Haemophilus B Conjugate Vaccine Tetanus Toxoid Conjugate for Intramuscular Injection

HIBERIX® is indicated for active immunization as a booster dose for the prevention of invasive disease caused by Haemophilus influenzae type b. HIBERIX is approved for use in children 15 months through 4 years of age (prior to fifth birthday).

HIBERIX is to be used as a booster dose in children who have received a primary series with a Haemophilus b Conjugate Vaccine that is licensed for primary immunization. HIBERIX is not approved for primary immunization.

The evaluation of effectiveness of HIBERIX as a booster dose was based on immune responses in children using serological endpoints that predict protection from invasive disease due to H. influenzae type b [see CLINICAL PHARMACOLOGY and Clinical Studies]. These protective antibody levels have not been evaluated in clinical trials in which a booster dose of HIBERIX is compared to a booster dose of a US-licensed Haemophilus b Conjugate Vaccine in children who previously received a primary series with a US-licensed Haemophilus b Conjugate Vaccine [see Clinical Studies].

Mechanism Of Action

Haemophilus influenzae is a gram-negative coccobacillus. Most strains of H. influenzae that cause invasive disease are type b. H. influenzae type b can cause invasive disease such as sepsis and meningitis.

Specific levels of antibodies to polyribosyl-ribitol-phosphate (anti-PRP) have been shown to correlate with protection against invasive disease due to H. influenzae type b. Based on data from passive antibody studies2 and a clinical efficacy study with unconjugated Haemophilus bpolysaccharide vaccine3, an anti-PRP concentration of 0.15 mcg/mL has been accepted as a minimal protective level. Data from an efficacy study with unconjugated Haemophilus b polysaccharide vaccine indicate that an anti-PRP concentration of ≥ 1.0 mcg/mL predicts protection through at least a 1-year period.4,5 These antibody levels have been used to evaluate the effectiveness of Haemophilus b Conjugate Vaccines, including HIBERIX.

Clinical Studies

Immunological Evaluation

In 6 clinical studies, the immune response to HIBERIX administered as a booster dose was evaluated in a total of 415 children 12 to 23 months of age. At the time of vaccination, 30 children were 12 to 14 months of age, 316 children were 15 to 18 months of age, and 69 children were 19 to 23 months of age. Among subjects, 43% to 60% were male. Among subjects for whom information on race/ethnicity was available, nearly all subjects were white. None of the studies included a comparator group that received a booster dose with a US-licensed Haemophilus b Conjugate Vaccine. Characteristics of 3 of these studies are presented in Table 2.

Table 2: Characteristics of 3 Open-Label Booster Immunization Studies of HIBERIX

Antibodies to PRP were measured in sera obtained immediately prior to and 1 month after booster vaccination with HIBERIX. Geometric mean concentrations and anti-PRP seroprotection rates are presented in Table 3.

Table 3: Anti-PRP GMCs and Seroprotection Rates Prior to and 1 Month Following a Booster Dose of HIBERIX, Per Protocol Immunogenicity Cohort

REFERENCES

2. Robbins JB, Parke JC, Schneerson R, et al. Quantitative measurement of “natural” and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res 1973;7:103-110.

3. Peltola H, Kaythy H, Sivonen A, et al. Haemophilus influenzae type b capsular polysaccharide vaccine in children: A double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics 1977;60:730-737.

4. Kaythy H, Peltola H, Karanko V, et al. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1983;147:1100.

5. Anderson P. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1984;149:1034.

Parents or guardians should be:

• informed of the potential benefits and risks of immunization with HIBERIX.
• informed about the potential for adverse reactions that have been temporally associated with administration of HIBERIX or other vaccines containing similar components.
• instructed to report any adverse events to their healthcare provider.
• given the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. There is the possibility that broad use of HIBERIX could reveal adverse reactions not observed in clinical trials.

In 7 clinical studies, 1,008 children received HIBERIX as a booster dose following primary vaccination with either HIBERIX (not approved for primary series in US, N = 530), Haemophilus b Conjugate Vaccine manufactured by Sanofi Pasteur SA (N = 235), Haemophilus b Conjugate Vaccine manufactured by Merck & Co., Inc. (N = 26), or Haemophilus b Conjugate Vaccine manufactured by Wyeth Pharmaceuticals Inc. (no longer licensed in the US, N = 217). None of the studies included a comparator group that received a booster dose with a US-licensed Haemophilus b Conjugate Vaccine. Studies were conducted in Europe, Canada, and Latin America. Across these studies, the mean age of subjects at the time of booster vaccination with HIBERIX ranged from 16 to 19 months. At the time of vaccination, 172 (17.1%) subjects were 11 to 14 months of age, 642 (63.7%) subjects were 15 to 18 months of age, and 194 (19.2%) subjects were 19 to 25 months of age. Approximately half of the subjects were male. Among subjects for whom information on race/ethnicity was available, nearly all subjects were white.

In these 7 studies, HIBERIX was administered concomitantly with non-US formulations (containing 2.5 mg 2-phenoxyethanol per dose as preservative) of one of the following US- licensed vaccines: INFANRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) (DTaP), KINRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine) (DTaP-IPV), or PEDIARIX® [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine] (DTaP-HBV-IPV). In the studies, DTaP-IPV and DTaP-HBV-IPV were administered in dosing regimens not approved in the US. Some subjects received DTaP-HBV (GlaxoSmithKline Biologicals, not licensed in US) concomitantly with HIBERIX.

In an open-label, multicenter study conducted in Germany, 371 children received a booster dose of HIBERIX administered concomitantly with DTaP-HBV- IPV. The mean age at the time of vaccination was 16 months. Subjects in this study had previously received a primary series with either HIBERIX (not approved for primary series in US, N = 92), Haemophilus b Conjugate Vaccine manufactured by Sanofi Pasteur SA (N = 96), or Haemophilus b Conjugate Vaccine manufactured by Wyeth Pharmaceuticals Inc. (no longer licensed in the US) (N = 183). All subjects previously received 3 doses of DTaP-HBV-IPV. Information on adverse events was collected by parents/guardians using standardized forms for 4 consecutive days following vaccination with HIBERIX (i.e., day of vaccination and the next 3 days). The reported frequencies of solicited local and general adverse events are presented in Table 1.

Table 1: Percentage of Children With Solicited Local And General Adverse Events Within 4 Days of Vaccinationa With HIBERIXb Coadministered With DTaP-HBV-IPVc, Intent to Treat Cohort (N = 371)

Two of 1,008 subjects reported a serious adverse event that occurred in the 31-day period following booster immunization with HIBERIX. One subject developed bilateral pneumonia 9 days post-vaccination and one subject experienced asthenia following accidental drug ingestion 18 days post-vaccination.

Postmarketing Experience

In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for HIBERIX since market introduction (1996) of this vaccine are listed below. This list includes serious events and/or events which have a plausible causal connection to HIBERIX. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to vaccination.

General Disorders and Administration Site Conditions: Extensive swelling of the vaccinated limb, injection site induration.

Immune System Disorders: Allergic reactions (including anaphylactic and anaphylactoid reactions), angioedema.

Nervous System Disorders: Convulsions (with or without fever), hypotonic- hyporesponsive episode, somnolence, syncope or vasovagal responses to injection.

Respiratory, Thoracic, and Mediastinal Disorders: Apnea.

Skin and Subcutaneous Tissue Disorders: Rash, urticaria.

Read the entire FDA prescribing information for Hiberix (Haemophilus B Conjugate Vaccine Tetanus Toxoid Conjugate for Intramuscular Injection)