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

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

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

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

"We are encouraged by the extended efficacy data for the HPV 16 component of GARDASIL. Studies to examine the long-term efficacy of GARDASIL are underway," said Laura A. Koutsky, Ph.D., MSPH, University of Washington, School of Public Health.

Dr. Koutsky and the University of Washington study site led this study extension. Merck & Co., Inc. is a co-author of the original data and the new analysis.

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

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

Efficacy of the prophylactic human papillomavirus (HPV) type 16 L1 virus-like particle (VLP) vaccine

In a follow-up study of 290 women from a randomized, placebo-controlled, proof-of-concept clinical trial, the HPV 16 component of GARDASIL remained efficacious against HPV 16 infection and associated precancerous lesions for an average follow-up time of 8.5 years after administration.

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

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

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

In second investigational study, reduction in abnormal Pap tests and procedures

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

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

 

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

Additional important information about GARDASIL

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

The health care provider should inform the patient, parent or guardian that vaccination does not substitute for routine cervical cancer screening. Women who receive GARDASIL should continue to undergo cervical cancer screening per standard of care.

GARDASIL is not recommended for use in pregnant women.

The duration of protection with GARDASIL is currently not known. Vaccination with GARDASIL may not result in protection in all vaccine recipients. GARDASIL is not intended to be used for treatment of active genital warts, cervical, vaginal and vulvar cancers, cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VaIN).

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

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

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

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

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 109 countries

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

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.

Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2008, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

Prescribing Information and Patient Product Information for GARDASIL® are attached and is also available at www.gardasil.com.

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

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 (1) 9/2008

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, and vaginal 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

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. (11).

WARNINGS AND PRECAUTIONS

 

  • Women who receive GARDASIL should continue to undergo cervical cancer screening. (17.1)
  • GARDASIL has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity. (14.2)

     

  • GARDASIL is not intended to be used for treatment of active genital warts; cervical, vulvar, and vaginal cancers; CIN; VIN; or VaIN. (5.1)
  • GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. (14.3)
  • Not all vulvar and vaginal cancers are caused by HPV and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV 16 and 18.

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)

Syncope has been reported following vaccination with GARDASIL, sometimes resulting in falling with injury; observation for 15 minutes after administration is recommended. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact 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)

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 can monitor maternal and fetal outcomes (8.1).
  • Children below the age of 9 years and pediatric males of any age. (8.4)
  • Women 27 years of age and older. (14.4).

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

Revised: 12/2008

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

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 Limitations of GARDASIL Use and Effectiveness

5.2 Immunocompromised Individuals

5.3 Managing Allergic Reactions

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

7.1 Use with RECOMBIVAX HB

7.2 Use with Hormonal Contraceptives

7.3 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

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 Women 16 Through 26 Years of Age

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

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

14.4 Other Studies

14.5 Immunogenicity

14.6 Studies with RECOMBIVAX HB

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Information for the Patient, Parent, or Guardian

17.2 FDA-Approved Patient Labeling

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

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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, and vaginal 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

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 (14.5).]

2.2 Method of Administration

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.

Do not administer GARDASIL intravenously, intradermally, or subcutaneously.

Syncope has been reported following vaccination with GARDASIL and may result in falling with injury; observation for 15 minutes after administration is recommended.

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

[OBJECT 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 Limitations of GARDASIL Use and Effectiveness

The health care provider should inform the patient, parent, or guardian that vaccination does not substitute for routine cervical cancer screening. Women who receive GARDASIL should continue to undergo cervical cancer screening per standard of care.

GARDASIL has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity. [See Clinical Studies (14.2).]

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

GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. [See Clinical Studies (14.3).]

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

5.2 Immunocompromised Individuals

The immunologic response to GARDASIL may be diminished in immunocompromised individuals [See Drug Interactions (7.3)].

5.3 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 has been reported following vaccination with GARDASIL and may result in falling with injury; observation for 15 minutes after administration is recommended.

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 26 Years of Age

In 5 clinical trials (3 Amorphous Aluminum Hydroxyphosphate Sulfate [AAHS]-controlled, 1 saline placebo-controlled, and 1 uncontrolled), 8878 subjects 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 subjects. The subjects who were monitored using VRC-aided surveillance included 5088 girls and women 9 through 26 years of age at enrollment who received GARDASIL and 3790 girls and women who received AAHS control or saline placebo. Few subjects (0.1%) discontinued due to adverse reactions. The race distribution of the study subjects 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.

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

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

Table 1 Injection-Site Adverse Reactions*

 

 

Adverse Reaction

(1 to 5 Days Postvaccination)

 

  GARDASIL

(N = 5088)

%

 

  AAHS Control **

(N = 3470)

%

 

  Saline Placebo

(N = 320)

%

 

Injection Site

Pain

Swelling

Erythema

Pruritus

Bruising

 

  83.9

25.4

24.7

3.2

2.8

 

  75.4

15.8

18.4

2.8

3.2

 

  48.6

7.3

12.1

0.6

1.6

 

he 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 2. Overall, 94.3% of girls and women who received GARDASIL judged their injection-site adverse reaction to be mild or moderate in intensity.

Table 2 Postdose Evaluation of Injection-Site Adverse Reactions

(1 to 5 Days Postvaccination)

 

    GARDASIL (% occurrence)

 

  AAHS Control* (% occurrence)

 

  Saline Placebo (% occurrence)

 

Adverse Reaction

 

  Post- dose

1

N** = 5011

 

  Post- dose

2

N = 4924

 

  Post- dose

3

N = 4818

 

  Post- dose

1

N = 3410

 

  Post- dose

2

N = 3351

 

  Post- dose

3

N = 3295

 

  Post- dose

1

N = 315

 

  Post- dose

2

N = 301

 

  Post- dose

3

N = 300

 

Pain Mild/Moderate

Severe

 

  63.4 62.5

0.9

 

  60.7 59.7

1.0

 

  62.7 61.2

1.5

 

  57.0 56.6

0.4

 

  47.8 47.3

0.5

 

  49.6 48.9

0.6

 

  33.7 33.3

0.3

 

  20.3 20.3

0.0

 

  27.3 27.0

0.3

 

Swelling*** Mild/Moderate

Severe

 

  10.2 9.6

0.6

 

  12.8 11.9

0.8

 

  15.1 14.2

0.9

 

  8.2 8.1

0.2

 

  7.5 7.2

0.2

 

  7.6 7.3

0.2

 

  4.4 4.4

0.0

 

  3.0 3.0

0.0

 

  3.3 3.3

0.0

 

Erythema*** Mild/Moderate

Severe

 

  9.2 9.0

0.2

 

  12.1 11.7

0.3

 

  14.7 14.3

0.4

 

  9.8 9.5

0.3

 

  8.4 8.4

0.1

 

  8.9 8.8

0.1

 

  7.3 7.3

0.0

 

  5.3 5.3

0.0

 

  5.7 5.7

0.0

 

*AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

**N = Number of subjects 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 3.

Table 3

Common Systemic Adverse Reactions (GARDASIL ‰¥ Control)*

 

 

Adverse Reactions

(1 to 15 Days Postvaccination)

 

  GARDASIL (N = 5088)

%

 

  AAHS control** or Saline Placebo (N = 3790)

%

 

Pyrexia Nausea

Dizziness

Diarrhea

Vomiting

Cough

Toothache

Upper respiratory tract infection

Malaise

Arthralgia

Insomnia

Nasal congestion

 

  13.0 6.7

4.0

3.6

2.4

2.0

1.5

1.5

1.4

1.2

1.2

1.1

 

  11.2 6.5

3.7

3.5

1.9

1.5

1.4

1.5

1.2

0.9

0.9

0.9

 

 
he adverse reactions in this table are those that were observed among recipients of GARDASIL at a frequency of at least 1.0% and greater than or equal to those observed among AAHS control or saline placebo recipients. **AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

 

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

An analysis of fever in girls and women by dose is shown in Table 4.

Table 4

Postdose Evaluation of Fever

(1 to 5 Days Postvaccination)

 

    GARDASIL (% occurrence)

 

  AAHS Control* or Saline Placebo (% occurrence)

 

Temperature (°F)

 

 

  Postdose 1 N** = 4945

 

 

 

Postdose 2 N = 4804

 

  Postdose 3 N = 4671

 

  Postdose 1 N = 3681

 

  Postdose 2 N = 3564

 

  Postdose 3 N = 3467

 

(>=)100 to <102   3.7   4.1   4.4   3.1   3.8   3.6
(>=)102   0.3   0.5   0.5   0.2   0.4   0.5
*AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate **N = Number of subjects with follow up

 

Serious Adverse Reactions in the Entire Study Population

A total of 237 subjects out of 25,274 total subjects (9- through 45-year-old girls and women; and 9- through 15-year-old boys) who received both GARDASIL (N = 13,686) and AAHS control (N = 11,004) or saline placebo (N = 584) reported a serious systemic adverse reaction following any vaccination visit during the clinical trials for GARDASIL.

Out of the entire study population (25,274 subjects), only 0.05% of the reported serious systemic adverse reactions were judged to be vaccine related by the study investigator. The most frequently reported serious systemic adverse reactions for GARDASIL compared to AAHS control or saline placebo and 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 (4 cases) vs. 0.01% AAHS Control (1 case)],

Pelvic inflammatory disease [0.02% GARDASIL (3 cases) vs. 0.04% AAHS Control (4 cases)],

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

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

Pyelonephritis [0.02% GARDASIL (2 cases) vs. 0.03% AAHS Control (3 cases)],

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

One case (0.007% GARDASIL: 0.0% AAHS Control or Saline Placebo) of bronchospasm; and 2 cases (0.02% 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 subject 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, 24 deaths were reported in 25,274 (GARDASIL N = 13,686; AAHS Control N = 11,004, saline placebo N = 584) subjects (9- through 45-year-old girls and women; and 9- through 15-year-old boys). The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (4 subjects who received GARDASIL and 3 AAHS Control subjects), followed by overdose/suicide (2 subjects who received GARDASIL and 2 subjects who received AAHS Control), and pulmonary embolus/deep vein thrombosis (1 subject who received GARDASIL and 1 AAHS Control subject). 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, and 1 case of systemic lupus erythematosus in the group that received GARDASIL; 1 case of asphyxia, and 1 case of acute lymphocytic leukemia in the AAHS Control; 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 5. This population includes all subjects who received at least one dose of GARDASIL or AAHS control or saline placebo, and had safety data available.

Table 5 Summary of Girls and Women 9 Through 26 Years of Age Who Reported an Incident Condition Potentially Indicative of Systemic Autoimmune Disorder After Enrollment in Clinical Trials of GARDASIL Regardless of Causality

 

Conditions   GARDASIL (N = 10,706)

 

  AAHS Control* or Saline Placebo (N = 9412)

 

  n (%)   n (%)
Arthralgia/Arthritis/Arthropathy**

Autoimmune Thyroiditis

Coeliac Disease

Diabetes Mellitus Insulin-dependent

Erythema Nodosum

Hyperthyroidism***

Hypothyroidism 

Inflammatory Bowel Disease¡

Multiple Sclerosis

Nephritis

Optic Neuritis

Pigmentation Disorder§

Psoriasis#

Raynaud's Phenomenon

Rheumatoid Arthritis  

Scleroderma/Morphea

Stevens-Johnson Syndrome

Systemic Lupus Erythematosus

Uveitis

 

  120 (1.1) 4 (0.0)

10 (0.1)

2 (0.0)

2 (0.0)

27 (0.3)

35 (0.3)

7 (0.1)

2 (0.0)

2 (0.0)

2 (0.0)

4 (0.0)

13 (0.1)

3 (0.0)

6 (0.1)

2 (0.0)

1 (0.0)

1 (0.0)

3 (0.0)

 

  98 (1.0) 1 (0.0)

6 (0.1)

2 (0.0)

4 (0.0)

21 (0.2)

38 (0.4)

10 (0.1)

4 (0.0)

5 (0.1)

0 (0.0)

3 (0.0)

15 (0.2)

4 (0.0)

2 (0.0)

1 (0.0)

0 (0.0)

3 (0.0)

1 (0.0)

 

All Conditions   245 (2.3)  

Posted: May 2009

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