BEQVEZ Solution for infusion Ref.[109832] Active ingredients: Fidanacogene elaparvovec

For one-time single-dose intravenous infusion only.

Initiate and administer BEQVEZ in hospitals and other clinical centers under the supervision of a physician experienced in the treatment of hemophilia.

For Patient Selection

Perform testing for pre-existing neutralizing antibodies to AAVRh74var using the FDA-approved companion diagnostic. DO NOT administer BEQVEZ to patients with a positive test for antibodies to AAVRh74var [see Indications and Usage (1) and Clinical Studies (14)].

Information on FDA-approved tests for the detection of AAVRh74var pre-existing neutralizing antibodies is available at http://www.fda.gov/companiondiagnostics.

• Perform factor IX (FIX) inhibitor testing prior to infusion. DO NOT administer BEQVEZ to patients with a positive test (≥0.6 Bethesda Units [BU]) or a prior history for factor IX inhibitor.
• Perform HIV testing prior to infusion. DO NOT administer BEQVEZ to patients with either CD4+ cell count <200 mm³ or viral load ≥20 copies/mL in case of serological evidence of HIV-1 or HIV-2 infection.
• DO NOT administer BEQVEZ to patients with hypersensitivity to factor IX replacement product.
• Perform liver health assessments, which include:
  • Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase [ALP], bilirubin, albumin).
  • Laboratory tests for active hepatitis B or C.
  • Elastography and/or ultrasound and other laboratory assessments for liver fibrosis.

2.1 Dose

The recommended dose of BEQVEZ is a single-dose intravenous infusion of 5 × 10¹¹ vector genomes per kg (vg/kg) of body weight.

To determine the patient’s required dose, the following calculation steps are needed:

1. Calculation of patient’s dose weight

The dosing of BEQVEZ is based on the patient’s body mass index (BMI) in kg/m².

2. Calculation of patient’s dose volume in milliliters (mL)

Dose weight in kilograms (kg) divided by 20 = dose in mL

The division factor 20 represents the amount of vector genomes per mL of the BEQVEZ suspension (1 × 10¹³ vg/mL) divided by the per kilogram dose (5 × 10¹¹ vg/kg).

Examples of dose volume calculation:

For the number of vials required [see How Supplied/Storage and Handling (16.1)].

2.2 Preparation

General Precautions Before Handling or Administering BEQVEZ:

• BEQVEZ contains genetically modified vectors. Personal protective equipment (including gloves, safety goggles, laboratory coat and sleeves) should be worn while preparing or administering BEQVEZ.
• Confirm that the patient’s identity matches the patient-specific identifier number on the outer carton.
• Prepare BEQVEZ for intravenous infusion by diluting in 0.9% sodium chloride with 0.25% human serum albumin (HSA).

Preparation of Diluent Solution (0.9% Sodium Chloride with 0.25% HSA):

• HSA used for preparation of this product must be commercially available and comply with all local and regional compendia. Either 20% w/v or 25% w/v HSA is recommended.
• Calculate the volume of HSA required to achieve a final concentration of 0.25% w/v HSA in a 200 mL final infusion volume.
• Calculate the volume of BEQVEZ required for the patient-specific treatment.
• Calculate the volume of 0.9% sodium chloride required to achieve a final infusion volume of 200 mL when combined with BEQVEZ and HSA.
• Combine the calculated volume of HSA with the calculated volume of 0.9% sodium chloride in an appropriate intravenous (IV) infusion bag. Materials compatible with BEQVEZ are listed below:

• Mix the diluent solution gently. Do not shake. Incubate the diluent solution in the infusion bag at room temperature (15°C to 30°C [59°F to 86°F]) for at least 10 minutes prior to adding BEQVEZ [see How Supplied/Storage and Handling (16.2)].

Product Vial Thawing:

• Store in the original package to avoid direct sunlight and ultraviolet light exposure.
• Store BEQVEZ upright in the original package. If cartons or individual vials are tipped over or inverted during storage and handling, place the carton or individual vials back in the upright orientation immediately.
• Remove the inner carton from the outer carton.
• Thaw BEQVEZ vials for 1 hour at room temperature 15 °C to 30 °C (59 °F to 86 °F) in the upright orientation in the inner carton.
• Vials may be gently swirled but not shaken or inverted.
• Prior to use, ensure that visible ice crystals are not present in the suspension.
• The total time at room temperature between removing vials from frozen storage until the beginning of dose preparation should be no more than 3 hours.
• Do not re-freeze vials.

Preparation of Suspension for Infusion:

• Visually inspect thawed product for particulate matter prior to administration. Do not use vials that contain visible particulates. The thawed suspension in the vial should appear clear to slightly opalescent, colorless to slightly brown.
• The formulation does not contain a preservative and is for single use only.
• Extract the calculated volume of BEQVEZ from the vials using aseptic technique and sterile componentry.
• Combine the extracted volume of BEQVEZ with the diluent solution (0.9% sodium chloride with 0.25% HSA) for a total infusion volume of 200 mL.
• Gently mix the suspension for infusion. Do not shake.
• The suspension for infusion should be equilibrated to ambient temperature before administration to the patient.

2.3 Administration

Administer BEQVEZ in a setting where personnel and equipment are immediately available to treat infusion-related reactions [see Warnings and Precautions (5.2)].

Administration of Diluted Suspension for Infusion:

• Use diluted BEQVEZ within 24 hours of dose preparation.
• An in-line 0.2 µm IV filter may be used for administration.
• Administer diluted suspension for infusion to the patient as a peripheral IV infusion over approximately 60 minutes (approximately 3 mL/min).
• DO NOT administer as an intravenous push or bolus.
• DO NOT infuse the diluted suspension 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 (5.2)]:
  • The rate of infusion may be reduced or stopped to manage the infusion reaction.
  • Administer treatment as needed to manage infusion reaction.
  • If the infusion is stopped, restart a slower rate when the infusion reaction has resolved.
  • If the infusion rate needs to be reduced, or stopped and restarted, BEQVEZ should be infused within 24 hours of dose preparation.
• After the entire content of the infusion bag is infused, flush the infusion line using local site procedures.
• For some patients, there will be an extra vial that may not need to be used (for patients who weigh 75-80 kg, 95-100 kg, or 115-120 kg). Dispose of any unused product or waste material in accordance with local guidelines for the handling of biological waste.

General Precautions After Handling or Administering BEQVEZ:

BEQVEZ may be transmitted to persons other than the patient receiving the treatment through patient excretions and secretions [see Clinical Pharmacology (12.3)]. Temporary vector shedding of intravenously administered AAV-based gene therapies occurs primarily through urine and feces, and to some extent saliva, mucus, and semen.

To minimize the risk of transmission to other persons, instruct patients regarding proper hand hygiene when coming into direct contact with patient secretions or excretions.

Follow these precautions for 6 months after BEQVEZ infusion, especially in the case of pregnancy or immunodeficiency of close contacts [see Use in Specific Populations (8.3)].

Monitoring Post-Administration:

Conduct the following laboratory tests after administration of BEQVEZ:

• Perform ALT, AST as in Table 1 to monitor for liver enzyme elevation which may indicate immunemediated hepatotoxicity. Liver enzyme elevation may result in decrease in factor IX activity. Perform factor IX activity testing as shown in Table 1.
• In patients with elevated transaminases and/or decline in factor IX activity, continue monitoring transaminases and factor IX activity until transaminases return to baseline and/or factor IX activity has plateaued.

Table 1. Recommended Hepatic Function (ALT and AST) and Factor IX Activity Monitoring:

It is recommended where possible to use the same laboratory facility for monitoring over time, particularly during the timeframe for corticosteroid treatment decision making, to minimize inter-laboratory variability.
^* Starting at Week 65.

• Consider implementing a course of corticosteroids as outlined in Table 2 for any of the following:
  • Single increase in either ALT or AST of ≥1.5-fold from baseline after screening and prior to infusion even if within the normal range.
  • Consecutive increases in transaminases (ALT or AST or both) on 2 subsequent blood tests even if within the normal range.
  • Factor IX activity decrease
    • In the absence of alternative etiology, a decrease that could trigger the risk of bleeding.
    • A decrease in factor IX activity on 2 consecutive blood tests especially if occurring during the first 4 months post-infusion.
• The recommended starting dose of oral corticosteroids is 60 to 100 mg once a day. Start to taper prednisolone/prednisone when the ALT and/or AST have declined for at least 2 consecutive lab draws and/or the levels have begun to normalize and any decline in factor IX activity has plateaued.
• Monitor for and manage adverse reactions secondary to corticosteroid use. Refer to the corticosteroid prescribing information for risks and required precautions.

Table 2. Recommended Treatment Regimen for Oral Corticosteroids:

^* Based on body weight.
^** See the paragraph below this table.
^*** Maintain at 20 mg/day until transaminases return to baseline, then reduce by 5 mg/day until 10 mg/day are achieved then reduce by 2.5 mg/week up to 5 mg daily.

If there is persistent transaminase elevation while on oral corticosteroids treatment alone, consult with a hepatologist as required to discuss use of combined oral and intravenous corticosteroids (methylprednisolone).

• Monitor Factor IX Activity
  • Monitor factor IX activity levels according to Table 1 to confirm adequate endogenous FIX activity levels to support discontinuation of pre-infusion FIX prophylaxis therapy. In the clinical studies, a prophylactic dose of factor IX replacement was given prior to BEQVEZ infusion and following that, patients discontinued prophylaxis. Exogenous factor IX or other hemostatic products may also be required in case of surgery, invasive procedures, trauma, or bleeds in the event that BEQVEZ-derived factor IX 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 FIX concentrates before and after BEQVEZ administration may impede assessment of endogenous, BEQVEZ-derived factor IX activity.
• Monitor patients for factor IX inhibitors (neutralizing antibodies to factor IX). Test for factor IX inhibitors especially if bleeding is not controlled, or plasma factor IX 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 (5.3)].

BEQVEZ is shipped and delivered frozen between -100°C to -60°C (-148°F to -76°F) in clear vials.

Upon receipt, immediately place in a freezer between -90°C to -60°C (-130°F to -76°F).

Store in the original package to avoid direct sunlight and ultraviolet light exposure.

Store upright in the original package. If cartons or individual vials are tipped over or inverted during storage and handling, place the carton or individual vials back in the upright orientation immediately.

Frozen vials in the inner carton will take up to 1 hour to thaw at room temperature (up to 30°C [86°F]). Vials may be gently swirled but not shaken or inverted. The total time at room temperature between removing vials from frozen storage until the beginning of dose preparation should be no more than 3 hours. Once thawed, the medicinal product should not be re-frozen and may be stored refrigerated at 2°C to 8°C (36°F to 46°F) in the inner carton up to 24 hours.

Following dilution in 0.9% sodium chloride with 0.25% HSA, chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 30°C (36°F to 86°F).