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日前，葛兰素史克公司(GlaxoSmithKline，GSK)宣布美国FDA已批准其破伤风白喉类百日咳三联疫苗[Tetanus Toxoid，Reduced Diphtheria Toxoid，Acellular Pertussis Vaccine，Adsorbed (Tdap)， Boostrix]用于19～64岁成人的免疫接种。此前，本品作为一种增强疫苗已获准用于10～18岁儿童与青少年。本品成为适用年龄最广(10～64岁)的Tdap疫苗。 BOOSTRIX®（减少了白喉类毒素，破伤风类毒素和无细胞百日咳疫苗，吸附） 完整处方信息BOOSTRIX。 美国首次批准：2005 日期：09/2012 1 Indications and Usage 2 Dosage and Administration 2.1 Preparation for Administration For the prefilled syringes, attach a sterile needle and administer intramuscularly. For the vials, use a sterile needle and sterile syringe to withdraw the 0.5‑mL dose and administer intramuscularly. Changing needles between drawing vaccine from a vial and injecting it into a recipient is not necessary unless the needle has been damaged or contaminated. Use a separate sterile needle and syringe for each individual. Do not administer this product intravenously, intradermally, or subcutaneously. 2.2 Dose and Schedule There are no data to support repeat administration of BOOSTRIX. Five years should elapse between the last dose of the recommended series of Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) and/or Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (Td) vaccine and the administration of BOOSTRIX. 2.3 Additional Dosing Information Wound Management: If tetanus prophylaxis is needed for wound management, BOOSTRIX may be given if no previous dose of any Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Tdap) has been administered. 3 Dosage Forms and Strengths 4 Contraindications 4.1 Hypersensitivity 4.2 Encephalopathy 5 Warnings and Precautions 5.1 Latex 5.2 Guillain-Barré Syndrome and Brachial Neuritis 5.3 Syncope 5.4 Progressive or Unstable Neurologic Disorders 5.5 Arthus-Type Hypersensitivity 5.6 Altered Immunocompetence 5.7 Prevention and Management of Acute Allergic Reactions 6 Adverse Reactions 6.1 Clinical Trials Experience In clinical studies, 4,949 adolescents (10 to 18 years of age) and 4,076 adults (19 years of age and older) were vaccinated with a single dose of BOOSTRIX. Of these adolescents, 1,341 were vaccinated with BOOSTRIX in a coadministration study with meningococcal conjugate vaccine [see Drug Interactions (7.1) and Clinical Studies (14.5)]. Of these adults, 1,104 were 65 years of age and older [see Clinical Studies (14.4)]. A total of 860 adults19 years of age and older received concomitant vaccination with BOOSTRIX and influenza vaccines in a coadministration study [see Drug Interactions (7.1) and Clinical Studies (14.5)]. An additional 1,092 adolescents 10 to 18 years of age received a non-US formulation of BOOSTRIX (formulated to contain 0.5 mg aluminum per dose) in non-US clinical studies. In a randomized, observer-blinded, controlled study in the US, 3,080 adolescents 10 to 18 years of age received a single dose of BOOSTRIX and 1,034 received the comparator Td vaccine, manufactured by MassBioLogics. There were no substantive differences in demographic characteristics between the vaccine groups. Among BOOSTRIX and comparator vaccine recipients, approximately 75% were 10 to 14 years of age and approximately 25% were 15 to 18 years of age. Approximately 98% of participants in this study had received the recommended series of 4 or 5 doses of either Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed (DTwP) or a combination of DTwP and DTaP in childhood. Subjects were monitored for solicited adverse events using standardized diary cards (day 0-14). Unsolicited adverse events were monitored for the 31-day period following vaccination (day 0-30). Subjects were also monitored for 6 months post-vaccination for non-routine medical visits, visits to an emergency room, onset of new chronic illness, and serious adverse events. Information regarding late onset adverse events was obtained via a telephone call 6 months following vaccination. At least 97% of subjects completed the 6-month follow-up evaluation. In a study conducted in Germany, BOOSTRIX was administered to 319 children 10 to 12 years of age previously vaccinated with 5 doses of acellular pertussis antigen-containing vaccines; 193 of these subjects had previously received 5 doses of INFANRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed). Adverse events were recorded on diary cards during the 15 days following vaccination. Unsolicited adverse events that occurred within 31 days of vaccination (day 0-30) were recorded on the diary card or verbally reported to the investigator. Subjects were monitored for 6 months post-vaccination for physician office visits, emergency room visits, onset of new chronic illness, and serious adverse events. The 6-month follow-up evaluation, conducted via telephone interview, was completed by 90% of subjects. The US adult (19 to 64 years of age) study, a randomized, observer-blinded study, evaluated the safety of BOOSTRIX (N = 1,522) compared with ADACEL® (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed) (N = 762), a Tdap vaccine manufactured by Sanofi Pasteur SA. Vaccines were administered as a single dose. There were no substantive differences in demographic characteristics between the vaccine groups. Subjects were monitored for solicited adverse events using standardized diary cards (day 0-14). Unsolicited adverse events were monitored for the 31-day period following vaccination (day 0-30). Subjects were also monitored for 6 months post-vaccination for serious adverse events, visits to an emergency room, hospitalizations, and onset of new chronic illness. Approximately 95% of subjects completed the 6-month follow-up evaluation. The US elderly (65 years of age and older) study, a randomized, observer-blinded study, evaluated the safety of BOOSTRIX (N = 887) compared with DECAVAC® (Tetanus and Diphtheria Toxoids Adsorbed) (N = 445), a US-licensed Td vaccine, manufactured by Sanofi Pasteur SA. Vaccines were administered as a single dose. Among all vaccine recipients, the mean age was approximately 72 years; 54% were female and 95% were white. Subjects were monitored for solicited adverse events using standardized diary cards (day 0-3). Unsolicited adverse events were monitored for the 31-day period following vaccination (day 0-30). Subjects were also monitored for 6 months post-vaccination for serious adverse events. Approximately 99% of subjects completed the 6-month follow-up evaluation. Solicited Adverse Events in the US Adolescent Study: Table 1 presents the solicited local adverse reactions and general adverse events within 15 days of vaccination with BOOSTRIX or Td vaccine for the total vaccinated cohort. The primary safety endpoint was the incidence of grade 3 pain (spontaneously painful and/or prevented normal activity) at the injection site within 15 days of vaccination. Grade 3 pain was reported in 4.6% of those who received BOOSTRIX compared with 4.0% of those who received the Td vaccine. The difference in rate of grade 3 pain was within the pre-defined clinical limit for non-inferiority (upper limit of the 95% CI for the difference [BOOSTRIX minus Td] ≤4%).
Td = Tetanus and Diphtheria Toxoids Adsorbed For Adult Use manufactured by MassBioLogics. N = Number of subjects in the total vaccinated cohort with local/general symptoms sheets completed. Grade 2 = Local: painful when limb moved; General: interfered with normal activity. Grade 3 = Local: spontaneously painful and/or prevented normal activity; General: prevented normal activity. a Day of vaccination and the next 14 days. b Statistically significantly higher (P <0.05) following BOOSTRIX as compared to Td vaccine. c Grade 3 injection site pain following BOOSTRIX was not inferior to Td vaccine (upper limit of two-sided 95% CI for the difference [BOOSTRIX minus Td] in the percentage of subjects ≤4%). d Mid-upper region of the vaccinated arm. e Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. f Oral temperatures or axillary temperatures. Unsolicited Adverse Events in the US Adolescent Study: The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (25.4% and 24.5% for BOOSTRIX and Td vaccine, respectively). Solicited Adverse Events in the German Adolescent Study: Table 2 presents the rates of solicited local adverse reactions and fever within 15 days of vaccination for those subjects who had previously been vaccinated with 5 doses of INFANRIX. No cases of whole arm swelling were reported. Two individuals (2/193) reported large injection site swelling (range 110 to 200 mm diameter), in one case associated with grade 3 pain. Neither individual sought medical attention. These episodes were reported to resolve without sequelae within 5 days.
N = Number of subjects with local/general symptoms sheets completed. Grade 2 = Painful when limb moved. Grade 3 = Spontaneously painful and/or prevented normal activity. aDay of vaccination and the next 14 days. bOral temperatures or axillary temperatures. Solicited Adverse Events in the US Adult (19 to 64 Years of Age) Study: Table 3 presents solicited local adverse reactions and general adverse events within 15 days of vaccination with BOOSTRIX or the comparator Tdap vaccine for the total vaccinated cohort.
Tdap = Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed, a Tdap vaccine manufactured by Sanofi Pasteur SA. N = Number of subjects in the total vaccinated cohort with local/general symptoms sheets completed. Grade 2 = Local: painful when limb moved; General: interfered with normal activity. Grade 3 = Local/General: prevented normal activity. a Day of vaccination and the next 14 days. b Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. c Oral temperatures. Unsolicited Adverse Events in the US Adult (19 to 64 Years of Age) Study: The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (17.8% and 22.2% for BOOSTRIX and Tdap vaccine, respectively). Solicited Adverse Events in the US Elderly (65 Years of Age and Older) Study: Table 4 presents solicited local adverse reactions and general adverse events within 4 days of vaccination with BOOSTRIX or the comparator Td vaccine for the total vaccinated cohort.
Td = Tetanus and Diphtheria Toxoids Adsorbed, a US-licensed Td vaccine, manufactured by Sanofi Pasteur SA. N = Number of subjects with a documented dose. Grade 2 = Local: painful when limb moved; General: interfered with normal activity. Grade 3 = Local/General: prevented normal activity. a Day of vaccination and the next 3 days. b Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. c Oral temperatures. Unsolicited Adverse Events in the US Elderly (65 Years of Age and Older) Study: The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (17.1% and 14.4% for BOOSTRIX and Td vaccine, respectively). Serious Adverse Events (SAEs): In the US and German adolescent safety studies, no serious adverse events were reported to occur within 31 days of vaccination. During the 6-month extended safety evaluation period, no serious adverse events that were of potential autoimmune origin or new onset and chronic in nature were reported to occur. In non-US adolescent studies in which serious adverse events were monitored for up to 37 days, one subject was diagnosed with insulin-dependent diabetes 20 days following administration of BOOSTRIX. No other serious adverse events of potential autoimmune origin or that were new onset and chronic in nature were reported to occur in these studies. In the US adult (19 to 64 years of age) study, serious adverse events were reported to occur during the entire study period (0-6 months) by 1.4% and 1.7% of subjects who received BOOSTRIX and the comparator Tdap vaccine, respectively. During the 6-month extended safety evaluation period, no serious adverse events of a neuroinflammatory nature or with information suggesting an autoimmune etiology were reported in subjects who received BOOSTRIX. In the US elderly (65 years of age and older) study, serious adverse events were reported to occur by 0.7% and 0.9% of subjects who received BOOSTRIX and the comparator Td vaccine, respectively, during the 31-day period after vaccination. Serious adverse events were reported to occur by 4.2% and 2.2% of subjects who received BOOSTRIX and the comparator Td vaccine, respectively, during the 6-month period after vaccination. Concomitant Vaccination With Meningococcal Conjugate Vaccine in Adolescents: In a randomized study in the US, 1,341 adolescents (11 to 18 years of age) received either BOOSTRIX administered concomitantly with MENACTRA® (Meningococcal (Groups A, C, Y, and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine), (Sanofi Pasteur SA), or each vaccine administered separately 1 month apart [see Drug Interactions (7.1) and Clinical Studies (14.5)]. Safety was evaluated in 446 subjects who received BOOSTRIX administered concomitantly with meningococcal conjugate vaccine at different injection sites, 446 subjects who received BOOSTRIX followed by meningococcal conjugate vaccine 1 month later, and 449 subjects who received meningococcal conjugate vaccine followed by BOOSTRIX 1 month later. Solicited local adverse reactions and general adverse events were recorded on diary cards for 4 days (day 0-3) following each vaccination. Unsolicited adverse events were monitored for the 31-day period following each vaccination (day 0-30). Table 5 presents the percentages of subjects experiencing local reactions at the injection site for BOOSTRIX and solicited general events following BOOSTRIX. The incidence of unsolicited adverse events reported in the 31 days after any vaccination was similar following each dose of BOOSTRIX in all cohorts.
MCV4 = MENACTRA (Meningococcal (Groups A, C, Y, and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine), Sanofi Pasteur SA. N = number of subjects in the total vaccinated cohort with local/general symptoms sheets completed. a BOOSTRIX+MCV4 = concomitant vaccination with BOOSTRIX and MENACTRA. b BOOSTRIX→MCV4 = BOOSTRIX followed by MCV4 1 month later. c MCV4→BOOSTRIX = MCV4 followed by BOOSTRIX 1 month later. d Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. e Oral temperatures. 6.2 Postmarketing Experience In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for BOOSTRIX in persons 10 years of age and older since market introduction of this vaccine are listed below. This list includes serious events or events which have causal connection to components of this or other vaccines or drugs. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to the vaccine. Blood and Lymphatic System Disorders: Lymphadenitis, lymphadenopathy. Cardiac Disorders: Myocarditis. General Disorders and Administration Site Conditions: Extensive swelling of the injected limb, injection site induration, injection site inflammation, injection site mass, injection site pruritus, injection site nodule, injection site warmth, local reaction. Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, myalgia. Nervous System Disorders: Convulsion, encephalitis, facial palsy, paraesthesia, syncope. Skin and Subcutaneous Tissue Disorders: Exanthem, Henoch-Schönlein purpura, rash, urticaria. 7 Drug Interactions 7.1 Concomitant Vaccine Administration BOOSTRIX was administered concomitantly with MENACTRA in a clinical study of subjects 11 to 18 years of age [see Clinical Studies (14.5)]. Post-vaccination geometric mean antibody concentrations (GMCs) to pertactin were lower following BOOSTRIX administered concomitantly with meningococcal conjugate vaccine compared to BOOSTRIX administered first. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to pertactin. BOOSTRIX was administered concomitantly with FLUARIX® (Influenza Virus Vaccine) in a clinical study of subjects 19 to 64 years of age [see Clinical Studies (14.5)]. Lower GMCs for antibodies to the pertussis antigens filamentous hemagglutinin (FHA) and pertactin were observed when BOOSTRIX was administered concomitantly with FLUARIX as compared with BOOSTRIX alone. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to FHA and pertactin. When BOOSTRIX is administered concomitantly with other injectable vaccines or Tetanus Immune Globulin, they should be given with separate syringes and at different injection sites. BOOSTRIX should not be mixed with any other vaccine in the same syringe or vial. 7.2 Immunosuppressive Therapies Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to BOOSTRIX. 8 Use in Specific Populations 8.1 Pregnancy Pregnancy Category B A developmental toxicity study has been performed in female rats at a dose approximately 40 times the human dose (on a mL/kg basis) and revealed no evidence of harm to the fetus due to BOOSTRIX. Animal fertility studies have not been conducted with BOOSTRIX. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, BOOSTRIX should be given to a pregnant woman only if clearly needed. In a developmental toxicity study, the effect of BOOSTRIX on embryo-fetal and pre-weaning development was evaluated in pregnant rats. Animals were administered INFANRIX by intramuscular injection once prior to gestation and BOOSTRIX by intramuscular injection during the period of organogenesis (gestation days 6, 8, 11, and 15), 0.1 mL/rat/occasion (approximately 40-fold excess relative to the projected human dose of BOOSTRIX on a body weight basis). The antigens in INFANRIX are the same as those in BOOSTRIX, but INFANRIX is formulated with higher quantities of these antigens. No adverse effects on pregnancy, parturition, lactation parameters, and embryo-fetal or pre-weaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis. Pregnancy Registry: GlaxoSmithKline maintains a surveillance registry to collect data on pregnancy outcomes and newborn health status outcomes following vaccination with BOOSTRIX during pregnancy. Women who receive BOOSTRIX during pregnancy should be encouraged to contact GlaxoSmithKline directly or their healthcare provider should contact GlaxoSmithKline by calling 1-888-452-9622. 8.3 Nursing Mothers It is not known whether BOOSTRIX is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BOOSTRIX is administered to a nursing woman. 8.4 Pediatric Use BOOSTRIX is not indicated for use in children younger than 10 years of age. Safety and effectiveness of BOOSTRIX in this age group have not been established. 8.5 Geriatric Use In clinical trials, 1,104 subjects 65 years of age and older received BOOSTRIX; of these subjects, 299 were 75 years of age and older. In the US elderly (65 years and older) study, immune responses to tetanus and diphtheria toxoids following BOOSTRIX were non-inferior to the comparator Td vaccine. Antibody responses to pertussis antigens following a single dose of BOOSTRIX in the elderly were non-inferior to those observed with INFANRIX administered as a 3-dose series in infants [see Clinical Studies (14.4)]. Solicited adverse events following BOOSTRIX were similar in frequency to those reported with the comparator Td vaccine [see Adverse Reactions (6.1)]. 11 Description BOOSTRIX (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed) is a noninfectious, sterile, vaccine for intramuscular administration. It contains tetanus toxoid, diphtheria toxoid, and pertussis antigens (inactivated pertussis toxin [PT] and formaldehyde-treated filamentous hemagglutinin [FHA] and pertactin). The antigens are the same as those in INFANRIX, but BOOSTRIX is formulated with reduced quantities of these antigens. Tetanus toxin is produced by growing Clostridium tetani in a modified Latham medium derived from bovine casein. The diphtheria toxin is produced by growing Corynebacterium diphtheriae in Fenton medium containing a bovine extract. The bovine materials used in these extracts are sourced from countries which the United States Department of Agriculture (USDA) has determined neither have nor are at risk of bovine spongiform encephalopathy (BSE). Both toxins are detoxified with formaldehyde, concentrated by ultrafiltration, and purified by precipitation, dialysis, and sterile filtration. The acellular pertussis antigens (PT, FHA, and pertactin) are isolated from Bordetella pertussis culture grown in modified Stainer-Scholte liquid medium. PT and FHA are isolated from the fermentation broth; pertactin is extracted from the cells by heat treatment and flocculation. The antigens are purified in successive chromatographic and precipitation steps. PT is detoxified using glutaraldehyde and formaldehyde. FHA and pertactin are treated with formaldehyde. Each antigen is individually adsorbed onto aluminum hydroxide. Each 0.5-mL dose is formulated to contain 5 Lf of tetanus toxoid, 2.5 Lf of diphtheria toxoid, 8 mcg of inactivated PT, 8 mcg of FHA, and 2.5 mcg of pertactin (69 kiloDalton outer membrane protein). Tetanus and diphtheria toxoid potency is determined by measuring the amount of neutralizing antitoxin in previously immunized guinea pigs. The potency of the acellular pertussis components (inactivated PT and formaldehyde-treated FHA and pertactin) is determined by enzyme-linked immunosorbent assay (ELISA) on sera from previously immunized mice. Each 0.5-mL dose contains aluminum hydroxide as adjuvant (not more than 0.39 mg aluminum by assay), 4.5 mg of sodium chloride, ≤100 mcg of residual formaldehyde, and ≤100 mcg of polysorbate 80 (Tween 80). BOOSTRIX is available in vials and 2 types of prefilled syringes. One type of prefilled syringe has a tip cap which may contain natural rubber latex and a plunger which does not contain latex. The other type has a tip cap and a rubber plunger which contain dry natural latex rubber. The vial stopper does not contain latex. [See How Supplied/Storage and Handling (16).] 12 Clinical Pharmacology 12.1 Mechanism of Action Tetanus: Tetanus is a condition manifested primarily by neuromuscular dysfunction caused by a potent exotoxin released by C. tetani. Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.2 A level ≥0.1 IU/mL by ELISA has been considered as protective. Diphtheria: Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL, measured by neutralization assays, is the lowest level giving some degree of protection; a level of 0.1 IU/mL by ELISA is regarded as protective.3 Diphtheria antitoxin levels ≥1.0 IU/mL by ELISA have been associated with long-term protection.3 Pertussis: Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. 13 Nonclinical Toxicology 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility BOOSTRIX has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility. 14 Clinical Studies The efficacy of the tetanus and diphtheria toxoid components of BOOSTRIX is based on the immunogenicity of the individual antigens compared to US-licensed vaccines using established serologic correlates of protection. The efficacy of the pertussis components of BOOSTRIX was evaluated by comparison of the immune response of adolescents and adults following a single dose of BOOSTRIX to the immune response of infants following a 3-dose primary series of INFANRIX. In addition, the ability of BOOSTRIX to induce a booster response to each of the antigens was evaluated. 14.1 Efficacy of INFANRIX The efficacy of a 3-dose primary series of INFANRIX in infants has been assessed in 2 clinical studies: A prospective efficacy trial conducted in Germany employing a household contact study design and a double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial conducted in Italy sponsored by the National Institutes of Health (NIH) (for details see INFANRIX prescribing information). Serological data from a subset of infants immunized with INFANRIX in the household contact study were compared with the sera of adolescents and adults immunized with BOOSTRIX [see Clinical Studies (14.2, 14.3)]. In the household contact study, the protective efficacy of INFANRIX, in infants, against WHO-defined pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was calculated to be 89% (95% CI: 77%, 95%). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX against ≥7 days of any cough was 67% (95% CI: 52%, 78%) and against ≥7 days of paroxysmal cough was 81% (95% CI: 68%, 89%) (for details see INFANRIX prescribing information). 14.2 Immunological Evaluation in Adolescents In a multicenter, randomized, controlled study conducted in the United States, the immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after administration of a single dose of vaccine to adolescent subjects (10 to 18 years of age). Of the subjects enrolled in this study, approximately 76% were 10 to 14 years of age and 24% were 15 to 18 years of age. Approximately 98% of participants in this study had received the recommended series of 4 or 5 doses of either DTwP or a combination of DTwP and DTaP in childhood. The racial/ethnic demographics were as follows: white 85.8%, black 5.7%, Hispanic 5.6%, Oriental 0.8%, and other 2.1%. Response to Tetanus and Diphtheria Toxoids : The antibody responses to the tetanus and diphtheria toxoids of BOOSTRIX compared with Td vaccine are shown in Table 6. One month after a single dose, anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL by ELISA) and booster response rates were comparable between BOOSTRIX and the comparator Td vaccine.
Td manufactured by MassBioLogics. ATP = according-to-protocol; CI = Confidence Interval. aMeasured by ELISA. bBooster response: In subjects with pre-vaccination <0.1 IU/mL, post-vaccination concentration ≥0.4 IU/mL. In subjects with pre-vaccination concentration ≥0.1 IU/mL, an increase of at least 4 times the pre-vaccination concentration. cSeroprotection rate or booster response rate to BOOSTRIX was non-inferior to Td (upper limit of two-sided 95% CI on the difference for Td minus BOOSTRIX ≤10%). dNon-inferiority criteria not prospectively defined for this endpoint. Response to Pertussis Antigens: The booster response rates of adolescents to the pertussis antigens are shown in Table 7. For each of the pertussis antigens the lower limit of the two-sided 95% CI for the percentage of subjects with a booster response exceeded the pre-defined lower limit of 80% for demonstration of an acceptable booster response.
ATP = according-to-protocol; CI = Confidence Interval. aBooster response: In initially seronegative subjects (<5 EL.U./mL), post-vaccination antibody concentrations ≥20 EL.U./mL. In initially seropositive subjects with pre-vaccination antibody concentrations ≥5 EL.U./mL and <20 EL.U./mL, an increase of at least 4 times the pre-vaccination antibody concentration. In initially seropositive subjects with pre-vaccination antibody concentrations ≥20 EL.U./mL, an increase of at least 2 times the pre-vaccination antibody concentration. The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX in the US adolescent study (N = 2,941-2,979) were compared with the GMCs observed in infants following a 3-dose primary series of INFANRIX administered at 3, 4, and 5 months of age (N = 631-2,884). Table 8 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one pertussis antigen; the majority of subjects in the study of INFANRIX had anti-PT serology data only). These infants were a subset of those who formed the cohort for the German household contact study in which the efficacy of INFANRIX was demonstrated [see Clinical Studies (14.1)]. Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-pertactin antibody concentrations observed in adolescents 1 month after a single dose of BOOSTRIX were non-inferior to those observed in infants following a primary vaccination series with INFANRIX.
GMC = geometric mean antibody concentration, measured in ELISA units; CI = Confidence Interval. Number of subjects for BOOSTRIX GMC evaluation: Anti-PT = 2,941, anti-FHA = 2,979, and anti-pertactin = 2,978. Number of subjects for INFANRIX GMC evaluation: Anti-PT = 2,884, anti-FHA = 685, and anti-pertactin = 631. aGMC following BOOSTRIX was non-inferior to GMC following INFANRIX (lower limit of 95% CI for the GMC ratio of BOOSTRIX/INFANRIX >0.67). 14.3 Immunological Evaluation in Adults (19 to 64 Years of Age) A multicenter, randomized, observer-blinded study, conducted in the United States, evaluated the immunogenicity of BOOSTRIX compared with the licensed comparator Tdap vaccine (Sanofi Pasteur SA). Vaccines were administered as a single dose to subjects (N = 2,284) who had not received a tetanus-diphtheria booster within 5 years. The immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after administration. Approximately 33% of patients were 19 to 29 years of age, 33% were 30 to 49 years of age and 34% were 50 to 64 years of age. Among subjects in the combined vaccine groups, 62% were female; 84% of subjects were white, 8% black, 1% Asian, and 7% were of other racial/ethnic groups. Response to Tetanus and Diphtheria Toxoids : The antibody responses to the tetanus and diphtheria toxoids of BOOSTRIX compared with the comparator Tdap vaccine are shown in Table 9. One month after a single dose, anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL by ELISA) were comparable between BOOSTRIX and the comparator Tdap vaccine.
Tdap = Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed manufactured by Sanofi Pasteur SA. ATP = according-to-protocol; CI = Confidence Interval. aMeasured by ELISA. bSeroprotection rates for BOOSTRIX were non-inferior to the comparator Tdap vaccine (lower limit of 95% CI on the difference of BOOSTRIX minus Tdap ≥-10%). cNon-inferiority criteria not prospectively defined for this endpoint. Response to Pertussis Antigens: Booster response rates to the pertussis antigens are shown in Table 10. For the FHA and pertactin antigens, the lower limit of the 95% CI for the booster responses exceeded the pre-defined limit of 80% demonstrating an acceptable booster response following BOOSTRIX. The PT antigen booster response lower limit of the 95% CI (74.9%) did not exceed the pre-defined limit of 80%.
ATP = according-to-protocol; CI = Confidence Interval. aBooster response: In initially seronegative subjects (<5 EL.U./mL), post-vaccination antibody concentrations ≥20 EL.U./mL. In initially seropositive subjects with pre-vaccination antibody concentrations ≥5 EL.U./mL and <20 EL.U./mL, an increase of at least 4 times the pre-vaccination antibody concentration. In initially seropositive subjects with pre-vaccination antibody concentrations ≥20 EL.U./mL, an increase of at least 2 times the pre-vaccination antibody concentration. bThe PT antigen booster response lower limit of the 95% CI did not exceed the pre-defined limit of 80%. cThe FHA and pertactin antigens booster response lower limit of the 95% CI exceeded the pre-defined limit of 80%. The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX in the US adult (19 to 64 years of age) study were compared with the GMCs observed in infants following a 3-dose primary series of INFANRIX administered at 3, 4, and 5 months of age. Table 11 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one pertussis antigen). These infants were a subset of those who formed the cohort for the German household contact study in which the efficacy of INFANRIX was demonstrated [see Clinical Studies (14.1)]. Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-pertactin antibody concentrations observed in adults 1 month after a single dose of BOOSTRIX were non-inferior to those observed in infants following a primary vaccination series with INFANRIX.
GMC = geometric mean antibody concentration; CI = Confidence Interval. Number of subjects for BOOSTRIX GMC evaluation: Anti-PT = 1,460, anti-FHA = 1,472, and anti-pertactin = 1,473. Number of subjects for INFANRIX GMC evaluation: Anti-PT = 2,884, anti-FHA = 685, and anti-pertactin = 631. aBOOSTRIX was non-inferior to INFANRIX (lower limit of 95% CI for the GMC ratio of BOOSTRIX/INFANRIX ≥0.67). 14.4 Immunological Evaluation in the Elderly (65 Years of Age and Older) The US elderly (65 years of age and older) study, a randomized, observer-blinded study, evaluated the immunogenicity of BOOSTRIX (N = 887) compared with a US-licensed comparator Td vaccine (N = 445) (Sanofi Pasteur SA). Vaccines were administered as a single dose to subjects who had not received a tetanus-diphtheria booster within 5 years. Among all vaccine recipients, the mean age was approximately 72 years of age; 54% were female and 95% were white. The immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after administration. Response to Tetanus and Diphtheria Toxoids and Pertussis Antigens: Immune responses to tetanus and diphtheria toxoids and pertussis antigens were measured 1 month after administration of a single dose of BOOSTRIX or a comparator Td vaccine. Anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL) were comparable between BOOSTRIX and the comparator Td vaccine (Table 12).
Td = Tetanus and Diphtheria Toxoids Adsorbed, a US-licensed Td vaccine, manufactured by Sanofi Pasteur SA. ATP = according-to-protocol; CI = Confidence Interval. aSeroprotection rates for BOOSTRIX were non-inferior to the comparator Td vaccine (lower limit of 95% CI on the difference of BOOSTRIX minus Td ≥-10%). bNon-inferiority criteria not prospectively defined for this endpoint. The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX were compared with the GMCs of infants following a 3-dose primary series of INFANRIX administered at 3, 4, and 5 months of age. Table 13 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one pertussis antigen). These infants were a subset of those who formed the cohort for the German household contact study in which the efficacy of INFANRIX was demonstrated [see Clinical Studies (14.1)]. Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-pertactin antibody concentrations in the elderly (65 years of age and older) 1 month after a single dose of BOOSTRIX were non-inferior to those of infants following a primary vaccination series with INFANRIX.
GMC = geometric mean antibody concentration; CI = Confidence Interval. Number of subjects for BOOSTRIX GMC evaluation: Anti-PT = 865, anti-FHA = 847, and anti-pertactin = 878. Number of subjects for INFANRIX GMC evaluation: Anti-PT = 2,884, anti-FHA = 685, and anti-pertactin = 631. aBOOSTRIX was non-inferior to INFANRIX (lower limit of 95% CI for the GMC ratio of BOOSTRIX/INFANRIX ≥0.67). 14.5 Concomitant Vaccine Administration Concomitant Administration With Meningococcal Conjugate Vaccine: The concomitant use of BOOSTRIX and a tetravalent meningococcal (groups A, C, Y, and W-135) conjugate vaccine (Sanofi Pasteur SA) was evaluated in a randomized study in healthy adolescents 11 to 18 years of age. A total of 1,341 adolescents were vaccinated with BOOSTRIX. Of these, 446 subjects received BOOSTRIX administered concomitantly with meningococcal conjugate vaccine at different injection sites, 446 subjects received BOOSTRIX followed by meningococcal conjugate vaccine 1 month later, and 449 subjects received meningococcal conjugate vaccine followed by BOOSTRIX 1 month later. Immune responses to diphtheria and tetanus toxoids (% of subjects with anti-tetanus and anti-diphtheria antibodies ≥1.0 IU/mL by ELISA), pertussis antigens (booster responses and GMCs), and meningococcal antigens (vaccine responses) were measured 1 month (range 30 to 48 days) after concomitant or separate administration of BOOSTRIX and meningococcal conjugate vaccine. For BOOSTRIX given concomitantly with meningococcal conjugate vaccine compared to BOOSTRIX administered first, non-inferiority was demonstrated for all antigens, with the exception of the anti-pertactin GMC. The lower limit of the 95% CI for the GMC ratio was 0.54 for anti-pertactin (pre-specified limit ≥0.67). For the anti-pertactin booster response, non-inferiority was demonstrated. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to pertactin. There was no evidence that BOOSTRIX interfered with the antibody responses to the meningococcal antigens when measured by serum bactericidal assays (rSBA) when given concomitantly or sequentially (meningococcal conjugate vaccine followed by BOOSTRIX or BOOSTRIX followed by meningococcal conjugate vaccine. Concomitant Administration With FLUARIX (Influenza Virus Vaccine): The concomitant use of BOOSTRIX and FLUARIX was evaluated in a multicenter, open-label, randomized, controlled study of 1,497 adults 19 to 64 years of age. In one group, subjects received BOOSTRIX and FLUARIX concurrently (n = 748). The other group received FLUARIX at the first visit, then 1 month later received BOOSTRIX (n = 749). Sera was obtained prior to and 1 month following concomitant or separate administration of BOOSTRIX and/or FLUARIX, as well as 1 month after the separate administration of FLUARIX. Immune responses following concurrent administration of BOOSTRIX and FLUARIX were non-inferior to separate administration for diphtheria (seroprotection defined as ≥0.1 IU/mL), tetanus (seroprotection defined as ≥0.1 IU/mL and based on concentrations ≥1.0 IU/mL), pertussis toxin (PT) antigen (anti-PT GMC) and influenza antigens (percent of subjects with hemagglutination-inhibition [HI] antibody titer ≥1:40 and ≥4-fold rise in HI titer). Non-inferiority criteria were not met for the anti-pertussis antigens FHA and pertactin. The lower limit of the 95% CI of the GMC ratio was 0.64 for anti-FHA and 0.60 for anti-pertactin and the pre-specified limit was ≥0.67. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to FHA and pertactin. 15 References
16 How Supplied/Storage and Handling BOOSTRIX is available in 0.5-mL single-dose vials and disposable prefilled TIP-LOK syringes (packaged without needles): NDC 58160-842-01 Vial (contains no latex) in Package of 10: NDC 58160-842-11 NDC 58160-842-05 Syringe (tip cap may contain latex; plunger contains no latex) in Package of 1: NDC 58160-842-34 NDC 58160-842-43 Syringe (tip cap may contain latex; plunger contains no latex) in Package of 10: NDC 58160-842-52 NDC 58160-842-41 Syringe (tip cap and plunger contain latex) in Package of 10: NDC 58160-842-51 Store refrigerated between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has been frozen.
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美国FDA批准联合疫苗Boostrix用于治疗成人白喉类百日咳简介：
日前，葛兰素史克公司(GlaxoSmithKline，GSK)宣布美国FDA已批准其破伤风白喉类百日咳三联疫苗[Tetanus Toxoid，Reduced Diphtheria Toxoid，Acellular Pertussis Vaccine，Adsorbed (Tdap)， Boostrix] ... 责任编辑：admin |
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