RIXUBIS

Baxter Healthcare Corporation

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese 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: 2013RECENT MAJOR CHANGESWarnings and Precautions (5.1) 01/2014INDICATIONS AND USAGERIXUBIS (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 STRENGTHSRIXUBIS is available as a lyophilized powder in single-use vials containing nominally 250, 500, 1000, 2000 or 3000 international units.CONTRAINDICATIONSDo 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) Side Effects 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 POPULATIONSPregnancy: No human or animal data. Use only if clearly needed. (8.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 RIXUBIS INDICATIONS AND USAGE
• 2 RIXUBIS DOSAGE AND ADMINISTRATION
  • 2.1 Dosing Guidelines
  • 2.2 Control and Prevention of Bleeding Episodes and Perioperative Management
  • 2.3 Routine Prophylaxis
  • 2.4 Preparation and Reconstitution
  • 2.5 Administration
• 3 DOSAGE FORMS AND STRENGTHS
• 4 RIXUBIS CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hypersensitivity Reactions
  • 5.2 Inhibitors
  • 5.3 Nephrotic Syndrome
  • 5.4 Thromboembolic Complications
  • 5.5 Monitoring Laboratory Tests
• 6 RIXUBIS ADVERSE REACTIONS
  • 6.1 Clinical Trial Experience
  • 6.2 Post-marketing Experience
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.1 Pregnancy
• 11 RIXUBIS DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

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.

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.

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:

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).

^a Area under the plasma concentration-time curve from time 0 to infinity hours post-infusion.

^b Calculated as (C_max – baseline factor IX) divided by the dose in IU/kg, where C_max 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).

^a Calculated as (C_30min – baseline factor IX) divided by the dose in IU/kg, where C_30min 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).

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.

* Where no drain was employed, response was assessed on postoperative day 3.

15 REFERENCES

• 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:

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.

FDA-approved Patient Labeling

RIXUBIS

[Coagulation Factor IX (Recombinant)]

This leaflet summarizes important information about RIXUBIS. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about RIXUBIS. If you have any questions after reading this, ask your healthcare provider.

What is RIXUBIS?

RIXUBIS is a medicine used to replace clotting factor (Factor IX) that is missing in people with hemophilia B. Hemophilia B is also called congenital factor IX deficiency or Christmas disease. Hemophilia B is an inherited bleeding disorder that prevents blood from clotting normally. RIXUBIS is used to prevent and control bleeding in people with hemophilia B. Your healthcare provider may give you RIXUBIS when you have surgery. RIXUBIS can reduce the number of bleeding episodes when used regularly (prophylaxis).

Who should not use RIXUBIS?

You should not use RIXUBIS if you

• are allergic to hamsters
• are allergic to any ingredients in RIXUBIS.

Tell your healthcare provider if you are pregnant or breastfeeding because RIXUBIS may not be right for you.

What should I tell my healthcare provider before using RIXUBIS?

You should tell your healthcare provider if you

• have or have had any medical problems
• take any medicines, including prescription and non-prescription medicines, such as over-the-counter medicines, supplements or herbal remedies
• have any allergies, including allergies to hamsters
• are breastfeeding. It is not known if RIXUBIS passes into your milk and if it can harm your baby
• are pregnant or planning to become pregnant. It is not known if RIXUBIS may harm your unborn baby
• have been told that you have inhibitors to factor IX (because RIXUBIS may not work for you).

How should I infuse RIXUBIS?

RIXUBIS is given directly into the bloodstream. RIXUBIS should be administered as ordered by your healthcare provider. You should be trained on how to do infusions by your healthcare provider or hemophilia treatment center. Many people with hemophilia B learn to infuse their RIXUBIS by themselves or with the help of a family member.

Your healthcare provider will tell you how much RIXUBIS to use based on your weight, the severity of your hemophilia B, and where you are bleeding. You may have to have blood tests done after getting RIXUBIS to be sure that your blood level of factor IX is high enough to clot your blood. Call your healthcare provider right away if your bleeding does not stop after taking RIXUBIS.

What are the possible side effects of RIXUBIS?

Allergic reactions have occurred with RIXUBIS. Call your healthcare provider or get emergency treatment right away if you get a rash or hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, lightheadedness, dizziness, nausea or fainting. Some common side effects of RIXUBIS were unusual taste in the mouth and limb pain. Tell your healthcare provider about any side effects that bother you or do not go away. These are not all the side effects possible with RIXUBIS. You can ask your healthcare provider for information that is written for healthcare professionals.

What are the RIXUBIS dosage strengths?

RIXUBIS comes in five different dosage strengths: 250, 500, 1000, 2000 and 3000 international units. The actual strength will be imprinted on the label and on the box. The five different strengths are color coded, as follows:

Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider.

How should I store RIXUBIS?

• 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 is removed from refrigeration. After storage at room temperature, do not return the product to the refrigerator.
• Do not use after the expiration date printed on the carton or vial.
• Reconstituted product (after mixing dry product with wet diluent) must be used within 3 hours and cannot be stored or refrigerated. Discard any RIXUBIS left in the vial at the end of your infusion.

What else should I know about RIXUBIS?

Your body may form inhibitors to factor IX. An inhibitor is part of the body’s defense system. If you form inhibitors, it may stop RIXUBIS from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to factor IX.

Medicines are sometimes prescribed for purposes other than those listed here. Do not use RIXUBIS for a condition for which it is not prescribed. Do not share RIXUBIS with other people, even if they have the same symptoms that you have.

Resources at Baxter available to patients

For information on patient assistance programs that are available to you, including the Baxter CARE Program, please contact the Baxter Insurance Assistance Helpline at 1-888-229-8379.

INSTRUCTIONS FOR USE

RIXUBIS

[Coagulation Factor IX (Recombinant)]

For intravenous use only

Do not attempt to do an infusion to yourself unless you have been taught how by your healthcare provider or hemophilia center.

Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using RIXUBIS. If you are unsure of the procedures, please call your healthcare provider before using RIXUBIS. Call your healthcare provider right away if bleeding is not controlled after using RIXUBIS. Your healthcare provider will prescribe the dose that you should take. Your healthcare provider may need to take blood tests from time to time. Talk to your healthcare provider before traveling. Plan to bring enough RIXUBIS for your treatment during this time. Dispose of all materials, including any leftover reconstituted RIXUBIS product, in an appropriate container.

• Prepare a clean flat surface and gather all the materials you will need for the infusion. Check the expiration date, and let the vial with the RIXUBIS concentrate and the Sterile Water for Injection, USP (diluent) warm up to room temperature. Wash your hands and put on clean exam gloves. If infusing yourself at home, the use of gloves is optional.
• Remove caps from the RIXUBIS concentrate and diluent vials to expose the centers of the rubber stoppers.

  

• Disinfect the stoppers with an alcohol swab (or other suitable solution suggested by your healthcare provider or hemophilia center) by rubbing the stoppers firmly for several seconds and allow them 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 of the package. Do not remove the BAXJECT II device from the package.
• Turn the package with the BAXJECT II device upside down and place it over the top of the diluent vial. Fully insert the clear plastic spike of the device into the center of the diluent vial stopper by pushing straight down. Grip the package at its edge and lift it off the device. Be careful not to touch the white plastic spike. Do not remove the blue cap from the BAXJECT II device. The diluent vial now has the BAXJECT II device connected to it and is ready to be connected to the RIXUBIS vial.

  

• To connect the diluent vial to the RIXUBIS vial, turn the diluent vial over and place it on top of the vial containing RIXUBIS concentrate. Fully insert the white plastic spike into the RIXUBIS vial stopper by pushing straight down. Diluent will flow into the RIXUBIS vial. This should be done right away to keep the liquid free of germs.

  

• Swirl the connected vials gently and continuously until the powder is completely dissolved. Do not shake. The RIXUBIS solution should look clear and colorless. If not, do not use it and notify Baxter immediately.

  

• Take off the blue cap from the BAXJECT II device and connect the syringe. Be careful to not inject air.

  

• Turn over the connected vials so that the RIXUBIS vial is on top. Draw the RIXUBIS solution into the syringe by pulling back the plunger slowly. Disconnect the syringe from the vials.

  

• If you are using more than one vial of RIXUBIS, the contents of more than one vial may be drawn into the same syringe. Make sure you mix each vial of RIXUBIS with the Sterile Water for Injection, USP that is provided in the box (following Steps 1-9). You will need a separate BAXJECT II device to mix each additional vial of RIXUBIS.
• Attach the infusion needle to the syringe using a winged (butterfly) infusion set, if available. Point the needle up and remove any air bubbles by gently tapping the syringe with your finger and slowly and carefully pushing air out of the syringe and needle.
• Apply a tourniquet and get the infusion site ready by wiping the skin well with an alcohol swab (or other suitable solution suggested by your healthcare provider or hemophilia center).
• Insert the needle into the vein and remove the tourniquet. Slowly infuse the RIXUBIS. Do not infuse any faster than 10 mL per minute.

  

• Take the needle out of the vein and use sterile gauze to put pressure on the infusion site for several minutes. Do not recap the needle. Place it with the used syringe in a hard-walled sharps container for proper disposal.
• Dispose of the used vials and BAXJECT II system in your hard-walled sharps container without taking them apart. Do not dispose of these supplies in ordinary household trash.
• Remove the peel-off label from the RIXUBIS vial and place it in your logbook. Clean any spilled blood with a freshly prepared mixture of 1 part bleach and 9 parts water, soap and water, or any household disinfecting solution.

Important: Contact your healthcare provider or local hemophilia treatment center if you experience any problems.

Baxter, Rixubis, and Baxject are trademarks of Baxter International Inc. registered in the U.S. Patent and Trademark Office.

Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
U.S. License No. 140

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

RIXUBIS

[COAGULATION FACTOR IX (RECOMBINANT)]

NDC 0944-3033-01

Rx Only

For Intravenous Use Only.

Directions for Use: See package insert.

Baxter Healthcare Corporation

Westlake Village, CA 91362 USA

U.S. License No. 140