Vaccine Information: ENGERIX-B (Page 3 of 4)

8.3 Nursing Mothers

It is not known whether ENGERIX-B is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ENGERIX-B is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of ENGERIX-B have been established in all pediatric age-groups. Maternally transferred antibodies do not interfere with the active immune response to the vaccine. [See Adverse Reactions (6), Clinical Studies (14.1, 14.3, 14.4).]

The timing of the first dose in infants weighing less than 2,000 g at birth depends on the HBsAg status of the mother. [See Warnings and Precautions (5.3).]

8.5 Geriatric Use

Clinical studies of ENGERIX-B used for licensure did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. However, in later studies it has been shown that a diminished antibody response and seroprotective levels can be expected in persons older than 60 years.5 [See Clinical Studies (14.2).]

11 DESCRIPTION

ENGERIX-B [Hepatitis B Vaccine (Recombinant)] is a sterile suspension of noninfectious hepatitis B virus surface antigen (HBsAg) for intramuscular administration. It contains purified surface antigen of the virus obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus. The HBsAg expressed in the cells is purified by several physicochemical steps and formulated as a suspension of the antigen adsorbed on aluminum hydroxide. The procedures used to manufacture ENGERIX-B result in a product that contains no more than 5% yeast protein.

Each 0.5-mL pediatric/adolescent dose contains 10 mcg of HBsAg adsorbed on 0.25 mg aluminum as aluminum hydroxide.

Each 1-mL adult dose contains 20 mcg of HBsAg adsorbed on 0.5 mg aluminum as aluminum hydroxide.

ENGERIX-B contains the following excipients: Sodium chloride (9 mg/mL) and phosphate buffers (disodium phosphate dihydrate, 0.98 mg/mL; sodium dihydrogen phosphate dihydrate, 0.71 mg/mL).

ENGERIX-B is available in vials and prefilled syringes. The tip caps of the prefilled syringes contain natural rubber latex; the plungers are not made with natural rubber latex. The vial stoppers are not made with natural rubber latex.

ENGERIX-B is formulated without preservatives.

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.1 Seroconversion is defined as antibody titers ≥1 mIU/mL.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

ENGERIX-B has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.

14 CLINICAL STUDIES

14.1 Efficacy in Neonates

Protective efficacy with ENGERIX-B has been demonstrated in a clinical trial in neonates at high risk of hepatitis B infection.6,7 Fifty-eight neonates born of mothers who were both HBsAg-positive and hepatitis B “e” antigen (HBeAg)-positive were given ENGERIX-B (10 mcg/0.5 mL) at 0, 1, and 2 months, without concomitant hepatitis B immune globulin (HBIG). Two infants became chronic carriers in the 12-month follow-up period after initial inoculation. Assuming an expected carrier rate of 70%, the protective efficacy rate against the chronic carrier state during the first 12 months of life was 95%.

14.2 Efficacy and Immunogenicity in Specific Populations

Homosexual Men

ENGERIX-B (20 mcg/1 mL) given at 0, 1, and 6 months was evaluated in homosexual men aged 16 to 59 years. Four of 244 subjects became infected with hepatitis B during the period prior to completion of the 3-dose immunization schedule. No additional subjects became infected during the 18-month follow-up period after completion of the immunization course.

Adults with Chronic Hepatitis C

In a clinical trial of 67 adults aged 25 to 67 years with chronic hepatitis C, ENGERIX-B (20 mcg/1 mL) was given at 0, 1, and 6 months. Of the subjects assessed at Month 7 (n = 31), 100% responded with seroprotective titers. The geometric mean antibody titer (GMT) was 1,260 mIU/mL (95% Confidence Interval [CI]: 709, 2,237).

Adults on Hemodialysis

Hemodialysis patients given hepatitis B vaccines respond with lower titers, which remain at protective levels for shorter durations than in normal subjects. In a clinical trial of 56 adults who had been on hemodialysis for a mean period of 56 months, ENGERIX-B (40 mcg/2 mL given as two 1-mL doses) was given at 0, 1, 2, and 6 months. Two months after the fourth dose, 67% (29/43) of patients had seroprotective antibody levels (≥10 mIU/mL) and the GMT among seroconverters was 93 mIU/mL.

Adults with Type 2 Diabetes Mellitus

In a descriptive study, 674 adult subjects with type 2 diabetes (diagnosed within the preceding 5 years) or without type 2 diabetes were enrolled and stratified by age and body mass index (BMI). The per-protocol immunogenicity cohort included 378 diabetic subjects and 189 matched control subjects who received ENGERIX-B (20 mcg/1 mL) at 0, 1, and 6 months. Among these subjects, the mean age was 54 years (range: 20 to 82 years); mean BMI was 32 kg/m2 (range: 17 to 64 kg/m2); 51% were male; 88% were white, 3% were American Indian or Alaskan Native, 3% were black, 2% were Asian, 4% were other racial groups; 2% were Hispanic or Latino.

The overall seroprotection rates (1 month after the third dose) were 75% (95% CI: 71, 80) in patients with diabetes and 82% (95% CI: 76, 87) in control subjects. The seroprotection rates in those with diabetes aged 20 to 39 years, 40 to 49 years, 50 to 59 years, and at least 60 years were 89%, 81%, 83%, and 58%, respectively. The seroprotection rates in those without diabetes in these same age-groups were 100%, 86%, 82%, and 70%, respectively. Subjects with diabetes and a BMI of at least 30 kg/m2 had a seroprotection rate of 72% compared with 80% in diabetic subjects with lower BMIs. In control subjects, seroprotection rates were 82% in those with a BMI of at least 30 kg/m2 and 83% in those with lower BMIs.

14.3 Immunogenicity in Neonates

In clinical studies, neonates were given ENGERIX-B (10 mcg/0.5 mL) at age 0, 1, and 6 months or at age 0, 1, and 2 months. The immune response to vaccination was evaluated in sera obtained 1 month after the third dose of ENGERIX-B.

Among infants administered ENGERIX-B at age 0, 1, and 6 months, 100% of evaluable subjects (n = 52) seroconverted by Month 7. The GMT was 713 mIU/mL. Of these, 97% had seroprotective levels (≥10 mIU/mL).

Among infants enrolled (n = 381) to receive ENGERIX-B at age 0, 1, and 2 months, 96% had seroprotective levels (≥10 mIU/mL) by Month 4. The GMT among seroconverters (n = 311) (antibody titer ≥1 mIU/mL) was 210 mIU/mL. A subset of these children received a fourth dose of ENGERIX-B at age 12 months. One month following this dose, seroconverters (n = 126) had a GMT of 2,941 mIU/mL.

14.4 Immunogenicity in Children and Adults

Persons Aged 6 Months through 10 Years

In clinical trials, children (N = 242) aged 6 months through 10 years were given ENGERIX-B (10 mcg/0.5 mL) at 0, 1, and 6 months. One to 2 months after the third dose, the seroprotection rate was 98% and the GMT of seroconverters was 4,023 mIU/mL.

Persons Aged 5 through 16 Years

In a separate clinical trial including both children and adolescents aged 5 through 16 years, ENGERIX-B (10 mcg/0.5 mL) was administered at 0, 1, and 6 months (n = 181) or 0, 12, and 24 months (n = 161). Immediately before the third dose of vaccine, seroprotection was achieved in 92.3% of subjects vaccinated on the 0-, 1-, and 6-month schedule and 88.8% of subjects on the 0-, 12-, and 24-month schedule (GMT: 118 mIU/mL versus 162 mIU/mL, respectively, P = 0.18). One month following the third dose, seroprotection was achieved in 99.5% of children vaccinated on the 0-, 1-, and 6-month schedule compared with 98.1% of those on the 0-, 12-, and 24-month schedule. GMTs were higher (P = 0.02) for children receiving vaccine on the 0-, 1-, and 6-month schedule compared with those on the 0-, 12-, and 24-month schedule (5,687 mIU/mL versus 3,159 mIU/mL, respectively).

Persons Aged 11 through 19 Years

In clinical trials with healthy adolescent subjects aged 11 through 19 years, ENGERIX-B (10 mcg/0.5 mL) given at 0, 1, and 6 months produced a seroprotection rate of 97% at Month 8 (n = 119) with a GMT of 1,989 mIU/mL (n = 118, 95% CI: 1,318, 3,020). Immunization with ENGERIX-B (20 mcg/1 mL) at 0, 1, and 6 months produced a seroprotection rate of 99% at Month 8 (n = 122) with a GMT of 7,672 mIU/mL (n = 122, 95% CI: 5,248, 10,965).

Persons Aged 16 through 65 Years

Clinical trials in healthy adult and adolescent subjects (aged 16 through 65 years) have shown that following a course of 3 doses of ENGERIX-B (20 mcg/1 mL) given at 0, 1, and 6 months, the seroprotection (antibody titers ≥10 mIU/mL) rate for all individuals was 79% at Month 6 (5 months after second dose) and 96% at Month 7 (1 month after third dose); the GMT for seroconverters was 2,204 mIU/mL at Month 7 (n = 110).

An alternate 3-dose schedule (20 mcg/1 mL given at 0, 1, and 2 months) designed for certain populations (e.g., individuals who have or might have been recently exposed to the virus and travelers to high-risk areas) was also evaluated. At Month 3 (1 month after third dose), 99% of all individuals were seroprotected and remained protected through Month 12. On the alternate schedule, a fourth dose of ENGERIX-B (20 mcg/1 mL) at 12 months produced a GMT of 9,163 mIU/mL at Month 13 (1 month after fourth dose) (n = 373).

Persons Aged 40 Years and Older

Among subjects aged 40 years and older given ENGERIX-B (20 mcg/1 mL) at 0, 1, and 6 months, the seroprotection rate 1 month after the third dose was 88% and the GMT for seroconverters was 610 mIU/mL (n = 50). In adults aged older than 40 years, ENGERIX-B produced anti-HBsAg antibody titers that were lower than those in younger adults.

14.5 Interchangeability with Other Hepatitis B Vaccines

A controlled study (N = 48) demonstrated that completion of a course of immunization with 1 dose of ENGERIX-B (20 mcg/1 mL) at Month 6 following 2 doses of RECOMBIVAX HB® [Hepatitis B Vaccine (Recombinant)] (10 mcg) at Months 0 and 1 produced a similar GMT (4,077 mIU/mL) to immunization with 3 doses of RECOMBIVAX HB (10 mcg) at Months 0, 1, and 6 (GMT: 2,654 mIU/mL). Thus, ENGERIX-B can be used to complete a vaccination course initiated with RECOMBIVAX HB.8

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