New England Journal of Medicine Publishes New Data on GARDASIL(R), Merck's Cervical Cancer Vaccine

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®) 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® is a registered trademark of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. Prescribing information and patient product information for GARDASIL® is attached and is also available at www.gardasil.com. MERCK & CO., INC. Whitehouse Station, NJ 08889, USA 9682301 ---------------------------------------------------------------------- GARDASIL(R) (Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine) DESCRIPTION GARDASIL* is a non-infectious recombinant, quadrivalent vaccine prepared from the highly purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (amorphous aluminum hydroxyphosphate sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer. GARDASIL is a sterile preparation for intramuscular administration. Each 0.5-mL dose contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg of HPV 18 L1 protein. Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, and water for injection. The product does not contain a preservative or antibiotics. After thorough agitation, GARDASIL is a white, cloudy liquid. CLINICAL PHARMACOLOGY Disease Burden Human Papillomavirus (HPV) causes squamous cell cervical cancer (and its histologic precursor lesions Cervical Intraepithelial Neoplasia (CIN) 1 or low grade dysplasia and CIN 2/3 or moderate to high grade dysplasia) and cervical adenocarcinoma (and its precursor lesion adenocarcinoma in situ (AIS)). HPV also causes approximately 35-50% of vulvar and vaginal cancers. Vulvar Intraepithelial Neoplasia (VIN) Grade 2/3 and Vaginal Intraepithelial Neoplasia (VaIN) Grade 2/3 are immediate precursors to these cancers. Cervical cancer prevention focuses on routine screening and early intervention. This strategy has reduced cervical cancer rates by approximately 75% in compliant individuals by monitoring and removing premalignant dysplastic lesions. HPV also causes genital warts (condyloma acuminata) which are growths of the cervicovaginal, vulvar, and the external genitalia that rarely progress to cancer. HPV 6, 11, 16, and 18 are common HPV types. HPV 16 and 18 cause approximately: -- 70% of cervical cancer, AIS, CIN 3, VIN 2/3, and VaIN 2/3 cases; and -- 50% of CIN 2 cases. HPV 6, 11, 16, and 18 cause approximately: -- 35 to 50% of all CIN 1, VIN 1, and VaIN 1 cases; and -- 90% of genital wart cases. Mechanism of Action HPV only infects humans, but animal studies with analogous (animal, not human) papillomaviruses suggest that the efficacy of L1 VLP vaccines is mediated by the development of humoral immune responses. CLINICAL STUDIES CIN 2/3 and AIS are the immediate and necessary precursors of squamous cell carcinoma and adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer; thus, they serve as surrogate markers for prevention of cervical cancer. Efficacy was assessed in 4 placebo-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of GARDASIL (Protocol 005, N = 2391) and the second evaluated all components of GARDASIL (Protocol 007, N = 551). The Phase III studies, termed FUTURE (Females United To Unilaterally Reduce Endo/Ectocervical Disease), evaluated GARDASIL in 5442 (FUTURE I or Protocol 013) and 12,157 (FUTURE II or Protocol 015) subjects. Together, these four studies evaluated 20,541 women 16 to 26 years of age at enrollment. The median duration of follow-up was 4.0, 3.0, 2.4, and 2.0 years for Protocol 005, Protocol 007, FUTURE I, and FUTURE II, respectively. Subjects received vaccine or placebo on the day of enrollment, and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies combined according to a prospective clinical plan. Prophylactic Efficacy GARDASIL is designed to prevent HPV 6-, 11-, 16-, and/or 18-related cervical cancer, cervical dysplasias, vulvar or vaginal dysplasias, or genital warts. GARDASIL was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of subjects regardless of baseline HPV status (i.e., Polymerase Chain Reaction (PCR) status or serostatus). Subjects who were infected with a particular vaccine HPV type (and who may already have had disease due to that infection) were not eligible for prophylactic efficacy evaluations for that type. The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population, consisting of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naive (PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit. Overall, 73% of subjects were naive (i.e., PCR negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment. A total of 27% of subjects had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these subjects, 74% had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were naive (PCR negative and seronegative) to the remaining 3 types. In subjects who were naive (PCR negative and seronegative) to all 4 vaccine HPV types, CIN, genital warts, VIN, and VaIN caused by any of the 4 vaccine HPV types were counted as endpoints. Among subjects who were positive (PCR positive and/or seropositive) for a vaccine HPV type at Day 1, endpoints related to that type were not included in the analyses of prophylactic efficacy. Endpoints related to the remaining types for which the subject was naive (PCR negative and seronegative) were counted. For example, in subjects who were HPV 18 positive (PCR positive and/or seropositive) at Day 1, lesions caused by HPV 18 were not counted in the prophylactic efficacy evaluations. Lesions caused by HPV 6, 11, and 16 were included in the prophylactic efficacy evaluations. The same approach was used for the other types. GARDASIL was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types in those who were PCR negative and seronegative at baseline (Table 1). Table 1 Analysis of Efficacy of GARDASIL in the PPE* Population** ---------------------------------------------------------------------- GARDASIL Placebo ---------------------- Population Number Number % Efficacy (95% CI) n of n of cases cases ====================================================================== HPV 16- or 18-related CIN 2/3 or AIS ---------------------------------------------------------------------- Protocol 005*** 755 0 750 12 100.0 (65.1, 100.0) ---------------------------------------------------------------------- Protocol 007 231 0 230 1 100.0 (-3734.9, 100.0) ---------------------------------------------------------------------- FUTURE I 2200 0 2222 19 100.0 (78.5, 100.0) ---------------------------------------------------------------------- FUTURE II 5301 0 5258 21 100.0+ (80.9, 100.0) ---------------------------------------------------------------------- Combined Protocols++ 8487 0 8460 53 100.0+ (92.9, 100.0) ------------------------------------------------====================== HPV 6-, 11-, 16-, 18-related CIN (CIN 1, CIN 2/3) or AIS ---------------------------------------------------------------------- Protocol 007 235 0 233 3 100.0 (-137.8, 100.0) ---------------------------------------------------------------------- FUTURE I 2240 0 2258 37 100.0+ (89.5, 100.0) ---------------------------------------------------------------------- FUTURE II 5383 4 5370 43 90.7 (74.4, 97.6) ---------------------------------------------------------------------- Combined Protocols 7858 4 7861 83 95.2 (87.2, 98.7) ====================================================================== HPV 6-, 11-, 16-, or 18-related Genital Warts ---------------------------------------------------------------------- Protocol 007 235 0 233 3 100.0 (-139.5, 100.0) ---------------------------------------------------------------------- FUTURE I 2261 0 2279 29 100.0 (86.4, 100.0) ---------------------------------------------------------------------- FUTURE II 5401 1 5387 59 98.3 (90.2, 100.0) ---------------------------------------------------------------------- Combined Protocols 7897 1 7899 91 98.9 (93.7, 100.0) ---------------------------------------------------------------------- * The PPE population consisted of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naive (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). **See Table 2 for analysis of vaccine impact in the general population. ***Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL. +P-values were computed for pre-specified primary hypothesis tests. All p-values were less than0.001, supporting the following conclusions: efficacy against HPV 16/18-related CIN 2/3 is greater than0% (FUTURE II); efficacy against HPV 16/18-related CIN 2/3 is greater than25% (Combined Protocols); and efficacy against HPV 6/11/16/18-related CIN is greater than20% (FUTURE I). ++Analyses of the combined trials were prospectively planned and included the use of similar study entry criteria. n = Number of subjects with at least 1 follow-up visit after Month 7. Note 1: Point estimates and confidence intervals are adjusted for person-time of follow-up. Note 2: The first analysis in the table (i.e., HPV 16- or 18-related CIN 2/3, AIS or worse) was the primary endpoint of the vaccine development plan. Note 3: FUTURE I refers to Protocol 013; FUTURE II refers to Protocol 015. ---------------------------------------------------------------------- GARDASIL was efficacious against HPV disease caused by each of the 4 vaccine HPV types. In a pre-defined analysis, the efficacy of GARDASIL against HPV 16/18-related disease was 100% (95% CI: 87.9%, 100.0%) for CIN 3 or AIS and 100% (95% CI: 55.5%, 100.0%) for VIN 2/3 or VaIN 2/3. The efficacy of GARDASIL against HPV 6-, 11-, 16-, and 18-related VIN 1 or VaIN 1 was 100% (95% CI: 75.8%, 100.0%). These analyses were conducted in the PPE population that consisted of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naive (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy in Subjects with Current or Prior Infection GARDASIL is a prophylactic vaccine. There was no clear evidence of protection from disease caused by HPV types for which subjects were PCR positive and/or seropositive at baseline. Individuals who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from clinical disease caused by the remaining vaccine HPV types. General Population Impact The general population of young American women includes women who are HPV-naive (PCR negative and seronegative) and women who are HPV-non-naive (PCR positive and/or seropositive), some of whom have HPV-related disease. The clinical trials population approximated the general population of American women with respect to prevalence of HPV infection and disease at enrollment. Analyses were conducted to evaluate the overall impact of GARDASIL with respect to HPV 6-, 11-, 16-, and 18-related cervical and genital disease in the general population. Here, analyses included events arising from HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination. The impact of GARDASIL in the general population is shown in Table 2. Impact was measured starting 1 month Postdose 1. Prophylactic efficacy denotes the vaccine's efficacy in women who are naive (PCR negative and seronegative) to the relevant HPV types at vaccination onset. General population impact denotes vaccine impact among women regardless of baseline PCR status and serostatus. The majority of CIN and genital warts, VIN, and VaIN detected in the group that received GARDASIL occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1. Table 2 General Population Impact for Vaccine HPV Types ---------------------------------------------------------------------- GARDASIL or HPV 16 L1 Placebo VLP Vaccine % Reduction Endpoints Analysis ---------------------- (95% CI) N Cases N Cases ====================================================================== Prophylactic Efficacy* 9342 1 9400 81 98.8 (92.9, 100.0) ----------------------------------------------------- HPV 16- or 18- HPV 16 related CIN 2/3 and/or HPV or AIS 18 Positive at Day 1 -- 121 -- 120 -- ----------------------------------------------------- General Population Impact** 9831 122 9896 201 39.0 (23.3, 51.7) ====================================================================== Prophylactic Efficacy* 8641 0 8667 24 100.0 (83.3, 100.0) ----------------------------------------------------- HPV 16- or 18- HPV 16 related VIN 2/3 and/or HPV and VaIN 2/3 18 Positive at Day 1 -- 8 -- 2 -- ----------------------------------------------------- General Population Impact** 8954 8 8962 26 69.1 (29.8, 87.9) ====================================================================== Prophylactic Efficacy* 8625 9 8673 143 93.7 (87.7, 97.2) ----------------------------------------------------- HPV 6-, 11-, HPV 6, HPV 16-, 18-related 11, HPV 16, CIN (CIN 1, CIN and/or HPV 2/3) or AIS 18 Positive at Day 1 -- 161*** -- 174*** -- ----------------------------------------------------- General Population Impact ** 8814 170 8846 317 46.4 (35.2, 55.7) ====================================================================== Prophylactic Efficacy* 8760 9 8786 136 93.4 (87.0, 97.0) ----------------------------------------------------- HPV 6-, 11-, HPV 6, HPV 16-, or 18- 11, HPV 16, related Genital and/or HPV Warts 18 Positive at Day 1 -- 49 -- 48+ -- ----------------------------------------------------- General Population Impact ** 8954 58 8962 184 68.5 (57.5, 77.0) ---------------------------------------------------------------------- *Includes all subjects who received at least 1 vaccination and who were naive (PCR negative and seronegative) to HPV 6, 11, 16, and/or 18 at Day 1. Case counting started at 1 Month Postdose 1. **Includes all subjects who received at least 1 vaccination (regardless of baseline HPV status at Day 1). Case counting started at 1 Month Postdose 1. ***Includes 2 subjects (1 in each vaccination group) who underwent colposcopy for reasons other than an abnormal Pap and 1 placebo subject with missing serology/PCR data at day 1. +Includes 1 subject with missing serology/PCR data at day 1. Note 1: The 16- and 18-related CIN 2/3 or AIS composite endpoint included data from studies 005, 007, 013, and 015. All other endpoints only included data from studies 007, 013, and 015. Note 2: Positive status at Day 1 denotes PCR positive and/or seropositive for the respective type at Day 1. Note 3: Percent reduction includes the prophylactic efficacy of GARDASIL as well as the impact of GARDASIL on the course of infections present at the start of the vaccination. Note 4: Table 2 does not include disease due to non-vaccine HPV types. ---------------------------------------------------------------------- GARDASIL does not prevent infection with the HPV types not contained in the vaccine. Cases of disease due to non-vaccine types were observed among recipients of GARDASIL and placebo in Phase II and Phase III efficacy studies. Among cases of CIN 2/3 or AIS caused by vaccine or non-vaccine HPV types in subjects in the general population who received GARDASIL, 79% occurred in subjects who had an abnormal Pap test at Day 1 and/or who were positive (PCR positive and/or seropositive) to HPV 6, 11, 16, and/or 18 at Day 1. An interim analysis of the general population impact for GARDASIL was performed from studies 007, 013, and 015 that had a median duration of follow-up of 1.9 years. GARDASIL reduced the overall rate of CIN 2/3 or AIS caused by vaccine or non-vaccine HPV types by 12.2% (95% CI: -3.2%, 25.3%), compared with placebo. An analysis of overall population impact for the HPV 16 L1 VLP vaccine was conducted from study 005 that had a median duration of follow-up of 3.9 years. The HPV 16 L1 VLP vaccine reduced the overall incidence of CIN 2/3 caused by vaccine or non-vaccine HPV types by 32.7% (95% CI: -34.7%, 67.3%) through a median duration of follow-up of 1.9 years (fixed case analysis) and by 45.3% (95% CI: 10.9%, 67.1%), through a median duration of follow-up of 3.9 years (end of study). GARDASIL reduced the incidence of definitive therapy (e.g., loop electrosurgical excision procedure, laser conization, cold knife conization) by 16.5% (95% CI: 2.9%, 28.2%), and surgery to excise external genital lesions by 26.5% (95% CI: 3.6%, 44.2%), compared with placebo for all HPV-related diseases. These analyses were performed in the general population of women which includes women regardless of baseline HPV PCR status or serostatus. GARDASIL has not been shown to protect against the diseases caused by all HPV types and will not treat existing disease caused by the HPV types contained in the vaccine. The overall efficacy of GARDASIL, described above, will depend on the baseline prevalence of HPV infection related to vaccine types in the population vaccinated and the incidence of HPV infection due to types not included in the vaccine. Immunogenicity Assays to Measure Immune Response Because there were few disease cases in subjects naive (PCR negative and seronegative) to vaccine HPV types at baseline in the group that received GARDASIL, it has not been possible to establish minimum anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 antibody levels that protect against clinical disease caused by HPV 6, 11, 16, and/or 18. The immunogenicity of GARDASIL was assessed in 8915 women (GARDASIL N = 4666; placebo N = 4249) 18 to 26 years of age and female adolescents 9 to 17 years of age (GARDASIL N = 1471; placebo N = 583). Type-specific competitive immunoassays with type-specific standards were used to assess immunogenicity to each vaccine HPV type. These assays measured antibodies against neutralizing epitopes for each HPV type. The scales for these assays are unique to each HPV type; thus, comparisons across types and to other assays are not appropriate. Immune Response to GARDASIL The primary immunogenicity analyses were conducted in a per-protocol immunogenicity (PPI) population. This population consisted of individuals who were seronegative and PCR negative to the relevant HPV type(s) at enrollment, remained HPV PCR negative to the relevant HPV type(s) through 1 month Postdose 3 (Month 7), received all 3 vaccinations, and did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Overall, 99.8%, 99.8%, 99.8%, and 99.5% of girls and women who received GARDASIL became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month Postdose 3 across all age groups tested. Anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs peaked at Month 7. GMTs declined through Month 24 and then stabilized through Month 36 at levels above baseline (Table 3). The duration of immunity following a complete schedule of immunization with GARDASIL has not been established. Table 3 Summary of Anti-HPV cLIA Geometric Mean Titers in the PPI* Population ---------------------------------------------------------------------- GARDASIL Aluminum-Containing Placebo N** = 276 N = 275 Study Time --------------------------------------------------------- Geometric Mean Titer Geometric Mean Titer n*** (95% CI) n (95% CI) mMU/mL+ mMU/mL ====================================================================== Anti-HPV 6 ---------------------------------------------------------------------- Month 07 208 582.2 (527.2, 642.8) 198 4.6 (4.3, 4.8) ---------------------------------------------------------------------- Month 24 192 93.7 (82.2, 106.9) 188 4.6 (4.3, 5.0) ---------------------------------------------------------------------- Month 36 183 93.8 (81.0, 108.6) 184 5.1 (4.7, 5.6) ---------------------------------------------------------------------- Anti-HPV 11 ---------------------------------------------------------------------- Month 07 208 696.5 (617.8, 785.2) 198 4.1 (4.0, 4.2) ---------------------------------------------------------------------- Month 24 190 97.1 (84.2, 112.0) 188 4.2 (4.0, 4.3) ---------------------------------------------------------------------- Month 36 174 91.7 (78.3, 107.3) 180 4.4 (4.1, 4.7) ---------------------------------------------------------------------- Anti-HPV 16 ---------------------------------------------------------------------- Month 07 193 3889.0 (3318.7, 4557.4) 185 6.5 (6.2, 6.9) ---------------------------------------------------------------------- Month 24 174 393.0 (335.7, 460.1) 175 6.8 (6.3, 7.4) ---------------------------------------------------------------------- Month 36 176 507.3 (434.6, 592.0) 170 7.7 (6.8, 8.8) ---------------------------------------------------------------------- Anti-HPV 18 ---------------------------------------------------------------------- Month 07 219 801.2 (693.8, 925.4) 209 4.6 (4.3, 5.0) ---------------------------------------------------------------------- Month 24 204 59.9 (49.7, 72.2) 199 4.6 (4.3, 5.0) ---------------------------------------------------------------------- Month 36 196 59.7 (48.5, 73.5) 193 4.8 (4.4, 5.2) ---------------------------------------------------------------------- * The PPI population consisted of individuals who received all 3 vaccinations within pre-defined day ranges, did not have major deviations from the study protocol, met predefined criteria for the interval between the Month 6 and Month 7 visit, and were naive (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). **Number of subjects randomized to the respective vaccination group who received at least 1 injection. ***Number of subjects in the per-protocol analysis with data at the specified study time point. +mMU = milli-Merck units. Note: These data are from Protocol 007. ---------------------------------------------------------------------- Table 4 compares anti-HPV GMTs 1 month Postdose 3 among subjects who received Dose 2 between Month 1 and Month 3 and subjects who received Dose 3 between Month 4 and Month 8 (Table 4). Table 4 Summary of GMTs for Variation of Dosing Regimen ---------------------------------------------------------------------- Anti-HPV 6 Anti-HPV 11 Variation of Dosing ----------------------------------------- Regimen N GMT N GMT (95% CI) (95% CI) ====================================================================== Dose 2 ---------------------------------------------------------------------- Early* 570.9 824.6 883 (542.2, 601.2) 888 (776.7, 875.5) ---------------------------------------------------------------------- On Time* 552.3 739.7 1767 (532.3, 573.1) 1785 (709.3, 771.5) ---------------------------------------------------------------------- Late* 447.4 613.9 313 (405.3, 493.8) 312 (550.8, 684.2) ---------------------------------------------------------------------- Dose 3 ---------------------------------------------------------------------- Early** 493.1 658.9 495 (460.8, 527.8) 501 (609.5, 712.2) ---------------------------------------------------------------------- On Time** 549.6 752.8 2081 (531.1, 568.8) 2093 (723.8, 782.9) ---------------------------------------------------------------------- Late** 589.0 865.3 335 (537.0, 645.9) 339 (782.6, 956.7) ---------------------------------------------------------------------- Anti-HPV 16 Anti-HPV 18 Variation of Dosing ------------------------------------------- Regimen N GMT N GMT (95% CI) (95% CI) ====================================================================== Dose 2 ---------------------------------------------------------------------- Early* 2625.3 517.7 854 (2415.1, 2853.9) 926 (482.9, 555.0) ---------------------------------------------------------------------- On Time* 2400.0 473.9 1737 (2263.9, 2544.3) 1894 (451.8, 497.1) ---------------------------------------------------------------------- Late* 1889.7 388.5 285 (1624.4, 2198.5) 334 (348.3, 433.3) ---------------------------------------------------------------------- Dose 3 ---------------------------------------------------------------------- Early** 2176.6 423.4 487 (1953.4, 2425.3) 521 (388.8, 461.2) ---------------------------------------------------------------------- On Time** 2415.0 486.0 2015 (2286.3, 2550.9) 2214 (464.7, 508.2) ---------------------------------------------------------------------- Late** 2765.9 498.5 326 (2408.7, 3176.2) 361 (446.2, 557.0) ---------------------------------------------------------------------- *Early = 36 to 50 days Postdose 1; On Time = 51 to 70 days Postdose 1; Late = 71 to 84 days Postdose 1. **Early = 80 to 105 days Postdose 2; On Time = 106 to 137 days Postdose 2; Late = 138 to 160 days Postdose 2. Note: GMT = Geometric mean titer in mMU/mL (mMU = milli-Merck units.) ---------------------------------------------------------------------- Bridging the Efficacy of GARDASIL from Young Adult Women to Adolescent Girls A clinical study compared anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs in 10- to 15-year-old girls with responses in 16- to 23-year-old adolescent and young adult women. Among subjects who received GARDASIL, 99.1 to 100% became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive by 1 month Postdose 3. Table 5 compares the 1 month Postdose 3 anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs in 9- to 15-year-old girls with those in 16- to 26-year-old adolescent and young adult women. Table 5 Immunogenicity Bridging Between 9- to 15-year-old Female Adolescents and 16- to 26-year-old Adult Women ---------------------------------------------------------------------- 9- to 15-year-old 16- to 26-year-old Female Adolescents Adult Women (Protocols 016 and 018) (Protocols 013 and 015) Assay N = 1121 N = 4229 (cLIA) -------------------------------------------------------- n GMT (95% CI) n GMT (95% CI) ====================================================================== Anti-HPV 6 915 928.7 (874.0, 986.8) 2631 542.6 (526.2, 559.6) ---------------------------------------------------------------------- Anti-HPV 11 915 1303.0 (1223.1, 1388.0) 2655 761.5 (735.3, 788.6) ---------------------------------------------------------------------- Anti-HPV 16 913 4909.2 (4547.6, 5299.5) 2570 2293.9 (2185.0, 2408.2) ---------------------------------------------------------------------- Anti-HPV 18 920 1039.8 (964.9, 1120.4) 2796 461.6 (444.0, 480.0) ---------------------------------------------------------------------- Note: GMT = Geometric mean titer in mMU/mL (mMU = milli-Merck units). ---------------------------------------------------------------------- Anti-HPV responses 1 month Postdose 3 among 9- to 15-year-old girls were non-inferior to anti-HPV responses in 16- to 26-year-old adolescent and young adult women in the combined database of immunogenicity studies for GARDASIL. On the basis of this immunogenicity bridging, the efficacy of GARDASIL in 9- to 15-year-old girls is inferred. Studies with Other Vaccines The safety and immunogenicity of co-administration of GARDASIL with hepatitis B vaccine (recombinant) (same visit, injections at separate sites) were evaluated in a randomized study of 1871 women aged 16 to 24 years at enrollment. Immune response to both hepatitis B vaccine (recombinant) and GARDASIL was non-inferior whether they were administered at the same visit or at a different visit. INDICATIONS AND USAGE GARDASIL is a vaccine indicated in girls and women 9-26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types 6, 11, 16, and 18: -- Cervical cancer -- Genital warts (condyloma acuminata) and the following precancerous or dysplastic lesions: -- Cervical adenocarcinoma in situ (AIS) -- Cervical intraepithelial neoplasia (CIN) grade 2 and grade 3 -- Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3 -- Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3 -- Cervical intraepithelial neoplasia (CIN) grade 1 CONTRAINDICATIONS Hypersensitivity to the active substances or to any of the excipients of the vaccine. Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of GARDASIL should not receive further doses of GARDASIL. PRECAUTIONS General As for any vaccine, vaccination with GARDASIL may not result in protection in all vaccine recipients. This vaccine is not intended to be used for treatment of active genital warts; cervical cancer; CIN, VIN, or VaIN. This vaccine will not protect against diseases that are not caused by HPV. GARDASIL has not been shown to protect against diseases due to non-vaccine HPV types. As with all injectable vaccines, appropriate medical treatment should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine. The decision to administer or delay vaccination because of a current or recent febrile illness depends largely on the severity of the symptoms and their etiology. Low-grade fever itself and mild upper respiratory infection are not generally contraindications to vaccination. Individuals with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, Human Immunodeficiency Virus (HIV) infection, or other causes, may have reduced antibody response to active immunization (see PRECAUTIONS, Drug Interactions). As with other intramuscular injections, GARDASIL should not be given to individuals with bleeding disorders such as hemophilia or thrombocytopenia, or to persons on anticoagulant therapy unless the potential benefits clearly outweigh the risk of administration. If the decision is made to administer GARDASIL to such persons, it should be given with steps to avoid the risk of hematoma following the injection. Information for the Patient, Parent, or Guardian The health care provider should inform the patient, parent, or guardian that vaccination does not substitute for routine cervical cancer screening. Women who receive GARDASIL should continue to undergo cervical cancer screening per standard of care. The health care provider should provide the vaccine information required to be given with each vaccination to the patient, parent, or guardian. The health care provider should inform the patient, parent, or guardian of the benefits and risks associated with vaccination. For risks associated with vaccination, see PRECAUTIONS and ADVERSE REACTIONS. GARDASIL is not recommended for use in pregnant women. The health care provider should inform the patient, parent, or guardian of the importance of completing the immunization series unless contraindicated. Patients, parents, or guardians should be instructed to report any adverse reactions to their health care provider. Drug Interactions Use with Other Vaccines Results from clinical studies indicate that GARDASIL may be administered concomitantly (at a separate injection site) with hepatitis B vaccine (recombinant) (see CLINICAL PHARMACOLOGY, Studies with Other Vaccines). Co-administration of GARDASIL with other vaccines has not been studied. Use with Hormonal Contraceptives In clinical studies, 13,293 subjects (vaccine = 6644; placebo = 6649) who had post-Month 7 follow-up used hormonal contraceptives for a total of 17,597 person-years (65.1% of the total follow-up time in the studies). Use of hormonal contraceptives or lack of use of hormonal contraceptives among study participants did not alter vaccine efficacy in the PPE population. Use with Systemic Immunosuppressive Medications Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines (see PRECAUTIONS, General). Carcinogenesis, Mutagenesis, Impairment of Fertility GARDASIL has not been evaluated for the potential to cause carcinogenicity or genotoxicity. GARDASIL administered to female rats at a dose of 120 mcg total protein, which corresponds to approximately 300-fold excess relative to the projected human dose, had no effects on mating performance, fertility, or embryonic/fetal survival. Pregnancy Pregnancy Category B: Reproduction studies have been performed in female rats at doses up to 300 times the human dose (on a mg/kg basis) and have revealed no evidence of impaired female fertility or harm to the fetus due to GARDASIL. However, it is not known whether GARDASIL can cause fetal harm when administered to a pregnant woman or if it can affect reproductive capacity. GARDASIL should be given to a pregnant woman only if clearly needed. An evaluation of the effect of GARDASIL on embryo-fetal, pre- and postweaning development was conducted using rats. One group of rats was administered GARDASIL twice prior to gestation, during the period of organogenesis (gestation day 6) and on lactation day 7. A second group of pregnant rats was administered GARDASIL during the period of organogenesis (gestation day 6) and on lactation day 7 only. GARDASIL was administered at 0.5 mL/rat/occasion (approximately 300-fold excess relative to the projected human dose on a mg/kg basis) by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring. The effect of GARDASIL on male fertility has not been studied. In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of GARDASIL. Women who were found to be pregnant before completion of a 3-dose regimen of GARDASIL were instructed to defer completion of their vaccination regimen until resolution of the pregnancy. During clinical trials, 2266 women (vaccine = 1115 vs. placebo = 1151) reported at least 1 pregnancy each. Overall, the proportions of pregnancies with an adverse outcome were comparable in subjects who received GARDASIL and subjects who received placebo. Overall, 40 and 41 subjects in the group that received GARDASIL or placebo, respectively (3.6% and 3.6% of all subjects who reported a pregnancy in the respective vaccination groups), experienced a serious adverse experience during pregnancy. The most common events reported were conditions that can result in Caesarean section (e.g., failure of labor, malpresentation, cephalopelvic disproportion), premature onset of labor (e.g., threatened abortions, premature rupture of membranes), and pregnancy-related medical problems (e.g., pre-eclampsia, hyperemesis). The proportions of pregnant subjects who experienced such events were comparable between the vaccination groups. There were 15 cases of congenital anomaly in pregnancies that occurred in subjects who received GARDASIL and 16 cases of congenital anomaly in pregnancies that occurred in subjects who received placebo. Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of GARDASIL or placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received GARDASIL compared to 0 cases of congenital anomaly in the group that received placebo. The congenital anomalies seen in pregnancies with estimated onset within 30 days of vaccination included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia and club foot. Conversely, in pregnancies with onset more than 30 days following vaccination, 10 cases of congenital anomaly were observed in the group that received GARDASIL compared with 16 cases of congenital anomaly in the group that received placebo. The types of anomalies observed were consistent (regardless of when pregnancy occurred in relation to vaccination) with those generally observed in pregnancies in women aged 16 to 26 years. Pregnancy Registry for GARDASIL Merck & Co., Inc. maintains a Pregnancy Registry to monitor fetal outcomes of pregnant women exposed to GARDASIL. Patients and health care providers are encouraged to report any exposure to GARDASIL during pregnancy by calling (800) 986-8999. Lactation It is not known whether vaccine antigens or antibodies induced by the vaccine are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GARDASIL is administered to a nursing woman. A total of 995 nursing mothers (vaccine = 500, placebo = 495) were given GARDASIL or placebo during the vaccination period of the clinical trials. GMTs in nursing and non-nursing mothers were as follows: The GMTs in nursing mothers were 595.9 (95% CI: 522.5, 679.5) for anti-HPV 6, 864.3 (95% CI: 754.0, 990.8) for anti-HPV 11, 3056.9 (95% CI: 2594.4, 3601.8) for anti-HPV 16, and 527.2 (95% CI: 450.9, 616.5) for anti-HPV 18. The GMTs for women who did not nurse during vaccine administration were 540.1 (95% CI: 523.5, 557.2) for anti-HPV 6, 746.3 (95% CI: 720.4, 773.3) for anti-HPV 11, 2290.8 (95% CI: 2180.7, 2406.3) for anti-HPV 16, and 456.0 (95% CI: 438.4, 474.3) for anti-HPV 18. Overall, 17 and 9 infants of subjects who received GARDASIL or placebo, respectively (representing 3.4% and 1.8% of the total number of subjects who were breast-feeding during the period in which they received GARDASIL or placebo, respectively), experienced a serious adverse experience. None was judged by the investigator to be vaccine related. In clinical studies, a higher number of breast-feeding infants (n = 6) whose mothers received GARDASIL had acute respiratory illnesses within 30 days post-vaccination of the mother as compared to infants (n = 2) whose mothers received placebo. In these studies, the rates of other adverse experiences in the mother and the nursing infant were comparable between vaccination groups. Pediatric Use The safety and efficacy of GARDASIL have not been evaluated in children younger than 9 years. Geriatric Use The safety and efficacy of GARDASIL have not been evaluated in adults above the age of 26 years. ADVERSE REACTIONS In 5 clinical trials (4 placebo-controlled), subjects were administered GARDASIL or placebo on the day of enrollment, and approximately 2 and 6 months thereafter. Few subjects (0.1%) discontinued due to adverse experiences. In all except 1 of the clinical trials, safety was evaluated using vaccination report card (VRC)-aided surveillance for 14 days after each injection of GARDASIL or placebo. The subjects who were monitored using VRC-aided surveillance included 5088 girls and women 9 through 26 years of age at enrollment who received GARDASIL and 3790 girls and women who received placebo. Common Adverse Experiences Vaccine-related Common Adverse Experiences The vaccine-related adverse experiences that were observed among female recipients of GARDASIL at a frequency of at least 1.0% and also at a greater frequency than that observed among placebo recipients are shown in Table 6. Table 6 Vaccine-related Injection-site and Systemic Adverse Experiences* ---------------------------------------------------------------------- Aluminum-Containing Saline GARDASIL Placebo Placebo Adverse Experience (N = 5088) (N = 3470) (N = 320) (1 to 5 Days Postvaccination) % % % ---------------------------------------------------------------------- Injection Site Pain 83.9 75.4 48.6 Swelling 25.4 15.8 7.3 Erythema 24.6 18.4 12.1 Pruritus 3.1 2.8 0.6 ---------------------------------------------------------------------- GARDASIL Placebo Adverse Experience (N = 5088) (N = 3790) (1 to 15 Days Postvaccination) % % ---------------------------------------------------------------------- Systemic Fever 10.3 8.6 Nausea 4.2 4.1 Dizziness 2.8 2.6 ---------------------------------------------------------------------- * The vaccine-related adverse experiences that were observed among recipients of GARDASIL were at a frequency of at least 1.0% and also at a greater frequency than that observed among placebo recipients. All-cause Common Systemic Adverse Experiences All-cause systemic adverse experiences for female subjects that were observed at a frequency of greater than or equal to 1% where the incidence in the vaccine group was greater than or equal to the incidence in the placebo group are shown in Table 7. Table 7 All-cause Common Systemic Adverse Experiences ---------------------------------------------------------------------- GARDASIL Placebo Adverse Experience (N = 5088) (N = 3790) (1 to 15 Days Postvaccination) % % ---------------------------------------------------------------------- Pyrexia 13.0 11.2 Nausea 6.7 6.6 Nasopharyngitis 6.4 6.4 Dizziness 4.0 3.7 Diarrhea 3.6 3.5 Vomiting 2.4 1.9 Myalgia 2.0 2.0 Cough 2.0 1.5 Toothache 1.5 1.4 Upper respiratory tract infection 1.5 1.5 Malaise 1.4 1.2 Arthralgia 1.2 0.9 Insomnia 1.2 0.9 Nasal congestion 1.1 0.9 ---------------------------------------------------------------------- Evaluation of Injection-site Adverse Experiences by Dose An analysis of injection-site adverse experiences in female subjects by dose is shown in Table 8. Overall, 94.3% of subjects who received GARDASIL judged their injection-site adverse experience to be mild or moderate in intensity. Table 8 Postdose Evaluation of Injection-site Adverse Experiences ---------------------------------------------------------------------- Aluminum-Containing Vaccine Placebo (% occurrence) (% occurrence) ====================================================================== Adverse Post- Post- Post- Post Post- Post- Post- Post Experience dose dose dose Any dose dose dose Any 1 2 3 Dose 1 2 3 Dose ---------------------------------------------------------------------- Pain 63.4 60.7 62.7 83.9 57.0 47.8 49.5 75.4 Mild/Moderate 62.5 59.7 61.2 81.1 56.6 47.3 48.9 74.1 Severe 0.9 1.0 1.5 2.8 0.4 0.5 0.6 1.3 ---------------------------------------------------------------------- Swelling* 10.2 12.8 15.1 25.4 8.2 7.5 7.6 15.8 Mild/Moderate 9.6 11.9 14.3 23.3 8.0 7.2 7.3 15.2 Severe 0.6 0.8 0.8 2.0 0.2 0.3 0.2 0.6 ---------------------------------------------------------------------- Erythema* 9.2 12.1 14.7 24.7 9.8 8.4 8.9 18.4 Mild/Moderate 9.0 11.7 14.3 23.7 9.5 8.3 8.8 18.0 Severe 0.2 0.3 0.4 0.9 0.3 0.1 0.1 0.4 ---------------------------------------------------------------------- Saline Placebo (% occurrence) ====================================================================== Adverse Post- Post- Post- Post Experience dose dose dose Any 1 2 3 Dose ---------------------------------------------------------------------- Pain 33.7 20.3 27.3 48.6 Mild/Moderate 33.3 20.3 27.0 48.0 Severe 0.3 0.0 0.3 0.6 ---------------------------------------------------------------------- Swelling* 4.4 3.0 3.3 7.3 Mild/Moderate 4.4 3.0 3.3 7.3 Severe 0.0 0.0 0.0 0.0 ---------------------------------------------------------------------- Erythema* 7.3 5.3 5.7 12.1 Mild/Moderate 7.3 5.3 5.7 12.1 Severe 0.0 0.0 0.0 0.0 ---------------------------------------------------------------------- *Intensity of swelling and erythema was measured by size (inches): Mild = 0 to (less than=)1; Moderate = greater than1 to (less than=)2; Severe = greater than2. ---------------------------------------------------------------------- Evaluation of Fever by Dose An analysis of fever in girls and women by dose is shown in Table 9. Table 9 Postdose Evaluation of Fever ---------------------------------------------------------------------- Vaccine Placebo (% occurrence) (% occurrence) ====================================================================== Temperature Postdose Postdose Postdose Postdose Postdose Postdose ((degree)F) 1 2 3 1 2 3 ---------------------------------------------------------------------- (greater than=) 100 to 102 3.7 4.1 4.4 3.1 3.8 3.6 ---------------------------------------------------------------------- (greater than=) 102 0.3 0.5 0.5 0.3 0.4 0.6 ---------------------------------------------------------------------- Serious Adverse Experiences A total of 102 subjects out of 21,464 total subjects (9- to 26-year-old girls and women and 9- to 15-year-old boys) who received both GARDASIL and placebo reported a serious adverse experience on Day 1-15 following any vaccination visit during the clinical trials for GARDASIL. The most frequently reported serious adverse experiences for GARDASIL compared to placebo and regardless of causality were: headache (0.03% GARDASIL vs. 0.02% Placebo), gastroenteritis (0.03% GARDASIL vs. 0.01% Placebo), appendicitis (0.02% GARDASIL vs. 0.01% Placebo), pelvic inflammatory disease (0.02% GARDASIL vs. 0.01% Placebo). One case of bronchospasm and 2 cases of asthma were reported as serious adverse experiences that occurred during Day 1-15 of any vaccination visit. Deaths Across the clinical studies, 17 deaths were reported in 21,464 male and female subjects. The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (4 subjects who received GARDASIL and 3 placebo subjects), followed by overdose/suicide (1 subject who received GARDASIL and 2 subjects who received placebo), and pulmonary embolus/deep vein thrombosis (1 subject who received GARDASIL and 1 placebo subject). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, and 1 case of arrhythmia in the group that received GARDASIL, and 1 case of asphyxia in the placebo group. Systemic Autoimmune Disorders In the clinical studies, subjects were evaluated for new medical conditions that occurred over the course of up to 4 years of follow up. The number of subjects who received both GARDASIL and placebo and developed a new medical condition potentially indicative of a systemic immune disorder is shown in Table 10. Table 10 Summary of Subjects Who Reported an Incident Condition Potentially Indicative of Systemic Autoimmune Disorder After Enrollment in Clinical Trials of GARDASIL ---------------------------------------------------------------------- GARDASIL Placebo Potential Autoimmune Disorder (N = 11,813) (N = 9701) ====================================================================== Specific Terms 3 (0.025%) 1 (0.010%) Juvenile arthritis 1 0 Rheumatoid arthritis 2 0 Systemic lupus erythematosus 0 1 Other Terms 6 (0.051%) 2 (0.021%) Arthritis 5 2 Reactive Arthritis 1 0 ---------------------------------------------------------------------- N = Number of subjects enrolled ---------------------------------------------------------------------- Safety in Concomitant Use with Other Vaccines The safety of GARDASIL when administered concomitantly with hepatitis B vaccine (recombinant) was evaluated in a placebo-controlled study. There were no statistically significant higher rates in systemic or injection-site adverse experiences among subjects who received concomitant vaccination compared with those who received GARDASIL or hepatitis B vaccine alone. Reporting of Adverse Events The US Department of Health and Human Services has established a Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine, including but not limited to the reporting of events required by the National Childhood Vaccine Injury Act of 1986. For information or a copy of the vaccine reporting form, call the VAERS toll-free number at 1-800-822-7967 or report on line to www.vaers.hhs.gov. DOSAGE AND ADMINISTRATION Dosage GARDASIL should be administered intramuscularly as 3 separate 0.5-mL doses according to the following schedule: First dose: at elected date Second dose: 2 months after the first dose Third dose: 6 months after the first dose Method of Administration GARDASIL should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh. GARDASIL must not be injected intravascularly. Subcutaneous and intradermal administration have not been studied, and therefore are not recommended. The prefilled syringe is for single use only and should not be used for more than 1 individual. For single-use vials a separate sterile syringe and needle must be used for each individual. The vaccine should be used as supplied; no dilution or reconstitution is necessary. The full recommended dose of the vaccine should be used. Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. After thorough agitation, GARDASIL is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the product if particulates are present or if it appears discolored. Single-dose Vial Use Withdraw the 0.5-mL dose of vaccine from the single-dose vial using a sterile needle and syringe free of preservatives, antiseptics, and detergents. Once the single-dose vial has been penetrated, the withdrawn vaccine should be used promptly, and the vial must be discarded. Prefilled Syringe Use Inject the entire contents of the syringe. Instructions for using the prefilled single-dose syringes preassembled with needle guard (safety) device (GRAPHIC OMITTED) NOTE: Please use the enclosed needle for administration. If a different needle is chosen, it should fit securely on the syringe and be no longer than 1 inch to ensure proper functioning of the needle guard device. Two detachable labels are provided which can be removed after the needle is guarded. Remove Syringe Tip Cap. Attach Luer Needle. Depress both Anti-Rotation Tabs to secure syringe and attach Luer Needle by twisting in clockwise direction. Remove Needle Sheath. Administer injection per standard protocol as stated above under DOSAGE AND ADMINISTRATION. Depress the Plunger while grasping the Finger Flange until the entire dose has been given. The Needle Guard Device will NOT activate to cover and protect the needle unless the ENTIRE dose has been given. Remove needle from the vaccine recipient. Release the Plunger and allow syringe to move up until the entire needle is guarded. For documentation of vaccination, remove detachable labels by pulling slowly on them. Dispose in approved sharps container. HOW SUPPLIED Vials No. 4045 -- GARDASIL is supplied as a carton of one 0.5-mL single-dose vial, NDC 0006-4045-00. No. 4045 -- GARDASIL is supplied as a carton of ten 0.5-mL single-dose vials, NDC 0006-4045-41. Syringes No. 4109 -- GARDASIL is supplied as a carton of one 0.5-mL single-dose prefilled Luer Lock syringe, preassembled with UltraSafe Passive(R)(1) delivery system. A one-inch, 25-gauge needle is provided separately in the package. NDC 0006-4109-31. No. 4109 -- GARDASIL is supplied as a carton of six 0.5-mL single-dose prefilled Luer Lock syringes, preassembled with UltraSafe Passive(R) delivery system. One-inch, 25-gauge needles are provided separately in the package. NDC 0006-4109-06. Storage Store refrigerated at 2 to 8(degree)C (36 to 46(degree)F). Do not freeze. Protect from light. ---------------------------------------------------------------------- Manuf. and Dist. by: MERCK & CO., INC., Whitehouse Station, NJ 08889, USA Issued July 2006 ---------------------------------------------------------------------- (1) UltraSafe Passive(R) delivery system is a Trademark of Safety Syringes, Inc. Printed in USA * Registered trademark of MERCK & CO., Inc., Whitehouse Station, NJ 08889, USA COPYRIGHT (C) 2006 MERCK & CO., Inc. All rights reserved 9682303 USPPI Patient Information about GARDASIL(R) (pronounced "gard-Ah-sill") Generic name: (Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine) Read this information with care before you or your child gets GARDASIL*. You or your child will need 3 doses of the vaccine. It is important to read this leaflet when you receive each dose. This leaflet does not take the place of talking with your health care professional about GARDASIL. What is GARDASIL and what is it used for? GARDASIL is a vaccine (injection/shot) that helps protect against the following diseases caused by Human Papillomavirus (HPV) Types in the vaccine (6, 11, 16, and 18): -- Cervical cancer (cancer of the lower end of the uterus or womb). -- Abnormal and precancerous cervical lesions. -- Abnormal and precancerous vaginal lesions. -- Abnormal and precancerous vulvar lesions. -- Genital warts. GARDASIL helps prevent these diseases - but it will not treat them. You or your child cannot get these diseases from GARDASIL. What other key information about GARDASIL should I know? -- Vaccination does not substitute for routine cervical cancer screening. Females who receive GARDASIL should continue cervical cancer screening. -- As with all vaccines, GARDASIL may not fully protect everyone who gets the vaccine. -- Gardasil will not protect against diseases due to non-vaccine HPV types. There are more than 100 HPV types; GARDASIL helps protect against 4 types (6, 11, 16, and 18). These 4 types have been selected for GARDASIL because they cause approximately 70% of cervical cancers and 90% of genital warts. -- This vaccine will not protect you against HPV types to which you may have already been exposed. -- GARDASIL also will not protect against other diseases that are not caused by HPV. -- GARDASIL works best when given before you or your child has any contact with certain types of HPV (i.e., HPV types 6, 11, 16, and 18). Who can receive GARDASIL? GARDASIL is for girls and women 9 through 26 years of age. See "Who should not receive GARDASIL?" below. Who should not receive GARDASIL? Anyone who: -- is allergic to any of the ingredients in the vaccine. A list of ingredients can be found at the end of this leaflet. -- has an allergic reaction after getting a dose of the vaccine. What should I tell my health care professional before I am vaccinated or my child is vaccinated with GARDASIL? It is very important to tell your health care professional if you or your child: -- has had an allergic reaction to the vaccine. -- has a bleeding disorder and cannot receive injections in the arm. -- has a weakened immune system, for example, due to a genetic defect or HIV infection. -- is pregnant or is planning to get pregnant. GARDASIL is not recommended for use in pregnant women. -- has any illness with a fever more than 100 degrees F (37.8 degrees C). -- takes or plans to take any medicines, even those you can buy over the counter. Your health care professional will decide if you or your child should receive the vaccine. How is GARDASIL given? GARDASIL is given as an injection. You or your child will receive 3 doses of the vaccine. Ideally the doses are given as: -- First dose: at a date you and your health care professional choose. -- Second dose: 2 months after the first dose. -- Third dose: 6 months after the first dose. Make sure that you or your child gets all 3 doses. This allows you or your child to get the full benefits of GARDASIL. If you or your child misses a dose, your health care professional will decide when to give the missed dose. What are the possible side effects of GARDASIL? As with all vaccines, there may be some side effects with GARDASIL. GARDASIL has been shown to be generally well tolerated in women and girls as young as 9 years of age. The most commonly reported side effects included: -- pain, swelling, itching, and redness at the injection site. -- fever. -- nausea. -- dizziness. -- vomiting. -- fainting. Fainting can occur after vaccination, most commonly among adolescents and young adults. Although fainting episodes are uncommon, patients should be observed for 15 minutes after they receive HPV vaccine. Allergic reactions that may include difficulty breathing, wheezing (bronchospasm), hives, and rash have been reported. Some of these reactions have been severe. If you or your child has any unusual or severe symptoms after receiving GARDASIL, contact your health care professional right away. For a more complete list of side effects, ask your health care professional. What are the ingredients in GARDASIL? The main ingredients are purified inactive proteins that come from HPV Types 6, 11, 16, and 18. It also contains amorphous aluminum hydroxyphosphate sulfate, sodium chloride, L-histidine, polysorbate 80, sodium borate, and water for injection. What are cervical cancer, precancerous lesions, and genital warts? Cancer of the cervix is a serious disease that can be life-threatening. This disease is caused by certain HPV types that can cause the cells in the lining of the cervix to change from normal to precancerous lesions. If these are not treated, they can turn cancerous. Genital warts are caused by certain types of HPV. They often appear as skin-colored growths. They are found on the inside or outside of the genitals. They can hurt, itch, bleed, and cause discomfort. These lesions are usually not precancerous. Sometimes, it takes multiple treatments to eliminate these lesions. What is Human Papillomavirus (HPV)? HPV is a common virus. In 2005, the Centers for Disease Control and Prevention (CDC) estimated that 20 million people in the United States had this virus. There are many different types of HPV; some cause no harm. Others can cause diseases of the genital area. For most people the virus goes away on its own. When the virus does not go away it can develop into cervical cancer, precancerous lesions, or genital warts, depending on the HPV type. See "What other key information about GARDASIL should I know?" Who is at risk for Human Papillomavirus? In 2005, the CDC estimated that at least 50% of sexually active people catch HPV during their lifetime. A male or female of any age who takes part in any kind of sexual activity that involves genital contact is at risk. Many people who have HPV may not show any signs or symptoms. This means that they can pass on the virus to others and not know it. Will GARDASIL help me if I already have Human Papillomavirus? You may benefit from GARDASIL if you already have HPV. This is because most people are not infected with all four types of HPV contained in the vaccine. In clinical trials, individuals with current or past infection with one or more vaccine-related HPV types prior to vaccination were protected from disease caused by the remaining vaccine HPV types. GARDASIL is not intended to be used for treatment for the above mentioned diseases. Talk to your health care professional for more information. This leaflet is a summary of information about GARDASIL. If you would like more information, please talk to your health care professional or visit www.gardasil.com. Issued April 2007 Manufactured and Distributed by: MERCK & CO., Inc. Whitehouse Station, NJ 08889, USA * Registered trademark of MERCK & CO., Inc. Whitehouse Station, NJ 08889, USA COPYRIGHT (C) 2006 MERCK & CO., Inc. All rights reserved