FDA批准Berinert用于治疗遗传性血管性水肿相关症状
美国食品药品监督管理局（FDA）于2009年10月9日批准Berinert用于治疗与遗传性血管性水肿（hereditary angioedema，HAE）相关的腹部症状和面部水肿，后者是一种罕见并可能致命的遗传性疾病，Berinert是用于治疗该病的一线药物。
Berinert获准用于治疗成人和青少年HAE患者，在被诊断为HAE的患者中，该病可自发性地发生，或在应激、手术和受到感染期间发生。在腹部发作期间的症状包括严重腹痛、恶心、呕吐、痉挛和腹泻。
FDA生物制品评估和研究中心的执行主任Karen Midthun博士表示，Berinert将增强对于发生与遗传性血管性水肿相关的急性腹部症状和面部水肿患者的治疗方案。
Berinert是一种从人血浆中提取的蛋白质产品。该蛋白质可控制凝血和炎症反应，而当其减少时则会导致局部组织水肿。在一项纳入了124名伴有C1酯酶抑制剂缺乏的成人和青少年的临床试验中，Berinert显示可有效治疗在HAE患者中发生的急性中重度腹部症状和面部水肿。
Berinert禁用于对C1酯酶抑制剂药物有致命性过敏反应史的患者。在该药的临床试验中，已报告的最严重的不良反应为HAE相关性疼痛的严重度增加。最常见的不良反应包括继发性HAE症状、头痛、腹痛、恶心、肌痉挛、疼痛、腹泻和呕吐。
Berinert由位于德国马尔堡（Marburg）市的CSL Behring公司生产。
FDA批准Berinert
FDA批准治疗遗传性血管性水肿病药（一种罕见的潜在威胁生命的遗传病）Berinert.Berinert被批准用于成人和青少年自发、应激状态、手术或感染引起的遗传性血管性水肿的治疗。
在腹部发作的症状包括严重腹痛，恶心，呕吐，痉挛和腹泻。
“Berinert将增强遗传性血管水肿引起的急性腹痛，面部肿胀病人的治疗选择，”FDA生物制品评价和研究中心主任克伦米德休恩说。
Berinert是从人血浆中的一种蛋白质
它调节凝血和炎症反应，当受损时，可导致局部组织肿胀。在124个C1酯酶抑制剂缺乏的成年人和青少年中进行临床试验，结果表明Berinert将在治疗遗传性血管水肿引起的急性中度至重度腹部症状与面部肿胀患者有效。
Berinert是禁用于对C1酯酶抑制剂有超敏反应史且有生命威胁的患者。最严重不良反应的临床研究报告是水肿引起的疼痛程度的增加。
最常见的不良反应包括并发水肿，头痛，腹痛，恶心，肌肉痉挛，腹痛，腹泻和呕吐。
BERINERT（人类C1酯酶抑制剂）试剂盒
Berinert 500 IU
1. Name of the medicinal product
Berinert® 500 IU
Powder and solvent for solution for injection / infusion
2. Qualitative and quantitative composition
Active substance: C1-esterase inhibitor, human
Berinert contains 500 IU C1-esterase inhibitor per injection vial.
The potency of C1-esterase inhibitor is expressed in International Units (IU), which are related to the current WHO Standard for C1-esterase inhibitor products.
The product contains 50 IU/ml C1-esterase inhibitor after reconstitution with 10 ml water for injections.
The total protein content of the reconstituted solution is 6.5 mg/ml.
Excipients with known effect:
Sodium up to 486 mg (approximately 21 mmol) per 100 ml solution.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Powder (white lyophilisate) and solvent for solution for injection / infusion.
4. Clinical particulars
4.1 Therapeutic indications
Hereditary angioedema type I and II (HAE)
Treatment and pre-procedure prevention of acute episodes.
4.2 Posology and method of administration
Treatment should be initiated under the supervision of a physician experienced in the treatment of C1-esterase inhibitor deficiency.
Posology
Adults
Treatment of acute angioedema attacks:
20 IU per kilogram body weight (20 IU/kg b.w.)
Pre-procedure prevention of angioedema attacks:
1000 IU less than 6 hours prior to a medical, dental, or surgical procedure.
Children
Treatment of acute angioedema attacks:
20 IU per kilogram body weight (20 IU/kg b.w.).
Pre-procedure prevention of angioedema attacks:
15 to 30 IU per kilogram body weight (15-30 IU/kg b.w.) less than 6 hours prior to a medical, dental, or surgical procedure. Dose should be selected taking into account clinical circumstances (e.g. type of procedure and disease severity).
Method of administration
Berinert is to be reconstituted according to section 6.6. The reconstituted solution is to be administered by slow i.v. injection or infusion (4 ml/minute).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
In patients with known tendency towards allergies, antihistamines and corticosteroids should be administered prophylactically.
If allergic or anaphylactic-type reactions occur, the administration of Berinert has to be stopped immediately (e.g. discontinue injection/infusion) and an appropriate treatment has to be initiated. Therapeutic measures depend on the kind and severity of the undesirable effect. The current medical standards for shock treatment are to be observed.
Patients with laryngeal oedema require particularly careful monitoring with emergency treatment in stand-by.
Unlicenced use or treatment of Capillary Leak Syndrome (CLS) with Berinert (see also section "4.8 Undesirable effects") is not advised.
Berinert contains up to 486 mg sodium (approximately 21 mmol) per 100 ml solution. To be taken into consideration by patients on a controlled sodium diet.
Home treatment and self-administration
There are limited data on the use of this medicinal product in home treatment or self-administration. Potential risks associated with home treatment are related to the administration itself as well as the handling of adverse drug reactions, particularly hypersensitivity. The decision on the use of home treatment for an individual patient should be made by the treating physician, who should ensure that appropriate training is provided and the use reviewed at intervals.
Virus safety
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as HIV, HBV, HCV and for the non-enveloped viruses HAV and parvovirus B19.
Appropriate vaccination (hepatitis A and B) should be generally considered for patients in regular/repeated receipt of human plasma-derived products.
It is strongly recommended that every time Berinert is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are limited amount of data that indicate no increased risk from the use of Berinert in pregnant women. Berinert is a physiological component of human plasma. Therefore, no studies on reproduction and developmental toxicity have been performed in animals and no adverse effects on fertility, pre- and postnatal development are expected in humans.
Therefore, Berinert should be given to a pregnant woman only if clearly needed.
Breastfeeding
It is unknown whether Berinert is excreted in human milk, but due to its high molecular weight, the transfer of Berinert into breast milk seems unlikely. However, breastfeeding is questionable in women suffering from hereditary angioedema. A decision must be made whether to discontinue breastfeeding or to discontinue the Berinert therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility
Berinert is a physiological component of human plasma. Therefore, no studies on reproduction and developmental toxicity have been performed in animals and no adverse effects on fertility, pre- and postnatal development are expected in humans.
4.7 Effects on ability to drive and use machines
Berinert has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
The following adverse reactions are based on post marketing experience as well as scientific literature. The following standard categories of frequency are used:
Very common:
 ≥
1/10

Common:
 ≥
1/100 and < 1/10
Uncommon:
 ≥
1/1,000 and < 1/100
Rare:
 ≥
1/10,000 and < 1/1,000
Very rare:
 <
1/10,000 (including reported single cases)
Undesired reactions with Berinert are rare.

Organ class	Very common	Common	Uncommon	Rare	Very rare
Vascular disorders				Development of thrombosis*
General disorders and administration site conditions				Rise in temperature, reactions at the injection side
Immune system disorders				Allergic or anaphylactic-type reactions (e.g. tachycardia, hyper- or hypotension, flushing, hives, dyspnoea, headache, dizziness, nausea)	Shock

* In treatment attempts with high doses of Berinert for prophylaxis or therapy of Capillary Leak Syndrome (CLS) before, during or after cardiac surgery under extracorporal circulation (unlicensed indication and dose), in single cases with fatal outcome.
For safety with respect to transmissible agents, see section 4.4.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the UK Yellow Card Scheme.
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
No case of overdose has been reported.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: C1-inhibitor, plasma derived
ATC code: B06AC01
C1-esterase inhibitor is a plasma glycoprotein with a molecular weight of 105 kD and a carbohydrate moiety of 40 %. Its concentration in human plasma ranges around 240 mg/l. Besides its occurrence in human plasma, also the placenta, the liver cells, monocytes and platelets contain C1-esterase inhibitor.
C1-esterase inhibitor belongs to the serine-protease-inhibitor-(serpin)-system of human plasma as do also other proteins like antithrombin III, alpha-2-antiplasmin, alpha-1-antitrypsin and others.
Under physiological conditions C1-esterase inhibitor blocks the classical pathway of the complement system by inactivating the enzymatic active components C1s and C1r. The active enzyme forms a complex with the inhibitor in a stoichiometry of 1:1.
Furthermore, C1-esterase inhibitor represents the most important inhibitor of the contact activation of coagulation by inhibiting factor XIIa and its fragments. In addition, it serves, besides alpha-2-macroglobulin, as the main inhibitor of plasma kallikrein.
The therapeutic effect of Berinert in hereditary angioedema is induced by the substitution of the deficient C1-esterase inhibitor activity.
5.2 Pharmacokinetic properties
The product is to be administered intravenously and is immediately available in the plasma with a plasma concentration corresponding to the administered dose.
Pharmacokinetic properties have been investigated in 40 patients (6 patients < 18 years) with hereditary angioedema. These included 15 patients under prophylactic treatment (with frequent/severe attacks), as well as 25 patients with less frequent/mild attacks and "on demand" treatment. The data were generated in an attack-free interval.
The median in-vivo recovery (IVR) was 86.7 % (range: 54.0 – 254.1 %). The IVR for children was slightly higher (98.2 %, range: 69.2 – 106.8 %)) than for adults (82.5 %, range: 54.0 – 254.1 %). Patients with severe attacks had a higher IVR (101.4 %) compared to patients with mild attacks (75.8 %, range: 57.2 – 195.9 %).
The median increase in activity was 2.3%/IU/kg b.w. (range: 1.4 – 6.9 %/IU/kg b.w.). No significant differences were seen between adults and children. Patients with severe attacks showed a slightly higher increase in activity than patients with mild attacks (2.9, range: 1.4 – 6.9 vs. 2.1, range: 1.5 – 5.1 %/IU/kg b.w.).
The maximum concentration of C1-esterase inhibitor activity in plasma was reached within 0.8 hours after administration of Berinert without significant differences between the patient groups.
The median half-life was 36.1 hours. It was slightly shorter in children than in adults (32.9 vs. 36.1 hours) and in patients with severe attacks than in patients with mild attacks (30.9 vs. 37.0).
5.3 Preclinical safety data
Berinert contains as active ingredient C1-esterase inhibitor. It is derived from human plasma and acts like an endogenous constituent of plasma. Single-dose application of Berinert in rats and mice and repeated-dose applications in rats did not show any evidence of toxicity.
Preclinical studies with repeated-dose application to investigate carcinogenicity and reproductive toxicity have not been conducted because they cannot be reasonably performed in conventional animal models due to the development of antibodies following the application of heterologous human proteins.
The in-vitro Ouchterlony test and the in-vivo PCA model in guinea pigs did not show any evidence of newly arising antigenic determinants in Berinert following pasteurisation.
6. Pharmaceutical particulars
6.1 List of excipients
Powder:
Glycine
Sodium chloride
Sodium citrate
Solvent:
Water for injections
6.2 Incompatibilities
Berinert should not be mixed with other medicinal products and diluents in the syringe/infusion set.
6.3 Shelf life
30 months
After reconstitution, from a microbiological point of view and as Berinert contains no preservative, the reconstituted product should be used immediately. The physico-chemical stability has been demonstrated for 48 hours at room temperature (max. 25°C). However, if it is not administered immediately, storage shall not exceed 8 hours at room temperature. The reconstituted product should only be stored in the vial.
6.4 Special precautions for storage
Do not store above 25 °C.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Powder: Injection vial of colourless glass Type II, sealed with bromobutyl rubber infusion stopper Type I, aluminium seal and plastic flip-off cap.
Solvent: 10 ml water for injections in an injection vial of colourless glass Type I, sealed with chlorobutyl rubber infusion stopper Type I, aluminium seal and plastic flip-off cap.
Administration set: 1 filter transfer device 20/20, 1 disposable 10 ml syringe, 1 venipuncture set, 2 alcohol swabs, 1 plaster
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Method of administration
General instructions
- The solution should be colourless and clear. After filtering/withdrawal (see below) reconstituted product should be inspected visually for particulate matter and discoloration prior to administration.
- Do not use solutions that are cloudy or have deposits.
- Reconstitution and withdrawal must be carried out under aseptic conditions. Use the syringe provided with the product.
Reconstitution
Bring the solvent to room temperature. Ensure product and solvent vial flip caps are removed and the stoppers are treated with an aseptic solution and allowed to dry prior to opening the Mix2Vial package.
1. Open the Mix2Vial package by peeling off the lid. Do not remove the Mix2Vial from the blister package! 
 

2. Place the solvent vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adapter end straight down through the solvent vial stopper.
 

3. Carefully remove the blister package from the Mix2Vial set by holding at the rim, and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial set.

4. Place the product vial on an even and firm surface. Invert the solvent vial with the Mix2Vial set attached and push the spike of the transparent adapter end straight down through the product vial stopper. The solvent will automatically flow into the product vial.

 
5. With one hand grasp the product-side of the Mix2Vial set, and with the other hand grasp the solvent-side and unscrew the set carefully into two pieces.
Discard the solvent vial with the blue Mix2Vial adapter attached.

6. Gently swirl the product vial with the transparent adapter attached until the substance is fully dissolved. Do not shake.

7. Draw air into an empty, sterile syringe. Use the syringe provided with the product. While the product vial is upright, connect the syringe to the Mix2Vial's Luer Lock fitting. Inject air into the product vial.

Withdrawal and application

8. While keeping the syringe plunger pressed, invert the system upside down and draw the solution into the syringe by pulling the plunger back slowly.

9. Now that the solution has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adapter from the syringe.
7. Marketing authorisation holder
CSL Behring GmbH
Emil-von-Behring-Strasse 76
35041 Marburg
Germany
8. Marketing authorisation number(s)
PL 15036/0030
9. Date of first authorisation/renewal of the authorisation
29 January 2009 / 12 December 2013
10. Date of revision of the text
13 November 2013
静脉注射Berinert获准由患者自行给药用于治疗遗传性血管性水肿
2012年1月3日，CSL Behring宣布，美国食品药品管理局(FDA)已批准Berinert,[C1酯酶抑制剂(人)]的新说明书，允许患者自行使用这种巴氏消毒、纳米过滤的药物，用于治疗遗传性血管性水肿(HAE)急性发作。经过扩展的说明书中还增加了新的适应证，即用于治疗危及生命的喉部HAE发作，以及面部和腹部发作。
在发生腹部或面部HAE发作时使用Berinert，已被证明可显著加快症状缓解(在临床试验中，给药后症状缓解的中位时间为48 min，而安慰剂组长达4h)。
Berinert用于预防的安全性和有效性尚未被确证。该药禁忌用于曾发生危及生命的C1酯酶抑制剂全身性不良反应的患者。在临床研究中，使用Berinert者报告的最常见严重不良反应为HAE相关疼痛的严重程度增加。在安慰剂对照临床试验中，味觉障碍是最常见的不良反应，Berinert组发生率超过4%，高于安慰剂组。不论是按照推荐剂量，还是超适应证或超推荐剂量，使用C1酯酶抑制剂(包括Berinert)的患者均已有发生血栓性事件的报告。
Berinert通过静脉注射给药。患者必须接受恰当的训练才能自行给药。
由于Berinert提取自人血浆，因此存在传播感染性病原体的风险，包括病毒和(理论上克雅氏病病原体)，这一风险无法被完全消除。
------------------------------------------------------
产地国家: 德国
原产地英文商品名:
BERINERT P 5000U(1Powder+Solvent)/box
原产地英文药品名:
CI ESTERASE INHIBITOR
中文参考商品译名:
BERINERT P 5000单位(1注射粉剂+稀释剂)/盒
中文参考药品译名:
CI酯酶抑制剂
生产厂家中文参考译名:
CSL Behring GmbH
生产厂家英文名:
CSL Behring GmbH