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Havrix

Havrix

CLINICAL PHARMACOLOGY

Mechanism of Action

The hepatitis A virus belongs to the picornavirus family. It is one of several hepatitis viruses that cause systemic disease with pathology in the liver.

The incubation period for hepatitis A averages 28 days (range: 15 to 50 days).1 The course of hepatitis A infection is extremely variable, ranging from asymptomatic infection to icteric hepatitis and death.

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

Clinical Studies

Pediatric Effectiveness Studies

Protective efficacy with HAVRIX (hepatitis a vaccine, inactivated) 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 (hepatitis a vaccine, inactivated) 360 EL.U. or ENGERIX-B at 0, 1, and 12 months. 19,037 children received a primary course (doses at 0 and 1 months) of HAVRIX (hepatitis a vaccine, inactivated) and 19,120 children received a primary course (doses at 0 and 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 (hepatitis a vaccine, inactivated) group, 2 cases were identified. These 2 cases were mild in terms of both biochemical and clinical indices of hepatitis A disease. Thus the calculated efficacy rate for prevention of clinical hepatitis A was 94% (95% Confidence Interval [CI]: 74, 98).

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 vaccinees who received HAVRIX (hepatitis a vaccine, inactivated) .

Using additional virological and serological analyses post hoc, the efficacy of HAVRIX (hepatitis a vaccine, inactivated) was confirmed. Up to 3 additional cases of 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% CI: 60, 94).

In a study designed to interrupt an epidemic of hepatitis A among Native Americans in Alaska, vaccination with a single dose of HAVRIX (hepatitis a vaccine, inactivated) (1440 EL.U./mL in adults, 720 EL.U./0.5 mL in children and adolescents) appeared to be efficacious.

Immunogenicity in Children and Adolescents

Immune Response to HAVRIX (hepatitis a vaccine, inactivated) 720 EL.U./0.5 mL at 11 Months of Age and Older: In a prospective, open-label, multicenter study, 1,085 children were enrolled into one of 5 groups:

  1. Children 11 to 13 months of age who received HAVRIX (hepatitis a vaccine, inactivated) on a 0- and 6-month schedule;
  2. Children 15 to 18 months of age who received HAVRIX (hepatitis a vaccine, inactivated) on a 0- and 6-month schedule;
  3. Children 15 to 18 months of age who received HAVRIX (hepatitis a vaccine, inactivated) coadministered with INFANRIX and Hib conjugate vaccine (PRP-T) (Sanofi Pasteur SA) at month 0 and HAVRIX (hepatitis a vaccine, inactivated) at month 6;
  4. Children 15 to 18 months of age who received INFANRIX coadministered with Hib conjugate vaccine (PRP-T) (Sanofi Pasteur SA) at month 0 and HAVRIX (hepatitis a vaccine, inactivated) at months 1 and 7;
  5. Children 23 to 25 months of age who received HAVRIX (hepatitis a vaccine, inactivated) on a 0- and 6-month schedule.

Among subjects in all groups, 52% were male; 61% of subjects were White, 9% Black, 3% Asian, and 27% were of other racial groups. The anti-hepatitis A antibody vaccine responses and GMTs, calculated on responders for groups 1, 2, and 5 are presented in Table 1. Vaccine response rates were similar among the 3 age groups that received HAVRIX (hepatitis a vaccine, inactivated) . One month after the second dose of HAVRIX (hepatitis a vaccine, inactivated) , the GMT in each of the younger age groups (11 to 13 and 15 to 18 months of age) was shown to be similar to that achieved in the 23 to 25 months of age group.

Table 1. Anti-hepatitis A Immune Response Following 2 Doses of HAVRIX (hepatitis a vaccine, inactivated) 720 EL.U./0.5 mL Administered 6 Months Apart in Children Given the First Dose of HAVRIX (hepatitis a vaccine, inactivated) at 11 to 13 Months of Age, 15 to 18 Months of Age, or 23 to 25 Months of Age

Age group   Vaccine Response GMT
(mIU/mL)
N % 95% CI
11-13 months (Group 1) 218 99 97, 100 1,461*
15-18 months (Group 2) 200 100 98, 100 1,635*
23-25 months (Group 5) 211 100 98, 100 1,911
Vaccine response = Seroconversion (anti-HAV 15 mIU/mL [lower limit of antibody measurement by assay]) in children initially seronegative or at least the maintenance of the pre-vaccination anti-HAV concentration in initially seropositive children.
CI = Confidence Interval; GMT = Geometric mean antibody titer.
*Calculated on vaccine responders one month post-dose 2. GMTs in children 11 to 13 months of age and 15 to 18 months of age were non-inferior (similar) to the GMT in children 23 to 25 months of age (i.e., the lower limit of the two-sided 95% CI on the GMT ratio for Group 1/Group 5 and for Group 2/Group 5 were both ≥ 0.5).

Immune Response to HAVRIX (hepatitis a vaccine, inactivated) 360 EL.U. at 2 Years of Age and Older: In 6 clinical studies of subjects 2 to 18 years of age (n = 762) who received 2 doses of HAVRIX (hepatitis a vaccine, inactivated) (360 EL.U.) given 1 month apart, the GMT ranged from 197 to 660 mIU/mL. Ninety-nine percent of subjects seroconverted following 2 doses. When a booster (third) dose of HAVRIX (hepatitis a vaccine, inactivated) 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 3,388 to 4,643 mIU/mL. In 1 study in which children were followed for an additional 6 months, all subjects remained seropositive.

Immune Response to HAVRIX (hepatitis a vaccine, inactivated) 720 EL.U./0.5 mL at 2 Years of Age and Older: In 4 clinical studies, children and adolescents (n = 314), ranging from 2 to 19 years of age, were immunized with 2 doses of HAVRIX (hepatitis a vaccine, inactivated) 720 EL.U./0.5 mL given 6 months apart. One month after the first dose, seroconversion (anti-HAV ≥ 20 mIU/mL [lower limit of antibody measurement by assay]) 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 2,495 mIU/mL to 3,644 mIU/mL.

In an 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 2,657 mIU/mL.

Also, HAVRIX (hepatitis a vaccine, inactivated) has been found to be efficacious in a clinical study of children at high risk of HAV infection [see Clinical Studies].

Immunogenicity in Adults

Over 400 healthy adults 18-50 years of age in 3 clinical studies were given a single 1440 EL.U. dose of HAVRIX (hepatitis a vaccine, inactivated) . All subjects were seronegative for hepatitis A antibodies at baseline. 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 [lower limit of antibody measurement by assay]). 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.

The GMTs obtained following a single dose of HAVRIX (hepatitis a vaccine, inactivated) 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.

In 2 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 3,318 mIU/mL to 5,925 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 (hepatitis a vaccine, inactivated) 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 (hepatitis a vaccine, inactivated) 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 (hepatitis a vaccine, inactivated) 1440 EL.U. on a 0- and 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, geometric mean antibody titers (GMTs) were lower for subjects with chronic liver disease than for healthy subjects. At month 7, the GMTs ranged from 478 mIU/mL (chronic hepatitis C) to 1,245 mIU/mL (healthy). 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%. The relevance of these data to the duration of protection afforded by HAVRIX (hepatitis a vaccine, inactivated) is unknown.

In subjects with chronic liver disease, local injection site reactions with HAVRIX (hepatitis a vaccine, inactivated) were similar among all 4 groups, and no serious adverse events attributed to the vaccine were reported in subjects with chronic liver disease.

Duration of Immunity

The duration of immunity following a complete schedule of immunization with HAVRIX (hepatitis a vaccine, inactivated) has not been established.

Immune Response to Concomitantly Administered Vaccines

Concomitant Administration With Hib Conjugate Vaccine (PRP-T): The concomitant administrationof Hib conjugate vaccine (PRP -T) (Sanofi Pasteur SA) and INFANRIX with HAVRIX (hepatitis a vaccine, inactivated) was evaluated in children receiving their first dose of HAVRIX (hepatitis a vaccine, inactivated) at 15 to 18 months of age followed by a second dose of HAVRIX (hepatitis a vaccine, inactivated) 6 months later. Anti-hepatitis A vaccine response was defined as seroconversion (anti-HAV ≥ 15 mIU/mL [lower limit of antibody measurement by assay]) in subjects initially seronegative or at least maintenance of pre-vaccination antibody concentration in subjects initially seropositive. One month after the second dose of HAVRIX (hepatitis a vaccine, inactivated) , the vaccine response (100%) in those receiving the first dose of HAVRIX (hepatitis a vaccine, inactivated) coadministered with INFANRIX and Hib conjugate vaccine (PRP-T) (Sanofi Pasteur SA) was shown to be non-inferior to that achieved (100%) in 15- to 18-month-olds who received HAVRIX (hepatitis a vaccine, inactivated) alone (lower limit of 95% CI on difference for coadministered vaccine group minus HAVRIX (hepatitis a vaccine, inactivated) alone group > -5%).

One month after vaccination with Hib conjugate vaccine (PRP-T) (Sanofi Pasteur SA), the seroprotection rates to this vaccine were shown to be non-inferior in subjects who received Hib conjugate vaccine (PRP-T) concomitantly with their first dose of HAVRIX (hepatitis a vaccine, inactivated) (100% achieved ≥ 1 mcg/mL of anti-PRP antibody; 95% CI: 97, 100) as compared to those who did not receive HAVRIX (hepatitis a vaccine, inactivated) (100% achieved ≥ 1 mcg/mL of anti-PRP antibody; 95% CI: 97, 100). Both groups received INFANRIX concomitantly with Hib conjugate vaccine (PRP-T) with and without HAVRIX (hepatitis a vaccine, inactivated) .

Concomitant Administration With Pneumococcal 7-Valent Conjugate Vaccine: In a US multicenter study, children 15 months of age (range 14 to 16 months) received one of 3 regimens: (Group 1) HAVRIX (hepatitis a vaccine, inactivated) coadministered with pneumococcal 7-valent conjugate vaccine (Wyeth Pharmaceuticals Inc.) followed by a second dose of HAVRIX (hepatitis a vaccine, inactivated) 6 to 9 months later; (Group 2) HAVRIX (hepatitis a vaccine, inactivated) administered alone followed by a second dose of HAVRIX (hepatitis a vaccine, inactivated) 6 to 9 months later; or (Group 3) pneumococcal 7-valent conjugate vaccine administered alone followed by a first dose of HAVRIX (hepatitis a vaccine, inactivated) one month later and a second dose of HAVRIX (hepatitis a vaccine, inactivated) 6 to 9 months after the first.

One month after the second dose, the anti-hepatitis A GMT of HAVRIX (hepatitis a vaccine, inactivated) coadministered with pneumococcal 7-valent conjugate vaccine was non-inferior to HAVRIX (hepatitis a vaccine, inactivated) given alone (Group 1 GMT = 1,518 mIU/mL; Group 2 GMT = 1,666 mIU/mL). The difference in anti-hepatitis A seropositivity rates between groups (HAVRIX (hepatitis a vaccine, inactivated) coadministered with pneumococcal 7-valent conjugate vaccine minus HAVRIX (hepatitis a vaccine, inactivated) alone) was marginally lower than the pre-defined non-inferiority limit of -5% (lower limit of the two-sided 95% CI -5.78%). However, in all 3 groups, the seropositivity rate ranged between 98% and 100% one month after the second dose of HAVRIX (hepatitis a vaccine, inactivated) (Group 1, 93/94; Group 2, 106/106; Group 3, 113/115).

One month after vaccination, non-inferiority was demonstrated with respect to GMTs for anti-pneumococcal antibodies to all 7 serotypes after the coadministration of pneumococcal 7-valent conjugate vaccine with HAVRIX (hepatitis a vaccine, inactivated) compared to pneumococcal 7-valent conjugate vaccine alone. At least 98% of subjects who received pneumococcal 7-valent conjugate vaccine coadministered with HAVRIX (hepatitis a vaccine, inactivated) and those who received pneumococcal 7-valent conjugate vaccine alone were seropositive for all 7 pneumococcal serotypes.

There are limited data on the coadministration of HAVRIX (hepatitis a vaccine, inactivated) with other vaccines.

REFERENCES

1. Centers for Disease Control. Prevention of hepatitis A through active or passive immunization: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 2006;55(RR-7):1-23.

2. Centers for Disease Control. Update: Prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007;56(41):1080-1084.

Last reviewed on RxList: 10/20/2008
This monograph has been modified to include the generic and brand name in many instances.

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