General precautions

• Prepare HEMGENIX using sterile technique under aseptic conditions, proper engineering controls (e.g., biological safety cabinet or isolator) and according to institutional policies.
• Do not expose HEMGENIX to the light of an ultraviolet radiation disinfection lamp.
• Confirm that the patient's identity matches with the patient-specific identifier number on the outer carton.
• Verify the required dose of HEMGENIX based on the patient's body weight.
• Confirm that the carton contains sufficient number of vials to prepare the diluted HEMGENIX patient-specific infusion bag.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Required supplies and materials:

Normal saline infusion bag(s)* of 500 mL (1 to 2 bags based on patient's body weight)
Labels** for the infusion bag(s) of 500 mL
IV Infusion line/drip chamber* primed with 0.9% normal saline
Infusion bag connector(s)
20 mL or larger Luer-lock syringes*
20 G Needles* or vial adaptors*
70% isopropyl alcohol
Sharps disposal container

The following Table shows the supplies and materials compatible with HEMGENIX:

**Information to be included on the infusion bag label:

• Product name: Diluted Hemgenix
• Patient identifier
• Expiration date/time (24 h from the vial removal from refrigerator)
• Storage condition: Room Temperature [15-25 °C (59-77 °F] protected from light.
• Contains genetically modified organisms
• Number of infusion bag: 1 of 2 bags / 2 of 2 bags

Preparation of 0.9% normal saline infusion bags

1. Prior to dilution, spike the infusion bag(s) of 0.9% normal saline solution with applicable connector.
2. Connect a luer-lock syringe at the mixing adapter site of the applicable connector.
3. Withdraw the volume equal to the calculated HEMGENIX dose (in mL) from the 500 mL infusion bag(s) of 0.9% normal saline solution. The volume to be withdrawn and number of infusion bag(s) needed will vary based on the patient body weight:

HEMGENIX injection to the 0.9% normal saline infusion bags

• Dilute HEMGENIX with 0.9% normal saline solution only prior to administration.

4.

Prior to dilution, inspect each of the HEMGENIX single-dose vials.

• If particulates, cloudiness, or discoloration is visible, DO NOT use the vial(s).

5.

Gently swirl the vials 3 times (about 10 seconds) to homogenize the HEMGENIX suspension.

• To avoid foaming, DO NOT shake the HEMGENIX vial(s).

6.

Remove the plastic flip-off cap from the vials and disinfect the rubber stopper with a sterilizing agent (for example sterile 70% isopropyl alcohol).

7.

Withdraw HEMGENIX from each vial using a 20 G needle/vial adapter and syringe.

• Use recommended 20 mL luer-lock or larger syringe that is suitable for volume measuring and a needle.
• DO NOT use filter needles during preparation of HEMGENIX.
• Use a new needle/vial adapter and syringe for each HEMGENIX vial.
• Dispose of the needle and syringe in an appropriate container.

8.

Slowly add the required HEMGENIX dose from the syringe(s) directly to the 0.9% normal saline solution in the infusion bag(s) (from step #3) to bring the total volume in each infusion bag back to 500 mL.

• DO NOT add HEMGENIX into the airspace of the bag to avoid foaming throughout this process.

9.

Repeat steps 7 and 8 with additional needles/vial adaptors and syringes to inject the total calculated HEMGENIX volume to the infusion bag(s) required for the patient dose.

10.

Gently invert the infusion bag(s) at least 3 times (about 10 seconds) to mix the solution and ensure even distribution of the diluted product.

• To avoid foaming, DO NOT shake the diluted HEMGENIX infusion bag(s).

11.

Label the infusion bag(s).

12.

Connect the infusion bag(s) to an infusion tube pre-filled with sterile 0.9% normal saline solution to reduce the risk of spillage and/or aerosol formation.

13.

Transport the diluted HEMGENIX infusion bag(s) in the transport container/bag protected from light to the administration site, avoiding any shaking or excessive agitation.

Required supplies and materials for administration:

Winged intravenous needle or catheter set*
Infusion pump
0.2 mcm in-line filter*
Antiseptic skin preps
70% isopropyl alcohol wipes
Gauze and tape, or transparent dressing
Sharps disposal container
Virucidal agent to treat spill/spill kit

The following Table shows the supplies and materials compatible for infusion of HEMGENIX:

Administer HEMGENIX as a single-dose intravenous infusion through a peripheral venous catheter:

1. Visually inspect diluted HEMGENIX prior to administration. The diluted HEMGENIX should be clear and colorless.
   • DO NOT use if particulates, cloudiness, or discoloration are visible.
   • Use the diluted HEMGENIX within 24 hours after the dose preparation [see How supplied/Storage and Handling (16.2)].
2. Use an integrated (in-line) 0.2 mcm filter made out of PES.
3. Subsequently, connect the pre-filled IV infusion line/drip chamber to the main intravenous line which has been primed with sterile 0.9% normal saline solution prior to use.
4. Infuse diluted HEMGENIX at a constant infusion rate of 500 mL/hour (8 mL/min).
   • DO NOT administer HEMGENIX as an intravenous push or bolus.
   • DO NOT infuse the diluted HEMGENIX solution in the same intravenous line with any other products.
   • DO NOT use a central line or port.
   In the event of an infusion reaction during administration [see Warnings and Precautions (5.1)]:
   • The rate of infusion may be reduced or stopped, to manage the infusion reaction.
     If the infusion is stopped, restart at a slower rate when the infusion reaction is resolved.
   • If the infusion rate needs to be reduced, or stopped and restarted, HEMGENIX should be infused within 24 hours after the dose preparation [see How supplied/Storage and handling (16.2)].
5. After the entire content of the bag(s) is infused, flush the IV infusion line/drip chamber at the same infusion rate with 0.9% normal saline solution to ensure all HEMGENIX is delivered.
   • Treat spills of HEMGENIX with a virucidal agent with proven activity against non-enveloped viruses.
   • Dispose of unused product and disposable materials that may have come in contact with HEMGENIX in accordance with local biosafety guidelines applicable for handling and disposal of the pharmaceutical waste.

Monitoring Post-Administration

Conduct the following tests after HEMGENIX administration [see Warnings and Precautions (5.2, 5.3, 5.4)]:

• Perform regular liver enzyme testing to monitor for liver enzyme elevations which may indicate immune-mediated hepatotoxicity:
  • Monitor ALT and AST (transaminase) levels by testing weekly for 3 months following administration of HEMGENIX. Continue to monitor transaminases in all patients who developed liver enzyme elevations until liver enzymes return to baseline.
  • In the event of ALT increase to above normal limits or to twice the patient`s baseline in the first 3 months post-dose, consider implementing a course of corticosteroids. For patients with clinically relevant ALT increases who need corticosteroid treatment, administer the recommended starting dose of 60 mg/day of oral prednisolone or prednisone, with a subsequent taper in response to normalization of the ALT levels (see Table 1):

  Table 1. Prednisolone Treatment Applied in Clinical Studies With HEMGENIX:

  Timeline	*Prednisolone Oral Dose (mg/day)
  * Medications equivalent to prednisolone may also be used. A combined immunosuppressant regimen or the use of other products can be considered in case of prednisolone treatment failure or contraindication.
  Week 1	60
  Week 2	40
  Week 3	30
  Week 4	30
  Maintenance dose until ALT level returns to baseline level	20
  Taper dose after ALT baseline level has been reached	Reduce daily dose by 5 mg/week

  
  In the clinical studies, the mean duration of corticosteroid use for elevated transaminases was 81.4 days [Standard Deviation (SD) 28.6] and ranged from 51 to 130 days [see Warnings and Precautions (5.2)].
• Monitor Factor IX activity (e.g., weekly for 3 months).
  • Monitor patients regularly for their Factor IX activity, in particular when exogenous Factor IX is administered. It may take several weeks before improved hemostatic control becomes apparent after HEMGENIX infusion; therefore, continued hemostatic support with exogenous human Factor IX may be needed during the first weeks after HEMGENIX infusion [see Clinical Pharmacology (12.3)].
  • The use of different assays may impact the test results; therefore, use the same assay and reagents to monitor patients over time, if feasible [see Monitoring Laboratory Tests (5.5)].
  • Use of exogenous Factor IX concentrates before and after HEMGENIX administration may impede assessment of endogenous, HEMGENIX-derived Factor IX activity.
• Perform regular alpha-fetoprotein (AFP) level testing and abdominal ultrasound (e.g., annually) in patients with preexisting risk factors for hepatocellular carcinoma (e.g., in patients with cirrhosis, advanced hepatic fibrosis, hepatitis B or C, non-alcoholic fatty liver disease (NAFLD), chronic alcohol consumption, non-alcoholic steatohepatitis (NASH), and advanced age).
• Monitor patients for human Factor IX inhibitors. Post-dose inhibitor testing should be performed if bleeding is not controlled, or plasma Factor IX activity levels decrease [see Warnings and Precautions (5.5)].