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CDC Finalizes Advisory Panel Recommendations for GARDASIL®, Merck's Cervical Cancer Vaccine
Business Wire, March 22, 2007
MERCK & CO., INC.
Whitehouse Station, NJ 08889, USA 9682301
----------------------------------------------------------------------
GARDASIL(R)
(Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant
Vaccine)
DESCRIPTION
GARDASIL* is a non-infectious recombinant, quadrivalent vaccine
prepared from the highly purified virus-like particles (VLPs) of the
major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1
proteins are produced by separate fermentations in 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
preformed aluminum-containing adjuvant (amorphous aluminum
hydroxyphosphate sulfate). The quadrivalent 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 and the final purification buffer.
GARDASIL is a sterile preparation for intramuscular
administration. Each 0.5-mL dose contains approximately 20 mcg of HPV
6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1
protein, and 20 mcg of HPV 18 L1 protein.
Each 0.5-mL dose of the vaccine contains approximately 225 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.
After thorough agitation, GARDASIL is a white, cloudy liquid.
CLINICAL PHARMACOLOGY
Disease Burden
Human Papillomavirus (HPV) causes squamous cell cervical cancer
(and its histologic precursor lesions Cervical Intraepithelial
Neoplasia (CIN) 1 or low grade dysplasia and CIN 2/3 or moderate to
high grade dysplasia) and cervical adenocarcinoma (and its precursor
lesion adenocarcinoma in situ (AIS)). HPV also causes approximately
35-50% of vulvar and vaginal cancers. Vulvar Intraepithelial Neoplasia
(VIN) Grade 2/3 and Vaginal Intraepithelial Neoplasia (VaIN) Grade 2/3
are immediate precursors to these cancers.
Cervical cancer prevention focuses on routine screening and early
intervention. This strategy has reduced cervical cancer rates by
approximately 75% in compliant individuals by monitoring and removing
premalignant dysplastic lesions.
HPV also causes genital warts (condyloma acuminata) which are
growths of the cervicovaginal, vulvar, and the external genitalia that
rarely progress to cancer. HPV 6, 11, 16, and 18 are common HPV types.
HPV 16 and 18 cause approximately:
-- 70% of cervical cancer, AIS, CIN 3, VIN 2/3, and VaIN 2/3
cases; and
-- 50% of CIN 2 cases.
HPV 6, 11, 16, and 18 cause approximately:
-- 35 to 50% of all CIN 1, VIN 1, and VaIN 1 cases; and
-- 90% of genital wart cases.
Mechanism of Action
HPV only infects humans, but animal studies with analogous
(animal, not human) papillomaviruses suggest that the efficacy of L1
VLP vaccines is mediated by the development of humoral immune
responses.
CLINICAL STUDIES
CIN 2/3 and AIS are the immediate and necessary precursors of
squamous cell carcinoma and adenocarcinoma of the cervix,
respectively. Their detection and removal has been shown to prevent
cancer; thus, they serve as surrogate markers for prevention of
cervical cancer.
Efficacy was assessed in 4 placebo-controlled, double-blind,
randomized Phase II and III clinical studies. The first Phase II study
evaluated the HPV 16 component of GARDASIL (Protocol 005, N = 2391)
and the second evaluated all components of GARDASIL (Protocol 007, N =
551). The Phase III studies, termed FUTURE (Females United To
Unilaterally Reduce Endo/Ectocervical Disease), evaluated GARDASIL in
5442 (FUTURE I or Protocol 013) and 12,157 (FUTURE II or Protocol 015)
subjects. Together, these four studies evaluated 20,541 women 16 to 26
years of age at enrollment. The median duration of follow-up was 4.0,
3.0, 2.4, and 2.0 years for Protocol 005, Protocol 007, FUTURE I, and
FUTURE II, respectively. Subjects received vaccine or placebo on the
day of enrollment, and 2 and 6 months thereafter. Efficacy was
analyzed for each study individually and for all studies combined
according to a prospective clinical plan.
Prophylactic Efficacy
GARDASIL is designed to prevent HPV 6-, 11-, 16-, and/or
18-related cervical cancer, cervical dysplasias, vulvar or vaginal
dysplasias, or genital warts. GARDASIL was administered without
prescreening for presence of HPV infection and the efficacy trials
allowed enrollment of subjects regardless of baseline HPV status
(i.e., Polymerase Chain Reaction (PCR) status or serostatus). Subjects
who were infected with a particular vaccine HPV type (and who may
already have had disease due to that infection) were not eligible for
prophylactic efficacy evaluations for that type.
The primary analyses of efficacy 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 (PCR negative
in cervicovaginal specimens and seronegative) to the relevant HPV
type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month
Postdose 3 (Month 7). Efficacy was measured starting after the Month 7
visit.
Overall, 73% of subjects were naive (i.e., PCR negative and
seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types
at enrollment.
A total of 27% of subjects had evidence of prior exposure to or
ongoing infection with at least 1 of the 4 vaccine HPV types. Among
these subjects, 74% 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 subjects who were naive (PCR negative and seronegative) to all
4 vaccine HPV types, CIN, genital warts, VIN, and VaIN caused by any
of the 4 vaccine HPV types were counted as endpoints.
Among subjects 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 subject was
naive (PCR negative and seronegative) were counted.
For example, in subjects 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.
GARDASIL was efficacious in reducing the incidence of CIN (any
grade including CIN 2/3); AIS; genital warts; VIN (any grade); and
VaIN (any grade) related to vaccine HPV types in those who were PCR
negative and seronegative at baseline (Table 1).
Table 1
Analysis of Efficacy of GARDASIL in the PPE* Population**
----------------------------------------------------------------------
GARDASIL Placebo
----------------------
Population Number Number % Efficacy (95% CI)
n of n of
cases cases
======================================================================
HPV 16- or 18-related CIN 2/3 or AIS
----------------------------------------------------------------------
Protocol 005*** 755 0 750 12 100.0 (65.1, 100.0)
----------------------------------------------------------------------
Protocol 007 231 0 230 1 100.0 (-3734.9, 100.0)
----------------------------------------------------------------------
FUTURE I 2200 0 2222 19 100.0 (78.5, 100.0)
----------------------------------------------------------------------
FUTURE II 5301 0 5258 21 100.0 (80.9, 100.0)
----------------------------------------------------------------------
Combined Protocols 8487 0 8460 53 100.0 (92.9, 100.0)
------------------------------------------------======================
HPV 6-, 11-, 16-, 18-related CIN (CIN 1, CIN 2/3) or AIS
----------------------------------------------------------------------
Protocol 007 235 0 233 3 100.0 (-137.8, 100.0)
----------------------------------------------------------------------
FUTURE I 2240 0 2258 37 100.0 (89.5, 100.0)
----------------------------------------------------------------------
FUTURE II 5383 4 5370 43 90.7 (74.4, 97.6)
----------------------------------------------------------------------
Combined Protocols 7858 4 7861 83 95.2 (87.2, 98.7)
======================================================================
HPV 6-, 11-, 16-, or 18-related Genital Warts
----------------------------------------------------------------------
Protocol 007 235 0 233 3 100.0 (-139.5, 100.0)
----------------------------------------------------------------------
FUTURE I 2261 0 2279 29 100.0 (86.4, 100.0)
----------------------------------------------------------------------
FUTURE II 5401 1 5387 59 98.3 (90.2, 100.0)
----------------------------------------------------------------------
Combined Protocols 7897 1 7899 91 98.9 (93.7, 100.0)
----------------------------------------------------------------------
* The PPE 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 Postdose 3 (Month 7).
**See Table 2 for analysis of vaccine impact in the general
population.
***Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL.
P-values were computed for pre-specified primary hypothesis tests.
All p-values were less than0.001, supporting the following
conclusions: efficacy against HPV 16/18-related CIN 2/3 is greater
than0% (FUTURE II); efficacy against HPV 16/18-related CIN 2/3 is
greater than25% (Combined Protocols); and efficacy against HPV
6/11/16/18-related CIN is greater than20% (FUTURE I).
Analyses of the combined trials were prospectively planned and
included the use of similar study entry criteria.
n = Number of subjects with at least 1 follow-up visit after Month 7.
Note 1: Point estimates and confidence intervals are adjusted for
person-time of follow-up.
Note 2: The first analysis in the table (i.e., HPV 16- or 18-related
CIN 2/3, AIS or worse) was the primary endpoint of the vaccine
development plan.
Note 3: FUTURE I refers to Protocol 013; FUTURE II refers to Protocol
015.
----------------------------------------------------------------------
GARDASIL was efficacious against HPV disease caused by each of the
4 vaccine HPV types.
In a pre-defined analysis, the efficacy of GARDASIL against HPV
16/18-related disease was 100% (95% CI: 87.9%, 100.0%) for CIN 3 or
AIS and 100% (95% CI: 55.5%, 100.0%) for VIN 2/3 or VaIN 2/3. The
efficacy of GARDASIL against HPV 6-, 11-, 16-, and 18-related VIN 1 or
VaIN 1 was 100% (95% CI: 75.8%, 100.0%). These analyses were conducted
in the PPE population that 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 Postdose 3 (Month 7).
Efficacy in Subjects with Current or Prior Infection
GARDASIL is a prophylactic vaccine.
There was no clear evidence of protection from disease caused by
HPV types for which subjects were PCR positive and/or seropositive at
baseline.
Individuals who were already infected with 1 or more
vaccine-related HPV types prior to vaccination were protected from
clinical disease caused by the remaining vaccine HPV types.
General Population Impact
The general population of young American women includes women who
are HPV-naive (PCR negative and seronegative) and women who are
HPV-non-naive (PCR positive and/or seropositive), some of whom have
HPV-related disease. The clinical trials population approximated the
general population of American women with respect to prevalence of HPV
infection and disease at enrollment. Analyses were conducted to
evaluate the overall impact of GARDASIL with respect to HPV 6-, 11-,
16-, and 18-related cervical and genital disease in the general
population. Here, analyses included events arising from HPV infections
that were present at the start of vaccination as well as events that
arose from infections that were acquired after the start of
vaccination.
The impact of GARDASIL in the general population is shown in Table
2. Impact was measured starting 1 month Postdose 1. Prophylactic
efficacy denotes the vaccine's efficacy in women who are naive (PCR
negative and seronegative) to the relevant HPV types at vaccination
onset. General population impact denotes vaccine impact among women
regardless of baseline PCR status and serostatus. The majority of CIN
and genital warts, VIN, and VaIN detected in the group that received
GARDASIL occurred as a consequence of HPV infection with the relevant
HPV type that was already present at Day 1.
Table 2
General Population Impact for Vaccine HPV Types
----------------------------------------------------------------------
GARDASIL or
HPV 16 L1 Placebo
VLP
Vaccine % Reduction
Endpoints Analysis ---------------------- (95% CI)
N Cases N Cases
======================================================================
Prophylactic
Efficacy* 9342 1 9400 81 98.8 (92.9, 100.0)
-----------------------------------------------------
HPV 16- or 18- HPV 16
related CIN 2/3 and/or HPV
or AIS 18 Positive
at Day 1 -- 121 -- 120 --
-----------------------------------------------------
General
Population
Impact** 9831 122 9896 201 39.0 (23.3, 51.7)
======================================================================
Prophylactic
Efficacy* 8641 0 8667 24 100.0 (83.3, 100.0)
-----------------------------------------------------
HPV 16- or 18- HPV 16
related VIN 2/3 and/or HPV
and VaIN 2/3 18 Positive
at Day 1 -- 8 -- 2 --
-----------------------------------------------------
General
Population
Impact** 8954 8 8962 26 69.1 (29.8, 87.9)
======================================================================
Prophylactic
Efficacy* 8625 9 8673 143 93.7 (87.7, 97.2)
-----------------------------------------------------
HPV 6-, 11-, HPV 6, HPV
16-, 18-related 11, HPV 16,
CIN (CIN 1, CIN and/or HPV
2/3) or AIS 18 Positive
at Day 1 -- 161*** -- 174*** --
-----------------------------------------------------
General
Population
Impact ** 8814 170 8846 317 46.4 (35.2, 55.7)
======================================================================
Prophylactic
Efficacy* 8760 9 8786 136 93.4 (87.0, 97.0)
-----------------------------------------------------
HPV 6-, 11-, HPV 6, HPV
16-, or 18- 11, HPV 16,
related Genital and/or HPV
Warts 18 Positive
at Day 1 -- 49 -- 48 --
-----------------------------------------------------
General
Population
Impact ** 8954 58 8962 184 68.5 (57.5, 77.0)
----------------------------------------------------------------------
*Includes all subjects who received at least 1 vaccination and who
were naive (PCR negative and seronegative) to HPV 6, 11, 16, and/or
18 at Day 1. Case counting started at 1 Month Postdose 1.
**Includes all subjects who received at least 1 vaccination
(regardless of baseline HPV status at Day 1). Case counting started
at 1 Month Postdose 1.
***Includes 2 subjects (1 in each vaccination group) who underwent
colposcopy for reasons other than an abnormal Pap and 1 placebo
subject with missing serology/PCR data at day 1.
Includes 1 subject with missing serology/PCR data at day 1.
Note 1: The 16- and 18-related CIN 2/3 or AIS composite endpoint
included data from studies 005, 007, 013, and 015. All other
endpoints only included data from studies 007, 013, and 015.
Note 2: Positive status at Day 1 denotes PCR positive and/or
seropositive for the respective type at Day 1.
Note 3: Percent reduction includes the prophylactic efficacy of
GARDASIL as well as the impact of GARDASIL on the course of
infections present at the start of the vaccination.
Note 4: Table 2 does not include disease due to non-vaccine HPV types.
----------------------------------------------------------------------
GARDASIL does not prevent infection with the HPV types not
contained in the vaccine. Cases of disease due to non-vaccine types
were observed among recipients of GARDASIL and placebo in Phase II and
Phase III efficacy studies.
Among cases of CIN 2/3 or AIS caused by vaccine or non-vaccine HPV
types in subjects in the general population who received GARDASIL, 79%
occurred in subjects who had an abnormal Pap test at Day 1 and/or who
were positive (PCR positive and/or seropositive) to HPV 6, 11, 16,
and/or 18 at Day 1.
An interim analysis of the general population impact for GARDASIL
was performed from studies 007, 013, and 015 that had a median
duration of follow-up of 1.9 years. GARDASIL reduced the overall rate
of CIN 2/3 or AIS caused by vaccine or non-vaccine HPV types by 12.2%
(95% CI: -3.2%, 25.3%), compared with placebo.
An analysis of overall population impact for the HPV 16 L1 VLP
vaccine was conducted from study 005 that had a median duration of
follow-up of 3.9 years. The HPV 16 L1 VLP vaccine reduced the overall
incidence of CIN 2/3 caused by vaccine or non-vaccine HPV types by
32.7% (95% CI: -34.7%, 67.3%) through a median duration of follow-up
of 1.9 years (fixed case analysis) and by 45.3% (95% CI: 10.9%,
67.1%), through a median duration of follow-up of 3.9 years (end of
study).
GARDASIL reduced the incidence of definitive therapy (e.g., loop
electrosurgical excision procedure, laser conization, cold knife
conization) by 16.5% (95% CI: 2.9%, 28.2%), and surgery to excise
external genital lesions by 26.5% (95% CI: 3.6%, 44.2%), compared with
placebo for all HPV-related diseases. These analyses were performed in
the general population of women which includes women regardless of
baseline HPV PCR status or serostatus. GARDASIL has not been shown to
protect against the diseases caused by all HPV types and will not
treat existing disease caused by the HPV types contained in the
vaccine. The overall efficacy of GARDASIL, described above, will
depend on the baseline prevalence of HPV infection related to vaccine
types in the population vaccinated and the incidence of HPV infection
due to types not included in the vaccine.
Immunogenicity
Assays to Measure Immune Response
Because there were few disease cases in subjects naive (PCR
negative and seronegative) to vaccine HPV types at baseline in the
group that received GARDASIL, 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 disease caused by HPV 6, 11, 16,
and/or 18.
The immunogenicity of GARDASIL was assessed in 8915 women
(GARDASIL N = 4666; placebo N = 4249) 18 to 26 years of age and female
adolescents 9 to 17 years of age (GARDASIL N = 1471; placebo N = 583).
Type-specific competitive 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 GARDASIL
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 Postdose 3 (Month 7), received
all 3 vaccinations, and did not deviate from the study protocol in
ways that could interfere with the effects of the vaccine.
Overall, 99.8%, 99.8%, 99.8%, and 99.5% of girls and women who
received GARDASIL became anti-HPV 6, anti-HPV 11, anti-HPV 16, and
anti-HPV 18 seropositive, respectively, by 1 month Postdose 3 across
all age groups tested. Anti-HPV 6, anti-HPV 11, anti-HPV 16, and
anti-HPV 18 GMTs peaked at Month 7. GMTs declined through Month 24 and
then stabilized through Month 36 at levels above baseline (Table 3).
The duration of immunity following a complete schedule of immunization
with GARDASIL has not been established.
Table 3
Summary of Anti-HPV cLIA Geometric Mean Titers in the PPI* Population
----------------------------------------------------------------------
GARDASIL Aluminum-Containing Placebo
N** = 276 N = 275
Study Time ---------------------------------------------------------
Geometric Mean Titer Geometric Mean Titer
n*** (95% CI) n (95% CI)
mMU/mL mMU/mL
======================================================================
Anti-HPV 6
----------------------------------------------------------------------
Month 07 208 582.2 (527.2, 642.8) 198 4.6 (4.3, 4.8)
----------------------------------------------------------------------
Month 24 192 93.7 (82.2, 106.9) 188 4.6 (4.3, 5.0)
----------------------------------------------------------------------
Month 36 183 93.8 (81.0, 108.6) 184 5.1 (4.7, 5.6)
----------------------------------------------------------------------
Anti-HPV 11
----------------------------------------------------------------------
Month 07 208 696.5 (617.8, 785.2) 198 4.1 (4.0, 4.2)
----------------------------------------------------------------------
Month 24 190 97.1 (84.2, 112.0) 188 4.2 (4.0, 4.3)
----------------------------------------------------------------------
Month 36 174 91.7 (78.3, 107.3) 180 4.4 (4.1, 4.7)
----------------------------------------------------------------------
Anti-HPV 16
----------------------------------------------------------------------
Month 07 193 3889.0 (3318.7, 4557.4) 185 6.5 (6.2, 6.9)
----------------------------------------------------------------------
Month 24 174 393.0 (335.7, 460.1) 175 6.8 (6.3, 7.4)
----------------------------------------------------------------------
Month 36 176 507.3 (434.6, 592.0) 170 7.7 (6.8, 8.8)
----------------------------------------------------------------------
Anti-HPV 18
----------------------------------------------------------------------
Month 07 219 801.2 (693.8, 925.4) 209 4.6 (4.3, 5.0)
----------------------------------------------------------------------
Month 24 204 59.9 (49.7, 72.2) 199 4.6 (4.3, 5.0)
----------------------------------------------------------------------
Month 36 196 59.7 (48.5, 73.5) 193 4.8 (4.4, 5.2)
----------------------------------------------------------------------
* The PPI population consisted of individuals who received all 3
vaccinations within pre-defined day ranges, did not have major
deviations from the study protocol, met predefined criteria for the
interval between the Month 6 and Month 7 visit, 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 Postdose 3 (Month 7).
**Number of subjects randomized to the respective vaccination group
who received at least 1 injection.
***Number of subjects in the per-protocol analysis with data at the
specified study time point.
mMU = milli-Merck units.
Note: These data are from Protocol 007.
----------------------------------------------------------------------
Table 4 compares anti-HPV GMTs 1 month Postdose 3 among subjects
who received Dose 2 between Month 1 and Month 3 and subjects who
received Dose 3 between Month 4 and Month 8 (Table 4).
Table 4
Summary of GMTs for Variation of Dosing Regimen
----------------------------------------------------------------------
Anti-HPV 6 Anti-HPV 11
Variation of Dosing -----------------------------------------
Regimen N GMT N GMT
(95% CI) (95% CI)
======================================================================
Dose 2
----------------------------------------------------------------------
Early* 570.9 824.6
883 (542.2, 601.2) 888 (776.7, 875.5)
----------------------------------------------------------------------
On Time* 552.3 739.7
1767 (532.3, 573.1) 1785 (709.3, 771.5)
----------------------------------------------------------------------
Late* 447.4 613.9
313 (405.3, 493.8) 312 (550.8, 684.2)
----------------------------------------------------------------------
Dose 3
----------------------------------------------------------------------
Early** 493.1 658.9
495 (460.8, 527.8) 501 (609.5, 712.2)
----------------------------------------------------------------------
On Time** 549.6 752.8
2081 (531.1, 568.8) 2093 (723.8, 782.9)
----------------------------------------------------------------------
Late** 589.0 865.3
335 (537.0, 645.9) 339 (782.6, 956.7)
----------------------------------------------------------------------
Anti-HPV 16 Anti-HPV 18
Variation of Dosing -------------------------------------------
Regimen N GMT N GMT
(95% CI) (95% CI)
======================================================================
Dose 2
----------------------------------------------------------------------
Early* 2625.3 517.7
854 (2415.1, 2853.9) 926 (482.9, 555.0)
----------------------------------------------------------------------
On Time* 2400.0 473.9
1737 (2263.9, 2544.3) 1894 (451.8, 497.1)
----------------------------------------------------------------------
Late* 1889.7 388.5
285 (1624.4, 2198.5) 334 (348.3, 433.3)
----------------------------------------------------------------------
Dose 3
----------------------------------------------------------------------
Early** 2176.6 423.4
487 (1953.4, 2425.3) 521 (388.8, 461.2)
----------------------------------------------------------------------
On Time** 2415.0 486.0
2015 (2286.3, 2550.9) 2214 (464.7, 508.2)
----------------------------------------------------------------------
Late** 2765.9 498.5
326 (2408.7, 3176.2) 361 (446.2, 557.0)
----------------------------------------------------------------------
*Early = 36 to 50 days Postdose 1; On Time = 51 to 70 days Postdose 1;
Late = 71 to 84 days Postdose 1.
**Early = 80 to 105 days Postdose 2; On Time = 106 to 137 days
Postdose 2; Late = 138 to 160 days Postdose 2.
Note: GMT = Geometric mean titer in mMU/mL (mMU = milli-Merck units.)
----------------------------------------------------------------------
Bridging the Efficacy of GARDASIL from Young Adult Women to
Adolescent Girls
A clinical study compared anti-HPV 6, anti-HPV 11, anti-HPV 16,
and anti-HPV 18 GMTs in 10- to 15-year-old girls with responses in 16-
to 23-year-old adolescent and young adult women. Among subjects who
received GARDASIL, 99.1 to 100% became anti-HPV 6, anti-HPV 11,
anti-HPV 16, and anti-HPV 18 seropositive by 1 month Postdose 3.
Table 5 compares the 1 month Postdose 3 anti-HPV 6, anti-HPV 11,
anti-HPV 16, and anti-HPV 18 GMTs in 9- to 15-year-old girls with
those in 16- to 26-year-old adolescent and young adult women.
Table 5
Immunogenicity Bridging Between 9- to 15-year-old Female Adolescents
and 16- to 26-year-old Adult Women
----------------------------------------------------------------------
9- to 15-year-old 16- to 26-year-old
Female Adolescents Adult Women
(Protocols 016 and 018) (Protocols 013 and 015)
Assay N = 1121 N = 4229
(cLIA) --------------------------------------------------------
n GMT (95% CI) n GMT (95% CI)
======================================================================
Anti-HPV 6 915 928.7 (874.0, 986.8) 2631 542.6 (526.2, 559.6)
----------------------------------------------------------------------
Anti-HPV 11 915 1303.0 (1223.1, 1388.0) 2655 761.5 (735.3, 788.6)
----------------------------------------------------------------------
Anti-HPV 16 913 4909.2 (4547.6, 5299.5) 2570 2293.9 (2185.0, 2408.2)
----------------------------------------------------------------------
Anti-HPV 18 920 1039.8 (964.9, 1120.4) 2796 461.6 (444.0, 480.0)
----------------------------------------------------------------------
Note: GMT = Geometric mean titer in mMU/mL (mMU = milli-Merck units).
----------------------------------------------------------------------
Anti-HPV responses 1 month Postdose 3 among 9- to 15-year-old
girls were non-inferior to anti-HPV responses in 16- to 26-year-old
adolescent and young adult women in the combined database of
immunogenicity studies for GARDASIL.
On the basis of this immunogenicity bridging, the efficacy of
GARDASIL in 9- to 15-year-old girls is inferred.
Studies with Other Vaccines
The safety and immunogenicity of co-administration of GARDASIL
with hepatitis B vaccine (recombinant) (same visit, injections at
separate sites) were evaluated in a randomized study of 1871 women
aged 16 to 24 years at enrollment. Immune response to both hepatitis B
vaccine (recombinant) and GARDASIL was non-inferior whether they were
administered at the same visit or at a different visit.
INDICATIONS AND USAGE
GARDASIL is a vaccine indicated in girls and women 9-26 years of
age for the prevention of the following diseases caused by Human
Papillomavirus (HPV) types 6, 11, 16, and 18:
-- Cervical cancer
-- Genital warts (condyloma acuminata)
and the following precancerous or dysplastic lesions:
-- Cervical adenocarcinoma in situ (AIS)
-- Cervical intraepithelial neoplasia (CIN) grade 2 and grade 3
-- Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
-- Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
-- Cervical intraepithelial neoplasia (CIN) grade 1
CONTRAINDICATIONS
Hypersensitivity to the active substances or to any of the
excipients of the vaccine.
Individuals who develop symptoms indicative of hypersensitivity
after receiving a dose of GARDASIL should not receive further doses of
GARDASIL.
PRECAUTIONS
General
As for any vaccine, vaccination with GARDASIL may not result in
protection in all vaccine recipients.
This vaccine is not intended to be used for treatment of active
genital warts; cervical cancer; CIN, VIN, or VaIN.
This vaccine will not protect against diseases that are not caused
by HPV.
GARDASIL has not been shown to protect against diseases due to
non-vaccine HPV types.
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.
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 PRECAUTIONS,
Drug Interactions).
As with other intramuscular injections, GARDASIL should not be
given to individuals with bleeding disorders such as hemophilia or
thrombocytopenia, or to persons on anticoagulant therapy unless the
potential benefits clearly outweigh the risk of administration. If the
decision is made to administer GARDASIL to such persons, it should be
given with steps to avoid the risk of hematoma following the
injection.
Information for the Patient, Parent, or Guardian
The health care provider should inform the patient, parent, or
guardian that vaccination does not substitute for routine cervical
cancer screening. Women who receive GARDASIL should continue to
undergo cervical cancer screening per standard of care.
The health care provider should provide the vaccine information
required to be given with each vaccination to the patient, parent, or
guardian.
The health care provider should inform the patient, parent, or
guardian of the benefits and risks associated with vaccination. For
risks associated with vaccination, see PRECAUTIONS and ADVERSE
REACTIONS.
GARDASIL is not recommended for use in pregnant women.
The health care provider should inform the patient, parent, or
guardian of the importance of completing the immunization series
unless contraindicated.
Patients, parents, or guardians should be instructed to report any
adverse reactions to their health care provider.
Drug Interactions
Use with Other Vaccines
Results from clinical studies indicate that GARDASIL may be
administered concomitantly (at a separate injection site) with
hepatitis B vaccine (recombinant) (see CLINICAL PHARMACOLOGY, Studies
with Other Vaccines). Co-administration of GARDASIL with other
vaccines has not been studied.
Use with Hormonal Contraceptives
In clinical studies, 13,293 subjects (vaccine = 6644; placebo =
6649) who had post-Month 7 follow-up used hormonal contraceptives for
a total of 17,597 person-years (65.1% of the total follow-up time in
the studies). Use of hormonal contraceptives or lack of use of
hormonal contraceptives among study participants did not alter vaccine
efficacy in the PPE population.
Use with Systemic Immunosuppressive Medications
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 PRECAUTIONS, General).
Carcinogenesis, Mutagenesis, Impairment of Fertility
GARDASIL has not been evaluated for the potential to cause
carcinogenicity or genotoxicity.
GARDASIL administered to female rats at a dose of 120 mcg total
protein, which corresponds to approximately 300-fold excess relative
to the projected human dose, had no effects on mating performance,
fertility, or embryonic/fetal survival.
Pregnancy
Pregnancy Category B:
Reproduction studies have been performed in female rats at doses
up to 300 times the human dose (on a mg/kg basis) and have revealed no
evidence of impaired female fertility or harm to the fetus due to
GARDASIL. However, it is not known whether GARDASIL can cause fetal
harm when administered to a pregnant woman or if it can affect
reproductive capacity. GARDASIL should be given to a pregnant woman
only if clearly needed. An evaluation of the effect of GARDASIL on
embryo-fetal, pre- and postweaning development was conducted using
rats. One group of rats was administered GARDASIL twice prior to
gestation, during the period of organogenesis (gestation day 6) and on
lactation day 7. A second group of pregnant rats was administered
GARDASIL during the period of organogenesis (gestation day 6) and on
lactation day 7 only. GARDASIL was administered at 0.5 mL/rat/occasion
(approximately 300-fold excess relative to the projected human dose on
a mg/kg basis) by intramuscular injection. 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 this study. In addition, there were no treatment-related
effects on developmental signs, behavior, reproductive performance, or
fertility of the offspring. The effect of GARDASIL on male fertility
has not been studied.
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.
During clinical trials, 2266 women (vaccine = 1115 vs. placebo =
1151) reported at least 1 pregnancy each. Overall, the proportions of
pregnancies with an adverse outcome were comparable in subjects who
received GARDASIL and subjects who received placebo. Overall, 40 and
41 subjects in the group that received GARDASIL or placebo,
respectively (3.6% and 3.6% of all subjects who reported a pregnancy
in the respective vaccination groups), experienced a serious adverse
experience during pregnancy. The most common events reported were
conditions that can result in Caesarean section (e.g., failure of
labor, malpresentation, cephalopelvic disproportion), premature onset
of labor (e.g., threatened abortions, premature rupture of membranes),
and pregnancy-related medical problems (e.g., pre-eclampsia,
hyperemesis). The proportions of pregnant subjects who experienced
such events were comparable between the vaccination groups.
There were 15 cases of congenital anomaly in pregnancies that
occurred in subjects who received GARDASIL and 16 cases of congenital
anomaly in pregnancies that occurred in subjects who received placebo.
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 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
0 cases of congenital anomaly in the group that received placebo. The
congenital anomalies seen in pregnancies with estimated onset within
30 days of vaccination included pyloric stenosis, congenital
megacolon, congenital hydronephrosis, hip dysplasia and club foot.
Conversely, in pregnancies with onset more than 30 days following
vaccination, 10 cases of congenital anomaly were observed in the group
that received GARDASIL compared with 16 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
aged 16 to 26 years.
Pregnancy Registry for GARDASIL
Merck & Co., Inc. maintains a Pregnancy Registry to monitor fetal
outcomes of pregnant women exposed to GARDASIL. Patients and health
care providers are encouraged to report any exposure to GARDASIL
during pregnancy by calling (800) 986-8999.
Lactation
It is not known whether vaccine antigens or antibodies induced by
the vaccine are excreted in human milk.
Because many drugs are excreted in human milk, caution should be
exercised when GARDASIL is administered to a nursing woman.
A total of 995 nursing mothers (vaccine = 500, placebo = 495) were
given GARDASIL or placebo during the vaccination period of the
clinical trials. GMTs in nursing and non-nursing mothers were as
follows:
The GMTs in nursing mothers were 595.9 (95% CI: 522.5, 679.5) for
anti-HPV 6, 864.3 (95% CI: 754.0, 990.8) for anti-HPV 11, 3056.9 (95%
CI: 2594.4, 3601.8) for anti-HPV 16, and 527.2 (95% CI: 450.9, 616.5)
for anti-HPV 18. The GMTs for women who did not nurse during vaccine
administration were 540.1 (95% CI: 523.5, 557.2) for anti-HPV 6, 746.3
(95% CI: 720.4, 773.3) for anti-HPV 11, 2290.8 (95% CI: 2180.7,
2406.3) for anti-HPV 16, and 456.0 (95% CI: 438.4, 474.3) for anti-HPV
18.
Overall, 17 and 9 infants of subjects who received GARDASIL or
placebo, respectively (representing 3.4% and 1.8% of the total number
of subjects who were breast-feeding during the period in which they
received GARDASIL or placebo, respectively), experienced a serious
adverse experience. None was judged by the investigator to be vaccine
related.
In clinical studies, a higher number of breast-feeding infants (n
= 6) whose mothers received GARDASIL had acute respiratory illnesses
within 30 days post-vaccination of the mother as compared to infants
(n = 2) whose mothers received placebo. In these studies, the rates of
other adverse experiences in the mother and the nursing infant were
comparable between vaccination groups.
Pediatric Use
The safety and efficacy of GARDASIL have not been evaluated in
children younger than 9 years.
Geriatric Use
The safety and efficacy of GARDASIL have not been evaluated in
adults above the age of 26 years.
ADVERSE REACTIONS
In 5 clinical trials (4 placebo-controlled), subjects were
administered GARDASIL or placebo on the day of enrollment, and
approximately 2 and 6 months thereafter. Few subjects (0.1%)
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 subjects who were monitored using VRC-aided
surveillance included 5088 girls and women 9 through 26 years of age
at enrollment who received GARDASIL and 3790 girls and women who
received placebo.
Common Adverse Experiences
Vaccine-related Common Adverse Experiences
The vaccine-related adverse experiences that were observed among
female recipients of GARDASIL at a frequency of at least 1.0% and also
at a greater frequency than that observed among placebo recipients are
shown in Table 6.
Table 6
Vaccine-related Injection-site and Systemic Adverse Experiences*
----------------------------------------------------------------------
Aluminum-Containing Saline
GARDASIL Placebo Placebo
Adverse Experience (N = 5088) (N = 3470) (N = 320)
(1 to 5 Days Postvaccination) % % %
----------------------------------------------------------------------
Injection Site
Pain 83.9 75.4 48.6
Swelling 25.4 15.8 7.3
Erythema 24.6 18.4 12.1
Pruritus 3.1 2.8 0.6
----------------------------------------------------------------------
GARDASIL Placebo
Adverse Experience (N = 5088) (N = 3790)
(1 to 15 Days Postvaccination) % %
----------------------------------------------------------------------
Systemic
Fever 10.3 8.6
Nausea 4.2 4.1
Dizziness 2.8 2.6
----------------------------------------------------------------------
* The vaccine-related adverse experiences that were observed among
recipients of GARDASIL were at a frequency of at least 1.0% and also
at a greater frequency than that observed among placebo recipients.
All-cause Common Systemic Adverse Experiences
All-cause systemic adverse experiences for female subjects that
were observed at a frequency of greater than or equal to 1% where the
incidence in the vaccine group was greater than or equal to the
incidence in the placebo group are shown in Table 7.
Table 7
All-cause Common Systemic Adverse Experiences
----------------------------------------------------------------------
GARDASIL Placebo
Adverse Experience (N = 5088) (N = 3790)
(1 to 15 Days Postvaccination) % %
----------------------------------------------------------------------
Pyrexia 13.0 11.2
Nausea 6.7 6.6
Nasopharyngitis 6.4 6.4
Dizziness 4.0 3.7
Diarrhea 3.6 3.5
Vomiting 2.4 1.9
Myalgia 2.0 2.0
Cough 2.0 1.5
Toothache 1.5 1.4
Upper respiratory tract infection 1.5 1.5
Malaise 1.4 1.2
Arthralgia 1.2 0.9
Insomnia 1.2 0.9
Nasal congestion 1.1 0.9
----------------------------------------------------------------------
Evaluation of Injection-site Adverse Experiences by Dose
An analysis of injection-site adverse experiences in female
subjects by dose is shown in Table 8. Overall, 94.3% of subjects who
received GARDASIL judged their injection-site adverse experience to be
mild or moderate in intensity.
Table 8
Postdose Evaluation of Injection-site Adverse Experiences
----------------------------------------------------------------------
Aluminum-Containing
Vaccine Placebo
(% occurrence) (% occurrence)
======================================================================
Adverse Post- Post- Post- Post Post- Post- Post- Post
Experience dose dose dose Any dose dose dose Any
1 2 3 Dose 1 2 3 Dose
----------------------------------------------------------------------
Pain 63.4 60.7 62.7 83.9 57.0 47.8 49.5 75.4
Mild/Moderate 62.5 59.7 61.2 81.1 56.6 47.3 48.9 74.1
Severe 0.9 1.0 1.5 2.8 0.4 0.5 0.6 1.3
----------------------------------------------------------------------
Swelling* 10.2 12.8 15.1 25.4 8.2 7.5 7.6 15.8
Mild/Moderate 9.6 11.9 14.3 23.3 8.0 7.2 7.3 15.2
Severe 0.6 0.8 0.8 2.0 0.2 0.3 0.2 0.6
----------------------------------------------------------------------
Erythema* 9.2 12.1 14.7 24.7 9.8 8.4 8.9 18.4
Mild/Moderate 9.0 11.7 14.3 23.7 9.5 8.3 8.8 18.0
Severe 0.2 0.3 0.4 0.9 0.3 0.1 0.1 0.4
----------------------------------------------------------------------
Saline Placebo
(% occurrence)
======================================================================
Adverse Post- Post- Post- Post
Experience dose dose dose Any
1 2 3 Dose
----------------------------------------------------------------------
Pain 33.7 20.3 27.3 48.6
Mild/Moderate 33.3 20.3 27.0 48.0
Severe 0.3 0.0 0.3 0.6
----------------------------------------------------------------------
Swelling* 4.4 3.0 3.3 7.3
Mild/Moderate 4.4 3.0 3.3 7.3
Severe 0.0 0.0 0.0 0.0
----------------------------------------------------------------------
Erythema* 7.3 5.3 5.7 12.1
Mild/Moderate 7.3 5.3 5.7 12.1
Severe 0.0 0.0 0.0 0.0
----------------------------------------------------------------------
*Intensity of swelling and erythema was measured by size (inches):
Mild = 0 to (less than=)1; Moderate = greater than1 to (less than=)2;
Severe = greater than2.
----------------------------------------------------------------------
Evaluation of Fever by Dose
An analysis of fever in girls and women by dose is shown in Table
9.
Table 9
Postdose Evaluation of Fever
----------------------------------------------------------------------
Vaccine Placebo
(% occurrence) (% occurrence)
======================================================================
Temperature Postdose Postdose Postdose Postdose Postdose Postdose
((degree)F) 1 2 3 1 2 3
----------------------------------------------------------------------
(greater than=)
100 to 102 3.7 4.1 4.4 3.1 3.8 3.6
----------------------------------------------------------------------
(greater than=)
102 0.3 0.5 0.5 0.3 0.4 0.6
----------------------------------------------------------------------
Serious Adverse Experiences
A total of 102 subjects out of 21,464 total subjects (9- to
26-year-old girls and women and 9- to 15-year-old boys) who received
both GARDASIL and placebo reported a serious adverse experience on Day
1-15 following any vaccination visit during the clinical trials for
GARDASIL. The most frequently reported serious adverse experiences for
GARDASIL compared to placebo and regardless of causality were:
headache (0.03% GARDASIL vs. 0.02% Placebo),
gastroenteritis (0.03% GARDASIL vs. 0.01% Placebo),
appendicitis (0.02% GARDASIL vs. 0.01% Placebo),
pelvic inflammatory disease (0.02% GARDASIL vs. 0.01% Placebo).
One case of bronchospasm and 2 cases of asthma were reported as
serious adverse experiences that occurred during Day 1-15 of any
vaccination visit.
Deaths
Across the clinical studies, 17 deaths were reported in 21,464
male and female subjects. The events reported were consistent with
events expected in healthy adolescent and adult populations. The most
common cause of death was motor vehicle accident (4 subjects who
received GARDASIL and 3 placebo subjects), followed by
overdose/suicide (1 subject who received GARDASIL and 2 subjects who
received placebo), and pulmonary embolus/deep vein thrombosis (1
subject who received GARDASIL and 1 placebo subject). In addition,
there were 2 cases of sepsis, 1 case of pancreatic cancer, and 1 case
of arrhythmia in the group that received GARDASIL, and 1 case of
asphyxia in the placebo group.
Systemic Autoimmune Disorders
In the clinical studies, subjects were evaluated for new medical
conditions that occurred over the course of up to 4 years of follow
up. The number of subjects who received both GARDASIL and placebo and
developed a new medical condition potentially indicative of a systemic
immune disorder is shown in Table 10.
Table 10
Summary of Subjects Who Reported an Incident Condition Potentially
Indicative of Systemic Autoimmune Disorder After Enrollment in
Clinical Trials of GARDASIL
----------------------------------------------------------------------
GARDASIL Placebo
Potential Autoimmune Disorder (N = 11,813) (N = 9701)
======================================================================
Specific Terms 3 (0.025%) 1 (0.010%)
Juvenile arthritis 1 0
Rheumatoid arthritis 2 0
Systemic lupus erythematosus 0 1
Other Terms 6 (0.051%) 2 (0.021%)
Arthritis 5 2
Reactive Arthritis 1 0
----------------------------------------------------------------------
N = Number of subjects enrolled
----------------------------------------------------------------------
Safety in Concomitant Use with Other Vaccines
The safety of GARDASIL when administered concomitantly with
hepatitis B vaccine (recombinant) was evaluated in a
placebo-controlled study. There were no statistically significant
higher rates in systemic or injection-site adverse experiences among
subjects who received concomitant vaccination compared with those who
received GARDASIL or hepatitis B vaccine alone.
Reporting of Adverse Events
The US Department of Health and Human Services has established a
Vaccine Adverse Event Reporting System (VAERS) to accept all reports
of suspected adverse events after the administration of any vaccine,
including but not limited to the reporting of events required by the
National Childhood Vaccine Injury Act of 1986. For information or a
copy of the vaccine reporting form, call the VAERS toll-free number at
1-800-822-7967 or report on line to www.vaers.hhs.gov.
DOSAGE AND ADMINISTRATION
Dosage
GARDASIL 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
Method of Administration
GARDASIL should be administered intramuscularly in the deltoid
region of the upper arm or in the higher anterolateral area of the
thigh.
GARDASIL must not be injected intravascularly. Subcutaneous and
intradermal administration have not been studied, and therefore are
not recommended.
The prefilled syringe is for single use only and should not be
used for more than 1 individual. For single-use vials a separate
sterile syringe and needle must be used for each individual.
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, GARDASIL is a white, cloudy liquid.
Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration. Do not use the
product if particulates are present or if it appears discolored.
Single-dose Vial Use
Withdraw the 0.5-mL dose of vaccine from the single-dose vial
using a sterile needle and syringe free of preservatives, antiseptics,
and detergents. Once the single-dose vial has been penetrated, the
withdrawn vaccine should be used promptly, and the vial must be
discarded.
Prefilled Syringe Use
Inject the entire contents of the syringe.
Instructions for using the prefilled single-dose syringes preassembled
with needle guard (safety) device
(GRAPHIC OMITTED)
NOTE: Please use the enclosed needle for administration. If a
different needle is chosen, it should fit securely on the syringe and
be no longer than 1 inch to ensure proper functioning of the needle
guard device. Two detachable labels are provided which can be removed
after the needle is guarded.
Remove Syringe Tip Cap. Attach Luer Needle. Depress both Anti-Rotation
Tabs to secure syringe and attach Luer Needle by twisting in clockwise
direction. Remove Needle Sheath. Administer injection per standard
protocol as stated above under DOSAGE AND ADMINISTRATION. Depress the
Plunger while grasping the Finger Flange until the entire dose has
been given. The Needle Guard Device will NOT activate to cover and
protect the needle unless the ENTIRE dose has been given. Remove
needle from the vaccine recipient. Release the Plunger and allow
syringe to move up until the entire needle is guarded. For
documentation of vaccination, remove detachable labels by pulling
slowly on them. Dispose in approved sharps container.
HOW SUPPLIED
Vials
No. 4045 -- GARDASIL is supplied as a carton of one 0.5-mL
single-dose vial, NDC 0006-4045-00.
No. 4045 -- GARDASIL is supplied as a carton of ten 0.5-mL
single-dose vials, NDC 0006-4045-41.
Syringes
No. 4109 -- GARDASIL is supplied as a carton of one 0.5-mL
single-dose prefilled Luer Lock syringe, preassembled with UltraSafe
Passive(R)(1) delivery system. A one-inch, 25-gauge needle is provided
separately in the package. NDC 0006-4109-31.
No. 4109 -- GARDASIL is supplied as a carton of six 0.5-mL
single-dose prefilled Luer Lock syringes, preassembled with UltraSafe
Passive(R) delivery system. One-inch, 25-gauge needles are provided
separately in the package. NDC 0006-4109-06.
Storage
Store refrigerated at 2 to 8(degree)C (36 to 46(degree)F). Do not
freeze. Protect from light.
----------------------------------------------------------------------
Manuf. and Dist. by:
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA
Issued July 2006
----------------------------------------------------------------------
(1) UltraSafe Passive(R) delivery system is a Trademark of Safety
Syringes, Inc.
Printed in USA
* Registered trademark of MERCK & CO., Inc., Whitehouse Station, NJ
08889, USA
COPYRIGHT (C) 2006 MERCK & CO., Inc.
All rights reserved
GARDASIL(R) 9682302
(Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18)
Recombinant Vaccine) 9682302
USPPI
Patient Information about
GARDASIL(R) (pronounced "gard-Ah-sill")
Generic name: (Quadrivalent Human Papillomavirus (Types 6, 11, 16,
18) Recombinant Vaccine)
Read this information with care before you or your child gets
GARDASIL*. You or your child will need 3 doses of the vaccine. It is
important to read this leaflet when you receive each dose. This
leaflet does not take the place of talking with your health care
professional about GARDASIL.
What is GARDASIL and what is it used for?
GARDASIL is a vaccine (injection/shot) that helps protect against
the following diseases caused by Human Papillomavirus (HPV) Types in
the vaccine (6, 11, 16, and 18):
-- Cervical cancer (cancer of the lower end of the uterus or
womb).
-- Abnormal and precancerous cervical lesions.
-- Abnormal and precancerous vaginal lesions.
-- Abnormal and precancerous vulvar lesions.
-- Genital warts.
GARDASIL helps prevent these diseases - but it will not treat
them.
You or your child cannot get these diseases from GARDASIL.
What other key information about GARDASIL should I know?
-- Vaccination does not substitute for routine cervical cancer
screening. Females who receive GARDASIL should continue
cervical cancer screening.
-- As with all vaccines, GARDASIL may not fully protect everyone
who gets the vaccine.
-- Gardasil will not protect against diseases due to non-vaccine
HPV types. There are more than 100 HPV types; GARDASIL helps
protect against 4 types (6, 11, 16, and 18). These 4 types
have been selected for GARDASIL because they cause
approximately 70% of cervical cancers and 90% of genital
warts.
-- This vaccine will not protect you against HPV types to which
you may have already been exposed.
-- GARDASIL also will not protect against other diseases that are
not caused by HPV.
-- GARDASIL works best when given before you or your child has
any contact with certain types of HPV (i.e., HPV types 6, 11,
16, and 18).
Who can receive GARDASIL?
GARDASIL is for girls and women 9 through 26 years of age.
See "Who should not receive GARDASIL?" below.
Who should not receive GARDASIL?
Anyone who:
-- is allergic to any of the ingredients in the vaccine. A list
of ingredients can be found at the end of this leaflet.
-- has an allergic reaction after getting a dose of the vaccine.
What should I tell my health care professional before I am
vaccinated or my child is vaccinated with GARDASIL?
It is very important to tell your health care professional if you
or your child:
-- has had an allergic reaction to the vaccine.
-- has a bleeding disorder and cannot receive injections in the
arm.
-- has a weakened immune system, for example, due to a genetic
defect or HIV infection.
-- is pregnant or is planning to get pregnant. GARDASIL is not
recommended for use in pregnant women.
-- has any illness with a fever more than 100(degree)F
(37.8(degree)C).
-- takes or plans to take any medicines, even those you can buy
over the counter.
Your health care professional will decide if you or your child
should receive the vaccine.
How is GARDASIL given?
GARDASIL is given as an injection.
You or your child will receive 3 doses of the vaccine. Ideally the
doses are given as:
-- First dose: at a date you and your health care professional
choose.
-- Second dose: 2 months after the first dose.
-- Third dose: 6 months after the first dose.
Make sure that you or your child gets all 3 doses. This allows you
or your child to get the full benefits of GARDASIL. If you or your
child misses a dose, your health care professional will decide when to
give the missed dose.
What are the possible side effects of GARDASIL?
As with all vaccines, there may be some side effects with
GARDASIL. GARDASIL has been shown to be generally well tolerated in
women and girls as young as 9 years of age.
The most commonly reported side effects included:
-- pain, swelling, itching, and redness at the injection site.
-- fever.
-- nausea.
-- dizziness.
Difficulty breathing (bronchospasm) has been reported very rarely.
If you or your child has any unusual or severe symptoms after
receiving GARDASIL, contact your health care professional right away.
For a more complete list of side effects, ask your health care
professional.
What are the ingredients in GARDASIL?
The main ingredients are purified inactive proteins that come from
HPV Types 6, 11, 16, and 18.
It also contains amorphous aluminum hydroxyphosphate sulfate,
sodium chloride, L-histidine, polysorbate 80, sodium borate, and water
for injection.
What are cervical cancer, precancerous lesions, and genital warts?
Cancer of the cervix is a serious disease that can be
life-threatening. This disease is caused by certain HPV types that can
cause the cells in the lining of the cervix to change from normal to
precancerous lesions. If these are not treated, they can turn
cancerous.
Genital warts are caused by certain types of HPV. They often
appear as skin-colored growths. They are found on the inside or
outside of the genitals. They can hurt, itch, bleed, and cause
discomfort. These lesions are usually not precancerous. Sometimes, it
takes multiple treatments to eliminate these lesions.
What is Human Papillomavirus (HPV)?
HPV is a common virus. In 2005, the Centers for Disease Control
and Prevention (CDC) estimated that 20 million people in the United
States had this virus. There are many different types of HPV; some
cause no harm. Others can cause diseases of the genital area. For most
people the virus goes away on its own. When the virus does not go away
it can develop into cervical cancer, precancerous lesions, or genital
warts, depending on the HPV type. See "What other key information
about GARDASIL should I know?"
Who is at risk for Human Papillomavirus?
In 2005, the CDC estimated that at least 50% of sexually active
people catch HPV during their lifetime. A male or female of any age
who takes part in any kind of sexual activity that involves genital
contact is at risk.
Many people who have HPV may not show any signs or symptoms. This
means that they can pass on the virus to others and not know it.
Will GARDASIL help me if I already have Human Papillomavirus?
You may benefit from GARDASIL if you already have HPV. This is
because most people are not infected with all four types of HPV
contained in the vaccine. In clinical trials, individuals with current
or past infection with one or more vaccine-related HPV types prior to
vaccination were protected from disease caused by the remaining
vaccine HPV types. GARDASIL is not intended to be used for treatment
for the above mentioned diseases. Talk to your health care
professional for more information.
This leaflet is a summary of information about GARDASIL. If you
would like more information, please talk to your health care
professional or visit www.gardasil.com.
Issued October 2006
Manufactured and Distributed by: MERCK & CO., Inc.
Whitehouse Station, NJ 08889, USA
* Registered trademark of MERCK & CO., Inc. Whitehouse Station, NJ
08889, USA COPYRIGHT (C) 2006 MERCK & CO., Inc. All rights reserved
COPYRIGHT 2007 Business Wire
COPYRIGHT 2008 Gale, Cengage Learning
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