Vaccine Information: HAVRIX (Page 2 of 3)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of HAVRIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

Infections and Infestations

Rhinitis.

Blood and Lymphatic System Disorders

Thrombocytopenia.

Immune System Disorders

Anaphylactic reaction, anaphylactoid reaction, serum sickness–like syndrome.

Nervous System Disorders

Convulsion, dizziness, encephalopathy, Guillain-Barré syndrome, hypoesthesia, multiple sclerosis, myelitis, neuropathy, paresthesia, somnolence, syncope.

Vascular Disorders

Vasculitis.

Respiratory, Thoracic, and Mediastinal Disorders

Dyspnea.

Hepatobiliary Disorders

Hepatitis, jaundice.

Skin and Subcutaneous Tissue Disorders

Angioedema, erythema multiforme, hyperhidrosis.

Congenital, Familial, and Genetic Disorders

Congenital anomaly.

Musculoskeletal and Connective Tissue Disorders

Musculoskeletal stiffness.

General Disorders and Administration Site Conditions

Chills, influenza-like symptoms, injection site reaction, local swelling.

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Vaccines and Immune Globulin

In clinical studies HAVRIX was administered concomitantly with the following vaccines [see Adverse Reactions (6.1), Clinical Studies (14.5)].

•

INFANRIX (DTaP);

•

Hib conjugate vaccine;

•

pneumococcal 7-valent conjugate vaccine;

•

MMR vaccine;

•

varicella vaccine.

HAVRIX may be administered concomitantly with immune globulin.

When concomitant administration of other vaccines or immune globulin is required, they should be given with different syringes and at different injection sites. Do not mix HAVRIX with any other vaccine or product in the same syringe.

7.2 Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater-than-physiologic doses), may reduce the immune response to HAVRIX.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There are no adequate and well-controlled studies of HAVRIX in pregnant women in the U.S. Available data do not suggest an increased risk of major birth defects and miscarriage in women who received HAVRIX during pregnancy (see Data).

There are no animal studies with HAVRIX to inform use during pregnancy.

Data

Human Data: In pre- and post-licensure clinical studies of HAVRIX, 175 pregnant women (177 outcomes, including two sets of twins) were inadvertently administered HAVRIX following their last menstrual period. After excluding ectopic pregnancies (n = 2), molar pregnancies (n = 1), elective terminations (n = 22, including one of a fetus with a birth defect), those that were lost to follow-up (n = 9), and those with an unknown exposure timing (n = 5), there were 138 known pregnancy outcomes with exposure during the first or second trimester. Of these, miscarriage was reported in 11% of pregnancies exposed prior to 20 weeks gestation (15/136) and major birth defects were reported in 3.3% (4/123) of live births. The rates of miscarriage and major birth defects were consistent with estimated background rates.

8.2 Lactation

Risk Summary

There is no information regarding the presence of HAVRIX in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HAVRIX and any potential adverse effects on the breastfed child from HAVRIX or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

The safety and effectiveness of HAVRIX, doses of 360 EL.U. or 720 EL.U., have been evaluated in more than 22,000 subjects aged 1 to 18 years.

The safety and effectiveness of HAVRIX have not been established in subjects younger than 12 months.

8.5 Geriatric Use

Clinical studies of HAVRIX did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in overall safety between these subjects and younger adult subjects.

8.6 Hepatic Impairment

Subjects with chronic liver disease had a lower antibody response to HAVRIX than healthy subjects [see Clinical Studies (14.3)].

11 DESCRIPTION

HAVRIX (Hepatitis A Vaccine) is a sterile suspension of inactivated virus for intramuscular administration. The virus (strain HM175) is propagated in MRC-5 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. 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.).

Each 1-mL adult dose of vaccine contains 1440 EL.U. of viral antigen, adsorbed on 0.5 mg of aluminum as aluminum hydroxide.

Each 0.5-mL pediatric dose of vaccine contains 720 EL.U. of viral antigen, adsorbed onto 0.25 mg of aluminum as aluminum hydroxide.

HAVRIX contains the following excipients: Amino acid supplement (0.3% w/v) in a phosphate-buffered saline solution and polysorbate 20 (0.05 mg/mL). From the manufacturing process, HAVRIX also contains residual MRC-5 cellular proteins (not more than 5 mcg/mL), formalin (not more than 0.1 mg/mL), and neomycin sulfate (not more than 40 ng/mL), an aminoglycoside antibiotic included in the cell growth media.

HAVRIX is formulated without preservatives.

HAVRIX is available in prefilled syringes. The tip caps of the prefilled syringes contain natural rubber latex; the plungers are not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The hepatitis A virus belongs to the picornavirus family. It is 1 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

HAVRIX has not been evaluated for its carcinogenic potential, mutagenic potential, or potential for impairment of fertility.

14 CLINICAL STUDIES

14.1 Pediatric Effectiveness Studies

Protective efficacy with HAVRIX has been demonstrated in a double-blind, randomized controlled study in school children (aged 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 [Hepatitis B Vaccine (Recombinant)] 10 mcg at 0, 1, and 12 months. Of these, 19,037 children received 2 doses of HAVRIX (0 and 1 months) and 19,120 children received 2 doses of control vaccine, ENGERIX-B (0 and 1 months). A total of 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 group receiving HAVRIX, 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.

Using additional virological and serological analyses post hoc, the efficacy of HAVRIX 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).

14.2 Immunogenicity in Children and Adolescents

Immune Response to HAVRIX 720 EL.U./0.5 mL at Age 11 to 25 Months (Study HAV 210)

In this prospective, open-label, multicenter study, 1,084 children were administered study vaccine in 1 of 5 groups:

(1) Children aged 11 to 13 months who received HAVRIX on a 0- and 6-month schedule;

(2) Children aged 15 to 18 months who received HAVRIX on a 0- and 6-month schedule;

(3) Children aged 15 to 18 months who received HAVRIX coadministered with INFANRIX and Haemophilus b (Hib) conjugate vaccine (no longer U.S.-licensed) at Month 0 and HAVRIX at Month 6;

(4) Children aged 15 to 18 months who received INFANRIX coadministered with Hib conjugate vaccine at Month 0 and HAVRIX at Months 1 and 7;

(5) Children aged 23 to 25 months who received HAVRIX on a 0- and 6-month schedule.

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

Table 2. Anti-Hepatitis A Immune Response following 2 Doses of HAVRIX 720 EL.U./0.5 mL Administered 6 Months Apart in Children Given the First Dose of HAVRIX at Age 11 to 13 Months, 15 to 18 Months, or 23 to 25 Months

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.
a Calculated on vaccine responders 1 month post-dose 2. GMTs in children aged 11 to 13 months and 15 to 18 months were non-inferior (similar) to the GMT in children aged 23 to 25 months (i.e., the lower limit of the 2-sided 95% CI on the GMT ratio for Group 1/Group 5 and for Group 2/Group 5 were both ≥0.5).
Age Group	n	Vaccine Response		GMT (mIU/mL)
		%	95% CI
11-13 months (Group 1)	218	99	97, 100	1,461a
15-18 months (Group 2)	200	100	98, 100	1,635a
23-25 months (Group 5)	211	100	98, 100	1,911

In 3 additional clinical studies (HAV 232, HAV 220, and HAV 231), children received either 2 doses of HAVRIX alone or the first dose of HAVRIX concomitantly administered with other routinely recommended U.S.-licensed vaccines followed by a second dose of HAVRIX. After the second dose of HAVRIX, there was no evidence for interference with the anti-HAV response in the children who received concomitantly administered vaccines compared with those who received HAVRIX alone. [See Adverse Reactions (6.1), Clinical Studies (14.5).]

Immune Response to HAVRIX 360 EL.U. among Individuals Aged 2 to 18 Years

In 6 clinical studies, 762 subjects aged 2 to 18 years received 2 doses of HAVRIX (360 EL.U.) given 1 month apart (GMT ranged from 197 to 660 mIU/mL). Ninety-nine percent of subjects seroconverted following 2 doses. When a third dose of HAVRIX 360 EL.U. was administered 6 months following the initial dose, all subjects were seropositive (anti-HAV ≥20 mIU/mL) 1 month following the third 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 720 EL.U./0.5 mL among Individuals Aged 2 to 19 Years

In 4 clinical studies, 314 children and adolescents ranging from age 2 to 19 years were immunized with 2 doses of HAVRIX 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 the 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.