The Government of Rwanda, together with QIAGEN N.V. (NASDAQ: QGEN, F:QIA) and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the launch, in Kigali, Rwanda, of a comprehensive national cervical cancer prevention program that includes vaccination with GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant] for appropriate girls 12 to 15 years of age and modern molecular diagnostic screening for women between the ages of 35 and 45.

Rwanda is the first nation in Africa to offer a comprehensive prevention program that incorporates both HPV vaccination and HPV testing. Rwanda has a population of 2.72 million women ages 15 years and older. Cervical cancer ranks as the most frequent cancer in women of all ages in Rwanda.

"It is our goal to create a comprehensive, coordinated program that includes HPV vaccination, cancer screening with HPV DNA testing, and treatment in order to address the nation's unmet needs for cervical cancer-related health services," said Dr. Richard Sezibera, Rwanda’s Minister of Health. "This vaccination and screening program brings us one step closer to reaching our goal of protecting the girls and women in our country. We are pleased to have the support of Merck and QIAGEN on this important government initiative."

During the first three years of the national prevention program the Ministry of Health, with the support of Merck, will offer GARDASIL to appropriate girls 12 to 15 years of age, while QIAGEN's DNA-based molecular diagnostic HPV tests – the digene HC2 HPV DNA Test and the careHPV Test – will be offered to women between the ages of 35 and 45. QIAGEN’s careHPV test has been designed to reach women where access to medical care is more challenging – the portable testing system can be performed in any health clinic setting by healthcare workers with minimal lab training.

Merck will provide more than two million doses of GARDASIL to the Government of Rwanda at no cost, while QIAGEN will provide 250,000 HPV screening tests at no cost along with all necessary equipment and training to successfully perform the tests. Thereafter, the Government of Rwanda will continue routine vaccination of appropriate 12 year old girls, and Merck will provide GARDASIL at a discounted access price that is made available for national vaccination programs in GAVI-eligible countries. Similarly, QIAGEN will make its HPV tests accessible under a tiered-market pricing structure designed to enable developing countries to establish and maintain the use of HPV testing within national cervical cancer screening and treatment programs.

"Over eighty-five percent of cervical cancer cases occur in the world's poorest countries, having an impact on the women affected, their families and their communities," said Dr. Mark Feinberg, chief public health and science officer, Merck Vaccines. "Reducing the incidence of cervical cancer is a very important public health goal. Through this collaboration with the Government of Rwanda, QIAGEN and numerous global public health organizations working in the country to introduce HPV vaccination and HPV DNA testing, women and girls in Rwanda will have greater access to a comprehensive cervical cancer prevention program. We hope this initiative by the Government of Rwanda provides a helpful model for other resource-limited countries to consider as they work to develop their own programs."

GARDASIL is approved in the United States for use in girls and young women 9 through 26 years of age for the prevention of cervical, vulvar, vaginal and anal 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 is also approved in the United States for use in boys and men ages 9 through 26 years of age for the prevention of anal cancer caused by HPV types 16 and 18, for the prevention of anal dysplasias and precancerous lesions caused by HPV types 6, 11, 16 and 18, and the prevention of genital warts caused by HPV types 6 and 11.

Merck and QIAGEN announced plans to launch a collaborative HPV vaccination and HPV screening program in September 2009 to help prevent cervical cancer. In addition to their own separate initiatives, the two companies committed to jointly provide up to five million doses of GARDASIL and 500,000 HPV tests to developing countries at no charge. As the first recipient of this collaborative effort, Rwanda will become the first GAVI-eligible country to implement a comprehensive program involving both HPV vaccination and HPV DNA-based molecular testing to improve access to cervical cancer prevention programs. QIAGEN and Merck continue to reach out to select GAVI-eligible countries to explore the feasibility of implementing cervical cancer reduction programs.

"Expanding access to HPV testing, regardless of where a woman lives, is a commitment of QIAGEN to help reduce the tremendous burden of cervical cancer, particularly in the developing world. Women in Rwanda, and in other countries where our DNA-based molecular diagnostic tests are available, are being screened for prevention of this potentially life-threatening disease with the most modern diagnostic detection technology available,” said Peer Schatz, chief executive officer of QIAGEN N.V. “In many countries women are the cornerstone of families and their communities. It is unfortunate that cervical cancer, which effective measures can help to prevent, often strikes women in their prime years of productivity. We are pleased to partner with the Republic of Rwanda and Merck to introduce this comprehensive program that will greatly expand access to HPV testing and vaccination, which together can help reduce the burden of this disease. We believe this program will demonstrate the positive impact that these types of collaborations can have in terms of improving healthcare.”

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 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.

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 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.

HPV testing

HPV testing can identify women with high-risk HPV infections that can cause cervical cancer. These tests enable diagnosis and treatment to be under taken before cervical cancer develops. The digene HPV Test is approved in Europe and FDA approved in the United States where it is used as a screening test. In the United States, it is approved to be used together with a Pap test in women 30 years and older. In Europe, it is CE marked and approved as an initial general population screening test either alone or together with a Pap test. It is also used as a follow-up to inconclusive Pap test results and as a post-cervical cancer treatment follow-up.

To help ensure that HPV testing can reach women in all regions of the world, QIAGEN has developed the careHPV Test, a portable HPV DNA test for public-health programs in low-resource countries that can be run in settings with no main electricity or running water and can provide same-day test results. The careHPV test is CE-marked and pending WHO prequalification. The cervical cancer prevention collaboration with Merck will include donations of both the digene HPV Test and the careHPV Test.

HPV and cervical cancer

HPV is a widespread virus that is transmitted through sexual contact. 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 will not clear the virus.

Cervical cancer is estimated to develop in approximately 500,000 women annually around the world. After breast cancer, cervical cancer is considered the second most common malignancy found in women. The World Health Organization estimates that only about five percent of women in the developing world have been screened for cervical disease in the previous five years compared to 75 percent in the developed world.

Other Merck and QIAGEN access efforts in the developing world

Merck is pursuing a systematic and thoughtful approach to improve access to GARDASIL in the developing world through four key pillars: innovation, partnerships, pricing and implementation. In 2007 at the Clinton Global Initiative, Merck made a pledge to donate at least three million doses of GARDASIL through the GARDASIL ® Access Program, which is enabling organizations and institutions in eligible lowest income countries to gain operational experience designing and implementing HPV vaccination projects.

The collaboration between Merck and QIAGEN represents a new commitment and approach that is in addition to, and distinct from, the charitable GARDASIL ® Access Program.

QIAGEN is working to improve access to cervical cancer screening through its QIAGEN cares corporate social responsibility program. Through the QIAGEN cares program, QIAGEN is developing the rapid, portable careHPV Test for low-resource settings and health clinics in the developing world and has committed to donating 1.5 million HPV tests to developing countries with the aim of expanding access to cervical cancer screening in areas with the highest disease burden. In addition to its donation to Rwanda, QIAGEN currently provides HPV tests to programs in China and India.

About the Government of Rwanda

Visit www.moh.gov.rw

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.

About QIAGEN

QIAGEN N.V., a Netherlands holding company, is the leading global provider of sample and assay technologies. Sample technologies are used to isolate and process DNA, RNA and proteins from biological samples such as blood or tissue. Assay technologies are used to make such isolated bio-molecules visible. QIAGEN has developed and markets more than 500 sample and assay products as well as automated solutions for such consumables. The company provides its products to molecular diagnostics laboratories, academic researchers, pharmaceutical and biotechnology companies, and applied testing customers for purposes such as forensics, animal or food testing and pharmaceutical process control. QIAGEN's assay technologies include one of the broadest panels of molecular diagnostic tests available worldwide. This panel includes the digene HPV Test, which is regarded as a "gold standard" in testing for high-risk types of human papillomavirus (HPV), the primary cause of cervical cancer, as well as a broad suite of solutions for infectious disease testing and companion diagnostics. QIAGEN employs nearly 3,600 people in over 30 locations worldwide. Further information about QIAGEN can be found at www.QIAGEN.com.

Merck's 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 United States 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 2010 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 ® are attached and 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

Photos/Multimedia Gallery Available: http://www.businesswire.com/cgi-bin/mmg.cgi?eid=6695132&lang=en

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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) 04/2011

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)
  • GARDASIL has not been demonstrated to prevent HPV-related CIN 2/3 or worse in women older than 26 years of age. (14.7)

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)

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

Revised: 04/2011

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 Studies in Women 27 Through 45 Years of Age
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.

GARDASIL has not been demonstrated to prevent HPV-related CIN 2/3 or worse in women older than 26 years of age. [See Clinical Studies (14.7).]

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

This package does not contain 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

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.

5.2 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 and Women (9 Through 45 Years of Age) and Boys and Men (9 Through 26 Years of Age)

In 7 clinical trials (5 Amorphous Aluminum Hydroxyphosphate Sulfate [AAHS]-controlled, 1 saline placebo-controlled, and 1 uncontrolled), 18,083 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 10,088 individuals 9 through 45 years of age at enrollment who received GARDASIL and 7,995 individuals who received AAHS control or saline placebo. Few individuals (0.2%) discontinued due to adverse reactions. The race distribution of the 9- through 26-year-old 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 24- through 45-year-old women in the safety population of Study 6 was as follows: 20.6% White; 43.2% Hispanic (Black and White); 0.2% Other; 4.8% Black; 31.2% Asian; and 0.1% American Indian. The race distribution of the 9- through 26-year-old 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 1Injection-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)%
   

SalinePlacebo(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

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 2.

Table 2Injection-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)%
 

SalinePlacebo(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 3Postdose 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)

AdverseReaction
   

Post-dose1N** =5011
   

Post-dose2N = 4924
   

Post-dose3N = 4818
   

Post-dose1N = 3410
   

Post-dose2N = 3351
   

Post-dose3N = 3295
   

Post-dose1N = 315
   

Post-dose2N = 301
   

Post-dose3N = 300

PainMild/ModerateSevere
   

63.462.50.9
   

60.759.71.0
   

62.761.21.5
   

57.056.60.4
   

47.847.30.5
   

49.648.90.6
   

33.733.30.3
   

20.320.30.0
   

27.327.00.3

Swelling***Mild/ModerateSevere
   

10.29.60.6
   

12.811.90.8
   

15.114.20.9
   

8.28.10.2
   

7.57.20.2
   

7.67.30.2
   

4.44.40.0
   

3.03.00.0
   

3.33.30.0

Erythema***Mild/ModerateSevere
   

9.29.00.2
   

12.111.70.3
   

14.714.30.4
   

9.89.50.3
   

8.48.40.1
   

8.98.80.1
   

7.37.30.0
   

5.35.30.0
   

5.75.70.0
*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 4Postdose 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)

AdverseReaction
 

Post-dose1N** =3003
 

Post-dose2N = 2898
 

Post-dose3N = 2826
   

Post-dose1N = 1950
 

Post-dose2N = 1854
 

Post-dose3N = 1799
   

Post-dose1N = 269
 

Post-dose2N = 263
 

Post-dose3N = 259

PainMild/ModerateSevere
 

44.744.50.2
 

36.936.40.5
 

34.434.10.3
   

38.437.90.4
 

28.228.20.1
 

25.825.50.3
   

27.527.50.0
 

20.520.20.4
 

16.216.20.0

Swelling***Mild/ModerateSevere
 

5.65.30.2
 

6.66.20.3
 

7.77.10.5
   

5.65.40.2
 

4.54.50.0
 

4.14.00.1
   

4.84.80.0
 

1.51.50.0
 

3.53.10.4

Erythema***Mild/ModerateSevere
 

7.26.80.3
 

8.07.70.2
 

8.78.30.3
   

8.38.00.2
 

6.36.20.1
 

5.75.60.1
   

7.17.10.0
 

5.75.70.0
 

5.05.00.0
*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 5Common 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 SalinePlacebo(N = 3790)%

PyrexiaNauseaDizzinessDiarrheaVomitingCoughToothacheUpper respiratory tract infectionMalaiseArthralgiaInsomniaNasal congestion
 

13.06.74.03.62.42.01.51.51.41.21.21.1
 

11.26.53.73.51.91.51.41.51.20.90.90.9
* 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 6Common 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 SalinePlacebo(N = 2303)%

HeadachePyrexiaOropharyngeal painDiarrheaNasopharyngitisNauseaUpper respiratory tract infectionAbdominal pain upperMyalgiaDizzinessVomiting
   

12.38.32.82.72.62.01.51.41.31.21.0
 

11.26.52.12.22.61.01.01.40.70.90.8
*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 Year s of Age

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

Table 7Postdose 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 1N** = 4945
 

Postdose 2N = 4804
 

Postdose 3N = 4671
   

Postdose 1N = 3681
 

Postdose 2N = 3564
 

Postdose 3N = 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 8Postdose 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 1N** = 2972
 

Postdose 2N = 2849
 

Postdose 3N = 2792
   

Postdose 1N = 2194
 

Postdose 2N = 2079
 

Postdose 3N = 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 9Summary of Girls and Women 9 Through 26 Years of Age Who Reported an Incident ConditionPotentially Indicative of a Systemic Autoimmune Disorder After Enrollment in Clinical Trials ofGARDASIL, Regardless of Causality
Conditions  

GARDASIL(N = 10,706)
 

AAHS Control* or SalinePlacebo(N = 9412)
  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 10Summary of Boys and Men 9 Through 26 Years of Age Who Reported an Incident ConditionPotentially Indicative of a Systemic Autoimmune Disorder After Enrollment in Clinical Trials ofGARDASIL, Regardless of Causality
Conditions    

GARDASIL(N = 3093)
 

AAHS Control* or SalinePlacebo(N = 2303)
    n (%)   n (%)
Alopecia Areata     2 (0.1)   0 (0.0)
Ankylosing Spondylitis 1 (0.0) 2 (0.1)

Arthralgia/Arthritis/Reactive 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.

Safety in Women 27 Through 45 Years of Age

The adverse reaction profile in women 27 through 45 years of age was comparable to the profile seen in girls and women 9 through 26 years of age.

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 of 16- through 26-year-old women, 13,912 (GARDASIL N = 6952; AAHS control or saline placebo N = 6960) who had post-Month 7 follow-up used hormonal contraceptives for a total of 33,859 person-years (65.8% of the total follow-up time in the studies).

In one clinical study of 24- through 45-year-old women, 1357 (GARDASIL N = 690; AAHS control N = 667) who had post-Month 7 follow-up used hormonal contraceptives for a total of 3400 person-years (31.5% of the total follow-up time in the study). Use of hormonal contraceptives or lack of use of hormonal contraceptives among study participants did not impair the immune response in the per protocol immunogenicity (PPI) 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 3819 women (GARDASIL N = 1894 vs. AAHS control or saline placebo N = 1925) 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 22.6% (446/1973) in women who received GARDASIL and 23.1% (460/1994) in women who received AAHS control or saline placebo.

Overall, 55 and 65 women in the group that received GARDASIL or AAHS control or saline placebo, respectively (2.9% and 3.4% 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 45 cases of congenital anomaly in pregnancies that occurred in women who received GARDASIL and 34 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, 40 cases of congenital anomaly were observed in the group that received GARDASIL compared with 33 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 45 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.

GARDASIL or AAHS control were given to a total of 1133 women (vaccine N = 582, AAHS control N = 551) during the relevant Phase III clinical studies.

Overall, 27 and 13 infants of women who received GARDASIL or AAHS control, respectively (representing 4.6% and 2.4% 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 = 7) 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.

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 6 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 16- through 26-year-old girls and women) and the second evaluated all components of GARDASIL (Study 2, N = 551 16- through 26-year-old girls and women). Two Phase III studies evaluated GARDASIL in 5442 (Study 3) and 12,157 (Study 4) 16- through 26-year-old girls and women. A third Phase III study, Study 5, evaluated GARDASIL in 4055 16- through 26-year-old boys and men, including a subset of 598 (GARDASIL = 299; placebo = 299) men who self-identified as having sex with men (MSM population). A fourth Phase III study, Study 6, evaluated GARDASIL in 3817 24- through 45-year-old women. Together, these six studies evaluated 28,413 individuals (20,541 girls and women 16 through 26 years of age at enrollment with a mean age of 20.0 years, 4055 boys and men 16 through 26 years of age at enrollment with a mean age of 20.5 years, and 3817 women 24 through 45 years of age at enrollment with a mean age of 34.3 years). The race distribution of the 16- through 26-year-old 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 16- through 26-year-old 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 race distribution of the 24- through 45-year-old women in the clinical trials was as follows: 20.6% White; 43.2% Hispanic (Black and White); 0.2% Other; 4.8% Black; 31.2% Asian; and 0.1% American Indian.

The median duration of follow-up was 4.0, 3.0, 3.0, 3.0, 2.3, and 4.0 years for Study 1, Study 2, Study 3, Study 4, Study 5, and Study 6, 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, 67% of 24- through 45-year-old 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, 33% of 24- through 45-year-old 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, 71% of 24- through 45-year-old 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 24- through 45-year-old individuals, 0.4% had been exposed to all 4 vaccine HPV 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 11Analysis of Efficacy of GARDASIL in the PPE* Population** of 16- Through 26-Year-Old Girls and Women forVaccine HPV Types
Population   GARDASIL   AAHS Control   % Efficacy (95% CI)
  N   Number of cases   N   Number of cases  
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)
    N**   Number of cases   N   Number of cases  
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- relatedEndpoint
  GARDASIL   AAHS Control   % Efficacy (95% CI)
  N**   Number of cases   N   Number of cases  
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 16L1 VLP Vaccine
  AAHS Control  

% Reduction (95% CI)
  N   Cases   N   Cases  

HPV 16- or 18-related CIN 2/3 orAIS
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 orPrior Exposure to HPV 16 or 18
  9836   146   9904   303   51.8 (41.1, 60.7)

HPV 16- or 18-related VIN 2/3 orVaIN 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 orPrior 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) orAIS
Prophylactic Efficacy*   8630   16   8680   309   94.8 (91.5, 97.1)

HPV 6, HPV 11, HPV 16, and/or HPV 18Positive at Day 1**
  2466   186#   2437   213#   --
 

Girls and Women Regardless of Current orPrior Exposure to Vaccine HPV Types
  8819   202   8854   522   61.5 (54.6, 67.4)

HPV 6-, 11-, 16-,or 18-relatedGenital Warts
Prophylactic Efficacy*   8761   10   8792   252   96.0 (92.6, 98.1)

HPV 6, HPV 11, HPV 16, and/or HPV 18Positive at Day 1**
  2501   51§   2475   55§   --
 

Girls and Women Regardless of Current orPrior Exposure to Vaccine HPV Types
  8955   61   8968   307   80.3 (73.9, 85.3)

HPV 6- or 11-related GenitalWarts
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 orPrior 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 15Effectiveness of GARDASIL in Prevention of Any HPV Type Related Genital Disease in Girls and Women 16Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine HPV Types

Endpoints Caused by Vaccine orNon-vaccine HPV Types
  Analysis   GARDASIL   AAHS Control  

% Reduction (95% CI)
    N   Cases   N   Cases  
CIN 2/3 or AIS Prophylactic Efficacy*   4616   77   4680   136   42.7 (23.7, 57.3)
 

Girls and WomenRegardless of Currentor Prior Exposure toVaccine 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)
 

Girls and WomenRegardless of Currentor Prior Exposure toVaccine 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)
 

Girls and WomenRegardless of Currentor Prior Exposure toVaccine 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)
 

Girls and WomenRegardless of Currentor Prior Exposure toVaccine 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 16Effectiveness of GARDASIL in Prevention of HPV Types 6-, 11-, 16-, or 18-Related AnogenitalDisease in Boys and Men 16 Through 26 Years of Age, Regardless of Current or Prior Exposure toVaccine HPV Types
Endpoint     Analysis   GARDASIL   AAHS

Control
 

% Reduction(95% CI)
      N   Cases   N   Cases    

ExternalGenitalLesions
Prophylactic Efficacy*   1775   13   1770   54   76.3 (56.0, 88.1)

HPV 6, HPV 11, HPV 16, and/orHPV 18 Positive at Day 1**
  460   14   453   26   --***
   

Boys and Men Regardless ofCurrent or Prior Exposure toVaccine or Non-Vaccine HPVTypes
  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/orHPV 18 Positive at Day 1**
  460   14   453   25   --***
   

Boys and Men Regardless ofCurrent or Prior Exposure toVaccine or Non-Vaccine HPVTypes
  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/orHPV 18 Positive at Day 1**
  460   2   453   1   --***
   

Boys and Men Regardless ofCurrent or Prior Exposure toVaccine or Non-Vaccine HPVTypes
  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/orHPV 18 Positive at Day 1**
  103   29   116   38   --***
   

Boys and Men Regardless ofCurrent or Prior Exposure toVaccine or Non-Vaccine HPVTypes
  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/orHPV 18 Positive at Day 1**
  103   11   116   20   --***
   

Boys and Men Regardless ofCurrent or Prior Exposure toVaccine or Non-Vaccine HPVTypes
  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 17Effectiveness of GARDASIL in Prevention of Any HPV Type Related Anogenital Disease in Boysand Men 16 Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine orNon-Vaccine HPV Types
Endpoint     Analysis   GARDASIL  

AAHSControl
 

% Reduction(95% CI)
 

 
  N Cases   N   Cases  

ExternalGenitalLesions
Prophylactic Efficacy*   1275 7   1270   37   81.5 (58.0, 93.0)
   

Boys and Men Regardless ofCurrent or Prior Exposure toVaccine or Non-Vaccine HPVTypes**
  1943 38   1937   92   59.3 (40.0, 72.9)
Condyloma     Prophylactic Efficacy*   1275 5   1270   33   85.2 (61.8, 95.5)
   

Boys and Men Regardless ofCurrent or Prior Exposure toVaccine or Non-Vaccine HPVTypes**
  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)
   

Boys and Men Regardless ofCurrent or Prior Exposure toVaccine or Non-Vaccine HPVTypes**
  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)
   

Boys and Men Regardless ofCurrent or Prior Exposure toVaccine or Non-Vaccine HPVTypes**
  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)
   

Boys and Men Regardless ofCurrent or Prior Exposure toVaccine or Non-Vaccine HPVTypes**
  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 Studies in Women 27 Through 45 Years of Age

Study 6 evaluated efficacy in 3253 women 27 through 45 years of age based on a combined endpoint of HPV 6-, 11-, 16- or 18-related persistent infection, genital warts, vulvar and vaginal dysplastic lesions of any grade, CIN of any grade, AIS, and cervical cancer. These women were randomized 1:1 to receive either GARDASIL or AAHS control. The efficacy for the combined endpoint was driven primarily by prevention of persistent infection. There was no statistically significant efficacy demonstrated for CIN 2/3, AIS, or cervical cancer. In post hoc analyses conducted to assess the impact of GARDASIL on the individual components of the combined endpoint, the results in the population of women naïve to the relevant HPV type at baseline were as follows: prevention of HPV 6-, 11-, 16- or 18-related persistent infection (80.5% [95% CI: 68.3, 88.6]), prevention of HPV 6-, 11-, 16- or 18-related CIN (any grade) (85.8% [95% CI: 52.4, 97.3]), and prevention of HPV 6-, 11-, 16- or 18-related genital warts (87.6% [95% CI: 7.3, 99.7]).

Efficacy for disease endpoints was diminished in a population impact assessment of women who were vaccinated regardless of baseline HPV status (full analysis set). In the full analysis set (FAS), efficacy was not demonstrated for the following endpoints: prevention of HPV 16- and 18-related CIN 2/3, AIS, or cervical cancer and prevention of HPV 6- and 11-related condyloma. No efficacy was demonstrated against CIN 2/3, AIS, or cervical cancer in the general population irrespective of HPV type (FAS any type analysis).

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 23,951 9- through 45-year-old girls and women (GARDASIL N = 12,634; AAHS control or saline placebo N = 11,317) 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 16- through 26-year-old girls and women, 99.8%, 99.8%, 99.8%, and 99.4% 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.

In clinical studies in 27- through 45-year-old women, 98.2%, 97.9%, 98.6%, and 97.1% 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 16- through 26-year-old boys and men, 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. Tables 20 and 21 display 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 18Summary of Month 7 Anti-HPV cLIA Geometric Mean Titers in the PPI* Population of Girls andWomen
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     9859   3329   99.8 (99.6, 99.9)   545.0 (530.1, 560.4)
27- through 34-year-old women     667   439   98.4 (96.7, 99.4)   435.6 (393.4, 482.4)
35- through 45-year-old women     957   644   98.1 (96.8, 99.0)   397.3 (365.2, 432.2)
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     9859   3353   99.8 (99.5, 99.9)   748.9 (726.0, 772.6)
27- through 34-year-old women     667   439   98.2 (96.4, 99.2)   577.9 (523.8, 637.5)
35- through 45-year-old women     957   644   97.7 (96.2, 98.7)   512.8 (472.9, 556.1)
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     9859   3249   99.8 (99.6, 100.0)   2409.2 (2309.0, 2513.8)
27- through 34-year-old women     667   435   99.3 (98.0, 99.9)   2342.5 (2119.1, 2589.6)
35- through 45-year-old women     957   657   98.2 (96.8, 99.1)   2129.5 (1962.7, 2310.5)
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     9859   3566   99.4 (99.1, 99.7)   475.2 (458.8, 492.1)
27- through 34-year-old women     667   501   98.0 (96.4, 99.0)   385.8 (347.6, 428.1)
35- through 45-year-old women     957   722   96.4 (94.8, 97.6)   324.6 (297.6, 354.0)
*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 19Summary 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 20Persistence of Anti-HPV cLIA Geometric Mean Titers in 9- Through 45-Year-Old Girls and Women

Assay (cLIA)/Time Point
 

9- to 15-Year-Old Girls(N* = 1122)
 

16- to 26-Year-Old Girlsand Women(N* = 9859)
 

27- to 34-Year-OldWomen(N* = 667)
 

35- to 45-Year-OldWomen(N* = 957)
  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   917   929.2   3329   545.0   439   435.6   644   397.3
        (874.6, 987.3)       (530.1, 560.4)       (393.4, 482.4)       (365.2, 432.2)
Month 24 214 156.1 2788 109.1 421 70.7 628 69.3
        (135.6, 179.6)       (105.2, 113.1)       (63.8, 78.5)       (63.7, 75.4)
Month 36(†) 356 129.4 - - 399 79.5 618 81.1
        (115.6, 144.8)               (72.0, 87.7)       (75.0, 87.8)
Month 48(‡) - - 2514 73.8 391 58.8 616 62.0
                (70.9, 76.8)       (52.9, 65.3)       (57.0, 67.5)
Anti-HPV 11                                
Month 07 917 1304.6 3353 748.9 439 577.9 644 512.8
        (1224.7, 1389.7)       (726.0, 772.6)       (523.8, 637.5)       (472.9, 556.1)
Month 24 214 218.0 2817 137.1 421 79.3 628 73.4
        (188.3, 252.4)       (132.1, 142.3)       (71.5, 87.8)       (67.4, 79.8)
Month 36(†) 356 148.0 -

-
399 81.8 618 77.4
        (131.1, 167.1)      

 
      (74.3, 90.1)       (71.6, 83.6)
Month 48(‡) - - 2538 89.4 391 67.4 616 62.7
                (85.9, 93.1)       (60.9, 74.7)       (57.8, 68.0)
Anti-HPV 16                                
Month 07 915 4918.5 3249 2409.2 435 2342.5 657 2129.5
        (4556.6, 5309.1)       (2309.0, 2513.8)       (2119.1, 2589.6)       (1962.7, 2310.5)
Month 24 211 944.2 2721 442.6 416 285.9 642 271.4
        (804.4, 1108.3)       (425.0, 460.9)       (254.4, 321.2)       (247.1, 298.1)
Month 36(†) 353 642.2 -

-
399 291.5 631 276.7
        (562.8, 732.8)      

 
      (262.5, 323.8)       (254.5, 300.8)
Month 48(‡) -

-
2474 326.2 394 211.8 628 192.8
       

 
      (311.8, 341.3)       (189.5, 236.8)       (176.5, 210.6)
Anti-HPV 18                                
Month 07 922 1042.6 3566 475.2 501 385.8 722 324.6
        (967.6, 1123.3)       (458.8, 492.1)       (347.6, 428.1)       (297.6, 354.0)
Month 24 214 137.7 3002 50.8 478 31.8 705 26.0
        (114.8, 165.1)       (48.2, 53.5)       (28.1, 36.0)       (23.5, 28.8)
Month 36(†) 357 87.0 -

-
453 32.1 689 27.0
        (74.8, 101.2)      

 
      (28.5, 36.3)       (24.5, 29.8)
Month 48(‡) - - 2710 33.2 444 25.2 688 21.2
                (31.5, 35.0)       (22.3, 28.5)       (19.2, 23.4)
*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 37 for 9- to 15-year-old 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 girls 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

Table 21Persistence of Anti-HPV cLIA Geometric Mean Titers in 9- Through 26-Year-Old Boys and Men
Assay (cLIA)/ Time Point  

9- to 15-Year-Old Boys(N* = 1072)
 

16- to 26-Year-Old Boys and Men(N* = 2026)
  n**  

GMT (95% CI) mMU***/mL
  n**  

GMT(95% CI) mMU***/mL
Anti-HPV 6                
Month 07       1037.5       447.2
    884   (963.5, 1117.3)   1094   (418.4, 477.9)
Month 24       134.1       80.3
    323   (119.5, 150.5)   907   (74.9, 86.0)
Month 36(†)       126.6       72.4
    342   (111.9, 143.2)   654   (68.0, 77.2)
Month 48   -   -   -   -
Anti-HPV 11                
Month 07       1386.8       624.5
    885   (1298.5, 1481.0)   1094   (588.6, 662.5)
Month 24       188.5       94.6
    324   (168.4, 211.1)   907   (88.4, 101.2)
Month 36(†)       148.8       80.3
    342   (131.1, 169.0)   654   (75.7, 85.2)
Month 48   -   -   -   -
Anti-HPV 16                
Month 07       6056.5       2401.5
    882   (5601.4, 6548.6)   1137   (2241.8, 2572.6)
Month 24       938.2       347.7
    322   (825.0, 1067.0)   938   (322.5, 374.9)
Month 36(†)       708.8       306.7
    341   (613.9, 818.3)   672   (287.5, 327.1)
Month 48   -   -   -   -
Anti-HPV 18                
Month 07       1357.4       402.6
    887   (1249.4, 1474.7)   1176   (374.6, 432.6)
Month 24       131.9       38.7
    324   (112.1, 155.3)   967   (35.2, 42.5)
Month 36(†)       113.0       33.4
    343   (94.7, 135.0)   690   (30.9, 36.1)
Month 48   -   -   -   -
*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.
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 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

9883616

1 Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.  Copyright © 2006, 2009, 2010, 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.  All rights reserved

9883616

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 GARDASIL 1. 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 April 2011

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

Copyright Business Wire 2010