Calculating Dose in Milliliters (mL) and Number of Vials Required

• Patient dose volume in mL:

  Body weight in kg multiplied by 3 = dose in mL.

  The multiplication factor 3 represents the per kilogram dose (6 × 1013 vg/kg) divided by the amount of vector genomes per mL of the ROCTAVIAN suspension (2 × 1013 vg/mL).
• Number of ROCTAVIAN vials to be thawed:

  Patient dose volume (mL) divided by 8 = number of vials to be thawed (round up to next whole number of vials).

  The division factor 8 represents the minimum volume of ROCTAVIAN extractable from a vial (8 mL).

ROCTAVIAN can be administered only once.

Required Equipment and Materials

• Flow rate-controlled syringe pump
• Syringes for ROCTAVIAN administration (the number of syringes will depend on the patient's dose volume and the syringe pump used and should be prepared prior to administration of ROCTAVIAN)
• 18- to 21-gauge sharp needles
• High-volume, in-line, low protein binding infusion filter with a pore size of 0.22 microns and maximum operating pressure adequate for the syringe pump or pump settings. Ensure availability of a sufficient number of replacement filters, according to the specifications for maximum filtered fluid volume.
• Syringe of 0.9% Sodium Chloride Injection, USP sodium chloride 9 mg/mL (0.9%) solution for priming and flushing the infusion line
• When assembling the infusion system, refer to the compatible materials with ROCTAVIAN suspension listed in Table 2.

General Precautions

• Do not expose ROCTAVIAN to the light of an ultraviolet radiation disinfection lamp.
• Prepare ROCTAVIAN using aseptic technique. Wear gloves and safety glasses during preparation and administration.
• Treat spills of ROCTAVIAN with a virucidal agent with proven activity against non-enveloped viruses and blot using absorbent materials.
• Dispose unused medicinal product and materials that may have come in contact with ROCTAVIAN in accordance with the local biosafety guidelines.

Thaw and Inspect

1.

Keep each vial in its carton until ready to thaw. ROCTAVIAN is sensitive to light.

2.

Thaw ROCTAVIAN at room temperature. Do not thaw or warm vials any other way. Thawing time is approximately 2 hours.

3.

Remove the required number of vials from their cartons.

4.

Inspect the vials for damage to the vial or cap. Do not use if damaged.

5.

Set the vials upright. To achieve optimal thawing, spread them out evenly or place them in racks that have been kept at room temperature.

6.

Visually confirm that all vials have been thawed. There should be no visible ice.

7.

Very gently invert each vial 5 times to mix. It is important to minimize foaming.

8.

Let the suspension settle for approximately 5 minutes before continuing.

9.

Visually inspect the fully thawed vials. Do not use a vial if the suspension is not clear, not colorless to pale yellow, or contains visible particles.

ROCTAVIAN contains no preservative. For microbiological safety, keep the thawed suspension in the vials until it is time for infusion.

If necessary, an intact vial (stopper not yet punctured) that has been thawed at room temperature can be stored refrigerated between 2 to 8°C (36 to 46°F) for up to 3 days, upright and protected from light (e.g., in the original carton).

Thawed ROCTAVIAN (in vials or syringes) can be held at room temperature, up to 25°C (77°F), for a maximum of 10 hours including hold time in intact vial, preparation time into the syringes, and duration of infusion.

Extraction into Syringes

10.

Using 18 to 21-gauge sharp needles, slowly extract ROCTAVIAN from the vials into the infusion-pump syringes. All infusion-pump syringes should be prepared prior to administering ROCTAVIAN. The contents of multiple vials may be combined into a single syringe.

Addition of In-line Filter and Priming of the Infusion System

11.

Insert the in-line filter close to the infusion site.

12.

Prime tubing and filter with ROCTAVIAN.

13.

When replacing filters during the infusion, use 0.9% Sodium Chloride Injection, USP, for priming and flushing.

Incompatibilities

Do not use infusion system components other than those described in Table 2. ROCTAVIAN must not be mixed or diluted with infusion solutions; 0.9% Sodium Chloride Injection, USP is used to prime and flush the infusion line.

Monitoring Post-Administration

Conduct the following tests after ROCTAVIAN administration [see Warnings and Precautions (5.2, 5.4, 5.5)].

• Perform regular ALT testing to monitor for elevations. Elevated liver enzymes, especially elevated ALT, may indicate immune-mediated hepatotoxicity and may be associated with decline in factor VIII activity.
  The monitoring schedule for ALT, and recommendations for corticosteroid use (initiation and taper) are based on the clinical efficacy and safety experience of 112 patients in a clinical study with ROCTAVIAN.
  • Monitor ALT weekly for at least 26 weeks following administration of ROCTAVIAN. See Table 3 for monitoring schedule. Monitor AST and creatine phosphokinase (CPK) as needed to help rule out alternative causes for ALT elevations (including potentially hepatotoxic medications or agents, alcohol consumption, or strenuous exercise). Consider repeating ALT testing within 24 to 48 hours to confirm ALT elevation prior to initiation of corticosteroid treatment and using the same laboratory to measure ALT activity at baseline and over time to minimize the impact of inter-laboratory variability on test results.
  • If ALT ≥ 1.5 × baseline or above ULN consider corticosteroid treatment. For patients who need corticosteroid therapy, the recommended starting dose is 60 mg with a subsequent taper upon return of ALT levels to baseline (see Table 4 below for recommendation on corticosteroid treatment).
  • Monitor ALT weekly, and as clinically indicated, during corticosteroid therapy. Continue to monitor ALT until its return to baseline.
  • Monitor for and manage adverse reactions secondary to corticosteroid use. Refer to the corticosteroid prescribing information for risks and required precautions.

There is limited information on the benefit of starting a corticosteroid course after the first year of ROCTAVIAN administration.

Other immunosuppressive therapies (e.g., tacrolimus, mycophenolate mofetil) may be considered if corticosteroids are contraindicated, ineffective or there are adverse reactions secondary to corticosteroid use necessitating discontinuation.

• Monitor Factor VIII Activity
  • Monitor factor VIII activity using the same schedule for ALT monitoring in Table 3 [see Warnings and Precautions (5.4)].
  • Consider more frequent monitoring in patients with factor VIII activity levels ≤ 5 IU/dL and evidence of bleeding, taking into account the stability of factor VIII levels since the previous measurement.
  • It may take several weeks after ROCTAVIAN infusion before ROCTAVIAN-derived factor VIII activity rises to a level sufficient for prevention of spontaneous bleeding episodes. Therefore, continued routine prophylaxis support with exogenous factor VIII or other hemostatic products used in the management of hemophilia A may be needed during the first few weeks after ROCTAVIAN infusion [see Clinical Pharmacology (12.3)]. Exogenous factor VIII or other hemostatic products may also be required in case of surgery, invasive procedures, trauma, or bleeds in the event that ROCTAVIAN-derived factor VIII activity is deemed insufficient for adequate hemostasis in such situations.
  • The use of different assays may impact test results; therefore, use the same assay and reagents to monitor patients over time, if feasible [see Warnings and Precautions (5.4)].
  • Use of exogenous factor VIII products before and after ROCTAVIAN administration may impede assessment of ROCTAVIAN-derived factor VIII activity.
• Monitor patients for factor VIII inhibitors (neutralizing antibodies to factor VIII). Test for factor VIII inhibitors especially if bleeding is not controlled, or plasma factor VIII activity levels decrease [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.6)].
• Perform regular liver ultrasound (e.g., annually) and alpha-fetoprotein (AFP) testing in patients with risk factors of hepatocellular carcinoma (e.g., hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) [see Warnings and Precautions (5.5)].