factor (VWF) indicated for on-demand treatment and control of bleeding episodes in adults diagnosed with von Willebrand disease (VWD).1

Von Willebrand factor (recombinant) is available in the following dosage form(s) and strength(s):

Von Willebrand factor (recombinant) is available as a lyophilized powder in single-use vials containing nominally 650 or 1300 international units von Willebrand factor activity (VWF:RCo).1

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

For intravenous use after reconstitution only.1

· For each bleeding episode, administer the first dose of von Willebrand factor (recombinant) with an approved recombinant (non-von Willebrand factor containing) factor VIII [antihemophilic factor (recombinant)] if factor VIII baseline levels are below 40% or are unknown.1

· Initial dose is 40 to 80 international units (IU) per kg body weight. Adjust the dosage based on the extent and location of bleeding.1

a If recombinant factor VIII is administered, see recombinant factor VIII package insert for reconstitution and administration instructions.

b A bleed could be considered major if red blood cell transfusion is either required or potentially indicated or if bleeding occurs in a critical anatomical site (e.g., intracranial or gastrointestinal hemorrhage).

· If recombinant factor VIII is required, give recombinant factor VIII within 10 minutes of completing von Willebrand factor (recombinant) infusion at a ratio of 1.3:1 (i.e., 30% more von Willebrand factor [recombinant] than recombinant factor VIII, based on the approximate mean recoveries of 1.5 and 2.0 IU/dL for von Willebrand factor [recombinant] and recombinant factor VIII, respectively). Consult the package insert for the specific factor VIII product for dosing recommendations.1

· Administer von Willebrand factor (recombinant) within 3 hours after reconstitution.1

Do not use in patients who have had life-threatening hypersensitivity reactions to von Willebrand factor (recombinant) or its components (mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and hamster or mouse proteins).1

Thromboembolic reactions, including disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, can occur, particularly in patients with known risk factors for thrombosis. Monitor for early signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope.1

In patients requiring frequent doses of von Willebrand factor (recombinant) with recombinant factor VIII, monitor plasma levels for FVIII:C activity because an excessive rise in factor VIII levels can increase the risk of thromboembolic complications.1

Hypersensitivity reactions, including anaphylaxis, may occur. Symptoms can include anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, wheezing, and/or acute respiratory distress. If signs and symptoms of severe allergic reactions occur, immediately discontinue administration of von Willebrand factor (recombinant) and provide appropriate supportive care.1

Von Willebrand factor (recombinant) contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster proteins less than or equal to 2 ng/IU von Willebrand factor (recombinant). Patients treated with this product may develop hypersensitivity reactions to non-human mammalian proteins.1

Neutralizing antibodies (inhibitors) to von Willebrand factor and/or factor VIII can occur. If the expected plasma levels of VWF activity (VWF:RCo) are not attained, perform an appropriate assay to determine if anti-VWF or anti-FVIII inhibitors are present. Consider other therapeutic options and direct the patient to a physician with experience in the care of either von Willebrand disease or hemophilia A. 1

In patients with high levels of inhibitors to VWF or factor VIII, von Willebrand factor (recombinant) therapy may not be effective and infusion of this protein may lead to severe hypersensitivity reactions. Since inhibitor antibodies can occur concomitantly with anaphylactic reactions, evaluate patients experiencing an anaphylactic reaction for the presence of inhibitors.1

· Monitor plasma levels of VWF:RCo and factor VIII activities in patients receiving von Willebrand factor (recombinant) to avoid sustained excessive von Willebrand factor and/or factor VIII activity levels, which may increase the risk of thrombotic events, particularly in patients with known clinical or laboratory risk factors.1

· Monitor for development of von Willebrand factor and/or factor VIII inhibitors when suspected. Perform appropriate inhibitor assays to determine if von Willebrand factor and/or factor VIII inhibitors are present if bleeding is not controlled with the expected dose of von Willebrand factor (recombinant).1

There are no studies of von Willebrand factor (recombinant) use in pregnant women. The background risk of major birth defects and miscarriage in the indicated population is unknown; however, the background risk of major birth defects in the U.S. general population is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Animal reproduction studies have not been conducted with von Willebrand factor (recombinant). It is not known whether von Willebrand factor (recombinant) can cause fetal harm when administered to a pregnant woman or whether it can affect reproduction capacity. Von Willebrand factor (recombinant) should be given to a pregnant woman only if clearly needed.1

There is no information regarding the presence of von Willebrand factor (recombinant) in human milk, its effects on the breastfed infant, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for von Willebrand factor (recombinant) and any potential adverse effects on the breastfed infant from von Willebrand factor (recombinant) or from the underlying maternal condition.1

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.1

Clinical trials of von Willebrand factor (recombinant) did not include subjects aged 65 and over to determine whether they respond differently compared to younger subjects.1

The most common adverse reaction observed (≥2% of subjects) was generalized pruritus.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:

Please see product labeling for drug interaction information.

In VWD patients, von Willebrand factor (recombinant) acts to promote hemostasis by mediating platelet adhesion to damaged vascular subendothelial matrix (e.g., collagen) and platelet aggregation, and as a carrier protein for factor VIII2, protecting it from rapid proteolysis. The adhesive activity of VWF depends on the size of its multimers, with large multimers being the most effective in supporting interactions with collagen and platelet receptors. The factor VIII binding capacity and affinity to von Willebrand factor (recombinant) is comparable to that of VWF present in plasma and platelets, allowing for von Willebrand factor (recombinant) to reduce factor VIII clearance.1

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).1

Advise patients of the early signs of hypersensitivity reactions, including anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, wheezing, and/or acute respiratory distress. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures. 1

Advise patients to contact their physician or treatment center for further treatment and/or assessment if they experience a lack of clinical response to von Willebrand factor therapy, as this may be a manifestation of an inhibitor. 1

Advise patients to consult with their physicians or healthcare provider prior to travel. While traveling, advise patients to bring an adequate supply of von Willebrand factor (recombinant) based on their current regimen of treatment. 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.