See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2013

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use BOOSTRIX sfely nd effectively. See full prescribing informtion for BOOSTRIX. BOOSTRIX (Tetnus Toxoid, Reduced Diphtheri Toxoid nd Acellulr Pertussis Vccine, Adsorbed) Suspension for Intrmusculr Injection Initil U.S. Approvl: INDICATIONS AND USAGE BOOSTRIX is vccine indicted for ctive booster immuniztion ginst tetnus, diphtheri, nd pertussis. BOOSTRIX is pproved for use s single dose in individuls 10 yers of ge nd older. (1) DOSAGE AND ADMINISTRATION A single intrmusculr injection (0.5 ml). (2.2) DOSAGE FORMS AND STRENGTHS Single-dose vils nd prefilled syringes contining 0.5-mL suspension for injection. (3) CONTRAINDICATIONS Severe llergic rection (e.g., nphylxis) fter previous dose of ny tetnus toxoid-, diphtheri toxoid-, or pertussis ntigen-contining vccine or to ny component of BOOSTRIX. (4.1) Encephlopthy (e.g., com, decresed level of consciousness, prolonged seizures) within 7 dys of dministrtion of previous pertussis ntigen-contining vccine. (4.2) WARNINGS AND PRECAUTIONS The tip cps of the prefilled syringes my contin nturl rubber ltex which my cuse llergic rections in ltex-sensitive individuls. (5.1) If Guillin-Brré syndrome occurred within 6 weeks of receipt of prior vccine contining tetnus toxoid, the risk of Guillin-Brré syndrome my be incresed following subsequent dose of tetnus toxoidcontining vccine, including BOOSTRIX. (5.2) Syncope (finting) cn occur in ssocition with dministrtion of injectble vccines, including BOOSTRIX. Procedures should be in plce to void flling injury nd to restore cerebrl perfusion following syncope. (5.3) Progressive or unstble neurologic conditions re resons to defer vccintion with pertussis-contining vccine, including BOOSTRIX. (5.4) Persons who experienced n Arthus-type hypersensitivity rection following prior dose of tetnus toxoid-contining vccine should not receive BOOSTRIX unless t lest 10 yers hve elpsed since the lst dose of tetnus toxoid-contining vccine. (5.5) ADVERSE REACTIONS Common solicited dverse events ( 15%) in dolescents (10 to 18 yers of ge) were pin, redness, nd swelling t the injection site, increse in rm circumference of injected rm, hedche, ftigue, nd gstrointestinl symptoms. (6.1) Common solicited dverse events ( 15%) in dults (19 to 64 yers of ge) were pin, redness, nd swelling t the injection site, hedche, ftigue, nd gstrointestinl symptoms. (6.1) The most common solicited dverse event ( 15%) in the elderly (65 yers of ge nd older) ws pin t the injection site. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct GlxoSmithKline t or VAERS t or DRUG INTERACTIONS In subjects 11 to 18 yers of ge, lower levels for ntibodies to pertctin were observed when BOOSTRIX ws dministered concomitntly with meningococcl conjugte vccine (serogroups A, C, Y, nd W-135) s compred to BOOSTRIX dministered first. (7.1) In subjects 19 to 64 yers of ge, lower levels for ntibodies to FHA nd pertctin were observed when BOOSTRIX ws dministered concomitntly with n inctivted influenz vccine s compred to BOOSTRIX lone. (7.1) Do not mix BOOSTRIX with ny other vccine in the sme syringe or vil. (7.1) USE IN SPECIFIC POPULATIONS Sfety nd effectiveness of BOOSTRIX hve not been estblished in pregnnt women. (8.1) Register women who receive BOOSTRIX while pregnnt in the pregnncy registry by clling (8.1) See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Preprtion for Administrtion 2.2 Dose nd Schedule 2.3 Additionl Dosing Informtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Hypersensitivity 4.2 Encephlopthy 5 WARNINGS AND PRECAUTIONS 5.1 Ltex 5.2 Guillin-Brré Syndrome nd Brchil Neuritis 5.3 Syncope 5.4 Progressive or Unstble Neurologic Disorders 5.5 Arthus-Type Hypersensitivity 5.6 Altered Immunocompetence 5.7 Prevention nd Mngement of Acute Allergic Rections 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Postmrketing Experience 7 DRUG INTERACTIONS 7.1 Concomitnt Vccine Administrtion 7.2 Immunosuppressive Therpies 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Efficcy of INFANRIX 14.2 Immunologicl Evlution in Adolescents 14.3 Immunologicl Evlution in Adults (19 to 64 Yers of Age) 14.4 Immunologicl Evlution in the Elderly (65 Yers of Age nd Older) 14.5 Concomitnt Vccine Administrtion 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing informtion re not listed. 1

2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE BOOSTRIX is indicted for ctive booster immuniztion ginst tetnus, diphtheri, nd pertussis. BOOSTRIX is pproved for use s single dose in individuls 10 yers of ge nd older. 2 DOSAGE AND ADMINISTRATION 2.1 Preprtion for Administrtion Shke vigorously to obtin homogeneous, turbid, white suspension before dministrtion. Do not use if resuspension does not occur with vigorous shking. Prenterl drug products should be inspected visully for prticulte mtter nd discolortion prior to dministrtion, whenever solution nd continer permit. If either of these conditions exists, the vccine should not be dministered. For the prefilled syringes, ttch sterile needle nd dminister intrmusculrly. For the vils, use sterile needle nd sterile syringe to withdrw the 0.5-mL dose nd dminister intrmusculrly. Chnging needles between drwing vccine from vil nd injecting it into recipient is not necessry unless the needle hs been dmged or contminted. Use seprte sterile needle nd syringe for ech individul. Do not dminister this product intrvenously, intrdermlly, or subcutneously. 2.2 Dose nd Schedule BOOSTRIX is dministered s single 0.5-mL intrmusculr injection into the deltoid muscle of the upper rm. There re no dt to support repet dministrtion of BOOSTRIX. Five yers should elpse between the lst dose of the recommended series of Diphtheri nd Tetnus Toxoids nd Acellulr Pertussis Vccine Adsorbed (DTP) nd/or Tetnus nd Diphtheri Toxoids Adsorbed For Adult Use (Td) vccine nd the dministrtion of BOOSTRIX. 2.3 Additionl Dosing Informtion Primry Series: The use of BOOSTRIX s primry series or to complete the primry series for diphtheri, tetnus, or pertussis hs not been studied. Wound Mngement: If tetnus prophylxis is needed for wound mngement, BOOSTRIX my be given if no previous dose of ny Tetnus Toxoid, Reduced Diphtheri Toxoid nd Acellulr Pertussis Vccine, Adsorbed (Tdp) hs been dministered. 3 DOSAGE FORMS AND STRENGTHS BOOSTRIX is suspension for injection vilble in 0.5-mL single-dose vils nd prefilled TIP-LOK syringes. 2

3 4 CONTRAINDICATIONS 4.1 Hypersensitivity A severe llergic rection (e.g., nphylxis) fter previous dose of ny tetnus toxoid-, diphtheri toxoid-, or pertussis ntigen-contining vccine or ny component of this vccine is contrindiction to dministrtion of BOOSTRIX [see Description (11)]. Becuse of the uncertinty s to which component of the vccine might be responsible, none of the components should be dministered. Alterntively, such individuls my be referred to n llergist for evlution if immuniztion with ny of these components is considered. 4.2 Encephlopthy Encephlopthy (e.g., com, decresed level of consciousness, prolonged seizures) within 7 dys of dministrtion of previous dose of pertussis ntigen-contining vccine tht is not ttributble to nother identifible cuse is contrindiction to dministrtion of ny pertussis ntigen-contining vccine, including BOOSTRIX. 5 WARNINGS AND PRECAUTIONS 5.1 Ltex The tip cps of the prefilled syringes my contin nturl rubber ltex which my cuse llergic rections in ltex-sensitive individuls. 5.2 Guillin-Brré Syndrome nd Brchil Neuritis If Guillin-Brré syndrome occurred within 6 weeks of receipt of prior vccine contining tetnus toxoid, the risk of Guillin-Brré syndrome my be incresed following subsequent dose of tetnus toxoid-contining vccine, including BOOSTRIX. A review by the Institute of Medicine (IOM) found evidence for cusl reltionship between receipt of tetnus toxoid nd both brchil neuritis nd Guillin-Brré syndrome Syncope Syncope (finting) cn occur in ssocition with dministrtion of injectble vccines, including BOOSTRIX. Syncope cn be ccompnied by trnsient neurologicl signs such s visul disturbnce, presthesi, nd tonic-clonic limb movements. Procedures should be in plce to void flling injury nd to restore cerebrl perfusion following syncope. 5.4 Progressive or Unstble Neurologic Disorders Progressive or unstble neurologic conditions (e.g., cerebrovsculr events nd cute encephlopthic conditions) re resons to defer vccintion with pertussis-contining vccine, including BOOSTRIX. It is not known whether dministrtion of BOOSTRIX to persons with n unstble or progressive neurologic disorder might hsten mnifesttions of the disorder or ffect the prognosis. Administrtion of BOOSTRIX to persons with n unstble or progressive neurologic disorder my result in dignostic confusion between mnifesttions of the underlying illness nd possible dverse effects of vccintion. 5.5 Arthus-Type Hypersensitivity Persons who experienced n Arthus-type hypersensitivity rection following prior dose of tetnus toxoid-contining vccine usully hve high serum tetnus ntitoxin level nd 3

4 should not receive BOOSTRIX or other tetnus toxoid-contining vccines unless t lest 10 yers hve elpsed since the lst dose of tetnus toxoid-contining vccine. 5.6 Altered Immunocompetence As with ny vccine, if dministered to immunosuppressed persons, including individuls receiving immunosuppressive therpy, the expected immune response my not be obtined. 5.7 Prevention nd Mngement of Acute Allergic Rections Prior to dministrtion, the helthcre provider should review the immuniztion history for possible vccine sensitivity nd previous vccintion-relted dverse rections to llow n ssessment of benefits nd risks. Epinephrine nd other pproprite gents used for the control of immedite llergic rections must be immeditely vilble should n cute nphylctic rection occur. 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils of vccine cnnot be directly compred to rtes in the clinicl trils of nother vccine, nd my not reflect the rtes observed in prctice. As with ny vccine, there is the possibility tht brod use of BOOSTRIX could revel dverse rections not observed in clinicl trils. In clinicl studies, 4,949 dolescents (10 to 18 yers of ge) nd 4,076 dults (19 yers of ge nd older) were vccinted with single dose of BOOSTRIX. Of these dolescents, 1,341 were vccinted with BOOSTRIX in codministrtion study with meningococcl conjugte vccine [see Drug Interctions (7.1) nd Clinicl Studies (14.5)]. Of these dults, 1,104 were 65 yers of ge nd older [see Clinicl Studies (14.4)]. A totl of 860 dults19 yers of ge nd older received concomitnt vccintion with BOOSTRIX nd influenz vccines in codministrtion study [see Drug Interctions (7.1) nd Clinicl Studies (14.5)]. An dditionl 1,092 dolescents 10 to 18 yers of ge received non-us formultion of BOOSTRIX (formulted to contin 0.5 mg luminum per dose) in non-us clinicl studies. In rndomized, observer-blinded, controlled study in the US, 3,080 dolescents 10 to 18 yers of ge received single dose of BOOSTRIX nd 1,034 received the comprtor Td vccine, mnufctured by MssBioLogics. There were no substntive differences in demogrphic chrcteristics between the vccine groups. Among BOOSTRIX nd comprtor vccine recipients, pproximtely 75% were 10 to 14 yers of ge nd pproximtely 25% were 15 to 18 yers of ge. Approximtely 98% of prticipnts in this study hd received the recommended series of 4 or 5 doses of either Diphtheri nd Tetnus Toxoids nd Pertussis Vccine Adsorbed (DTwP) or combintion of DTwP nd DTP in childhood. Subjects were monitored for solicited dverse events using stndrdized diry crds (dy 0-14). Unsolicited dverse events were monitored for the 31-dy period following vccintion (dy 0-30). Subjects were lso monitored for 6 months post-vccintion for non-routine medicl visits, visits to n emergency room, onset of new chronic illness, nd serious dverse events. Informtion regrding 4

5 lte onset dverse events ws obtined vi telephone cll 6 months following vccintion. At lest 97% of subjects completed the 6-month follow-up evlution. In study conducted in Germny, BOOSTRIX ws dministered to 319 children 10 to 12 yers of ge previously vccinted with 5 doses of cellulr pertussis ntigen-contining vccines; 193 of these subjects hd previously received 5 doses of INFANRIX (Diphtheri nd Tetnus Toxoids nd Acellulr Pertussis Vccine Adsorbed). Adverse events were recorded on diry crds during the 15 dys following vccintion. Unsolicited dverse events tht occurred within 31 dys of vccintion (dy 0-30) were recorded on the diry crd or verblly reported to the investigtor. Subjects were monitored for 6 months post-vccintion for physicin office visits, emergency room visits, onset of new chronic illness, nd serious dverse events. The 6- month follow-up evlution, conducted vi telephone interview, ws completed by 90% of subjects. The US dult (19 to 64 yers of ge) study, rndomized, observer-blinded study, evluted the sfety of BOOSTRIX (N = 1,522) compred with ADACEL (Tetnus Toxoid, Reduced Diphtheri Toxoid nd Acellulr Pertussis Vccine Adsorbed) (N = 762), Tdp vccine mnufctured by Snofi Psteur SA. Vccines were dministered s single dose. There were no substntive differences in demogrphic chrcteristics between the vccine groups. Subjects were monitored for solicited dverse events using stndrdized diry crds (dy 0-14). Unsolicited dverse events were monitored for the 31-dy period following vccintion (dy 0-30). Subjects were lso monitored for 6 months post-vccintion for serious dverse events, visits to n emergency room, hospitliztions, nd onset of new chronic illness. Approximtely 95% of subjects completed the 6-month follow-up evlution. The US elderly (65 yers of ge nd older) study, rndomized, observer-blinded study, evluted the sfety of BOOSTRIX (N = 887) compred with DECAVAC (Tetnus nd Diphtheri Toxoids Adsorbed) (N = 445), US-licensed Td vccine, mnufctured by Snofi Psteur SA. Vccines were dministered s single dose. Among ll vccine recipients, the men ge ws pproximtely 72 yers; 54% were femle nd 95% were white. Subjects were monitored for solicited dverse events using stndrdized diry crds (dy 0-3). Unsolicited dverse events were monitored for the 31-dy period following vccintion (dy 0-30). Subjects were lso monitored for 6 months post-vccintion for serious dverse events. Approximtely 99% of subjects completed the 6-month follow-up evlution. Solicited Adverse Events in the US Adolescent Study: Tble 1 presents the solicited locl dverse rections nd generl dverse events within 15 dys of vccintion with BOOSTRIX or Td vccine for the totl vccinted cohort. The primry sfety endpoint ws the incidence of grde 3 pin (spontneously pinful nd/or prevented norml ctivity) t the injection site within 15 dys of vccintion. Grde 3 pin ws reported in 4.6% of those who received BOOSTRIX compred with 4.0% of those who received the Td vccine. The difference in rte of grde 3 pin ws within the pre-defined clinicl limit for non-inferiority (upper limit of the 95% CI for the difference [BOOSTRIX minus Td] 4%). 5

6 Tble 1. Rtes of Solicited Locl Adverse Rections or Generl Adverse Events Within the 15- dy Post-Vccintion Period in Adolescents 10 to 18 Yers of Age (Totl Vccinted Cohort) BOOSTRIX (N = 3,032) % Td (N = 1,013) % Locl Pin, ny b Pin, grde 2 or 3 b Pin, grde 3 c Redness, ny Redness, >20 mm Redness, 50 mm Swelling, ny Swelling, >20 mm Swelling, 50 mm Arm circumference increse, >5 mm d Arm circumference increse, >20 mm d Arm circumference increse, >40 mm d Generl Hedche, ny Hedche, grde 2 or 3 b Hedche, grde Ftigue, ny Ftigue, grde 2 or Ftigue, grde Gstrointestinl symptoms, ny e Gstrointestinl symptoms, grde 2 or 3 e Gstrointestinl symptoms, grde 3 e Fever, 99.5 F (37.5 C) f Fever, >100.4 F (38.0 C) f Fever, >102.2 F (39.0 C) f Td = Tetnus nd Diphtheri Toxoids Adsorbed For Adult Use mnufctured by MssBioLogics. N = Number of subjects in the totl vccinted cohort with locl/generl symptoms sheets completed. Grde 2 = Locl: pinful when limb moved; Generl: interfered with norml ctivity. Grde 3 = Locl: spontneously pinful nd/or prevented norml ctivity; Generl: prevented norml ctivity. Dy of vccintion nd the next 14 dys. b Sttisticlly significntly higher (P <0.05) following BOOSTRIX s compred to Td vccine. c Grde 3 injection site pin following BOOSTRIX ws not inferior to Td vccine (upper limit of two-sided 95% CI for the difference [BOOSTRIX minus Td] in the percentge of subjects 4%). d Mid-upper region of the vccinted rm. e Gstrointestinl symptoms included nuse, vomiting, dirrhe, nd/or bdominl pin. f Orl tempertures or xillry tempertures. 6

7 Unsolicited Adverse Events in the US Adolescent Study: The incidence of unsolicited dverse events reported in the 31 dys fter vccintion ws comprble between the 2 groups (25.4% nd 24.5% for BOOSTRIX nd Td vccine, respectively). Solicited Adverse Events in the Germn Adolescent Study: Tble 2 presents the rtes of solicited locl dverse rections nd fever within 15 dys of vccintion for those subjects who hd previously been vccinted with 5 doses of INFANRIX. No cses of whole rm swelling were reported. Two individuls (2/193) reported lrge injection site swelling (rnge 110 to 200 mm dimeter), in one cse ssocited with grde 3 pin. Neither individul sought medicl ttention. These episodes were reported to resolve without sequele within 5 dys. Tble 2. Rtes of Solicited Adverse Events Reported Within the 15-dy Post-Vccintion Period Following Administrtion of BOOSTRIX in Adolescents 10 to 12 Yers of Age Who Hd Previously Received 5 Doses of INFANRIX BOOSTRIX (N = 193) % Pin, ny 62.2 Pin, grde 2 or Pin, grde Redness, ny 47.7 Redness, >20 mm 15.0 Redness, 50 mm 10.9 Swelling, ny 38.9 Swelling, >20 mm 17.6 Swelling, 50 mm 14.0 Fever, 99.5 F (37.5 C) b 8.8 Fever, >100.4 F (38.0 C) b 4.1 Fever, >102.2 F (39.0 C) b 1.0 N = Number of subjects with locl/generl symptoms sheets completed. Grde 2 = Pinful when limb moved. Grde 3 = Spontneously pinful nd/or prevented norml ctivity. Dy of vccintion nd the next 14 dys. b Orl tempertures or xillry tempertures. Solicited Adverse Events in the US Adult (19 to 64 Yers of Age) Study: Tble 3 presents solicited locl dverse rections nd generl dverse events within 15 dys of vccintion with BOOSTRIX or the comprtor Tdp vccine for the totl vccinted cohort. 7

8 Tble 3. Rtes of Solicited Locl Adverse Rections or Generl Adverse Events Within the 15-dy Post-Vccintion Period in Adults 19 to 64 Yers of Age (Totl Vccinted Cohort) BOOSTRIX (N = 1,480) % Tdp (N = 741) % Locl Pin, ny Pin, grde 2 or Pin, grde Redness, ny Redness, >20 mm Redness, 50 mm Swelling, ny Swelling, >20 mm Swelling, 50 mm Generl Hedche, ny Hedche, grde 2 or Hedche, grde Ftigue, ny Ftigue, grde 2 or Ftigue, grde Gstrointestinl symptoms, ny b Gstrointestinl symptoms, grde 2 or 3 b Gstrointestinl symptoms, grde 3 b Fever, 99.5 F (37.5 C) c Fever, >100.4 F (38.0 C) c Fever, >102.2 F (39.0 C) c Tdp = Tetnus Toxoid, Reduced Diphtheri Toxoid nd Acellulr Pertussis Vccine Adsorbed, Tdp vccine mnufctured by Snofi Psteur SA. N = Number of subjects in the totl vccinted cohort with locl/generl symptoms sheets completed. Grde 2 = Locl: pinful when limb moved; Generl: interfered with norml ctivity. Grde 3 = Locl/Generl: prevented norml ctivity. Dy of vccintion nd the next 14 dys. b Gstrointestinl symptoms included nuse, vomiting, dirrhe, nd/or bdominl pin. c Orl tempertures. Unsolicited Adverse Events in the US Adult (19 to 64 Yers of Age) Study: The incidence of unsolicited dverse events reported in the 31 dys fter vccintion ws comprble between the 2 groups (17.8% nd 22.2% for BOOSTRIX nd Tdp vccine, respectively). Solicited Adverse Events in the US Elderly (65 Yers of Age nd Older) Study: Tble 4 presents solicited locl dverse rections nd generl dverse events within 4 dys of 8

9 vccintion with BOOSTRIX or the comprtor Td vccine for the totl vccinted cohort. Tble 4. Rtes of Solicited Locl Adverse Rections or Generl Adverse Events Within 4 Dys of Vccintion in the Elderly 65 Yers of Age nd Older (Totl Vccinted Cohort) BOOSTRIX % Td % Locl (N = 882) (N = 444) Pin, ny Pin, grde 2 or Pin, grde Redness, ny Redness, >20 mm Redness, 50 mm Swelling, ny Swelling, >20 mm Swelling, 50 mm Generl (N = 882) (N = 445) Ftigue, ny Ftigue, grde 2 or Ftigue, grde Hedche, ny Hedche, grde 2 or Hedche, grde Gstrointestinl symptoms, ny b Gstrointestinl symptoms, grde 2 or 3 b Gstrointestinl symptoms, grde 3 b Fever, 99.5 F (37.5 C) c Fever, >100.4 F (38.0 C) c Fever, >102.2 F (39.0 C) c Td = Tetnus nd Diphtheri Toxoids Adsorbed, US-licensed Td vccine, mnufctured by Snofi Psteur SA. N = Number of subjects with documented dose. Grde 2 = Locl: pinful when limb moved; Generl: interfered with norml ctivity. Grde 3 = Locl/Generl: prevented norml ctivity. Dy of vccintion nd the next 3 dys. b Gstrointestinl symptoms included nuse, vomiting, dirrhe, nd/or bdominl pin. c Orl tempertures. Unsolicited Adverse Events in the US Elderly (65 Yers of Age nd Older) Study: The incidence of unsolicited dverse events reported in the 31 dys fter vccintion ws comprble between the 2 groups (17.1% nd 14.4% for BOOSTRIX nd Td vccine, respectively). Serious Adverse Events (SAEs): In the US nd Germn dolescent sfety studies, no 9

10 serious dverse events were reported to occur within 31 dys of vccintion. During the 6-month extended sfety evlution period, no serious dverse events tht were of potentil utoimmune origin or new onset nd chronic in nture were reported to occur. In non-us dolescent studies in which serious dverse events were monitored for up to 37 dys, one subject ws dignosed with insulin-dependent dibetes 20 dys following dministrtion of BOOSTRIX. No other serious dverse events of potentil utoimmune origin or tht were new onset nd chronic in nture were reported to occur in these studies. In the US dult (19 to 64 yers of ge) study, serious dverse events were reported to occur during the entire study period (0-6 months) by 1.4% nd 1.7% of subjects who received BOOSTRIX nd the comprtor Tdp vccine, respectively. During the 6- month extended sfety evlution period, no serious dverse events of neuroinflmmtory nture or with informtion suggesting n utoimmune etiology were reported in subjects who received BOOSTRIX. In the US elderly (65 yers of ge nd older) study, serious dverse events were reported to occur by 0.7% nd 0.9% of subjects who received BOOSTRIX nd the comprtor Td vccine, respectively, during the 31-dy period fter vccintion. Serious dverse events were reported to occur by 4.2% nd 2.2% of subjects who received BOOSTRIX nd the comprtor Td vccine, respectively, during the 6-month period fter vccintion. Concomitnt Vccintion With Meningococcl Conjugte Vccine in Adolescents: In rndomized study in the US, 1,341 dolescents (11 to 18 yers of ge) received either BOOSTRIX dministered concomitntly with MENACTRA (Meningococcl (Groups A, C, Y, nd W-135) Polyscchride Diphtheri Toxoid Conjugte Vccine), (Snofi Psteur SA), or ech vccine dministered seprtely 1 month prt [see Drug Interctions (7.1) nd Clinicl Studies (14.5)]. Sfety ws evluted in 446 subjects who received BOOSTRIX dministered concomitntly with meningococcl conjugte vccine t different injection sites, 446 subjects who received BOOSTRIX followed by meningococcl conjugte vccine 1 month lter, nd 449 subjects who received meningococcl conjugte vccine followed by BOOSTRIX 1 month lter. Solicited locl dverse rections nd generl dverse events were recorded on diry crds for 4 dys (dy 0-3) following ech vccintion. Unsolicited dverse events were monitored for the 31-dy period following ech vccintion (dy 0-30). Tble 5 presents the percentges of subjects experiencing locl rections t the injection site for BOOSTRIX nd solicited generl events following BOOSTRIX. The incidence of unsolicited dverse events reported in the 31 dys fter ny vccintion ws similr following ech dose of BOOSTRIX in ll cohorts. 10

11 Tble 5. Rtes of Solicited Locl Adverse Rections or Generl Adverse Events Reported Within the 4-dy Post-Vccintion Period following Administrtion of BOOSTRIX in Individuls 11 to 18 Yers of Age (Totl Vccinted Cohort) BOOSTRIX+MCV4 (N = 441) % BOOSTRIX MCV4 b (N = ) % MCV4 BOOSTRIX c (N = 441) % Locl (t injection site for BOOSTRIX) Pin, ny Redness, ny Swelling, ny Generl (following dministrtion of BOOSTRIX) Ftigue Hedche Gstrointestinl symptoms d Fever, 99.5 F (37.5 C) e MCV4 = MENACTRA (Meningococcl (Groups A, C, Y, nd W-135) Polyscchride Diphtheri Toxoid Conjugte Vccine), Snofi Psteur SA. N = number of subjects in the totl vccinted cohort with locl/generl symptoms sheets completed. BOOSTRIX+MCV4 = concomitnt vccintion with BOOSTRIX nd MENACTRA. b BOOSTRIX MCV4 = BOOSTRIX followed by MCV4 1 month lter. c MCV4 BOOSTRIX = MCV4 followed by BOOSTRIX 1 month lter. d Gstrointestinl symptoms included nuse, vomiting, dirrhe, nd/or bdominl pin. e Orl tempertures. 6.2 Postmrketing Experience In ddition to reports in clinicl trils, worldwide voluntry reports of dverse events received for BOOSTRIX in persons 10 yers of ge nd older since mrket introduction of this vccine re listed below. This list includes serious events or events which hve cusl connection to components of this or other vccines or drugs. Becuse these events re reported voluntrily from popultion of uncertin size, it is not possible to relibly estimte their frequency or estblish cusl reltionship to the vccine. Blood nd Lymphtic System Disorders: Lymphdenitis, lymphdenopthy. Immune System Disorders: Allergic rections, including nphylctic nd nphylctoid rections. Crdic Disorders: Myocrditis. Generl Disorders nd Administrtion Site Conditions: Extensive swelling of the injected limb, injection site indurtion, injection site inflmmtion, injection site mss, injection 11

12 site pruritus, injection site nodule, injection site wrmth, injection site rection. Musculoskeletl nd Connective Tissue Disorders: Arthrlgi, bck pin, mylgi. Nervous System Disorders: Convulsions (with nd without fever), encephlitis, fcil plsy, loss of consciousness, presthesi, syncope. Skin nd Subcutneous Tissue Disorders: Angioedem, exnthem, Henoch- Schönlein purpur, rsh, urticri. 7 DRUG INTERACTIONS 7.1 Concomitnt Vccine Administrtion BOOSTRIX ws dministered concomitntly with MENACTRA in clinicl study of subjects 11 to 18 yers of ge [see Clinicl Studies (14.5)]. Post-vccintion geometric men ntibody concentrtions (GMCs) to pertctin were lower following BOOSTRIX dministered concomitntly with meningococcl conjugte vccine compred to BOOSTRIX dministered first. It is not known if the efficcy of BOOSTRIX is ffected by the reduced response to pertctin. BOOSTRIX ws dministered concomitntly with FLUARIX (Influenz Virus Vccine) in clinicl study of subjects 19 to 64 yers of ge [see Clinicl Studies (14.5)]. Lower GMCs for ntibodies to the pertussis ntigens filmentous hemgglutinin (FHA) nd pertctin were observed when BOOSTRIX ws dministered concomitntly with FLUARIX s compred with BOOSTRIX lone. It is not known if the efficcy of BOOSTRIX is ffected by the reduced response to FHA nd pertctin. When BOOSTRIX is dministered concomitntly with other injectble vccines or Tetnus Immune Globulin, they should be given with seprte syringes nd t different injection sites. BOOSTRIX should not be mixed with ny other vccine in the sme syringe or vil. 7.2 Immunosuppressive Therpies Immunosuppressive therpies, including irrdition, ntimetbolites, lkylting gents, cytotoxic drugs, nd corticosteroids (used in greter thn physiologic doses), my reduce the immune response to BOOSTRIX. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Pregnncy Ctegory B A developmentl toxicity study hs been performed in femle rts t dose pproximtely 40 times the humn dose (on ml/kg bsis) nd reveled no evidence of hrm to the fetus due to BOOSTRIX. Animl fertility studies hve not been conducted with BOOSTRIX. There re no dequte nd well-controlled studies in pregnnt women. Becuse niml reproduction studies re not lwys predictive of humn response, BOOSTRIX should be given to pregnnt womn only if clerly needed. In developmentl toxicity study, the effect of BOOSTRIX on embryo-fetl nd prewening development ws evluted in pregnnt rts. Animls were dministered INFANRIX by intrmusculr injection once prior to gesttion nd BOOSTRIX by intrmusculr injection 12

13 during the period of orgnogenesis (gesttion dys 6, 8, 11, nd 15), 0.1 ml/rt/occsion (pproximtely 40-fold excess reltive to the projected humn dose of BOOSTRIX on body weight bsis). The ntigens in INFANRIX re the sme s those in BOOSTRIX, but INFANRIX is formulted with higher quntities of these ntigens. No dverse effects on pregnncy, prturition, lcttion prmeters, nd embryo-fetl or pre-wening development were observed. There were no vccine-relted fetl mlformtions or other evidence of tertogenesis. Pregnncy Registry: GlxoSmithKline mintins surveillnce registry to collect dt on pregnncy outcomes nd newborn helth sttus outcomes following vccintion with BOOSTRIX during pregnncy. Women who receive BOOSTRIX during pregnncy should be encourged to contct GlxoSmithKline directly or their helthcre provider should contct GlxoSmithKline by clling Nursing Mothers It is not known whether BOOSTRIX is excreted in humn milk. Becuse mny drugs re excreted in humn milk, cution should be exercised when BOOSTRIX is dministered to nursing womn. 8.4 Peditric Use BOOSTRIX is not indicted for use in children younger thn 10 yers of ge. Sfety nd effectiveness of BOOSTRIX in this ge group hve not been estblished. 8.5 Geritric Use In clinicl trils, 1,104 subjects 65 yers of ge nd older received BOOSTRIX; of these subjects, 299 were 75 yers of ge nd older. In the US elderly (65 yers nd older) study, immune responses to tetnus nd diphtheri toxoids following BOOSTRIX were non-inferior to the comprtor Td vccine. Antibody responses to pertussis ntigens following single dose of BOOSTRIX in the elderly were non-inferior to those observed with INFANRIX dministered s 3-dose series in infnts [see Clinicl Studies (14.4)]. Solicited dverse events following BOOSTRIX were similr in frequency to those reported with the comprtor Td vccine [see Adverse Rections (6.1)]. 11 DESCRIPTION BOOSTRIX (Tetnus Toxoid, Reduced Diphtheri Toxoid nd Acellulr Pertussis Vccine, Adsorbed) is noninfectious, sterile, vccine for intrmusculr dministrtion. It contins tetnus toxoid, diphtheri toxoid, nd pertussis ntigens (inctivted pertussis toxin [PT] nd formldehyde-treted filmentous hemgglutinin [FHA] nd pertctin). The ntigens re the sme s those in INFANRIX, but BOOSTRIX is formulted with reduced quntities of these ntigens. Tetnus toxin is produced by growing Clostridium tetni in modified Lthm medium derived from bovine csein. The diphtheri toxin is produced by growing Corynebcterium diphtherie in Fenton medium contining bovine extrct. The bovine mterils used in these extrcts re sourced from countries which the United Sttes Deprtment of Agriculture (USDA) hs determined neither hve nor re t risk of bovine spongiform encephlopthy (BSE). Both 13

14 toxins re detoxified with formldehyde, concentrted by ultrfiltrtion, nd purified by precipittion, dilysis, nd sterile filtrtion. The cellulr pertussis ntigens (PT, FHA, nd pertctin) re isolted from Bordetell pertussis culture grown in modified Stiner-Scholte liquid medium. PT nd FHA re isolted from the fermenttion broth; pertctin is extrcted from the cells by het tretment nd floccultion. The ntigens re purified in successive chromtogrphic nd precipittion steps. PT is detoxified using glutrldehyde nd formldehyde. FHA nd pertctin re treted with formldehyde. Ech ntigen is individully dsorbed onto luminum hydroxide. Ech 0.5-mL dose is formulted to contin 5 Lf of tetnus toxoid, 2.5 Lf of diphtheri toxoid, 8 mcg of inctivted PT, 8 mcg of FHA, nd 2.5 mcg of pertctin (69 kilodlton outer membrne protein). Tetnus nd diphtheri toxoid potency is determined by mesuring the mount of neutrlizing ntitoxin in previously immunized guine pigs. The potency of the cellulr pertussis components (inctivted PT nd formldehyde-treted FHA nd pertctin) is determined by enzyme-linked immunosorbent ssy (ELISA) on ser from previously immunized mice. Ech 0.5-mL dose contins luminum hydroxide s djuvnt (not more thn 0.39 mg luminum by ssy), 4.5 mg of sodium chloride, 100 mcg of residul formldehyde, nd 100 mcg of polysorbte 80 (Tween 80). BOOSTRIX is vilble in vils nd prefilled syringes. The tip cps of the prefilled syringes my contin nturl rubber ltex; the plungers re not mde with nturl rubber ltex. The vil stoppers re not mde with nturl rubber ltex. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action Tetnus: Tetnus is condition mnifested primrily by neuromusculr dysfunction cused by potent exotoxin relesed by C. tetni. Protection ginst disese is due to the development of neutrlizing ntibodies to the tetnus toxin. A serum tetnus ntitoxin level of t lest 0.01 IU/mL, mesured by neutrliztion ssys, is considered the minimum protective level. 2 A level 0.1 IU/mL by ELISA hs been considered s protective. Diphtheri: Diphtheri is n cute toxin-medited infectious disese cused by toxigenic strins of C. diphtherie. Protection ginst disese is due to the development of neutrlizing ntibodies to the diphtheri toxin. A serum diphtheri ntitoxin level of 0.01 IU/mL, mesured by neutrliztion ssys, is the lowest level giving some degree of protection; level of 0.1 IU/mL by ELISA is regrded s protective. 3 Diphtheri ntitoxin levels 1.0 IU/mL by ELISA hve been ssocited with long-term protection. 3 Pertussis: Pertussis (whooping cough) is disese of the respirtory trct cused by B. pertussis. The role of the different components produced by B. pertussis in either the pthogenesis of, or the immunity to, pertussis is not well understood. 14

15 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility BOOSTRIX hs not been evluted for crcinogenic or mutgenic potentil, or for impirment of fertility. 14 CLINICAL STUDIES The efficcy of the tetnus nd diphtheri toxoid components of BOOSTRIX is bsed on the immunogenicity of the individul ntigens compred to US-licensed vccines using estblished serologic correltes of protection. The efficcy of the pertussis components of BOOSTRIX ws evluted by comprison of the immune response of dolescents nd dults following single dose of BOOSTRIX to the immune response of infnts following 3-dose primry series of INFANRIX. In ddition, the bility of BOOSTRIX to induce booster response to ech of the ntigens ws evluted Efficcy of INFANRIX The efficcy of 3-dose primry series of INFANRIX in infnts hs been ssessed in 2 clinicl studies: A prospective efficcy tril conducted in Germny employing household contct study design nd double-blind, rndomized, ctive Diphtheri nd Tetnus Toxoids (DT)-controlled tril conducted in Itly sponsored by the Ntionl Institutes of Helth (NIH) (for detils see INFANRIX prescribing informtion). Serologicl dt from subset of infnts immunized with INFANRIX in the household contct study were compred with the ser of dolescents nd dults immunized with BOOSTRIX [see Clinicl Studies (14.2, 14.3)]. In the household contct study, the protective efficcy of INFANRIX, in infnts, ginst WHO-defined pertussis (21 dys or more of proxysml cough with infection confirmed by culture nd/or serologic testing) ws clculted to be 89% (95% CI: 77%, 95%). When the definition of pertussis ws expnded to include cliniclly milder disese, with infection confirmed by culture nd/or serologic testing, the efficcy of INFANRIX ginst 7 dys of ny cough ws 67% (95% CI: 52%, 78%) nd ginst 7 dys of proxysml cough ws 81% (95% CI: 68%, 89%) (for detils see INFANRIX prescribing informtion) Immunologicl Evlution in Adolescents In multicenter, rndomized, controlled study conducted in the United Sttes, the immune responses to ech of the ntigens contined in BOOSTRIX were evluted in ser obtined pproximtely 1 month fter dministrtion of single dose of vccine to dolescent subjects (10 to 18 yers of ge). Of the subjects enrolled in this study, pproximtely 76% were 10 to 14 yers of ge nd 24% were 15 to 18 yers of ge. Approximtely 98% of prticipnts in this study hd received the recommended series of 4 or 5 doses of either DTwP or combintion of DTwP nd DTP in childhood. The rcil/ethnic demogrphics were s follows: white 85.8%, blck 5.7%, Hispnic 5.6%, Orientl 0.8%, nd other 2.1%. Response to Tetnus nd Diphtheri Toxoids: The ntibody responses to the tetnus nd diphtheri toxoids of BOOSTRIX compred with Td vccine re shown in Tble 6. One month fter single dose, nti-tetnus nd nti-diphtheri seroprotective rtes ( 0.1 IU/mL by 15

16 ELISA) nd booster response rtes were comprble between BOOSTRIX nd the comprtor Td vccine. Tble 6. Antibody Responses to Tetnus nd Diphtheri Toxoids Following BOOSTRIX Compred With Td Vccine in Adolescents 10 to 18 Yers of Age (ATP Cohort for Immunogenicity) % 0.1 IU/mL (95% CI) % 1.0 IU/mL (95% CI) % Booster Response b (95% CI) N Anti-Tetnus BOOSTRIX 2,469-2,516 Pre-vccintion 97.7 (97.1, 98.3) 36.8 (34.9, 38.7) Post-vccintion 100 (99.8, 100) c 99.5 (99.1, 99.7) d 89.7 (88.4, 90.8) c Td Pre-vccintion 96.8 (95.4, 97.9) 39.9 (36.5, 43.4) Post-vccintion 100 (99.6, 100) 99.8 (99.1, 100) 92.5 (90.5, 94.2) Anti-Diphtheri BOOSTRIX 2,463-2,515 Pre-vccintion 85.8 (84.3, 87.1) 17.1 (15.6, 18.6) Post-vccintion 99.9 (99.7, 100) c 97.3 (96.6, 97.9) d 90.6 (89.4, 91.7) c Td Pre-vccintion 84.8 (82.1, 87.2) 19.5 (16.9, 22.4) Post-vccintion 99.9 (99.3, 100) 99.3 (98.4, 99.7) 95.9 (94.4, 97.2) Td mnufctured by MssBioLogics. ATP = ccording-to-protocol; CI = Confidence Intervl. Mesured by ELISA. b Booster response: In subjects with pre-vccintion <0.1 IU/mL, post-vccintion concentrtion 0.4 IU/mL. In subjects with pre-vccintion concentrtion 0.1 IU/mL, n increse of t lest 4 times the pre-vccintion concentrtion. c Seroprotection rte or booster response rte to BOOSTRIX ws non-inferior to Td (upper limit of two-sided 95% CI on the difference for Td minus BOOSTRIX 10%). d Non-inferiority criteri not prospectively defined for this endpoint. Response to Pertussis Antigens: The booster response rtes of dolescents to the pertussis ntigens re shown in Tble 7. For ech of the pertussis ntigens the lower limit of the two-sided 95% CI for the percentge of subjects with booster response exceeded the predefined lower limit of 80% for demonstrtion of n cceptble booster response. 16

17 Tble 7. Booster Responses to the Pertussis Antigens Following BOOSTRIX in Adolescents 10 to 18 Yers of Age (ATP Cohort for Immunogenicity) BOOSTRIX N % Booster Response (95% CI) Anti-PT 2, (83.0, 85.9) Anti-FHA 2, (94.2, 95.9) Anti-pertctin 2, (94.5, 96.1) ATP = ccording-to-protocol; CI = Confidence Intervl. Booster response: In initilly seronegtive subjects (<5 EL.U./mL), post-vccintion ntibody concentrtions 20 EL.U./mL. In initilly seropositive subjects with pre-vccintion ntibody concentrtions 5 EL.U./mL nd <20 EL.U./mL, n increse of t lest 4 times the pre-vccintion ntibody concentrtion. In initilly seropositive subjects with pre-vccintion ntibody concentrtions 20 EL.U./mL, n increse of t lest 2 times the pre-vccintion ntibody concentrtion. The GMCs to ech of the pertussis ntigens 1 month following single dose of BOOSTRIX in the US dolescent study (N = 2,941-2,979) were compred with the GMCs observed in infnts following 3-dose primry series of INFANRIX dministered t 3, 4, nd 5 months of ge (N = 631-2,884). Tble 8 presents the results for the totl immunogenicity cohort in both studies (vccinted subjects with serology dt vilble for t lest one pertussis ntigen; the mjority of subjects in the study of INFANRIX hd nti-pt serology dt only). These infnts were subset of those who formed the cohort for the Germn household contct study in which the efficcy of INFANRIX ws demonstrted [see Clinicl Studies (14.1)]. Although serologic correlte of protection for pertussis hs not been estblished, nti-pt, nti- FHA, nd nti-pertctin ntibody concentrtions observed in dolescents 1 month fter single dose of BOOSTRIX were non-inferior to those observed in infnts following primry vccintion series with INFANRIX. 17

18 Tble 8. Rtio of GMCs to Pertussis Antigens Following One Dose of BOOSTRIX in Adolescents 10 to 18 Yers of Age Compred With 3 Doses of INFANRIX in Infnts (Totl Immunogenicity Cohort) GMC Rtio: BOOSTRIX/INFANRIX (95% CI) Anti-PT 1.90 (1.82, 1.99) Anti-FHA 7.35 (6.85, 7.89) Anti-pertctin 4.19 (3.73, 4.71) GMC = geometric men ntibody concentrtion, mesured in ELISA units; CI = Confidence Intervl. Number of subjects for BOOSTRIX GMC evlution: Anti-PT = 2,941, nti-fha = 2,979, nd nti-pertctin = 2,978. Number of subjects for INFANRIX GMC evlution: Anti-PT = 2,884, nti-fha = 685, nd nti-pertctin = 631. GMC following BOOSTRIX ws non-inferior to GMC following INFANRIX (lower limit of 95% CI for the GMC rtio of BOOSTRIX/INFANRIX >0.67) Immunologicl Evlution in Adults (19 to 64 Yers of Age) A multicenter, rndomized, observer-blinded study, conducted in the United Sttes, evluted the immunogenicity of BOOSTRIX compred with the licensed comprtor Tdp vccine (Snofi Psteur SA). Vccines were dministered s single dose to subjects (N = 2,284) who hd not received tetnus-diphtheri booster within 5 yers. The immune responses to ech of the ntigens contined in BOOSTRIX were evluted in ser obtined pproximtely 1 month fter dministrtion. Approximtely 33% of ptients were 19 to 29 yers of ge, 33% were 30 to 49 yers of ge nd 34% were 50 to 64 yers of ge. Among subjects in the combined vccine groups, 62% were femle; 84% of subjects were white, 8% blck, 1% Asin, nd 7% were of other rcil/ethnic groups. Response to Tetnus nd Diphtheri Toxoids: The ntibody responses to the tetnus nd diphtheri toxoids of BOOSTRIX compred with the comprtor Tdp vccine re shown in Tble 9. One month fter single dose, nti-tetnus nd nti-diphtheri seroprotective rtes ( 0.1 IU/mL by ELISA) were comprble between BOOSTRIX nd the comprtor Tdp vccine. 18

19 Tble 9. Antibody Responses to Tetnus nd Diphtheri Toxoids Following One Dose of BOOSTRIX Compred With the Comprtor Tdp Vccine in Adults 19 to 64 Yers of Age (ATP Cohort for Immunogenicity) % 0.1 IU/mL (95% CI) % 1.0 IU/mL (95% CI) N Anti-Tetnus BOOSTRIX 1,445-1,447 Pre-vccintion 95.9 (94.8, 96.9) 71.9 (69.5, 74.2) Post-vccintion 99.6 (99.1, 99.8) b 98.3 (97.5, 98.9) b Tdp Pre-vccintion 97.2 (95.8, 98.3) 74.7 (71.4, 77.8) Post-vccintion 100 (95.5, 100) 99.3 (98.4, 99.8) Anti-Diphtheri BOOSTRIX 1,440-1,444 Pre-vccintion 85.2 (83.3, 87.0) 23.7 (21.5, 26.0) Post-vccintion 98.2 (97.4, 98.8) b 87.9 (86.1, 89.5) c Tdp Pre-vccintion 89.2 (86.7, 91.3) 26.5 (23.3, 29.9) Post-vccintion 98.6 (97.5, 99.3) 92.0 (89.8, 93.9) Tdp = Tetnus Toxoid, Reduced Diphtheri Toxoid nd Acellulr Pertussis Vccine, Adsorbed mnufctured by Snofi Psteur SA. ATP = ccording-to-protocol; CI = Confidence Intervl. Mesured by ELISA. b Seroprotection rtes for BOOSTRIX were non-inferior to the comprtor Tdp vccine (lower limit of 95% CI on the difference of BOOSTRIX minus Tdp -10%). c Non-inferiority criteri not prospectively defined for this endpoint. Response to Pertussis Antigens: Booster response rtes to the pertussis ntigens re shown in Tble 10. For the FHA nd pertctin ntigens, the lower limit of the 95% CI for the booster responses exceeded the pre-defined limit of 80% demonstrting n cceptble booster response following BOOSTRIX. The PT ntigen booster response lower limit of the 95% CI (74.9%) did not exceed the pre-defined limit of 80%. 19

20 Tble 10. Booster Responses to the Pertussis Antigens Following One Dose of BOOSTRIX in Adults 19 to 64 Yers of Age (ATP Cohort for Immunogenicity) BOOSTRIX % Booster Response N (95% CI) Anti-PT 1, (74.9, 79.3) b Anti-FHA 1, (95.8, 97.7) c Anti-pertctin 1, (91.8, 94.4) c ATP = ccording-to-protocol; CI = Confidence Intervl. Booster response: In initilly seronegtive subjects (<5 EL.U./mL), post-vccintion ntibody concentrtions 20 EL.U./mL. In initilly seropositive subjects with pre-vccintion ntibody concentrtions 5 EL.U./mL nd <20 EL.U./mL, n increse of t lest 4 times the prevccintion ntibody concentrtion. In initilly seropositive subjects with pre-vccintion ntibody concentrtions 20 EL.U./mL, n increse of t lest 2 times the pre-vccintion ntibody concentrtion. b The PT ntigen booster response lower limit of the 95% CI did not exceed the pre-defined limit of 80%. c The FHA nd pertctin ntigens booster response lower limit of the 95% CI exceeded the predefined limit of 80%. The GMCs to ech of the pertussis ntigens 1 month following single dose of BOOSTRIX in the US dult (19 to 64 yers of ge) study were compred with the GMCs observed in infnts following 3-dose primry series of INFANRIX dministered t 3, 4, nd 5 months of ge. Tble 11 presents the results for the totl immunogenicity cohort in both studies (vccinted subjects with serology dt vilble for t lest one pertussis ntigen). These infnts were subset of those who formed the cohort for the Germn household contct study in which the efficcy of INFANRIX ws demonstrted [see Clinicl Studies (14.1)]. Although serologic correlte of protection for pertussis hs not been estblished, nti-pt, nti-fha, nd ntipertctin ntibody concentrtions observed in dults 1 month fter single dose of BOOSTRIX were non-inferior to those observed in infnts following primry vccintion series with INFANRIX. 20

21 Tble 11. Rtio of GMCs to Pertussis Antigens Following One Dose of BOOSTRIX in Adults 19 to 64 Yers of Age Compred With 3 Doses of INFANRIX in Infnts (Totl Immunogenicity Cohort) GMC Rtio: BOOSTRIX/INFANRIX (95% CI) Anti-PT 1.39 (1.32, 1.47) Anti-FHA 7.46 (6.86, 8.12) Anti-pertctin 3.56 (3.10, 4.08) GMC = geometric men ntibody concentrtion; CI = Confidence Intervl. Number of subjects for BOOSTRIX GMC evlution: Anti-PT = 1,460, nti-fha = 1,472, nd nti-pertctin = 1,473. Number of subjects for INFANRIX GMC evlution: Anti-PT = 2,884, nti-fha = 685, nd nti-pertctin = 631. BOOSTRIX ws non-inferior to INFANRIX (lower limit of 95% CI for the GMC rtio of BOOSTRIX/INFANRIX 0.67) Immunologicl Evlution in the Elderly (65 Yers of Age nd Older) The US elderly (65 yers of ge nd older) study, rndomized, observer-blinded study, evluted the immunogenicity of BOOSTRIX (N = 887) compred with US-licensed comprtor Td vccine (N = 445) (Snofi Psteur SA). Vccines were dministered s single dose to subjects who hd not received tetnus-diphtheri booster within 5 yers. Among ll vccine recipients, the men ge ws pproximtely 72 yers of ge; 54% were femle nd 95% were white. The immune responses to ech of the ntigens contined in BOOSTRIX were evluted in ser obtined pproximtely 1 month fter dministrtion. Response to Tetnus nd Diphtheri Toxoids nd Pertussis Antigens: Immune responses to tetnus nd diphtheri toxoids nd pertussis ntigens were mesured 1 month fter dministrtion of single dose of BOOSTRIX or comprtor Td vccine. Anti-tetnus nd nti-diphtheri seroprotective rtes ( 0.1 IU/mL) were comprble between BOOSTRIX nd the comprtor Td vccine (Tble 12). 21

22 Tble 12. Immune Responses to Tetnus nd Diphtheri Toxoids Following BOOSTRIX or Comprtor Td Vccine in the Elderly 65 Yers of Age nd Older (ATP Cohort for Immunogenicity) BOOSTRIX (N = ) Td (N = ) Anti-T % 0.1 IU/mL (95% CI) 96.8 (95.4, 97.8) 97.5 (95.6, 98.7) % 1.0 IU/mL (95% CI) 88.8 (86.5, 90.8) 90.0 (86.8, 92.6) Anti-D % 0.1 IU/mL (95% CI) 84.9 (82.3, 87.2) 86.6 (83.0, 89.6) % 1.0 IU/mL (95% CI) 52.0 (48.6, 55.4) b 51.2 (46.3, 56.0) Td = Tetnus nd Diphtheri Toxoids Adsorbed, US-licensed Td vccine, mnufctured by Snofi Psteur SA. ATP = ccording-to-protocol; CI = Confidence Intervl. Seroprotection rtes for BOOSTRIX were non-inferior to the comprtor Td vccine (lower limit of 95% CI on the difference of BOOSTRIX minus Td -10%). b Non-inferiority criteri not prospectively defined for this endpoint. The GMCs to ech of the pertussis ntigens 1 month following single dose of BOOSTRIX were compred with the GMCs of infnts following 3-dose primry series of INFANRIX dministered t 3, 4, nd 5 months of ge. Tble 13 presents the results for the totl immunogenicity cohort in both studies (vccinted subjects with serology dt vilble for t lest one pertussis ntigen). These infnts were subset of those who formed the cohort for the Germn household contct study in which the efficcy of INFANRIX ws demonstrted [see Clinicl Studies (14.1)]. Although serologic correlte of protection for pertussis hs not been estblished, nti-pt, nti-fha, nd nti-pertctin ntibody concentrtions in the elderly (65 yers of ge nd older) 1 month fter single dose of BOOSTRIX were non-inferior to those of infnts following primry vccintion series with INFANRIX. 22