Recombivax HB

RECOMBIVAX HB®

MSD

Hepatitis B Vaccine (Recombinant)

Vaccine

Action And Clinical Pharmacology: Hepatitis B virus is one of at least 3 hepatitis viruses that cause a systemic infection, with major pathology in the liver. The others are hepatitis A virus, and 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 type B hepatitis is relatively long; 6 weeks to 6 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 3 factors: (1) Age – Infants and younger children usually experience milder initial disease than older persons; (2) Dose of Virus – The higher the dose, the more likely acute icteric hepatitis B will result; and, (3) Severity of Associated Underlying Disease – Underlying malignancy or pre-existing hepatic disease predisposes to increased mortality and morbidity.

Persistence of viral infection (the chronic hepatitis B virus carrier state) occurs in 5 to 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 recognized acute hepatitis. It has been estimated that more than 170 million people in the world today are persistently infected with hepatitis B virus. The Centers for Disease Control (CDC) estimate that there are approximately 0.5 to 1.0 million chronic carriers of hepatitis B virus in the USA and that this pool of carriers grows by 2 to 3% (8 000 to 16 000 individuals) annually. Chronic carriers represent the largest human reservoir of hepatitis B virus.

The serious complications and sequelae of hepatitis B virus infection include massive hepatic necrosis, cirrhosis of the liver, chronic active hepatitis, and hepatocellular carcinoma. Chronic carriers of HBsAg appear to be at increased risk of developing hepatocellular carcinoma, which accounts for 80 to 90% of primary liver carcinomas. Although a number of etiologic factors are associated with development of hepatocellular carcinoma, the single most important etiologic factor appears to be active infection with the hepatitis B virus.

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; polyarteritis nodosa; membranous glomerulonephritis; and infantile papular acrodermatitis.

Although the vehicles for transmission of the virus are predominantly 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 for days on environmental surfaces. 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 parenteral ones may be quite common. Perinatal transmission of hepatitis B infection from infected mother to child, at, or shortly after birth, can occur if the mother is a 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. Among infants born to women whose sera are positive for both the hepatitis B surface antigen and the e antigen, 85 to 90% are infected and become chronic carriers.

Hepatitis B is endemic throughout the world, and is a serious medical problem in population groups at increased risk (see Indications). The prevalence of HBsAg in the general population varies between less than 0.5% in the U.S. and Western Europe, 1 to 2% in South America and Southern Europe, 3 to 5% in North Africa and in many parts of the Federation of Russia (formerly known as USSR) and 9 to 10% and higher in sub-Saharan Africa and Southeast Asia. The overall prevalence of serologic markers of infection varies between 7 and 10% in the U.S. and 60 and 80% in Southeast Asia or Africa. Even in countries like those in Northern and Western Europe and other highly developed countries with a relatively low prevalence of hepatitis B, certain populations are at high risk of acquiring the disease and have cumulative infection rates of up to 70% (see Indications). In countries or areas with a high prevalence rate, the entire population is at risk and infection tends to occur during childhood.

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.

Clinical studies have established that hepatitis B vaccine (recombinant), when injected into the deltoid muscle, induced protective levels of antibody in greater than 90% of healthy individuals who received the recommended 3 dose regimen. 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. A protective antibody (anti-HBs) level has been defined as 10 or more sample ratio units (SRU) as determined by radioimmunoassay or a positive by enzyme immunoassay.

Responsiveness to the vaccine was age dependent. The seroconversion rate for children 1 to 10 years of age was 100%. In contrast, the conversion rate for adults ranged from 95 to 98% for those from 20 to 39 years of age and 91% for those of 40 years of age or older.

Immunocompromised persons respond less well to Recombivax HB than do healthy individuals. Vaccine-induced levels of anti-HBs are lower in predialysis and hemodialysis patients than are the levels in healthy individuals. Eighty-six percent of predialysis and hemodialysis patients who received three 40 µg doses of Recombivax HB developed protective levels of anti-HBs.

The protective efficacy of 5 µg doses of Recombivax HB has been demonstrated in neonates born of mothers positive for both HBsAg and HBeAg. In a clinical study of infants who received 1 dose of Hepatitis B Immune Globulin (HBIg) at birth followed by the recommended 3-dose regimen of Recombivax HB, efficacy in prevention of chronic hepatitis B infection was 96% in 47 infants at 6 months and 100% in 19 infants at 9 months.

The duration of protective effect of Recombivax HB is unknown at present, and the need for booster doses not defined. However, a booster dose or revaccination with the dialysis formulation 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.

Recent studies have established the relative efficacies of immune globulin and/or hepatitis B vaccine in accidental percutaneous or permucosal exposure to HBsAg-positive blood; or sexual exposure to HBsAg-positive persons (see Dosage).

It has been demonstrated that doses of up to 5 mL of Hepatitis B Immune Globulin, when administered simultaneously with the first dose of Recombivax HB at separate body sites, did not interfere with the induction of protective antibodies against hepatitis B virus elicited by the 3-dose vaccine regimen.

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.

Indications And Clinical Uses: For immunization against infection caused by all known subtypes of hepatitis B virus.

Hepatitis B vaccine (recombinant) will not prevent hepatitis caused by other agents, such as hepatitis A virus, non-A, non-B hepatitis viruses, or other viruses known to infect the liver.

Vaccination with hepatitis B vaccine (recombinant) is recommended in persons of all ages, especially those who are or will be at increased risk of infection with hepatitis B virus.

The incidence of infection is known to vary greatly in different geographic areas and in different populations throughout the world. Vaccination strategy should vary accordingly.

Areas with High Prevalence: In these areas, most of the population are at risk of acquiring hepatitis B, often at a young age. Therefore, vaccination should be targeted to infants born to HBsAg-positive mothers, infants and children and susceptible adults.

Areas with Low Prevalence: In these areas vaccination may be limited to those who are in groups identified as being at increased risk of infection. The following categories might be identified in low-prevalence areas:

A. Infants born to HBsAg-positive mothers.

B. 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 (i.e., body fluids and tissues); dental hygienists and dental nurses; laboratory personnel handling blood, blood products and other patient specimens (i.e., body fluids and tissues); and dental, medical and nursing students, preferably soon after acceptance in the university.

C. Selected Patients and Patient Contacts: patients and staff in hemodialysis units and hematology/oncology units; patients requiring frequent and/or large-volume blood transfusions or clotting factor concentrates (e.g., persons with hemophilia, thalassemia); patients (residents) and staff of institutions for the mentally handicapped; classroom contacts of deinstitutionalized mentally handicapped persons who have persistent hepatitis B antigenemia and who show aggressive behavior; and household and other intimate contacts of persons with persistent hepatitis B antigenemia.

D. Military Personnel Identified as Being at Increased Risk.

E. Morticians and Embalmers.

F. Blood Bank and Plasma Fractionation Workers.

G. 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; homosexually active males and female prostitutes.

H. Prisoners.

I. Users of Illicit Injectable Drugs.

Contra-Indications: Hypersensitivity to any component of the vaccine.

Manufacturers’ Warnings In Clinical States: Because of the long incubation period for hepatitis B, it is possible for unrecognized infection to be present at the time hepatitis B vaccine (recombinant) is given. Hepatitis B vaccine (recombinant) may not prevent hepatitis B in such patients.

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

Precautions: General: Persons with immuno-deficiency or those receiving immunosuppressive therapy require larger vaccine doses and respond less well than healthy individuals.

As with any parenteral vaccine, epinephrine should be available for immediate use should an anaphylactoid reaction occur.

Any serious active infection is reason for delaying use of hepatitis B vaccine (recombinant), except when, in the opinion of the physician, withholding the vaccine entails a greater risk.

Caution and appropriate care should be exercised in administering hepatitis B vaccine (recombinant) to individuals with severely compromised cardiopulmonary status or to others in whom a febrile or systemic reaction could pose a significant risk.

Pregnancy: Animal reproduction studies have not been conducted with hepatitis B vaccine (recombinant). It is also not known whether hepatitis B vaccine (recombinant) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Hepatitis B vaccine (recombinant) should be given to a pregnant woman only if clearly needed.

Lactation : It is not known whether hepatitis B vaccine (recombinant) is excreted in human milk. However, studies with hepatitis B vaccine (recombinant) in 12 lactating women have failed to reveal evidence of this vaccine being secreted.

Children: Hepatitis B vaccine (recombinant) has been shown to be generally well-tolerated and highly immunogenic in infants and children of all ages. Newborns have responded well; maternally transferred antibodies did not interfere with the active immune response to the vaccine. See Dosage for recommended pediatric dosage and recommended dosage for infants born to HBsAg-positive mothers. The safety profile and effectiveness of the dialysis formulation in children have not been established.

Adverse Reactions: Hepatitis B vaccine (recombinant) is generally well tolerated. No serious adverse reactions attributable to vaccination were reported during the course of clinical trials involving administration of hepatitis B vaccine (recombinant) to over 1 000 individuals. The frequency of complaints was somewhat lower following the second and third vaccine doses compared with the first dose. As with any vaccine, there is the possibility that broad use of the vaccine could reveal rare adverse reactions not observed in clinical trials.

No adverse reactions were reported during clinical trials which could be related to yeast.

In a group of studies 3 258 doses of hepatitis B vaccine (recombinant) were administered to 1 252 healthy adults.

Other incidences reported in less than 1% of injections:

Cardiovascular: hypotension.

Hemic/lymphatic: lymphadenopathy.

Integumentary; angioedema.

Psychiatric/behavioral: insomnia/disturbed sleep.

Urogenital: dysuria.

Additional Adverse Effects: The following additional adverse reactions have been reported with use of the marketed vaccine; however, in many instances a causal relationship to the vaccine has not been established.

Hematologic: Increased erythrocyte sedimentation rate.

Hypersensitivity: Anaphylaxis and symptoms of immediate hypersensitivity reactions including edema, dyspnea, chest discomfort, bronchial spasm, or palpitation have been reported within the first few hours after vaccination. An apparent hypersensitivity syndrome (serum-sickness-like) of delayed onset has been reported days to weeks after vaccination, including: arthritis (usually transient), and dermatologic reactions such as erythema multiforme, ecchymoses and erythema nodosum (see Precautions).

Nervous system: Peripheral neuropathy including Bell’s Palsy; Guillain-Barr© syndrome, and optic neuritis.

Special Senses: tinnitus.

Dosage And Administration: The deltoid muscle is the preferred site for i.m. injection in adults. The anterolateral thigh is the recommended site for i.m. injection in infants and children. Data suggest that injections given in the buttocks are given frequently into fatty tissue instead of into muscle. Such injections may result in lower seroconversion rate than is expected.

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

It is recommended to record lot numbers when the vaccine is administered to a recipient.

I.M.: Do not inject i.v. or intradermally. Hepatitis B vaccine (recombinant)] is for i.m. injection. It may, however, be administered s.c. to persons at risk of hemorrhage following i.m. injections. However, when other aluminum-adsorbed vaccines have been administered s.c., an increased incidence of local reactions including subcutaneous nodules has been observed. Therefore, s.c. administration should be used only in persons (e.g., hemophiliacs) at risk of hemorrhage following i.m. injections.

Shake well before withdrawal and 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, Recombivax HB is a slightly opaque, white suspension.

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.

The immunization regimen consists of 3 doses of vaccine given according to the following schedule: 1st dose: at elected date; 2nd dose: 1 month later; 3rd dose: 6 months after the first dose.

Recombivax HB Dialysis Formulation: Recombivax HB dialysis formulation (40 µg/mL) is intended only for adult predialysis/dialysis patients.

Dosage for Infants Born to HBsAg-positive Mothers: Infants born to HBsAg-positive mothers are at high risk of becoming chronic carriers of hepatitis B virus and of developing the chronic sequelae of hepatitis B virus infection. Well-controlled studies have shown that administration of three 0.5 mL doses of hepatitis B immune globulin starting at birth is 75% effective in preventing establishment of the chronic carrier state in these infants during the first year of life. Protection is transient under these circumstances and the effectiveness of the passively administered hepatitis B immune globulin declines thereafter. Results from clinical studies indicate that administration of one 0.5 mL dose of hepatitis B immune globulin at birth and three 5 µg (0.5 mL) doses, the first dose given within 1 week after birth, was 96% effective in preventing establishment of the chronic carrier state in infants born to HBsAg- and HBeAg-positive mothers. Testing for HBsAg and anti-HBs is recommended at 12 to 15 months to monitor the final success or failure of therapy. If HBsAg is not detectable, and anti-HBs is present, the child has been protected.

Acute Exposure to Blood Containing HBsAg: There are no prospective studies directly testing the efficacy of a combination of hepatitis B immune globulin and hepatitis B vaccine (recombinant) in preventing clinical hepatitis B following percutaneous, ocular or mucous membrane exposure to hepatitis B virus. However, recent studies have established the relative efficacies of immune globulins and/or hepatitis B vaccine in various exposure situations. Since most persons with such exposures (e.g., health care workers) are candidates for the hepatitis B vaccine and since combined hepatitis B immune globulin plus vaccine is more efficacious than hepatitis B immune globulin 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:

Hepatitis B immune globulin (0.06 mL/kg ) should be given as soon as possible after exposure and within 24 hours if possible. Hepatitis B vaccine 1 mL (10 µg/1 mL) should be given i.m. within 7 days of exposure and second and third doses given 1 and 6 months, respectively, after the first dose.

For Syringe Use Only: Withdraw the recommended dose from the vial using a sterile needle and syringe free of preservatives, antiseptics, and detergents.

Availability And Storage: Adults: Each 1 mL dose of sterile suspension contains: hepatitis B surface antigen 10 µg adsorbed onto approximately 0.5 mg of aluminum hydroxide. Formaldehyde-treated. Thimerosal (mercury derivative) 1:20 000 added as a preservative. Single dose vials of 1 mL; 3-dose vials of 3 mL.

Children: Each 0.5 mL dose of pediatric, sterile suspension, contains: hepatitis B surface antigen 5 µg adsorbed onto approximately 0.25 mg of aluminum hydroxide. Formaldehyde-treated. Thimerosal (mercury derivative) 1:20 000 added as a preservative. Single dose vials of 0.5 mL.

Adult Dialysis Formulation: Each 1 mL dose of sterile suspension contains: hepatitis B surface antigen 40 µg adsorbed onto approximately 0.5 mg of aluminum hydroxide. Formaldehyde-treated. Single dose vials of 1 mL.

Store unopened and opened vials at 2 to 8°C. Storage above or below the recommended temperature may reduce potency. Do not freeze because freezing destroys potency. The vaccine is used directly as supplied. No dilution or reconstitution is necessary. Do not use vaccine after the expiration date.

RECOMBIVAX HB® MSD Hepatitis B Vaccine (Recombinant) Vaccine

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