Vaccine Information: RECOMBIVAX HB

RECOMBIVAX HB — hepatitis b virus subtype adw hbsag surface protein antigen injection, suspension
REMEDYREPACK INC.

DESCRIPTION

RECOMBIVAX HB® Hepatitis B Vaccine (Recombinant) is a non-infectious subunit viral vaccine derived from hepatitis B surface antigen (HBsAg) produced in yeast cells. A portion of the hepatitis B virus gene, coding for HBsAg, is cloned into yeast, and the vaccine for hepatitis B is produced from cultures of this recombinant yeast strain according to methods developed in the Merck Research Laboratories.

The antigen is harvested and purified from fermentation cultures of a recombinant strain of the yeast Saccharomyces cerevisiae containing the gene for the adw subtype of HBsAg. The fermentation process involves growth of Saccharomyces cerevisiae on a complex fermentation medium which consists of an extract of yeast, soy peptone, dextrose, amino acids and mineral salts. The HBsAg protein is released from the yeast cells by cell disruption and purified by a series of physical and chemical methods. The purified protein is treated in phosphate buffer with formaldehyde and then coprecipitated with alum (potassium aluminum sulfate) to form bulk vaccine adjuvanted with amorphous aluminum hydroxyphosphate sulfate. Each dose contains less than 1% yeast protein. The vaccine produced by the Merck method has been shown to be comparable to the plasma-derived vaccine in terms of animal potency (mouse, monkey, and chimpanzee) and protective efficacy (chimpanzee and human).

The vaccine against hepatitis B, prepared from recombinant yeast cultures, is free of association with human blood or blood products.

Each lot of hepatitis B vaccine is tested for sterility.

RECOMBIVAX HB is a sterile suspension for intramuscular injection. However, for persons at risk of hemorrhage following intramuscular injection, the vaccine may be administered subcutaneously. (See DOSAGE AND ADMINISTRATION).

RECOMBIVAX HB Hepatitis B Vaccine (Recombinant) is supplied in three formulations. (See HOW SUPPLIED.)

Pediatric/Adolescent Formulation (Without Preservative), 10 mcg/mL: each 0.5 mL dose contains 5 mcg of hepatitis B surface antigen.

Adult Formulation (Without Preservative), 10 mcg/mL: each 1 mL dose contains 10 mcg of hepatitis B surface antigen.

Dialysis Formulation (Without Preservative), 40 mcg/mL: each 1 mL dose contains 40 mcg of hepatitis B surface antigen.

All formulations contain approximately 0.5 mg of aluminum (provided as amorphous aluminum hydroxyphosphate sulfate, previously referred to as aluminum hydroxide) per mL of vaccine. In each formulation, hepatitis B surface antigen is adsorbed onto approximately 0.5 mg of aluminum (provided as amorphous aluminum hydroxyphosphate sulfate) per mL of vaccine. The vaccine contains <15 mcg/mL residual formaldehyde. The vaccine is of the adw subtype. RECOMBIVAX HB is indicated for vaccination of persons at risk of infection from hepatitis B virus including all known subtypes. 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.

CLINICAL PHARMACOLOGY

Hepatitis B virus is one of several hepatitis viruses that cause a systemic infection, with a major pathology in the liver. These include hepatitis A virus, hepatitis D virus, and hepatitis C and E viruses, previously referred to as non-A, non-B hepatitis viruses.

Hepatitis B virus is an important cause of viral hepatitis. There is no specific treatment for this disease. The incubation period for hepatitis B is relatively long; six weeks to six months may elapse between exposure and the onset of clinical symptoms. The prognosis following infection with hepatitis B virus is variable and dependent on at least three factors: (1) Age — Infants and younger children usually experience milder initial disease than older persons;{1} (2) Dose of virus — The higher the dose, the more likely acute icteric hepatitis B will result;{1} and, (3) Severity of associated underlying disease — Underlying malignancy or pre-existing hepatic disease predisposes to increased morbidity and mortality.{1}

Persistence of viral infection (the chronic hepatitis B virus carrier state) occurs in 5-10% of persons following acute hepatitis B, and occurs more frequently after initial anicteric hepatitis B than after initial icteric disease. Consequently, carriers of hepatitis B surface antigen (HBsAg) frequently give no history of having had recognized acute hepatitis. The Centers for Disease Control and Prevention (CDC) estimates that there are more than 300 million chronic carriers worldwide and 1.25 million chronic carriers of hepatitis B virus in the USA.{29,30} Chronic carriers represent the largest human reservoir of hepatitis B virus.

Serious complications and sequelae of hepatitis B virus infection include massive hepatic necrosis, cirrhosis of the liver and chronic active hepatitis. More than one million people worldwide die each year of hepatitis B-associated acute and chronic liver disease.{33} In the United States, hepatitis B-virus-related acute and chronic liver disease causes approximately 4-5000 deaths annually.{29,30}

Hepatocellular carcinoma is another serious complication of hepatitis B virus infection. Studies have demonstrated the link between chronic hepatitis B infection and hepatocellular carcinoma; 80% of primary liver cancers are caused by hepatitis B virus infection. The CDC has recognized hepatitis B vaccine as the first anti-cancer vaccine because it can prevent primary liver cancer.{34}

There is also evidence that several diseases other than hepatitis have been associated with hepatitis B virus infection through an immunologic mechanism involving antigen-antibody complexes. Such diseases include a syndrome with rash, urticaria, and arthralgia resembling serum sickness; periarteritis nodosa; membranous glomerulonephritis; and infantile papular acrodermatitis.{3,4}

Although the vehicles for transmission of the virus are often blood and blood products, viral antigen has also been found in tears, saliva, breast milk, urine, semen and vaginal secretions. Hepatitis B virus is capable of surviving at least a month{29} on environmental surfaces exposed to body fluids containing hepatitis B virus. Infection may occur when hepatitis B virus, transmitted by infected body fluids, is implanted via mucous surfaces or percutaneously introduced through accidental or deliberate breaks in the skin.

Transmission of hepatitis B virus infection is often associated with close interpersonal contact with an infected individual and with crowded living conditions. In such circumstances, transmission by inoculation via routes other than overt percutaneous ones may be quite common.{1} Perinatal transmission of hepatitis B infection from infected mother to child, at or shortly after birth, can occur if the mother is a hepatitis B surface antigen (HBsAg) carrier or if the mother has an acute hepatitis B infection in the third trimester. Infection in infancy by the hepatitis B virus usually leads to the chronic carrier state. Without prophylaxis, infants born to women whose sera are positive for both the hepatitis B surface antigen and the e antigen have an 85-90% likelihood of being infected and becoming a chronic carrier.{5,6} Well-controlled studies have shown that administration of three 0.5 mL doses of Hepatitis B Immune Globulin (Human) — HBIG starting at birth is 75% effective in preventing establishment of the chronic carrier state in these infants during the first year of life.{6} However, the protective effect of HBIG is transient.

Hepatitis B is endemic throughout the world and is a serious medical problem in population groups at increased risk. Because vaccination limited to high-risk individuals has failed to substantially lower the overall incidence of hepatitis B infection, both the Advisory Committee on Immunization Practices (ACIP) and the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) have also endorsed universal infant immunization as part of a comprehensive strategy for the control of hepatitis B infection.{7,8} In addition, the ACIP also recommends hepatitis B vaccination for all infants and children born after November 21, 1991 and catch-up vaccination of children at high risk of infection (children <11 years of age in households of Pacific Islander ethnicity or of first generation immigrants/refugees from countries with an intermediate or high endemicity of infection).{30} These advisory groups further recommend broad-based vaccination of adolescents. The ACIP recommends that all individuals not previously vaccinated with hepatitis B vaccine be vaccinated at 11-12 years of age with the age-appropriate dose of vaccine and that the vaccination schedule take into account the feasibility of delivering three doses of vaccine to this age group. In addition, older unvaccinated adolescents with identified risk factors for hepatitis B virus infection should also be vaccinated.{30} Similarly, the AAP recommends that universal immunization of all adolescents should be implemented when resources permit with emphasis on those individuals in high-risk settings.{8} A National Institutes of Health Consensus Development Conference Panel on the management of hepatitis C recommends the immunization of all hepatitis C virus (HCV) positive individuals with hepatitis B vaccine.{35} (Refer to INDICATIONS AND USAGE.)

Numerous epidemiological studies have shown that persons who develop anti-HBs following active infection with the hepatitis B virus are protected against the disease on re-exposure to the virus.{9}

Clinical studies have shown that RECOMBIVAX HB when injected into the deltoid muscle induced protective levels of antibody in 96% of 1213 healthy adults who received the recommended 3-dose regimen. Antibody responses varied with age; a protective level of antibody was induced in 98% of 787 young adults 20-29 years of age, 94% of 249 adults 30-39 years of age and in 89% of 177 adults ≥40 years of age.{10} Studies with hepatitis B vaccine derived from plasma have shown that a lower response rate (81%) to vaccine may be obtained if the vaccine is administered as a buttock injection.{11} Seroconversion rates and geometric mean antibody titers were measured 1 to 2 months after the third dose. Multiple clinical studies have defined a protective antibody (anti-HBs) level as 1) 10 or more sample ratio units (SRU) as determined by radioimmunoassay or 2) a positive result as determined by enzyme immunoassay.{2} Note: 10 SRU is comparable to 10 mIU/mL of antibody.{12,13,14,15}

RECOMBIVAX HB was shown to be highly immunogenic in clinical studies involving infants, children, and adolescents. Three 5 mcg doses of vaccine induced a protective level of antibody in 100% of 92 infants, 99% of 129 children, and in 99% of 112 adolescents{10} (see DOSAGE AND ADMINISTRATION).

The protective efficacy of three 5 mcg doses of RECOMBIVAX HB has been demonstrated in neonates born of mothers positive for both HBsAg and HBeAg (a core-associated antigenic complex which correlates with high infectivity). In a clinical study of infants who received one dose of HBIG at birth followed by the recommended three-dose regimen of RECOMBIVAX HB, chronic infection had not occurred in 96% of 130 infants after nine months of follow-up.{16} The estimated efficacy in prevention of chronic hepatitis B infection was 95% as compared to the infection rate in untreated historical controls.{17} Significantly fewer neonates became chronically infected when given one dose of HBIG at birth followed by the recommended three-dose regimen of RECOMBIVAX HB when compared to historical controls who received only a single dose of HBIG.{6} Testing for HBsAg and anti-HBs is recommended at 12-15 months of age. If HBsAg is not detectable, and anti-HBs is present, the child has been protected.

As demonstrated in the above study, HBIG, when administered simultaneously with RECOMBIVAX HB at separate body sites, did not interfere with the induction of protective antibodies against hepatitis B virus elicited by the vaccine.

For adolescents (11 through 15 years of age), the immunogenicity of a two-dose regimen (10 mcg at 0 and 4-6 months) was compared with that of the standard three-dose regimen (5 mcg at 0, 1, and 6 months) in an open, randomized, multicenter study. The proportion of adolescents receiving the two-dose regimen who developed a protective level of antibody one month after the last dose (99% of 255 subjects) appears similar to that among adolescents who received the three-dose regimen (98% of 121 subjects). After adolescents (11 through 15 years of age) received the first 10-mcg dose of the two-dose regimen, the proportion who developed a protective level of antibody was approximately 72%.{10}

In one published study, the seroprotection rates in individuals with chronic HCV infection given the standard regimen of RECOMBIVAX HB was approximately 70%.{36} In a second published study of intravenous drug users given an accelerated schedule of RECOMBIVAX HB, infection with HCV did not affect the response to RECOMBIVAX HB.{37}

As with other hepatitis B vaccines, 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. However, long-term follow-up (5 to 9 years) of approximately 3000 high-risk vaccinees (infants of carrier mothers, male homosexuals, Alaskan Natives) who developed an anti-HBs titer of ≥10 mIU/mL when given a similar plasma-derived vaccine at intervals of 0, 1, and 6 months showed that no subjects developed clinically apparent hepatitis B infection and that 5 subjects developed antigenemia, even though up to half of the subjects failed to maintain a titer at this level.{18-21} Persistence of vaccine-induced immunologic memory among healthy vaccinees who responded to a primary course of plasma-derived or recombinant hepatitis B vaccine has been demonstrated by an anamnestic antibody response to a booster dose of RECOMBIVAX HB given 5-12 years later.{22}

Predialysis and dialysis adult patients respond less well to hepatitis B vaccines than do healthy individuals; however, vaccination of adult patients early in the course of their renal disease produces higher seroconversion rates than vaccination after dialysis has been initiated.{30} In addition, the responses to these vaccines may be lower if the vaccine is administered as a buttock injection. When 40 mcg of Hepatitis B Vaccine (Recombinant), was administered in the deltoid muscle, 89% of 28 participants developed anti-HBs with 86% achieving levels ≥10 mIU/mL. However, when the same dosage of this vaccine was administered inappropriately either in the buttock or a combination of buttock and deltoid, 62% of 47 participants developed anti-HBs with 55% achieving levels of ≥10 mIU/mL.{10}

A booster dose or revaccination with RECOMBIVAX HB Dialysis Formulation may be considered in predialysis/dialysis patients if the anti-HBs level is less than 10 mIU/mL.{23}

Reports in the literature describe a more virulent form of hepatitis B associated with superinfections or coinfections by delta virus, an incomplete RNA virus. Delta virus can only infect and cause illness in persons infected with hepatitis B virus since the delta agent requires a coat of HBsAg in order to become infectious. Therefore, persons immune to hepatitis B virus infection should also be immune to delta virus infection.{2}

Although there have been no clinical studies in which a three-dose vaccine series was initiated with HEPTAVAX-B® (Hepatitis B Vaccine) and completed with RECOMBIVAX HB, or vice versa, extensive in vitro and in vivo studies have demonstrated that these two vaccines are immunologically comparable.{22,24-28}

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