2.1 Dosing Guidelines

2.2 On-demand Treatment and Control of Bleeding Episodes and Perioperative Management of Bleeding

A guide for dosing RIXUBIS in the on-demand treatment and control of bleeding episodes and perioperative management of bleeding is provided in Table 1 and Table 2, respectively. Ensure the factor IX activity level is achieved and maintained in the corresponding period.

2.3 Routine Prophylaxis

The dose for previously treated patients (PTPs) is 60 to 80 international units per kg twice weekly for patients <12 years of age and is 40 to 60 international units per kg twice weekly for patients ≥12 years of age. Adjust the dose based on 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:

1. Use aseptic technique during reconstitution procedure.
2. Allow the RIXUBIS vial (dry factor concentrate) and Sterile Water for Injection, USP vial (diluent) to reach room temperature.
3. Remove caps from the factor concentrate and diluent vials.
4. Cleanse stoppers with germicidal solution and allow the stopper to dry prior to use. Place the vials on a flat surface.
5. 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.
6. Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial stopper (Figure B).
7. 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.
8. 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.
9. 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 Takeda Pharmaceuticals.
• 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 by screwing it clockwise until the syringe is secured (Figure E). Do not over tighten.
3. Do not inject air.
4. 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).
5. Disconnect the syringe by unscrewing it counterclockwise; attach a suitable needle to the syringe 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.
6. Maximum infusion rate of 10 mL/min.

Figure A	Figure B	Figure C
Figure D	Figure E	Figure F

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 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).

6.1 Clinical Trials 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 trial, 99 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. Eleven subjects (11.1%) were <6 years of age, 12 (12.1%) were 6 to <12 years of age, 3 (3%) were adolescents (12 to <16 years of age), and 73 (73.7%) were adults (16 years of age and older). The subjects received a total of 14,018 infusions with a median of 163 infusions of RIXUBIS (range 8 to 327 infusions), for a median of 156 exposure days (range 8 to 316 days).

A total of 337 adverse events were reported in 80 (80.8%) of the 99 subjects. Adverse reactions that occurred in >1% of subjects are shown in Table 3.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of RIXUBIS. 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)

Skin and Subcutaneous Tissue Disorders: Urticaria, rash

The following class adverse reactions have been seen with another recombinant factor IX: inadequate factor IX recovery, inhibitor development, anaphylaxis, angioedema, hypotension, and thrombosis.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety, efficacy and pharmacokinetics of RIXUBIS have been evaluated in 23 previously treated pediatric patients. Twelve (52.2%) were 6 to <12 years of age and 11 subjects (47.8%) were <6 years of age. Previously treated pediatric subjects 6 to <12 years of age were previously treated with plasma-derived and/or recombinant factor IX concentrate(s) for a minimum of 150 exposure days (based on the subject's medical records). Subjects <6 years of age were previously treated with plasma-derived and/or recombinant factor IX concentrate(s) for > 50 exposure days (based on the subject's medical records).

Incremental recovery was observed to be 22% lower in pediatric patients (<12 years) and dose adjustment is needed [see Dosage and Administration (2) and Clinical Pharmacology (12.3)]. The mean incremental recovery (in [IU/dL]/[IU/kg]) at the initial pharmacokinetics evaluation was 0.67 (± 0.16) in subjects of both age cohorts, with lower values in the younger age cohort (0.59 ± 0.13) and higher values in the older age group (0.73 ± 0.16). Clearance was higher in the younger age cohort, with a mean clearance of 10.6 ± 1.7 mL/(kg.hr) (median: 10.5; range: 8.1-14.4) in the <6 years age cohort compared to a mean clearance of 8.7 ± 1.2 mL/(kg.hr) (median: 8.6; range: 6.9-10.8) in the 6 to <12 years age cohort.

In a prospective, open-label, uncontrolled multicenter trial with patients <12 years of age, a total of 41 infusions were given for the treatment of 26 bleeding episodes (7 joint, 19 muscle and soft tissue). Bleeding was controlled in all episodes. In 23 of 26 (88.5%) of the episodes, hemostasis was achieved with one or two infusions. The mean annualized bleeding episode rate (ABR) for children <12 years of age was 2.7 bleeds per patient per year ± 3.14 with a median of 2 ranging from 0 to 10.8. See Clinical Studies (14) for patients 12 to <16 years of age. The median ABR during prophylaxis was comparable among children, adolescents and adults.

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)].

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

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.

On-demand Treatment of Bleeding Episodes in PTPs ≥12 Years of Age

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; 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).

On-demand Treatment of Bleeding Episodes in PTPs <12 Years of Age

A total of 26 bleeding episodes were treated with RIXUBIS, of which 23 bleeds were due to injury, 2 spontaneous and 1 of unknown origin; 19 bleeds were non-joint (soft tissue, muscle, body cavity, intracranial and other) and 7 were joint bleeds of which 1 was a bleed into a target joint. Of the 26 bleeding episodes, 15 were minor, 9 moderate, and 2 major (Minor: little or no pain; little or no change in the range of motion of affected joint (if joint bleeding event); mild restriction of mobility and activity; Moderate: mild to moderate pain; some decrease in range of motion of affected joint (if joint bleeding event); moderate decrease in mobility and activity; Major/life threatening: significant pain; substantial decrease in range of motion of affected joint (if joint bleeding event); incapacity; life threatening). Treatment was individualized based on the severity, cause and site of bleed. The majority (23; 88.5%) were treated with 1 to 2 infusions. Of the treated bleeding episodes 15 (57.7%) received 1 infusion, 8 (30.8%) received 2 infusions, and 3 (11.5%) were treated with 3 infusions. Hemostatic efficacy at resolution of a bleed was rated excellent or good in 96.2% of all treated bleeding episodes.

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 trial duration. The following are the surgical procedures and results of the assessment of the hemostatic response at various points.

Fourteen surgeries (11 major; 3 minor), included in the intraoperative assessment had a rating of 'excellent'. At discharge from hospital 11/14 surgeries (8 major) had a rating of 'excellent' and 3/14 (3 major) had a rating of 'good'.

The rating of excellent, good, fair and none at 72 hours post-surgery was based on the hemostasis achieved as compared to that expected in hemostatically normal subjects.

Routine Prophylaxis and Control of Bleeding in PTPs ≥12 Years of Age

The efficacy of RIXUBIS has been evaluated in a prospective, open-label, uncontrolled multicenter trial, 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 trial 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 for ≥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 trial.

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 10).

Routine Prophylaxis and Control of Bleeding in PTPs <12 Years of Age

The efficacy of RIXUBIS has been evaluated in a clinical trial, in which a total of 23 male, (PTPs) between 1.8 and 11.8 years (median age 7.10 years) with 11 subjects <6 years, received RIXUBIS for prophylaxis and control of bleeding episodes. PTPs were defined as subjects who were exposed to a factor IX-containing product on ≥150 days for subjects aged 6 to <12 years and on ≥50 days for subjects aged <6 years. All subjects had severe (factor IX level <1%) or moderately severe (factor IX level ≤2%) hemophilia B. Subjects with a history of or a detectable FIX inhibitor ≥0.6 BU, a history of severe allergic reactions following exposure to FIX, evidence of severe chronic liver disease (INR >1.4), impaired renal function, a CD4 count <200 cells/mm3 or any hemostatic effect other than hemophilia B were excluded from participation. All 23 subjects received prophylactic treatment with RIXUBIS for a minimum of 3 months and were included in the efficacy evaluation for prophylaxis (see Table 11).

How Supplied

RIXUBIS is available as single-dose vials containing the following product strengths:

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.

Not made with natural rubber latex.

Storage and Handling

• Store at refrigerated temperature [2°C to 8°C (36°F to 46°F)] or room temperature [not to exceed 30°C (86°F)] for up to 36 months. Do not freeze.
• Do not use beyond the expiration date printed on the carton or vial.