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DESCRIPTION

ActHIB®, Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), produced by Sanofi Pasteur SA, is a sterile, lyophilized powder which is reconstituted at the time of use with either saline diluent (0.4% Sodium Chloride) or Sanofi Pasteur Inc. Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed (whole-cell pertussis vaccine DTP) or Tripedia®, Sanofi Pasteur Inc. Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) (when reconstituted known as TriHIBit®) for intramuscular use only. The vaccine consists of the Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate, PRP), a high molecular weight polymer prepared from the Haemophilus influenzae type b (HiB) strain 1482 grown in a semi-synthetic medium, covalently bound to tetanus toxoid. (1) 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. (2) 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 which is characterized as high molecular weight conjugate.

When ActHIB vaccine is reconstituted with saline diluent, each single dose of 0.5 mL is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, and 8.5% of sucrose.

When ActHIB vaccine is combined with Sanofi Pasteur Inc. DTP vaccine by reconstitution, each single dose (0.5 mL) is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, 8.5% of sucrose, 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid and an estimate of 4 protective units of pertussis vaccine. Thimerosal (mercury derivative) 1:10,000 is added as a preservative to Sanofi Pasteur Inc. DTP vaccine. (Refer to product insert for Sanofi Pasteur Inc. whole-cell DTP.)

When ActHIB vaccine is combined with Tripedia vaccine (TriHIBit vaccine) by reconstitution for booster dose, each single dose (0.5 mL) is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, 8.5% of sucrose, 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid and 46.8 mcg of pertussis antigens. The 0.6 mL vial of Tripedia vaccine is formulated without preservatives but contains a trace amount of thimerosal [(mercury derivative), (≤0.3 mcg mercury/dose)] from the manufacturing process. (Refer to product insert for Tripedia vaccine.)

The reconstituted vaccine, using saline diluent, appears clear and colorless. The reconstituted vaccine, using Sanofi Pasteur Inc. DTP vaccine, appears whitish in color. TriHIBit vaccine, the reconstituted vaccine, using Tripedia vaccine, is a homogenous white suspension.

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%. (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%. (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. (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. (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. (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. (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. (11) Adults can be colonized with H influenzae type b from children infected with the organism. (12)

The response to ActHIB vaccine is typical of a T-dependent immune response to antigen. The prominent isotype of anti-capsular PRP antibody induced by ActHIB vaccine is IgG. (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 vaccine. (14)

Antibody to H influenzae capsular polysaccharide (anti-PRP) titers 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. (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. (4) The immunogenicity and safety of ActHIB vaccine has been demonstrated in the United States and worldwide. ActHIB vaccine induced, on average anti-PRP levels ≥1.0 mcg/mL in 90% of infants after the primary series and in more than 98% of infants after a booster dose.(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 (16) (TABLE 1) and in Minnesota, Missouri and Texas (17) (TABLE 2) in infants immunized with ActHIB vaccine 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.

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 vaccine at six weeks, four and six months of age, 75% of Native Americans in Alaska showed an anti-PRP antibody titer of ≥1.0 mcg/mL. (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 vaccine. GMT 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. (18)

These trials demonstrated that ActHIB vaccine 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. (18)

ActHIB vaccine 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 vaccine given at two-month intervals induced anti-PRP antibody titers of ≥1.0 mcg/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 vaccine.(19)

ActHIB VACCINE 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 Sanofi Pasteur Inc. whole-cell DTP vaccine was used to reconstitute lyophilized ActHIB vaccine (TABLE 3). (14),(18)

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 vaccine separately. Interference with the antibody response to the pertussis component has been suggested with a DTP vaccine unlicensed in the US. (20) Percentages of subjects achieving antibody titers over 1 mcg/mL and GMT to PRP in 2-month-old infants following immunization with ActHIB vaccine combined with Sanofi Pasteur Inc. DTP by reconstitution was similar when compared to infants who received DTP and ActHIB vaccine separately (84% versus 85% and 4.3 mcg/mL versus 4.8 mcg/mL). (14), (18)

TriHIBit VACCINE, ActHIB VACCINE COMBINED WITH TRIPEDIA 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 vaccine, Tripedia vaccine and ActHIB vaccine combination vaccine, was similar to that achieved when the two vaccines were given concomitantly at different sites with separate needles and syringes (TABLE 4). (18) All children had received three doses of a Haemophilus b conjugate vaccine (HibTITER or ActHIB vaccine) and three doses of a whole-cell DTP vaccine prior to entry into this clinical trial.

Geometric mean titers in response to diphtheria, tetanus and pertussis (PT and FHA) were also similar between groups. (Refer to product insert for Tripedia vaccine.) 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

ActHIB vaccine or ActHIB vaccine combined with Sanofi Pasteur Inc. 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 vaccine, ActHIB vaccine combined with Tripedia vaccine 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 Sanofi Pasteur Inc. whole-cell DTP, Tripedia vaccine or 0.4% Sodium Chloride diluent may be used for reconstitution of lyophilized ActHIB vaccine. TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, should not be administered to infants younger than 15 months of age.

As with any vaccine, vaccination with ActHIB vaccine reconstituted with Sanofi Pasteur Inc. DTP or ActHIB vaccine reconstituted with Tripedia vaccine (TriHIBit vaccine) or 0.4% Sodium Chloride diluent may not protect 100% of 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 VACCINE IS CONTRAINDICATED IN CHILDREN WITH A HISTORY OF HYPERSENSITIVITY TO ANY COMPONENT OF THE VACCINE AND TO ANY COMPONENT OF DTP OR TRIPEDIA VACCINE WHEN COMBINED BY RECONSTITUTION WITH THESE VACCINES. ANY CONTRAINDICATION FOR DTP IS A CONTRAINDICATION FOR ActHIB VACCINE RECONSTITUTED WITH DTP. ANY CONTRAINDICATION FOR TRIPEDIA VACCINE IS A CONTRAINDICATION FOR TriHIBit VACCINE, ActHIB VACCINE RECONSTITUTED WITH TRIPEDIA VACCINE. (Refer to product inserts for Sanofi Pasteur Inc. whole-cell DTP and Tripedia vaccine.)

WARNINGS

If ActHIB vaccine or ActHIB vaccine reconstituted with Sanofi Pasteur Inc. DTP or ActHIB vaccine reconstituted with Tripedia vaccine (TriHIBit vaccine) 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, (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. (22) (Refer to product inserts for Sanofi Pasteur Inc. whole-cell DTP and Tripedia vaccine.)

TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine 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, and to possible sensitivity to dry natural latex rubber, 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 Sanofi Pasteur Inc. whole-cell DTP and Tripedia vaccine.)

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 vaccine, Sanofi Pasteur Inc. DTP and Tripedia vaccine.

Minor illnesses such as upper respiratory infection with or without low-grade fever are not contraindications for use of ActHIB vaccine. (23)

As reported with Haemophilus b polysaccharide vaccines, (24) cases of H influenzae type b disease may occur subsequent to vaccination and prior to the onset of protective effects of the vaccine. (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. (25)

Antigenuria has been detected in some instances following receipt of ActHIB vaccine; therefore, urine antigen detection may not have definitive diagnostic value in suspected H influenzae type b disease within one week of immunization. (26)

Special care should be taken to ensure that ActHIB vaccine reconstituted with Sanofi Pasteur Inc. DTP or Tripedia vaccine or saline diluent (0.4% Sodium Chloride) is not injected into a blood vessel.

Administration of ActHIB vaccine reconstituted with Sanofi Pasteur Inc. DTP or ActHIB vaccine reconstituted with Tripedia vaccine (TriHIBit vaccine) or saline diluent (0.4% Sodium Chloride) is not contraindicated in individuals with HIV infection. (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.

Caution: The stopper of the diluent vial contains dry natural latex rubber which may cause allergic reactions. The lyophilized vaccine vial contains no rubber of any kind.

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 vaccine reconstituted with Sanofi Pasteur Inc. DTP or ActHIB vaccine reconstituted with Tripedia vaccine (TriHIBit vaccine) 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 vaccine reconstituted with saline or DTP, or ActHIB vaccine reconstituted with Tripedia vaccine (TriHIBit vaccine). 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. (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. (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. (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 Statements (VISs) which are required to be given with each immunization.

DRUG INTERACTIONS

When Sanofi Pasteur Inc. DTP is used to reconstitute ActHIB vaccine or Tripedia vaccine is used to reconstitute ActHIB vaccine (TriHIBit vaccine) 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. (23)

If ActHIB vaccine reconstituted with Sanofi Pasteur Inc. DTP or ActHIB vaccine reconstituted with Tripedia vaccine (TriHIBit vaccine) 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 vaccine 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 vaccine was given at the same time, at separate sites, with IPV or MMR. (18) In addition, more than 47,000 infants in Finland have received a third dose of ActHIB vaccine concomitantly with MMR vaccine with no increase in serious or unexpected adverse events. (18)

No significant impairment of antibody response to Measles, Mumps and Rubella was noted in 15- to 20-month-old children who received TriHIBit vaccine, ActHIB vaccine reconstituted with Tripedia vaccine, 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 vaccine reconstituted with 0.4% Sodium Chloride or Sanofi Pasteur Inc. DTP or ActHIB vaccine reconstituted with Tripedia vaccine (TriHIBit vaccine). (18)

As with other intramuscular injections, use with caution in patients on anticoagulant therapy.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

ActHIB vaccine reconstituted with Sanofi Pasteur Inc. DTP or ActHIB vaccine reconstituted with Tripedia vaccine (TriHIBit vaccine) has not been eva luated for its carcinogenic, mutagenic potential or impairment of fertility.