Gardasil 9

Gardasil 9

vaccine, human papillomavirus 9-valent

Manufacturer:

Merck Sharp & Dohme

Distributor:

Zuellig
Full Prescribing Info
Contents
Human papillomavirus 9-valent (types 6, 11, 16, 18, 31, 33, 45, 52, 58) recombinant.
Description
Chemistry: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9), is a non-infectious recombinant 9-valent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The L1 proteins are produced by separate fermentations using recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on pre-formed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate Sulfate or AAHS). The 9-valent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant formulation and the final purification buffer.
Composition: Active Ingredients: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is a sterile preparation for intramuscular administration.
Each 0.5 mL dose contains human papillomavirus L1 protein of each type adsorbed on amorphous aluminum hydroxyphosphate sulfate adjuvant as follows: Type 6 (30 mcg), Type 11 (40 mcg), Type 16 (60 mcg), Type 18 (40 mcg), Type 31 (20 mcg), Type 33 (20 mcg), Type 45 (20 mcg), Type 52 (20 mcg), Type 58 (20 mcg).
Vaccine is prepared from fermentation cultures of a recombinant strain of yeast Saccharomyces cerevisiae containing the genes for the human papillomavirus L1 protein of each type (6, 11, 16, 18, 31, 33, 45, 52, 58).
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is available as a 0.5 mL single-dose prefilled syringe. A one-inch 23 gauge and one-inch 25 gauge sterile needles are provided separately in the package.
Inactive Ingredients (List of excipients): Each 0.5-mL dose of the vaccine contains approximately 500 mcg of aluminum (as Amorphous Aluminum Hydroxyphosphate Sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, and water for injection. The product does not contain a preservative or antibiotics.
Prior to agitation, HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) may appear as a clear liquid with a white precipitate. After thorough agitation, HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is a white, cloudy liquid.
Action
Therapeutic Class: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is a recombinant vaccine that protects against 9 genotypes of Human Papillomavirus (HPV).
Pharmacology: Pharmacodynamics: Mechanism of Action: HPV only infects human beings. Animal studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines may involve the development of humoral immune responses. Human beings develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown.
Clinical Studies: Disease Burden: HPV infection is very common; in the absence of vaccination, the majority of sexually active individuals will become infected with HPV during their lifetime.
Most HPV infections clear without sequelae but some progress to HPV-related diseases including cervical cancers and their precursors (Cervical Intraepithelial Neoplasia or CIN grades 1, 2, and 3), anal, vulvar, vaginal, and penile cancers and their precursors (Anal Intraepithelial Neoplasia or AIN, Vulvar Intraepithelial Neoplasia or VIN, Vaginal Intraepithelial Neoplasia or VaIN and Penile Intraepithelial Neoplasia or PIN), genital warts, and lesions in the aerodigestive tract including oropharyngeal cancers and recurrent respiratory papillomatosis.
Worldwide, over 530,000 cases of cervical cancer are diagnosed annually. Cervical cancer prevention focuses on repeat screening (e.g., Papanicolaou's [Pap] testing and/or Human Papillomavirus [HPV] testing) and early intervention. This strategy has reduced cancer rates by approximately 75% in the developed world but has shifted the burden from managing cervical cancer to monitoring and treating a large number of premalignant lesions.
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is a recombinant vaccine with L1 proteins resembling 9 HPV types. Because the L1 proteins contain no viral DNA, they cannot infect cells or reproduce. HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) contains the 4 HPV types (6, 11, 16, and 18) that are in GARDASIL plus an additional 5 HPV types (31, 33, 45, 52, and 58) adsorbed on amorphous aluminum hydroxyphosphate adjuvant (AAHS). The attribution of the 9 HPV types in HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) to HPV-related disease worldwide is presented in Table 1.

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Clinical Studies: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) includes the same four HPV types contained in GARDASIL (HPV 6, 11, 16, 18) and five additional HPV types (31, 33, 45, 52, and 58).
Efficacy Data for GARDASIL: GARDASIL was first licensed in 2006. Efficacy was assessed in 6 AAHS-controlled, double-blind, randomized Phase II and III clinical studies evaluating 28,413 individuals (20,541 girls and women 16 through 26 years of age, 4,055 boys and men 16 through 26 years of age, 3,817 women 24 through 45 years of age). The efficacy and long-term effectiveness of GARDASIL against HPV 6-, 11-, 16-, and 18-related disease endpoints have been demonstrated in clinical studies in the PPE (Per Protocol Efficacy) population. The PPE population consisted of individuals who received all 3 vaccinations with GARDASIL in the base study within 1 year of enrollment without major deviations from the study protocol, were seronegative to the relevant HPV type(s) (types 6, 11, 16 and 18) prior to dose 1, and among subjects 16 years and older at enrollment in the base study, PCR negative to the relevant HPV type(s) prior to dose 1 through one month postdose 3 (Month 7).
GARDASIL was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN 2/3; and VaIN 2/3 related to vaccine HPV types 6, 11, 16, or 18 in girls and women in the PPE population (see table 2). In addition, girls and women who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from precancerous cervical lesions and external genital lesions caused by the other vaccine HPV types. Individuals who had prior infection that had been resolved before vaccination (PCR negative and seropositive at baseline) were protected from reinfection or recurrence of infection leading to clinical disease with the same HPV type. GARDASIL was efficacious in reducing the incidence of genital warts related to vaccine HPV types 6 and 11 in boys and men in the PPE population. Efficacy against penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer was not demonstrated as the number of cases was too limited to reach statistical significance (Table 6). GARDASIL was efficacious in reducing the incidence of anal intraepithelial neoplasia (AIN) grades 1 (both condyloma and non-acuminate), 2, and 3 related to vaccine HPV types 6, 11, 16, and 18 in boys and men in the PPE population (see Table 2).

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A minimum anti-HPV level that provides protection against HPV infection and disease has not been defined. Also, immune responses to vaccines are typically lower in older individuals compared to younger individuals. Therefore, to confirm the utility of GARDASIL to prevent cervical, vulvar, and vaginal cancers and related diseases caused by the types targeted by the vaccine in individuals up to and including age 45 years, an efficacy study was conducted.
GARDASIL was highly efficacious in reducing the incidence of persistent infection; CIN (any grade); and external genital lesions (EGL) caused by HPV types 6, 11, 16, and 18. GARDASIL was also highly efficacious in reducing the incidence of a HPV 16/18-related Pap Test diagnosis of ASC-US (Atypical Squamous Cells of Undetermined Significance) positive for high-risk HPV. The primary analyses of efficacy, with respect to HPV types 6, 11, 16, and 18, were conducted in the per-protocol efficacy (PPE) population. Efficacy was measured starting after the Month 7 visit.
On the basis of these efficacy findings, the efficacy of GARDASIL with respect to prevention of cervical, vulvar, and vaginal cancers and related diseases in individuals up to and including age 45 years can be inferred. (See Table 3.)

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Long-term follow-up studies: A subset of subjects is currently being followed up for 10 to 14 years after GARDASIL vaccination for safety, immunogenicity and protection against clinical diseases related to HPV types 6/11/16/18.
Currently, persistence of antibody response has been observed for 8 years in adolescents who were 9 through 15 years of age at time of vaccination; 9 years in girls and women, 16 through 23 years of age at time of vaccination; 6 years in boys and men, 16 through 26 years of age at time of vaccination, and women, 24 through 45 years of age at time of vaccination.
Clinical protection has been observed in all subjects (including those who were seronegative for anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18): no cases of HPV diseases were observed after a follow-up of approximately 6.9 years in girls who were 9 through 15 years of age at time of vaccination; 6.5 years in boys, 9 through 15 years of age at time of vaccination; 8 years in girls and women, 16 through 23 years of age at time of vaccination; 6 years in boys and men, 16 through 26 years of age at time of vaccination, and women, 24 through 45 years of age at time of vaccination.
Clinical Trials for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9): Efficacy and/or immunogenicity of the three dose regimen of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) were assessed in seven clinical studies. Clinical studies evaluating the efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) against placebo were not acceptable because HPV vaccination represents the standard of care for protection against HPV infection and disease in many countries. Therefore, the pivotal clinical study (Protocol 001) evaluated the efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) to prevent HPV-related cervical, vulvar, and vaginal disease using GARDASIL as a comparator.
Efficacy against HPV Types 6, 11, 16, and 18 was primarily assessed using a bridging strategy that demonstrates comparable immunogenicity (as measured by Geometric Mean Titers [GMT]) of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) compared with GARDASIL (Protocols 001, 002, and 009).
The analysis of efficacy for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) was evaluated in the PPE population of 16- through 26-year-old girls and women, who were naïve to the relevant HPV type(s) prior to dose one and through 1 month Postdose 3 (Month 7). Overall, approximately 52% of subjects were negative to all vaccine HPV types by both PCR and serology at Day 1.
The primary analysis of efficacy against HPV Types 31, 33, 45, 52, and 58 is based on a combined endpoint of Cervical Intraepithelial Neoplasia (CIN) 2, CIN 3, Adenocarcinoma in situ (AIS), invasive cervical carcinoma, Vulvar Intraepithelial Neoplasia (VIN) 2/3, Vaginal Intraepithelial Neoplasia (VaIN) 2/3, vulvar cancer, or vaginal cancer. Other endpoints evaluated include cervical, vulvar and vaginal disease of any grade; persistent infection; cytological abnormalities and invasive procedures. For all endpoints, the efficacy against the HPV Types in HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) was evaluated compared to GARDASIL.
The efficacy is further extended to 9- through 15-year-old adolescents and to 16- through 26-year-old boys and men, for all endpoints studied, using immunological bridging. The immunogenicity bridging analyses were performed in the per-protocol immunogenicity (PPI) population consisting of individuals who received all 3 vaccinations within pre-defined day ranges, met pre-defined criteria for the interval between the Month 6 and Month 7 visit, did not have major deviations from the study protocol, and were naive [PCR negative (in girls and women 16 through 26 years of age; Protocols 001 and 002) and seronegative (Protocols 001, 002, 003, 005, 007 and 009)] to the relevant HPV type(s) prior to dose 1 and through Month 7.
Protocol 001 evaluated efficacy and immunogenicity of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) to prevent infection and disease caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in 16- through 26-year-old girls and women (N = 14,204: 7,099 receiving HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9); 7,105 receiving GARDASIL). Two immunological bridging studies evaluated HPV types 6, 11, 16 and 18 (Protocols 002 and 009) and HPV types 31, 33, 45, 52, and 58 (Protocol 002). Protocol 002 evaluated immunogenicity of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in girls and boys 9 through 15 years of age and women 16 through 26 years of age [N=3,066: 1,932 girls; 666 boys; and 468 women receiving HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9)]. Protocol 009 evaluated immunogenicity in girls 9 through 15 years of age [N=600; 300 receiving HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and 300 receiving GARDASIL]. Protocol 003 evaluated immunogenicity of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in boys and men 16 through 26 years of age and in girls and women 16 through 26 years of age [1,103 Heterosexual Men [HM]; 313 Men Who Have Sex with Men [MSM]; and 1,099 women receiving HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9)]. Protocol 006 evaluated administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) to girls and women 12 through 26 years of age previously vaccinated with GARDASIL (N=921; 615 receiving HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and 306 receiving placebo). Protocols 005 and 007 evaluated HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) concomitantly administered with vaccines recommended routinely in girls and boys 11 through 15 years of age (N=2,295). Together, these seven studies evaluated 15,875 individuals who received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) (9,152 girls and women 16 through 26 years of age at enrollment with a mean age of 21.7 years; 3,498 girls 9 through 15 years of age at enrollment with a mean age of 12.0 years; 1,416 boys and men 16 through 26 years of age at enrollment with a mean age of 21.1 years; and 1,809 boys 9 through 15 years of age at enrollment with a mean age of 12.1 years.
One clinical trial (Protocol 010) assessed the two dose regimen of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9). Protocol 010 evaluated the immunogenicity of 2 doses of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in girls and boys 9 through 14 years of age and 3 doses of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in girls 9 through 14 years of age and women 16 through 26 years of age; (N=1,518; 753 girls; 451 boys and 314 women). The mean age for the girls and boys 9 through 14 years of age was 11.5 years; the mean age for girls and women 16 through 26 years of age was 21.0 years.
The totality of results from the clinical studies support that HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) was efficacious against HPV disease and persistent infection caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. Therefore the efficacy for cervical, vulvar, vaginal, and anal diseases, genital warts and persistent infection that was demonstrated in the original clinical studies for GARDASIL can be extended to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9). In clinical studies, protective efficacy has been shown to last up to 5.6 years postdose 3 in duration for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
The decision to vaccinate an individual should take into account the risk for previous HPV exposure and potential benefit from vaccination.
Comparison of Immune Responses Between HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and GARDASIL for HPV Types 6, 11, 16, and 18 in the Clinical Studies for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9): Studies Supporting the Efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) Against HPV Types 6, 11, 16, 18: Because of the high efficacy of GARDASIL, there is no known immune correlate of protection. The minimal anti-HPV response associated with protection against HPV 6-, 11-, 16-, and 18-related infection and disease has not been established. In addition, the existence of HPV Types 6, 11, 16, and 18 antigens in both the formulations for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and the active comparator vaccine (GARDASIL) should result in no or few infection and disease endpoints associated with these HPV types. A low number of efficacy endpoints in both vaccination groups preclude a direct measurement of efficacy using disease endpoints associated with these HPV types.
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) efficacy against HPV 6-, 11-, 16-, and 18-related infection and disease was inferred from comparative studies to the quadrivalent HPV (Types 6, 11, 16, 18) vaccine, GARDASIL, in which HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) elicited immune responses as measured by GMT. These studies were designed to evaluate immunologic non-inferiority of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) to GARDASIL. Therefore, the efficacy findings from the pivotal clinical studies for GARDASIL against HPV Type 6-, 11-, 16-, and 18-related disease were extended to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) by demonstrating that the immune responses elicited by HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) were non-inferior to the immune responses elicited by GARDASIL.
Comparison of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) with GARDASIL immunogenicity with respect to HPV types 6, 11, 16, and 18 were conducted in a population of 16- through 26-year-old women from Protocol 001 and 9- through 15-year-old girls from Protocol 009. The primary analyses were conducted in the per-protocol immunogenicity population which included subjects who received all 3 vaccinations within pre-defined day ranges, met pre-defined criteria for the interval between the Month 6 and Month 7 visit, did not have major deviations from the study protocol, and were naïve [PCR negative (in girls and women 16 through 26 years of age; Protocol 001) and seronegative (Protocols 001 and 009) prior to dose one] to the relevant HPV type(s) and who remained PCR-negative (in girls and women 16 through 26 years of age; Protocol 001) to the relevant HPV type(s) through Month 7.
A statistical analysis of non-inferiority was performed based on Month 7 cLIA anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs between individuals administered HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and individuals administered GARDASIL. Immune responses, measured by GMT, for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) were non-inferior to immune responses for GARDASIL (Table 4). Therefore, efficacy for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) against persistent infection and disease related to HPV Types 6, 11, 16, or 18 can be inferred to be comparable to that of GARDASIL. See Table 4.

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Prophylactic Efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) for HPV Types 31, 33, 45, 52, and 58 in Girls and Women 16 through 26 Years of Age: Studies Supporting Efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) Against HPV Types 31, 33, 45, 52, and 58: The efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in 16- through 26- year-old women was assessed in an active comparator-controlled, double-blind, randomized clinical study (Protocol 001) that included a total of 14,204 women [HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) = 7,099; GARDASIL = 7,105], who were enrolled and vaccinated without pre-screening for the presence of HPV infection. Subjects were followed up to 67 months postdose 3, with a median duration of 43 months.
The primary efficacy is based on evaluation of a composite clinical endpoint of HPV 31-, 33-, 45-, 52-, and 58-related cervical cancer, vulvar cancer, vaginal cancer, CIN 2/3 or AIS, VIN 2/3, and VaIN 2/3. The efficacy is further supported by evaluation of HPV 31-, 33-, 45-, 52-, and 58-related cervical, vulvar, and vaginal disease of any grade, and persistent infection. In addition, the study also evaluated the impact of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) on the rates of HPV 31-, 33-, 45-, 52-, and 58-related abnormal Pap tests, cervical and external genital procedures (i.e., biopsies) and cervical definitive therapy procedures.
Efficacy was evaluated in the PPE population of 16- through 26-year-old women, who were naïve to the relevant HPV type(s) prior to dose one and through Month 7. Efficacy was measured starting after the Month 7 visit. HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) was efficacious in preventing HPV 31-, 33-, 45-, 52-, and 58-related persistent infection and disease (Table 5). HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) also reduced the incidence of HPV 31-, 33-, 45-, 52-, and 58-related Pap test abnormalities, cervical procedures (i.e., biopsies), and cervical definitive therapy procedures (including loop electrosurgical excision procedure [LEEP] or conization). See Table 5.

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Additional Efficacy Evaluation of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) Against HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58: Since the efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) could not be evaluated against placebo, the following exploratory analyses were conducted.
Efficacy Evaluation of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) Against Cervical High Grade Diseases Caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in the PPE:
Impact of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) Against Cervical Biopsy and Definite Therapy Related to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in the PPE: The efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) against cervical biopsy related to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 compared to Gardasil was 95.9% (95% CI 92.7; 97.9) with 11/6,016 versus 262/6,018 cases. The efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) against cervical definitive therapy (including loop electrosurgical excision procedure [LEEP] or conization) related to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 compared to Gardasil was 90.7% (95% CI 76.3; 97.0) with 4/6,016 versus 43/6,018 cases. These results reflect efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (Gardasil 9) versus Gardasil against procedures associated with HPV types 31, 33, 45, 52, and 58 since both vaccines are efficacious in preventing disease related to HPV types 6, 11, 16, 18.
Immunogenicity of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9): Assays to Measure Immune Response: The minimum anti-HPV titer that confers protective efficacy has not been determined.
Because there were few disease cases in individuals naïve (PCR negative and seronegative) to vaccine HPV types at baseline in the group that received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) it has not been possible to establish minimum antibody levels that protect against clinical disease caused by vaccine HPV types.
Type-specific immunoassays with type-specific standards were used to assess immunogenicity to each vaccine HPV type. These assays measured antibodies against neutralizing epitopes for each HPV type. The scales for these assays are unique to each HPV type; thus, comparisons across types and to other assays are not appropriate.
Immune Response to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) at Month 7 In Clinical Studies: The primary immunogenicity analyses were conducted in a per-protocol immunogenicity (PPI) population. This population consisted of individuals who received all 3 vaccinations within pre-defined day ranges, met pre-defined criteria for the interval between the Month 6 and Month 7 visit, did not have major deviations from the study protocol, and were naïve [PCR negative (in girls and women 16 through 26 years of age) and seronegative prior to dose one] to the relevant HPV type(s) and who remained PCR-negative (in girls and women 16 through 26 years of age) to the relevant HPV type(s) through Month 7.
Immunogenicity was measured by (1) the percentage of individuals who were seropositive for antibodies against the relevant vaccine HPV type, and (2) the Geometric Mean Titer (GMT).
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) induced robust anti-HPV 6, anti-HPV 11, anti-HPV 16, anti-HPV 18, anti-HPV 31, anti-HPV 33, anti-HPV 45, anti-HPV 52, and anti-HPV 58 responses measured at Month 7 (Table 6). In clinical studies 99.6% to 100% who received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) became seropositive for antibodies against all 9 vaccine types by Month 7 across all groups tested. See Table 6.

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Table 6 displays the Month 7 immunogenicity data for girls and women and boys. Anti-HPV responses at Month 7 among 9- through 15-year-old girls were comparable to anti-HPV responses in 16- through 26-year-old women in the combined database of immunogenicity studies for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9). Anti-HPV responses at Month 7 among 9- through 15-year-old boys were comparable to anti-HPV responses in both 16- through 26-year-women and 9- through 15-year-old girls.
On the basis of this immunogenicity bridging, the efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in 9- through 15-year-old girls and boys is inferred.
Study Supporting the Effectiveness of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) against Vaccine HPV Types in 16- through 26-Year-Old Boys and Men: Effectiveness of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) against persistent infection and disease related to vaccine HPV types in 16- through 26-year-old boys and men was inferred from non-inferiority comparison in Protocol 003 of GMTs following vaccination with HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) among 16- to 26-year-old boys and men with those among 16- through 26-year-old girls and women. The primary analyses were conducted in the per-protocol population, which included subjects who received all 3 vaccinations within pre-defined day ranges, met pre-defined criteria for the interval between the Month 6 and Month 7 visit, did not have major deviations from the study protocol, and were seronegative to the relevant HPV type(s) prior to dose 1. Anti-HPV GMTs at Month 7 among 16- through 26-year-old boys and men (HM) were non-inferior to anti-HPV GMTs among 16- through 26-year-old girls and women (Table 7). Anti-HPV GMTs at Month 7 among 16- through 26-year-old MSM (HIV-negative) were lower than in 16- through 26-year-old HM. The GMT fold difference in 16- through 26-year-old MSM relative to the HM was 0.6 to 0.8; anti-HPV GMTs for the MSM subjects ranged between 157.5 and 2294.0 mMU/mL. The fold differences observed with HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) for MSM compared to HM were generally similar to those previously observed with GARDASIL. In Protocol 003, 99.6% to 100% in the HM population and 99.4 to 100% in the MSM population who received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) became seropositive for antibodies against all 9 vaccine types by Month 7. See Table 7.

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On the basis of this immunogenicity bridging, the efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in 16- through 26-year-old boys and men is inferred.
Women 27 Years of Age and Older: No studies have been conducted in women older than 26 years of age. In women 27-through 45 years of age, efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) for the 4 original types is expected based on (1) high efficacy of GARDASIL in women 16-through 45 years of age and (2) comparable immunogenicity of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and GARDASIL in girls and women 9-through 26 years of age.
Immune Responses to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) Using a 2-dose Schedule in Individuals 9 through 14 Years of Age: Protocol 010 measured HPV antibody responses to the 9 HPV types after HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) vaccination in the following cohorts: girls and boys 9- through 14 years old receiving 2 doses at a 6 month or 12-month interval (+/- 1 month); girls 9- through 14 years old receiving 3 doses (at 0, 2, 6 months); and women 16- through 26 years old receiving 3 doses (at 0, 2, 6 months).
GMTs were non-inferior in girls and boys who received 2 doses of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) (at either 0, 6 months or 0, 12 months) to GMTs in 16- through 26 year old girls and women who received 3 doses of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) (at 0, 2, 6 months) for each of the 9 vaccine HPV types. On the basis of this immunogenicity bridging, the efficacy of a 2-dose regimen of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in 9- through 14 year old girls and boys is inferred. One month following the last dose of the assigned regimen, between 97.9% and 100% of subjects across all groups became seropositive for antibodies against the 9 vaccine HPV types (Table 8).
In the same study, in girls and boys 9 through 14 years-old, GMTs at one month after the last vaccine dose were numerically lower for some vaccine types after a 2-dose schedule than in girls 9- through 14 years old after a 3-dose schedule (HPV types 18, 31, 45, and 52 after 0, 6 months and HPV type 45 after 0, 12 months; Table 8). The clinical relevance of these findings is unknown.
Duration of protection of a 2-dose schedule of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) has not been established. See Table 8.

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Variation in Dosing Regimen in 16-through 26-Year-Old Women: All individuals evaluated for efficacy in the PPE population of Protocol 001 received all 3 vaccinations within a 1-year period, regardless of the interval between doses. An analysis of immune response data suggests that flexibility of ±1 month for Dose 2 (i.e., Month 1 to Month 3 in the vaccination regimen) and flexibility of ±2 months for Dose 3 (i.e., Month 4 to Month 8 in the vaccination regimen) do not substantially impact the immune responses to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) (see Administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) In Individuals Who Have Been Previously Vaccinated With GARDASIL under Dosage & Administration).
Persistence of Immune Response to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9): The persistence of antibody response following a complete schedule of vaccination with HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is being studied in a subset of individuals who will be followed up for at least 10 years after vaccination for safety, immunogenicity and effectiveness.
In 9- through 15-year old boys and girls (Protocol 002), persistence of antibody response has been demonstrated for at least 3 years; depending on HPV type, 93 to 99 % of subjects were seropositive.
In 16-through 26 year-old girls and women (Protocol 001), persistence of antibody response has been demonstrated for at least 3.5 years; depending on HPV type, 78-98% of subjects were seropositive. Efficacy was maintained in all subjects regardless of seropositivity status for any vaccine HPV type through the end of the study (up to 67 months postdose 3; median follow-up duration of 43 months).
GMTs for HPV-6, -11, -16 and -18 were numerically comparable in subjects who received Gardasil or HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) for at least 3.5 years.
Administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) to Individuals Previously Vaccinated with GARDASIL: Protocol 006 evaluated the immunogenicity of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in 921 girls and women (12 through 26 years of age) who had previously been vaccinated with GARDASIL. Prior to enrollment in the study, over 99% of subjects had received 3 injections of GARDASIL within a one year period. The time interval between the last injection of GARDASIL and the first injection of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) ranged from approximately 12 to 36 months.
Seropositivity to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in the per protocol population ranged from 98.3 to 100% by Month 7 in individuals who received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9). The GMTs to HPV Types 31, 33, 45, 52, and 58 were lower than in the population who had not previously received GARDASIL in Protocols 001, 002, 005, 007 and 009. Efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in preventing infection and disease related to HPV Types 31, 33, 45, 52, and 58 in individuals previously vaccinated with GARDASIL has not been assessed.
Concomitant Use of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) with Other Vaccines: Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)]: In Protocol 005, the safety and immunogenicity of co-administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] (same visit, injections at separate sites) were evaluated in a study of 1,237 boys and girls 11 through 15 years of age at enrollment.
One group received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in one limb and both Menactra and Adacel, as separate injections, in the opposite limb concomitantly on Day 1 (n = 619). The second group received the first dose of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) on Day 1 in one limb then Menactra and Adacel, as separate injections, at Month 1 in the opposite limb (n = 618). Subjects in both vaccination groups received the second dose of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) at Month 2 and the third dose at Month 6. Immunogenicity was assessed for all vaccines 1 month post completion of the vaccination series [1 dose for Menactra and Adacel and 3 doses for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9)].
Concomitant administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) with Menactra and Adacel did not interfere with the antibody response to any of the vaccine antigens when HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) was given concomitantly with Menactra and Adacel or separately.
Repevax [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content) (dTap-IPV)]: In Protocol 007, the safety and immunogenicity of co-administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) with Repevax [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content) (dTap-IPV)] (same visit, injections at separate sites) were evaluated in a study of 1,053 boys and girls 11 through 15 years of age at enrollment.
One group received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in one limb and Repevax in the opposite limb concomitantly on Day 1 (n = 525). The second group received the first dose of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) on Day 1 in one limb then Repevax at Month 1 in the opposite limb (n = 528). Subjects in both vaccination groups received the second dose of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) at Month 2 and the third dose at Month 6. Immunogenicity was assessed for all vaccines 1 month post completion of the vaccination series [1 dose for Repevax and 3 doses for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9)].
Concomitant administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) with Repevax did not interfere with the antibody response to any of the vaccine antigens when HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) was given concomitantly with Repevax or separately.
Serious Adverse Events in Clinical Trials of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9): Serious adverse events were collected throughout the entire study period for the seven integrated clinical studies for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9). Out of the 15,778 individuals who were administered HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and had safety follow-up, 356 reported a serious adverse event; representing 2.3% of the population. Four individuals administered HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) reported at least one serious adverse event that was determined to be vaccine-related. Four vaccine-related serious adverse events that occurred during the study period were pyrexia, allergy to vaccine, asthmatic crisis, and headache.
Toxicology: Animal Toxicology: Carcinogenesis: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) has not been evaluated for the potential to cause carcinogenicity.
Mutagenesis: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) has not been evaluated for the potential to cause genotoxicity.
Reproduction: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) administered to female rats at a dose approximately 240 times the human dose (mg/kg basis) had no effects on mating performance, fertility, or embryonic/fetal survival.
Development: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) administered to female rats at a dose approximately 160 times the human dose (mg/kg basis) had no effects on development, behavior, reproductive performance or fertility of the offspring. Antibodies against all 9 HPV types were transferred to the offspring during the period of gestation and lactation.
Repeat Dose Toxicity and Local Tolerance: A repeat dose toxicity study has been performed in rats at a dose approximately 250 times the human dose (mg/kg basis) and revealed no special hazards to humans.
Indications/Uses
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is a vaccine indicated in girls and women from 9 years of age onward for the prevention of cervical, vulvar, vaginal, and anal cancer; precancerous or dysplastic lesions; genital warts; and persistent infections caused by Human Papillomavirus (HPV).
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is indicated to prevent the following diseases: Cervical, vulvar, vaginal, and anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58; Genital warts (condyloma acuminata) caused by HPV types 6 and 11.
And persistent infections and the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58: Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS); Cervical intraepithelial neoplasia (CIN) grade 1; Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3; Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3; VIN grade 1 and VaIN grade 1; Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is indicated in boys and men from 9 years of age onward for the prevention of anal cancer, anal precancerous or dysplastic lesions; external genital lesions (including genital warts); and persistent infections caused by HPV.
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is indicated to prevent the following diseases: Anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58; Genital warts (condyloma acuminata) caused by HPV types 6 and 11.
And persistent infections and the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58: Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.
Dosage/Direction for Use
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) should be administered intramuscularly as 3 separate 0.5-mL doses according to the following schedule: First dose: at elected date; Second dose: 2 months after the first dose; Third dose: 6 months after the first dose.
Individuals are encouraged to adhere to the 0, 2, and 6 months vaccination schedule. However, in clinical studies, efficacy has been demonstrated in individuals who have received all 3 doses within a 1-year period. The second dose should be administered at least 1 month after the first dose, and the third dose should be administered at least 3 months after the second dose. All three doses should be given within a 1-year period.
Alternatively, in individuals 9 through 14 years of age, HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) can be administered according to a 2-dose schedule; the second dose should be administered between 5 and 13 months after the first dose. If the second vaccine dose is administered earlier than 5 months after the first dose, a third dose should always be administered.
The use of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) should be in accordance with official recommendations.
Method of Administration: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) must not be injected intravascularly. Neither subcutaneous nor intradermal administration has been studied. These methods of administration are not recommended.
Administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in Individuals Who Have Been Previously Vaccinated with GARDASIL: It is recommended that individuals who receive a first dose of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) complete the vaccination course with HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
Studies using a mixed regimen (interchangeability) of HPV vaccines were not performed for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
Overdosage
There have been no reports of administration of higher than recommended doses of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
Contraindications
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is contraindicated in patients with hypersensitivity to either HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) or GARDASIL or any of the inactive ingredients in either vaccine.
Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) or GARDASIL should not receive further doses of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
Special Precautions
As for any vaccine, vaccination with HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) may not result in protection in all vaccine recipients.
This vaccine is not intended to be used for treatment of active external genital lesions; cervical, vulvar, vaginal, or anal cancers; CIN, VIN, VaIN, or AIN.
This vaccine will not protect against diseases that are not caused by HPV.
As with all injectable vaccines, appropriate medical treatment should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine.
Syncope (fainting) may follow any vaccination, especially in adolescents and young adults. Syncope, sometimes associated with falling, has occurred after HPV vaccination. Therefore, vaccinees should be carefully observed for approximately 15 minutes after administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
The decision to administer or delay vaccination because of a current or recent febrile illness depends largely on the severity of the symptoms and their etiology. Low-grade fever itself and mild upper respiratory infection are not generally contraindications to vaccination.
Individuals with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, Human Immunodeficiency Virus (HIV) infection, or other causes, may have reduced antibody response to active immunization. (See Immunocompromised Individuals as follows and Use with Steroids under Interactions.)
This vaccine should be given with caution to individuals with thrombocytopenia or any coagulation disorder because bleeding may occur following an intramuscular administration in these individuals.
Immunocompromised Individuals: The immunologic response to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) may be diminished in immunocompromised individuals (see Use with Steroids under Interactions).
Use in Children: The safety and efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) have not been evaluated in children younger than 9 years.
Use in Elderly: The safety and efficacy of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) have not been evaluated in individuals aged 65 years and over.
Use in Pregnancy: Studies in Female Rats: Reproduction studies have been performed in female rats at a dose approximately 240 times the human dose (mg/kg basis) and have revealed no evidence of impaired female fertility or harm to the fetus due to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
An evaluation of the effect of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) on embryo-fetal, pre- and postweaning development was conducted in studies using rats. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring. HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) induced a specific antibody response against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in pregnant rats following one or multiple intramuscular injections. Antibodies against all 9 HPV types were transferred to the offspring during the period of gestation and lactation.
Clinical Studies in Humans: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, pregnancy should be avoided during the vaccination regimen for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
In clinical studies, women underwent serum or urine pregnancy testing prior to administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9). Women who were found to be pregnant before completion of a 3-dose regimen of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) were instructed to defer completion of their vaccination regimen until resolution of the pregnancy.
The overall proportion of pregnancies occurring at any time during the studies that resulted in an adverse outcome defined as the combined numbers of spontaneous abortion, late fetal death and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), was 12.9% (174/1,353) in women who received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and 14.4% (187/1,303) in women who received GARDASIL. The proportions of adverse outcomes observed were consistent with pregnancy outcomes observed in the general population.
Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) or GARDASIL. For pregnancies with estimated onset within 30 days of vaccination, no cases of congenital anomaly were observed in women who have received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) or GARDASIL. In pregnancies with onset more than 30 days following vaccination, 30 and 23 cases of congenital anomaly were observed in women who have received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and GARDASIL, respectively. The types of anomalies observed were consistent (regardless of when pregnancy occurred in relation to vaccination) with those generally observed in pregnancies in the general population.
Thus, there is no evidence to suggest that administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) adversely affects fertility, pregnancy, or infant outcomes.
Use in Lactation: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) may be administered to lactating women.
It is not known whether vaccine antigens or antibodies induced by the vaccine are excreted in human milk.
A total of 92 women were breast feeding during the vaccination period of the clinical studies for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9). In these studies, vaccine immunogenicity was comparable between nursing women and women who did not nurse. In addition, the adverse experience profile for nursing women was comparable to that of the women in the overall safety population. There were no vaccine-related serious adverse experiences reported in infants who were nursing during the vaccination period.
Use In Pregnancy & Lactation
Pregnancy: Studies in Female Rats: Reproduction studies have been performed in female rats at a dose approximately 240 times the human dose (mg/kg basis) and have revealed no evidence of impaired female fertility or harm to the fetus due to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
An evaluation of the effect of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) on embryo-fetal, pre- and postweaning development was conducted in studies using rats. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring. HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) induced a specific antibody response against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in pregnant rats following one or multiple intramuscular injections. Antibodies against all 9 HPV types were transferred to the offspring during the period of gestation and lactation.
Clinical Studies in Humans: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, pregnancy should be avoided during the vaccination regimen for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
In clinical studies, women underwent serum or urine pregnancy testing prior to administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9). Women who were found to be pregnant before completion of a 3-dose regimen of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) were instructed to defer completion of their vaccination regimen until resolution of the pregnancy.
The overall proportion of pregnancies occurring at any time during the studies that resulted in an adverse outcome defined as the combined numbers of spontaneous abortion, late fetal death and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), was 12.9% (174/1,353) in women who received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and 14.4% (187/1,303) in women who received GARDASIL. The proportions of adverse outcomes observed were consistent with pregnancy outcomes observed in the general population.
Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) or GARDASIL. For pregnancies with estimated onset within 30 days of vaccination, no cases of congenital anomaly were observed in women who have received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) or GARDASIL. In pregnancies with onset more than 30 days following vaccination, 30 and 23 cases of congenital anomaly were observed in women who have received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and GARDASIL, respectively. The types of anomalies observed were consistent (regardless of when pregnancy occurred in relation to vaccination) with those generally observed in pregnancies in the general population.
Thus, there is no evidence to suggest that administration of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) adversely affects fertility, pregnancy, or infant outcomes.
Use in Lactation: HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) may be administered to lactating women.
It is not known whether vaccine antigens or antibodies induced by the vaccine are excreted in human milk.
A total of 92 women were breast feeding during the vaccination period of the clinical studies for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9). In these studies, vaccine immunogenicity was comparable between nursing women and women who did not nurse. In addition, the adverse experience profile for nursing women was comparable to that of the women in the overall safety population. There were no vaccine-related serious adverse experiences reported in infants who were nursing during the vaccination period.
Adverse Reactions
Clinical Trials Experience: Clinical Trials Experience with HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and GARDASIL: The safety of HUMAN PAPILOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) was evaluated in 7 clinical studies (Protocols 001, 002, 003, 005, 006, 007, 009) that included 15,776 individuals who received at least one dose of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and had safety follow-up. Protocol 001 and Protocol 009 included 7,378 individuals who received at least one dose of GARDASIL and had safety follow-up. The vaccines were administered on the day of enrollment and the subsequent doses administered approximately 2 and 6 months thereafter. Safety was evaluated using vaccination report card (VRC)-aided surveillance for 14 days after each injection of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) or GARDASIL.
The individuals who were monitored using VRC-aided surveillance included 9,102 girls and women 16 through 26 years of age, 1,394 boys and men 16 through 26 years of age and 5,280 girls and boys 9 through 15 years of age (3,481 girls and 1,799 boys) at enrollment who received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9); and 7,078 girls and women 16 through 26 years of age and 300 girls 9 through 15 years of age at enrollment who received GARDASIL.
Systemic and Injection-Site Adverse Reactions in Clinical Trials of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9): The vaccine-related adverse experiences that were observed among recipients of either HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) or GARDASIL at a frequency of at least 1% are shown in Tables 9 and 10. Few individuals [HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) = 0.1% vs. GARDASIL <0.1%] discontinued due to adverse experiences after receiving either vaccine. The safety profile was similar between HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and GARDASIL in women, men, girls and boys. See Tables 9 and 10.

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Solicited Systemic and Injection-Site Adverse Reactions in Clinical Trials of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9): Temperature and injection-site pain, swelling, and erythema were solicited using VRC-aided surveillance for 5 days after each injection of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) during the clinical studies. The incidence and severity of solicited adverse reactions that occurred within 5 days following each dose of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) are shown in Table 11.

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Clinical Trials Experience for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in Individuals Who Have Been Previously Vaccinated with GARDASIL: A clinical study (Protocol 006) evaluated the safety of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) in 12- through 26-year-old girls and women who had previously been vaccinated with 3 doses of GARDASIL. The time interval between the last injection of GARDASIL and the first injection of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) ranged from approximately 12 to 36 months. Individuals were administered HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) or saline placebo and safety was evaluated using VRC-aided surveillance for 14 days after each injection of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) or saline placebo in these individuals. The individuals who were monitored included 608 individuals who received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and 305 individuals who received saline placebo. Few (0.5%) individuals who received HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) discontinued due to adverse reactions. The vaccine-related adverse experiences that were observed among recipients of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) at a frequency of at least 1.0% and also at a greater frequency than that observed among saline placebo recipients are shown in Table 12. Overall, the safety profile was similar between individuals vaccinated with HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) who were previously vaccinated with GARDASIL and those who were naïve to HPV vaccination. See Table 12.

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Clinical Trials Experience for Concomitant Administration of HUMAN PAPILLOMAVIRUS 9 VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) with Other Vaccines: The safety of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) when administered concomitantly with other vaccines was evaluated in clinical studies.
There was an increase in injection-site swelling reported at the injection site for HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) when HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) was administered concomitantly with Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content) (dTap-IPV) or Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap) and Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine as compared to non-concomitant vaccination. The majority of injection-site swelling seen with concomitant administration with other vaccines was reported as being mild to moderate in intensity.
Post-marketing Experience: The post-marketing adverse experiences were reported voluntarily from uncertain size, therefore, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure.
The safety profile of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) and GARDASIL are similar. The post-marketing adverse experience with GARDASIL is relevant to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) since the vaccines are similar in composition and contain L1 HPV proteins of 4 of the same HPV types.
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
In addition to the adverse reactions reported in the clinical studies, the following adverse experiences have been spontaneously reported during post-approval use of HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9): Nervous system disorders: syncope sometimes accompanied by tonic-clonic movements.
Gastrointestinal disorders: vomiting.
GARDASIL
Additionally, the following post-marketing adverse experiences have been spontaneously reported for GARDASIL: Infections and infestations: cellulitis.
Blood and lymphatic system disorders: idiopathic thrombocytopenic purpura, lymphadenopathy.
Immune system disorders: hypersensitivity reactions including anaphylactic/anaphylactoid reactions, bronchospasm, and urticaria.
Nervous system disorders: acute disseminated encephalomyelitis, Guillain-Barré syndrome.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia.
General disorders and administration site conditions: asthenia, chills, malaise.
Drug Interactions
Use with other Vaccines: Results from clinical studies indicate that HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) may be administered concomitantly (at a separate injection site) with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine], Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)], and Repevax [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content)] (dTap-IPV).
Use with Hormonal Contraceptives: In 7,269 women (16 through 26 years of age, from Protocols 001 and 002), 60.2% used hormonal contraceptives during the vaccination period of the clinical studies. Use of hormonal contraceptives did not appear to affect the type specific immune responses to HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9).
Use with Steroids: Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines (see Immunocompromised Individuals under Precautions).
Caution For Usage
Instruction for Use: The vaccine should be used as supplied; no dilution or reconstitution is necessary. The full recommended dose of the vaccine should be used.
Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine.
After thorough agitation, HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Discard the product if particulates are present or if it appears discolored.
Prefilled Syringe Use: The prefilled syringe is for single use only and should not be used for more than one individual. Inject the entire contents of the syringe.
Storage
Special Precautions for Storage: Store refrigerated at 2 to 8°C (36 to 46°F). Do not freeze. Protect from light.
HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) should be administered as soon as possible after being removed from refrigeration. HUMAN PAPILLOMAVIRUS 9-VALENT (TYPES 6, 11, 16, 18, 31, 33, 45, 52, 58) RECOMBINANT VACCINE (GARDASIL 9) can be administered provided total (cumulative multiple excursion) time out of refrigeration (at temperatures between 8°C and 25°C) does not exceed 72 hours. Cumulative multiple excursions between 0°C and 2°C are also permitted as long as the total time between 0°C and 2°C does not exceed 72 hours. These are not, however, recommendations for storage.
Discard the product if it is frozen, particulates are present, or if it appears discolored.
ATC Classification
J07BM03 - papillomavirus (human types 6, 11, 16, 18, 31, 33, 45, 52, 58) ; Belongs to the class of papillomavirus vaccines.
Presentation/Packing
Vaccine (inj) (pre-filled syr) 0.5 mL x 1's.
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