Vaccine Information: HEPLISAV-B (Page 2 of 3)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of HEPLISAV-B. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

Immune System Disorders
Anaphylaxis and other hypersensitivity reactions including urticaria, pruritus, and rash.

Nervous System Disorders
Dizziness, paresthesia

Gastrointestinal Disorders
Gastrointestinal symptoms including nausea, vomiting, diarrhea, and abdominal pain

General Disorders and Administration Site Conditions
Injection site pruritus

7 DRUG INTERACTIONS

7.1 Use with Immune Globulin

There are no data to assess the concomitant use of HEPLISAV-B with immune globulin. When concomitant administration of HEPLISAV-B 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 HEPLISAV-B.

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 HEPLISAV-B during pregnancy. Women who receive HEPLISAV-B during pregnancy are encouraged to contact 1-844-443-7734.

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 clinical studies of HEPLISAV-B in pregnant women. Available human data on HEPLISAV- B administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

In a developmental toxicity study, 0.3 mL of a vaccine formulation containing 2.5 mcg HBsAg and 3000 mcg cytosine phosphoguanine (CpG) 1018 adjuvant was administered to female rats prior to mating and during gestation. These animal studies revealed no evidence of harm to the fetus due to this vaccine formulation [see Data ].

Data

Animal Data

Developmental toxicity studies were conducted in female rats. Animals were administered 0.3 mL of a vaccine formulation containing 2.5 mcg HBsAg and 3000 mcg CpG 1018 adjuvant twice prior to mating, and on gestation days 6 and 18 (a single human dose of HEPLISAV-B contains 20 mcg HBsAg and 3000 mcg CpG 1018 adjuvant). No adverse effects on pre-natal and post-natal development up to the time of weaning were observed. There were no vaccine-related fetal malformations or variations observed.

8.2 Lactation

Risk Summary

It is not known whether HEPLISAV-B is excreted in human milk. Data are not available to assess the effects of HEPLISAV-B 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 HEPLISAV-B and any potential adverse effects on the breastfed child from HEPLISAV- B 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 HEPLISAV-B have not been established in individuals less than 18 years of age.

8.5 Geriatric Use

Clinical trials included 909 adults 65 through 70 years of age who received HEPLISAV-B.

Among subjects who received HEPLISAV-B, a seroprotective level of antibody to HBsAg was achieved in 90% of those 65 through 70 years of age compared to 96% of those aged 18 through 64 years of age.

Safety and effectiveness of HEPLISAV-B in adults older than 70 years of age were extrapolated from findings in subjects younger than 70 years of age.

8.6 Adults on Hemodialysis

Safety and effectiveness of HEPLISAV-B have not been established in adults on hemodialysis.

11 DESCRIPTION

HEPLISAV-B [Hepatitis B Vaccine (Recombinant), Adjuvanted] is a sterile solution for intramuscular injection.

The HBsAg is expressed in a recombinant strain of Hansenula polymorpha yeast. The fermentation process involves growth of the recombinant H. polymorpha on chemically-defined fermentation media containing vitamins and mineral salts.

The HBsAg is expressed intra-cellularly in the yeast cells. It is released from the yeast cells by cell disruption and purified by a series of physicochemical steps. Each dose may contain residual amounts of yeast protein (≤5.0% of total protein), yeast DNA (<20 picogram), and deoxycholate (<0.9 ppm) from the HBsAg manufacturing process.

HEPLISAV-B is prepared by combining the purified HBsAg together with the CpG 1018 adjuvant, a 22-mer phosphorothioate linked oligodeoxynucleotide in a phosphate buffered saline (sodium chloride, 9.0 mg/mL; sodium phosphate, dibasic dodecahydrate, 1.75 mg/mL; sodium phosphate, monobasic dihydrate, 0.48 mg/mL; and polysorbate 80, 0.1 mg/mL).

Each 0.5-mL dose is formulated to contain 20 mcg of HBsAg and 3000 mcg of CpG 1018 adjuvant.

HEPLISAV-B is available in prefilled syringes. The tip caps and stoppers of the prefilled syringes are not made with natural rubber latex.

HEPLISAV-B is formulated without preservatives. [see How Supplied/Storage and Handling (16)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Infection with hepatitis B virus can have serious consequences including acute massive hepatic necrosis and chronic active hepatitis. Chronically infected persons are at increased risk for cirrhosis and hepatocellular carcinoma.

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

HEPLISAV-B has not been evaluated for carcinogenicity, mutagenic potential or male infertility in animals. Vaccination of female rats with a vaccine formulation containing 2.5 mcg HBsAg and 3000 mcg CpG 1018 adjuvant had no effect on fertility [see Use in Specific Populations (8)].

14 CLINICAL STUDIES

14.1 Evaluation of Seroprotection

The immunogenicity of HEPLISAV-B was evaluated in comparison with a licensed hepatitis B vaccine (Engerix-B) in 3 randomized, active controlled, observer-blinded, multi-center Phase 3 clinical trials of adults. HEPLISAV-B was given as a 2-dose regimen at 0 and 1 months followed by saline placebo at 6 months. Engerix-B was given at 0, 1, and 6 months.

The trials compared the seroprotection rates (% with antibody concentration ≥ 10 mIU/mL) induced by HEPLISAV-B and Engerix-B. Noninferiority was met if the lower bound of the 95% confidence interval of the difference in seroprotection rates (HEPLISAV-B minus Engerix-B) was greater than -10%.

Study 1: Seroprotection in Adults 18 through 55 Years of Age In Study 1, the immunogenicity population comprised 1511 participants who received HEPLISAV-B and 521 who received Engerix-B. The mean age was 40 years for both groups. The primary analysis compared the seroprotection rate at Week 12 for HEPLISAV-B with that at Week 28 for Engerix-B. Non-inferiority of the seroprotection rate induced by HEPLISAV-B compared to Engerix-B was demonstrated (Table 3).

	Table 3Study 1: Seroprotection Rate of HEPLISAV-B and Engerix-B (ages 18 through 55 years)
Timepoint	HEPLISAV-BN = 1511	Engerix-BN = 521	Difference in SPRs(HEPLISAV-B minus Engerix-B)
	SPR (95% CI)	SPR (95% CI)	Difference (95% CI)
* Noninferiority was met because the lower bound of the 95% confidence interval of the difference in SPRs was greater than -10%.
Week 12 (HEPLISAV-B)Week 28 (Engerix-B)	95% (93.9, 96.1)	81.3% (77.8, 84.6)	13.7% (10.4, 17.5)*
CI = confidence interval; N = number of subjects in the analysis population in the group; SPR = seroprotection rate (% with anti-HBs ≥ 10 mIU/mL).
Clinical trial number: NCT00435812

Study 2: Seroprotection in Adults 40 through 70 Years of Age In Study 2, the immunogenicity population comprised 1121 subjects who received HEPLISAV-B and 353 subjects who received Engerix-B. The mean age was 54 years for both groups. The primary analysis compared the seroprotection rate at Week 12 for HEPLISAV-B with that at Week 32 for Engerix-B. Non- inferiority of the seroprotection rate induced by HEPLISAV-B compared to Engerix-B was demonstrated (Table 4).

	Table 4Study 2: Seroprotection Rate of HEPLISAV-B and Engerix-B (ages 40 through 70 years)
Timepoint	HEPLISAV-BN = 1121	Engerix-BN = 353	Difference in SPRs(HEPLISAV-B minus Engerix-B)
	SPR (95% CI)	SPR (95% CI)	Difference (95% CI)
* Noninferiority was met because the lower bound of the 95% confidence interval of the difference in SPRs was greater than -10%.
Week 12 (HEPLISAV-B)Week 32 (Engerix-B)	90.1% (88.2, 91.8)	70.5% (65.5, 75.2)	19.6% (14.7, 24.8)*
CI = confidence interval; N = number of subjects in the analysis population in the group; SPR = seroprotection rate (% with anti-HBs ≥ 10 mIU/mL).
The SPR following HEPLISAV-B was statistically significantly higher than following Engerix-B (lower bound of the 95% confidence interval of the difference in SPRs was greater than 0%).
Clinical trial number: NCT01005407

Study 3: Seroprotection in Adults 18 through 70 Years of Age Including those with Type 2 Diabetes Mellitus In Study 3, the immunogenicity population comprised 4537 subjects who received HEPLISAV-B and 2289 subjects who received Engerix-B. The mean age was 51 years and 14% of subjects had type 2 diabetes mellitus (defined as having a clinical diagnosis of type 2 diabetes and taking at least an oral or non-insulin injectable hypoglycemic agent and/or insulin).

The primary analysis compared the seroprotection rate at Week 28 for HEPLISAV-B (n= 640) with that at Week 28 for Engerix-B (n= 321) in subjects with type 2 diabetes mellitus. Non-inferiority of the seroprotection rate induced by HEPLISAV-B compared to Engerix-B was demonstrated (Table 5).

	Table 5Study 3: Seroprotection Rate of HEPLISAV-B and Engerix-B (subjects with type 2 diabetes mellitus ages 18 through 70 years)
Timepoint	HEPLISAV-BN = 640	Engerix-BN = 321	Difference in SPRs(HEPLISAV-B minus Engerix-B)
	SPR (95% CI)	SPR (95% CI)	Difference (95% CI)
* Noninferiority was met because the lower bound of the 95% confidence interval of the difference in SPRs was greater than -10%.
Week 28	90.0% (87.4, 92.2)	65.1% (59.6, 70.3)	24.9% (19.3, 30.7)*
CI = confidence interval; N = number of subjects in the analysis population in the group; SPR = seroprotection rate (% with anti-HBs ≥ 10 mIU/mL).
The SPR following HEPLISAV-B was statistically significantly higher than following Engerix-B (lower bound of the 95% confidence interval of the difference in SPRs was greater than 0%).
Clinical trial number: NCT02117934

A secondary analysis compared the seroprotection rate at Week 24 for HEPLISAV-B with that at Week 28 for Engerix-B in the total study population. Non-inferiority of the seroprotection rate induced by HEPLISAV-B compared to Engerix-B was demonstrated (Table 6).

	Table 6Study 3: Seroprotection Rate of HEPLISAV-B and Engerix-B (total study population ages 18 through 70 years)
Timepoint	HEPLISAV-BN = 4376	Engerix-BN = 2289	Difference in SPRs(HEPLISAV-B minus Engerix-B)
	SPR (95% CI)	SPR (95% CI)	Difference (95% CI)
* Noninferiority was met because the lower bound of the 95% confidence interval of the difference in SPRs was greater than -10%.
Week 24 (HEPLISAV-B)Week 28 (Engerix-B)	95.4% (94.8, 96.0)	81.3% (79.6, 82.8))	14.2% (12.5, 15.9)*
CI = confidence interval; N = number of subjects in the analysis population in the group; SPR = seroprotection rate (% with anti-HBs ≥ 10 mIU/mL).
Clinical trial number: NCT02117934
The SPR following HEPLISAV-B was statistically significantly higher than following Engerix-B (lower bound of the 95% confidence interval of the difference in SPRs was greater than 0%.).

Another secondary analysis compared the seroprotection rate at Week 24 for HEPLISAV-B with that at Week 28 for Engerix-B, by age group. For each age stratum non-inferiority of the seroprotection rate induced by HEPLISAV-B compared to Engerix-B was demonstrated (Table 7).

Age(years)	Table 7Study 3: Seroprotection Rates of HEPLISAV-B and Engerix-B * (ages 18 — 70 years)
	HEPLISAV-B *		Engerix-B *		Difference in SPRs(HEPLISAV-B minus Engerix-B)
	N	SPR (95% CI)	N	SPR (95% CI)	Difference (95% CI)
* Week 24 for HEPLISAV-B and Week 28 for Engerix-B † Noninferiority was met because the lower bound of the 95% confidence interval of the difference in SPRs was greater than -10%.
18-29	174	100.0% (97.9, 100.0)	99	93.9% (87.3, 97.7)	6.1% (2.8, 12.6)†
30-39	632	98.9% (97.7, 99.6)	326	92.0% (88.5, 94.7)	6.9% (4.2, 10.4)†
40-49	974	97.2% (96.0, 98.2)	518	84.2% (80.7, 87.2)	13.1% (9.9, 16.6)†
50-59	1439	95.2% (94.0, 96.3)	758	79.7% (76.6, 82.5)	15.5% (12.6, 18.7)†
60-70	1157	91.6% (89.9, 93.1)	588	72.6% (68.8, 76.2)	19.0% (15.2, 23.0)†
CI = confidence interval; N = number of subjects in the analysis population in the group; SPR = seroprotection rate (% with anti-HBs ≥ 10 mIU/mL).
Clinical trial number: NCT02117934
The SPR following HEPLISAV-B was statistically significantly higher than following Engerix-B (lower bound of the 95% confidence interval of the difference in SPRs was greater than 0%).