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 MENHIBRIX could reveal adverse reactions not
observed in clinical trials.
A total of 7,521 infants received at least one dose of
MENHIBRIX in 6 clinical studies.1-6 In 5 of these studies, 6,686
children received 4 consecutive doses of MENHIBRIX.2-6 Across all studies,
approximately half of participants were female; 50% were white, 41% were
Hispanic, 4% were black, 1% were Asian and 4% were of other racial/ethnic
Two randomized, controlled, pivotal trials enrolled
participants to receive 4 doses of MENHIBRIX or a monovalent Haemophilus b
Conjugate (Hib) vaccine, administered at 2, 4, 6, and 12 to 15 months of age
(Study 009/0105 and Study 011/0126). Together, these
trials evaluated safety in 8,571 infants who received at least one dose of
MENHIBRIX (N = 6,414) or Hib vaccine (N = 2,157).5,6
In Study 009/0105, conducted in the United
States, Australia, and Mexico, 4,180 infants were randomized 3:1 to receive
MENHIBRIX or a control US-licensed Hib vaccine. Safety data are available for
3,136 infants who received MENHIBRIX and 1,044 infants who received a control
Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) (PRP-T, manufactured
by Sanofi Pasteur SA) at 2, 4, and 6 months of age. For dose 4 administered at
12 to 15 months of age, safety data are available for 2,769 toddlers who
received MENHIBRIX and 923 toddlers who received a control Haemophilus b
Conjugate Vaccine (Meningococcal Protein Conjugate) (PRP-OMP, manufactured by
Merck and Co., Inc.). With doses 1, 2, and 3 of MENHIBRIX or PRP-T, infants
concomitantly received PEDIARIX® [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus
Vaccine] and Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein)
(PCV7, manufactured by Wyeth Pharmaceuticals, Inc.). With dose 4 of MENHIBRIX
or PRP-OMP, toddlers concomitantly received PCV7, Measles, Mumps, and Rubella
Virus Vaccine Live (MMR, manufactured by Merck & Co., Inc.), and Varicella
Virus Vaccine Live (manufactured by Merck & Co., Inc.).
Data on solicited adverse events were collected by
parents/guardians using standardized forms for 4 consecutive days following
vaccination with MENHIBRIX or control Hib vaccine (i.e., day of vaccination and
the next 3 days).5 Children were monitored for unsolicited adverse events
that occurred in the 31-day period following vaccination and were monitored for
serious adverse events, new onset chronic disease, rash, and conditions
prompting emergency department visits or physician office visits during the
entire study period (6 months following the last vaccine administered). Among
participants in both groups, 66% were from the United States, 19% were from
Mexico, and 14% were from Australia. Forty-eight percent of participants were female;
64% were white, 22% were Hispanic, 6% were black, 1% were Asian, and 7% were of
other racial/ethnic groups.
In the second pivotal study (Study 011/0126),
conducted in the United States and Mexico and evaluating the same vaccines and
vaccination schedule, participants were monitored for serious adverse events,
new onset chronic disease, rash, and conditions prompting emergency department
visits during the entire study period (6 months following the last vaccine administered).
Among participants in both groups, 30% were from the United States and 70% were
In addition to the pivotal studies, safety data are
available from 4 studies which either did not include a fourth dose of
MENHIBRIX1, used a dosing regimen not approved in the United States2,3,
or incorporated a comparator vaccine which was not licensed in the United
States.4 In these studies, participants were monitored for
unsolicited adverse events and serious adverse events occurring in the 31–day
period following vaccination. In 2 of these studies3,4, participants
were monitored for serious adverse events, new onset chronic disease, rash, and
conditions prompting emergency department visits or physician office visits
through 6 months after the last vaccination.
Solicited Adverse Events
The reported frequencies of solicited local and systemic adverse
events from US participants in Study 009/010 are presented in Table 1.5
Because of differences in reported rates of solicited adverse events between US
and non-US participants, only the solicited adverse event data in US
participants are presented. Among the US participants included in Table 1, 48%
were female; 76% were white, 10% were black, 4% were Hispanic, 2% were Asian,
and 8% were of other racial/ethnic groups.
Table 1: Percentage of US Children from Study 009/010
With Solicited Local and General Adverse Events within 4 Days of Vaccinationa With
MENHIBRIX or Haemophilus b Conjugate Vaccine (Total Vaccinated Cohort)
||Haemophilus b Conjugate Vaccineb,c
|Pain, grade 3e
|Redness, > 30 mm
|Swelling, > 30 mm
|Irritability, grade 3f
|Drowsiness, grade 3g
|Loss of appetite, any
|Loss of appetite, grade 3h
|Fever, ≥ 100.4°Fi
|Fever, ≥ 102.2°Fi
|Fever, ≥ 104°Fi
|Total Vaccinated Cohort = all participants who received
at least one dose of either vaccine.
N = number of participants who completed the symptom sheet for a given symptom
at the specified dose.
a Within 4 days of vaccination defined as day of vaccination and the
next 3 days.
b Co-administered with PEDIARIX and PCV7 at doses 1, 2, 3 and PCV7,
MMR and varicella vaccines at dose 4.
c US-licensed monovalent Haemophilus b Conjugate Vaccine
manufactured by Sanofi Pasteur SA for doses 1, 2, and 3 (PRP-T) and by Merck
& Co., Inc for dose 4 (PRP-OMP).
d Local reactions at the injection site for MENHIBRIX or Haemophilus
b Conjugate Vaccine.
e Cried when limb was moved/spontaneously painful.
f Crying that could not be comforted/prevented normal daily
g Prevented normal daily activities.
h Not eating at all.
i Across both treatment groups, 54%, 56%, and 59% of participants
had temperatures measured rectally following doses 1, 2, and 3, respectively;
45%, 44%, and 40% of participants had temperatures measured by the axillary
route for doses 1, 2, and 3, respectively. For dose 4, > 90% of participants
had temperatures measured via the axillary route.
The reported rates of some solicited adverse events in
participants from Australia and Mexico varied from those in the United States.5
For example, in Australia, pain after dose 1 was reported in 28.4% of
participants who received MENHIBRIX and 33.3% of control participants, while in
Mexico pain after dose 1 was reported in 73.7% of participants who received MENHIBRIX
and 79.4% of control participants. Fever after dose 1 was reported in 10.4% of participants
who received MENHIBRIX and 10.7% of control participants in Australia, while it
was reported in 44.0% of participants who received MENHIBRIX and 35.7% of
control participants in Mexico. The reported incidences of pain and fever in US
participants after dose 1 are provided in Table 1.
Unsolicited Adverse Events
Among participants who received MENHIBRIX or Hib control
vaccine co-administered with US-licensed vaccines at 2, 4, 6 and 12 to 15
months of age1,3-5, the incidence of unsolicited adverse events
reported within the 31-day period following study vaccination (doses 1, 2, and
3) was comparable between MENHIBRIX (61.9%; 2,578/4,166) and PRP-T (62.5%;
1,042/1,666). The incidence of unsolicited adverse events reported within the
31-day period following dose 4 was also comparable between MENHIBRIX (42.5%;
1,541/3,630) and PRP-OMP (41.4%; 520/1,257).
Serious Adverse Events
Following doses 1, 2, and 31,3-6, 1.8%
(137/7,444) of participants who received MENHIBRIX and 2.1% (59/2,779) of
participants who received PRPT reported at least one serious adverse event
within the 31-day period. Up to 6 months following the last vaccine
administered (doses 1, 2, and 3) or until administration of dose 43-6,
4.8% (365/7,362) of participants who received MENHIBRIX and 5.0% (134/2,697) of
participants in the PRP-T group reported at least one serious adverse event.
Following dose 43-6, 0.5% (35/6,640) of
participants who received MENHIBRIX and 0.5% (12/2,267) of participants who
received PRP-OMP reported at least one serious adverse event within the 31-day
period. Up to 6 months following the last vaccine administered (dose 4), 2.5%
(165/6,640) of participants who received MENHIBRIX and 2.0% (46/2,267) of participants
who received PRP-OMP reported at least one serious adverse event.
The following adverse events have been spontaneously
reported during post-approval use of HIBERIX® (Haemophilus b Conjugate Vaccine
[Tetanus Toxoid Conjugate]) in the United States and other countries. These
events are relevant because the Haemophilus b capsular polysaccharide tetanus
toxoid conjugate is included as a component antigen in both MENHIBRIX and
HIBERIX. Because these events are reported voluntarily from a population of uncertain
size, it is not possible to reliably estimate their frequency or to establish a
causal relationship to vaccine exposure.
The following adverse events were included based on one
or more of the following factors: seriousness, frequency of reporting, or
strength of evidence for a causal relationship to HIBERIX.
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), hypotonichyporesponsive episode, somnolence, syncope or
vasovagal responses to injection.
Respiratory, Thoracic, and Mediastinal Disorders: Apnea.
Skin and Subcutaneous Tissue Disorders: Rash,