Haemophilus-b
It is the same vaccine as haemophilus-b conjugate vaccine, whose details are given below.
HAEMOPHILUS HILUS INFLUENZAE TYPE B CONJUGATE VACCINE
ACTIONS/CLINICAL PHARMACOLOGY:
H Influenzae type b was the leading cause of invasive bacterial disease among
children in the United States prior to licensing of Haemophilus b conjugate
vaccines. Based on its active surveillance areas, the Centers for Disease
Control and Prevention (CDC) now estimate that H Influenzae type b disease in
children under the age of 5 years has been reduced by 95%. (REF. 3) Before
effective vaccines were introduced, it was estimated that one in 200 children
developed invasive H Influenzae type b disease by the age of 5 years. In
children less than 5 years of age, the mortality rate for invasive H Influenzae
type b disease ranged between 3% and 6%. (REF. 3) In more than 60% of these
children, meningitis was the clinical syndrome and permanent sequelae ranging
from mild hearing loss to mental retardation affecting 20% to 30% of all
survivors. (REF. 3) Ninety-five percent of the cases of invasive H Influenzae
disease among children < 5 years of age were caused by organisms with the type b
polysaccharide capsule. Approximately two-thirds of all cases of invasive H
Influenzae type b disease affected infants and children < 15 months of age, a
group for which a vaccine was not available until late 1990. (REF. 4, 5)
Incidence rates of invasive H Influenzae type b disease have been shown to be
increased in certain high-risk groups, such as native Americans (both American
Indians and Eskimos), blacks, individuals of lower socioeconomic status, and
patients with asplenia, sickle cell disease, Hodgkin's disease, and antibody
deficiency syndromes. (REF. 5, 6) Studies also have suggested that the risk of
acquiring primary invasive H Influenzae type b disease for children under 5
years of age appears to be greater for those who attend day-care facilities.
(REF. 7, 8, 9, 10)
The potential for person to person transmission of the organism among
susceptible individuals has been recognized. Studies of secondary spread of
disease in household contacts of index patients have shown a substantially
increased risk among exposed household contacts under 4 years of age. (REF. 11)
Adults can be colonized with H Influenzae type b from children infected with the
organism. (REF. 12)
The response to ActHIB(R) is typical of a T- dependent immune response to
antigen. The prominent isotype of anti-capsular PRP antibody induced by
ActHIB(R) is IgG. (REF. 13) A substantial booster response has been demonstrated
in children 12 months of age or older who previously received two or three
doses. Bactericidal activity against H Influenzae type b is demonstrated in
serum after immunization and statistically correlates with the anti-PRP antibody
response induced by ActHIB(R). (REF. 14)
Antibody to H Influenzae capsular polysaccharide (anti-PRP) titers of > 1.0
mcgm/mL following vaccination with unconjugated PRP vaccine correlated with
long-term protection against invasive H Influenzae type b disease in children
older than 24 months of age. (REF. 15) Although the relevance of this threshold
to clinical protection after immunization with conjugate vaccines is not known,
particularly in light of the induced, immunologic memory, this level continues
to be considered as indicative of long- term protection. (REF. 4) The
immunogenicity and safety of ActHIB(R) has been demonstrated in the United
States and worldwide. ActHIB(R) induced, on average anti-PRP levels >/= 1.0
mcgm/mL in 90% of infants after the primary series and in more than 98% of
infants after a booster dose. (REF. 14)
Two clinical trials supported by the National Institutes of Health (NIH) have
compared the anti-PRP antibody responses to three Haemophilus b conjugate
vaccines in racially mixed populations of children. These studies were done in
Tennessee (REF. 16) (Table 1) and in Minnesota, Missouri and Texas (REF. 17)
(Table 2) in infants immunized with ActHIB(R) and other Haemophilus b conjugate
vaccines at 2, 4 and 6 months of age. All Haemophilus b conjugate vaccines were
administered concomitantly with Poliovirus Vaccine Live Oral and DTP vaccines at
separate sites.
TABLE 1 (REF. 16)
ANTI-PRP ANTIBODY RESPONSES IN
2-MONTH-OLD INFANTS
NIH TRIAL IN TENNESSEE
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
GEOMETRIC MEAN TITER (G
VACCINE N* (MCGM/ML)
POST POST THIRD POST
PRE IMMUNIZATION SECOND IMMUNIZATION IMMUNIZATION THIRD IMMUNIZATION
>%/1.0
MCGM/ML
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
PRP-T#
(ActHIB(R)) 65 0.10 0.30 3.64 83%
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
PRP-OMP@
(PedvaxHIB(R)) 64 0.11 0.84 N/A 50%**
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
HbOC*/*
(HibTITER(R)) 61 0.07 0.13 3.08 75%
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
TABLE 2 (REF. 17)
ANTI-PRP ANTIBODY RESPONSES IN
2-MONTH-OLD INFANTS
NIH TRIAL IN MINNESOTA, MISSOURI AND TEXAS
------------------------------------------------------------------------------------------------------------------------------------------------
GEOMETRIC MEAN TITER (GMT)
VACCINE N* (MCGM/ML)
POST
THIRD$
POST POST IMMUNI-
PRE- SECOND THIRDSEC. ZATION
IMMUNI- IMMUNI- IMMUNI- % >/=1.0
ZATION ZATION ZATION MCGM/ML
----------------------------------------------------------------------------------------------------------------------------------------------------
PRP-T#
(ActHIB(R)) 142 0.25 1.25 6.37 97%
----------------------------------------------------------------------------------------------------------------------------------------------------
PRP-OMP@
(PedvaxHIB(R)) 149 0.18 4.00 N/A 85%**
----------------------------------------------------------------------------------------------------------------------------------------------------
HbOC*/*
(HibTITER(R)) 167 0.17 0.45 6.31 90%
----------------------------------------------------------------------------------------------------------------------------------------------------
* N = Number of Children
$ Sera were obtained after the third dose from 86 and 110 infants, in
PRP-T and HbOC vaccine groups, respectively.
# Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)
@ Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)
** Seroconversion after the recommended 2-dose primary immunization
series is shown.
*/* Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate)
N/A Not applicable in this comparison trial although third dose data have
been published. (REF. 16, 17)
Native American populations have had high rates of H Influenzae type b disease
and have been observed to have low immune responses to Haemophilus b conjugate
vaccines. Following three doses of ActHIB(R) at six weeks, four and six months
of age, 75% of Native Americans in Alaska showed an anti-PRP antibody titer of
>/= 1.0 mcgm/mL. (REF. 18)
Children 12 to 24 months of age who had not previously received Haemophilus b
conjugate vaccination were immunized with a single dose of ActHIB(R). GMT anti-
PRP antibody responses were 5.12 mcgm/mL (90% responding with >/= 1.0 mcgm/mL)
for children 12 to 15 months of age and 4.4 mcgm/mL (82% responding with >/= 1.0
mcgm/mL) for children 17 to 24 months of age. (REF. 18)
These trials demonstrated that ActHIB(R) consistently conferred an anti-PRP
antibody response previously shown to correlate with protection, when
administered either as a regimen of three doses at least four to eight weeks
apart in infants 2 to 6 months of age or as a single dose in children 12 months
of age and older. (REF. 18)
ActHIB(R) has been found to be immunogenic in children with sickle cell anemia,
a condition which may cause increased susceptibility to Haemophilus b disease.
Two doses of ActHIB(R) given at two-month intervals induced anti-PRP antibody
titers of >/= 1.0 mcgm/mL in 89% of these children with a mean age of 11 months.
This is comparable to anti-PRP antibody levels demonstrated in normal children
of similar age following two doses of ActHIB(R). (REF. 19)
ActHIB(R) COMBINED WITH WHOLE-CELL PERTUSSIS VACCINE (DTP) BY RECONSTITUTION FOR
PRIMARY IMMUNIZATION
Comparative clinical trials demonstrated that a similar anti-PRP response was
achieved in infants as young as 2 months old when one dose of CLI whole-cell DTP
vaccine was used to reconstitute lyophilized ActHIB(R) (Table 3). (REF. 14, 18)
TABLE 3 (REF. 18)
ANTI-PRP RESPONSES IN 2-MONTH-OLD INFANTS FOLLOWING IMMUNIZATION WITH
ACTHIB(R) COMBINED WITH CONNAUGHT LABORATORIES, INC. DTP BY RECONSTITUTION
------------------------------------------------------------------------------------------------------------------------------------------------------
GEOMETRIC MEAN TITER (GMT)
STUDY N* (MCGM/ML)
SITE
POST
THIRD
POST POST IMMUNI-
PRE- SECOND THIRD ZATION
IMMUNI- IMMUNI- IMMUNI- % >/=1.0
ZATION ZATION ZATION MCGM/ML
--------------------------------------------------------------------------------------------------------------------------------------------------------
US 45 0.13 0.55 4.49 91
--------------------------------------------------------------------------------------------------------------------------------------------------------
US 135 0.12 0.43 4.46 85
--------------------------------------------------------------------------------------------------------------------------------------------------------
Chile 94 0.09 4.31 6.94 96
--------------------------------------------------------------------------------------------------------------------------------------------------------
* N = Number of Children
Antibody responses to diphtheria, tetanus and pertussis antigens were also
measured in this trial. Post dose three antibody responses to all measured
vaccine antigens were similar, within each study, when infants who received the
combined vaccine were compared to infants who received whole-cell DTP and
ActHIB(R) separately. Interference with the antibody response to the pertussis
component has been suggested with a DTP vaccine unlicensed in the US. (REF. 20)
Percentages of subjects achieving antibody titers over 1 mcgm/mL and GMT to PRP
in 2-month-old infants following immunization with ActHIB(R) combined with CLI
DTP by reconstitution was similar when compared to infants who received DTP and
ActHIB(R) separately (84% versus 85% and 4.3 mcgm/mL versus 4.8 mcgm/mL). (REF.
14, 18)
TriHIBit(TM), ActHIB(R) COMBINED WITH TRIPEDIA(R) VACCINE BY RECONSTITUTION FOR
BOOSTER DOSE
Randomized comparative clinical trials demonstrated that the anti-PRP response
achieved in 15 to 20-month-old children after one dose of TriHIBit(TM),
Tripedia(R) and ActHIB(R) combination vaccine, was similar to that achieved when
the two vaccines were given concomitantly at different sites with separate
needles and syringes (Table 4). (REF. 18) All children had received three doses
of a Haemophilus b conjugate vaccine (HibTITER(R) or ActHIB(R)) and three doses
of a whole-cell DTP vaccine prior to entry into this clinical trial.
TABLE 4 (REF. 18)
ANTI-PRP RESPONSES IN 15 TO 20-MONTH-OLD
CHILDREN FOLLOWING IMMUNIZATION WITH
TRIHIBIT(TM) COMPARED TO ACTHIB(R) AND TRIPEDIA(R)
GIVEN CONCOMITANTLY AT SEPARATE SITES
----------------------------------------------------------------------------------------------------------------------------------------------
IMMUNOGENICITY
----------------------------------------------------------------------------------------------------------------------------------------------
PRE-DOSE POST-DOSE
-----------------------------------------------------------------------------------------------
Separate Separate
TriHIBit(TM) Injections TriHIBit(TM) Injections
-----------------------------------------------------------------------------------------------------------------------------------------------
N* 88 94 93 98
---------------------------------------------------------------------------------------------------------------------------------------------- -
Anti-PRP
(mcgm/mL) 0.89 1.15 90.30 80.90
% >1
mcgm/mL 45.50 53.20 100.00 100.00
--------------------------------------------------------------------------------------------------------------------------------------------
* N = Number of Children
Geometric mean titers in response to diphtheria, tetanus and pertussis (PT and
FHA) were also similar between groups. (REFER TO PRODUCT INSERT FOR
TRIPEDIA(R).) A difference in four-fold antibody response to FHA was noted in
this trial. However, the clinical significance of this difference is not known
at present.
INDICATIONS AND USAGE:
NOTE: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)--ActHIB(R)
is identical to Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)--
OmniHIB(R) (distributed by SmithKline Beecham Pharmaceuticals); and is
manufactured by Pasteur Merieux Serums & Vaccins S.A.
ActHIB(R) or ActHIB(R) combined with CLI DTP vaccine by reconstitution is
indicated for the active immunization of infants and children 2 through 18
months of age for the prevention of invasive disease caused by H Influenzae type
b and/or diphtheria, tetanus and pertussis.
TriHIBit(TM), ActHIB(R) combined with Tripedia(R) by reconstitution, is
indicated for the active immunization of children 15 to 18 months of age for
prevention of invasive disease caused by H Influenzae type b and diphtheria,
tetanus and pertussis.
Antibody levels associated with protection may not be achieved earlier than two
weeks following the last recommended dose.
ONLY CLI WHOLE-CELL DTP, TRIPEDIA(R) OR 0.4% SODIUM CHLORIDE DILUENT MAY BE USED
FOR RECONSTITUTION OF LYOPHILIZED ACTHIB(R). TRIHIBIT(TM), ACTHIB(R) COMBINED
WITH TRIPEDIA(R) BY RECONSTITUTION, SHOULD NOT BE ADMINISTERED TO INFANTS
YOUNGER THAN 15 MONTHS OF AGE.
As With Any Vaccine, Vaccination With ActHIB(R) Reconstituted With CLI DTP Or
ActHIB(R) Reconstituted With Tripedia(R) (TriHIBit(TM)) Or 0.4% Sodium Chloride
Diluent May Not Protect 100% Of Susceptible Individuals.
A single injection containing diphtheria, tetanus, pertussis and Haemophilus b
conjugate antigens may be more acceptable to parents and may increase compliance
with vaccination programs. Therefore, in these situations it may be the judgment
of the physician that it is of benefit to administer a single injection of
whole-cell DTP or DTaP and Haemophilus b conjugate vaccines.
CONTRAINDICATIONS:
ActHIB(R) IS CONTRAINDICATED IN CHILDREN WITH A HISTORY OF HYPERSENSITIVITY TO
ANY COMPONENT OF THE VACCINE AND TO ANY COMPONENT OF DTP OR Tripedia(R) WHEN
COMBINED BY RECONSTITUTION WITH THESE VACCINES. ANY CONTRAINDICATION FOR DTP IS
A CONTRAINDICATION FOR ActHIB(R) RECONSTITUTED WITH DTP. ANY CONTRAINDICATION
FOR Tripedia(R) IS A CONTRAINDICATION FOR TriHIBit(TM), ActHIB(R) RECONSTITUTED
WITH Tripedia(R). (REFER TO PRODUCT INSERTS FOR CLI WHOLE-CELL DTP AND
TRIPEDIA(R).)
WARNINGS:
If ActHIB(R) or ActHIB(R) reconstituted with CLI DTP or ActHIB(R) reconstituted
with Tripedia(R) (TriHIBit(TM)) is administered to immunosuppressed persons or
persons receiving immunosuppressive therapy, the expected antibody responses may
not be obtained. This includes patients with asymptomatic or symptomatic HIV-
infection, (REF. 21) severe combined immunodeficiency, hypogammaglobulinemia, or
agammaglobulinemia; altered immune states due to diseases such as leukemia,
lymphoma, or generalized malignancy; or an immune system compromised by
treatment with corticosteroids, alkylating drugs, antimetabolites or radiation.
(REF. 22) (REFER TO PRODUCT INSERTS FOR CLI WHOLE-CELL DTP AND TRIPEDIA(R).)
TRIHIBIT(TM), ACTHIB(R) COMBINED WITH TRIPEDIA(R) BY RECONSTITUTION, SHOULD NOT
BE ADMINISTERED TO INFANTS YOUNGER THAN 15 MONTHS OF AGE.
PRECAUTIONS:
GENERAL
Care is to be taken by the health-care provider for the safe and effective use
of this vaccine.
EPINEPHRINE INJECTION (1:1000) MUST BE IMMEDIATELY AVAILABLE SHOULD AN
ANAPHYLACTIC OR OTHER ALLERGIC REACTIONS OCCUR DUE TO ANY COMPONENT OF THE
VACCINE.
Prior to an injection of any vaccine, all known precautions should be taken to
prevent adverse reactions. This includes a review of the patient's history with
respect to possible sensitivity and any previous adverse reactions to the
vaccine or similar vaccines, previous immunization history, current health
status (see CONTRAINDICATIONS; WARNINGS sections), and a current knowledge of
the literature concerning the use of the vaccine under consideration. (REFER TO
PRODUCT INSERTS FOR CLI WHOLE-CELL DTP AND TRIPEDIA(R).)
The health-care provider should ask the parent or guardian about the recent
health status of the infant or child to be immunized including the infant's or
child's previous immunization history prior to administration of ActHIB(R), CLI
DTP and Tripedia(R).
Minor illnesses such as upper respiratory infection with or without low-grade
fever are not contraindications for use of ActHIB(R). (REF. 23)
As reported with Haemophilus b polysaccharide vaccines, (REF. 24) cases of H
Influenzae type b disease may occur subsequent to vaccination and prior to the
onset of protective effects of the vaccine. (REF. 18) (See INDICATIONS AND USAGE
section.)
The evidence favors rejection of a causal relation between immunization with Hib
conjugate vaccines and early-onset Hib disease. (REF. 25)
Antigenuria has been detected in some instances following receipt of ActHIB(R);
therefore, urine antigen detection may not have definitive diagnostic value in
suspected H Influenzae type b disease within one week of immunization. (REF. 26)
Special care should be taken to ensure that ActHIB(R) reconstituted with CLI DTP
or Tripedia(R) or saline diluent (0.4% Sodium Chloride) is not injected into a
blood vessel.
Administration of ActHIB(R) reconstituted with CLI DTP or ActHIB(R)
reconstituted with Tripedia(R) (TriHIBit(TM)) or saline diluent (0.4% Sodium
Chloride) is not contraindicated in individuals with HIV infection. (REF. 22)
A separate, sterile syringe and needle or a sterile disposable unit should be
used for each patient to prevent transmission of hepatitis or other infectious
agents from person to person. Needles should not be recapped and should be
properly disposed.
INFORMATION FOR PATIENT
The health-care provider should inform the parent or guardian of the benefits
and risks of the vaccine.
Prior to administration of ActHIB(R) reconstituted with CLI DTP or ActHIB(R)
reconstituted with Tripedia(R) (TriHIBit(TM)) or saline diluent (0.4% Sodium
Chloride), the parent or guardian should be asked about the recent health status
of the infant or child to be immunized.
The physician should inform the parent or guardian about the significant adverse
reactions that have been temporally associated with the administration of
ActHIB(R) reconstituted with saline or DTP, or ActHIB(R) reconstituted with
Tripedia(R) (TriHIBit(TM)). The parent or guardian should be instructed to
report any serious adverse reactions to their health-care provider.
As part of the child's immunization record, the date, lot number and
manufacturer of the vaccine administered should be recorded. (REF. 27, 28, 29)
The US Department of Health and Human Services has established a new Vaccine
Adverse Event Reporting System (VAERS) to accept all reports of suspected
adverse events after the administration of any vaccine, including but not
limited to the reporting of events required by the National Childhood Vaccine
Injury Act of 1986. (REF. 27) The toll-free number for VAERS forms and
information is 1-800-822-7967.
The National Vaccine Injury Compensation Program, established by the National
Childhood Vaccine Injury Act of 1986, requires physicians and other health-care
providers who administer vaccines to maintain permanent vaccination records and
to report occurrences of certain adverse events to the US Department of Health
and Human Services. Reportable events include those listed in the Act for each
vaccine and events specified in the package insert as contraindications to
further doses of the vaccine. (REF. 28, 29)
The health-care provider should inform the parent or guardian of the importance
of completing the immunization series.
The health-care provider should provide the Vaccine Information Materials (VIMs)
which are required to be given with each immunization.
DRUG INTERACTIONS
When CLI DTP is used to reconstitute ActHIB(R) or Tripedia(R) is used to
reconstitute ActHIB(R) (TriHIBit(TM)) and administered to immunosuppressed
persons or persons receiving immunosuppressive therapy, the expected antibody
response may not be obtained.
Immunosuppressive therapies, including irradiation, antimetabolites, alkylating
agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic
doses), may reduce the immune response to vaccines. Short-term (<2 weeks)
corticosteroid therapy or intra-articular, bursal, or tendon injections with
corticosteroids should not be immunosuppressive. Although no specific studies
with pertussis vaccine are available, if immunosuppressive therapy will be
discontinued shortly, it is reasonable to defer vaccination until the patient
has been off therapy for one month; otherwise, the patient should be vaccinated
while still on therapy. (REF. 23)
If ActHIB(R) reconstituted with CLI DTP or ActHIB(R) reconstituted with
Tripedia(R) (TriHIBit(TM)) has been administered to persons receiving
immunosuppressive therapy, a recent injection of immunoglobulin or having an
immunodeficiency disorder, an adequate immunologic response may not be obtained.
In clinical trials, ActHIB(R) was administered, at separate sites, concomitantly
with one or more of the following vaccines: DTP, DTaP, Poliovirus Vaccine Live
Oral (OPV), Measles, Mumps and Rubella vaccine (MMR), Hepatitis B vaccine and
occasionally Inactivated Poliovirus Vaccine (IPV). No impairment of the antibody
response to the individual antigens, diphtheria, tetanus and pertussis, was
demonstrated when ActHIB(R) was given at the same time, at separate sites, with
IPV or MMR. (REF. 18) In addition, more than 47,000 infants in Finland have
received a third dose of ActHIB(R) concomitantly with MMR vaccine with no
increase in serious or unexpected adverse events. (REF. 18)
No significant impairment of antibody response to Measles, Mumps and Rubella was
noted in 15- 20-month-old children who received TriHIBit(TM), ActHIB(R)
reconstituted with Tripedia(R), concomitantly with MMR. No data are available to
the manufacturer concerning the effects on immune response of OPV, IPV or
Hepatitis B vaccine when given concurrently with ActHIB(R) reconstituted with
0.4% Sodium Chloride or CLI DTP or ActHIB(R) reconstituted with Tripedia(R)
(TriHIBit(TM)). (REF. 18)
As with other intramuscular injections, use with caution in patients on
anticoagulant therapy.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
ActHIB(R) reconstituted with CLI DTP or ActHIB(R) reconstituted with Tripedia(R)
(TriHIBit(TM)) has not been evaluated for its carcinogenic, mutagenic potential
or impairment of fertility.
PREGNANCY
REPRODUCTIVE STUDIES - PREGNANCY CATEGORY C
Animal reproduction studies have not been conducted with ActHIB(R) reconstituted
with CLI DTP or ActHIB(R) reconstituted with Tripedia(R) (TriHIBit(TM)) or
saline diluent (0.4% Sodium Chloride). It is also not known whether ActHIB(R)
reconstituted with CLI DTP or ActHIB(R) reconstituted with Tripedia(R)
(TriHIBit(TM)) or saline diluent (0.4% Sodium Chloride) can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity.
ActHIB(R) reconstituted with CLI DTP or ActHIB(R) reconstituted with Tripedia(R)
(TriHIBit(TM)) or saline diluent (0.4% Sodium Chloride) is NOT recommended for
use in a pregnant woman and is not approved for use in children 5 years of age
or older.
PEDIATRIC USE
SAFETY AND EFFECTIVENESS OF TriHIBit(TM), ActHIB(R) RECONSTITUTED WITH
Tripedia(R), IN INFANTS BELOW THE AGE OF 15 MONTHS HAVE NOT BEEN ESTABLISHED.
(See DOSAGE AND ADMINISTRATION section.)
SAFETY AND EFFECTIVENESS OF ActHIB(R) RECONSTITUTED WITH CLI DTP OR SALINE
DILUENT (0.4% SODIUM CHLORIDE) IN INFANTS BELOW THE AGE OF SIX WEEKS HAVE NOT
BEEN ESTABLISHED. (See DOSAGE AND ADMINISTRATION section.)
DRUG INTERACTIONS:
When CLI DTP is used to reconstitute ActHIB(R) or Tripedia(R) is used to
reconstitute ActHIB(R) (TriHIBit(TM)) and administered to immunosuppressed
persons or persons receiving immunosuppressive therapy, the expected antibody
response may not be obtained.
Immunosuppressive therapies, including irradiation, antimetabolites, alkylating
agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic
doses), may reduce the immune response to vaccines. Short-term (<2 weeks)
corticosteroid therapy or intra-articular, bursal, or tendon injections with
corticosteroids should not be immunosuppressive. Although no specific studies
with pertussis vaccine are available, if immunosuppressive therapy will be
discontinued shortly, it is reasonable to defer vaccination until the patient
has been off therapy for one month; otherwise, the patient should be vaccinated
while still on therapy. (REF. 23)
If ActHIB(R) reconstituted with CLI DTP or ActHIB(R) reconstituted with
Tripedia(R) (TriHIBit(TM)) has been administered to persons receiving
immunosuppressive therapy, a recent injection of immunoglobulin or having an
immunodeficiency disorder, an adequate immunologic response may not be obtained.
In clinical trials, ActHIB(R) was administered, at separate sites, concomitantly
with one or more of the following vaccines: DTP, DTaP, Poliovirus Vaccine Live
Oral (OPV), Measles, Mumps and Rubella vaccine (MMR), Hepatitis B vaccine and
occasionally Inactivated Poliovirus Vaccine (IPV). No impairment of the antibody
response to the individual antigens, diphtheria, tetanus and pertussis, was
demonstrated when ActHIB(R) was given at the same time, at separate sites, with
IPV or MMR. (REF. 18) In addition, more than 47,000 infants in Finland have
received a third dose of ActHIB(R) concomitantly with MMR vaccine with no
increase in serious or unexpected adverse events. (REF. 18)
No significant impairment of antibody response to Measles, Mumps and Rubella was
noted in 15- 20-month-old children who received TriHIBit(TM), ActHIB(R)
reconstituted with Tripedia(R), concomitantly with MMR. No data are available to
the manufacturer concerning the effects on immune response of OPV, IPV or
Hepatitis B vaccine when given concurrently with ActHIB(R) reconstituted with
0.4% Sodium Chloride or CLI DTP or ActHIB(R) reconstituted with Tripedia(R)
(TriHIBit(TM)). (REF. 18)
As with other intramuscular injections, use with caution in patients on
anticoagulant therapy.
(See also PRECAUTIONS section).
ADVERSE REACTIONS:
NOTE: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) - ActHIB(R) is
identical to Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)-
OmniHIB(R) (distributed by SmithKline Beecham Pharmaceuticals); and is
manufactured by Pasteur Merieux Serums & Vaccins S.A.
More than 7,000 infants and young children (= 2 years of age) have received at
least one dose of ActHIB(R) during US clinical trials. Of these, 1,064 subjects
12 to 24 months of age who received ActHIB(R) alone reported no serious or life
threatening adverse reactions.
Adverse reactions commonly associated with a first ActHIB(R) immunization of
children 12 to 15 months of age who were previously unimmunized with any
Haemophilus b conjugate vaccine, include local pain, redness and swelling at the
injection site. Systemic reactions include fever, irritability and lethargy.
(REF. 14, 18)
In a multicenter trial, ActHIB(R) was administered to US infants at 2, 4, and 6
months of age concomitantly, at separate sites, with CLI DTP. The adverse events
observed are summarized in Table 5.
TABLE 5 (REF. 14)
PERCENTAGE OF INFANTS PRESENTING WITH LOCAL OR SYSTEMIC REACTIONS AT 6, 24,
AND 48 HOURS
OF IMMUNIZATION WITH ACTHIB(TM) ADMINISTERED SIMULTANEOUSLY,
AT SEPARATE SITES, WITH CLI DTP VACCINE
------------------------------------------------------------------------------------------------------------------------------------------------------------------
AGE AT IMMUNIZATION
---------------------------------------------------------------------------------------------------------------------------------------------
REACTION 2 Months 4 Months 6 Months
(n=365) (n=364) (n=365)
6 Hrs. 24 48 Hrs. 6 Hrs. 24 48 Hrs 6 24 Hrs. 48
Hrs. Hrs. Hrs. Hrs.
--------------------------------------------------------------------------------------------------------------------------------------------------------------------
LOCAL$
Tenderness 46.3% 11.5% 2.2% 23.4% 7.4% 1.1% 19.2% 6.0% 1.1%
Erythema 14.3% 4.1% 0.3% 8.8% 5.8% 0.6% 11.5% 6.9% 1.6%
Induration 22.5% 6.3% 1.9% 12.4% 4.7% 0.8% 9.6% 3.8% 1.1%
---------------------------------------------------------------------------------------------------------------------------------------------------------------------
SYSTEMIC*
Fever >100.8 deg 20.1% 1.3% 0.6% 14.6% 6.6% 1.4% 15.7% 8.8% 0.8%
F#
Irritability 72.6% 21.9% 12.6% 48.4% 25.0% 13.2% 44.1% 25.2% 10.1%
Drowsiness 57.5% 29.9% 10.4% 44.2% 18.1% 7.4% 32.6% 13.4% 2.5%
Anorexia 15.3% 5.8% 4.9% 8.0% 5.0% 3.0% 5.5% 4.9% 2.2%
Diarrhea 4.4% 6.6% 5.2% 5.0% 4.7% 4.7% 4.7% 6.3% 3.6%
Vomiting 2.7% 4.1% 2.7% 2.5% 3.3% 2.8% 2.2% 2.7% 1.9%
-------------------------------------------------------------------------------------------------------------------------------------------------
Persistent Crying Percentage of infants within 72 hours after immunization
was 1.6% after dose one, 0.6% after dose two, and 0.3%
after dose three.
----------------------------------------------------------------------------
$ Local reactions were evaluated at the ActHIB(R) injection site.
* The adverse reaction profile is defined by the concomitant use of CLI DTP
vaccine.
# The number of individuals observed at each time point for fever varied from
357 to 363.
----------------------------------------------------------------------------
In general, the rates of minor systemic reactions after ActHIB(R) and DTP
immunization were comparable to those usually reported after DTP vaccine alone.
(REF. 30, 31, 32, 33)
When ActHIB(R) reconstituted with CLI whole-cell DTP was administered in infants
at 2, 4, and 6 months of age, the systemic adverse experience profile (Table 6)
was comparable to that observed when the two vaccines were given separately
(Table 5). An increase in the rates of local reactions was observed within the
24-hour period after immunization. (REF. 18)
TABLE 6 (REF. 18)
PERCENTAGE OF INFANTS PRESENTING WITH LOCAL OR SYSTEMIC REACTIONS AT 6, 24,
AND 48 HOURS
OF IMMUNIZATION WITH ACTHIB(TM) COMBINED WITH CLI DTP VACCINE BY
RECONSTITUTION
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AGE AT IMMUNIZATION
----------------------------------------------------------------------------------------------------------------------------------------------------------------
REACTION 2 Months 4 Months 6 Months
(n=204) (n=199) (n=200)
6 Hrs. 24 48 Hrs 6 Hrs. 24 48 Hrs 6 24 Hrs 48
Hrs. Hrs. Hrs. Hrs.
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
LOCAL
Tenderness 47.1% 18.6% 3.4% 33.2% 17.6% 4.0% 25.0% 17.0% 3.5%
Erythema >1" 11.8% 2.5% 0.0% 11.6% 9.1% 2.5% 10.5% 13.5% 3.5%
Induration 31.4% 17.2% 3.9% 26.1% 20.1% 7.5% 28.5% 22.5% 10.0%
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
SYSTEMIC
Fever >100.4 deg F 24.6% 2.0% 0.5% 15.8% 6.1% 3.6% 13.0% 10.3% 3.1%
Irritability 70.6% 22.1% 12.8% 56.8% 31.2% 19.1% 40.5% 28.2% 15.9%
Drowsiness 60.3% 23.5% 11.3% 42.2% 20.6% 9.6% 30.3% 12.3% 5.6%
Anorexia 17.7% 6.4% 2.9% 10.1% 7.5% 5.5% 5.1% 4.6% 4.1%
Diarrhea 2.5% 5.4% 1.5% 3.5% 3.5% 2.5% 2.6% 4.1% 5.6%
Vomiting 2.9% 5.4% 2.9% 3.0% 5.0% 3.0% 3.6% 3.6% 1.5%
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
Persistent Crying Percentage of infants within 72 hours after immunization
was 0.0% after dose one, 0.0% after dose two, and 0.005%
after dose three.
----------------------------------------------------------------------------
In a third US trial when ActHIB(R) was combined with DTP by reconstitution,
approximately 1,450 doses were administered to infants starting at 2 months of
age. Adverse reactions observed at 6 and 24 hours respectively after the first
immunization (n = 498) were tenderness 66.9% and 30.7%; erythema (>1") 8.6% and
2.2%; induration 38.2% and 21.7%; irritability 77.9% and 35.7%; drowsiness 63.7%
and 34.1%; anorexia 26.1% and 12.9%; diarrhea 6.8% and 9.0%; and vomiting 3.4%
and 3.8%. (REF. 18) One hypotonic/hyporesponsive episode (HHE) was seen in an
infant following the second dose in this trial. This is consistent with the HHE
incidence rate observed with DTP vaccination alone. (REF. 4)
Adverse reactions associated with ActHIB(R) generally subsided after 24 hours
and usually do not persist beyond 48 hours after immunization.
No data are available on the safety of a booster dose of ActHIB(R) combined with
CLI DTP vaccine by reconstitution given in 15 to 20-month-old children.
In a US trial, safety of TriHIBit(TM), ActHIB(R) combined with Tripedia(R) by
reconstitution, in 110 children aged 15 to 20 months was compared to ActHIB(R)
given with Tripedia(R) at separate sites to 110 children. All children received
three doses of Haemophilus b conjugate vaccine (ActHIB(R) or HibTITER(R)) and
three doses of whole-cell DTP at approximately 2, 4 and 6 months of age.
TABLE 7 (REF. 18)
PERCENTAGE OF 15 TO 20-MONTH-OLD CHILDREN PRESENTING WITH LOCAL OR SYSTEMIC
REACTIONS
AT 6, 24 AND 48 HOURS OF IMMUNIZATION WITH TRIHIBIT(TM) COMPARED TO
ACTHIB(TM) AND TRIPEDIA(R)
GIVEN CONCOMITANTLY AT SEPARATE SITES
----------------------------------------------------------------------------
6 HRS. POST-DOSE 24 HRS. POST-DOSE 48 HRS. POST-DOSE
REACTION Separate Separate Separate
Injections* TriHI Injec- TriHI- Injec- TriHIBit(TM)
Bit(TM) tions* Bit(TM) tions*
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
LOCAL n=110 n=110 n=110 n=110 n=110 n=110
Tenderness 17.3/20.0 19.1 8.2/8.2 10.0 1.8/0.9 1.8
Erythema >1" 0.9/0.0 3.6 2.7/0.9 3.6 0.9/0.0 1.8
Induration** 3.6/5.5 2.7 2.7/3.6 8.2 4.5/0.9 3.6
Swelling 3.6/3.6 3.6 2.7/1.8 5.5 0.9/0.0 4.5
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
SYSTEMIC n=103-110 n=102- 109 n=105-110 n=103-108 n=104-110 n=103-109
Fever >102.2 deg F 0 2.0 1.0 1.9 1.9 0
Irritability 27.3 22.9 20.9 17.6 12.7 10.1
Drowsiness 36.4 30.3 17.3 13.9 12.7 11.0
Anorexia 12.7 9.2 10.0 6.5 6.4 2.8
Vomiting 0.9 1.8 0.9 1.9 0.9 2.8
Persistent Cry 0 0 0 0 0 0
Unusual Cry 0 0 0 0 0 0.9
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* Tripedia(R) injection site/ActHIB(R) injection site.
** Induration is defined as hardness with or without swelling.
----------------------------------------------------------------------------
TriHIBit(TM), ActHIB(R) combined with Tripedia(R) by reconstitution, was
administered to approximately 850 children, aged 15 to 20 months. All children
received three doses of a Haemophilus b conjugate vaccine (ActHIB(R) or
HibTITER(R)) and three doses of whole-cell DTP at approximately 2, 4, and 6
months of age. Local reactions were typically mild and usually resolved within
the 24 to 48 hour period after immunization. The most common local reactions
were pain and tenderness at the injection site. Systemic reactions occurring
were usually mild and resolved within 72 hours of immunization. The reaction
rates were similar to those observed in Table 7 when TriHIBit(TM), ActHIB(R)
reconstituted with Tripedia(R) was administered and when Tripedia(R) was
administered alone as a booster. (REF. 18)
In a randomized, double-blind US clinical trial, ActHIB(R) was given
concomitantly with DTP to more than 5,000 infants and hepatitis B vaccine was
given with DTP to a similar number. In this large study, deaths due to sudden
infant death syndrome (SIDS) and other causes were observed but were not
different in the two groups. In the first 48 hours following immunization, two
definite and three possible seizures were observed after ActHIB(R) and DTP in
comparison with none after hepatitis B vaccine and DTP. (REF. 18) This rate of
seizures following ActHIB(R) and DTP was not greater than previously reported in
infants receiving DTP alone. (REFER TO PRODUCT INSERT FOR CLI DTP.) Other
adverse reactions reported with administration of other Haemophilus b conjugate
vaccines include urticaria, seizures, hives, renal failure and Guillain-Barre
syndrome (GBS). (REF. 18, 34) A cause and effect relationship among any of these
events and the vaccination has not been established.
When ActHIB(R) was given with DTP and inactivated poliovirus vaccine to more
than 100,000 Finnish infants, the rate and extent of serious adverse reactions
were not different from those seen when other Haemophilus b conjugate vaccines
were evaluated in Finland (i.e. HibTITER(R), ProHIBiT(R)). (REF. 18)
However, the number of subjects studied with TriHIBit(TM), ActHIB(R) combined
with Tripedia(R) by reconstitution, was inadequate to detect rare serious
adverse events.
REPORTING OF ADVERSE EVENTS
Reporting by the parent or guardian of all adverse events occurring after
vaccine administration should be encouraged. Adverse events following
immunization with vaccine should be reported by the health-care provider to the
US Department of Health and Human Services (DHHS) Vaccine Adverse Event
Reporting System (VAERS). Reporting forms and information about reporting
requirements or completion of the form can be obtained from VAERS through a
toll-free number 1-800-822-7967. (REF. 26, 27, 28)
HEALTH-CARE PROVIDERS ALSO SHOULD REPORT THESE EVENTS TO THE DIRECTOR OF MEDICAL
AFFAIRS, CONNAUGHT LABORATORIES, INC., ROUTE 611, PO BOX 187, SWIFTWATER, PA
18370 OR CALL 1-800-822-2463.
DOSAGE AND ADMINISTRATION:
NOTE: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) - ActHIB(R) is
identical to Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) -
OmniHIB(R) (distributed by SmithKline Beecham Pharmaceuticals); and is
manufactured by Pasteur Merieux Serums & Vaccins S.A.
BEFORE THE AGE OF 6 MTHS - .5 ML AT 6,10,14 WEEKS FOLLOWED BY A BOOSTER AFTER 12 MTHS OF LAST INJECTION.
FOR CHILDREN NOT VACCINATED BEFORE 6 MTHS OF AGE - 2 DOSE AND BOOSTER AFTER 12 MTHS OF LAST INJECTION.
FOR CHILDREN NOT VACCINATED BEFORE 1 YR. OF AGE - 1 DOSE ONLY
IF HIB VACCINE NOT INITIATED BEFORE THE AGE OF 6 MTHS & CHILD HAS RECIEVED DPT & HEPATITIS-B SEPARATELY THEN AT 7 - 11 MTHS HIB PRO 2 DOSES , AT 2 MTHS APART. BOOSTER OF HIB PRO + DPT AT 18 MTHS.
OR
AT 12 - 14 MTHS ONE DOSE OF HIBPRO & BOOSTER 2 MTHS LATER
OR
AT 15 - 59 MTHS ONLY ONE DOSE OF HOBPRO , NO BOOSTER DOSE IS REQUIRED.
Parenteral drug products should be inspected visually for particulate matter
and/or discoloration prior to administration, whenever solution and container
permit. If these conditions exist, the vaccine should not be administered.
RECONSTITUTION:
Using Connaught Laboratories, Inc. DTP, cleanse both the DTP and ActHIB(R) vial
rubber stoppers with a suitable germicide prior to reconstitution. Thoroughly
agitate the vial of CLI DTP then withdraw a 0.6 mL dose and inject into the vial
of lyophilized ActHIB(R). After reconstitution and thorough agitation, the
combined vaccines will appear whitish in color. Withdraw and administer 0.5 mL
dose of the combined vaccines intramuscularly. Vaccine should be used within 24
hours after reconstitution. Refer to Figures 1, 2, 3, 4, and 5.
To prepare TriHIBit(TM), cleanse both the Tripedia(R) and ActHIB(R) vial rubber
stoppers with a suitable germicide prior to reconstitution. Thoroughly agitate
the vial of CLI Tripedia(R) then withdraw a 0.6 mL dose and inject into the vial
of lyophilized ActHIB(R). After reconstitution and thorough agitation, the
combined vaccines will appear whitish in color. Withdraw and administer 0.5 mL
dose of the combined vaccines intramuscularly. Vaccine should be used
immediately (WITHIN 30 MINUTES) after reconstitution. Refer to Figures 1, 2, 3,
4, and 5.
Using saline diluent (0.4% Sodium Chloride) cleanse the vaccine vial rubber
stopper with a suitable germicide and inject the entire volume of diluent
contained in the vial or syringe into the vial of lyophilized vaccine. Thorough
agitation is advised to ensure complete reconstitution. The entire volume of
reconstituted vaccine is then drawn back into the syringe before injecting one
0.5 mL dose intramuscularly. The vaccine will appear clear and colorless.
Vaccine should be used within 24 hours after reconstitution. Refer to Figures 1,
2, 3, 4, and 5.
INSTRUCTIONS FOR RECONSTITUTION OF ActHIB(R) WITH CLI DTP OR RECONSTITUTION OF
ActHIB(R) WITH TRIPEDIA(R) (TriHIBit(TM)) OR SALINE DILUENT (0.4% SODIUM
CHLORIDE):
FIGURE 1. Cleanse stopper and agitate the vial of DTP, Tripedia(R), or 0.4%
Sodium Chloride used to reconstitute ActHIB(R).
FIGURE 2. Withdraw volume of DTP, Tripedia(R), or 0.4% Sodium Chloride as
indicated.
FIGURE 3. Cleanse the ActHIB(R) stopper, insert syringe needle through the
rubber stopper and inject volume as directed.
FIGURE 4. Agitate vial thoroughly.
FIGURE 5. After reconstitution with either DTP, or reconstitution with
Tripedia(R) (TriHIBit(TM)) or with 0.4% Sodium Chloride withdraw 0.5 mL, of
reconstituted vaccine and administer INTRAMUSCULARLY.
Before injection, the skin over the site to be injected should be cleansed with
a suitable germicide. After insertion of the needle, aspirate to ensure that the
needle has not entered a blood vessel.
DO NOT INJECT INTRAVENOUSLY.
Each dose of ActHIB(R) reconstituted with CLI DTP or ActHIB(R) reconstituted
with Tripedia(R) (TriHIBit(TM) or saline diluent (0.4% Sodium Chloride) is
administered intramuscularly in the outer aspect of the vastus lateralis (mid-
thigh) or deltoid. The vaccine should not be injected into the gluteal area or
areas where there may be a nerve trunk. During the course of primary
immunizations, injections should not be made more than once at the same site.
When ActHIB(R) is reconstituted with CLI DTP, the combined vaccines are
indicated for infants and children 2 through 18 months of age for intramuscular
administration in accordance with the schedule indicated in Table 8. (REF. 14)
When ActHIB(R) is reconstituted with Tripedia(R) (TriHIBit(TM)), the combined
vaccines are indicated for children 15 to 18 months of age for intramuscular
administration in accordance with the schedule in Table 8. (REF. 14)
TABLE 8 (REF. 14)
RECOMMENDED IMMUNIZATION SCHEDULE
FOR ACTHIB(R) AND DTP OR TRIPEDIA(R)
For Previously Unvaccinated Children
--------------------------------------------------------------------------------------------------------------------------------------
DOSE AGE IMMUNIZATION
--------------------------------------------------------------------------------------------------------------------------------------
First, Second At 2, 4 and ActHIB(R) reconstituted
and Third 6 months with DTP or with
saline diluent
(0.4% Sodium Chloride)
-------------------------------------------------------------------------------------------------------------------------------------
Fourth At 15 to ActHIB(R) reconstituted
18 months with DTP or with
Tripedia(R) (TriHIBit(TM))
or with saline diluent
(0.4% Sodium Chloride)
------------------------------------------------------------------------------------------------------------------------------------
Fifth At 4 to DTP or Tripedia(R)
6 years
-----------------------------------------------------------------------------------------------------------------------------------
FOR PREVIOUSLY UNVACCINATED CHILDREN
The number of doses of Haemophilus b Conjugate Vaccine indicated depends on the
age at which immunization is begun. A child 7 to 11 months of age should receive
2 doses of Haemophilus b Conjugate Vaccine at 8-week intervals and a booster
dose at 15 to 18 months of age. A child 12 to 14 months of age should receive 1
dose of Haemophilus b Conjugate Vaccine followed by a booster 2 months later.
Preterm infants should be vaccinated according to their chronological age from
birth. (REF. 35)
Interruption of the recommended schedule with a delay between doses should not
interfere with the final immunity achieved with ActHIB(R) reconstituted with CLI
DTP or ActHIB(R) reconstituted with Tripedia(R) (TriHIBit(TM)) or saline diluent
(0.4% Sodium Chloride). There is no need to start the series over again,
regardless of the time elapsed between doses.
It is acceptable to administer a booster dose of TriHIBit(TM), ActHIB(R)
reconstituted with Tripedia(R), following a primary series of Haemophilus b
conjugate and whole-cell DTP vaccines, or a primary series of a combination
vaccine containing whole-cell DTP.
REFERENCES:
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Influenzae type b and pneumococcal type 6A polysaccharide-protein conjugate.
Infect Immun 40: 245-246, 1983
2. Mueller JH, et al. Production of diphtheria toxin of high potency (100 Lf)
on a reproducible medium. J Immunol 40: 21-32, 1941
3. Adams WG, et al. Decline of Childhood Haemophilus Influenzae Type b (Hib)
Disease in the Hib Vaccine Era. JAMA 269: 221-226, 1993
4. Recommendations of the Immunization Practices Advisory Committee (ACIP).
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7. Istre GR, et al. Risk factors for primary invasive Haemophilus Influenzae
disease: Increased risk from day care attendance and school-aged household
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8. Redmond SR, et al. Haemophilus Influenzae type b disease. An epidemiologic
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9. Murphy TV, et al. County-wide surveillance of invasive Haemophilus
infections: Risk of associated cases in Child Care Programs (CCPs). Twenty-third
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10. Fleming D, et al. Haemophilus Influenzae b (Hib) disease - secondary spread
in day care. Twenty-fourth Interscience Conference on Antimicrobial Agents
and Chemotherapy (Abstract #967) 261, 1984
11. CDC. Prevention of secondary cases of Haemophilus Influenzae type b disease.
MMWR 31: 672-680, 1982
12. Michaels RH, et al. Pharyngeal colonization with Haemophilus Influenzae type
b: A longitudinal study of families with a child with meningitis or
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1991
14. Data on file, Pasteur Merieux Serums & Vaccins S.A.
15. Peltola H, et al. Prevention of Haemophilus Influenzae type b bacteremic
infections with the capsular polysaccharide vaccine. N Engl J Med 310: 1561-
1566, 1984
16. Decker MD, et al. Comparative trial in infants of four conjugate
Haemophilus Influenzae type b vaccines. J Pediatr 120: 184-189, 1992
17. Granoff DM, et al. Differences in the immunogenicity of three Haemophilus
Influenzae type b conjugate vaccines in infants. J Pediatr 121: 187-194, 1992
18. Data on file, Connaught Laboratories, Inc.
19. Kaplan SL, et al. Immunogenicity of Haemophilus Influenzae type b
polysaccharide- tetanus protein conjugate vaccine in children with sickle
hemoglobinopathy or malignancies, and after systemic Haemophilus Influenzae
type b infection. J Pediatr 120: 367-370, 1992
20. Clemens JD, et al. Impact of Haemophilus Influenzae Type b
Polysaccharide-Tetanus Protein Conjugate Vaccine on responses to concurrently
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22. ACIP. General recommendations on immunization. MMWR 38: 205-227, 1989
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24. FDA Workshop on Haemophilus b Polysaccharide Vaccine - A Preliminary Report.
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25. IOM. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on
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CJ, Johnston Jr. RB, eds. 1993. National Academy Press. Washington DC, pp. 236-
273, 1993
26. Rothstein EP, et al. Comparison of antigenuria after immunization with three
Haemophilus Influenzae type b conjugate vaccines. Pediatr Infect Dis J 10:
311-314, 1991
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28. CDC. National Childhood Vaccine Injury Act: Requirements for permanent
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29. National Childhood Vaccine Injury Act of 1986 (Amended 1987)
30. Cody CL, et al. Nature and rates of adverse reactions associated with DTP
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31. Barkin RM, et al. Diphtheria-tetanus- pertussis vaccine: reactogenicity of
commercial products. Pediatr 63: 256-260, 1979
32. Baraff LJ, et al. DTP-associated reactions: an analysis by injection site,
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34. D'Cruz OF, et al. Acute inflammatory demyelinating polyradiculoneuropathy
(Guillain-Barre Syndrome) after immunization with Haemophilus Influenzae type
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