ENGERIX-B - GlaxoSmithKline Biologicals SA

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.

Administer ENGERIX‑B intramuscularly. 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.

Persons from Birth through 19 Years

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

Persons Aged 20 Years and Older

Primary immunization for persons aged 20 years 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/mL¹ [see Clinical Studies (14.2)].

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.

Whenever administration of a booster dose is appropriate, the dose of ENGERIX-B is 0.5 mL for children aged 10 years and younger and 1 mL for persons aged 11 years and older. Studies have demonstrated a substantial increase in antibody titers after booster vaccination with ENGERIX-B. See Section 2.3 for information on booster vaccination for adults on hemodialysis.

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 may be administered concomitantly with immune globulin with different syringes and at different administration sites. ENGERIX‑B can be given on either dosing schedule (0, 1, and 6 months or 0, 1, 2, and 12 months).

Syncope (fainting) can occur in association with administration of injectable vaccines, including ENGERIX‑B. Procedures should be in place to avoid injury from fainting.

Hepatitis B vaccine should be deferred for infants with a birth weight <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 born weighing <2,000 g to HBsAg-positive mothers should receive vaccine and HBIG within 12 hours after birth. Infants born weighing <2,000 g to mothers of unknown HBsAg status should receive vaccine and HBIG within 12 hours after birth if the mother’s HBsAg status cannot be determined within the first 12 hours of life. The birth dose in infants born weighing <2,000 g 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)].

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.

Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of ENGERIX-B.

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).

Immunocompromised persons may have a diminished immune response to ENGERIX‑B, including individuals receiving immunosuppressant therapy. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater‑than‑physiologic doses), may reduce the immune response to ENGERIX-B.

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

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

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 participants were monitored for 4 days post‑administration. Frequency of adverse reactions tended to decrease with successive doses of ENGERIX‑B.

Using a symptom checklist, the most frequently reported adverse reactions were injection site soreness (22%) and fatigue (14%). Other reactions 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.

In a clinical trial, 416 adults with type 2 diabetes and 258 control participants without type 2 diabetes who were seronegative for hepatitis B markers received at least 1 dose of ENGERIX‑B. Participants were monitored for solicited adverse reactions for 4 days following each vaccination. The most frequently reported solicited adverse reactions in the entire study population were injection site pain (reported in 39% of diabetic participants and 45% of control participants) and fatigue (reported in 29% of diabetic participants and 27% of control participants). Serious adverse events were monitored through 30 days following the last vaccination. Serious adverse events (SAEs) occurred in 3.8% of diabetic participants and 1.6% of controls. No SAEs were deemed related to ENGERIX‑B.

The following adverse reactions have been identified during post-approval use of ENGERIX-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 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.

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 a hepatitis B vaccine, including ENGERIX-B.

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There are no adequate and well-controlled studies of ENGERIX-B in pregnant women in the U.S. Available data do not suggest an increased risk of major birth defects and miscarriage in women who received ENGERIX-B during pregnancy (see Data).

There are no animal studies with ENGERIX-B to inform use during pregnancy. A developmental toxicity study was performed in female rats administered a vaccine with the same hepatitis B surface antigen component and quantity as ENGERIX-B prior to mating and during gestation (0.2 mL at each occasion). This study revealed no adverse effects on fetal or pre-weaning development (see Data).

Data

Human Data: In an evaluation of pre- and post-licensure clinical trials of ENGERIX-B, 58 pregnant women were inadvertently administered ENGERIX-B following their last menstrual period. After excluding elective terminations (n = 6), those with an unknown outcome (n = 3), those with exposure in the third trimester (n = 1), and those with an unknown exposure timing (n = 22), there were 26 pregnancies with known outcomes with exposure in the first or second trimester. Miscarriage was reported in 11.5% of pregnancies with exposure prior to 20 weeks of gestation (3/26) and major birth defects were reported in 0% (0/23) of live births born to women with exposure during the first or second trimester. The rates of miscarriage and major birth defects were consistent with estimated background rates.

No pregnancy registry for ENGERIX-B was conducted. TWINRIX [Hepatitis A & Hepatitis B (Recombinant) Vaccine] is a bivalent vaccine containing the same hepatitis B surface antigen component and quantity as used in ENGERIX-B. Therefore, clinical data accrued with TWINRIX are relevant to ENGERIX-B. A pregnancy exposure registry was maintained for TWINRIX from 2001 to 2015. The registry prospectively enrolled 245 women who received a dose of TWINRIX during pregnancy or within 28 days prior to conception. After excluding induced abortions (n = 6, including one of a fetus with congenital anomalies), those lost to follow-up (n = 142), those with exposure in the third trimester (n = 1), and those with an unknown exposure timing (n = 9), there were 87 pregnancies with known outcomes with exposure within 28 days prior to conception, or in the first or second trimesters. Miscarriage was reported for 9.6% of pregnancies with exposure to TWINRIX prior to 20 weeks gestation (8/83). Major birth defects were reported for 3.8% of live born infants whose mothers were exposed within 28 days prior to conception or during the first or second trimester (3/80). The rates of miscarriage and major birth defects were consistent with estimated background rates.

Animal Data: In a developmental toxicity study, female rats were administered TWINRIX, which contains the same hepatitis B surface antigen component and quantity as ENGERIX-B, by intramuscular injection on Day 30 prior to mating and on gestation Days 6, 8, 11, and 15. The total dose was 0.2 mL (divided) at each occasion (a single human dose is 1 mL). No adverse effects on pre-weaning development up to post-natal Day 25 were observed. There were no fetal malformations or variations.

Risk Summary

There is no information regarding the presence of ENGERIX-B in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENGERIX-B and any potential adverse effects on the breastfed child from ENGERIX-B or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

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 (5.2)].

Clinical studies of ENGERIX‑B used for licensure did not include sufficient numbers of participants aged 65 years and older to determine whether they respond differently from younger participants. However, in later studies it has been shown that a diminished antibody response and seroprotective levels can be expected in persons older than 60 years⁵ [see Clinical Studies (14.2)].

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.

ENGERIX‑B has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. Vaccination of female rats with TWINRIX, which contains the same HBsAg component and quantity as ENGERIX-B, had no effect on fertility [see Use in Specific Populations (8.1)].

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%.

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 participants became infected with hepatitis B during the period prior to completion of the 3‑dose immunization schedule. No additional participants 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 participants 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 individuals. 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 participants 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 participants and 189 matched control participants who received ENGERIX-B (20 mcg/1 mL) at 0, 1, and 6 months. Among these participants, 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 participants. 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. Participants with diabetes and a BMI of at least 30 kg/m² had a seroprotection rate of 72% compared with 80% in diabetic participants with lower BMIs. In control participants, seroprotection rates were 82% in those with a BMI of at least 30 kg/m² and 83% in those with lower BMIs.

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 participants (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.

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 participants vaccinated on the 0‑, 1‑, and 6‑month schedule and 88.8% of participants 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 participants 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 participants (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 participants 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.

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