HibTITER
Lederle Laboratories
[CPI Pack Insert]
Permitted in sport
Pregnancy Category B2
Use: Active immunisation against Haemophilus influenzae type B
infections in children 2 months-5 years
Contraindications: IV admin.
Precautions: Immunosuppression; fever, acute illness;
pregnancy, lactation, infants < 6 weeks
Adverse Reactions: Irritability; sleepiness; prolonged crying;
appetite loss; vomiting, diarrhoea; rash; fever; local erythema,
warmth, swelling, tenderness

HibTITER (Injection) Rx
Haemophilus B conjugate vaccine
Eagan Haemophilus influenza type B (purified capsular
polysaccharide); bound to Diphtheria protein conjugate 25 mcg;
NaCl 0.9%; thiomersal (multidose vial); Gluten free.
Pack(s): 10 mcg/0.5 mL .Fields[1]: $35.33
Pack(s): 10 mcg/0.5 mL .Fields[20]:
Dose: 2-6 months: 3 x 2 monthly 0.5 mL IM doses. 7-11
months (previously unvaccinated): 2 x 2 monthly 0.5 mL IM
doses. 12-14 months (previously unvaccinated): 1 x 0.5 mL IM
dose. All vaccinated children to receive a 0.5 mL IM booster at
greater than or equal to 15 months (but not < 2 months after
previous dose). 15-60 months (previously unvaccinated): 1 x 0.5
mL IM dose; no booster required

Composition
Haemophilus B conjugate vaccine (Diphtheria CRM[197]
protein conjugate).

Description
HibTITER is a sterile solution of a conjugate of oligosaccharides of the capsular antigen of Haemophilus influenzae type B (Haemophilus B) and Diphtheria CRM[197] protein dissolved in sodium chloride 0.9%. The oligosaccharides are derived from
highly purified capsular polysaccharide, polyribosylribitol phosphate, isolated from Haemophilus B strain Eagan grown in a chemically defined medium, and coupled by reductive amination directly to highly purified CRM[197]. CRM[197] is a nontoxic
variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheria C7 (beta197) grown in a casamino acids and yeast extract based medium which is
ultrafiltered before use. The conjugate is purified to remove unreacted protein, oligosaccharides and reagents; sterilised by filtration; and filled into vials.

The vaccine is a clear, colourless solution. Each single 0.5 mL dose is formulated to contain purified Haemophilus B saccharide 10 microgram and approximately CRM[197] protein 25 microgram. Thiomersal is included in the multidose presentation
as a preservative.

Actions
Pharmacology.
Immunogenicity.
Linkage of Haemophilus B saccharides to a protein such as CRM[197] results in an enhanced antibody response (predominantly IgG) to the saccharide and immunological memory. Laboratory evidence indicates that the native state of the CRM[197] protein and the use of oligosaccharides in the formulation of HibTITER enhances its T helper potential and thus its immunogenicity.

The vaccine generated an immune response characteristic of a protein antigen; IgG anti-PRP antibodies of IgG[1] subclass predominated and the immune system was primed for a booster response to HibTITER, and there is some evidence suggesting
natural increases in antibody levels over time after vaccination. Data from passive antibody studies indicate that a pre-existing level of antibody to PRP of 0.15 microgram/mL correlates with protection.

Antibody generated by HibTITER has been found to have high avidity, a measure of the functional affinity of antibody to bind to antigen. High avidity antibody is more potent than low avidity antibody in serum bactericidal assays. The contribution to clinical protection is unknown.

In infants vaccinated initially at one to six months of age in ten centres in the United States and who received three doses at approximately two month intervals, anti-PRP antibody levels greater than or equal to 1 microgram/mL were attained by more
than 90% of infants of all ages after two doses and by more than 98% after three doses. One month after the third vaccination, the geometric mean antibody levels were 16.8, 26.8, and 30.0 microgram/mL in infants initially vaccinated at one to two, three
to four, and five to six months of age respectively. In infants vaccinated initially at one to six months of age, the percentage with levels greater than or equal to 1 microgram/mL were 27.9, 90.3, and 99.2% after the first, second and third dose of vaccine respectively (see Table 1). Long-term persistence of the antibody response was observed. More than 80% of the 235 infants who received three doses of vaccine had an anti-PRP antibody level greater than or equal to 1 microgram/mL at two years of age. Data from field trials indicate that a level of greater than or equal to 1.0 microgram/mL three weeks after vaccination is associated with long-term protection.

One month after the second dose, 99.5% of the infants vaccinated at 7 to 11 months of age and 100% of the infants vaccinated at 12 to 14 months of age responded with anti-PRP antibody levels greater than or equal to 1 microgram/mL and the geometric mean antibody levels were 27.93 and 32.66 microgram/mL, respectively (see Table 1); 100% of the infants' sera had bactericidal activity.

A single dose of HibTITER administered to 377 children 15 to 23 months of age resulted in a geometric mean antibody level of 11.35 microgram/mL and more than 97% had anti-PRP antibody levels greater than or equal to 1 microgram/mL (see Table 1); 92.2% of the infants' sera had bactericidal activity.

When evaluated in an in vitro complement mediated bactericidal assay, none of the prevaccinated sera of the one to six month old infants killed H. influenzae type B. Two months after the second dose of vaccine, 95% of the infants' sera had bactericidal activity, and one month after the third dose, 98% of the sera had bactericidal activity.

Immunogenicity has been reported in a total of 422 infants in six postlicensure studies in the United States. After three doses, titres ranged from 2.37 to 8.45 microgram/mL with 67 to 94% attaining greater than or equal to 1 microgram/mL. Please refer to
table 1. Immunogenicity of HibTITER was evaluated in 26 children 22 months to 5 years of age who had not responded to earlier vaccination with Haemophilus B polysaccharide vaccine. One dose of HibTITER was immunogenic in all 26 children and generated antibody levels of greater than or equal to 1 microgram/mL in 25 of the 26 infants. HibTITER has been found to be immunogenic in children with sickle-cell disease, a condition which may cause increased susceptibility to Haemophilus B disease. In 20 of these infants aged two to six months, three doses of HibTITER given at two month intervals generated a geometric mean anti-PRP antibody level of 22.1
microgram/mL and 100% of the subjects had a level greater than or equal to 1 microgram/mL one month after the third dose. 90% of the infants had a level greater than or equal to 1 microgram/mL 18 months after the initial vaccination.

In one immunogenicity study involving 124 subjects, no impairment of the antibody response to the individual antigens occurred when HibTITER was given at the same time as Diphtheria-Tetanus-Pertussis Vaccine, Adsorbed (DTP) (separate sites) plus Oral Polio Vaccine (OPV) to children 18 months of age or Measles, Mumps and Rubella Vaccine (MMR) to children 15 months of age.

Protective efficacy.
HibTITER was shown to be effective in a large scale controlled trial in a multi-ethnic population in northern California carried out between February 1988 and June 1990. There were no vaccine failures in infants who received three doses of HibTITER and 12 cases of Haemophilus B disease (six cases of meningitis) in the control group. The estimate of efficacy is 100% (p = 0.0002) with 95% confidence intervals 68 to 100%.

Overall, in the northern California population immunised from February 1988 through to January 1992, including prelicensure study population and the children immunised postlicensure, there were no cases of Haemophilus B disease in fully vaccinated infants less than two years of age. Five cases of disease occurred in children who only received one dose of HibTITER and one case occurred in a 31/2 year old child who did not receive a booster dose as recommended.

A comparative clinical trial was performed in Finland where approximately 53,000 infants received HibTITER at four and six months of age and a booster dose at 14 months in a trial conducted from January 1988 through to December 1990. Only
two children developed Haemophilus B disease after receiving the two dose primary vaccination schedule. One child became ill at 15 months of age and the other at 18 months of age; neither child received the scheduled booster at 14 months of age. No
vaccine failure has been reported in children who received the two dose primary series and the booster dose at 14 months of age. Based on more than 32,000 person years of follow-up time, the estimate of efficacy is about 95% when compared to
historical control groups followed between 1985 and 1988. Historical controls were used since all infants received one of two Haemophilus B conjugate vaccines during the period of the trial.

Evidence of efficacy postmarketing includes significant reductions in Haemophilus B disease that are closely associated with increases in the net doses of Haemophilius B conjugate vaccine distributed in the United States. In the Northern California Kaiser
Permanente there has been a 94% decrease in Haemophilus disease incidence in 1991 for children younger than 18 months of age, compared to 1984 to 1988, when HibTITER was not available for this age group. Furthermore, active surveillance by
the Centers for Disease Control and Prevention (CDC) has shown a 71% decrease in Haemophilus B disease in children less than 15 months old, between 1989 and 1991, which corresponds temporally and geographically with increases in net doses of Haemophilus B conjugate vaccine distributed in the United States. As with all vaccines, this conjugate vaccine cannot be expected to be 100% effective. There have been rare reports to the Vaccine Event Reporting System (VAERS) of Haemophilus B disease following full primary immunisation.


Indications
Immunisation of children two months to five years of age against invasive diseases caused by Haemophilus influenzae type B.

Contraindications
Hypersensitivity to any component of the vaccine, including Diphtheria toxoid (or thiomersal in the multidose presentation).

Warnings
If the vaccine is used in persons deficient in producing antibody, whether due to genetic defect or to immunosuppressive therapy, the expected immune response may not be obtained.

Deferral of administration of vaccine may be considered in individuals receiving immunosuppressive therapy.

As with any vaccine, HibTITER may not protect 100% of individuals receiving the vaccine. Also, as reported with other vaccines, cases of Haemophilus B disease may occur prior to the onset of the protective effects of the vaccine.HibTITER will not protect against H. influenzae other than type B strains or other microorganisms that cause meningitis or septic disease.

Carcinogenesis, mutagenesis, impairment of fertility.

HibTITER has not been evaluated for its carcinogenic or mutagenic potential or impairment of fertility.

Use in pregnancy.
(Category B2)

There is no convincing evidence of risk to the fetus from immunisation of pregnant women using inactivated virus vaccines, bacterial vaccines or toxoids.

Precautions
General.
Prior to an injection of any vaccine, all reasonable precautions should be taken to prevent adverse reactions. Any significant acute illness or temperature over 38 deg. C is reason for delaying use of HibTITER until the child has recovered except when, in
the opinion of the doctor, withholding the vaccine entails a greater risk. A minor afebrile illness such as a mild upper respiratory infection is not usually reason to defer immunisation.

As with the injection of any biological material, adrenaline should be available for immediate use should an anaphylactic or other allergic reaction occur.

Antigenuria has been detected following administration of Haemophilus B conjugate vaccine, and therefore antigen detection may not have diagnostic value in suspected
Haemophilus B disease within two weeks of immunisation.

The vaccine should not be injected intradermally or intravenously since the safety and immunogenicity of these routes have not been evaluated. The vaccine should be given intramuscularly. Special care should be taken to ensure that the injection does not
enter a blood vessel. A separate, sterile syringe and needle or a sterile disposable unit
should be used for each patient to prevent transmission of infectious agents from one person to another. It should be noted that immunisation with HibTITER does not
substitute for routine diphtheria immunisation.

Adverse Reactions
In clinical studies involving healthy children, HibTITER was generally well tolerated.

The adverse reactions shown in Table 2 were seen with HibTITER up to 48 hours postvaccination in 401 infants initially vaccinated at 1 to 6 months of age. All these side effects were infrequent, mild and transient with no serious sequelae. No differences in the rates of these complaints were reported after dose 1, 2 or 3. The side effects associated with a single vaccination of HibTITER given to 354 infants of 15 to 23 months of age are also detailed in Table 2. Please refer to table 2. One hyporesponsive episode with a single seizure was observed when HibTITER was given with DTP and inactivated polio vaccine (IPV) at a separate site. In addition to the reactions shown in Table 2, rash, hives (urticaria), erythema multiforme, convulsions, vomiting and diarrhoea, and Guillain-Barre syndrome have been observed in postmarketing studies. However, a cause and effect relationship among any of these events and the vaccination has not been established.

Interactions
HibTITER may be administered simultaneously but at different sites to other routine paediatric vaccines, e.g. DTP, OPV and MMR.

Dosage and Administration
HibTITER is for intramuscular use only. Do not inject intravenously.

HibTITER should be inspected visually for extraneous particulate matter and/or discolouration prior to administration. If these anomalies exist, HibTITER should not be administered.

Children.
HibTITER is indicated for children two months to five years of age for the prevention of invasive Haemophilus B disease. For infants two to six months of age, the immunising dose is three separate injections of 0.5 mL given at approximately two month intervals intramuscularly, preferably in the outer aspect of the vastus lateralis (mid thigh). Previously unvaccinated infants from seven to eleven months of age should receive two separate intramuscular injections as described, approximately two months apart. Children from 12 to 14 months of age who have not been vaccinated previously should receive one intramuscular injection. All vaccinated children should receive a single booster dose at 15 months of age or older, but not less than two months after the previous dose. Previously unvaccinated children 15 to 60 months of age should receive a single intramuscular injection of HibTITER as described. Children older than 15 months of age can, alternatively, be vaccinated in the deltoid muscle.

Preterm infants should be vaccinated with HibTITER according to their chronological age, from birth. Please refer to table 3.

Interruption of the recommended schedules with a delay between doses does not necessitate starting the series over again, regardless of the length of time elapsed between doses. No data are available to support the interchangeability of HibTITER or other Haemophilus B conjugate vaccines with one another. Therefore, it is recommended that the same conjugate vaccine be used throughout each immunisation schedule.

Each dose of 0.5 mL is formulated to contain purified Haemophilus B saccharide 10 microgram and CRM[197] protein approximately 25 microgram.

Before injection, the skin over the site to be injected should be cleansed with a suitable antiseptic. After insertion of the needle, aspirate to ensure that the needle has not entered a blood vessel.

Use in neonates.
The safety and effectiveness of HibTITER in infants below the age of 6 weeks have not been established.

Concomitant use with other vaccines.
Limited studies have been conducted where HibTITER was administered concomitantly with the primary vaccination series of DTP and OPV, or concomitantly with MMR, in which individual antigen responses were measured. While no impairment of immune response to HibTITER or other individual tested antigens was demonstrated in these studies, there is a suggestion that some Haemophilus influenzae type B conjugated vaccines may impair antibody response to DTP antigens, although protective levels are still achieved.

Presentation
Vial, 1 dose: 1's, 20's.

Storage
Store at 2 to 8 deg. C. (Refrigerate. Do not freeze.)

Poisons Schedule
S4.