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.
Solicited Adverse Events
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)
||% Grade 3
|Loss of appetite
|N = all subjects for whom safety data were available.
a Within 4 days of vaccination defined as day of vaccination and the
next 3 days. b In this study, 92 subjects previously received 3 doses of
HIBERIX (not approved for primary immunization in the US), 96 subjects
previously received 3 doses of a US-licensed Haemophilus b Conjugate Vaccine
(manufactured by Sanofi Pasteur SA), and 183 subjects previously received 3
doses of a Haemophilus
b Conjugate Vaccine that is no longer licensed in the US.
c In this study, DTaP-HBV-IPV was given to subjects who previously
received 3 doses of DTaP-HBV-IPV. In the US, PEDIARIX is approved for use as a
3-dose primary series; use as a fourth consecutive dose is not approved in the
d Local reactions at the injection site for HIBERIX.
e Grade 3 redness or swelling defined as > 20 mm.
f Grade 3 pain defined as causing crying when limb moved.
g Fever defined as ≥ 100.4°F
( ≥ 38.0°C) rectally or ≥ 99.5°F ( ≥ 37.5°C)
axillary, oral or tympanic; Grade 3 fever defined as > 103.1°F ( > 39.5°C)
rectally or > 102.2°F ( > 39.0°C) axillary, oral or tympanic.
h Grade 3 fussiness defined as persistent crying and could not be
comforted. i Grade 3 for these symptoms defined as preventing normal daily
Serious Adverse Events
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.
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,