hibtiter

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DESCRIPTION
Haemophilus b Conjugate Vaccine (Diphtheria CRM 197 Protein Conjugate) HibTITERis a sterile solution of a conjugate of oligosaccharides of the capsular antigenof Haemophilus influenzae type b (Haemophilus b) and diphtheria CRM 197 protein(CRM 197 ) dissolved in 0.9% sodium chloride hibtiter. The oligosaccharides are derivedfrom highly purified capsular polysaccharide, polyribosylribitol phosphate,isolated from Haemophilus b strain Eagan grown in a chemically defined medium(a mixture of mineral salts, amino acids, and cofactors) hibtiter. The oligosaccharidesare purified and sized by diafiltrations through a series of ultrafiltrationmembranes, and coupled by reductive amination directly to highly purified CRM197 hibtiter. 1,2 CRM 197 is a nontoxic variant of diphtheria toxin isolated from culturesof Corynebacterium diphtheriae C7 ((beta)197) grown in a casamino acids andyeast extract-based medium that is ultrafiltered before use hibtiter. CRM 197 is purifiedthrough ultrafiltration, ammonium sulfate precipitation, and ion-exchange chromatographyto high purity hibtiter. The conjugate is purified to remove unreacted protein, oligosaccharides,and reagents; sterilized by filtration; and filled into vials hibtiter. HibTITER is intendedfor intramuscular use hibtiter.

The vaccine is a clear, colorless solution hibtiter. Each single dose of 0.5 mL is formulatedto contain 10 µg of purified Haemophilus b saccharide and approximately25 µg of CRM 197 protein hibtiter. The potency of HibTITER is determined by chemicalassay for polyribosylribitol hibtiter.

CLINICAL PHARMACOLOGY
For several decades Haemophilus influenzae type b (Haemophilus b) was the mostcommon cause of invasive bacterial disease, including meningitis, in young childrenin the United States hibtiter. Although nonencapsulated H hibtiter. influenzae are common andsix capsular polysaccharide types are known, strains with the type b capsulecaused most of the invasive Haemophilus diseases hibtiter. 3

Haemophilus b diseases occurred primarily in children under 5 years of ageprior to immunization with Haemophilus influenzae type b vaccines hibtiter. In the US,the cumulative risk of developing invasive Haemophilus b disease during thefirst 5 years of life was estimated to be about 1 in 200 hibtiter. Approximately 60%of cases were meningitis hibtiter. Cellulitis, epiglottitis, pericarditis, pneumonia,sepsis, or septic arthritis made up the remaining 40% hibtiter. An estimated 12,000 casesof Haemophilus b meningitis occurred annually prior to the routine use of conjugatevaccines in toddlers hibtiter. 3,4 The mortality rate can be 5%, and neurologic sequelaehave been observed in up to 38% of survivors hibtiter. 5

The incidence of invasive Haemophilus b disease peaks between 6 months and1 year of age, and approximately 55% of disease occurs between 6 and 18 monthsof age hibtiter. 3 Interpersonal transmission of Haemophilus b occurs and risk of invasivedisease is increased in children younger than 4 years of age who are exposedin the household to a primary case of disease hibtiter. Clusters of cases in childrenin day care have been reported and recent studies suggest that the rate of secondarycases may also be increased among children exposed to a primary case in thedaycare setting hibtiter. 3,6

The incidence of invasive Haemophilus b disease is increased in certain children,such as those who are native Americans, black, or from lower socioeconomic status,and those with medical conditions such as asplenia, sickle cell disease, malignanciesassociated with immunosuppression, and antibody deficiency syndromes hibtiter. 3,4,6

The protective activity of antibody to Haemophilus b polysaccharide was demonstratedby passive antibody studies in animals and in children with agammaglobulinemiaor with Haemophilus b disease 7 and confirmed with the efficacy study of Haemophilusb polysaccharide (HbPs) vaccine hibtiter. 8 Data from passive antibody studies indicatethat a preexisting titer of antibody to HbPs of 0.15 µg/mL correlateswith protection hibtiter. 9 Data from a Finnish field trial in children 18 to 71 monthsof age indicate that a titer of > 1.0 µg/mL 3 weeks after vaccinationis associated with long-term protection hibtiter. 10,11

Linkage of Haemophilus b saccharides to a protein such as CRM 197 convertsthe saccharide (HbO) to a T-dependent (HbOC) antigen, and results in an enhancedantibody response to the saccharide in young infants that primes for an anamnesticresponse and is predominantly of the IgG class hibtiter. 12 Laboratory evidence indicatesthat the native state of the CRM 197 protein and the use of oligosaccharidesin the formulation of HibTITER enhances its immunogenicity hibtiter. 13-15

Prior to licensure, the immunogenicity of HibTITER was evaluated in US infantsand children hibtiter. 15 Infants 1 to 6 months of age at first immunization receivedthree doses at approximately 2-month intervals hibtiter. 16 Children 7 to 11 and 12 to14 months of age received 2 doses at the same interval hibtiter. 15 Children 15 to 23months of age received a single dose hibtiter. 17 HibTITER was highly immunogenic inall age groups studied, with 97% to 100% of 1,232 infants attaining titers of>/= 1 µg/mL and 92% to 100% for bactericidal activity hibtiter. 15-17

Long-term persistence of the antibody response was observed hibtiter. More than 80%of 235 infants who received three doses of vaccine had an anti-HbPs antibodylevel >/= 1 µg/mL at 2 years of age hibtiter. 18

The vaccine generated an immune response characteristic of a protein antigen hibtiter. IgG anti-HbPs antibodies of IgG 1 subclass predominated and the immune systemwas primed for a booster response to HibTITER hibtiter. There is some evidence suggestingnatural increases in antibody levels over time after vaccination, most probablythe result of contact with Haemophilus type b organisms or cross-reactive antigens hibtiter. 18 These studies were carried out at a time when significant levels of Haemophilusb disease were still present in the community hibtiter.

Antibody generated by HibTITER has been found to have high avidity, a measureof the functional affinity of antibody to bind to antigen hibtiter. High-avidity antibodyis more potent than low-avidity antibody in serum bactericidal assays hibtiter. 19 Thecontribution to clinical protection is unknown hibtiter.

Immunogenicity of HibTITER was evaluated in 26 children 22 months to 5 yearsof age who had not responded to earlier vaccination with Haemophilus b polysaccharidevaccine hibtiter. One dose of HibTITER was immunogenic in all 26 children and generatedtiters of >/= 1 µg/mL in 25 of the 26 infants hibtiter. 20 HibTITER has beenfound to be immunogenic in children with sickle cell disease, a condition thatmay cause increased susceptibility to Haemophilus b disease hibtiter. 21 HibTITER hasalso been shown to be immunogenic in native American infants, such as the groupof 50 studied in Alaska who received three doses at 2, 4, and 6 months of age hibtiter. 20 Antibody levels achieved were comparable to those seen in healthy US infantswho received their first dose at 1 to 2 months of age and subsequent doses at4 to 6 months of age hibtiter. 15,16,20

Postlicensure surveillance of immunogenicity was conducted during the distributionof the first 30 million doses of HibTITER and during the time period over whichHaemophilus b disease in children has been decreasing significantly in areasof extensive vaccine usage hibtiter. 20,22-29 After three doses, titers ranged from 2.37to 8.45 µg/mL with 67% to 94% attaining >/= 1 µg/mL hibtiter. 20,24,25

Persistence of antibody was examined in several cohorts of subjects that receivedeither a selected commercial lot or that were part of the initial efficacy trialin northern California hibtiter. Geometric mean titers for these cohorts were between0.51 and 1.96 just prior to boosting at 15 to 18 months hibtiter. These lots not onlyinduced persistent antibody but also provided effective priming for a boosterdose with commercial lots, with postboosting titers greater than 1.0 µg/mLin 80% to 97% of subjects hibtiter. 20

HibTITER (HbOC) was shown to be effective in a large-scale controlled clinicaltrial in a multiethnic population in northern California carried out betweenFebruary 1988 and June 1990 hibtiter. 30,31 There were no (0) vaccine failures in infantswho received three doses of HibTITER and 12 cases of Haemophilus b disease (6cases of meningitis) in the control group hibtiter. The estimate of efficacy is 100%( P = .0002) with 95% confidence intervals of 68% to 100% hibtiter. Through the end of1991, with an additional 49,000 person-years of follow-up, there were stillno cases of Haemophilus b disease in fully vaccinated infants less than 2 yearsof age hibtiter. 22,23 One case of disease has been reported in a 3 1/2-year-old childwho did not receive a booster dose as recommended hibtiter.

A comparative clinical trial was performed in Finland where approximately 53,000infants received HibTITER at 4 and 6 months of age and a booster dose at 14months in a trial conducted from January 1988 through December 1990 hibtiter. Only twochildren developed Haemophilus b disease after receiving the two-dose primaryimmunization schedule hibtiter. One child became ill at 15 months of age and the otherat 18 months of age; neither child received the scheduled booster at 14 monthsof age hibtiter. No vaccine failure has been reported in children who received the two-doseprimary series and the booster dose at 14 months of age hibtiter. Based on more than32,000 person-years of follow-up time, the estimate of efficacy is about 95%when compared to historical control groups followed between 1985 and 1988 hibtiter. 20Historical controls were used since all infants received one of two Haemophilusb conjugate vaccines during the period of the trial hibtiter.

Evidence of efficacy postlicensure includes significant reductions in Haemophilusb disease that are closely associated with increases in the net doses of Haemophilusb Conjugate Vaccine distributed in the US hibtiter. 20,22-29 In the northern CaliforniaKaiser Permanente there has been a 94% decrease in Haemophilus disease incidencein 1991 for children younger than 18 months of age, compared to 1984-1988, whenHibTITER was not available for this age group hibtiter. 22,23 Furthermore, active surveillanceby the Centers for Disease Control and Prevention (CDC) has shown a 71% decreasein Haemophilus b disease in children less than 15 months old, between 1989 and1991, which corresponds temporally and geographically with increases in netdoses of Haemophilus b conjugate vaccine distributed in the US hibtiter. 26 As with allvaccines, this conjugate vaccine cannot be expected to be 100% effective hibtiter. Therehave been rare reports to the Vaccine Adverse Event Reporting System (VAERS)of Haemophilus b disease following full primary immunization hibtiter.

INDICATIONS AND USAGE
Haemophilus b Conjugate Vaccine (Diphtheria CRM 197 Protein Conjugate) HibTITERis indicated for the immunization of children 2 months to 71 months of age againstinvasive diseases caused by H hibtiter. influenza type b hibtiter.

As with any vaccine, HibTITER may not protect 100% of individuals receivingthe vaccine hibtiter.

The American Academy of Pediatrics (AAP), the Advisory Committee on ImmunizationPractices (ACIP) and the American Academy of Family Physicians (AAFP) encouragethe routine simultaneous administration of Haemophilus influenzae type b vaccineswith other currently recommended vaccines, but at different sites (see DRUGINTERACTIONS ) hibtiter. 32,33,34,35

CONTRAINDICATIONS
Hypersensitivity to any component of the vaccine, including diphtheria toxoid,is a contraindication to the use of HibTITER hibtiter.

The occurrence of an allergic or anaphylactic reaction following a prior doseof HibTITER is a contraindication to the use of HibTITER hibtiter.

The decision to administer or delay vaccination because of a current or recentfebrile illness depends largely on the severity of the symptoms and their etiology hibtiter. Although a severe or even moderate febrile illness is sufficient reason to postponevaccinations, minor illnesses, such as a mild respiratory infection with orwithout low-grade fever, are not generally contraindications hibtiter.

WARNINGS
HibTITER WILL NOT PROTECT AGAINST H hibtiter. INFLUENZA OTHER THAN TYPE b STRAINS, NORWILL HibTITER PROTECT AGAINST OTHER MICROORGANISMS THAT CAUSE MENINGITIS ORSEPTIC DISEASE hibtiter.

AS WITH ANY INTRAMUSCULAR INJECTION, HibTITER SHOULD BE GIVEN WITH CAUTIONTO INFANTS OR CHILDREN WITH THROMBOCYTOPENIA OR ANY COAGULATION DISORDER, ORTO THOSE RECEIVING ANTICOAGULANT THERAPY (SEE DRUG INTERACTIONS ) hibtiter.

ANTIGENURIA HAS BEEN DETECTED FOLLOWING RECEIPT OF HAEMOPHILUS b CONJUGATEVACCINE 36 AND THEREFORE ANTIGEN DETECTION IN URINE MAY NOT HAVE DIAGNOSTICVALUE IN SUSPECTED HAEMOPHILUS b DISEASE WITHIN 2 WEEKS OF IMMUNIZATION hibtiter.

The vial stopper contains dry natural rubber that may cause hypersensitivityreactions when handled by or when the product is injected in persons with knownor possible latex sensitivity hibtiter.

PRECAUTIONS
GENERAL

CARE IS TO BE TAKEN BY THE HEALTH CARE PROVIDER FOR SAFE AND EFFECTIVE USEOF THIS PRODUCT hibtiter.
PRIOR TO ADMINISTRATION OF ANY DOSE OF HibTITER, THE PARENT OR GUARDIAN SHOULDBE ASKED ABOUT THE PERSONAL HISTORY, FAMILY HISTORY, AND RECENT HEALTH STATUSOF THE VACCINE RECIPIENT hibtiter. THE HEALTH CARE PROVIDER SHOULD ASCERTAIN PREVIOUSIMMUNIZATION HISTORY, CURRENT HEALTH STATUS, AND OCCURRENCE OF ANY SYMPTOMSAND/OR SIGNS OF AN ADVERSE EVENT AFTER PREVIOUS IMMUNIZATION IN THE CHILD TOBE IMMUNIZED, IN ORDER TO DETERMINE THE EXISTENCE OF ANY CONTRAINDICATION TOIMMUNIZATION WITH HibTITER AND TO ALLOW AN ASSESSMENT OF BENEFITS AND RISKS hibtiter.
BEFORE THE INJECTION OF ANY BIOLOGICAL, THE HEALTH CARE PROVIDER SHOULD TAKEALL PRECAUTIONS KNOWN FOR THE PREVENTION OF ALLERGIC OR ANY OTHER SIDE REACTIONS hibtiter. This should include: a review of the patient's history regarding possible sensitivity;the ready availability of epinephrine 1:1,000 and other appropriate agents usedfor control of immediate allergic reactions; and a knowledge of the recent literaturepertaining to use of the biological concerned, including the nature of sideeffects and adverse reactions that may follow its use hibtiter.
Children with impaired immune responsiveness, whether due to the use of immunosuppressivetherapy (including irradiation, corticosteroids, antimetabolites, alkylatingagents, and cytotoxic agents), a genetic defect, human immunodeficiency virus(HIV) infection, or other causes, may have reduced antibody response to activeimmunization procedures hibtiter. 37,38 Deferral of administration of vaccine may beconsidered in individuals receiving immunosuppressive therapy hibtiter. 37 Other groupsshould receive this vaccine according to the usual recommended schedule hibtiter. 37-39(See DRUG INTERACTIONS .)
This product is not contraindicated based on the presence of human immunodeficiencyvirus infection hibtiter. 40
As reported with Haemophilus b polysaccharide vaccine, cases of Haemophilusb disease may occur prior to the onset of the protective effects of the vaccine hibtiter. 3,41
The vaccine should not be injected intradermally, subcutaneously, or intravenouslysince the safety and immunogenicity of these routes have not been evaluated hibtiter. The vaccine should be given intramuscularly hibtiter.
A separate sterile syringe and needle or a sterile disposable unit should beused for each individual patient to prevent transmission of infectious agentsfrom one person to another hibtiter. Needles should be disposed of properly and shouldnot be recapped hibtiter.
Special care should be taken to prevent injection into a blood vessel hibtiter.
The vaccine is to be administered immediately after being drawn up into a syringe hibtiter. Single dose 0.5 mL vial contains no preservative hibtiter. Use one dose per vial; donot re-enter vial hibtiter. Discard unused portions hibtiter.

ALTHOUGH SOME ANTIBODY RESPONSE TO DIPHTHERIA TOXIN OCCURS, IMMUNIZATION WITHHibTITER DOES NOT SUBSTITUTE FOR ROUTINE DIPHTHERIA IMMUNIZATION hibtiter.

The vial stopper contains dry natural rubber that may cause hypersensitivityreactions when handled by or when the product is injected in persons with knownor possible latex sensitivity hibtiter.

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