Study 1 in adults ≥18 years of age

Study 1 was a randomized, double-blind, active-controlled, multicenter study that enrolled subjects in the United States (US), Canada, Belgium and Finland in which 796 subjects received at least 1 dose of PREHEVBRIO and 811 subjects received at least 1 dose of Engerix-B. In the total study population at baseline the mean age was 57 years, 81% were age ≥45 years; 62% were women; 90% were White, 8% Black, 1% Asian, and 10% Hispanic/Latino; 37% were obese (body mass index [BMI] >30 kg/m 2), 14% were current smokers and 8% had Type 2 diabetes mellitus. Demographic and baseline characteristics were similar in both vaccine groups.

Solicited Local and Systemic Adverse Reactions

Subjects were monitored for local and systemic adverse reactions using diary cards for a 7-day period starting on the day of vaccination. The percentages of subjects who reported local and systemic reactions in Study 1 are shown by age subgroup in Table 1 to Table 3.

The median duration of local and systemic solicited adverse reactions was 1-2 days in both treatment groups. Among all subjects who received PREHEVBRIO, the frequencies of the most commonly reported solicited reactions extending beyond the 7-day assessment period were as follows: fatigue (4.1%), injection site pain (2.0%), headache (1.9%) and myalgia (1.9%).

Study 2 in adults 18 through 45 years of age

Study 2 was a randomized, double-blind, active-controlled, multicenter study that enrolled subjects in the US, Canada, Belgium, Finland, Germany and the United Kingdom in which 2,124 subjects received at least 1 dose of PREHEVBRIO and 712 subjects received at least 1 dose of Engerix-B. In the total study population at baseline, the mean age was 34 years; 58% were women; 92% were White, 6% Black, 2% Asian, and 10% Hispanic/Latino; 18% were obese (BMI >30 kg/m 2) and 19% were current smokers. Demographic and baseline characteristics were similar in both vaccine groups.

Solicited Local and Systemic Adverse Reactions

Subjects were monitored for local and systemic adverse reactions using diary cards for a 7-day period starting on the day of vaccination. The percentages of subjects who reported local and systemic reactions in Study 2 are shown in Table 4.

The median duration of local and systemic solicited adverse reactions was 1-2 days in both treatment groups. Among all subjects who received PREHEVBRIO, the frequencies of the most commonly reported solicited reactions extending beyond the 7-day assessment period were as follows: fatigue (3.5%), injection site pain (2.0%), headache (1.9%) and myalgia (1.8%).

Unsolicited Adverse Events (AEs)

In both studies, unsolicited adverse events, including serious and non-serious events, that occurred within 28 days following each vaccination were recorded on a diary card by all subjects.

In both studies combined, unsolicited AEs that occurred within 28 days of any vaccination were reported by 48.3% and 48.4% of subjects who received PREHEVBRIO or Engerix-B, respectively. Unsolicited AEs in subjects who received PREHEVBRIO for which available information suggests a causal relationship to vaccination include injection site bruising (1.4%), dizziness/vertigo (1.1%), general pruritus/itchiness (0.2%), arthralgia (0.2%), urticaria/hives (0.2%) and lymphadenopathy/lymph node pain (0.1%).

Serious Adverse Events (SAEs)

In both studies, SAEs were collected from first vaccination through 6 months following the last vaccination. In both studies combined, SAEs were reported by 0.9% and 0.6% within 28 days of vaccination with PREHEVBRIO or Engerix-B, respectively. SAEs were reported by 2.5% of subjects in the PREHEVBRIO group and 1.6% in the Engerix-B group from the first vaccination through 6 months following the third vaccination. There were no notable patterns or numerical imbalances between vaccination groups for specific categories of serious adverse events that would suggest a causal relationship to PREHEVBRIO.

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.

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.

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).

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).