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

6.2 Postmarketing Experience

The following additional adverse events have been spontaneously reported during the post-marketing use of Pentacel worldwide, since 1997. Between 1997 and 2007, Pentacel was primarily used in Canada. 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 Pentacel.

  • Cardiac disorders
    Cyanosis
  • Gastrointestinal disorders
    Vomiting, diarrhea
  • General disorders and administration site conditions
    Injection site reactions (including inflammation, mass, abscess and sterile abscess), extensive swelling of the injected limb (including swelling that involved adjacent joints), vaccination failure/therapeutic response decreased (invasive H. influenzae type b disease)
  • Immune system disorders
    Anaphylaxis/anaphylactic reaction, hypersensitivity (such as rash and urticaria)
  • Infections and infestations
    Meningitis, rhinitis, viral infection
  • Metabolism and nutrition disorders
    Decreased appetite
  • Nervous system disorders
    Somnolence, HHE, depressed level of consciousness
  • Psychiatric disorders
    Screaming
  • Respiratory, thoracic and mediastinal disorders
    Apnea, cough
  • Skin and subcutaneous tissue disorders
    Erythema, skin discoloration
  • Vascular disorders Pallor

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

In clinical trials, Pentacel was administered concomitantly with one or more of the following US licensed vaccines: hepatitis B vaccine, 7-valent pneumococcal conjugate vaccine, MMR and varicella vaccines. [See Adverse Reactions (6) and Clinical Studies (14).] When Pentacel is given at the same time as another injectable vaccine(s), the vaccine(s) should be administered with different syringes and at different injection sites.

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 Pentacel. [See Warnings and Precautions (5.6).]

7.3 Drug/Laboratory Test Interactions

Antigenuria has been detected in some instances following receipt of ActHIB. Urine antigen detection may not have definite diagnostic value in suspected H. influenzae type b disease within one week following receipt of Pentacel. (6)

8 USE IN SPECIFIC POPULATIONS

8.4 Pediatric Use

The safety and effectiveness of Pentacel was established in the age group 6 weeks through 18 months on the basis of clinical studies. [See Adverse Reactions (6.1) and Clinical Studies (14).] The safety and effectiveness of Pentacel in the age group 19 months through 4 years is supported by evidence in children 6 weeks through 18 months. The safety and effectiveness of Pentacel in infants less than 6 weeks of age and in children 5 to 16 years of age have not been established.

11 DESCRIPTION

Pentacel consists of a Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus (DTaP-IPV) component and an ActHIB® component combined through reconstitution for intramuscular injection. ActHIB (Haemophilus b Conjugate Vaccine [Tetanus Toxoid Conjugate]), consists of H. influenzae type b capsular polysaccharide (polyribosyl-ribitol-phosphate [PRP]) covalently bound to tetanus toxoid (PRP-T). The DTaP-IPV component is supplied as a sterile liquid used to reconstitute the lyophilized ActHIB component to form Pentacel. Pentacel is a uniform, cloudy, white to off-white (yellow tinge) suspension.

Each 0.5 mL dose contains 15 Lf diphtheria toxoid, 5 Lf tetanus toxoid, acellular pertussis antigens [20 mcg detoxified pertussis toxin (PT), 20 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), 5 mcg fimbriae types 2 and 3 (FIM)], inactivated polioviruses [40 D-antigen units (DU) Type 1 (Mahoney), 8 DU Type 2 (MEF-1), 32 DU Type 3 (Saukett)] and 10 mcg PRP of H. influenzae type b covalently bound to 24 mcg of tetanus toxoid (PRP-T).

Other ingredients per 0.5 mL dose include 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant, polysorbate 80 (approximately 10 ppm by calculation), 42.5 mg sucrose, <2 mcg residual formaldehyde, <50 ng residual glutaraldehyde, ≤50 ng residual bovine serum albumin, 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative), <4 pg of neomycin and <4 pg polymyxin B sulfate.

Corynebacterium diphtheriae is grown in modified Mueller’s growth medium. (7) After purification by ammonium sulfate fractionation, the diphtheria toxin is detoxified with formaldehyde and diafiltered.

Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion. (8) 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 acellular pertussis vaccine antigens are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium (9) 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 separately onto aluminum phosphate.

Poliovirus Type 1, Type 2 and Type 3 are each grown in separate cultures of MRC-5 cells, a line of normal human diploid cells, by the microcarrier method. (10) (11) The cells are grown in CMRL (Connaught Medical Research Laboratories) 1969 medium, supplemented with calf serum. For viral growth, the culture medium is replaced by Medium 199, without calf serum. After clarification and filtration, the viral suspensions are concentrated by ultrafiltration, and purified by liquid chromatography steps. The monovalent viral suspensions are inactivated with formaldehyde. Monovalent concentrates of each inactivated poliovirus are combined to produce a trivalent poliovirus concentrate.

The adsorbed diphtheria, tetanus and acellular pertussis antigens are combined with aluminum phosphate (as adjuvant), 2-phenoxyethanol (not as a preservative) and water for injection, into an intermediate concentrate. The trivalent poliovirus concentrate is added and the DTaP-IPV component is diluted to its final concentration. The DTaP-IPV component does not contain a preservative.

Both diphtheria and tetanus toxoids induce at least 2 neutralizing units per mL in the guinea pig potency test. The potency of the acellular pertussis antigens is evaluated by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA). The potency of inactivated poliovirus antigens is determined by measuring antibody-mediated neutralization of poliovirus in sera from immunized rats.

PRP, a high molecular weight polymer, is prepared from the Haemophilus influenzae type b strain 1482 grown in a semi-synthetic medium. (12) The tetanus toxoid for conjugation to PRP is prepared by ammonium sulfate purification, and formalin inactivation of the toxin from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium. (13) The toxoid is filter sterilized prior to the conjugation process. The ActHIB component does not contain a preservative. Potency of the ActHIB component is specified on each lot by limits on the content of PRP polysaccharide and protein per dose and the proportion of polysaccharide and protein that is characterized as high molecular weight conjugate.

The vial stoppers for the DTaP-IPV and ActHIB components of Pentacel are not made with natural rubber latex.

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. (14) Levels of 1.0 IU/mL have been associated with long-term protection. (15)

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. (14) (16) A tetanus antitoxoid level ≥0.1 IU/mL as measured by the ELISA used in clinical studies of Pentacel 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.

Poliomyelitis

Polioviruses, of which there are three serotypes (Types 1, 2, and 3) are enteroviruses. The presence of poliovirus type-specific neutralizing antibodies has been correlated with protection against poliomyelitis. (17)

Invasive Disease Due to H. influenzae Type b

H. influenzae type b can cause invasive disease such as meningitis and sepsis. Anti-PRP antibody has been shown to correlate with protection against invasive disease due to H. influenzae type b.

Based on data from passive antibody studies (18) and an efficacy study with H. influenzae type b polysaccharide vaccine in Finland, (19) a post-vaccination anti-PRP level of 0.15 mcg/mL has been accepted as a minimal protective level. Data from an efficacy study with H. influenzae type b polysaccharide vaccine in Finland indicate that a level >1.0 mcg/mL 3 weeks after vaccination predicts protection through a subsequent one-year period. (20) (21) These levels have been used to evaluate the effectiveness of Haemophilus b Conjugate Vaccines, including the ActHIB component of Pentacel.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14 CLINICAL STUDIES

The efficacy of Pentacel is based on the immunogenicity of the individual antigens compared to separately administered vaccines. Serological correlates of protection exist for diphtheria, tetanus, poliomyelitis, and invasive disease due to H. influenzae type b. [See Clinical Pharmacology (12.1).] The efficacy against pertussis, for which there is no well established serological correlate of protection, was based, in part, on a comparison of pertussis immune responses following Pentacel in US children to responses following DAPTACEL (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) manufactured by Sanofi Pasteur Limited) in an efficacy study conducted in Sweden (Sweden I Efficacy Trial). While Pentacel and DAPTACEL contain the same pertussis antigens, manufactured by the same process, Pentacel contains twice as much detoxified PT and four times as much FHA as DAPTACEL.

Immune responses to Pentacel were evaluated in four US studies: Studies 494-01, P3T06, 494-03, and M5A10. The vaccination schedules of Pentacel, Control vaccines, and concomitantly administered vaccines used in Studies 494-01, P3T06, and 494-03 are provided in Table 1. [See Adverse Reactions (6.1).] In Study M5A10, participants were randomized to receive Pentacel or separately administered DAPTACEL, IPOL, and ActHIB at 2, 4, and 6 months of age. 7-valent pneumococcal conjugate (PCV7, Wyeth Pharmaceuticals Inc.) at 2, 4, and 6 months of age, and Hepatitis B vaccine (Merck and Co. or GlaxoSmithKline Biologicals) at 2 and 6 months of age, were administered concomitantly with Pentacel or Control vaccines. (22)

14.1 Diphtheria

The proportions of participants achieving diphtheria antitoxin seroprotective levels one month following three and four doses of Pentacel or DAPTACEL in Study P3T06 are provided in Table 3.

14.2 Tetanus

The proportions of participants achieving tetanus antitoxoid seroprotective levels one month following three and four doses of Pentacel or DAPTACEL in Study P3T06 are provided in Table 3.

Table 3: Study P3T06 Diphtheria Antitoxin and Tetanus Antitoxoid Responses One Month Following Dose 3 and Dose 4 of Pentacel or DAPTACEL + IPOL + ActHIB in US Children Vaccinated at 2, 4, 6, and 15-16 Months of Age
Pentacel DAPTACEL + IPOL + ActHIB
Per Protocol Immunogenicity population.
*
Seroprotection rate following Pentacel vaccine is not inferior to DAPTACEL vaccine (upper limit of 90% CI of the difference DAPTACEL – Pentacel is <10%).
Non-inferiority criteria were not pre-specified.
With the ELISA used in this study, a tetanus antitoxoid level of 1.0 IU/mL is 10 times the protective level.
Post-Dose 3 N = 331-345 N = 1,037-1,099
Diphtheria Antitoxin % ≥0.01 IU/mL * % ≥0.10 IU/mL Tetanus Antitoxoid % ≥0.10 IU/mL 100.0% 98.8% 99.7% 100.0% 98.5% 100.0%
Post-Dose 4 N = 341-352 N = 328-334
Diphtheria Antitoxin % ≥0.10 IU/mL * % ≥1.0 IU/mL Tetanus Antitoxoid % ≥0.10 IU/mL * % ≥1.0 IU/mL 100.0% 96.5% 100.0% 92.9% 100.0% 95.7% 100.0% 99.4%

14.3 Pertussis

In a clinical pertussis vaccine efficacy study conducted in Sweden during 1992-1995 (Sweden I Efficacy Trial), 2,587 infants received DAPTACEL and 2,574 infants received a non-US licensed DT vaccine as placebo at 2, 4, and 6 months of age. (1) 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 of vaccine 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%, 88.6%). The protective efficacy of DAPTACEL against mild pertussis (≥1 day of cough with laboratory confirmation) was 77.9% (95% CI 72.6%, 82.2%). Protection against pertussis by DAPTACEL was sustained for the 2-year follow-up period.

Based on comparisons of the immune responses to DAPTACEL in US infants (Post-Dose 3) and Canadian children (Post-Dose 4) relative to infants who participated in the Sweden I Efficacy Trial, it was concluded that 4 doses of DAPTACEL were needed for primary immunization against pertussis in US children. (1)

In a serology bridging analysis, immune responses to FHA, PRN and FIM in a subset of infants who received three doses of DAPTACEL in the Sweden I Efficacy Trial were compared to the Post-Dose 3 and Post-Dose 4 responses in a subset of US children from Study 494-01 who received Pentacel (Table 4). Available stored sera from infants who received DAPTACEL in the Sweden I Efficacy Trial and sera from children who received PCV7 concomitantly with the first three doses of Pentacel in Study 494-01 (Table 1) were assayed in parallel. Data on levels of antibody to PT using an adequately specific assay were not available for this serology bridging analysis.

Geometric mean antibody concentrations (GMCs) and seroconversion rates for antibodies to FHA, PRN and FIM one month following Dose 3 of DAPTACEL in the subset of infants from the Sweden I Efficacy Trial and one month following Dose 3 and Dose 4 of Pentacel in a subset of infants from US Study 494-01 are presented in Table 4. Seroconversion was defined as 4-fold rise in antibody level (Post-Dose 3/Pre-Dose 1 or Post-Dose 4/Pre-Dose 1). For anti-FHA and anti-FIM, the non-inferiority criteria were met for seroconversion rates, and for anti-FHA, anti-PRN, and anti-FIM, the non-inferiority criteria were met for GMCs, following Dose 4 of Pentacel relative to Dose 3 of DAPTACEL. The non-inferiority criterion for anti-PRN seroconversion following Dose 4 of Pentacel relative to Dose 3 of DAPTACEL was not met [upper limit of 95% CI for difference in rate (DAPTACEL minus Pentacel) = 13.24%]. Whether the lower anti-PRN seroconversion rate following Dose 4 of Pentacel in US children relative to Dose 3 of DAPTACEL in Swedish infants correlates with diminished efficacy of Pentacel against pertussis is unknown.

Table 4: FHA, PRN and FIM Antibody Responses One Month Following Dose 3 of DAPTACEL in a Subset of Infants Vaccinated at 2, 4, and 6 Months of Age in the Sweden I Efficacy Trial and One Month Following Dose 3 and Dose 4 of Pentacel in a Subset of Infants Vaccinated at 2, 4, 6, and 15-16 Months of Age in US Study 494-01
Post-Dose 3 DAPTACEL Sweden I Efficacy Trial N = 80 Post-Dose 3 Pentacel * US Study 494-01 N = 730-995 Post-Dose 4 Pentacel US Study 494-01 N = 507-554
Analyzed sera were from subsets of the Per Protocol Immunogenicity populations in each study. Data on anti-PT levels using an adequately specific assay were not available.
*
Non-inferiority criteria were not pre-specified for the comparisons of immune responses to Pentacel vaccine Post-Dose 3 vs. DAPTACEL vaccine Post-Dose 3.
Pre-specified non-inferiority analyses compared immune responses to Pentacel vaccine Post-Dose 4 vs. DAPTACEL vaccine Post-Dose 3.
Fold rise was calculated as Post-Dose 3/Pre-Dose 1 antibody level or Post-Dose 4/Pre-Dose 1 antibody level.
§
Percent achieving 4-fold rise or GMC Post-Dose 4 Pentacel vaccine is not inferior to Post-Dose 3 DAPTACEL vaccine [upper limit of 95% CI for difference in rates (DAPTACEL minus Pentacel) <10% and upper limit of 90% CI for GMC ratio (DAPTACEL/Pentacel) <1.5].
Non-inferiority criterion is not met for percent achieving 4-fold rise in anti-PRN Post-Dose 4 Pentacel vaccine relative to Post-Dose 3 DAPTACEL vaccine [upper limit of 95% CI for difference in rates (DAPTACEL minus Pentacel) = 13.24%, exceeds the non-inferiority criterion of <10%].
Anti-FHA % achieving 4-fold rise GMC (EU/mL) 68.8 40.70 79.8 71.46 91.7§ 129.85§
Anti-PRN % achieving 4-fold rise GMC (EU/mL) 98.8 111.26 74.4 38.11 89.2 90.82§
Anti-FIM % achieving 4-fold rise GMC (EU/mL) 86.3 339.31 86.5 265.02 91.5§ 506.57§

In a separate study, Study P3T06, US infants were randomized to receive either Pentacel or DAPTACEL + IPOL + ActHIB at 2, 4, 6, and 15-16 months of age (Table 1). The pertussis immune responses (GMCs and seroconversion rates) one month following the third and fourth doses were compared between the two groups (Table 5). Seroconversion was defined as a 4-fold rise in antibody level (Post-Dose 3/Pre-Dose 1 or Post-Dose 4/Pre-Dose 1). Data on anti-PT responses obtained from an adequately specific assay were available on only a non-random subset of study participants. The subset of study participants was representative of all study participants with regard to Pre-Dose 1, Post-Dose 3 and Post-Dose 4 GMCs of antibodies to FHA, PRN and FIM. For each of the pertussis antigens, non-inferiority criteria were met for seroconversion rates and GMCs following Dose 3 of Pentacel relative to Dose 3 of DAPTACEL. Following Dose 4 of Pentacel relative to Dose 4 of DAPTACEL, non-inferiority criteria were met for all comparisons except for anti-PRN GMCs [upper limit of 90% CI for ratio of GMCs (DAPTACEL/Pentacel) = 2.25]. Whether the lower anti-PRN GMC following Dose 4 of Pentacel relative to Dose 4 of DAPTACEL in US children correlates with diminished efficacy of Pentacel against pertussis is unknown.

Table 5: Pertussis Antibody Responses One Month Following Doses 3 and 4 of Pentacel or DAPTACEL + IPOL + ActHIB in US Infants Vaccinated at 2, 4, 6, and 15-16 Months of Age in Study P3T06
Per Protocol Immunogenicity population for anti-FHA, anti-PRN, and anti-FIM. Non-random subset of per Protocol Immunogenicity population for anti-PT. See text for further information on the subset evaluated.
*
Fold rise was calculated as Post-Dose 3/Pre-Dose 1 antibody level or Post-Dose 4/Pre-Dose 1 antibody level.
Percent achieving 4-fold rise or GMC Post-Dose 3 Pentacel vaccine not inferior to Post-Dose 3 DAPTACEL vaccine [upper limit of 95% CI for GMC ratio (DAPTACEL/Pentacel) <1.5 and upper limit of 95% CI for differences in rates (DAPTACEL minus Pentacel) <10%].
Percent achieving 4-fold rise or GMC Post-Dose 4 Pentacel vaccine not inferior to Post-Dose 4 DAPTACEL vaccine [upper limit of 95% CI for GMC ratio (DAPTACEL/Pentacel) <1.5 and upper limit of 95% CI for differences in rates (DAPTACEL minus Pentacel) <10%].
§
Percent achieving 4-fold rise or GMC Post-Dose 3 Pentacel vaccine not inferior to Post-Dose 3 DAPTACEL vaccine [upper limit of 90% CI for GMC ratio (DAPTACEL/Pentacel) <1.5 and upper limit of 90% CI for differences in rates (DAPTACEL minus Pentacel) <10%].
Percent achieving 4-fold rise or GMC Post-Dose 4 Pentacel vaccine not inferior to Post-Dose 4 DAPTACEL vaccine [upper limit of 90% CI for GMC ratio (DAPTACEL/Pentacel) <1.5 and upper limit of 90% CI for differences in rates (DAPTACEL minus Pentacel) <10%].
#
Non-inferiority criterion is not met for GMC Post-Dose 4 Pentacel vaccine relative to Post-Dose 4 DAPTACEL vaccine [upper limit of 90% CI for GMC ratio (DAPTACEL/Pentacel) = 2.25, which exceeds the non-inferiority criterion of <1.5].
Post-Dose 3PentacelN = 143 Post-Dose 3DAPTACEL + IPOL + ActHIBN = 481-485 Post-Dose 4PentacelN = 113 Post-Dose 4DAPTACEL + ActHIBN = 127-128
Anti-PT% achieving 4-fold rise * 95.8 87.3 93.8 91.3
Anti-PTGMC (EU/mL) 102.62 61.88 107.89 100.29
Post-Dose 3PentacelN = 218-318 Post-Dose 3DAPTACEL + IPOL + ActHIBN = 714-1,016 Post-Dose 4PentacelN = 230-367 Post-Dose 4DAPTACEL + ActHIBN = 237-347
Anti-FHA% achieving 4-fold rise * 81.9§ 60.9 88.4 79.3
Anti-FHAGMC (EU/mL) 73.68§ 29.22 107.89 64.02
Anti-PRN% achieving 4-fold rise * 74.2§ 75.4 92.7 98.3
Anti-PRNGMC (EU/mL) 36.05§ 43.25 93.59# 186.07
Anti-FIM% achieving 4-fold rise * 91.7§ 86.3 93.5 91.6
Anti-FIMGMC (EU/mL) 268.15§ 267.18 553.39 513.54

Study 006 was a study conducted in the US, where infants were randomized to receive 3 doses of VAXELIS at 2, 4, and 6 months of age and Pentacel at 15 months of age (N = 2,406), or control group vaccines (4 doses of Pentacel at 2, 4, 6, and 15 months of age + RECOMBIVAX HB [Hepatitis B Vaccine (Recombinant)] at 2 and 6 months of age; N = 402). All subjects received concomitant Prevnar 13 (Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein]) at 2, 4, 6, and 15 months of age.

Participants were evaluated for immune responses to pertussis antigens one month following the dose of Pentacel administered at 15 months of age. The non-inferiority criteria for antibody vaccine response rates and GMCs for all pertussis antigens were met following the fourth dose except for GMCs for PRN (lower bound of 2-sided 95% CI for GMC ratio [VAXELIS group/Control group vaccines] was 0.66, which was below the non-inferiority criterion >0.67). (22)

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