DAPTACEL: Package Insert and Label Information (Page 2 of 3)

6.2 Data from Post-Marketing Experience

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

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

  • Blood and lymphatic disorders
    Lymphadenopathy
  • Cardiac disorders
    Cyanosis
  • Gastro-intestinal disorders
    Nausea, diarrhea
  • General disorders and administration site conditions
    Local reactions: injection site pain, injection site rash, injection site nodule, injection site mass, extensive swelling of injected limb (including swelling that involves adjacent joints).
  • Infections and infestations
    Injection site cellulitis, cellulitis, injection site abscess
  • Immune system disorders
    Hypersensitivity, allergic reaction, anaphylactic reaction (edema, face edema, swelling face, pruritus, rash generalized) and other types of rash (erythematous, macular, maculo-papular)
  • Nervous system disorders
    Convulsions: febrile convulsion, grand mal convulsion, partial seizures
    HHE, hypotonia, somnolence, syncope
  • Psychiatric disorders
    Screaming

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

In clinical trials, DAPTACEL was administered concomitantly with one or more of the following US licensed vaccines: Hib conjugate vaccine, IPV, hepatitis B vaccine, pneumococcal conjugate vaccine, Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate vaccine, MMR vaccine, and varicella vaccine. [See Adverse Reactions (6.1) and Clinical Studies (14.4).] When DAPTACEL is given at the same time as another injectable vaccine(s), the vaccines should be administered with different syringes and at different injection sites.

In cases where DAPTACEL and Menactra are to be administered to children 4 through 6 years of age, the two vaccines should be administered concomitantly or Menactra should be administered prior to DAPTACEL. Administration of Menactra one month after DAPTACEL has been shown to reduce meningococcal antibody responses to Menactra. [See Adverse Reactions (6.1) and Clinical Studies (14.4).]

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 DAPTACEL.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

DAPTACEL is not approved for use in individuals 7 years of age and older. Human or animal data are not available to assess vaccine-associated risks in pregnancy.

8.2 Lactation

DAPTACEL is not approved for use in individuals 7 years of age and older. Human or animal data are not available to assess the impact of DAPTACEL on milk production, its presence in breast milk, or its effects on the breastfed infant.

8.4 Pediatric Use

DAPTACEL is not indicated for use in infants below 6 weeks of age or children 7 years of age or older. Safety and effectiveness of DAPTACEL in these age groups have not been established.

11 DESCRIPTION

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

Each 0.5 mL dose contains 15 Lf diphtheria toxoid, 5 Lf tetanus toxoid and acellular pertussis antigens [10 mcg detoxified pertussis toxin (PT), 5 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), and 5 mcg fimbriae types 2 and 3 (FIM)].

Other ingredients per 0.5 mL dose include 1.5 mg aluminum phosphate (0.33 mg of aluminum) as the adjuvant, ≤5 mcg residual formaldehyde, <50 ng residual glutaraldehyde and 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative).

The acellular pertussis vaccine components are produced from 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. The FIM components are extracted and co-purified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. PT is detoxified with glutaraldehyde. FHA is treated with formaldehyde, and the residual aldehydes are removed by ultrafiltration. The individual antigens are adsorbed separately onto aluminum phosphate.

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

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

Both diphtheria and tetanus toxoids induce at least 2 units of antitoxin per mL in the guinea pig potency test. The potency of the acellular pertussis vaccine components is determined by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Diphtheria

Diphtheria is an acute toxin-mediated disease caused by toxigenic strains of C diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. Antitoxin levels of at least 0.1 IU/mL are generally regarded as protective. (5) Levels of 1.0 IU/mL have been associated with long-term protection. (6)

Tetanus

Tetanus is an acute disease caused by an extremely potent neurotoxin produced by C tetani. Protection against disease is due to the development of neutralizing antibodies to tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assay is considered the minimum protective level. (5) (7) A tetanus antitoxin level ≥0.1 IU/mL as measured by the ELISA used in clinical studies of DAPTACEL is considered protective.

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 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

DAPTACEL has not been evaluated for carcinogenic or mutagenic potential or impairment of fertility.

14 CLINICAL STUDIES

14.1 Diphtheria

In a US study in which children received 4 doses of DAPTACEL at 2, 4, 6 and 15-17 months of age, after the third dose, 100% (N = 1,099) achieved diphtheria antitoxin levels of ≥0.01 IU/mL and 98.5% achieved diphtheria antitoxin levels of ≥0.10 IU/mL. Among a random subset of children who received the fourth dose of DAPTACEL at 15-16 months of age, 96.5% (N = 659) achieved diphtheria antitoxin levels of ≥1.0 IU/mL after the fourth dose.

14.2 Tetanus

In a US study in which children received 4 doses of DAPTACEL at 2, 4, 6 and 15-17 months of age, after the third dose, 100% (N = 1,037) achieved tetanus antitoxin levels of ≥0.10 IU/mL. Among a random subset of children who received the fourth dose of DAPTACEL at 15-16 months of age, 98.8% (N = 681) achieved tetanus antitoxin levels of ≥1.0 IU/mL after the fourth dose.

14.3 Pertussis

A randomized, double-blinded, placebo-controlled efficacy and safety study was conducted in Sweden during 1992-1995 (Sweden I Efficacy Trial) under the sponsorship of the National Institute of Allergy and Infectious Diseases. A total of 9,829 infants received 1 of 4 vaccines: DAPTACEL (N = 2,587); another investigational acellular pertussis vaccine (N = 2,566); whole-cell pertussis DTP vaccine (N = 2,102); or DT vaccine as placebo (Swedish National Bacteriological Laboratory, N = 2,574). Infants were immunized at 2, 4 and 6 months of age. The mean length of follow-up was 2 years after the third dose of vaccine. The protective efficacy of DAPTACEL against pertussis after 3 doses using the World Health Organization (WHO) case definition (≥21 consecutive days of paroxysmal cough with culture or serologic confirmation or epidemiologic link to a confirmed case) was 84.9% (95% confidence interval [CI] 80.1 to 88.6). The protective efficacy of DAPTACEL against mild pertussis (≥1 day of cough with laboratory confirmation) was 77.9% (95% CI 72.6 to 82.2). Protection against pertussis by DAPTACEL was sustained for the 2-year follow-up period.

In order to assess the antibody response to the pertussis antigens of DAPTACEL in the US population, 2 lots of DAPTACEL, including the lot used in the Sweden I Efficacy Trial, were administered to US infants in the US Bridging Study. In this study, antibody responses following 3 doses of DAPTACEL given to US children at 2, 4 and 6 months of age were compared to those from a subset of the infants enrolled in the Sweden I Efficacy Trial. Assays were performed in parallel on the available sera from the US and Swedish infants. Antibody responses to all the antigens were similar except for those to the PRN component. For both lots of DAPTACEL, the geometric mean concentration (GMC) and percent response to PRN in US infants (Lot 006, N = 107; Lot 009, N = 108) were significantly lower after 3 doses of vaccine than in Swedish infants (N = 83). In separate US and Canadian studies in which children received DAPTACEL at 2, 4 and 6 months of age, with a fourth dose at either 17-20 months (Canadian study) or 15-16 months (random subset from US study) of age, antibody responses to each pertussis antigen following the fourth dose (Canadian study N = 275; US study N = 237-347) were at least as high as those seen in the Swedish infants after 3 doses. While a serologic correlate of protection for pertussis has not been established, the antibody response to all antigens in North American infants after 4 doses of DAPTACEL at 2, 4, 6 and 15-20 months of age was comparable to that achieved in Swedish infants in whom efficacy was demonstrated after 3 doses of DAPTACEL at 2, 4 and 6 months of age.

14.4 Concomitantly Administered Vaccines

In the US Bridging study, DAPTACEL was given concomitantly with Hib conjugate vaccine (Sanofi Pasteur SA) according to local practices. Anti-PRP immune response was evaluated in 261 infants who received 3 doses of Hib conjugate vaccine. One month after the third dose, 96.9% achieved anti-PRP antibody levels of at least 0.15 mcg/mL and 82.7% achieved antibody levels of at least 1.0 mcg/mL.

In the US study in which infants received DAPTACEL concomitantly with Hib conjugate (tetanus toxoid conjugate) vaccine, IPV, 7-valent pneumococcal conjugate vaccine, and hepatitis B vaccine [see Adverse Reactions (6.1)], at 7 months of age, 100.0% of subjects (N = 1,050-1,097) had protective neutralizing antibody levels (≥1:8 1/dil) for poliovirus types 1, 2 and 3; and 92.4% (N = 998) achieved anti-hepatitis B surface antigen levels ≥10.0 mIU/mL. Although there is no established serologic correlate of protection for any of the pneumococcal serotypes, at 7 months of age 91.3%-98.9% (N = 1,027-1,029) achieved anti-pneumococcal polysaccharide levels ≥0.5 mcg/mL for serotypes 4, 9V, 14, 18C, 19F and 23F and 80.7% (N = 1,027) achieved an anti-pneumococcal polysaccharide level ≥0.5 mcg/mL for serotype 6B. The mumps seroresponse rate was lower when DAPTACEL was administered concomitantly (86.6%; N = 307) vs. non-concomitantly (90.1%; N = 312) with the first dose of MMR vaccine [upper limit of 90% confidence interval for difference in rates (non-concomitant minus concomitant) >5%]. There was no evidence for interference in the immune response to the measles, rubella, and varicella antigens or to the fourth dose of the 7-valent pneumococcal conjugate vaccine with concomitant administration of DAPTACEL.

In a randomized, parallel-group, US multi-center clinical trial conducted in children 4 through 6 years of age, DAPTACEL was administered as follows: concomitantly with IPV (Sanofi Pasteur SA) followed 30 days later by Menactra [Group A]; concomitantly with Menactra followed 30 days later by IPV [Group B]; or 30 days after concomitant administration of Menactra and IPV [Group C]. Sera were obtained approximately 30 days after each respective vaccination. When DAPTACEL was administered concomitantly with Menactra [Group B], antibody responses to PT, FHA and PRN (GMC), tetanus (% participants with antibody concentrations ≥1.0 IU/mL), and diphtheria (%participants with antibody concentrations ≥1.0 IU/mL) were non-inferior to those observed when DAPTACEL (and IPV) were administered [Group A]. The anti-FIM GMCs were marginally lower when DAPTACEL and Menactra were administered concomitantly but the clinical significance is unknown because there are no established serological correlates of protection for pertussis. When DAPTACEL (and IPV) were administered 30 days prior to Menactra [Group A], significantly lower serum-bactericidal assay-human complement (SBA-H) GMTs to all 4 meningococcal serogroups were observed compared to when Menactra (and IPV) were administered 30 days prior to DAPTACEL [Group C]. When DAPTACEL was administered concomitantly with Menactra [Group B], SBA-H GMTs to meningococcal serogroups A, C, and W-135 were non-inferior to those observed when Menactra (and IPV) were administered [Group C]. The non-inferiority criterion was marginally missed for meningococcal serogroup Y. [See Drug Interactions (7.1).]

15 REFERENCES

1
Stratton KR, et al. editors. Adverse events associated with childhood vaccines; evidence bearing on causality. Washington D.C.: National Academy Press. 1994. p. 67-117.
2
Stainer DW, Scholte MJ. A simple chemically defined medium for the production of phase I Bordetella pertussis. J Gen Microbiol 1970;63:211-20.
3
Stainer DW. Production of diphtheria toxin. In: Manclark CR, editor. Proceedings of an informal consultation on the World Health Organization requirements for diphtheria, tetanus, pertussis and combined vaccines. United States Public Health Service, Bethesda, MD. DHHS 91-1174. 1991. p. 7-11.
4
Mueller JH, Miller PA. Variable factors influencing the production of tetanus toxin. J Bacteriol 1954;67(3):271-7.
5
Department of Health and Human Services, Food and Drug Administration. Biological products; bacterial vaccines and toxoids; implementation of efficacy review; proposed rule. Federal Register 1985;50(240):51002-117.
6
Wharton M, et al. Diphtheria Toxoid. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia, PA: W. B. Saunders 2004 p. 211-28.
7
Wassilak SGF, et al. Tetanus Toxoid. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia, PA: W. B. Saunders 2004 p. 745-81.

16 HOW SUPPLIED/STORAGE AND HANDLING

The vial stopper for this product is not made with natural rubber latex.

DAPTACEL is supplied in a single-dose vial (NDC No. 49281-286-58):

in packages of 1 vial: NDC No. 49281-286-01;

in packages of 5 vials: NDC No. 49281-286-05;

in packages of 10 vials: NDC No. 49281-286-10.

DAPTACEL should be stored at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Product which has been exposed to freezing should not be used. Do not use after expiration date shown on the label.

17 PATIENT COUNSELING INFORMATION

Inform the parent or guardian of the following:

  • The potential benefits and risks of immunization with DAPTACEL.
  • The common adverse reactions that have occurred following administration of DAPTACEL or other vaccines containing similar components.
  • Other adverse reactions can occur. Call healthcare provider with any adverse reactions of concern.

Provide the Vaccine Information Statements (VIS), which are required by the National Childhood Vaccine Injury Act of 1986.

Manufactured by:
Sanofi Pasteur Limited
Toronto Ontario Canada

Distributed by:
Sanofi Pasteur Inc.
Swiftwater PA 18370 USA

US Patents: 4500639, 4687738, 4784589, 4997915, 5444159, 5667787, 5877298.

DAPTACEL® is a registered trademark of Sanofi Pasteur Limited.

R11-0220 USA

PRINCIPAL DISPLAY PANEL — 0.5 mL Vial Label

6 wks — 6 yrs
DTaP

NDC 49281-286-58

Diphtheria and Tetanus
Toxoids and Acellular
Pertussis Vaccine
Adsorbed

DAPTACEL®

Rx only

Single-dose (0.5 mL) IM onlySanofi Pasteur Limited

PRINCIPAL DISPLAY PANEL -- 0.5 mL Vial Label
(click image for full-size original)

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