Gardasil

Gardasil

Manufacturer:

MSD

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Quadrivalent human papillomavirus (HPV) (types 6, 11, 16, 18) recombinant vaccine.
Description
Each 0.5-mL dose of vaccine of solution for injection contains human papillomavirus (HPV) 6 L1 protein approximately 20 mcg, HPV 11 L1 protein 40 mcg, HPV 16 L1 protein 40 mcg and HPV 18 L1 protein 20 mcg.
It also contains the following inactive ingredients: Aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant) approximately 225 mcg, sodium chloride 9.56 mg, L-histidine 0.78 mg, polysorbate 80 50 mcg, sodium borate 35 mcg and water for injection. Gardasil does not contain a preservative or antibiotics.
Action
Gardasil is a recombinant, quadrivalent vaccine that protects against human papillomavirus (HPV).
Pharmacology: Disease Burden: Worldwide, over 490,000 cases of cervical cancer are diagnosed annually. Cervical cancer prevention focuses on repeat screening [eg, Papanicolaou's (Pap) testing and/or 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 infection is necessary for the development of squamous cell cervical cancer [and its precursor lesions cervical intraepithelial neoplasia (CIN) 1 and CIN 2/3] and cervical adenocarcinoma [and its precursor lesion adenocarcinoma in situ (AIS)]. HPV also causes a subset of vulvar and vaginal cancers and their precursor lesions vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN).
Human papillomavirus infection is very common. Most HPV infections clear without sequelae but some progress to cervical cancer and/or other HPV-related diseases. In the absence of vaccination, over 50% of sexually active individuals will become infected with HPV during their lifetime. Men play an important role in transmission of HPV to their sexual partners. Several prospective studies have shown a high level of HPV concordance between couples who recently became infected, indicating transmission of HPV between the couples (male to female, and female to male). These data consistently support the sexually transmitted nature of HPV and the role of men in infecting women, who subsequently can develop HPV-related anogenital cancers and warts. Based on these various lines of evidence, it is expected that decreasing the risk of HPV infection in men through vaccination should decrease the risk of infection in their sexual partners, thereby providing additional public health benefit.
Infection with HPV types 6, 11, 16 and 18 can cause abnormal Pap test results and low-grade dysplastic lesions (CIN 1, VIN 1 and VaIN 1). HPV 6- and HPV 11-related lesions are unlikely to progress to cancer but are clinically indistinguishable from premalignant lesions caused by HPV 16 and HPV 18.
Infection with HPV 6 and HPV 11 also causes genital warts (condyloma acuminata), which are growths of the cervicovaginal, vulvar, perianal and intra-anal mucosa and the external genitalia that rarely progress to cancer. The lifetime risk for acquisition of genital warts has been estimated to exceed 10%. The incidence of this lesion is generally comparable between men and women.
Recurrent respiratory papillomatosis (RRP), a disease of infants and adults, is also caused by HPV 6 and HPV 11. RRP is characterized by repeated growth of warts in the respiratory tract. In the US, 5900 cases are diagnosed annually. Therapy requires repeated surgery.
Human papillomavirus infection is strongly associated with anal cancer. The great majority of anal cancers are squamous cell carcinoma (SCC). Anal canal SCC are HPV positive in 80-90% of cases in men and women. HPV 16 (73%) and HPV 18 (5%) are the most common associated types. Approximately 100,000 new cases of anal cancer are estimated to occur annually around the world and the rate of anal cancer cases has been increasing. There are no routine screening tests for this cancer in healthy people.
HPV is accepted as a cause of head and neck cancer, and emerging data show an increase over the past several decades in the proportion of head and neck cancers caused by HPV. The majority of HPV-related head and neck cancers occur in the oropharynx, specifically in the tonsillar area of Waldeyer's Ring. Of oropharyngeal cancers, 60-70% are caused by HPV, and of these, approximately 90% are associated with HPV 16. Overall, approximately 2/3 of these cases occur in men. Oral HPV infection and seropositivity for HPV 16 have been associated with a significantly elevated risk of development for head and neck cancer.
Gardasil is a recombinant vaccine with L1 proteins resembling HPV types 6, 11, 16 and 18. HPV types 16 and 18 causes approximately: 70% of cervical cancer, AIS and CIN 3 cases; 50% of CIN 2 cases; 70% of HPV-related vulvar and vaginal cancer VIN 2/3, and VaIN 2/3 cases; 90% of HPV-related anal cancers; 70% of HPV-related AIN 2/3; and 60% of HPV-related penile cancers.
Human papillomavirus types 6, 11, 16 and 18 causes approximately: 35-50% of all CIN 1, VIN 1 and VaIN 1 cases.
Human papillomavirus types 6 and 11 cause approximately: 90% of genital wart and RRP cases; and 9-12% of CIN 1 cases. Human papillomavirus type 16 causes approximately: 90% of OPSCC.
Mechanism of Action: Gardasil contains L1 virus-like particles (VLPs), which are proteins that resemble wild-type virions. Because the virus-like particles contain no viral DNA, they cannot infect cells or reproduce.
In preclinical studies, induction of anti-papillomavirus antibodies with L1 VLP vaccines resulted in protection against infection. Administration of serum from vaccinated to unvaccinated animals resulted in the transfer of protection against HPV to the unvaccinated animals. These data suggest that the efficacy of L1 VLP vaccines is mediated by the development of humoral immune responses.
Clinical Studies: In female individuals, CIN 2/3 and AIS are the immediate precursors of invasive SCC and invasive adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent invasive cancer (secondary prevention); thus, their primary prevention through vaccination will prevent invasive cancer.
Invasive cervical cancer cannot be used as an endpoint for efficacy studies of HPV vaccines because of the importance of employing secondary prevention measures. Therefore, the immediate precursors, CIN 2 (moderate-grade cervical dysplasia), CIN 3 (high-grade cervical dysplasia including carcinoma in situ) and AIS are the most appropriate endpoints for the demonstration of the prevention of cervical cancer by HPV vaccines.
Cervical intraepithelial neoplasia 3 and AIS are classified as stage 0 cervical cancers according to International Federation of Obstetrics and Gynaecology (FIGO). VIN 2/3 and VaIN 2/3 are the immediate precursors to HPV-related vulvar and vaginal cancer, respectively.
In men, up to 84% of penile/perineal/perianal intraepithelial neoplasia (PIN) 1 (low grade) and over 90% of PIN 3 (high grade) has been associated with HPV. HPV 16 is the most common type detected. Erythoplasia of Queyrat (EQ), Bowen's disease (BD) and bowenoid papulosis (BP) are clinical presentations of high-grade PIN. As high as 33% of BD and EQ have been associated with invasive cancer. BP rarely progresses to malignancy.
The efficacy of Gardasil was assessed in 6 placebo-controlled, double-blind, randomized phase II and III clinical studies. The 1st phase II study evaluated the HPV 16 component of Gardasil (Protocol 005, n=2391 girls and women) and the 2nd evaluated all components of Gardasil (Protocol 007, n=551 girls and women). Three phase III studies, termed Females United To Unilaterally Reduce Endo/Ectocervical Disease (FUTURE), evaluated Gardasil in 5442 (FUTURE I), 12,157 (FUTURE II) and 3817 (FUTURE III) girls and women. A 4th phase III study, Protocol 020, evaluated Gardasil in 4055 boys and men, including a subset of 598 (GARDASIL =299; placebo =299) men who self-identified as having sex with men (MSM population). Together, these studies evaluated 24,358 girls and women, 16 through 45 years and 4055 boys and men, 16 through 26 years of age at enrollment. The median duration of follow-up was 4 years, 3 years, 3 years, 3 years, 4 years and 2.9 years for Protocol 005, Protocol 007, FUTURE I, FUTURE II, FUTURE III and Protocol 020, respectively. Individuals received vaccine or placebo on the day of enrollment and 2 months and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies conducted in girls and women combined.
The studies did not have a screening phase. Thus, individuals who had been exposed to a vaccine HPV type prior to enrollment were included in the studies. Overall, 73% of 16- through 26-year old girls and women and 67% of 24- through 45-year old women were naive to all 4 vaccine HPV types at enrollment. Overall, 83% of 16- through 26-year old boys and men were naive to all 4 vaccine HPV types at enrollment. The naive individuals continued to be at risk for infection and disease caused by all 4 vaccine HPV types. Among the 24- through 45-year old women, only 0.4% had been exposed to all 4 vaccine HPV types. Among the 16- through 26-year old boys and men, only 0.2% had been exposed to all 4 vaccine HPV types.
A total of 27% of 16-year old through 26-year old girls and women, 33% of 24-year old through 45-year old women, and 17% of 16-year old through 26-year old boys and men had evidence of prior exposure to or ongoing infection with at least 1 of the 4-vaccine HPV types. Among these individuals, 74% of 16-year old through 26-year old girls and women, 71% of 24-year old through 45-year old women and 78% of 16-year old through 26-year old boys and men had evidence of prior exposure to or ongoing infection with only 1 of the 4-vaccine HPV types and were naive (PCR negative and seronegative) to the remaining 3 types.
In individuals who were naive (PCR negative and seronegative) to all 4-vaccine HPV types, CIN, genital warts, VIN, VaIN, PIN and persistent infection caused by any of the 4 vaccine HPV types were counted as endpoints.
Among individuals who were positive (PCR positive and/or seropositive) for a vaccine HPV type at day 1, endpoints related to that type were not included in the analyses of prophylactic efficacy. Endpoints related to the remaining types for which the individual was naive (PCR negative and seronegative) were counted. For example, in individuals who were HPV 18 positive (PCR positive and/or seropositive) at day 1, lesions caused by HPV 18 were not counted in the prophylactic efficacy evaluations. Lesions caused by HPV 6, 11 and 16 were included in the prophylactic efficacy evaluations. The same approach was used for the other types.
Prophylactic Efficacy-HPV Types 6, 11, 16 and 18 in 16-Year Old Through 26-Year Old Girls and Women: Gardasil was efficacious in reducing the incidence of cervical, vulvar and vaginal cancers; CIN (any grade); AIS; noninvasive cervical cancer (CIN 3 and AIS); and external genital lesions, including condyloma acuminata, VIN (any grade) and VaIN (any grade) caused by HPV types 6, 11, 16 and 18.
The primary analyses of efficacy, with respect to HPV types 6, 11, 16 and 18, were conducted in the per-protocol efficacy (PPE) population, consisting of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naive to the relevant HPV type(s) prior to dose 1 and through 1 month post-dose 3 (month 7). Efficacy was measured starting after the month 7 visit (see Table 1).

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Supplemental Analysis of Efficacy for Cancer Endpoints in 16-Year Old Through 26-Year Old Girls and Women: In a supplemental analysis, the efficacy of Gardasil was evaluated against HPV 16/18-related FIGO stage 0 cervical cancer (CIN 3 and AIS) and for the immediate precursors to vulvar and vaginal cancer (VIN 2/3 or VaIN 2/3) in the PPE population and a modified intention-to-treat-2 (MITT-2) population. The MITT-2 population consisted of individuals who were naive to the relevant HPV type(s) (types 6, 11, 16 and 18) prior to dose 1, received at least 1 dose of vaccine or placebo and had at least 1 follow-up visit post-day 30. The MITT-2 population differs from the PPE population in that it includes individuals with major protocol violations and who became infected with a vaccine HPV type during the vaccination period. Efficacy was measured starting 30 days post-dose 1 for the MITT-2 population. (See Table 2.)

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Prophylactic efficacy against overall persistent infection or disease in an extension phase of Protocol 007, that included data through month 60, was 95.8% (95% CI: 83.8%, 99.5%). In the group that received Gardasil, no cases due to waning immunity were observed.
Gardasil was equally efficacious against HPV disease caused by HPV types 6, 11, 16 and 18.
Efficacy in 16-Year Old Through 26-Year Old Women with Current or Prior Infection with HPV Types 6, 11, 16 or 18: Individuals who were already infected with ≥1 vaccine-related HPV types prior to vaccination were protected from clinical disease caused by the remaining vaccine HPV types.
Individuals who received Gardasil, but had ongoing HPV infection at the time of vaccination had a 21.6% (95% CI: <0%, 42.1%) lower incidence of CIN (CIN 1 or CIN 2/3) or AIS resulting from this infection as compared with placebo. Ongoing infection was defined as infection with a vaccine HPV type at enrollment, but no evidence of immune response to it.
Efficacy Against Non-Vaccine HPV Types: The cross-protective efficacy of Gardasil was evaluated in the combined database of the FUTURE I and FUTURE II trials (n=17,599). The primary endpoint of this analysis was the combined incidence of HPV 31- and HPV 45-related CIN (grades 1, 2, 3) or AIS. The secondary endpoint of this analysis was the combined incidence of HPV 31-, 33-, 45-, 52- and 58-related CIN (grades 1, 2, 3) or AIS. Analyses were also conducted to evaluate efficacy with respect to CIN (grades 1, 2, 3) or AIS caused by non-vaccine HPV types individually. The primary analysis conducted in individuals who were naive to the relevant HPV types being analysed at day 1 (MITT-2 population) is shown in Table 3. Current data is insufficient to establish the effectiveness of Gardasil against non-vaccine HPV types. (See Table 3.)

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Protection Against the Overall Burden of Cervical, Vulvar and Vaginal HPV Disease in 16-Year Old Through 26-Year Old Girls and Women: The impact of Gardasil against the overall risk for cervical, vulvar and vaginal HPV disease (ie, disease caused by any HPV type) was evaluated in a prespecified analysis of 17,599 individuals enrolled in FUTURE I and FUTURE II. Among individuals who were naive to at least 1 of 14 common HPV types and/or had a Pap test that was negative for squamous intraepithelial lesion (SIL) at day 1 (MITT-2 population), administration of Gardasil reduced the incidence of CIN 2/3 or AIS caused by vaccine- or non-vaccine HPV types by 33.8% (95% CI: 20.7%, 44.8%).
Further efficacy analyses were conducted in 2 clinically relevant populations: An HPV-naive population (negative to 14 common HPV types and had a Pap test that was negative for SIL at day 1), approximating a population of sexually-naive individuals plus individuals shortly after sexual debut; and the general study population of individuals regardless of baseline HPV status, some of whom had HPV-related disease at vaccination onset.
Among HPV-naive individuals and among the general study population (including individuals with HPV infection at vaccination onset), Gardasil reduced the overall incidence of CIN 2/3 or AIS; of VIN 2/3 or VaIN 2/3; of CIN (any grade) or AIS; and of genital warts. These reductions were primarily due to reductions in lesions caused by HPV types 6, 11, 16 and 18. Among HPV-naive individuals and the general study population, the benefit of the vaccine with respect to the overall incidence of CIN 2/3 or AIS (caused by any HPV type) became more apparent over time. This is because Gardasil does not impact the course of infections that are present at vaccination onset. Such infected individuals may already have CIN 2/3 or AIS at vaccination onset and some will develop CIN 2/3 or AIS during follow-up.
Gardasil has not been shown to protect against the diseases caused by every HPV type and will not treat existing disease. The overall efficacy of Gardasil will vary with the baseline prevalence of HPV infection and disease, the incidence of infections against which Gardasil has shown protection, and those infections against which Gardasil has not been shown to protect.
Impact on the Rates of Pap Test Abnormalities and Cervical, Vulvar and Vaginal Procedures in 16-Year Old Through 26-Year Old Girls and Women: The impact of Gardasil on rates of abnormal Pap tests and cervical procedures (colposcopic biopsy, definitive therapy) regardless of causal HPV types was evaluated in 18,150 individuals enrolled in Protocol 007, FUTURE I and FUTURE II. The impact of Gardasil on rates of genital excisional procedures to treat lesions caused by any HPV type was evaluated in 5442 individuals enrolled in FUTURE I. Two populations were considered: An HPV-naive population (negative to 14 common HPV types and had a Pap test that was negative for SIL at day 1), approximating a population of sexually-naive individuals plus individuals shortly after sexual debut; and the general study population of individuals regardless of baseline HPV status, some of whom had HPV-related disease at vaccination onset.
In both populations, Gardasil reduced the proportions of individuals who experienced a Pap test abnormality suggestive of CIN, a colposcopic biopsy, a definitive cervical therapy procedure (Loop Electro-Excision Procedure or Cold-Knife Conization), a vulvar or vaginal biopsy, or a definitive excisional procedure of the vagina or vulva.
In addition, administration of Gardasil to a generally HPV naive population of 16-year old through 26-year old individuals reduced the incidence of HPV 16- and HPV 18-related Pap abnormalities (ASC-US HR positive, LSIL or worse) by 92.4% (95% CI: 83.7%, 97%) and 96.9% (95% CI: 81.6%, 99.9%) in the FUTURE I study.
Efficacy in 24-Year Old Through 45-Year Old Women: A minimum anti-HPV level that provides protection against HPV infection and disease has not been defined and 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 (FUTURE III, P019) was conducted.
Study P019 evaluated efficacy in 3253 women 27years through 45 years based on a combined endpoint of HPV 6-, 11-, 16- or 18-related persistent infection, genital warts, vulvar and vaginal dysplastic lesions of any grade, CIN of any grade, AIS, and cervical cancer. These women were randomized 1:1 to receive either Gardasil or amorphous aluminum hydroxyphosphate sulfate (AHHS) control. The efficacy for the combined endpoint was driven primarily by prevention of persistent infection. There was no statistically significant efficacy demonstrated for CIN2/3, AIS or cervical cancer. In post hoc analyses conducted to assess the impact of Gardasil on the individual components of the combined endpoint, the results in the population of women naive to the relevant HPV type at baseline were as follows: Prevention of HPV 6-, 11-, 16- or 18-related persistent infection [80.5% (95% CI: 68.3, 88.6)], prevention of HPV 6-, 11-, 16- or 18-related CIN (any grade) [85.8% (95% CI: 52.4, 97.3)], and prevention of HPV 6, 11-, 16- or 18-related genital warts [87.6% (95% CI: 7.3, 99.7)].
Efficacy for disease endpoints was diminished in a population impact assessment of women who were vaccinated regardless of baseline HPV status (full analysis set, FAS). In the FAS, efficacy was not demonstrated for the following endpoints; prevention of HPV 16- and 18-related CIN 2/3, AIS, or cervical cancer and prevention of HPV-6 and 11-related condyloma. No efficacy was demonstrated against CIN 2/3, AIS, or cervical cancer in the general population irrespective of HPV type (FAS any type analysis).
Analyses of efficacy were conducted in the per-protocol efficacy (PPE) population. Efficacy was measured starting after the Month 7 visit. (See Table 4.)

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Prophylactic Efficacy-HPV Types 6, 11, 16 and 18 in 16-Year Old Through 26-Year Old Boys and Men: In clinical studies in boys and men, efficacy was evaluated using the following endpoints: External genital warts; penile/perineal/PIN grades 1/2/3 or penile/perineal/perianal cancer; and persistent infection. High grade PIN is associated with certain types of penile/perineal/perianal cancers. Persistent infection is a predictor of clinical disease.
The primary analyses of efficacy were conducted in the PPE population. This population consisted of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naive (PCR negative and seronegative) to the relevant HPV type(s) (types 6, 11, 16, and 18) prior to dose 1 and through 1 month post-dose 3 (month 7). Efficacy was measured starting after the month 7 visit.
Gardasil was efficacious in reducing the incidence of external genital lesions (Condyloma and PIN grades 1/2/3) and persistent infection related to vaccine HPV types 6, 11, 16 or 18 in those who were PCR negative and seronegative at baseline (see Table 5).

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Prophylactic Efficacy – Anal Disease Caused by HPV Types 6, 11, 16, and 18 in Boys and Men 16 Years Through 26 Years in the MSM Sub-study: A sub-study of Protocol 020 evaluated the efficacy of Gardasil against anal disease (anal intraepithelial neoplasia and anal cancer) in a population of 598 MSM. In this sub-study, cases of AIN 2/3 were the efficacy endpoints used to assess prevention of HPV-related anal cancer. The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population of Protocol 020.
Gardasil was efficacious in reducing the incidence of anal intraepithelial neoplasia (AIN) grades 1 (both condyloma and nonacuminate), 2, and 3 related to vaccine HPV types 6, 11, 16, and 18 in those boys and men who were PCR negative and seronegative at baseline (see Table 6.)

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Immunogenicity: Assays to Measure Immune Response: Type-specific assays 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, rather than the total antibodies directed at the VLPs in the vaccine. The scales for these assays are unique to each HPV type; thus, comparisons across types and to other assays are not meaningful. The assays used to measure the immune responses to Gardasil were demonstrated to correlate with the capacity to neutralize live HPV virions.
Because of the very high efficacy of Gardasil in clinical trials, it has not been possible to establish minimum anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 antibody levels that protect against clinical HPV disease.
The immunogenicity of Gardasil was assessed in 23,951 9-year old through 45-year old girls and women (Gardasil n=12,634; placebo n=11,317) and 5417 9-year old through 26-year old boys and men (Gardasil n=3109; placebo n=2308).
The primary immunogenicity analyses were conducted in a per-protocol immunogenicity (PPI) population. This population consisted of individuals who were seronegative and PCR-negative to the relevant HPV type(s) at enrollment, remained HPV PCR negative to the relevant HPV type(s) through 1 month post-dose 3 (month 7), received all 3 vaccinations and did not deviate from the study protocol in ways that could interfere with the effects of Gardasil.
Immunogenicity was measured by the percentage of individuals who were seropositive for antibodies against the relevant vaccine HPV type; and the geometric mean titer (GMT).
Immune Response to Gardasil at Month 7 in 9-Year Old Through 45-Year Old Girls and Women (Time Point Approximating Peak Immunogenicity): In the PPI population of 9-year old through 45-year old, seropositivity at month 7 ranged from 96.4-99.9% across all 4 vaccine types and across populations defined by age range. Anti-HPV GMTs for all types decreased with age. This finding is expected, as the immune responses to vaccines generally decrease with age at vaccination. The efficacy of Gardasil remained high despite the observed age-related decrease in anti-HPV GMTs.
Immune Response to Gardasil at Month 7 in 9-Year Old Through 26-Year Old Boys and Men (Time Point Approximating Peak Immunogenicity): In the PPI population of 9 through 26-year olds, seropositivity at month 7 ranged from 97.4-99.9% across all 4 vaccine types and across populations defined by age range. Anti-HPV GMTs for all types decreased with age. This finding is expected, as the immune responses to vaccines generally decrease with age at vaccination. The efficacy of Gardasil remained high despite the observed age-related decrease in anti-HPV GMTs.
Bridging the Efficacy of Gardasil from Adults to Adolescents: A clinical study compared anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 responses in 10-year old through 15-year old adolescent girls with responses in 16-year old through 23-year old girls and women. Among the girls and women who received Gardasil, 99.1-100% became anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 seropositive, by 1 month post-dose 3. Anti-HPV responses in 10-year old through 15-year old adolescent girls were significantly superior to those observed in 16-year old through 23-year old girls and women.
Similar outcomes were observed in a comparison of the anti-HPV responses 1 month post-dose 3 among 9-year old through 15-year old adolescent girls with anti-HPV responses in 16-year old through 26-year old girls and women in the combined database of immunogenicity studies for Gardasil.
Anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 responses (GMTs) were compared between 9-year old through 15-year old adolescent boys and 16-year old through 26-year old boys and men. Among individuals who received Gardasil, 97.4-99.9% became anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 seropositive by 1 month post-dose 3. Anti-HPV responses in 9-year old through 15-year old adolescent boys were significantly superior to those observed in 16-year old through 26-year old boys and men.
On the basis of this immunogenicity bridging, the efficacy of Gardasil in 9-year old through 15-year old adolescent girls is comparable to the efficacy of Gardasil observed in 16-year old through 26-year old girls and women. Additionally, the efficacy of Gardasil in 9-year old through 15-year old adolescent boys is comparable to the efficacy of Gardasil observed in studies in 16-year old through 26-year old boys and men.
Persistence of The Immune Response to Gardasil: The duration of immunity following a complete schedule of immunization with Gardasil has not been established. After peaking at month 7, anti-GMTs for all HPV types decreased through month 24 and then stabilized at levels above baseline.
In Protocol 007, peak anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 GMTs were observed at month 7. The GMTs decreased through month 24 and then stabilized until at least month 60 (see figure).

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Evidence of Anamnestic (Immune Memory) Responses: Evidence of an anamnestic response was seen in vaccinated individuals who were seropositive to relevant HPV type(s) prior to vaccination.
In a study to evaluate the capacity to induce immune memory, individuals who received a 3-dose primary series of vaccine were given a challenge dose of Gardasil 5 years after the onset of vaccination. These individuals exhibited a rapid and strong anamnestic response that exceeded the anti-HPV GMTs observed 1-month post-dose 3 (month 7). The GMTs 1 week post-challenge dose were 0.9-fold, 2.2-fold, 1.2-fold and 1.4-fold higher than the post-dose 3 GMTs for types 6, 11, 16 and 18, respectively. The GMTs 1 month post-challenge dose were 1.3-fold, 4.2-fold, 1.5-fold and 1.7-fold higher than the post-dose 3 GMTs for types 6, 11, 16 and 18, respectively. At 1-week post-challenge dose, 87.2%, 94.9%, 86.4% and 95.2% of individuals had anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 GMTs higher than those detected at month 60.
Persistence of Immune Response in Phase III Studies of 9-Year Old Through 45-Year Old Girls and Women for Gardasil: Anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositivity was highest at Month 7, and then declined at persistence time points. At Month 48, anti-HPV seropositivity was highest among 9-year olds through 15-year olds and lowest among 35-year olds through 45-year-olds.
The decline in the percent seropositivity for anti-HPV 18 responses was greater than the decline in the percent seropositivity for anti-HPV 6, anti-HPV 11, and anti-HPV 16 responses.
Persistence of Immune Response in Phase III Studies of 9-Year Old Through 26-Year Old Boys and Men for Gardasil: Anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositivity was highest at Month 7, and then generally declined at persistence time points. At Month 36, anti-HPV seropositivity was highest among 9-year olds through 15-year-olds and lowest among 16-year olds through 26-year-olds. The decline in the percent seropositivity for anti-HPV 18 responses was greater than the decline in the percent seropositivity for anti-HPV 6, anti-HPV 11, and anti-HPV 16 responses.
Schedule Flexibility: All individuals evaluated in the PPE populations of the phase II and III studies received the 3-dose regimen of Gardasil 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 (ie, month 1-3 in the vaccination regimen) and flexibility of ±2 months for dose 3 (ie, month 4-8 in the vaccination regimen) does not substantially impact the immune responses to Gardasil (see Dosage & Administration).
Studies with Other Vaccines: The safety and immunogenicity of co-administration of Gardasil with HBvaxPRO [hepatitis B vaccine (recombinant)] (same visit, injections at separate sites) were evaluated in a randomized study of 1871 women 16-24 years at enrollment. Immune response and safety profile to both HBvaxPRO and Gardasil were similar whether they were administered at the same visit or at a different visit.
Repevax [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content)]: The safety and immunogenicity of co-administration of Gardasil with Repevax (same visit, injections at separate sites) were evaluated in a randomized study of 843 boys and girls 11-17 years at enrollment. Concomitant administration of Gardasil with Repevax does not interfere with the antibody response to any of the components of either vaccine. In addition, the safety profile was generally similar (See Concomitant Administration with Other Vaccines under Side Effects).
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)]: The safety and immunogenicity of co-administration of Gardasil with Menactra (same visit, injections at separate sites) were evaluated in a randomized study of 1040 boys and girls 11-17 years at enrollment. Concomitant administration of Gardasil with Menactra does not interfere with the antibody response to any of the components of any of the vaccines. In addition, the safety profile was generally similar (See Concomitant Administration with Other Vaccines under Side Effects).
Indications/Uses
GARDASIL 9 is a vaccine indicated in girls and women from 9 through 45 years of age for the prevention of cervical, vulvar, vaginal, and anal cancer; premalignant genital lesions (cervical, vulvar and vaginal); premalignant anal lesions; HPV infections; cervical adenocarcinoma in situ (AIS); and external genital warts (Condyloma acuminata) causally related to Human Papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 45, 52, and 58.
GARDASIL 9 is indicated in boys and men from 9 through 45 years of age for the prevention of premalignant lesions and HPV infections caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58; anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58 and genital warts (Condyloma acuminata) caused by HPV types 6 and 11.
Dosage/Direction for Use
Dosage: Gardasil should be administered IM as 3 separate 0.5-mL doses according to the following schedule: 1st Dose: At elected date; 2nd Dose: 2 months after the 1st dose; 3rd Dose: 6 months after the 1st dose.
Individuals are encouraged to adhere to the 0 month, 2 months 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. If an alternate vaccination schedule is necessary, the 2nd dose should be administered at least 1 month after the 1st dose and the 3rd dose should be administered at least 3 months after the 2nd dose.
The need for a booster dose has not been established. The duration of protection is currently unknown.
Administration: Gardasil should be administered IM in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.
Gardasil must not be injected intravascularly. Neither SC nor intradermal administration has been studied. These methods of administration are not recommended.
The pre-filled syringe is for single use only and should not be used for >1 individual.
Gardasil should be used as supplied; no dilution or reconstitution is necessary. The full recommended dose of Gardasil should be used.
Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of Gardasil.
After thorough agitation, Gardasil is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Discard Gardasil if particulates are present or if it appears discolored.
Pre-filled Syringe Use: Inject the entire contents of the syringe.
Overdosage
There have been reports of administration of higher than recommended doses of Gardasil. In general, the adverse event profile reported with overdose was comparable to recommended single doses of Gardasil.
Contraindications
Hypersensitivity to quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine or to any of the excipients of Gardasil.
Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of Gardasil should not receive further doses of Gardasil.
Special Precautions
General: As for any vaccine, vaccination with Gardasil may not result in protection in all vaccine recipients.
Gardasil is not intended to be used for treatment of active external genital lesions; cervical, vulvar, vaginal or anal cancers; Cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN) or AIN.
Gardasil will not protect against diseases that are not caused by human papillomavirus (HPV).
Vaccination does not substitute for routine cervical cancer screening. Women who receive Gardasil should continue to undergo cervical cancer screening per standard of care.
As with all injectable vaccines, appropriate medical treatment should always be readily available in case of rare anaphylactic reactions following the administration of Gardasil.
Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with Gardasil. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position. Vaccinees should be carefully observed for approximately 15 min after administration of Gardasil (see Post-Marketing Reports under Side Effects).
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 Interactions).
Gardasil should be given with caution to individuals with thrombocytopenia or any coagulation disorder because bleeding may occur following an IM administration in these individuals.
Use in Other Special Populations: The safety, immunogenicity and efficacy of Gardasil have not been fully evaluated in HIV-infected individuals.
Use in pregnancy: Studies in Female Rats: Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development. Gardasil induced a specific antibody response against HPV types 6, 11, 16 and 18 in pregnant rats following 1 or multiple IM injections. Antibodies against all 4 HPV types were transferred to the offspring during gestation and possibly during lactation.
Clinical Studies in Humans: There are, however, 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 Gardasil.
In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of Gardasil. Women who were found to be pregnant before completion of a 3-dose regimen of Gardasil were instructed to defer completion of their vaccination regimen until resolution of the pregnancy. Such non-standard regimens resulted in postdose 3 anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 responses that were comparable to those observed in women who received a standard 0-month, 2-month and 6-month vaccination regimen (see Dosage & Administration).
During clinical trials, 3819 women (vaccine n=1894 versus placebo n=1925) reported at least 1 pregnancy. The overall proportions of pregnancies 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), were 22.6% (446/1973) in individuals who received Gardasil and 23.1% (460/1994) in individuals who received placebo.
Further sub-analyses were done to evaluate pregnancies with estimated onset within 30 days or >30 days from administration of a dose of Gardasil or placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received Gardasil compared to 1 case of congenital anomaly in the group that received placebo. The congenital anomalies seen included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia and club foot. Conversely, in pregnancies with onset >30 days following vaccination, 40 cases of congenital anomaly were observed in the group that received Gardasil compared with 33 cases of congenital anomaly in the group that received placebo. The types of anomalies observed were consistent (regardless of when pregnancy occurred in relation to vaccination) with those generally observed in pregnancies in women 16-45 years.
Use in lactation: It is not known whether vaccine antigens or antibodies induced by the vaccine are excreted in human milk. However, since many drugs are excreted in human milk, caution should be exercised when Gardasil is administered to a nursing woman.
Gardasil or placebo were given to a total of 1133 women who were breastfeeding at any time during the relevant phase III clinical studies. In these studies, the rates of adverse experiences in the mother and the nursing infant were comparable between vaccination groups. In addition, vaccine immunogenicity was comparable among nursing mothers and women who did not nurse during Gardasil administration.
Use in children: The safety and efficacy of Gardasil have not been evaluated in children <9 years.
Use In Pregnancy & Lactation
Use in pregnancy: Studies in Female Rats: Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development. Gardasil induced a specific antibody response against HPV types 6, 11, 16 and 18 in pregnant rats following 1 or multiple IM injections. Antibodies against all 4 HPV types were transferred to the offspring during gestation and possibly during lactation.
Clinical Studies in Humans: There are, however, 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 Gardasil.
In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of Gardasil. Women who were found to be pregnant before completion of a 3-dose regimen of Gardasil were instructed to defer completion of their vaccination regimen until resolution of the pregnancy. Such non-standard regimens resulted in postdose 3 anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 responses that were comparable to those observed in women who received a standard 0-month, 2-month and 6-month vaccination regimen (see Dosage & Administration).
During clinical trials, 3819 women (vaccine n=1894 versus placebo n=1925) reported at least 1 pregnancy. The overall proportions of pregnancies 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), were 22.6% (446/1973) in individuals who received Gardasil and 23.1% (460/1994) in individuals who received placebo.
Further sub-analyses were done to evaluate pregnancies with estimated onset within 30 days or >30 days from administration of a dose of Gardasil or placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received Gardasil compared to 1 case of congenital anomaly in the group that received placebo. The congenital anomalies seen included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia and club foot. Conversely, in pregnancies with onset >30 days following vaccination, 40 cases of congenital anomaly were observed in the group that received Gardasil compared with 33 cases of congenital anomaly in the group that received placebo. The types of anomalies observed were consistent (regardless of when pregnancy occurred in relation to vaccination) with those generally observed in pregnancies in women 16-45 years.
Use in lactation: It is not known whether vaccine antigens or antibodies induced by the vaccine are excreted in human milk. However, since many drugs are excreted in human milk, caution should be exercised when Gardasil is administered to a nursing woman.
Gardasil or placebo were given to a total of 1133 women who were breastfeeding at any time during the relevant phase III clinical studies. In these studies, the rates of adverse experiences in the mother and the nursing infant were comparable between vaccination groups. In addition, vaccine immunogenicity was comparable among nursing mothers and women who did not nurse during Gardasil administration.
Side Effects
Clinical Trials: In 7 clinical trials (6 placebo-controlled), individuals were administered Gardasil or placebo on the day of enrollment and approximately 2 months and 6 months thereafter. Gardasil demonstrated a favorable safety profile when compared with placebo (aluminum- or non-aluminum-containing). Few individuals (0.2%) discontinued due to adverse experiences. In all except 1 of the clinical trials, safety was evaluated using vaccination report card (VRC)-aided surveillance for 14 days after each injection of Gardasil or placebo. The individuals who were monitored using VRC-aided surveillance included 10,088 individuals (6995 girls and women 9-45 years and 3093 boys and men 9-26 years at enrollment) who received Gardasil and 7995 individuals who received placebo.
The vaccine-related adverse experiences were observed among recipients of Gardasil at a frequency of at least 1% and also at a greater frequency than that observed among placebo recipients are listed according to frequency and system organ class.
The frequency classifications are as follows: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000).
Vaccine-Related Clinical Adverse Experiences in 9-Year Old Through 45-Year Old Girls and Women: Nervous System Disorders: Very Common: Headache. Common: Dizziness.
Gastrointestinal Disorders: Common: Nausea.
Musculoskeletal and Connective Tissue Disorders: Common: Pain in extremity.
General Disorders and Administration Site Conditions: Very Common: Pyrexia.
The following injection site reactions occurred at a greater incidence in the group that received Gardasil compared with either the amorphous aluminum hydroxyphosphate sulfate adjuvant-containing or the saline placebo group: Very Common: Erythema, pain and swelling. Common: Pruritus and hematoma.
Most injection site reactions were mild to moderate.
In addition, bronchospasm was reported very rarely as a serious adverse experience.
Vaccine-Related Clinical Adverse Experiences in 9-Year Old Through 26-Year Old Boys and Men: Nervous System Disorders: Common: Headache.
General Disorders and Administration Site Conditions: Common: Pyrexia.
The following injection site reactions occurred at a greater incidence in the group that received Gardasil compared with either the amorphous aluminum hydroxyphosphate sulfate adjuvant-containing or the saline placebo group: Very Common: Erythema, pain and swelling.
The following injection site reaction occurred at a greater incidence in the group that received Gardasil compared with the amorphous aluminum hydroxyphosphate sulfate adjuvant-containing placebo group: Common: Hematoma.
Most injection site reactions were mild to moderate.
Concomitant Administration with Other Vaccines: The safety of Gardasil when administered concomitantly with other vaccines was evaluated in clinical studies.
The frequency of adverse experiences observed with concomitant administration with hepatitis B vaccine (recombinant) was similar to the frequency when Gardasil was administered alone.
There was an increase in headache and injection site swelling when Gardasil was given concomitantly with Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content).
There was an increase in injection site swelling when Gardasil was given concomitantly with Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap).
The majority of these adverse experiences seen with concomitant administration with other vaccines were reported as being mild to moderate in intensity.
Post-Marketing Reports: The following adverse experiences have been spontaneously reported during post-approval use of Gardasil. Because these experiences were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure.
Infections and Infestations: Cellulitis.
Blood and Lymphatic System Disorders: Idiopathic thrombocytopenic purpura, lymphadenopathy.
Nervous System Disorders: Acute disseminated encephalomyelitis, dizziness, Guillain-Barre syndrome, headache, syncope sometimes accompanied by tonic-clonic movements.
Gastrointestinal Disorders: Nausea, vomiting.
Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia.
General Disorders and Administration Site Conditions: Asthenia, chills, fatigue, malaise.
Immune System Disorders: Hypersensitivity reactions including anaphylactic/anaphylactoid reactions, bronchospasm and urticaria.
Drug Interactions
Use with Other Vaccines: Results from clinical studies indicate that Gardasil may be administered concomitantly (at a separate injection site) with HBvaxPRO [hepatitis B vaccine (recombinant)]. 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)].
Use with Common Medications: In clinical studies for girls and women (16-26 years), 11.9%, 9.5%, 6.9% and 4.3% of individuals used analgesics, anti-inflammatory drugs, antibiotics and vitamin preparations, respectively. In a clinical study in women (24-45 years), 30.6%, 20.2%, 11.6%, and 7.5% of individuals used analgesics, anti-inflammatory drugs, antibiotics, and vitamin preparations, respectively. Conversely in a clinical study in boys and men (16-26 years), 10.3%, 7.8%, 6.8%, 3.4% and 2.6% of individuals used analgesics, anti-inflammatory drugs, antibiotics, antihistamines and vitamin preparations, respectively. The efficacy, immunogenicity and safety of Gardasil were not impacted by the use of these medications.
Use with Hormonal Contraceptives: In clinical studies, 50.2% of women (16-45 years) who received Gardasil used hormonal contraceptives. Use of hormonal contraceptives did not appear to affect the immune responses to Gardasil.
Use with Steroids: In clinical studies for girls and women (16-26 years), 1.7% (n=158), 0.6% (n=56) and 1% (n=89) of individuals used inhaled, topical and parenteral immunosuppressants, respectively. In a clinical study in women (24-45 years), 1.4% (n=27) used corticosteroids for systemic use. In a clinical study in boys and men (16-26 years), 1% (n=21) used corticosteroids for systemic use. The corticosteroids for all individuals were administered close to the time of administration of a dose of Gardasil. These medicines did not appear to affect the immune responses to Gardasil. Very few individuals in the clinical studies were taking steroids, and the amount of immunosuppression is presumed to have been low.
Use with Systemic Immunosuppressive Medications: There are no data on the concomitant use of potent immunosuppressants with Gardasil. Individuals receiving therapy with immunosuppressive agents (systemic doses of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may not respond optimally to active immunization (see General under Precautions).
Storage
Store refrigerated at 2-8°C (36-46°F). Do not freeze. Protect from light.
Gardasil should be administered as soon as possible after being removed from refrigeration. It can be out of refrigeration (at temperatures at or below 25°C/77°F), for a total time of not more than 72 hrs.
ATC Classification
J07BM01 - papillomavirus (human types 6, 11, 16, 18) ; Belongs to the class of papillomavirus vaccines.
Presentation/Packing
Vaccine inj (pre-filled syringe, sterile) 0.5 mL x 1's.
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