Limitation of Use

AFSTYLA is not indicated for the treatment of von Willebrand disease.

2.1 Dosing Guidelines

• Dose 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.
• Each vial of AFSTYLA states the actual amount of Factor VIII activity in International Units (IU) as determined by chromogenic assay. One IU corresponds to the activity of Factor VIII contained in 1 milliliter (mL) of normal human plasma.
• Plasma Factor VIII levels can be monitored using either a chromogenic assay or a one-stage clotting assay – routinely used in US clinical laboratories. If the one-stage clotting assay is used, multiply the result by a conversion factor of 2 to determine the patient's Factor VIII activity level [see Warnings and Precautions (5.3)].

2.2 Preparation and Reconstitution

• Reconstitute AFSTYLA using aseptic technique with diluent provided in the kit.
• Visually inspect the reconstituted solution for particulate matter prior to administration. The solution should be free from visible particles. Do not use if particulate matter is observed.

The procedures provided in Table 3 are general guidelines for the preparation and reconstitution of AFSTYLA.

Table 3. AFSTYLA Reconstitution Instructions

1. Ensure that the AFSTYLA vial and diluent vial are at room temperature. Prepare and administer using aseptic technique.
2. Place the AFSTYLA vial, diluent vial, and Mix2Vial ® transfer set on a flat surface.
3. Remove AFSTYLA and diluent vial flip caps. Wipe the stoppers with the sterile alcohol swab provided and allow the stoppers to dry prior to opening the Mix2Vial transfer set package.
4. Open the Mix2Vial transfer set package by peeling away the lid (Fig. 1). Leave the Mix2Vial transfer set in the clear package.	Fig. 1
5. Place the diluent vial on a flat surface and hold the vial tightly. Grip the Mix2Vial transfer set together with the clear package and push the plastic spike at the blue end of the Mix2Vial transfer set firmly through the center of the stopper of the diluent vial (Fig. 2).	Fig. 2
6. Carefully remove the clear package from the Mix2Vial transfer set. Make sure that you pull up only the clear package, not the Mix2Vial transfer set (Fig. 3).	Fig. 3
7. With the AFSTYLA vial placed firmly on a flat surface, invert the diluent vial with the Mix2Vial transfer set attached and push the plastic spike of the transparent adapter firmly through the center of the stopper of the AFSTYLA vial (Fig. 4). The diluent will automatically transfer into the AFSTYLA vial.	Fig. 4
8. With the diluent and AFSTYLA vial still attached to the Mix2Vial transfer set, gently swirl the AFSTYLA vial to ensure that the AFSTYLA is fully dissolved (Fig. 5). Do not shake the vial.	Fig. 5
9. With one hand, grasp the AFSTYLA side of the Mix2Vial transfer set and with the other hand grasp the blue diluent-side of the Mix2Vial transfer set, and unscrew the set into two pieces. (Fig. 6).	Fig. 6
10. Draw air into an empty, sterile syringe. While the AFSTYLA vial is upright, screw the syringe to the Mix2Vial transfer set. Inject air into the AFSTYLA vial. While keeping the syringe plunger pressed, invert the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly. (Fig. 7).	Fig. 7
11. Now that the concentrate has been transferred into the syringe, firmly grasp the barrel of the syringe (keeping the plunger facing down) and unscrew the syringe from the Mix2Vial transfer set (Fig. 8).	Fig. 8
12. After reconstitution, infuse immediately or within 4 hours. Reconstituted AFSTYLA may be stored at room temperature, not to exceed 25°C (77°F), for up to 4 hours. Do not freeze. Protect from direct sunlight.
13. Record treatment – Remove the peel-off portion of the label from each vial used, and affix it to the patient's treatment diary/log book or scan the vial if recording the infusion electronically.
14. If the dose requires more than one vial, use a separate, unused Mix2Vial ® transfer set for each product vial. Repeat step 10 to pool the contents of the vial into one syringe.

2.3 Administration

• Use aseptic technique when administering AFSTYLA.
• Do not mix AFSTYLA with other medicinal products.
• Administer by intravenous injection. The rate of administration should be determined by the patient's comfort level. Do not exceed infusion rate of 10 mL per minute.
• Administer AFSTYLA at room temperature within 4 hours after reconstitution.
• AFSTYLA is for single use only. Following administration, discard any unused solution and all administration equipment in an appropriate manner as per local requirements.
• If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteremia and catheter site thrombosis should be considered.

5.1 Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, are possible with AFSTYLA. Inform patients of the early signs of hypersensitivity reactions that may progress to anaphylaxis (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension and pruritus). Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.

For patients with previous hypersensitivity reactions, consider premedication with antihistamines.

5.2 Neutralizing Antibodies

Formation of neutralizing antibodies (inhibitors) to Factor VIII can occur following administration of Factor VIII products. Monitor patients for the development of neutralizing antibodies (inhibitors) by appropriate clinical observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled after AFSTYLA administration, the presence of an inhibitor (neutralizing antibody) should be suspected [see Warnings and Precautions (5.3)].

Contact a specialized hemophilia treatment center if a patient develops an inhibitor.

5.3 Monitoring Laboratory Tests

• Monitor plasma Factor VIII activity in patients receiving AFSTYLA using either the chromogenic assay or the one-stage clotting assay, which is routinely used in US clinical laboratories. The chromogenic assay result most accurately reflects the clinical hemostatic potential of AFSTYLA and is preferred. The one-stage clotting assay result underestimates the Factor VIII activity level compared to the chromogenic assay result by approximately one-half. If the one-stage clotting assay is used, multiply the result by a conversion factor of 2 to determine the patient's Factor VIII activity level. Incorrect interpretation of the Factor VIII activity obtained by the one-stage clotting assay could lead to unnecessary additional dosing, higher chronic dosing, or investigations for an inhibitor.
• Monitor for the development of Factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected plasma Factor VIII activity levels are not attained or if bleeding is not controlled with the expected dose of AFSTYLA. Use Bethesda Units (BU) to report inhibitor levels.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

The safety, efficacy and pharmacokinetics of AFSTYLA have been eva luated in 258 previously treated patients (PTPs) with severe hemophilia A (<1% endogenous Factor VIII activity) who received at least one dose of AFSTYLA as part of either routine prophylaxis, on-demand treatment of bleeding episodes or perioperative management in two completed clinical trials (an adult/adolescent study [≥12 to 65 years of age] and a pediatric study [<12 years of age]), and an ongoing extension study (0 to ≤65 years of age). Patients with a history of, or current FVIII inhibitors, or any first order family history of FVIII inhibitors, patients with known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein, and patients with evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months prior to Day 1 of the study were excluded from study participation.

Eighty-four (32.6%) subjects were children <12 years of age (35 [13.6%] 0 to <6 years and 49 [19.0%] ≥6 to <12 years), 14 (5.4%) were adolescents (≥12 to <18 years), and 160 (62.0%) were adults (≥18 to ≤65 years). There have been a total of 28,418 exposure days (EDs), with at least 28,492 injections of AFSTYLA administered. In the completed studies, a total of 185 subjects achieved at least 50 EDs, of whom 60 subjects achieved ≥100 EDs.

Adverse reactions (ARs) (summarized in Table 4) were reported for 14 of 258 (5.4%) subjects in all studies. An adverse reaction of hypersensitivity resulted in the withdrawal of one subject. No subject developed neutralizing antibodies (inhibitors) to Factor VIII or antibodies to host cell proteins. No events of anaphylaxis or thrombosis were reported.

6.2 Immunogenicity

All subjects were monitored for inhibitory and binding antibodies to AFSTYLA, and binding antibodies to chinese hamster ovary (CHO) host cell proteins prior to the first infusion of AFSTYLA, at defined intervals during the studies and at the end of study visit.

No subjects developed neutralizing antibodies (inhibitors) to Factor VIII or antibodies against CHO host cell proteins at any time during the clinical studies. Four subjects in the adult/adolescent study and 10 subjects in the pediatric study were negative for non-neutralizing anti-drug antibodies (ADAs) at screening and turned positive during the clinical study. Two of the adult/adolescent subjects and 3 of the pediatric subjects who developed ADAs were negative at end of study visit. No adverse events were associated with the development of ADAs. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of 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. For these reasons, it may be misleading to compare the incidence of antibodies to AFSTYLA with the incidence of antibodies to other products.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and efficacy studies with AFSTYLA have been performed in 98 previously treated pediatric patients <18 years of age. Fourteen adolescent subjects ≥12 to <18 years were enrolled in the adult/adolescent safety and efficacy study. Thirty-five subjects 0 to <6 years and 49 subjects ≥6 to <12 years were enrolled in a pediatric safety and efficacy study [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. Because clearance (based on per kg body weight) has been shown to be higher in the pediatric population 0 to <12 years, more frequent or higher doses of AFSTYLA based on body weight may be needed [see Clinical Pharmacology (12.3)].

8.5 Geriatric Use

Clinical studies of AFSTYLA did not include subjects over 65 years to determine whether or not they respond differently from younger subjects.