Adacel TDaP: Package Insert and Label Information (Page 2 of 4)

6.2 Postmarketing Experience

The following adverse events of Adacel have been spontaneously reported in the US and other countries. Because these events are reported voluntarily from a population of uncertain size, it may not be possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

The following adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Adacel.

  • Immune system disorders
    Anaphylactic reaction, hypersensitivity reaction (angioedema, edema, rash, hypotension)
  • Nervous system disorders
    Paresthesia, hypoesthesia, Guillain-Barré syndrome, brachial neuritis, facial palsy, convulsion, syncope, myelitis
  • Cardiac disorders
    Myocarditis
  • Skin and subcutaneous tissue disorders
    Pruritus, urticaria
  • Musculoskeletal and connective tissue disorders
    Myositis, muscle spasm
  • General disorders and administration site conditions
    Large injection site reactions (>50 mm), extensive limb swelling from the injection site beyond one or both joints Injection site bruising, sterile abscess, Arthus hypersensitivity

7 DRUG INTERACTIONS

7.1 Concomitant Vaccine Administration

When Adacel is administered concomitantly with other injectable vaccines or Tetanus Immune Globulin, they should be given with separate syringes and at different injection sites. Adacel should not be mixed with any other vaccine in the same syringe or vial.

Trivalent Inactivated Influenza Vaccine (TIV)

In a clinical study Adacel (first vaccination) was administered concomitantly with a US-licensed trivalent inactivated influenza vaccine (TIV). [See ADVERSE REACTIONS (6.1) and CLINICAL STUDIES (14).]

No interference in tetanus and diphtheria seroprotection rates and responses to influenza vaccine, detoxified pertussis toxin (PT), fimbriae types 2 and 3 (FIM) or filamentous hemagglutinin (FHA) were observed when Adacel vaccine was administered concomitantly with TIV compared to separate administration. A lower pertactin (PRN) GMC was observed when Adacel was administered concomitantly with TIV compared to separate administration.

7.2 Immunosuppressive Treatments

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to vaccines. [See WARNINGS AND PRECAUTIONS (5.6).]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Adacel during pregnancy. Women who receive Adacel during pregnancy are encouraged to contact directly, or have their healthcare professional contact, Sanofi Pasteur Inc. at 1-800-822-2463 (1-800-VACCINE).

Risk Summary

All pregnancies have a risk of birth defect, loss or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There are no adequate and well-controlled studies of Adacel administration in pregnant women in the U.S.

Available data suggest the rates of major birth defects and miscarriage in women who receive Adacel within 30 days prior to pregnancy or during pregnancy are consistent with estimated background rates. ( See Data)

Two developmental toxicity studies were performed in female rabbits given 0.5 mL (a single human dose) of Adacel twice prior and during gestation. The studies revealed no evidence of harm to the fetus due to Adacel. ( See Data)

Data

Human Data

An assessment of data from the ongoing pregnancy registry over 12 years (2005-2017) included 1518 reports of exposure to Adacel vaccine from 30 days before or at any time during pregnancy. Of these reports, 543 had known pregnancy outcomes available and were enrolled in the registry prior to the outcomes being known. Among the 543 pregnancies with known outcomes, the timing of Adacel vaccination was not known for 126 of the pregnancies.

Of the prospectively followed pregnancies for whom the timing of Adacel vaccination was known, 374 women received Adacel during the 30 days prior to conception through the second trimester. Outcomes among these prospectively followed pregnancies included 5 infants with major birth defects and 25 cases of miscarriage.

Animal Data

The effect of Adacel on embryo-fetal and pre-weaning development was evaluated in two developmental toxicity studies in female rabbits. Animals were administered 0.5 mL (a single human dose) of Adacel twice prior to gestation, during the period of organogenesis (gestation day 6) and later during pregnancy on gestation day 29. No adverse effects on pregnancy, parturition, lactation, embryo-fetal or pre-weaning development were observed. There were no vaccine related fetal malformations or other evidence of teratogenesis noted in this study.

8.2 Lactation

Risk Summary

It is not known whether Adacel vaccine components are excreted in human milk. Data are not available to assess the effect of administration of Adacel on breast-fed infants or on milk production/excretion.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Adacel and any potential adverse effects on the breastfed child from Adacel or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Adacel is not approved for individuals less than 10 years of age. Safety and effectiveness of Adacel in persons less than 10 years of age in the U.S. have not been established.

8.5 Geriatric Use

Adacel is not approved for use in individuals 65 years of age and older.

In a clinical study, individuals 65 years of age and older received a single dose of Adacel. Based on prespecified criteria, persons 65 years of age and older who received a dose of Adacel had lower geometric mean concentrations of antibodies to PT, PRN and FIM when compared to infants who had received a primary series of DAPTACEL® , Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP). [See CLINICAL STUDIES (14) for description of DAPTACEL.]

11 DESCRIPTION

Adacel is a sterile isotonic suspension of tetanus and diphtheria toxoids and pertussis antigens adsorbed on aluminum phosphate, for intramuscular injection.

Each 0.5 mL dose contains 5 Lf tetanus toxoid (T), 2 Lf diphtheria toxoid (d), and acellular pertussis antigens [2.5 mcg detoxified pertussis toxin (PT), 5 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), 5 mcg fimbriae types 2 and 3 (FIM)]. Other ingredients per 0.5 mL dose include 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant, ≤5 mcg residual formaldehyde, <50 ng residual glutaraldehyde and 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative). The antigens are the same as those in DAPTACEL; however, Adacel is formulated with reduced quantities of diphtheria and detoxified PT.

The acellular pertussis vaccine components are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium (2) modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA and PRN are isolated separately from the supernatant culture medium. FIM are extracted and copurified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. PT is detoxified with glutaraldehyde, FHA is treated with formaldehyde, and the residual aldehydes are removed by ultrafiltration. The individual antigens are adsorbed onto aluminum phosphate.

The tetanus toxin is produced from Clostridium tetani grown in modified Mueller-Miller casamino acid medium without beef heart infusion. (3) Tetanus toxin is detoxified with formaldehyde and purified by ammonium sulfate fractionation and diafiltration. Corynebacterium diphtheriae is grown in modified Mueller’s growth medium. (4) After purification by ammonium sulfate fractionation, diphtheria toxin is detoxified with formaldehyde and diafiltered.

The adsorbed diphtheria, tetanus and acellular pertussis components are combined with aluminum phosphate (as adjuvant), 2-phenoxyethanol (not as a preservative) and water for injection. Adacel does not contain a preservative.

In the guinea pig potency test, the tetanus component induces at least 2 neutralizing units/mL of serum and the diphtheria component induces at least 0.5 neutralizing units/mL of serum. The potency of the acellular pertussis vaccine components is evaluated by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA).

Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tetanus

Tetanus is a disease 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 tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assay is considered the minimum protective level. (5) (6)

Diphtheria

Diphtheria is an acute toxin-mediated disease caused by toxigenic strains of C diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. Antitoxin levels of at least 0.1 IU/mL are generally regarded as protective. (5) Levels of 1.0 IU/mL have been associated with long-term protection. (7)

Pertussis

Pertussis (whooping cough) is a respiratory disease caused by B pertussis. This Gram-negative coccobacillus produces a variety of biologically active components, though their role in either the pathogenesis of, or immunity to, pertussis has not been clearly defined.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Adacel has not been evaluated for carcinogenic or mutagenic potential, or impairment of male fertility.

14 CLINICAL STUDIES

The effectiveness of the tetanus toxoid and diphtheria toxoid used in Adacel was based on the immune response to these antigens compared to a US licensed Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (Td) vaccine manufactured by Sanofi Pasteur Inc., Swiftwater, PA. The primary measures for immune response to the diphtheria and tetanus toxoids were the percentage of participants attaining an antibody level of at least 0.1 IU/mL.

The effectiveness of the pertussis antigens used in Adacel was evaluated based on a comparison of pertussis antibody levels achieved in recipients of Adacel with those obtained in infants after three or four doses of DAPTACEL. For the first dose of Adacel, the comparisons were to infants who received three doses of DAPTACEL in the Sweden I Efficacy trial. For the second dose of Adacel, for the evaluation of FHA, PRN, and FIM antibody levels, the comparisons were to infants who received three doses of DAPTACEL in the Sweden I Efficacy trial; for evaluation of PT antibody levels, the comparison was to infants who received four doses of DAPTACEL in a US safety and immunogenicity study (Study M5A10). In the Sweden I Efficacy Trial, three doses of DAPTACEL vaccine were shown to confer a protective efficacy of 84.9% (95% CI: 80.1%, 88.6%) against WHO defined pertussis (21 days of paroxysmal cough with laboratory-confirmed B pertussis infection or epidemiological link to a confirmed case). The protective efficacy against mild pertussis (defined as at least one day of cough with laboratory-confirmed B pertussis infection) was 77.9% (95% CI: 72.6%, 82.2%). (8)

In addition, the ability of Adacel to elicit a booster response (defined as rise in antibody concentration after vaccination) to the tetanus, diphtheria and pertussis antigens following vaccination was evaluated.

14.1 Immunological Evaluation in Adolescents and Adults, 11 through 64 Years of Age Following a First Vaccination with Adacel

Study Td506 was a comparative, multi-center, randomized, observer-blind, controlled trial which enrolled 4,480 participants; 2,053 adolescents (11-17 years of age) and 2,427 adults (18-64 years of age). Enrollment was stratified by age to ensure adequate representation across the entire age range. Participants had not received a tetanus or diphtheria toxoid containing vaccine within the previous 5 years. After enrollment participants were randomized to receive one dose of either Adacel or Td vaccine. A total of 4,461 randomized participants were vaccinated. The per-protocol immunogenicity subset included 1,270 Adacel recipients and 1,026 Td vaccine recipients. Sera were obtained before and approximately 35 days after vaccination. [Blinding procedures for safety assessments are described in ADVERSE REACTIONS (6). ]

Demographic characteristics were similar within age groups and between the vaccine groups. A total of 76% of the adolescents and 1.1% of the adults reported a history of receiving 5 previous doses of diphtheria-tetanus-pertussis containing vaccines. Anti-tetanus and anti-diphtheria seroprotection rates (≥0.1 IU/mL) and booster response rates were comparable between Adacel and Td vaccines. (See Table 4 and Table 5.) Adacel induced pertussis antibody levels that were non-inferior to those of Swedish infants who received three doses of DAPTACEL vaccine (Sweden I Efficacy Study). (See Table 6.) Acceptable booster responses to each of the pertussis antigens were also demonstrated, ie, the percentage of participants with a booster response exceeded the predefined lower limit. (See Table 7.)

Table 4: Pre-vaccination and Post-vaccination Antibody Responses and Booster Response Rates to Tetanus Toxoid Following A First Vaccination with Adacel Vaccine as Compared to Td Vaccine in Adolescents and Adults 11 through 64 Years of Age (Td506)
Anti-Tetanus toxoid (IU/mL)
Pre-vaccination 1 Month Post-vaccination
Age Group (years) Vaccine N * % ≥0.10(95% CI) % ≥1.0(95% CI) % ≥0.10(95% CI) % ≥1.0(95% CI) % Booster (95% CI)
*
N = number of participants in the per-protocol population with available data.
Booster response is defined as: A 4-fold rise in antibody concentration, if the pre-vaccination concentration was equal to or below the cut-off value and a 2-fold rise in antibody concentration if the pre-vaccination concentration was above the cut-off value. The cut-off value for tetanus was 2.7 IU/mL.
Seroprotection rates at ≥0.10 IU/mL and booster response rates to Adacel were non-inferior to Td vaccine (upper limit of the 95% CI on the difference for Td vaccine minus Adacel <10%).
§
Seroprotection rates at ≥1.0 IU/mL were not prospectively defined as a primary endpoint.
Tetanus and Diphtheria Toxoids Adsorbed manufactured by Sanofi Pasteur Inc., Swiftwater, PA.
11-17 Adacel 527 99.6(98.6, 100.0) 44.6(40.3, 49.0) 100.0(99.3, 100.0) 99.6§(98.6, 100.0) 91.7(89.0, 93.9)
Td 516 99.2(98.0, 99.8) 43.8(39.5, 48.2) 100.0(99.3, 100.0) 99.4(98.3, 99.9) 91.3(88.5, 93.6)
18-64 Adacel 742-743 97.3(95.9, 98.3) 72.9(69.6, 76.1) 100.0(99.5, 100.0) 97.8§(96.5, 98.8) 63.1(59.5, 66.6)
Td 509 95.9(93.8, 97.4) 70.3(66.2, 74.3) 99.8(98.9, 100.0) 98.2(96.7, 99.2) 66.8(62.5, 70.9)
Table 5: Pre-vaccination and Post-vaccination Antibody Responses and Booster Response Rates to Diphtheria Toxoid Following A First Vaccination with Adacel as Compared to Td Vaccine in Adolescents and Adults 11 through 64 Years of Age (Td506)
Anti-Diphtheria toxin (IU/mL)
Pre-vaccination 1 Month Post-vaccination
Age Group(years) Vaccine N * % ≥0.10(95% CI) % ≥1.0(95% CI) % ≥0.10(95% CI) % ≥1.0(95% CI) % Booster (95% CI)
*
N = number of participants in the per-protocol population with available data.
Booster response is defined as: A 4-fold rise in antibody concentration, if the pre-vaccination concentration was equal to or below the cut-off value and a 2-fold rise in antibody concentration if the pre-vaccination concentration was above the cut-off value. The cut-off value for diphtheria was 2.56 IU/mL.
Seroprotection rates at ≥0.10 IU/mL and booster response rates to Adacel were non-inferior to Td vaccine (upper limit of the 95% CI on the difference for Td vaccine minus Adacel <10%).
§
Seroprotection rates at ≥1.0 IU/mL were not prospectively defined as a primary endpoint.
Tetanus and Diphtheria Toxoids Adsorbed manufactured by Sanofi Pasteur Inc., Swiftwater, PA.
11-17 Adacel 527 72.5(68.5, 76.3) 15.7(12.7, 19.1) 99.8(98.9, 100.0) 98.7§(97.3, 99.5) 95.1(92.9, 96.8)
Td 515-516 70.7(66.5, 74.6) 17.3(14.1, 20.8) 99.8(98.9, 100.0) 98.4(97.0, 99.3) 95.0(92.7, 96.7)
18-64 Adacel 739-741 62.6(59.0, 66.1) 14.3(11.9, 17.0) 94.1(92.1, 95.7) 78.0§(74.8, 80.9) 87.4(84.8, 89.7)
Td 506-507 63.3(59.0, 67.5) 16.0(12.9, 19.5) 95.1(92.8, 96.8) 79.9(76.1, 83.3) 83.4(79.9, 86.5)
Table 6: Ratio of Pertussis Antibody Geometric Mean Concentrations (GMCs)* Observed One Month Following A First Vaccination with Adacel in Adolescents and Adults 11 through 64 Years of Age Compared with Those Observed in Infants One Month following Vaccination at 2,4 and 6 Months of Age in the Efficacy Trial with DAPTACEL (Sweden I Efficacy Study)
Adolescents 11-17 Years of Age Adults 18-64 Years of Age
Adacel /DAPTACEL GMC Ratio(95% CIs) Adacel §/DAPTACEL GMC Ratio(95% CIs)
*
Antibody GMCs, measured in arbitrary ELISA units were calculated separately for infants, adolescents and adults.
N = 524 to 526, number of adolescents in the per-protocol population with available data for Adacel.
N = 80, number of infants who received DAPTACEL with available data post dose 3 (Sweden Efficacy I).
§
N = 741, number of adults in the per-protocol population with available data for Adacel.
GMC following Adacel was non-inferior to GMC following DAPTACEL (lower limit of 95% CI on the ratio of GMC for Adacel divided by DAPTACEL >0.67).
Anti-PT 3.6(2.8, 4.5) 2.1(1.6, 2.7)
Anti-FHA 5.4(4.5, 6.5) 4.8(3.9, 5.9)
Anti-PRN 3.2(2.5, 4.1) 3.2(2.3, 4.4)
Anti-FIM 5.3(3.9, 7.1) 2.5(1.8, 3.5)
Table 7: Booster Response Rates to the Pertussis Antigens Observed One Month Following a First Vaccination with Adacel in Adolescents and Adults 11 through 64 Years of Age
Adolescents 11-17Years of Age Adults 18-64Years of Age PredefinedAcceptable Rates *%
N %(95% CI) N %(95% CI)
*
The acceptable response rate for each antigen was defined as the lower limit of the 95% CI for the rate being no more than 10% lower than the response rate observed in previous clinical trials.
A booster response for each antigen was defined as a 4-fold rise in antibody concentration if the pre-vaccination concentration was equal to or below the cut-off value and a 2-fold rise in antibody concentration if the pre-vaccination concentration was above the cut-off value. The cut-off values for pertussis antigens were established based on antibody data from both adolescents and adults in previous clinical trials. The cut-off values were 85 EU/mL for PT, 170 EU/mL for FHA, 115 EU/mL for PRN and 285 EU/mL for FIM.
N = number of participants in the per-protocol population with available data.
Anti-PT 524 92.0(89.3, 94.2) 739 84.4(81.6, 87.0) 81.2
Anti-FHA 526 85.6(82.3, 88.4) 739 82.7(79.8, 85.3) 77.6
Anti-PRN 525 94.5(92.2, 96.3) 739 93.8(91.8, 95.4) 86.4
Anti-FIM 526 94.9(92.6, 96.6) 739 85.9(83.2, 88.4) 82.4

Study Td519 assessed the comparative immunogenicity of a first vaccination with Adacel administered to adolescents (10 to <11 years of age and 11 to <12 years of age) [See ADVERSE REACTIONS (6.1).] In this study non-inferiority was demonstrated for booster responses to tetanus and diphtheria toxoids, GMCs to the pertussis antigens (PT, FHA, PRN and FIM) and booster responses to the pertussis antigens PT, FHA and PRN. For FIM, non-inferiority was not demonstrated as the lower bound of the 95% CI of the difference in booster response rates (-5.96%) did not meet the predefined criterion (>-5% when the booster response in the older age group was >95%).

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