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

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

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

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

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

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

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

Important information about GARDASIL

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

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

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

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

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

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

Select safety information

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

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

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

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

Dosage and administration for GARDASIL

GARDASIL is a ready-to-use, three-dose, intramuscular vaccine. GARDASIL should be administered in three separate intramuscular injections in the deltoid region of the upper arm or in the higher anterolateral area of the thigh. The following dosage schedule is recommended: First dose at elected date, second dose two months after the first dose and the third dose six months after the first dose.

GARDASIL is approved in 121 countries

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

About Merck

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

Forward-Looking Statement

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

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

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

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

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

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

RECENT MAJOR CHANGES

INDICATIONS AND USAGE

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

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

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

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

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

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

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

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

Limitations of GARDASIL Use and Effectiveness:

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

DOSAGE AND ADMINISTRATION

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

DOSAGE FORMS AND STRENGTHS

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

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

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

ADVERSE REACTIONS

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

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

DRUG INTERACTIONS

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

USE IN SPECIFIC POPULATIONS

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

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

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

Revised: 12/2010

FULL PRESCRIBING INFORMATION: CONTENTS*

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

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Girls and Women

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

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

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

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

1.2 Boys and Men

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

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

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

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

1.3 Limitations of GARDASIL Use and Effectiveness

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

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

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

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

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

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

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

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

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

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

2.2 Method of Administration

For intramuscular use only.

Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. GARDASIL should not be diluted or mixed with other vaccines. After thorough agitation, GARDASIL is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the product if particulates are present or if it appears discolored.

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

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

Single-Dose Vial Use

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

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

Prefilled Syringe With Needle Guard (Safety) Device

Instructions for using the prefilled single-dose syringes preassembled with needle guard (safety) device

(Graphic Omitted)

NOTE: Please use the enclosed needle for administration. If a different needle is chosen, it should fit securely on the syringe and be no longer than 1 inch to ensure proper functioning of the needle guard device. Two detachable labels are provided which can be removed after the needle is guarded.

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

Remove Syringe Tip Cap and Needle Cap. Attach Luer Needle by pressing both Anti-Rotation Tabs to secure syringe and by twisting the Luer Needle in a clockwise direction until secured to the syringe. Remove Needle Sheath. Administer injection per standard protocol as stated above under DOSAGE AND ADMINISTRATION. Depress the Plunger while grasping the Finger Flange until the entire dose has been given. The Needle Guard Device will NOT activate to cover and protect the needle unless the ENTIRE dose has been given. While the Plunger is still depressed, remove needle from the vaccine recipient. Slowly release the Plunger and allow syringe to move up until the entire needle is guarded. For documentation of vaccination, remove detachable labels by pulling slowly on them. Dispose in approved sharps container.

Prefilled Syringe Without Needle Guard (Safety) Device

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

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Syncope

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, Women, Boys, and Men 9 Through 26 Years of Age

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

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

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

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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

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

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

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

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

6.2 Postmarketing Experience

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

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

Respiratory, thoracic and mediastinal disorders: Pulmonary embolus.

Gastrointestinal disorders: Nausea, pancreatitis, vomiting.

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

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

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.

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

Infections and infestations: cellulitis.

Vascular disorders: Deep venous thrombosis.

7 DRUG INTERACTIONS

7.1 Use with RECOMBIVAX HB

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

7.2 Use with Menactra and Adacel

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

7.3 Use with Hormonal Contraceptives

In clinical studies, 13,293 women (GARDASIL N = 6644; AAHS control or saline placebo N = 6649) who had post-Month 7 follow-up used hormonal contraceptives for a total of 17,597 person-years (65.1% of the total follow-up time in the studies). Use of hormonal contraceptives or lack of use of hormonal contraceptives among study participants did not alter immune response in the per protocol efficacy (PPE) population.

7.4 Use with Systemic Immunosuppressive Medications

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines [see Use in Specific Populations (8.6)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B:

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

An evaluation of the effect of GARDASIL on embryo-fetal, pre- and postweaning development was conducted using rats. One group of rats was administered GARDASIL twice prior to gestation, during the period of organogenesis (gestation Day 6) and on lactation Day 7. A second group of pregnant rats was administered GARDASIL during the period of organogenesis (gestation Day 6) and on lactation Day 7 only. GARDASIL was administered at 0.5 mL/rat/occasion (120 mcg total protein which is equivalent to the recommended human dose) by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring.

Clinical Studies in Humans

In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of GARDASIL. Women who were found to be pregnant before completion of a 3-dose regimen of GARDASIL were instructed to defer completion of their vaccination regimen until resolution of the pregnancy.

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

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

Overall, 54 and 63 women in the group that received GARDASIL or AAHS control or saline placebo, respectively (3.0% and 3.5% of all women who reported a pregnancy in the respective vaccination groups), experienced a serious adverse reaction during pregnancy. The most common events reported were conditions that can result in Caesarean section (e.g., failure of labor, malpresentation, cephalopelvic disproportion), premature onset of labor (e.g., threatened abortions, premature rupture of membranes), and pregnancy-related medical problems (e.g., pre-eclampsia, hyperemesis). The proportions of pregnant women who experienced such events were comparable between the groups receiving GARDASIL and AAHS control or saline placebo.

There were 40 cases of congenital anomaly in pregnancies that occurred in women who received GARDASIL and 30 cases of congenital anomaly in pregnancies that occurred in women who received AAHS control or saline placebo.

Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of GARDASIL or AAHS control or saline placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received GARDASIL compared to 1 case of congenital anomaly in the group that received AAHS control or saline placebo. The congenital anomalies seen in pregnancies with estimated onset within 30 days of vaccination included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, and club foot. Conversely, in pregnancies with onset more than 30 days following vaccination, 35 cases of congenital anomaly were observed in the group that received GARDASIL compared with 29 cases of congenital anomaly in the group that received AAHS control or saline placebo.

Pregnancy Registry for GARDASIL

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a Pregnancy Registry to monitor fetal outcomes of pregnant women exposed to GARDASIL. Patients and health care providers are encouraged to report any exposure to GARDASIL during pregnancy by calling (800) 986-8999.

8.3 Nursing Mothers

Women 16 Through 26 Years of Age

It is not known whether GARDASIL is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GARDASIL is administered to a nursing woman.

A total of 995 nursing mothers (vaccine N = 500, AAHS control N = 495) were given GARDASIL or AAHS control during the vaccination period of the clinical trials.

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

In a post-hoc analysis of clinical studies, a higher number of breast-feeding infants (n = 6) whose mothers received GARDASIL had acute respiratory illnesses within 30 days post vaccination of the mother as compared to infants (n = 2) whose mothers received AAHS control. In these studies, the rates of other adverse reactions in the mother and the nursing infant were comparable between vaccination groups.

8.4 Pediatric Use

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

8.5 Geriatric Use

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

8.6 Immunocompromised Individuals

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

10 OVERDOSAGE

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

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

11 DESCRIPTION

GARDASIL, Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant, is a non-infectious recombinant quadrivalent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate Sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer.

GARDASIL is a sterile suspension for intramuscular administration. Each 0.5-mL dose contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg of HPV 18 L1 protein.

Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as Amorphous Aluminum Hydroxyphosphate Sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, <7 mcg yeast protein/dose, and water for injection. The product does not contain a preservative or antibiotics.

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

GARDASIL has not been evaluated for the potential to cause carcinogenicity or genotoxicity.

GARDASIL administered to female rats at a dose of 120 mcg total protein, which is equivalent to the recommended human dose, had no effects on mating performance, fertility, or embryonic/fetal survival.

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

14 CLINICAL STUDIES

CIN 2/3 and AIS are the immediate and necessary precursors of squamous cell carcinoma and adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer; thus, they serve as surrogate markers for prevention of cervical cancer. In the clinical studies in girls and women aged 16 through 26 years, cases of CIN 2/3 and AIS were the efficacy endpoints to assess prevention of cervical cancer. In addition, cases of VIN 2/3 and VaIN 2/3 were the efficacy endpoints to assess prevention of HPV-related vulvar and vaginal cancers, and observations of external genital lesions were the efficacy endpoints for the prevention of genital warts.

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

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

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

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

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

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

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

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

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

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

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

The primary analyses of efficacy with respect to HPV types 6, 11, 16, and 18 were conducted in the per-protocol efficacy (PPE) population, consisting of girls and women who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit.

GARDASIL was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types 6, 11, 16, or 18 in those who were PCR negative and seronegative at baseline (Table 11).

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

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.

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).

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.

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.

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.

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.

14.6 Overall Population Impact

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

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

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

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

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

14.7 Other Studies

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

14.8 Immunogenicity

Assays to Measure Immune Response

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

Because there were few disease cases in individuals naïve (PCR negative and seronegative) to vaccine HPV types at baseline in the group that received GARDASIL, it has not been possible to establish minimum anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 antibody levels that protect against clinical disease caused by HPV 6, 11, 16, and/or 18.

The immunogenicity of GARDASIL was assessed in 20,132 9- through 26-year-old girls and women (GARDASIL N = 10,723; AAHS control or saline placebo N = 9409) and 5417 9- through 26-year-old boys and men (GARDASIL N = 3109; AAHS control or saline placebo N = 2308).

Type-specific immunoassays with type-specific standards were used to assess immunogenicity to each vaccine HPV type. These assays measured antibodies against neutralizing epitopes for each HPV type. The scales for these assays are unique to each HPV type; thus, comparisons across types and to other assays are not appropriate.

Immune Response to GARDASIL

The primary immunogenicity analyses were conducted in a per-protocol immunogenicity (PPI) population. This population consisted of individuals who were seronegative and PCR negative to the relevant HPV type(s) at enrollment, remained HPV PCR negative to the relevant HPV type(s) through 1 month postdose 3 (Month 7), received all 3 vaccinations, and did not deviate from the study protocol in ways that could interfere with the effects of the vaccine.

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

In clinical studies in girls and women, at least 99.8%, 99.8%, 99.8%, and 99.5% who received GARDASIL became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested.

In clinical studies in boys and men, at least 98.9%, 99.2%, 98.8%, and 97.4% who received GARDASIL became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested.

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

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

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

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

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

Duration of the Immune Response to GARDASIL

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

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

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

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

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

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

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

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

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

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

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

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

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

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

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

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

17 PATIENT COUNSELING INFORMATION

[See FDA-Approved Patient Labeling.]

Inform the patient, parent, or guardian:

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

Printed in USA

9883615

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

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

9883615

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

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

What is GARDASIL?

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

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

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

• Anal cancer
• Genital warts
• Precancerous anal lesions

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

What important information about GARDASIL should I know?

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

Who should not get GARDASIL?

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

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

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

Tell your health care provider if you:

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

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

How is GARDASIL given?

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

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

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

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

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

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

What are the possible side effects of GARDASIL?

The most common side effects with GARDASIL are:

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

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

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

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

• difficulty breathing
• wheezing (bronchospasm)
• hives
• rash

Tell your health care provider if you have:

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

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

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

What are the ingredients in GARDASIL?

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

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

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

Whitehouse Station, NJ 08889, USA

Issued December 2010

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