Merck Launches National Advertising Campaign for GARDASIL(R), Merck's New Cervical Cancer Vaccine

Merck & Co., Inc. announced today the launch of a national print, television and online advertising campaign for the world’s first cervical cancer vaccine, GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]. GARDASIL was approved by the FDA on June 8 – and provisionally recommended by the Advisory Committee on Immunization Practices (ACIP) on June 29 – for girls and women aged 9-261. GARDASIL is the world’s first and only vaccine indicated for the prevention of HPV types 16- and 18-related cervical cancer, cervical pre-cancers (CIN 2/3 and AIS), vulvar pre-cancers (VIN 2/3) and vaginal pre-cancers (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. Adding to Merck's ongoing cervical cancer and HPV education efforts, the new campaign, called One Less, encourages females who are eligible for the vaccine to begin their vaccination series and to also continue to see their doctor for regular healthcare and screening. "The full public health benefit of reducing the burden of cervical cancer and HPV disease may be achieved through broad public awareness and vaccination with GARDASIL, which is the driving force behind One Less," said Bev Lybrand, vice president & general manager, HPV Franchise, GARDASIL, Merck Vaccine Division. "Merck is committed to educating and providing access to women and girls who may benefit from this critical vaccine." One Less is the continuation of Merck's commitment to disease and vaccine education. GARDASIL is for girls and women ages 9-26 years of age. If these girls and women have already been infected with HPV, they may still benefit from GARDASIL because it is unlikely that they have been infected with all four types of the virus covered by the vaccine. To inform and encourage these girls and women, the campaign focuses on a strong and positive message that is designed to empower them to want to become (or help their daughters want to become) "one less" person who will battle cervical cancer. The campaign also focuses on important information about GARDASIL. GARDASIL may not fully protect everyone, and GARDASIL does not prevent all types of cervical cancer, so ongoing cervical cancer screenings will be important. GARDASIL is not recommended for use in pregnant women and GARDASIL will not treat cervical cancer. GARDASIL can cause injection site-pain, -swelling, -itching and -redness as well as fever, dizziness or nausea. For more information about this campaign and to view the commercials, visit www.gardasil.com. Committed to public awareness In addition to One Less, Merck will continue to separately support HPV disease education including the Tell Someone and the Make the Connection multi-lingual disease awareness programs to ensure an understanding about the important link between cervical cancer and HPV and the need to continue regular screening. Merck also provides support and grant funding to national and local organizations to help disseminate disease information to broad and diverse audiences, including those with outreach to underserved communities. Access to GARDASIL There is broad private and public coverage for GARDASIL. Health insurers covering approximately 94 percent of privately insured lives in the U.S. (currently more than 100 insurance plans) have decided to reimburse GARDASIL. GARDASIL was added to the Vaccines for Children (VFC) Program on November 1. Many lives not covered by Managed Care will now be covered under the VFC Program. Merck has also initiated a new patient assistance program for vaccines. Through this new 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 aged 19 and older who are uninsured and who are unable to afford vaccines. Merck is also actively working to accelerate the availability of GARDASIL in the developing world: Merck is working with PATH to develop HPV vaccination programs that will facilitate the introduction of GARDASIL to the most impoverished nations. This initiative is funded by a grant to PATH from the Bill & Melinda Gates Foundation. Merck has also announced a partnership with India's Council of Medical Research to study GARDASIL. Merck will make our new vaccines, including GARDASIL, available at dramatically lower prices to developing world countries. 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 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. Selected important information about GARDASIL GARDASIL is contraindicated in individuals who are hypersensitive to the active substances or to any of the excipients of the vaccine. 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 non-vaccine HPV types. Vaccine-related adverse experiences that were observed in clinical trials 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). About HPV disease 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 2006, there will be approximately 9,700 new cases of cervical cancer and 3,700 deaths in the United States. In addition, 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. HPV types 16 and 18 account for approximately 70 percent of cases of cervical cancer, AIS (non-invasive cervical cancer), CIN 3, VIN 2/3 and VaIN 2/3, and account for 50 percent of CIN 2 lesions. HPV 6 and 11 cause approximately 90 percent of genital wart cases. These four types of HPV also cause approximately 35 to 50 percent of all low-grade cervical, vaginal and vulvar lesions (CIN I, VIN I and VaIN I). 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. Worldwide availability of GARDASIL GARDASIL has been approved in more than 40 countries including the European Union, Mexico, Australia, Taiwan, Canada, New Zealand and Brazil. Additional applications for GARDASIL are currently under review with regulatory agencies in more than 50 countries around the world. Other Information about GARDASIL In 1995, Merck entered into a license agreement and collaboration with CSL Limited relating to technology used in GARDASIL. GARDASIL also is the subject of other third-party licensing agreements. 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 cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference. Prescribing information and patient product information for GARDASIL® is attached and is also available at www.gardasil.com. 1 The ACIP recommended that GARDASIL be administered to 11- and 12- year-old females and to females aged 13 to 26 who have not previously been vaccinated, and that nine- and 10-year-old females can be vaccinated with GARDASIL at the discretion of their physicians. GARDASIL® is a registered trademark of Merck & Co., Inc, Whitehouse Station, N.J., U.S.A. GARDASIL(R) 9682302(Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18)Recombinant Vaccine) DESCRIPTION GARDASIL* is a non-infectious recombinant, quadrivalent vaccineprepared from the highly purified virus-like particles (VLPs) of themajor capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1proteins are produced by separate fermentations in recombinantSaccharomyces cerevisiae and self-assembled into VLPs. Thefermentation process involves growth of S. cerevisiae onchemically-defined fermentation media which include vitamins, aminoacids, mineral salts, and carbohydrates. The VLPs are released fromthe yeast cells by cell disruption and purified by a series ofchemical and physical methods. The purified VLPs are adsorbed onpreformed aluminum-containing adjuvant (amorphous aluminumhydroxyphosphate sulfate). The quadrivalent HPV VLP vaccine is asterile liquid suspension that is prepared by combining the adsorbedVLPs of each HPV type and additional amounts of thealuminum-containing adjuvant and the final purification buffer. GARDASIL is a sterile preparation for intramuscularadministration. Each 0.5-mL dose contains approximately 20 mcg of HPV6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1protein, and 20 mcg of HPV 18 L1 protein. Each 0.5-mL dose of the vaccine contains approximately 225 mcg ofaluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant),9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg ofpolysorbate 80, 35 mcg of sodium borate, and water for injection. Theproduct 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 IntraepithelialNeoplasia (CIN) 1 or low grade dysplasia and CIN 2/3 or moderate tohigh grade dysplasia) and cervical adenocarcinoma (and its precursorlesion adenocarcinoma in situ (AIS)). HPV also causes approximately35-50% of vulvar and vaginal cancers. Vulvar Intraepithelial Neoplasia(VIN) Grade 2/3 and Vaginal Intraepithelial Neoplasia (VaIN) Grade 2/3are immediate precursors to these cancers. Cervical cancer prevention focuses on routine screening and earlyintervention. This strategy has reduced cervical cancer rates byapproximately 75% in compliant individuals by monitoring and removingpremalignant dysplastic lesions. HPV also causes genital warts (condyloma acuminata) which aregrowths of the cervicovaginal, vulvar, and the external genitalia thatrarely 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 L1VLP vaccines is mediated by the development of humoral immuneresponses. CLINICAL STUDIES CIN 2/3 and AIS are the immediate and necessary precursors ofsquamous cell carcinoma and adenocarcinoma of the cervix,respectively. Their detection and removal has been shown to preventcancer; thus, they serve as surrogate markers for prevention ofcervical cancer. Efficacy was assessed in 4 placebo-controlled, double-blind,randomized Phase II and III clinical studies. The first Phase II studyevaluated 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 ToUnilaterally Reduce Endo/Ectocervical Disease), evaluated GARDASIL in5442 (FUTURE I or Protocol 013) and 12,157 (FUTURE II or Protocol 015)subjects. Together, these four studies evaluated 20,541 women 16 to 26years 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, andFUTURE II, respectively. Subjects received vaccine or placebo on theday of enrollment, and 2 and 6 months thereafter. Efficacy wasanalyzed for each study individually and for all studies combinedaccording to a prospective clinical plan. Prophylactic Efficacy GARDASIL is designed to prevent HPV 6-, 11-, 16-, and/or18-related cervical cancer, cervical dysplasias, vulvar or vaginaldysplasias, or genital warts. GARDASIL was administered withoutprescreening for presence of HPV infection and the efficacy trialsallowed enrollment of subjects regardless of baseline HPV status(i.e., Polymerase Chain Reaction (PCR) status or serostatus). Subjectswho were infected with a particular vaccine HPV type (and who mayalready have had disease due to that infection) were not eligible forprophylactic efficacy evaluations for that type. The primary analyses of efficacy were conducted in theper-protocol efficacy (PPE) population, consisting of individuals whoreceived all 3 vaccinations within 1 year of enrollment, did not havemajor deviations from the study protocol, and were naive (PCR negativein cervicovaginal specimens and seronegative) to the relevant HPVtype(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 monthPostdose 3 (Month 7). Efficacy was measured starting after the Month 7visit. Overall, 73% of subjects were naive (i.e., PCR negative andseronegative for all 4 vaccine HPV types) to all 4 vaccine HPV typesat enrollment. A total of 27% of subjects had evidence of prior exposure to orongoing infection with at least 1 of the 4 vaccine HPV types. Amongthese subjects, 74% had evidence of prior exposure to or ongoinginfection with only 1 of the 4 vaccine HPV types and were naive (PCRnegative and seronegative) to the remaining 3 types. In subjects who were naive (PCR negative and seronegative) to all4 vaccine HPV types, CIN, genital warts, VIN, and VaIN caused by anyof the 4 vaccine HPV types were counted as endpoints. Among subjects who were positive (PCR positive and/orseropositive) for a vaccine HPV type at Day 1, endpoints related tothat type were not included in the analyses of prophylactic efficacy.Endpoints related to the remaining types for which the subject wasnaive (PCR negative and seronegative) were counted. For example, in subjects who were HPV 18 positive (PCR positiveand/or seropositive) at Day 1, lesions caused by HPV 18 were notcounted in the prophylactic efficacy evaluations. Lesions caused byHPV 6, 11, and 16 were included in the prophylactic efficacyevaluations. The same approach was used for the other types. GARDASIL was efficacious in reducing the incidence of CIN (anygrade including CIN 2/3); AIS; genital warts; VIN (any grade); andVaIN (any grade) related to vaccine HPV types in those who were PCRnegative 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 than 0.001, supporting the following conclusions: efficacy against HPV 16/18-related CIN 2/3 is greater than 0% (FUTURE II); efficacy against HPV 16/18-related CIN 2/3 is greater than 25% (Combined Protocols); and efficacy against HPV 6/11/16/18-related CIN is greater than 20% (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 the4 vaccine HPV types. In a pre-defined analysis, the efficacy of GARDASIL against HPV16/18-related disease was 100% (95% CI: 87.9%, 100.0%) for CIN 3 orAIS and 100% (95% CI: 55.5%, 100.0%) for VIN 2/3 or VaIN 2/3. Theefficacy of GARDASIL against HPV 6-, 11-, 16-, and 18-related VIN 1 orVaIN 1 was 100% (95% CI: 75.8%, 100.0%). These analyses were conductedin the PPE population that consisted of individuals who received all 3vaccinations within 1 year of enrollment, did not have majordeviations from the study protocol, and were naive (PCR negative andseronegative) 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 byHPV types for which subjects were PCR positive and/or seropositive atbaseline. Individuals who were already infected with 1 or morevaccine-related HPV types prior to vaccination were protected fromclinical disease caused by the remaining vaccine HPV types. General Population Impact The general population of young American women includes women whoare HPV-naive (PCR negative and seronegative) and women who areHPV-non-naive (PCR positive and/or seropositive), some of whom haveHPV-related disease. The clinical trials population approximated thegeneral population of American women with respect to prevalence of HPVinfection and disease at enrollment. Analyses were conducted toevaluate the overall impact of GARDASIL with respect to HPV 6-, 11-,16-, and 18-related cervical and genital disease in the generalpopulation. Here, analyses included events arising from HPV infectionsthat were present at the start of vaccination as well as events thatarose from infections that were acquired after the start ofvaccination. The impact of GARDASIL in the general population is shown in Table2. Impact was measured starting 1 month Postdose 1. Prophylacticefficacy denotes the vaccine's efficacy in women who are naive (PCRnegative and seronegative) to the relevant HPV types at vaccinationonset. General population impact denotes vaccine impact among womenregardless of baseline PCR status and serostatus. The majority of CINand genital warts, VIN, and VaIN detected in the group that receivedGARDASIL occurred as a consequence of HPV infection with the relevantHPV 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-, 16-,HPV 6, HPV 18-related CIN 11, HPV 16, (CIN 1, CIN 2/3) and/or HPV 161*** 174*** or AIS 18 Positive at Day 1 -- -- -- ----------------------------------------------------- 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-, 16-,HPV 6, HPV or 18-related 11, HPV 16, Genital Warts and/or HPV 48+ 18 Positive at Day 1 -- 49 -- -- ----------------------------------------------------- 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 notcontained in the vaccine. Cases of disease due to non-vaccine typeswere observed among recipients of GARDASIL and placebo in Phase II andPhase III efficacy studies. Among cases of CIN 2/3 or AIS caused by vaccine or non-vaccine HPVtypes in subjects in the general population who received GARDASIL, 79%occurred in subjects who had an abnormal Pap test at Day 1 and/or whowere 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 GARDASILwas performed from studies 007, 013, and 015 that had a medianduration of follow-up of 1.9 years. GARDASIL reduced the overall rateof 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 VLPvaccine was conducted from study 005 that had a median duration offollow-up of 3.9 years. The HPV 16 L1 VLP vaccine reduced the overallincidence of CIN 2/3 caused by vaccine or non-vaccine HPV types by32.7% (95% CI: -34.7%, 67.3%) through a median duration of follow-upof 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 ofstudy). GARDASIL reduced the incidence of definitive therapy (e.g., loopelectrosurgical excision procedure, laser conization, cold knifeconization) by 16.5% (95% CI: 2.9%, 28.2%), and surgery to exciseexternal genital lesions by 26.5% (95% CI: 3.6%, 44.2%), compared withplacebo for all HPV-related diseases. These analyses were performed inthe general population of women which includes women regardless ofbaseline HPV PCR status or serostatus. GARDASIL has not been shown toprotect against the diseases caused by all HPV types and will nottreat existing disease caused by the HPV types contained in thevaccine. The overall efficacy of GARDASIL, described above, willdepend on the baseline prevalence of HPV infection related to vaccinetypes in the population vaccinated and the incidence of HPV infectiondue to types not included in the vaccine. Immunogenicity Assays to Measure Immune Response Because there were few disease cases in subjects naive (PCRnegative and seronegative) to vaccine HPV types at baseline in thegroup that received GARDASIL, it has not been possible to establishminimum anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 antibodylevels 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 femaleadolescents 9 to 17 years of age (GARDASIL N = 1471; placebo N = 583). Type-specific competitive immunoassays with type-specificstandards were used to assess immunogenicity to each vaccine HPV type.These assays measured antibodies against neutralizing epitopes foreach HPV type. The scales for these assays are unique to each HPVtype; thus, comparisons across types and to other assays are notappropriate. Immune Response to GARDASIL The primary immunogenicity analyses were conducted in aper-protocol immunogenicity (PPI) population. This populationconsisted of individuals who were seronegative and PCR negative to therelevant HPV type(s) at enrollment, remained HPV PCR negative to therelevant HPV type(s) through 1 month Postdose 3 (Month 7), receivedall 3 vaccinations, and did not deviate from the study protocol inways that could interfere with the effects of the vaccine. Overall, 99.8%, 99.8%, 99.8%, and 99.5% of girls and women whoreceived GARDASIL became anti-HPV 6, anti-HPV 11, anti-HPV 16, andanti-HPV 18 seropositive, respectively, by 1 month Postdose 3 acrossall age groups tested. Anti-HPV 6, anti-HPV 11, anti-HPV 16, andanti-HPV 18 GMTs peaked at Month 7. GMTs declined through Month 24 andthen stabilized through Month 36 at levels above baseline (Table 3).The duration of immunity following a complete schedule of immunizationwith GARDASIL has not been established. Table 3Summary of Anti-HPV cLIA Geometric Mean Titers in the PPI* Population---------------------------------------------------------------------- Aluminum- GARDASIL Containing N** = 276 Placebo N = 275 Study Time --------------------------------------------- Geometric Mean Titer Geometric Mean n*** (95% CI) n Titer (95% mMU/mL+ CI) 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 subjectswho received Dose 2 between Month 1 and Month 3 and subjects whoreceived 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 --------------------------------------- N GMT N GMT Variation of Dosing Regimen (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)----------------------------------------------------------------------*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.)---------------------------------------------------------------------- Anti-HPV 16 Anti-HPV 18 ----------------------------------------- N GMT N GMT Variation of Dosing Regimen (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 toAdolescent 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 whoreceived 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 withthose in 16- to 26-year-old adolescent and young adult women. Table 5Immunogenicity Bridging Between 9- to 15-year-old Female Adolescents and 16- to 26-year-old Adult Women---------------------------------------------------------------------- 9- to 15-year-old Female 16- to 26-year-old Adult Adolescents 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-oldgirls were non-inferior to anti-HPV responses in 16- to 26-year-oldadolescent and young adult women in the combined database ofimmunogenicity studies for GARDASIL. On the basis of this immunogenicity bridging, the efficacy ofGARDASIL in 9- to 15-year-old girls is inferred. Studies with Other Vaccines The safety and immunogenicity of co-administration of GARDASILwith hepatitis B vaccine (recombinant) (same visit, injections atseparate sites) were evaluated in a randomized study of 1871 womenaged 16 to 24 years at enrollment. Immune response to both hepatitis Bvaccine (recombinant) and GARDASIL was non-inferior whether they wereadministered at the same visit or at a different visit. INDICATIONS AND USAGE GARDASIL is a vaccine indicated in girls and women 9-26 years ofage for the prevention of the following diseases caused by HumanPapillomavirus (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 theexcipients of the vaccine. Individuals who develop symptoms indicative of hypersensitivityafter receiving a dose of GARDASIL should not receive further doses ofGARDASIL. PRECAUTIONS General As for any vaccine, vaccination with GARDASIL may not result inprotection in all vaccine recipients. * Registered trademark of MERCK & CO., Inc. Whitehouse Station, NJ08889, USA COPYRIGHT (C) 2006 MERCK & CO., Inc. All rights reserved GARDASIL(R) (Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18)Recombinant Vaccine) This vaccine is not intended to be used for treatment of activegenital warts; cervical cancer; CIN, VIN, or VaIN. This vaccine will not protect against diseases that are not causedby HPV. GARDASIL has not been shown to protect against diseases due tonon-vaccine HPV types. As with all injectable vaccines, appropriate medical treatmentshould always be readily available in case of rare anaphylacticreactions following the administration of the vaccine. The decision to administer or delay vaccination because of acurrent or recent febrile illness depends largely on the severity ofthe symptoms and their etiology. Low-grade fever itself and mild upperrespiratory infection are not generally contraindications tovaccination. Individuals with impaired immune responsiveness, whether due tothe use of immunosuppressive therapy, a genetic defect, HumanImmunodeficiency Virus (HIV) infection, or other causes, may havereduced antibody response to active immunization (see PRECAUTIONS,Drug Interactions). As with other intramuscular injections, GARDASIL should not begiven to individuals with bleeding disorders such as hemophilia orthrombocytopenia, or to persons on anticoagulant therapy unless thepotential benefits clearly outweigh the risk of administration. If thedecision is made to administer GARDASIL to such persons, it should begiven with steps to avoid the risk of hematoma following theinjection. Information for the Patient, Parent, or Guardian The health care provider should inform the patient, parent, orguardian that vaccination does not substitute for routine cervicalcancer screening. Women who receive GARDASIL should continue toundergo cervical cancer screening per standard of care. The health care provider should provide the vaccine informationrequired to be given with each vaccination to the patient, parent, orguardian. The health care provider should inform the patient, parent, orguardian of the benefits and risks associated with vaccination. Forrisks associated with vaccination, see PRECAUTIONS and ADVERSEREACTIONS. GARDASIL is not recommended for use in pregnant women. The health care provider should inform the patient, parent, orguardian of the importance of completing the immunization seriesunless contraindicated. Patients, parents, or guardians should be instructed to report anyadverse reactions to their health care provider. Drug Interactions Use with Other Vaccines Results from clinical studies indicate that GARDASIL may beadministered concomitantly (at a separate injection site) withhepatitis B vaccine (recombinant) (see CLINICAL PHARMACOLOGY, Studieswith Other Vaccines). Co-administration of GARDASIL with othervaccines 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 fora total of 17,597 person-years (65.1% of the total follow-up time inthe studies). Use of hormonal contraceptives or lack of use ofhormonal contraceptives among study participants did not alter vaccineefficacy in the PPE population. Use with Systemic Immunosuppressive Medications Immunosuppressive therapies, including irradiation,antimetabolites, alkylating agents, cytotoxic drugs, andcorticosteroids (used in greater than physiologic doses), may reducethe immune responses to vaccines (see PRECAUTIONS, General). Carcinogenesis, Mutagenesis, Impairment of Fertility GARDASIL has not been evaluated for the potential to causecarcinogenicity or genotoxicity. GARDASIL administered to female rats at a dose of 120 mcg totalprotein, which corresponds to approximately 300-fold excess relativeto 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 dosesup to 300 times the human dose (on a mg/kg basis) and have revealed noevidence of impaired female fertility or harm to the fetus due toGARDASIL. However, it is not known whether GARDASIL can cause fetalharm when administered to a pregnant woman or if it can affectreproductive capacity. GARDASIL should be given to a pregnant womanonly if clearly needed. An evaluation of the effect of GARDASIL onembryo-fetal, pre- and postweaning development was conducted usingrats. One group of rats was administered GARDASIL twice prior togestation, during the period of organogenesis (gestation day 6) and onlactation day 7. A second group of pregnant rats was administeredGARDASIL during the period of organogenesis (gestation day 6) and onlactation day 7 only. GARDASIL was administered at 0.5 mL/rat/occasion(approximately 300-fold excess relative to the projected human dose ona mg/kg basis) by intramuscular injection. No adverse effects onmating, fertility, pregnancy, parturition, lactation, embryo-fetal orpre- and postweaning development were observed. There were novaccine-related fetal malformations or other evidence of teratogenesisnoted in this study. In addition, there were no treatment-relatedeffects on developmental signs, behavior, reproductive performance, orfertility of the offspring. The effect of GARDASIL on male fertilityhas not been studied. In clinical studies, women underwent urine pregnancy testing priorto administration of each dose of GARDASIL. Women who were found to bepregnant before completion of a 3-dose regimen of GARDASIL wereinstructed to defer completion of their vaccination regimen untilresolution of the pregnancy. During clinical trials, 2266 women (vaccine = 1115 vs. placebo =1151) reported at least 1 pregnancy each. Overall, the proportions ofpregnancies with an adverse outcome were comparable in subjects whoreceived GARDASIL and subjects who received placebo. Overall, 40 and41 subjects in the group that received GARDASIL or placebo,respectively (3.6% and 3.6% of all subjects who reported a pregnancyin the respective vaccination groups), experienced a serious adverseexperience during pregnancy. The most common events reported wereconditions that can result in Caesarean section (e.g., failure oflabor, malpresentation, cephalopelvic disproportion), premature onsetof 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 experiencedsuch events were comparable between the vaccination groups. There were 15 cases of congenital anomaly in pregnancies thatoccurred in subjects who received GARDASIL and 16 cases of congenitalanomaly in pregnancies that occurred in subjects who received placebo. Further sub-analyses were conducted to evaluate pregnancies withestimated onset within 30 days or more than 30 days fromadministration of a dose of GARDASIL or placebo. For pregnancies withestimated onset within 30 days of vaccination, 5 cases of congenitalanomaly were observed in the group that received GARDASIL compared to0 cases of congenital anomaly in the group that received placebo. Thecongenital anomalies seen in pregnancies with estimated onset within30 days of vaccination included pyloric stenosis, congenitalmegacolon, congenital hydronephrosis, hip dysplasia and club foot.Conversely, in pregnancies with onset more than 30 days followingvaccination, 10 cases of congenital anomaly were observed in the groupthat received GARDASIL compared with 16 cases of congenital anomaly inthe group that received placebo. The types of anomalies observed wereconsistent (regardless of when pregnancy occurred in relation tovaccination) with those generally observed in pregnancies in womenaged 16 to 26 years. Pregnancy Registry for GARDASIL Merck & Co., Inc. maintains a Pregnancy Registry to monitor fetaloutcomes of pregnant women exposed to GARDASIL. Patients and healthcare providers are encouraged to report any exposure to GARDASILduring pregnancy by calling (800) 986-8999. Lactation It is not known whether vaccine antigens or antibodies induced bythe vaccine are excreted in human milk. Because many drugs are excreted in human milk, caution should beexercised when GARDASIL is administered to a nursing woman. A total of 995 nursing mothers (vaccine = 500, placebo = 495) weregiven GARDASIL or placebo during the vaccination period of theclinical trials. GMTs in nursing and non-nursing mothers were asfollows: The GMTs in nursing mothers were 595.9 (95% CI: 522.5, 679.5) foranti-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 vaccineadministration 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-HPV18. Overall, 17 and 9 infants of subjects who received GARDASIL orplacebo, respectively (representing 3.4% and 1.8% of the total numberof subjects who were breast-feeding during the period in which theyreceived GARDASIL or placebo, respectively), experienced a seriousadverse experience. None was judged by the investigator to be vaccinerelated. In clinical studies, a higher number of breast-feeding infants (n= 6) whose mothers received GARDASIL had acute respiratory illnesseswithin 30 days post-vaccination of the mother as compared to infants(n = 2) whose mothers received placebo. In these studies, the rates ofother adverse experiences in the mother and the nursing infant werecomparable between vaccination groups. Pediatric Use The safety and efficacy of GARDASIL have not been evaluated inchildren younger than 9 years. Geriatric Use The safety and efficacy of GARDASIL have not been evaluated inadults above the age of 26 years. ADVERSE REACTIONS In 5 clinical trials (4 placebo-controlled), subjects wereadministered GARDASIL or placebo on the day of enrollment, andapproximately 2 and 6 months thereafter. Few subjects (0.1%)discontinued due to adverse experiences. In all except 1 of theclinical trials, safety was evaluated using vaccination report card(VRC)-aided surveillance for 14 days after each injection of GARDASILor placebo. The subjects who were monitored using VRC-aidedsurveillance included 5088 girls and women 9 through 26 years of ageat enrollment who received GARDASIL and 3790 girls and women whoreceived placebo. Common Adverse Experiences Vaccine-related Common Adverse Experiences The vaccine-related adverse experiences that were observed amongfemale recipients of GARDASIL at a frequency of at least 1.0% and alsoat a greater frequency than that observed among placebo recipients areshown in Table 6. Table 6 Vaccine-related Injection-site and Systemic Adverse Experiences*---------------------------------------------------------------------- GARDASIL Aluminum- SalineAdverse Experience (N = ContainingPlacebo(1 to 5 Days Postvaccination) 5088) Placebo (N = % (N = 3470) 320) % %---------------------------------------------------------------------- Injection SitePain 83.9 75.4 48.6Swelling 25.4 15.8 7.3Erythema 24.6 18.4 12.1Pruritus 3.1 2.8 0.6---------------------------------------------------------------------- GARDASIL PlaceboAdverse Experience (N = (N = 3790)(1 to 15 Days Postvaccination) 5088) % %---------------------------------------------------------------------- SystemicFever 10.3 8.6Nausea 4.2 4.1Dizziness 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 thatwere observed at a frequency of greater than or equal to 1% where theincidence in the vaccine group was greater than or equal to theincidence in the placebo group are shown in Table 7. Table 7 All-cause Common Systemic Adverse Experiences----------------------------------------------------------------Adverse Experience GARDASIL Placebo(1 to 15 Days Postvaccination) (N = 5088) (N = 3790) % %---------------------------------------------------------------- Pyrexia 13.0 11.2Nausea 6.7 6.6Nasopharyngitis 6.4 6.4Dizziness 4.0 3.7Diarrhea 3.6 3.5Vomiting 2.4 1.9Myalgia 2.0 2.0Cough 2.0 1.5Toothache 1.5 1.4Upper respiratory tract infection 1.5 1.5Malaise 1.4 1.2Arthralgia 1.2 0.9Insomnia 1.2 0.9Nasal congestion 1.1 0.9---------------------------------------------------------------- Evaluation of Injection-site Adverse Experiences by Dose An analysis of injection-site adverse experiences in femalesubjects by dose is shown in Table 8. Overall, 94.3% of subjects whoreceived GARDASIL judged their injection-site adverse experience to bemild or moderate in intensity. Table 8 Postdose Evaluation of Injection-site Adverse Experiences---------------------------------------------------------------------- Vaccine Aluminum-Containing (% occurrence) Placebo (% 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 75.4Mild/Moderate 62.5 59.7 61.2 81.1 56.6 47.3 48.9 74.1Severe 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 15.8Mild/Moderate 9.6 11.9 14.3 23.3 8.0 7.2 7.3 15.2Severe 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 18.4Mild/Moderate 9.0 11.7 14.3 23.7 9.5 8.3 8.8 18.0Severe 0.2 0.3 0.4 0.9 0.3 0.1 0.1 0.4----------------------------------------------------------------------*Intensity of swelling and erythema was measured by size (inches): Mild = 0 toless than or equal to 1; Moderate = greater than 1 to less than or equal to 2; Severe = greater than 2.---------------------------------------------------------------------- Saline Placebo (% occurrence)====================================================================== Adverse Post-Post-Post-Post Experience dose dose dose Any 1 2 3 Dose----------------------------------------------------------------------Pain 33.7 20.3 27.3 48.6Mild/Moderate 33.3 20.3 27.0 48.0Severe 0.3 0.0 0.3 0.6----------------------------------------------------------------------Swelling* 4.4 3.0 3.3 7.3Mild/Moderate 4.4 3.0 3.3 7.3Severe 0.0 0.0 0.0 0.0----------------------------------------------------------------------Erythema* 7.3 5.3 5.7 12.1Mild/Moderate 7.3 5.3 5.7 12.1Severe 0.0 0.0 0.0 0.0----------------------------------------------------------------------*Intensity of swelling and erythema was measured by size (inches): Mild = 0 toless than or equal to 1; Moderate = greater than 1 to less than or equal to 2; Severe = greater than 2.---------------------------------------------------------------------- Evaluation of Fever by Dose An analysis of fever in girls and women by dose is shown in Table9. Table 9 Postdose Evaluation of Fever---------------------------------------------------------------------- Vaccine Placebo (% occurrence) (% occurrence)====================================================================== Temperature PostdosePostdose PostdosePostdosePostdose Postdose ( 1 2 3 1 2 3 (degree)F)---------------------------------------------------------------------- greater than or equal to 100 to less than 102 3.7 4.1 4.4 3.1 3.8 3.6---------------------------------------------------------------------- greater than or equal to 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- to26-year-old girls and women and 9- to 15-year-old boys) who receivedboth GARDASIL and placebo reported a serious adverse experience on Day1-15 following any vaccination visit during the clinical trials forGARDASIL. The most frequently reported serious adverse experiences forGARDASIL 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 asserious adverse experiences that occurred during Day 1-15 of anyvaccination visit. Deaths Across the clinical studies, 17 deaths were reported in 21,464male and female subjects. The events reported were consistent withevents expected in healthy adolescent and adult populations. The mostcommon cause of death was motor vehicle accident (4 subjects whoreceived GARDASIL and 3 placebo subjects), followed byoverdose/suicide (1 subject who received GARDASIL and 2 subjects whoreceived placebo), and pulmonary embolus/deep vein thrombosis (1subject who received GARDASIL and 1 placebo subject). In addition,there were 2 cases of sepsis, 1 case of pancreatic cancer, and 1 caseof arrhythmia in the group that received GARDASIL, and 1 case ofasphyxia in the placebo group. Systemic Autoimmune Disorders In the clinical studies, subjects were evaluated for new medicalconditions that occurred over the course of up to 4 years of followup. The number of subjects who received both GARDASIL and placebo anddeveloped a new medical condition potentially indicative of a systemicimmune 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 1Other 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 withhepatitis B vaccine (recombinant) was evaluated in aplacebo-controlled study. There were no statistically significanthigher rates in systemic or injection-site adverse experiences amongsubjects who received concomitant vaccination compared with those whoreceived GARDASIL or hepatitis B vaccine alone. Reporting of Adverse Events The US Department of Health and Human Services has established aVaccine Adverse Event Reporting System (VAERS) to accept all reportsof suspected adverse events after the administration of any vaccine,including but not limited to the reporting of events required by theNational Childhood Vaccine Injury Act of 1986. For information or acopy of the vaccine reporting form, call the VAERS toll-free number at1-800-822-7967 or report on line to www.vaers.hhs.gov. DOSAGE AND ADMINISTRATION Dosage GARDASIL should be administered intramuscularly as 3 separate0.5-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 deltoidregion of the upper arm or in the higher anterolateral area of thethigh. GARDASIL must not be injected intravascularly. Subcutaneous andintradermal administration have not been studied, and therefore arenot recommended. The prefilled syringe is for single use only and should not beused for more than 1 individual. For single-use vials a separatesterile syringe and needle must be used for each individual. The vaccine should be used as supplied; no dilution orreconstitution is necessary. The full recommended dose of the vaccineshould be used. Shake well before use. Thorough agitation immediately beforeadministration 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 particulatematter and discoloration prior to administration. Do not use theproduct 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 vialusing a sterile needle and syringe free of preservatives, antiseptics,and detergents. Once the single-dose vial has been penetrated, thewithdrawn vaccine should be used promptly, and the vial must bediscarded. Prefilled Syringe Use Inject the entire contents of the syringe. Instructions for using the prefilled single-dose syringespreassembled with needle guard (safety) device (OBJECT OMITTED) NOTE: Please use the enclosed needle for administration. If adifferent needle is chosen, it should fit securely on the syringe andbe no longer than 1 inch to ensure proper functioning of the needleguard device. Two detachable labels are provided which can be removedafter the needle is guarded. At any of the following steps, avoid contact with the TriggerFingers to keep from activating the safety device prematurely. Remove Syringe Tip Cap and Needle Cap. Attach Luer Needle bypressing both Anti-Rotation Tabs to secure syringe and by twisting theLuer Needle in a clockwise direction until secured to the syringe.Remove Needle Sheath. Administer injection per standard protocol asstated above under DOSAGE AND ADMINISTRATION. Depress the Plungerwhile grasping the Finger Flange until the entire dose has been given.The Needle Guard Device will NOT activate to cover and protect theneedle unless the ENTIRE dose has been given. While the Plunger isstill depressed, remove needle from the vaccine recipient. Slowlyrelease the Plunger and allow syringe to move up until the entireneedle is guarded. For documentation of vaccination, remove detachablelabels by pulling slowly on them. Dispose in approved sharpscontainer. HOW SUPPLIED Vials No. 4045 -- GARDASIL is supplied as a carton of one 0.5-mLsingle-dose vial, NDC 0006-4045-00. No. 4045 -- GARDASIL is supplied as a carton of ten 0.5-mLsingle-dose vials, NDC 0006-4045-41. Syringes No. 4109 -- GARDASIL is supplied as a carton of one 0.5-mLsingle-dose prefilled Luer Lock syringe, preassembled with UltraSafePassive(R)1 delivery system. A one-inch, 25-gauge needle is providedseparately in the package. NDC 0006-4109-31. No. 4109 -- GARDASIL is supplied as a carton of six 0.5-mLsingle-dose prefilled Luer Lock syringes, preassembled with UltraSafePassive(R) delivery system. One-inch, 25-gauge needles are providedseparately in the package. NDC 0006-4109-06. Storage Store refrigerated at 2 to 8(degree)C (36 to 46(degree)F). Do notfreeze. Protect from light. Issued October 2006 Printed in USA (1) UltraSafe Passive(R) delivery system is a Trademark of SafetySyringes, Inc. 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 getsGARDASIL*. You or your child will need 3 doses of the vaccine. It isimportant to read this leaflet when you receive each dose. Thisleaflet does not take the place of talking with your health careprofessional about GARDASIL. What is GARDASIL and what is it used for? GARDASIL is a vaccine (injection/shot) that helps protect againstthe following diseases caused by Human Papillomavirus (HPV) Types inthe 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 treatthem. 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 amvaccinated or my child is vaccinated with GARDASIL? It is very important to tell your health care professional if youor 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 childshould 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 thedoses 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 youor your child to get the full benefits of GARDASIL. If you or yourchild misses a dose, your health care professional will decide when togive the missed dose. What are the possible side effects of GARDASIL? As with all vaccines, there may be some side effects withGARDASIL. GARDASIL has been shown to be generally well tolerated inwomen 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 afterreceiving GARDASIL, contact your health care professional right away. For a more complete list of side effects, ask your health careprofessional. What are the ingredients in GARDASIL? The main ingredients are purified inactive proteins that come fromHPV Types 6, 11, 16, and 18. It also contains amorphous aluminum hydroxyphosphate sulfate,sodium chloride, L-histidine, polysorbate 80, sodium borate, and waterfor injection. What are cervical cancer, precancerous lesions, and genital warts? Cancer of the cervix is a serious disease that can belife-threatening. This disease is caused by certain HPV types that cancause the cells in the lining of the cervix to change from normal toprecancerous lesions. If these are not treated, they can turncancerous. Genital warts are caused by certain types of HPV. They oftenappear as skin-colored growths. They are found on the inside oroutside of the genitals. They can hurt, itch, bleed, and causediscomfort. These lesions are usually not precancerous. Sometimes, ittakes multiple treatments to eliminate these lesions. What is Human Papillomavirus (HPV)? HPV is a common virus. In 2005, the Centers for Disease Controland Prevention (CDC) estimated that 20 million people in the UnitedStates had this virus. There are many different types of HPV; somecause no harm. Others can cause diseases of the genital area. For mostpeople the virus goes away on its own. When the virus does not go awayit can develop into cervical cancer, precancerous lesions, or genitalwarts, depending on the HPV type. See "What other key informationabout GARDASIL should I know?" Who is at risk for Human Papillomavirus? In 2005, the CDC estimated that at least 50% of sexually activepeople catch HPV during their lifetime. A male or female of any agewho takes part in any kind of sexual activity that involves genitalcontact is at risk. Many people who have HPV may not show any signs or symptoms. Thismeans 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 isbecause most people are not infected with all four types of HPVcontained in the vaccine. In clinical trials, individuals with currentor past infection with one or more vaccine-related HPV types prior tovaccination were protected from disease caused by the remainingvaccine HPV types. GARDASIL is not intended to be used for treatmentfor the above mentioned diseases. Talk to your health careprofessional for more information. This leaflet is a summary of information about GARDASIL. If youwould like more information, please talk to your health careprofessional 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, NJ08889, USA COPYRIGHT (C) 2006 MERCK & CO., Inc. All rights reserved