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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

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 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 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.

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 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.