Infusion-related reactions, including hypersensitivity and anaphylaxis, occurred in 33% of subjects during clinical trials with etranacogene dezaparvovec. Closely monitor for signs and symptoms of an infusion-related reaction throughout the infusion period and for at least 3 hours after the end of the infusion. Do not infuse etranacogene dezaparvovec faster than 500 mL/hour. If an infusion-related reaction develops during administration, the infusion may be slowed or stopped. Restart infusion at a lower rate once the infusion reaction has resolved. Consider treatment with a corticosteroid or antihistamine for management of an infusion-related reaction. Infusion-related reaction symptoms occurred during infusion in 7 subjects and after infusion in 12 subjects. Symptoms resolved on the day or day 1 after infusion in 11 subjects and within 8 days after infusion in 8 subjects. Infusions were temporarily discontinued in 3 subjects and restarted at a slower infusion rate after treatment with antihistamines and/or corticosteroids. The infusion was stopped and not restarted in 1 subject. Symptoms may include chest tightness, headache (18%), abdominal pain (less than 5%), lightheadedness, flu-like symptoms (14%), shivering, flushing (less than 5%), rash, and hypertension. Dizziness occurred in 5% or more of subjects. Abdominal discomfort, chest discomfort [chest pain (unspecified)], chills, eye pruritus, fever, hives, injection site reaction, and sinus tachycardia occurred in less than 5% of subjects. Hypersensitivity or anaphylactoid reactions occurred in 2 subjects (4%). A subject experienced a hypersensitivity reaction at 12 minutes after initiation of administration of etranacogene dezaparvovec consisting of high blood pressure, red eyes, feeling warm, dizziness, coughing, dyspnea, elevated heart rate, shivering, and leg cramps. The infusion was stopped and not restarted; only 10% of the etranacogene dezaparvovec dose was administered. The patient recovered on the same day after treatment with intravenous diphenhydramine and intramuscular epinephrine. Another subject experienced a hypersensitivity reaction at 10 minutes after initiation of administration of etranacogene dezaparvovec consisting of itching, tightness of throat, and swelling of the right side of the neck. The dose was not interrupted and administered in full. All symptoms resolved on the same day without treatment.[68294]

Intravenous administration of a liver-directed adeno-associated virus (AAV) vector could potentially lead to liver transaminase elevations (transaminitis). Transaminitis, particularly when observed in the first 3 months after etranacogene dezaparvovec administration, is presumed to occur due to immune-mediated injury of transduced hepatocytes (hepatotoxicity) and may reduce the therapeutic efficacy of the AAV-vector based gene therapy. Monitor alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations weekly for 3 months after administration of etranacogene dezaparvovec. Continue to monitor transaminases in any person who develops elevated liver enzymes until liver enzymes return to baseline. If ALT increases to above the upper limit of normal or to twice the baseline value in the first 3 months post-dose, consider initiating a course of corticosteroids, along with factor IX activity monitoring: prednisone or prednisolone 60 mg/day PO for 1 week, 40 mg/day PO for 1 week, 30 mg/day PO for 2 weeks, 20 mg/day PO until ALT returns to baseline, then taper dosage by 5 mg/week to discontinue. The mean duration of corticosteroid use for elevated transaminases was 81.4 days (range, 51 to 130 days) in clinical trials. Medications equivalent to prednisone or prednisolone may also be used. A combined immunosuppressant regimen or the use of other products can be considered in case of prednisone or prednisolone treatment failure or contraindication. Elevated hepatic enzymes (i.e., ALT and AST) were reported in 42% of subjects in clinical trials. Most subjects had asymptomatic, mild elevations in transaminases. Elevated ALT concentrations occurred most often during the first 4 months after etranacogene dezaparvovec administrations. Some subjects had a late onset of elevated ALT concentrations between months 6 to 24; however all of these ALT values were less than 2 times the upper limit of normal (ULN) except for 1 subject. An additional 3 subjects had AST elevations between months 6 to 12. In a single subject, an ALT elevation more than 5 times the ULN occurred 24 days after etranacogene dezaparvovec administration and resolved by 51 days post-administration. There was a single subject who had an AST elevation more than 5 times the ULN that occurred 11 months post-administration and resolved to less than 2 times the ULN 8 days later. The majority of elevated ALT values returned to baseline; however, ALT values never resolved to normal at 2-year follow up in 9 subjects.[68294]

After treatment with etranacogene dezaparvovec, all subjects experienced antibody formation of neutralizing anti-adeno-associated virus serotype 5 (AAV5) antibodies. In clinical studies, sustained humoral immune response to infused AAV5 capsid was observed in all subjects after treatment with etranacogene dezaparvovec. The neutralizing anti-AAV5 antibody concentrations raised above the upper limit of quantification by week 3 post-administration and remained elevated, as measured at month 24 post-dose. In a subject with a preexisting neutralizing anti-AAV5 antibody titer of 1:3,212, no human factor IX expression was observed, and restart of the exogenous factor IX prophylaxis was needed for bleeding events. Readministration of etranacogene dezaparvovec in the presence of high anti-AAV5 antibody titer has not been evaluated.[68294]

Integration of liver-targeting adeno-associated viral (AAV) vector DNA into the genome may carry the theoretical risk of developing a new primary malignancy of hepatocellular carcinoma. In clinical trials, a single subject with preexisting risk factors for developing hepatic cancer developed a hepatocellular carcinoma, which was assessed as not likely related to etranacogene dezaparvovec treatment based on vector integration site analyses and whole genome sequencing. Etranacogene dezaparvovec-associated clonal expansion or carcinogenicity was not observed in clinical trials.[68294]

Fatigue and malaise were reported in 12% of subjects given etranacogene dezaparvovec in clinical trials. Nausea was reported in 7% of subjects given etranacogene dezaparvovec in clinical trials.[68294]

Preexisting neutralizing anti-adeno-associated viral vector (AAV) antibody formation may impede transgene expression at desired therapeutic concentrations in AAV-vector based gene therapies. A validated neutralizing anti-adeno-associated virus serotype 5 (AAV5) antibody assay is currently not available. In clinical trials with etranacogene dezaparvovec, an unvalidated clinical trial assay was utilized to assess preexisting neutralizing anti-AAV5 antibodies. The subgroup with detectable preexisting neutralizing anti-AAV5 antibodies up to titers of 1:678 had mean factor IX activity that was numerically lower compared to the subgroup without preexisting neutralizing anti-AAV5 antibodies. Subjects with and without preexisting neutralizing AAV5 antibodies demonstrated hemostatic protection. Persons who intend to receive treatment with etranacogene dezaparvovec are encouraged to enroll in a study to measure preexisting anti-AAV5 neutralizing antibodies by calling the manufacturer for etranacogene dezaparvovec. The study evaluates the effect of preexisting anti-AAV5 neutralizing antibodies on the risk of bleeding.[68294]

Prior to administration of etranacogene dezaparvovec, perform liver health assessments, including enzyme testing [i.e., alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin] and hepatic ultrasound and elastography. In case of radiological liver abnormalities and/or sustained liver enzyme elevations, consider a consultation with hepatologist to assess eligibility for etranacogene dezaparvovec. Integration of liver-targeting adeno-associated viral (AAV) vector DNA into the genome may carry the theoretical risk of developing a new primary malignancy of hepatocellular carcinoma. Persons with preexisting risk factors for hepatocellular carcinoma, such as advanced (geriatric) age and hepatic disease, including cirrhosis, advanced hepatic fibrosis, hepatitis B or C, metabolic dysfunction-associated steatotic liver disease (MASLD), chronic ethanol ingestion, and metabolic dysfunction-associated steatohepatitis (MASH), should receive abdominal ultrasound screenings and be monitored annually for alpha-fetoprotein (AFP) elevations in the 5 years after etranacogene dezaparvovec administration.[68294]

Obtain factor IX inhibitor titer testing prior to administration of etranacogene dezaparvovec. In the event of a positive test result for human factor IX inhibitors, perform a retest within 2 weeks. If the initial factor IX inhibitor test and the retest are positive, do not administer etranacogene dezaparvovec. Also monitor for development of factor IX inhibitors after administration of etranacogene dezaparvovec. Perform an assay that detects factor IX inhibitors if bleeding is not controlled, or plasma factor IX activity concentrations decrease. 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. This is important to consider particularly when changing the laboratory and/or reagents used in the assay. Therefore, the same assay and reagents are recommended to be used to monitor factor IX activity over time. The results of factor IX activity tests are lower if measured with chromogenic substrate assay (CSA) compared to OSA. Use of exogenous factor IX concentrates before and after etranacogene dezaparvovec may result in laboratory test interference and impede assessment of endogenous etranacogene dezaparvovec-derived factor IX activity.[68294]

Advise patients to avoid cell, organ, tissue, and blood donation after receiving treatment with etranacogene dezaparvovec.[68294]

There is no information on etranacogene dezaparvovec use during human pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No adverse effects on mating rate, fertility indices, or fetal weights were observed in healthy mice given an intravenous predecessor of etranacogene dezaparvovec 6 days prior to mating. Vector DNA was not detected in the uterus, placenta, or fetus.[68294]

There is no information on etranacogene dezaparvovec use during breast-feeding.[68294]