Prescription Drugs

CLINICAL PHARMACOLOGY For several decades Haemophilus influenzae type b (Haemophilus b) was the most common cause of invasive bacterial disease, including meningitis, in young children in the United States. Although nonencapsulated H. influenzae are common and six capsular polysaccharide types are known, strains with the type b capsule caused most of the invasive Haemophilus diseases.3 Haemophilus b diseases occurred primarily in children under 5 years of age prior to immunization with Haemophilus influenzae type b vaccines. In the US, the cumulative risk of developing invasive Haemophilus b disease during the first 5 years of life was estimated to be about 1 in 200. Approximately 60% of cases were meningitis. Cellulitis, epiglottitis, pericarditis, pneumonia, sepsis, or septic arthritis made up the remaining 40%. An estimated 12,000 cases of Haemophilus b meningitis occurred annually prior to the routine use of conjugate vaccines in toddlers.3,4 The mortality rate can be 5%, and neurologic sequelae have been observed in up to 38% of survivors.5 The incidence of invasive Haemophilus b disease peaks between 6 months and 1 year of age, and approximately 55% of disease occurs between 6 and 18 months of age.3 Interpersonal transmission of Haemophilus b occurs and risk of invasive disease is increased in children younger than 4 years of age who are exposed in the household to a primary case of disease. Clusters of cases in children in day care have been reported and recent studies suggest that the rate of secondary cases may also be increased among children exposed to a primary case in the daycare setting.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, malignancies associated with immunosuppression, and antibody deficiency syndromes.3,4,6 The protective activity of antibody to Haemophilus b polysaccharide was demonstrated by passive antibody studies in animals and in children with agammaglobulinemia or with Haemophilus b disease7 and confirmed with the efficacy study of Haemophilus b polysaccharide (HbPs) vaccine.8 Data from passive antibody studies indicate that a preexisting titer of antibody to HbPs of 0.15 µg/mL correlates with protection.9 Data from a Finnish field trial in children 18 to 71 months of age indicate that a titer of > 1.0 µg/mL 3 weeks after vaccination is associated with long-term protection.10,11 Linkage of Haemophilus b saccharides to a protein such as CRM197 converts the saccharide (HbO) to a T-dependent (HbOC) antigen, and results in an enhanced antibody response to the saccharide in young infants that primes for an anamnestic response and is predominantly of the IgG class.12 Laboratory evidence indicates that the native state of the CRM197 protein and the use of oligosaccharides in the formulation of HibTITER (diphtheria crm197 protein conjugate) enhances its immunogenicity.13–15 Prior to licensure, the immunogenicity of HibTITER (diphtheria crm197 protein conjugate) was evaluated in US infants and children.15 Infants 1 to 6 months of age at first immunization received three doses at approximately 2-month intervals.16 Children 7 to 11 and 12 to 14 months of age received 2 doses at the same interval.15 Children 15 to 23 months of age received a single dose.17 HibTITER (diphtheria crm197 protein conjugate) was highly immunogenic in all age groups studied, with 97% to 100% of 1,232 infants attaining titers of ≥ 1 µg/mL and 92% to 100% for bactericidal activity.15–17 Long-term persistence of the antibody response was observed. More than 80% of 235 infants who received three doses of vaccine had an anti-HbPs antibody level ≥ 1 µg/mL at 2 years of age.18 The vaccine generated an immune response characteristic of a protein antigen. IgG anti-HbPs antibodies of IgG1 subclass predominated and the immune system was primed for a booster response to HibTITER (diphtheria crm197 protein conjugate) . There is some evidence suggesting natural increases in antibody levels over time after vaccination, most probably the result of contact with Haemophilus type b organisms or cross-reactive antigens.18 These studies were carried out at a time when significant levels of Haemophilus b disease were still present in the community. Antibody generated by HibTITER (diphtheria crm197 protein conjugate) 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.19 The contribution to clinical protection is unknown. Immunogenicity of HibTITER (diphtheria crm197 protein conjugate) 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 (diphtheria crm197 protein conjugate) was immunogenic in all 26 children and generated titers of ≥ 1 µg/mL in 25 of the 26 infants.20 HibTITER (diphtheria crm197 protein conjugate) has been found to be immunogenic in children with sickle cell disease, a condition that may cause increased susceptibility to Haemophilus b disease.21 HibTITER (diphtheria crm197 protein conjugate) has also been shown to be immunogenic in native American infants, such as the group of 50 studied in Alaska who received three doses at 2, 4, and 6 months of age.20 Antibody levels achieved were comparable to those seen in healthy US infants who received their first dose at 1 to 2 months of age and subsequent doses at 4 to 6 months of age.15,16,20 Postlicensure surveillance of immunogenicity was conducted during the distribution of the first 30 million doses of HibTITER (diphtheria crm197 protein conjugate) and during the time period over which Haemophilus b disease in children has been decreasing significantly in areas of extensive vaccine usage.20,22–29 After three doses, titers ranged from 2.37 to 8.45 µg/mL with 67% to 94% attaining ≥ 1 µg/mL.20,24,25 Persistence of antibody was examined in several cohorts of subjects that received either a selected commercial lot or that were part of the initial efficacy trial in northern California. Geometric mean titers for these cohorts were between 0.51 and 1.96 just prior to boosting at 15 to 18 months. These lots not only induced persistent antibody but also provided effective priming for a booster dose with commercial lots, with postboosting titers greater than 1.0 µg/mL in 80% to 97% of subjects.20 HibTITER (diphtheria crm197 protein conjugate) (HbOC) was shown to be effective in a large-scale controlled clinical trial in a multiethnic population in northern California carried out between February 1988 and June 1990.30,31 There were no (0) vaccine failures in infants who received three doses of HibTITER (diphtheria crm197 protein conjugate) and 12 cases of Haemophilus b disease (6 cases of meningitis) in the control group. The estimate of efficacy is 100% (P= .0002) with 95% confidence intervals of 68% to 100%. Through the end of 1991, with an additional 49,000 person-years of follow-up, there were still no cases of Haemophilus b disease in fully vaccinated infants less than 2 years of age.22,23 One case of disease has been reported in a 3 1/2-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 (diphtheria crm197 protein conjugate) at 4 and 6 months of age and a booster dose at 14 months in a trial conducted from January 1988 through December 1990. Only two children developed Haemophilus b disease after receiving the two-dose primary immunization 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 1988.20 Historical controls were used since all infants received one of two Haemophilus b conjugate vaccines during the period of the trial. Evidence of efficacy postlicensure includes significant reductions in Haemophilus b disease that are closely associated with increases in the net doses of Haemophilus b Conjugate Vaccine distributed in the US.20,22–29 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 1984-1988, when HibTITER (diphtheria crm197 protein conjugate) was not available for this age group.22,23 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 US.26 As with all vaccines, this conjugate vaccine cannot be expected to be 100% effective. There have been rare reports to the Vaccine Adverse Event Reporting System (VAERS) of Haemophilus b disease following full primary immunization. REFERENCES 3. Wenger JD, Ward JL, Broome CV. Prevention of Haemophilus influenzae type b disease: vaccines and passive prophylaxis. In: Remington JS, Swartz MS, eds. Current Clinical Topics in Infectious Diseases. New York, NY: McGraw-Hill Inc; 1989;10: 306-339. 4. Recommendation of the Immunization Practices Advisory Committee (ACIP) – polysaccharide vaccine for prevention of Haemophilus influenzae type b disease. MMWR. 1985;34:201-205. 5. Sell SH. Long term sequelae of bacterial meningitis in children. Pediatr Infect Dis J. 1983;2:90-93. 6. Broome CV. Epidemiology of Haemophilus influenzae type b infections in the United States. Pediatr Infect Dis J. 1987;6:779-782. 7. Alexander HE. The productive or curative element in type b Haemophilus influenzae rabbit serum. Yale J Biol Med. 1944;16:425-434. 8. Peltola H, Kayhty H, Sivonen A. Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics. 1977;60:730-737. 9. Robbins JB, Parke JC Jr, Schneerson R. Quantitative measurement of “natural” and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res. 1973;7:103-110. 10. Kayhty H, Peltola H, Karanko V, et al. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis. 1983;147:1100. 11. Kayhty H, Karanko V, Peltola H, et al. Serum antibodies after vaccination with Haemophilus influenzae type b capsular polysaccharide and responses to reimmunization: no evidence immunologic tolerance or memory. Pediatrics. 1984;74:857-865. 12. Weinberg GA, Granoff DM. Polysaccharide-protein conjugate vaccines for the prevention of Haemophilus influenzae type b disease. J Pediatr. 1988;113:621-631. 13. Makela O, Péterfy F, Outshoorn IG, et al. Immunogenic properties of a (1-6) dextran, its protein conjugates, and conjugates of its breakdown products in mice. Scand J Immunol. 1984;19:541-550. 14. Anderson P, Pichichero ME, Insel RA. Immunogens consisting of oligosaccharides from Haemophilus influenzae type b coupled to diphtheria toxoid or the toxin protein CRM197. J Clin Invest. 1985;76:52-59. 15. Madore DV, Phipps DC, Eby R, et al. Immune response of young children vaccinated with Haemophilus influenzae type b conjugate vaccines. In: Cruse JM, Lewis RE, eds. Contributions to Microbiology and Immunology: Conjugate Vaccines. New York, NY: Karger Medical and Scientific Publishers; 1989;10:125-150. 16. Madore DV, Phipps DC, Eby R, et al. Safety and immunologic response to Haemophilus influenzae type b oligosaccharide-CRM197 conjugate vaccine in 1- to 6-month-old infants. Pediatrics. 1990;85:331-337. 17. Madore DV, Johnson CL, Phipps DC, et al. Safety and immunogenicity of Haemophilus influenzae type b oligosaccharide-CRM197 conjugate vaccine in infants aged 15-23 months. Pediatrics. 1990;86:527-534. 18. Rothstein EP, Madore DV, Long S. Antibody persistence four years after primary immunization of infants and toddlers with Haemophilus influenzae type b CRM197 conjugate vaccine. J Pediatr. 1991; 119:655-657. 19. Schlesinger Y, Granoff DM. Avidity and bactericidal activity of antibodies elicited by different Haemophilus influenzae type b conjugate vaccines. JAMA. 1992;267:1489-1494. 20. Unpublished data available from Lederle Laboratories. 21. Gigliotti F, Feldman S, Wang WC, et al. Immunization of young infants with sickle cell disease with a Haemophilus influenzae type b saccharide-diphtheria CRM197 protein conjugate vaccine. J Pediatr. 1989;114:1006-1010. 22. Black SB, Shinefield HR, The Kaiser Permanente Pediatric Vaccine Study Group. Immunization with oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine on a large health maintenance organization population: extended follow-up and impact on Haemophilus influenzae disease epidemiology. Pediatric Infect Dis J. 1992;11:610-613. 23. Black SB, Shinefield HR, Fireman B, et al. Safety, immunogenicity, and efficacy in infancy of oligosaccharide conjugate Haemophilus influenzae type b vaccine in a United States Population: possible implications for optimal use. J Infect Dis. 1992;165 (suppl 1):S139-S143. 24. Granoff DM, Anderson EL, Osterholm MT, et al. Differences in the immunogenicity of three Haemophilus influenzae type b conjugate vaccines in infants. J Pediatr. 1992;121:187-194. 25. Decker MD, Edwards KM, Bradley R, et al. Comparative trial in infants of four conjugate Haemophilus influenzae type b vaccines. J Pediatr. 1992;120:184-189. 26. Adams WG, Deaver KA, Cochi SL, et al. Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era. JAMA. 1993;269:221-226. 27. Murphy TV, White KE, Pastor P, et al. Declining incidence of Haemophilus influenzae type b disease since introduction of vaccination. JAMA. 1993;269:246-248. 28. Broadhurst LE, Erickson RL, Kelley PW. Decreases in invasive Haemophilus influenzae diseases in US Army children, 1984 through 1991. JAMA. 1993;269:227-231. 29. Shapiro ED. Infections caused by Haemophilus influenzae type b: the beginning of the end? JAMA. 1993;269:264-266. 30. Black SB, Shinefield HR, Lampert D, et al. Safety and immunogenicity of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in infancy. Pediatr Infect Dis J. 1991;10:92-96. 31. Black SB, Shinefield HR, Fireman B, et al. Efficacy in infancy of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in a United States Population of 61,080 children. Pediatr Infect Dis J. 1991;10:97-104.

HibTITER® (diphtheria crm197 protein conjugate) (Diphtheria CRM197Protein Conjugate) Haemophilus b Conjugate Vaccine DESCRIPTION Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) HibTITER (diphtheria crm197 protein conjugate) is a sterile solution of a conjugate of oligosaccharides of the capsular antigen of Haemophilus influenzae type b (Haemophilus b) and diphtheria CRM197 protein (CRM197) dissolved in 0.9% sodium chloride. The oligosaccharides are derived from 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). The oligosaccharides are purified and sized by diafiltrations through a series of ultrafiltration membranes, and coupled by reductive amination directly to highly purified CRM197.1,2 CRM197 is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae C7 (β197) grown in a casamino acids and yeast extract-based medium that is ultrafiltered before use. CRM197 is purified through ultrafiltration, ammonium sulfate precipitation, and ion-exchange chromatography to high purity. The conjugate is purified to remove unreacted protein, oligosaccharides, and reagents; sterilized by filtration; and filled into vials. HibTITER (diphtheria crm197 protein conjugate) is intended for intramuscular use. The vaccine is a clear, colorless solution. Each single dose of 0.5 mL is formulated to contain 10 µg of purified Haemophilus b saccharide and approximately 25 µg of CRM197 protein. The potency of HibTITER (diphtheria crm197 protein conjugate) is determined by chemical assay for polyribosylribitol. REFERENCES 1. United States Patent Number 4,902,506 by Anderson PW, Eby filed May 5, 1986 issued February 20, 1990. 2. Seid RC Jr, Boykins RA, Liu DF, et al. Chemical evidence for covalent linkage of a semi-synthetic glycoconjugate vaccine for Haemophilus influenzae type b disease. Glycoconjugate J. 1989;6:489-498.

INDICATIONS Haemophilus b Conjugate Vaccine (Diphtheria CRM197Protein Conjugate) HibTITER (diphtheria crm197 protein conjugate) is indicated for the immunization of children 2 months to 71 months of age against invasive diseases caused by H. influenzae type b. As with any vaccine, HibTITER (diphtheria crm197 protein conjugate) may not protect 100% of individuals receiving the vaccine. The American Academy of Pediatrics (AAP), the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP) encourage the routine simultaneous administration of Haemophilus influenzae type b vaccines with other currently recommended vaccines, but at different sites (see DRUG INTERACTIONS).32,33,34,35 DOSAGE AND ADMINISTRATION HibTITER (diphtheria crm197 protein conjugate) is for intramuscular use only. Any parenteral drug product should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit. If these conditions exist, or if cloudy, HibTITER (diphtheria crm197 protein conjugate) should not be administered. Before injection, the skin over the site to be injected should be cleansed with a suitable germicide. After insertion of the needle, aspirate to help avoid inadvertent injection into a blood vessel. The vaccine should be injected intramuscularly, preferably into the midlateral muscles of the thigh or deltoid, with care to avoid major peripheral nerve trunks. Do not inject in the gluteal area. The vaccine is to be administered immediately after being drawn up into a syringe. Single dose 0.5 mL vial contains no preservative. Use one dose per vial; do not re-enter vial. Discard unused portions. The vaccine is not to be mixed with other vaccines/products in the same syringe. HibTITER (diphtheria crm197 protein conjugate) is indicated for children 2 months to 71 months of age for the prevention of invasive Haemophilus b disease. For infants 2 to 6 months of age, the immunizing dose is three separate injections of 0.5 mL given at approximately 2-month intervals. Previously unvaccinated infants from 7 through 11 months of age should receive two separate injections approximately 2 months apart. Children from 12 through 14 months of age who have not been vaccinated previously receive one injection. All vaccinated children receive a single booster dose at 15 months of age or older, but not less than 2 months after the previous dose. Previously unvaccinated children 15 to 71 months of age receive a single injection of HibTITER (diphtheria crm197 protein conjugate) .32,33 Preterm infants should be vaccinated with HibTITER (diphtheria crm197 protein conjugate) according to their chronological age, from birth.32 Recommended Immunization Schedule Age at First Immunization (Mo) No. of Doses Booster 2 -6 3 Yes 7 - 11 2 Yes 12 - 14 1 Yes 15 and over 1 No Interruption of the recommended schedules with a delay between doses does not interfere with the final immunity achieved nor does it necessitate starting the series over again, regardless of the length of time elapsed between doses.32,33 Data support that HibTITER (diphtheria crm197 protein conjugate) may be interchanged with other Haemophilus influenzae type b conjugate vaccines for the primary immunization series and booster dose.55,56,57 Each dose of 0.5 mL is formulated to contain 10 µg of purified Haemophilus b saccharide and approximately 25 µg of CRM197 protein. Storage DO NOT FREEZE. Store refrigerated away from freezer compartments at 2°C-8°C (36°F-46°F). Discard if the vaccine has been frozen. HOW SUPPLIED Vial, 1 Dose (5 per package) – Product No. 0005-0104-32 REFERENCES 32. Recommendations of the AAP: Haemophilus influenzae type b conjugate vaccines: recommendations for immunization of infants and children 2 months of age and older: update. Pediatrics. 1991;88:169-172. 33. Recommendation of the ACIP: Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. MMWR. 1991;40:1-7. 34. Centers for Disease Control and Prevention. General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR. 2002;51(No. RR-2);1-36. 35. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000: 26, 266-72. 55. Greenberg DP, Lieberman JM, Marcy SM, et al. Enhanced antibody responses in infants given different sequences of heterogenous Haemophilus influenzae type b conjugate vaccines. J Pediatr. 1995;126:206-11. 56. Anderson EL, Decker MD, Englund JA, et al. Interchangeability of conjugated Haemophilus influenzae type b vaccines in infants. JAMA. 1995;273:849-53. 57. Scheifele D, Law B, Mitchell L, Ochnio J. Study of booster doses of two Haemophilus influenzae type b conjugate vaccines including their interchangeability. Vaccine. 1996;14(15):1399-1406. This product's label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll free at 1-800-934-5556. Manufactured by: Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101.

PATIENT INFORMATION PRIOR TO ADMINISTRATION OF HibTITER (diphtheria crm197 protein conjugate) , HEALTH CARE PERSONNEL SHOULD INFORM THE PARENT, GUARDIAN OR OTHER RESPONSIBLE ADULT, OF THE RECOMMENDED IMMUNIZATION SCHEDULE FOR PROTECTION AGAINST HAEMOPHILUS b DISEASE AND THE BENEFITS AND RISKS TO THE CHILD RECEIVING THIS VACCINE. GUIDANCE SHOULD BE PROVIDED ON MEASURES TO BE TAKEN SHOULD ADVERSE EVENTS OCCUR, SUCH AS, ANTIPYRETIC MEASURES FOR ELEVATED TEMPERATURES AND THE NEED TO REPORT ADVERSE EVENTS TO THE HEALTH CARE PROVIDER. Parents should be provided with vaccine information pamphlets at the time of each vaccination, as stated in the National Childhood Vaccine Injury Act.42 PATIENTS, PARENTS, OR GUARDIANS SHOULD BE INSTRUCTED TO REPORT ANY SERIOUS ADVERSE REACTIONS TO THEIR HEALTH CARE PROVIDER. REFERENCES 42. CDC. Vaccine Adverse Event Reporting System – United States. MMWR. 1990;39:730-733.

OVERDOSE There have been reports of overdose with HibTITER (diphtheria crm197 protein conjugate) . Many cases were due to inadvertent coadministration with another Haemophilus b conjugate-containing vaccine. Most individuals were asymptomatic. In general, adverse events reported with overdosage have also been reported with recommended single doses of HibTITER (diphtheria crm197 protein conjugate) . CONTRAINDICATIONS Hypersensitivity to any component of the vaccine, including diphtheria toxoid, is a contraindication to the use of HibTITER (diphtheria crm197 protein conjugate) . The occurrence of an allergic or anaphylactic reaction following a prior dose of HibTITER (diphtheria crm197 protein conjugate) is a contraindication to the use of HibTITER (diphtheria crm197 protein conjugate) .

SIDE EFFECTS Adverse reactions associated with HibTITER (diphtheria crm197 protein conjugate) have been evaluated in 401 infants who were vaccinated initially at 1 to 6 months of age and were given 1,118 doses independent of DTP vaccine. Observations were made during the day of vaccination and days 1 and 2 postvaccination. A temperature > 38.3°C was recorded at least once during the observation period following 2% of the vaccinations. Local erythema, warmth, or swelling ( ≥ 2 cm) was observed following 3.3% of vaccinations. The incidence of temperature > 38.3°C was greater during the first postvaccination day than during the day of vaccination or the second postvaccination day. The incidence of local erythema, warmth, or swelling was similar during the day of vaccination and the first postvaccination day; it was lower during the second postvaccination day. All side effects have been infrequent, mild, and transient with no serious sequelae (Table 1). No difference in the rates of these complaints was reported after dose 1, 2, or 3. TABLE 1: Number of Subjects (Percent) Manifesting Side Effects Associated with HibTITER (diphtheria crm197 protein conjugate) Administered Independently from DTP* (Infants Vaccinated Initially at 1-6 Months of Age) Dose 1 n = 401 Dose 2 n = 383 Dose 3 n = 334 Symptoms Same Day As Vacc. +1 Day +2 Days Same Day As Vacc. +1 Day +2 Days Same Day As Vacc. +1 Day +2 Days Temp > 38.3°C 0 2 2 2 3 2 2 6 5 - < 1% < 1% < 1% < 1% < 1% < 1% 1.8% 1.5% Redness > 2 cm 1 0 0 1 6 0 5 4 0 < 1% - - < 1% 1.6% - 1.5% 1.2% - Warmth ≥ 2 cm 1 1 0 2 1 0 1 6 0 < 1% < 1% - < 1% < 1% - < 1% 1.8% - Swelling ≥ 2 cm 5 1 0 2 2 0 1 0 0 1.2% < 1% - < 1% < 1% - < 1% - - *DTP and HibTITER given 2 weeks apart with DTP having been given first. The following complaints were also observed after 1,118 vaccinations with HibTITER (diphtheria crm197 protein conjugate) : irritability (133), sleepiness (91), prolonged crying [ ≥ 4 hours] (38), appetite loss (23), vomiting (9), diarrhea (2), and rash (1). Additional safety data with HibTITER (diphtheria crm197 protein conjugate) are available from the efficacy studies conducted in young infants.30 There were 79,483 doses given to 30,844 infants at approximately 2, 4, and 6 months of age in California, usually at the same time as DTP (but at a separate injection site) and OPV; approximately 100,000 doses have been given to 53,000 infants at 4 and 6 months in Finland at the same time as a combined DTP and inactivated polio (IPV) vaccine (but at a separate injection site). The rate and type of reactions associated with the vaccinations were no different from those seen when DTP or DTP-IPV was administered alone. These included fever, local reactions, rash, and one hyporesponsive episode with a single seizure. The safety of HibTITER (diphtheria crm197 protein conjugate) was also evaluated in the California study by direct phone questioning of the parents or guardians of 6,887 vaccine recipients. The incidence and type of side effects reported within 24 hours of vaccination were similar to those cited in Table 1. In addition, analysis of emergency room (ER) visits within 30 days and hospitalization within 60 days after receipt of 23,800 doses of HibTITER (diphtheria crm197 protein conjugate) showed no increase in the rates of any type of ER visit or hospitalization. Table 2 details the side effects associated with a single vaccination of HibTITER (diphtheria crm197 protein conjugate) given (without DTP) to infants of 15 to 23 months of age. TABLE 2: Selected Adverse Reactions* in Children of 15-23 Months of Age Following Vaccination with HibTITER (diphtheria crm197 protein conjugate) Adverse Reaction No. of Subjects Reaction Within 24 h % Postvaccination At 48 h Fever > 38.3°C 354 1.4 0.6 Erythema 354 2.0 – Swelling 354 1.7 – Tenderness 354 3.7 0.3 * The following complaints were reported after vaccination of these 354 children in the indicated number of children: diarrhea (9), vomiting (5), prolonged crying [ > 4 hours] (4), and rashes (2). Similar results have been observed in the analysis of 2,285 subjects of 18 to 60 months of age, vaccinated as part of a postmarketing safety study of HibTITER (diphtheria crm197 protein conjugate) .20 These data were collected by telephone survey 24 to 48 hours postvaccination. Additional observations included irritability, restless sleep, and Gl symptoms (diarrhea, vomiting, and loss of appetite) in the group that received HibTITER (diphtheria crm197 protein conjugate) alone. A cause and effect relationship between these observations and the vaccinations has not been established. Post Approval Experience The following adverse reactions have been identified during post approval use of HibTITER (diphtheria crm197 protein conjugate) . Because these reactions 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 drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to the vaccine for post marketing surveillance information. Injection Site Reactions Injection site reactions including hypersensitivity (including urticaria), induration, inflammation, mass, and skin discoloration. Systemic Events Anaphylactoid/anaphylactic reactions (including shock), angioneurotic edema, convulsions,53 erythema multiforme, facial edema, febrile seizures, Guillain-Barré syndrome,54headache, hives (urticaria), hypersensitivity reaction, lethargy, and malaise. Also reported, hypotonia or hyporesponsive-hypotonic-episodes (in many instances pertussis-containing vaccine was coadministered). There have been spontaneous reports of apnea in temporal association with the administration of HibTITER (diphtheria crm197 protein conjugate) . In most cases HibTITER (diphtheria crm197 protein conjugate) was administered concomitantly with other vaccines including DTP, DTaP, hepatitis B vaccine, IPV, OPV, pneumococcal 7-valent conjugate vaccine, MMR, and/or meningococcal group C conjugate vaccine (not licensed in the US). In addition, in some of the reports existing medical conditions such as prematurity and/or history of apnea were present. Reporting of Adverse Reactions Any suspected adverse events following immunization should be reported by the healthcare professional to the US Department of Health and Human Services (DHHS). The National Vaccine Injury Compensation Program requires that the manufacturer and lot number of the vaccine administered be recorded by the healthcare professional in the vaccine recipient's permanent medical record (or in a permanent office log or file), along with the date of administration of the vaccine and the name, address, and title of the person administering the vaccine. The DHHS has established the 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 1986.42 The VAERS FDA web site is: http://www.fda.gov/cber/vaers/vaers.htm The VAERS toll-free number for VAERS forms and information is 800-822-7967. DRUG INTERACTIONS Children receiving therapy with immunosuppressive agents (large amounts of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may not respond optimally to active immunization.37,38,39 (See PRECAUTIONS, General.) As with other intramuscular injections, HibTITER (diphtheria crm197 protein conjugate) should be given with caution to children on anticoagulant therapy. No impairment of the antibody response to the individual antigens was demonstrated when HibTITER (diphtheria crm197 protein conjugate) was given at the same time but at separate sites as diphtheria tetanus pertussis vaccine (DTP) plus oral polio vaccine (OPV) to children 2 to 20 months of age or measles-mumps-rubella (MMR) to children 15 ± 1 month of age.20,43,44 There are no clinical studies where a direct comparison of the immune responses to HibTITER (diphtheria crm197 protein conjugate) was compared with the concurrent administration of diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP), hepatitis B vaccine (Hep B), inactivated poliovirus vaccine (IPV), 7-valent Conjugate Vaccine-Diphtheria CRM197Protein (Prevnar), or Varicella vaccine. However, in clinical trials where HibTITER (diphtheria crm197 protein conjugate) and DTaP or HibTITER (diphtheria crm197 protein conjugate) , DTaP, IPV, and Hep B vaccines were administered concurrently with or without Prevnar in children at 2, 4, and 6 months of age, the percentage of children achieving Hib antibody levels of ≥ 0.15 or ≥ 1.0 µg/mL were similar.45,46 In one study where children 12-15 months of age were administered a booster dose of HibTITER (diphtheria crm197 protein conjugate) concurrently with DTaP and Prevnar, some suppression of the Hib antibody response was observed, but over 97% of children achieved titers of ≥ 1.0 µg/mL.47,48 However, in another study where a booster dose of HibTITER (diphtheria crm197 protein conjugate) was administered to children at 12-15 months of age concurrently with or without Prevnar the percentage of children achieving Hib antibody levels of ≥ 0.15 or ≥ 1.0 µg/mL was found to be similar.49,50 HibTITER (diphtheria crm197 protein conjugate) and DTaP administered concurrently with and without Prevnar at 2, 4, and 6, and 12-15 months of age did not impair immune responses to the seven Pneumococcal vaccine serotypes in Prevnar.47,48,51,52 There are no clinical trials where the local and systemic reactogenicity of HibTITER (diphtheria crm197 protein conjugate) was directly compared with the concurrent administration of DTaP, Hep B, IPV, Prevnar, or Varicella vaccines. The American Academy of Pediatrics (AAP), the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP) encourage routine simultaneous administration of DTaP, IPV, Haemophilus influenzae type b vaccine, pneumococcal conjugate vaccine, measles-mumps-rubella (MMR), varicella vaccine and hepatitis B vaccine for children who are the recommended age to receive these vaccines and for whom no specific contraindications exist at the time of the visit, unless, in the judgment of the provider, complete vaccination of the child will not be compromised by administering different vaccines at different visits. Simultaneous administration is particularly important if the child might not return for subsequent vaccinations.32,33,34,35 REFERENCES 20. Unpublished data available from Lederle Laboratories. 30. Black SB, Shinefield HR, Lampert D, et al. Safety and immunogenicity of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in infancy. Pediatr Infect Dis J. 1991;10:92-96. 32. Recommendations of the AAP: Haemophilus influenzae type b conjugate vaccines: recommendations for immunization of infants and children 2 months of age and older: update. Pediatrics. 1991;88:169-172. 33. Recommendation of the ACIP: Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. MMWR. 1991;40:1-7. 34. Centers for Disease Control and Prevention. General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR. 2002;51(No. RR-2);1-36. 35. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000: 26, 266-72. 37. American Academy of Pediatrics: Report of the Committee on Infectious Diseases. 22nd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1991. 38. Recommendation of the ACIP: Immunization of children infected with human T-lymphotrophic virus type III/lymphadenopathy-associated virus. MMWR. 1986;35(38):595-606. 39. Immunization of children infected with human immunodeficiency virus – supplementary ACIP statement. MMWR. 1988;37(12):181-183. 42. CDC. Vaccine Adverse Event Reporting System – United States. MMWR. 1990;39:730-733. 43. Paradiso PR. Combined childhood immunizations. JAMA. 1992;268:1685. 44. Paradiso PR, Hogerman DA, Madore DV, et al. Safety and immunogenicity of a combined diphtheria, tetanus, pertussis and Haemophilus influenzae type b vaccine in young infants. Pediatrics. 1993;92(6):827-32. 45. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P12. 46. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P16. 47. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P7. 48. Shinefield H, Black S, Ray P, et al. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatr Infect Dis J. 1999;18:757-63. 49. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P3. 50. Rennels MB, Edwards KM, Keyserling HL, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics. 1998;101(4):604-11. 51. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P8. 52. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19:187-95. 53. Milstein JB, Gross TP, Kuritsky JN. Adverse reactions reported following receipt of Haemophilus influenzae type b vaccine: an analysis after one year of marketing. Pediatrics. 1987;80:270-274. 54. D'Cruz DF, Shapiro ED, Spiegelman KN, et al. Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome) after immunization with Haemophilus influenzae type b conjugate vaccine. J Pediatr. 1989;115:743-746.

WARNINGS HibTITER (diphtheria crm197 protein conjugate) WILL NOT PROTECT AGAINST H. INFLUENZAE OTHER THAN TYPE b STRAINS, NOR WILL HibTITER (diphtheria crm197 protein conjugate) PROTECT AGAINST OTHER MICROORGANISMS THAT CAUSE MENINGITIS OR SEPTIC DISEASE. AS WITH ANY INTRAMUSCULAR INJECTION, HibTITER (diphtheria crm197 protein conjugate) SHOULD BE GIVEN WITH CAUTION TO INFANTS OR CHILDREN WITH THROMBOCYTOPENIA OR ANY COAGULATION DISORDER, OR TO THOSE RECEIVING ANTICOAGULANT THERAPY (SEE DRUG INTERACTIONS). ANTIGENURIA HAS BEEN DETECTED FOLLOWING RECEIPT OF HAEMOPHILUS b CONJUGATE VACCINE36 AND THEREFORE ANTIGEN DETECTION IN URINE MAY NOT HAVE DIAGNOSTIC VALUE IN SUSPECTED HAEMOPHILUS b DISEASE WITHIN 2 WEEKS OF IMMUNIZATION. The vial stopper contains dry natural rubber that may cause hypersensitivity reactions when handled by or when the product is injected into persons with known or possible latex sensitivity. PRECAUTIONS General CARE IS TO BE TAKEN BY THE HEALTH CARE PROVIDER FOR SAFE AND EFFECTIVE USE OF THIS PRODUCT. PRIOR TO ADMINISTRATION OF ANY DOSE OF HibTITER (diphtheria crm197 protein conjugate) , THE PARENT OR GUARDIAN SHOULD BE ASKED ABOUT THE PERSONAL HISTORY, FAMILY HISTORY, AND RECENT HEALTH STATUS OF THE VACCINE RECIPIENT. THE HEALTH CARE PROVIDER SHOULD ASCERTAIN PREVIOUS IMMUNIZATION HISTORY, CURRENT HEALTH STATUS, AND OCCURRENCE OF ANY SYMPTOMS AND/OR SIGNS OF AN ADVERSE EVENT AFTER PREVIOUS IMMUNIZATION IN THE CHILD TO BE IMMUNIZED, IN ORDER TO DETERMINE THE EXISTENCE OF ANY CONTRAINDICATION TO IMMUNIZATION WITH HibTITER (diphtheria crm197 protein conjugate) AND TO ALLOW AN ASSESSMENT OF BENEFITS AND RISKS. BEFORE THE INJECTION OF ANY BIOLOGICAL, THE HEALTH CARE PROVIDER SHOULD TAKE ALL PRECAUTIONS KNOWN FOR THE PREVENTION OF ALLERGIC OR ANY OTHER SIDE REACTIONS. 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 used for control of immediate allergic reactions; and a knowledge of the recent literature pertaining to use of the biological concerned, including the nature of side effects and adverse reactions that may follow its use. Children with impaired immune responsiveness, whether due to the use of immunosuppressive therapy (including irradiation, corticosteroids, antimetabolites, alkylating agents, and cytotoxic agents), a genetic defect, human immunodeficiency virus (HIV) infection, or other causes, may have reduced antibody response to active immunization procedures.37,38 Deferral of administration of vaccine may be considered in individuals receiving immunosuppressive therapy.37 Other groups should receive this vaccine according to the usual recommended schedule.37–39 (See DRUG INTERACTIONS.) Minor illnesses, such as mild respiratory infection with or without low-grade fever, are not generally contraindications to vaccination. The decision to administer or delay vaccination because of a current or recent febrile illness depends largely on the severity of the symptoms and their etiology. The administration of HibTITER® (diphtheria crm197 protein conjugate) should be postponed in subjects suffering from acute severe febrile illness. This product is not contraindicated based on the presence of human immunodeficiency virus infection.40 As reported with Haemophilus b polysaccharide vaccine, cases of Haemophilus b disease may occur prior to the onset of the protective effects of the vaccine.3,41 The vaccine should not be injected intradermally, subcutaneously, or intravenously since the safety and immunogenicity of these routes have not been evaluated. The vaccine should be given intramuscularly. A separate sterile syringe and needle or a sterile disposable unit should be used for each individual patient to prevent transmission of infectious agents from one person to another. Needles should be disposed of properly and should not be recapped. Special care should be taken to prevent injection into a blood vessel. The vaccine is to be administered immediately after being drawn up into a syringe. Single dose 0.5 mL vial contains no preservative. Use one dose per vial; do not re-enter vial. Discard unused portions. As with any vaccine, HibTITER® (diphtheria crm197 protein conjugate) may not protect 100% of individuals receiving the vaccine. ALTHOUGH SOME ANTIBODY RESPONSE TO DIPHTHERIA TOXIN OCCURS, IMMUNIZATION WITH HibTITER (diphtheria crm197 protein conjugate) DOES NOT SUBSTITUTE FOR ROUTINE DIPHTHERIA IMMUNIZATION. The vial stopper contains dry natural rubber that may cause hypersensitivity reactions when handled by or when the product is injected into persons with known or possible latex sensitivity. Carcinogenesis, Mutagenesis, Impairment of Fertility HibTITER (diphtheria crm197 protein conjugate) 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 HibTITER (diphtheria crm197 protein conjugate) . It is also not known whether HibTITER (diphtheria crm197 protein conjugate) can cause fetal harm when administered to a pregnant woman or can affect reproduction capability. HibTITER (diphtheria crm197 protein conjugate) is NOT recommended for use in a pregnant woman. Geriatric Use This vaccine is NOT recommended for use in adult populations. Pediatric Use The safety and effectiveness of HibTITER (diphtheria crm197 protein conjugate) in children below the age of 6 weeks have not been established. REFERENCES 3. Wenger JD, Ward JL, Broome CV. Prevention of Haemophilus influenzae type b disease: vaccines and passive prophylaxis. In: Remington JS, Swartz MS, eds. Current Clinical Topics in Infectious Diseases. New York, NY: McGraw-Hill Inc; 1989;10: 306-339. 20. Unpublished data available from Lederle Laboratories. 30. Black SB, Shinefield HR, Lampert D, et al. Safety and immunogenicity of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in infancy. Pediatr Infect Dis J. 1991;10:92-96 32. Recommendations of the AAP: Haemophilus influenzae type b conjugate vaccines: recommendations for immunization of infants and children 2 months of age and older: update. Pediatrics. 1991;88:169-172. 33. Recommendation of the ACIP: Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. MMWR. 1991;40:1-7. 34. Centers for Disease Control and Prevention. General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR. 2002;51(No. RR-2);1-36. 35. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000: 26, 266-72. 36. Jones RG, Bass JW, Weisse ME, et al. Antigenuria after immunization with Haemophilus influenzae oligosaccharide CRM197 conjugate (HbOC) vaccine. Pediatr Infect Dis J. 1991;10:557-559. 37. American Academy of Pediatrics: Report of the Committee on Infectious Diseases. 22nd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1991. 38. Recommendation of the ACIP: Immunization of children infected with human T-lymphotrophic virus type III/lymphadenopathy-associated virus. MMWR. 1986;35(38):595-606. 39. Immunization of children infected with human immunodeficiency virus – supplementary ACIP statement. MMWR. 1988;37(12):181-183. 40. General Recommendations on Immunization: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR. 1989;38(13):221. 41. Spinola SM, Sheaffer CI, Philbrick KB, et al. Antigenuria after Haemophilus influenzae type b polysaccharide immunization: a prospective study. J Pediatr. 1986;109:835-837. 42. CDC. Vaccine Adverse Event Reporting System – United States. MMWR. 1990;39:730-733. 43. Paradiso PR. Combined childhood immunizations. JAMA. 1992;268:1685. 44. Paradiso PR, Hogerman DA, Madore DV, et al. Safety and immunogenicity of a combined diphtheria, tetanus, pertussis and Haemophilus influenzae type b vaccine in young infants. Pediatrics. 1993;92(6):827-32. 45. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P12. 46. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P16. 47. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P7. 48. Shinefield H, Black S, Ray P, et al. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatr Infect Dis J. 1999;18:757-63. 49. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P3. 50. Rennels MB, Edwards KM, Keyserling HL, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics. 1998;101(4):604-11. 51. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P8. 52. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19:187-95. 53. Milstein JB, Gross TP, Kuritsky JN. Adverse reactions reported following receipt of Haemophilus influenzae type b vaccine: an analysis after one year of marketing. Pediatrics. 1987;80:270-274. 54. D'Cruz DF, Shapiro ED, Spiegelman KN, et al. Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome) after immunization with Haemophilus influenzae type b conjugate vaccine. J Pediatr. 1989;115:743-746.