New England Journal of Medicine Publishes New Data on Gardasil, Merck's Cervical Cancer Vaccine

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)-May 10, 2007--Today, the New England Journal of Medicine is publishing results from two Phase III studies of Merck's cervical cancer vaccine, Gardasil (Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine). In the first study, Gardasil provided 100 percent protection against cervical, vaginal and vulvar diseases caused by the four HPV types Gardasil is designed to protect against, HPV types 6, 11, 16, and 18. In the second study, GARDASIL provided 98 percent protection against advanced cervical pre-cancers caused by the two primary cancer-causing HPV types, HPV 16 and 18. These significant results, observed in 15- to 26-year-old women who were not infected with the relevant HPV types when they began the study, were sustained through an average of three years of participation in the trials, including an additional year of follow up since data were presented to the U.S. Food and Drug Administration (FDA) for approval of GARDASIL.

"In these two studies, GARDASIL demonstrated significant protection against serious HPV-related diseases, including high-grade cervical pre-cancers, in women not previously exposed to the relevant HPV types targeted by the vaccine," said Kevin Ault, M.D., associate professor, Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta. "Widespread immunization of 11- to 26-year-old girls and women with GARDASIL, along with continued screening, will help decrease the burden of cervical cancer and other HPV-related diseases."

It is estimated that in 2007, cervical cancer will strike more than 11,000 women in the U.S. and nearly 500,000 women around the world. GARDASIL helps protect against the four HPV types - 6, 11, 16 and 18 - that cause the most disease, including 70 percent of cervical cancer cases and 90 percent of cases of genital warts. All four types cause a large number of "abnormal" Pap test results and low-grade cervical lesions.

"My fellow investigators around the world are proud of these data and their contribution to our understanding of the impact of GARDASIL on risk for development of cervical, vulvar, and vaginal diseases caused by HPV 6, 11, 16, and 18," said Eliav Barr, M.D., executive director of Biologics Clinical Research and head of the HPV Vaccine Program, Merck Research Laboratories. "In women not infected with the four HPV types targeted by GARDASIL, GARDASIL reduced cervical disease caused by the relevant HPV types. And, across the larger study population, GARDASIL also reduced the overall burden of cervical, vulvar, and vaginal HPV diseases caused by HPV types targeted by the vaccine and by other HPV types."

GARDASIL was approved by the FDA on June 8, 2006, and is recommended for use by girls and women ages 11 to 26 by the U.S. Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices. GARDASIL is indicated for the prevention of HPV types 16- and 18- related cervical cancer, non-invasive cervical cancer (cervical intraepithelial neoplasia (CIN) grade 3 and adenocarcinoma in situ (AIS)), cervical pre-cancers (cervical intraepithelial neoplasia (CIN) grade 2), vulvar pre-cancers (vulvar intraepithelial neoplasia (VIN) 2/3)) and vaginal pre-cancers (vaginal intraepithelial neoplasia (VaIN) 2/3), and for the prevention of genital warts and low-grade cervical lesions (CIN 1) caused by HPV types 6, 11, 16 and 18. GARDASIL is contraindicated in individuals who are hypersensitive to the active substances or to any of the excipients of the vaccine.

Studies assessed CIN 2/3, the most meaningful efficacy measure

The studies, FUTURE I and FUTURE II, are phase III, prospective, double-blind, placebo-controlled randomized studies conducted in 29 countries. The women who participated in the trials were 15 to 26 years old at enrollment; they received three doses of either GARDASIL or placebo at day one, month two and month six. The primary analyses of these trials evaluated the efficacy of GARDASIL compared to placebo in women who were free of infection with the relevant HPV types (6, 11, 16 and/or 18) when they started the study, remained free of infection with the relevant HPV types through month seven, received all three doses of GARDASIL within one year and had no protocol violations.

FUTURE I was designed to evaluate the impact of GARDASIL on the incidence of cervical lesions and pre-cancers (CIN 1-3), vulvar and vaginal external lesions and pre-cancers (VIN 1-3 and VaIN 1-3) and external genital warts caused by the four HPV types targeted by the vaccine (HPV 6, 11, 16 and 18). FUTURE II was designed to evaluate the impact of GARDASIL on pre-cancers and non-invasive cancers (CIN 2/3, AIS) caused by HPV 16 and 18. Prevention of advanced, or high grade cervical pre-cancerous lesions -- CIN 2/3 or AIS -- has been identified by the FDA and World Health Organization as the most meaningful indicator of cancer efficacy for a cervical cancer vaccine.

Results showed that GARDASIL provided significant protection in women not previously exposed to HPV types targeted by the vaccine

In FUTURE I, after an average follow-up of three years, GARDASIL provided 100 percent protection from HPV 6-, 11-, 16- and 18-related VIN 1-3, VaIN 1-3 and genital warts; no cases were observed in the vaccine group (n=2,261) compared to 60 cases in the placebo group (n=2,279). GARDASIL was also 100 percent effective for the prevention of HPV 6-, 11-, 16-, or 18-related CIN 1-3; there were no cases observed in the vaccine group (n=2,241) compared to 65 cases in the placebo group (n=2,258).

In FUTURE II, after an average follow-up of three years, GARDASIL was 98 percent effective in preventing high-grade cervical pre-cancers associated with HPV types 16 and 18; one case of CIN 3 was observed in the vaccine group (n=5,305) compared to 42 cases in the placebo group (n=5,260).

Studies assessed efficacy of GARDASIL in the general population of women

The studies also assessed the efficacy of GARDASIL in the general population of women, including those infected with HPV (and who may have had HPV-related disease) at the start of the trials. In FUTURE I, GARDASIL reduced the rate of cervical lesions caused by vaccine or other HPV types by 20 percent; 344 cases were observed in the vaccine group (n= 2,723); 421 cases were observed in the placebo group (n=2,732). GARDASIL reduced the rate of vaginal or vulvar lesions and genital warts caused by vaccine or other HPV types by 34 percent; 104 cases were observed in the vaccine group (n= 2,723); 157 cases were observed in the placebo group (n=2,732). In FUTURE II, vaccination with GARDASIL reduced the rate of CIN 2/3 and AIS caused by vaccine or other HPV types by 17 percent; 219 cases were observed in the vaccine group (n= 6,087); 266 cases were observed in the placebo group (n=6,080). In both studies, the majority of lesions occurred among women who were already HPV-infected at the start of vaccination. Vaccination with GARDASIL did not change the course of these pre-existing infections. Infections present at the start of vaccination caused most of the lesions in the early period of follow-up; however, over three years, the impact of the vaccine became more apparent, as lesions caused by new infections with vaccine HPV types were observed in the placebo group but not in the vaccine group.

In both studies, the adverse events observed were similar to what has been previously reported.

Additional important information about GARDASIL

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.

Vaccination with GARDASIL may not result in protection in all vaccine recipients. GARDASIL is not intended to be used for treatment of active genital warts; cervical cancer; CIN, VIN, or VaIN. GARDASIL has not been shown to protect against disease due to other HPV types.

In clinical studies for GARDASIL, vaccine-related adverse experiences that were observed at a frequency of at least 1.0 percent among recipients of GARDASIL and also greater than those observed among recipients of placebo, respectively, were pain (83.9 percent vs. 75.4 percent), swelling (25.4 percent vs. 15.8 percent), erythema (24.6 percent vs. 18.4 percent), fever (10.3 percent vs. 8.6 percent), nausea (4.2 percent vs. 4.1 percent), pruritis (3.1 percent vs. 2.8 percent) and dizziness (2.8 percent vs. 2.6 percent).

Dosage and administration for GARDASIL

GARDASIL is a ready-to-use, three-dose, intramuscular vaccine. GARDASIL should be administered in three separate intramuscular injections in the upper arm or upper anterior thigh over a six-month period. The following dosage schedule is recommended: first dose at elected date, second dose two months after the first dose and the third dose six months after the first dose.

GARDASIL is widely available throughout the United States

There is broad private and public health insurance coverage for GARDASIL. Health plans covering approximately 98 percent of privately insured lives in the U.S. (currently more than 140 insurance plans) have implemented coverage for GARDASIL; however, individual benefit coverage and rates provided by health plans may vary.

GARDASIL was also added to the Vaccines for Children (VFC) Program on November 1, 2006, providing coverage for many who do not have private health insurance. All of the 55 immunization projects in the U.S. have adopted GARDASIL and most are filling provider orders.

Merck has also initiated a new patient assistance program for vaccines. Through this program, currently available in private physicians' offices and private clinics, Merck is making available, free of charge, GARDASIL and other Merck vaccines indicated for use in individuals ages 19 and older who are uninsured and who are unable to afford vaccines.

GARDASIL is approved in 70 countries

GARDASIL (sold in some countries as SILGARD(R)) has been approved in 70 countries, including the United States, the 27 countries of the European Union, Mexico, Australia, Taiwan, Canada, New Zealand and Brazil, and additional applications are currently under review with regulatory agencies in many more countries around the world.

Merck will donate free vaccine to the non-profit organization PATH to support demonstration studies designed to accelerate the availability of cervical cancer vaccines in the most impoverished nations. PATH is funded by a grant from the Bill & Melinda Gates Foundation. Merck is also working with India's Council of Medical Research to study GARDASIL in India. Merck will make its new vaccines, including GARDASIL, available to developing world countries at dramatically lower prices.

HPV is a common infection

In the United States, approximately 20 million people are infected with HPV, and approximately 80 percent of females will have acquired HPV by age 50. For most people, HPV goes away on its own; however in some, certain high-risk types of HPV, if unrecognized and untreated, can lead to cervical cancer. Cervical cancer is the second most common cause of cancer death in women worldwide, resulting in nearly a half-million diagnoses and 240,000 deaths each year. It is estimated that in 2007, there will be approximately 11,150 new cases of cervical cancer and 3,700 deaths in the United States. Approximately 6,000 cases of vulvar or vaginal cancer are diagnosed annually in the U.S.

Certain low-risk types of HPV cause genital warts and can lead to abnormal Pap results. Approximately one million cases of genital warts occur each year in the United States and an estimated 32 million cases occur worldwide. Additionally, there are an estimated 4.7 million abnormal Pap results that require follow-up each year in the United States. At least 3 million of these results are caused by some type of HPV.

Other Information about GARDASIL

In 1995, Merck entered into a license agreement and research collaboration with CSL Limited of Australia relating to technology used in GARDASIL. GARDASIL also is the subject of other third-party licensing agreements.

Merck recently announced that it submitted a supplemental Biologics License Application (sBLA) to the FDA that includes efficacy data showing GARDASIL offers some protection against additional cervical cancer causing HPV types responsible for greater than 10 percent of cervical cancers, data on protection against additional gynecological cancers -- vaginal and vulvar -- and data on immune memory.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

GARDASIL(R) is a registered trademark of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A.

Prescribing information and patient product information for GARDASIL(R) is attached and is also available at www.gardasil.com. -0-

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

----------------------------------------------------------------------

                             

Posted: May 2007

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