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

5.1 Hepatotoxicity

Intravenous administration of a liver-directed AAV vector could potentially lead to liver transaminase elevations. Transaminase elevations, particularly when observed in the first 4 months after BEQVEZ administration, is presumed to occur due to immune-mediated injury of transduced hepatocytes and may reduce the therapeutic efficacy of the AAV vector-based gene therapy.

In clinical studies with BEQVEZ, transaminase elevations (defined as ≥1.5 x baseline) occurred in 29 of 45 and 7 of 15 patients in study 1 and study 2 respectively. Twenty-eight (62%) patients in clinical study 1 received corticosteroids for transaminase elevation and/or decline in factor IX activity. The mean time to corticosteroid initiation was 45 days. The mean duration of corticosteroid treatment was 113 days (range: 41 to 276 days). Three (20%) patients in clinical study 2 received corticosteroids for transaminase elevation and/or decline in factor IX activity with time to initiation and duration of corticosteroid use within the range seen in clinical study 1.

Monitor ALT, AST and factor IX activity levels once or twice weekly for at least 4 months and institute corticosteroid treatment in response to transaminase elevation and/or decrease in FIX activity, as required [see Dosage and Administration (2.3)]. Monitor for and manage adverse reactions secondary to corticosteroid therapy.

For the first year following administration of BEQVEZ, advise patients to limit alcohol consumption, as alcohol may impact liver enzyme elevation and potentially reduce factor IX activity over time.

5.2 Infusion Reactions

Infusion reactions, including hypersensitivity reactions and anaphylaxis, may occur. Symptoms of hypersensitivity may include but are not limited to hypotension, pyrexia, palpitation, nausea, vomiting, chills or headache. Closely monitor patients for clinical signs and symptoms of infusion reactions throughout the infusion period and for at least 3 hours after end of infusion. In the event of an infusion reaction during administration, the infusion may be slowed or stopped. If the infusion is stopped, restart at a slower rate when the infusion reaction has resolved. Consider treatment with an antihistamine, corticosteroid or other measures for management of an infusion reaction.

5.3 Malignancy

The 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 [see Nonclinical Toxicology (13)].

Monitor patients with risk factors for hepatocellular carcinoma (e.g., hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) with regular liver ultrasound (e.g., annually) and alpha-fetoprotein testing for 5 years following BEQVEZ [see Dosage and Administration (2.3)].

In the event that a malignancy occurs, contact Pfizer Inc. at 1-800-438-1985 to obtain instructions on collecting patient samples for testing.

5.4 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 is observed at the lower factor IX activity levels (0.025 IU/mL). This is important to consider particularly when changing the laboratory and/or reagents used in the assay. It is recommended where possible 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 [see Dosage and Administration (2.3)].

In clinical study 1 with BEQVEZ, silica-based OSA returned consistently higher values of factor IX activity compared to ellagic acid-based OSA and chromogenic substrate assay (CSA). Generally, values of the ellagic acid-based OSA aligned with values of CSA [see Table 4, Clinical Pharmacology (12.2)].

Based on clinical trials (central laboratory), the approximate conversion factor between a silica-based OSA and ellagic acid-based OSA/CSA is 2. For example, a factor IX activity level of 10 IU/dL using CSA calculates approximately to a level of 20 IU/dL using silica-based OSA. At low factor IX activity levels (0.05 IU/mL) the conversion factor is approximately 2.5.

Factor IX Inhibitors

Monitor patients through appropriate clinical observations and laboratory tests for the development of inhibitors to factor IX after BEQVEZ administration. Perform an assay that detects factor IX inhibitors if bleeding is not controlled, or plasma factor IX activity levels decrease.

The most common adverse reaction (incidence ≥5%) reported in clinical studies was an increase in transaminases.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of BEQVEZ was evaluated in 60 [45 patients in clinical study 1 (NCT03861273) and 15 patients in clinical study 2 (NCT02484092)] patients who received the recommended dose (5 × 10¹¹ vg/kg) in two open-label clinical studies.

No serious adverse reactions were reported in patients treated with BEQVEZ. The most common adverse reactions observed in ≥5% of patients post-dose are listed in Table 3:

Table 3. Adverse Reactions (Incidence ≥5%) Following Treatment with BEQVEZ:

^* Includes terms alanine transaminase (ALT) increased, aspartate transaminase (AST) increased, hepatic enzyme increased, hepatic function abnormal, liver function test abnormal, transaminases increased.

Not all transaminase elevations were reported as adverse reactions [see Warnings and Precautions (5.1)].

No interaction studies have been performed.

The use of BEQVEZ in patients receiving hepatotoxic medication or using hepatotoxic substances is limited. Use of hepatotoxic medications or substances may reduce the efficacy of BEQVEZ, and the risk of serious hepatic reactions may increase following administration.

Prior to BEQVEZ administration, review the patient’s existing medications to determine if they should be modified to prevent anticipated interactions described in this section.

Monitor concomitant medications after BEQVEZ administration and evaluate the need to change concomitant medications based on patient’s hepatic status and risk.

Vaccinations

Prior to BEQVEZ infusion, ensure patients are up to date on their vaccinations. If concomitant corticosteroid administration is needed following BEQVEZ infusion, delay administration of live vaccines until the patient has been weaned off corticosteroids [see Dosage and Administration (2.3)].

Risk Summary

BEQVEZ is not intended for administration in women. There are no data from the use of BEQVEZ in pregnant women. No animal reproductive studies have been conducted with BEQVEZ.

In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Risk Summary

There is no information regarding the presence of BEQVEZ in human milk, the effect on the breastfed infant, and the effects on milk production.

BEQVEZ is not intended for administration in women.

No studies in animals or clinical studies have been performed to evaluate the potential effects of BEQVEZ on fertility in humans.

Contraception

Males

Vector DNA was shed in semen but declined to undetectable levels in semen within a mean of 1 to 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 BEQVEZ [see Clinical Pharmacology (12.3)].

The safety and efficacy of BEQVEZ in pediatric patients have not been established.

The clinical study did not have any patient ≥65 years of age. The safety and efficacy of BEQVEZ have not been established in geriatric patients.

BEQVEZ has not been studied in patients with renal impairment.

BEQVEZ has not been studied in patients with hepatic impairment.

8.8 Human Immunodeficiency Virus (HIV) Positive Patients

Clinical studies of BEQVEZ included a limited number of HIV patients, which precludes a determination of whether the efficacy and safety data differ when compared to patients without HIV infection.

8.9 Factor IX Inhibitors

The safety and effectiveness of BEQVEZ in patients with prior or active factor IX inhibitors have not been established [see Clinical Pharmacology (12.6)]. Patients with history of or active factor IX inhibitors should not take BEQVEZ.

After administration of BEQVEZ, patients should be monitored for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests [see Warnings and Precautions (5.4)].