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

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BEQVEZ contains genetically modified vectors. Personal protective equipment (including gloves, safety goggles, laboratory coat and sleeves) should be worn while preparing or administering BEQVEZ.

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Confirm that the patient’s identity matches the patient-specific identifier number on the outer carton.

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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)

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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.

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Calculate the volume of HSA required to achieve a final concentration of 0.25% w/v HSA in a 200 mL final infusion volume.

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Calculate the volume of BEQVEZ required for the patient-specific treatment.

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Calculate the volume of 0.9% sodium chloride required to achieve a final infusion volume of 200 mL when combined with BEQVEZ and HSA.

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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:

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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

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

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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.

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Remove the inner carton from the outer carton.

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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.

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Vials may be gently swirled but not shaken or inverted.

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Prior to use, ensure that visible ice crystals are not present in the suspension.

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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.

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Do not re-freeze vials.

Preparation of Suspension for Infusion

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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.

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The formulation does not contain a preservative and is for single use only.

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Extract the calculated volume of BEQVEZ from the vials using aseptic technique and sterile componentry.

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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.

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Gently mix the suspension for infusion. Do not shake.

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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

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Use diluted BEQVEZ within 24 hours of dose preparation.

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

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Administer diluted suspension for infusion to the patient as a peripheral IV infusion over approximately 60 minutes (approximately 3 mL/min).

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DO NOT administer as an intravenous push or bolus.

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DO NOT infuse the diluted suspension in the same intravenous line with any other products.

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DO NOT use a central line or port.

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In the event of an infusion reaction during administration [see Warnings and Precautions (5.2)]:

o

The rate of infusion may be reduced or stopped to manage the infusion reaction.

o

Administer treatment as needed to manage infusion reaction.

o

If the infusion is stopped, restart a slower rate when the infusion reaction has resolved.

o

If the infusion rate needs to be reduced, or stopped and restarted, BEQVEZ should be infused within 24 hours of dose preparation.

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After the entire content of the infusion bag is infused, flush the infusion line using local site procedures.

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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:

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Perform ALT, AST as in Table 1 to monitor for liver enzyme elevation which may indicate immune-mediated hepatotoxicity. Liver enzyme elevation may result in decrease in factor IX activity. Perform factor IX activity testing as shown in Table 1.

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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.

•

Consider implementing a course of corticosteroids as outlined in Table 2 for any of the following:

o

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.

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Consecutive increases in transaminases (ALT or AST or both) on 2 subsequent blood tests even if within the normal range.

o

Factor IX activity decrease

▪

In the absence of alternative etiology, a decrease that could trigger the risk of bleeding.

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A decrease in factor IX activity on 2 consecutive blood tests especially if occurring during the first 4 months post-infusion.

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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.

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Monitor for and manage adverse reactions secondary to corticosteroid use. Refer to the corticosteroid prescribing information for risks and required precautions.

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

o

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.

o

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)].

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Use of exogenous FIX concentrates before and after BEQVEZ administration may impede assessment of endogenous, BEQVEZ-derived factor IX activity.

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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)].

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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)].

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.

6.1 Clinical Trials Experience

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:

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

8.1 Pregnancy

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.

8.2 Lactation

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.

8.3 Females and Males of Reproductive Potential

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)].

8.4 Pediatric Use

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

8.5 Geriatric Use

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.

8.6 Hepatic Impairment

BEQVEZ has not been studied in patients with hepatic impairment.

8.7 Renal Impairment

BEQVEZ has not been studied in patients with renal 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)].

12.1 Mechanism of Action

BEQVEZ (fidanacogene elaparvovec-dzkt) is a 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).

The AAVRh74var capsid is able to transduce hepatocytes, the natural site of factor IX synthesis. Single intravenous infusion of BEQVEZ results in cell transduction and increase in circulating factor IX activity in patients with hemophilia B.

12.2 Pharmacodynamics

BEQVEZ therapy results in continuous endogenous coagulation factor IX expression.

The pharmacodynamic effect of BEQVEZ was assessed by measuring circulating factor IX activity level following administration of 5 × 1011 vg/kg of BEQVEZ. Factor IX activity level over time obtained from clinical study 1 is presented in Table 4. At Month 15, 86% (30 out of 35) patients had FIX activity ≥5% based on one-stage SynthASil assay and 68% (23 out of 34) and 71% (25 out of 35) based on one-stage Actin-FSL assay and chromogenic assay, respectively. At Month 24, 82% (18 out of 22) patients had FIX activity ≥5% based on one-stage SynthASil assay, and 64% (14 out of 22) based on one-stage Actin-FSL assay and chromogenic assay.

Up to 6 years of follow-up FIX activity data is available from patients receiving the recommended dose of 5 × 1011 vg/kg in clinical study 2 (NCT02484092/NCT03307980). FIX activity remained stable over time, with mean factor IX activity (one-stage assay with Actin-FSL reagent) at 27.9% at Month 15 (n=9), 24.9% at Month 24 (n=14), 21.5% at Month 48 (Year 4, n=11) and 21.5% at Month 72 (Year 6, n=5).

Specific Populations

There is a trend of higher mean FIX activity (Week 12 to Month 15) with age, higher BMI, as well as in White race. Patients ≥35 years old (n=17) had 1.9-fold higher mean FIX activity as compared to patients 18 to <35 years old (n=28). Patients with BMI ≥25 kg/m2 (n=29) had 1.5-fold higher mean FIX activity as compared to patients with <25 kg/m2 (n=16). Patients in White race group (n=29) had 1.6-fold higher mean FIX activity as compared to patients in Non-white race group (n=12).

12.3 Pharmacokinetics

Biodistribution (Within the Body) and Vector Shedding (Excretion/Secretion)

BEQVEZ vector DNA levels were measured and quantified in blood and various shedding matrices using a quantitative polymerase chain reaction (qPCR) assay. This assay is sensitive and specific to BEQVEZ vector DNA, but could also detect DNA fragments. Saliva, semen, and urine samples from a subset of patients in the clinical study 1 were further characterized by measuring encapsidated vector DNA by a modified assay.

Nonclinical Biodistribution

Biodistribution of BEQVEZ was evaluated approximately 92 days after intravenous administration in healthy male non-human primates (NHPs) at dose levels up to 5 × 1012 vg/kg. Vector DNA was detected in all tissues assessed, including the testes. The highest levels of vector DNA were detected in the liver, spleen, and inguinal lymph nodes.

Clinical Data

Vector shedding after infusion with BEQVEZ was assessed in 60 patients at multiple time points in clinical studies (clinical study 1 and clinical study 2). In clinical study 1 a subset of patients (n=17) provided optional samples at early timepoints (2, 24 and 72 hours post-infusion) to better define parameters such as maximum vector DNA level (Cmax) and time to maximum vector DNA level (Tmax). The maximum vector DNA concentrations were found in plasma followed by saliva, peripheral blood mononuclear cells (PBMC), semen and urine. The mean Tmax was 1.2 days for plasma and saliva and 1.6 days for urine. The mean Tmax was 3.8 days and 7.4 days for semen and PBMC, respectively. For pooled analysis of clinical data (N=60 patients), full clearance of vector DNA was defined as having 3 consecutive negative results (i.e., below quantification limit). Vector DNA fully cleared from plasma, saliva, and semen within a mean of 1 to 4 months after infusion and PBMC was the slowest fluid to full clearance within a mean of 12 months. In semen, the maximum observed time for vector DNA full clearance was 154 days. In urine, the peak vector DNA concentration was very low relative to plasma and declined to full clearance within a mean of 4 weeks after infusion.

12.6 Immunogenicity

The administration of BEQVEZ has the potential to generate immunity in the form of neutralizing antibodies against the vector capsid, the transgene (virus-derived factor IX) and as a cellular response against the transduced cells producing factor IX.

In clinical studies, all patients receiving treatment were required to screen negative for anti-AAVRh74var neutralizing antibodies and negative (<0.6 BU) for factor IX inhibitors in a Nijmegen modified Bethesda assay following a lifetime minimum of 50 exposure days to factor IX replacement therapy. No patients developed factor IX inhibitors during the clinical studies using BEQVEZ.

A sustained increase in neutralizing anti-AAVRh74var antibodies has been observed after administration of BEQVEZ in all patients who participated in clinical studies and had neutralizing antibody (nAb) assessment.

In clinical study 1, anti-AAVRh74var antibody titers were assessed annually following BEQVEZ administration. Mean (SD) titer at Week 52 was 101,230.98 (118,479.743) and at the last time point tested, Week 156, mean (SD) titer was 132,527.56 (121,891.612).

BEQVEZ-treated patients were tested for cellular immune responses to overall capsid pool and overall factor IX pool using an IFN-γ enzyme-linked immunosorbent spot (ELISpot) assay.

ELISpot results did not show a trend of presumed T-cell response (based on limited positive ELISpot) as a function of time during the 1-year post-infusion period in either clinical study 1 or clinical study 2.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, reproductive toxicity, and impairment of fertility studies have not been conducted with BEQVEZ. In a 2-year vector integration study in NHPs administered 5 × 1012 vg/kg, vector DNA was mostly detected in the form of episomal DNA that was not integrated into the host genome. The integration sites were generally random with a low frequency, and there was no indication of significant clonal expansion.

16.1 How Supplied

BEQVEZ is supplied as a clear to slightly opalescent, colorless to slightly brown suspension with each mL containing 1 × 1013 vg.

BEQVEZ is shipped frozen (−100 °C to −60 °C [−148 °F to −76 °F]) in plastic vials with an elastomeric stopper and plastic snap fit cap with an extractable volume of 1 mL.

BEQVEZ is provided as a customized kit containing the number of vials (NDC 0069-0422-01) required to meet dosing requirements for each patient [see Dosage and Administration (2.1)]. The customized kit is accompanied with patient’s specific identifier number (Pfizer Patient Identifier) on the outer carton.

The kit sizes and National Drug Codes (NDC) are provided in Table 6.

16.2 Storage and Handling

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).