havrix 1440

DESCRIPTION
HAVRIX (Hepatitis A Vaccine, Inactivated) is a noninfectious hepatitis A vaccinedeveloped and manufactured by GlaxoSmithKline Biologicals havrix 1440. The virus (strainHM175) is propagated in MRC 5 human diploid cells havrix 1440. After removal of the cellculture medium, the cells are lysed to form a suspension havrix 1440. This suspension ispurified through ultrafiltration and gel permeation chromatography procedures havrix 1440. Treatment of this lysate with formalin ensures viral inactivation havrix 1440. 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.) havrix 1440.

HAVRIX is supplied as a sterile suspension for intramuscular administration havrix 1440. 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 havrix 1440. After shaking, the vaccine is a slightly turbid white suspension havrix 1440.

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

There are 2 pediatric dose formulations, each with its own dosing schedule(see DOSAGE AND ADMINISTRATION ) havrix 1440. The formulations are: Not less than 360 EL.U havrix 1440. of viral antigen/0.5 mL; not less than 720 EL.U havrix 1440. of viral antigen/0.5 mL havrix 1440. Eachdose is adsorbed onto 0.25 mg of aluminum as aluminum hydroxide havrix 1440.

The vaccine preparations also contain 0.5% (w/v) of 2-phenoxyethanol as a preservative havrix 1440. Other excipients are: Amino acid supplement (0.3% w/v) in a phosphate-bufferedsaline solution and polysorbate 20 (0.05 mg/mL) havrix 1440. Residual MRC 5 cellular proteins(not more than 5 mcg/mL) and traces of formalin (not more than 0.1 mg/mL) arepresent havrix 1440. Neomycin sulfate, an aminoglycoside antibiotic, is included in thecell growth media; only trace amounts (not more than 40 ng/mL) remain followingpurification havrix 1440.

CLINICAL PHARMACOLOGY
The hepatitis A virus (HAV) belongs to the picornavirus family havrix 1440. Only one serotypeof HAV has been described havrix 1440. 1

Hepatitis A is highly contagious with the predominant mode of transmissionbeing person-to-person via the fecal-oral route havrix 1440. 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 havrix 1440. 1

The level of economic development influences the prevalence of hepatitis Aand the age at which it is most likely to occur havrix 1440. In developing countries withpoor hygiene and sanitation, about 90% of children are infected by age 5 years havrix 1440. 1 As conditions improve, the prevalence decreases and the age at which infectionoccurs increases havrix 1440. Hence it is more likely to occur in adulthood, when diseaseis generally more severe and more likely to be fatal havrix 1440. 1 In the United States,attack rates for hepatitis A infection are cyclical and vary by population havrix 1440. The rates have increased gradually from 9.2 per 100,000 in 1983 to 14.6 per100,000 in 1989 havrix 1440. 8

The incubation period for hepatitis A averages 28 days (range: 15 to 50 days) havrix 1440. 9 The course of hepatitis A infection is extremely variable, ranging from asymptomaticinfection to icteric hepatitis havrix 1440. However, most adults (76% to 97%) become symptomatic havrix 1440. 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 havrix 1440. 10 Recovery is generally complete and followed by protectionagainst HAV infection havrix 1440. However, illness may be prolonged, and relapse of clinicalillness and viral shedding have been described havrix 1440. 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 havrix 1440. 10 In older patients and persons with underlying liver disease,it is generally much more severe havrix 1440. 1 This is reflected in mortality rates havrix 1440. 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 havrix 1440. 1 Indeed, while67% of cases occur in children, over 70% of deaths occur in those over the ageof 49 years havrix 1440. 1

There is no chronic carrier state havrix 1440. The virus replicates in the liver and isexcreted in bile havrix 1440. 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 havrix 1440. 12 Children and infants may shed HAV for longerperiods than adults, possibly lasting as long as several weeks after the onsetof clinical illness havrix 1440. 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 havrix 1440. 11

The presence of antibodies to HAV (anti-HAV) confers protection against hepatitisA infection havrix 1440. However, the lowest titer needed to confer protection has not beendetermined havrix 1440.

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 havrix 1440. In this experiment,chimpanzees immunized with either preparation developed passive-active immunitywhen challenged with wild-type HAV havrix 1440. No animal in either group developed clinicalillness havrix 1440.

In vitro studies in a randomly selected subset of human subjects (n = 80) showedanti-HAV induced by HAVRIX to have functional activity havrix 1440. This was demonstratedby a neutralization assay and a competitive inhibition assay using a panel ofmonoclonal antibodies known to have neutralizing activity havrix 1440.

Immunogenicity in Adults: In 3 clinical studies involving over 400 healthyadult volunteers given a single 1440 EL.U havrix 1440. dose of HAVRIX, specific humoralantibodies against HAV were elicited in more than 96% of subjects when measured1 month after vaccination havrix 1440. By day 15, 80% to 98% of vaccinees had already seroconverted(anti-HAV >/=20 mIU/mL [the lower limit of antibody measurement by currentassay]) havrix 1440. 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 havrix 1440. 15

The GMTs obtained following a single dose of HAVRIX are at least several timeshigher than that expected following receipt of IG havrix 1440.

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 havrix 1440. 15

In 2 clinical trials in which a booster dose of 1440 EL.U havrix 1440. 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 havrix 1440. The titers obtained from this additional dose approximate those observed severalyears after natural infection havrix 1440.

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

Immunogenicity of HAVRIX was studied in subjects with chronic liver diseaseof various etiologies havrix 1440. 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 havrix 1440. ona 0- and 6-month schedule havrix 1440. 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) havrix 1440. At each time point,GMTs were lower for subjects with chronic liver disease than for healthy subjects havrix 1440. 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 havrix 1440. The relevance of these datato the duration of protection afforded by HAVRIX is unknown havrix 1440. One month afterthe first dose, seroconversion rates in adults with chronic liver disease werelower than in healthy adults havrix 1440. However, 1 month after the booster dose at month6, seroconversion rates were similiar in all groups; rates ranged from 94.7%to 98.1% havrix 1440.

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 havrix 1440. given 1 month apart ranged from 197 to 660 mIU/mL havrix 1440. Ninety-nine percent of subjects seroconverted following 2 doses havrix 1440. When a booster(third) dose of HAVRIX 360 EL.U havrix 1440. 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 havrix 1440. In 1 study in which childrenwere followed for an additional 6 months, all subjects remained seropositive havrix 1440. Solicited adverse effects were similar in frequency and nature to those seenfollowing administration of ENGERIX-B ® [Hepatitis B Vaccine (Recombinant)] havrix 1440.

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 havrix 1440. One month after the first dose, seroconversion ranged from 96.8%to 100%, with GMTs of 194 mIU/mL to 305 mIU/mL havrix 1440. In studies in which sera wereobtained 2 weeks following the initial dose, seroconversion ranged from 91.6%to 96.1% havrix 1440. 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 havrix 1440. 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 havrix 1440. One month later, all subjects were seropositive, with aGMT of 2,657 mIU/mL havrix 1440. 15

Also, HAVRIX has been found to be highly efficacious in a clinical study ofchildren at high risk of HAV infection (see below) havrix 1440.

At present, the duration of protection afforded by HAVRIX has not been established havrix 1440. Therefore it is unknown if the protection provided to immunized children willlast until adulthood havrix 1440.

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