2.1 Preparation for Administration

Shake well before use. With thorough agitation, ENGERIX-B is a homogeneous, turbid white suspension. Do not administer if it appears otherwise. 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.

For the prefilled syringes, attach a sterile needle and administer intramuscularly.

For the vials, use a sterile needle and sterile syringe to withdraw the vaccine dose and administer intramuscularly. Changing needles between drawing vaccine from a vial and injecting it into a recipient is not necessary unless the needle has been damaged or contaminated. Use a separate sterile needle and syringe for each individual.

2.2 Administration

ENGERIX-B should be administered by intramuscular injection. The preferred administration site is the anterolateral aspect of the thigh for infants younger than 1 year and the deltoid muscle in older children (whose deltoid is large enough for an intramuscular injection) and adults. ENGERIX‑B should not be administered in the gluteal region; such injections may result in suboptimal response.

ENGERIX-B may be administered subcutaneously to persons at risk of hemorrhage (e.g., hemophiliacs). However, hepatitis B vaccines administered subcutaneously are known to result in a lower antibody response. Additionally, when other aluminum-adsorbed vaccines have been administered subcutaneously, an increased incidence of local reactions including subcutaneous nodules has been observed. Therefore, subcutaneous administration should be used only in persons who are at risk of hemorrhage with intramuscular injections.

Do not administer intravenously or intradermally.

2.3 Recommended Dose and Schedule

Persons From Birth Through 19 Years of Age: Primary immunization for infants (born of hepatitis B surface antigen [HBsAg]-negative or HBsAg-positive mothers), children (birth through 10 years of age), and adolescents (11 through 19 years of age) consists of a series of 3 doses (0.5 mL each) given on a 0-, 1-, and 6-month schedule.

Persons 20 Years of Age and Older: Primary immunization for persons 20 years of age and older consists of a series of 3 doses (1 mL each) given on a 0-, 1-, and 6-month schedule.

Adults on Hemodialysis: Primary immunization consists of a series of 4 doses (2 mL each) given as a single 2-mL dose or two 1-mL doses on a 0-, 1-, 2-, and 6-month schedule. In hemodialysis patients, antibody response is lower than in healthy persons and protection may persist only as long as antibody levels remain above 10 mIU/mL. Therefore, the need for booster doses should be assessed by annual antibody testing. A 2-mL booster dose (as a single 2-mL dose or two 1-mL doses) should be given when antibody levels decline below 10 mIU/mL.1[See Clinical Studies (14.2).]

HBsAg = Hepatitis B surface antigen

a0.5 mL (10 mcg); 1 mL (20 mcg).

bInfants born to HBsAg-positive mothers should also receive hepatitis B immune globulin (HBIG) [see Dosage and Administration (2.5)].

cGiven as a single 2-mL dose or as two 1-mL doses.

2.4 Alternate Dosing Schedules

There are alternate dosing and administration schedules which may be used for specific populations (e.g., neonates born of hepatitis B–infected mothers, persons who have or might have been recently exposed to the virus, and travelers to high-risk areas) (Table 2). For some of these alternate schedules, an additional dose at 12 months is recommended for prolonged maintenance of protective titers.

HBsAg = Hepatitis B surface antigen

a0.5 mL (10 mcg); 1 mL (20 mcg).

bInfants born to HBsAg-positive mothers should also receive hepatitis B immune globulin (HBIG) [see Dosage and Administration (2.5)].

cFor children and adolescents for whom an extended administration schedule is acceptable based on risk of exposure.

2.5 Booster Vaccinations

Whenever administration of a booster dose is appropriate, the dose of ENGERIX-B is 0.5 mL for children 10 years of age and younger and 1 mL for persons 11 years of age and older. Studies have demonstrated a substantial increase in antibody titers after booster vaccination with ENGERIX-B. See Section 2.2 for information on booster vaccination for adults on hemodialysis.

2.6 Known or Presumed Exposure to Hepatitis B Virus

Persons with known or presumed exposure to the hepatitis B virus (e.g., neonates born of infected mothers, persons who experienced percutaneous or permucosal exposure to the virus) should be given hepatitis B immune globulin (HBIG) in addition to ENGERIX-B in accordance with Advisory Committee on Immunization Practices recommendations and with the package insert for HBIG. ENGERIX-B can be given on either dosing schedule (0, 1, and 6 months or 0, 1, 2, and 12 months).

5.1 Latex

ENGERIX-B is available in vials and 2 types of prefilled syringes. One type of prefilled syringe has a tip cap which may contain natural rubber latex. The other type has a tip cap and a rubber plunger which contain dry natural latex rubber. Use of these syringes may cause allergic reactions in latex-sensitive individuals. The vial stopper does not contain latex. [See How Supplied/Storage and Handling (16).]

5.2 Syncope

Syncope (fainting) can occur in association with administration of injectable vaccines, including ENGERIX-B. Syncope can be accompanied by transient neurological signs such as visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope.

5.3 Infants Weighing Less Than 2,000 g

Hepatitis B vaccine should be deferred for infants weighing <2,000 g if the mother is documented to be HBsAg negative at the time of the infant’s birth. Vaccination can commence at chronological age 1 month or hospital discharge. Infants weighing <2,000 g born to HBsAg-positive mothers or mothers of unknown HBsAg status should receive vaccine and hepatitis B immune globulin (HBIG) within 12 hours if HBsAg status cannot be determined; the birth dose should not be counted as the first dose in the vaccine series and it should be followed with a full 3-dose standard regimen (total of 4 doses).2 [See Dosage and Administration (2).]

5.4 Apnea in Premature Infants

Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including ENGERIX-B, to infants born prematurely should be based on consideration of the infant’s medical status, and the potential benefits and possible risks of vaccination. For ENGERIX-B, this assessment should include consideration of the mother’s hepatitis B antigen status and the high probability of maternal transmission of hepatitis B virus to infants born of mothers who are HBsAg positive if vaccination is delayed.

5.5 Preventing and Managing Allergic Vaccine Reactions

Prior to immunization, the healthcare provider should review the immunization history for possible vaccine sensitivity and previous vaccination-related adverse reactions to allow an assessment of benefits and risks. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur. [See Contraindications (4).]

5.6 Moderate or Severe Acute Illness

To avoid diagnostic confusion between manifestations of an acute illness and possible vaccine adverse effects, vaccination with ENGERIX-B should be postponed in persons with moderate or severe acute febrile illness unless they are at immediate risk of hepatitis B infection (e.g., infants born of HBsAg-positive mothers).

5.7 Altered Immunocompetence

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

5.8 Multiple Sclerosis

Results from 2 clinical studies indicate that there is no association between hepatitis B vaccination and the development of multiple sclerosis,3 and that vaccination with hepatitis B vaccine does not appear to increase the short‑term risk of relapse in multiple sclerosis.4

5.9 Limitations of Vaccine Effectiveness

Hepatitis B has a long incubation period. ENGERIX-B may not prevent hepatitis B infection in individuals who had an unrecognized hepatitis B infection at the time of vaccine administration. Additionally, it may not prevent infection in individuals who do not achieve protective antibody titers.

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 most common solicited adverse events were injection site soreness (22%) and fatigue (14%).

In 36 clinical studies, a total of 13,495 doses of ENGERIX-B were administered to 5,071 healthy adults and children who were initially seronegative for hepatitis B markers, and healthy neonates. All subjects were monitored for 4 days post-administration. Frequency of adverse events tended to decrease with successive doses of ENGERIX-B.

Using a symptom checklist, the most frequently reported adverse events were injection site soreness (22%) and fatigue (14%). Other events are listed below. Parent or guardian completed forms for children and neonates. Neonatal checklist did not include headache, fatigue, or dizziness.

Incidence 1% to 10% of Injections: Nervous System Disorders: Dizziness, headache.

General Disorders and Administration Site Conditions: Fever (>37.5°C), injection site erythema, injection site induration, injection site swelling.

Incidence <1% of Injections: Infections and Infestations: Upper respiratory tract illnesses.

Blood and Lymphatic System Disorders: Lymphadenopathy.

Metabolism and Nutrition Disorders: Anorexia.

Psychiatric Disorders: Agitation, insomnia.

Nervous System Disorders: Somnolence, tingling.

Vascular Disorders: Flushing, hypotension.

Gastrointestinal Disorders: Abdominal pain/cramps, constipation, diarrhea, nausea, vomiting.

Skin and Subcutaneous Tissue Disorders: Erythema, petechiae, pruritus, rash, sweating, urticaria.

Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, myalgia, pain/stiffness in arm, shoulder, or neck.

General Disorders and Administration Site Conditions: Chills, influenza-like symptoms, injection site ecchymosis, injection site pain, injection site pruritus, irritability, malaise, weakness.

6.2 Postmarketing Experience

In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for ENGERIX-B since market introduction (1990) are listed below. This list includes serious adverse events or events which have a suspected causal connection to components of ENGERIX-B.

The following adverse events have been identified during postapproval use of ENGERIX-B. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

Infections and Infestations: Herpes zoster, meningitis.

Blood and Lymphatic System Disorders: Thrombocytopenia.

Immune System Disorders: Allergic reaction, anaphylactoid reaction, anaphylaxis. An apparent hypersensitivity syndrome (serum sickness-like) of delayed onset has been reported days to weeks after vaccination, including: arthralgia/arthritis (usually transient), fever, and dermatologic reactions such as urticaria, erythema multiforme, ecchymoses, and erythema nodosum.

Nervous System Disorders: Encephalitis, encephalopathy, migraine, multiple sclerosis, neuritis, neuropathy including hypoesthesia, paresthesia, Guillain-Barré syndrome and Bell’s palsy, optic neuritis, paralysis, paresis, seizures, syncope, transverse myelitis.

Eye Disorders: Conjunctivitis, keratitis, visual disturbances.

Ear and Labyrinth Disorders: Earache, tinnitus, vertigo.

Cardiac Disorders: Palpitations, tachycardia.

Vascular Disorders: Vasculitis.

Respiratory, Thoracic and Mediastinal Disorders: Apnea, bronchospasm including asthma-like symptoms.

Gastrointestinal Disorders: Dyspepsia.

Skin and Subcutaneous Tissue Disorders: Alopecia, angioedema, eczema, erythema multiforme including Stevens-Johnson syndrome, erythema nodosum, lichen planus, purpura.

Musculoskeletal and Connective Tissue Disorders: Arthritis, muscular weakness.

General Disorders and Administration Site Conditions: Injection site reaction.

Investigations: Abnormal liver function tests.

7.1 Concomitant Administration With Vaccines and Immune Globulin

ENGERIX-B may be administered concomitantly with immune globulin.

When concomitant administration of other vaccines or immune globulin is required, they should be given with different syringes and at different injection sites. Do not mix ENGERIX-B with any other vaccine or product in the same syringe or vial.

8.1 Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with ENGERIX-B. It is also not known whether ENGERIX-B can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ENGERIX-B should be given to a pregnant woman only if clearly needed.

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) and Clinical Studies (14.1, 14.3, 14.4).]

8.5 Geriatric Use

Clinical studies of ENGERIX-B used for licensure did not include sufficient numbers of subjects 65 years of age 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 of age.5

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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 16 to 59 years of age. 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 25 to 67 years of age 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.

14.3 Immunogenicity in Neonates

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

Among infants administered ENGERIX-B at 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 0, 1, and 2 months of age, 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 12 months of age. One month following this dose, seroconverters (N = 126) had a GMT of 2,941 mIU/mL.

14.4 Immunogenicity in Children and Adults

Persons 6 Months Through 10 Years of Age: In clinical trials, children (N = 242) 6 months through 10 years of age 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 5 Through 16 Years of Age: In a separate clinical trial including both children and adolescents 5 through 16 years of age, 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: 117.9 mIU/mL versus 162.1 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 to 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 to those on the 0-, 12-, and 24-month schedule (5,687.4 mIU/mL versus 3,158.7 mIU/mL, respectively).

Persons 11 Through 19 Years of Age: In clinical trials with healthy adolescent subjects 11 through 19 years of age, 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 16 Through 65 Years of Age: Clinical trials in healthy adult and adolescent subjects (16 through 65 years of age) 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 40 Years of Age and Older: Among subjects 40 years of age 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 older than 40 years of age, 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® (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