美国食品与药物管理局FDA批准罕用药物RiaSTAP用于治疗罕见遗传性缺陷即先天性纤维蛋白原缺乏症患者的出血症状。如果不进行治疗，此类患者存在致命性出血的潜在风险。 纤维蛋白原可促进血块形成和防止出血，因此在血液凝固过程中起重要作用。先天性纤维蛋白原缺乏症患者自身无法产生足够数量的纤维蛋白原。纤维蛋白原在肝脏中产生，血浆中的正常浓度为250～400 mg/dL。 FDA生物制品评估和研究中心主任Jesse Goodman 博士称：“该产品为数量很少的先天性纤维蛋白原缺乏症患者提供了急需的治疗方案。如果此类患者出血发生于脑部或其他器官后未得到治疗，可能会引起失血、器官损伤甚至死亡。” 在美国仅有150～300例纤维蛋白原缺乏症患者。此类患者通常是在出生时因发生脐带部位出血而确诊。存在此缺陷的儿童需要限制活动以降低因微小创伤发生出血的风险。 RiaSTAP是一种静脉应用的纤维蛋白原浓缩液，提取自健康人的血浆。该产品适用于无纤维蛋白原或纤维蛋白原水平低的无纤维蛋白原血症患者，或纤维蛋白原水平低于50mg/dL的低纤维蛋白原血症患者。 该产品并不适用于异常纤维蛋白原血症患者，此类患者的纤维蛋白原水平正常，但是纤维蛋白原功能存在缺陷，因此存在出血或凝血并发症风险。 RiaSTAP的批准是基于一项纳入15例无纤维蛋白原血症患者的研究结果。该研究结果显示，患者在接受RiaSTAP 70mg/kg剂量治疗后，纤维蛋白原达到了防止出血的预期目标水平。此外，15例患者中有14例血浆检测结果显示最大血块硬度（可能预测临床益处的替代指标）增加。RiaSTAP的最常见不良反应为发热和头痛。 RiaSTAP的临床益处将在一项上市后研究中进一步验证。该研究将纳入无纤维蛋白原血症和低纤维蛋白原血症两类患者。 罕用药（Orphan drugs）是指应用于治疗罕见疾病的药物或生物制品。研发此类产品的制造商有资格从政府部门获得特定利益以作为交换。RiaSTAP[纤维蛋白原浓缩液（人源性）]的开发符合FDA加速批准规则。 该药由德国马尔堡的CSL Behring公司制造。 ------------------------------------------------ 产地国家: 美国 原产地英文商品名: RIASTAP POWDER FOR RECONSTITUTION 900-1300mg/vial 原产地英文药品名: FIBRINOGEN 中文参考商品译名: RIASTAP重组粉剂 900-1300毫克/瓶 中文参考药品译名: 纤维蛋白原 生产厂家中文参考译名: CSL Behring 生产厂家英文名: CSL Behring HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RiaSTAP ® safely and effectively. See full prescribing information for RiaSTAP. RiaSTAP, Fibrinogen Concentrate (Human) Lyophilized Powder for Reconstitution, For Intravenous Use Initial U.S. Approval: 2009 INDICATIONS AND USAGE RiaSTAP, Fibrinogen Concentrate (Human) is a human blood coagulation factor indicated for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. (1) DOSAGE AND ADMINISTRATION For intravenous use only. Dose (mg/kg body weight) =   [Target level (mg/dL) - measured level (mg/dL)]       1.7 (mg/dL per mg/kg body weight) Dose when fibrinogen level is unknown: 70 mg/kg body weight. (2.1) Monitoring of patient's fibrinogen level is recommended during treatment. A target fibrinogen level of 100 mg/dL should be maintained until hemostasis is obtained. (2.1) Injection rate should not exceed 5 mL per minute. (2.3) DOSAGE FORMS AND STRENGTHS RiaSTAP is available as a single-use vial containing 900 mg to 1300 mg lyophilized fibrinogen concentrate powder for reconstitution. (3) The actual fibrinogen potency for each lot is printed on the vial label and carton. (3) CONTRAINDICATIONS Known anaphylactic or severe systemic reactions to human plasma-derived products (4) WARNINGS AND PRECAUTIONS Monitor patients for early signs of anaphylaxis or hypersensitivity reactions and if necessary, discontinue administration and institute appropriate treatment. (5.1) Thrombotic events have been reported in patients receiving RiaSTAP. Weigh the benefits of administration versus the risks of thrombosis. (5.2) RiaSTAP is made from pooled human plasma. Products made from human plasma may contain infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. (5.3) ADVERSE REACTIONS The most serious adverse reactions observed are thrombotic episodes (pulmonary embolism, myocardial infarction, deep vein thrombosis) and anaphylactic reactions. (6) The most common adverse reactions observed in clinical studies (frequency >1%) were fever and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS Pediatric: Shorter half-life and faster clearance than in adults has been observed. (8.4) See 17 for PATIENT COUNSELING INFORMATION. Revised: 5/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE RiaSTAP®, Fibrinogen Concentrate (Human) is a human blood coagulation factor indicated for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. 2 DOSAGE AND ADMINISTRATION For intravenous use only. 2.1 Treatment of Congenital Fibrinogen Deficiency RiaSTAP dosing, duration of dosing and frequency of administration should be individualized based on the extent of bleeding, laboratory values, and the clinical condition of the patient. RiaSTAP dose when baseline fibrinogen level is known. Dose should be individually calculated for each patient based on the target plasma fibrinogen level based on the type of bleeding, actual measured plasma fibrinogen level and body weight, using the following formula [see Clinical Pharmacology (12.3)]: [Target level (mg/dL) - measured level (mg/dL)] 1.7 (mg/dL per mg/kg body weight) RiaSTAP dose when baseline fibrinogen level is not known. If the patient's fibrinogen level is not known, the recommended dose is 70 mg per kg of body weight administered intravenously. Monitor patient's fibrinogen level during treatment with RiaSTAP. Maintain a target fibrinogen level of 100 mg/dL until hemostasis is obtained. 2.2 Preparation and Reconstitution The procedures below are provided as general guidelines for preparation and reconstitution of RiaSTAP. Use aseptic technique when preparing and reconstituting RiaSTAP. Reconstitute RiaSTAP at room temperature as follows: 1.Remove the cap from the product vial to expose the central portion of the rubber stopper. 2.Clean the surface of the rubber stopper with an antiseptic solution and allow it to dry. 3.Using an appropriate transfer device or syringe, transfer 50 mL of Sterile Water for Injection into the product vial. 4.Gently swirl the product vial to ensure the product is fully dissolved. Do not shake the vial. After reconstitution, the RiaSTAP solution should be colorless and clear to slightly opalescent. Inspect visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates. Discard partially used vials. RiaSTAP is stable for 8 hours after reconstitution when stored at 20-25°C; administer within this time period. 2.3 Administration Do not mix RiaSTAP with other medicinal products or intravenous solutions. Administer through a separate injection site. Use aseptic technique when administering RiaSTAP. Administer RiaSTAP at room temperature by slow intravenous injection at a rate not exceeding 5 mL per minute. 3 DOSAGE FORMS AND STRENGTHS RiaSTAP is available as a single-use vial containing 900 mg to 1300 mg lyophilized fibrinogen concentrate powder for reconstitution with 50 mL of Sterile Water for Injection. The actual fibrinogen potency for each lot is printed on the vial label and carton. 4 CONTRAINDICATIONS RiaSTAP is contraindicated in patients with known anaphylactic or severe systemic reactions to human plasma-derived products [see Description (11)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Allergic reactions may occur. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension) occur, immediately discontinue administration [see Patient Counseling Information (17)]. The treatment required depends on the nature and severity of the reaction. 5.2 Thrombosis Thrombosis may occur spontaneously in patients with congenital fibrinogen deficiency with or without the use of fibrinogen replacement therapy.1 Thromboembolic events have been reported in patients treated with RiaSTAP. Weigh the benefits of RiaSTAP administration versus the risk of thrombosis. Monitor patients receiving RiaSTAP for signs and symptoms of thrombosis [see Patient Counseling Information (17)]. 5.3 Transmissible Infectious Agents RiaSTAP is made from human plasma. Products made from human plasma may contain infectious agents (e.g., viruses and theoretically the Creutzfeldt-Jakob disease agent [CJD]) that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by a process demonstrated to inactivate and/or remove certain viruses during manufacturing [see Description (11)]. Despite these measures, such products may still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products [see Patient Counseling Information (17)]. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring Pharmacovigilance at 1-866-915-6958. 6 ADVERSE REACTIONS The most serious adverse reactions reported in clinical studies or through postmarketing surveillance following RiaSTAP treatment are thromboembolic episodes, including myocardial infarction, pulmonary embolism, deep vein thrombosis, arterial thrombosis, and allergic-anaphylactic reactions. The most common adverse reactions observed in more than one subject in clinical studies (frequency >1%) were fever and headache. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. 6.2 Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. The following adverse reactions, identified by system organ class, have shown a possible causal relationship with RiaSTAP. Allergic-anaphylactic reactions: anaphylaxis, dyspnea, rash Cardiovascular: thromboembolic complications such as myocardial infarction, pulmonary embolism, and deep vein thrombosis [see Warnings and Precautions (5.2)] General/Body as a Whole: chills, nausea, vomiting 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no studies of RiaSTAP use in pregnant women. Animal reproduction studies have not been conducted with RiaSTAP. It is not known whether RiaSTAP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RiaSTAP should be used during pregnancy only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 8.2 Lactation Risk Summary There is no information regarding the presence of RiaSTAP 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 RiaSTAP and any potential adverse effects on the breastfed infant from RiaSTAP or from the underlying maternal condition. 8.4 Pediatric Use RiaSTAP studies have included subjects below the age of 16 years. In the pharmacokinetic study [see Clinical Pharmacology (12.3)], 2 children aged 8 and 11 years and 3 adolescents aged 12, 14 and 16 years were studied. Subjects <16 years of age (n = 4) had shorter half-life (69.9 ± 8.5 h) and faster clearance (0.7 ± 0.1 mg/L) compared with adults (half-life: 82.3 ± 20.0 h, clearance: 0.53 ± 0.1 mg/L). The number of subjects <16 years of age in this study limits statistical interpretation. 8.5 Geriatric Use The safety and efficacy of RiaSTAP in the geriatric population has not been studied. There were an insufficient number of subjects in this age group to determine whether they respond differently from younger subjects. 11 DESCRIPTION RiaSTAP is a sterile, heat-treated, lyophilized fibrinogen (coagulation factor I) concentrate powder manufactured from pooled human plasma. Fibrinogen (factor I) is a soluble plasma glycoprotein with a molecular weight of about 340 kDa. The native molecule is a dimer and consists of three pairs of polypeptide chains (Aα, Bβ and γ). Fibrinogen is a physiological substrate of three enzymes: thrombin, factor XIIIa, and plasmin. Each vial contains 900 to 1300 mg fibrinogen, 400 to 700 mg human albumin, 375 to 660 mg L-arginine hydrochloride, 200 to 350 mg sodium chloride and 50 to 100 mg sodium citrate. Sodium hydroxide and hydrochloric acid may have been used to adjust the pH. The pH of the reconstituted RiaSTAP is in a range of 6.5 to 7.5. Viral Clearance All plasma used in the manufacture of RiaSTAP is tested using serological assays for hepatitis B surface antigen and for antibodies to Human Immunodeficiency Virus (HIV)-1/2 and Hepatitis C Virus (HCV). As an additional safety measure, the plasma is tested with Nucleic Acid Testing (NAT) for Hepatitis B Virus (HBV), HCV and HIV-1 and found to be non-reactive (negative). The plasma is also screened for Hepatitis A Virus (HAV) and Human Parvovirus B19 (B19V) by NAT. Only plasma that passed virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU of B19V DNA per mL. RiaSTAP is manufactured from cryoprecipitate into a glycine precipitate, which is then further purified by multiple precipitation/adsorption steps. The manufacturing process has been demonstrated to reduce the risk of virus transmission in an additive manner: cryoprecipitation, heat treatment (+60ºC for 20 hours in an aqueous solution), two subsequent glycine precipitation steps (initial and main glycine precipitation steps), and lyophilization. These steps have been validated independently in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses. The results of virus clearance validation studies for RiaSTAP manufacturing process are summarized in Table 1. Table 3: Cumulative (Log10) Virus Reduction Factors for RiaSTAP Manufacturing Step Virus Reduction Factor (log10) Enveloped viruses Non-enveloped viruses HIV BVDV WNV PRV HAV CPV Studies using human parvovirus B19, which are considered experimental in nature, have demonstrated a virus reduction factor of ≥4.5 log10 by heat treatment n.d. not determined Cryoprecipitation n.d. n.d. n.d. 1.6 n.d. 1.9 Heat Treatment ≥5.7 ≥9.1 ≥8.3 5.4 5.9 1.4 Glycine precipitations (two subsequent steps) 3.9 2.1 n.d. 1.8 1.0 1.6 Lyophilization n.d. n.d. n.d. n.d. 1.7 n.d. Cumulative virus reduction (log10) ≥9.6 ≥11.2 ≥8.3 8.8 8.6 4.9 HIV, human immunodeficiency virus, a model for HIV-1 and HIV-2 BVDV, bovine viral diarrhea virus, a model for Hepatitis C virus (HCV) and West Nile Virus (WNV) WNV, West Nile virus PRV, Pseudorabies virus, a model for large enveloped DNA viruses HAV, Hepatitis A virus CPV, canine parvovirus, a model for B19V  12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action During the coagulation process, thrombin cleaves the Aα and Bβ chains releasing fibrinopeptides A and B (FPA and FPB, respectively).2 FPA is separated rapidly and the remaining molecule is a soluble fibrin monomer (fibrin I). The slower removal of FPB results in formation of fibrin II that is capable of polymerization that occurs by aggregation of fibrin monomers.2 The resulting fibrin is stabilized in the presence of calcium ions and by activated factor XIII, which acts as a transglutaminase. Factor XIIIa-induced cross-linking of fibrin polymers renders the fibrin clot more elastic and more resistant to fibrinolysis.3 Cross-linked fibrin is the end result of the coagulation cascade, and provides tensile strength to a primary hemostatic platelet plug and structure to the vessel wall. 12.2 Pharmacodynamic Action Administration of RiaSTAP to patients with congenital fibrinogen deficiency replaces missing or low levels of coagulation factor. Normal levels are in the range of 200 to 450 mg/dL.4 12.3 Pharmacokinetics A prospective, open label, uncontrolled, multicenter pharmacokinetic study was conducted in 5 females and 9 males with congenital fibrinogen deficiency (afibrinogenemia), ranging in age from 8 to 61 years (2 children, 3 adolescents, 9 adults). Each subject received a single intravenous dose of 70 mg/kg RiaSTAP. Blood samples were collected to determine fibrinogen activity at baseline and up to 14 days after infusion. The pharmacokinetic parameters of RiaSTAP are summarized in Table 2. No statistically relevant difference in fibrinogen activity was observed between males and females. Subjects <16 years of age (n=4) had shorter half-life (69.9 ± 8.5 h) and faster clearance (0.73 ± 0.14 mg/L) compared with subjects ≥16 years of age (half-life of 82.5 ± 20.0 h and clearance of 0.53 ± 0.07 mg/L). The number of subjects <16 years of age in this study limits statistical interpretation. The incremental in vivo recovery (IVR) was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was 1.7 mg/dL (range 1.30 – 2.73 mg/dL) increase per mg/kg. The median in vivo recovery indicates that a dose of 70 mg/kg will increase fibrinogen plasma concentration in patients by approximately 120 mg/dL. The pharmacokinetic analysis using fibrinogen antigen data (ELISA) was concordant with the fibrinogen activity (Clauss assay). Table 2. Pharmacokinetic Parameters (n=14) for Fibrinogen Activity Parameters   Mean ± SD (range) Half-life [hours] 78.7 ± 18.13 (55.73-117.26) Cmax [mg/dL] 140 ± 27 (100-210) AUC for dose of 70 mg/kg [mg*hr/mL] 124.3 ± 24.16 (81.73-156.40) Clearance [mL/h/kg] 0.59 ± 0.13 (0.45-0.86) Mean residence time [hours] 92.8 ± 20.11 (66.14-126.44) Volume of distribution at steady state [mL/kg] 52.7 ± 7.48 (36.22-67.67) 14 CLINICAL STUDIES The efficacy of RiaSTAP is based on maximum clot firmness, a measure of clot structural integrity that reflects the underlying effectiveness of the fibrinogen present to form a fibrin clot. A pharmacokinetic study evaluated single-dose PK [see Clinical Pharmacology (12.3)] and maximum clot firmness (MCF) in subjects with afibrinogenemia. MCF was determined by thromboelastometry (ROTEM) testing and was used to demonstrate functional activity of replacement fibrinogen when a fixed dose of RiaSTAP was administered. Clot firmness is a functional parameter that depends on activation of coagulation, fibrinogen content of the sample and polymerization/crosslinking of the fibrin network. Thromboelastometry has been shown to be a functional marker for assessment of fibrinogen content and for effects of fibrinogen supplementation on clinical efficacy.5 For each subject, MCF was determined before (baseline) and one hour after single dose administration of RiaSTAP. RiaSTAP was found to be effective in increasing clot firmness in subjects with congenital fibrinogen deficiency (afibrinogenemia) as measured by thromboelastometry. The study results demonstrated that MCF values were significantly higher after administration of RiaSTAP than at baseline (see Table 3). Mean change from pre-infusion to 1 hour post-infusion was 8.9 mm in the primary analysis (9.9 mm for subjects <16years old and 8.5 mm for subjects ≥16 to <65 years old). Mean change in MCF values closely approximated levels expected from adding known amounts of fibrinogen to plasma in vitro.6 Table 3. MCF [mm] (ITT population)  Time point n Mean ± SD Median (range) MCF = maximum clot firmness; mm = millimeter; ITT = intention-to-treat. Pre-infusion 13 0 ± 0 0 (0-0) 1 hour post-infusion 13 10.3 ± 2.7 10.0 (6.5-16.5) Mean change (primary analysis)* 15† 8.9 ± 4.4 9.5 (0-16.5) p-value was <0.0001. The mean change was set to 0 for 2 subjects with missing MCF data.   15 REFERENCES 1.Peyvandi F, Haertal S, Knaub S, et al. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost 2006; 4:1634-7. 2.Kreuz W, Meili E, Peter-Salonen K, et al. Pharmacokinetic properties of a pasteurized fibrinogen concentrate. Transfusion and Apheresis Science 2005; 32:239-46. 3.Colman R, Clowes A, George J, et al. Overview of Hemostasis. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice (5th ed.). Colman R, Clowes A, George J, Goldhaber S, Marder VJ (eds.). Lippincott Williams & Wilkins, Philadelphia 2006:11-14. 4.Kreuz W, Meili E, Peter-Salonen K, et al. Efficacy and tolerability of a pasteurized human fibrinogen concentrate in patients with congenital fibrinogen deficiency. Transfusion and Apheresis Science 2005; 32:247-253. 5.Fries D, Innerhofer P, Reif C, et al. The Effect of Fibrinogen Substitution on Reversal of Dilutional Coagulopathy: An In Vitro Model. Anesth Analg 2006; 102:347-351. 6.Kalina U, Stöhr HA, Bickhard H, et. al. Rotational thromboelastography for monitoring of fibrinogen concentrate therapy in fibrinogen deficiency. Blood Coagulation and Fibrinolysis. 2008; 19:777-783. 16 HOW SUPPLIED/STORAGE AND HANDLING RiaSTAP is supplied in a single-use vial. Each carton contains one vial of RiaSTAP. Components are not made with natural rubber latex. RiaSTAP contains no preservative. The actual potency of fibrinogen concentrate in milligram (mg) is stated on each RiaSTAP vial label and carton. The product presentation includes a package insert and the following component: Presentation Carton NDC Number Component 900-1300 mg 63833-891-51 RiaSTAP in a single-use vial (NDC 63833-891-90) When stored at temperatures of 2-25°C (36-77°F), RiaSTAP is stable for the period indicated by the expiration date on the carton and vial label (up to 60 months). Do not use RiaSTAP beyond the expiration date. Keep RiaSTAP in its original carton until ready to use. Do not freeze. Protect from light. 17 PATIENT COUNSELING INFORMATION Allergic Reactions Inform patients of the early signs of allergic or hypersensitivity reactions to RiaSTAP, including hives, chest tightness, wheezing, hypotension, and anaphylaxis. Advise them to notify their physician immediately if they experience any of these symptoms [see Warnings and Precautions (5.1)]. Thrombosis Inform patients that thrombosis with or without embolization has been reported with the use of RiaSTAP. Any symptoms of thrombotic events such as unexplained pleuritic, chest and/or leg pain or edema, hemoptysis, dyspnea, tachypnea or unexplained neurologic symptoms should be reported to their physician immediately [see Warnings and Precautions (5.2)]. Transmissible Infectious Agents Inform patients that RiaSTAP is made from human plasma (part of the blood) and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Explain that the risk of transmitting an infection agent using RiaSTAP has been reduced by screening plasma donors, testing the donated plasma for certain virus infections, and incorporating a process demonstrated to inactivate and/or remove certain viruses during manufacturing. Symptoms of possible virus infection include headache, fever, nausea, vomiting, weakness, malaise, diarrhea, or, in the case of hepatitis, jaundice [see Warnings and Precautions (5.3)]. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=903dc8d0-39da-462c-9dac-004e0c7a26cc