Prescription Drugs

CLINICAL PHARMACOLOGY Haemophilus influenzae type b (Haemophilus b) was a leading cause of serious systemic bacterial disease in the United States. Prior to licensure of Haemophilus b Conjugate Vaccines, it was the most common cause of bacterial meningitis, accounting for an estimated 12,000 cases annually, primarily among children under five years of age. The mortality rate was 5%, and neurologic sequelae were observed in as many as 25%-35% of survivors1. Most cases of Haemophilus influenzae meningitis among children are caused by capsular strains of type b, although this capsular type represents only one of the six types known for this species. In addition to bacterial meningitis, Haemophilus b is responsible for other invasive diseases, including epiglottitis, sepsis, cellulitis, septic arthritis, osteomyelitis, pericarditis, and pneumonia.1 In the United States prior to licensure of Haemophilus b Conjugate Vaccines, approximately one of every 1000 children under five years of age developed systemic Haemophilus b disease each year, and a child's cumulative risk of developing systemic Haemophilus b disease at some time during the first five years of life was approximately one in 200. Attack rates peaked between six months and one year of age and declined thereafter.1 Approximately 75%-85% of Haemophilus b disease occurs among children less than 24 months of age.2,3,4 Incidence rates of Haemophilus b disease are increased in certain high-risk groups, such as native Americans (both American Indian and Eskimos), blacks, individuals of lower socioeconomic status, and patients with asplenia, sickle cell disease, Hodgkin's disease, and antibody deficiency syndromes.1,4 Recent studies also have suggested that the risk of acquiring primary Haemophilus b disease for children under five years of age appears to be greater for those who attend day-care facilities.5,6,7,8 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 four years of age.9 Adults can be colonized with Haemophilus influenzaetype b from children infected with 10 the organism. In 1974, a randomized controlled trial was conducted in Finland, which allowed the evaluation of clinical efficacy of a non-conjugated Haemophilus type b polysaccharide vaccine in children 3 to 71 months of age.11 Approximately 98,000 children, half of whom received the Haemophilus b vaccine, were enrolled in the field trial and followed for a four-year period for the occurrence of Haemophilus b disease. Among children 18 to 71 months of age, 90% protective efficacy (95% confidence limits, 55%-98%) was demonstrated for the four-year follow-up period in prevention of all forms of invasive Haemophilus b disease. Based on evidence from this 1974 Finnish efficacy trial, from passive protection in the infant rat model, and from experience with agammaglobulinemic children, an antibody concentration of ≥ 0.15 µg/mL has been correlated with protection.11,12,13,14 Antibody levels of ≥ 1 µg/mL were correlated with long-term protection in three-week post-vaccination serum. Anti-capsular antibodies induced by ProHIBiT (haemophilus b conjugate vaccine) ® in children 18 months of age and older had bactericidal activity, opsonic activity and were also active in passive protection assays.15,16,17 The development of stable humoral immunity requires the recognition of foreign material by at least two separate sets of lymphocytes. These sets are the B-lymphocytes which are precursors of antibody forming cells, and the T-lymphocytes which modulate the function of B-cells. Some antigens such as polysaccharides are capable of stimulating B-cells directly to produce antibody (T-independent). The responses to many other antigens are augmented by helper T-lymphocytes (T-dependent).18 The manufacturing process utilizes a technology of covalent bonding the capsular polysaccharide of Haemophilus influenzae type b to diphtheria toxoid, to produce an antigen which is postulated to convert a T-independent antigen into a T-dependent antigen.19,20 The protein carries both its own antigenic determinants and those of the covalently bound polysaccharide. As a result of the conjugation to protein, the polysaccharide is presented as a T-dependent antigen resulting in both an enhanced antibody response and an immunologic memory. In studies conducted with ProHIBiT (haemophilus b conjugate vaccine) ® in several locations throughout the US, the antibody responses of 18- to 26-month-old children were measured (Table 1).15 In other studies, the antibody responses to licensed Haemophilus b polysaccharide vaccines were measured in a comparable age group (Table 1).15 The data shown in Table 1 were obtained from sera tested in one laboratory using a single radioimmunoassay (RIA). Mean antibody levels induced by ProHIBiT (haemophilus b conjugate vaccine) ® in children 18 to 20 months of age are 30-fold higher than those induced by polysaccharide vaccines in the same age group.15 The RIA procedure used by Connaught Laboratories, Inc. to estimate antibody responses to the Haemophilus b vaccines has been shown to correlate with the assay used by the Finland National Public Health Institute.21 Antibody levels ( ≥ 1.0 µg/mL) estimated by the Finnish assay were correlated with protection.11 TABLE 115: Immunogenicity Studies of ProHIBiT (haemophilus b conjugate vaccine) ® and Polysaccharide Vaccines* Vaccine Age Group No. of Subjects Anti-Polysaccharide GMT (µg/mL) % Subjects Responding with ≥ 1.0 µg/mL** Pre Post ProHIBiT® 15 to 17 Mo. 43 0.017 1.12 53% 18 to 21 Mo. 173 0.025 2.85 75% 22 to 26 Mo. 37 0.021 2.96 73% POLYSACCHARIDE 18 to 20 Mo. 51 0.021 0.100 24% 24 to 27 Mo. 84 0.035 0.520 43% * Only subjects whose sera had preimmunization levels ≤ 0.60 µg/mL were included in this analysis. ** A subset of these data was obtained from a randomized comparison of the two vaccines, in which the percentage of children 18 to 20 months of age responding with ≥ 1.0 µg/mL was 75% for ProHIBiT (haemophilus b conjugate vaccine) ® (n=12) and 27% for the polysaccharide (n=11). Following immunization of 16 to 24-month-old children with a single dose of ProHIBiT (haemophilus b conjugate vaccine) ®, 89% (109/123) had antibody levels ≥ 0.15 µg/mL 12 months post-immunization, compared to 93% one month post-immunization.15 The immunogenicity of ProHIBiT (haemophilus b conjugate vaccine) ® as a booster vaccination administered to children 12 months of age has been studied in the United States, Finland and Canada.15 Based on the study conducted by Drs. Edwards and Decker at Vanderbilt University, it was demonstrated that ProHIBiT (haemophilus b conjugate vaccine) ® induce booster responses in children immunized with any of four different Hib conjugate vaccines as well as or better than the homologous vaccine.15 No impairment of the immune response to ProHIBiT (haemophilus b conjugate vaccine) ® was observed in a group of 36 patients with sickle cell disease (SS, SC, S-thalassemia), aged 1.5 to 5.0 years (mean 3.3 years).15,22,23 Satisfactory immune responses were obtained following administration of ProHIBiT (haemophilus b conjugate vaccine) ® in children 2 to 6 years of age with acute leukemia who had been on chemotherapy < 1 year.24 However, similar children with chemotherapy > 1 year frequently failed to respond to the vaccine. REFERENCES 1. Recommendations of the Immunization Practices Advisory Committee (ACIP). Polysaccharide vaccine for prevention of Haemophilus influenzae type b disease. MMWR 34: 201-205, 1985 2. Cochi SL, et al. Immunization of US children with Haemophilus influenzae type b polysaccharide vaccine: A cost-effectiveness model of strategy assessment. JAMA 253: 521-529, 1985 3. Murphy TV, et al. Prospective surveillance of Haemophilus influenzae type b disease in Dallas County, Texas, and in Minnesota. Pediatr 79: 173-179, 1987 4. Broome CV. Epidemiology of Haemophilus influenzae type b infections in the United States. Pediatr Infect Dis J 6: 779-782, 1987 5. Istre GR, et al. Risk factors for primary invasive Haemophilus influenzae disease: Increased risk from day care attendance and school-aged household members. J Pediatr 106: 190-195, 1985 6. Redmond SR, et al. Haemophilus influenzae type b disease. An epidemiologic study with special reference to day-care centers. JAMA 252: 2581-2584, 1984 7. Murphy TV, et al. County-wide surveillance of invasive Haemophilus infections: Risk of associated cases in Child Care Programs (CCPs). Twenty-third Interscience Conference on Antimicrobial Agents and Chemotherapy (Abstract #788) 229, 1983 8. Fleming D, et al. Haemophilus influenzae b (Hib) disease – secondary spread in day care. Twenty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy (Abstract #967) 261, 1984 9. CDC. Prevention of secondary cases of Haemophilus influenzae type b disease. MMWR 31: 672-680, 1982 10. Michaels RH, et al. Pharyngeal colonization with Haemophilus influenzae type b: A longitudinal study of families with a child with meningitis or epiglottitis due to H. influenzae type b. J Infec Dis 136: 222-227, 1977 11. Peltola H, et al. Prevention of Haemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 310: 1561-1566, 1984 12. Smith DH, et al. Responses of children immunized with the capsular polysaccharide of Haemophilus influenzae, type b. Pediatr 52: 637-644, 1973 13. Robbins JB, et al. Quantitative measurement of “natural” and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res 7: 103-110, 1973 14. Robbins JB, et al. A review of the efficacy trials with Haemophilus influenzae type b polysaccharide vaccines. In: Sell, S.H., Wright, P.E. eds. Haemophilus influenzae. New York: Elsevier Biomedical. 255-263, 1982 15. Unpublished data available from Connaught Laboratories, Inc. 16. Granoff DM, et al. Immunogenicity of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in adults. J Pediatr 105: 22-27, 1984 17. Cates KL. Serum opsonic activity for Haemophilus influenzae type b in infants immunized with polysaccharide-protein conjugate vaccines. J Infec Dis 152:1076-1077,1985 18. Benacerraf B, et al. Textbook of Immunology. Cellular interactions. Williams and Wilkins, p 22,1979 19. Schneerson R, et al. Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates. J Exp Med 152:361-376,1980 20. Lepow ML, et al. Safety and immunogenicity of Haemophilus influenzae type b-polysaccharide diphtheria toxoid conjugate vaccine in infants 9 to 15 months of age. J Pediatr 106:185-189,1985 21. Greenberg DP, et al. Variability in quantitation of Haemophilus influenzae type b anticapsular antibody (anti-PRP) by radioimmunoassay (RIA). Twenty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy (Abstract #209) 133,1986 22. Frank AL, et al. Haemophilus influenzae Type b immunization of children with sickle cell diseases. Pediatr 82:571-575,1988 23. Plotkin SA, et al. Vaccines. Haemophilus influenzae vaccines. W.B. Saunders Co. p 318,1988 24. Gigliotti F, et al. Response of children with acute lymphoblastic leukemia (ALL) to H. influenzae type b (Hib) conjugate vaccine. The Society for Pediatric Research (Serial #11595), 1988

CLINICAL PHARMACOLOGY Prior to the introduction of Haemophilus b Conjugate Vaccines, Haemophilus influenzae type b (Hib) was the most frequent cause of bacterial meningitis and a leading cause of serious, systemic bacterial disease in young children worldwide.1,2,3,4 Hib disease occurred primarily in children under 5 years of age in the United States prior to the initiation of a vaccine program and was estimated to account for nearly 20,000 cases of invasive infections annually, approximately 12,000 of which were meningitis. The mortality rate from Hib meningitis is about 5%. In addition, up to 35% of survivors develop neurologic sequelae including seizures, deafness, and mental retardation.5,6 Other invasive diseases caused by this bacterium include cellulitis, epiglottitis, sepsis, pneumonia, septic arthritis, osteomyelitis and pericarditis. Prior to the introduction of the vaccine, it was estimated that 17% of all cases of Hib disease occurred in infants less than 6 months of age.7 The peak incidence of Hib meningitis occurs between 6 to 11 months of age. Forty-seven percent of all cases occur by one year of age with the remaining 53% of cases occurring over the next four years.2,20 Among children under 5 years of age, the risk of invasive Hib disease is increased in certain populations including the following: Daycare attendees8,9 Lower socio-economic groups10 Blacks11 (especially those who lack the Km(1) immunoglobulin allotype)12 Caucasians who lack the G2m(n or 23) immunoglobulin allotype13 Native Americans14,15,16 Household contacts of cases17 Individuals with asplenia, sickle cell disease, or antibody deficiency syndromes18,19 An important virulence factor of the Hib bacterium is its polysaccharide capsule (PRP). Antibody to PRP (anti-PRP) has been shown to correlate with protection against Hib disease.3,21 While the anti-PRP level associated with protection using conjugated vaccines has not yet been determined, the level of anti-PRP associated with protection in studies using bacterial polysaccharide immune globulin or nonconjugated PRP vaccines ranged from > 0.15 to > 1.0 mcg/mL.22-28 Nonconjugated PRP vaccines are capable of stimulating B-lymphocytes to produce antibody without the help of T-lymphocytes (T-independent). The responses to many other antigens are augmented by helper T-lymphocytes (T-dependent). PedvaxHIB is a PRP-conjugate vaccine in which the PRP is covalently bound to the OMPC carrier29 producing an antigen which is postulated to convert the T-independent antigen (PRP alone) into a T-dependent antigen resulting in both an enhanced antibody response and immunologic memory. Clinical Evaluation of PedvaxHIB PedvaxHIB, in a lyophilized formulation (lyophilized PedvaxHIB), was initially evaluated in 3,486 Native American (Navajo) infants, who completed the primary two-dose regimen in a randomized, double-blind, placebo-controlled study (The Protective Efficacy Study). At the time of the study, this population had a much higher incidence of Hib disease than the United States population as a whole and also had a lower antibody response to Haemophilus b Conjugate Vaccines, including PedvaxHIB.14,15,16,30,33 Each infant in this study received two doses of either placebo or lyophilized PedvaxHIB with the first dose administered at a mean of 8 weeks of age and the second administered approximately two months later; DTP and OPV were administered concomitantly. Antibody levels were measured in a subset of each group (TABLE 1). TABLE 1 Antibody Responses in Navajo Infants Vaccine No. of Subjects Time % Subjects with Anti-PRP GMT (mcg/mL) > 0.15 mcg/mL > 1.0 mcg/mL Lyophilized PedvaxHIB* 416** Pre-Vaccination 44 10 0.16 416 Post-Dose 1 88 52 0.95 416 Post-Dose 2 91 60 1.43 Placebo* 461** Pre-Vaccination 44 9 0.16 461 Post-Dose 1 21 2 0.09 461 Post-Dose 2 14 1 0.08 Lyophilized PedvaxHIB 27† Prebooster 70 33 0.51 27 Postbooster‡ 100 89 8.39 * Post-Vaccination values obtained approximately 1-3 months after each dose. ** The Protective Efficacy Study † Immunogenicity Trial34 ‡ Booster given at 12 months of age; Post-Vaccination values obtained 1 month after administration of booster dose. Most subjects were initially followed until 15 to 18 months of age. During this time, 22 cases of invasive Hib disease occurred in the placebo group (8 cases after the first dose and 14 cases after the second dose) and only 1 case in the vaccine group (none after the first dose and 1 after the second dose). Following the primary two-dose regimen, the protective efficacy of lyophilized PedvaxHIB was calculated to be 93% with a 95% confidence interval of 57%-98% (p=0.001, two- tailed). In the two months between the first and second doses, the difference in number of cases of disease between placebo and vaccine recipients (8 vs. 0 cases, respectively) was statistically significant (p=0.008, two-tailed); however, a primary two-dose regimen is required for infants 2-14 months of age. At termination of the study, placebo recipients were offered vaccine. All original participants were then followed two years and nine months from termination of the study. During this extended follow-up, invasive Hib disease occurred in an additional seven of the original placebo recipients prior to receiving vaccine and in one of the original vaccine recipients (who had received only one dose of vaccine). No cases of invasive Hib disease were observed in placebo recipients after they received at least one dose of vaccine. Efficacy for this follow-up period, estimated from person- days at risk, was 96.6% (95 C.I., 72.2-99.9%) in children under 18 months of age and 100% (95 C.I., 23.5-100%) in children over 18 months of age.33 Since protective efficacy with lyophilized PedvaxHIB was demonstrated in such a high risk population, it would be expected to be predictive of efficacy in other populations. The safety and immunogenicity of lyophilized PedvaxHIB were evaluated in infants and children in other clinical studies that were conducted in various locations throughout the United States. PedvaxHIB was highly immunogenic in all age groups studied.31,32 Lyophilized PedvaxHIB induced antibody levels greater than 1.0 mcg/mL in children who were poor responders to nonconjugated PRP vaccines. In a study involving such a subpopulation,33,34 34 children ranging in age from 27 to 61 months who developed invasive Hib disease despite previous vaccination with nonconjugated PRP vaccines were randomly assigned to 2 groups. One group (n=14) was vaccinated with lyophilized PedvaxHIB and the other group (n=20) with a nonconjugated PRP vaccine at a mean interval of approximately 12 months after recovery from disease. All 14 children vaccinated with lyophilized PedvaxHIB but only 6 of 20 children re- vaccinated with a nonconjugated PRP vaccine achieved an antibody level of > 1.0 mcg/mL. The 14 children who had not responded to revaccination with the nonconjugated PRP vaccine were then vaccinated with a single dose of lyophilized PedvaxHIB; following this vaccination, all achieved antibody levels of > 1.0 mcg/mL. In addition, lyophilized PedvaxHIB has been studied in children at high risk of Hib disease because of genetically-related deficiencies [Blacks who were Km(1) allotype negative and Caucasians who were G2m(23) allotype negative] and are considered hyporesponsive to nonconjugated PRP vaccines on this basis.35 The hyporesponsive children had anti-PRP responses comparable to those of allotype positive children of similar age range when vaccinated with lyophilized PedvaxHIB. All children achieved anti-PRP levels of > 1.0 mcg/mL. The safety and immunogenicity of Liquid PedvaxHIB were compared with those of lyophilized PedvaxHIB in a randomized clinical study involving 903 infants 2 to 6 months of age from the general U.S. population. DTP and OPV were administered concomitantly to most subjects. The antibody responses induced by each formulation of PedvaxHIB were similar. TABLE 2 shows antibody responses from this clinical study in subjects who received their first dose at 2 to 3 months of age. TABLE 2 Antibody Responses to Liquid and Lyophilized PedvaxHIB in Infants From the General U.S. Population Formulation Age (Months) Time No. of Subjects % Subjects with anti-PRP Anti-PRP GMT (mcg/mL) > 0.15 mcg/mL > 1.0 mcg/mL Pre-Vaccination 487 32 7 0.12 Liquid 2-3 Post-Dose 1* 480 94 64 1.55 PedvaxHIB Post-Dose 2** 393 97 80 3.22 (7.5 mcg PRP) 12-15 Prebooster 284 80 30 0.49 Postbooster** 284 99 95 10.23 24† Persistence 94 97 55 1.29 Pre-Vaccination 171 37 6 0.13 Lyophilized 2-3 Post-Dose 1* 169 97 72 1.88 PedvaxHIB Post-Dose 2** 133 99 81 2.69 (15 mcg PRP) 12-15 Prebooster 87 71 28 0.39 Postbooster** 87 99 91 7.64 24† Persistence 37 97 54 1.10 * Approximately two months Post-Vaccination ** Approximately one month Post-Vaccination † Approximately A booster dose of PedvaxHIB is required in infants who complete the primary two-dose regimen before 12 months of age. This booster dose will help maintain antibody levels during the first two years of life when children are at highest risk for invasive Hib disease. (See TABLE 2 and DOSAGE AND ADMINISTRATION.) In four United States studies, antibody responses to lyophilized PedvaxHIB were evaluated in several subpopulations of infants initially vaccinated between 2 to 3 months of age. (See TABLE 3.) TABLE 3 Antibody Responses* After Two Doses of Lyophilized PedvaxHIB Among Infants Initially Vaccinated at 2-3 Months of Age By Racial/Ethnic Group Racial/Ethnic Groups No. of Subjects LYOPHILIZED Anti-PRP GMT (mcg/mL) % Subjects With Anti-PRP > 0.15 mcg/mL > 1.0 mcg/mL Native American† 54 96 70 2.47 Caucasian 201 99 82 3.52 Hispanic 76 99 88 3.54 Black 23 100 96 5.40 * One month after the second dose † Apache and Navajo In two United States studies, antibody responses to Liquid PedvaxHIB were evaluated in several subpopulations of infants initially vaccinated between 2 to 3 months of age. (See TABLE 4.) TABLE 4 Antibody Responses* After Two Doses of Liquid PedvaxHIB Among Infants Initially Vaccinated at 2-3 Months of Age By Racial/Ethnic Group Racial/Ethnic Groups No. of Subjects LIQUID Anti-PRP GMT (mcg/mL) % Subjects With Anti-PRP > 0.15 mcg/mL > 1.0 mcg/mL Native American** 90 97 78 2.76 Caucasian 143 94 72 2.16 Hispanic 184 98 85 4.34 Black 18 100 94 7.58 * One month after the second dose ** Apache and Navajo Antibodies to the OMPC of N. meningitidis have been demonstrated in vaccinee sera, but the clinical relevance of these antibodies has not been established.33 Interchangeability of Licensed Haemophilus b Conjugate Vaccines and PedvaxHIB Published studies have examined the interchangeability of other licensed Haemophilus b Conjugate Vaccines and PedvaxHIB.42,43,44,45,52 According to the American Academy of Pediatrics, excellent immune responses have been achieved when different vaccines have been interchanged in the primary series. If PedvaxHIB is given in a series with one of the other products licensed for infants, the recommended number of doses to complete the series is determined by the other product and not by PedvaxHIB. PedvaxHIB may be interchanged with other licensed Haemophilus b Conjugate Vaccines for the booster dose.52 Use with Other Vaccines Results from clinical studies indicate that Liquid PedvaxHIB can be administered concomitantly with DTP, OPV, eIPV (enhanced inactivated poliovirus vaccine), VARIVAX* [Varicella Virus Vaccine Live (Oka/Merck)], M-M-R* II (Measles, Mumps, and Rubella Virus Vaccine Live) or RECOMBIVAX HB* [Hepatitis B Vaccine (Recombinant)].33 No impairment of immune response to individual tested vaccine antigens was demonstrated. The type, frequency and severity of adverse experiences observed in these studies with PedvaxHIB were similar to those seen when the other vaccines were given alone. In addition, a PRP-OMPC-containing product, COMVAX* [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine], was given concomitantly with a booster dose of DTaP [diphtheria, tetanus, acellular pertussis] at approximately 15 months of age, using separate sites and syringes for injectable vaccines. No impairment of immune response to these individually tested vaccine antigens was demonstrated. COMVAX has also been administered concomitantly with the primary series of DTaP to a limited number of infants. PRP antibody responses are satisfactory for COMVAX, but immune responses are currently unavailable for DTaP (see Manufacturer's Product Circular for COMVAX). No serious vaccine-related adverse events were reported.33 REFERENCES 1. Cochi, S. L., et al: Immunization of U.S. children with Haemophilus influenzae type b polysaccharide vaccine: A cost- effectiveness model of strategy assessment. JAMA 253: 521-529, 1985. 2. Schlech, W. F., III, et al: Bacterial meningitis in the United States, 1978 through 1981. The National Bacterial Meningitis Surveillance Study. JAMA 253: 1749-1754, 1985. 3. Peltola, H., et al: Prevention of Haemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 310: 1561-1566, 1984. 4. Cadoz, M., et al: Etude epidemiologique des cas de meningitis purulentes hospitalises a Dakar pendant la decemie 1970-1979. Bull WHO 59: 575-584, 1981. 5. Sell, S. H., et al: Long-term Sequelae of Haemophilus influenzae meningitis. Pediatr 49: 206-217, 1972. 6. Taylor, H. G., et al: Intellectual, neuropsychological, and achievement outcomes in children six to eight years after recovery from Haemophilus influenzae meningitis. Pediatr 74: 198-205, 1984. 7. Hay, J. W., et al: Cost-benefit analysis of two strategies for prevention of Haemophilus influenzae type b infection. Pediatr 80(3): 319-329, 1987. 8. Redmond, S. R., et al: Haemophilus influenzae type b disease: an epidemiologic study with special reference to daycare centers. JAMA 252: 2581-2584, 1984. 9. Istre, G. R., et al: Risk factors for primary invasive Haemophilus influenzae disease: increased risk from daycare attendance and school age household members. J Pediatr 106: 190-195, 1985. 10. Fraser, D.W., et al: Risk factors in bacterial meningitis: Charleston County, South Carolina. J Infect Dis 127: 271-277, 1973. 11. Tarr, P. I., et al: Demographic factors in the epidemiology of Haemophilus influenzae meningitis in young children. J Pediatr 92: 884-888, 1978. 12. Granoff, D. M., et al: Response to immunization with Haemophilus influenzae type b polysaccharide-pertussis vaccine and risk of Haemophilus meningitis in children with Km(1) immunoglobulin allotype. J Clin Invest 74: 1708-1714, 1984. 13. Ambrosino, D. M., et al: Correlation between G2m(n) immunoglobulin allotype and human antibody response and susceptibility to polysaccharide encapsulated bacteria. J Clin Invest 75: 1935-1942, 1985. 14. Coulehan, J. L, et al: Epidemiology of Haemophilus influenzae type b disease among Navajo Indians. Pub Health Rep 99: 404-409, 1984. 15. Losonsky, G. A., et al: Haemophilus influenzae disease in the White Mountain Apaches: molecular epidemiology of a high risk population. Pediatr Infect Dis J 3: 539-547, 1985. 16. Ward, J. I., et al: Haemophilus influenzae disease in Alaskan Eskimos: characteristics of a population with an unusual incidence of disease. Lancet 1: 1281-1285, 1981. 17. Ward, J. I., et al: Haemophilus influenzae meningitis: a national study of secondary spread in household contacts. N Engl J Med 301: 122-126, 1979. 18. Ward, J., et al: Haemophilus influenzae bacteremia in children with sickle cell disease. J Pediatr 88: 261-263, 1976. 19. Bartlett, A. V., et al: Unusual presentations of Haemophilus influenzae infections in immunocompromised patients. J Pediatr 102: 55-58, 1983. 20. Recommendations of the Immunization Practices Advisory Committee. Polysaccharide vaccine for prevention of Haemophilus influenzae type b disease. MMWR 34(15): 201-205, 1985. 21. Santosham, M., et al: Prevention of Haemophilus influenzae type b infections in high-risk infants treated with bacterial polysaccharide immune globulin. N Engl J Med 317: 923-929, 1987. 22. Siber, G. R., et al: Preparation of human hyperimmune globulin to Haemophilus influenzae b, Streptococcus pneumoniae, and Neisseria meningitidis. Infect Immun 45: 248-254, 1984. 23. Smith, D. H., et al: Responses of children immunized with the capsular polysaccharide of Haemophilus influenzae type b. Pediatr 52: 637-645, 1973. 24. Robbins, J. B., et al: Quantitative measurement of 'natural' and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res 7: 103-110, 1973. 25. Kaythy, H., et al: The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 147: 1100, 1983. 26. Peltola, H., et al: 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. Pediatr 60: 730-737, 1977. 27. Ward, J. I., et al: Haemophilus influenzae type b vaccines: Lessons For the Future. Pediatr 81: 886-893, 1988. 28. Daum, R. S., et al: Haemophilus influenzae type b vaccines: Lessons From the Past. Pediatr 81: 893-897, 1988. 29. Marburg, S., et al: Bimolecular chemistry of macromolecules: Synthesis of bacterial polysaccharide conjugates with Neisseria meningitidis membrane protein. J Am Chem Soc 108: 5282-5287, 1986. 30. Letson, G. W., et al: Comparison of active and combined passive/active immunization of Navajo children against Haemophilus influenzae type b. Pediatr Infect Dis J 7(111): 747-752, 1988. 31. Einhorn, M. S., et al: Immunogenicity in infants of Haemophilus influenzae type b polysaccharide in a conjugate vaccine with Neisseria meningitidis outer-membrane protein. Lancet 2: 299-302, 1986. 32. Ahonkhai, V.I., et al: Haemophilus influenzae type b Conjugate Vaccine (Meningococcal Protein Conjugate) (PedvaxHIB TM): Clinical Evaluation. Pediatr 85(4): 676-681, 1990. 33. Data on file at Merck Research Laboratories. 34. Granoff, D. M., et al: Immunogenicity of Haemophilus influenzae type b polysaccharide-outer membrane protein conjugate vaccine in patients who acquired Haemophilus disease despite previous vaccination with type b polysaccharide vaccine. J. Pediatr. 114(6): 925-933, June 1989. 35. Lenoir, A. A., et al: Response to Haemophilus influenzae type b (H. influenzae type b) polysaccharide N. meningitidis outer membrane protein (PS-OMP) conjugate vaccine in relation to Km(1) and G2m(23) allotypes. Twenty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy (Abstract #216) 133, 1986. 42. Recommendations of the Immunization Practices Advisory Committee. Recommendations for use of Haemophilus b Conjugate Vaccines and a combined diphtheria, tetanus, pertussis, and Haemophilus b vaccine. MMWR 42(RR-13): 1-15, 1993. 43. Daum, R. S., et al: Interchangeability of Haemophilus influenzae type b vaccines for the primary series (mix and match): a preliminary analysis [Abstract 976]. Pediatr Res 33: 166A, 1993. 44. Greenberg, D. P., et al: Enhanced antibody responses in infants given different sequences of heterogenous Haemophilus influenzae type b Conjugate Vaccines. J Pediatr 126: 206-211, 1995. 45. Anderson, E. L., et al: Interchangeability of Conjugated Haemophilus influenzae type b Vaccines in Infants. JAMA 273: 849-853, 1995. 52. American Academy of Pediatrics. Recommended Childhood Immunization Schedule - United States, January- December 1998. Pediatr 101(1): 154-157, 1998.

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. 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.3 A booster response for IgG has been demonstrated in children 12 months of age or older who previously received two or three doses of ActHIB vaccine. Bactericidal activity against H influenzae type b was demonstrated in serum after immunization and correlated with the anti-PRP antibody response induced by ActHIB vaccine.4 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.5 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.6 In clinical studies, ActHIB vaccine induced, on average, anti-PRP levels ≥ 1.0 mcg/mL in 90% of infants after the primary series (2, 4, and 6 months) and in more than 98% of infants following a booster dose given at 15 to 19 months of age.4 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 Tennessee7 (TABLE 1) and in Minnesota, Missouri, and Texas (8) (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 whole cell DTP vaccines at separate sites. Neither Poliovirus Vaccine Live Oral nor whole cell DTP vaccines are licensed or distributed in the US. TABLE 1: Anti-PRP Antibody Responses Following a Two or Three Dose Series of a Haemophilus b Vaccine at 2, 4, and 6 Months of Age - Tennessee7 VACCINE Na GEOMETRIC MEAN CONCENTRATION (GMC) (mcg/mL) Post Third Immunization % ≥ 1.0 mcg/mL PreImmunization at 2 months Post Second Immunization at 6 months Post Third Immunization at 7 months PRP-Tb (ActHIB vaccine) 65 0.10 0.30 3.64 83% PRP-OMPc (PedvaxHIB®) 64 0.11 0.84 N/A 50%d HbOCe (HibTITER®) 61 0.07 0.13 3.08 75% a N = Number of Children b Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) c Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) d Seroconversion after the recommended 2-dose primary immunization series is shown e Haemophilus b Conjugate Vaccine (Diphtheria CRMW7 Protein Conjugate) N/A Not applicable in this comparison trial although third dose data have been published7 TABLE 2: Anti-PRP Antibody Responses Following a Two or Three Dose Series of a Haemophilus b Vaccine at 2, 4, and 6 Months of Age - Minnesota, Missouri, and Texas8 VACCINE Na GEOMETRIC MEAN CONCENTRATION (GMC) (mcg/mL) Post Thirdb Immunization % ≥ 1.0 mcg/mL Pre Immunization at 2 months Post Second Immunization At 6 months Post Thirdb Immunization At 7 months PRP-Tc (ActHIB vaccine) 142 0.25 1.25 6.37 97% PRP-OMPd (PedvaxHIB) 149 0.18 4.00 N/A 85%e HbOCf (HibTITER) 167 0.17 0.45 6.31 90% a N = Number of Children b Sera were obtained after the third dose from 86 and 110 infants, in PRP-T and HbOC vaccine groups, respectively c Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) d Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) e Seroconversion after the recommended 2-dose primary immunization series is shown f Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) N/A Not applicable in this comparison trial although third dose data have been published8 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. In a clinical study enrolling Alaskan Native Americans, following the administration of a three dose series of ActHIB at 6 weeks, 4 months, and 6 months of age, 75% of subjects achieved an anti-PRP antibody titer of ≥ 1.0 mcg/mL at 7 months of age (1 month after the last vaccination).9 In four separate studies, 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 (TABLE 3). GMC 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.10 TABLE 3: Anti-PRP Antibody Responses in 12- to 24-month-old Children Immunized with a Single Dose of ActHIB10 AGE GROUP Na GEOMETRIC MEAN CONCENTRATION (GMC) (mcg/mL) % SUBJECTS WITH ≥ 1.0 mcg/mL Pre Immunization Post Immunizationb Pre Immunization Post Immunizationb 12 to 15 months 256 0.06 5.12 1.6 90.2 17 to 24 months 81 0.10 4.40 3.7 81.5 a N = Number of Children b Post immunization responses measured at approximately 1 month after vaccination 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. Following two doses of ActHIB vaccine given at two-month intervals, 89% of these children (mean age 11 months) had anti-PRP antibody titers of ≥ 1.0 mcg/mL. This is comparable to anti-PRP antibody levels demonstrated in normal children of similar age following two doses of ActHIB vaccine.11 TriHIBit Vaccine (ActHIB vaccine combined with Tripedia vaccine by reconstitution) Randomized comparative clinical trials demonstrated that the anti-PRP response achieved in 15- to 20-month-old children 1 month after one dose of TriHIBit vaccine (ActHIB vaccine reconstituted with Tripedia vaccine) was similar to that achieved when the ActHIB and Tripedia vaccines were given concomitantly at different sites with separate needles and syringes (TABLE 4).10 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. TABLE 4: Anti-PRP Responses in 15- to 20-month-old Children Following Immunization with TriHIBit Vaccine Compared to ActHIB Vaccine and Tripedia Vaccine Given Concomitantly at Separate Sites10 IMMUNOGENICITY Pre-Dose Post-Dose (1 month post-vaccination) TriHIBit vaccine Separate Injectionsa TriHIBit vaccine Separate Injectionsa Nb 88 94 93 98 Anti-PRP (mcg/mL) 0.89 1.15 90.30 80.90 % > 1 mcg/mL 45.50 53.20 100.00 100.00 a ActHIB and Tripedia administered concomitantly at separate sites b N= Number of Children For data on the antibody responses to diphtheria, tetanus and pertussis (PT and FHA) antigens in this study, refer to the Tripedia vaccine product insert. REFERENCES 3 Holmes SJ, et al. Immunogenicity of four Haemophilus influenzae type b conjugate vaccines in 17- to 19-month-old children. J Pediatr 118:364-371, 1991. 4 Data on file, Sanofi Pasteur SA. 5 Peltola H, et al. Prevention of Haemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 310:1561-1566, 1984. 6 Recommendations of the Immunization Practices Advisory Committee (ACIP). Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. MMWR 40:No. RR-1, 1991. 7 Decker MD, et al. Comparative trial in infants of four conjugate Haemophilus influenza type b vaccines. J Pediatr 120:184-189, 1992. 8 Granoff DM, et al. Differences in the immunogenicityof three Haemophilus influenzae type b conjugate vaccines in infants. J Pediatr 121:187-194, 1992. 9 Bulkow LR, et al. Comparative immunogenicity of four Haemophilus influenzae type b conjugate vaccines in Alaska Native infants. Pediatr Infect Dis J 12:484-92, 1993. 10 Data on file, Sanofi Pasteur Inc. 11 Kaplan SL, et al. Immunogenicity of Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine in children with sickle hemoglobinopathy or malignancies, and after systemic Haemophilus influenzae type b infection. J Pediatr 120:367-370, 1992.

ProHIBiT® Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate) DESCRIPTION ProHIBiT®, Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate), for intramuscular use, is a sterile solution, prepared from the purified capsular polysaccharide, a polymer of ribose, ribitol and phosphate (PRP) of the Eagen Haemophilus influenzae type b strain covalently bound to diphtheria toxoid (D) and dissolved in sodium phosphate buffered isotonic sodium chloride solution. The polysaccharide-protein conjugate molecule is referred to as PRP-D. Thimerosal (mercury derivative) 1:10,000 is added as a preservative. The vaccine is a clear, colorless solution. Each single dose of 0.5 mL is formulated to contain 25 µg of purified capsular polysaccharide and 18 µg of diphtheria toxoid protein.

Find Lowest Prices on Liquid PedvaxHIB® [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] DESCRIPTION PedvaxHIB* [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] is a highly purified capsular polysaccharide (polyribosylribitol phosphate or PRP) of Haemophilus influenzae type b (Haemophilus b, Ross strain) that is covalently bound to an outer membrane protein complex (OMPC) of the B11 strain of Neisseria meningitidis serogroup B. The covalent bonding of the PRP to the OMPC which is necessary for enhanced immunogenicity of the PRP is confirmed by quantitative analysis of the conjugate's components following chemical treatment which yields a unique amino acid. The potency of PedvaxHIB is determined by assay of PRP. Haemophilus influenzae type b and Neisseria meningitidis serogroup B are grown in complex fermentation media. The PRP is purified from the culture broth by purification procedures which include ethanol fractionation, enzyme digestion, phenol extraction and diafiltration. The OMPC from Neisseria meningitidis is purified by detergent extraction, ultracentrifugation, diafiltration and sterile filtration. Liquid PedvaxHIB is ready to use and does not require a diluent. Each 0.5 mL dose of Liquid PedvaxHIB is a sterile product formulated to contain: 7.5 mcg of Haemophilus b PRP, 125 mcg of Neisseria meningitidis OMPC and 225 mcg of aluminum as amorphous aluminum hydroxyphosphate sulfate (previously referred to as aluminum hydroxide), in 0.9% sodium chloride, but does not contain lactose or thimerosal. Liquid PedvaxHIB is a slightly opaque white suspension. This vaccine is for intramuscular administration and not for intravenous injection. (See DOSAGE AND ADMINISTRATION.)

Find Lowest Prices on ActHIB® Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) Intramuscular Administration Only DESCRIPTION ActHIB ®, Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), produced by Sanofi Pasteur SA, is a sterile, lyophilized powder which is reconstituted with either saline diluent (0.4% Sodium Chloride) or Tripedia®, Sanofi Pasteur Inc. Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) (when reconstituted known as TriHIBit®) for intramuscular administration 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 The culture medium contains milk derived raw materials (casein derivatives). Further manufacturing process steps reduce residual formaldehyde to levels below 0.5 micrograms (mcg) per dose by calculation. The toxoid is filter sterilized prior to the conjugation process. Potency of ActHIB vaccine is specified on each lot by limits on the content of PRP polysaccharide and protein in each dose and the proportion of polysaccharide and protein in the vaccine which is characterized as high molecular weight conjugate. When ActHIB is reconstituted with saline diluent (0.4% Sodium Chloride), each 0.5 mL dose is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, and 8.5% of sucrose. When ActHIB is reconstituted with Tripedia vaccine to formulate TriHIBit vaccine, each 0.5 mL dose contains10 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. Tripedia vaccine (vial presentation 0.6 mL) 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.) REFERENCES 1 Chu CY, et al. Further studies on the immunogenicity of Haemophilus influenzae type b and pneumococcal type 6A polysaccharide-protein conjugate. Infect Immun 40:245-246, 1983. 2 Mueller JH, et al. Production of diphtheria toxin of high potency (100 Lf) on a reproducible medium. J Immunol 40:21-32, 1941.

INDICATIONS ProHIBiT (haemophilus b conjugate vaccine) ® is indicated for immunization against invasive diseases caused by Haemophilus influenzaetype b.25,26 ProHIBiT (haemophilus b conjugate vaccine) ® may be administered as a booster vaccination at 12 to 15 months of age in children who received primary immunization with Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) or Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) as illustrated in Tables 2, 3, 4 and 5. This vaccine also may be administered as primary immunization at 15 months of age in children who have not received primary immunization with any licensed Haemophilus b Conjugate Vaccine. TABLE 215: ProHIBiT (haemophilus b conjugate vaccine) ® Booster Induced Anti-PRP Antibody Responses in 12-Month-Old Children Primed with Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) Geometric Mean Titers (GMT) % of Infants Anti-PRP Antibody Titer ≥ 0.15 µg/mL % of Infants Anti-PRP Antibody Titer ≥ 1.00 µg/mL Pre-immunization N=24 0.322 71% 17% Post-immunization N=24 21.277* 100% 96%** TABLE 315: ProHIBiT (haemophilus b conjugate vaccine) ® Booster Induced Anti-PRP Antibody Responses in 15-Month-Old Children Primed with Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) Geometric Mean Titers (GMT) % of Infants Anti-PRP Antibody Titer ≥ 0.15 µg/mL % of Infants Anti-PRP Antibody Titer ≥ 1.00 µg/mL Pre-immunization N=29 0.526 86% 28% Post-immunization N=29 31.314* 100% 100%** * Comparison of the booster immunogenicity data at 12 and 15 months showed equivalent antibody titers (p = 0.3115), analysis of variance. **Comparison of the percentages of 12- and 15-month-old infants who responded with a PRP antibody response ≥ 1.00 µg/mL showed no significant difference (p = 0.267), Chi-square test. TABLE 415: ProHIBiT (haemophilus b conjugate vaccine) ® Booster Induced Anti-PRP Antibody Responses in 12-Month-Old Children Primed with Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) Geometric Mean Titers (GMT) % of Infants Anti-PRP Antibody Titer ≥ 0.15 µg/mL % of Infants Anti-PRP Antibody Titer ≥ 1.00 µg/mL Pre-immunization N=29 0.911 93% 34% Post-immunization N=29 26.062* 100% 97%** TABLE 515: ProHIBiT (haemophilus b conjugate vaccine) ® Booster Induced Anti-PRP Antibody Responses in 15-Month-Old Children Primed with Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) Geometric Mean Titers (GMT) % of Infants Anti-PRP Antibody Titer ≥ 0.15 µg/mL % of Infants Anti-PRP Antibody Titer ≥ 1.00 µg/mL Pre-immunization N=32 0.675 86% 40.6% Post-immunization N=32 44.156* 100% 100%** * Comparison of the booster immunogenicity data at 12 and 15 months showed equivalent antibody titers (p = 0.1104), analysis of variance. ** Comparison of the percentages of 12 and 15-month-old infants who responded with a PRP antibody response ≥ 1.00 µg/mL showed no significant difference (p = 0.290), Chi-square test. Children With Symptomatic Human Immunodeficiency Virus (Hiv) Infection Immunization with Haemophilus b Conjugate Vaccine is recommended by the American Academy of Pediatrics (Red Book) and Immunization Practices Advisory Committee (ACIP) for children who are immunosuppressed in association with AIDS or any other immunodeficiency disease.26,27 ProHIBiT (haemophilus b conjugate vaccine) ® will not protect against Haemophilus influenzae other than type b or other microorganisms that cause meningitis or septic disease. No impairment of the immune response to the individual antigens was demonstrated when ProHIBiT (haemophilus b conjugate vaccine) ® and Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed (DTP) were given at the same time in separate syringes at different sites.15,28 Limited data are available on concomitant administration of ProHIBiT (haemophilus b conjugate vaccine) ® with MMR, and OPV (IPV). Fourteen-month-old Finnish children boosted with PRP-D received MMR concomitantly. Pre and 4 weeks post sera from a small subset (11 patients), showed no significant difference in antibody response to Measles, Mumps, or Rubella antigens when compared to a group that received MMR alone. A group of 25 Finnish infants received concomitant DTP, PRP-D, and IPV was compared to a group of 25 receiving DTP and IPV only. No significant difference in response to Type 1, Type 2, or Type 3 polio antigens was noted. Response to oral Polio Vaccine was evaluated in 31 infants immunized with PRP-D who also received OPV concomitantly. No difference in response to Type 1, Type 2, or Type 3 antigens was observed when compared to 22 infants receiving placebo and OPV.15,29 ProHIBiT (haemophilus b conjugate vaccine) ® IS NOT RECOMMENDED FOR USE IN CHILDREN YOUNGER THAN 12 MONTHS OF AGE. DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for extraneous particulate matter and/or discoloration prior to administration whenever solution and container permit. If these conditions exist, the vaccine should not be administered. The immunizing dose is a single injection of 0.5 mL given intramuscularly in the outer aspect area of the vastus lateralis (mid-thigh) or deltoid. Each 0.5 mL dose contains 25 µg of purified capsular polysaccharide and 18 µg of conjugated diphtheria toxoid protein. Before injection, the skin over the site to be injected should be cleansed with a suitable germicide. After insertion of the needle, aspirate to ensure that the needle has not entered a blood vessel. DO NOT INJECT INTRAVENOUSLY. A booster dose of ProHIBiT (haemophilus b conjugate vaccine) ® should be administered to children 12 to 15 months of age previously immunized with any licensed Hib conjugate vaccine. A single dose of ProHIBiT (haemophilus b conjugate vaccine) ® should be administered to children 15 months of age and older, not previously immunized with a Hib conjugate vaccine. HOW SUPPLIED Vial, 1 Dose (5 per package) – Product No. 49281-541-01 Vial, 5 Dose – Product No. 49281-541-05 Vial, 10 Dose – Product No. 49281-541-10 Storage Store between 2° – 8°C (35° – 46°F). DO NOT FREEZE. REFERENCES 15. Unpublished data available from Connaught Laboratories, Inc. 20. Lepow ML, et al. Safety and immunogenicity of Haemophilus influenzae type b-polysaccharide diphtheria toxoid conjugate vaccine in infants 9 to 15 months of age. J Pediatr 106:185-189,1985 25. ACIP - Update. Prevention of Haemophilus influenzae type b disease. MMWR 37:13-16,1988 26. Report of the Committee on Infectious Diseases, ed 22. Elk Grove Village, IL, American Academy of Pediatrics, 1991 27. ACIP Immunization of children infected with human immunodeficiency virus - Supplementary ACIP statement. MMWR 37: 181-183, 1988 28. Hendley JO, et al. Immunogenicity of Haemophilus influenzae type b capsular polysaccharide vaccines in 18-month-old infants. Pediatr 80: 351-354,1987 29. Eskola J, et al. Simultaneous administration of Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine with routine diphtheria-tetanus-pertussis and inactivated poliovirus vaccinations of childhood. Pediatr Infect Dis J 7: 480- 484,1988 32. National Childhood Vaccine Injury Act of 1986 (Amended 1987) 33. National Childhood Vaccine Injury Act: Requirements for permanent vaccination records and for reporting of selected events after vaccination. MMWR 37:197-200,1988 34. Berkowitz CD, et al. Safety and immunogenicity of Haemophilus influenzae type b polysaccharide and polysaccharide diphtheria toxoid conjugate vaccines in children 15 to 24 months of age. J Pediatr 110:509-514,1987 35. Eskola J, et al. Efficacy of Haemophilus influenzae type b polysaccharide diphtheria toxoid conjugate vaccine in infancy. N Engl J Med 317: 717-722,1987 36. D'Cruz OF, et al. Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré Syndrome) after immunization with Haemophilus influenzae type b conjugate vaccine. J Pediatr 115: 743-746,1989 37. Vaccine Adverse Event Reporting System - United States. MMWR 39: 730-733,1990 Manufactured by: Connaught Laboratories, Inc. Swiftwater, Pennsylvania 18370, USA. Product Information as of July 1992.

INDICATIONS Liquid PedvaxHIB is indicated for routine vaccination against invasive disease caused by Haemophilus influenzae type b in infants and children 2 to 71 months of age. Liquid PedvaxHIB will not protect against disease caused by Haemophilus influenzae other than type b or against other microorganisms that cause invasive disease such as meningitis or sepsis. As with any vaccine, vaccination with Liquid PedvaxHIB may not result in a protective antibody response in all individuals given the vaccine. BECAUSE OF THE POTENTIAL FOR IMMUNE TOLERANCE, Liquid PedvaxHIB IS NOT RECOMMENDED FOR USE IN INFANTS YOUNGER THAN 6 WEEKS OF AGE. (See PRECAUTIONS.) Revaccination Infants completing the primary two-dose regimen before 12 months of age should receive a booster dose (see DOSAGE AND ADMINISTRATION). DOSAGE AND ADMINISTRATION Liquid PedvaxHIB FOR INTRAMUSCULAR ADMINISTRATION DO NOT INJECT INTRAVENOUSLY If there is an interruption or delay between doses in the primary series, there is no need to repeat the series, but dosing should be continued at the next clinic visit. (See CONTRAINDICATIONS and PRECAUTIONS.) 2 to 14 Months of Age Infants 2 to 14 months of age should receive a 0.5 mL dose of vaccine ideally beginning at 2 months of age followed by a 0.5 mL dose 2 months later (or as soon as possible thereafter). When the primary two-dose regimen is completed before 12 months of age, a booster dose is required (see below and TABLE 6). Infants born prematurely, regardless of birth weight, should be vaccinated at the same chronological age and according to the same schedule and precautions as full-term infants and children.46 15 Months of Age and Older Children 15 months of age and older previously unvaccinated against Hib disease should receive a single 0.5 mL dose of vaccine. Booster Dose In infants completing the primary two-dose regimen before 12 months of age, a booster dose (0.5 mL) should be administered at 12 to 15 months of age, but not earlier than 2 months after the second dose. Vaccination regimens for Liquid PedvaxHIB by age group are outlined in TABLE 6. TABLE 6 Vaccination Regimens for Liquid PedvaxHIB By Age Groups Age (Months) at First Dose Primary Age (Months) at Booster Dose 2-10 2 doses, 2 mo. apart 12-15 11-14 2 doses, 2 mo. apart - 15-71 1 dose - Interchangeability PedvaxHIB may be interchanged with other licensed Haemophilus b Conjugate Vaccines for the primary and booster doses.52 (See CLINICAL PHARMACOLOGY.) Use with Other Vaccines Results from clinical studies indicate that Liquid PedvaxHIB can be administered concomitantly with DTP, OPV, eIPV (enhanced inactivated poliovirus vaccine), VARIVAX [Varicella Virus Vaccine Live (Oka/Merck)], M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live) or RECOMBIVAX HB [Hepatitis B Vaccine (Recombinant)]. No impairment of immune response to these individually tested vaccine antigens was demonstrated. The type, frequency and severity of adverse experiences observed in these studies with PedvaxHIB were similar to those seen with the other vaccines when given alone. (See CLINICAL PHARMACOLOGY.) In addition, a PRP-OMPC-containing product, COMVAX [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine], was given concomitantly with a booster dose of DTaP [diphtheria, tetanus, acellular pertussis] at approximately 15 months of age, using separate sites and syringes for injectable vaccines. No impairment of immune response to these individually tested vaccine antigens was demonstrated. COMVAX has also been administered concomitantly with the primary series of DTaP to a limited number of infants. PRP antibody responses are satisfactory for COMVAX, but immune responses are currently unavailable for DTaP (see Manufacturer's Product Circular for COMVAX). No serious vaccine-related adverse events were reported.33 Parenteral drug products should be inspected visually for extraneous particulate matter and discoloration prior to administration whenever solution and container permit. Liquid PedvaxHIB is a slightly opaque white suspension. (See DESCRIPTION.) The vaccine should be used as supplied; no reconstitution is necessary. Shake well before withdrawal and use. Thorough agitation is necessary to maintain suspension of the vaccine. Inject 0.5 mL intramuscularly, preferably into the anterolateral thigh or the outer aspect of the upper arm. The buttocks should not be used for active vaccination of infants and children, because of the potential risk of injury to the sciatic nerve. HOW SUPPLIED Liquid PedvaxHIB is supplied as follows: No. 4897 - A box of 10 single-dose vials of liquid vaccine, NDC 0006-4897-00. Storage Store vaccine at 2-8°C (36-46°F). DO NOT FREEZE. REFERENCES 33. Data on file at Merck Research Laboratories. 52. American Academy of Pediatrics. Recommended Childhood Immunization Schedule - United States, January- December 1998. Pediatr 101(1): 154-157, 1998. Manuf. and Dist. by: MERCK & CO., INC., West Point, PA 19486, USA. Issued January 2001. FDA Rev date: 1/1/2001

INDICATIONS ActHIB vaccine is indicated for the active immunization of infants and children 2 months through 5 years of age for the prevention of invasive disease caused by H influenzae type b. TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, is indicated for the active immunization of children 15 through 18 months of age for prevention of invasive disease caused by H influenzae type b and diphtheria, tetanus and pertussis. Vaccination with ActHIB vaccine reconstituted with saline diluent (0.4% Sodium Chloride) or Tripedia vaccine (TriHIBit vaccine) may not protect 100% of individuals. DOSAGE AND ADMINISTRATION For intramuscular injection only The ActHIB vaccine, reconstituted with saline diluent (0.4% Sodium Chloride), appears clear and colorless. TriHIBit vaccine, the reconstituted vaccine using Tripedia vaccine, is a homogenous white suspension. Parenteral drug products should be inspected visually for particulate matter and/or discoloration prior to administration, whenever solution and container permit. If these conditions exist, the vaccine should not be administered. Reconstitution ActHIB is to be reconstituted only with the accompanying saline diluent (0.4% Sodium Chloride) or Tripedia vaccine to formulate TriHIBit vaccine. TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, should not be administered to infants younger than 15 months of age. To prepare ActHIB vaccine, withdraw 0.6 mL of saline diluent (0.4% Sodium Chloride) and inject into the vial of lyophilized ActHIB vaccine. Agitate the vial to ensure complete reconstitution. The vaccine will appear clear and colorless. Withdraw a 0.5 mL dose of the reconstituted vaccine and inject intramuscularly. After reconstitution with saline diluent (0.4% Sodium Chloride), ActHIB vaccine should be administered promptly or stored refrigerated between 2° to 8°C (35° to 46°F) and administered within 24 hours. If the vaccine is not administered promptly, agitate the vial again before injection. Refer to Figures 1, 2, 3, 4, and 5. To prepare TriHIBit vaccine, thoroughly agitate the vial of Sanofi Pasteur Inc. Tripedia vaccine then withdraw 0.6 mL and inject into the vial of lyophilized ActHIB vaccine. After reconstitution and thorough agitation, the combined vaccines will appear whitish in color. Withdraw a 0.5 Ml dose of the combined vaccines and inject intramuscularly. TriHIBit vaccine (ActHIB reconstituted with Tripedia vaccine) should be administered within 30 minutes of reconstitution. Refer to Figures 1, 2, 3, 4, and 5. Instructions for Reconstitution of ActHIB Vaccine with Saline Diluent (0.4% Sodium Chloride) or Tripedia Vaccine (TriHIBit Vaccine) Figure 1. Agitate vial prior to disinfecting the vial stopper to avoid possible contamination. Figure 2. Withdraw 0.6 mL of 0.4% Sodium Chloride or Tripedia vaccine as indicated. Figure 3. Cleanse the ActHIB vaccine stopper, insert the syringe needle into the vial, and inject the total volume of diluent. Figure 4. Agitate vial thoroughly. Figure 5. After reconstitution, cleanse vial stopper. Using a new needle and syringe, withdraw 0.5 mL of reconstituted vaccine and administer intramuscularly. Before injection, the skin over the site to be injected should be cleansed with a suitable germicide. Each dose of ActHIB vaccine reconstituted with saline diluent (0.4% Sodium Chloride) or Tripedia vaccine (TriHIBit vaccine) is administered intramuscularly in the outer aspect of the vastus lateralis (mid-thigh) or deltoid. The vaccine should not be injected into the gluteal area or areas where there may be a nerve trunk. A 0.5 mL dose of ActHIB is approved for intramuscular administration in infants and children, 2 months through 5 years of age as a 4-dose series. The series consists of a primary immunization course of 3 doses administered at 2, 4, and 6 months of age, followed by one booster dose, administered at 15-18 months of age. The booster dose at 15-18 months of age may be given as TriHibit vaccine (ActHIB reconstituted with Tripedia). For previously unvaccinated children, the number of doses of Haemophilus b Conjugate Vaccine needed depends on the age at which the immunization series is begun. A previously unvaccinated infant, 7 to 11 months of age, should receive as primary immunizations, two doses of Haemophilus b Conjugate Vaccine at 8-week intervals, followed by a booster dose at 15 to 18 months of age. A previously unvaccinated child 12 to 14 months of age should receive one dose of Haemophilus b Conjugate Vaccine followed by a booster dose at 15 to 18 months of age (doses to be separated by an interval of 8 weeks). A previously unvaccinated child 15 months through 5 years of age should receive one dose of ActHIB vaccine. Preterm infants should be vaccinated according to their chronological age from birth.19 Interruption of the recommended schedule with a delay between doses should not interfere with the final immunity achieved with ActHIB vaccine reconstituted with saline diluent (0.4% Sodium Chloride) or with Tripedia vaccine (TriHIBit vaccine). There is no need to start the series over again, regardless of the time elapsed between doses. HOW SUPPLIED ActHIB Vaccine Reconstituted with Saline Diluent (0.4% Sodium Chloride) Single-dose, lyophilized vaccine vial (NDC 49281-547-58) packaged with single-dose diluent vial (NDC 49281-546-05). Supplied as package of 5 vials each (NDC 49281-545-05). TriHIBit Vaccine, ActHIB Vaccine Reconstituted with Tripedia Vaccine Single-dose, lyophilized vaccine vial (NDC 49281-545-50) packaged with single-dose diluent vial of Tripedia vaccine (NDC 49281-298-01). Supplied as package of 5 vials each (NDC 49281-59705). Storage Store lyophilized vaccine packaged with saline diluent (0.4% Sodium Chloride) or Tripedia vaccine at 2° to 8°C (35° to 46°F). DO NOT FREEZE. REFERENCES 19 American Academy of Pediatrics. Immunization in Special Clinical Circumstances. In: Peter G, ed. 1994 Red Book: Report of the Committee on Infectious Diseases. 23rd ed. Elk Grove Village, IL 51-52, 1994. Manufactured by: Sanofi Pasteur SA, Lyon France, US Govt License #1724. Distributed by: Sanofi Pasteur Inc., Swiftwater PA 18370 USA, 1-800-VACCINE (1-800-822-2463). Revised: Jan 2014

PATIENT INFORMATION Parents should be fully informed of the benefits and risks of immunization with Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate). Information sheets are available from the Centers for Disease Control and Prevention (CDC) or the State Health Department. Prior to administration of Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate), the parent or guardian should be asked about the recent health status of the infant or child to be injected. The physician should inform the parents or guardian about the significant adverse reactions that have been temporally associated with Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate) administration, informed consent should be obtained and recorded, and the parent should inform the physician if any of these events occur. As part of the child's immunization record, the date, lot number and manufacturer of the vaccine administered should be recorded.32,33 REFERENCES 32. National Childhood Vaccine Injury Act of 1986 (Amended 1987) 33. National Childhood Vaccine Injury Act: Requirements for permanent vaccination records and for reporting of selected events after vaccination. MMWR 37:197-200,1988

PATIENT INFORMATION The healthcare provider should provide the vaccine information required to be given with each vaccination to the patient, parent, or guardian. The healthcare provider should inform the patient, parent, or guardian of the benefits and risks associated with vaccination. For risks associated with vaccination, see ADVERSE REACTIONS. Patients, parents, and guardians should be instructed to report any serious adverse reactions to their healthcare provider who in turn should report such events to the U. S. Department of Health and Human Services through the Vaccine Adverse Event Reporting System (VAERS), 1-800-822-7967.47 REFERENCES 47. Vaccine Adverse Event Reporting System - United States. MMWR 39(41): 730-733, October 19, 1990.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE No information provided. CONTRAINDICATIONS HYPERSENSITIVITY TO ANY COMPONENT OF THE VACCINE, INCLUDING THIMEROSAL AND DIPHTHERIA TOXOID, IS A CONTRAINDICATION TO USE OF THIS VACCINE.

OVERDOSE No information provided. CONTRAINDICATIONS Hypersensitivity to any component of the vaccine or the diluent. Persons who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections of the vaccine.

OVERDOSE No information provided. CONTRAINDICATIONS ActHIB vaccine is contraindicated in children with a history of hypersensitivity to any component of the vaccine and to any component of Tripedia vaccine when it is used to reconstitute ActHIB. Any contraindication for Tripedia vaccine is a contraindication for TriHIBit vaccine, ActHIB vaccine reconstituted with Tripedia vaccine. (Refer to product insert for Tripedia vaccine.) TriHIBit vaccine (ActHIB reconstituted with Tripedia) is contraindicated in children who have shown symptoms of encephalopathy (e.g., coma, decreased level of consciousness, prolonged seizures) within 7 days of administration of a previous dose of a pertussis-containing vaccine that is not attributable to another identifiable cause. TriHIBit is contraindicated in children who have a progressive neurologic disorder, including infantile spasms, uncontrolled epilepsy, or progressive encephalopathy. Pertussis-containing vaccines should not be administered to individuals with these conditions until a treatment regimen has been established and the condition has stabilized.

SIDE EFFECTS When ProHIBiT (haemophilus b conjugate vaccine) ® alone was given to over 1,000 adults and children, no serious adverse reactions were observed.15,20,25,34 Thrombocytopenia was seen in one adult but a causative relationship was not established. When ProHIBiT (haemophilus b conjugate vaccine) ® was given with DTP and Inactivated Poliovirus Vaccine (IPV) to 55,000 Finnish children, the rate and extent of serious adverse reactions were not different from those seen when DTP or IPV were administered alone.25,35 Allergic reactions such as urticaria were infrequently observed.15,35 Adverse reactions following vaccination with ProHIBiT (haemophilus b conjugate vaccine) ® (without DTP) in subjects 15 to 24 months of age are summarized in Table 6.34 TABLE 634: Percentage of Subjects 15 to 24 Months of Age Developing Local or Systemic Reactions to One Dose of Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate) No. of Subjects* 6 Hours Reaction 24 Hours 48 Hours Fever > 38.3°C 281 1.1 2.1 1.8 Erythema 285 – 2.5 0.4 Induration 285 – 1.0 0.4 Tenderness 285 – 4.6 0.7 * Not all subjects had measurements at all time periods. Other adverse reactions temporally associated with administration of ProHIBiT (haemophilus b conjugate vaccine) ® including diarrhea, vomiting, and crying were reported at a frequency of ≤ 1.2%. Fever of 39°C or more occurred in < 1%, while irritability, sleepiness, or anorexia were reported in 16.1%.34 Adverse reactions in clinical evaluations among 689 children, 7 to 14 months of age, 24 hours after receiving a single dose of ProHIBiT (haemophilus b conjugate vaccine) ® , were observed and compared to 139 children who received a saline placebo. There were no significant differences in the reaction rates for fever, erythema, induration, and tenderness between the two groups.15 A post-marketing surveillance study was conducted between April 1988 and July 1989 in the United States in 50,007 children 16 to 60 months of age. At Southern California Kaiser Permanente, 29,309 of these children were followed closely to determine the number of systemic and local reactions occurring within 6, 24, and 48 hours post-vaccination with ProHIBiT (haemophilus b conjugate vaccine) ® alone. These reactions are summarized in Table 7.15 TABLE 715: Post-Marketing Surveillance Study in Subjects 16-60 Months of Age Experiencing Adverse Reactions (n=29,309) 6 Hours Reaction % 24 Hours 48 Hours Fever > 38.9°C 2 2 2 Analgesic Given 23 12 8 Irritability 17 14 10 Drowsiness 13 8 5 Unusual Crying 2 2 2 Vomiting/Poor Eating 7 7 7 Redness 2 1 1 Swelling 2 2 1 Tenderness 25 12 5 In 50 children who had received licensed Haemophilis b Conjugate Vaccine in infancy and a booster dose of ProHIBiT (haemophilus b conjugate vaccine) ® at 12 months of age, the adverse experience profile was similar as summarized in Table 8.15 TABLE 815: Adverse Experiences with ProHIBiT (haemophilus b conjugate vaccine) ® given as a Booster at 12 to 15 Months of Age Primary Series either with Haemophilus b Conjugate Vaccine (Diphtheria CRM197Protein Conjugate) or Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) (n=50) 6 Hours Reaction % 24 Hours 48 Hours Fever > 38.9°C 0 0 2 Analgesic Given 14 8 6 Irritability 28 18 14 Drowsiness 20 4 6 Unusual Crying 0 0 0 Vomiting/Poor Eating 10 10 6 Hypotonic/Hyporesponsive 0 0 0 Redness 4 6 4 Swelling 4 0 0 Tenderness 4 0 0 Other adverse reactions reported with administration of ProHIBiT (haemophilus b conjugate vaccine) ® included urticaria, seizure, and renal failure.15,34 Guillain-Barré syndrome (GBS) rarely has been reported.36 However, a cause and effect relationship for these adverse events has not been established. Reporting of Adverse Events Reporting by parents or guardians of all adverse events occurring after vaccine administration should be encouraged. Adverse events following immunization with vaccine should be reported by the health-care provider to the US Department of Health and Human Services (DHHS) Vaccine Adverse Event Reporting System (VAERS). Reporting forms and information about reporting requirements or completion of the form can be obtained from VAERS through a toll-free number 1-800-822-7967.32,33,37 Health-care providers also should report these events to the Director of Medical Affairs, Connaught Laboratories, Inc., a Pasteur Mérieux Connaught Company, Route 611, P. O. Box 187, Swiftwater, PA 18370 or call 1-800-822-2463. DRUG INTERACTIONS No information provided.

SIDE EFFECTS Liquid PedvaxHIB In a multicenter clinical study (n=903) comparing the effects of Liquid PedvaxHIB with those of lyophilized PedvaxHIB, 1,699 doses of Liquid PedvaxHIB were administered to 678 healthy infants 2 to 6 months of age from the general U.S. population. DTP and OPV were administered concomitantly to most subjects. Both formulations of PedvaxHIB were generally well tolerated and no serious vaccine-related adverse reactions were reported. During a three-day period following primary vaccination with Liquid PedvaxHIB in these infants, the most frequently reported ( > 1%) adverse reactions, without regard to causality, excluding those shown in TABLE 5, in decreasing order of frequency, were: irritability, sleepiness, injection site pain/soreness, injection site erythema ( ≤ 2.5 cm diameter, see also TABLE 5), injection site swelling/induration ( ≤ 2.5 cm diameter, see also TABLE 5), unusual high-pitched crying, prolonged crying ( > 4 hr), diarrhea, vomiting, crying, pain, otitis media, rash, and upper respiratory infection. Selected objective observations reported by parents over a 48-hour period in these infants following primary vaccination with Liquid PedvaxHIB are summarized in TABLE 5. TABLE 5 Fever or Local Reactions in Subjects First Vaccinated at 2 to 6 Months of Age with Liquid PedvaxHIB* Reaction No. of Subjects Evaluated Post-Dose 1 (hr) No. of Subjects Evaluated Post-Dose 2 (hr) 6 24 48 6 24 48 Percentage Percentage Fever** > 38.3°C ( ≥ 101°F) Rectal 222 18.1 4.4 0.5 206 14.1 9.4 2.8 Erythema > 2.5 cm diameter 674 2.2 1.0 0.5 562 1.6 1.1 0.4 Swelling > 2.5 cm diameter 674 2.5 1.9 0.9 562 0.9 0.9 1.3 * DTP and OPV were administered concomitantly to most subjects. ** Fever was also measured by another method or reported as normal for anadditional 345 infants after dose 1 and for an additional 249 infants after dose 2;however, these data are not included in this table. Adverse reactions during a three-day period following administration of the booster dose were generally similar in type and frequency to those seen following primary vaccination. Lyophilized PedvaxHIB In The Protective Efficacy Study (see CLINICAL PHARMACOLOGY), 4,459 healthy Navajo infants 6 to 12 weeks of age received lyophilized PedvaxHIB or placebo. Most of these infants received DTP/OPV concomitantly. No differences were seen in the type and frequency of serious health problems expected in this Navajo population or in serious adverse experiences reported among those who received lyophilized PedvaxHIB and those who received placebo, and none was reported to be related to lyophilized PedvaxHIB. Only one serious reaction (tracheitis) was reported as possibly related to lyophilized PedvaxHIB and only one (diarrhea) as possibly related to placebo. Seizures occurred infrequently in both groups (9 occurred in vaccine recipients, 8 of whom also received DTP; 8 occurred in placebo recipients, 7 of whom also received DTP) and were not reported to be related to lyophilized PedvaxHIB. In early clinical studies involving the administration of 8,086 doses of lyophilized PedvaxHIB alone to 5,027 healthy infants and children 2 months to 71 months of age, lyophilized PedvaxHIB was generally well tolerated. No serious adverse reactions were reported. In a subset of these infants, urticaria was reported in two children, and thrombocytopenia was seen in one child. A cause and effect relationship between these side effects and the vaccination has not been established. Potential Adverse Reactions The use of Haemophilus b Polysaccharide Vaccines and another Haemophilus b Conjugate Vaccine has been associated with the following additional adverse effects: early onset Hib disease and Guillain-Barre syndrome. A cause and effect relationship between these side effects and the vaccination was not established.36,37,39,40,41,49 Post-Marketing Adverse Reactions The following additional adverse reactions have been reported with the use of the lyophilized and liquid formulations of PedvaxHIB: Hemic and Lymphatic System Lymphadenopathy Hypersensitivity Rarely, angioedema Nervous System Febrile seizures Skin Sterile injection site abscess DRUG INTERACTIONS No information provided. REFERENCES 36. Mortimer, E. A.: Efficacy of Haemophilus b polysaccharide vaccine: An enigma. JAMA 260: 1454, 1988. 37. Meekison, W., et al: Post-marketing surveillance of adverse effects following ProHIBiT vaccine. British Columbia Canada Diseases Weekly Report 15-28: 143-145, 1989. 38. Goepp, J. G., et al: Persistent urinary antigen excretion in infants vaccinated with Haemophilus influenzae type b capsular polysaccharide conjugated with outer membrane protein from Neisseria meningitidis. Pediatr Infect Dis J 11(1): 2-5, 1992. 39. Milstein, J. B., et al: Adverse reactions reported following receipt of Haemophilus influenzae type b vaccine: An analysis after one year of marketing. Pediatr 80: 270, 1987. 40. Black, S., et al: b-CAPSA 1 Haemophilus influenzae type b capsular polysaccharide vaccine safety. Pediatr 79: 321-325, 1987. 41. D'Cruz, O. F., et al: Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome) after immunization with Haemophilus influenzae type b Conjugate Vaccine. J Pediatr 115: 743-746, 1989. 49. Keyserling, H.L., et al: Program and Abstracts of the 30th ICAAC, (Abstract #63), 1990.

SIDE EFFECTS More than 7,000 infants and young children ( ≤ 2 years of age) have received at least one dose of ActHIB vaccine during US clinical trials. Of these, 1,064 subjects 12 to 24 months of age who received ActHIB vaccine alone reported no serious or life threatening adverse reactions. Adverse reactions commonly associated with a first ActHIB vaccine immunization of children 12 to 15 months of age who were previously unimmunized with any Haemophilus b conjugate vaccine, include local pain, redness, and swelling at the injection site. Systemic reactions include fever, irritability, and lethargy.4,10 Adverse reactions associated with ActHIB vaccine generally subsided after 24 hours and usually do not persist beyond 48 hours after immunization. In a US trial, safety of TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, in 110 children aged 15 to 20 months was compared to ActHIB vaccine given with Tripedia vaccine at separate sites to 110 children. All children received three doses of Haemophilus b conjugate vaccine (ActHIB vaccine or HibTITER) and three doses of whole-cell DTP at approximately 2, 4, and 6 months of age. Table 5: Local and Systemic Reactions at 6, 24, and 48 Hours Following Immunization with ActHIB and Tripedia Vaccines Given Concomitantly at Separate Sites Compared to TriHIBita Vaccine in Children 15- to 20-months-old10 Adverse Event 6 Hrs. Post-dose 24 Hrs. Post-dose 48 Hrs. Post-dose Separate Injectionsb N = 110 TriHIBit vaccine N = 110 Separate Injectionsb N = 110 TriHIBit vaccine N = 110 Separate Injectionsb N = 110 TriHIBit vaccine N = 110 Local (%) Tenderness 17.3/20.0 19.1 8.2/8.2 10.0 1.8/0.9 1.8 Erythema > 1” 0.9/0.0 3.6 2.7/0.9 3.6 0.9/0.0 1.8 Indurationc 3.6/5.5 2.7 2.7/3.6 8.2 4.5/0.9 3.6 Swelling 3.6/3.6 3.6 2.7/1.8 5.5 0.9/0.0 4.5 Systemic (%) N = 103-110 N = 102-109 N = 105-110 N = 103-108 N = 104-110 N = 103-109 Fever > 102.2°F (39.0°C) 0 2.0 1.0 1.9 1.9 0 Irritability 27.3 22.9 20.9 17.6 12.7 10.1 Drowsiness 36.4 30.3 17.3 13.9 12.7 11.0 Anorexia 12.7 9.2 10.0 6.5 6.4 2.8 Vomiting 0.9 1.8 0.9 1.9 0.9 2.8 Persistent Cry 0 0 0 0 0 0 Unusual Cry 0 0 0 0 0 0.9 a TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution b Tripedia vaccine injection site/ActHIB vaccine injection site c Induration is defined as hardness with or without swelling TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, was administered to approximately 850 children, aged 15 to 20 months. All children received three doses of a Haemophilus b conjugate vaccine (ActHIB vaccine or HibTITER) and three doses of whole-cell DTP at approximately 2, 4, and 6 months of age. Local reactions were typically mild and usually resolved within the 24 to 48 hour period after immunization. The most common local reactions were pain and tenderness at the injection site. Systemic reactions occurring were usually mild and resolved within 72 hours of immunization. The reaction rates were similar to those observed in TABLE 5 when TriHIBit vaccine, ActHIB vaccine reconstituted with Tripedia vaccine, was administered and when Tripedia vaccine was administered alone as a booster.10 The number of subjects studied with TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, was inadequate to detect rare serious adverse events. Reporting of Adverse Events Reporting by the parent or guardian of all adverse events occurring after vaccine administration should be encouraged. Adverse events following immunization with vaccine should be reported by the health-care provider to the US Department of Health and Human Services (DHHS) Vaccine Adverse Event Reporting System (VAERS). Reporting forms and information about reporting requirements or completion of the form can be obtained from VAERS through a tollfree number 1-800-822-7967.15,16,18 Health-care providers also should report these events to Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 or call 1-800-822-2463. Post-Marketing Experience The following events have been spontaneously reported during the post-approval use of ActHIB. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Immune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions (including urticaria, angioedema) Nervous System Disorders: Convulsions General Disorders and Administration Site Conditions: Extensive limb swelling, peripheral edema, pruritus, and rash DRUG INTERACTIONS When 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.14 If ActHIB vaccine reconstituted with saline diluent (0.4% Sodium Chloride) 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.10 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.10 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 saline diluent (0.4% Sodium Chloride) or Tripedia vaccine (TriHIBit vaccine).10 Use with caution in patients on anticoagulant therapy. REFERENCES 4 Data on file, Sanofi Pasteur SA. 10 Data on file, Sanofi Pasteur Inc. 14 ACIP. Diphtheria, Tetanus, and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures. MMWR 40:No. RR-10, 1991. 15 Vaccine Adverse Event Reporting System United States. MMWR 39:730-733, 1990. 16 CDC. National Childhood Vaccine Injury Act: Requirements for permanent vaccination records and for reporting of selected events after vaccination. MMWR 37:197-200, 1988. 18 Rothstein EP, et al. Comparison of antigenuria after immunization with three Haemophilus influenzae type b conjugate vaccines. Pediatr Infect Dis J 10:311-314, 1991.

WARNINGS If ProHIBiT (haemophilus b conjugate vaccine) ® is used in persons with malignancies or those receiving immunosuppressive therapy or who are otherwise immunocompromised, the expected immune response may not be obtained. As with any vaccine, vaccination with ProHIBiT (haemophilus b conjugate vaccine) ® may not protect 100% of susceptible individuals. PRECAUTIONS General As with the injection of any biological material, Epinephrine Injection (1:1000) should be available for immediate use should an anaphylactic or other allergic reaction occur. 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 hypersensitivity to the vaccine or similar vaccines. Any febrile illness or infection likely to be accompanied by fever is reason to delay the use of ProHIBiT (haemophilus b conjugate vaccine) ®, since fever may result occasionally from administration of ProHIBiT (haemophilus b conjugate vaccine) ® alone. As reported with Haemophilus b polysaccharide vaccine,30 cases of Haemophilus b disease may occur in the week after vaccination, prior to the onset of protective effects of the vaccine.15 Antigenuria has been detected following receipt of Haemophilus b Conjugate Vaccine.31 Antigen detection may not have diagnostic value in suspected Haemophilus b disease within two weeks of immunization. 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 hepatitis or other infectious agents from person to person. Needles should not be recapped and should be disposed of properly. ALTHOUGH SOME IMMUNE RESPONSE TO THE DIPHTHERIA TOXOID COMPONENT MAY OCCUR, IMMUNIZATION WITH ProHIBiT (haemophilus b conjugate vaccine) ® DOES NOT SUBSTITUTE FOR ROUTINE DIPHTHERIA IMMUNIZATION. Carcinogenesis, Mutagenesis, Impairment OF Fertility ProHIBiT (haemophilus b conjugate vaccine) ® has not been evaluated for its carcinogenic, mutagenic potential or impairment of fertility. Pregnancy Reproductive Studies – Pregnancy Category Animal reproduction studies have not been conducted with ProHIBiT (haemophilus b conjugate vaccine) ®. It is also not known whether ProHIBiT (haemophilus b conjugate vaccine) ® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ProHIBiT (haemophilus b conjugate vaccine) ® is NOT recommended for use in a pregnant woman. Pediatric Use ProHIBiT (haemophilus b conjugate vaccine) ® IS NOT RECOMMENDED FOR USE IN CHILDREN YOUNGER THAN 12 MONTHS OF AGE. REFERENCES 15. Unpublished data available from Connaught Laboratories, Inc. 30. FDA Workshop on Haemophilus b Polysaccharide Vaccine - A Preliminary Report, MMWR 36: 529-531,1987 31. Scheifele D, et al. Antigenuria after receipt of Haemophilus b Diphtheria Toxoid Conjugate Vaccine. Pediatr Infect Dis J 8:887-888,1989

WARNINGS No information provided. PRECAUTIONS General As for any vaccine, adequate treatment provisions, including epinephrine, should be available for immediate use should an anaphylactoid reaction occur. Special care should be taken to ensure that the injection does not enter a blood vessel. It is important to use a separate sterile syringe and needle for each patient to prevent transmission of hepatitis B or other infectious agents from one person to another. As with other vaccines, Liquid PedvaxHIB may not induce protective antibody levels immediately following vaccination. As reported with Haemophilus b Polysaccharide Vaccine36 and another Haemophilus b Conjugate Vaccine37, cases of Hib disease may occur in the week after vaccination, prior to the onset of the protective effects of the vaccines. There is insufficient evidence that Liquid PedvaxHIB given immediately after exposure to natural Haemophilus influenzae type b will prevent illness. The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and on the etiology of the disease. The Advisory Committee on Immunization Practices (ACIP) has recommended that vaccination should be delayed during the course of an acute febrile illness. All vaccines can be administered to persons with minor illnesses such as diarrhea, mild upper-respiratory infection with or without low-grade fever, or other low-grade febrile illness. Persons with moderate or severe febrile illness should be vaccinated as soon as they have recovered from the acute phase of the illness.46 If PedvaxHIB is used in persons with malignancies or those receiving immunosuppressive therapy or who are otherwise immunocompromised, the expected immune response may not be obtained. Instructions to Healthcare Provider The healthcare provider should determine the current health status and previous vaccination history of the vaccinee. The healthcare provider should question the patient, parent, or guardian about reactions to a previous dose of PedvaxHIB or other Haemophilus b Conjugate Vaccines. Laboratory Test Interactions Sensitive tests (e.g., Latex Agglutination Kits) may detect PRP derived from the vaccine in urine of some vaccinees for at least 30 days following vaccination with lyophilized PedvaxHIB;38 in clinical studies with lyophilized PedvaxHIB, such children demonstrated normal immune response to the vaccine. Carcinogenesis, Mutagenesis, Impairment of Fertility Liquid PedvaxHIB has not been evaluated for carcinogenic or mutagenic potential, or potential to impair fertility. Pregnancy Pregnancy Category C: Animal reproduction studies have not been conducted with PedvaxHIB. Liquid PedvaxHIB is not recommended for use in individuals 6 years of age and older. Pediatric Use Safety and effectiveness in infants below the age of 2 months and in children 6 years of age and older have not been established. In addition, Liquid PedvaxHIB should not be used in infants younger than 6 weeks of age because this will lead to a reduced anti-PRP response and may lead to immune tolerance (impaired ability to respond to subsequent exposure to the PRP antigen).49-51 Liquid PedvaxHIB is not recommended for use in individuals 6 years of age and older because they are generally not at risk of Hib disease. Geriatric Use This vaccine is NOT recommended for use in adult populations. REFERENCES 36. Mortimer, E. A.: Efficacy of Haemophilus b polysaccharide vaccine: An enigma. JAMA 260: 1454, 1988. 37. Meekison, W., et al: Post-marketing surveillance of adverse effects following ProHIBiT vaccine. British Columbia Canada Diseases Weekly Report 15-28: 143-145, 1989. 38. Goepp, J. G., et al: Persistent urinary antigen excretion in infants vaccinated with Haemophilus influenzae type b capsular polysaccharide conjugated with outer membrane protein from Neisseria meningitidis. Pediatr Infect Dis J 11(1): 2-5, 1992. 46. Recommendations of the Immunization Practices Advisory Committee. General Recommendations on Immunization. MMWR 43(RR-1), 1994. 47. Vaccine Adverse Event Reporting System - United States. MMWR 39(41): 730-733, October 19, 1990. 48. Institute of Medicine Adverse Events Associated With Childhood Vaccines Evidence Bearing on Causality. National Academy Press, Washington, D.C., 260-261, 1994. 49. Keyserling, H.L., et al: Program and Abstracts of the 30th ICAAC, (Abstract #63), 1990. 50. Ward, J.I., et al: Program and Abstracts of the 32nd ICAAC, (Abstract #984), 1992. 51. Lieberman, J.M., et al: Infect Dis, (Abstract #1028), 1993.

WARNINGS The stopper of the diluent vial contains natural rubber latex which may cause allergic reactions. The lyophilized vaccine vial is not made with natural rubber latex. If ActHIB vaccine 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 infection12, 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.13 (Refer to product insert for Tripedia vaccine.) 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 natural rubber latex, previous immunization history, current health status (see CONTRAINDICATIONS and WARNINGS sections), and a current knowledge of the literature concerning the use of the vaccine under consideration. (Refer to product insert for 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 or Tripedia vaccine. If Guillain-Barre syndrome has occurred within 6 weeks of receipt of a prior vaccine containing tetanus toxoid, the decision to give any tetanus toxoid-containing vaccine, including ActHIB or TriHIBit, should be based on careful consideration of the potential benefits and possible risks. Minor illnesses such as upper respiratory infection with or without low-grade fever are not contraindications for use of ActHIB vaccine.14 Immunization with ActHIB vaccine does not substitute for routine tetanus immunization. Information For Parents And Guardians Of Vaccine Recipients 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 saline diluent (0.4% Sodium Chloride) or Tripedia vaccine (TriHIBit vaccine), the parent or guardian should be asked about the recent health status of the infant or child to be immunized. The health-care provider should inform the parent or guardian of the importance of completing the immunization series. 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 diluent (0.4% Sodium Chloride) 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.15,16,17 The US Department of Health and Human Services has established a 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 1986.15 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.16,17 The health-care provider should provide the Vaccine Information Statements (VISs), which are required to be given with each immunization. Carcinogenesis, Mutagenesis, Impairment Of Fertility ActHIB vaccine reconstituted with saline diluent (0.4% Sodium Chloride) or Tripedia vaccine (TriHIBit vaccine) has not been evaluated for its carcinogenic, mutagenic potential or impairment of fertility. Pregnancy Category C Animal reproduction studies have not been conducted with ActHIB vaccine reconstituted with saline diluent (0.4% Sodium Chloride) or Tripedia vaccine (TriHIBit vaccine). It is also not known whether ActHIB vaccine reconstituted with saline diluent (0.4% Sodium Chloride) or Tripedia vaccine (TriHIBit vaccine) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ActHIB vaccine reconstituted with saline diluent (0.4% Sodium Chloride) or Tripedia vaccine (TriHIBit vaccine) is not approved for use in pregnant women. Pediatric Use Safety and effectiveness of ActHIB vaccine reconstituted with saline diluent (0.4% Sodium Chloride) in infants below the age of 6 weeks have not been established. (See DOSAGE AND ADMINISTRATION section.) Safety and effectiveness of TriHIBit vaccine, ActHIB vaccine reconstituted with Tripedia vaccine, in infants below the age of 15 months have not been established. (See DOSAGE AND ADMINISTRATION section.) REFERENCES 10 Data on file, Sanofi Pasteur Inc. 12 Steinhoff MC, et al. Antibody responses to Haemophilus influenzae type b vaccines in men with human immunodeficiency virus infection. N Engl J Med 325(26):1837-1842, 1991. 13 ACIP. General recommendations on immunization. MMWR 38:205-227, 1989. 14 ACIP. Diphtheria, Tetanus, and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures. MMWR 40:No. RR-10, 1991. 15 Vaccine Adverse Event Reporting System United States. MMWR 39:730-733, 1990. 16 CDC. National Childhood Vaccine Injury Act: Requirements for permanent vaccination records and for reporting of selected events after vaccination. MMWR 37:197-200, 1988. 17 National Childhood Vaccine Injury Act of 1986 (Amended 1987).