Engerix -B

ENGERIX®-B

SmithKline Beecham

Hepatitis B Vaccine (Recombinant)

Vaccine

Action And Clinical Pharmacology: Hepatitis B vaccine (recombinant) contains purified hepatitis B surface antigen (HBsAg). It is the product of recombinant DNA technology developed by SmithKline Beecham Biologicals, s.a., Belgium. The HBsAg gene from the hepatitis B virus has been cloned by genetic engineering into Saccharomyces cerevisiae.

In vitro experiments have shown that the yeast-derived HBsAg in hepatitis B vaccine (recombinant) contains all the epitopes (antigenic sites) that have been found in the HBsAg in plasma-derived vaccines.

In vivo, the human antibody response to hepatitis B vaccine (recombinant) is similar to the response to plasma-derived vaccines with respect to epitope specificity and avidity. There is no significant modification of the anti-yeast antibody titre after vaccination with hepatitis B vaccine (recombinant).

These studies indicate that hepatitis B vaccine (recombinant) is immunologically similar to the plasma-derived vaccines and provides similar protective efficacy.

In comparative studies commercial plasma-derived vaccines and hepatitis B vaccine (recombinant) exhibited comparable potency in mice and guinea pigs, and comparable protective efficacy in chimpanzees. Hepatitis B vaccine (recombinant) is also highly immunogenic in rabbits, goats and monkeys.

The yeast-derived vaccine hepatitis B vaccine (recombinant) possesses the same immunogenic properties as have been demonstrated by plasma-derived hepatitis B vaccines. Hepatitis B vaccine (recombinant) induces the production of specific antibodies against the surface antigen of hepatitis B virus (anti-HBs).

Since no substances of human origin are used in the production of hepatitis B vaccine (recombinant), the potential for transmission of diseases associated with blood and blood products is eliminated. Potency, safety and sterility are verified for each lot.

It is generally accepted that an anti-HBs titre greater than 10 IU/L correlates with protection against hepatitis B virus infection. More than 90% of healthy adults, children and neonates developed protective anti-HBs titres 1 month after completing a primary vaccination schedule of hepatitis B vaccine (recombinant).

There are data to support 2 schedules of dosing. The 3 dose schedule is 0, 1 and 6 months. The 4 dose schedule is 0, 1, 2 and 12 months. For further details see Dosage.

Females generally seroconvert more quickly than males. As well, anti-HBs titres are higher in females than in males after 3 doses of yeast-derived or plasma-derived vaccine. However, protective anti-HBs titres develop in the same proportion in both sexes.

Anti-HBs titres tend to be slightly lower in older subjects than they are in younger subjects. This influence of age is found for both yeast-derived and plasma-derived vaccines.

The anti-HBs response in children is similar to that in adults.

In ongoing studies, the anti-HBs response in neonates of both carrier and noncarrier mothers to hepatitis B has been shown to be similar to that obtained in adults and children with regard to seroconversion rate and anti-HBs titres attained. Preliminary data indicate that administration of hepatitis B immunoglobulin (HBIG) to the neonate at birth does not appear to affect the immune response to hepatitis B vaccine (recombinant).

The response to hepatitis B vaccine (recombinant) in homosexual males may be slower than it is in heterosexual males. This has also been observed with plasma-derived vaccine. However, the percentages of subjects reaching protective anti-HBs titres 1 month after the third dose of vaccine given at month 6 are similar in the two groups.

The anti-HBs response to the recombinant yeast-derived vaccine is at least as high as that obtained by plasma-derived vaccines in patients affected by thalassemia major.

The anti-HBs response to hepatitis B vaccine (recombinant) in residents of institutions for the mentally retarded is similar to that observed in the general population.

The anti-HBs response of patients on chronic hemodialysis is known to be impaired. However, experience from clinical studies shows that 2 months after 4 double doses i.e., 40 µg (at months 0, 1, 2 and 6), 67% of vaccinees developed protective antibody titres. Anti-HBs titres remained relatively low compared to anti-HBs titres in healthy subjects. These results are similar to those that have been reported with plasma-derived vaccines.

The anti-HBs response in drug addicts does not differ from the response in the general population.

Vaccination against hepatitis B is expected in the long-term to reduce the overall incidence of both hepatitis B and chronic complications such as chronic active hepatitis and cirrhosis.

The hepatitis B virus induces a severe form of viral hepatitis. Other causative agents are hepatitis A virus and the non-A, non-B hepatitis viruses. Hepatitis D virus, a defective virus requiring the keeper function of the hepatitis B virus, occurs either as a coinfection or superinfection in a HBsAg carrier.

There is no specific treatment for hepatitis. The incubation period may be as long as 6 months, followed by a very complex clinical course of an acute or chronic nature, often leading to hospitalization.

Transmission of the virus occurs through percutaneous contact with contaminated blood, serum or plasma. Infection may also occur by the exposure of mucous surfaces, or intact or damaged skin to other body fluids such as saliva, mucosal secretions and semen.

Viral hepatitis caused by hepatitis B virus is a major worldwide health problem, though the incidence and epidemiology vary widely among geographical areas and population subgroups.

In Canada, the United States and Northern Europe, 4 to 6% of the population are infected during their lifetime (mostly young adults); between 5 and 10% of infections lead to persistent viremia (carrier state).

Certain population subgroups in these areas, however, are at high risk (see Indications).

In Asia, infection often occurs early in life, leading to a hepatitis B marker prevalence of more than 70% in the general population and a carrier rate of up to 20%.

It is estimated that the reservoir of persistent hepatitis B surface antigen carriers amounts to 200 million people worldwide. Carriers are at a high risk of developing chronic liver disease which may lead to cirrhosis or primary hepatocellular carcinoma.

Indications And Clinical Uses: For active immunization against hepatitis B virus infection. The vaccine will not protect against infection caused by hepatitis A and non-A non-B hepatitis viruses. As hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection or carrier state, it can be expected that hepatitis D will also be prevented by vaccination.

The vaccine can be administered at any age from birth onwards. It may be used to start a primary course of vaccination or as a booster dose. It may also be used to complete a primary course of vaccination started with plasma-derived or yeast-derived vaccines or as a booster dose in subjects who have previously received a primary course of vaccination with plasma-derived or yeast-derived vaccines.

In areas of low prevalence of hepatitis B, vaccination is strongly recommended in subjects who are at increased risk of infection. These include the following groups: Health Care Personnel: oral surgeons and dentists; physicians and surgeons, nurses, dental nurses, dental hygienists, podiatrists; i.v. teams and operating room personnel; paramedical personnel in close contact with patients; staff in hemodialysis, nephrology, hepatology, hematology and oncology units; laboratory personnel handling blood and other clinical specimens; blood bank and plasma fractionation workers; pathologists and morgue attendants; cleaning staff who handle waste in hospitals; emergency and first aid workers; ambulance staff; dental, medical and nursing students.

Patients: patients receiving frequent blood transfusions or clotting factor concentrates, such as those in oncology units and those with thalassemia, sickle-cell anemia, cirrhosis, hemophilia, etc.; patients on hemodialysis.

Personnel and Residents of Institutions: persons with frequent and/or close contacts with high-risk groups; prisoners and prison staff; residents and staff of institutions for the mentally retarded (those who are in contact with aggressive biting residents being at highest risk).

Persons at Increased Risk Due to Their Sexual Practices: sexually promiscuous persons; persons who repeatedly contract sexually transmitted disease; homosexually active males; prostitutes.

Persons who use injectable drugs illicitly.

Travellers to areas of high endemicity and their close contacts.

Household contacts of any of the above groups and of patients with acute or chronic hepatitis B infection.

Infants born of HBsAg-positive mothers.

Others: police; firefighters; armed forces personnel; morticians and embalmers; those who through their work or personal lifestyle may be exposed to the hepatitis B virus.

In areas of both low and high prevalence vaccination should be offered to young children and neonates at risk as well as to adult high risk groups.

Contra-Indications: Hypersensitivity to any component of the vaccine. As for any vaccine, hepatitis B vaccine (recombinant) should not be administered to subjects with severe febrile infections. Vaccination of a subject with febrile symptoms, with a respiratory infection, or with a contagious or any other disease should be postponed until after recovery. However, the presence of a trivial infection does not contraindicate vaccination.

Manufacturers’ Warnings In Clinical States: Because hepatitis B has a long incubation period it is possible that there may be latent infection at the time of vaccination. Hepatitis B vaccine (recombinant) may not prevent hepatitis B in such cases.

Patients who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections of hepatitis B vaccine (recombinant) (see Contraindications).

Hepatitis B vaccine (recombinant) should not be administered in the gluteal region or intradermally since these routes of administration may not result in an optimum immune response. Intradermal administration may also result in severe local reactions. The vaccine must never be administered i.v.

In dialysis patients and subjects who have an impairment of the immune system, adequate antibody concentrations may not be maintained after a primary vaccination course of 40 µg doses. Such patients may therefore require repeated administrations of the vaccine.

The immune response to hepatitis B vaccines is related to a number of factors, including older age, male gender, obesity, smoking habits and route of administration. In subjects who may respond less well to the administration of the hepatitis B vaccine (e.g., more than 40 years of age, etc.), additional doses may be considered.

Precautions: A new sterile syringe and a new sterile needle should always be used so as to prevent the transmission from one subject to another of infectious agents, such as the hepatitis B virus, non-A non-B hepatitis virus, or the human immunodeficiency virus (HIV).

Pregnancy: The effect of the antigen on fetal development is unknown and therefore vaccination of pregnant women cannot be recommended. However, vaccination of a pregnant woman may be considered in order to prevent hepatitis B in high-risk situations.

As with all biologicals, a solution of 1 in 1 000 epinephrine should always be readily available for immediate use in case of a rare anaphylactic reaction.

Adverse Reactions: Hepatitis B vaccine (recombinant) is generally well tolerated.

The most frequently occurring adverse events, usually mild and transient, are associated with the injection site and include soreness, erythema and induration.

The following adverse events have been reported following widespread use of the vaccine. The frequencies of the adverse events below are calculated taking into account, as the numerator, the total number of spontaneous adverse events reported, and as the denominator, the total number of doses distributed, in those countries with a reliable reporting system for spontaneous adverse events. In many instances, the causal relationship to the vaccine has not been established.

Rare (>1:200 000): Body as a Whole: fatigue, fever, malaise, influenza-like symptoms.

Central and Peripheral Nervous System: dizziness, headache, paresthesia.

Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain.

Liver and Biliary: abnormal liver function tests.

Musculoskeletal: arthralgia, myalgia.

Skin and Appendages: rash, pruritus, urticaria.

Very Rare (1:200 000 to 1:500 000): Cardiovascular: syncope.

Heart Rate and Rhythm: tachycardia.

Musculoskeletal: arthritis.

Respiratory: bronchospasm-like symptoms.

White Cell and Reticulo-Endothelial: lymphadenopathy.

Cardiovascular: hypotension.

Central and Peripheral Nervous System: Bell’s Palsy, migraine, paralysis, neuropathy, neuritis (including Guillain-Barré Syndrome, optic neuritis, multiple sclerosis), transverse myelitis, vertigo.

Gastrointestinal: dyspepsia.

Hearing and Vestibular: tinnitus, earache.

Heart Rate and Rhythm: palpitations.

Platelet Bleeding and Clotting: thrombocytopenia, purpura.

Resistance Mechanism: herpes zoster.

Skin and Appendages: angioedema, eczema, erythema multiforme, erythema nodosum.

Vision: conjunctivitis, visual disturbances.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No information available.

Dosage And Administration:

Schedule: The recommended schedule is 3 doses administered at 0, 1 and 6 months.

For more rapid protection a 4 dose schedule (0, 1, 2 and 12 months) results in the development of protective anti-HBs titres by 3 months. The fourth dose (at 12 months) is required to maintain prolonged protective anti-HBs titres.

For hemodialysis patients, a 4 dose schedule at 0, 1, 2 and 6 months is recommended.

Dosage And Administration: Adults 20 years and over: A dose of 20 µg of antigen protein in 1 mL suspension is recommended for adults.

Neonates, Infants, Children and Adolescents up to 19 years: A dose of 10 µg of antigen protein in 0.5 mL suspension is recommended for neonates, infants, children and adolescents up to 19 years of age inclusive. However, if compliance to the full 0, 1, 6 month schedule cannot be assured in 11- to 19-year-old adolescents, a 20 µg dose should be used to ensure seroprotection. When the pediatric presentation is not available, other presentations may be used for withdrawing the appropriate dose.

Hemodialysis and Immunocompromised Patients: A 2 mL dose (40 µg) is recommended.

Hepatitis B vaccine (recombinant) can effectively boost anti-HBs responses initially elicited by either plasma-derived or yeast-derived vaccines.

For individuals in whom a primary vaccination schedule has been initiated with a plasma-derived vaccine, dosing may be continued with hepatitis B vaccine (recombinant).

Booster Doses: Experience with plasma-derived vaccines has shown that anti-HBs titres gradually decline over time. It is expected that this will also be true for hepatitis B vaccine (recombinant). Hepatitis B vaccine (recombinant) can effectively boost anti-HBs responses initially elicited by either plasma-derived or yeast-derived vaccines.

The timing for a hepatitis B vaccine booster dose will depend upon the anti-HBs titre reached after the completion of the primary immunization schedule. From available data, general guidelines for a booster dose can be made: After the 0, 1, 2 month primary immunization schedule a booster dose is recommended 12 months after the first dose. The next booster will probably not be required for at least another 8 years.

After the 0, 1, 6 month primary immunization schedule a booster dose will probably not be required earlier than 5 years after the primary course.

For hemodialysis and immunocompromised patients, a booster (40 µg) may be required sooner. Regular serological monitoring is recommended to ensure that antibodies are and remain at protective levels.

Administration: Check the expiry date of the vaccine carefully. Do not use vaccine beyond its expiry date.

Shake the vaccine well before use so as to resuspend the sediment of fine white particles of adjuvant (aluminum hydroxide) which settles during storage.

Clean the skin at the site of injection with a suitable antiseptic and dry with a piece of dry sterile cotton. Disinfect the rubber stopper with antiseptic; wipe it dry with a dry sterile cotton swab; then, using a sterile needle, withdraw the vaccine from the vial into a sterile syringe.

Engerix-B should be injected i.m. In adults the injection should be given in the deltoid region. In neonates and infants it may be preferable to inject the vaccine in the anterolateral thigh because of the small size of their deltoid muscle. In special circumstances the vaccine may be administered s.c. in patients with severe bleeding tendencies (e.g., hemophiliacs).

Engerix-B must not be given i.v. or intradermally.

This vaccine may be administered simultaneously with hepatitis B immunoglobulin (HBIG); however, it must be administered at a separate injection site.

Notification of Reactions: It is desirable that all unusual reactions regardless of the vaccine, be reported to the manufacturer as well as to the provincial epidemiologist.

Availability And Storage: 0.5 mL: Each 0.5 mL single pediatric dose vial contains: hepatitis B surface antigen 10 µg adsorbed onto AI++0.25 mg as aluminum hydroxide with thimerosal 0.005% as preservative.

1 mL: Each 1 mL single adult dose vial contains: hepatitis B surface antigen 20 µg adsorbed onto AI++0.5 mg as aluminum hydroxide with thimerosal 0.005% as preservative.

10 mL: Each 10 mL multidose vial for mass immunization programs contains: hepatitis B surface antigen 200 µg adsorbed onto Al++5 mg as aluminum hydroxide with thimerosal 0.005% as preservative.

The vaccine is a slightly opaque, white, sterile suspension. A slow settling of the white, aluminum hydroxide may occur during storage leaving a clear, colorless, supernatant liquid. Cartons of 1 with prescribing information leaflet.

Ship under refrigeration. Store between 2 and 8°C. Do not freeze. Vaccine that has been frozen is no longer potent and should be discarded. Potency of unopened vaccine is not significantly affected by short exposure to room temperature (up to 7 days). For multidose vaccine, discard unused portion no longer than 24 hours after first puncture. When stored at 2 to 8°C, Engerix-B is stable until the expiry date shown on the label.

ENGERIX®-B SmithKline Beecham Hepatitis B Vaccine (Recombinant) Vaccine

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