fidanacogene elaparvovec (Rx)

>10%

Transaminases increased (13.3-53.3%)

Contraindications

None

Cautions

Hepatotoxicity

• IV administration of a liver-directed AAV vector could lead to liver enzyme elevations, especially ALT elevation
• Transaminase elevations, particularly when observed in the first 4 months after administration, is presumed to occur due to immune-mediated injury of transduced hepatocytes and may reduce therapeutic efficacy of the AAV vector-based gene therapy
• Monitor ALT, AST, and factor IX activity levels 1-2x weekly for at least 4 months and institute corticosteroid treatment in response to transaminase elevation and/or decrease in FIX activity, as required
• Monitor for and manage adverse reactions secondary to corticosteroid therapy
• For the first year following administration, advise patients to limit alcohol consumption, since it may impact liver enzyme elevation and potentially reduce factor IX activity over time

Infusion reactions

• Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, may occur
• Symptoms include but are not limited to hypotension, pyrexia, palpitation, nausea, vomiting, chills, or headache
• Monitor patients during and for at least 3 hr after completing infusion
• If infusion reaction occurs, slow or stop administration
• Restart at a lower rate once infusion reaction has resolved
• Discontinue infusion for anaphylaxis
• Consider management of an infusion reaction with a corticosteroid, antihistamine, and other measures

Malignancy

• Integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development; integration of AAV vector DNA into the host cell DNA in other tissues may also occur
• Monitor for hepatocellular malignancy in patients with risk factors for hepatocellular carcinoma (eg, hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) with regular ultrasound (eg, annually) and alpha-fetoprotein testing for 5 years after administration
• If any malignancy occurs after treatment, contact t Pfizer Inc. at 1-800-438-1985 to obtain instructions on collecting patient samples for testing

Monitoring laboratory tests

• Factor IX assays

  • When using an in vitro activated partial thromboplastin time (aPTT)-based one-stage clotting assay (OSA) for determining factor IX activity, plasma factor IX activity results can be affected by both the type of aPTT reagent, and the reference standard used in the assay
  • Higher inter-laboratory and inter-reagent variability in OSA results observed at lower factor IX activity levels (0.025 IU/mL)
  • Consider this, particularly when changing laboratory and/or reagents used in the assay
  • Recommended to use the same laboratory (applicable to both, chromogenic or one-stage assays) for factor IX activity monitoring over time, particularly during the timeframe for corticosteroid treatment decision making, to minimize the impact of inter-laboratory variability

• Factor IX inhibitors

  • Monitor patients through appropriate clinical observations and laboratory tests for development of inhibitors to factor IX after fidanacogene elaparvovec administration
  • Perform an assay that detects factor IX inhibitors if bleeding uncontrolled, or plasma factor IX activity levels decrease

Drug interaction overview

• Vaccinations

  • Do NOT administer live vaccines while on immunosuppressive therapy
  • Before infusion, ensure patients are up-to-date on their vaccinations
  • Consider adjusting individual vaccination schedules to accommodate concomitant immunosuppressive therapy

Pregnancy

Not intended for administration in women

There are no data regarding use in pregnant women

No animal reproductive studies have been conducted

Contraception

• Males

  • Vector DNA was shed in semen but declined to undetectable levels in semen within a mean of 1-4 months after infusion
  • Male patients should refrain from donating sperm, be abstinent or use a male condom for up to 6 months after receiving fidanacogene elaparvovec

Fertility

• No studies in animals or clinical studies have been performed to evaluate potential effects on fertility in humans

Lactation

Not intended for administration in women.

Data are not available regarding presence of fidanacogene elaparvovec in human milk, effect on breastfed infants, and effects on milk production

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Gene therapy designed to introduce in the transduced cells a functional copy of the factor IX gene encoding a high-activity FIX variant (FIX-R338L, hFIX Padua)

AAVRh74var capsid is able to transduce hepatocytes, the natural site of factor IX synthesis

A single IV infusion results in cell transduction and increase in circulating factor IX activity in patients with hemophilia B

IV Preparation

General precautions

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

0.9%NaCl/0.25% HSA diluent preparation

• HSA used for preparation of this product must be commercially available and comply with all local and regional compendia
• Use either 20% w/v or 25% w/v HSA
• Calculate HSA volume required to achieve a final concentration of 0.25% w/v HSA in a 200 mL final infusion volume
• Calculate volume of fidanacogene elaparvovec required for the patient-specific treatment
• Calculate volume of 0.9% NaCl required to achieve a final infusion volume of 200 mL when combined with fidanacogene elaparvovec and HSA
• Combine calculated HAS volume with calculated volume of 0.9% NaCl in an appropriate IV infusion bag (PVC, EVA, or polyolefin [polyethylene and/or polypropylene])
• Infusion set material: PVC, polybutadiene, polyurethane, or polyethylene
• Mix diluent solution gently; do NOT shake
• Incubate diluent solution in infusion bag at room temperature (15-30ºC [59-86ºF]) for at least 10 minutes before adding fidanacogene elaparvovec

Product vial thawing

• Remove inner carton from outer carton
• Frozen vials in the inner carton will take up to 1 hr to thaw at room temperature (up to 30ºC [86ºF]) in upright orientation in inner carton
• Vials may be gently swirled, but not shaken or inverted
• Before use, ensure that visible ice crystals are not present in suspension
• Total time at room temperature between removing vials from frozen storage until the beginning of dose preparation should not exceed 3 hr
• Once thawed, do not refreeze
• May refrigerate at 2-8ºC (36-46ºF) in inner carton up to 24 hr

Preparation of suspension for infusion

• Visually inspect thawed product for particulate matter before administration
• Do not use vials containing visible particulates
• Thawed suspension should appear clear to slightly opalescent, colorless to slightly brown
• Does not contain a preservative and is for single use only
• Extract calculated dose volume from vials using aseptic technique and sterile componentry
• Combine extracted dose volume with 0.9% NaCl/0.25% HAS diluent solution for total infusion volume of 200 mL
• Gently mix suspension for infusion; do NOT shake
• Suspension for infusion should be equilibrated to ambient temperature before administration

IV Administration

Administer in a setting where personnel and equipment are immediately available to treat infusion-related reactions

Use diluted within 24 hr of dose preparation

An in-line 0.2 μm IV filter may be used for administration

Administer as a peripheral IV infusion over ~60 minutes (~3 mL/min); do not infuse in IV line with any other medicinal

Do NOT administer IV push or bolus

Do NOT use a central line or port

Flush infusion line using local site procedures after entire content of infusion bag is infused

For some patients, there will be an extra vial that may not need to be used (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 handling of biological waste

If infusion reaction occurs

• Reduced rate or stop infusion to manage reaction
• Administer treatment as needed to manage infusion reaction
• If infusion stopped, restart at slower rate when reaction resolved
• If infusion rate needs to be reduced, or stopped and restarted, dilution be infused within 24 hr of dose preparation

General precautions after handling or administering

• Fidanacogene elaparvovec may be transmitted to persons other than the patient receiving treatment through patient excretions and secretions
• Temporary vector shedding of IV administered AAV-based gene therapies occurs primarily through urine and feces, and to some extent saliva, mucus, and semen
• Minimize 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 infusion, especially in the case of pregnancy or immunodeficiency of close contacts

Conduct the following laboratory tests after administration

• Perform ALT, AST to monitor for liver enzyme elevation which may indicate immune-mediated hepatotoxicity
• Liver enzyme elevation may result in decreased factor IX activity
• 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
• Perform regular liver ultrasound (eg, annually) and alpha-fetoprotein (AFP) testing in patients with risk factors of hepatocellular carcinoma (eg, hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age)

• ALT, AST, FIX monitoring schedule

  • Weeks 1-16: 1-2 x weekly
  • Weeks 17-18: Weekly
  • Weeks 19-52: At weeks 24, 32, 42, and 52
  • Year 2 through year 3: Quarterly
  • Year 4 through year 6: Twice yearly
  • >6 years: Annually

Corticosteroids

• Consider implementing a course of corticosteroids 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 normal range
  • Consecutive increases in transaminases (ALT or AST or both) on 2 subsequent blood tests even if within normal rang
  • Factor IX activity decrease that could trigger risk of bleeding, or a decrease in FIX activity on 2 consecutive blood tests especially if occurring during the first 4 months post-infusion
  • Recommended starting dose (prednisolone/prednisone): 60-100 mg qDay; start taper when ALT/AST declines for at least 2 consecutive lab draws and/or levels begin to normalize and any decline in FIX activity has plateaued

• Recommended treatment regimen for oral corticosteroids (prednisolone/prednisone)

  • Week 1: 60-100 mg/day*
  • Week 2: 60 mg/day
  • Week 3: 40 mg/day
  • Week 4: 30 mg/day
  • Week 5: 30 mg/day
  • Week 6: 20 mg/day**
  • Week 7: 15 mg/day
  • Week 8: 10 mg/day
  • *Based on body weight
  • **Maintain 20 mg/day until transaminases return to baseline; then reduce by 5 mg/day until 10 mg/day achieved then reduce by 2.5 mg/week up to 5 mg/day
  • If there is persistent transaminase elevation while on oral corticosteroids treatment alone, consult with hepatologist as required to discuss use of combined oral and intravenous corticosteroids (methylprednisolone)

Storage

Shipping

• Shipped and delivered frozen between −100ºC to −60ºC (−148ºF to −76ºF)

Unopened package

• Upon receipt, immediately place in freezer between −90ºC to −60ºC (−130ºF to −76ºF)
• Store in original package to avoid direct sunlight and ultraviolet light exposure
• Store upright in original package
• If cartons or individual vials are tipped over or inverted during storage and handling, place carton or individual vials back in upright orientation immediately

Thawed

• Refrigerate at 2-8ºC (36-46ºF) in inner carton up to 24 hr
• Do not re-freeze

Dilution

• Store at 2-30ºC (36-86ºF) for up to 24 hr