Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Diphtheria Diphtheria is an acute toxin-mediated disease caused by toxigenic strains of C diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. Antitoxin levels of at least 0.1 IU/mL are generally regarded as protective.5 Levels of 1.0 IU/mL have been associated with long-term protection.6 Tetanus Tetanus is an acute disease caused by an extremely potent neurotoxin produced by C tetani. Protection against disease is due to the development of neutralizing antibodies to tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assay is considered the minimum protective level.5,7 A tetanus antitoxin level ≥ 0.1 IU/mL as measured by the ELISA used in clinical studies of DAPTACEL vaccine is considered protective. Pertussis Pertussis (whooping cough) is a respiratory disease caused by Bpertussis. This Gram-negative coccobacillus produces a variety of biologically active components, though their role in either the pathogenesis of, or immunity to, pertussis has not been clearly defined. Non-Clinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility DAPTACEL vaccine has not been evaluated for carcinogenic or mutagenic potential or impairment of fertility. Clinical Studies Diphtheria In a US study in which children received 4 doses of DAPTACEL vaccine at 2, 4, 6 and 15­17 months of age, after the third dose, 100% (N = 1,099) achieved diphtheria antitoxin levels of ≥ 0.01 IU/mL and 98.5% achieved diphtheria antitoxin levels of ≥ 0.10 IU/mL. Among a random subset of children who received the fourth dose of DAPTACEL vaccine at 15-16 months of age, 96.5% (N = 659) achieved diphtheria antitoxin levels of ≥ 1.0 IU/mL after the fourth dose. Tetanus In a US study in which children received 4 doses of DAPTACEL vaccine at 2, 4, 6 and 15-17 months of age, after the third dose, 100% (N = 1,037) achieved tetanus antitoxin levels of > 0.10 IU/mL. Among a random subset of children who received the fourth dose of DAPTACEL vaccine at 15-16 months of age, 98.8% (N = 681) achieved tetanus antitoxin levels of > 1.0 IU/mL after the fourth dose. Pertussis A randomized, double-blinded, placebo-controlled efficacy and safety study was conducted in Sweden during 1992-1995 (Sweden I Efficacy Trial) under the sponsorship of the National Institute of Allergy and Infectious Diseases. A total of 9,829 infants received 1 of 4 vaccines: DAPTACEL vaccine (N = 2,587); another investigational acellular pertussis vaccine (N = 2,566); whole-cell pertussis DTP vaccine (N = 2,102); or DT vaccine as placebo (Swedish National Bacteriological Laboratory, N = 2,574). Infants were immunized at 2, 4 and 6 months of age. The mean length of follow-up was 2 years after the third dose of vaccine. The protective efficacy of DAPTACEL vaccine against pertussis after 3 doses using the World Health Organization (WHO) case definition ( ≥ 21 consecutive days of paroxysmal cough with culture or serologic confirmation or epidemiologic link to a confirmed case) was 84.9% (95% confidence interval [CI] 80.1 to 88.6). The protective efficacy of DAPTACEL vaccine against mild pertussis ( ≥ 1 day of cough with laboratory confirmation) was 77.9% (95% CI 72.6 to 82.2). Protection against pertussis by DAPTACEL vaccine was sustained for the 2-year follow-up period. In order to assess the antibody response to the pertussis antigens of DAPTACEL vaccine in the US population, 2 lots of DAPTACEL vaccine, including the lot used in the Sweden I Efficacy Trial, were administered to US infants in the US Bridging Study. In this study, antibody responses following 3 doses of DAPTACEL vaccine given to US children at 2, 4 and 6 months of age were compared to those from a subset of the infants enrolled in the Sweden I Efficacy Trial. Assays were performed in parallel on the available sera from the US and Swedish infants. Antibody responses to all the antigens were similar except for those to the PRN component. For both lots of DAPTACEL vaccine, the geometric mean concentration (GMC) and percent response to PRN in US infants (Lot 006, N = 107; Lot 009, N = 108) were significantly lower after 3 doses of vaccine than in Swedish infants (N = 83). In separate US and Canadian studies in which children received DAPTACEL vaccine at 2, 4 and 6 months of age, with a fourth dose at either 17-20 months (Canadian study) or 15-16 months (random subset from US study) of age, antibody responses to each pertussis antigen following the fourth dose (Canadian study N = 275; US study N = 237-347) were at least as high as those seen in the Swedish infants after 3 doses. While a serologic correlate of protection for pertussis has not been established, the antibody response to all antigens in North American infants after 4 doses of DAPTACEL vaccine at 2, 4, 6 and 15-20 months of age was comparable to that achieved in Swedish infants in whom efficacy was demonstrated after 3 doses of DAPTACEL vaccine at 2, 4 and 6 months of age. Concomitantly Administered Vaccines In the US Bridging study, DAPTACEL vaccine was given concomitantly with Hib conjugate vaccine (Sanofi Pasteur SA) according to local practices. Anti-PRP immune response was evaluated in 261 infants who received 3 doses of Hib conjugate vaccine. One month after the third dose, 96.9% achieved anti-PRP antibody levels of at least 0.15 mcg/mL and 82.7% achieved antibody levels of at least 1.0 mcg/mL. In the US study in which infants received DAPTACEL vaccine concomitantly with Hib conjugate (tetanus toxoid conjugate) vaccine, IPV, 7-valent pneumococcal conjugate vaccine, and hepatitis B vaccine [see ADVERSE REACTIONS], at 7 months of age, 100.0% of subjects (N = 1,050­1,097) had protective neutralizing antibody levels ( ≥ 1:8 1/dil) for poliovirus types 1, 2 and 3; and 92.4% (N = 998) achieved anti-hepatitis B surface antigen levels > 10.0 mlU/mL. Although there is no established serologic correlate of protection for any of the pneumococcal serotypes, at 7 months of age 91.3%-98.9% (N = 1,027-1,029) achieved anti-pneumococcal polysaccharide levels ≥ 0.5 mcg/mL for serotypes 4, 9V, 14, 18C, 19F and 23F and 80.7% (N = 1,027) achieved an anti-pneumococcal polysaccharide level ≥ 0.5 mcg/mL for serotype 6B. The mumps seroresponse rate was lower when DAPTACEL vaccine was administered concomitantly (86.6%; N = 307) vs. non-concomitantly (90.1%; N = 312) with the first dose of MMR vaccine [upper limit of 90% confidence interval for difference in rates (non-concomitant minus concomitant) ≥ 5%]. There was no evidence for interference in the immune response to the measles, rubella, and varicella antigens or to the fourth dose of the 7-valent pneumococcal conjugate vaccine with concomitant administration of DAPTACEL vaccine. REFERENCES 5. Department of Health and Human Services, Food and Drug Administration. Biological products; bacterial vaccines and toxoids; implementation of efficacy review; proposed rule. Federal Register 1985;50(240):51002-117. 6. Wharton M, et al. Diphtheria Toxoid. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia, PA: W. B. Saunders 2004 p. 211-28. 7. Wassilak SGF, et al. Tetanus Toxoid. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia, PA: W. B. Saunders 2004 p. 745-81.

CLINICAL PHARMACOLOGY Immunization against diphtheria, tetanus and pertussis, using a conventional whole-cell pertussis DTP vaccine (Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed) has been routine practice during infancy and childhood in the United States since the late 1940s. Widespread immunization in the United States has played a major role in dramatically reducing the incidence of cases and deaths from each of these diseases.3 Diphtheria Diphtheria is a disease resulting from infection of the respiratory tract or skin with Corynebacterium diphtheriue. The disease can be localized to the site of infection or can be associated with systemic toxicity, which may include myocarditis and neuritis and is caused by diphtheria exotoxin, an extracellular protein metabolite of toxigenic strains of C. diphtheriae. Humans are the only known reservoir for C. diphtheriue. More than 200,000 cases of diphtheria, primarily among children, were reported in the United States in 1921, before the general use of diphtheria toxoid vaccine.3 Approximately 5-10% of cases were fatal; the highest case-fatality rates were in the very young and the elderly. Immunization programs with diphtheria toxoid introduced in the 1940s had a significant impact on the epidemiology of the disease. Only 24 cases of respiratory diphtheria were reported in the United States from 1980 to 1989, and 15 cases from 1990 to 1994; however, the case-fatality rate has remained constant at about 5-10%.3, 4 Although diphtheria is currently a rare disease in the United States, the disease has remained endemic in many developing countries and recent outbreaks have occurred in areas of the former Soviet Union.5 A complete vaccination series with diphtheria toxoid substantially reduces the risk and severity of disease, and protection is thought to last for at least 10 years.3 Serum antitoxin concentrations of at least 0.01 antitoxin units per ml are generally regarded as protective.6, 7 Vaccination does not eliminate carriage of C. diphtheriae from the pharynx, nose, or skin.3 Efficacy of the diphtheria toxoid used in Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM was determined on the basis of immunogenicity studies, with a comparison to a serological correlate of protection (³ 0.01 antitoxin units per ml) established by the Panel on Review of Bacterial Vaccines and Toxoids.7In a clinical study with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM, 99.7% of 299 U. S. infants had protective titers to diphtheria toxin (³ 0.01 antitoxin units per ml) in sera obtained one month after the third dose; vaccination at 2,4, and 6 months of age. Tetanus Tetanus is a disease characterized by neuromuscular dysfunction resulting from the effects of a potent exotoxin elaborated by Chlostridium tetani, a microorganism which is commonly found in the outdoor environment (usually soil). Persons with the disease exhibit muscular rigidity and spasms that can either be localized or generalized, depending on host factors and the site of inoculation. With the routine use of tetanus toxoid, the occurrence of tetanus in the United States has decreased markedly, from 560 reported cases in 1947 to an average of 57 cases reported annually from 1985-1994.3, 4 Tetanus in the United States is primarily a disease of older adults. Of 99 cases with complete information reported to the Centers for Disease Control and Prevention during 1987-1988, 68% were ³50 years of age, only 6 were <20 years of age. No cases of neonatal tetanus were reported. Overall, the case fatality rate was 21%. The disease continues to occur almost exclusively among persons who are unvaccinated or inadequately vaccinated or whose vaccination histories are unknown or uncertain.8 Spores of C. tetani are ubiquitous. Serologic tests indicate that naturally acquired immunity to tetanus toxin does not occur in the United States. Thus, universal primary immunization with subsequent maintenance of adequate antitoxin levels by means of timed boosters is needed to protect all age groups.3 Tetanus toxoid is a highly effective antigen, and a completed primary series generally induces protective levels of at least 0.01 antitoxin units per ml, a level which has been reported to be protective.7 It is thought that protection persists for at least 10 years.3, 9 Efficacy of the tetanus toxoid in Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM was determined on the basis of immunogenicity studies with a comparison to a serological correlate of protection (³ 0.01 antitoxin units per ml) established by the Panel on Review of Bacterial Vaccines and Toxoids.7 In a clinical study with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM, 100% of 299 U. S. infants had a protective level of tetanus toxoid (³0.01 antitoxin units per ml) in sera obtained one month after the third dose; vaccination at 2,4, and 6 months of age. Pertussis Pertussis (whooping cough) is a disease of the respiratory tract caused by Boraktella pertussis. Pertussis is highly communicable (attack rates in unimmunized household contacts of up to 90% have been reported) and can cause severe disease, particularly among the very young.3 Since immunization against pertussis became widespread, the number of reported cases and associated mortality in the United States have declined from an average annual incidence and mortality of 150 cases and 6 deaths per 100,000, respectively, in the early 1940s, to annual reported incidences of 1.6, 2.6, and 1.8 cases per 100,000 population in 1992, 1993, and 1994, respectively, and estimated annual incidences of 2.0 and 2.4 cases per 100,000 population for 1995 and 1996, respectively.10, 11 Precise epidemiologic data do not exist because bacteriological confirmation of pertussis can be obtained in less than half of the suspected cases. Most reported illness from B. pertussis occurs in infants and young children in whom complications can be severe. From 1980 to 1989, of 10,749 pertussis cases reported nationally in infants less than 1 year of age, 69% were hospitalized, 22% had pneumonia, 3% had seizures, 0.9% had encephalopathy, and 0.6% died.12 Older children and adults, in whom classic signs are often absent, may go undiagnosed and may serve as reservoirs of disease.l3 Routine vaccination with whole-cell DTP vaccine has significantly reduced pertussis-related morbidity and mortality. However, concerns regarding reactogenicity of whole-cell DTP vaccine have spurred development of safer pertussis vaccines. The role of diierent components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- EU, which contains one pertussis antigen, pertussis toxoid, has been shown to be effective in preventing World Health Organization (WHO)-defined pertussis after three doses of vaccine administered at 3, 5, and 12 months of age. Efficacy: Between 1991-1994, a double-blind, randomized, placebo-controlled efficacy trial of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- EU was conducted in Göteborg, Sweden, where pertussis is endemic and pertussis immunization had been stopped in 1979. Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- EU contains the same amount of pertussis toxoid (40 mcg) per dose as Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM, but contains more diphtheria toxoid (25 Lf vs. 15 Lf) and more tetanus toxoid (7 Lf vs. 6 Lf) per dose than Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM. A total of 3,450 healthy infants from 96 Child Health Centers were randomized to receive Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- EU (n=1,724) or Statens Seruminstitut Diphtheria and Tetanus Toxoids Adsorbed Vaccine (DT) (n=1,726) at 3, 5, and 12 months of age. 14, 15 Cases of pertussis were identified by obtaining nasopharyngeal cultures for B. pertussis and acute and convalescent serum samples in all subjects and family members with coughing episodes lasting ³7 days. Duration of cough and severity of symptoms were determined by telephone interview and/or office visit at approximately 4 weeks and again at 60 days after report of cough lasting ³7 days. The main observation period started 30 days after the third dose of vaccine and lasted a mean of 17 months. During this period, WHO defined pertussis (paroxysmal cough for ³21 days with one or more of the following: positive culture, positive culture in a family member, or a significant rise in serum PT-IgG or PHA-IgG) was identified in 72 (4.3%) of 1,682 Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- EU recipients and 240 (14.3%) of 1,676 DT recipients. 14, 15, 16 Case rates per 100 person-years of follow-up were 2.89 in the Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- EU group and 10.17 in the DT group. Starting one month after the third dose, the protective efficacy of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU against WHO-defined pertussis was 72% (95% CI: 62% to 78%). Protective efficacy against WHO defined pertussis for the period starting 30 days after the second dose of vaccine up until administration of the third dose was 60% (95% CI:13% to 83%) (10 cases in 1,708 Cettiva TM - EU recipients, 25 cases in 1,717 DT recipients).l5 When the definition of pertussis was expanded to include clinically milder disease with respect to type and duration of cough, with infection confirmed by culture and/or serologic testing, the efficacy of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU during the main observation period was 63% (95% CI: 52% to 71%) against ³21 days of any cough and 54% (95% CI: 43% to 64%) against ³7 days of any cough.14 After the main observation period, follow-up was continued for an additional 6 month period during which the study was unblinded. During this period the efficacy of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU remained high against WHO-defined pertussis at 77% (95% CI:65% to 85%) in children whose median age was then 36.5 months.15, 17 Protective efficacy was also estimated in vaccine recipients who had household exposure to WHO-defined pertussis during the main observation period. Nineteen (19) of 88 Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU recipients and 50 of 63 DT recipients were identified with a secondary case of pertussis (defined as paroxysmal cough for ³21 days with infection confirmed by culture and/or serologic testing and with an onset between 6-60 days after onset in the primary case). The protective efficacy of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) m-EU in preventing WHO-defined pextussis after household exposure was 73% (95% CI: 57% to 86%) based on comparing the proportion of exposed subjects who were identified with pettussis in each vaccine group. 15, 18 Effectiveness: An epidemiologic, open-label, Mass Vaccination Project was initiated in June 1995 in the Göteborg region of Sweden to study the safety and effectiveness of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU and pertussis toxoid vaccines in infants and children. Effectiveness was determined by regional surveillance of pertussis cultures. Nasopharyngeal cultures were obtained from coughing individuals of all ages with suspected pertussis at the discretion of their treating physician. Cultures were analyzed by the single regional reference laboratory (Department of Clinical Bacteriology, Sahlgrenska Hospital, Göteborg, Sweden) as proof of an established surveillance system from which pertussis culture data have been generated and reported since 1976. Table 1 depicts the monthly positive pertussis cultures collected from July 1989 through December 1997 (two and one half years into the project). Between 1989 and 1994 (the period before initiation of the Mass Vaccination Project), the yearly number of positive pertussis cultures varied, ranging from 575 out of 2,934 total cultures to 1,081 out of 4,272 total cultures. By the second year of the Mass Vaccination Project (July 1996 - June 1997), a total of 108 out of 784 cultures were positive for pertussis, the majority from children not participating in the Project with the remainder from children having received at least 1 dose of vaccine, During the next 6 months (July 1997 - December 1997), 30 cultures out of a total of 299 were pertussis positive, the majority from children not participating in the Project. TABLE 1. POSITIVE PERTUSSIS CULTURES IN THE WEBORG REGION OF SWEDEN (1989-1997) Before Pertussis Immunization* Period of Mass Immunization with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM-EU and Pertussis Toxoid Year 1989- 1990 1990- 1991 1991- 1992 1992- 1993 1993- 1994 1994- 1995 1995- 1996 1996- 1997 1997- Month July 61 78 55 52 90 67 104 14 3 August 44 92 55 72 100 96 100 37 6 September 54 70 56 73 86 70 75 18 11 October 84 130 60 82 99 78 93 8 7 November 97 105 61 66 126 96 100 8 3 December 76 62 35 66 88 118 53 8 0 January 76 121 58 78 138 113 48 9 February 59 102 40 72 86 55 30 1 March 60 81 37 81 75 50 28 2 April 51 73 18 92 50 85 15 1 May 73 64 41 69 88 69 22 1 June 47 46 59 92 55 63 8 1 Total Positive 782 1024 575 895 1081 960 676 108 30 Total Cultures 3150 3801 2934 3608 4272 4105 2809 784 299 *National recommendation for routine pediatric pertussis vaccination reinstituted January 1996 Immune Response to Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM: In a study of Swedish infants comparing Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM to Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU, serum antibody levels to PT after three doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM administered at 2, 4, and 6 months of age (n=116) were significantly higher than those after two doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU administered at 3 and 5 months of age (n=103), but were significantly lower than those observed after three doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU administered at 3, 5, and 12 months of age (n=101).15 The antibody response to PT after a fourth dose of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - administered at 15 months of age (n=114) was similar to that after the third dose of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM -EU at 12 months of age (n=101). 15 In a study of U. S. infants, serum antibody titers to PT following four doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - administered at 2, 4, 6, and 15-21 months of age (n=89) were similar to those achieved following three doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU administered at 3, 5, and 12 months of age [subset of Swedish children from the efficacy trial (n=232)].15 While a serologic correlate of protection for pertussis has not been established, the antibody response to PT in U.S. infants after doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM at 2, 4, 6, and 15-21 months of age was comparable to that achieved in Swedish infants in whom efficacy was demonstrated after three doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU at 3,5, and 12 months of age. Immune Response To Simultaneously Administered Vaccines: In a clinical study conducted in the United States, infants received Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - at 2, 4, and 6 months of age, and at each time point, the majority were simultaneously immunized with Haemophilus infruenzue type b conjugate vaccine (HibTITER, 96-99%), polio vaccine live oral (OPV) (83-97%), and hepatitis B vaccine (18-80%). Immune responses to these simultaneously administered vaccines were evaluated in a subset. After a third dose of OPV, 95-96% of infants had protective neutralizing antibody to poliovirus types 1 and 3 (n=219).l5 After the third dose of HibTITER, 61% of infants achieved anti-PRP antibody levels ³1 mcg/ml (n=249), compared to 73% of infants (n=77) who received HibTITER simultaneously with whole-cell DTP in the same study; these rates (61% vs. 73%) are not significantly different (p=0.078), but the study design lacked statistical power (80%) to rule out a difference of 15% (a=5%). After two doses of hepatitis B vaccine administered concurrently with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM, 99% had anti-HBsAg titers ³10 MIU/ml (n=101) 15; the total number of hepatitis B vaccine doses received by these infants is unknown because the number of doses received prior to entry into the study at 2 months of age was not recorded. One-hundred thirty-three (133) infants who received 3 doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM in the above study received a fourth dose of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM at 15-21 months of age and were simultaneously immunized with measles, mumps, and rubella (MMR) vaccine and HibTITER. Anti-PRP antibody levels ³1.0 mcg/ml were achieved in 100% of subjects (n=84); antibodies to measles, mumps, and rubella were detected in 91-95% of subjects (n=55). 15 In another study of 221 children who received Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM at 4 to 6 years of age, 89% and 16% simultaneously received polio, and measles, mumps, and rubella vaccination, respectively. Antibodies to measles, mumps and rubella were detected in 100% of tested subjects (n=32) and neutralization titers to polio types 1, 2, and 3 were achieved in 99% of tested subjects (n=105; 102 with OPV and 3 with inactivated polio vaccine). 15

DAPTACEL (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) Intramuscular Injection DESCRIPTION DAPTACEL vaccine is a sterile isotonic suspension of pertussis antigens and diphtheria and tetanus toxoids adsorbed on aluminum phosphate, for intramuscular injection. Each 0.5 mL dose contains 15 Lf diphtheria toxoid, 5 Lf tetanus toxoid and acellular pertussis antigens [10 mcg detoxified pertussis toxin (PT), 5 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), and 5 mcg fimbriae types 2 and 3 (FIM)]. Other ingredients per 0.5 mL dose include 1.5 mg aluminum phosphate (0.33 mg of aluminum) as the adjuvant, ≤ 5 mcg residual formaldehyde, < 50 ng residual glutaraldehyde and 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative). The acellular pertussis vaccine components are produced from Bordetellapertussis cultures grown in Stainer-Scholte medium² modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA and PRN are isolated separately from the supernatant culture medium. The FIM components are extracted and co-purified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. PT is detoxified with glutaraldehyde. FHA is treated with formaldehyde, and the residual aldehydes are removed by ultrafiltration. The individual antigens are adsorbed separately onto aluminum phosphate. Corynebacterium diphtheriae is grown in modified Mueller's growth medium.3 After purification by ammonium sulfate fractionation, diphtheria toxin is detoxified with formaldehyde and diafiltered. Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion.4 Tetanus toxin is detoxified with formaldehyde and purified by ammonium sulfate fractionation and diafiltration. Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate. The adsorbed diphtheria, tetanus and acellular pertussis components are combined with aluminum phosphate (as adjuvant), 2-phenoxyethanol (not as a preservative) and water for injection. Both diphtheria and tetanus toxoids induce at least 2 units of antitoxin per mL in the guinea pig potency test. The potency of the acellular pertussis vaccine components is determined by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA). REFERENCES 2. Stainer DW, Scholte MJ. A simple chemically defined medium for the production of phase I Bordetella pertussis. J Gen Microbiol 1970;63:211-20. 3. Stainer DW. Production of diphtheria toxin. In: Manclark CR, editor. Proceedings of an informal consultation on the World Health Organization requirements for diphtheria, tetanus, pertussis and combined vaccines. United States Public Health Service, Bethesda, MD. DHHS 91-1174. 1991. p. 7-11. 4. Mueller JH, Miller PA. Variable factors influencing the production of tetanus toxin. J Bacteriol 1954;67(3):271-7.

Certiva™ (diphtheria and tetanus toxoids and acellular pertussis) Vaccine Adsorbed DESCRIPTION Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM (Diphtheria and Tetanus sterile combination of diphtheria, Toxoids and Acellular Pertussis Vaccine Adsorbed) is a tetanus, and pertussis toxoids (one pertussis antigen, inactivated pertussis toxin), adsorbed onto aluminum hydroxide.1 It is intended for intramuscular injection only. After shaking, Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM is a homogeneous white suspension. The pertussis toxin (PT) is isolated from Phase 1 Boraktella pertussis grown in modified Stainer-Scholte medium. After purification by afIinity chromatography, which includes the use of fetuin, a bovine serum protein, as an aflinity ligand, PT is detoxified using hydrogen peroxide. Diphtheria toxin is derived from Corynebacterium diphtheriae grown in Stainers Diphtheria Culture Medium, containing casein hydrolysate, and is purified by fractional precipitation with ammonium sulfate. Tetanus toxin is derived from Clostridium tetani grown in modified Mueller and Miller Medium, containing casein hydrolysate, and is purified by precipitation with ammonium sulfate.2 The purified diphtheria and tetanus toxins are detoxified using formaldehyde. Each antigen is individually adsorbed onto aluminum hydroxide. 2 Each 0.5 ml dose of vaccine is formulated to contain 15 Lf diphtheria toxoid, 6 Lf tetanus toxoid, 40 mcg pertussis toxoid, 0.5 mg aluminum as aluminum hydroxide, and is preserved with 0.01% thimerosal (mercury derivative). The product may contain residual fetuin. The residual free formaldehyde content by assay is less than or equal to 10 ppm. The diphtheria and tetanus toxoids each induce not less than 2 units of antitoxin per ml in the guinea pig potency test. The potency of the pertussis toxoid is evaluated by measurement of antibody titers to pertussis toxin in immunized mice using an ELISA. Diphtheria and tetanus toxoid bulks for further manufacturing use are produced by Statens Seruminstitut, Copenhagen, Denmark. The pertussis toxoid is manufactured by North American Vaccine, Inc., Beltsville, Maryland. Final formulation and release of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM are conducted by North American Vaccine, Inc.

INDICATIONS DAPTACEL® is a vaccine indicated for active immunization against diphtheria, tetanus and pertussis as a five-dose series in infants and children 6 weeks through 6 years of age (prior to seventh birthday). DOSAGE AND ADMINISTRATION Immunization Series DAPTACEL vaccine is to be administered as a 5 dose series at 2, 4 and 6 months of age (at intervals of 6-8 weeks), at 15-20 months of age and at 4-6 years of age. The first dose may be given as early as 6 weeks of age. Four doses of DAPTACEL vaccine constitute a primary immunization course for pertussis. The fifth dose is a booster for pertussis immunization. Three doses of DAPTACEL vaccine constitute a primary immunization course for diphtheria and tetanus. The fourth and fifth doses are boosters for diphtheria and tetanus immunization. [See Clinical Studies] DAPTACEL vaccine should be used as the fifth dose of the DTaP series in children who initially received 4 doses of Pentacel® [(Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) vaccine, Sanofi Pasteur Limited]. Pentacel and DAPTACEL vaccines contain the same pertussis antigens, manufactured by the same process, although Pentacel vaccine contains twice the amount of detoxified pertussis toxin (PT) and four times the amount of filamentous hemagglutinin (FHA) as DAPTACEL vaccine. Data are not available on the safety and effectiveness of using mixed sequences of DAPTACEL vaccine and DTaP vaccines from different manufacturers for successive doses of the DTaP vaccination series. DAPTACEL vaccine may be used to complete the immunization series in infants who have received 1 or more doses of whole-cell pertussis DTP. However, the safety and efficacy of DAPTACEL vaccine in such infants have not been fully demonstrated. If a decision is made to withhold any recommended dose of pertussis vaccine, [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS], Diphtheria and Tetanus Toxoids Adsorbed For Pediatric Use (DT) should be administered. Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exist, the product should not be administered. After removing the “flip-off' cap, cleanse the vaccine vial stopper with a suitable germicide. Do not remove either the rubber stopper or the metal seal holding it in place. Just before use, shake the vial well, until a uniform, white, cloudy suspension results. Using a sterile needle and syringe and aseptic technique, withdraw and administer a single 0.5 mL dose of DAPTACEL vaccine intramuscularly. Use a separate sterile needle and syringe for each injection. Changing needles between withdrawing the vaccine from the vial and injecting it into a recipient is not necessary unless the needle has been damaged or contaminated. In infants younger than 1 year, the anterolateral aspect of the thigh provides the largest muscle and is the preferred site of injection. In older children, the deltoid muscle is usually large enough for injection. The vaccine should not be injected into the gluteal area or areas where there may be a major nerve trunk. Do not administer this product intravenously or subcutaneously. DAPTACEL vaccine should not be combined through reconstitution or mixed with any other vaccine. HOW SUPPLIED Dosage Forms And Strengths DAPTACEL vaccine is a suspension for injection in 0.5 mL single dose vials. See DESCRIPTION for a complete listing of ingredients. Storage And Handling The vial stopper for this product is not made with natural rubber latex. DAPTACEL vaccine is supplied in a single dose vial (NDC No. 49281-286-58): in packages of 1 vial: NDC No. 49281-286-01; in packages of 5 vials: NDC No. 49281-286-05; in packages of 10 vials: NDC No. 49281-286-10. DAPTACEL vaccine should be stored at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Product which has been exposed to freezing should not be used. Do not use after expiration date shown on the label. Manufactured by: Sanofi Pasteur Limited, Toronto Ontario Canada. Distributed by: Sanofi Pasteur Inc., Swiftwater PA 18370 USA

INDICATIONS Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM is indicated for active immunization against diphtheria, tetanus, and pertussis (whooping cough) in infants and children 6 weeks to 7 years of age (prior to seventh birthday). Completion of a primary series of pertussis vaccination early in life is strongly recommended because of the substantial risks of complications of pertussis in infancy. 3 This product is not recommended for immunizing persons on or after their seventh birthday (See DOSAGE AND ADMINISTRATION). In instances where the pertussis vaccine component is contraindicated, Diphtheria and Tetanus Toxoids Adsorbed (For Pediatric Use) (DT) should be used for each of the remaining doses (See CONTRAINDICATIONS). Tetanus Immune Globulin (Human TIG) and/or equine Diphtheria Antitoxiizn should be used if passive immunization is required.3 Individuals who have recovered from culture-confirmed pertussis do not need additional doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM but should receive additional doses of DT to complete the recommended immunization series. Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM is not to be used for treatment of actual infection with diphtheria, tetanus or pertussis. As with any vaccine, vaccination with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM may not protect 100% of recipients. DOSAGE AND ADMINISTRATION General The vaccine should be inspected visually for extraneous particulate matter and/or discoloration prior to administration. If these conditions exist, the vaccine should not be used. Shake vial well to obtain a homogeneous suspension before withdrawing each dose. Inject 0.5 ml of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM intramuscularly only. The preferred injection sites are the anterolateral aspect of the thigh and the deltoid muscle of the upper arm. The vaccine should not be injected into the gluteal area or areas where there may be a major nerve trunk. Before injection, the skin over the injection site should be cleansed with suitable germicide. After insertion of the needle, aspirate to ensure that the needle has not entered a blood vessel. Fractional doses (doses < 0.5 ml) should not be given since the safety and efficacy of fractional doses have not been determined. IMMUNIZATION SERIES A 0.5 ml intramuscular injection of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM is recommended for administration at 2, 4, and 6 months of age, at intervals of six to eight weeks, with a fourth dose given at 15-20 months of age (see CLINICAL PHARMACOLOGY). The interval between the third and fourth doses should be at least 6 months. The customary age for the first dose is two months of age, but the vaccine may be given starting at six weeks of age. It is recommended that Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM be given for all doses in the series because no interchangeability data on DTaP vaccines exist. Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM may be used to complete the immunization series in infants who have received one or two doses of whole-cell DTP vaccine. However, the safety and efficacy of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM in such infants have not been evaluated. Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM as a fourth dose is recommended at 15-20 months of age in children who have received three doses of whole-cell DTP vaccine. The interval between the third and fourth dose should be at least 6 months. Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM as a fifth dose is recommended at 4-6 years of age (prior to the seventh birthday) in children who have received 4 doses of a whole-cell DTP vaccine or 3 doses of a whole-cell DTP vaccine followed by one dose of a DTaP vaccine. A fifth dose is not needed if the fourth dose was given on or after the fourth birthday. At this time, there are no data to establish the frequency of adverse events following a fifth dose of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM in children who previously received 4 doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM. ADDITIONAL DOSING INFORMATION If any recommended dose of pertussis vaccine cannot be given, DT (For Pediatric Use) should be given as needed to complete the series. Interruption of the recommended schedule with a delay between doses should not interfere with the final immunity achieved with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM. There is no need to start the series over again regardless of the time elapsed between doses. A reduced or fractional dose (dose < 0.5 ml) should not be given, because the safety and efficacy of reduced doses have not been determined.19 Pre-term infants should be vaccinated according to their chronological age from birth.19 Persons 7 years of age or older should not be immunized with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM. They should receive Tetanus and Diphtheria Toxoids (Td) for adult use for routine booster immunization against tetanus and diphtheria. SIMULTANEOUS VACCINE ADMINISTRATION In clinical trials, Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM was routinely administered, at separate sites, concomitantly with one or more of the following vaccines: polio vaccine live oral (OPV), hepatitis B vaccine, Haemophilus influenzae type b conjugate vaccine (Hib), and measles, mumps and rubella vaccine (MMR) (see CLINICAL PHARMACOLOGY). No data are available on the simultaneous administration of inactivated polio vaccine (IPV) as a primary series or varicella vaccine with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM. When concomitant administration of other vaccines is required, they should be given with different syringes and at different injection sites. The ACIP encourages routine simultaneous administration of acellular DTaP, Hib, IPV or OPV, hepatitis B, MMR and varicella vaccines for children who are at the recommended age to receive these vaccines and for whom no specific contraindications exist at the time of the visit, unless, in the judgment of the provider, complete vaccination of the child will not be compromised by administering vaccines at different visits. 19, 22 Simultaneous administration is particularly important if the child might not return for subsequent vaccinations. HOW SUPPLIED Vial, 15 Dose (7.5 ml) -- Product No. 40121 STORAGE Store between 2-8o C (35-46 o F). DO NOT FREEZE. REFERENCES 1. Sekura R et. al. Clinical, metabolic and antibody responses of adult volunteers to an investigational vaccine composed of pertussis toxin inactivated by hydrogen peroxide. J Pediatrics 1988; 113: 806-8 13. 2. Aggetbeck I- I, Fenger C, and Heron I. Booster vaccination against diphtheria, tetanus in man. Comparison of calcium phosphate and aluminum hydroxide as adjuvants-II. Vaccine 1995; 13: 1366-1374. 3. Diphtheria, Tetanus and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures, Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991; 4O( RR-10): l-28. 4. C.C. Summary of notifiable diseases, United States, 1994. MMWR 1995; 43(53): 70-71. 5. C.C. Diphtheria Epidemic - New Independent States of the Former Soviet Union, 1990-1994. MMWR 1995; 44(10): 177-181. 6. Ipsen J. Immunization of adults against diphtheria and tetanus. N Engl J Med 1954 Sep 16; 251(12): 459-466. 7. DHHS, FDA, Biological products; bacterial vaccines and toxoids: implementation of efficacy review; proposed rule. Federal Register 1985; 50(240): 5 1002-5 1117. 8. C.C. Tetanus -United States, 1987 and 1988. MMWR 1990; 39(3): 37-44. 9. Diphtheria, Tetanus and Pertussis: Guidelines for Vaccine Prophylaxis and Other Preventive Measures, Recommendation of the Immunization Practices Advisory Committee (ACIP). MMWR 1985 July 12; 34(27): 405-426. 10. Pertussis- United States, January 1992-June 1995. MMWR 1995 Jul21; 44(28): 525-527. 11. Atkinson W, ed.; Epidemiology and Prevention of Vaccine- Preventable Diseases (The Pink Book"); 4th Edition; Atlanta, Centers for Disease Control and Prevention; September 1997. 12. Farizo KM et. al. Epidemiologic features of pertussis in the United States 1980-1989. Clin Infect Dis 1992; 14: 708-719. 13. Nennig MF, et. al. Prevalence and incidence of adult pertussis in an urban population. JAMA 1996; 275: 1672-1674. 14. Trollfors B, et. al. A placebocontrolled trial of a pertussis- toxoid vaccine. N Engl J Med 1995; 333: 1045-1050. 15. Data on file Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) m at North American Vaccine, Inc. 16. Case Definition of Pertussis. (citation) World Health Organization (WHO) Meeting 1991 Jan 10-11. Technical Report No. 01 Al-lS12S. . . 17. Taranger J, et. al. Unchanged efficacy of a pertussis toxoid vaccine throughout the two years after the third vaccination of infants. Pediatr. Infect. Dis. J. 1997; 16: 180-184. 18. Trollfors B., et. al. EfIicacy of a monocomponent pertussis toxoid vaccine after household exposure to pertussis. 1 Pediatr. 1997; 130: 532-536. 19. ACIP. General recommendations on immunization. MMWR 1994; 43( RR-1). 20. C.C. Update: Vaccine side effects, adverse reactions, contraindications, and precautions. Recommendations of the Advisory Committee on Immunization Practices. MMWR 1996; 45( RR-12): 1-35. 21. American Academy of Pediatrics. Report of the Committee on Infectious Diseases (Red Book). American Academy of Pediatrics, Evanston (IL); 24th edition; 1997: pg. 404. 22. C.C. Pertussis vaccination: Use of acellular pertussis vaccines among infants and young children. Recommendations of the Advisory committee on Immunization Practices (ACIP). MMWR 1997; 46( RR-7) 1: 25. 23. Sutter, RW., et al. Attributable risk of DTP (Diphtheria and Tetanus Toxoids and Pertussis Vaccine) injection in provoking paralytic poliomyelitis during a large outbreak in Oman. J Infect Dis 1992; 165: 444-449. 24. Livengood, J. R, et. al. Family history of convulsions and use of pertussis vaccine. J Pediatr 1989; 115527-53 1. 25. Stetler, H. C., et. al. History of convulsions and use of pertussis vaccine. J Pediatr 1985; 107: 175-179. 26. Howson CP, et. al. Adverse effects of pertussis and rubella vaccines: Pertussis vaccines and CNS disorders. Institute of Medicine (IOM); Washington (DC): National Academy Press; 199 1. 27. Stratton RR, et. al. DPT vaccine and chronic nervous system dysfunction: A New Analysis. Institute of Medicine (IOM). Washington, DC: National Academy Press, 1994 (Supplement). 28. C.C. Use of vaccines and immune globulins for persons with altered immunocompetence. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1993; Vol. 42 (No. RR-4): 1-3. 29. National Childhood Vaccine Injury Act: Requirements for Permanent Vaccination Records and for Reporting of Selected Events after Vaccination. MMWR 1988 Apr 8; 37(13): 197-200. 30. C.C. Vaccine Adverse Event Reporting System-United States. MMWR 1990; 39: 730-733. 31. Willinger M., et. al. Infant sleep position and risk for sudden infant death syndrome: Report of meeting held January 13 and 14, 1994. National Institutes of Health, Bethesda, MD. Pediatrics 1994; 93: 814-819. 32. Epidemiological Center, National Board of Health and Welfare, Sweden, 1997. Causes of death in Sweden, 1995. 33. Guyer B, et. al. Annual summary of vital statistics- 1996. Pediatrics 1997; 100( 6): 905-918. 34. Stratton KR, et. al. Adverse events associated with childhood vaccines-- evidence bearing on causality. Institute of Medicine (IOM). Washington (DC): National Academy Press; 1994. 35. Jacob J, et. al. Increased intracranial pressure after diphtheria, tetanus and pertussis immunization. Am J Dis Child 1979; 133: 217-218. 36. Walker AM, et. al. Neurologic events following diphtheria- tetanus- pertussis immunization. Pediatrics 1988; 8 11345-349. 37. Wilson GS. Allergic manifestations-- Post-vaccinal neuritis. In: The hazards of immunization. London, England. The Athlone Press; 1967. p. 153-156. 38. Tsairis P, et. al. Natural history of brachial plexus neuropathy. Arch Neural 1972; 27: 109-117. 39. Blumstein GI, et. al. Peripheral neuropathy following tetanus toxoid administration. JAMA 1966; 198: 1030-1031. 40. C.C. Adverse events following immunization. MMWR Surveillance Report 1985- 86; No. 3; issued Feb 1989. 41. Schlenska GK. Unusual neurological complications following tetanus- toxoid administration. J Neural 1977; 2 15: 299-302. 42. Miller, D. L., et. al. Pertussis immunisation and serious acute neurological illness in children. Br Med J 1981; 282: 1595-1599.. 43. Miller, D. L., et. al. Pertussis immunisation and serious acute neurological illnesses in children. Br Med J 1993; 307: 1171- l 176. 44. Pollock TM, et. al. A 7- year survey of disorders attributed to vaccination in North West Thames region. Lancet 1983; 1: 753-757. 45. Griffin MR, et. al. Risk of seizures and encephalopathy after immunization with the diphtheria- tetanus-pertussis vaccine. JAMA 1990; 263( 12): 1641-1645. 46. Shields WD, et. al. Relationship of pertussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study. J Pediatr 1988; 113: 801-805. 47. Bellman MH, et. al. Infantile spasms and pertussis immunizatiop. Lancet 1983 7 May: 1031-1034. 48. Walker AM, et. al. Diphtheria- tetanus- pertussis immunization and sudden infant death syndrome. Am J Public Health 1987; 77: 945-971. 49. Griffm, M. R, et. al. Risk of sudden infant death syndrome after immunization with the diphtheria- tetanus-pertussis vaccine. N Engl J Med 1988; 319: 618-623.

PATIENT INFORMATION Before administration of DAPTACEL vaccine, health-care personnel should inform the parent or guardian of the benefits and risks of the vaccine and the importance of completing the immunization series unless a contraindication to further immunization exists. The health-care provider should inform the parent or guardian about the potential for adverse reactions that have been temporally associated with DAPTACEL vaccine and other vaccines containing similar components. The health-care provider should provide the Vaccine Information Statements (VIS) which are required by the National Childhood Vaccine Injury Act of 1986 to be given with each immunization. The parent or guardian should be instructed to report adverse reactions to their health-care provider.

PATIENT INFORMATION INFORMATION FOR VACCINE RECIPIENTS AND PARENTS Parents or guardians of infants and children to be vaccinated should be fully informed of the benefits and risks of vaccination with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM and the importance of completing the immunization series, unless contraindicated. The physician should inform the parents or guardians about the potential for adverse reactions that have been temporally associated with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM and other pertussis vaccine administrations. The parents or guardians of infants and children with family history of convulsions or other central nervous system disorders should be advised of the potential increased risk of seizures following DTP vaccinations. Prior to each immunization, the parent or guardian should be provided with the Vaccine Information Materials (VIMs), as required by the National Childhood Vaccine Injury Act of 1986. 26 Parents or guardians should be instructed to report any severe or unusual reactions to their health-care provider. The U. S. 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. 29, 30 The toll-free number for VAERS forms and information is 1-800-822-7967.

OVERDOSE No information provided. CONTRAINDICATIONS Hypersensitivity A severe allergic reaction (eg, anaphylaxis) after a previous dose of DAPTACEL vaccine or any other tetanus toxoid, diphtheria toxoid, or pertussis-containing vaccine, or any other component of this vaccine is a contraindication to administration of DAPTACEL vaccine. [See DESCRIPTION] Because of uncertainty as to which component of the vaccine may be responsible, none of the components should be administered. Alternatively, such individuals may be referred to an allergist for evaluation if further immunizations are to be considered. Encephalopathy Encephalopathy (eg, coma, decreased level of consciousness, prolonged seizures) within 7 days of a previous dose of a pertussis containing vaccine that is not attributable to another identifiable cause is a contraindication to administration of any pertussis-containing vaccine, including DAPTACEL vaccine. Progressive Neurologic Disorder Progressive neurologic disorder, including infantile spasms, uncontrolled epilepsy, or progressive encephalopathy is a contraindication to administration of any pertussis-containing vaccine, including DAPTACEL vaccine. Pertussis vaccine should not be administered to individuals with such conditions until a treatment regimen has been established and the condition has stabilized.

SIDE EFFECTS Data From Clinical Studies Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to vaccine use and for approximating rates of those events. Approximately 18,000 doses of DAPTACEL vaccine have been administered to infants and children in 9 clinical studies. Of these, 3 doses of DAPTACEL vaccine were administered to 4,998 children, 4 doses of DAPTACEL vaccine were administered to 1,725 children, and 5 doses of DAPTACEL vaccine were administered to 485 children. A total of 989 children received 1 dose of DAPTACEL vaccine following 4 prior doses of Pentacel vaccine. In a randomized, double-blinded pertussis vaccine efficacy trial, the Sweden I Efficacy Trial, conducted in Sweden during 1992-1995, the safety of DAPTACEL vaccine was compared with DT and a whole-cell pertussis DTP vaccine. A standard diary card was kept for 14 days after each dose and follow-up telephone calls were made 1 and 14 days after each injection. Telephone calls were made monthly to monitor the occurrence of severe events and/or hospitalizations for the 2 months after the last injection. There were fewer of the solicited common local and systemic reactions following DAPTACEL vaccine than following the whole-cell pertussis DTP vaccine. As shown in Table 1, the 2,587 infants who received DAPTACEL vaccine at 2, 4 and 6 months of age had similar rates of reactions within 24 hours as recipients of DT and significantly lower rates than infants receiving whole-cell pertussis DTP. Table 1: Percentage of Infants from Sweden I Efficacy Trial with Local or Systemic Reactions within 24 Hours Post-Dose 1, 2 and 3 of DAPTACEL vaccine compared with DT and Whole-Cell Pertussis DTP Vaccines EVENT Dose 1 (2 MONTHS) Dose 2 (4 MONTHS) Dose 3 (6 MONTHS) DAPTACEL vaccine N = 2,587 DT N = 2,574 DTP N = 2,102 DAPTACEL vaccine N = 2,563 DT N = 2,555 DTP N = 2,040 DAPTACEL vaccine N = 2,549 DT N = 2,538 DTP N = 2,001 Local Tenderness (Any) 8.0* 8.4 59.5 10.1* 10.3 60.2 10.8* 10 50 Redness ≥ 2 cm 0.3* 0.3 6 1.0* 0.8 5.1 3.7* 2.4 6.4 Swelling ≥ 2 cm 0.9* 0.7 10.6 1.6* 2 10 6.3*† 3.9 10.5 Systemic Fever‡ ≥ 38°C (100.4°F) 7.8* 7.6 72.3 19.1* 18.4 74.3 23.6* 22.1 65.1 Fretfulness§ 32.3 33 82.1 39.6 39.8 85.4 35.9 37.7 73 Anorexia 11.2* 10.3 39.2 9.1* 8.1 25.6 8.4* 7.7 17.5 Drowsiness 32.7* 32 56.9 25.9* 25.6 50.6 18.9* 20.6 37.6 Crying ≥ 1 hour 1.7* 1.6 11.8 2.5* 2.7 9.3 1.2* 1 3.3 Vomiting 6.9* 6.3 9.5 5.2** 5.8 7.4 4.3 5.2 5.5 DT: Swedish National Biologics Laboratories DTP: whole-cell pertussis DTP, Sanofi Pasteur Inc. N = Number of evaluable subjects * p < 0.001: DAPTACEL vaccine versus whole-cell pertussis DTP † p < 0.0001: DAPTACEL vaccine versus DT ‡ Rectal temperature § Statistical comparisons were not made for this variable ** p < 0.003: DAPTACEL vaccine versus whole-cell pertussis DTP The incidence of serious and less common selected systemic events in the Sweden I Efficacy Trial is summarized in Table 2. Table 2: Selected Systemic Events: Rates Per 1,000 Doses after Vaccination at 2, 4 and 6 Months of Age in Sweden I Efficacy Trial EVENT Dose 1 (2 MONTHS) Dose 2 (4 MONTHS) Dose 3 (6 MONTHS) DAPTACEL vaccine N = 2,587 DT N = 2,574 DTP N = 2,102 DAPTACEL vaccine N = 2,565 DT N = 2,556 DTP N = 2,040 DAPTACEL vaccine N = 2,551 DT N = 2,539 DTP N = 2,002 Rectal temperature ≥ 40°C (104°F) within 48 hours of vaccination 0.39 0.78 3.33 0 0.78 3.43 0.39 1.18 6.99 Hypotonic- hypo- responsive episode within 24 hours of vaccination 0 0 1.9 0 0 0.49 0.39 0 0 Persistent crying ≥ 3 hours within 24 hours of vaccination 1.16 0 8.09 0.39 0.39 1.96 0 0 1 Seizures within 72 hours of vaccination 0 0.39 0 0 0.39 0.49 0 0.39 0 DT: Swedish National B iologics Laboratories DTP: whole-cell pertussis DTP, Sanofi Pasteur Inc. N = Number of evaluable subjects In the Sweden I Efficacy Trial, one case of whole limb swelling and generalized symptoms, with resolution within 24 hours, was observed following dose 2 of DAPTACEL vaccine. No episodes of anaphylaxis or encephalopathy were observed. No seizures were reported within 3 days of vaccination with DAPTACEL vaccine. Over the entire study period, 6 seizures were reported in the DAPTACEL vaccine group, 9 in the DT group and 3 in the whole-cell pertussis DTP group, for overall rates of 2.3, 3.5 and 1.4 per 1,000 vaccinees, respectively. One case of infantile spasms was reported in the DAPTACEL vaccine group. There were no instances of invasive bacterial infection or death. In a US study, children received 4 doses of DAPTACEL vaccine at 2, 4, 6 and 15-17 months of age. A total of 1,454 children received DAPTACEL vaccine and were included in the safety analyses. Of these, 51.7% were female, 77.2% Caucasian, 6.3% Black, 6.5% Hispanic, 0.9% Asian and 9.1% other races. The use of DAPTACEL vaccine as a fifth dose of DTaP vaccine was evaluated in 2 subsequent US clinical studies. In one study, a total of 485 children received DAPTACEL vaccine at 4-6 years of age following 4 prior doses of DAPTACEL vaccine in infancy (DAPTACEL-primed). In a separate study, a total of 989 children received DAPTACEL vaccine at 4-6 years of age following 4 prior doses of Pentacel vaccine in infancy (Pentacel-primed). The children included in these fifth dose studies were non-random subsets of participants from previous DAPTACEL or Pentacel studies. The subsets were representative of all children who received 4 doses of DAPTACEL or Pentacel vaccine in the earlier studies with regard to frequencies of solicited local and systemic adverse events following the fourth dose. In the US 4-dose DAPTACEL study, at 2, 4, and 6 months of age, DAPTACEL vaccine was administered concomitantly with Haemophilus influenzae type b (Hib) conjugate vaccine (tetanus toxoid conjugate) (Sanofi Pasteur SA), inactivated poliovirus vaccine (IPV) (Sanofi Pasteur SA), and 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.). Infants had received the first dose of hepatitis B vaccine at 0 months of age. At 2 and 6 months of age, hepatitis B vaccine (recombinant) (Merck & Co., Inc.) was also administered concomitantly with DAPTACEL vaccine. Based on random assignment, the fourth dose of DAPTACEL vaccine was administered either alone; concomitantly with Hib conjugate (tetanus toxoid conjugate) vaccine; or concomitantly with Hib conjugate (tetanus toxoid conjugate) vaccine, 7-valent pneumococcal conjugate vaccine, measles, mumps, rubella (MMR) vaccine (Merck & Co., Inc.), and varicella vaccine (Merck & Co., Inc.). In the fifth dose studies, DAPTACEL vaccine was administered concomitantly with IPV (all DAPTACEL-primed subjects and 47% of Pentacel-primed subjects) and MMR vaccine. In the US studies, the occurrence of solicited local and systemic adverse events listed in Table 3 was recorded daily by parents or guardians for Days 0-7 following vaccination. For Days 0 and 1 following the first three doses of DAPTACEL vaccine, signs and symptoms of HHE also were solicited. Periodic telephone calls were made to inquire about adverse events. Serious adverse events were monitored during the three studies, through 6 months following the last dose of DAPTACEL vaccine. The incidence and severity of selected solicited local and systemic adverse events that occurred within 3 days following each dose of DAPTACEL vaccine are shown in Table 3. The incidence of redness, tenderness and swelling at the DAPTACEL injection site increased with the fourth and fifth doses, with the highest rates reported after the fifth dose. The incidence of redness, tenderness and swelling at the DAPTACEL injection site was similarly increased when DAPTACEL vaccine was given as a fifth dose of DTaP vaccine in Pentacel-primed children. Table 3: Number (Percentage) of Children from US Studies with Selected Solicited Local and Systemic Adverse Events by Severity Occurring Between 0 to 3 Days after Each Dose of DAPTACEL Vaccine Dose 1* Dose 2* Dose 3* Dose 4* Dose 5 N= 1390-1406 % N= 1346-1360 % N = 1301-1312 % N= 1118-1144 % DAPTACEL-primed* N = 473-481 % Pentacel-primed* N = 936-981 % Injection Site Reactions (DAPTACEL vaccine injection site) Redness > 5 mm 6.2 7.1 9.6 17.3 35.8 20.2 25 - 50 mm 0.6 0.5 1.9 6.3 10.4 6.8 > 50 mm 0.4 0.1 0 3.1 15.8 6.6 Swelling > 5 mm 4 4 6.5 11.7 23.9 12 25 - 50 mm 1.2 0.6 1 3.2 5.8 4.1 > 50 mm 0.4 0.1 0.1 1.6 7.7 2.9 Tenderness † Any 48.8 38.2 40.9 49.5 61.5 50 Moderate 16.5 9.9 10.6 12.3 11.2 7.4 Severe 4.1 2.3 1.7 2.2 1.7 0.3 Increase in Arm Circumference‡ > 5 mm - - - - 38.3 28.6 20 - 40 mm - - - - 14 7.6 > 40 mm - - - - 1.5 1.2 Interference with Normal Activity of the Arm§ Any - - - - 20.4 8.8 Moderate - - - - 5.6 1.7 Severe 0.4 0 Systemic Reactions Fever** ≥ 38.0°C 9.3 16.1 15.8 10.5 6.1 4.6 > 38.5-39.5°C 1.5 3.9 4.8 2.7 2.1 2 > 39.5°C 0.1 0.4 0.3 0.7 0.2 0.2 Decreased Activity/Lethargy†† Any 51.1 37.4 33.2 25.3 21 12.6 Moderate 23 14.4 12.1 8.2 5.8 3.6 Severe 1.2 1.4 0.6 1 0.8 0.4 Inconsolable Crying‡‡ Any 58.5 51.4 47.9 37.1 14.1 7.2 Moderate 14.2 12.6 10.8 7.7 3.5 1.9 Severe 2.2 3.4 1.4 1.5 0.4 0.3 Fussiness/Irritability §§ Any 75.8 70.7 67.1 54.4 34.9 22.9 Moderate 27.7 25 22 16.3 7.5 5.3 Severe 5.6 5.5 4.3 3.9 0.4 0.5 * In one U.S. study, children received four doses of DAPTACEL vaccine. A non-random subset of these children received a fifth dose of DAPTACEL vaccine in a subsequent study. A non-random subset of children previously vaccinated with 4 doses of Pentacel vaccine in previous clinical studies received a dose of DAPTACEL vaccine at 4-6 years of age as the fifth dose of DTaP vaccine in another clinical study. † Doses 1-4 - Moderate: subject cries when site is touched; Severe: subject cries when leg or arm is moved. Dose 5 - Moderate: interfered with activities, but did not require medical care or absenteeism; Severe: incapacitating, unable to perform usual activities, may have/or required medical care or absenteeism. ‡ The circumference of the DAPTACEL vaccine-injected arm at the level of the axilla was monitored following the fourth and fifth doses only. Increase in arm circumference was calculated by subtracting the baseline circumference pre-vaccination (Day 0) from the circumference post-vaccination. § Moderate: decreased use of arm, but did not require medical care or absenteeism; Severe: incapacitating, refusal to move arm, may have/or required medical care or absenteeism. ** For Doses 1-3, 53.7% of temperatures were measured rectally, 45.1% were measured axillary, 1.0% were measured orally, and 0.1% were measured by an unspecified route. For Dose 4, 35.7% of temperatures were measured rectally, 62.3% were measured axillary, 1.5% were measured orally, and 0.5% were measured by an unspecified route. For Dose 5 in DAPTACEL-primed children, 0.2% of temperatures were measured rectally, 11.3% were measured axillary, and 88.4% were measured orally. For Dose 5 in Pentacel-primed children, 0.2% of temperatures were measured rectally, 0.5% were measured tympanically, 17% were measured axillary, and 81.7% were measured orally. Fever is based upon actual temperatures recorded with no adjustments to the measurement for route. †† Dose 1-4 - Moderate: interferes with and limits daily activity, less interactive; Severe: disabling (not interested in usual daily activity, subject cannot be coaxed to interact with caregiver). Dose 5 - Moderate: interfered with activities, but did not require medical care or absenteeism; Severe: incapacitating, unable to perform usual activities, may have/or required medical care or absenteeism. ‡‡ Doses 1-4 - Moderate: 1 to 3 hours inconsolable crying; Severe: > 3 hours inconsolable crying. Dose 5 - Moderate: interfered with activities, but did not require medical care or absenteeism; Severe: incapacitating, unable to perform usual activities, may have/or required medical care or absenteeism. §§ Doses 1-4 - Moderate: Irritability for 1 to 3 hours; Severe: irritability for > 3 hours. Dose 5 - Moderate: interfered with activities, but did not require medical care or absenteeism; Severe: incapacitating, unable to perform usual activities, may have/or required medical care or absenteeism. In the US study in which children received 4 doses of DAPTACEL vaccine, of 1,454 subjects who received DAPTACEL vaccine, 5 (0.3%) subjects experienced a seizure within 60 days following any dose of DAPTACEL vaccine. One seizure occurred within 7 days post-vaccination: an infant who experienced an afebrile seizure with apnea on the day of the first vaccination. Three other cases of seizures occurred between 8 and 30 days post-vaccination. Of the seizures that occurred within 60 days post-vaccination, 3 were associated with fever. In this study, there were no reported cases of HHE following DAPTACEL vaccine. There was one death due to aspiration 222 days post-vaccination in a subject with ependymoma. Within 30 days following any dose of DAPTACEL vaccine, 57 (3.9%) subjects reported at least one serious adverse event. During this period, the most frequently reported serious adverse event was bronchiolitis, reported in 28 (1.9%) subjects. Other serious adverse events that occurred within 30 days following DAPTACEL vaccine include three cases of pneumonia, two cases of meningitis and one case each of sepsis, pertussis (post-dose 1), irritability and unresponsiveness. In the US study in which DAPTACEL vaccine was administered as a fifth DTaP dose in DAPTACEL-primed subjects, within 30 days following the fifth consecutive dose of DAPTACEL vaccine, 1 (0.2%) subject reported 2 serious adverse events (bronchospasm and hypoxia). In the US study in which DAPTACEL vaccine was administered as a fifth DTaP dose in Pentacel-primed subjects, within 30 days following DAPTACEL, 4 (0.4%) subjects reported one or more serious adverse events (asthma and pneumonia; idiopathic thrombocytopenic purpura; vomiting; cellulitis not at the injection site). In these two studies, there were no reports of seizures within 30 days following DAPTACEL vaccine in either the DAPTACEL-primed subjects or Pentacel-primed subjects. In another study (Sweden II Efficacy Trial), 3 DTaP vaccines and a whole-cell pertussis DTP vaccine, none of which are licensed in the US, were evaluated to assess relative safety and efficacy. This study included HCPDT, a vaccine made of the same components as DAPTACEL vaccine but containing twice the amount of detoxified PT and four times the amount of FHA (20 mcg detoxified PT and 20 mcg FHA). HHE was observed following 29 (0.047%) of 61,220 doses of HCPDT; 16 (0.026%) of 61,219 doses of an acellular pertussis vaccine made by another manufacturer; and 34 (0.056%) of 60,792 doses of a whole-cell pertussis DTP vaccine. There were 4 additional cases of HHE in other studies using HCPDT vaccine for an overall rate of 33 (0.047%) in 69,525 doses. Data From Post-Marketing Experience The following adverse events have been spontaneously reported during the post-marketing use of DAPTACEL vaccine in the US and other countries. Because these events are reported voluntarily from a population of uncertain size, it may not be possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. The following adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to DAPTACEL vaccine. Blood and Lymphatic Disorders Lymphadenopathy Cardiac Disorders Cyanosis Gastro-intestinal Disorders Nausea, diarrhea General Disorders and Administration Site Conditions Local reactions: injection site pain, injection site rash, injection site nodule, injection site mass, extensive swelling of injected limb (including swelling that involves adjacent joints). Infections and Infestations Injection site cellulitis, cellulitis, injection site abscess Immune System Disorders Hypersensitivity, allergic reaction, anaphylactic reaction (edema, face edema, swelling face, pruritus, rash generalized) and other types of rash (erythematous, macular, maculo-papular) Nervous System Disorders Convulsions: febrile convulsion, grand mal convulsion, partial seizures HHE, hypotonia, somnolence, syncope Psychiatric Disorders Screaming DRUG INTERACTIONS Concomitant Administration With Other Vaccines In clinical trials, DAPTACEL vaccine was administered concomitantly with one or more of the following US licensed vaccines: Hib conjugate vaccine, IPV, hepatitis B vaccine, pneumococcal conjugate vaccine, MMR vaccine, and varicella vaccine. [See ADVERSE REACTIONS and Clinical Studies] When DAPTACEL vaccine is given at the same time as another injectable vaccine(s), the vaccines should be administered with different syringes and at different injection sites. Immunosuppressive Treatments Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to DAPTACEL vaccine.

SIDE EFFECTS In clinical studies in the United States and Sweden, 11,560 doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM (10,608 intramuscular, 952 subcutaneous) and 30,951 doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU (5,574 with thimerosal; 25,377 without thimerosal; all subcutaneous) have been administered.15 In these studies, 3,698 infants received 10,615 doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM as a 3-dose series at 2, 4, and 6 months of age; 682 of these infants received a 4th consecutive dose of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM at 15-24 months of age; no children have received 5 consecutive doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM. Forty-two (42) children received Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM as a 4th dose at 15-22 months of age, following 3 doses of whole-cell DTP vaccine; 221 children received Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM as a 5 th dose at 4-6 years of age, following 3 doses of whole-cell DTP and a 4 th dose of whole-cell DTP or acellular DTaP vaccine. In addition, 1,875 infants received 5,574 doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU as a 3-dose series at 3, 5 and 12 months of age. 14, 15 In an ongoing study, 11,859 infants are completing a 3-dose series at 3, 5, and 12 months of age and have been evaluated after 25,377 doses to date.15 In a comparative study, local and systemic adverse reactions commonly associated with whole-cell DTP vaccination occurred less frequently after vaccination with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM. 15 Studies have shown, however, that the rate of erythema, swelling, and fever increased with successive doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM (Tables 2, 3, and 6). In a double-blind safety and immunogenicity study in the United States, 1,303 infants were randomized to receive Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM (n=977) or U.S. licensed whole-cell DTP vaccine manufactured by Lederle Laboratories (n=326) at 2, 4, and 6 months of age. At each time point, 96-99% of subjects also received Huemophihs infuenzae type b conjugate vaccine, 83-97% received polio vaccine live oral, and 18-80% received hepatitis B vaccine. Safety data were actively collected using standardized diary cards and follow-up telephone calls at 1, 3, and 7 days after each vaccination, and are available for 972 and 323 infants, respectively, who received at least one dose of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM or whole-cell D.P. Local injection site reactions and systemic reactions such as fever (³ 38o C), irritability, decreased appetite, and drowsiness were significantly less frequent after Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM than after whole-cell DTP (Table 2). Within 7 days after vaccination, there were no deaths and five hospitalizations (3 Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM recipients: 1 with cold/high fever on day 6, 1 with ear infection on day 6, 1 with febrile seizure and respiratory infection on day 4; 2 whole-cell DTP recipients: 1 with diarrhea on day 4, 1 with hives/allergic reaction on day 4), none judged to be vaccine-related by the investigators. 15 TABLE 2. ADVERSE EVENTS (%) OCCURRING WITHIN 72 HOURS AFTER INTRAMUSCULAR VACCINATION OF U. S. INFANTS WITH CERTIVA (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM OR WHOLE-CELL DTP AT 2,4, AND 6 MONTHS OF AGE Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM Reaction % Whole-Cell Pertussis DTP Reaction % p-values1 Dose 1 2 Mos. Dose 2 4 Mos. Dose 3 6 Mos. Dose 1 2 Mos. Dose 2 4 Mos. Dose 3 6 Mos. Combined Dose DTaP; DTP N=972 N=898 N=868 N=323 N=295 N=279 N=2,738: 897 Local Redness (any) 5.2 8.5 13.0 22.1 29.9 27.2

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Management Of Acute Allergic Reactions Epinephrine hydrochloride solution (1:1,000) and other appropriate agents and equipment must be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs. Adverse Reactions Following Prior Pertussis Vaccination If any of the following events occur within the specified period after administration of a whole-cell pertussis vaccine or a vaccine containing an acellular pertussis component, the decision to administer DAPTACEL vaccine should be based on careful consideration of potential benefits and possible risks. [See DOSAGE AND ADMINISTRATION] Temperature of ≥ 40.5°C (105°F) within 48 hours, not attributable to another identifiable cause. Collapse or shock-like state (hypotonic-hyporesponsive episode (HHE)) within 48 hours. Persistent, inconsolable crying lasting ≥ 3 hours within 48 hours. Seizures with or without fever within 3 days. Guillain-Barre Syndrome And Brachial Neuritis A review by the Institute of Medicine found evidence for a causal relation between tetanus toxoid and both brachial neuritis and Guillain-Barre syndrome.1 If Guillain-Barre syndrome occurred within 6 weeks of receipt of a prior vaccine containing tetanus toxoid, the risk for Guillain-Barre syndrome may be increased following DAPTACEL vaccine. Infants and Children With A History Of Previous Seizures For infants or children with a history of previous seizures, an appropriate antipyretic may be administered (in the dosage recommended in its prescribing information) at the time of vaccination with a vaccine containing an acellular pertussis component (including DAPTACEL vaccine) and for the following 24 hours, to reduce the possibility of post-vaccination fever. Limitations Of Vaccine Effectiveness Vaccination with DAPTACEL vaccine may not protect all individuals. Altered Immunocompetence If DAPTACEL vaccine is administered to immunocompromised persons, including persons receiving immunosuppressive therapy, the expected immune response may not be obtained. [See Immunosuppressive Treatments] Apnea In Premature Infants Apnea following intramuscular vaccination has been observed in some infants born prematurely. The decision about when to administer an intramuscular vaccine, including DAPTACEL, to an infant born prematurely should be based on consideration of the individual infant's medical status and the potential benefits and possible risks of vaccination. Syncope Syncope (fainting) has been reported following vaccination with DAPTACEL. Procedures should be in place to prevent falling injury and manage syncopal reactions. Use In Specific Populations Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with DAPTACEL vaccine. It is also not known whether DAPTACEL vaccine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Pediatric Use DAPTACEL vaccine is not indicated for infants below 6 weeks of age or children 7 years of age or older. Safety and effectiveness of DAPTACEL vaccine in these age groups have not been established. REFERENCES 1. Stratton KR, et al. editors. Adverse events associated with childhood vaccines; evidence bearing on causality. Washington D.C.: National Academy Press. 1994. p. 67-117.

WARNINGS The ACIP and AAP state that if any of the following events occur in temporal relation to receipt of DTP or DTaP, the decision to give subsequent doses of vaccine containing the pertussis component should be carefirlly considered. There may be circumstances, such as a high incidence of pertussis, in which the potential benefits outweigh possible risks, particularly because these events have not been proven to cause permanent sequelae. The following events were previously considered contraindications and are ACIP22: Temperature of ³105° F (³40.5° C) within 48 hours, cause. Collapse or shock-like state (hypotonic hyporesponsive episode) within 48 hours. Persistent crying lasting 23 hours, occurring within 48 hours. Convulsions with or without fever, occurring within 3 days. Data on the use of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM in children with a personal history of convulsion or an evolving or changing disorder of the central nervous system are not available. In the opinion of the manufacturer, the presence of a personal history of convulsion or an evolving or changing disorder of the central nervous system is considered a warning against further immunization with this vaccine. The ACIP and AAP recommend considering deferral of immunization against pertussis in children with progressive neurologic disorder, personal history of convulsion, and known or suspected neurologic conditions which predispose to seizures or neurologic deterioration until now considered precautions by the not attributable to another identifiable the childs health status has been fully assessed, a treatment regimen established and the condition stabilized. 3, 20, 21, 22 Children with a personal or family history of convulsion may have an increased risk of seizure following DTP vaccination compared with children without such histories. 24, 25 However, the ACIP recognizes in certain instances that infants and children with stable neurologic conditions, including well-controlled seizures, may be vaccinated and that the occurrence of single seizures (temporally unassociated with D.P. does not contraindicate DTP vaccination if the seizures can be satisfactorily explained. In addition, the ACIP does not consider a family history of convulsions or other central nervous system disorders to be a contraindication to pertussis vaccination. 20, 22, 25 Data on the use of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM in these infants and children are not available. The decision to administer a pertussis-containing vaccine to children with stable central nervous system disorders, such as well-controlled seizures or satisfactorily explained single seizures, must be made by the attending physician on a case-by-case basis, taking into account all relevant factors and an assessment of the potential risks and benefits for each child. The physician should review the full text of the ACIP and AAP guidelines prior to considering vaccination for such children. In addition, the parent or guardian should be advised of the potential increased risk involved (See PATIENT INFORMATION). For children at higher risk of seizures than the general population, the ACIP recommends that acetaminophen or ibuprofen may be administered at the time of DTaP vaccination and for 24 hours thereafter (using an age-appropriate dose and dosing interval) to reduce the possibility of post-vaccination fever.22 A committee from the Institute of Medicine (IOM) has concluded that evidence is consistent with a causal relationship between whole-cell DTP and acute neurologic illness, and under special circumstances, between whole-cell DTP and chronic neurologic disease in the context of the National Childhood Encephalopathy Study (NCES) report. 26, 27 However, the IOM committee concluded that evidence was insufficient to indicate whether or not whole-cell DTP vaccine increased the overall risk of chronic neurological disease.27 The ACIP indicated that the results of the NCES were insufficient to determine whether DTP administration before the acute neurological event influenced the potential for neurologic dysfunction 10 years later. 20 Acute encephalopathy or permanent neurological injury have not been reported in clinical trials after administration of CertivaTM, but experience with this vaccine is insufficient to rule this out (See ADVERSE REACTIONS). Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM should not be given to infants or children with thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection unless the potential benefit clearly outweighs the risk of administration. If the decision is made to administer CertivaTM to children with coagulation disorders, it should be given with caution (See DRUG lNTERACTIONS).19 PRECAUTIONS Care is to be taken by the physician for the safe and effective use of this vaccine. Prior to administration of any dose of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM, the physician should review the childs medical history. The physician should also review the childs previous immunization history for possible vaccine sensitivity and occurrence of any symptoms or signs of an adverse event after immunization, in order to determine the existence of any contraindication to immunization with CertivaTM and to allow an assessment of benefits and risks (See CONTRAINDICATIONS and ADVERSE REACTIONS). Before the injection of any biological, the physician should take all precautions known for the prevention of allergic or any other side reactions, including understanding the use of the biological concerned and the nature of the side effects and adverse reactions that may follow its use. Epinephrine injection (1:1,000) and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur. Children with impaired immune responsiveness, whether due to the use of immunosuppressive therapy (including irradiation, corticosteroids, antimetabolites, alkylating agents, and cytotoxic agents), a genetic defect, human immunodeficiency virus (HIV) infection, or other causes, may have reduced immune response to active immunization procedures. Deferral of immunization may be considered in individuals receiving immunosuppressive therapy. Other groups should receive this vaccine according to the usual recommended schedule (See DRUG INTERACTIONS).28 Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM is not contraindicated based on the presence of HIV infection. 3 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 subject to prevent transmission of hepatitis or other infectious agents from person to person. Needles should not be recapped but should be disposed of properly. Caution: the packaging stopper of this product contains natural rubber latex which may cause allergic reactions. Information for Vaccine Recipients and Parents Parents or guardians of infants and children to be vaccinated should be fully informed of the benefits and risks of vaccination with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM and the importance of completing the immunization series, unless contraindicated. The physician should inform the parents or guardians about the potential for adverse reactions that have been temporally associated with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM and other pertussis vaccine administrations. The parents or guardians of infants and children with family history of convulsions or other central nervous system disorders should be advised of the potential increased risk of seizures following DTP vaccinations. Prior to each immunization, the parent or guardian should be provided with the Vaccine Information Materials (VIMs), as required by the National Childhood Vaccine Injury Act of 1986. 26 Parents or guardians should be instructed to report any severe or unusual reactions to their health-care provider. The U. S. 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. 29, 30 The toll-free number for VAERS forms and information is 1-800-822-7967. Drug Interactions See DRUG INTERACTIONS section. Carcinogenesis, Mutagenesis, Impairment of Fertility Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) m has not been evaluated for its carcinogenic or mutagenic potentials or impairment of fertility. Pregnancy Reproductive Studies: Pregnancy Category C:Animal reproduction studies have not been conducted with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM. It is not known whether Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM is NOT recommended for use in a pregnant woman. This vaccine is not recommended for persons 7 years of age or older (See Pediatric Use below). Pediatric Use SAFETY AND EFFECTIVENESS OF CertivaTM IN INFANTS BELOW 6 WEEKS OF AGE HAVE NOT BEEN ESTABLISHED (SEE DOSAGE AND ADMINISTRATION). THIS VACCINE IS NOT RECOMMENDED FOR PERSONS 7 YEARS OF AGE AND OLDER Tetanus and Diphtheria Toxoids Adsorbed for adult use (Td) is to be used in individuals 7 years of age or older.