HEPATITIS A VACCINE
Recommendations for use of Hepatitis A vaccine and IG
Preexposure Prophylaxis"
Hepatitis A vaccination provides preexposure protection from HAV infection. It is recommended for persons who are at increased risk for infection and for any person wishing to obtain immunity.
Persons who seek immunological protection, but are allergic to vaccine components should receive IG. The administration must be repeated if protection is required for periods exceeding 5 months.
Postexposure Prophylaxis9'12
Persons who have been exposed to HAV and who have not previously been vaccinated should be administered a dose of IG (0.02ml/kg) within two weeks of exposure. Persons who have received a dose of hepatitis A vaccine at least 2 weeks before exposure to HAV do not need IG.
Mass postexposure vaccination to contain the spread of HAV in established outbreaks has been well documented and proven efficacious in ceasing emerging epidemics.
Hepatitis A Vaccines
The use of gammaglobulin has provided passive, short-term protection. Vaccines give active and long lasting protection against hepatitis A.
Live Attenuated HAV Vaccine6" "3
Inexpensive, live, attenuated vaccines have been produced from H2-strain in China, and millions of Chinese have been vaccinated. The H2-strain vaccine does not induce seroconversion if given orally, but nearly all of the individuals that were given the vaccine subcutaneously developed antibodies. This attenuated HAV is not transmitted orally although it is shed in stools in little amounts. The vaccine
gave 100% protection against HAV infection during a 4 year period at 11 primary schools.
Inactivated HAV Vaccines
The first inactivated HAV vaccine became available for IM injection in Europe in 1991 and was approved in the United States in 1995. Subsequently three more vaccines came. All are similar in terms of efficacy and side-effect profile. They are given parenterally, as a two-dose series, 6-18 months apart. Although one dose of vaccine provides at least short-term protection, the manufacturers currently recommend two doses to ensure long-term protection.
Inactivated vaccines are manufactured from cell-culture-adapted HAV propagated in human fibroblasts or from HAV purified from infected human diploid cell cultures and inactivated with formalin.
A combination vaccine containing inactivated hepatitis A and recombinant hepatitis B vaccines has been licensed since 1996 for use in children aged one year or older in several countries. The combination vaccine is given as a three-dose series, using a 0, 1,6 month schedule.
FIRST CHOICE ( LIVE ATTENUATED HAV VACCINE )
Description
Biovac A is a Freeze-dried live attenuated hepatitis A vaccine indicated for prophylaxis against HAV infection. It is made from master seed virus, the H2 attenuated stain of HAY cultured in human diploid cells.
Biovac A is available as I ml single dose vial for subcutaneous administration.
Pharmacodynamics
Biovac A confers immunity against HAV infection by the induction of specific antibodies against the virus. The vaccine confers immunity against HAV virus by inducing antibody titres greater than those obtained after passive immunization with immunoglobulin.
Indications
Biovac A is indicated for active immunization against infection caused by HAV in persons over I year of age. It can be used for primary immunization. It is recommended for pre-exposure prophylaxis of individuals at increased risk of infection, as well as post-exposure prophylaxis.
Thus the vaccine is indicated in the following conditions:
β’ Residents of communities with high endemic rates or recurrent outbreaks of HAV
β’ Travellers to countries where Hepatitis A is endemic, especially when the travel involves rural or primitive conditions
β’ Members of the armed forces, emergency relief workers and others likely to be posted abroad at short notice to areas with high rates of HAV infection
β’ Residents and staff of institutions where there is an ongoing problem with HAV transmission
β’ Inmates of correctional facilities in which there is an ongoing problem with HAV infection
β’ People with life style determined risks of infection, including those
engaging in oral or intravenous illicit drug use in unsanitary conditions
β’ People with chronic liver disease who may be at increased risk of fulminant hepatitis A
β’ Patients with hemophilia A or B receiving plasma-derived replacement clotting factors
β’ Zoo-keepers, veterinarians and researchers who handle non-human primates
Dosage And Administration
Add 1.0 ml sterile water for injection and shake well till the powder completely dissolves. Then inject a single dose of I ml subcutaneously over the deltoid muscleof upper arm.
No booster dose is required.
Adverse Effects
Adverse events to Biovac Aare usually mild and confined to the first few days after vaccination with spontaneous recovery.
Local: pain at the site of injection, redness, swelling, hematoma, induration/edema, pruritus. These usually subside within 72 hours and no specific treatment is needed. Relevant treatment may be given whenever needed.
Systemic: fever (>37.5Β°C axillary), asthenia/drowsiness, headache myalgia, arthralgia, gastrointestinal disorders, behavioural changes, skin disorders.
Contraindications
β’ Hypersensitivity to the vaccine or any component of the formulation.
β’ Acute infectious disease or other serious illness.
β’ Acute febrile illness with temperature above 37.5 degree centigrade.
β’ Immunodeficiencystates.
β’ A history of anaphylaxis or any other serious allergic reaction to vaccines.
A minor afebrile illness or mild upper respiratory tract infection is not usually a reason to defer immunization with the vaccine.
Usage In Pregnant And Lactating Women
The effect of the vaccine on embryo foetal development has not been assessed. Biovac A is not recommended in pregnancy unless there is a high risk of hepatitis A infection. The vaccine should be given to a pregnant woman only if clearly needed.
There are no data on the effect of administration of the vaccine during lactation. Biovac A is therefore not recommended during lactation.
Protection Against Infection Due To Other Viruses
Biovac A does not provide protection against infection caused by hepatitis B virus, hepatitis C virus, delta virus, hepatitis E virus, or by other liver pathogens.
Storage Conditions
Biovac Ashould be kept and transported at a temperature of 2Β°C to 8Β°C in a dark place.
SECOND CHOICE ( INACTIVATED HAV VACCINE )
DESCRIPTION:
Havrix (Hepatitis A Vaccine, Inactivated) is a noninfectious hepatitis A vaccine
developed and manufactured by SmithKline Beecham Biologicals. 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
homogenous 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 adsorbed 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.
ACTIONS/CLINICAL PHARMACOLOGY:
The hepatitis A virus (HAV) belongs to the picornavirus family. Only one
serotype of HAV has been described. (REF. 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 handlers (REF.
2); (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 waters (REF. 3); (5) during travel to areas of the
world with poor hygienic conditions (REF. 4,5); (6) among institutionalized
children and adults (REF. 6); (7) in day-care centers where children have not
been toilet trained (REF. 7); (8) by parenteral transmission, either blood
transfusions or sharing needles with infected people. (REF. 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. (REF.
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. (REF. 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. (REF. 8)
The incubation period for hepatitis A averages 28 days (range: 15 to 50 days).
(REF. 9) The course of hepatitis A infection is extremely variable, ranging from
asymptomatic infection to icteric hepatitis. However, most adults (76% to 97%)
(REF. 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. (REF. 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. (REF. 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. (REF. 10) In older patients and persons with underlying liver
disease, (REF. 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 >/=49 years of age.
(REF. 1) Indeed, while 67% of cases occur in children, over 70% of deaths occur
in those over the age of 49 years. (REF. 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. (REF. 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. (REF. 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 (REF. 1,14) and fecal shedding of HAV may recur at this
time. (REF. 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 Havrix 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 Havrix 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 Havrix, 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 vaccinees had already
seroconverted (anti-HAV >/=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. (REF. 15)
The GMTs obtained following a single dose of Havrix 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. (REF. 15)
In two clinical trials in which a booster dose of 1440 EL.U. was given 6 months
following the initial dose, 100% of vaccinees (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 Havrix 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 Havrix 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 Havrix 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, GMT's were lower
for subjects with chronic liver disease than for healthy subjects. At month 7,
the GMT;s ranged from 478 mIU/mL (chronic hepatitis C) to 1245 mIU/mL (healthy),
as determined by a commercial ELISA. The relevance of these data to the duration
of protection afforded by Havrix 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 Havrix 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 Havrix 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 Engerix-B(R) (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 Havrix 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 mlU/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. (REF. 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. (REF. 15)
Also, Havrix has been found to be highly efficacious in a clinical study of
children at high risk of HAV infection (see below).
At present, the duration of protection afforded by Havrix has not been
established. Therefore it is unknown if the protection provided to immunized
children will last until adulthood.
Protective Efficacy: Protective efficacy with Havrix 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 Havrix 360 EL.U. or Engerix-B at 0,
1, 12 months. 19,037 children received a primary course (0, 1 months) of Havrix
and 19,120 children received a primary course (0, 1 months) of Engerix-B. 38,157
children entered surveillance at day 138 and were observed for an additional 8
months. Using the protocol-defined endpoint (>/=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 Havrix 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%). (REF. 16)
In outbreak investigations occurring in the trial, 26 clinical cases of
hepatitis A (of a total of 34 occurring in the trial) occurred. No cases
occurred in Havrix vaccinees.
Using additional virological and serological analyses post hoc, the efficacy of
Havrix 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 Havrix (1440 EL.U./mL in
adults, 720 EL.U./0.5 mL in children and adolescents), appeared to be
efficacious. (REF. 15)
INDICATIONS AND USAGE:
Havrix is indicated for active immunization of persons >/=2 years of age against
disease caused by hepatitis A virus (HAV).
Havrix 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 Havrix 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 areas 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.
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 A(REF.17) (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 Havrix 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, Havrix 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.*(REF.17) PEOPLE WITH CHRONIC
LIVER DISEASE INCLUDING:
-- Alcoholic cirrhosis
-- Chronic hepatitis B
-- Chronic hepatitis C
-- Autoimmune hepatitis
-- Primary biliary cirrhosis
CONTRAINDICATIONS:
Havrix 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 Havrix injection should not receive further
Havrix 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 Havrix 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.
Havrix 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. (REF. 17)
Care is to be taken by the health-care provider for the safe and effective use
of Havrix.
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 Havrix is not injected into a blood
vessel.
INFORMATION FOR PATIENTS
Patients, parents or guardians should be fully informed of the benefits and
risks of immunization with Havrix.
Havrix 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
Havrix has not been established.
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
Havrix.
As with other intramuscular injections, Havrix 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.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Havrix has not been evaluated for its carcinogenic potential, mutagenic
potential or potential for impairment of fertility.
PREGNANCY: PREGNANCY CATEGORY C.
Animal reproduction studies have not been conducted with Havrix. It is also not
known whether Havrix can cause fetal harm when administered to a pregnant woman
or can affect reproduction capacity. Havrix should be given to a pregnant woman
only if clearly needed.
NURSING MOTHERS
It is not known whether Havrix is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when Havrix is administered
to a nursing woman.
PEDIATRIC USE
Havrix is well tolerated and highly immunogenic and effective in children >/=2
years of age. (See ACTIONS/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
Havrix.
As with other intramuscular injections, Havrix 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.
(See Also PRECAUTIONS)
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, Havrix (Hepatitis A Vaccine, Inactivated) 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 Havrix. 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 deg 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.
ADDITIONAL SAFETY DATA
Safety data were obtained from two additional sources in which large populations
were vaccinated. In an outbreak setting in which 4,930 individuals were
immunized with a single dose of either 720 EL.U. or 1440 EL.U. of Havrix, 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
Havrix. The most commonly reported adverse events following administration of
Havrix were injection-site pain (9.5%) and tenderness (8.1%), which were
reported following first doses of Havrix. Other adverse events were infrequent
and comparable to the control vaccine Engerix-B. 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, Havrix 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 Havrix 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.
(REF. 18)
DOSAGE AND ADMINISTRATION:
Havrix should be administered by intramuscular injection. Do Not Inject
Intravenously, Intradermally Or Subcutaneously. In adults, the injection should
be given in the deltoid region. Havrix should not be administered in the gluteal
region; such injections may result in suboptimal response.
Havrix may be administered concomitantly with IG, although the ultimate antibody
titer obtained is likely to be lower than when the vaccine is given alone.
Havrix has been administered simultaneously with Engerix-B 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 (=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.
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, Havrix
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 these two schedules:
--------------------------------------------------------------------------------------------------------------------------------------------
Group Dose Schedule
--------------------------------------------------------------------------------------------------------------------------------------------
Children and adol- Primary course: two doses,
escents (2 through 360 EL.U./0.5 mL given 1 month
18 years of age) apart (month 0
and month 1)
Booster: 6 to 12 months
360 EL.U./0.5 mL after primary
course
---------------------------------------------------------------------------------------------------------------------------------------------
OR
---------------------------------------------------------------------------------------------------------------------------------------------
Primary course: one dose
720 EL.U./0.5 mL (month 0)
Booster: 6 to 12 months
720 EL.U./0.5 mL after primary
course
------------------------------------------------------------------------------------------------------------------------------------------
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.
STORAGE
Store between 2 deg and 8 deg C (36 deg and 46 deg F). Do not freeze; discard if
product has been frozen. Do not dilute to administer.
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; 153:378.
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. ACIP: Use of vaccines and immune globulins in
persons with altered immunocompetence. MMWR. 1993;42 (No. RR-4). 18. Centers for
Disease Control: Vaccine Adverse Event Reporting System-United States. MMWR.
1990;39:730-733.
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