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Pentacel

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Pentacel

CLINICAL PHARMACOLOGY

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

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.13,15 A tetanus antitoxoid level ≥ 0.1 IU/mL as measured by the ELISA used in clinical studies of Pentacel vaccine is considered protective.

Pertussis

Pertussis (whooping cough) is a respiratory disease caused by Bpertussis. 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.16

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 studies17 and an efficacy study with H influenzae type b polysaccharide vaccine in Finland,18 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.19,20 These levels have been used to evaluate the effectiveness of Haemophilus b Conjugate Vaccines, including the ActHIB vaccine component of Pentacel vaccine.

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Clinical Studies

The efficacy of Pentacel vaccine 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] 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 vaccine in US children to responses following DAPTACEL vaccine (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 vaccines contain the same pertussis antigens, manufactured by the same process, Pentacel vaccine contains twice as much detoxified PT and four times as much FHA as DAPTACEL vaccine.

Immune responses to Pentacel vaccine were evaluated in four US studies: Studies 494-01, P3T06, 494-03, and M5A10. The vaccination schedules of Pentacel vaccine, Control vaccines, and concomitantly administered vaccines used in Studies 494-01, P3T06, and 494-03 are provided in Table 1. [See ADVERSE REACTIONS] In Study M5A10, participants were randomized to receive Pentacel vaccine or separately administered DAPTACEL, IPOL, and ActHIB vaccines at 2, 4, and 6 months of age. 7-valent pneumococcal conjugate vaccine (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 vaccine or Control vaccines.

Diphtheria

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

Tetanus

The proportions of participants achieving tetanus antitoxoid seroprotective levels one month following three and four doses of Pentacel vaccine or DAPTACEL vaccine 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 Vaccine or DAPTACEL + IPOL + ActHIB Vaccines in US Children Vaccinated at 2, 4, 6, and 15-16 Months of Age

Post-Dose 3 Pentacel Vaccine DAPTACEL + IPOL + ActHIB Vaccines
N = 331-345 N = 1,037-1,099
Diphtheria Antitoxin
% ≥ 0.01 IU/mL * 100.0% 100.0%
% ≥ 0.10 IU/mL† 98.8% 98.5%
Tetanus Antitoxoid
% ≥ 0.10 IU/mL† 99.7% 100.0%
Post-Dose 4 N = 341-352 N = 328-334
Diphtheria Antitoxin
% ≥ 0.10 IU/mL* 100.0% 100.0%
% ≥ 1.0 IU/mL † 96.5% 95.7%
Tetanus Antitoxoid
% ≥ 0.10 IU/mL* 100.0% 100.0%
% ≥ 1.0 IU/mL †† 92.9% 99.4%
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.

Pertussis

In a clinical pertussis vaccine efficacy study conducted in Sweden during 1992-1995 (Sweden I Efficacy Trial), 2,587 infants received DAPTACEL vaccine 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 vaccine 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 vaccine against mild pertussis ( ≥ 1 day of cough with laboratory confirmation) was 77.9% (95% CI 72.6%, 82.2%). Protection against pertussis by DAPTACEL vaccine was sustained for the 2-year follow-up period.

Based on comparisons of the immune responses to DAPTACEL vaccine 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 vaccine 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 vaccine 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 vaccine (Table 4). Available stored sera from infants who received DAPTACEL vaccine in the Sweden I Efficacy Trial and sera from children who received PCV7 concomitantly with the first three doses of Pentacel vaccine 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 vaccine in the subset of infants from the Sweden I Efficacy Trial and one month following Dose 3 and Dose 4 of Pentacel vaccine 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 antiFHA, anti-PRN, and anti-FIM, the non-inferiority criteria were met for GMCs, following Dose 4 of Pentacel vaccine relative to Dose 3 of DAPTACEL vaccine. The non-inferiority criterion for anti-PRN seroconversion following Dose 4 of Pentacel vaccine relative to Dose 3 of DAPTACEL vaccine 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 vaccine in US children relative to Dose 3 of DAPTACEL vaccine in Swedish infants correlates with diminished efficacy of Pentacel vaccine against pertussis is unknown.

Table 4: FHA, PRN and FIM Antibody Responses One Month Following Dose 3 of DAPTACEL Vaccine 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 Vaccine 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 Vaccine Sweden I Efficacy Trial
N = 80
Post-Dose 3
Pentacel Vaccine*
US Study 494-01
N = 730-995
Post-Dose 4
Pentacel Vaccine† US Study 494-01
N = 507-554
Anti-FHA % achieving 4-fold riset GMC (EU/mL) 68.8 79.8 91.7§
Anti-PRN % achieving 4-fold riset GMC (EU/mL) 40.70 71.46 129.85§
98.8 74.4 89.2**
111.26 38.11 90.82§
Anti-FIM % achieving 4-fold riset GMC (EU/mL) 86.3 86.5 91.5§
339.31 265.02 506.57§
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%].

In a separate study, Study P3T06, US infants were randomized to receive either Pentacel vaccine or DAPTACEL + IPOL + ActHIB vaccines 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 vaccine 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 vaccine relative to Dose 3 of DAPTACEL vaccine. Following Dose 4 of Pentacel vaccine relative to Dose 4 of DAPTACEL vaccine, 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 vaccine relative to Dose 4 of DAPTACEL vaccine in US children correlates with diminished efficacy of Pentacel vaccine against pertussis is unknown.

Table 5: Pertussis Antibody Responses One Month Following Doses 3 and 4 of Pentacel Vaccine or DAPTACEL + IPOL + ActHIB Vaccines in US Infants Vaccinated at 2, 4, 6, and 15-16 Months of Age in Study P3T06

  Post-Dose 3 Pentacel Vaccine Post-Dose 3 DAPTACEL +IPOL + Act HIB Vaccines Post-Dose 4 Pentacel Vaccine Post-Dose 4 DAPTACEL + ActHIB Vaccines
N = 143 N = 481-485 N = 113 N = 127-128
Anti-PT % achieving 4-fold rise* GMC (EU/mL) 95.8† 87.3 93.8‡ 91.3
102.62† 61.88 107.89‡ 100.29
  N = 218-318 N = 714-1,016 N = 230-367 N = 237-347
Anti-FHA % achieving 4-fold rise* GMC (EU/mL) 81.9§ 60.9 88.4** 79.3
73.68§ 29.22 107.94** 64.02
Anti-PRN % achieving 4-fold rise* GMC (EU/mL) 74.2§ 75.4 92.7** 98.3
36.05§ 43.25 93.59tt 186.07
Anti-FIM % achieving 4-fold rise* GMC (EU/mL) 91.7§ 86.3 93.5** 91.6
268.15§ 267.18 553.39** 513.54
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].

Poliomyelitis

In Study P3T06 (Table 1), in which infants were randomized to receive the first three doses of Pentacel vaccine or DAPTACEL + IPOL + ActHIB vaccines at 2, 4, and 6 months of age, one month following the third dose of study vaccines, ≥ 99.4% of participants in both groups (Pentacel: N = 338-350), (DAPTACEL + IPOL + ActHIB: N = 1,050-1,097) achieved neutralizing antibody levels of ≥ 1:8 for Poliovirus types 1, 2, and 3.

In Study 494-01 (Table 1), in which infants were randomized to receive Pentacel vaccine or HCPDT + POLIOVAX + ActHIB vaccines, GMTs (1/dil) of antibodies to Poliovirus types 1, 2, and 3 one month following Dose 4 of Pentacel vaccine (N = 851-857) were 2,304, 4,178, and 4,415, respectively, and one month following Dose 4 of POLIOVAX vaccine (N = 284-287) were 2,330, 2,840, and 3,300, respectively.

Invasive Disease Due To H influenzae Type b

Anti-PRP seroprotection rates and GMCs one month following Dose 3 of Pentacel vaccine or separately administered ActHIB vaccine in studies 494-01, P3T06, and M5A10 are presented in Table 6. In Study 494-01, non-inferiority criteria were not met for the proportion of participants who achieved an anti-PRP level ≥ 1.0 mcg/mL and for anti-PRP GMCs following Pentacel vaccine compared with separately administered ActHIB vaccine. In each of Studies P3T06 and M5A10, the non-inferiority criterion was met for the proportion of participants who achieved an anti-PRP level ≥ 1.0 mcg/mL following Pentacel vaccine compared with separately administered ActHIB vaccine. In Study M5A10, the non-inferiority criterion was met for anti-PRP GMCs following Pentacel vaccine compared with separately administered ActHIB vaccine.

Table 6: Anti-PRP Seroprotection Rates and GMCs One Month Following Three Doses of Pentacel Vaccine or Separate DTaP + IPV + ActHIB Vaccines Administered at 2, 4, and 6 Months of Age in Studies 494-01, P3T06, and M5A10

  Study 494-01
Pentacel Vaccine
N = 1,127
HCPDT + POLIOVAX + ActHIB Vaccines
N = 401
% achieving anti-PRP ≥ 0.15 mcg/mL 95.4* 98.3
% achieving anti-PRP ≥ 1.0 mcg/mL 79.1† 88.8
Anti-PRP GMC (mcg/mL) 3.19‡ 6.23
  Study P3T06
Pentacel Vaccine
N = 365
DAPTACEL + IPOL +ActHIB Vaccines
N = 1,128
% achieving anti-PRP ≥ 0.15 mcg/mL 92.3* 93.3
% achieving anti-PRP ≥ 1.0 mcg/mL 72.1* 70.8
Anti-PRP GMC (mcg/mL) 2.31 § 2.29
  Study M5A10
  Pentacel Vaccine
N = 826
DAPTACEL + IPOL +ActHIB Vaccines
N = 421
% achieving anti-PRP ≥ 0.15 mcg/mL 93.8** 90.3
% achieving anti-PRP ≥ 1.0 mcg/mL 75.1** 74.8
Anti-PRP GMC (mcg/mL) 2.52†† 2.38
Per Protocol Immunogenicity population for all studies.
IPV indicates Poliovirus Vaccine Inactivated.
* Percent achieving specified level following Pentacel vaccine not inferior to ActHIB vaccine [upper limit of 90% CI for difference in rates (ActHIB minus Pentacel) < 10%].
† Non-inferiority criterion not met for percent achieving anti-PRP ≥ 1.0 mcg/mL following Pentacel vaccine relative to ActHIB vaccine [upper limit of 90% CI for difference in rates (ActHIB minus Pentacel), 12.9%, exceeds the non-inferiority criterion < 10%].
‡ Non-inferiority criterion not met for GMC following Pentacel vaccine relative to ActHIB vaccine [upper limit of 90% CI of GMC ratio (ActHIB/Pentacel), 2.26, exceeds the non-inferiority criterion < 1.5].
§ Non-inferiority criterion not pre-specified.
** Percent achieving specified level following Pentacel vaccine not inferior to ActHIB vaccine [upper limit of 95% CI for difference in rates (ActHIB minus Pentacel) < 10%].
††GMC following Pentacel vaccine not inferior to ActHIB vaccine [upper limit of 90% CI of GMC ratio (ActHIB/Pentacel) < 1.5].

In Study 494-01, at 15 months of age prior to receipt of Dose 4 of study vaccines, 68.6% of Pentacel vaccine recipients (N = 829) and 80.8% of separately administered ActHIB vaccine recipients (N = 276) had an anti-PRP level ≥ 0.15 mcg/mL. Following Dose 4 of study vaccines, 98.2% of Pentacel vaccine recipients (N = 874) and 99.0% of separately administered ActHIB vaccine recipients (N = 291) had an anti-PRP level ≥ 1.0 mcg/mL.

In Study P3T06, at 15 months of age prior to receipt of Dose 4 of study vaccines, 65.4% of Pentacel vaccine recipients (N = 335) and 60.7% of separately administered ActHIB vaccine recipients (N = 323) had an anti-PRP level ≥ 0.15 mcg/mL. Following Dose 4 of study vaccines, 97.8% of Pentacel vaccine recipients (N = 361) and 95.9% of separately administered ActHIB vaccine recipients (N = 340) had an anti-PRP level ≥ 1.0 mcg/mL.

Concomitantly Administered Vaccines

In Study P3T06, (Table 1) there was no evidence for reduced antibody responses to hepatitis B vaccine (percent of participants with anti-HBsAg ≥ 10 mlU/mL and GMCs) or PCV7 (percent of participants with antibody levels ≥ 0.15 mcg/mL and ≥ 0.5 mcg/mL and GMCs to each serotype) administered concomitantly with Pentacel vaccine (N = 321-325) relative to these vaccines administered concomitantly with DAPTACEL + IPOL + ActHIB vaccines (N = 998-1,029). The immune responses to hepatitis B vaccine and PCV7 were evaluated one month following the third dose.

In Study 494-03, (Table 1) there was no evidence for interference in the immune response to the fourth dose of PCV7 (percent of participants with antibody levels ≥ 0.15 mcg/mL and ≥ 0.5 mcg/mL and GMCs to each serotype) administered at 15 months of age concomitantly with Pentacel vaccine (N = 155) relative to this vaccine administered concomitantly with MMR and varicella vaccines (N = 158). There was no evidence for interference in the immune response to MMR and varicella vaccines (percent of participants with pre-specified seroresponse level) administered at 15 months of age concomitantly with Pentacel vaccine (N = 154) relative to these vaccines administered concomitantly with PCV7 (N = 144). The immune responses to MMR, varicella vaccine and the fourth dose of PCV7 were evaluated one month post-vaccination.

REFERENCES

1 DAPTACEL® [full prescribing information]. Toronto, ON: Sanofi Pasteur; 2011.

13 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.

14 Vitek CR, Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia, PA: W. B. Saunders; 2008. p. 139-56.

15 Wassilak SGF, et al. Tetanus toxoid. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia, PA: W.B. Saunders; 2008. p. 805-39.

16 Sutter RW, et al. Defining surrogate serologic tests with respect to predicting protective vaccine efficacy: Poliovirus vaccination. In: Williams JC, et al. eds. Combined vaccines and simultaneous administration. Current issues and perspectives. New York, NY: The New York Academy of Sciences. 1995:289-99.

17 Robbins JB, et al. Quantitative measurement of “natural” and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res 1973;7:103-10.

18 Peltola H, et al. Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics 1977;60:730-7.

19 Kayhty H, et al. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1983; 147:1100.

20 Anderson P. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1984;149:1034.

Last reviewed on RxList: 8/18/2014
This monograph has been modified to include the generic and brand name in many instances.

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