OBIZUR

Limitations of Use:

• Safety and efficacy of OBIZUR has not been established in patients with baseline anti-porcine factor VIII inhibitor titer greater than 20 BU.
• OBIZUR is not indicated for the treatment of von Willebrand disease.

• Dose, dosing frequency, and duration of treatment with OBIZUR depend on the location and severity of bleeding episode, target factor VIII levels, and the patient's clinical condition. Monitor replacement therapy in cases of major surgery or life-threatening bleeding episodes.
• Each vial of OBIZUR has the recombinant porcine factor VIII potency in units stated on the vial.
• Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses. Titrate dose and frequency based on factor VIII recovery levels and individual clinical response.
• Initial dosing below the recommended 200 U/kg has been associated with lack of efficacy.

A guide for dosing OBIZUR for the on-demand treatment and control of bleeding episodes is provided in Table 1. Maintain the factor VIII activity within the target range. Plasma levels of factor VIII should not exceed 200% of normal or 200 units per dL.

• Use aseptic technique during the reconstitution procedure.
• If the patient needs more than one vial of OBIZUR per injection, reconstitute each vial according to the following instructions:

1. 1.Bring the OBIZUR vial and the pre-filled diluent syringe to room temperature.
2. 2.Remove the plastic cap from the OBIZUR vial (Figure A).

Figure A

Figure A

1. 3.Wipe the rubber stopper with an alcohol swab (not supplied) and allow it to dry prior to use.
2. 4.Peel back the cover of the vial adapter package. (Figure B). Do not touch the luer-lock (tip) in the center of the vial adapter. Do not remove the vial adapter from the plastic package.

Figure B

Figure B

1. 5.Place the vial adapter package on a clean surface with the luer-lock pointing up.
2. 6.Snap off the tamper resistant cap of the pre-filled syringe (Figure C).

Figure C

Figure C

1. 7.While firmly holding the vial adapter package, connect the pre-filled syringe to the vial adapter by pushing the syringe tip down onto the luer lock in the center of the vial adapter, and turning it clockwise until the syringe is secured. Do not over tighten (Figure D).

Figure D

Figure D

1. 8.Remove the vial adapter from the plastic package (Figure E).

Figure E

Figure E

1. 9.Place the OBIZUR vial on a clean, flat, hard surface. Place the vial adapter over the OBIZUR vial and firmly push the filter spike of the vial adapter through the center of the OBIZUR vial's rubber circle until the clear plastic cap snaps onto the vial (Figure F).

Figure F

Figure F

1. 10.Push the plunger down to slowly inject all of the diluent from the syringe into the OBIZUR vial.
2. 11.Gently swirl (in a circular motion) the OBIZUR vial without removing the syringe until all of the powder is fully dissolved (Figure G). The reconstituted solution should be inspected visually for particulate matter before administration. Do not use if particulate matter or discoloration is observed.

Figure G

Figure G

1. 12.With one hand hold the vial and vial adapter, and with the other hand firmly grasp the barrel of the pre-filled syringe and in a counterclockwise motion unscrew the syringe from the vial adapter (Figure H).

Figure H

Figure H

1. 13.Use OBIZUR within 3 hours after reconstitution when stored at room temperature.

For intravenous use after reconstitution only.

• Inspect the reconstituted OBIZUR solution for particulate matter and discoloration prior to administration. The solution should be clear and colorless in appearance. Do not administer if particulate matter or discoloration is observed.
• Do not administer OBIZUR in the same tubing or container with other medicinal products for infusion.

1. 1.Once all vials have been reconstituted, connect a large syringe to the vial adapter by gently pushing the syringe tip down onto the luer lock in the center of the vial adapter, and turning clockwise until the syringe is secured.
2. 2.Invert the vial; push the air in the syringe into the vial and withdraw the reconstituted OBIZUR into the syringe (Figure I).

Figure I

Figure I

1. 3.Unscrew the large syringe counterclockwise from the vial adapter and repeat this process for all reconstituted vials of OBIZUR until the total volume to be administered is reached.
2. 4.Administer the reconstituted OBIZUR intravenously at a rate of 1 to 2 mL per minute.

Hypersensitivity reactions can occur with OBIZUR. OBIZUR contains trace amounts of hamster proteins. Early signs of allergic reactions, which can progress to anaphylaxis, include angioedema, chest-tightness, dyspnea, hypotension, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if allergic or anaphylactic-type reactions occur.

Inhibitory antibodies to OBIZUR have occurred in patients treated with OBIZUR. Lack of efficacy could be due to inhibitory antibodies to OBIZUR.

Anamnestic reactions with rise in human factor VIII and/or recombinant factor VIII, porcine sequence inhibitors have also been reported in patients treated with OBIZUR. These anamnestic rises also may result in lack of efficacy.

Consider evaluating for presence of anti-recombinant porcine factor VIII (anti-rpFVIII) antibodies prior to initiation of treatment with OBIZUR. In instances where positive anti-rpFVIII antibody results are detected after treatment with OBIZUR is initiated, factor VIII levels may be used to decide whether treatment with OBIZUR should be continued [see Warnings and Precautions (5.3)].

Monitor patients for the development of antibodies to OBIZUR by appropriate assays [see Warnings and Precautions (5.3)]. If the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled after OBIZUR administration, suspect the presence of an anti-porcine factor VIII antibody.

If such inhibitory antibodies are suspected and there is a lack of efficacy, consider management options such as discontinuing OBIZUR and initiating other therapeutics such as a Factor VIII bypassing agent.

• Perform one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and maintained [see Dosage and Administration (2)].
  • Monitor factor VIII activity 30 minutes and 3 hours after initial dose.
  • Monitor factor VIII activity 30 minutes after subsequent doses.
• Monitor the development of inhibitory antibodies to OBIZUR. Perform a Nijmegen Bethesda inhibitor assay with recombinant porcine factor VIII as substrate for recombinant porcine factor VIII antibodies if expected plasma factor VIII activity levels are not attained or if bleeding is not controlled with the expected dose of OBIZUR. Use Bethesda Units (BU) to report inhibitor levels. Contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) if additional information is needed regarding testing.

Because clinical trials are conducted under widely varying conditions, adverse reaction (AR) 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.

The safety and efficacy of OBIZUR was evaluated in a multi-center, prospective, open-label, clinical trial that investigated adult patients with acquired hemophilia A. Twenty-nine adult subjects were enrolled in the study, received at least one dose of OBIZUR and were evaluable for safety [see Clinical Studies (14)]. Of the 29 adult subjects, 10 were between the ages of 42 and 65, and 19 were 65 years of age or older (18 Caucasian, 6 African-American, and 5 Asian). Ten (34%) subjects were female.

The safety and efficacy of OBIZUR have not been established in pediatric patients.

Of the 29 subjects within the trial, the average age was 70 years of age. Nineteen subjects were 65 years of age or older. Clinical studies suggest that OBIZUR is safe and effective in the adult population [see Adverse Reactions (6) and Clinical Studies (14)]. While no differences were observed between geriatric and adult responses to OBIZUR, these findings are inconclusive given the small number of subjects enrolled in either group.

Dose adjustments in the geriatric population have not been studied. Specific hazards associated with the concomitant use of OBIZUR with other drugs in the elderly population have not been studied in the clinical trial.

OBIZUR temporarily replaces the inhibited endogenous factor VIII that is needed for effective hemostasis in patients with acquired hemophilia A.

Patients with acquired hemophilia A (AHA) have normal factor VIII genes but develop autoantibodies against their own factor VIII (i.e., inhibitors). These autoantibodies neutralize circulating human factor VIII and create a functional deficiency of this procoagulant protein. AHA results in a prolonged clotting time as measured by the activated partial thromboplastin time (aPTT) assay, a conventional in vitro test for biological activity of factor VIII. Treatment with OBIZUR should normalize the aPTT during treatment; however, aPTT normalization should not be used as a measure of efficacy.

A formal pharmacokinetic study of OBIZUR in patients diagnosed with AHA has not been conducted. There are insufficient pharmacokinetic data in patients treated with OBIZUR.

Long-term studies in animals to evaluate the carcinogenic potential of OBIZUR, or studies to determine genotoxicity and the effects of OBIZUR on fertility, have not been performed.

How Supplied

OBIZUR is supplied as a white lyophilized powder in single-dose vials in the following package size:

Each package contains one package insert and one of each of the components listed below:

• Single-dose vial of OBIZUR [NDC 0944-5011-01]
• Pre-filled syringe with 1 mL Sterile Water for Injection [NDC 0944-0011-01]
• Vial adapter with filter

The actual amount of OBIZUR in units is stated on the label of each vial.

Not made with natural rubber latex.

Storage and Handling

• Store OBIZUR at refrigeration temperature of 2° to 8°C [36° to 46°F]. Do not freeze.
• Store vials in the original package to protect from light.
• Do not use beyond the expiration date printed on the carton or vial.
• Use OBIZUR within 3 hours after reconstitution. Discard any unused reconstituted product if not used within 3 hours after reconstitution.
• Do not use OBIZUR if the reconstituted solution is cloudy or has particulate matter.