RECOMBIVAX HB is indicated for vaccination against infection caused by all known subtypes of hepatitis B virus. RECOMBIVAX HB Dialysis Formulation is indicated for vaccination of adult predialysis and dialysis patients against infection caused by all known subtypes of hepatitis B virus.

Vaccination with RECOMBIVAX HB is recommended for:

1) Infants including those born to HBsAg positive mothers (high-risk infants).

2) Children born after November 21, 1991.³⁰

3) Adolescents (see CLINICAL PHARMACOLOGY).

4) Other persons of all ages in areas of high prevalence or those who are or may be at increased risk of infection with hepatitis B virus, such as:³⁰

· Health Care Personnel

Dentists and oral surgeons.

Physicians and surgeons.

Nurses.

Paramedical personnel and custodial staff who may be exposed to the virus via blood or other patient specimens.

Dental hygienists and dental nurses.

Laboratory personnel handling blood, blood products, and other patient specimens. Dental, medical and nursing students.

· Selected Patients and Patient Contacts

Staff in hemodialysis units and hematology/oncology units.

Hemodialysis patients and patients with early renal failure before they require hemodialysis.

Patients requiring frequent and/or large volume blood transfusions or clotting factor concentrates (e.g., persons with hemophilia, thalassemia).

Individuals with hepatitis C virus infection.³⁶

Clients (residents) and staff of institutions for the mentally handicapped.

Classroom contacts of deinstitutionalized mentally handicapped persons who have persistent hepatitis B surface antigenemia and who show aggressive behavior.

Household and other intimate contacts of persons with persistent hepatitis B surface antigenemia.

· Sub-populations with a known high incidence of the disease, such as:

Alaskan Natives.

Pacific Islanders.

Refugees from areas where hepatitis B virus infection is endemic.

Adoptees from countries where hepatitis B virus infection is endemic.

· International Travelers

· Military Personnel identified as being at increased risk

· Morticians and Embalmers

· Blood bank and plasma fractionation workers

· Persons at Increased Risk of the Disease Due to Their Sexual Practices, such as:

Persons who have heterosexual activity with multiple partners.

Persons who repeatedly contract sexually transmitted diseases.

Homosexual and bisexual adolescent and adult men.

Female prostitutes.

· Prisoners

· Injection drug users

Neither dosage strength will prevent hepatitis caused by other agents, such as hepatitis A virus, hepatitis C virus, hepatitis E virus or other viruses known to infect the liver.

Revaccination See CLINICAL PHARMACOLOGY.

Results from clinical studies indicate that RECOMBIVAX HB can be administered concomitantly with DTP (Diphtheria, Tetanus and whole cell Pertussis), OPV (oral Poliomyelitis vaccine), M-M-R^* II (Measles, Mumps, and Rubella Virus Vaccine Live), Liquid PedvaxHIB^* [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] or a booster dose of DTaP [Diphtheria, Tetanus, acellular Pertussis], using separate sites and syringes for injectable vaccines. No impairment of immune response to individually tested vaccine antigens was demonstrated.

The type, frequency and severity of adverse experiences observed in these studies with RECOMBIVAX HB were similar to those seen when the other vaccines were given alone.

In addition, an HBsAg-containing product, COMVAX^* [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine], was given concomitantly with eIPV (enhanced inactivated Poliovirus vaccine) or VARIVAX^* [Varicella Virus Vaccine Live (Oka/Merck)], using separate sites and syringes for injectable vaccines. No impairment of immune response to these individually tested vaccine antigens was demonstrated. No serious vaccine-related adverse events were reported.

COMVAX has also been administered concomitantly with the primary series of DTaP to a limited number of infants. No serious vaccine-related adverse events were reported.¹⁰ Separate sites and syringes should be used for simultaneous administration of injectable vaccines.

The vaccination regimen for each population consists of 3 doses of vaccine given according to the following schedule:

First dose: at elected date

Second dose: 1 month later

Third dose: 6 months after the first dose

For infants born of mothers who are HBsAg positive or mothers of unknown HBsAg status, treatment recommendations are described in the subsection titled: Guidelines For Treatment of Infants Born of HBsAg Positive Mothers or Mothers of Unknown HBsAg Status.

An alternate two-dose regimen is available for routine vaccination of adolescents (11 through 15 years of age). The regimen consists of two doses of vaccine (10 mcg) given according to the following schedule: First injection: at elected date

Second injection: 4-6 months later

Table 1 summarizes the dose and formulation of RECOMBIVAX HB for specific populations, regardless of the risk of infection with hepatitis B virus.

RECOMBIVAX HB is for intramuscular injection. The deltoid muscle is the preferred site for intramuscular injection in adults. Data suggest that injections given in the buttocks frequently are given into fatty tissue instead of into muscle. Such injections have resulted in a lower seroconversion rate than was expected. The anterolateral thigh is the recommended site for intramuscular injection in infants and young children.

For persons at risk of hemorrhage following intramuscular injection, RECOMBIVAX HB may be administered subcutaneously. However, 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 (e.g., hemophiliacs) who are at risk of hemorrhage following intramuscular injections.

The vaccine should be used as supplied; no dilution or reconstitution is necessary. The full recommended dose of the vaccine should be used.

For All Formulations Without Preservative: Once the single-dose vial has been penetrated, the withdrawn vaccine should be used promptly, and the vial must be discarded.

For All Formulations With and Without Preservative: Shake well before use. Thorough agitation at the time of administration is necessary to maintain suspension of the vaccine.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. After thorough agitation, the vaccine is a slightly opaque, white suspension.

For Vials With and Without Preservative: Withdraw the recommended dose from the vial using a sterile needle and syringe free of preservatives, antiseptics, and detergents.

It is important to use a separate sterile syringe and needle for each individual patient to prevent transmission of hepatitis and other infectious agents from one person to another. Needles should be disposed of properly and should not be recapped.

Injection must be accomplished with a needle long enough to ensure intramuscular deposition of the vaccine.

Each infant should receive three 5 mcg doses of RECOMBIVAX HB irrespective of the mother's HBsAg status (see Table 1). The ACIP recommends that if the mother is determined to be HBsAg positive within 7 days of delivery, the infant also should be given a dose of HBIG (0.5 mL) immediately. The first dose of RECOMBIVAX HB may be given at the same time as HBIG, but it should be administered in the opposite anterolateral thigh.⁷

RECOMBIVAX HB is for intramuscular injection. The deltoid muscle is the preferred site for intramuscular injection in adults. Data suggest that injections given in the buttocks frequently are given into fatty tissue instead of into muscle. Such injections have resulted in a lower seroconversion rate than was expected. The anterolateral thigh is the recommended site for intramuscular injection in infants and young children.

For persons at risk of hemorrhage following intramuscular injection, RECOMBIVAX HB may be administered subcutaneously. However, 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 (e.g., hemophiliacs) who are at risk of hemorrhage following intramuscular injections.

The vaccine should be used as supplied; no dilution or reconstitution is necessary. The full recommended dose of the vaccine should be used.

For All Formulations Without Preservative: Once the single-dose vial has been penetrated, the withdrawn vaccine should be used promptly, and the vial must be discarded.

For All Formulations With and Without Preservative: Shake well before use. Thorough agitation at the time of administration is necessary to maintain suspension of the vaccine.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. After thorough agitation, the vaccine is a slightly opaque, white suspension.

For Vials With and Without Preservative: Withdraw the recommended dose from the vial using a sterile needle and syringe free of preservatives, antiseptics, and detergents.

It is important to use a separate sterile syringe and needle for each individual patient to prevent transmission of hepatitis and other infectious agents from one person to another. Needles should be disposed of properly and should not be recapped.

Injection must be accomplished with a needle long enough to ensure intramuscular deposition of the vaccine.

Each infant should receive three 5 mcg doses of RECOMBIVAX HB irrespective of the mother's HBsAg status (see Table 1). The ACIP recommends that if the mother is determined to be HBsAg positive within 7 days of delivery, the infant also should be given a dose of HBIG (0.5 mL) immediately. The first dose of RECOMBIVAX HB may be given at the same time as HBIG, but it should be administered in the opposite anterolateral thigh.⁷

The duration of the protective effect of RECOMBIVAX HB in healthy vaccinees is unknown at present and the need for booster doses is not yet defined (see CLINICAL PHARMACOLOGY).

A booster dose or revaccination with RECOMBIVAX HB Dialysis Formulation (blue color code) may be considered in predialysis/dialysis patients if the anti-HBs level is less than 10 mIU/mL 1 to 2 months after the third dose.²³ The ACIP recommends that the need for booster doses of vaccine should be assessed by annual antibody testing and a booster dose given when antibody levels decline to <10 mIU/mL.³⁰

There are no prospective studies directly testing the efficacy of a combination of HBIG and RECOMBIVAX HB in preventing clinical hepatitis B following percutaneous, ocular or mucous membrane exposure to hepatitis B virus. However, since most persons with such exposures (e.g., health-care workers) are candidates for RECOMBIVAX HB and since combined HBIG plus vaccine is more efficacious than HBIG alone in perinatal exposures, the following guidelines are recommended for persons who have been exposed to hepatitis B virus such as through (1) percutaneous (needlestick), ocular, mucous membrane exposure to blood known or presumed to contain HBsAg, (2) human bites by known or presumed HBsAg carriers, that penetrate the skin, or (3) following intimate sexual contact with known or presumed HBsAg carriers.

HBIG (0.06 mL/kg) should be given intramuscularly as soon as possible after exposure and within 24 hours if possible. RECOMBIVAX HB (see dosage recommendation) should be given intramuscularly at a separate site within 7 days of exposure and second and third doses given one and six months, respectively, after the first dose.

PEDIATRIC/ADOLESCENT FORMULATION (PRESERVATIVE-FREE)

No. 4980 - RECOMBIVAX HB for use in infants, children, and adolescents is supplied as 5 mcg/0.5 mL of HBsAg in a 0.5 mL single-dose vial, color coded with a yellow cap and stripe on the vial labels and cartons and an orange banner on the vial labels and cartons stating "Preservative Free", NDC 0006-4980-00.

No. 4981 - RECOMBIVAX HB for use in infants, children, and adolescents is supplied as 5 mcg/0.5 mL of HBsAg in a 0.5 mL single-dose vial, in a box of 10 single-dose vials, color coded with a yellow cap and stripe on the vial labels and cartons and an orange banner on the vial labels and cartons stating "Preservative Free", NDC 0006-4981-00.

No. 4994 - RECOMBIVAX HB for use in infants, children, and adolescents is supplied as 5 mcg/0.5 mL of HBsAg in a 0.5 mL pre-filled single-dose Luer-Lok^** syringe in a box of 10 pre-filled single-dose syringes, color coded with a yellow plunger rod and stripe on the syringe labels and cartons and an orange banner on the syringe labels and cartons stating "Preservative Free", NDC 0006-4994-41.

PEDIATRIC/ADOLESCENT FORMULATION

No. 4769 RECOMBIVAX HB for use in infants, children, and adolescents is supplied as 5 mcg/0.5 mL of HBsAg in a 0.5 mL single-dose vial, color coded with a yellow cap and stripe on the vial labels and cartons, NDC 0006-4769-00.

No. 4876 - RECOMBIVAX HB for use in infants, children, and adolescents is supplied as 5 mcg/0.5 mL of HBsAg in a 0.5 mL single-dose vial, in a box of 10 single-dose vials, color coded with a yellow cap and stripe on the vial labels and cartons, NDC 0006-4876-00.

ADULT FORMULATION (PRESERVATIVE FREE)

No. 4995 - RECOMBIVAX HB for use in adults and adolescents (11 through 15 years of age) is supplied as 10 mcg/mL of HBsAg in a 1 mL single-dose vial, color coded with a green cap and stripe on the vial labels and cartons and an orange banner on the vial labels and cartons stating "Preservative Free", NDC 0006-4995-00.

No. 4995 - RECOMBIVAX HB for use in adults and adolescents (11 through 15 years of age) is supplied as 10 mcg/mL of HBsAg in a 1 mL single-dose vial, in a box of 10 single-dose vials, color coded with a green cap and stripe on the vial labels and cartons and an orange banner on the vial labels and cartons stating "Preservative Free", NDC 0006-4995-41.

ADULT FORMULATION

No. 4775 - RECOMBIVAX HB for use in adults and adolescents (11 through 15 years of age) is supplied as 10 mcg/mL of HBsAg in a 1 mL single-dose vial, color coded with a green cap and stripe on the vial labels and cartons, NDC 0006-4775-00.

No. 4773 - RECOMBIVAX HB for use in adults and adolescents (11 through 15 years of age) is supplied as 10 mcg/mL of HBsAg in a 3 mL multiple-dose vial, color coded with a green cap and stripe on the vial labels and cartons, NDC 0006-4773-00.

No. 4872 - RECOMBIVAX HB for use in adults and adolescents (11 through 15 years of age) is supplied as 10 mcg/mL of HBsAg in a 1 mL single-dose vial, in a box of 10 single-dose vials, color coded with a green cap and stripe on the vial labels and cartons, NDC 0006-4872-00.

No. 4873 - RECOMBIVAX HB for use in adults and adolescents (11 through 15 years of age) is supplied as 10 mcg/mL of HBsAg in a 3 mL multiple-dose vial, in a box of 10 multi-dose vials, color coded with a green cap and stripe on the vial labels and cartons, NDC 0006-4873-00. DIALYSIS FORMULATION (PRESERVATIVE FREE) No. 4992 - RECOMBIVAX HB Dialysis Formulation is supplied as 40 mcg/mL of HBsAg in a 1 mL single-dose vial, color coded with a blue cap and stripe on the vial labels and cartons and an orange banner on the vial labels and cartons stating "Preservative Free", NDC 0006-4992-00. DIALYSIS FORMULATION

No. 4776 - RECOMBIVAX HB Dialysis Formulation is supplied as 40 mcg/mL of HBsAg in a 1 mL single-dose vial, color coded with a blue cap and stripe on the vial labels and cartons, NDC 0006-4776-00.

Store vials and syringes at 2-8°C (36-46°F). Storage above or below the recommended temperature may reduce potency.

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2. Recommendation of the Immunization Practices Advisory Committee (ACIP): Protection against viral hepatitis, MMWR 39(RR-2): 5-22, Feb. 9, 1990.

3. Balistreri, W.F.: Viral Hepatitis, Unique aspects of infection during childhood, Consultant 24(4): 131-153 passim, April 1984.

4. Robinson, W.S.: Hepatitis B. Virus and Hepatitis Delta Virus in "Principles and Practice of Infectious Diseases," G.L. Mandell, R.G. Douglas, and J.E. Bennett (eds), Churchill Livingstone, 1204-1231, 1990.

5. Stevens, C.E.; Toy, P.T.; Tong, M.J.; Taylor, P.E.; Vyas, G.N.; Nair, P.V.; Gudavalli, M.; Krugman, S.: Perinatal hepatitis B virus transmission in the United States, JAMA; 253(12): 1740-1745, 1985.

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7. Recommendations of the Immunization Practices Advisory Committee (ACIP): Hepatitis B Virus: A Comprehensive Strategy for Eliminating Transmission in the United States Through Universal Childhood Vaccination, MMWR 40(RR-13): 1-25, November 22, 1991.

8. Universal Hepatitis B Immunization, Committee on Infectious Diseases, Pediatrics 89(4): 795-800, 1992.

9. Melnick, J.L.: Historical aspects of hepatitis B vaccine in "Hepatitis B Vaccine Inserm Symposium No. 18," P. Maupas and P. Guesry (eds), Elsevier/North-Holland Biomedical Press, p. 23-31, 1981.

10. Data on file at Merck Research Laboratories.

11. Centers for Disease Control: Suboptimal response to hepatitis B vaccine given by injection into the buttock. MMWR

34 (8): 105-113, March 1, 1985.

12. Hadler, S.C., et al.: Long-term immunogenicity and Efficacy of Hepatitis B Vaccine in Homosexual Men, NEJM 315(4): 209-214, 1986.

13. Szmuness, W.; Stevens, C.E.; Horley, H.J., et al.: Hepatitis B Vaccine. Demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. NEJM 303: 833-841, 1980.

14. Francis, D.P.; Hadler, S.C.; Thompson, S.E., et al.: The prevention of hepatitis B with vaccine. Report of the Centers for Disease Control Multi-center Efficacy Trial among Homosexual Men. Ann. Int. Med. 97: 362-366, 1982.

15. Szmuness, W.; Stevens, C.E.; Horley, H.J., et al.: Hepatitis B vaccine in medical staff of hemodialysis units. Efficacy and subtype cross-protection, NEJM 307: 1481-1486, 1982.

16. Stevens, C.E.; Taylor, P.E.; Tong, M.J., et al.: Prevention of perinatal hepatitis B virus infection with hepatitis B immune globulin and hepatitis B vaccine. IN: Zuckerman, A.J. (ed.), Viral Hepatitis and Liver Diseases, Alan R. Liss, 1988, pp. 982-983.

17. Stevens, C.E.; Taylor, P.E.; Tong, M.J., et al.: Yeast-Recombinant Hepatitis B Vaccine, Efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission, JAMA 257(19): 2612-2616, 1987.

18. Wainwright, R.B.; McMahon, B.J.; Bulkow, L.R., et al.: Duration of immunogenicity and efficacy of hepatitis B vaccine in a Yupik Eskimo population, Preliminary Results of an 8-Year Study in "Viral Hepatitis and Liver Disease," F.B.

Hollinger, S.M. Lemon, and H. Margolis (eds), Williams & Wilkins, 762-766, 1990.

19. Hadler, S.C.; Coleman, P.J.; O'Malley, P., et al.: Evaluation of Long-Term Protection by Hepatitis B Vaccine for Seven to Nine Years in Homosexual Men in "Viral Hepatitis and Liver Disease," F.B. Hollinger, S.M. Lemon, and H.

Margolis (eds), Williams & Wilkins, 766-768, 1990.

20. Tong, M.J.; Stevens, C.E.; Taylor, P.E., et al.: Prevention of hepatitis B infection in infants born to HBeAg positive HBsAg carrier mothers in the United States. "An Update, 1989, Progress in Hepatitis B Immunization," P. Coursaget and M.J. Tong (eds), Colloque INSERM/John Libbey Eurotext Ltd., Vol. 194, 339-345, 1990.

21. Hwang, L-Y.; Lee, C-Y.; and Beasley, R.P.: Five-Year Follow-up of HBV Vaccination with Plasma-derived Vaccine in Neonates: Evaluation of Immunogenicity and Efficacy Against Perinatal Transmission in "Viral Hepatitis and Liver Disease," F.B. Hollinger, S.M. Lemon, and H. Margolis (eds), Williams & Wilkins, 759-761, 1990.

22. West, D.J.; Calandra, G.B.: Vaccine induced immunologic memory for hepatitis B surface antigen; implications for policy on booster vaccination, Vaccine, 14(11): 1019-1027, 1996.

23. Recommendations of the Immunization Practices Advisory Committee (ACIP): Update on Hepatitis B Prevention, MMWR 36(23): 353-366, June 19, 1987.

24. Emini, E.A.; Ellis, R.W.; Miller, W.J.; McAleer, W.J.; Scolnick, E.M. and Gerety, R.J.: Production and immunological analysis of recombinant hepatitis B vaccine, J. of Infection, 13(Sup. A): 3-9, 1986.

25. Brown, S.E.; Stanley, C.; Howard, C.R.; Zuckerman, A.J.; Steward, M.W.: Antibody responses to recombinant and plasma derived hepatitis B vaccines, Brit. Med. J., 292: 159-161, 1986.

26. Yamamoto, S.; Kuroki, T.; Kurai, K.; Iino, S.: Comparison of results for Phase I studies with recombinant and plasma-derived hepatitis B vaccines, and controlled study comparing intramuscular and subcutaneous injections of recombinant hepatitis B vaccine, J. of Infection, 13(Sup. A): 53-60, 1986.

27. Jilg, W.; Schmidt, M.; Zoulek, G.; Lorbeer, B.; Wilske, B.; Deinhardt, F.: Clinical evaluation of a recombinant hepatitis B vaccine, Lancet, 1174-1175, Nov. 24, 1984.

28. Schalm, S.W.; Heytink, R.A.; Kruining, H.; Bakker-Bendik, M.: Immunogenicity of recombinant yeast hepatitis-B vaccine, Neth. J. Med. 29: 28, 1986.

29. Centers for Disease Control: Epidemiology and prevention of vaccine-preventative diseases, W. Atkinson, L. Furphy, J. Gantt, M. Mayfield, G. Phyne (eds), chapter 9.

30. Recommendations of the Advisory Committee on Immunization Practices (ACIP): Hepatitis B virus infection: a comprehensive strategy to eliminate transmission in the United States, 1996 update, MMWR (draft January 13, 1996).

31. Thimerosal in Vaccines: A Joint Statement of the American Academy of Pediatrics and the Public Health Service, MMWR 48(26): 563-565, July 09, 1999.

32. Vaccine Adverse Event Reporting System - United States. MMWR 39(41): 730-733, October 19, 1990.

33. Zajac, B.A.; West, D.J.; McAleer, W.J.; Scolnick, E.M.: Overview of Clinical Studies with Hepatitis B Vaccine Made by Recombinant DNA, J. of Infection, 13(Sup. A): 39-45, July 1986.

34. WHO Bulletin, Expanded Programme on Immunization, Hepatitis B Vaccine Making Global Progress. October, 1996.

35. Centers for Disease Control and Prevention, Federal Register, February 23, 1999, 64(35): 9044-9045.

36. National Institutes of Health, National Institutes of Health Consensus Development Conference Panel Statement: Management of Hepatitis C, Hepatology, 26(Suppl. 1): 2S-10S, 1997.

37. Wiedmann, M.; Liebert, U.G.; Oesen, U.; Porst, H.; Wiese, M.; Schroeder, S.; Halm, U.; Mossner, J.; Berr, F.: Decreased immunogenicity of recombinant hepatitis B vaccine in chronic hepatitis C, Hepatology, 31: 230-234, 2000.

38. Minniti, F.; Baldo, V.; Trivello, R.; Bricolo, R.; Di Furia, L.; Renzulli, G.; Chiaramonte, M.: Response to HBV vaccine in relation to anti-HCV and anti-HBc positivity: a study in intravenous drug addicts, Vaccine, 17: 3083-3085, 1999.

Manuf. And Dist. By: Syringes of RECOMBIVAX HB are also manufactured by: Evans Vaccines Ltd., Gaskill Road, Speke, Liverpool L24 9GR, England, Issued August 2002 Printed in USA

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