2015年10月20日，美国食品和药品监管局（FDA）批准Coagadex，凝血因子X （人），为遗传性因子X （10）缺乏。直至今天的孤儿药物批准，对有遗传性因子X缺乏患者不能得到特异性凝血因子替代治疗。
在健康个体中，因子X蛋白活化帮助机体内正常血液凝固的酶。因子X缺乏是一致遗传病，等同地影响男性和妇女，其中血液不能凝固。有此病患者通常用新鲜-冰冻血浆或血浆-来源凝血酶原复合物浓缩物（含维生素K-依赖蛋白组合的血浆产品）以停止或预防出血。纯制的因子X浓缩物的可供利用性对有这个罕见出血病患者增加治疗选择。
FDA的生物制品评价和研究中心主任Karen Midthun，M.D.说：“Coagadex的批准对患有这个罕见但严重疾病患者是一个重要进展。”
Coagadex，是来自人血浆，是适用为年龄12和以上有遗传性因子X缺乏为按需治疗和出血发作的控制个体，和为在有轻度遗传性因子X缺乏患者围手术（从为手术住院时间延伸至出院时间的阶段）出血的处理。
在一项多-中心，非-随机化研究涉及16例参加者（208次出血发作）对自发性，创伤性和大量经期（月经过多）出血发作的治疗中评价Coagadex的安全性和疗效。Coagadex被证实是有中度至严重遗传性因子X缺乏参加者中有效控制出血发作。还在5例正在进行手术有轻度至严重因子X缺乏参加者评价Coagadex。5例个体接受Coagadex为围手术处理7次外科手术。 Coagadex被证实是有效地控制有轻度缺乏参加者手术期间和手术后失血。没有中度或严重因子X缺乏个体为重大手术的围手术处理接受Coagadex，而在任何一个研究都没有确定安全性关注问题。
FDA授权Coagadex对这些使用孤儿产品指定。孤儿产品指定是给予意向治疗罕见病为了促进它们的发展。Coagadex还被授权快速通道指定和优先审评。
Coagadex是由联合王国Hertfordshire，Elstree的Bio Products Laboratory Limited制造
批准日期：2015年10月20日；公司：Bio Products Laboratory有限公司
COAGADEX®(凝血因子X(人)凝血因子X(人))
——为静脉注射溶液冰冻干燥粉
适应证和用途
COAGADEX，凝血因子X(人)，是一种血浆来源人血凝血因子适用在成年和儿童(年龄12岁和以上)有遗传因子X缺乏为：
• 按需治疗和出血发作的控制
• 有轻度遗传性因子X缺乏患者中出血的围手术处理.
使用的限制
未曽在有中度和严重遗传性因子X缺乏患者研究重大手术出血的围手术处理。
剂量和给药方法
只为重建后静脉使用
⑴ 每小瓶COAGADEX含以国际单位(IU)的标记量因子X。
⑵ 治疗的剂量和时间依赖于因子X缺乏的严重程度，出血的位置和程度和患者的临床情况。
⑶ 为出血发作的治疗：每kg体重使用25IU，间隔24小时重复直至出血停止。
⑷ 为围手术处理：
① 手术前，升高血浆因子X水平至70-90IU/dL。
② 手术后，维持血浆因子X水平在最低50IU/dL直至患者不再处于由于手术出血风险。
③ 所需剂量(IU) =体重(kg)×想要因子X升高(IU/dL或正常的%)×0.5
剂型和规格
COAGADEX是可得到为冰冻干燥粉为重建在一次性使用小瓶含名义上(约) 250IU或500 IU的因子X活性。当用药盒供应的无菌注射用水重建，最终浓度是约100IU/mL。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use COAGADEX ® safely and effectively. See full prescribing information for COAGADEX ®.
COAGADEX ® (Coagulation Factor X (Human))
Lyophilized Powder for Solution for Intravenous Injection
Initial U.S. Approval: [2015]
INDICATIONS AND USAGE
COAGADEX, Coagulation Factor X (Human), is a plasma-derived human blood coagulation factor indicated in adults and children (aged 12 years and above) with hereditary Factor X deficiency for:
On-demand treatment and control of bleeding episodes (1)
Perioperative management of bleeding in patients with mild hereditary Factor X deficiency (1).
Limitation of Use
Perioperative management of bleeding in major surgery in patients with moderate and severe hereditary Factor X deficiency has not been studied.
DOSAGE AND ADMINISTRATION
For intravenous use only after reconstitution.
Each vial of COAGADEX contains the labeled amount of Factor X in international units (IU) (2).
The dosage and duration of treatment depend on the severity of the Factor X deficiency, on the location and extent of the bleeding and on the patient's clinical condition (2.1).
For treatment of bleeding episodes: use 25 IU per kg body weight, repeated at intervals of 24 hours until the bleed stops (2.1).
For perioperative management:
Pre-surgery, raise plasma Factor X levels to 70-90 IU/dL.
Post-surgery, maintain plasma Factor X levels at a minimum of 50 IU/dL until the patient is no longer at risk of bleeding due to surgery.
Required dose (IU) = Body weight (kg) × Desired Factor X rise (IU/dL or % of normal) × 0.5
DOSAGE FORMS AND STRENGTHS
COAGADEX is available as a lyophilized powder for reconstitution in single-use vials containing nominally (approximately) 250 IU or 500 IU of Factor X activity. When reconstituted using the Sterile Water for Injection supplied with the kit, the final concentration is approximately 100 IU/mL (3).
CONTRAINDICATIONS
Do not use in patients who have had life-threatening hypersensitivity reactions to COAGADEX or any of the components (4).
WARNINGS AND PRECAUTIONS
Hypersensitivity reactions, including anaphylaxis, are possible. Should symptoms occur, discontinue COAGADEX and administer appropriate treatment (5.1).
Development of neutralizing antibodies (inhibitors) may occur. If expected plasma Factor X activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures Factor X inhibitor concentration (5.2).
COAGADEX is made from human blood and therefore carries a risk of transmitting infectious agents, e.g. viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob Disease (CJD) agent (5.4).
ADVERSE REACTIONS
The most common adverse drug reactions (frequency ≥ 5% of subjects) observed in clinical trials were infusion site erythema, infusion site pain, fatigue and back pain (6).
To report SUSPECTED ADVERSE REACTIONS, contact BPL Inc, at 1-866-398-0825 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 10/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
COAGADEX, Coagulation Factor X (Human), is a plasma-derived human blood coagulation Factor indicated in adults and children (aged 12 years and above) with hereditary Factor X deficiency for:
On-demand treatment and control of bleeding episodes
Perioperative management of bleeding in patients with mild hereditary Factor X deficiency.
Limitation of Use
Perioperative management of bleeding in major surgery in patients with moderate and severe hereditary Factor X deficiency has not been studied.
2 DOSAGE AND ADMINISTRATION
For intravenous use after reconstitution only.
2.1 Dose
Dose and duration of the treatment depend on the severity of the Factor X deficiency, location and extent of the bleeding, and on the patient's clinical condition.
Base the dose and frequency on the individual clinical response. Do not administer more than 60 IU/kg daily.
Each vial of COAGADEX is labeled with the actual Factor X potency/content in International Units (IU).
Estimate the expected in vivo peak increase in Factor X level expressed as IU/dL (or % of normal) using the following formula:
Estimated Increment of Factor X (IU/dL or % of normal) = [Total Dose (IU)/Body Weight (kg)] × 2
The dose to achieve a desired in vivo peak increase in Factor X level may be calculated using the following formula:
Dose (IU) = Body Weight (kg) × Desired Factor X Rise (IU/dL) × 0.5
Note: The desired Factor X rise is the difference between the patient's plasma Factor X level and the desired level. The dosing formula is based on the observed recovery of 2 IU/dL per IU/kg.
On-demand Treatment and Control of Bleeding Episodes
Infuse 25 IU/kg of COAGADEX when the first sign of bleeding occurs. Repeat at intervals of 24 hours until the bleed stops.
Perioperative Management of Bleeding
Measure post-infusion plasma Factor X levels for each patient before and after surgery, to ensure that hemostatic levels are obtained and maintained.
Pre-surgery: Calculate the dose of COAGADEX to raise plasma Factor X levels to 70-90 IU/dL using the following formula:
Required dose (IU) = Body Weight (kg) × Desired Factor X Rise (IU/dL) × 0.5
Post-surgery: Repeat dose as necessary to maintain plasma Factor X levels at a minimum of 50 IU/dL until the patient is no longer at risk of bleeding due to surgery.
2.2 Preparation and Reconstitution
The procedures below are provided as general guidelines for the preparation and reconstitution of COAGADEX.
Always work on a clean surface and wash your hands before performing the following procedures.
To reconstitute, use the diluent (Sterile Water for Injection) and transfer device (Mix2Vial) provided in the COAGADEX carton.
To administer, you will also need a syringe and suitable needle (not provided in the COAGADEX carton).
Bring the vials of COAGADEX and the Sterile Water for Injection to room temperature before mixing.
The reconstitution is performed as follows:
Table 1 COAGADEX Reconstitution Instructions  
Step 1

Remove the cap from the vial of COAGADEX and clean the top of the rubber stopper with an alcohol swab (not supplied) and allow to dry prior to opening the Mix2Vial package.
Repeat this step with the vial of sterile water.
Step 2
Peel back the top of the Mix2Vial package. Do not remove the device from the package.
Step 3

Place the blue end of the Mix2Vial over the water vial and push straight down until the spike penetrates the rubber stopper and snaps into place.
Remove the plastic outer packaging from the Mix2Vial and discard it. Do not touch the exposed end of the device.
Step 4

With the COAGADEX vial placed on a flat surface, invert the water vial with the Mix2Vial device still attached.
Place the clear end of the Mix2Vial on the product vial and push straight down until the spike penetrates the rubber stopper and snaps into place.
The water will automatically transfer into the COAGADEX vial by the vacuum contained within it. Do not use if the water is not pulled into the vial of COAGADEX.
Step 5

Gently swirl the COAGADEX vial to make sure that the powder is fully dissolved. Do not shake the vial.
The reconstituted solution should be clear or a slightly pearl-like solution. Do not use if particulate matter or discoloration is observed and contact BPL.
Step 6
Separate the empty water vial and blue part of the Mix2Vial from the clear part that is attached to the COAGADEX vial by unscrewing counter-clockwise.

Step 7
Draw air into an empty, sterile syringe (not supplied) by pulling the plunger to the volume of water added.
Connect the syringe to the clear part of the Mix2Vial and push the air in the syringe into the vial.
Step 8

Immediately invert the COAGADEX vial. The solution will automatically be drawn into the syringe. Draw the remaining solution into the syringe by pulling the plunger back slowly.
Disconnect the filled syringe from the device.
Use the product immediately after reconstitution. Do not store the reconstituted product.
2.3 Administration
For intravenous administration only
If the dose requires more than one vial of COAGADEX:
Reconstitute each vial (steps 1 to 5) using a new Mix2Vial for each vial.
Draw up all the solution into a single syringe (steps 6 to 8).
Visually inspect the final solution for particulate matter and discoloration prior to administration, and whenever solution and container permit. Do not use if particulate matter or discoloration is observed.
Attach a suitable needle to the syringe.
Administer by intravenous infusion at a rate of 10 mL/min, but no more than 20 mL/min.
3 DOSAGE FORMS AND STRENGTHS
COAGADEX is available as lyophilized powder for reconstitution in single-use vials containing nominally (approximately) 250 IU or 500 IU of Factor X activity. The exact potency/content is listed on the vial label. When reconstituted using the Sterile Water for Injection supplied with the kit, the final concentration is approximately 100 IU per mL.
Factor X activity in COAGADEX is defined in IU and determined using an in vitro chromogenic assay and a Factor X concentrate reference standard calibrated against the World Health Organization (WHO) 3rd International Standard for Blood Coagulation Factors II and X, Concentrate.
4 CONTRAINDICATIONS(What is this?)
COAGADEX is contraindicated in patients who have had life-threatening hypersensitivity reactions to COAGADEX or any of the components [see Description (11)].
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Allergic type hypersensitivity reactions, including anaphylaxis, are possible. Early signs of hypersensitivity reactions including angioedema, infusion site inflammation (e.g. burning, stinging, erythema), chills, cough, dizziness, fever, flushing, generalized urticaria, headache, hives, hypotension, lethargy, musculoskeletal pains, nausea, pruritus, rash, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing. If hypersensitivity symptoms occur, discontinue use of the product immediately and administer appropriate emergency treatment.
COAGADEX contains traces of human proteins other than Factor X.
5.2 Neutralizing Antibodies
The formation of neutralizing antibodies (inhibitors) to Factor X may occur. Monitor all patients treated with COAGADEX for the development of inhibitors by appropriate clinical observations and laboratory tests. If expected Factor X activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures Factor X inhibitor concentration.
5.3 Transmissible Infectious Agents
As COAGADEX is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may be present in the product. The risk that the product will transmit viruses 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 inactivating and removing certain viruses during manufacture. Despite these measures, this product may still potentially transmit diseases.
All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare providers to BPL Inc. at 1-866-398-0825.
5.4 Monitoring and Laboratory Tests
Monitor plasma Factor X activity by performing a validated test (e.g. one-stage clotting assay), to confirm that adequate Factor X levels have been achieved and maintained [see Dosage and Administration (2)].
Monitor for the development of Factor X inhibitors. Perform a Nijmegen-Bethesda inhibitor assay if expected Factor X plasma levels are not attained, or if bleeding is not controlled with the expected dose of COAGADEX. Use Nijmegen-Bethesda Units (BU) to report inhibitor levels.
6 ADVERSE REACTIONS
The most common adverse drug reactions (frequency ≥ 5% of subjects) observed in clinical trials were infusion site erythema, infusion site pain, fatigue, and back pain.
6.1 Clinical Trials Experience
As clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in clinical practice.
During the clinical development of COAGADEX involving two multicenter, open-label, non-randomized clinical studies, 18 individual subjects with hereditary Factor X deficiency received at least one dose of COAGADEX.
Sixteen subjects aged 12 to 58 years with moderate to severe hereditary Factor X deficiency (basal FX:C < 5 IU/dL) received doses of COAGADEX for pharmacokinetic evaluation, on-demand treatment and control of bleeding episodes, and/or perioperative management of minor surgical or dental procedures. A total of 468 infusions were administered, including 242 for on-demand treatment and control of bleeding episodes, 6 for perioperative management and 31 for PK assessments. Spontaneous, traumatic and menorrhagic bleeding episodes were treated with an on-demand dose of 25 IU/kg for up to 2 years.
Two subjects aged 55 and 59 years with mild hereditary Factor X deficiency (basal FX:C 6 IU/dL and 8 IU/dL) received COAGADEX for perioperative management of four major surgical procedures. There were 40 exposure days to COAGADEX.
Six adverse reactions were reported in 2 of the 18 subjects. These were infusion site erythema (2 reports in 1 subject [5.6%]), fatigue (2 reports in 1 subject [5.6%]), back pain (1 report [5.6%]) and infusion site pain (1 report [5.6%]).
6.2 Immunogenicity
All subjects underwent Factor X inhibitor testing (inhibitor screen and Nijmegen-Bethesda assay) at baseline, end of study and at 3-monthly intervals in between. For subjects who underwent surgery, inhibitor testing was done pre-surgery and on discharge. All inhibitor tests were negative. Additionally, comparison of pharmacokinetic (PK) parameters at the repeat PK assessment with those at first dose did not suggest development of any inhibitors to Factor X.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to COAGADEX in the studies described above with the incidence of antibodies in other studies or to other products.
7 DRUG INTERACTIONS
Drug interaction studies have not been performed. Use with caution in patients who are receiving other plasma products that may contain Factor X, (e.g. fresh frozen plasma, prothrombin complex concentrates). Based on the mechanism of action, COAGADEX is likely to be counteracted by direct and indirect Factor Xa inhibitors [see Clinical Pharmacology (12.1)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no data with COAGADEX use in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted using COAGADEX. It is not known whether COAGADEX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. COAGADEX should be given to a pregnant woman 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 COAGADEX in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for COAGADEX and any potential adverse effects on the breast-fed infant from COAGADEX or from the underlying maternal condition.
8.4 Pediatric Use
Safety and efficacy in patients under the age of 12 years have not been studied.
8.5 Geriatric Use
Clinical studies of COAGADEX did not include any subjects aged 65 and over to determine whether they respond differently from younger subjects. Individualize dose selection for geriatric patients.
10 OVERDOSAGE
One case of accidental overdosage was reported in the clinical trials, in which a subject received approximately 80 IU/kg Factor X to treat a bleed. No adverse events were reported relating to this overdose.
11 DESCRIPTION
COAGADEX is a plasma-derived, sterile, purified concentrate of human coagulation Factor X that contains sucrose as a stabilizer. It is formulated as a lyophilized powder for solution for intravenous administration. When reconstituted with Sterile Water for Injection, COAGADEX contains nominally (approximately) 100 IU/mL of coagulation Factor X and the following inactive ingredients: chloride, phosphate, citrate, sucrose and sodium. Each vial of COAGADEX is labeled with the actual Factor X activity/content expressed in IU per vial. Factor X activity in IU is determined using an in vitro chromogenic assay and a Factor X concentrate reference standard calibrated against the WHO 3rd International Standard for Blood Coagulation Factors II and X, Concentrate.
COAGADEX contains no added biological components such as heparin, albumin or anti-thrombin. The content of Factor II and Factor IX are ≤ 1 IU/mL of the reconstituted product. Factor Xa and Factor IIa were not detectable by Non-activated Partial Thromboplastin Time (NaPTT) or Fibrinogen Clotting Time (FCT) tests for potential thrombogenicity, and comprised < 10 parts per million by weight when tested by more sensitive analytical methods. The specific activity of COAGADEX is typically 80-137 IU per mg protein. The product contains no preservatives.
COAGADEX is manufactured from plasma, obtained from healthy US donors, who have passed viral screening tests. All donors are subjected to medical examinations, laboratory tests, and a review of their medical history before being allowed to donate blood or plasma.
All plasma donations are screened for antibody to human immunodeficiency virus (HIV)-1/2 and hepatitis C virus (HCV), and hepatitis B surface antigen (HBsAg). Additional testing of donations is carried out in plasma mini-pools (512 donations per pool) with nucleic acid amplification testing (NAT) for HIV, hepatitis B virus (HBV), HCV, hepatitis A virus (HAV) and human parvovirus B19. Furthermore, each manufacturing pool is tested to be negative for HBsAg and anti-HIV-1/2 antibodies. Also, manufacturing pools are non-reactive by nucleic acid test for HAV, HBV, HCV, and HIV-1. The limit for human parvovirus B19 in the manufacturing pools is set not to exceed 104 IU/mL.
Three processing steps specifically designed to remove or inactivate viruses are:
1) Solvent/detergent treatment targeted to inactivate enveloped viruses;
2) A 15-nm filtration step designed to remove small viruses including non-enveloped viruses; and
3) Terminal dry-heat treatment at 80°C for 72 hours in the final container to inactivate enveloped and non-enveloped viruses.
The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled-down process model. Overall virus reduction was calculated only from steps that were mechanistically independent from each other. Table 2 presents the contribution of each process step to virus reduction and the overall process reduction.
Table 2 Viral Reduction by Process Step

Process Log10 Reduction of Virus (LRV) over manufacturing step
Virus	Type (Envelope/ Genome)	Size (nm)	Solvent/ detergent	15-nm filtration	Terminal dry-heat treatment	Total LRV
HIV	Env/RNA	80-100	> 4.6	> 6.8	5.5	> 16.9
SIN	Env/RNA	60-70	6.0	NT	NT	6.0
BVDV	Env/RNA	50-70	> 5.1	> 4.5	> 5.2	> 14.8
HSV	Env/DNA	120-200	> 5.4	5.8	3.5	> 14.7
IBR	Env/DNA	120-200	> 5.3	NT	NT	> 5.3
WNV	Env/RNA	40-60	4.9	NT	NT	4.9
HAV	Non-Env/RNA	25-30	NA	> 5.0	> 6.1	> 11.1
CPV	Non-Env/RNA	18-24	NA	4.3*	4.2	8.5

Studies using human parvovirus B19, which are considered experimental in nature, have demonstrated a virus reduction factor of > 5.9 log 10 by 15-nm filtration using a PCR method

HIV:	Human immunodeficiency virus
SIN:	Sindbis virus, model for HCV
WNV:	West Nile Virus
BVDV:	Bovine viral diarrhea virus, model for HCV
IBR:	Infectious bovine rhinotracheitis, bovine herpesvirus model for enveloped DNA viruses including HBV
HAV:	Hepatitis A virus
HSV:	Herpes simplex virus
CPV:	Canine parvovirus, model for human parvovirus B19
NA:	Not applicable, solvent/detergent treatment step is limited to the inactivation of enveloped viruses
NT:	Not tested

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
COAGADEX temporarily replaces the missing Factor X needed for effective hemostasis. Factor X is an inactive zymogen, which can be activated by Factor IXa (via the intrinsic pathway) or by Factor VIIa (via the extrinsic pathway). Factor X is converted from its inactive form to the active form (Factor Xa) by the cleavage of a 52-residue peptide from the heavy chain. Factor Xa associates with Factor Va on a phospholipid surface to form the prothrombinase complex, which activates prothrombin to thrombin in the presence of calcium ions. Thrombin then acts upon soluble fibrinogen and Factor XIII to generate a cross-linked fibrin clot.
12.2 Pharmacodynamics
The administration of COAGADEX increases plasma levels of Factor X and can temporarily correct the coagulation defect in these patients, as reflected by decrease in the aPTT and PT.
12.3 Pharmacokinetics
In a clinical study of COAGADEX in subjects with severe or moderate Factor X deficiency (basal FX:C <5 IU/dL), the pharmacokinetics of COAGADEX were assessed after intravenous infusion (mean [range] infusion rate 5.9 [1.3-17.1] mL/min) of 25 IU/kg COAGADEX. Pharmacokinetic (PK) parameters were calculated from plasma Factor X:C activity measurements after subtraction of the pre-dose value. The PK assessment was repeated at least 6 months after the first dose. The PK parameters following a single dose are summarized in Table 3. The pharmacokinetics of COAGADEX were similar following the single and repeat dosing.
Table 3 Mean PK Parameters of COAGADEX Following a Single 25 IU/kg Dose

First Dose Mean (CV%) (n=16)
CV: Coefficiant of variation
Cmax (IU/mL)	0.504 (17.2)
Half-life (hr)	30.3 (22.8)
AUC0-144h (IU.hr/mL)	17.1 (21.0)
AUC(0-∞) (IU.hr/mL)	18.0 (20.9)
Vss (mL/kg)	56.3 (24.0)
CL (mL/kg/hr)	1.35 (21.7)
MRT (hr)	41.8 (21.7)
Incremental recovery (IU/dL per IU/kg)*	2.08 (18.1)

* Using peak increment within 1 hour post-dose 
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Nonclinical studies evaluating the carcinogenic or mutagenic potential of COAGADEX have not been conducted. No animal studies regarding impairment of fertility following COAGADEX dosing were conducted; however, no macroscopic or microscopic pathologies in reproductive organs were observed in rats dosed every other day with 6 times the maximum recommended clinical dose of 60 IU/kg COAGADEX for 28 days.
14 CLINICAL STUDIES
On-demand Treatment and Control of Bleeding Episodes
In a multicenter, open-label, non-randomized clinical trial to evaluate the pharmacokinetics, safety and efficacy of COAGADEX, 16 subjects with moderate to severe hereditary Factor X deficiency (FX:C < 5 IU/dL) received a dose of 25 IU/kg COAGADEX to treat spontaneous, traumatic and menorrhagic bleeding episodes. If hemostasis was not achieved with a single dose of COAGADEX, additional doses could be given until the bleed stopped. Subjects could also continue with treatment after the bleed had stopped to reduce the risk of recurrence of a given bleed. Subjects were aged 12-58 years, including 6 pediatric subjects aged 12 to 17 years. Six subjects were male, 10 were female, and 12 were Caucasian.
The efficacy of COAGADEX in treating bleeding episodes was assessed by the subject and/or investigator for each new bleeding episode, using a bleed-specific ordinal rating scale of excellent, good, poor and unassessable. This rating scale was based on the number of infusions required to treat the bleed and the interval between infusions, and differed for each type of bleed (overt, covert or menorrhagic). Each bleed was reviewed by a Data Review Committee for its suitability for the efficacy evaluation. Of the 208 bleeding episodes treated with COAGADEX, 187 bleeding episodes in 15 subjects were evaluated for efficacy. Of these 187 bleeding episodes, 79 (42%) occurred spontaneously, 47 (25%) were traumatic and 61 (33%) were menorrhagic. Seventy three (39%) were mucosal in origin, 63 (34%) were joint bleeds, 26 (14%) were muscle bleeds, and 25 (13%) were located elsewhere.
Ninety eight (53%) were major bleeding episodes, and 88 (47%) were minor bleeds (one bleed not assessed). COAGADEX was considered to be good (7%) or excellent (91%) in treating 98% of bleeding episodes. Of the 187 bleeding episodes in the efficacy analysis, 155 bleeds (83%) were treated with one infusion, 28 bleeds (15%) with two infusions, 3 bleeds (2%) with three infusions and 1 bleed (0.5%) with four infusions. The mean dose per infusion and total dose of Coagadex were 25.4 IU/kg and 30.4 IU/kg, respectively. Four bleeding episodes in two subjects were considered treatment failures.
The recommended dose of 25 IU/kg COAGADEX to treat a bleed was maintained during the study for 14 of the 16 subjects. The other two subjects used doses up to 30 IU/kg and 33 IU/kg.
Perioperative Management of Bleeding
The safety and efficacy of COAGADEX for perioperative management was evaluated in five subjects aged 14-59 years with mild (n=2), moderate (n=1), and severe (n=2) disease, who underwent a total of seven surgical procedures.
For all surgical procedures, COAGADEX was assessed as excellent (no post-operative bleeding, no requirement of blood transfusions, and blood loss was no more than 'as expected') in controlling blood loss during and after surgery. For major surgeries, a median of 13 infusions (range 2 to 15 infusions) and a median cumulative dose of 181 IU/kg (range 45 to 210 IU/kg) were required to maintain hemostasis. For minor surgeries, a median of 2.5 infusions (range 1 to 4 infusions) and a median cumulative dose of 89 IU/kg (range 51 to 127 IU/kg) were required to maintain hemostasis.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
COAGADEX is supplied in single-use glass vials containing a nominal (approximate) 250 IU or 500 IU (approximately 100 IU/mL after reconstitution) of Factor X activity, packaged with 2.5 mL or 5 mL of Sterile Water for Injection, respectively, and a Mix2Vial transfer device.
The vials are closed with a synthetic rubber stopper. The stopper is secured with an aluminum overseal with a flip-off polypropylene cap.
Strength   Kit  NDC Number
250 IU   Range 64208-7752-1

500 IU   Range 64208-7753-1

Storage and Handling
Store COAGADEX in its original package to protect it from light.
Store the COAGADEX package in a refrigerator or at room temperature (36°F to 86°F). Do not freeze.
Do not use COAGADEX or the Sterile Water for Injection after the expiration date printed on the vial and carton labels.
Use reconstituted COAGADEX within one hour of reconstitution.
Do not use COAGADEX if the reconstituted solution is cloudy or contains any particles.
17 PATIENT COUNSELING INFORMATION
Advise the patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Inform patients to immediately report the following early signs and symptoms of hypersensitivity reactions to their healthcare professional: angioedema, infusion site inflammation (e.g. burning, stinging, erythema), chills, cough, dizziness, fever, flushing, generalized urticaria, headache, hives, hypotension, lethargy, musculoskeletal pains, nausea, pruritus, rash, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing [see Warnings and Precautions (5.1)].
Inform patients that the development of inhibitors to Factor X is a possible complication of treatment with COAGADEX. Advise the patients to contact their healthcare provider for further treatment and/or assessment if they experience a lack of clinical response to COAGADEX because this may be a manifestation of an inhibitor [see Warnings and Precautions (5.2)].
Inform patients that COAGADEX is made from human plasma and may contain infectious agents that can cause diseases. While the risk that COAGADEX can transmit an infection has been reduced by screening plasma donors for prior exposure, testing donated plasma, and inactivating or removing certain viruses during manufacturing, patients should report any symptoms that concern them [see Warnings and Precautions (5.3)].
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ad20e6ff-98bc-47e6-aa00-7fb441edd2b0&audience=consumer