ENGERIX-B Suspension for injection Ref.[10805] Active ingredients: Hepatitis B, purified antigen

5.1 Latex

The tip caps of the prefilled syringes contain natural rubber latex which may cause allergic reactions.

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 at Birth

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)].

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.

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.

The most common solicited adverse reactions 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 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 subjects without type 2 diabetes who were seronegative for hepatitis B markers received at least 1 dose of ENGERIX-B. Subjects 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 subjects and 45% of control subjects) and fatigue (reported in 29% of diabetic subjects and 27% of control subjects). Serious adverse events were monitored through 30 days following the last vaccination. Serious adverse events (SAEs) occurred in 3.8% of diabetic subjects 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.

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.

7.2 Interference with Laboratory 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 (5.3)].

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 years⁵ [See Clinical Studies (14.2)].