“Hepatitis A vaccine, inactivated is a noninfectious hepatitis A vaccine.

The virus (strain HM175) is propagated in MRC5 human diploid cells”

Mosby’s GenRx®, 10^th ed.

Copyright © 2000 Mosby, Inc.

Hepatitis A Vaccine (003158)

CATEGORIES:

Indications: Immunization, hepatitis A

Pregnancy Category C

FDA Approved 1995 Feb

FDA DRUG CLASS: Vaccines/Antisera

BRAND NAMES: Havrix (US);

DESCRIPTION:

Hepatitis A vaccine, inactivated is a noninfectious hepatitis A vaccine.  The virus (strain HM175) is propagated in MRC5 human diploid cells. After removal of the cell culture medium, the cells are lysed to form a suspension. This suspension is purified through ultrafiltration and gel permeation chromatography procedures. Treatment of this lysate with formalin ensures viral inactivation. Havrix contains a sterile suspension of inactivated virus; viral antigen activity is referenced to a standard using an enzyme linked immunosorbent assay (ELISA), and is therefore expressed in terms of ELISA Units (EL.U.).

Havrix is supplied as a sterile suspension for intramuscular administration. The vaccine is ready for use without reconstitution; it must be shaken before administration to assure a uniform suspension. After shaking, the vaccine is a homogeneous white turbid suspension.

Each 1 ml adult dose of vaccine consists of not less than 1440 EL.U. of viral antigen, adsorbed on 0.5 mg of aluminum, as aluminum hydroxide.

There are two pediatric dose formulations, each with its own dosing schedule (see DOSAGE AND ADMINISTRATION). The formulations are: not less than 360 EL.U. of viral antigen/0.5 ml; not less than 720 EL.U. of viral antigen/0.5 ml. Each dose is absorbed onto 0.25 mg of aluminum, as aluminum hydroxide.

The vaccine preparations also contain 0.5% (w/v) of 2-phenoxyethanol as a preservative. Other excipients are: amino acid supplement (0.3% w/v) in a phosphate-buffered saline solution and polysorbate 20 (0.05 mg/ml).  Residual MRC5 cellular proteins (not more than 5 mcg/adult dose) and traces of formalin (not more than 0.1 mg/ml) are present.

CLINICAL PHARMACOLOGY:

The hepatitis A virus (HAV) belongs to the picornavirus family. Only one

serotype of HAV has been described.1

Hepatitis A is highly contagious with the predominant mode of transmission

being person-to-person via the fecal-oral route. Infection has been shown

to be spread (1) by contaminated water or food; (2) by infected food

handlers2; (3) after breakdown in usual sanitary conditions or after floods

or natural disasters; (4) by ingestion of raw or undercooked shellfish

(oysters, clams, mussels) from contaminated waters3; (5) during travel to

areas of the world with poor hygienic conditions4,5; (6) among

institutionalized children and adults6; (7) in day-care centers where

children have not been toilet trained7; (8) by parenteral transmission,

either blood transfusions or sharing needles with infected people.1

The level of economic development influences the prevalence of hepatitis A

and the age at which it is most likely to occur. In developing countries

with poor hygiene and sanitation, about 90% of children are infected by age

5 years.1 As conditions improve, the prevalence decreases and the age at

which infection occurs increases. Hence it is more likely to occur in

adulthood, when disease is generally more severe and more likely to be

fatal.1 In the United States, attack rates for hepatitis A infection are

cyclical and vary by population. The rates have increased gradually from

9.2 per 100,000 in 1983 to 14.6 per 100,000 in 1989.8

The incubation period for hepatitis A averages 28 days (range: 15 to 50

days).9 The course of hepatitis A infection is extremely variable, ranging

from asymptomatic infection to icteric hepatitis. However, most adults (76%

to 97%)10 become symptomatic. Symptoms range from mild and transient to

severe and prolonged and may include fever, nausea, vomiting and diarrhea

in the prodromal phase, followed by jaundice in up to 88% of adults, as

well as hepatomegaly and biochemical evidence of hepatocellular damage.10

Recovery is generally complete and followed by protection against HAV

infection. However, illness may be prolonged, and relapse of clinical

illness and viral shedding have been described.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 source of infection.10 In older patients and persons with underlying

liver disease,1 it is generally much more severe. This is reflected in

mortality rates. While an overall case fatality rate of 0.6% has been

reported, a case fatality rate of 2.7% has been reported in patients been

reported in patients [Image]49 years of age.1 Indeed, while 67% of cases

occur in children, over 70% of deaths occur in those over the age of 49

years.1

There is no chronic carrier state. The virus replicates in the liver and is

excreted in bile. The highest concentrations of HAV are found in stools of

infected persons during the 2-week period immediately before the onset of

jaundice and decline after jaundice appears.12 Children and infants may

shed HAV for longer periods than adults, possibly lasting as long as

several weeks after the onset of clinical illness.13 Chronic shedding of

HAV in feces has not been demonstrated, but relapses of hepatitis A can

occur in as many as 20% of patients1,14 and fecal shedding of HAV may recur

at this time.11

The presence of antibodies to HAV (anti-HAV) confers protection against hepatitis A infection. However, the lowest titer needed to confer protection has not been determined.

In a chimpanzee challenge study, the quality of protection afforded by immune globulin (IG) prepared from initially seronegative human volunteers vaccinated with hepatitis A vaccine was comparable to that afforded by commercial IG. In this experiment chimpanzees immunized with either preparation developed passive-active immunity, when challenged with wild-type HAV. No animal in either group developed clinical illness.

In vitro studies in a randomly selected subset of human subjects (n=80) showed anti-HAV induced by hepatitis A vaccine to have functional activity.  This was demonstrated by a neutralization assay and a competitive inhibition assay using a panel of monoclonal antibodies known to have neutralizing activity.

Immunogenicity in Adults: In three clinical studies involving over 400

healthy adult volunteers given a single 1440 EL.U. dose of hepatitis A

vaccine, specific humoral antibodies against HAV were elicited in more than

96% of subjects when measured 1 month after vaccination. By day 15, 80% to

98% of vaccines had already seroconverted (anti-HAV [Image]20 mIU/ml [the

lower limit of antibody measurement by current assay]). Geometric mean

titers (GMTs) of seroconverters ranged from 264 to 339 mIU/ml at day 15 and

increased to a range of 335 to 637 mIU/ml by 1 month following

vaccination.15

The GMTs obtained following a single dose of hepatitis A vaccine are at least several times higher than that expected following receipt of IG.

In a clinical study using 2.5 to 5 times the standard dose of IG (standard

dose = 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 2.15

In two clinical trials in which a booster dose of 1440 EL.U. was given 6 months following the initial dose, 100% of vaccines (n=269) were seropositive 1 month after the booster dose, with GMTs ranging from 3318 mIU/ml to 5925 mIU/ml. The titers obtained from this additional dose approximate those observed several years after natural infection.

In a subset of vaccinees (n=89), a single dose of hepatitis A vaccine 1440 EL.U. elicited specific anti-HAV neutralizing antibodies in more than 94% of vaccinees when measured 1 month after vaccination. These neutralizing antibodies persisted until month 6. One hundred percent of vaccinees had neutralizing antibodies when measured 1 month after a booster dose given at month 6.

Immunogenicity of hepatitis A vaccine was studied in subjects with chronic liver disease of various etiologies. 189 healthy adults and 220 adults with either chronic hepatitis B (n=46), chronic hepatitis C (n=104) or moderate chronic liver disease of other etiology (n=70) were vaccinated with hepatitis A vaccine 1440 EL.U. on a 0, 6 month schedule. 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), primary sclerosing cholangitis (n=4) and unspecified (n=13). At each time point, GMTs were lower for subjects with chronic liver disease than for healthy subjects. At month 7, the GMTs ranged from 478 mlU/ml (chronic hepatitis C) to 1245 mlU/ml (healthy), as determined by a commercial ELISA. The relevance of these data to the duration of protection afforded by hepatitis A vaccine is unknown. One month after the first dose, seroconversion rates in adults with chronic liver disease were lower than in healthy adults. However, 1 month after the booster dose at month 6, seroconversion rates were similar in all groups; rates ranged from 94.7% to 98.1%.

Immunogenicity in Children and Adolescents: In six clinical studies involving pediatric vaccinees (n=762) ranging from 1 to 18 years of age, the GMT following two doses of hepatitis A vaccine 360 EL.U. given 1 month apart ranged from 197 to 660 mIU/ml. Ninety-nine percent of subjects seroconverted following two doses. When a booster (third) dose of hepatitis A vaccine 360 EL.U. was administered 6 months following the initial dose, all subjects were seropositive 1 month following the booster dose with GMTs rising to a range of 3388 to 4643 mIU/ml. In one study in which children were followed for an additional 6 months, all subjects remained seropositive. Solicited adverse effects were similar in frequency and nature to those seen following administration of hepatitis B vaccine (Recombinant).

In four clinical studies, children and adolescents (n=314), ranging from 2

to 19 years of age, were immunized with two doses of the hepatitis A

vaccine 720 EL.U./0.5 ml given six months apart. One month after the first

dose, seroconversion ranged from 96.8% to 100%, with GMTs of 194 mIU/ml to

305 mIU/ml. In studies in which sera were obtained 2 weeks following the

initial dose, seroconversion ranged from 91.6% to 96.1%. One month

following a booster dose at month 6, all subjects were seropositive with

GMTs ranging from 2495 mIU/ml to 3644 mIU/ml.15

In one additional study in which the booster dose was delayed until 1 year

following the initial dose, 95.2% of the subjects were seropositive just

prior to administration of the booster dose. One month later, all subjects

were seropositive with a GMT of 2657 mIU/ml.15

Also, hepatitis A vaccine has been found to be highly efficacious in a clinical study of children at high risk of HAV infection (see Protective Efficay).

At present, the duration of protection afforded by hepatitis A vaccine has not been established. Therefore it is unknown if the protection provided to immunized children will last until adulthood.

Protective Efficacy

Protective efficacy with hepatitis A vaccine has been demonstrated in a double-blind, randomized controlled study in school children (age 1 to 16 years) in Thailand who were at high risk of HAV infection. A total of 40,119 children were randomized to be vaccinated with either hepatitis A vaccine 360 EL.U. or hepatitis B vaccine (Recombinant) at 0, 1, 12 months.

19,037 children received a primary course (0, 1 months) of hepatitis A

vaccine and 19,120 children received a primary course (0, 1 months) of

hepatitis B vaccine (Recombinant). 38,157 children entered surveillance at

day 138 and were observed for an additional 8 months. Using the

protocol-defined endpoint ([Image]2 days absence from school, ALT level >45

U/ml, and a positive result in the HAVAB-M test). 32 cases of clinical

hepatitis A occurred in the control group; in the hepatitis A vaccine

group, two cases were identified. These two cases were mild both in terms

of biochemical and clinical indices of hepatitis A disease. Thus the

calculated efficacy rate for prevention of clinical hepatitis A was 94%

(95% confidence intervals 74% to 98%).16

In outbreak investigations occurring in the trial, 26 clinical cases of hepatitis A (of total of 34 occurring in the trial) occurred. No cases occurred in hepatitis A vaccine vaccinees.

Using additional virological and serological analyses post hoc, the efficacy of hepatitis A vaccine was confirmed. Up to three additional cases of very mild clinical illness may have occurred in vaccinees. Using available testing, these illnesses could neither be proven nor disproven to have been caused by HAV. By including these as cases, the calculated efficacy rate for prevention of clinical hepatitis A would be 84% (95% confidence intervals 60% to 94%).

In a study designed to interrupt an epidemic of hepatitis A among Native

Americans in Alaska, vaccination with a single dose of hepatitis A vaccine

(1440 EL.U./ml in adults, 720 EL.U./0.5 ml in children and adolescents),

appeared to be efficacious.15

INDICATIONS AND USAGE:

Hepatitis A vaccine is indicated for active immunization of person [Image]2 years of age against disease caused by hepatitis A virus (HAV).

Hepatitis A vaccine will not prevent hepatitis caused by other agents such as hepatitis B virus, hepatitis C virus, hepatitis E virus or other pathogens known to infect the liver.

Immunization with hepatitis A vaccine is indicated for those people desiring protection against hepatitis A. Primary immunization should be completed at least 2 weeks prior to expected exposure to HAV. Individuals who are, or will be, at increased risk of infection by HAV include:

·        Travelers: Persons traveling to area of higher endemicity for hepatitis A. These areas include, but are not limited to, Africa, Asia (except Japan), the Mediterranean basin, Eastern Europe, the Middle East, Central and South America, Mexico, and parts of the Caribbean.  Current CDC advisories should be consulted with regard to specific locales.

·        Military personnel .

·        People living in, or relocating to, areas of high endemicity.

·        Certain ethnic and geographic populations that experience cyclic hepatitis A epidemics such as: Native peoples of Alaska and the Americas.

People With Chronic Liver Disease Including:

·        Alcoholic cirrhosis.

·        Chronic hepatitis B.

·        Chronic hepatitis C.

·        Autoimmune hepatitis.

·        Primary biliary cirrhosis.

Others:

·        Persons engaging in high-risk sexual activity (such as men having sex with men)

·        Residents of a community experiencing an outbreak of hepatitis A

·        Users of illicit injectable drugs

·        Persons who have clotting-factor disorders (hemophiliacs and other recipients of therapeutic blood products). Hepatitis A transmission has been documented in persons with clotting disorders. Susceptible persons in this category, especially those who receive solvent-detergent-treated clotting-factor concentrates, should be vaccinated against hepatitis A17 (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Although the epidemiology of hepatitis A does not permit the identification of other specific populations at high risk of disease, outbreaks of hepatitis A or exposure to hepatitis A virus have been described in a variety of populations in which hepatitis A vaccine may be useful:

·        Certain institutional workers (e.g., caretakers for the developmentally challenged.

·        Employees of child day-care centers.

·        Laboratory workers who handle live hepatitis A virus.

·        Handlers of primate animals that may be harboring HAV.

·        People Exposed to Hepatitis A: For those requiring both immediate and long-term protection, heptatitis A vaccine may be administered concomitantly with IG.

The ACIP has issued the following recommendations regarding food handlers:

“Persons who work as food handlers can contract hepatitis A and transmit

HAV to others. To decrease the frequency of evaluations of food handlers

with hepatitis A and the need for postexposure prophylaxis of patrons,

vaccination may be considered where state or local health authorities or

private employers determine that such vaccination is cost-effective.”17

CONTRAINDICATIONS:

Hepatitis A vaccine is contraindicated in people with known hypersensitivity to any component of the vaccine.

WARNINGS:

There have been rare reports of anaphylaxis/anaphylactoid reactions following commercial use of the vaccine in other countries. Patients experiencing hypersensitivity reactions after a hepatitis A vaccine injection should not receive further hepatitis A vaccine injections. (See CONTRAINDICATIONS.)

Hepatitis A has a relatively long incubation period (15 to 50 days).  Hepatitis A vaccine may not prevent hepatitis A infection in individuals who have an unrecognized hepatitis A infection at the time of vaccination.  Additionally, it may not prevent infection in individuals who do not achieve protective antibody titers (although the lowest titer needed to confer protection has not been determined).

PRECAUTIONS:

General

As with any parenteral vaccine, epinephrine should be available for use in case of anaphylaxis or anaphylactoid reaction.

As with any vaccine, administration of hepatitis A vaccine should be delayed, if possible, in people with any febrile illness, except when, in the opinion of the physician, withholding vaccine entails the greater risk.

Hepatitis A vaccine should be administered with caution to people with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects.

As with any vaccine, if administered to immunosuppressed persons or persons

receiving immunosuppressive therapy, the expected immune response may not

be obtained.17

Care is to be taken by the healthcare provider for the safe and effective use of hepatitis A vaccine.

Prior to an injection of any vaccine, all known precautions should be taken to prevent adverse reactions. This includes a review of the patient’s history with respect to possible hypersensitivity to the vaccine or similar vaccines.

A separate sterile syringe and needle (for single-dose vial) or a sterile disposable unit (prefilled syringe) must be used for each patient to prevent the transmission of infectious agents from person to person.  Needles should not be recapped and should be properly disposed.

Special care should be taken to ensure that hepatitis A vaccine is not injected into a blood vessel.

Information for the Patient

Patients, parents or guardians should be fully informed of the benefits and risks of immunization with hepatitis A vaccine.

Hepatitis A vaccine is indicated in a variety of situations (see

INDICATIONS AND USAGE). For persons traveling to endemic or epidemic areas, current CDC advisories should be consulted with regard to specific locales.

Travelers should take all necessary precautions to avoid contact with or ingestion of contaminated food or water.

The duration of immunity following a complete schedule of immunization with hepatitis A vaccine has not been established.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Hepatitis A vaccine has not been evaluated for its carcinogenic potential, mutagenic potential or potential for impairment of fertility.

Pregnancy Category C

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

Nursing Mothers

It is not known whether hepatitis A vaccine is excreted in human milk.  Because many drugs are excreted in human milk, caution should be exercised when hepatitis A vaccine is administered to a nursing woman.

Pediatric Use

Hepatitis A vaccine is well tolerated and highly immunogenic and effective in children [Image]2 years of age. (See CLINICAL PHARMACOLOGY for immunogenicity and efficacy data. See DOSAGE AND ADMINISTRATION for recommended dosage.)

DRUG INTERACTIONS:

Preliminary results suggest that the concomitant administration of a wide variety of other vaccines is unlikely to interfere with the immune response to hepatitis A vaccine.

As with other intramuscular injections, hepatitis A vaccine should be given with caution to individuals on anticoagulant therapy.

When concomitant administration of other vaccines or IG is required, they should be given with different syringes and at different injection sites.

ADVERSE REACTIONS:

During clinical trials involving more than 31,000 individuals receiving doses ranging from 360 EL.U. to 1440 EL.U. and during extensive postmarketing experience in Europe, hepatitis A vaccine has been generally well tolerated. As with all pharmaceuticals, however, it is possible that expanded commercial use of the vaccine could reveal rare adverse events not observed in clinical studies.

The frequency of solicited adverse events tended to decrease with successive doses of hepatitis A vaccine. Most events reported were considered by the subjects as mild and did not last for more than 24 hours.

Of solicited adverse events in clinical trials, the most frequently reported by volunteers was injection-site soreness (56% of adults and 21% of children); however, less than 0.5% of soreness was reported as severe.  Headache was reported by 14% of adults and less than 9% of children. Other solicited and unsolicited events occurring during clinical trials are listed below:

Incidence 1% to 10% of Injections

Local Reactions At Injection Site: Induration, redness, swelling.

Body as a Whole: Fatigue, fever (>37.5°C), malaise.

Gastrointestinal: Anorexia, nausea.

Incidence <1% of Injections

Local Reaction at Injection Site: Hematoma.

Dermatologic: Pruritus, rash, urticaria.

Respiratory: Pharyngitis, other upper respiratory tract infections.

Gastrointestinal: Abdominal pain, diarrhea, dysgeusia, vomiting.

Musculoskeletal: Arthralgia, elevation of creatine phosphokinase, myalgia.

Hematologic: Lymphadenopathy.

Central Nervous System: Hypertonic episode, insomnia, photophobia, vertigo.

Addtional Safety Data

Safety data were obtained from two additional sources in which large populations were vaccinated. In an outbreak setting in which 4930 individuals were immunized with a single dose of either 720 EL.U. or 1440 EL.U. of hepatitis A vaccine, the vaccine was well-tolerated and no serious adverse events due to vaccination were reported. Overall, less than 10% of vaccinees reported solicited general adverse events following the vaccine.  The most common solicited local adverse event was pain at the injection site, reported in 22.3% of subjects at 24 hours and decreasing to 2.4% by 72 hours.

In a field efficacy trial, 19,037 children received the 360 EL.U. dose of hepatitis A vaccine. The most commonly reported adverse events following administration of hepatitis A vaccine were injection-site pain (9.5%) and tenderness (8.1%), which were reported following first doses of hepatitis A vaccine. Other adverse events were infrequent and comparable to the control vaccine hepatitis B vaccine (Recombinant). Additionally, no serious adverse events due to the vaccine were reported. The large trial further allowed for analysis of rare adverse events, including hospitalization and death.  No significant differences were found between the cohorts.

In subjects with chronic liver disease. Hepatitis A vaccine was safe and well-tolerated. Local injection site reactions were similar among all four groups and no serious adverse reactions attributed to the vaccine were reported in subjects with chronic liver disease.

Postmarketing Reports

Rare voluntary reports of adverse events in people receiving hepatitis A vaccine that have been reported since market introduction of the vaccine include the following:

Local: Localized edema.

While no causal relationship has been established, the following rare events have been reported:

Body as a Whole: Anaphylaxis/anaphylactoid reactions, somnolence.

Cardiovascular: Syncope.

Hepatobiliary: Jaundice, hepatitis.

Dermatologic: Erythema multiforme, hyperhydrosis, angioedema.

Respiratory: Dyspnea.

Hematologic: Lymphadenopathy.

Central Nervous System: Convulsions, encephalopathy, dizziness, neuropathy, myelitis, paresthesia, Guillain-Barre syndrome, multiple sclerosis.  Other: Congenital abnormality.

Reporting of Adverse Events

The U.S. Department of Health and Human Services has established the

Vaccine Adverse Events Reporting System (VAERS) to accept reports of

suspected adverse events after the administration of any vaccine,

including, but not limited to, the reporting of events required by the

National Childhood Vaccine Injury Act of 1986. The toll-free number for

VAERS forms and information is 1-800-822-7967.18

DOSAGE AND ADMINISTRATION:

Hepatitis A vaccine should be administered by intramuscular injection. Do not inject intravenously, intradermally or subcutaneously. In adults, the injection should be given in the deltoid region. Hepatitis A vaccine should not be administered in the gluteal region; such injections may result in suboptimal response.

Hepatitis A vaccine may be administered concomitantly with IG, although the ultimate antibody titer obtained is likely to be lower than when the vaccine is given alone. Hepatitis A vaccine has been administered simultaneously with hepatitis B vaccine (recombinant) without interference with their respective immune responses.

For individuals with clotting-factor disorders who are at risk of

hemorrhage following intramuscular injection, the ACIP recommends that when

any intramuscular vaccine is indicated for such patients, “... it should be

administered intramuscularly if, in the opinion of a physician familiar

with the patient’s bleeding risk, the vaccine can be administered with

reasonable safety by this route. If the patient receives antihemophilia or

other similar therapy, intramuscular vaccination can be scheduled shortly

after such therapy is administered. A fine needle ([Image]23 gauge) can be

used for the vaccination and firm pressure applied to the site (without

rubbing) for at least two minutes. The patient or family should be

instructed concerning the risk of hematoma from the injection.”20

When concomitant administration of other vaccines or IG is required, they should be given with different syringes and at different injection sites.

Preparation for Administration: Shake vial or syringe well before withdrawal and use. Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration. With thorough agitation, hepatitis A vaccine is a turbid white suspension.  Discard if it appears otherwise.

The vaccine should be used as supplied; no dilution or reconstitution is necessary. The full recommended dose of the vaccine should be used. After removal of the appropriate volume from a single-dose vial, any vaccine remaining in the vial should be discarded.

Primary immunization for adults consists of a single dose of 1440 EL.U. in 1 ml. Primary immunization for children and adolescents (2 through 18 years of age) may follow either of the two schedules found in TABLE 1.

TABLE 1 Children and adolescents (2 through 18 years of age)

 Dose                          Schedule

 Primary course: 360           Two doses, given 1 month apart (month 0 and

 EL.U./0.5 ml                  month 1)

 Booster: 360                  6 to 12 months after primary course

EL.U./0.5 ml

OR

Primary course: 720           one dose (month 0)

EL.U./0.5 ml

Booster: 720                  6 to 12 months after primary course

EL.U./0.5 ml

Individuals should not be alternated between the 360 EL.U. and 720 EL.U.  doses. Those who receive an initial 360 EL.U. dose should continue on the 360 EL.U. dosing schedule. Likewise, those individuals who receive a single 720 EL.U. primary dose should receive a 720 EL.U. booster dose.

For all age groups, a booster dose is recommended anytime between 6 and 12 months after the initiation of the primary dose in order to ensure the highest antibody titers.

In those with an impaired immune system, adequate anti-HAV response may not be obtained after the primary immunization course. Such patients may therefore require administration of additional doses of vaccine.

REFERENCES:

1.   Hadler SC: Global impact of hepatitis A virus infection changing patterns. In Hollinger FB, Lemon SM, Margolis H (eds):Viral Hepatitis and Liver Disease. Baltimore, Williams & Wilkins, 1991, pp. 14-20.

2.   Dienstag JL, Routenberg JA, Purcell RH, et al. : Foodhandler-associated outbreak of hepatitis type A. An immune electron microscopic study. Ann Intern Med. 1975;83:647.

3.      Mackowiak PA, Caraway CT, Portnoy BL: Oyster-associated hepatitis.

Lessons from the Louisiana experience. Am J Epidemiol. 1976;103:181.

4.   Woodson RD, Clinton JJ: Hepatitis prophylaxis abroad. Effectiveness of immune serum globulin in protecting Peace Corps volunteers. JAMA.  1969;1009:1053.

5.   Krugman S, Giles JP: Viral hepatitis. New light on an old disease. JAMA.

1970;212:1019.

6.   Mosley JW: Hepatitis types B and non-B. Epidemiologic background. JAMA.

1975;233:967.

7.   Hadler SC, Erben JJ, Francis DP, et al. : Risk factors for hepatitis A in daycare centers. J Infect Dis. 1982;145:255.

8.   Shapiro CN, Shaw SE, Mandel EJ, Hadler SC: Epidemiology of hepatitis A in the United States. In Hollinger FB, Lemon SM, Margolis H (eds): Viral Hepatitis and Liver Disease. Baltimore, Williams & Wilkins, 1991, pp.  71-76.

9.   Centers for Disease Control: Protection against viral hepatitis:

Recommendations of the Immunization Practices Advisory Committee (ACIP).

MMWR. 1990;39(No. RR-2):1- 26.

10. Lemon SM: Type A viral hepatitis: new developments in an old disease.

N. Engl J Med. Oct. 24, 1985;313(17):1059-1067.

11. Sjogren MH, Tanno H, Fay O, et al. : Hepatitis A virus in stool during clinical relapse. Ann Intern Med. 1987;106:221-226.

12. Hollinger FB, Ticehurst J: Hepatitis A Virus. In Hollinger FB, Robinson WS, Purcell RH, et al. (eds): Viral Hepatitis. New York, Raven Press, 1990, pp. 1-37.

13.      Tassopoulos NC, Papaevangelou GJ, Ticehurst JR, et al. : Fecal excretion of Greek strains of hepatitis A virus in patients with hepatitis A and in experimentally infected chimpanzees. J Infect Dis. 1986;

154:231-237.

14. Chiriaco P, Gaudalupi C, Armigliato MK, et al. : Polyphasic course of hepatitis type A in children. J Infect Dis. 1986; 153:37B.

15. Data on file, SmithKline Beecham Pharmaceuticals.

16. Innis BL, Snitbhan R, Kunasol P, et al. : Protection against hepatitis A by an inactivated vaccine. JAMA. 1994;271(17):1328-1364.

17. Centers for Disease Control and Prevention: Prevention of hepatitis A through active or passive immunization. Reccomendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1996;45(No. RR-15):21-23.

18. ACIP: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR. 1993;42 (No. RR-4).

19. Centers for Disease Control; Vaccine Adverse Event Reporting System-United States. MMWR. 1990;39:730- 733.

HOW SUPPLIED:

360 EL.U./0.5 ml: in single-dose vials.

720 EL.U./0.5 ml: in single-dose vials and prefilled syringes.

1440 EL.U./ml: in single-dose vials and prefilled syringes.  Storage: Store between 2-8°C (36-46°F). Do not freeze; discard if product has been frozen. Do not dilute to administer.

MD Consult L.L.C.   http://www.mdconsult.com

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ALL INFORMATION, DATA, AND MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR LEGAL ADVICE.  THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH YOUR HEALTH CARE PROVIDER.