Hepatitis B Vaccine, adjuvanted (Heplisav-B)

Hepatitis B Vaccine, adjuvanted (Heplisav-B)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand

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Black Box Warning

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Overview

Hepatitis B Vaccine, adjuvanted (Heplisav-B) is a Acetylcholine release inhibitor, Adrenergic receptor agonist that is FDA approved for the (type of indication of drug) of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

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Condition 2

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Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition 1

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• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

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Condition 2

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Non–Guideline-Supported Use

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Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition 1

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Condition 2

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Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition 1

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

• Dosing Information/Recommendation

• (Dosage)

Condition 2

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

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Non–Guideline-Supported Use

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Contraindications

CONTRAINDICATIONS

Warnings

Warning Title See full prescribing information for complete Boxed Warning. Condition Name: (Content)

Conidition 1

(Description)

Conidition 2

(Description)

Conidition 3

(Description)

Adverse Reactions

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.
• A total of 9597 individuals 18 through 70 years of age received at least 1 dose of HEPLISAV-B in 5 clinical trials conducted in the United States, Canada, and Germany. Data from three of these trials are provided below.

Study 1 in Subjects 18 through 55 Years of Age

• Study 1 was a randomized, observer-blind, active-controlled, multicenter study in Canada and Germany in which 1810 subjects received at least 1 dose of HEPLISAV-B and 605 subjects received at least 1 dose of Engerix-B® [Hepatitis B Vaccine (Recombinant)]. Enrolled subjects had no history of hepatitis B vaccination or infection. HEPLISAV-B was given as a 2-dose regimen at 0 and 1 month followed by saline placebo at 6 months. Engerix-B was given at 0, 1, and 6 months. In the total study population, the mean age was 40

years; 46% of the subjects were men; 93% were white, 2% black, 3% Asian and 3% Hispanic; 26% were obese, 10% had hypertension, 8% had dyslipidemia, and 2% had diabetes mellitus. These 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 are shown in Table 1.

This image is provided by the National Library of Medicine.

Unsolicited Adverse Events:

• Unsolicited adverse events within 28 days following any injection, including placebo, were reported by 42.0% of HEPLISAV-B recipients and 41.3% of Engerix-B recipients.

Serious Adverse Events (SAEs)

• Subjects were monitored for serious adverse events for 7 months after the first dose of vaccine. The percentage of subjects reporting serious adverse events was 1.5% in the HEPLISAV-B group and 2.1% in the Engerix-B group. No acute myocardial infarctions were reported. No deaths were reported.

Potentially Immune-mediated Adverse Events

• Potentially immune-mediated adverse events that occurred within 7 months of the first dose of vaccine were reported in 0.2% (n = 4) of HEPLISAV-B recipients and 0.7% (n = 4) of Engerix-B recipients. The following events were reported in the HEPLISAV-B group in one subject each: granulomatosis with polyangiitis, lichen planus, Guillain-Barré syndrome, and Grave’s disease. The following events were reported in the Engerix-B group in one subject each: Bell’s palsy, Raynaud’s phenomenon, and Grave’s disease. One additional Engerix-B recipient with a history of mixed connective tissue disease had pANCA-positive vasculitis.

Study 2 in Subjects 40 through 70 Years of Age

• Study 2 was a randomized, observer-blind, active-controlled, multicenter study in Canada and the United States in which 1968 subjects received at least 1 dose of HEPLISAV-B and 481 subjects received at least 1 dose of Engerix-B. HEPLISAV-B was given as a 2-dose regimen at 0 and 1 month followed by saline placebo at 6 months. Enrolled subjects had no history of hepatitis B vaccination or infection. Engerix-B was given at 0, 1, and 6 months. In the total population, the mean age was 54 years; 48% of subjects were men; 82% were white, 15% black, 1% Asian and 6% Hispanic; 44% were obese, 30% had hypertension, 30% had dyslipidemia, and 8% had diabetes mellitus. These 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 experienced local and systemic reactions are shown in Table 2.

Unsolicited Adverse Events:

• Unsolicited adverse events within 28 days following any injection, including placebo, were reported by 35.4% of HEPLISAV-B recipients and 36.2% of Engerix-B recipients.

Serious Adverse Events

• Subjects were monitored for serious adverse events for 12 months after the first dose of vaccine. The percentage of subjects reporting serious adverse events was 3.9% in the HEPLISAV-B group and 4.8% in the Engerix-B group. Acute myocardial infarction occurred in 0.1% (n=2) of HEPLISAV-B recipients and 0.2% (n=1) of Engerix-B recipients.

Autoimmune Adverse Events

• Subjects were monitored for the occurrence of new-onset potentially immune-mediated adverse events for 12 months after the first dose of vaccine. Events were adjudicated as to whether they were autoimmune by an external group of experts blinded to treatment assignment. As determined by the adjudicators, new-onset autoimmune adverse events were reported in 0.2% (n=3) of HEPLISAV-B recipients: two subjects with hypothyroidism and one subject with vitiligo. None of these events was considered related to vaccination by the expert group. No new-onset autoimmune adverse events were reported in the Engerix-B group. Although not referred to the external group of experts, one HEPLISAV-B recipient was determined to have Tolosa-Hunt syndrome which is presumed to have an immune-mediated etiology. This event was not considered related to vaccination.

Deaths

• One subject (0.05%) died of a pulmonary embolism in the HEPLISAV-B group and 1 subject (0.2%) died of heart failure in the Engerix-B group. Neither death was considered related to vaccination.

Study 3 in Subjects 18 through 70 Years of Age

• Study 3 was a randomized, observer-blind, active-controlled, multicenter study in the United States in which 5587 subjects received at least 1 dose of HEPLISAV-B and 2781 subjects received at least 1 dose of Engerix-B. Enrolled subjects had no history of hepatitis B vaccination or infection. HEPLISAV-B was given as a 2-dose regimen at 0 and 1 month followed by saline placebo at 6 months. Engerix-B was given at 0, 1, and 6 months. In the total study population, the mean age was 50 years; 51% were men; 71% were white, 26% black, 1% Asian, and 9% Hispanic; 48% were obese, 36% had hypertension, 32% had dyslipidemia, and 14% had type 2 diabetes mellitus. These demographic and baseline characteristics were similar in both vaccine groups.

Unsolicited Medically-Attended Adverse Events

• Subjects were monitored for unsolicited medically-attended adverse events, those for which a subject sought medical care, for 13 months after the first dose of vaccine. Overall, medically-attended adverse events were reported in 46.0% of HEPLISAV-B recipients and 46.2% of Engerix-B recipients. Herpes zoster was reported in 0.7% of HEPLISAV-B recipients and 0.3% of Engerix-B recipients. Unsolicited medically-attended adverse events within 28 days following any injection, including placebo, were reported by 20.1% of both HEPLISAV-B and Engerix-B recipients.

Serious Adverse Events

• Subjects were monitored for serious adverse events for 13 months after the first dose of vaccine. The percentage of subjects who reported serious adverse events was 6.2% in the HEPLISAV-B group and 5.3% in the Engerix-B group. Acute myocardial infarction (AMI) was reported in 0.25% (n=14) of HEPLISAV-B recipients and 0.04% (n=1) of Engerix-B recipients. An analysis of serious adverse events likely representing myocardial infarction (MI) was conducted using the standard Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) for MI. This analysis identified a total of 19 HEPLISAV-B subjects (0.3%) and 3 Engerix-B subjects (0.1%) with events included in the SMQ for MI (these events include the 15 reports of AMI). Additional evidence, including information on temporal relationship and baseline risk factors, does not support a causal relationship between HEPLISAV-B administration and AMI. Among the 19 events identified as MI in HEPLISAV-B recipients, three occurred within 14 days, nine occurred within 53-180 days, and seven occurred more than 180 days following any dose of HEPLISAV-B. Among the three events identified as MI in EngerixB recipients, one each occurred 13, 115, and 203 days following any dose. All 19 HEPLISAV-B recipients and 3 Engerix-B recipients reported one or more baseline risk factors for cardiovascular disease.

Autoimmune Adverse Events

• Subjects were monitored for the occurrence of new-onset potentially immune-mediated adverse events for 13 months after the first dose of vaccine. Events were adjudicated as to whether they were autoimmune by an external group of experts who were blinded to treatment assignment. As determined by the adjudicators, new-onset autoimmune adverse events were reported in 0.1% (n=4) of HEPLISAV-B recipients [one each of: alopecia areata, polymyalgia rheumatica, ulcerative colitis, and autoimmune thyroiditis (with concurrent diagnosis of papillary thyroid carcinoma)]. None of these events was considered to be related to vaccination by the external experts. No new-onset autoimmune adverse events were reported in the Engerix-B group.

Deaths

• During the study death was reported in 25 subjects (0.4%) in the HEPLISAV-B group and 7 subjects (0.3%) in the Engerix-B group. No death was considered related to vaccination.

Postmarketing Experience

(Description)

Drug Interactions

• Use with Immune Globulin
• Interference with Laboratory Tests

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.

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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

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 HEPLISAVB 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.

Data (Animal)

• 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.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hepatitis B Vaccine, adjuvanted (Heplisav-B) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Hepatitis B Vaccine, adjuvanted (Heplisav-B) during labor and delivery.

Nursing Mothers

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 HEPLISAVB or from the underlying maternal condition. For preventive vaccines, the underlying condition is susceptibility to disease prevented by the vaccine.

Pediatric Use

• Safety and effectiveness of HEPLISAV-B have not been established in individuals less than 18 years of age.

Geriatic 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.

Gender

There is no FDA guidance on the use of Hepatitis B Vaccine, adjuvanted (Heplisav-B) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Hepatitis B Vaccine, adjuvanted (Heplisav-B) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Hepatitis B Vaccine, adjuvanted (Heplisav-B) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Hepatitis B Vaccine, adjuvanted (Heplisav-B) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Hepatitis B Vaccine, adjuvanted (Heplisav-B) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Hepatitis B Vaccine, adjuvanted (Heplisav-B) in patients who are immunocompromised.

Adults on Hemodialysis

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

Administration and Monitoring

Administration

• HEPLISAV-B is a clear to slightly opalescent, colorless to slightly yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered.
• Administer HEPLISAV-B by intramuscular injection in the deltoid region using a sterile needle and syringe.

Monitoring

There is limited information regarding Hepatitis B Vaccine, adjuvanted (Heplisav-B) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Hepatitis B Vaccine, adjuvanted (Heplisav-B) and IV administrations.

Overdosage

There is limited information regarding Hepatitis B Vaccine, adjuvanted (Heplisav-B) overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Hepatitis B Vaccine, adjuvanted (Heplisav-B)
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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.

Structure

There is limited information regarding Hepatitis B Vaccine, adjuvanted (Heplisav-B) Structure in the drug label.

Pharmacodynamics

There is limited information regarding Hepatitis B Vaccine, adjuvanted (Heplisav-B) Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Hepatitis B Vaccine, adjuvanted (Heplisav-B) Pharmacokinetics in the drug label.

Nonclinical Toxicology

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.

Clinical Studies

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).

This image is provided by the National Library of Medicine.

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. Noninferiority of the seroprotection rate induced by HEPLISAV-B compared to Engerix-B was demonstrated (Table 4).

This image is provided by the National Library of Medicine.

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 noninsulin 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).

This image is provided by the National Library of Medicine.

• 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).

This image is provided by the National Library of Medicine.

• 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).

This image is provided by the National Library of Medicine.

How Supplied

• Package of 5 single dose vials (NDC number: 43528-002-05)
• Package of 5 single dose prefilled syringes (NDC number: 43528-003-05) (packaged without needles)
• The tip caps and stoppers of the prefilled syringes and vial stoppers are not made with natural rubber latex.

Storage

• Store in a refrigerator at 2°C to 8°C (35°F to 46°F).
• Do not freeze; discard if the vaccine has been frozen.
• Do not use the vaccine after the expiration date shown on the vial or prefilled syringe label.

Images

Drug Images

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Patient Counseling Information

• Inform vaccine recipient of the potential benefits and risks associated with vaccination, as well as the importance of completing the immunization series.
• Emphasize that HEPLISAV-B contains non-infectious purified HBsAg and cannot cause hepatitis B infection.
• Advise vaccine recipient to report any adverse events to their healthcare provider or to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967 and www.vaers.hhs.gov.
• Provide the Vaccine Information Statements, which are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

Precautions with Alcohol

Alcohol-Hepatitis B Vaccine, adjuvanted (Heplisav-B) interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

• Heplisav-B

Look-Alike Drug Names

There is limited information regarding Hepatitis B Vaccine, adjuvanted (Heplisav-B) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.