Gardasil related Press Releases

Kaiser Permanente Study Finds Gardasil does not Trigger Lupus, Rheumatoid Arthritis or Type 1 Diabetes after Vaccination

Jennifer Levin — Thu, 02 Feb 2012 07:05:35 -0500

Kaiser Permanente Study Finds Gardasil does not Trigger Lupus, Rheumatoid Arthritis or Type 1 Diabetes after Vaccination
Two-year study tracked results for 190,000 girls and women

January 25, 2012

PASADENA, Calif. - Gardasil, the human papillomavirus vaccine that is now recommended for male and female adolescents and young adults, does not trigger autoimmune conditions such as lupus, rheumatoid arthritis, type 1 diabetes or multiple sclerosis after vaccination in young women, according to a new study in the Journal of Internal Medicine.

Kaiser Permanente researchers used electronic health records to conduct an observational safety study of 189,629 females aged 9 to 26 years old in California who were followed for six months after receiving each dose of the quadrivalent HPV vaccine in 2006-2008. Researchers found no increase in 16 pre-specified autoimmune conditions in the vaccinated population compared to a matched group of unvaccinated girls and women.

The quadrivalent HPV vaccine was licensed by the U.S. Food and Drug Administration in 2006 and recommended for young women and girls to protect against genital warts, which infects 6.2 million people annually, is the most common sexually transmitted infection in the United States, and can lead to cervical cancer in women. But autoimmune reactions have been a longstanding concern surrounding vaccination and many parents withhold the vaccine from their children because of perceived safety concerns. However, most speculated associations have stemmed from case reports that have not been confirmed by large, controlled epidemiologic studies. This study presents findings from a well-designed, post-licensure safety study of the vaccine on a large, ethnically diverse population, researchers said.

"This kind of safety information may help parents with vaccination decisions," said study lead author Chun Chao, PhD, a research scientist at the Kaiser Permanente Department of Research & Evaluation in Pasadena, Calif. "These findings offer some assurance that among a large and generalizable female population, no safety signal for autoimmune conditions was found following HPV4 vaccination in routine clinical use."

The study looked for autoimmune conditions such as immune thrombocytopenia, autoimmune hemolytic anemia, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, type 1 diabetes, Hashimoto's disease, Graves' disease, multiple sclerosis, acute disseminated encephalomyelitis, other demyelinating diseases of the central nervous system, vaccine-associated demyelination, Guillain-Barré syndrome, neuromyelitis optica, optic neuritis and uveitis.

Previous safety data on the HPV vaccine has been collected in clinical trials, as well as through the Vaccine Adverse Event Reporting System. Both have important limitations in assessing the safety profile of the vaccine. Clinical trials often include a highly selected population, with sample sizes too small, and follow-up too short, to observe rare safety events such as autoimmune conditions. The VAERS reports are often hard to interpret due to the lack of a proper comparison group and limited ability to determine whether the onset of the condition really preceded vaccination.

On the other hand, the present study, conducted at Kaiser Permanente in California, employed methods that involved in-depth medical-chart review to ensure the accuracy of diagnosis and that onset of disease was after vaccination. In addition, disease incidence in the vaccinated group was compared with a comparable unvaccinated group. As a result, this study offers important complementary safety information for the HPV vaccine.

The study was funded by Merck & Co., which manufactures Gardasil.

Other authors on the study included: Nicola P. Klein, MD, John Hansen, MPH, Kamala Deosaransingh, MPH, and Michael Emery, of the Kaiser Permanente Vaccine Study Center; Christine M. Velicer, PhD, and Kai-Li Liaw, PhD, of the Department of Epidemiology, Merck Research Laboratories; Bradley Ackerson, MD, of the Department of Pediatrics, Kaiser Permanente South Bay (Calif.) Medical Center; Lina S. Sy, MPH, Jeff M. Slezak, Harpreet Takhar, MPH, T. Craig Cheetham, PharmD, Steven J. Jacobsen, MD, of the Department of Research & Evaluation, Kaiser Permanente Southern California.

About the Kaiser Permanente Department of Research & Evaluation
The Department of Research & Evaluation (R & E) conducts high quality, innovative research into disease etiology, prevention, treatment and care delivery. Investigators conduct epidemiology, health sciences, and behavioral research as well as clinical trials. Areas of interest include diabetes and obesity, cancer, HIV/AIDS, cardiovascular disease, aging and cognition, pregnancy outcomes, women's and children's health, quality and safety, and pharmacoepidemiology. Located in Pasadena, Calif., the department focuses on translating research to practice quickly to benefit the health and lives of Kaiser Permanente Southern California members and the general population. Visit www.kp.org/research.

About Kaiser Permanente
Kaiser Permanente is committed to helping shape the future of health care. We are recognized as one of America's leading health care providers and not-for-profit health plans. Founded in 1945, our mission is to provide high-quality, affordable health care services and to improve the health of our members and the communities we serve. We serve approximately 8.9 million members in nine states and the District of Columbia. Care for members and patients is focused on their total health and guided by their personal physicians, specialists and team of caregivers. Our expert and caring medical teams are empowered and supported by industry-leading technology advances and tools for health promotion, disease prevention, state-of-the art care delivery and world-class chronic disease management. Kaiser Permanente is dedicated to care innovations, clinical research, health education and the support of community health. For more information, go to: www.kp.org/newscenter.

Contact:
Sandra Hernandez-Millett, Kaiser Permanente Southern California, 626-405-5384
Emily Schwartz, Golin Harris for Kaiser Permanente, 415-318-4371

US FDA Approves New Indication for Merck's HPV Vaccine, GARDASIL®

Wed, 22 Dec 2010 17:22:35 -0500

GARDASIL now Approved for Prevention of Anal Cancer and AIN

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)-- Merck, known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has approved GARDASIL^® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] for the prevention of anal cancer caused by human papillomavirus (HPV) types 16 and 18 and for the prevention of anal intraepithelial neoplasia (AIN) grades 1, 2 and 3 (anal dysplasias and precancerous lesions) caused by HPV types 6, 11, 16 and 18, in males and females 9 through 26 years of age.

“We are pleased that with this new indication for GARDASIL against HPV-related anal cancer and disease, both males and females can be protected against cancer, which further reinforces the importance of vaccinating both genders," said Richard M. Haupt, M.D., MPH, executive director, Merck Research Laboratories. "GARDASIL is the only HPV vaccine available for use in both males and females, and the only one indicated to help prevent cervical, vaginal, vulvar and anal cancers and pre-cancers, as well as genital warts, caused by certain types of HPV."

In the United States, an estimated 75 to 80 percent of males and females will be infected with HPV in their lifetime. For most, HPV will clear on its own. However, for those who don't clear certain types, HPV can cause cervical, vaginal and vulvar cancers in women and anal cancer and genital warts in men and women. There is no way to predict who will or won't clear the virus.

GARDASIL helps protect against the four types of HPV, specifically types 6, 11, 16, and 18, that cause the most disease. It is estimated that HPV types 16 and 18 account for approximately 80 percent of anal cancers, 75 percent of cervical cancers, 70 percent of vaginal cancers and 40 to 50 percent of vulvar cancers. HPV types 6 and 11 cause approximately 90 percent of all genital warts cases.

Anal cancer affects both men and women, with approximately 60 percent of cases occurring in women. According to the American Cancer Society, it is estimated that approximately 2,000 men and more than 3,000 women will have been diagnosed with anal cancer in 2010. There is no standardized screening recommended for the general population for anal cancer and many people are diagnosed when the disease is more advanced.

GARDASIL^® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] was approved in the United States in 2006 and is also indicated for use in girls and young women 9 through 26 years of age for the prevention of cervical, vulvar and vaginal cancers caused by HPV types 16 and 18; genital warts (condylomata acuminata) caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18. GARDASIL is also approved in the U.S. for use in boys and men ages 9 through 26 years of age for the prevention of genital warts caused by HPV types 6 and 11.

Important information about GARDASIL

GARDASIL does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening.

Recipients of GARDASIL should not discontinue anal cancer screening if it has been recommended by a health care provider.

GARDASIL has not been demonstrated to provide protection against diseases from vaccine and non-vaccine HPV types to which a person has previously been exposed through sexual activity.

GARDASIL is not intended to be used for treatment of active external genital lesions; cervical, vulvar, vaginal, and anal cancers; cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, or anal intraepithelial neoplasia.

GARDASIL has not been demonstrated to protect against disease due to HPV types not contained in the vaccine.

Not all vulvar, vaginal, and anal cancers are caused by HPV, and GARDASIL protects only against those vulvar, vaginal, and anal cancers caused by HPV 16 and 18.

Select safety information

GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL.

Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with GARDASIL. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion.

GARDASIL^® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] is not recommended for use in pregnant women.

The most common adverse reaction was headache. Common adverse reactions that were observed among recipients of GARDASIL at a frequency of at least 1.0 percent and greater than placebo were: fever, nausea, dizziness; and injection-site pain, swelling, erythema, pruritus and bruising.

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 deltoid region of the upper arm or in the higher anterolateral area of the thigh. 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 approved in 121 countries

GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant] (sold in some countries as SILGARD^®) has been approved in 121 countries, and additional applications are currently under review with regulatory agencies in many more countries around the world.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2009 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Prescribing Information and Patient Product Information for GARDASIL^® is available at
http://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf and
http://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_ppi.pdf.

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use GARDASIL safely and effectively. See full prescribing information for GARDASIL.

GARDASIL
[Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant]
Suspension for intramuscular injection
Initial U.S. Approval: 2006

RECENT MAJOR CHANGES

Indications and Usage (1)
	Girls and Women (1.1)	12/2010
	Boys and Men (1.2)	12/2010
	Limitations of GARDASIL Use and Effectiveness (1.3)	12/2010

INDICATIONS AND USAGE

GARDASIL is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine:

Cervical, vulvar, vaginal, and anal cancer caused by HPV types 16 and 18
Genital warts (condyloma acuminata) caused by HPV types 6 and 11

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:

Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS)
Cervical intraepithelial neoplasia (CIN) grade 1
Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3

GARDASIL is indicated in boys and men 9 through 26 years of age for the prevention of the following diseases caused by HPV types included in the vaccine:

Anal cancer caused by HPV types 16 and 18
Genital warts (condyloma acuminata) caused by HPV types 6 and 11

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:

Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3. (1)

Limitations of GARDASIL Use and Effectiveness:

GARDASIL does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening. (1.3) (17)
Recipients of GARDASIL should not discontinue anal cancer screening if it has been recommended by a health care provider. (1.3) (17)
GARDASIL has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a person has previously been exposed through sexual activity. (1.3) (14.4) (14.5)
GARDASIL is not intended to be used for treatment of active external genital lesions; cervical, vulvar, vaginal, and anal cancers; CIN; VIN; VaIN, or AIN. (1.3)
GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. (1.3) (14.4) (14.5)
Not all vulvar, vaginal, and anal cancers are caused by HPV, and GARDASIL protects only against those vulvar, vaginal, and anal cancers caused by HPV 16 and 18. (1.3)
GARDASIL does not protect against genital diseases not caused by HPV. (1.3)
Vaccination with GARDASIL may not result in protection in all vaccine recipients. (1.3)

DOSAGE AND ADMINISTRATION

0.5-mL suspension for intramuscular injection at the following schedule: 0, 2 months, 6 months. (2.1)

DOSAGE FORMS AND STRENGTHS

0.5-mL suspension for injection as a single-dose vial and prefilled syringe. (3) (11)

CONTRAINDICATIONS

Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of GARDASIL. (4) (11)

WARNINGS AND PRECAUTIONS

Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with GARDASIL. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position. (5.1)

ADVERSE REACTIONS

The most common adverse reaction was headache. Common adverse reactions (frequency of at least 1.0% and greater than AAHS control or saline placebo) are fever, nausea, dizziness; and injection-site pain, swelling, erythema, pruritus, and bruising. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

DRUG INTERACTIONS

GARDASIL may be administered concomitantly with RECOMBIVAX HB (7.1) or with Menactra and Adacel. (7.2)

USE IN SPECIFIC POPULATIONS

Safety and effectiveness of GARDASIL have not been established in the following populations:

Pregnant women. Physicians are encouraged to register pregnant women exposed to GARDASIL by calling 1-800-986-8999 so that Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., can monitor maternal and fetal outcomes. (8.1)
Children below the age of 9 years. (8.4)
Immunocompromised individuals. Response to GARDASIL may be diminished. (8.6)
Individuals 27 years of age and older. (8.1) (14.7)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 12/2010

FULL PRESCRIBING INFORMATION: CONTENTS*

1			INDICATIONS AND USAGE
			1.1 Girls and Women
			1.2 Boys and Men
			1.3 Limitations of GARDASIL Use and Effectiveness
2			DOSAGE AND ADMINISTRATION
			2.1 Dosage
			2.2 Method of Administration
3			DOSAGE FORMS AND STRENGTHS
4			CONTRAINDICATIONS
5			WARNINGS AND PRECAUTIONS
			5.1 Syncope
			5.2 Managing Allergic Reactions
6			ADVERSE REACTIONS
			6.1 Clinical Trials Experience
			6.2 Postmarketing Experience
7			DRUG INTERACTIONS
			7.1 Use with RECOMBIVAX HB
			7.2 Use with Menactra and Adacel
			7.3 Use with Hormonal Contraceptives
			7.4 Use with Systemic Immunosuppressive Medications
8			USE IN SPECIFIC POPULATIONS
			8.1 Pregnancy
			8.3 Nursing Mothers
			8.4 Pediatric Use
			8.5 Geriatric Use
			8.6 Immunocompromised Individuals
10			OVERDOSAGE
11			DESCRIPTION
12			CLINICAL PHARMACOLOGY
			12.1 Mechanism of Action
13			NONCLINICAL TOXICOLOGY
			13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14			CLINICAL STUDIES
			14.1 Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in Girls and Women 16 Through 26 Years of Age
			14.2 Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in Boys and Men 16 Through 26 Years of Age
			14.3 Prophylactic Efficacy – Anal Disease Caused by HPV Types 6, 11, 16, and 18 in Boys and Men 16 Through 26 Years of Age in the MSM Sub-study
			14.4 Population Impact in Girls and Women 16 Through 26 Years of Age
			14.5 Population Impact in Boys and Men 16 Through 26 Years of Age
			14.6 Overall Population Impact
			14.7 Other Studies
			14.8 Immunogenicity
			14.9 Studies with RECOMBIVAX HB [hepatitis B vaccine (recombinant)]
			14.10 Studies with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)]
16			HOW SUPPLIED/STORAGE AND HANDLING
17			PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Girls and Women

GARDASIL®¹ is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine:

Cervical, vulvar, vaginal, and anal cancer caused by HPV types 16 and 18
Genital warts (condyloma acuminata) caused by HPV types 6 and 11

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:

Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS)
Cervical intraepithelial neoplasia (CIN) grade 1
Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3

1.2 Boys and Men

GARDASIL is indicated in boys and men 9 through 26 years of age for the prevention of the following diseases caused by HPV types included in the vaccine:

Anal cancer caused by HPV types 16 and 18
Genital warts (condyloma acuminata) caused by HPV types 6 and 11

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:

Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3

1.3 Limitations of GARDASIL Use and Effectiveness

The health care provider should inform the patient, parent, or guardian that vaccination does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening. Women who receive GARDASIL should continue to undergo cervical cancer screening per standard of care. [See Patient Counseling Information (17).]

Recipients of GARDASIL should not discontinue anal cancer screening if it has been recommended by a health care provider. [See Patient Counseling Information (17).]

GARDASIL has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a person has previously been exposed through sexual activity. [See Clinical Studies (14.4, 14.5).]

GARDASIL is not intended to be used for treatment of active external genital lesions; cervical, vulvar, vaginal, and anal cancers; CIN; VIN; VaIN; or AIN.

GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. [See Clinical Studies (14.4, 14.5).]

Not all vulvar, vaginal, and anal cancers are caused by HPV, and GARDASIL protects only against those vulvar, vaginal, and anal cancers caused by HPV 16 and 18.

GARDASIL does not protect against genital diseases not caused by HPV.

Vaccination with GARDASIL may not result in protection in all vaccine recipients.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

GARDASIL should be administered intramuscularly as a 0.5-mL dose at the following schedule: 0, 2 months, 6 months. [See Clinical Studies (14.8).]

2.2 Method of Administration

For intramuscular use only.

Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. GARDASIL should not be diluted or mixed with other vaccines. 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.

GARDASIL should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.

Syncope has been reported following vaccination with GARDASIL and may result in falling with injury; observation for 15 minutes after administration is recommended. [See Warnings and Precautions (5.1).]

Single-Dose Vial Use

Withdraw the 0.5-mL dose of vaccine from the single-dose vial using a sterile needle and syringe and use promptly.

Prefilled Syringe Use With and Without Needle Guard (Safety) Device

Prefilled Syringe With Needle Guard (Safety) Device

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.

At any of the following steps, avoid contact with the Trigger Fingers to keep from activating the safety device prematurely.

Remove Syringe Tip Cap and Needle Cap. Attach Luer Needle by pressing both Anti-Rotation Tabs to secure syringe and by twisting the Luer Needle in a clockwise direction until secured to the syringe. 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. While the Plunger is still depressed, remove needle from the vaccine recipient. Slowly 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.

Prefilled Syringe Without Needle Guard (Safety) Device

This package does not contain a needle guard (safety device) or a needle. Shake well before use. Attach the needle by twisting in a clockwise direction until the needle fits securely on the syringe. Administer the entire dose as per standard protocol.

3 DOSAGE FORMS AND STRENGTHS

GARDASIL is a suspension for intramuscular administration available in 0.5-mL single dose vials and prefilled syringes. See Description (11) for the complete listing of ingredients.

4 CONTRAINDICATIONS

Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of GARDASIL. [See Description (11).]

5 WARNINGS AND PRECAUTIONS

5.1 Syncope

5.2 Managing Allergic Reactions

Appropriate medical treatment and supervision must be readily available in case of anaphylactic reactions following the administration of GARDASIL.

6 ADVERSE REACTIONS

Overall Summary of Adverse Reactions

Headache, fever, nausea, and dizziness; and local injection site reactions (pain, swelling, erythema, pruritus, and bruising) occurred after administration with GARDASIL.

Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with GARDASIL and may result in falling with injury; observation for 15 minutes after administration is recommended. [See Warnings and Precautions (5.1).]

Anaphylaxis has been reported following vaccination with GARDASIL.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

Studies in Girls, Women, Boys, and Men 9 Through 26 Years of Age

In 6 clinical trials (4 Amorphous Aluminum Hydroxyphosphate Sulfate [AAHS]-controlled, 1 saline placebo-controlled, and 1 uncontrolled), 14,273 individuals were administered GARDASIL or AAHS control or saline placebo on the day of enrollment, and approximately 2 and 6 months thereafter, and safety was evaluated using vaccination report cards (VRC)-aided surveillance for 14 days after each injection of GARDASIL or AAHS control or saline placebo in these individuals. The individuals who were monitored using VRC-aided surveillance included 8180 individuals 9 through 26 years of age at enrollment who received GARDASIL and 6093 individuals who received AAHS control or saline placebo. Few individuals (0.2%) discontinued due to adverse reactions. The race distribution of the girls and women in the safety population was as follows: 62.3% White; 17.6% Hispanic (Black and White); 6.8% Asian; 6.7% Other; 6.4% Black; and 0.3% American Indian. The race distribution of the boys and men in the safety population was as follows: 42.0% White; 19.7% Hispanic (Black and White); 11.0% Asian; 11.2% Other; 15.9% Black; and 0.1% American Indian.

Common Injection-Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age

The injection site adverse reactions that were observed among recipients of GARDASIL at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 1.

Table 1 Injection-Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age*
Adverse Reaction (1 to 5 Days Postvaccination)	GARDASIL (N = 5088) %	AAHS Control** (N = 3470) %	Saline Placebo (N = 320) %
Injection Site
Pain	83.9	75.4	48.6
Swelling	25.4	15.8	7.3
Erythema	24.7	18.4	12.1
Pruritus	3.2	2.8	0.6
Bruising	2.8	3.2	1.6
The injection-site adverse reactions 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 AAHS control or saline placebo recipients. *AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Common Injection-Site Adverse Reactions in Boys and Men 9 Through 26 Years of Age

Table 2 Injection-Site Adverse Reactions in Boys and Men 9 Through 26 Years of Age*
Adverse Reaction (1 to 5 Days Postvaccination)	GARDASIL (N = 3093) %	AAHS Control ** (N = 2029) %	Saline Placebo (N = 274) %
Injection Site
Pain	61.4	50.8	41.6
Erythema	16.7	14.1	14.5
Swelling	13.9	9.6	8.2
Hematoma	1.0	0.3	3.3
The injection-site adverse reactions 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 AAHS control or saline placebo recipients. *AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Evaluation of Injection-Site Adverse Reactions by Dose in Girls and Women 9 Through 26 Years of Age

An analysis of injection-site adverse reactions in girls and women by dose is shown in Table 3. Of those girls and women who reported an injection-site reaction, 94.3% judged their injection-site adverse reaction to be mild or moderate in intensity.

Table 3 Postdose Evaluation of Injection-Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age (1 to 5 Days Postvaccination)
	GARDASIL (% occurrence)			AAHS Control* (% occurrence)			Saline Placebo (% occurrence)
Adverse Reaction	Post- dose 1 N** = 5011	Post- dose 2 N = 4924	Post- dose 3 N = 4818	Post- dose 1 N =3410	Post- dose 2 N = 3351	Post- dose 3 N = 3295	Post- dose 1 N =315	Post- dose 2 N = 301	Post- dose 3 N = 300
Pain	63.4	60.7	62.7	57.0	47.8	49.6	33.7	20.3	27.3
Mild/Moderate	62.5	59.7	61.2	56.6	47.3	48.9	33.3	20.3	27.0
Severe	0.9	1.0	1.5	0.4	0.5	0.6	0.3	0.0	0.3
Swelling***	10.2	12.8	15.1	8.2	7.5	7.6	4.4	3.0	3.3
Mild/Moderate	9.6	11.9	14.2	8.1	7.2	7.3	4.4	3.0	3.3
Severe	0.6	0.8	0.9	0.2	0.2	0.2	0.0	0.0	0.0
Erythema***	9.2	12.1	14.7	9.8	8.4	8.9	7.3	5.3	5.7
Mild/Moderate	9.0	11.7	14.3	9.5	8.4	8.8	7.3	5.3	5.7
Severe	0.2	0.3	0.4	0.3	0.1	0.1	0.0	0.0	0.0
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate N = Number of individuals with follow-up **Intensity of swelling and erythema was measured by size (inches): Mild = 0 to ≤1; Moderate = >1 to ≤2; Severe = >2.

Evaluation of Injection-Site Adverse Reactions by Dose in Boys and Men 9 Through 26 Years of Age

An analysis of injection-site adverse reactions in boys and men by dose is shown in Table 4. Of those boys and men who reported an injection-site reaction, 96.4% judged their injection-site adverse reaction to be mild or moderate in intensity.

Table 4 Postdose Evaluation of Injection-Site Adverse Reactions in Boys and Men 9 Through 26 Years of Age (1 to 5 Days Postvaccination)
	GARDASIL (% occurrence)			AAHS Control* (% occurrence)			Saline Placebo (% occurrence)
Adverse Reaction	Post- dose 1 N** = 3003	Post- dose 2 N = 2898	Post- dose 3 N = 2826	Post- dose 1 N = 1950	Post- dose 2 N = 1854	Post- dose 3 N = 1799	Post- dose 1 N = 269	Post- dose 2 N = 263	Post- dose 3 N = 259
Pain	44.7	36.9	34.4	38.4	28.2	25.8	27.5	20.5	16.2
Mild/Moderate	44.5	36.4	34.1	37.9	28.2	25.5	27.5	20.2	16.2
Severe	0.2	0.5	0.3	0.4	0.1	0.3	0.0	0.4	0.0
Swelling***	5.6	6.6	7.7	5.6	4.5	4.1	4.8	1.5	3.5
Mild/Moderate	5.3	6.2	7.1	5.4	4.5	4.0	4.8	1.5	3.1
Severe	0.2	0.3	0.5	0.2	0.0	0.1	0.0	0.0	0.4
Erythema***	7.2	8.0	8.7	8.3	6.3	5.7	7.1	5.7	5.0
Mild/Moderate	6.8	7.7	8.3	8.0	6.2	5.6	7.1	5.7	5.0
Severe	0.3	0.2	0.3	0.2	0.1	0.1	0.0	0.0	0.0
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate N = Number of individuals with follow-up **Intensity of swelling and erythema was measured by size (inches): Mild = 0 to ≤1; Moderate = >1 to ≤2; Severe = >2.

Common Systemic Adverse Reactions in Girls and Women 9 Through 26 Years of Age

Headache was the most commonly reported systemic adverse reaction in both treatment groups (GARDASIL = 28.2% and AAHS control or saline placebo = 28.4%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (GARDASIL = 13.0% and AAHS control or saline placebo = 11.2%).

Adverse reactions that were observed among recipients of GARDASIL, at a frequency of greater than or equal to 1.0% where the incidence in the GARDASIL group was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 5.

Table 5 Common Systemic Adverse Reactions in Girls and Women 9 Through 26 Years of Age (GARDASIL ≥Control)*
Adverse Reactions (1 to 15 Days Postvaccination)	GARDASIL (N = 5088) %	AAHS Control or Saline Placebo** (N = 3790) %
Pyrexia	13.0	11.2
Nausea	6.7	6.5
Dizziness	4.0	3.7
Diarrhea	3.6	3.5
Vomiting	2.4	1.9
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
The adverse reactions in this table are those that were observed among recipients of GARDASIL at a frequency of at least 1.0% and greater than or equal to those observed among AAHS control or saline placebo recipients. *AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Common Systemic Adverse Reactions in Boys and Men 9 Through 26 Years of Age

Headache was the most commonly reported systemic adverse reaction in both treatment groups (GARDASIL = 12.3% and AAHS control or saline placebo = 11.2%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (GARDASIL = 8.3% and AAHS control or saline placebo = 6.5%).

Adverse reactions that were observed among recipients of GARDASIL, at a frequency of greater than or equal to 1.0% where the incidence in the group that received GARDASIL was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 6.

Table 6 Common Systemic Adverse Reactions in Boys and Men 9 Through 26 Years of Age (GARDASIL ≥Control)*
Adverse Reactions (1 to 15 Days Postvaccination)	GARDASIL (N = 3093) %	AAHS Control or Saline Placebo** (N = 2303) %
Headache	12.3	11.2
Pyrexia	8.3	6.5
Oropharyngeal pain	2.8	2.1
Diarrhea	2.7	2.2
Nasopharyngitis	2.6	2.6
Nausea	2.0	1.0
Upper respiratory tract infection	1.5	1.0
Abdominal pain upper	1.4	1.4
Myalgia	1.3	0.7
Dizziness	1.2	0.9
Vomiting	1.0	0.8
The adverse reactions in this table are those that were observed among recipients of GARDASIL at a frequency of at least 1.0% and greater than or equal to those observed among AAHS control or saline placebo recipients. *AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Evaluation of Fever by Dose in Girls and Women 9 Through 26 Years of Age

An analysis of fever in girls and women by dose is shown in Table 7.

Table 7 Postdose Evaluation of Fever in Girls and Women 9 Through 26 Years of Age (1 to 5 Days Postvaccination)
	GARDASIL (% occurrence)			*AAHS Control or Saline Placebo** (% occurrence)
Temperature (°F)	Postdose 1 N** = 4945	Postdose 2 N = 4804	Postdose 3 N = 4671	Postdose 1 N = 3681	Postdose 2 N = 3564	Postdose 3 N = 3467
≥100 to <102	3.7	4.1	4.4	3.1	3.8	3.6
≥102	0.3	0.5	0.5	0.2	0.4	0.5
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate *N = Number of individuals with follow-up

Evaluation of Fever by Dose in Boys and Men 9 Through 26 Years of Age

An analysis of fever in boys and men by dose is shown in Table 8.

Table 8 Postdose Evaluation of Fever in Boys and Men 9 Through 26 Years of Age (1 to 5 Days Postvaccination)
	GARDASIL (% occurrence)			*AAHS Control or Saline Placebo** (% occurrence)
Temperature (°F)	Postdose 1 N** = 2972	Postdose 2 N = 2849	Postdose 3 N = 2792	Postdose 1 N = 2194	Postdose 2 N = 2079	Postdose 3 N = 2046
≥100 to <102	2.4	2.5	2.3	2.1	2.2	1.6
≥102	0.6	0.5	0.5	0.5	0.3	0.3
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate *N = Number of individuals with follow-up

Serious Adverse Reactions in the Entire Study Population

Across the clinical studies, 258 individuals (GARDASIL N = 128 or 0.8%; placebo N = 130 or 1.0%) out of 29,323 (GARDASIL N = 15,706; AAHS control N = 13,023; or saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men) reported a serious systemic adverse reaction.

Of the entire study population (29,323 individuals), 0.04% of the reported serious systemic adverse reactions were judged to be vaccine related by the study investigator. The most frequently (frequency of 4 cases or greater with either GARDASIL, AAHS control, saline placebo, or the total of all three) reported serious systemic adverse reactions, regardless of causality, were:

Headache [0.02% GARDASIL (3 cases) vs. 0.02% AAHS control (2 cases)],

Gastroenteritis [0.02% GARDASIL (3 cases) vs. 0.02% AAHS control (2 cases)],

Appendicitis [0.03% GARDASIL (5 cases) vs. 0.01% AAHS control (1 case)],

Pelvic inflammatory disease [0.02% GARDASIL (3 cases) vs. 0.03% AAHS control (4 cases)],

Urinary tract infection [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (2 cases)],

Pneumonia [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (2 cases)],

Pyelonephritis [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (3 cases)],

Pulmonary embolism [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (2 cases)].

One case (0.006% GARDASIL; 0.0% AAHS control or saline placebo) of bronchospasm; and 2 cases (0.01% GARDASIL; 0.0% AAHS control or saline placebo) of asthma were reported as serious systemic adverse reactions that occurred following any vaccination visit.

In addition, there was 1 individual in the clinical trials, in the group that received GARDASIL, who reported two injection-site serious adverse reactions (injection-site pain and injection-site joint movement impairment).

Deaths in the Entire Study Population

Across the clinical studies, 40 deaths (GARDASIL N = 21 or 0.1%; placebo N = 19 or 0.1%) were reported in 29,323 (GARDASIL N = 15,706; AAHS control N = 13,023, saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men). The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (5 individuals who received GARDASIL and 4 individuals who received AAHS control), followed by drug overdose/suicide (2 individuals who received GARDASIL and 6 individuals who received AAHS control), gun shot wound (1 individual who received GARDASIL and 3 individuals who received AAHS control), and pulmonary embolus/deep vein thrombosis (1 individual who received GARDASIL and 1 individual who received AAHS control). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, 1 case of arrhythmia, 1 case of pulmonary tuberculosis, 1 case of hyperthyroidism, 1 case of post-operative pulmonary embolism and acute renal failure, 1 case of traumatic brain injury/cardiac arrest, 1 case of systemic lupus erythematosus, 1 case of cerebrovascular accident, 1 case of breast cancer, and 1 case of nasopharyngeal cancer in the group that received GARDASIL; 1 case of asphyxia, 1 case of acute lymphocytic leukemia, 1 case of chemical poisoning, and 1 case of myocardial ischemia in the AAHS control group; and 1 case of medulloblastoma in the saline placebo group.

Systemic Autoimmune Disorders in Girls and Women 9 Through 26 Years of Age

In the clinical studies, 9- through 26-year-old girls and women were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received GARDASIL or AAHS control or saline placebo are shown in Table 9. This population includes all girls and women who received at least one dose of GARDASIL or AAHS control or saline placebo, and had safety data available.

Table 9 Summary of Girls and Women 9 Through 26 Years of Age Who Reported an Incident Condition Potentially Indicative of a Systemic Autoimmune Disorder After Enrollment in Clinical Trials of GARDASIL, Regardless of Causality
Conditions	GARDASIL (N = 10,706)	*AAHS Control or Saline Placebo** (N = 9412)
Conditions	n (%)	n (%)
Arthralgia/Arthritis/Arthropathy**	120 (1.1)	98 (1.0)
Autoimmune Thyroiditis	4 (0.0)	1 (0.0)
Celiac Disease	10 (0.1)	6 (0.1)
Diabetes Mellitus Insulin-dependent	2 (0.0)	2 (0.0)
Erythema Nodosum	2 (0.0)	4 (0.0)
Hyperthyroidism***	27 (0.3)	21 (0.2)
Hypothyroidism(†)	35 (0.3)	38 (0.4)
Inflammatory Bowel Disease(‡)	7 (0.1)	10 (0.1)
Multiple Sclerosis	2 (0.0)	4 (0.0)
Nephritis(¶)	2 (0.0)	5 (0.1)
Optic Neuritis	2 (0.0)	0 (0.0)
Pigmentation Disorder(§)	4 (0.0)	3 (0.0)
Psoriasis(#)	13 (0.1)	15 (0.2)
Raynaud's Phenomenon	3 (0.0)	4 (0.0)
Rheumatoid Arthritis(††)	6 (0.1)	2 (0.0)
Scleroderma/Morphea	2 (0.0)	1 (0.0)
Stevens-Johnson Syndrome	1 (0.0)	0 (0.0)
Systemic Lupus Erythematosus	1 (0.0)	3 (0.0)
Uveitis	3 (0.0)	1 (0.0)
All Conditions	245 (2.3)	218 (2.3)
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate Arthralgia/Arthritis/Arthropathy includes the following terms: Arthralgia, Arthritis, Arthritis reactive, and Arthropathy **Hyperthyroidism includes the following terms: Basedow's disease, Goiter, Toxic nodular goiter, and Hyperthyroidism ^†Hypothyroidism includes the following terms: Hypothyroidism and thyroiditis ^‡Inflammatory bowel disease includes the following terms: Colitis ulcerative, Crohn's disease, and Inflammatory bowel disease ^¶Nephritis includes the following terms: Nephritis, Glomerulonephritis minimal lesion, Glomerulonephritis proliferative ^§Pigmentation disorder includes the following terms: Pigmentation disorder, Skin depigmentation, and Vitiligo ^#Psoriasis includes the following terms: Psoriasis, Pustular psoriasis, and Psoriatic arthropathy ^††Rheumatoid arthritis includes juvenile rheumatoid arthritis. One woman counted in the rheumatoid arthritis group reported rheumatoid arthritis as an adverse experience at Day 130. N = Number of individuals enrolled n = Number of individuals with specific new Medical Conditions NOTE: Although an individual may have had two or more new Medical Conditions, the individual is counted only once within a category. The same individual may appear in different categories.

Systemic Autoimmune Disorders in Boys and Men 9 Through 26 Years of Age

In the clinical studies, 9- through 26-year-old boys and men were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received GARDASIL or AAHS control or saline placebo are shown in Table 10. This population includes all boys and men who received at least one dose of GARDASIL or AAHS control or saline placebo, and had safety data available.

Table 10 Summary of Boys and Men 9 Through 26 Years of Age Who Reported an Incident Condition Potentially Indicative of a Systemic Autoimmune Disorder After Enrollment in Clinical Trials of GARDASIL, Regardless of Causality
Conditions	GARDASIL (N = 3093)	*AAHS Control or Saline Placebo** (N = 2303)
Conditions	n (%)	n (%)
Alopecia Areata
Ankylosing Spondylitis	2 (0.1)	0 (0.0)
Arthralgia/Arthritis/Reactive	1 (0.0)	2 (0.1)
Arthritis	30 (1.0)	17 (0.7)
Autoimmune Thrombocytopenia	1 (0.0)	0 (0.0)
Diabetes Mellitus Type 1	3 (0.1)	2 (0.1)
Hyperthyroidism	0 (0.0)	1 (0.0)
Hypothyroidism**	3 (0.1)	0 (0.0)
Inflammatory Bowel Disease***	1 (0.0)	2 (0.1)
Myocarditis	1 (0.0)	1 (0.0)
Proteinuria	1 (0.0)	0 (0.0)
Psoriasis	0 (0.0)	4 (0.2)
Skin Depigmentation	1 (0.0)	0 (0.0)
Vitiligo	2 (0.1)	5 (0.2)
All Conditions	46 (1.5)	34 (1.5)
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate Hypothyroidism includes the following terms: Hypothyroidism and Autoimmune thyroiditis **Inflammatory bowel disease includes the following terms: Colitis ulcerative and Crohn's disease N = Number of individuals who received at least one dose of either vaccine or placebo n = Number of individuals with specific new Medical Conditions NOTE: Although an individual may have had two or more new Medical Conditions, the individual is counted only once within a category. The same individual may appear in different categories.

Safety in Concomitant Use with RECOMBIVAX HB [hepatitis B vaccine (recombinant)] in Girls and Women 16 Through 23 Years of Age

The safety of GARDASIL when administered concomitantly with RECOMBIVAX HB^®1 [hepatitis B vaccine (recombinant)] was evaluated in an AAHS-controlled study of 1871 girls and women with a mean age of 20.4 years [see Clinical Studies (14.9)]. The race distribution of the study individuals was as follows: 61.6% White; 23.8% Other; 11.9% Black; 1.6% Hispanic (Black and White); 0.8% Asian; and 0.3% American Indian. The rates of systemic and injection-site adverse reactions were similar among girls and women who received concomitant vaccination as compared with those who received GARDASIL or RECOMBIVAX HB [hepatitis B vaccine (recombinant)].

Safety in Concomitant Use with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)]

The safety of GARDASIL when administered concomitantly with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] was evaluated in a randomized study of 1040 boys and girls with a mean age of 12.6 years [see Clinical Studies (14.10)]. The race distribution of the study subjects was as follows: 77.7% White; 1.4% Multi-racial; 12.3% Black; 6.8% Hispanic (Black and White); 1.2% Asian; 0.4% American Indian, and 0.2% Indian.

There was an increase in injection-site swelling reported at the injection site for GARDASIL (concomitant = 10.9%, non-concomitant = 6.9%) when GARDASIL was administered concomitantly with Menactra and Adacel as compared to non-concomitant (separated by 1 month) vaccination. The majority of injection-site swelling adverse experiences were reported as being mild to moderate in intensity.

6.2 Postmarketing Experience

The following adverse events have been spontaneously reported during post-approval use of GARDASIL. Because these events were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure.

Blood and lymphatic system disorders: Autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, lymphadenopathy.

Respiratory, thoracic and mediastinal disorders: Pulmonary embolus.

Gastrointestinal disorders: Nausea, pancreatitis, vomiting.

General disorders and administration site conditions: Asthenia, chills, death, fatigue, malaise.

Immune system disorders: Autoimmune diseases, hypersensitivity reactions including anaphylactic/anaphylactoid reactions, bronchospasm, and urticaria.

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.

Nervous system disorders: Acute disseminated encephalomyelitis, dizziness, Guillain-Barré syndrome, headache, motor neuron disease, paralysis, seizures, syncope (including syncope associated with tonic-clonic movements and other seizure-like activity) sometimes resulting in falling with injury, transverse myelitis.

Infections and infestations: cellulitis.

Vascular disorders: Deep venous thrombosis.

7 DRUG INTERACTIONS

7.1 Use with RECOMBIVAX HB

Results from clinical studies indicate that GARDASIL may be administered concomitantly (at a separate injection site) with RECOMBIVAX HB [hepatitis B vaccine (recombinant)] [see Clinical Studies (14.9)].

7.2 Use with Menactra and Adacel

Results from clinical studies indicate that GARDASIL may be administered concomitantly (at a separate injection site) with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] [see Clinical Studies (14.10)].

7.3 Use with Hormonal Contraceptives

In clinical studies, 13,293 women (GARDASIL N = 6644; AAHS control or saline placebo N = 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 immune response in the per protocol efficacy (PPE) population.

7.4 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 Use in Specific Populations (8.6)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B:

Reproduction studies have been performed in female rats at doses equivalent to the recommended human dose and have revealed no evidence of impaired female fertility or harm to the fetus due to GARDASIL. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, GARDASIL should be used during pregnancy 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 (120 mcg total protein which is equivalent to the recommended human dose) 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.

Clinical Studies in Humans

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.

GARDASIL is not indicated for women 27 years of age or older. However, safety data in women 16 through 45 years of age was collected, and 3620 women (GARDASIL N = 1796 vs. AAHS control or saline placebo N = 1824) reported at least 1 pregnancy each.

The overall proportions of pregnancies that resulted in an adverse outcome, defined as the combined numbers of spontaneous abortion, late fetal death, and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), were 23.3% (423/1812) in women who received GARDASIL and 24.1% (438/1820) in women who received AAHS control or saline placebo.

Overall, 54 and 63 women in the group that received GARDASIL or AAHS control or saline placebo, respectively (3.0% and 3.5% of all women who reported a pregnancy in the respective vaccination groups), experienced a serious adverse reaction 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 women who experienced such events were comparable between the groups receiving GARDASIL and AAHS control or saline placebo.

There were 40 cases of congenital anomaly in pregnancies that occurred in women who received GARDASIL and 30 cases of congenital anomaly in pregnancies that occurred in women who received AAHS control or saline 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 AAHS control or saline placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received GARDASIL compared to 1 case of congenital anomaly in the group that received AAHS control or saline 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, 35 cases of congenital anomaly were observed in the group that received GARDASIL compared with 29 cases of congenital anomaly in the group that received AAHS control or saline placebo.

Pregnancy Registry for GARDASIL

Merck Sharp & Dohme Corp., a subsidiary of 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.

8.3 Nursing Mothers

Women 16 Through 26 Years of Age

It is not known whether GARDASIL is 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 N = 500, AAHS control N = 495) were given GARDASIL or AAHS control during the vaccination period of the clinical trials.

Overall, 21 and 10 infants of women who received GARDASIL or AAHS control, respectively (representing 4.2% and 2.0% of the total number of women who were breast-feeding during the period in which they received GARDASIL or AAHS control, respectively), experienced a serious adverse reaction.

In a post-hoc analysis of 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 AAHS control. In these studies, the rates of other adverse reactions in the mother and the nursing infant were comparable between vaccination groups.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients below 9 years of age.

8.5 Geriatric Use

The safety and effectiveness of GARDASIL have not been evaluated in a geriatric population, defined as individuals aged 65 years and over.

8.6 Immunocompromised Individuals

The immunologic response to GARDASIL may be diminished in immunocompromised individuals [see Drug Interactions (7.4)].

10 OVERDOSAGE

There have been reports of administration of higher than recommended doses of GARDASIL.

In general, the adverse event profile reported with overdose was comparable to recommended single doses of GARDASIL.

11 DESCRIPTION

GARDASIL, Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant, is a non-infectious recombinant quadrivalent vaccine prepared from the 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 suspension 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, <7 mcg yeast protein/dose, and water for injection. The product does not contain a preservative or antibiotics.

After thorough agitation, GARDASIL is a white, cloudy liquid.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

HPV only infects human beings. Animal studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines may involve the development of humoral immune responses. Human beings develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 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 is equivalent to the recommended human dose, had no effects on mating performance, fertility, or embryonic/fetal survival.

The effect of GARDASIL on male fertility has been studied in male rats at an intramuscular dose of 0.5 mL/rat/occasion (120 mcg total protein which is equivalent to the recommended human dose). One group of male rats was administered GARDASIL once, 3 days prior to cohabitation, and a second group of male rats was administered GARDASIL three times, at 6 weeks, 3 weeks, and 3 days prior to cohabitation. There were no treatment-related effects on reproductive performance including fertility, sperm count, and sperm motility. There were no treatment-related gross or histomorphologic and weight changes on the testes.

14 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. In the clinical studies in girls and women aged 16 through 26 years, cases of CIN 2/3 and AIS were the efficacy endpoints to assess prevention of cervical cancer. In addition, cases of VIN 2/3 and VaIN 2/3 were the efficacy endpoints to assess prevention of HPV-related vulvar and vaginal cancers, and observations of external genital lesions were the efficacy endpoints for the prevention of genital warts.

In clinical studies in boys and men aged 16 through 26 years, efficacy was evaluated using the following endpoints: external genital warts and penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer. In addition, cases of AIN grades 1/2/3 and anal cancer made up the composite efficacy endpoint used to assess prevention of HPV-related anal cancer.

Anal HPV infection, AIN, and anal cancer were not endpoints in the studies conducted in women. The similarity of HPV-related anal disease in men and women supports bridging the indication of prevention of AIN and anal cancer to women.

Efficacy was assessed in 5 AAHS-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of GARDASIL (Study 1, N = 2391 girls and women) and the second evaluated all components of GARDASIL (Study 2, N = 551 girls and women). Two Phase III studies evaluated GARDASIL in 5442 (Study 3) and 12,157 (Study 4) girls and women. A third Phase III study, Study 5, evaluated GARDASIL in 4055 boys and men, including a subset of 598 (GARDASIL = 299; placebo = 299) men who self-identified as having sex with men (MSM population). Together, these five studies evaluated 24,596 individuals (20,541 girls and women 16 through 26 years of age at enrollment with a mean age of 20.0 years and 4055 boys and men 16 through 26 years of age at enrollment with a mean age of 20.5 years). The race distribution of the girls and women in the clinical trials was as follows: 70.4% White; 12.2% Hispanic (Black and White); 8.8% Other; 4.6% Black; 3.8% Asian; and 0.2% American Indian. The race distribution of the boys and men in the clinical trials was as follows: 35.2% White; 20.5% Hispanic (Black and White); 14.4% Other; 19.8% Black; 10.0% Asian; and 0.1% American Indian.

The median duration of follow-up was 4.0, 3.0, 3.0, 3.0, and 2.3 years for Study 1, Study 2, Study 3, Study 4, and Study 5, respectively. Individuals received vaccine or AAHS control on the day of enrollment and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies in girls and women combined according to a prospective clinical plan.

Overall, 73% of 16- through 26-year-old girls and women and 83% of 16- through 26-year-old boys and men were naïve (i.e., PCR [Polymerase Chain Reaction] negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment.

A total of 27% of 16- through 26-year-old girls and women and 17% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these individuals, 74% of 16- through 26-year-old girls and women and 78% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were naïve (PCR negative and seronegative) to the remaining 3 types.

In individuals who were naïve (PCR negative and seronegative) to all 4 vaccine HPV types, CIN, genital warts, VIN, VaIN, PIN, and persistent infection caused by any of the 4 vaccine HPV types were counted as endpoints.

Among individuals who were positive (PCR positive and/or seropositive) for a vaccine HPV type at Day 1, endpoints related to that type were not included in the analyses of prophylactic efficacy. Endpoints related to the remaining types for which the individual was naïve (PCR negative and seronegative) were counted.

For example, in individuals who were HPV 18 positive (PCR positive and/or seropositive) at Day 1, lesions caused by HPV 18 were not counted in the prophylactic efficacy evaluations. Lesions caused by HPV 6, 11, and 16 were included in the prophylactic efficacy evaluations. The same approach was used for the other types.

14.1 Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in Girls and Women 16 Through 26 Years of Age

GARDASIL was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of girls and women regardless of baseline HPV status (i.e., PCR status or serostatus). Girls and women with current or prior HPV infection with an HPV type contained in the vaccine were not eligible for prophylactic efficacy evaluations for that type.

The primary analyses of efficacy with respect to HPV types 6, 11, 16, and 18 were conducted in the per-protocol efficacy (PPE) population, consisting of girls and women who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (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.

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 6, 11, 16, or 18 in those who were PCR negative and seronegative at baseline (Table 11).

In addition, girls and women who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from precancerous cervical lesions and external genital lesions caused by the other vaccine HPV types.

Table 11 Analysis of Efficacy of GARDASIL in the PPE* Population of 16- Through 26-Year-Old Girls and Women for Vaccine HPV Types**
Population	GARDASIL		AAHS Control		% Efficacy (95% CI)
Population	N	Number of cases	N	Number of cases	% Efficacy (95% CI)
HPV 16- or 18-related CIN 2/3 or AIS
Study 1***	755	0	750	12	100.0 (65.1, 100.0)
Study 2	231	0	230	1	100.0 (-3744.9, 100.0)
Study 3	2201	0	2222	36	100.0 (89.2, 100.0)
Study 4	5306	2	5262	63	96.9 (88.2, 99.6)
Combined Protocols^†	8493	2	8464	112	98.2 (93.5, 99.8)
HPV 16-related CIN 2/3 or AIS
Combined Protocols^†	7402	2	7205	93	97.9 (92.3, 99.8)
HPV 18-related CIN 2/3 or AIS
Combined Protocols^†	7382	0	7316	29	100.0 (86.6, 100.0)
HPV 16- or 18-related VIN 2/3
Study 2	231	0	230	0	Not calculated
Study 3	2219	0	2239	6	100.0 (14.4, 100.0)
Study 4	5322	0	5275	4	100.0 (-50.3, 100.0)
Combined Protocols^†	7772	0	7744	10	100.0 (55.5, 100.0)
HPV 16- or 18-related VaIN 2/3
Study 2	231	0	230	0	Not calculated
Study 3	2219	0	2239	5	100.0 (-10.1, 100.0)
Study 4	5322	0	5275	4	100.0 (-50.3, 100.0)
Combined Protocols^†	7772	0	7744	9	100.0 (49.5, 100.0)
HPV 6-, 11-, 16-, or 18-related CIN (CIN 1, CIN 2/3) or AIS
Study 2	235	0	233	3	100.0 (-138.4, 100.0)
Study 3	2241	0	2258	77	100.0 (95.1, 100.0)
Study 4	5388	9	5374	145	93.8 (88.0, 97.2)
Combined Protocols^†	7864	9	7865	225	96.0 (92.3, 98.2)
HPV 6-, 11-, 16-, or 18-related Genital Warts
Study 2	235	0	233	3	100.0 (-139.5, 100.0)
Study 3	2261	0	2279	58	100.0 (93.5, 100.0)
Study 4	5404	2	5390	132	98.5 (94.5, 99.8)
Combined Protocols^†	7900	2	7902	193	99.0 (96.2, 99.9)
HPV 6- and 11-related Genital Warts
Combined Protocols^†	6932	2	6856	189	99.0 (96.2, 99.9)
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 naïve (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 14 for analysis of vaccine impact in the general population. Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL ^†Analyses of the combined trials were prospectively planned and included the use of similar study entry criteria. N = Number of individuals with at least 1 follow-up visit after Month 7 CI = Confidence Interval 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: Table 11 does not include cases due to non-vaccine HPV types.** AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Prophylactic efficacy against overall cervical and genital disease related to HPV 6, 11, 16, and 18 in an extension phase of Study 2, that included data through Month 60, was noted to be 100% (95% CI: 12.3%, 100.0%) among girls and women in the per protocol population naïve to the relevant HPV types.

GARDASIL was efficacious against HPV disease caused by HPV types 6, 11, 16, and 18 in girls and women who were naïve for those specific HPV types at baseline.

14.2 Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in Boys and Men 16 Through 26 Years of Age

The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population. This population consisted of boys and men who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (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 was measured starting after the Month 7 visit.

GARDASIL was efficacious in reducing the incidence of genital warts related to vaccine HPV types 6 and 11 in those boys and men who were PCR negative and seronegative at baseline (Table 12). Efficacy against penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer was not demonstrated as the number of cases was too limited to reach statistical significance.

Table 12 *Analysis of Efficacy of GARDASIL in the PPE Population of 16- Through 26-Year-Old Boys and Men for Vaccine HPV Types**
Endpoint	GARDASIL		AAHS Control		% Efficacy (95% CI)
Endpoint	N**	Number of cases	N	Number of cases	% Efficacy (95% CI)
External Genital Lesions HPV 6-, 11-, 16-, or 18- related
External Genital Lesions	1394	3	1404	32	90.6 (70.1, 98.2)
Condyloma	1394	3	1404	28	89.3 (65.3, 97.9)
PIN 1/2/3	1394	0	1404	4	100.0 (-52.1, 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 naïve (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). *N = Number of individuals with at least 1 follow-up visit after Month 7 CI = Confidence Interval AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

14.3 Prophylactic Efficacy – Anal Disease Caused by HPV Types 6, 11, 16, and 18 in Boys and Men 16 Through 26 Years of Age in the MSM Sub-study

A sub-study of Study 5 evaluated the efficacy of GARDASIL against anal disease (anal intraepithelial neoplasia and anal cancer) in a population of 598 MSM. The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population of Study 5.

GARDASIL was efficacious in reducing the incidence of anal intraepithelial neoplasia (AIN) grades 1 (both condyloma and non-acuminate), 2, and 3 related to vaccine HPV types 6, 11, 16, and 18 in those boys and men who were PCR negative and seronegative at baseline (Table 13).

Table 13 *Analysis of Efficacy of GARDASIL for Anal Disease in the PPE Population of 16- Through 26-Year-Old Boys and Men in the MSM Sub-study for Vaccine HPV Types**
HPV 6-, 11-, 16-, or 18- related Endpoint	GARDASIL		AAHS Control		% Efficacy (95% CI)
HPV 6-, 11-, 16-, or 18- related Endpoint	N**	Number of cases	N	Number of cases	% Efficacy (95% CI)
AIN 1/2/3	194	5	208	24	77.5 (39.6, 93.3)
AIN 2/3	194	3	208	13	74.9 (8.8, 95.4)
AIN 1	194	4	208	16	73.0 (16.3, 93.4)
Condyloma Acuminatum	194	0	208	6	100.0 (8.2, 100.0)
Non-acuminate	194	4	208	11	60.4 (-33.5, 90.8)
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 naïve (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). *N = Number of individuals with at least 1 follow-up visit after Month 7 CI = Confidence Interval AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

14.4 Population Impact in Girls and Women 16 Through 26 Years of Age

Effectiveness of GARDASIL in Prevention of HPV Types 6-, 11-, 16-, or 18-Related Genital Disease in Girls and Women 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types

The clinical trials included girls and women regardless of current or prior exposure to vaccine HPV types, and additional analyses were conducted to evaluate the impact of GARDASIL with respect to HPV 6-, 11-, 16-, and 18-related cervical and genital disease in these girls and women. Here, analyses included events arising among girls and women regardless of baseline PCR status and serostatus, including 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 girls and women regardless of current or prior exposure to a vaccine HPV type is shown in Table 14. Impact was measured starting 1 month Postdose 1. Prophylactic efficacy denotes the vaccine’s efficacy in girls and women who are naïve (PCR negative and seronegative) to the relevant HPV types at Day 1. Vaccine impact in girls and women who were positive for vaccine HPV infection, as well as vaccine impact among girls and women regardless of baseline vaccine HPV PCR status and serostatus are also presented. The majority of CIN and genital warts, VIN, and VaIN related to a vaccine HPV type 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.

There was no clear evidence of protection from disease caused by HPV types for which girls and women were PCR positive regardless of serostatus at baseline.

Table 14 Effectiveness of GARDASIL in Prevention of HPV 6, 11, 16, or 18-Related Genital Disease in Girls and Women 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types
Endpoint	Analysis	GARDASIL or HPV 16 L1 VLP Vaccine		AAHS Control		% Reduction (95% CI)
Endpoint	Analysis	N	Cases	N	Cases	% Reduction (95% CI)
HPV 16- or 18- related CIN 2/3 or AIS	Prophylactic Efficacy*	9346	4	9407	155	97.4 (93.3, 99.3)
	HPV 16 and/or HPV 18 Positive at Day 1**	2870	142	2898	148***	--^†
	Girls and Women Regardless of Current or Prior Exposure to HPV 16 or 18^‡	9836	146	9904	303	51.8 (41.1, 60.7)
HPV 16- or 18- related VIN 2/3 or VaIN 2/3	Prophylactic Efficacy*	8642	1	8673	34	97.0 (82.4, 99.9)
	HPV 16 and/or HPV 18 Positive at Day 1**	1880	8	1876	4	--^†
	Girls and Women Regardless of Current or Prior Exposure to HPV 16 or 18^‡	8955	9	8968	38	76.3 (50.0, 89.9)
HPV 6-, 11-, 16-, 18-related CIN (CIN 1, CIN 2/3) or AIS	Prophylactic Efficacy*	8630	16	8680	309	94.8 (91.5, 97.1)
	HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1**	2466	186^#	2437	213^#	--^†
	Girls and Women Regardless of Current or Prior Exposure to Vaccine HPV Types^‡	8819	202	8854	522	61.5 (54.6, 67.4)
HPV 6-, 11-, 16-, or 18-related Genital Warts	Prophylactic Efficacy*	8761	10	8792	252	96.0 (92.6, 98.1)
	HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1**	2501	51^§	2475	55^§	--^†
	Girls and Women Regardless of Current or Prior Exposure to Vaccine HPV Types^‡	8955	61	8968	307	80.3 (73.9, 85.3)
HPV 6- or 11- related Genital Warts	Prophylactic Efficacy*	7769	9	7792	246	96.4 (93.0, 98.4)
	HPV 6 and/or HPV 11 Positive at Day 1**	1186	51	1176	54	--^†
	Girls and Women Regardless of Current or Prior Exposure to Vaccine HPV Types^‡	8955	60	8968	300	80.1 (73.7, 85.2)
Includes all individuals who received at least 1 vaccination and who were HPV-naïve (i.e., seronegative and PCR negative) at Day 1 to the vaccine HPV type being analyzed. Case counting started at 1 month postdose 1. Includes all individuals who received at least 1 vaccination and who were HPV positive or had unknown HPV status at Day 1, to at least one vaccine HPV type. Case counting started at Day 1. Out of the 148 AAHS control cases of 16/18 CIN 2/3, 2 women were missing serology or PCR results for Day 1. ^†There is no expected efficacy since GARDASIL has not been demonstrated to provide protection against disease from vaccine HPV types to which a person has previously been exposed through sexual activity. ^‡Includes all individuals who received at least 1 vaccination (regardless of baseline HPV status at Day 1). Case counting started at 1 month postdose 1. ^#Includes 2 AAHS control women with missing serology/PCR data at Day 1. ^§Includes 1 woman with missing serology/PCR data at Day 1. CI = Confidence Interval N = Number of individuals who have at least one follow-up visit after Day 1 Note 1: The 16- and 18-related CIN 2/3 or AIS composite endpoint included data from studies 1, 2, 3, and 4. All other endpoints only included data from studies 2, 3, and 4. Note 2: Positive status at Day 1 denotes PCR positive and/or seropositive for the respective type at Day 1. Note 3: Table 14 does not include disease due to non-vaccine HPV types.** AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Effectiveness of GARDASIL in Prevention of Any HPV Type Related Genital Disease in Girls and Women 16 Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine HPV Types

The impact of GARDASIL against the overall burden of dysplastic or papillomatous cervical, vulvar, and vaginal disease regardless of HPV detection, results from a combination of prophylactic efficacy against vaccine HPV types, disease contribution from vaccine HPV types present at time of vaccination, the disease contribution from HPV types not contained in the vaccine, and disease in which HPV was not detected.

Additional efficacy analyses were conducted in 2 populations: (1) a generally HPV-naïve population (negative to 14 common HPV types and had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1), approximating a population of sexually-naïve girls and women and (2) the general study population of girls and women regardless of baseline HPV status, some of whom had HPV-related disease at Day 1.

Among generally HPV-naïve girls and women and among all girls and women in the study population (including girls and women with HPV infection at Day 1), GARDASIL reduced the overall incidence of CIN 2/3 or AIS; of VIN 2/3 or VaIN 2/3; of CIN (any grade) or AIS; and of Genital Warts (Table 15). These reductions were primarily due to reductions in lesions caused by HPV types 6, 11, 16, and 18 in girls and women naïve (seronegative and PCR negative) for the specific relevant vaccine HPV type. Infected girls and women may already have CIN 2/3 or AIS at Day 1 and some will develop CIN 2/3 or AIS during follow-up, either related to a vaccine or non-vaccine HPV type present at the time of vaccination or related to a non-vaccine HPV type not present at the time of vaccination.

Table 15 Effectiveness of GARDASIL in Prevention of Any HPV Type Related Genital Disease in Girls and Women 16 Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine HPV Types
Endpoints Caused by Vaccine or Non-vaccine HPV Types	Analysis	GARDASIL		AAHS Control		% Reduction (95% CI)
	Analysis	N	Cases	N	Cases	% Reduction (95% CI)
CIN 2/3 or AIS	Prophylactic Efficacy*	4616	77	4680	136	42.7 (23.7, 57.3)
CIN 2/3 or AIS	Girls and Women Regardless of Current or Prior Exposure to Vaccine or Non- Vaccine HPV Types**	8559	421	8592	516	18.4 (7.0, 28.4)
VIN 2/3 and VaIN 2/3	Prophylactic Efficacy*	4688	7	4735	31	77.1 (47.1, 91.5)
VIN 2/3 and VaIN 2/3	Girls and Women Regardless of Current or Prior Exposure to Vaccine or Non- Vaccine HPV Types**	8688	30	8701	61	50.7 (22.5, 69.3)
CIN (Any Grade) or AIS	Prophylactic Efficacy*	4616	272	4680	390	29.7 (17.7, 40.0)
CIN (Any Grade) or AIS	Girls and Women Regardless of Current or Prior Exposure to Vaccine or Non- Vaccine HPV Types**	8559	967	8592	1189	19.1 (11.9, 25.8)
Genital Warts	Prophylactic Efficacy*	4688	29	4735	169	82.8 (74.3, 88.8)
Genital Warts	Girls and Women Regardless of Current or Prior Exposure to Vaccine or Non- Vaccine HPV Types**	8688	132	8701	350	62.5 (54.0, 69.5)
Includes all individuals who received at least 1 vaccination and who had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1 and were naïve to 14 common HPV types at Day 1. Case counting started at 1 month postdose 1. *Includes all individuals who received at least 1 vaccination (regardless of baseline HPV status or Pap test result at Day 1). Case counting started at 1 month postdose 1. CI = Confidence Interval AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

14.5 Population Impact in Boys and Men 16 Through 26 Years of Age

Effectiveness of GARDASIL in Prevention of HPV Types 6-, 11-, 16-, or 18-Related Anogenital Disease in Boys and Men 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types

Study 5 included boys and men regardless of current or prior exposure to vaccine HPV types, and additional analyses were conducted to evaluate the impact of GARDASIL with respect to HPV 6-, 11-, 16-, and 18-related anogenital disease in these boys and men. Here, analyses included events arising among boys and men regardless of baseline PCR status and serostatus, including 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 boys and men regardless of current or prior exposure to a vaccine HPV type is shown in Table 16. Impact was measured starting at Day 1. Prophylactic efficacy denotes the vaccine’s efficacy in boys and men who are naïve (PCR negative and seronegative) to the relevant HPV types at Day 1. Vaccine impact in boys and men who were positive for vaccine HPV infection, as well as vaccine impact among boys and men regardless of baseline vaccine HPV PCR status and serostatus are also presented. The majority of anogenital disease related to a vaccine HPV type 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.

There was no clear evidence of protection from disease caused by HPV types for which boys and men were PCR positive regardless of serostatus at baseline.

Table 16 Effectiveness of GARDASIL in Prevention of HPV Types 6-, 11-, 16-, or 18-Related Anogenital Disease in Boys and Men 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types
Endpoint	Analysis	GARDASIL		AAHS Control		% Reduction (95% CI)
Endpoint	Analysis	N	Cases	N	Cases
External Genital Lesions	Prophylactic Efficacy*	1775	13	1770	54	76.3 (56.0, 88.1)
	HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1**	460	14	453	26	--***
	Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types^†	1943	27	1937	80	66.7 (48.0, 79.3)
Condyloma	Prophylactic Efficacy*	1775	10	1770	49	80.0 (59.9, 90.9)
	HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1**	460	14	453	25	--***
	Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types^†	1943	24	1937	74	68.1 (48.8, 80.7)
PIN 1/2/3	Prophylactic Efficacy*	1775	4	1770	5	20.7 (-268.4, 84.3)
	HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1**	460	2	453	1	--***
	Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types^†	1943	6	1937	6	0.3 (-272.8, 73.4)
AIN 1/2/3	Prophylactic Efficacy*	259	9	261	39	76.9 (51.4, 90.1)
	HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1**	103	29	116	38	--***
	Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types^†	275	38	276	77	50.3 (25.7, 67.2)
AIN 2/3	Prophylactic Efficacy*	259	7	261	19	62.5 (6.9, 86.7)
	HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1**	103	11	116	20	--***
	Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types^†	275	18	276	39	54.2 (18.0, 75.3)
Includes all individuals who received at least 1 vaccination and who were HPV-naïve (i.e., seronegative and PCR negative) at Day 1 to the vaccine HPV type being analyzed. Case counting started at Day 1. Includes all individuals who received at least 1 vaccination and who were HPV positive or had unknown HPV status at Day 1, to at least one vaccine HPV type. Case counting started at Day 1. **There is no expected efficacy since GARDASIL has not been demonstrated to provide protection against disease from vaccine HPV types to which a person has previously been exposed through sexual activity. ^†Includes all individuals who received at least 1 vaccination. Case counting started at Day 1. CI = Confidence Interval AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Effectiveness of GARDASIL in Prevention of Any HPV Type Related Anogenital Disease in Boys and Men 16 Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine HPV Types

The impact of GARDASIL against the overall burden of dysplastic or papillomatous anogenital disease regardless of HPV detection, results from a combination of prophylactic efficacy against vaccine HPV types, disease contribution from vaccine HPV types present at time of vaccination, the disease contribution from HPV types not contained in the vaccine, and disease in which HPV was not detected.

Additional efficacy analyses from Study 5 were conducted in 2 populations: (1) a generally HPV-naïve population that consisted of boys and men who are seronegative and PCR negative to HPV 6, 11, 16, and 18 and PCR negative to HPV 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 at Day 1, approximating a population of sexually-naïve boys and men and (2) the general study population of boys and men regardless of baseline HPV status, some of whom had HPV-related disease at Day 1.

Among generally HPV-naïve boys and men and among all boys and men in Study 5 (including boys and men with HPV infection at Day 1), GARDASIL reduced the overall incidence of anogenital disease (Table 17). These reductions were primarily due to reductions in lesions caused by HPV types 6, 11, 16, and 18 in boys and men naïve (seronegative and PCR negative) for the specific relevant vaccine HPV type. Infected boys and men may already have anogenital disease at Day 1 and some will develop anogenital disease during follow-up, either related to a vaccine or non-vaccine HPV type present at the time of vaccination or related to a non-vaccine HPV type not present at the time of vaccination.

Table 17 Effectiveness of GARDASIL in Prevention of Any HPV Type Related Anogenital Disease in Boys and Men 16 Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine HPV Types
Endpoint	Analysis	GARDASIL		AAHS Control		% Reduction (95% CI)
Endpoint	Analysis	N	Cases	N	Cases	% Reduction (95% CI)
External Genital Lesions	Prophylactic Efficacy*	1275	7	1270	37	81.5 (58.0, 93.0)
External Genital Lesions	Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types**	1943	38	1937	92	59.3 (40.0, 72.9)
Condyloma	Prophylactic Efficacy*	1275	5	1270	33	85.2 (61.8, 95.5)
Condyloma	Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types**	1943	33	1937	85	61.8 (42.3, 75.3)
PIN 1/2/3	Prophylactic Efficacy*	1275	2	1270	4	50.7 (-244.3, 95.5)
PIN 1/2/3	Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types**	1943	8	1937	7	-13.9 (-269.0, 63.9)
AIN 1/2/3	Prophylactic Efficacy*	129	12	126	28	54.9 (8.4, 79.1)
AIN 1/2/3	Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types**	275	74	276	103	25.7 (-1.1, 45.6)
AIN 2/3	Prophylactic Efficacy*	129	8	126	18	52.5 (-14.8, 82.1)
AIN 2/3	Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types**	275	44	276	59	24.3 (-13.8, 50.0)
Includes all individuals who received at least 1 vaccination and who were seronegative and PCR negative at enrollment to HPV 6, 11, 16 and 18, and PCR negative at enrollment to HPV 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59. Case counting started at Day 1. *Includes all individuals who received at least 1 vaccination. Case counting started at Day 1. CI = Confidence Interval AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

14.6 Overall Population Impact

The subject characteristics (e.g. lifetime sex partners, geographic distribution of the subjects) influence the HPV prevalence of the population and therefore the population benefit can vary widely.

The overall efficacy of GARDASIL will vary with the baseline prevalence of HPV infection and disease, the incidence of infections against which GARDASIL has shown protection, and those infections against which GARDASIL has not been shown to protect.

The efficacy of GARDASIL for HPV types not included in the vaccine (i.e., cross-protective efficacy) is a component of the overall impact of the vaccine on rates of disease caused by HPV. Cross-protective efficacy was not demonstrated against disease caused by non-vaccine HPV types in the combined database of the Study 3 and Study 4 trials.

GARDASIL does not protect against genital disease not related to HPV. One woman who received GARDASIL in Study 3 developed an external genital well-differentiated squamous cell carcinoma at Month 24. No HPV DNA was detected in the lesion or in any other samples taken throughout the study.

In 18,150 girls and women enrolled in Study 2, Study 3, and Study 4, GARDASIL reduced definitive cervical therapy procedures by 23.9% (95% CI: 15.2%, 31.7%).

14.7 Other Studies

Data are insufficient to establish effectiveness of GARDASIL in women 27 through 45 years of age.

14.8 Immunogenicity

Assays to Measure Immune Response

The minimum anti-HPV titer that confers protective efficacy has not been determined.

Because there were few disease cases in individuals naïve (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 20,132 9- through 26-year-old girls and women (GARDASIL N = 10,723; AAHS control or saline placebo N = 9409) and 5417 9- through 26-year-old boys and men (GARDASIL N = 3109; AAHS control or saline placebo N = 2308).

Type-specific 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.

Immunogenicity was measured by (1) the percentage of individuals who were seropositive for antibodies against the relevant vaccine HPV type, and (2) the Geometric Mean Titer (GMT).

In clinical studies in girls and women, at least 99.8%, 99.8%, 99.8%, and 99.5% 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.

In clinical studies in boys and men, at least 98.9%, 99.2%, 98.8%, and 97.4% 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.

Across all populations, anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs peaked at Month 7 (Table 18 and Table 19). GMTs declined through Month 24 and then stabilized through Month 36 at levels above baseline. Table 20 displays the persistence of anti-HPV cLIA geometric mean titers by gender and age group. The duration of immunity following a complete schedule of immunization with GARDASIL has not been established.

Table 18 Summary of Month 7 Anti-HPV cLIA Geometric Mean Titers in the PPI* Population of Girls and Women
Population	N**	n***	% Seropositive (95% CI)	GMT (95% CI) mMU^†/mL
Anti-HPV 6
9- through 15-year-old girls	1122	917	99.9 (99.4, 100.0)	929.2 (874.6, 987.3)
16- through 26-year-old girls and women	9862	3333	99.8 (99.6, 99.9)	545.2 (530.3, 560.6)
Anti-HPV 11
9- through 15-year-old girls	1122	917	99.9 (99.4, 100.0)	1304.6 (1224.7, 1389.7)
16- through 26-year-old girls and women	9862	3357	99.8 (99.5, 99.9)	749.0 (726.1, 772.7)
Anti-HPV 16
9- through 15-year-old girls	1122	915	99.9 (99.4, 100.0)	4918.5 (4556.6, 5309.1)
16- through 26-year-old girls and women	9862	3253	99.8 (99.6, 100.0)	2411.3 (2311.1, 2515.9)
Anti-HPV 18
9- through 15-year-old girls	1122	922	99.8 (99.2, 100.0)	1042.6 (967.6, 1123.3)
16- through 26-year-old girls and women	9862	3571	99.4 (99.1, 99.7)	475.6 (459.2, 492.6)
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 naïve (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 individuals randomized to the respective vaccination group who received at least 1 injection. **Number of individuals contributing to the analysis. cLIA = Competitive Luminex Immunoassay CI = Confidence Interval GMT = Geometric Mean Titers ^†mMU = milli-Merck Units


Table 19 Summary of Month 7 Anti-HPV cLIA Geometric Mean Titers in the PPI* Population of Boys and Men
Population	N**	n***	% Seropositive (95% CI)	GMT (95% CI) mMU^†/mL
Anti-HPV 6
9- through 15-year-old boys	1072	884	99.9 (99.4, 100.0)	1037.5 (963.5, 1117.3)
16- through 26-year-old boys and men	2026	1093	98.9 (98.1, 99.4)	447.8 (418.9, 478.6)
Anti-HPV 11
9- through 15-year-old boys	1072	885	99.9 (99.4, 100.0)	1386.8 (1298.5, 1481.0)
16- through 26-year-old boys and men	2026	1093	99.2 (98.4, 99.6)	624.3 (588.4, 662.3)
Anti-HPV 16
9- through 15-year-old boys	1072	882	99.8 (99.2, 100.0)	6056.5 (5601.3, 6548.7)
16- through 26-year-old boys and men	2026	1136	98.8 (97.9, 99.3)	2403.3 (2243.4, 2574.6)
Anti-HPV 18
9- through 15-year-old boys	1072	887	99.8 (99.2, 100)	1357.4 (1249.4, 1474.7)
16- through 26-year-old boys and men	2026	1175	97.4 (96.3, 98.2)	402.6 (374.6, 432.7)
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 naïve (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 individuals randomized to the respective vaccination group who received at least 1 injection. **Number of individuals contributing to the analysis. cLIA = Competitive Luminex Immunoassay CI = Confidence Interval GMT = Geometric Mean Titers ^†mMU = milli-Merck Units

Table 20 Persistence of Anti-HPV cLIA Geometric Mean Titers by Gender and Age Group
Assay (cLIA)/ Time Point	9- to 15-year-old Boys *(N = 1072)**		16- to 26-year-old Boys and Men *(N = 2026)**		9- to 15-year-old Girls *(N = 1122)**		16- to 26-year-old Girls and Women *(N = 9859)**
Assay (cLIA)/ Time Point	n**	GMT (95% CI) mMU/mL*	n**	GMT (95% CI) mMU/mL*	n**	GMT (95% CI) mMU/mL*	n**	GMT (95% CI) mMU/mL*
Anti-HPV 6
Month 07		1037.5		447.8		929.2		545.2
	884	(963.5, 1117.3)	1093	(418.9,478.6)	917	(874.6, 987.3)	3333	(530.3, 560.6)
Month 24		134.1		79.8		156.1		109.1
	323	(119.5, 150.6)	942	(74.6, 85.4)	214	(135.6, 179.6)	2792	(105.2, 113.1)
Month 36(†)		130.1		71.5		129.4
	385	(117.1, 144.5)	848	(66.6, 76.7)	356	(115.6, 144.8)	-	-
Month 48(‡)								74.6
	-	-	-	-	-	-	2375	(71.6, 77.7)
Anti-HPV 11
Month 07		1386.8		624.3		1304.6		749.0
	885	(1298.5, 1481.0)	1093	(588.4, 662.3)	917	(1224.7, 1389.7)	3357	(726.1, 772.7)
Month 24		188.5		94.6		218.0		137.0
	324	(168.3, 211.2)	942	(88.5, 101.1)	214	(188.3, 252.4)	2821	(132.0, 142.2)
Month 36(†)		156.1		82.6		148.0
	385	(140.4,173.6)	848	(76.9, 88.7)	356	(131.1, 167.1)	-	-
Month 48(‡)								90.3
	-	-	-	-	-	-	2399	(86.6, 94.1)
Anti-HPV 16
Month 07		6056.5		2403.3		4918.5		2411.3
	882	(5601.3, 6548.7)	1136	(2243.4, 2574.6)	915	(4556.6, 5309.1)	3253	(2311.1, 2515.9)
Month 24		938.2		342.6		944.2		442.6
	322	(824.3, 1067.9)	980	(318.1, 369.0)	211	(804.4, 1108.3)	2725	(425.0, 460.9)
Month 36(†)		726.6		293.1		642.2
	384	(644.4, 819.3)	878	(270.8, 317.4)	353	(562.8, 732.8)	-	-
Month 48(‡)								334.6
	-	-	-	-	-	-	2330	(319.4, 350.5)
Anti-HPV 18
Month 07		1357.4		402.6		1042.6		475.6
	887	(1249.4, 1474.7)	1175	(374.6, 432.7)	922	(967.6, 1123.3)	3571	(459.2, 492.6)
Month 24		131.9		38.4		137.7		50.8
	324	(112.1, 155.2)	1012	(35.0, 42.1)	214	(114.8, 165.1)	3007	(48.2, 53.5)
Month 36(†)		113.3		33.1		87.0
	387	(97.5, 131.7)	906	(30.0, 36.5)	357	(74.8, 101.2)	-	-
Month 48(‡)								33.8
	-	-	-	-	-	-	2536	(32.0, 35.7)
N = Number of individuals randomized in the respective group who received at least 1 injection. n = Number of individuals in the indicated immunogenicity population. **mMU = milli-Merck Units ^†Month 36 time point for 16- to 26-year-old boys and men; Month 37 for 9- to 15-year-old boys and girls. No serology samples were collected at this time point for 16- to 26-year-old girls and women. ^‡Month 48/End-of-study visits for 16- to 26-year-old girls and women were generally scheduled earlier than Month 48. Mean visit timing was Month 44. The studies in 9- to 15-year-old boys and girls and 16- to 26-year-old boys and men were planned to end prior to 48 months and therefore no serology samples were collected. cLIA = Competitive Luminex Immunoassay CI = Confidence Interval GMT = Geometric Mean Titers

Tables 18 and 19 display the Month 7 immunogenicity data for girls and women and boys and men. Anti-HPV responses 1 month postdose 3 among 9- through 15-year-old adolescent girls were non-inferior to anti-HPV responses in 16- through 26-year-old girls and women in the combined database of immunogenicity studies for GARDASIL. Anti-HPV responses 1 month postdose 3 among 9- through 15-year-old adolescent boys were non-inferior to anti-HPV responses in 16- through 26-year-old boys and men in Study 5.

On the basis of this immunogenicity bridging, the efficacy of GARDASIL in 9- through 15-year-old adolescent girls and boys is inferred.

GMT Response to Variation in Dosing Regimen in 18- Through 26-Year-Old Women

Girls and women evaluated in the PPE population of clinical studies received all 3 vaccinations within 1 year of enrollment. An analysis of immune response data suggests that flexibility of ±1 month for Dose 2 (i.e., Month 1 to Month 3 in the vaccination regimen) and flexibility of ±2 months for Dose 3 (i.e., Month 4 to Month 8 in the vaccination regimen) do not impact the immune responses to GARDASIL.

Duration of the Immune Response to GARDASIL

The duration of immunity following a complete schedule of immunization with GARDASIL has not been established. The peak anti-HPV GMTs for HPV types 6, 11, 16, and 18 occurred at Month 7. Anti-HPV GMTs for HPV types 6, 11, 16, and 18 were similar between measurements at Month 24 and Month 60 in Study 2.

14.9 Studies with RECOMBIVAX HB [hepatitis B vaccine (recombinant)]

The safety and immunogenicity of co-administration of GARDASIL with RECOMBIVAX HB [hepatitis B vaccine (recombinant)] (same visit, injections at separate sites) were evaluated in a randomized, double-blind, study of 1871 women aged 16 through 24 years at enrollment. The race distribution of the girls and women in the clinical trial was as follows: 61.6% White; 1.6% Hispanic (Black and White); 23.8% Other; 11.9% Black; 0.8% Asian; and 0.3% American Indian.

Subjects either received GARDASIL and RECOMBIVAX HB (n = 466), GARDASIL and RECOMBIVAX HB-matched placebo (n = 468), RECOMBIVAX HB and GARDASIL-matched placebo (n = 467) or RECOMBIVAX-matched placebo and GARDASIL-matched placebo (n = 470) at Day 1, Month 2 and Month 6. Immunogenicity was assessed for all vaccines 1 month post completion of the vaccination series.

Concomitant administration of GARDASIL with RECOMBIVAX HB [hepatitis B vaccine (recombinant)] did not interfere with the antibody response to any of the vaccine antigens when GARDASIL was given concomitantly with RECOMBIVAX HB or separately.

14.10 Studies with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)]

The safety and immunogenicity of co-administration of GARDASIL with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] (same visit, injections at separate sites) were evaluated in an open-labeled, randomized, controlled study of 1040 boys and girls 11 through 17 years of age at enrollment. The race distribution of the subjects in the clinical trial was as follows: 77.7% White; 6.8% Hispanic (Black and White); 1.4% Multi-racial; 12.3% Black; 1.2% Asian; 0.2% Indian; and 0.4% American Indian.

One group received GARDASIL in one limb and both Menactra and Adacel, as separate injections, in the opposite limb concomitantly on Day 1 (n = 517). The second group received the first dose of GARDASIL on Day 1 in one limb then Menactra and Adacel, as separate injections, at Month 1 in the opposite limb (n = 523). Subjects in both vaccination groups received the second dose of GARDASIL at Month 2 and the third dose at Month 6. Immunogenicity was assessed for all vaccines 1 month post completion of the vaccination series (1 dose for Menactra and Adacel and 3 doses for GARDASIL).

Concomitant administration of GARDASIL with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] did not interfere with the antibody response to any of the vaccine antigens when GARDASIL was given concomitantly with Menactra and Adacel or separately.

16 HOW SUPPLIED/STORAGE AND HANDLING

All presentations for GARDASIL contain a suspension of 120 mcg L1 protein from HPV types 6, 11, 16, and 18 in a 0.5-mL dose. GARDASIL is supplied in vials and syringes.

Carton of one 0.5-mL single-dose vial. NDC 0006-4045-00.

Carton of ten 0.5-mL single-dose vials. NDC 0006-4045-41.

Carton of six 0.5-mL single-dose prefilled Luer Lock syringes, preassembled with UltraSafe Passive^®2 delivery system. One-inch, 25-gauge needles are provided separately in the package. NDC 0006-4109-06.

Carton of six 0.5-mL single-dose prefilled Luer Lock syringes with tip caps. NDC 0006-4109-09.

Store refrigerated at 2 to 8°C (36 to 46°F). Do not freeze. Protect from light.

GARDASIL should be administered as soon as possible after being removed from refrigeration.

GARDASIL can be out of refrigeration (at temperatures at or below 25°C/77°F), for a total time of not more than 72 hours.

17 PATIENT COUNSELING INFORMATION

[See FDA-Approved Patient Labeling.]

Inform the patient, parent, or guardian:

Vaccination does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening. Women who receive GARDASIL should continue to undergo cervical cancer screening per standard of care.
Recipients of GARDASIL should not discontinue anal cancer screening if it has been recommended by a health care provider.
GARDASIL has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a person has previously been exposed through sexual activity.
Since syncope has been reported following vaccination sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended.
Vaccine information is required to be given with each vaccination to the patient, parent, or guardian.
Information regarding benefits and risks associated with vaccination.
GARDASIL is not recommended for use in pregnant women.
Importance of completing the immunization series unless contraindicated.
Report any adverse reactions to their health care provider.

Printed in USA

9883615

¹ Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Copyright © 2006, 2009, 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved

² UltraSafe Passive^® delivery system is a Trademark of Safety Syringes, Inc.

9883615

USPPI
Patient Information about
GARDASIL^® (pronounced “gard-Ah-sill”)
Generic name: [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant]

Read this information with care before getting GARDASIL¹. You (the person getting GARDASIL) will need 3 doses of the vaccine. It is important to read this leaflet when you get each dose. This leaflet does not take the place of talking with your health care provider about GARDASIL.

What is GARDASIL?

GARDASIL is a vaccine (injection/shot) that is used for girls and women 9 through 26 years of age to help protect against the following diseases caused by Human Papillomavirus (HPV):

Cervical cancer
Vulvar and vaginal cancers
Anal cancer
Genital warts
Precancerous cervical, vaginal, vulvar, and anal lesions

GARDASIL is used for boys and men 9 through 26 years of age to help protect against the following diseases caused by HPV:

Anal cancer
Genital warts
Precancerous anal lesions

The diseases listed above have many causes, and GARDASIL only protects against diseases caused by certain kinds of HPV (called Type 6, Type 11, Type 16, and Type 18). Most of the time, these 4 types of HPV are responsible for the diseases listed above.
GARDASIL cannot protect you from a disease that is caused by other types of HPV, other viruses, or bacteria.
GARDASIL does not treat HPV infection.
You cannot get HPV or any of the above diseases from GARDASIL.

What important information about GARDASIL should I know?

You should continue to get routine cervical cancer screening.
GARDASIL may not fully protect everyone who gets the vaccine.
GARDASIL will not protect against HPV types that you already have.

Who should not get GARDASIL?

You should not get GARDASIL if you have, or have had:

an allergic reaction after getting a dose of GARDASIL.
a severe allergic reaction to yeast, amorphous aluminum hydroxyphosphate sulfate, polysorbate 80.

What should I tell my health care provider before getting GARDASIL?

Tell your health care provider if you:

are pregnant or planning to get pregnant. GARDASIL is not recommended for use in pregnant women.
have immune problems, like HIV infection, cancer, or you take medicines that affect your immune system.
have a fever over 100°F (37.8°C).
had an allergic reaction to another dose of GARDASIL.
take any medicines, even those you can buy over the counter.

Your health care provider will help decide if you should get the vaccine.

How is GARDASIL given?

GARDASIL is a shot that is usually given in the arm muscle. You will need 3 shots given on the following schedule:

Dose 1: at a date you and your health care provider choose.
Dose 2: 2 months after Dose 1.
Dose 3: 6 months after Dose 1.

Fainting can happen after getting GARDASIL. Sometimes people who faint can fall and hurt themselves. For this reason, your health care provider may ask you to sit or lie down for 15 minutes after you get GARDASIL. Some people who faint might shake or become stiff. This may require evaluation or treatment by your health care provider.

Make sure that you get all 3 doses on time so that you get the best protection. If you miss a dose, talk to your health care provider.

Can other vaccines and medications be given at the same time as GARDASIL?

GARDASIL can be given at the same time as RECOMBIVAX HB^®1 [hepatitis B vaccine (recombinant)] or Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)].

What are the possible side effects of GARDASIL?

The most common side effects with GARDASIL are:

pain, swelling, itching, bruising, and redness at the injection site
headache
fever
nausea
dizziness
vomiting
fainting

There was no increase in side effects when GARDASIL was given at the same time as RECOMBIVAX HB [hepatitis B vaccine (recombinant)].

There was more injection-site swelling at the injection site for GARDASIL when GARDASIL was given at the same time as Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)].

Tell your health care provider if you have any of the following problems because these may be signs of an allergic reaction:

difficulty breathing
wheezing (bronchospasm)
hives
rash

Tell your health care provider if you have:

swollen glands (neck, armpit, or groin)
joint pain
unusual tiredness, weakness, or confusion
chills
generally feeling unwell
leg pain
shortness of breath
chest pain
aching muscles
muscle weakness
seizure
bad stomach ache
bleeding or bruising more easily than normal
skin infection

Contact your health care provider right away if you get any symptoms that concern you, even several months after getting the vaccine.

For a more complete list of side effects, ask your health care provider.

What are the ingredients in GARDASIL?

The ingredients are proteins of HPV Types 6, 11, 16, and 18, amorphous aluminum hydroxyphosphate sulfate, yeast protein, sodium chloride, L-histidine, polysorbate 80, sodium borate, and water for injection.

This leaflet is a summary of information about GARDASIL. If you would like more information, please talk to your health care provider or visit www.gardasil.com.

Manufactured and Distributed by: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Whitehouse Station, NJ 08889, USA

Issued December 2010

CONTACT:

Merck
Media:
Lee Davies, 917-679-6368
Kelley Dougherty, 215-652-0059
or
Investors:
Joe Romanelli, 908-423-5088

KEYWORDS: United States North America New Jersey

INDUSTRY KEYWORDS: Health Biotechnology Infectious Diseases Oncology Pharmaceutical Other Health FDA

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FDA Advisory Committee Supports Approval of GARDASIL® for Prevention of Anal Cancer and AIN in both Men and Women

Maureen Martino — Mon, 22 Nov 2010 14:02:52 -0500

FDA Advisory Committee Supports Approval of GARDASIL® for Prevention of Anal Cancer and AIN in both Men and Women

WHITEHOUSE STATION, NJ - Nov. 17, 2010 - Merck announced today that the U.S. Food and Drug Administration's (FDA) Vaccines and Related Biological Products Advisory Committee has advised that the data presented support an indication for GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] for the prevention of anal cancer and anal intraepithelial neoplasia (AIN) in both males and females 9 through 26 years of age.

"We are pleased with the outcome of today's meeting and look forward to continued discussions with the FDA as it evaluates the data for the proposed indication," said Elizabeth Garner, M.D., MPH, director, clinical research, Merck Research Laboratories. "Today's discussion brings us closer to being able to also provide GARDASIL to men and women for the prevention of anal cancer and AIN."

The Committee's input will be considered by the FDA in its review of the supplemental Biologics License Application (sBLA) that Merck submitted for GARDASIL in early 2010. The FDA is not bound by the Committee's guidance, but takes its advice into consideration when reviewing vaccines.

The efficacy of GARDASIL against HPV-related anal disease was studied in a population of men who have sex with men because of the known high risk of anal infection and disease that occurs in this group. Merck submitted the sBLA for use of GARDASIL in both men and women because anal cancer affects both men and women and the disease is similar in both genders. Up to 90 percent of anal cancers are caused by HPV, with HPV 16 and 18 causing approximately 80 percent of those cases.

GARDASIL is approved in the U.S. for use in girls and young women 9 through 26 years of age for the prevention of cervical, vulvar and vaginal cancers caused by HPV types 16 and 18; genital warts (condylomata acuminata) caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18. HPV types 16 and 18 account for approximately 75 percent of cervical cancer cases, and HPV types 6 and 11 account for approximately 90 percent of genital warts cases. GARDASIL is also approved in the U.S. for use in boys and men ages 9 through 26 years of age for the prevention of genital warts caused by HPV types 6 and 11.

Important information about GARDASIL
GARDASIL does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening.

GARDASIL has not been demonstrated to provide protection against diseases from vaccine and non-vaccine HPV types to which a person has previously been exposed through sexual activity.

GARDASIL is not intended to be used for treatment of active external genital lesions; cervical, vulvar, and vaginal cancers; cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia.

GARDASIL has not been demonstrated to protect against disease due to HPV types not contained in the vaccine.
Not all vulvar and vaginal cancers are caused by HPV, and GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant] protects only against those vulvar and vaginal cancers caused by HPV Types 16 and 18.

Select safety information
GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL.

GARDASIL is not recommended for use in pregnant women.

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 deltoid region of the upper arm or in the higher anterolateral area of the thigh. 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 approved in 121 countries
GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant] (sold in some countries as SILGARD®) has been approved in 121 countries, and additional applications are currently under review with regulatory agencies in many more countries around the world.

About Merck
Today's Merck is a global healthcare leader. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-Looking Statement
This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2009 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

PPD to Present at World Vaccine Congress 2010 Conference

Mon, 19 Apr 2010 17:18:55 -0400

WILMINGTON, N.C.--(BUSINESS WIRE)-- PPD, Inc. (Nasdaq: PPDI) today announced Mark Esser, Ph.D., associate director of immunology, and Lisa Kierstead, Ph.D., associate director, labs, will present at the 10^th annual World Vaccine Congress 2010 Conference in Chantilly, Va., on April 19-22.

Dr. Esser will discuss the role of vaccine biomarkers in accelerating clinical trials. He will highlight how antibody and functional biomarker assays can be implemented to accelerate Phase I, dose ranging, concomitant and Phase IV marketing vaccine studies and the use of biomarkers in licensing and post-licensing marketing studies of human papillomavirus (HPV) vaccines. His presentation is Wednesday, April 21, at 3:15 p.m. ET.

Dr. Esser has extensive experience in developing and validating biomarker assays to support clinical development programs for vaccines and therapeutic proteins against infectious diseases and cancer. At Merck & Co., he was a member of the team that successfully achieved licensure of GARDASIL^® for the prevention of HPV infection. In February 2010, R&D Directions named Dr. Esser one of its 10 most notable scientists in research and development for his significant contributions in vaccine development.

Dr. Kierstead will speak on peripheral blood mononuclear cells (PBMC) and their impact on clinical trials. She will highlight the parameters affecting PBMS integrity and critical factors to ensure the quality of PBMCs. Her presentation is Thursday, April 22, at 10:15 p.m. ET.

Dr. Kierstead joined PPD through its acquisition of the Merck vaccine testing laboratory in Wayne, Pa. She is expanding PPD’s well-established PBMC services and oversees assay development to support detection of humoral and cellular immunogenicity to vaccines. Dr. Kierstead spent eight years at Merck in clinical assay development for T-cell immunity and cell-based assays.

Last month, PPD announced the launch of its Vaccines & Biologics Center of Excellence, a first-in-kind comprehensive network of integrated, world-class laboratory services focused specifically on vaccine and biologic drug development.

The World Vaccine Congress conference is the largest vaccine industry event in North America, providing a forum to explore an area expected to double in revenue by 2013. PPD is a platinum sponsor of this year’s event.

PPD is a leading global contract research organization, celebrating 25 years of providing drug discovery, development and lifecycle management services. Our clients and partners include pharmaceutical, biotechnology, medical device, academic and government organizations. With offices in 41 countries and more than 10,500 professionals worldwide, PPD applies innovative technologies, therapeutic expertise and a commitment to quality to help clients and partners accelerate the delivery of safe and effective therapeutics and maximize the returns on their R&D investments. For more information, visit www.ppdi.com.

Except for historical information, all of the statements, expectations and assumptions contained in this news release, including expectations and assumptions about the information presented during these presentations are forward-looking statements that involve a number of risks and uncertainties. Although PPD attempts to be accurate in making these forward-looking statements, it is possible that future circumstances might differ from the assumptions on which such statements are based. In addition, other important factors which could cause results to differ materially include the following: the ability to attract and retain key personnel; risks associated with and dependence on collaborative relationships; competition within the outsourcing industry; success in sales growth; loss of large contracts; increased cancellation rates; economic conditions and outsourcing trends in the pharmaceutical, biotechnology, medical device, academic and government industry segments; rapid technological advances that make our products and services less competitive; and the other risk factors set forth from time to time in the SEC filings for PPD, copies of which are available free of charge upon request from the PPD investor relations department.

CONTACT:

PPD, Inc.
Media:
Sue Ann Pentecost, 919-456-5890
sueann.pentecost@ppdi.com
or
Analysts/Investors:
Luke Heagle, 910-558-7585
luke.heagle@ppdi.com

KEYWORDS: United States North America North Carolina Virginia

INDUSTRY KEYWORDS: Technology Data Management Health Biotechnology Clinical Trials Genetics Hospitals Medical Devices Other Health Research Science

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FDA Advisory Committee Recommends Approval for Use of GARDASIL in Boys and Men

Calisha Myers — Thu, 10 Sep 2009 11:57:07 -0400

FDA Advisory Committee Recommends Approval for Use of GARDASIL in Boys and Men

Committee Agrees that Clinical Data Support the Efficacy and Safety of Merck's GARDASIL in 9- to 26-Year-Old Boys and Men

WHITEHOUSE STATION, N.J., Sept. 9, 2009 - Merck & Co., Inc. announced today that the U.S. Food and Drug Administration's (FDA) Vaccines and Related Biological Products Advisory Committee agreed that efficacy, immunogenicity and safety data from clinical trials in males support the use of GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant] in boys and men 9 through 26 years of age for the prevention of genital warts caused by human papillomavirus (HPV) types 6 and 11.

"Merck has been committed to pursuing the use of GARDASIL in both males and females since the vaccine was discovered over a decade ago," said Peter S. Kim, Ph.D., executive vice president, and president of Merck Research Laboratories. "We are pleased that the Advisory Committee agrees that the data support the use of GARDASIL in boys and men."

The committee's recommendation will be considered by the FDA in its review of the supplemental Biologics License Application (sBLA) that Merck submitted for GARDASIL in December 2008. The FDA is not bound by the committee's guidance, but takes its advice into consideration when reviewing vaccines. Merck expects a decision from the FDA in the fourth quarter of 2009 after the agency has completed its review of Merck's application.

"Today's discussion with the Advisory Committee brings the public health community closer to being able to provide GARDASIL to both men and women," said Anna R. Giuliano, Ph.D., Moffitt Cancer Center.

GARDASIL has been approved for use in the U.S. since June 2006 and is currently indicated for use in girls and young women 9 through 26 years of age for the prevention of cervical, vulvar and vaginal cancers caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18. More than 50 million doses have been distributed worldwide through June 2009, although the number of doses administered is not known.

Data for use of GARDASIL in boys and men presented
Clinical trials presented to the Advisory Committee evaluated the efficacy, immunogenicity and safety of GARDASIL in boys and men 9 to 26 years of age. Vaccine efficacy in males was evaluated in a randomized, double-blind, placebo-controlled trial. A total of 4,055 men were enrolled and received at least one dose of GARDASIL or placebo. Of these, 3,457 were heterosexual men aged 16 to 23 years and 598 were men who have sex with men aged 16 to 26 years.

The per-protocol efficacy (PPE) population was the predefined primary population for the demonstration of efficacy in 16- to 26-year-old men. As defined, this population included subjects who were not infected with HPV vaccine types at the start of the study, nor did they become infected with HPV vaccine types during the course of the vaccination series. These subjects were seronegative and HPV DNA negative to HPV vaccine types at day one, and HPV DNA negative through the vaccination series to month seven. This population also received the three shot series within a one-year time period and generally did not deviate from the protocol. The cases of the primary endpoint of external genital lesions (EGL) were counted starting after month seven.

Analyses were also conducted in the Full Analysis Set (FAS) population. The FAS population included all participants who received at least one dose of vaccine or placebo and endpoint cases were counted after day one, the day after the first dose of vaccine was given. The key difference from the PPE population was that the FAS also included participants who had been previously exposed, were already infected with HPV types, or became infected before the completion of the three-dose vaccine series (not specific to 6, 11, 16 and 18).
Per protocol efficacy
In the PPE analysis, GARDASIL was 90.4 percent efficacious (95 percent CI: 69.2, 98.1) against HPV 6, 11, 16 and 18-related EGL. Of 34 cases of EGL, 31 were genital warts. All cases of genital warts were positive for HPV 6 and/or 11 (three cases in the vaccine group and 28 in the placebo group). GARDASIL was 89.3 percent efficacious (95 percent CI: 65.5, 97.9) against HPV 6/11-related external genital warts.

There were three cases of HPV 6/11/16/18-related penile/perianal/perineal intraepithelial neoplasia (PIN) in the PPE analysis and all were in the placebo group. No cases of penile/perianal/perineal cancers were observed in the vaccine or placebo groups during the study. Although vaccine efficacy against HPV 6/11/16/18-related PIN 1 or worse was 100 percent (95 percent CI: <0, 100), there was no statistical significance due to the small number of cases seen in the study.

Full analysis set
In the FAS analysis, GARDASIL was 65.5 percent efficacious (95 percent CI: 45.8, 78.6) against HPV 6, 11, 16 and 18 EGL. Of 104 cases of EGL, 95 were genital warts positive for HPV 6 and/or 11 (24 cases in the vaccine group and 71 in the placebo group). GARDASIL was 66.8 percent efficacious (95 percent CI: 46.5, 80.0) against HPV 6/11-related external genital warts in this analysis.

Immunogenicity
In immunogenicity studies, GARDASIL generated robust immune responses to HPV types 6, 11, 16 and 18 in 9- to 15-year old boys and 16- to 26-year old men.

Immunobridging studies in 9- to 15-year old boys demonstrated that boys had approximately two to three fold higher HPV type-specific antibody levels at month seven compared to 16- to 26-year old men. These data established the non-inferiority of the peak immune response as measured at month seven for all four HPV-types in boys as compared to men.

Safety data for GARDASIL
Compared with placebo recipients, a slightly higher proportion of vaccinees reported injection site (64.1 percent GARDASIL; 53.6 percent placebo) and systemic adverse experiences (37.2 percent GARDASIL; 32.6 percent placebo), the majority of which were reported as mild to moderate intensity. Subjects who reported a severe intensity systemic adverse experience and/or an injection-site adverse experience were comparable between the two groups (systemic adverse experiences reported: 4.3 percent in the GARDASIL group versus 3.0 percent in the placebo group; injection-site adverse experiences reported: 2.0 percent in the GARDASIL group versus 1.0 percent in the placebo group). Overall, the safety profile observed in boys and men 9 to 26 years of age in clinical studies was consistent with the safety profile observed in clinical studies in girls and women 9 to 26 years of age.

Important information about GARDASIL
GARDASIL does not substitute for routine cervical cancer screening, and women who receive GARDASIL should continue to undergo screening.

GARDASIL has not been demonstrated to provide protection against diseases from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity. GARDASIL is not intended to be used for treatment of active genital warts; cervical, vulvar, and vaginal cancers; cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VaIN).

GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. Not all vulvar and vaginal cancers are caused by HPV, and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV Types 16 and 18.

Select safety information
GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL.

GARDASIL is not recommended for use in pregnant women.

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 deltoid region of the upper arm or in the higher anterolateral area of the thigh. 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.

About HPV
There are more than 100 types of HPV, of which about 30 to 40 types can infect the genital areas of women and men. HPV types 6 and 11 cause approximately 90 percent of genital warts cases. About one million people (both males and females) have visible genital warts at any point in time. There are currently no routine HPV screening methods in place for men.

GARDASIL is approved in 112 countries
GARDASIL (sold in some countries as SILGARD®) has been approved in 112 countries, and additional applications are currently under review with regulatory agencies in many more countries around the world.

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 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, 2008, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

Merck's Gardasil has been updated to include the clinical efficacy and safety of the vaccine for women up to 45 years of age

Calisha Myers — Thu, 10 Sep 2009 11:07:31 -0400

The product information of Gardasil® has been updated to include the clinical efficacy and safety of the vaccine for women up to 45 years of age

Lyon, 9th September 2009
- The product information of the four-type (6,11,16,18) human papillomavirus (HPV) vaccine Gardasil® has been updated to include the clinical efficacy and safety information of the vaccine for women up to 45 years of age.*,1

In a clinical study which included 3,819† women between 24 and 45 years of age, among those who were not infected with the relevant virus type at vaccination‡ and who received all three doses of the vaccine (3,351 women§, Gardasil® prevented 90.5%** of HPV 6-, 11-, 16-, or 18-related persistent infection, cervical lesions (CIN††) of any grade, adenocarcinoma in situ (AIS), cervical cancer, vulvar and vaginal lesions and genital warts.1,2

Gardasil® was generally well tolerated and demonstrated a good safety profile with fever as well as redness, swelling and pain at the injection site as the most commonly reported side effects.1,2

"Vaccination recommendations or campaigns from health authorities will continue to focus on adolescent girls. However, women may remain at risk of HPV infection and developing related diseases during their adult life. Women should be aware of the efficacy and safety of Gardasil® up to 45 years. They should make an informed decision about individual vaccination following discussion with their doctors taking into account their personal and HPV disease histories, says

Professor Xavier Bosch from the Catalan Institute of Oncology in Barcelona, Spain.

All women should continue regular screening for early detection of cervical cancer whether they have been vaccinated or not. Gardasil® is a preventive vaccine and can therefore not treat preexisting infections or disease. The vaccine cannot protect against all HPV types.

Gardasil® is the only HPV vaccine to have clinical efficacy and safety for women up to 45 years added to its product information. Gardasil® is a four-type (6,11,16,18) HPV vaccine. In addition to unsurpassed and sustained cervical cancer protection, Gardasil® can protect from cervical, vulvar and vaginal pre-cancer, and from genital warts caused by HPV types 6, 11, 16 and 18. These four types together cause the vast majority of HPV-related genital diseases.1,3,4,5

Studies of GARDASIL, Merck's Cervical Cancer Vaccine, and HPV 16 Vaccine Component of GARDASIL Presented at Conference

Calisha Myers — Mon, 11 May 2009 11:38:06 -0400

Studies of GARDASIL, Merck's Cervical Cancer Vaccine, and HPV 16 Vaccine Component of GARDASIL Presented at International Papillomavirus Conference

Data from an Extension of a Phase II Study for an Average of 8.5 Years Evaluating the ongoing efficacy of HPV 16 Component of GARDASIL Presented
Investigational Study with GARDASIL: Data Presented on Reduction in Abnormal Pap Tests and Cervical Procedures in Women Naïve to Multiple HPV types

MALMOE, Sweden, May 8, 2009 - In a study of an extended follow up of 290 women naïve to HPV type 16, the HPV 16 component of GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant] was efficacious against HPV 16 infection for an average of 8.5 years after administration. The women enrolled in this study are a subset of the original Phase II HPV 16 proof-of-concept study published in 2002. Follow up ranged from 7.2 years to up to 9.5 years.

In a different study, in women ages 16 to 26 who were naïve to 14 common HPV types, GARDASIL reduced the number of abnormal Pap test results by 17 to 45 percent, depending on the abnormality, and reduced colposcopies by 20 percent, cervical biopsies by 22 percent and reduced surgery and other invasive treatments by 42 percent.

"We are encouraged by the extended efficacy data for the HPV 16 component of GARDASIL. Studies to examine the long-term efficacy of GARDASIL are underway," said Laura A. Koutsky, Ph.D., MSPH, University of Washington, School of Public Health. Dr. Koutsky and the University of Washington study site led this study extension. Merck & Co., Inc. is a co-author of the original data and the new analysis.

GARDASIL is currently indicated for use in girls and young women 9 through 26 years of age for the prevention of cervical, vulvar and vaginal cancers caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18.

HPV types 16 and 18 are responsible for approximately 70 percent of cervical cancer cases, and HPV types 6 and 11 are responsible for approximately 90 percent of genital warts and about 10 percent of low-grade cervical changes/lesions/dyplasias.

Efficacy of the prophylactic human papillomavirus (HPV) type 16 L1 virus-like particle (VLP) vaccine
In a follow-up study of 290 women from a randomized, placebo-controlled, proof-of-concept clinical trial, the HPV 16 component of GARDASIL remained efficacious against HPV 16 infection and associated precancerous lesions for an average follow-up time of 8.5 years after administration.

These women had participated in a Phase IIb randomized-controlled trial of the prophylactic HPV 16 L1 virus-like particle (VLP) vaccine between November 1998 and January 2004. They were enrolled in an extended follow-up study between March 2006 and May 2008 to evaluate the vaccine's long-term efficacy. Participants had not been infected with HPV 16 at the start of the study and through month seven (one month after the completion of the three-dose series).

During the extended follow-up period, no one in the vaccine group developed HPV 16 infection (vaccine efficacy = 100 percent; 95 percent confidence interval (CI): 25 to 100 percent) or HPV 16-associated cervical lesions (cervical intraepithelial neoplasia, or CIN) (vaccine efficacy = 100 percent; 95 percent CI: <0 to 100 percent). In the placebo group, six women developed HPV 16 infection and three women developed HPV 16-associated CIN during the follow-up period. Following participation in the initial study, all subjects were offered vaccination with GARDASIL. Only those subjects who chose not to be vaccinated and who explicitly consented to being part of the extension study were enrolled.

During the combined trial and extended follow-up period - mean of 8.5 years, vaccine efficacy against HPV 16 infection was 96 percent; (95 percent CI: 73 to 100 percent) and 100 percent against cervical lesions associated with HPV 16 (95 percent CI: 47 to 100 percent). In the placebo group, 21 women developed HPV 16 infection and eight women developed HPV 16-associated cervical lesions, including 7 cases of CIN 2 or worse.

In second investigational study, reduction in abnormal Pap tests and procedures
In two other randomized, placebo-controlled, efficacy trials of GARDASIL, a total of 17,622 women received either three doses of GARDASIL or placebo over six months. Pap testing occurred at the start of the study and then at intervals of 6 to 12 months. An analysis of the reduction of healthcare utilization endpoints (Pap tests and cervical procedures) was conducted in a population of women who were naive to 14 common HPV types and had a normal Pap test on day 1.

After an average follow-up of 3.6 years when compared to women receiving placebo (n=4679), women who received GARDASIL (n=4616) had significant reductions in the following abnormal Pap test results:

ASC-US: atypical squamous cells of undetermined significance associated with a high-risk type of HPV (17 to 22 percent reduction),
LSIL: low-grade squamous intraepithelial lesion (17 percent reduction),
ASC-H: atypical squamous cells/cannot exclude high-grade squamous intraepithelial lesion (36 percent reduction), and
HSIL: high-grade squamous intraepithelial lesion (45 percent reduction).

Additional important information about GARDASIL
GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of 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.

GARDASIL is not recommended for use in pregnant women.

The duration of protection with GARDASIL is currently not known. 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, vaginal and vulvar cancers, cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VaIN).

GARDASIL has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity. GARDASIL has not been shown to protect against diseases due to HPV types not contained in the vaccine.

Not all vulvar and vaginal cancers are caused by human papillomavirus (HPV), and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV types 16 and 18.

In clinical studies for GARDASIL, headache was the most commonly reported adverse reaction with near equal frequency in the GARDASIL and control group (28.2 percent vs. 28.4 percent). Vaccine-related adverse reactions that were observed at a frequency of at least 1.0 percent among recipients of GARDASIL and also greater than those observed among control group, respectively, were pain (83.9 percent vs. 75.4 percent), swelling (25.4 percent vs. 15.8 percent), erythema (24.7 percent vs. 18.4 percent), fever (13.0 percent vs. 11.2 percent), nausea (6.7 percent vs. 6.5 percent), pruritis (3.2 percent vs. 2.8 percent), dizziness (4.0 percent vs. 3.7 percent) and bruising (2.8 percent vs. 3.2 percent).

In addition, syncope has been reported following vaccination with GARDASIL, sometimes resulting in falling with injury. Observation for 15 minutes after administration is recommended.

GARDASIL is approved in 109 countries
GARDASIL (sold in some countries as SILGARD®) has been approved in 109 countries, and additional applications are currently under review with regulatory agencies in many more countries around the world.

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, 2008, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

Merck & Co., Inc. Receives Complete Response Letter from the Food and Drug Administration for Use of GARDASIL in Older Women

Calisha Myers — Fri, 09 Jan 2009 11:09:01 -0500

Merck & Co., Inc. Receives Complete Response Letter from the Food and Drug Administration for Use of GARDASIL® in Women Ages 27 through 45

WHITEHOUSE STATION, N.J., Jan. 9, 2009 - Merck & Co., Inc. announced today that the U.S. Food and Drug Administration has issued a second complete response letter regarding the supplemental biologics license application (sBLA) for the use of GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant] in women ages 27 though 45. The agency has completed its review of the response that Merck provided in July 2008 and has recommended that Merck submit additional data when the 48 month study has been completed. The initial sBLA included data collected through an average of 24 months from enrollment into the study, which is when the number of pre-specified endpoints had been met. Following a review of the final results of the study, Merck anticipates providing a response to the agency in the fourth quarter of 2009. The letter does not affect current indications for GARDASIL in females ages 9 through 26 nor does the letter relate to the sBLA that was submitted in December 2008 for the use of GARDASIL in males.

"Merck is committed to continuing to pursue the use of GARDASIL in this important group of women - many of whom remain at risk for HPV-related disease throughout their lifetimes," said Peter S. Kim, president, Merck Research Laboratories.

Merck reconfirmed its 2009 total sales (as recorded by the Company) guidance of $23.7 to $24.2 billion. The Company also reconfirmed its full-year 2009 non-GAAP EPS range of $3.15 to $3.30, excluding certain items, and the 2009 GAAP EPS range of $2.95 to $3.17. The Company will update the other elements of its 2009 guidance on its February 3, 2009 earnings conference call.

Additional Important Information about GARDASIL
GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL.

GARDASIL is not recommended for use in pregnant women.

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, vaginal and vulvar cancers, cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VaIN).

Not all vulvar and vaginal cancers are caused by human papillomavirus (HPV), and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV types 16 and 18.

The most common adverse reaction was headache. Common adverse reactions that were observed among recipients of GARDASIL at a frequency of at least 1.0 percent and greater than placebo were fever, nausea, dizziness; and injection-site pain, swelling, erythema, pruritus, and bruising.

In addition, syncope has been reported following vaccination with GARDASIL, sometimes resulting in falling with injury. Observation for 15 minutes after administration is recommended.

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 deltoid region of the upper arm or in the higher anterolateral area of the thigh. 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.

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, 2007, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

GARDASIL® is a registered trademark of Merck & Co., Inc., Whitehouse Station, N.J., USA

Gardasil, Merck's Cervical Cancer Vaccine, Demonstrated Efficacy in Preventing HPV-Related Disease in Males in Phase III Study

Calisha Myers — Thu, 13 Nov 2008 09:27:32 -0500

Gardasil, Merck's Cervical Cancer Vaccine, Demonstrated Efficacy in Preventing HPV-Related Disease in Males in Phase III Study

Pivotal Study Evaluating Efficacy of GARDASIL in Males in Preventing HPV 6, 11, 16 and 18-Related External Genital Lesions

WHITEHOUSE STATION, N.J., Nov. 13, 2008 - GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant], the cervical cancer vaccine from Merck & Co., Inc., prevented 90 percent of external genital lesions caused by human papillomavirus (HPV) types 6, 11, 16 and 18 in a pivotal Phase III study in men aged 16 to 26. These are the only data evaluating efficacy of any HPV vaccine in preventing disease in males, and were presented for the first time this week at the European Research Organization on Genital Infection and Neoplasia (EUROGIN) International Multidisciplinary Conference.

The initial planned analysis of this study, an analysis of male study participants aged 16 to 26 who had not been infected with at least one of the four HPV types before the start of the study through one month after receiving their third dose of the vaccine or placebo, has been completed. This analysis was predetermined in the study protocol to be conducted after at least 32 cases of external genital lesions were observed. The study is ongoing, and additional data will be submitted to global regulatory agencies once available.

Merck remains on track to submit a supplemental Biologics License Application for GARDASIL to the U.S. Food and Drug Administration by the end of 2008 for the use of GARDASIL in boys and men ages 9 to 26 for the prevention of external genital lesions caused by HPV types 6, 11, 16 and 18. Other regulatory submissions around the world will occur as planned.

GARDASIL is not currently approved for males in the United States. GARDASIL is indicated for use in girls and young women 9 through 26 years of age for the prevention of cervical, vulvar and vaginal cancers caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18.

GARDASIL Reduced External Genital Lesions in Males by 90 Percent
The placebo-controlled, Phase III study was designed to determine the efficacy of GARDASIL in males against HPV 6, 11, 16, and 18-related external genital lesions, a composite endpoint that included: 1) genital warts (condylomata), 2) penile/perineal/perianal intraepithelial neoplasia (or PIN; PIN 2/3 can be pre-cursors to cancer) and 3) penile/perineal/perianal cancer. Penile/perineal/perianal is defined as related to or affecting the penis (penile), the area between the anus and the scrotum (perineal), or the opening of the rectum to the outside of the body (perianal).

The study evaluated approximately 3,400 heterosexual males 16 through 23 years of age and approximately 600 men 16 to 26 years of age who have sex with men. Participants were randomized in a 1-to-1 ratio to receive either GARDASIL or placebo at day one, two months and six months, with 36 months of planned follow-up from day one. At the time of vaccination, participants had no evidence of genital lesions, no history of genital warts and five or fewer lifetime sexual partners.

In the study, GARDASIL was 90.4 percent effective at reducing external genital lesions (3 cases in the vaccine group vs. 31 cases in placebo group; 95 percent CI: 69.2, 98.1, p-value <0.001). The three cases seen among those vaccinated with GARDASIL were cases of genital warts, resulting in GARDASIL being 89.4 percent effective in preventing genital warts (95 percent CI: 65.5, 97.9). For penile/perineal/perianal intraepithelial neoplasia or PIN, there were no cases in the vaccine group vs. 3 cases of PIN 1 or PIN 2/3 in the placebo group. There were no cases of penile/perineal/perianal cancer in either vaccine or placebo group. At the time of this analysis, the study had a mean duration of about 29 months.

No vaccine-related serious adverse events were reported in this study. A slightly higher proportion of study participants reported injection-site adverse events in the vaccine group compared to placebo (60.1 percent vs. 53.7 percent).

GARDASIL Also Achieved Statistical Significance on Both Secondary Endpoints
Two secondary endpoints also were evaluated in this pivotal study and results from these analyses were presented at EUROGIN. GARDASIL was 85.6 percent effective at reducing persistent infection (15 cases in the vaccine group vs. 101 cases in the placebo group; 95 percent CI: 75.1, 92.2, p-value <0.001). Persistent infection is when the same HPV type is detected through swabs or biopsies over two or more consecutive visits six months apart. In addition, GARDASIL was 44.7 percent effective at reducing "anytime" HPV DNA detection (136 cases in the vaccine group vs. 241 cases in the placebo group; 95 percent CI: 31.5, 55.6, p-value <0.001). "Anytime" HPV DNA detection means HPV DNA is found through swabs or biopsies at any visit; persistent infection is a part of "anytime" HPV DNA detection.

Additional Important Information about GARDASIL
GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL.

GARDASIL is not recommended for use in pregnant women.

Not all vulvar and vaginal cancers are caused by human papillomavirus (HPV), and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV types 16 and 18.

The most common adverse reaction was headache. Common adverse reactions that were observed among recipients of GARDASIL at a frequency of at least 1.0 percent and greater than placebo were fever, nausea, dizziness; and injection-site pain, swelling, erythema, pruritus, and bruising.

In addition, syncope has been reported following vaccination with GARDASIL, sometimes resulting in falling with injury. Observation for 15 minutes after administration is recommended.

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 deltoid region of the upper arm or in the higher anterolateral area of the thigh. 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.

Human Papillomavirus: A Virus that Affects Both Men and Women
According to the Centers for Disease Control and Prevention, in the U.S. alone, an estimated 20 million men and women are currently infected with HPV, and another 6.2 million people become newly infected each year. For most, HPV goes away on its own. However, certain low-risk types of HPV can cause external genital lesions. More than one million cases of external genital lesions in men and women occur each year in the U.S. and more than 30 million occur each year worldwide. In addition for women, certain high-risk types of HPV, if unrecognized and untreated, can lead to cervical cancer.

HPV is a virus that can infect the genital region of men and women. There are an estimated 30 to 40 types of genital HPV. HPV transmission can happen with any kind of intimate genital contact with someone who has HPV; sexual intercourse is not needed. Most sexually active people will have HPV at some time in their lives.

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.

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, 2007, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

FDA Approves Expanded Uses for Gardasil to Include Preventing Certain Vulvar and Vaginal Cancers

Calisha Myers — Mon, 15 Sep 2008 12:03:19 -0400

FDA Approves Expanded Uses for Gardasil to Include Preventing Certain Vulvar and Vaginal Cancers

September 12, 2008

The U.S. Food and Drug Administration today announced the approval of the vaccine Gardasil for the prevention of vaginal and vulvar cancer caused by Human Papillomavirus (HPV) types 16 and 18 in girls and women ages 9 to 26. These two HPV types cause 70 percent of cervical cancers, and are known to also cause some vulvar and vaginal cancers, but the percentages are not well defined.

"There is now strong evidence showing that this vaccine can help prevent vulvar and vaginal cancers due to the same viruses for which it also helps protect against cervical cancer," said Jesse L. Goodman, M.D., M.P.H., director of the FDA's Center for Biologics Evaluation and Research. "While vulvar and vaginal cancers are rare, the opportunity to help prevent them is potentially an important additional benefit from immunization against HPV."

The FDA originally approved Gardasil in 2006 for girls and women ages 9 to 26 for the prevention of cervical cancer caused by HPV types 16 and 18, precancerous genital lesions caused by HPV types 6, 11, 16, and 18 and genital warts caused by HPV types 6 and 11.

HPV includes more than 100 related viruses and more than 30 types can be transmitted via sexual contact. According to the U.S. Centers for Disease Control and Prevention, HPV is the most common sexually transmitted infection in the United States with 6.2 million Americans becoming infected with genital HPV each year.

For most women, the body's own defense system will clear HPV, thereby preventing serious health problems. However, some HPV types can cause abnormal cell growth in areas of the cervix, vagina, vulva, and other areas that years later may turn into cancer.

Regarding the prevention of vulvar and vaginal cancer, Gardasil's manufacturer, Merck & Co. Inc., followed more than 15,000 participants from the original studies for about two additional years. Approximately half had received Gardasil as part of the original study-the other half did not receive Gardasil and served as a control group.

Among females who tested negative for HPV types 16 or 18 at the start of the study, Gardasil was highly effective in preventing these types of HPV-related precancerous vulvar and vaginal lesions, which are considered to be the precursors for cancer. In the control group that did not receive the vaccine, 10 individuals developed precancerous vulvar lesions and nine developed precancerous vaginal lesions, all related to HPV types 16 or 18. No one in the Gardasil group developed either kind of precancerous lesion due to HPV types 16 or 18.

There was no evidence for benefit among women found to have been previously infected, prior to immunization, with the HPV types included in the vaccine. Therefore, to receive Gardasil's full potential for benefit, it is important to be vaccinated prior to becoming infected with the HPV strains contained in the vaccine.

Gardasil's label has been revised to note that presently available information is insufficient to support use beyond age 26, the current FDA-approved age. Also, new information has been added showing that Gardasil does not protect against diseases caused by HPV types not contained in the vaccine.

No vaccine is 100 percent effective, and Gardasil does not protect against HPV infections that a woman may already have at the time of vaccination. Therefore, all women should get regular Pap tests, even after they have been vaccinated. Routine Pap screening remains critically important to detect precancerous changes, which would allow treatment before cancer develops.

Since the FDA approved Gardasil in 2006, the majority of reported adverse events have not been serious. The most commonly reported adverse events have included syncope (fainting), pain at the injection site, headache, nausea, and fever. Fainting is common after injections and vaccinations, especially in adolescents. Falls after fainting may sometimes cause serious injuries, such as head injuries, which can be prevented with simple steps, such as keeping the vaccinated person seated for up to 15 minutes after vaccination. This observation period is also recommended to watch for severe allergic reactions, which can occur after any immunization.

As part of the original approval, Merck committed to a safety surveillance study of 44,000 individuals in a managed care organization. The study is assessing short- and long-term safety for all of Gardasil's approved uses.

As with all vaccines, the FDA and the CDC continue to closely monitor Gardasil's safety. Updated safety information on Gardasil was published on July 22 and can be found at www.fda.gov/cber/safety/gardasil071408.htm.

Product approval information for Gardasil can be found at www.fda.gov/cber/products/gardasil.htm.
Merck & Co. Inc. is located in Whitehouse Station, N.J.