Vaccine Information: PREHEVBRIO (Page 2 of 3)

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Immune Globulin

There are no data to assess the concomitant use of PREHEVBRIO with immune globulin. When concomitant administration of PREHEVBRIO and immune globulin is required, they should be given with different syringes at different injection sites.

7.2 Interference with Laboratory Tests

Hepatitis B surface antigen (HBsAg) derived from hepatitis B vaccines has been transiently detected in blood samples following vaccination. Serum HBsAg detection may not have diagnostic value within 28 days after receipt of PREHEVBRIO.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PREHEVBRIO during pregnancy. Women who receive PREHEVBRIO during pregnancy are encouraged to contact 1-888-421-8808 (toll-free).

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In clinically recognized pregnancies in the US general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20%.

There are no adequate and well-controlled studies of PREHEVBRIO in pregnant women. Available human data on PREHEVBRIO administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

A developmental toxicity study has been performed in female rats administered the equivalent of a single human dose of PREHEVBRIO on four occasions; twice prior to mating, twice during gestation. The study revealed no evidence of harm to the fetus due to the vaccine [see Animal Data below].

Data

Animal Data

A developmental toxicity study has been performed in female rats using a dose equivalent to the adult human dose. In the study, female rats received 0.5 mL (2 x 0.25 mL injections) of a vaccine formulation containing 10 mcg HBsAg (S, pre-S1, pre-S2) adsorbed on to aluminum hydroxide by intramuscular injection 30 days and 15 days prior to mating and on gestation days 4 and 15. No adverse effects of pre-weaning development were observed. There was no evidence of fetal malformations or variations.

8.2 Lactation

Risk Summary

It is not known whether PREHEVBRIO is excreted in human milk. Data are not available to assess the effects of PREHEVBRIO on the breastfed infant or on milk production/excretion.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PREHEVBRIO and any potential adverse effects on the breastfed child from PREHEVBRIO or from the underlying maternal condition. For preventive vaccines, the underlying condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness of PREHEVBRIO have not been established in individuals less than 18 years of age.

8.5 Geriatric Use

Study 1 included 296 adults 65 through 86 years of age who received PREHEVBRIO. Among subjects who received PREHEVBRIO, a seroprotective level of antibody to HBsAg was achieved in 83.6% of those ≥ 65 years of age compared to 94.8% in adults 45 through 64 years of age and 99.2% in adults 18 through 44 years of age [see Evaluation of Immunogenicity (14.1)].

Frequencies of local and systemic solicited adverse reactions were generally lower in elderly subjects ≥65 years of age than in younger subjects [see Adverse Reactions (6)].

8.6 Adults on Hemodialysis

Safety and effectiveness of PREHEVBRIO have not been established in adults on hemodialysis.

11 DESCRIPTION

PREHEVBRIO [Hepatitis B Vaccine (Recombinant)] is a sterile suspension for intramuscular injection.

PREHEVBRIO contains the small (S), middle (pre-S2) and large (pre-S1) hepatitis B surface antigens, co-purified from genetically modified CHO (Chinese Hamster Ovary) cells cultured in growth medium containing vitamins, amino acids, minerals, and fetal bovine serum.

The hepatitis B surface antigens are co-purified from the supernatant of CHO cells by a series of physicochemical steps as virus-like particles containing CHO cell membrane lipids.

Each 1.0 mL dose is formulated to contain 10 mcg hepatitis B surface antigens (S, pre-S1 and pre-S2) adsorbed on aluminum hydroxide [Al(OH)3 ] as an adjuvant (aluminum content of 0.5 mg/mL).

Each 1.0 mL dose of PREHEVBRIO also contains sodium chloride (NaCl) (8.45 mg/dose), potassium chloride (KCl) (0.02 mg/dose), disodium hydrogen phosphate dodecahydrate (Na2 HPO4 .12H2 O) (0.38 mg/dose), potassium dihydrogen phosphate anhydrous (KH2 PO4 ) (0.02 mg/dose) and water for injections (WFI). Each dose may contain residual amounts of CHO cell proteins (up to 2.5 ng/dose), CHO cell DNA (up to 10 pg/dose), Bovine Serum Albumin (up to 2.5 ng/dose) and Formaldehyde (up to 500 ng/dose) from the manufacturing process.

PREHEVBRIO does not contain a preservative.

The vial stoppers are not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

PREHEVBRIO induces antibodies to HBsAg. Antibody concentrations ≥10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B virus infection.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

PREHEVBRIO has not been evaluated for carcinogenic, mutagenic potential or male infertility in animals. In a developmental toxicity study in rats with a vaccine formulation containing 10 mcg HBsAg (S, pre-S1, pre-S2) adsorbed on to aluminum hydroxide there were no effects on female fertility [see Animal Data (8.1)].

14 CLINICAL STUDIES

14.1 Evaluation of Immunogenicity

The immunogenicity of PREHEVBRIO was evaluated in comparison with a US-licensed hepatitis B vaccine (Engerix-B) in 2 randomized, active controlled, double-blind, multi-center Phase 3 clinical trials in adults. PREHEVBRIO and Engerix-B were administered according to a 0-, 1- and 6-month schedule. For subject baseline characteristics, see section 6.1.

The trials compared the seroprotection rates (SPR), defined as the proportion of participants with anti-HBs titers ≥ 10 mIU/mL, induced by PREHEVBRIO and Engerix-B. Non-inferiority was met if the lower bound of the 95% confidence interval (CI) of the difference in SPR (PREHEVBRIO minus Engerix-B) was greater than -5%.

Study 1 in adults ≥18 years of age

The immunogenicity population included 718 subjects who received PREHEVBRIO and 723 subjects who received Engerix-B. The mean age was 57 years in both groups. The primary analysis compared the SPR, 4 weeks after receiving the third dose of PREHEVBRIO or Engerix-B in subjects ≥ 18 years of age. The SPR induced by PREHEVBRIO compared to Engerix-B was non-inferior in subjects ≥ 18 years of age (Table 5).

Table 5: Study 1: Seroprotection Rate (SPR) 4 Weeks After Receiving the Third Dose of PREHEVBRIO or Engerix-B

Abbreviations: N=number of subjects in the analysis set; SPR= Seroprotection Rate (percent of subjects with anti-HBs titers ≥10 mIU/mL)

a Per-protocol set (PPS). PPS included all subjects in the full analysis set who received all 3 vaccinations, had an evaluable serum immunogenicity sample at baseline and at the time point of interest, were seronegative at baseline, and had no major protocol violations leading to exclusion.

b Full analysis set (FAS). FAS included all subjects who received at least 1 vaccination and provided at least 1 evaluable serum immunogenicity sample both at baseline and after baseline. Subjects were seronegative at baseline.

c Non-inferiority was met because the lower bound of the 95% CI of the difference in SPR (PREHEVBRIO — Engerix-B) was > -5%.

d The SPR following PREHEVBRIO was statistically significantly higher than following Engerix-B (lower bound of the 95% CI of the difference in SPR was > 0%).

e Exploratory analysis

Study Population PREHEVBRIO N PREHEVBRIO SPR (95% CI) Engerix-B N Engerix-B SPR (95% CI) Difference in SPR; PREHEVBRIO – Engerix-B (95% CI)
All Adults (Age 18+) a 718 91.4 (89.1, 93.3) 723 76.5 (73.2, 79.5) 14.9 (11.2, 18.6) c
Age 45+ b 625 89.4 (86.8, 91.7) 627 73.1 (69.4, 76.5) 16.4 (12.2, 20.7) d
Age 18-44 125 99.2 (95.6, 100.0) 135 91.1 (85.0. 95.3) e
Age 45-64 325 94.8 (91.8, 96.6) 322 80.1 (75.3, 84.3) e
Age 65 + 268 83.6 (78.6, 87.8) 266 64.7 (58.6, 70.4) e

Study 2 in adults 18 through 45 years of age

The immunogenicity population included 1,753 subjects who received PREHEVBRIO and 592 subjects who received Engerix-B. The mean age was 34 years in the PREHEVBRIO group and 33 years in the Engerix-B group. The study compared the SPR, 4 weeks after receiving the third dose of PREHEVBRIO or Engerix-B in all subjects. The SPR induced by PREHEVBRIO compared to Engerix-B was non-inferior (Table 6).

Table 6: Study 2: Seroprotection Rate (SPR) 4 Weeks After Receiving the Third Dose of PREHEVBRIO or Engerix-B

SPR= Seroprotection Rate (percent of subjects with anti-HBs titers ≥10 mIU/mL)

* Non-inferiority was met because the lower bound of the 95% CI of the difference in SPR (PREHEVBRIO — Engerix-B) was > -5%.

Study Population PREHEVBRIO N PREHEVBRIO SPR (95% CI) Engerix-B N Engerix-B SPR (95% CI) Difference in SPR; PREHEVBRIO –Engerix-B (95% CI)
Age 18-45 1753 99.3 (98.7. 99.6) 592 94.8 (92.7, 96.4) 4.5 (2.9, 6.6) *

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