ActHIB: Package Insert and Label Information (Page 2 of 3)

6.2 Postmarketing Experience

The following events have been spontaneously reported during the post-approval use of ActHIB vaccine. Because these events 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 vaccine exposure.

  • Immune system disorders:
    Anaphylaxis, other allergic/hypersensitivity reactions (including urticaria, angioedema)
  • Nervous system disorders:
    Convulsions
  • General disorders and administration site conditions: Extensive limb swelling, peripheral edema, pruritus, rash (including generalized rash)

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

In clinical trials, ActHIB vaccine was administered, at separate sites, concomitantly with one or more of the following vaccines: DTaP; Measles, Mumps and Rubella vaccine (MMR); Hepatitis B vaccine; and Inactivated Poliovirus Vaccine (IPV). No impairment of the antibody response to the individual antigens was demonstrated when ActHIB vaccine was given at the same time but separate sites with these vaccines. (2)

7.2 Immunosuppressive Treatments

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses) may reduce the immune response to ActHIB vaccine [see Altered Immunocompetence (5.3)].

7.3 Interference with Laboratory Tests

Haemophilus b capsular polysaccharide derived from Haemophilus b Conjugate Vaccines has been detected in the urine of some vaccinees. Urine antigen detection may not have a diagnostic value in suspected disease due to H. influenzae type b within 1 to 2 weeks after receipt of a H. influenzae type b-containing vaccine, including ActHIB [see Warnings and Precautions (5.6)].(3)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

ActHIB is not approved for use in individuals 6 years of age and older. No human or animal data are available to assess vaccine-associated risks in pregnancy.

8.2 Lactation

ActHIB is not approved for use in individuals 6 years of age and older. Human or animal data are not available to assess the impact of ActHIB on milk production, its presence in breast milk, or its effects on the breastfed infant.

8.4 Pediatric Use

Safety and effectiveness of ActHIB have not been established in infants below the age of 6 weeks and children and adolescents 6 years of age and older [see Dosage and Administration (2.1)].

11 DESCRIPTION

ActHIB vaccine is a sterile, lyophilized powder to be reconstituted with saline diluent (0.4% Sodium Chloride) for intramuscular administration only. The vaccine consists of the Haemophilus influenzae type b capsular polysaccharide (polyribosyl-ribitol-phosphate, PRP), a high-molecular-weight polymer prepared from the H. influenzae type b strain 1482 grown in a semi-synthetic medium, covalently bound to tetanus toxoid. (4) The lyophilized ActHIB vaccine powder and saline diluent contain no preservative. The tetanus toxoid is prepared by extraction, ammonium sulfate purification, and formalin inactivation of the toxin from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium. (5) The culture medium contains milk-derived raw materials (casein derivatives). Further manufacturing process steps reduce residual formaldehyde to levels below 0.5 micrograms (mcg) per dose by calculation. The toxoid is filter sterilized prior to the conjugation process. Potency of ActHIB vaccine is specified on each lot by limits on the content of PRP polysaccharide and protein in each dose and the proportion of polysaccharide and protein in the vaccine that is characterized as high molecular weight conjugate.

When ActHIB is reconstituted with saline diluent (0.4% Sodium Chloride), each 0.5-mL dose is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid and 8.5% of sucrose.

The vial stoppers for ActHIB vaccine and diluent are not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Haemophilus influenzae (H. influenzae) is a gram-negative coccobacillus. Most strains of H. influenzae that cause invasive disease (e.g., sepsis and meningitis) are H. influenzae type b.

The response to ActHIB vaccine is typical of a T-dependent immune response to antigens. The prominent isotype of anti-capsular PRP antibody induced by ActHIB vaccine is IgG. (6) A booster response for IgG has been demonstrated in children 12 months of age or older who previously received two or three doses of ActHIB vaccine. Bactericidal activity against H. influenzae type b was demonstrated in serum after immunization and correlated with the anti-PRP antibody response induced by ActHIB vaccine. (1)

Antibody titers to H. influenzae capsular polysaccharide (anti-PRP) of >1.0 mcg/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. (7) 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. (8) In clinical studies, ActHIB vaccine induced, on average, anti-PRP levels ≥1.0 mcg/mL in 90% of infants after the primary series (2, 4, and 6 months) and in more than 98% of infants following a booster dose given at 15 to 19 months of age. (1)

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

ActHIB vaccine has not been evaluated for its carcinogenic or mutagenic potential or impairment of male fertility.

14 CLINICAL STUDIES

14.1 Immunogenicity of ActHIB Vaccine in Children 2, 4, and 6 Months of Age

Two clinical trials supported by the National Institutes of Health (NIH) have compared the anti-PRP antibody responses to three Haemophilus influenzae type b conjugate vaccines in racially mixed populations of children. These studies were done in Tennessee (9) (Table 3) and in Minnesota, Missouri, and Texas (10) (Table 4) in infants immunized with ActHIB vaccine and other Haemophilus influenzae type b conjugate vaccines at 2, 4, and 6 months of age. All Haemophilus influenzae type b conjugate vaccines were administered concomitantly with OPV and whole-cell DTP vaccines at separate sites. Neither OPV nor whole-cell DTP vaccines are licensed or distributed in the US currently.

Table 3: Anti-PRP Antibody Responses Following a Two or Three Dose Series of a Haemophilus influenzae type b Vaccine at 2, 4, and 6 Months of Age – Tennessee (9)
Vaccine N * Geometric Mean Concentration (GMC) (mcg/mL) Post Third Immunization % ≥1.0 mcg/mL
Pre-Immunization at 2 months Post Second Immunization at 6 months Post Third Immunization at 7 months
N/A = Not applicable in this comparison trial although third dose data have been published
*
N = Number of children
Haemophilus influenzae type b Conjugate Vaccine (Tetanus Toxoid Conjugate)
Haemophilus influenzae type b Conjugate Vaccine (Meningococcal Protein Conjugate)
§
Seroconversion after the recommended 2-dose primary immunization series is shown
Haemophilus influenzae type b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate)
PRP-T (ActHIB vaccine) 65 0.10 0.30 3.64 83%
PRP-OMP (PedvaxHIB®) 64 0.11 0.84 N/A 50%§
HbOC (HibTITER®) 61 0.07 0.13 3.08 75%
Table 4: Anti-PRP Antibody Responses Following a Two or Three Dose Series of a Haemophilus influenzae type b Vaccine at 2, 4, and 6 Months of Age — Minnesota, Missouri, and Texas (10)
Vaccine N * Geometric Mean Concentration (GMC) (mcg/mL) Post Third Immunization % ≥1.0 mcg/mL
Pre-Immunization at 2 months Post Second Immunization at 6 months Post Third Immunization at 7 months
N/A = Not applicable in this comparison trial although third dose data have been published (10)
*
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 influenzae type b Conjugate Vaccine (Tetanus Toxoid Conjugate)
§
Haemophilus influenzae type b Conjugate Vaccine (Meningococcal Protein Conjugate)
Seroconversion after the recommended 2-dose primary immunization series is shown
#
Haemophilus influenzae type b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate)
PRP-T (ActHIB vaccine) 142 0.25 1.25 6.37 97%
PRP-OMP §(PedvaxHIB) 149 0.18 4.00 N/A 85%
HbOC #(HibTITER) 167 0.17 0.45 6.31 90%

Native American populations have had high rates of H. influenzae type b disease and have been observed to have low immune responses to Haemophilus influenzae type b conjugate vaccines. In a clinical study enrolling Alaskan Native Americans, following the administration of a three-dose series of ActHIB vaccine at 6 weeks, 4 months, and 6 months of age, 75% of subjects achieved an anti-PRP antibody titer of ≥1.0 mcg/mL at 7 months of age (1 month after the last vaccination). (11)

14.2 Immunogenicity of ActHIB Vaccine in Children 12 to 24 Months of Age

In four separate studies, children 12 to 24 months of age who had not previously received Haemophilus influenzae type b conjugate vaccination were immunized with a single dose of ActHIB vaccine (Table 5). Geometric Mean Concentration (GMC) of anti-PRP antibody responses were 5.12 mcg/mL (90% responding with ≥1.0 mcg/mL) for children 12 to 15 months of age and 4.4 mcg/mL (82% responding with ≥1.0 mcg/mL) for children 17 to 24 months of age. (2)

Table 5: Anti-PRP Antibody Responses in 12- to 24-month-old Children Immunized with a Single Dose of ActHIB
Age Group N * Geometric Mean Concentration (GMC) (mcg/mL) % Subjects With ≥1.0 mcg/mL
Pre-Immunization Post-Immunization Pre-Immunization Post-Immunization
*
N = Number of children
Post immunization responses measured at approximately 1 month after vaccination
12 to 15 months 256 0.06 5.12 1.6 90.2
17 to 24 months 81 0.10 4.40 3.7 81.5

ActHIB vaccine has been found to be immunogenic in children with sickle cell anemia, a condition that may cause increased susceptibility to Haemophilus influenzae type b disease. Following two doses of ActHIB vaccine given at two-month intervals, 89% of these children (mean age 11 months) had anti-PRP antibody titers of ≥1.0 mcg/mL. This is comparable to anti-PRP antibody levels demonstrated in children without sickle-cell anemia of similar age following two doses of ActHIB vaccine. (12)

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