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):

1. 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).
2. 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:

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 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 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.

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. eva luate 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

eva luate 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 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 eva luation 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.

8.1 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.