Vaccine Information: PREHEVBRIO

PREHEVBRIO- recombinant hepatitis b surface antigen (isoform s/sci-b-vac), recombinant hepatitis b surface antigen (isoform m/sci-b-vac) and recombinant hepatitis b surface antigen (isoform l /sci-b-vac) injection, suspension
VBI Vaccines (Delaware) Inc.

1 INDICATIONS AND USAGE

PREHEVBRIO is indicated for prevention of infection caused by all known subtypes of hepatitis B virus.

PREHEVBRIO is approved for use in adults 18 years of age and older.

2 DOSAGE AND ADMINISTRATION

For intramuscular injection.

2.1 Dosage and Schedule

Administer a series of three doses (1.0 mL each) of PREHEVBRIO on a 0-, 1- and 6-month schedule.

2.2 Administration

Shake the vial of PREHEVBRIO well to obtain a slightly opaque, white suspension.

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 PREHEVBRIO by intramuscular injection.

3 DOSAGE FORMS AND STRENGTHS

PREHEVBRIO is an injectable suspension, for intramuscular use supplied as a single-dose vial. A single dose of PREHEVBRIO is 1.0 mL [see How Supplied/Storage and Handling (16.1)].

4 CONTRAINDICATIONS

Do not administer PREHEVBRIO to individuals with a history of severe allergic reaction (e.g., anaphylaxis) after a previous dose of any hepatitis B vaccine or to any component of PREHEVBRIO [see Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Managing Allergic Reactions

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of PREHEVBRIO.

5.2 Immunocompromised Individuals

Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to PREHEVBRIO.

5.3 Limitations of Vaccine Effectiveness

Hepatitis B has a long incubation period. PREHEVBRIO may not prevent hepatitis B infection in individuals who have an unrecognized hepatitis B infection at the time of vaccine administration.

6 ADVERSE REACTIONS

Individuals 18 through 44 years of age: The most common local reactions following each dose of PREHEVBRIO were injection site pain (52.0 – 58.3%) and tenderness (52.6 – 59.6%). The most common systemic reactions following each dose of PREHEVBRIO were headache (17.2 – 25.8%), fatigue (20.1- 28.3%) and myalgia (22.2 – 29.9%).

Individuals 45 through 64 years of age: The most common local reactions following each dose of PREHEVBRIO were injection site pain (42.2 – 48.8%) and tenderness (43.2 – 50.5%). The most common systemic reactions following each dose of PREHEVBRIO were headache (13.8 – 21.3%), fatigue (14.3 – 19.7%) and myalgia (16.7 – 24.1%).

Individuals ≥ 65 years of age: The most common local reactions following each dose of PREHEVBRIO were injection site pain (26.7 – 34.8%) and tenderness (30.2 – 32.8%). The most common systemic reactions following each dose of PREHEVBRIO were headache (7.3 – 12.2%), fatigue (11.5 – 14.5%) and myalgia (11.5 — 16.6%).

6.1 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.

The safety of PREHEVBRIO was evaluated in 2 active-controlled clinical studies (Studies 1 and 2) involving 4,443 subjects who received at least 1 dose of PREHEVBRIO (n = 2,920) or Engerix-B [Hepatitis B Vaccine (Recombinant)] (n = 1,523) administered according to a 0-, 1- and 6-months schedule.

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/m2), 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.

Table 1: Study 1: Percent of Subjects Who Reported Local or Systemic Reactions Within 7 Days of Vaccination (18 through 44 years of age)
PREHEVBRIO Dose 1 (N=145) % PREHEVBRIO Dose 2 (N=141) % PREHEVBRIO Dose 3 (N= 134) % Engerix-B Dose 1 (N=154) % Engerix-B Dose 2 (N=152) % Engerix-B Dose 3 (N=148) %

a Grade 3 or greater pain and headache: defined as use of narcotic pain reliever or prevents daily activity; or ER visit or hospitalization

b Grade 3 or greater tenderness: defined as significant discomfort at rest; or ER visit or hospitalization

c Grade 3 or greater itching, fatigue and myalgia: defined as prevents daily activity; or ER visit or hospitalization

d Grade 3 or greater redness: defined as > 10 cm or skin necrosis or exfoliative dermatitis

e Grade 3 or greater swelling: defined as > 10 cm or prevents daily activity; or skin necrosis.

f Grade 3 or greater diarrhea and nausea/vomiting: defined as prevents daily activity or requires outpatient IV hydration; or ER visit or hospitalization.

Local Reaction
Pain 58.6 50.4 46.3 33.8 28.9 31.8
Pain, Grade 3 or greater a 0 0 0 0 0 0
Tenderness 53.8 50.4 42.5 32.5 32.2 36.5
Tenderness, Grade 3 or greater b 0.7 0 0.7 0.6 0.7 0.7
Itching 2.1 3.5 6.0 7.1 3.9 7.4
Itching, Grade 3 or greater c 0 0 0 0 0.7 1.4
Redness (≥ 2.5 cm) 0.7 1.4 1.5 0.6 1.3 0
Redness, Grade 3 or greater d 0 0 0 0 0 0
Swelling (≥ 2.5 cm) 2.8 1.4 0.7 0 1.3 2.0
Swelling, Grade 3 or greater e 0 0 0 0 0.7 1.4
Systemic Reaction
Headache 33.8 24.1 20.9 29.9 19.1 13.5
Headache, Grade 3 or greater a 1.4 0.7 0 1.3 0.7 0
Fatigue 29.7 22.0 22.4 31.8 20.4 20.3
Fatigue, Grade 3 or greater c 1.4 0.7 0 0.6 2.0 1.4
Myalgia 27.6 24.1 21.6 20.8 11.8 10.1
Myalgia, Grade 3 or greater c 0.7 0 0 0 1.3 0
Diarrhea 9.7 5.7 4.5 9.7 5.9 7.4
Diarrhea, Grade 3 or greater f 0.7 0 0 0 0.7 0
Nausea/Vomiting 8.3 4.3 4.5 7.8 6.6 6.1
Nausea/Vomiting, Grade 3 or greater f 0 0.7 0 0 0.7 0
Fever (≥100.4°F) 0.7 0.7 0 1.3 0 0.7
Fever, Grade 3 or greater (≥102.1°F) 0.7 0 0 0 0 0
Table 2: Study 1: Percent of Subjects Who Reported Local or Systemic Reactions Within 7 Days of Vaccination (45 through 64 years of age)
PREHEVBRIO Dose 1 (N=355) % PREHEVBRIO Dose 2 (N=350) % PREHEVBRIO Dose 3 (N=343) % Engerix-B Dose 1 (N=361) % Engerix-B Dose 2 (N=357) % Engerix-B Dose 3 (N=349) %

a Grade 3 or greater pain and headache: defined as use of narcotic pain reliever or prevents daily activity; or ER visit or hospitalization

b Grade 3 or greater tenderness: defined as significant discomfort at rest; or ER visit or hospitalization

c Grade 3 or greater itching, fatigue and myalgia: defined as prevents daily activity; or ER visit or hospitalization

d Grade 3 or greater redness: defined as > 10 cm or skin necrosis or exfoliative dermatitis

e Grade 3 or greater swelling: defined as > 10 cm or prevents daily activity; or skin necrosis.

f Grade 3 or greater diarrhea and nausea/vomiting: defined as prevents daily activity or requires outpatient IV hydration; or ER visit or hospitalization.

Local Reaction
Pain 46.8 44.9 39.4 22.2 15.4 17.2
Pain, Grade 3 or greater a 0 0 0.3 0 0 0
Tenderness 48.7 42.6 40.5 23.8 16.5 17.5
Tenderness, Grade 3 or greater b 0.8 0.6 0.3 0 0 0.3
Itching 4.5 3.1 3.8 3.9 2.0 3.4
Itching, Grade 3 or greater c 0 0.3 0 0 0 0
Redness (≥ 2.5 cm) 1.7 0.6 0.3 1.1 0.3 1.1
Redness, Grade 3 or greater d 0 0 0 0.8 0.3 0.6
Swelling (≥ 2.5 cm) 1.4 0.3 0.9 0 0.6 0.3
Swelling, Grade 3 or greater e 0 0 0.3 0 0 0
Systemic Reaction
Headache 21.4 13.7 15.7 20.5 11.2 14.0
Headache, Grade 3 or greater a 0 0 0.3 0.3 0.3 0.3
Fatigue 16.6 16.9 12.5 22.2 11.5 12.3
Fatigue, Grade 3 or greater c 0.6 0 0.3 0.6 0.3 0.6
Myalgia 21.4 20.0 15.5 16.1 8.4 9.5
Myalgia, Grade 3 or greater c 0.6 0 0 0 0 0
Diarrhea 4.8 4.0 3.2 6.4 3.6 3.7
Diarrhea, Grade 3 or greater f 0 0 0 0 0 0
Nausea/Vomiting 4.2 2.9 2.3 6.4 3.6 2.6
Nausea/Vomiting, Grade 3 or greater f 0 0 0 0 0 0
Fever (≥100.4°F) 0.6 0 0 0.3 0.3 0.6
Fever, Grade 3 or greater (≥102.1°F) 0 0 0 0 0 0.3
Table 3: Study 1: Percent of Subjects Who Reported Local or Systemic Reactions Within 7 Days of Vaccination (Age ≥ 65 years of age)
PREHEVBRIO Dose 1 (N=296) % PREHEVBRIO Dose 2 (N=288) % PREHEVBRIO Dose 3 (N=281) % Engerix-B Dose 1 (N=296) % Engerix-B Dose 2 (N=292) % Engerix-B Dose 3 (N= 288) %

a Grade 3 or greater pain and headache: defined as use of narcotic pain reliever or prevents daily activity; or ER visit or hospitalization

b Grade 3 or greater tenderness: defined as significant discomfort at rest; or ER visit or hospitalization

c Grade 3 or greater itching, fatigue and myalgia: defined as prevents daily activity; or ER visit or hospitalization

d Grade 3 or greater redness: defined as > 10 cm or skin necrosis or exfoliative dermatitis

e Grade 3 or greater swelling: defined as > 10 cm or prevents daily activity; or skin necrosis.

f Grade 3 or greater diarrhea and nausea/vomiting: defined as prevents daily activity or requires outpatient IV hydration; or ER visit or hospitalization.

Local Reaction
Pain 34.8 28.8 26.7 16.2 12.0 11.1
Pain, Grade 3 or greater a 0 0 0 0.3 0 0
Tenderness 32.8 30.2 31.0 14.2 12.0 10.1
Tenderness, Grade 3 or greater b 0 0 0 0 0 0
Itching 6.1 3.8 5.0 4.1 1.4 2.4
Itching, Grade 3 or greater c 0 0 0 0 0 0
Redness (≥ 2.5 cm) 1.0 0.3 1.4 0.7 0.3 0
Redness, Grade 3 or greater d 0.3 0 0.4 0 0.3 0
Swelling (≥ 2.5 cm) 1.0 0.7 1.1 1.4 0.3 0.3
Swelling, Grade 3 or greater e 0.3 0 0 0 0.3 0
Systemic Reaction
Headache 12.2 7.3 7.8 12.8 5.8 6.9
Headache, Grade 3 or greater a 0 0 0 0 0 0
Fatigue 14.5 11.5 12.5 17.9 9.9 10.1
Fatigue, Grade 3 or greater c 0 0 0 0.7 0 0.3
Myalgia 16.6 11.5 13.2 12.8 8.2 6.9
Myalgia, Grade 3 or greater c 0 0 0 0 0.3 0
Diarrhea 6.4 4.2 1.1 6.4 2.4 3.5
Diarrhea, Grade 3 or greater f 0.3 0 0 0.3 0 0
Nausea/Vomiting 3.7 0.7 1.1 1.7 1.7 0.7
Nausea/Vomiting, Grade 3 or greater f 0 0 0 0.3 0 0.3
Fever (≥100.4°F) 0 0 0.7 0 0 0.7
Fever, Grade 3 or greater (≥102.1°F) 0 0 0 0 0 0

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/m2) 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.

Table 4: Study 2: Percent of Subjects Who Reported Local or Systemic Reactions Within 7 Days of Vaccination (18 through 45 years of age)
PREHEVBRIO Dose 1 (N=2122) a % PREHEVBRIO Dose 2 (N=2071) % PREHEVBRIO Dose 3 (N=1967) % Engerix-B Dose 1 (N=712) % Engerix-B Dose 2 (N=701) % Engerix-B Dose 3 (N=671) %

a Two subjects without solicited adverse event data following dose 1 of PREHEVBRIO were excluded from this analysis.

b Grade 3 or greater pain and headache: defined as use of narcotic pain reliever or prevents daily activity; or ER visit or hospitalization

c Grade 3 or greater tenderness: defined as significant discomfort at rest; or ER visit or hospitalization

d Grade 3 or greater itching, fatigue and myalgia: defined as prevents daily activity; or ER visit or hospitalization

e Grade 3 or greater redness: defined as > 10 cm or skin necrosis or exfoliative dermatitis

f Grade 3 or greater swelling: defined as > 10 cm or prevents daily activity; or skin necrosis

g Grade 3 or greater diarrhea and nausea/vomiting: defined as prevents daily activity or requires outpatient IV hydration; or ER visit or hospitalization.

Local Reaction
Pain 58.2 52.2 52.5 35.1 29.2 32.5
Pain, Grade 3 or greater b 0.3 0.3 0.4 0.1 0 0.3
Tenderness 59.9 52.9 55.5 37.6 30.4 33.8
Tenderness, Grade 3 or greater c 0.8 0.9 0.8 0.6 0.1 0.1
Itching 5.7 5.7 6.7 6.6 5.3 5.4
Itching, Grade 3 or greater d 0 0 0.1 0.3 0.1 0
Redness (≥ 2.5 cm) 1.1 1.1 1.3 0.6 0.4 1.0
Redness, Grade 3 or greater e 0.2 0 0.2 0.1 0.1 0.1
Swelling (≥ 2.5 cm) 1.2 0.9 1.1 0.6 0 0.4
Swelling, Grade 3 or greater f 0.1 0 0.1 0 0 0
Systemic Reaction
Headache 25.1 16.7 17.4 24.2 15.0 18.3
Headache, Grade 3 or greater b 0.3 0.2 0.5 0.4 0.4 0.6
Fatigue 28.4 19.8 20.2 27.1 17.8 22.1
Fatigue, Grade 3 or greater d 0.5 0.8 0.6 0.4 0.6 0.6
Myalgia 30.3 21.9 23.6 17.7 13.0 18.5
Myalgia, Grade 3 or greater d 0.3 0.6 0.5 0.4 0.1 0.4
Diarrhea 7.4 5.0 4.4 9.6 4.9 5.4
Diarrhea, Grade 3 or greater g 0.2 0.1 0.1 0 0 0
Nausea/Vomiting 6.7 3.7 4.7 7.0 3.6 3.9
Nausea/Vomiting, Grade 3 or greater g 0 0 0.2 0 0.1 0
Fever (≥100.4°F) 0.3 0.3 0.6 0.4 0.3 0.9
Fever, Grade 3 or greater (≥102.1°F) 0 0.1 0.1 0.1 0 0

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.

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