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Merck to Donate Three Million Doses of Gardasil(R), Its Cervical Cancer Vaccine, to Support Vaccination Programs in Lowest Income Nations

Posted on: Wednesday, 26 September 2007, 12:00 CDT

Merck & Co., Inc. today committed to donate at least three million doses of GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine], the cervical cancer vaccine, for use in demonstration projects in lowest income nations throughout the world. The program, part of Merck's comprehensive approach to bringing newer vaccines to the developing world, was announced today as Merck's commitment at the Clinton Global Initiative.

"By donating three million doses of GARDASIL over the next five years, we are committing to the vaccination of one million females against cervical cancer, a disease that takes the lives of nearly 250,000 women each year," said Margaret G. McGlynn, president, Merck Vaccines and Infectious Disease. "Our company is fully committed to making GARDASIL available to those who need it and we will continue to work with our partners in the international community to develop sustainable solutions to bring GARDASIL and other vaccines to the developing world." GARDASIL is proven to help protect against diseases that are caused by four types of the human papillomavirus: HPV types 16 and 18 which cause 70 percent of cervical cancer cases, and HPV types 6 and 11 which cause 90 percent of genital wart cases.

Merck is pursuing a systematic approach to the global introduction of two of its vaccines, ROTATEQ® (rotavirus vaccine, live, oral pentavalent) and GARDASIL, and is committed to making both vaccines available to developing world nations at dramatically lower prices at which Merck will not profit. Merck has made an important stride toward making ROTATEQ available in the developing world through its partnership with the Nicaraguan Ministry of Health which was announced at the Clinton Global Initiative in September 2006. This joint partnership marks the first time that a vaccine was introduced into a lowest income country in the same year it was approved by the U.S. Food and Drug Administration (FDA). Merck also continues to support GAVI initiatives designed to increase access to all vaccines, including rotavirus vaccines, in lowest income countries.

There are enormous challenges to achieving high immunization rates in developing world nations, and historically, there has been a significant delay between the introduction of new vaccines in developed countries and when they are widely available in developing countries.

"Much progress is being made to shorten the delay, but HPV vaccination in the developing world has not yet been prioritized by the international community," said Ciro de Quadros, president emeritus and director for international programs, Sabin Vaccine Institute. "The GARDASIL access program will empower resource-poor nations and their partners to develop programs to bring this critical vaccine to people in need."

To implement this program, Merck will establish a partnership with a non-governmental organization to establish formal criteria for the program and to review proposals from developing world nations working independently and/or with non-governmental organizations, governments, or international organizations. Merck will provide free doses of GARDASIL for use in these programs.

"This program is modeled on Merck's pioneering public-private partnerships that have brought Mectizan, our HIV medicines and ROTATEQ to the developing world," said Mark Feinberg, vice president, policy, public health and medical affairs, Merck Vaccines and Infectious Disease. "In just the first year of Merck's collaboration with the government of Nicaragua, we demonstrated that a developing nation can successfully introduce a new vaccine as quickly as developed nations. For GARDASIL, we know that this program is an interim step, and an important one that will create models of successful HPV vaccination in resource-poor countries." GARDASIL is indicated to help prevent cervical cancer, precancerous and low-grade cervical lesions, vulvar and vaginal precancers and genital warts caused by human papillomavirus (HPV) types 6, 11, 16 and 18.

Cervical cancer is the second most common cause of cancer death in women worldwide, resulting in nearly 500,000 diagnoses each year. Merck launched GARDASIL, the world's first cervical cancer vaccine, in the U.S. and other developed world nations in 2006. Since that time, GARDASIL has been approved in 85 nations, including 12 of the lowest income countries. Worldwide, Merck has distributed more than 10 million doses of GARDASIL as of June 30, 2007.

Select safety and additional information about GARDASIL

GARDASIL is contraindicated in individuals who are hypersensitive to the active substances or to any of the excipients of the vaccine.

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

Vaccination with GARDASIL may not result in protection in all vaccine recipients. GARDASIL is not intended to be used for treatment of active genital warts; cervical cancer; CIN, VIN, or VaIN. GARDASIL has not been shown to protect against disease due to other HPV types.

In clinical studies for GARDASIL, vaccine-related adverse experiences that were observed at a frequency of at least 1.0 percent among recipients of GARDASIL and also greater than those observed among recipients of placebo, respectively, were pain (83.9 percent vs. 75.4 percent), swelling (25.4 percent vs. 15.8 percent), erythema (24.6 percent vs. 18.4 percent), fever (10.3 percent vs. 8.6 percent), nausea (4.2 percent vs. 4.1 percent), pruritis (3.1 percent vs. 2.8 percent) and dizziness (2.8 percent vs. 2.6 percent).

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

Select safety and additional information about ROTATEQ

ROTATEQ should not be administered to infants with a demonstrated history of hypersensitivity to any component of the vaccine.

No safety or efficacy data are available for the administration of ROTATEQ to infants who are potentially immunocompromised, including those who have received blood products within 42 days of vaccination.

More than 71,000 infants were evaluated in three placebo-controlled clinical trials. Serious adverse events occurred in 2.4 percent of recipients of ROTATEQ when compared to 2.6 percent of placebo recipients within the 42-day period of a dose of ROTATEQ. Hematochezia, reported as a serious adverse event for ROTATEQ compared to placebo, was less than 0.1 percent vs. less than 0.1 percent. The most frequently reported serious adverse events for ROTATEQ compared to placebo were bronchiolitis (0.6 percent vs. 0.7 percent), gastroenteritis (0.2 percent vs. 0.3 percent), pneumonia (0.2 percent vs. 0.2 percent), fever (0.1 percent vs. 0.1 percent), and urinary tract infection (0.1 percent vs. 0.1 percent).

In a subset of more than 11,000 infants in these trials, the presence of adverse events was reported for 42 days after each dose. Fever was observed at similar rates in vaccine and placebo recipients (42.6 percent vs. 42.8 percent). Adverse events that occurred at a statistically higher incidence within 42 days of any dose among recipients of ROTATEQ as compared with placebo recipients were diarrhea (24.1 percent vs. 21.3 percent), vomiting (15.2 percent vs. 13.6 percent), otitis media (14.5 percent vs. 13.0 percent), nasopharyngitis (6.9 percent vs. 5.8 percent), and bronchospasm (1.1 percent vs. 0.7 percent).

In post-marketing experience, cases of intussusception have been reported in temporal association with ROTATEQ.

As with any vaccine, vaccination with ROTATEQ may not result in complete protection in all recipients.

The first dose of ROTATEQ should be administered between six and 12 weeks of age, with the subsequent doses administered at four- to 10-week intervals. The third dose should not be given after 32 weeks of age. ROTATEQ was approved by the FDA on February 3, 2006.

Through June 2007, Merck has distributed more than six million doses of ROTATEQ. ROTATEQ has been approved in more than 60 countries around the world.

Merck's Leadership in Bringing Vaccines to the Developing World

Through Merck's partnership with the Nicaraguan Ministry of Health, aimed at demonstrating the public health impact of a full rotavirus vaccination program, all infants born in Nicaragua in a three-year period will receive free doses of ROTATEQ. To date, more than 100,000 infants have been vaccinated with ROTATEQ in Nicaragua in the first year since this partnership was initiated. This program adds to the evidence base supporting the efforts of the global public health community to accelerate the introduction of routine rotavirus vaccination in resource-poor countries.

With regard to GARDASIL, Merck is providing vaccines and technical support at no cost to PATH to support demonstration studies in India, Peru and Vietnam. These studies are designed to accelerate the availability of cervical cancer vaccines to resource scarce areas. Merck is also working with India's Council of Medical Research to study GARDASIL in India. In addition, Merck has ongoing clinical trials in patient populations relevant to the developing world.

Other Information about GARDASIL

In 1995, Merck entered into a license agreement and research collaboration with CSL Limited of Australia relating to technology used in GARDASIL. GARDASIL also is the subject of other third-party licensing agreements.

About Merck

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

Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

GARDASIL is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, U.S.A.

ROTATEQ is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, U.S.A.

Prescribing information and patient product information for ROTATEQ® is attached and is also available at www.rotateq.com.

Prescribing information and patient product information for GARDASIL® is attached and is also available at www.gardasil.com.

RotaTeq(R) 9714304 (Rotavirus Vaccine, Live, Oral, Pentavalent)

DESCRIPTION

RotaTeq* is a live, oral pentavalent vaccine that contains 5 live reassortant rotaviruses. The rotavirus parent strains of the reassortants were isolated from human and bovine hosts. Four reassortant rotaviruses express one of the outer capsid proteins (G1, G2, G3, or G4) from the human rotavirus parent strain and the attachment protein (P7) from the bovine rotavirus parent strain. The fifth reassortant virus expresses the attachment protein, P1A (genotype P(8)), hereafter referred to as P1(8), from the human rotavirus parent strain and the outer capsid protein G6 from the bovine rotavirus parent strain (see Table 1).

Table 1 ---------------------------------------------------------------------- Reassortant Bovine Outer Rotavirus Surface Parent Protein Human Rotavirus Strain and Composition Minimum Dose Parent Strains Outer (Human Levels and Outer Surface Surface Rotavirus (10(6) Name of Protein Protein Component infectious Reassortant Compositions Composition in Bold) units) ---------------------------------------------------------------------- G1 WI79 - G1, P1(8) G1, P7(5) 2.2 ------------------------------- -------------------------- G2 SC2 - G2, P2(6) WC3 - G6, G2, P7(5) 2.8 ------------------------------- P7(5) -------------------------- G3 WI78 - G3, P1(8) G3, P7(5) 2.2 ------------------------------- -------------------------- G4 BrB - G4, P2(6) G4, P7(5) 2.0 ------------------------------- -------------------------- P1(8) WI79 - G1, P1(8) G6, P1(8) 2.3 ----------------------------------------------------------------------

The reassortants are propagated in Vero cells using standard cell culture techniques in the absence of antifungal agents.

The reassortants are suspended in a buffered stabilizer solution. Each vaccine dose contains sucrose, sodium citrate, sodium phosphate monobasic monohydrate, sodium hydroxide, polysorbate 80, cell culture media, and trace amounts of fetal bovine serum. RotaTeq contains no preservatives.

RotaTeq is a pale yellow clear liquid that may have a pink tint.

CLINICAL PHARMACOLOGY

Rotavirus is a leading cause of severe acute gastroenteritis in infants and young children, with over 95% of these children infected by the time they are 5 years old.(1) The most severe cases occur among infants and young children between 6 months and 24 months of age.(2)

Mechanism of Action

The exact immunologic mechanism by which RotaTeq protects against rotavirus gastroenteritis is unknown (see CLINICAL STUDIES, Immunogenicity). RotaTeq is a live viral vaccine that replicates in the small intestine and induces immunity.

CLINICAL STUDIES

Overall, 72,324 infants were randomized in 3 placebo-controlled, phase 3 studies conducted in 11 countries on 3 continents. The data demonstrating the efficacy of RotaTeq in preventing rotavirus gastroenteritis come from 6,983 of these infants from the US (including Navajo and White Mountain Apache Nations) and Finland who were enrolled in 2 of these studies: the Rotavirus Efficacy and Safety Trial (REST) and Study 007. The third trial, Study 009, provided clinical evidence supporting the consistency of manufacture and contributed data to the overall safety evaluation.

The racial distribution of the efficacy subset was as follows: White (RotaTeq 68%, placebo 69%); Hispanic-American (RotaTeq 10%, placebo 9%); Black (2% in both groups); Multiracial (RotaTeq 4%, placebo 5%); Asian (less than 1% in both groups); Native American (RotaTeq 15%, placebo 14%), and Other (less than 1% in both groups). The gender distribution was 52% male and 48% female in both vaccination groups.

The efficacy evaluations in these studies included: 1) Prevention of any grade of severity of rotavirus gastroenteritis; 2) Prevention of severe rotavirus gastroenteritis, as defined by a clinical scoring system; and 3) Reduction in hospitalizations due to rotavirus gastroenteritis.

The vaccine was given as a three-dose series to healthy infants with the first dose administered between 6 and 12 weeks of age and followed by two additional doses administered at 4- to 10-week intervals. The age of infants receiving the third dose was 32 weeks of age or less. Oral polio vaccine administration was not permitted; however, other childhood vaccines could be concomitantly administered. Breast-feeding was permitted in all studies.

The case definition for rotavirus gastroenteritis used to determine vaccine efficacy required that a subject meet both of the following clinical and laboratory criteria: (1) greater than or equal to 3 watery or looser-than-normal stools within a 24-hour period and/or forceful vomiting; and (2) rotavirus antigen detection by enzyme immunoassay (EIA) in a stool specimen taken within 14 days of onset of symptoms. The severity of rotavirus acute gastroenteritis was determined by a clinical scoring system that took into account the intensity and duration of symptoms of fever, vomiting, diarrhea, and behavioral changes.

The primary efficacy analyses included cases of rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 that occurred at least 14 days after the third dose through the first rotavirus season postvaccination.

Analyses were also done to evaluate the efficacy of RotaTeq against rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 at any time following the first dose through the first rotavirus season postvaccination among infants who received at least one vaccination (Intent-to-treat, ITT).

Rotavirus Efficacy and Safety Trial

Primary efficacy against any grade of severity of rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 74.0% (95% CI: 66.8, 79.9) and the ITT efficacy was 60.0% (95% CI: 51.5, 67.1). Primary efficacy against severe rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 98.0% (95% CI: 88.3, 100.0), and ITT efficacy was 96.4%, (95% CI: 86.2, 99.6). See Table 2.

Table 2 Efficacy of RotaTeq against any grade of severity of and severe* G1-4 rotavirus gastroenteritis through the first rotavirus season postvaccination in REST ---------------------------------------------------------------------- Per Protocol Intent-to-Treat+ RotaTeq Placebo RotaTeq Placebo ---------------------------------------------------------------------- Subjects vaccinated 2,834 2,839 2,834 2,839 Gastroenteritis cases Any grade of severity 82 315 150 371 Severe* 1 51 2 55 ---------------------------------------------------------------------- Efficacy estimate % and (95% confidence interval) ---------------------------------------------------------------------- Any grade of severity 74.0 60.0 (66.8, 79.9) (51.5, 67.1) Severe* 98.0 96.4 (88.3, 100.0) (86.2, 99.6) ---------------------------------------------------------------------- *Severe gastroenteritis defined by a clinical scoring system based on the intensity and duration of symptoms of fever, vomiting, diarrhea, and behavioral changes +ITT analysis includes all subjects in the efficacy cohort who received at least one dose of vaccine.

The efficacy of RotaTeq against severe disease was also demonstrated by a reduction in hospitalizations for rotavirus gastroenteritis among all subjects enrolled in REST. RotaTeq reduced hospitalizations for rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 through the first two years after the third dose by 95.8% (95% CI: 90.5, 98.2). The ITT efficacy in reducing hospitalizations was 94.7% (95% CI: 89.3, 97.3) as shown in Table 3.

Table 3 Efficacy of RotaTeq in reducing G1-4 rotavirus-related hospitalizations in REST ---------------------------------------------------------------------- Per Protocol Intent-to-Treat* RotaTeq Placebo RotaTeq Placebo ---------------------------------------------------------------------- Subjects vaccinated 34,035 34,003 34,035 34,003 Number of hospitalizations 6 144 10 187 ---------------------------------------------------------------------- Efficacy estimate % and 95.8 94.7 (95% confidence interval) (90.5, 98.2) (89.3, 97.3) ---------------------------------------------------------------------- *ITT analysis includes all subjects who received at least one dose of vaccine.

Study 007

Primary efficacy against any grade of severity of rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 72.5% (95% CI: 50.6, 85.6) and the ITT efficacy was 58.4% (95% CI: 33.8, 74.5). Primary efficacy against severe rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 100% (95% CI: 13.0, 100.0) and ITT efficacy against severe rotavirus disease was 100%, (95% CI: 30.2, 100.0) as shown in Table 4.

Table 4 Efficacy of RotaTeq against any grade of severity of and severe* G1-4 rotavirus gastroenteritis through the first rotavirus season postvaccination in Study 007 ---------------------------------------------------------------------- Per Protocol Intent-to-Treat+ RotaTeq Placebo RotaTeq Placebo ---------------------------------------------------------------------- Subjects vaccinated 650 660 650 660 Gastroenteritis cases Any grade of severity 15 54 27 64 Severe* 0 6 0 7 ---------------------------------------------------------------------- Efficacy estimate % and (95% confidence interval) ---------------------------------------------------------------------- Any grade of severity 72.5 58.4 (50.6, 85.6) (33.8, 74.5) Severe* 100.0 100.0 (13.0, 100.0) (30.2, 100.0) ---------------------------------------------------------------------- *Severe gastroenteritis defined by a clinical scoring system bas ed on the intensity and duration of symptoms of fever, vomiting, diarrhea, and behavioral change +ITT analysis includes all subjects in the efficacy cohort who received at least one dose of vaccine.

Multiple Rotavirus Seasons

The efficacy of RotaTeq through a second rotavirus season was evaluated in a single study (REST). Efficacy against any grade of severity of rotavirus gastroenteritis caused by rotavirus serotypes G1, G2, G3, and G4 through the two rotavirus seasons after vaccination was 71.3% (95% CI: 64.7, 76.9). The efficacy of RotaTeq in preventing cases occurring only during the second rotavirus season postvaccination was 62.6% (95% CI: 44.3, 75.4). The efficacy of RotaTeq beyond the second season postvaccination was not evaluated.

Rotavirus Gastroenteritis Regardless of Serotype

The rotavirus serotypes identified in the efficacy subset of REST and Study 007 were G1, P1(8); G2, P1(4); G3, P1(8); G4, P1(8); and G9, P1(8).

In REST, the efficacy of RotaTeq against any grade of severity of naturally occurring rotavirus gastroenteritis regardless of serotype was 71.8% (95% CI: 64.5, 77.8) and efficacy against severe rotavirus disease was 98.0% (95% CI: 88.3, 99.9). The ITT efficacy starting at dose 1 was 50.9% (95% CI: 41.6, 58.9) for any grade of severity of rotavirus disease and was 96.4% (95% CI: 86.3, 99.6) for severe rotavirus disease.

In Study 007, the primary efficacy of RotaTeq against any grade of severity of rotavirus gastroenteritis regardless of serotype was 72.7% (95% CI: 51.9, 85.4) and efficacy against severe rotavirus disease was 100% (95% CI: 12.7, 100). The ITT efficacy starting at dose 1 was 48.0% (95% CI: 21.6, 66.1) for any grade of severity of rotavirus disease and was 100% (95% CI: 30.4, 100.0) for severe rotavirus disease.

Rotavirus Gastroenteritis By Serotype

The efficacy against any grade of severity of rotavirus gastroenteritis by serotype in REST is shown in Table 5.

Table 5 Serotype-specific efficacy of RotaTeq against any grade of severity of rotavirus gastroenteritis among infants in REST through the first rotavirus season postvaccination (Per Protocol) ---------------------------------------------------------------------- Number of cases % Efficacy RotaTeq Placebo (95% Confidence Serotype identified by PCR (N=2,834) (N=2,839) Interval) ---------------------------------------------------------------------- Serotypes present in RotaTeq ---------------------------------------------------------------------- G1, P1(8) 72 286 74.9 (67.3, 80.9) ---------------------------------------------------------------------- G2, P1(4) 6 17 63.4 (2.6, 88.2) ---------------------------------------------------------------------- G3, P1(8) 1 6 NS ---------------------------------------------------------------------- G4, P1(8) 3 6 NS ---------------------------------------------------------------------- Serotypes not present in RotaTeq ---------------------------------------------------------------------- G9, P1(8) 1 3 NS ---------------------------------------------------------------------- Unidentified* 11 15 NS ---------------------------------------------------------------------- N=number vaccinated NS=not significant ---------------------------------------------------------------------- *Includes rotavirus antigen-positive samples in which the specific serotype could not be identified by PCR

Immunogenicity

A relationship between antibody responses to RotaTeq and protection against rotavirus gastroenteritis has not been established. In phase 3 studies, 92.9% to 100% of 439 recipients of RotaTeq achieved a 3-fold or more rise in serum anti-rotavirus IgA after a three-dose regimen when compared to 12.3%-20.0% of 397 placebo recipients.

INDICATIONS AND USAGE

RotaTeq is indicated for the prevention of rotavirus gastroenteritis in infants and children caused by the serotypes G1, G2, G3, and G4 when administered as a 3-dose series to infants between the ages of 6 to 32 weeks. The first dose of RotaTeq should be administered between 6 and 12 weeks of age (see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

A demonstrated history of hypersensitivity to any component of the vaccine.

Infants who develop symptoms suggestive of hypersensitivity after receiving a dose of RotaTeq should not receive further doses of RotaTeq.

PRECAUTIONS

General

Prior to administration of RotaTeq, the health care provider should determine the current health status and previous vaccination history of the infant, including whether there has been a reaction to a previous dose of RotaTeq or other rotavirus vaccine.

Febrile illness may be reason for delaying use of RotaTeq except when, in the opinion of the physician, withholding the vaccine entails a greater risk. Low-grade fever (less than 100.5 degrees F (38.1 degrees C)) itself and mild upper respiratory infection do not preclude vaccination with RotaTeq.

The level of protection provided by only one or two doses of RotaTeq was not studied in clinical trials.

As with any vaccine, vaccination with RotaTeq may not result in complete protection in all recipients.

Regarding post-exposure prophylaxis, no clinical data are available for RotaTeq when administered after exposure to rotavirus.

Intussusception

Following administration of a previously licensed live rhesus rotavirus-based vaccine, an increased risk of intussusception was observed.(3) In REST (n=69,625), the data did not show an increased risk of intussusception for RotaTeq when compared to placebo.

In post-marketing experience, cases of intussusception have been reported in temporal association with RotaTeq. See ADVERSE REACTIONS, Intussusception and Post-marketing Reports.

Immunocompromised Populations

No safety or efficacy data are available for the administration of RotaTeq to infants who are potentially immunocompromised including:

-- Infants with blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system.

-- Infants on immunosuppressive therapy (including high-dose systemic corticosteroids). RotaTeq may be administered to infants who are being treated with topical corticosteroids or inhaled steroids.

-- Infants with primary and acquired immunodeficiency states, including HIV/AIDS or other clinical manifestations of infection with human immunodeficiency viruses; cellular immune deficiencies; and hypogammaglobulinemic and dysgammaglobulinemic states. There are insufficient data from the clinical trials to support administration of RotaTeq to infants with indeterminate HIV status who are born to mothers with HIV/AIDS.

-- Infants who have received a blood transfusion or blood products, including immunoglobulins within 42 days.

No safety or efficacy data are available for administration of RotaTeq to infants with a history of gastrointestinal disorders including infants with active acute gastrointestinal illness, infants with chronic diarrhea and failure to thrive, and infants with a history of congenital abdominal disorders, abdominal surgery, and intussusception. Therefore, caution is advised when considering administration of RotaTeq to these infants.

Shedding and Transmission

Shedding was evaluated among a subset of subjects in REST 4 to 6 days after each dose and among all subjects who submitted a stool antigen rotavirus positive sample at any time. RotaTeq was shed in the stools of 32 of 360 (8.9%, 95% CI (6.2%, 12.3%)) vaccine recipients tested after dose 1; 0 of 249 (0.0%, 95% CI (0.0%, 1.5%)) vaccine recipients tested after dose 2; and in 1 of 385 (0.3%, 95% CI (less than 0.1%, 1.4%)) vaccine recipients after dose 3. In phase 3 studies, shedding was observed as early as 1 day and as late as 15 days after a dose. Transmission was not evaluated.

Caution is advised when considering whether to administer RotaTeq to individuals with immunodeficient close contacts such as:

-- Individuals with malignancies or who are otherwise immunocompromised; or

-- Individuals receiving immunosuppressive therapy.

There is a theoretical risk that the live virus vaccine can be transmitted to non-vaccinated contacts. The potential risk of transmission of vaccine virus should be weighed against the risk of acquiring and transmitting natural rotavirus.

Information for Parents/Guardians

Parents or guardians should be given a copy of the required vaccine information and be given the "Patient Information" appended to this insert. Parents and/or guardians should be encouraged to read the patient information that describes the benefits and risks associated with the vaccine and ask any questions they may have during the visit. See PRECAUTIONS and Patient Information.

Drug Interactions

Immunosuppressive therapies including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to vaccines.

For administration of RotaTeq with other vaccines, see DOSAGE AND ADMINISTRATION, Use with Other Vaccines.

Carcinogenesis, Mutagenesis, Impairment of Fertility

RotaTeq has not been evaluated for its carcinogenic or mutagenic potential or its potential to impair fertility.

Pediatric Use

Safety and efficacy have not been established in infants less than 6 weeks of age or greater than 32 weeks of age.

Data are available from clinical studies to support the use of RotaTeq in pre-term infants according to their age in weeks since birth (see ADVERSE REACTIONS, Safety in Pre-Term Infants).

Data are available from clinical studies to support the use of RotaTeq in infants with controlled gastroesophageal reflux disease.

ADVERSE REACTIONS

71,725 infants were evaluated in 3 placebo-controlled clinical trials including 36,165 infants in the group that received RotaTeq and 35,560 infants in the group that received placebo. Parents/guardians were contacted on days 7, 14, and 42 after each dose regarding intussusception and any other serious adverse events. The racial distribution was as follows: White (69% in both groups); Hispanic-American (14% in both groups); Black (8% in both groups); Multiracial (5% in both groups); Asian (2% in both groups); Native American (RotaTeq 2%, placebo 1%), and Other (less than 1% in both groups). The gender distribution was 51% male and 49% female in both vaccination groups.

Because clinical trials are conducted under conditions that may not be typical of those observed in clinical practice, the adverse reaction rates presented below may not be reflective of those observed in clinical practice.

Serious Adverse Events

Serious adverse events occurred in 2.4% of recipients of RotaTeq when compared to 2.6% of placebo recipients within the 42-day period of a dose in the phase 3 clinical studies of RotaTeq. The most frequently reported serious adverse events for RotaTeq compared to placebo were:

bronchiolitis (0.6% RotaTeq vs. 0.7% Placebo), gastroenteritis (0.2% RotaTeq vs. 0.3% Placebo), pneumonia (0.2% RotaTeq vs. 0.2% Placebo), fever (0.1% RotaTeq vs. 0.1% Placebo), and urinary tract infection (0.1% RotaTeq vs. 0.1% Placebo).

Deaths

Across the clinical studies, 52 deaths were reported. There were 25 deaths in the RotaTeq recipients compared to 27 deaths in the placebo recipients. The most commonly reported cause of death was sudden infant death syndrome, which was observed in 8 recipients of RotaTeq and 9 placebo recipients.

Intussusception

In REST, 34,837 vaccine recipients and 34,788 placebo recipients were monitored by active surveillance to identify potential cases of intussusception at 7, 14, and 42 days after each dose, and every 6 weeks thereafter for 1 year after the first dose.

For the primary safety outcome, cases of intussusception occurring within 42 days of any dose, there were 6 cases among RotaTeq recipients and 5 cases among placebo recipients (see Table 6). The data did not suggest an increased risk of intussusception relative to placebo.

Table 6 Confirmed cases of intussusception in recipients of RotaTeq as compared with placebo recipients during REST ---------------------------------------------------------------------- RotaTeq Placebo (n=34,837) (n=34,788) ---------------------------------------------------------------------- Confirmed intussusception cases within 42 days of any dose 6 5 Relative risk (95% CI)+ 1.6 (0.4, 6.4) ---------------------------------------------------------------------- Confirmed intussusception cases within 365 days of dose 1 13 15 Relative risk (95% CI) 0.9 (0.4, 1.9) ---------------------------------------------------------------------- + Relative risk and 95% confidence interval based upon group sequential design stopping criteria employed in REST.

Among vaccine recipients, there were no confirmed cases of intussusception within the 42-day period after the first dose, which was the period of highest risk for the rhesus rotavirus-based product (see Table 7).

Table 7 Intussusception cases by day range in relation to dose in REST ---------------------------------------------------------------------- Dose 1 Dose 2 Dose 3 Any Dose ---------------------------------------------------------------------- Day Range RotaTeq Placebo RotaTeq Placebo RotaTeq Placebo RotaTeq Placebo ---------------------------------------------------------------------- 1-7 0 0 1 0 0 0 1 0 ---------------------------------------------------------------------- 1-14 0 0 1 0 0 1 1 1 ---------------------------------------------------------------------- 1-21 0 0 3 0 0 1 3 1 ---------------------------------------------------------------------- 1-42 0 1 4 1 2 3 6 5 ----------------------------------------------------------------------

All of the children who developed intussusception recovered without sequelae with the exception of a 9-month-old male who developed intussusception 98 days after dose 3 and died of post-operative sepsis. There was a single case of intussusception among 2,470 recipients of RotaTeq in a 7-month-old male in the phase 1 and 2 studies (716 placebo recipients).

Hematochezia

Hematochezia reported as an adverse experience occurred in 0.6% (39/6,130) of vaccine and 0.6% (34/5,560) of placebo recipients within 42 days of any dose. Hematochezia reported as a serious adverse experience occurred in less than 0.1% (4/36,150) of vaccine and less than 0.1% (7/35,536) of placebo recipients within 42 days of any dose.

Seizures

All seizures reported in the phase 3 trials of RotaTeq (by vaccination group and interval after dose) are shown in Table 8.

Table 8 Seizures reported by day range in relation to any dose in the phase 3 trials of RotaTeq ---------------------------------------------------------------------- Day range 1-7 1-14 1-42 ---------------------------------------------------------------------- RotaTeq 10 15 33 ---------------------------------------------------------------------- Placebo 5 8 24 ----------------------------------------------------------------------

Seizures reported as serious adverse experiences occurred in less than 0.1% (27/36,150) of vaccine and less than 0.1% (18/35,536) of placebo recipients (not significant). Ten febrile seizures were reported as serious adverse experiences, 5 were observed in vaccine recipients and 5 in placebo recipients.

Kawasaki Disease

In the phase 3 clinical trials, infants were followed for up to 42 days of vaccine dose. Kawasaki disease was reported in 5 of 36,150 vaccine recipients and in 1 of 35,536 placebo recipients with unadjusted relative risk 4.9 (95% CI 0.6, 239.1).

Most Common Adverse Events

Solicited Adverse Events

Detailed safety information was collected from 11,711 infants (6,138 recipients of RotaTeq) which included a subset of subjects in REST and all subjects from Studies 007 and 009 (Detailed Safety Cohort). A Vaccination Report Card was used by parents/guardians to record the child's temperature and any episodes of diarrhea and vomiting on a daily basis during the first week following each vaccination. Table 9 summarizes the frequencies of these adverse events and irritability.

Table 9 Solicited adverse experiences within the first week after doses 1, 2, and 3 (Detailed Safety Cohort) ---------------------------------------------------------------------- Adverse experience Dose 1 Dose 2 Dose 3 RotaTeq Placebo RotaTeq Placebo RotaTeq Placebo ---------------------------------------------------------------------- Elevated n=5,616 n=5,077 n=5,215 n=4,725 n=4,865 n=4,382 temperature* 17.1% 16.2% 20.0% 19.4% 18.2% 17.6% ---------------------------------------------------------------------- n=6,130 n=5,560 n=5,703 n=5,173 n=5,496 n=4,989 Vomiting 6.7% 5.4% 5.0% 4.4% 3.6% 3.2%

Diarrhea 10.4% 9.1% 8.6% 6.4% 6.1% 5.4%

Irritability 7.1% 7.1% 6.0% 6.5% 4.3% 4.5% ---------------------------------------------------------------------- * Temperature (greater than =)100.5 degrees F (38.1 degrees C) rectal equivalent obtained by adding 1 degree F to otic and oral temperatures and 2 degrees F to axillary temperatures

Other Adverse Events

Parents/guardians of the 11,711 infants were also asked to report the presence of other events on the Vaccination Report Card for 42 days after each dose.

Fever was observed at similar rates in vaccine (N=6,138) and placebo (N=5,573) recipients (42.6% vs. 42.8%). Adverse events that occurred at a statistically higher incidence (i.e., 2-sided p-value less than 0.05) within the 42 days of any dose among recipients of RotaTeq as compared with placebo recipients are shown in Table 10.

Table 10 ---------------------------------------------------------------------- Adverse events that occurred at a statistically higher incidence within 42 days of any dose among recipients of RotaTeq as compared with placebo recipients ---------------------------------------------------------------------- RotaTeq Placebo Adverse event N=6,138 N=5,573 ---------------------------------------------------------------------- n (%) n (%) ---------------------------------------------------------------------- Diarrhea 1,479 (24.1%) 1,186 (21.3%) Vomiting 929 (15.2%) 758 (13.6%) Otitis media 887 (14.5%) 724 (13.0%) Nasopharyngitis 422 (6.9%) 325 (5.8%) Bronchospasm 66 (1.1%) 40 (0.7%) ----------------------------------------------------------------------

Safety in Pre-Term Infants

RotaTeq or placebo was administered to 2,070 pre-term infants (25 to 36 weeks gestational age, median 34 weeks) according to their age in weeks since birth in REST. All pre-term infants were followed for serious adverse experiences; a subset of 308 infants was monitored for all adverse experiences. There were 4 deaths throughout the study, 2 among vaccine recipients (1 SIDS and 1 motor vehicle accident) and 2 among placebo recipients (1 SIDS and 1 unknown cause). No cases of intussusception were reported. Serious adverse experiences occurred in 5.5% of vaccine and 5.8% of placebo recipients. The most common serious adverse experience was bronchiolitis, which occurred in 1.4% of vaccine and 2.0% of placebo recipients. Parents/guardians were asked to record the child's temperature and any episodes of vomiting and diarrhea daily for the first week following vaccination. The frequencies of these adverse experiences and irritability within the week after dose 1 are summarized in Table 11.

Table 11 Solicited adverse experiences within the first week of doses 1, 2, and 3 among pre-term infants ---------------------------------------------------------------------- Dose 1 Dose 2 Dose 3 Adverse event RotaTeq Placebo RotaTeq Placebo RotaTeq Placebo ---------------------------------------------------------------------- N=127 N=133 N=124 N=121 N=115 N=108 Elevated temperature* 18.1% 17.3% 25.0% 28.1% 14.8% 20.4% ---------------------------------------------------------------------- N=154 N=154 N=137 N=137 N=135 N=129 Vomiting 5.8% 7.8% 2.9% 2.2% 4.4% 4.7%

Diarrhea 6.5% 5.8% 7.3% 7.3% 3.7% 3.9%

Irritability 3.9% 5.2% 2.9% 4.4% 8.1% 5.4% ---------------------------------------------------------------------- * Temperature =greater than 100.5 degrees F (38.1 degrees C) rectal equivalent obtained by adding 1 degree F to otic and oral temperatures and 2 degrees F to axillary temperatures

Post-marketing Reports

The following adverse events have been identified during post-approval use of RotaTeq from reports to the Vaccine Adverse Event Reporting System (VAERS).

Reporting of adverse events following immunization to VAERS is voluntary, and the number of doses of vaccine administered is not known; therefore, it is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to vaccine exposure using VAERS data.

In post-marketing experience, the following adverse events have been reported in infants who have received RotaTeq:

Gastrointestinal disorders:

Intussusception

Hematochezia

Skin and subcutaneous tissue disorders:

Urticaria

Infections and infestations

Kawasaki disease

Reporting Adverse Events

Parents or guardians should be instructed to report any adverse events to their health care provider.

Health care providers should report all adverse events to the U.S. Department of Health and Human Services' Vaccine Adverse Events Reporting System (VAERS).

VAERS accepts all reports of suspected adverse events after the administration of any vaccine, including but not limited to the reporting of events required by the National Childhood Vaccine Injury Act of 1986. For information or a copy of the vaccine reporting form, call the VAERS toll-free number at 1-800-822-7967 or report on line to www.vaers.hhs.gov.(4)

DOSAGE AND ADMINISTRATION

FOR ORAL USE ONLY. NOT FOR INJECTION.

The vaccination series consists of three ready-to-use liquid doses of RotaTeq administered orally starting at 6 to 12 weeks of age, with the subsequent doses administered at 4- to 10-week intervals. The third dose should not be given after 32 weeks of age (see CLINICAL STUDIES).

There are no restrictions on the infant's consumption of food or liquid, including breast milk, either before or after vaccination with RotaTeq.

Do not mix the RotaTeq vaccine with any other vaccines or solutions. Do not reconstitute or dilute (see INSTRUCTIONS FOR USE).

Each dose is supplied in a container consisting of a squeezable plastic, latex-free dosing tube with a twist-off cap, allowing for direct oral administration. The dosing tube is contained in a pouch (see INSTRUCTIONS FOR USE).

Use with Other Vaccines

In clinical trials, RotaTeq was routinely administered concomitantly with diphtheria and tetanus toxoids and acellular pertussis (DTaP), inactivated poliovirus vaccine (IPV), H. influenzae type b conjugate vaccine (Hib), hepatitis B vaccine, and pneumococcal conjugate vaccine (see CLINICAL STUDIES). The safety data available are in the ADVERSE REACTIONS section.

There was no evidence for reduced antibody responses to the diphtheria or tetanus toxoid components of DTaP or to the other vaccines that were concomitantly administered with RotaTeq. However, insufficient immunogenicity data are available to confirm lack of interference of immune responses when RotaTeq is concomitantly administered with childhood vaccines to prevent pertussis.

INSTRUCTIONS FOR USE

To administer the vaccine:

Tear open the pouch and remove the dosing tube.

Clear the fluid from the dispensing tip by holding tube vertically and tapping cap.

Open the dosing tube in 2 easy motions:

1. Puncture the dispensing tip by screwing cap clockwise until it becomes tight.

2. Remove cap by turning it counterclockwise.

Administer dose by gently squeezing liquid into infant's mouth toward the inner cheek until dosing tube is empty. (A residual drop may remain in the tip of the tube.)

If for any reason an incomplete dose is administered (e.g., infant spits or regurgitates the vaccine), a replacement dose is not recommended, since such dosing was not studied in the clinical trials. The infant should continue to receive any remaining doses in the recommended series.

Discard the empty tube and cap in approved biological waste containers according to local regulations.

HOW SUPPLIED

No. 4047 - RotaTeq, 2 mL, a suspension for oral use, is a pale yellow clear liquid that may have a pink tint. It is supplied as follows:

NDC 0006-4047-31 package of 1 individually pouched single-dose tube

NDC 0006-4047-41 package of 10 individually pouched single-dose tubes.

Storage

Store and transport refrigerated at 2-8 degrees C (36-46 degrees F). RotaTeq should be administered as soon as possible after being removed from refrigeration. For information regarding stability under conditions other than those recommended, call 1-800-MERCK-90.

Protect from light.

RotaTeq should be discarded in approved biological waste containers according to local regulations.

The product must be used before the expiration date.

REFERENCES

1. Parashar UD et al. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003;9(5):565-572.

2. Parashar UD, Holman RC, Clarke MJ, Bresee JS, Glass RI. Hospitalizations associated with rotavirus diarrhea in the United States, 1993 through 1995: surveillance based on the new ICD-9-CM rotavirus-specific diagnostic code. J Infect Dis 1998;177:13-7.

3. Murphy TV, Gargiullo PM, Massoudi MS et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001;344:564-572.

4. Centers for Disease Control and Prevention. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR 2002;51(RR-2):1-35.

Issued June 2007

Printed in USA

* Registered trademark of MERCK & CO., Inc., Whitehouse Station, NJ, 08889 USA COPYRIGHT (C) 2006, 2007 MERCK & CO., Inc. All rights reserved 9714304 Patient Information RotaTeq(R)** (pronounced "RO-tuh-tek") rotavirus vaccine, live, oral, pentavalent

You should read this information before your child receives the RotaTeq vaccine and ask your child's doctor any questions you may have. Your child will need 3 doses of the vaccine over the course of a few months. So read the leaflet before your child receives each dose of the vaccine in case any of the information about the vaccine changes. This leaflet is a summary of certain information about the vaccine. If you would like additional information, your health care provider can give you more complete information about this vaccine that is written for health care professionals. This leaflet does not take the place of talking with your child's doctor.

What is RotaTeq and How Does it Work?

RotaTeq is a vaccine that can help protect your child from getting a virus infection that can cause fever, vomiting, and diarrhea. The vaccine is given by mouth at 3 different times, each about one to two months apart. Nearly all children become infected with the rotavirus by the time they are 5 years old.

RotaTeq helps protect against diarrhea and vomiting only if they are caused by the rotavirus. It does not protect against diarrhea and vomiting that are caused by anything else.

RotaTeq may not fully protect all children that get the vaccine, and if your child already has the virus it will not help them.

What are the Symptoms of a Rotavirus Infection?

Infection with the Rotavirus is the most common cause of severe diarrhea in infants. Sometimes the diarrhea and vomiting can be severe and lead to the loss of body fluids (dehydration) and even to death.

Signs that your infant is dehydrated include:

-- Sleepiness

-- Dry mouth and tongue

-- Fussiness

-- Dry diaper for several hours

If your infant shows signs that they are dehydrated, you should call the doctor immediately.

What should I tell the doctor before my child gets RotaTeq?

There are some things your doctor should know before your child gets the vaccine. You should tell your doctor if your child:

-- Has any illness with fever. A mild fever or cold by itself is not a reason to delay taking the vaccination.

-- Has diarrhea or has been vomiting.

-- Has not been gaining weight.

-- Is not growing as expected.

-- Has a blood disorder.

-- Has any type of cancer.

-- Has a weak immune system because of a disease (this includes HIV/AIDS).

-- Gets treatment or takes medicines that may weaken the immune system (such as high doses of steroids) or has received a blood transfusion or blood products within the past 42 days.

-- Was born with gastrointestinal problems, or has had a blockage or abdominal surgery.

-- Has regular close contact with a member of the family or household who has a weakened immune system. For example, a person in the house with cancer or one who is taking medicines that may weaken their immune system.

Who should not receive RotaTeq?

Your child should not get the vaccine if:

-- He or she had an allergic reaction after getting a dose of this vaccine.

-- He or she is allergic to any of the ingredients of the vaccine. A list of ingredients can be found at the end of this leaflet.

What important information should I know about RotaTeq?

Intussusception is a serious and life-threatening event that occurs when a part of the intestine (the tube that goes from the stomach to the anus) gets blocked or twisted. Cases of intussusception can occur when no vaccine has been given and the cause is usually unknown. However, a different rotavirus vaccine was associated with intussusception and is no longer available.

In clinical trials, RotaTeq was studied in 70,000 infants (35,000 infants received RotaTeq and 35,000 received placebo), and no increased risk of intussusception was found. However, since RotaTeq has been on the market, cases of intussusception in infants who received RotaTeq have been reported to the Vaccine Adverse Event Reporting System (VAERS). Intussusception occurred at various times after vaccination with RotaTeq. Some of these infants required hospitalization and surgery on their intestine or a special enema to treat this problem.

Call your child's doctor right away if your child has vomiting, diarrhea, severe stomach pain, blood in their stool or change in their bowel movements as these may be signs of intussusception. It is important to contact your doctor if you have questions or if your child has any of these symptoms, at any time after vaccination, even if it has been several weeks since the last vaccine dose.

What are the possible side effects of RotaTeq?

The most common side effects reported after taking RotaTeq were diarrhea, vomiting, fever, runny nose and sore throat, wheezing or coughing, and ear infection.

Other reported side effects include hives.

These are NOT all the possible side effects of RotaTeq. You can ask your doctor or health care provider for a more complete list.

If your child seems to be having any side effects that are not mentioned in this leaflet, please call your doctor or other health care provider. If the condition continues or worsens, you should seek medical attention.

You, as a parent or guardian, may also report any adverse reactions to your child's health care provider or directly to the Vaccine Adverse Event Reporting System (VAERS). The VAERS toll-free number is 1-800-822-7967 or report online to www.vaers.hhs.gov.

Can RotaTeq be given with other vaccines?

Your child may get RotaTeq at the same time as other childhood vaccines.

How is RotaTeq given?

The vaccine is given by mouth. Your child will receive 3 doses of the vaccine. The first dose is given when your child is 6 to 12 weeks of age, the second dose is given 4 to 10 weeks later and the third dose is given 4 to 10 weeks after the second dose. The last (third) dose should be given to your child by 32 weeks of age.

Your health care provider will gently squeeze the vaccine into your child's mouth (see Figure 1). Your infant may spit out some or all of it. If this happens, the dose does not need to be given again during that visit.

What do I do if my child misses a dose of RotaTeq?

All 3 doses of the vaccine should be given to your child by 32 weeks of age. Your health care provider will tell you when your child should come for the follow-up doses. It is important to keep those appointments. If you forget or are not able to go back at the planned time, ask your health care provider for advice.

What else should I know about RotaTeq?

This leaflet gives a summary of certain information about the vaccine. If you have any questions or concerns about RotaTeq, talk to your health care provider. You can also visit www.rotateq.com.

What are the ingredients in RotaTeq?

Active Ingredient: 5 live rotavirus strains (G1, G2, G3, G4, and P1).

Inactive Ingredients: sucrose, sodium citrate, sodium phosphate monobasic monohydrate, sodium hydroxide, polysorbate 80 and also fetal bovine serum.

Rx only

Issued June 2007

Registered trademark of MERCK & Co., Inc., Whitehouse Station, NJ, 08889 USA COPYRIGHT (C) 2006, 2007 MERCK & Co., Inc. All rights reserved

MERCK & CO., INC. Whitehouse Station, NJ 08889, USA 9682305 ----------------------------------------------------------------------

GARDASIL(R)

(Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant)

DESCRIPTION

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

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

Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, and water for injection. The product does not contain a preservative or antibiotics.

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

CLINICAL PHARMACOLOGY

Disease Burden

Human Papillomavirus (HPV) causes squamous cell cervical cancer (and its histologic precursor lesions Cervical Intraepithelial Neoplasia (CIN) 1 or low grade dysplasia and CIN 2/3 or moderate to high grade dysplasia) and cervical adenocarcinoma (and its precursor lesion adenocarcinoma in situ (AIS)). HPV also causes approximately 35-50% of vulvar and vaginal cancers. Vulvar Intraepithelial Neoplasia (VIN) Grade 2/3 and Vaginal Intraepithelial Neoplasia (VaIN) Grade 2/3 are immediate precursors to these cancers.

Cervical cancer prevention focuses on routine screening and early intervention. This strategy has reduced cervical cancer rates by approximately 75% in compliant individuals by monitoring and removing premalignant dysplastic lesions.

HPV also causes genital warts (condyloma acuminata) which are growths of the cervicovaginal, vulvar, and the external genitalia that rarely progress to cancer. HPV 6, 11, 16, and 18 are common HPV types.

HPV 16 and 18 cause approximately:

-- 70% of cervical cancer, AIS, CIN 3, VIN 2/3, and VaIN 2/3 cases; and

-- 50% of CIN 2 cases.

HPV 6, 11, 16, and 18 cause approximately:

-- 35 to 50% of all CIN 1, VIN 1, and VaIN 1 cases; and

-- 90% of genital wart cases.

Mechanism of Action

HPV only infects humans, but animal studies with analogous (animal, not human) papillomaviruses suggest that the efficacy of L1 VLP vaccines is mediated by the development of humoral immune responses.

CLINICAL STUDIES

CIN 2/3 and AIS are the immediate and necessary precursors of squamous cell carcinoma and adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer; thus, they serve as surrogate markers for prevention of cervical cancer.

Efficacy was assessed in 4 placebo-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of GARDASIL (Protocol 005, N = 2391) and the second evaluated all components of GARDASIL (Protocol 007, N = 551). The Phase III studies, termed FUTURE (Females United To Unilaterally Reduce Endo/Ectocervical Disease), evaluated GARDASIL in 5442 (FUTURE I or Protocol 013) and 12,157 (FUTURE II or Protocol 015) subjects. Together, these four studies evaluated 20,541 women 16 to 26 years of age at enrollment. The median duration of follow-up was 4.0, 3.0, 2.4, and 2.0 years for Protocol 005, Protocol 007, FUTURE I, and FUTURE II, respectively. Subjects received vaccine or placebo on the day of enrollment, and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies combined according to a prospective clinical plan.

Prophylactic Efficacy

GARDASIL is designed to prevent HPV 6-, 11-, 16-, and/or 18-related cervical cancer, cervical dysplasias, vulvar or vaginal dysplasias, or genital warts. GARDASIL was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of subjects regardless of baseline HPV status (i.e., Polymerase Chain Reaction (PCR) status or serostatus). Subjects who were infected with a particular vaccine HPV type (and who may already have had disease due to that infection) were not eligible for prophylactic efficacy evaluations for that type.

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

Overall, 73% of subjects were naive (i.e., PCR negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment.

A total of 27% of subjects had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these subjects, 74% had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were naive (PCR negative and seronegative) to the remaining 3 types.

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

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

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

GARDASIL was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types in those who were PCR negative and seronegative at baseline (Table 1).

Table 1 Analysis of Efficacy of GARDASIL in the PPE* Population** ---------------------------------------------------------------------- GARDASIL Placebo Population --------------------------- % Efficacy (95% CI) Number

Source: Business Wire

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