2013年6月27日，美国食品药品管理局(FDA)已批准Rixubis［凝血因子Ⅸ（重组）］用于成年B型血友病患者的常规预防性治疗、出血发作控制和术前管理。B型血友病是第二常见的血友病类型，是血液中自然产生的一种控制出血的蛋白质——凝血因子Ⅸ数量不足造成的。据百特公司介绍，Rixubis是唯一一种同时囊括对此类患者的常规预防和出血发作控制适应证的重组因子Ⅸ。
这一批准令是基于一项Ⅰ/Ⅲ期研究的数据。该研究结果显示，每周2次使用Rixubis预防性治疗6个月，中位年出血率可达到2.0，43%的患者未发生出血。在这项研究中，无一患者产生对因子Ⅸ的抑制性抗体，且未报告有过敏病例。
临床研究中最常见的不良反应为味觉障碍、四肢疼痛和furin抗体阳性。
使用含因子Ⅸ的产品时，曾报告有发生超敏反应（包括过敏）的病例。早期过敏反应体征可进展为过敏，包括血管神经系统水肿、胸部压迫感、低血压、嗜睡、恶心、呕吐、感觉异常、烦躁不安、喘息和呼吸困难。
接受Rixubis治疗的患者可能产生对因子Ⅸ的中和抗体（抑制剂）。应通过适当的临床观察和实验室检测，定期评估患者是否产生因子Ⅸ抑制剂。如在使用预期剂量的情况下未达到预期的因子IX血浆活性水平，或出血未能控制，应进行测定因子Ⅸ抑制剂浓度的分析。产生因子Ⅸ抑制剂的患者如再次暴露于Rixubis，发生重度超敏反应的风险增高。
批准日期： 2013年6月26日；公司: Baxter International Inc.
RIXUBIS[凝血因子IX(重组)Coagulation factor IX(Recombinant)]
为静脉注射，为溶液冻干粉
美国初次批准：2013
适应证和用途
（1）在有血友病B成年中控制和预防出血发作。
（2）在有血友病B成年中围手术期处理。
（3） 在有血友病B成年中常规预防防止或减少出血发作频数。
RIXUBIS不适用于对诱发免疫耐受性有血友病B患者。
剂量和给药方法
只为配制重建后静脉使用。
控制和预防出血发作和围手术期处理：
每公斤体重1个国际单位RIXUBIS增加因子IX的循环活性0.9国际单位/dL。
初始剂量：
需要国际单位=体重(kg)×愿望因子IX增加(正常%或IU/dL)×观测到恢复倒数(IU/kg每IU/dL).
维持剂量依赖于出血或手术类型，止血挑战的强度，和直至实现伤口适当愈合天数。
常规预防:
每公斤体重40至60国际单位每周2次。
剂型和规格
可得到单次使用小瓶中含冰冻干燥粉RIXUBIS标称值250，500，1000，2000或3000国际单位。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use RIXUBIS safely and effectively. See full prescribing information for RIXUBIS. RIXUBIS [Coagulation Factor IX (Recombinant)]For Intravenous Injection, Lyophilized Powder for Solution
Initial U.S. Approval: 2013
RECENT MAJOR CHANGES
Warnings and Precautions (5.1) 01/2014
INDICATIONS AND USAGE
RIXUBIS (Coagulation Factor IX [Recombinant]) is an antihemophilic factor indicated for:
Control and prevention of bleeding episodes in adults with hemophilia B. (1)
Perioperative management in adults with hemophilia B. (1)
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults with hemophilia B. (1)
RIXUBIS is not indicated for induction of immune tolerance in patients with Hemophilia B.
DOSAGE AND ADMINISTRATION
For intravenous use after reconstitution only. (2)
Control and prevention of bleeding episodes and perioperative management:
One international unit of RIXUBIS per kg of body weight increases the circulating activity of factor IX by 0.9 international units/dL. (2.1)
Initial Dose:
Required international units = body weight (kg) x desired factor IX increase (% of normal or IU/dL) x reciprocal of observed recovery
(IU/kg per IU/dL). (2.1)
The maintenance dose depends on the type of bleed or surgery, the intensity of the hemostatic challenge, and number of days until adequate wound healing is achieved. (2.2)
Routine prophylaxis:
40 to 60 international units per kg twice weekly. (2.3)
DOSAGE FORMS AND STRENGTHS
RIXUBIS is available as a lyophilized powder in single-use vials containing nominally 250, 500, 1000, 2000 or 3000 international units. (3)
CONTRAINDICATIONS
Do not use in patients with:
Known hypersensitivity to RIXUBIS or its excipients including hamster protein. (4)
Disseminated intravascular coagulation (DIC). (4)
Signs of fibrinolysis. (4)
WARNINGS AND PRECAUTIONS
Hypersensitivity reactions have been reported with RIXUBIS. Anaphylaxis and other hypersensitivity reactions may occur. Should symptoms occur, discontinue RIXUBIS and administer appropriate treatment. Patients may also develop hypersensitivity to hamster (CHO) protein, which is present in trace amounts in the product. (5.1)
Development of neutralizing antibodies (inhibitors) to RIXUBIS may occur. If expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor IX inhibitor concentration. (5.2)
Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in hemophilia B patients with factor IX inhibitors. (5.3)
The use of factor IX containing products has been associated with the development of thromboembolic complications. (5.4)
ADVERSE REACTIONS
The most common adverse reactions observed in >1% of subjects in clinical studies were: dysgeusia, pain in extremity, and positive test for furin antibody. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Pregnancy: No human or animal data. Use only if clearly needed. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 2/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
RIXUBIS (Coagulation Factor IX [Recombinant]) is an antihemophilic factor indicated for:
Control and prevention of bleeding episodes in adults with hemophilia B.
Perioperative management in adults with hemophilia B.
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults with hemophilia B.
RIXUBIS is not indicated for induction of immune tolerance in patients with hemophilia B [see Warnings and Precautions (5.3)].
2 DOSAGE AND ADMINISTRATION
For intravenous use after reconstitution only.
Each vial of RIXUBIS has the recombinant Factor IX (rFIX) potency in international units stated on the vial.
Initiate treatment under the supervision of a physician experienced in the treatment of hemophilia.
Dosage and duration of treatment with RIXUBIS depend on the severity of factor IX deficiency, the location and extent of bleeding, the patient’s clinical condition, age, and pharmacokinetic parameters of factor IX, such as incremental recovery and half-life.
Dosing of RIXUBIS may differ from that of plasma-derived factor IX products [see Clinical Pharmacology (12)]. Subjects at the low end of the observed factor IX recovery range may require dose adjustment of RIXUBIS.
Monitor patients using a factor IX activity assay to ensure that the desired factor IX activity plasma level has been attained. If necessary, adjust the dose and the frequency of repeated infusions as appropriate.
Evaluate the patient for the development of factor IX inhibitors if the expected factor IX activity plasma levels are not attained or if bleeding is not controlled with an appropriate dose [see Warnings and Precautions (5.2)].
2.1 Dosing Guidelines
Calculating Initial Dose
The initial dose of RIXUBIS is calculated based on the empirical finding that one international unit of RIXUBIS per kg body weight is expected to increase the circulating level of factor IX by 0.9 international units/dL of plasma (0.9% of normal) in adult patients.
A guide for calculating the initial dose of RIXUBIS for treatment of bleeding episodes is as follows:
Initial Dose = body weight (kg) x desired factor IX increase (% of normal or IU/dL) x reciprocal of observed recovery (IU/kg per IU/dL)
Incremental Recovery in Previously Treated Patients (PTPs)
Base the calculation of the dose on the patient’s individual incremental recovery using serial factor IX activity assays, due to the wide range of inter-individual differences in incremental recovery. Titrate the dose based on the patient's clinical response and individual pharmacokinetics, in particular incremental recovery and half-life.
For an incremental recovery of 0.9 international units/dL of plasma (0.9% of normal), the dose is calculated as follows:
Dose (international units) = body weight (kg) x desired factor IX increase (% of normal or IU/dL) x 1.1 dL/kg
Examples (assuming patient’s baseline factor IX level is <1% of normal):
A dose of 4550 international units of RIXUBIS, administered to a 70 kg patient, should be expected to result in a peak post-infusion factor IX increase of 4550 international units x {[0.9 IU/dL]/[IU/kg]}/[70 kg] = 58.5 international units/dL (58.5 % of normal).
A peak level of 70% is required in a 60 kg patient. The appropriate dose would be 60 kg x 70 international units/dL/{[0.9 IU/dL]/[IU/kg]} = 4667 international units.
2.2 Control and Prevention of Bleeding Episodes and Perioperative Management
A guide for dosing RIXUBIS in the control and prevention of bleeding episodes and perioperative management is provided in Table 1 and Table 2, respectively. Ensure the factor IX activity level is achieved and maintained in the corresponding period.
Table 1 Dosing for Control and Prevention of Bleeding Episodes

Type of Bleeding Episodes	Circulating Factor IX Level Required (% or IU/dL)	Dosing Interval (hours)	Duration of Therapy (days)
Minor Uncomplicated hemarthrosis, superficial muscular or soft tissue	20-30	12-24	At least 1 day, until healing is achieved
Moderate Intramuscular or soft tissue with dissection, mucous membranes, hematuria	25-50	12-24	2-7 days, until bleeding stops and healing is achieved
Major Pharyngeal, retropharyngeal, retroperitoneal, CNS	50-100	12-24	7-10 days, until bleeding stops and healing is achieved

Adapted from Roberts and Eberst1
Table 2 Dosing for Perioperative Management

Type of Surgery	Circulating Factor IX Level Required (% or IU/dL)	Dosing Interval (hours)	Duration of Therapy (days)
Minor e.g., tooth extraction	30-60	24	At least 1 day, until healing is achieved
Major e.g., intracranial, intraabdominal, intrathoracic, joint replacement	80-100	8-24	7-10 days, until bleeding stops and healing is achieved

2.3 Routine Prophylaxis
The dose for previously treated patients (PTPs) is 40 to 60 international units per kg twice weekly. Titration of dose may be necessary depending upon the individual patient’s age, bleeding pattern, and physical activity.
2.4 Preparation and Reconstitution
The procedures below are provided as general guidelines for the preparation and reconstitution of RIXUBIS. Always work on a clean surface and wash hands before performing the following procedures:
Use aseptic technique during reconstitution procedure.
Allow the RIXUBIS vial (dry factor concentrate) and Sterile Water for Injection, USP vial (diluent) to reach room temperature.
Remove caps from the factor concentrate and diluent vials.
Cleanse stoppers with germicidal solution and allow to dry prior to use. Place the vials on a flat surface.
Open the BAXJECT II device package by peeling away the lid, without touching the inside (Figure A). Do not remove the device from the package. Note that the BAXJECT II device is intended for use with a single vial of RIXUBIS and Sterile Water for Injection, USP only; therefore, reconstituting and withdrawing a second vial into the syringe requires a second BAXJECT II device.
Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial stopper (Figure B).
Grip the BAXJECT II package at its edge and pull the package off the device (Figure C). Do not remove the blue cap from the BAXJECT II device. Do not touch the exposed white plastic spike.
Turn the system over so that the diluent vial is on top. Quickly insert the white plastic spike fully into the RIXUBIS vial stopper by pushing straight down (Figure D). The vacuum will draw the diluent into the RIXUBIS vial.
Swirl gently until the powder is completely dissolved. Do not refrigerate after reconstitution. Use within 3 hours of reconstitution.
2.5 Administration
For intravenous bolus infusion only.
The safety and efficacy of RIXUBIS administration by continuous infusion has not been established.
Inspect parenteral drug products for particulate matter and discoloration prior to administration. The solution should be clear and colorless in appearance. Do not use RIXUBIS if you notice any particulates or turbidity in the solution and notify Baxter.
Perform product administration and handling of the administration set and needles with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single-use.
Administer RIXUBIS at room temperature and within 3 hours of reconstitution. Discard any unused product.
1. Use a plastic syringe with this product.
2. Remove the blue cap from the BAXJECT II device. Connect the syringe to the BAXJECT II device (Figure E). Do not inject air.
3. Turn the system upside down (factor concentrate vial now on top). Draw the factor concentrate into the syringe by pulling the plunger back slowly (Figure F).
4. Disconnect the syringe; attach a suitable needle and inject intravenously by  bolus infusion. If a patient is to receive more than one vial of RIXUBIS, the contents of multiple vials may be drawn into the same syringe.
5. Maximum infusion rate of 10mL/min.

3 DOSAGE FORMS AND STRENGTHS
RIXUBIS is a white or almost white lyophilized powder in single-use vials containing nominally 250, 500, 1000, 2000 or 3000 international units. 
4 CONTRAINDICATIONS
RIXUBIS is contraindicated in patients who have:
Known hypersensitivity to RIXUBIS or its excipients including hamster protein
Disseminated Intravascular Coagulation (DIC) [see Warnings and Precautions (5.4)]
Signs of fibrinolysis [see Warnings and Precautions (5.4)]
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Hypersensitivity reactions have been reported with RIXUBIS. Anaphylaxis and other hypersensitivity reactions are possible. The risk is highest during the early phases of initial exposure to factor IX concentrates in previously untreated patients (PUPs), in particular in patients with high-risk gene mutations. Early signs of allergic reactions, which can progress to anaphylaxis, include angioedema, chest tightness, hypotension, lethargy, nausea, vomiting, paresthesia, restlessness, wheezing, and dyspnea. Immediately discontinue administration and initiate appropriate treatment if allergic- or anaphylactic-type reactions occur. In case of severe allergic reactions, alternative hemostatic measures should be considered.
There have been reports in the literature showing an association between the occurrence of a factor IX inhibitor and allergic reactions. Evaluate patients experiencing allergic reactions for the presence of an inhibitor.
RIXUBIS contains trace amounts of Chinese hamster ovary (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
5.2 Inhibitors
Evaluate patients regularly for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor IX inhibitor concentration if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an expected dose. Contact a specialized hemophilia treatment center if a patient develops an inhibitor.
Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis if re-exposed to RIXUBIS. RIXUBIS may not be effective in patients with high titer factor IX inhibitors and other therapeutic options should be considered.
5.3 Nephrotic Syndrome
Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B patients with factor IX inhibitors. The safety and efficacy of using RIXUBIS for immune tolerance induction have not been established.
5.4 Thromboembolic Complications
The use of factor IX containing products has been associated with the development of thromboembolic complications (e.g., pulmonary embolism, venous thrombosis, and arterial thrombosis). Due to the potential risk for thromboembolic complications, monitor patients for early signs of thromboembolic and consumptive coagulopathy, when administering RIXUBIS to patients with liver disease, with signs of fibrinolysis, peri- and post-operatively, or at risk for thromboembolic events or DIC. The benefit of treatment with RIXUBIS should be weighed against the risk of these complications in patients with DIC or those at risk for DIC or thromboembolic events.
5.5 Monitoring Laboratory Tests
Monitor factor IX activity plasma levels by the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained [see Dosage and Administration (2)].
Monitor for the development of inhibitors if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with the recommended dose of RIXUBIS. Assays used to determine if factor IX inhibitor is present should be titered in Bethesda Units (BUs).
6 ADVERSE REACTIONS
The most common adverse reactions observed in >1% of subjects in clinical studies were dysgeusia, pain in extremity, and positive furin antibody test.
6.1 Clinical Trial Experience
Because 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 trials of another drug and may not reflect the rates observed in clinical practice.
During clinical development, in a combined study, 91 male previously treated patients (PTPs; exposed to a factor IX-containing product for ≥150 days) received at least one infusion of RIXUBIS as part of either on-demand treatment of bleeding episodes, perioperative management of major and minor surgical, dental, or other invasive procedures, routine prophylaxis, or pharmacokinetic evaluation of RIXUBIS. Six subjects (6.6%) were <6 years of age, 10 (11%) were 6 to <12 years of age, 3 (3.3%) were adolescents (12 to <16 years of age), and 72 (79%) were adults (16 years of age and older). The subjects received a total of 7,353 infusions with a median of 85 infusions of RIXUBIS (range 3 to 212 infusions), for a median of 83 exposure days (range 83 to 209 days).
A total of 161 adverse events were reported in 48 (52.7%) of the 91 subjects. Adverse reactions that occurred in >1% of subjects are shown in Table 3.
Table 3 Summary of Adverse Reactions 

System Organ Class	Adverse Reactions (AR)	Number of ARs (N)	Number of Subjects (N=91) n (%)	Percent per Infusion (N=7353)
Nervous System Disorders	Dysgeusia	2	1 (1.1%)	0.03%
Musculoskeletal and Connective Tissue Disorders	Pain in extremity	1	1 (1.1%)	0.01%
Investigations	Positive furin antibody testa	1	1 (1.1%)	0.01%
	Factor IX or furin antibodies of indeterminate specificitya	9	7 (7.7%)	0.12%

a See Immunogenicity
Immunogenicity
All 91 subjects were monitored for inhibitory and binding antibodies to factor IX, and binding antibodies to CHO protein and furin, at the following time points: at screening, at 72 hours following the first infusion of RIXUBIS and the commercial recombinant factor IX product in the crossover portion of the pharmacokinetic study, after 5 and 13 weeks following first exposure to RIXUBIS, and thereafter every 3 months. Antibodies against furin were tested by an in-house enzyme-linked immunosorbent assay (ELISA). A titer of 1:20 or 1:40 was considered to be indeterminate for the above validated assay, as these titers were too low to be verified by the confirmatory assay.
No subjects developed neutralizing antibodies to factor IX. Thirteen subjects (14.3%) developed low-titer, non-neutralizing antibodies against factor IX at one or more time points. Two of these 13 subjects were found to have these antibodies at screening, prior to receiving RIXUBIS. No clinical adverse findings were observed in any of these 13 subjects.
Thirteen subjects (14.3%) had signals for antibodies against furin (indeterminate specificity). Four of these 13 subjects expressed signals for antibodies at screening, prior to RIXUBIS treatment. An additional subject had an antibody signal after treatment with the comparator product and prior to RIXUBIS treatment. Another additional subject had a positive titer of 1:80 that was not present when checked at a later time point and therefore considered transient. A second subject had a positive antibody signal after the data cutoff date that was also transient. No clinical adverse findings were observed in any of these 15 subjects.
In a study of 500 normal volunteers, using the same assay as in the clinical trial, 7% had titers of 1:20 or 1:40 and 1.2% had higher titers ranging from 1:80 to 1:320. These antibodies are thought to be part of a natural immune system response. To date, these antibodies have not been associated with any clinical adverse findings.
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.
Thrombogenicity
There was no clinical evidence of thromboembolic complications in any of the subjects. Out-of-range values for thrombogenicity markers (thrombin-antithrombin III, prothrombin fragment 1.2, and D-dimer), determined during the pharmacokinetic portion of the combined study, did not reveal any pattern indicative of clinically relevant thrombogenicity with either RIXUBIS or a comparator factor IX-containing product.
6.2 Post-marketing Experience
Because the following reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders: Hypersensitivity (including symptoms such as dyspnea, pruritus)
The following class adverse reactions have been seen with another recombinant factor IX: inadequate factor IX recovery, inhibitor development, anaphylaxis, angioedema, hypotension, and thrombosis.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
Animal reproduction studies have not been conducted with RIXUBIS. It is also not known whether RIXUBIS can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RIXUBIS should be given to a pregnant woman only if clearly needed.
8.3 Nursing Mothers
It is not known whether RIXUBIS is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this product is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of RIXUBIS in pediatric patients have not been established.
8.5 Geriatric Use
Clinical studies of RIXUBIS did not include subjects aged 65 and over. It is not known whether elderly patients respond differently than younger patients. Dose selection for an elderly patient should be individualized [see Dosage and Administration (2)].
8.1 Pregnancy
Pregnancy Category C
Animal reproduction studies have not been conducted with RIXUBIS. It is also not known whether RIXUBIS can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RIXUBIS should be given to a pregnant woman only if clearly needed.
11 DESCRIPTION
RIXUBIS [Coagulation Factor IX (Recombinant)] is a purified protein produced by recombinant DNA technology. Its amino acid sequence is identical to that of the Ala-148 allelic form of plasma derived factor IX, and its structural and functional characteristics are similar to those of plasma derived factor IX. RIXUBIS is produced by a genetically engineered CHO cell line. No human or animal proteins are added during any stage of manufacturing or formulation of RIXUBIS. The CHO cell line secretes recombinant factor IX into a defined cell culture medium that does not contain hormones, and the recombinant factor IX is purified by a chromatography purification process that does not require a monoclonal antibody step. The process includes validated virus inactivation/removal steps, namely solvent/detergent treatment and 15 nm nanofiltration. RIXUBIS is predominantly a single component by sodium dodecyl sulfate-polyacrylamide gel electrophoresis evaluation. The specific activity of RIXUBIS is ≥200 international units per milligram of protein. Factor IX preactivation, the percent of Factor IXa/Factor IX as measured by activity assays, is ≤0.03%. The potency in international units is determined using an in vitro thromboplastin time (aPTT)-based one-stage clotting assay calibrated against the World Health Organization (WHO) International Standard for Factor IX concentrate. Factor IX potency results can be affected by the type of aPTT reagent and reference standard used in the assay; differences of up to 40% have been observed.
RIXUBIS is formulated as a sterile, nonpyrogenic lyophilized powder to be reconstituted with Sterile Water for Injection for intravenous administration. It does not contain any preservatives and is available in single-use vials containing the labeled amount of factor IX activity, expressed in international units. Each vial contains nominally 250, 500, 1000, 2000 or 3000 international units of recombinant coagulation factor IX. After reconstitution of the lyophilized powder, all dosage strengths yield a clear, colorless solution. The concentrations of excipients are:

Excipient	Concentration
L-histidine	20 mM
sodium chloride	60 mM
calcium chloride	4 mM
Mannitol	110 mM
Sucrose	35 mM
polysorbate 80	0.005%

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Patients with hemophilia B are deficient in coagulation factor IX, which is required for effective hemostasis. Treatment with RIXUBIS temporarily replaces the missing coagulation factor IX.
12.2 Pharmacodynamics
The administration of RIXUBIS increases plasma levels of factor IX, and can temporarily correct the coagulation defect in these patients by decreasing the aPTT.
12.3 Pharmacokinetics
A randomized, blinded, controlled, crossover pharmacokinetic study of RIXUBIS and another commercial recombinant factor IX product was conducted in non-bleeding subjects (≥15 years of age). The subjects received either of the products as an intravenous infusion. The dose range of RIXUBIS and the other recombinant factor IX product ranged from 71.3 to 79.4 international units/kg and 70.1 to 80 international units/kg, respectively. The pharmacokinetic parameters were calculated from factor IX activity measurements in blood samples obtained up to 72 hours following each infusion.
The pharmacokinetic evaluation was repeated for RIXUBIS in a prospective, open-label, uncontrolled study with RIXUBIS in subjects who participated in the initial crossover pharmacokinetic study and had then received RIXUBIS for 26 ± 1 (mean ± SD) weeks for routine prophylaxis, and accumulated at least 30 exposure days to RIXUBIS. The dose range of RIXUBIS in this repeat pharmacokinetic study was 64.5 to 79.2 international units/kg.
RIXUBIS was equivalent to the other recombinant factor IX product based on area under the plasma concentration-time curve (AUC). Table 4 presents the pharmacokinetic parameters for all evaluable subjects (per protocol analysis).
Table 4 Pharmacokinetic Parameters for RIXUBIS Following Single and Repeat Dosing

Parameter	Initial Crossover Study (N=25)	Repeat Evaluation (N=23)
AUC0-inf (IU·hrs/dL)a Mean (SD) Min; Max	1207 (242) 850; 1710	1305 (300) 838; 1864
Incremental recovery at Cmax (IU/dL:IU/kg)b Mean (SD) Min; Max	0.87 (0.22) 0.53; 1.35	0.95 (0.25) 0.52; 1.38
Half-life (hrs) Mean (SD) Min; Max	26.7 (9.6) 15.8; 52.3	25.4 (6.9) 16.2; 42.2
Cmax (IU/dL) Mean (SD) Min; Max	66.2 (15.8) 41.7; 100.3	72.7 (19.7) 38.5; 106.3
Mean Residence Time (hrs) Mean (SD) Min; Max	30.8 (7.3) 22.3; 47.8	29.9 (4.2) 21.3; 37.5
VSS c (mL/kg) Mean (SD) Min; Max	201.9 (77.4) 110.0; 394.0	178.6 (45.2) 112.0; 272.0
Clearance [mL/(kg·hr)] Mean (SD) Min; Max	6.4 (1.3) 4.3; 9.1	6.0 (1.5) 4.1; 9.5

a Area under the plasma concentration-time curve from time 0 to infinity hours post-infusion.
b Calculated as (Cmax – baseline factor IX) divided by the dose in IU/kg, where Cmax is the maximum post-infusion factor IX measurement.
c Volume of distribution at steady state.
Data from PTPs who underwent repeat in vivo recovery testing for up to 26 weeks demonstrated that the incremental Factor IX recovery was consistent over time (Table 5).
Table 5 Incremental Recovery for RIXUBIS 30 Minutes After Infusion

Day 1 (N=73)	Week 5 (N=71)	Week 13 (N=68)	Week 26 (N=55)	At study completion/ terminationb (N=23)
Incremental recovery 30 min after infusion (IU/dL:IU/kg)a Mean ± SD Median (range)	0.79 ± 0.20 0.78 (0.26-1.35)	0.83 ± 0.21 0.79 (0.46-1.48)	0.85 ± 0.25 0.83 (0.14-1.47)	0.89 ± 0.12 0.88 (0.52-1.29)	0.87 ± 0.20 0.89 (0.52-1.32)

a Calculated as (C30min – baseline factor IX) divided by the dose in IU/kg, where C30min is the factor IX measurement
30 minutes after infusion.
b If not coinciding with week 26 visit.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Nonclinical studies evaluating the carcinogenic and mutagenic potential of RIXUBIS have not been conducted.
No adverse effects on reproductive organs were observed by macroscopic and microscopic pathological investigations in repeated dose toxicity studies. No investigations on impairment of fertility have been conducted.
14 CLINICAL STUDIES
The efficacy of RIXUBIS has been evaluated in a prospective, open-label, uncontrolled multicenter study, in which a total of 73 male PTPs between 12 and 65 years of age received RIXUBIS either for routine prophylaxis or on-demand treatment. In addition, there is an ongoing prospective, open-label, uncontrolled, multicenter study where 14 PTPs underwent minor or major surgeries receiving RIXUBIS for perioperative management. PTPs were defined as subjects who were exposed to a factor IX containing product at ≥150 days. All subjects had severe (factor IX level <1%) or moderately severe (factor IX level ≤2%) hemophilia B. The majority of subjects (88%) had arthropathy and/or target joints (66%) at screening. Subjects with history of a detectable factor IX inhibitor ≥0.6 BU, history of severe allergic reactions following exposure to factor IX containing products, evidence of severe chronic liver disease (INR >1.4), impaired renal function, CD4 count <200 cells/mm3, or any hemostatic defect other than hemophilia B, were excluded from the study.
Routine Prophylaxis
Of 59 subjects who received RIXUBIS for routine prophylaxis, 56 subjects received the product for a minimum of 3 months and were included in the efficacy evaluation. The prophylactic regimen consisted of 40 to 60 international units/kg RIXUBIS twice weekly. An additional 14 subjects received RIXUBIS on-demand for treatment of bleeding episodes only. These subjects had to have at least 12 documented bleeding episodes requiring treatment within 12 months prior to enrollment.
In the on-demand arm, the mean treatment duration was 3.5 ± 1 months (median 3.4, ranging from 1.2 to 5.1 months) and the mean total annualized bleeding rate (ABR was 33.9 ± 17.37 with a median of 27 ranging from 12.9 to 73.1.
In the prophylaxis arm the mean ABR was 4.3 for all bleeds, 1.7 for spontaneous bleeds, and 2.9 for joint bleeds (Table 6).
Table 6 Efficacy of Prophylaxis with RIXUBIS (N=56) 

Treatment duration (months) Mean ± SD Median (range)	6.0 ± 0.65 6.0 (5.4-9.1)
Number of infusions per week Mean ± SD Median (range)	1.8 ± 0.11 1.8 (1.5-1.9)
Dose per infusion (IU/kg) Mean ± SD Median (range)	49.4 ± 4.92 50.5 (40.0-62.8)
Total ABR Mean ± SD Median (range)	4.3 ± 5.80 2.0 (0.0-23.4)
ABR for joint bleeds Mean ± SD Median (range)	2.9 ± 4.25 0.0 (0.0-21.5)
ABR for spontaneous bleeds Mean ± SD Median (range)	1.7 ± 3.26 0.0 (0.0-15.6)
Subjects with zero bleeding episodes % (n)	42.9% (24)

Treatment of Bleeding Episodes
A total of 249 bleeding episodes were treated with RIXUBIS, of which 115 bleeds were recorded for subjects treated on prophylaxis and 134 bleeds for those with the on-demand regimen. There were 197 joint bleeds and 52 non-joint bleeds (soft tissue, muscle, body cavity and other). Of the 249 bleeding episodes, 15 were major, 163 were moderate, and 71 were minor (see Table 1 for definitions of major, moderate and minor). Treatment was individualized based on the severity, cause, and site of bleed. The majority (211; 84.7%) were treated with 1 to 2 infusions. Of these, 153 (61.4%) were treated with 1 infusion and 58 (23.3%) were treated with 2 infusions. No non-responders were reported.
Hemostatic efficacy at resolution of a bleed was rated excellent or good in 96% of all treated bleeding episodes (Excellent is defined as full relief of pain and cessation of objective signs of bleeding after a single infusion; no additional infusion is required for the control of bleeding; or Good is defined as definite pain relief and/or improvement in signs of bleeding after a single infusion; possibly requires more than one infusion for complete resolution).
Perioperative Management
The efficacy analysis of RIXUBIS in perioperative management included 14 surgeries performed in 14 PTPs between 19 and 54 years of age undergoing major or minor surgical (see Table 2 for definitions of major and minor), dental or other surgical invasive procedures. Eleven procedures (including 7 orthopedic and 1 dental surgeries) were major, 3 procedures (including 2 dental extractions) were minor.
Subjects undergoing major surgeries also underwent a pharmacokinetic evaluation. All subjects were dosed based on their most recent individual incremental recovery. The recommended initial loading dose of RIXUBIS was used to ensure that during surgery factor IX activity levels of 80-100% for major surgeries and 30-60% for minor surgeries were maintained. RIXUBIS was administered by intravenous bolus infusions. Hemostasis was maintained throughout the study duration. The surgical procedures and the results of the assessment of the hemostatic response at various points in time are provided in Table 7.
Table 7 Efficacy of RIXUBIS for Surgical Procedures

Procedure (category, number of subjects)	Assessment of Response
	Intra-operative	At time of drain removal or on post-operative day 3*	At time of discharge
Removal of intramedullary nail (Major, n=1)	Excellent	Good	Excellent
Joint replacement (Major, n=5)	Excellent	Good (3) Excellent (2)	Excellent (3) Good (2)
Open synovectomy (Major, n=1)	Excellent	Excellent	Excellent
Excision neurofibroma (Major, n=1)	Excellent	Excellent	Excellent
Hernioplastic (Major, n=2)	Excellent	Excellent	Good (1) Excellent (1)
Tooth extraction (Major, n=1)	Excellent	Excellent	Excellent
Tooth extraction (Minor, n=2)	Excellent	Excellent	Excellent
Intra-articular injection (Minor, n=1)	Excellent	Not applicable	Excellent

* Where no drain was employed, response was assessed on postoperative day 3.
15 REFERENCES
1.Roberts HR, Eberst ME. Current management of hemophilia B. Hematol Oncol Clin North Am. 1993;7(6):1269-1280.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
RIXUBIS is available as single-use vials containing the following product strengths:

Color Code	Nominal Strength (international units)	Kit NDC
Light Blue	250	0944-3026-02
Pink	500	0944-3028-02
Green	1000	0944-3030-02
Orange	2000	0944-3032-02
Silver	3000	0944-3034-02

Actual factor IX activity in international units is stated on the unit carton and vial label.
Each kit also contains 5 mL of Sterile Water for Injection and a BAXJECT II transfer device.
Storage and Handling
Store at refrigerated temperature; 2° to 8°C (36° to 46°F) for up to 24 months. Do not freeze.
May store at room temperature not to exceed 30°C (86°F) for up to 12 months within the 24 month time period. Write on the carton the date RIXUBIS was removed from refrigeration.
After storage at room temperature, do not return the product to the refrigerator.
Do not use beyond the expiration date printed on the carton or vial.
17 PATIENT COUNSELING INFORMATION
See FDA-approved Patient Labeling (Patient Information and Instructions for Use)
Advise patients to report any adverse reactions or problems following RIXUBIS administration to their physician or healthcare provider.
Inform patients of the early signs of hypersensitivity reactions (including hives, generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Instruct patients to discontinue use of the product and contact their physician if these symptoms occur.
Advise patients to contact their physician or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to factor IX replacement therapy, as in some cases this may be a manifestation of an inhibitor.
Ask patients to follow the specific preparation and administration procedures provided by their physician.
Inform patients to follow the recommendations in the FDA-approved patient labeling.
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250 I.E. Pulver und Lösungsmittel zur Herstellung einer Injektionslösung
500 I.E. Pulver und Lösungsmittel zur Herstellung einer Injektionslösung
1000 I.E. Pulver und Lösungsmittel zur Herstellung einer Injektionslösung
2000 I.E. Pulver und Lösungsmittel zur Herstellung einer Injektionslösung
3000 I.E. Pulver und Lösungsmittel zur Herstellung einer Injektionslösung