hepatitis a vaccination havrix

DESCRIPTION
HAVRIX (Hepatitis A Vaccine, Inactivated) is a noninfectious hepatitis A vaccinedeveloped and manufactured by GlaxoSmithKline Biologicals hepatitis a vaccination havrix. The virus (strainHM175) is propagated in MRC 5 human diploid cells hepatitis a vaccination havrix. After removal of the cellculture medium, the cells are lysed to form a suspension hepatitis a vaccination havrix. This suspension ispurified through ultrafiltration and gel permeation chromatography procedures hepatitis a vaccination havrix. Treatment of this lysate with formalin ensures viral inactivation hepatitis a vaccination havrix. HAVRIX containsa sterile suspension of inactivated virus; viral antigen activity is referencedto a standard using an enzyme linked immunosorbent assay (ELISA), and is thereforeexpressed in terms of ELISA Units (EL.U.) hepatitis a vaccination havrix.

HAVRIX is supplied as a sterile suspension for intramuscular administration hepatitis a vaccination havrix. The vaccine is ready for use without reconstitution; it must be shaken beforeadministration since a fine white deposit with a clear colorless supernatantmay form on storage hepatitis a vaccination havrix. After shaking, the vaccine is a slightly turbid white suspension hepatitis a vaccination havrix.

Each 1-mL adult dose of vaccine consists of not less than 1440 EL.U hepatitis a vaccination havrix. of viralantigen, adsorbed on 0.5 mg of aluminum as aluminum hydroxide hepatitis a vaccination havrix.

There are 2 pediatric dose formulations, each with its own dosing schedule(see DOSAGE AND ADMINISTRATION ) hepatitis a vaccination havrix. The formulations are: Not less than 360 EL.U hepatitis a vaccination havrix. of viral antigen/0.5 mL; not less than 720 EL.U hepatitis a vaccination havrix. of viral antigen/0.5 mL hepatitis a vaccination havrix. Eachdose is adsorbed onto 0.25 mg of aluminum as aluminum hydroxide hepatitis a vaccination havrix.

The vaccine preparations also contain 0.5% (w/v) of 2-phenoxyethanol as a preservative hepatitis a vaccination havrix. Other excipients are: Amino acid supplement (0.3% w/v) in a phosphate-bufferedsaline solution and polysorbate 20 (0.05 mg/mL) hepatitis a vaccination havrix. Residual MRC 5 cellular proteins(not more than 5 mcg/mL) and traces of formalin (not more than 0.1 mg/mL) arepresent hepatitis a vaccination havrix. Neomycin sulfate, an aminoglycoside antibiotic, is included in thecell growth media; only trace amounts (not more than 40 ng/mL) remain followingpurification hepatitis a vaccination havrix.

CLINICAL PHARMACOLOGY
The hepatitis A virus (HAV) belongs to the picornavirus family hepatitis a vaccination havrix. Only one serotypeof HAV has been described hepatitis a vaccination havrix. 1

Hepatitis A is highly contagious with the predominant mode of transmissionbeing person-to-person via the fecal-oral route hepatitis a vaccination havrix. Infection has been shown tobe spread (1) by contaminated water or food; (2) by infected food handlers 2; (3) after breakdown in usual sanitary conditions or after floods or naturaldisasters; (4) by ingestion of raw or undercooked shellfish (oysters, clams,mussels) from contaminated waters 3 ; (5) during travel to areas of the worldwith poor hygienic conditions 4,5 ; (6) among institutionalized children andadults 6 ; (7) in day-care centers where children have not been toilet trained7 ; (8) by parenteral transmission, either blood transfusions or sharing needleswith infected people hepatitis a vaccination havrix. 1

The level of economic development influences the prevalence of hepatitis Aand the age at which it is most likely to occur hepatitis a vaccination havrix. In developing countries withpoor hygiene and sanitation, about 90% of children are infected by age 5 years hepatitis a vaccination havrix. 1 As conditions improve, the prevalence decreases and the age at which infectionoccurs increases hepatitis a vaccination havrix. Hence it is more likely to occur in adulthood, when diseaseis generally more severe and more likely to be fatal hepatitis a vaccination havrix. 1 In the United States,attack rates for hepatitis A infection are cyclical and vary by population hepatitis a vaccination havrix. The rates have increased gradually from 9.2 per 100,000 in 1983 to 14.6 per100,000 in 1989 hepatitis a vaccination havrix. 8

The incubation period for hepatitis A averages 28 days (range: 15 to 50 days) hepatitis a vaccination havrix. 9 The course of hepatitis A infection is extremely variable, ranging from asymptomaticinfection to icteric hepatitis hepatitis a vaccination havrix. However, most adults (76% to 97%) become symptomatic hepatitis a vaccination havrix. 10 Symptoms range from mild and transient to severe and prolonged and may includefever, nausea, vomiting, and diarrhea in the prodromal phase, followed by jaundicein up to 88% of adults, as well as hepatomegaly and biochemical evidence ofhepatocellular damage hepatitis a vaccination havrix. 10 Recovery is generally complete and followed by protectionagainst HAV infection hepatitis a vaccination havrix. However, illness may be prolonged, and relapse of clinicalillness and viral shedding have been described hepatitis a vaccination havrix. 11

Hepatitis A infection is often asymptomatic in children under 2 years of age,who nonetheless excrete the virus in their stool and thereby serve as a sourceof infection hepatitis a vaccination havrix. 10 In older patients and persons with underlying liver disease,it is generally much more severe hepatitis a vaccination havrix. 1 This is reflected in mortality rates hepatitis a vaccination havrix. Whilean overall case fatality rate of 0.6% has been reported, a case fatality rateof 2.7% has been reported in patients >/=49 years of age hepatitis a vaccination havrix. 1 Indeed, while67% of cases occur in children, over 70% of deaths occur in those over the ageof 49 years hepatitis a vaccination havrix. 1

There is no chronic carrier state hepatitis a vaccination havrix. The virus replicates in the liver and isexcreted in bile hepatitis a vaccination havrix. The highest concentrations of HAV are found in stools of infectedpersons during the 2-week period immediately before the onset of jaundice anddecline after jaundice appears hepatitis a vaccination havrix. 12 Children and infants may shed HAV for longerperiods than adults, possibly lasting as long as several weeks after the onsetof clinical illness hepatitis a vaccination havrix. 13 Chronic shedding of HAV in feces has not been demonstrated,but relapses of hepatitis A can occur in as many as 20% of patients, 1,14 andfecal shedding of HAV may recur at this time hepatitis a vaccination havrix. 11

The presence of antibodies to HAV (anti-HAV) confers protection against hepatitisA infection hepatitis a vaccination havrix. However, the lowest titer needed to confer protection has not beendetermined hepatitis a vaccination havrix.

In a chimpanzee challenge study, the quality of protection afforded by immuneglobulin (IG) prepared from initially seronegative human volunteers vaccinatedwith HAVRIX was comparable to that afforded by commercial IG hepatitis a vaccination havrix. In this experiment,chimpanzees immunized with either preparation developed passive-active immunitywhen challenged with wild-type HAV hepatitis a vaccination havrix. No animal in either group developed clinicalillness hepatitis a vaccination havrix.

In vitro studies in a randomly selected subset of human subjects (n = 80) showedanti-HAV induced by HAVRIX to have functional activity hepatitis a vaccination havrix. This was demonstratedby a neutralization assay and a competitive inhibition assay using a panel ofmonoclonal antibodies known to have neutralizing activity hepatitis a vaccination havrix.

Immunogenicity in Adults: In 3 clinical studies involving over 400 healthyadult volunteers given a single 1440 EL.U hepatitis a vaccination havrix. dose of HAVRIX, specific humoralantibodies against HAV were elicited in more than 96% of subjects when measured1 month after vaccination hepatitis a vaccination havrix. By day 15, 80% to 98% of vaccinees had already seroconverted(anti-HAV >/=20 mIU/mL [the lower limit of antibody measurement by currentassay]) hepatitis a vaccination havrix. Geometric mean titers (GMTs) of seroconverters ranged from 264 to 339mIU/mL at day 15 and increased to a range of 335 to 637 mIU/mL by 1 month followingvaccination hepatitis a vaccination havrix. 15

The GMTs obtained following a single dose of HAVRIX are at least several timeshigher than that expected following receipt of IG hepatitis a vaccination havrix.

In a clinical study using 2.5 to 5 times the standard dose of IG (standarddose = 0.02 to 0.06 mL/kg), the GMT in recipients was 146 mIU/mL at 5 days post-administration,77 mIU/mL at month 1, and 63 mIU/mL at month 2 hepatitis a vaccination havrix. 15

In 2 clinical trials in which a booster dose of 1440 EL.U hepatitis a vaccination havrix. was given 6 monthsfollowing the initial dose, 100% of vaccinees (n = 269) were seropositive 1month after the booster dose, with GMTs ranging from 3,318 mIU/mL to 5,925 mIU/mL hepatitis a vaccination havrix. The titers obtained from this additional dose approximate those observed severalyears after natural infection hepatitis a vaccination havrix.

In a subset of vaccinees (n = 89), a single dose of HAVRIX 1440 EL.U hepatitis a vaccination havrix. elicitedspecific anti-HAV neutralizing antibodies in more than 94% of vaccinees whenmeasured 1 month after vaccination hepatitis a vaccination havrix. These neutralizing antibodies persisteduntil month 6 hepatitis a vaccination havrix. One hundred percent of vaccinees had neutralizing antibodieswhen measured 1 month after a booster dose given at month 6 hepatitis a vaccination havrix.

Immunogenicity of HAVRIX was studied in subjects with chronic liver diseaseof various etiologies hepatitis a vaccination havrix. 189 healthy adults and 220 adults with either chronichepatitis B (n = 46), chronic hepatitis C (n = 104), or moderate chronic liverdisease of other etiology (n = 70) were vaccinated with HAVRIX 1440 EL.U hepatitis a vaccination havrix. ona 0- and 6-month schedule hepatitis a vaccination havrix. The last group consisted of alcoholic cirrhosis (n= 17), autoimmune hepatitis (n = 10), chronic hepatitis/cryptogenic cirrhosis(n = 9), hemochromatosis (n = 2), primary biliary cirrhosis (n = 15), primarysclerosing cholangitis (n = 4), and unspecified (n = 13) hepatitis a vaccination havrix. At each time point,GMTs were lower for subjects with chronic liver disease than for healthy subjects hepatitis a vaccination havrix. At month 7, the GMTs ranged from 478 mIU/mL (chronic hepatitis C) to 1,245 mIU/mL(healthy), as determined by a commercial ELISA hepatitis a vaccination havrix. The relevance of these datato the duration of protection afforded by HAVRIX is unknown hepatitis a vaccination havrix. One month afterthe first dose, seroconversion rates in adults with chronic liver disease werelower than in healthy adults hepatitis a vaccination havrix. However, 1 month after the booster dose at month6, seroconversion rates were similiar in all groups; rates ranged from 94.7%to 98.1% hepatitis a vaccination havrix.

Immunogenicity in Children and Adolescents: In 6 clinical studies involvingpediatric vaccinees (n = 762) ranging from 1 to 18 years of age, the GMT following2 doses of HAVRIX 360 EL.U hepatitis a vaccination havrix. given 1 month apart ranged from 197 to 660 mIU/mL hepatitis a vaccination havrix. Ninety-nine percent of subjects seroconverted following 2 doses hepatitis a vaccination havrix. When a booster(third) dose of HAVRIX 360 EL.U hepatitis a vaccination havrix. was administered 6 months following the initialdose, all subjects were seropositive 1 month following the booster dose, withGMTs rising to a range of 3,388 to 4,643 mIU/mL hepatitis a vaccination havrix. In 1 study in which childrenwere followed for an additional 6 months, all subjects remained seropositive hepatitis a vaccination havrix. Solicited adverse effects were similar in frequency and nature to those seenfollowing administration of ENGERIX-B ® [Hepatitis B Vaccine (Recombinant)] hepatitis a vaccination havrix.

In 4 clinical studies, children and adolescents (n = 314), ranging from 2 to19 years of age, were immunized with 2 doses of HAVRIX 720 EL.U./0.5 mL given6 months apart hepatitis a vaccination havrix. One month after the first dose, seroconversion ranged from 96.8%to 100%, with GMTs of 194 mIU/mL to 305 mIU/mL hepatitis a vaccination havrix. In studies in which sera wereobtained 2 weeks following the initial dose, seroconversion ranged from 91.6%to 96.1% hepatitis a vaccination havrix. One month following a booster dose at month 6, all subjects were seropositive,with GMTs ranging from 2,495 mIU/mL to 3,644 mIU/mL hepatitis a vaccination havrix. 15

In 1 additional study in which the booster dose was delayed until 1 year followingthe initial dose, 95.2% of the subjects were seropositive just prior to administrationof the booster dose hepatitis a vaccination havrix. One month later, all subjects were seropositive, with aGMT of 2,657 mIU/mL hepatitis a vaccination havrix. 15

Also, HAVRIX has been found to be highly efficacious in a clinical study ofchildren at high risk of HAV infection (see below) hepatitis a vaccination havrix.

At present, the duration of protection afforded by HAVRIX has not been established hepatitis a vaccination havrix. Therefore it is unknown if the protection provided to immunized children willlast until adulthood hepatitis a vaccination havrix.

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