Dose

•

Dosage and duration of treatment depend on the severity of the Factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.

•

Each vial label of KOVALTRY states the Factor VIII potency in international units (IU). One IU is defined by the current WHO (World Health Organization) international standard (IS) for Factor VIII concentrate.

•

Potency assignment for KOVALTRY is determined using a chromogenic substrate assay. A field study involving 41 clinical laboratories from around the world measured recoveries of KOVALTRY spiked into hemophilic plasma. The results of the field study indicated that the Factor VIII activity of KOVALTRY can be accurately measured in plasma using either a one-stage clotting or chromogenic substrate assay according to routine methods of the testing laboratory.

•

The required dose for a desired Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formula:

Required dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal or IU/dL)
x reciprocal of expected/observed recovery (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg)

The expected in vivo peak increase of Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formula:

Estimated increment of Factor VIII (IU/dL or % of normal) = [Total dose (IU)/body weight (kg)]
x 2 (IU/dL per IU/kg)

Examples (assuming patient’s baseline Factor VIII is <1%):

•

A peak of 50% [50 IU/dL] is required in a 20 kg child. In this situation, the required dose of KOVALTRY would be 20 kg x 50 IU/dL x 0.5 (for recovery of 2 IU/dL per IU/kg) = 500 IU

•

A dose of 2000 IU of KOVALTRY administered to a 50 kg patient should be expected to result in post-infusion Factor VIII increase of 2000 IU / 50 kg (body weight) x 2 IU/dL per IU/kg = 80 IU/dL (80% of normal)

•

Adjust dose to the patient’s clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, incremental recovery) and clinical responses to KOVALTRY.

•

On-demand Treatment and Control of Bleeding Episodes

A guide for dosing KOVALTRY for the on-demand treatment and control of bleeding episodes is provided in Table 1. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1.

Perioperative Management of Bleeding

A guide for dosing KOVALTRY during surgery (perioperative management) is provided in Table 2. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2. During major surgery, monitoring with appropriate laboratory tests, including serial Factor VIII activity assays, is highly recommended [see Warnings and Precautions (5.5)].

Routine Prophylaxis

•

Individualize the patient’s dose based on clinical response.

•

Adults and adolescents: 20 to 40 IU of KOVALTRY per kg of body weight two or three times per week.

•

Children ≤12 years old: 25 to 50 IU of KOVALTRY per kg body weight twice weekly, three times weekly, or every other day according to individual requirements [see Use in Specific Populations (8.4)].

Preparation and Reconstitution

•

Reconstitute and administer KOVALTRY with the components provided with each package. If any component of the package is opened or damaged, do not use this component.

The procedures below are provided as general guidelines for the reconstitution of KOVALTRY using the sterile vial adapter with a 15 micrometer filter and a prefilled diluent syringe, which together serve as an alternative needleless reconstitution system.

Usability Testing of Vial Adapter

Usability testing was conducted with 60 users, including 15 pediatric hemophilia A patients (between 10-17 years of age), 15 adult hemophilia A patients (≥18 years of age), 15 caregivers, and 15 healthcare providers. To mimic real life, the pediatric and adult patients and the caregivers were given minimal training, which included participants performing a supervised reconstitution and later performing a single unaided reconstitution. Healthcare providers were untrained in this study and could learn the procedure from the provided Instructions for Use. All participants were able to successfully and safely use the vial adapter device for reconstitution.

Reconstitution

•

Work on a clean surface and wash hands thoroughly using soap and warm water before performing the procedures.

•

Reconstitute KOVALTRY with the components provided with each package. If any component of the package is opened or damaged, do not use this component.

•

Filter the reconstituted product to remove potential particulate matter in the solution. Filtering is achieved by using the vial adapter.

1. Warm both unopened KOVALTRY vial and prefilled diluent syringe in your hands to a comfortable temperature (do not exceed 37°C or 99°F).
2. Remove the protective cap from the vial (A). Aseptically cleanse the rubber stopper with a sterile alcohol swab, being careful not to handle the rubber stopper.
3. Place the product vial on a firm, non-skid surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step.
4. Holding the syringe by the barrel, snap the syringe cap off the tip (C). Do not touch the syringe tip with your hand or any surface. Set the syringe aside for further use.
5. Now remove and discard the adapter plastic housing (D).
6. Attach the prefilled syringe to the vial adapter thread by turning clockwise (E).
7. Remove the clear plastic plunger rod from the carton. Grasp the plunger rod by the top plate. Avoid touching the sides and threads of the plunger rod. Attach the plunger rod by turning it clockwise into the threaded rubber stopper of the prefilled syringe (F).
8. Inject the diluent slowly by pushing down on the plunger rod (G).
9. Swirl vial gently until all powder on all sides of the vial is dissolved (H). Do not shake vial. Be sure that all powder is completely dissolved. Do not use if solution contains visible particles or is cloudy.
10. Push down on the plunger to push all air back into the vial. Then while holding the plunger down, turn the vial with syringe upside-down (invert) so the vial is now above the syringe (I).
11. Withdraw all the solution into the syringe by pulling the plunger rod back slowly and smoothly (J). Tilt the vial to the side and back to make sure all the solution has been drawn toward the large opening in the rubber stopper and into the syringe. Remove as much air as possible before removing the syringe from the vial by slowly and carefully pushing the air back into the vial.
12. Detach the syringe with plunger rod from the vial adapter by turning counter-clockwise. Attach the syringe to the administration set provided and inject intravenously (K). Note: follow instructions for infusion set provided.

Pooling

If the dose requires more than one vial, reconstitute each vial as described above with the diluent syringe provided. Use a larger plastic syringe (not provided) to combine the content of the vials into the syringe.

Administration

For intravenous use only.

•

Inspect reconstituted KOVALTRY visually for particulate matter and discoloration prior to administration. Do not use if you notice any particulate matter or discoloration.

•

Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for no longer than 3 hours.

•

Infuse KOVALTRY intravenously over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient.