Gardasil Product Monograph

SUMMARY PRODUCT INFORMATION

DESCRIPTION

GARDASIL^® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] is a recombinant, quadrivalent vaccine that protects against Human Papillomavirus (HPV). It is a sterile liquid suspension prepared from the highly purified virus-like particles (VLPs) of the recombinant major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae (yeast) CANADE 3C-5 (Strain 1895) and self-assembled into VLPs.

INDICATIONS AND CLINICAL USE

GARDASIL^® is a vaccine indicated in girls and women 9- through 45 years of age for the prevention of infection caused by the Human Papillomavirus (HPV) types 6, 11, 16, and 18 and the following diseases associated with the 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 adenocarcinoma in situ (AIS)
• Cervical intraepithelial neoplasia (CIN) grade 2 and grade 3
• Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
• Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
• Cervical intraepithelial neoplasia (CIN) grade 1

GARDASIL^® is indicated in girls and women 9- through 26 years of age for the prevention of:

• Anal cancer caused by HPV types 16 and 18
• Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 caused by HPV types 6, 11, 16, and 18

GARDASIL^® is indicated in boys and men 9 through 26 years of age for the prevention of infection caused by HPV types 6, 11, 16, and 18 and the following diseases associated with the HPV types included in the vaccine:

• Anal cancer caused by HPV types16 and 18
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11 And anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 caused by HPV types 6, 11, 16, and 18

Pediatrics (< 9 years of age):

The safety and efficacy of GARDASIL^® have not been evaluated in children younger than 9 years.

Geriatrics (> 65 years of age):

The safety and efficacy of GARDASIL^® have not been evaluated in adults above the age of 45 years.

CONTRAINDICATIONS

• Patients who are hypersensitive to the active substances or to any of the excipients of the vaccine. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

• Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of

  GARDASIL^® should not receive further doses of GARDASIL^®.

WARNINGS AND PRECAUTIONS

General

As for any vaccine, vaccination with GARDASIL^® may not result in protection in all vaccine recipients.

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

This vaccine will not protect against diseases that are not caused by HPV.

GARDASIL^® has not been shown to protect against diseases due to all HPV types.

As with all injectable vaccines, appropriate medical treatment should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine.

Syncope (fainting) may follow any vaccination, especially in adolescents and young adults. Syncope, sometimes associated with falling, has occurred after vaccination with GARDASIL^®. Therefore, vaccinees should be carefully observed for approximately 15 minutes after administration of GARDASIL^® (See ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Routine monitoring and Pap test in women should continue to be performed as indicated, regardless of GARDASIL^® administration. Recipients of GARDASIL^® should not discontinue anal cancer screening if it has been recommended by a health care provider. Appropriate precautions against sexually transmitted diseases should continue to be used.

Febrile Illness

The decision to administer or delay vaccination because of a current or recent febrile illness depends largely on the severity of the symptoms and their etiology. Low-grade fever itself and mild upper respiratory infection are not generally contraindications to vaccination.

Immunocompromised individuals

Individuals with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, Human Immunodeficiency Virus (HIV) infection, or other causes, may have reduced antibody response to active immunization (see DRUG INTERACTIONS). No specific data are available from the use of GARDASIL^® in these individuals.

Individuals with Bleeding Disorders

This vaccine should be given with caution to individuals with thrombocytopenia or any coagulation disorder only if the benefit clearly outweighs the risk of bleeding following an intramuscular administration in these individuals.

Special Populations

The safety, immunogenicity, and efficacy of GARDASIL^® have not been evaluated in HIV-infected individuals.

Pregnant Women:

Studies in Female Rats

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development. GARDASIL^® induced a specific antibody response against HPV Types 6, 11, 16, and 18 in pregnant rats following one or multiple intramuscular injections. Antibodies against all 4 HPV types were transferred to the offspring during gestation and possibly during lactation (see TOXICOLOGY, ANIMAL TOXICOLOGY, Reproductive Toxicology and Development Toxicology).

Clinical Studies in Humans

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, pregnancy should be avoided during the vaccination regimen for GARDASIL^®.

In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of GARDASIL^®. Women who were found to be pregnant before completion of a 3-dose regimen of GARDASIL^® were instructed to defer completion of their vaccination regimen until resolution of the pregnancy. Such non-standard regimens resulted in Postdose 3 anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 responses that were comparable to those observed in women who received a standard 0, 2 and 6 month vaccination regimen (see DOSAGE AND ADMINISTRATION).

Pregnant women exposed to GARDASIL^® are encouraged to report their exposure or suspected adverse reactions by contacting Merck Canada Inc., at 1-800-567-2594 or the Vaccine Safety Section at Public Health Agency of Canada at 1-866-844-0018 or www.phac-aspc.gc.ca/im/vs-sv/index-eng.php.

During clinical trials, 3819 women (vaccine N = 1894 vs placebo N = 1925) reported at least one pregnancy. The overall proportions of pregnancies that resulted in an adverse outcome, defined as the combined numbers of spontaneous abortion, late fetal death, and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), were 22.6% (446/1973) in individuals who received GARDASIL^® and 23.1% (460/1994) in individuals who received placebo.

Overall, 55 and 65 individuals in the group that received GARDASIL^® or placebo, respectively (2.9% and 3.4% of all individuals who reported a pregnancy in the respective vaccination groups), experienced a serious adverse experience during pregnancy. The most common events reported were conditions that can result in Caesarean section (e.g., failure of labor, malpresentation, cephalopelvic disproportion), premature onset of labor (e.g., threatened abortions, premature rupture of membranes), and pregnancy-related medical problems (e.g., pre-eclampsia, hyperemesis). The proportions of pregnant individuals who experienced such events were comparable between the groups receiving GARDASIL^® and placebo.

There were 45 cases of congenital anomaly in pregnancies that occurred in individuals who received GARDASIL^® and 34 cases of congenital anomaly in pregnancies that occurred in individuals who received placebo.

Further sub-analyses were done to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of GARDASIL^® or placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received GARDASIL^® compared to 1 case of congenital anomaly in the group that received placebo. Conversely, in pregnancies with onset more than 30 days following vaccination, 40 cases of congenital anomaly were observed in the group that received GARDASIL^® compared with 33 cases of congenital anomaly in the group that received placebo.

The types of anomalies observed were consistent (regardless of when pregnancy occurred in relation to vaccination) with those generally observed in pregnancies in women aged 16 through 45 years.

Nursing Women:

It is not known whether vaccine antigens or antibodies induced by the vaccine are excreted in human milk.

GARDASIL^® may be administered to lactating women.

GARDASIL^® or AAHS control were given to a total of 1133 women (vaccine N = 582, placebo N = 551) during the relevant Phase III clinical studies. In these studies, the rates of adverse experiences in the mother and the nursing infant were comparable between vaccination groups. In addition, vaccine immunogenicity was comparable among nursing mothers and women who did not nurse during the vaccine administration.

Overall, 27 and 13 infants of individuals who received GARDASIL^® or placebo, respectively (representing 4.6% and 2.4% of the total number of individuals who were breast-feeding during the period in which they received GARDASIL^® or placebo, respectively), experienced a serious adverse experience. None was judged by the investigator to be vaccine related.

In clinical studies, a higher number of breast-fed infants (n = 7) whose mothers received GARDASIL^® had acute respiratory illnesses within 30 days post-vaccination of the mother as compared to infants (n = 2) whose mothers received AAHS placebo.

Pediatrics (< 9 years of age):

The safety and efficacy of GARDASIL^® have not been evaluated in children younger than 9 years.

Geriatrics (> 65 years of age):

The safety and efficacy of GARDASIL^® have not been evaluated in adults above the age of 45 years.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

In clinical trials, GARDASIL^® was generally well tolerated when compared to placebo (Amorphous Aluminum Hydroxyphosphate Sulfate (AAHS) Adjuvant or saline).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another vaccine. Adverse drug reaction information from clinical trials is useful for identifying vaccine-related adverse events and for approximating rates.

In 7 clinical trials (6 placebo-controlled), individuals were administered GARDASIL^® or placebo on the day of enrollment, and approximately 2 and 6 months thereafter. In those clinical trials, a total of 15,706 individuals received GARDASIL^® and 13,617 individuals received placebo. GARDASIL^® demonstrated a favorable safety profile when compared with placebo (AAHS Adjuvant or saline). Few individuals (0.2%) discontinued due to adverse experiences. In all except one of the clinical trials, safety was evaluated using vaccination report card (VRC)-aided surveillance for 14 days after each injection of GARDASIL^® or placebo. The individuals who were monitored using VRC-aided surveillance included 10,088 individuals (6995 girls and women 9 through 45 years of age and 3093 boys and men 9 through 26 years of age at enrollment) who received GARDASIL^® and 7995 individuals who received placebo.

The vaccine-related adverse experiences 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 placebo recipients are shown in Tables 1-2.

Table 1 - Vaccine-Related Injection-Site and Systemic Adverse Experiences in 9- Through 45-Year-Old Girls and Women*

Of those girls and women who reported an injection site reaction, 94.2% judged their injection-site adverse reaction to be mild or moderate in intensity.

In addition, bronchospasm was reported very rarely as a serious adverse experience.

Table 2 - Vaccine-Related Injection-Site and Systemic Adverse Experiences in 9- Through 26-Year-Old Boys and Men*

Of those boys and men who reported an injection site reaction, 96.4% judged their injection-site adverse reaction to be mild or moderate in intensity.

All-cause Common Systemic Adverse Experiences

All-cause systemic adverse experiences for recipients of GARDASIL^®, that were observed at a frequency of greater than or equal to 1% where the incidence in the vaccine group was greater than or equal to the incidence in the placebo group, are shown in Tables 3-4.

Table 3 - All-cause Common Systemic Adverse Experiences in Girls and Women 9 Through 45 Years of Age (GARDASIL^® ≥ Control)*

Table 4: All-cause Common Systemic Adverse Experiences in Boys and Men 9 Through 26 Years of Age (GARDASIL^® ≥ Control)*

Adverse Reactions

Serious Adverse Experiences in the Entire Study Population

A total of 258 individuals out of 29,323 total individuals (9- through 45-year-old girls and women, and 9- through 26-year-old boys and men) who received both GARDASIL^® and placebo reported a serious systemic adverse experience following any vaccination visit during the clinical trials for GARDASIL^®. Out of the entire study population (29,323 individuals), only 0.04% of the reported serious systemic adverse experiences were judged to be vaccine related by the study investigator. The most frequently reported serious systemic adverse experiences for GARDASIL^® compared to placebo and regardless of causality were:

Headache [0.02% GARDASIL^® (3 cases) vs. 0.02% Placebo (2 cases)], Gastroenteritis [0.02% GARDASIL^® (3 cases) vs. 0.02% Placebo (2 cases)], Appendicitis [0.03% GARDASIL^® (5 cases) vs. 0.01% Placebo (1 case)], Pelvic inflammatory disease [0.02% GARDASIL^® (3 cases) vs. 0.03% Placebo (4 cases)], Urinary tract infection [0.01% GARDASIL^® (2 cases) vs. 0.02% Placebo (2 cases)], Pneumonia [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (2 cases)], Pyelonephritis [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (3 cases)], Pulmonary embolism [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (2 cases)].

One case (0.006% GARDASIL^®: 0.0% Placebo) of bronchospasm and 2 cases (0.01% GARDASIL^®: 0.0% Placebo) of asthma were reported as serious systemic adverse experiences that occurred following any vaccination visit.

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

Deaths in the Entire Study Population

Across the clinical studies, 39 deaths were reported in 29,323 (GARDASIL^® N = 15,706; Placebo N = 13,617) individuals (9- through 45-year-old girls and women, and 9- through 26-year-old boys and men). The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (5 individuals who received GARDASIL^® and 4 individuals who received placebo), followed by drug overdose/suicide (2 individuals who received GARDASIL^® and 6 individuals who received placebo), gun shot wound (1 individual who received GARDASIL^® and 3 individuals who received placebo), and pulmonary embolus/deep vein thrombosis (1 individual who received GARDASIL^® and 1 individual who received placebo). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, 1 case of arrhythmia, 1 case of pulmonary tuberculosis, 1 case of hyperthyroidism, 1 case of post-operative pulmonary embolism and acute renal failure, 1 case of traumatic brain injury/cardiac arrest, 1 case of systemic lupus erythematosus, 1 case of cerebrovascular accident, 1 case of breast cancer, and 1 case of nasopharyngeal cancer in the group that received GARDASIL^®; and 1 case of asphyxia, 1 case of acute lymphocytic leukemia, 1 case of chemical poisoning, and 1 case of myocardial ischaemia in the placebo group.

Systemic Autoimmune Disorders

In the clinical studies, male (ages 9 through 26) and female (ages 9 through 45) individuals 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 placebo are shown in Tables 5-6. This population includes all individuals who received at least one dose of GARDASIL^® or placebo, and had safety data available.

Table 5 - Summary of Girls and Women 9 Through 45 Years of Age Who Reported an Incident Condition Potentially Indicative of Systemic Autoimmune Disorder After Enrollment in Clinical Trials of GARDASIL^® Regardless of Causality

Table 6: Summary of Boys and Men 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

Post-Market Adverse Drug Reactions

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

Infections and infestations: cellulitis

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

Respiratory, thoracic and mediastinal disorders: pulmonary embolus.

Nervous system disorders: acute disseminated encephalomyelitis, dizziness, Guillain-Barré syndrome, headache, motor neuron disease, paralysis, syncope sometimes accompanied by tonic-clonic movements, transverse myelitis.

Gastrointestinal disorders: nausea, pancreatitis, vomiting.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia.

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

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

DRUG INTERACTIONS

Drug-Drug Interactions

Use with Other Vaccines

Results from clinical studies indicate that GARDASIL^® may be administered concomitantly (at a separate injection site) with Menactra* [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine], Adacel* [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)], and RECOMBIVAX HB^® [hepatitis B vaccine (recombinant)] (see CLINICAL TRIALS, Studies with Other Vaccines).

The frequency of adverse experiences observed, in a placebo-controlled study with concomitant administration with hepatitis B vaccine (recombinant), was similar to the frequency when GARDASIL^® was administered alone.

In another placebo-controlled study, there was an increase in injection-site swelling when GARDASIL^® was given concomitantly with Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap). The majority of injection-site swelling adverse experiences were reported as being mild to moderate in intensity.

Use with Common Medications

In clinical studies for girls and women (aged 16 to 26 years), 11.9%, 9.5%, 6.9%, and 4.3% of individuals used analgesics, anti-inflammatory drugs, antibiotics, and vitamin preparations, respectively. In a clinical study in women (aged 24 to 45 years), 30.6%, 20.2%, 11.6%, and 7.5% of individuals used analgesics, anti-inflammatory drugs, antibiotics, and vitamin preparations, respectively. Conversely in a clinical study in boys and men (aged 16 to 26 years), 10.3%, 7.8%, 6.8%, 3.4% and 2.6% of individuals used analgesics, anti-inflammatory drugs, antibiotics, antihistamines, and vitamin preparations, respectively. The efficacy, immunogenicity, and safety of the vaccine were not impacted by the use of these medications.

Use with Hormonal Contraceptives

In clinical studies, 50.2% of women (aged 16 to 45 years) who received GARDASIL^® used hormonal contraceptives. Use of hormonal contraceptives did not appear to affect the immune responses to GARDASIL^®.

Use with Steroids

In clinical studies for girls and women (aged 16 to 26 years), 1.7% (n = 158), 0.6% (n = 56), and 1.0% (n = 89) of individuals used inhaled, topical, and parenteral immunosuppressants, respectively. In a clinical study in women (aged 24 to 45 years), 1.4% (n = 27) used corticosteroids for systemic use. In a clinical study in boys and men (aged 16 to 26 years), 1.0% (n = 21) used corticosteroids for systemic use. The corticosteroids for all individuals were administered close to the time of administration of a dose of GARDASIL^®. These medicines did not appear to affect the immune responses to GARDASIL^®. Very few individuals in the clinical studies were taking steroids, and the amount of immunosuppression is presumed to have been low.

Use with Systemic Immunosuppressive Medications

There are no data on the concomitant use of potent immunosuppressants with GARDASIL^®. Individuals receiving therapy with immunosuppressive agents (systemic doses of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may not respond optimally to active immunization (See WARNINGS AND PRECAUTIONS, General).

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established. There was no evidence from the clinical studies database of impact of GARDASIL^® administration on the performance characteristics of the Pap test and some commercially available HPV tests.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

GARDASIL^® should be administered intramuscularly as 3 separate 0.5 mL-doses according to the following schedule:

First dose: at elected date

Second dose: 2 months after the first dose

Third dose: 6 months after the first dose

Individuals are encouraged to adhere to the 0, 2, and 6 months vaccination schedule. However, in clinical studies, efficacy has been demonstrated in individuals who have received all 3 doses within a 1-year period. The second dose should be administered at least 1 month after the first dose, and the third dose should be administered at least 3 months after the second dose. All three doses should be given within a 1-year period (see CLINICAL TRIALS, Schedule Flexibility).

Alternatively, in individuals 9 through 13 years of age, GARDASIL^® can be administered according to a 2-dose (0, 6 months or 0, 12 months) schedule. The administration of the second dose at an interval of less than 6 months after the first dose has not been formally evaluated. If the second vaccine dose is administered earlier than 6 months after the first dose, a third dose should be considered.

The use of GARDASIL^® should be in accordance with official recommendations.

It is recommended that individuals who receive a first dose of GARDASIL^® complete the vaccination course with GARDASIL^®.

The need for a booster dose has not been established.

Administration

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

GARDASIL^® must not be injected intravascularly. Neither subcutaneous nor intradermal administration has been studied. These methods of administration are not recommended.

The prefilled syringe is for single use only and should not be used for more than one individual. For single-use vials, a separate sterile syringe and needle must be used for each individual.

The vaccine should be used as supplied; no dilution or reconstitution is necessary. The full recommended dose of the vaccine should be used.

Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine.

After thorough agitation, GARDASIL^® is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Discard the product if particulates are present or if it appears discolored.

Instructions for Use

Single-Dose Vial Use

Withdraw the 0.5 mL dose of vaccine from the single-dose vial using a sterile needle and syringe free of preservatives, antiseptics, and detergents. Once the single-dose vial has been penetrated, the withdrawn vaccine should be used promptly, and the vial must be discarded.

Prefilled Syringe Use

Inject the entire contents of the syringe.

OVERDOSAGE

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

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

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Disease Burden

Cervical cancer is caused by different types of Human Papillomavirus (HPV) infection.^1,2,3,4,5

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.^6,7,8

HPV infection is very common.⁹ Most HPV infections clear without sequelae but some progress to cervical cancer and/or other HPV-related diseases. It is estimated that 75% of sexually active Canadians will have at least one HPV infection during their lifetime,¹⁰ with the highest prevalence observed in women aged 20-24 years.^11,12 Women remain at high risk for HPV acquisition and disease caused by HPV 6, 11, 16 and 18 up to the age of 45.^11,13,14 Men play an important role in transmission of HPV to their sexual partners. Several prospective studies have shown a high level of HPV concordance between couples who recently became infected, indicating transmission of HPV between the couples (male to female, and female to male). These data consistently support the sexually transmitted nature of HPV and the role of men in infecting women, who subsequently can develop HPV-related anogenital cancers and warts. Based on these various lines of evidence it is expected that decreasing the risk of HPV infection in men through vaccination should decrease the risk of infection in their sexual partners, thereby providing additional public health benefit.

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.^12,15,16 In 2001, more than 1350 Canadian women were diagnosed with cervical cancer and 400 women died from it.¹⁷ After breast cancer, cervical cancer is the most common cancer in Canadian women between the ages of 20 and 44.¹⁸

HPV also causes genital warts (condyloma acuminata) which are growths of the cervicovaginal, vulvar, perianal and intra-anal mucosa, and the external genitalia that rarely progress to cancer, but cause significant psychosocial impact and disease recurrence.¹⁹ The lifetime risk for acquisition of genital warts has been estimated to exceed 10%.^20,21 The risk of acquisition of genital warts for both males and females is highest between the ages of 15-34, but the risk of incident infection remains throughout life.²²

Based on two recent epidemiologic studies from BC and Manitoba, anogenital warts (AGWs) are associated with a significant burden of illness and costs to the Canadian healthcare system.^22,23 Of note is the similarity in findings between the two studies with respect to the incidence of genital warts. In BC overall incidence was found to be 1.26 per 1000 population, at an average cost of $190 per episode for treatment which, translates into approximately $1million in annual, direct medical costs.²³ Similarly, in Manitoba the incidence of genital warts in males was found to be 1.54 per 1000, whilst for females it was 1.23 per 1000,²² resulting in an average cost of $200 per individual treated.²⁴ If the Manitoba rates are generalizable to Canada, then in 2006 (based 2004 Manitoba rates and the 2006 Canadian census population) there would have been 41,450 incident cases, 48,600 prevalent cases, and 617,950 people who had been diagnosed with AGWs since 1985.²²

HPV infection is strongly associated with anal cancer. The great majority of anal cancers are squamous cell carcinoma (SCC). Anal canal SCC are HPV positive in 80 to 90% of cases in men and women. HPV 16 (73%) and HPV 18 (5%) are the most common associated types. Approximately 100,000 new cases of anal cancer are estimated to occur annually around the world and the rate of anal cancer cases has been increasing. There are no routine screening tests for this cancer in healthy people.

HPV is accepted as an important cause of head and neck cancer, and emerging data show an increase over the past several decades in the proportion of head and neck cancers caused by HPV. The majority of HPV-related head and neck cancers occur in the oropharynx, specifically in the tonsillar area of Waldeyer's Ring. Of oropharyngeal cancers, 60-70% are caused by HPV, and of these, approximately 90% are associated with HPV 16. Overall, approximately 2/3 of these cases occur in men. Oral HPV infection and seropositivity for HPV 16 have been associated with a significantly elevated risk for development of head and neck cancer.

HPV 6, 11, 16, and 18 are common HPV types.

HPV types 16 and 18 cause approximately:

• 70% of cervical cancer, AIS, and CIN 3 cases;
• 50% of CIN 2 cases;
• 70% of HPV-related vulvar and vaginal cancer, VIN 2/3, and VaIN 2/3 cases;
• 90% of HPV-related anal cancers;
• 70% of HPV-related AIN 2/3; and
• 60% of HPV-related penile cancers.

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

• 35 to 50% of all CIN 1, VIN 1, and VaIN 1 cases.

HPV types 6 and 11 cause approximately:

• 90% of genital wart cases; ^{2,25,26,27,28} and
• 9 to 12% of CIN 1 cases.

HPV type 16 causes approximately:

• 90% of HPV-related Oropharyngeal squamous cell carcinomas.

HPV 31, 33, 52, 56, 58, and 59 are high-risk HPV types. These types are responsible for:

• 11.6% of cervical cancer cases;
• 32.2% of CIN 1 cases;
• 39.3% of CIN 2 cases; and
• 24.3% of CIN 3 or AIS cases.

A recent Canadian study evaluated the prevalence of HPV in liquid-based specimens from a sample of 8700 women throughout British Columbia who were attending for routine cytology screening at high-volume primary care screening sites. This study found that HPV types 31, 33, 52 and 58 were responsible for:

• 9.8% of LSILs (Low grade Squamous Intraepithelial Lesion, encompassing: HPV/mild dysplasia/CIN I);

• 18.8% of HSILs (High grade Squamous Intraepithelial Lesion, encompassing:

  moderate and severe dysplasia, carcinoma in situ, CIN II and CIN III).²⁹

Mechanism of Action

GARDASIL^® contains L1 VLPs, which are proteins that resemble wild-type virions. Because the virus-like particles contain no viral DNA, they cannot infect cells or reproduce.

HPV only infects humans, but animal studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines is mediated by the development of humoral immune responses.

In preclinical studies, induction of anti-papillomavirus antibodies with L1 VLP vaccines resulted in protection against infection. Administration of serum from vaccinated to unvaccinated animals resulted in the transfer of protection against HPV to the unvaccinated animals. These data suggest that the efficacy of L1 VLP vaccines is mediated by the development of humoral immune responses.^30,31,32

STORAGE AND STABILITY

Store refrigerated at 2°C to 8°C. Do not freeze. Protect from light.

GARDASIL^® should be administered as soon as possible after being removed from refrigeration. GARDASIL^® can be administered provided total (cumulative multiple excursion) time out of refrigeration (at temperatures between 8°C and 25°C) does not exceed 72 hours. Cumulative multiple excursions between 0°C and 2°C are also permitted as long as the total time between

0°C and 2°C does not exceed 72 hours. These are not, however, recommendations for storage.

Discard the product if it is frozen, particulates are present, or if it appears discoloured.

DOSAGE FORMS, COMPOSITION AND PACKAGING

GARDASIL^® is a sterile preparation for intramuscular administration supplied as a 0.5-mL single-dose vial or a 0.5 mL single-dose prefilled Luer Lock syringe. After thorough agitation, GARDASIL^® is a white, cloudy liquid.

COMPOSITION

Active Ingredients

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

Inactive Ingredients

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

PACKAGING

Vials

GARDASIL^® is supplied in 3 mL single-dose Type I glass vials containing one 0.5 mL dose of liquid vaccine.

GARDASIL^® is available in packages of 1 and 10 single-dose vials.

Syringes

GARDASIL^® is supplied in 1.5 mL single-dose Type I glass prefilled Luer Lock syringes, containing one 0.5 mL dose of liquid vaccine in a carton. One needle is provided separately in the carton.

Vials and prefilled syringes components are latex free.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18)

Recombinant Vaccine]

Product Characteristics

The quadrivalent Human Papillomavirus Virus-Like Particle vaccine (HPV VLP vaccine) is a sterile liquid suspension prepared from the highly purified virus-like particles (VLPs) of the recombinant major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae (yeast) CANADE 3C-5 (Strain 1895) and self-assembled into VLPs. The VLPs for each type are purified and adsorbed on AAHS-containing adjuvant (amorphous aluminum hydroxyphosphate sulfate). The quadrivalent HPV VLP vaccine is prepared by combining the adsorbed VLPs of each HPV type, the AAHS-containing adjuvant formulation, and a buffer.

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

CLINICAL TRIALS

Study demographics and trial design

Table 7 - Summary of patient demographics for clinical trials in HPV Disease Efficacy

Study #

Gender

005

Female

007

Female

Study #

Gender

007 (Cont’d)

Female

013

(FUTURE I)

Female

015

(FUTURE II)

Female

Study #

Gender

019

(FUTURE III)

Female

020

Male

Study Results

Clinical Studies

In females, cervical intraepithelial neoplasia 2/3 (CIN 2/3) and cervical adenocarcinoma in situ (AIS) are the immediate and necessary precursors of invasive squamous cell carcinoma and invasive adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent invasive cancer (secondary prevention); thus, they serve as surrogate markers for the prevention of cervical cancer.

Vulvar intraepithelial neoplasia 2/3 (VIN 2/3) and vaginal intraepithelial neoplasia 2/3 (VaIN 2/3) are the immediate precursors to HPV-related vulvar and vaginal cancer, respectively.³³

In men, up to 84% of penile/perineal/perianal intraepithelial neoplasia (PIN) 1 (low grade) and over 90% of PIN 3 (high grade) has been associated with HPV. HPV 16 is the most common type detected. Erythoplasia of Queyrat (EQ), Bowen's disease (BD), and bowenoid papulosis (BP) are clinical presentations of high-grade PIN. As high as 33% of BD and EQ have been associated with invasive cancer. BP rarely progresses to malignancy.

The efficacy of GARDASIL^® was assessed in 6 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 girls and women) and the second evaluated all components of GARDASIL^® (Protocol 007, N = 551 girls and women). Two Phase III studies, termed FUTURE (Females United To Unilaterally Reduce Endo/Ectocervical Disease), evaluated GARDASIL^® in 5442 (FUTURE I) and 12,157 (FUTURE II) 16- through 26-year-old girls and women. A third Phase III study, Protocol 020, evaluated GARDASIL^® in 4055 16- through 26-year-old boys and men, including a subset of 598 (GARDASIL^® = 299; placebo =

299) men who self-identified as having sex with men (MSM population). A fourth Phase III study (FUTURE III) evaluated GARDASIL^® in 3817 24- through 45-year-old women. Together, these six studies evaluated 28,413 individuals (20,541 girls and women 16 through 26 years, 4055 boys and men 16 through 26 years, and 3817 women 24 through 45 years of age at enrollment). The median duration of follow-up was 4.0, 3.0, 3.0, 3.0, 2.9, and 4.0 years for Protocol 005, Protocol 007, FUTURE I, FUTURE II, Protocol 020, and FUTURE III, respectively. Individuals 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 conducted in girls and women combined.

Overall, 73% of 16- through 26-year-old girls and women, 67% of 24- through 45-year-old women, and 83% of 16- through 26-year-old boys and men were naïve (i.e., PCR negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment. The naïve individuals continued to be at risk for infection and disease caused by all 4 vaccine HPV types.

A total of 27% of 16- through 26-year-old girls and women, 33% of 24- through 45-year-old women, and 17% of 16-through 26-year-old-boys and men had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these individuals, 74% of 16- through 26-year-old girls and women, 71% of 24- through 45-year-old women, and 78% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were naïve (PCR negative and seronegative) to the remaining 3 types. Among 24- through 45-year-old subjects, only 0.4% had been exposed to all 4 vaccine HPV types. Among the 16- through 26-year-old boys and men, only 0.2% had been exposed to all 4 vaccine HPV types.

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

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

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

Definition of Clinical Trial Populations

The primary analyses of efficacy was 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 naïve to the relevant HPV type(s) prior to dose one and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit. In individuals who were naïve (PCR negative and seronegative) to all 4 vaccine HPV types, CIN, genital warts, AIN, VIN and VaIN caused by any of the 4 vaccine HPV types were counted as endpoints. Among individuals who were positive (HPV 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.

The “MITT-2 population” and the "HNRT population" consisted of individuals who were naïve to the relevant HPV types(s) (Types 6, 11, 16, and 18) prior to dose 1, received at least one dose of vaccine or placebo, and had at least one follow-up visit post-Day 30. The MITT-2 population differs from the PPE population in that it includes individuals with major protocol violations and also individuals who became infected with a vaccine HPV type during the vaccination period. Cases were counted starting after Day 30 for MITT2 and Day 1 for HNRT.

The “HPV-naïve population” of 16- through 26-year-old girls and women consisted of individuals who received at least one dose of vaccine or placebo, had at least one follow-up visit post-Day 30, and were negative to 14 common HPV types and had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1, approximating a population of sexually-naïve individuals plus individuals shortly after sexual debut. Cases were counted starting after Day 30. The “HPV-naïve population” of 16- through 26-year-old boys and men consisted of individuals who received at least one dose of vaccine or placebo, had at least one follow-up visit post-Day 30, and were negative to 14 common HPV types, approximating a population of sexually-naïve individuals plus individuals shortly after sexual debut. Cases were counted starting after Day 1.

The “general study population” consisted of individuals who received at least one dose of vaccine or placebo and had at least one follow-up visit post-Day 30, regardless of baseline HPV status. Some individuals in this population had HPV-related disease at vaccination onset. Of the 16- through 26-year-old girls and women in this population, 12.5% had a positive Pap test; 15.0% were PCR positive; and 19.8% were seropositive to HPV types 6, 11, 16, or 18. Of the 16- through 26-year-old boys and men in this population, 12.2% were PCR positive and 7.6% were seropositive to HPV types 6, 11, 16, or 18. Cases were counted starting after Day 30 for the general study population of girls and women and after Day 1 for the general study population of boys and men.

Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in 16- Through 26-Year-Old Girls and Women

GARDASIL^® is primarily designed to prevent cervical, vulvar, and vaginal cancers; cervical dysplasias; vulvar or vaginal dysplasias; or genital warts caused by HPV types 6, 11, 16, and 18. GARDASIL^® was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of individuals regardless of baseline HPV status (i.e.,

Polymerase Chain Reaction [PCR] status or serostatus). Individuals 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 with respect to HPV types 6, 11, 16, and 18 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 naïve (PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit.

GARDASIL^® was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types in those who were PCR negative and seronegative at baseline (Table 8).

Table 8 - Analysis of Efficacy of GARDASIL^® in the PPE* Population** of 16- Through 26-Year-Old Girls and Women

association with the vaccine HPV types cannot be completely ruled out. However, given that these cases occurred in the context of mixed infection, with the dominant type being the non-vaccine HPV type, it is likely that the relevant vaccine HPV type was not the causal HPV type.

^‡Analyses of the combined trials were prospectively planned and included the use of similar study entry criteria. n = Number of individuals with at least 1 follow-up visit after Month 7.

CI = Confidence interval.

Note 1: Point estimates and confidence intervals are adjusted for person-time of follow-up. Note 2: The first analysis in the table (i.e., HPV 16- or 18-related CIN 2/3, AIS or worse) was the primary endpoint of the vaccine development plan.

Note 3: P-values were computed for pre-specified primary hypothesis tests. All p-values were <0.001, supporting the following conclusions: efficacy against HPV 16/18-related CIN 2/3 is >0% (FUTURE II); efficacy against HPV 16/18-related CIN 2/3 is >25% (Combined Protocols); and efficacy against HPV 6-, 11-, 16-, and 18-related CIN is >20% (FUTURE I).

Note 4: FUTURE I refers to Protocol 013; FUTURE II refers to Protocol 015.

In a supplemental analysis, in 16- through 26-year-old girls and women, the efficacy of GARDASIL^® was evaluated against HPV 16/18-related FIGO (International Federation of Obstetrics and Gynaecology) Stage 0 cervical cancer (CIN 3 and AIS) and for the immediate precursors to vulvar and vaginal cancer (VIN 2/3 or VaIN 2/3) in the per-protocol efficacy (PPE) population and a modified intention to treat-2 (MITT-2) population. The MITT-2 population consisted of individuals who were naïve to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1, received at least one dose of vaccine or placebo, and had at least one follow-up visit post-Day 30. The MITT-2 population differs from the PPE population in that it includes individuals with major protocol violations and who became infected with a vaccine HPV type during the vaccination period. Efficacy was measured starting 30 days Postdose 1 for the MITT-2 population (Table 9).

Table 9 - Supplemental Analyses of Cancer-related Endpoints: Efficacy Against HPV 16/18-related Invasive Cancer Precursors for the Combined Protocols in the PPE* and MITT-2** Populations of 16- Through 26-Year-Old Girls and Women

Prophylactic efficacy against overall persistent infection or disease in an extension phase of Protocol 007, that included data through Month 60, was 95.8% (95% CI: 83.8%, 99.5%). In the group that received GARDASIL^®, no cases due to waning immunity were observed.

GARDASIL^® was efficacious against HPV disease caused by HPV types 6, 11, 16, and 18.

Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in Women 24 Through 45 Years of Age

A minimum anti-HPV level that provides protection against HPV infection and disease has not been defined. Also, immune responses to vaccines are typically lower in older individuals compared to younger individuals. Therefore, to confirm the utility of GARDASIL^® to prevent cervical, vulvar, and vaginal cancers and related diseases caused by the types targeted by the vaccine in women up to and including age 45 years, an efficacy study (FUTURE III) was conducted. FUTURE III study builds on the efficacy database established in women ages 16 through 26 to extend the indication of efficacy of GARDASIL^® to a population of women through age 45.

For women 26- 45 years of age, prevention of vulvar and vaginal lesions and vulvar and vaginal cancers due to vaccine HPV types has not been demonstrated, although prevention of persistent infection was shown (see Table 10).

The primary analyses of efficacy, with respect to HPV types 6, 11, 16, and 18, were conducted in the per-protocol efficacy (PPE) population (Table 10). The efficacy of GARDASIL^® against the combined incidence of HPV 6-, 11-, 16-, or 18-related persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancers was 88.7% (95% CI: 78.1, 94.8). The efficacy of GARDASIL^® against the combined incidence of HPV 16- or 18-related persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancers was 84.7% (95% CI: 67.5, 93.7).

Table 10 - Analysis of Efficacy of GARDASIL^® in the PPE* Population of 24- Through 45-Year-Old Women for Vaccine HPV Types

Prophylactic Efficacy – External Genital Disease Associated with HPV Types 6, 11, 16, and 18 in 16- Through 26-Year-Old Boys and Men

In clinical studies in boys and men, efficacy was evaluated using the following endpoints: external genital warts; penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer; and persistent infection. High grade PIN is associated with certain types of penile/perineal/perianal cancers. Persistent infection is a predictor of clinical disease.

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

GARDASIL^® was efficacious in reducing the incidence of genital warts (Condyloma) caused by HPV types 6 and 11 and infection related to vaccine HPV types 6, 11, 16, or 18 in those who were PCR negative and seronegative at baseline (Table 11).

Table 11 - Analysis of Efficacy of GARDASIL^® in the PPE* Population of 16- Through 26-Year-Old Boys and Men for Vaccine HPV Types

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

A sub-study of Protocol 020 evaluated the efficacy of GARDASIL^® against anal disease (anal intraepithelial neoplasia and anal cancer) in a population of 598 MSM. In this sub-study, efficacy was evaluated using the combined incidence of HPV 6-, 11-, 16-, or 18-related anal intraepithelial neoplasia (AIN, grades 1/2/3) or Anal Cancer. The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population of Protocol 020.

GARDASIL^® was efficacious in reducing the combined incidence of anal intraepithelial neoplasia (AIN) grades 1 (both condyloma and non-acuminate), 2, and 3 related to vaccine HPV types 6, 11, 16, and 18 in those boys and men who were PCR negative and seronegative at baseline (Table 12).

Table 12 - Analysis of Efficacy of GARDASIL^® for Anal Disease in the PPE* Population of 16- Through 26-Year-Old Boys and Men in the MSM Sub-study for Vaccine HPV Types

Several of the AIN 2/3 lesions contained multiple oncogenic types (including non-vaccine HPV types). An additional analysis was conducted to determine vaccine efficacy against lesions likely to be causally associated with vaccine HPV types. This post-hoc analysis (clinical case assignment) assigned causal association of an HPV type with the lesion based on the presence of the HPV type in swab and/or biopsy samples prior to detection of the lesion. Based on this case assignment, the analysis excluded 2 AIN2+ cases (2 in the vaccine group and 0 in the control group) which were not considered to be causally associated with vaccine HPV type infections acquired during the trial. Based on this analysis there was 1 case of HPV 6/11/16/18 AIN 2+ in the vaccine group (AIN 3 attributed to HPV 6) and 13 cases in the control group (Efficacy 91.7%; 95% CI: 44.6%; 99.8%).

Efficacy in 16- Through 45-Year-Old Girls and Women with Current Infection with HPV Types 6, 11, 16, or 18

GARDASIL^® is a prophylactic vaccine. There was no evidence of protection from disease caused by vaccine HPV types for which individuals were PCR positive and seropositive at baseline.

Efficacy in women (16 to 45 years) with evidence of a prior infection with a vaccine HPV type (seropositive) that was no longer detectable at vaccination onset (PCR negative)

GARDASIL^® appears to prevent reacquisition or recurrence of infection leading to clinical disease among women with evidence of a prior infection that has resolved by vaccination onset. However, a significant difference between GARDASIL^® and placebo was only noted for low grade lesions (CIN 1 and benign EGL) for girls and women age 16- 26 years. The efficacy of GARDASIL^® against HPV 6-, 11-, 16-, and 18-related persistent infection was 66.8% (95% CI: 3.8, 90.5) in women 24 to 45 years of age.

Individuals of 16- 26 year old who received GARDASIL^®, but had ongoing HPV infection at the time of vaccination had a 19.7% (95% CI: -9.5%, 41.2%) lower incidence of CIN (CIN 1 or CIN 2/3) or AIS resulting from this infection as compared with placebo. Ongoing infection was defined as infection with a vaccine HPV type at enrollment, but no evidence of immune response to it (PCR positive and seronegative). However, the decrease was not statistically significant and the clinical significance of this finding has not been determined.

Individuals who were already infected with one or more vaccine-related HPV types prior to vaccination were protected from clinical disease caused by the remaining vaccine HPV types.

General Population Impact – HPV 6-, 11-, 16-, or 18-related Disease in 16- Through 26-Year-Old Girls and Women

The general population of individuals includes women who are HPV-naïve (PCR negative and seronegative) and women who are HPV-non-naïve (PCR positive and/or seropositive), some of whom have HPV-related disease. Analyses were conducted to evaluate the overall impact of GARDASIL^® with respect to HPV 6-, 11-, 16-, and 18-related cervical and genital disease in the general population. Here, analyses included events arising from HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination.

The impact of GARDASIL^® in the general population is shown in Table 13. Impact was measured starting 1 month Postdose 1. Prophylactic efficacy denotes the vaccine’s efficacy in women who are naïve (PCR negative and seronegative) to the relevant HPV types at vaccination onset. General population impact denotes vaccine impact among women regardless of baseline PCR status and serostatus. The majority of CIN and genital warts, VIN, and VaIN detected in the group that received GARDASIL^® occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1.

Table 13 - General Population Impact for Vaccine HPV Types in 16- Through 26-Year-Old Girls and Women

The impact of GARDASIL^® on the rate of HPV 6- or 11-related genital warts was assessed in the general study population. Administration of GARDASIL^® to the general population reduced the incidence of HPV 6- and HPV 11-related genital warts. The benefit of the vaccine with respect to the overall incidence of HPV 6- and HPV 11-related genital warts became more apparent over time (Figure 1).

Figure 1 - Cumulative Incidence of Genital Warts (Caused by HPV Types 6 and 11) Among the General Study Population of Women Including Those with HPV Infection at Vaccination Onset in the Phase III Clinical Trials (FUTURE I and FUTURE II)

General Population Impact – HPV 6-, 11-, 16-, or 18-related Disease in 24- Through 45-Year-Old Women

The impact of GARDASIL^® in the general population is shown in Table 14. The efficacy of GARDASIL^® against the combined incidence of HPV 6-, 11-, 16-, or 18-related persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancers was 47.2% (95% CI: 33.5, 58.2). The efficacy of GARDASIL^® against the combined incidence of HPV 16- or 18-related persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancers was 41.6% (95% CI: 24.3, 55.2).

Table 14 - Analysis of Efficacy of GARDASIL^® in the General Study Population of 24- Through 45-Year-Old Women for Vaccine HPV Types

General Population Impact – HPV 6-, 11-, 16-, or 18-related Disease in 16- Through 26-Year-Old Boys and Men

The general population of individuals includes boys and men who are HPV-naïve (PCR negative and seronegative) and boys and men who are HPV-non-naïve (PCR positive and/or seropositive), some of whom have HPV-related disease. Analyses were conducted to evaluate the overall impact of GARDASIL^® with respect to HPV 6-, 11-, 16-, and 18-related cervical and genital disease in the general population. Here, analyses included events arising from HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination.

The impact of GARDASIL^® in the general population is shown in Table 15. Prophylactic efficacy denotes the vaccine’s efficacy in boys and men who are naïve (PCR negative and seronegative) to the relevant HPV types at vaccination onset. General population impact denotes

vaccine impact among boys and men regardless of baseline PCR status and serostatus. The majority of HPV disease detected in the group that received GARDASIL^® occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1.

Table 15 - General Population Impact for Vaccine HPV Types in 16- Through 26-Year-Old Boys and Men

Results of Analysis of Efficacy for HPV Types Other Than the Four Types Included in GARDASIL^® in 16- Through 26-Year-Old Girls and Women

The cross-protective efficacy of GARDASIL^® was evaluated in the combined database of the FUTURE I and FUTURE II trials (N = 17,599). Efficacy was evaluated for the combined incidence of HPV 31- and HPV 45-related CIN 2/3 or AIS, HPV 31-, 33-, 52-, and 58-related CIN 2/3 or AIS, and HPV 31-, 33-, 45-, 52-, and 58-related CIN 2/3 or AIS (Table 16). Analyses were also conducted to evaluate efficacy with respect to CIN 2/3 or AIS caused by non-vaccine HPV types individually (Tables 17 and 18).

Table 16 - Impact of GARDASIL^® on the Rates of CIN 2/3 or AIS for the Combined FUTURE I and FUTURE II Disease Cross Protection Data Set in 16- Through 26-Year-Old Girls and Women

Table 17 - Analysis of Efficacy Against CIN 2/3 or AIS Due to Any HPV Type for the Combined FUTURE I and FUTURE II Data Set in the MITT 2 Population* for Individual Vaccine and Non-Vaccine HPV Types in 16- Through 26-Year-Old Girls and Women

Table 18 - Analysis of Efficacy Against CIN 2/3 or AIS Due to Any HPV Type for the Combined FUTURE I and FUTURE II Data Set in the General Population (Including HPV Infected Girls and Women)* for Individual Vaccine and Non-Vaccine HPV Types in 16- Through 26-Year-Old Girls and Women

Impact on the Rates of Pap Test Abnormalities and Cervical, Vulvar, and Vaginal Procedures in 16- Through 26-Year-Old Girls and Women

The impact of GARDASIL^® on rates of abnormal Pap tests and cervical procedures (colposcopic biopsy, definitive therapy) regardless of causal HPV types was evaluated in 18,150 individuals enrolled in Protocol 007, FUTURE I and FUTURE II. The impact of GARDASIL^® on rates of genital excisional procedures to treat lesions caused by any HPV type was evaluated in 5442 individuals enrolled in FUTURE I. Two populations were considered: (1) an HPV-naïve population (negative to 14 common HPV types and had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1), approximating a population of sexually-naïve individuals plus individuals shortly after sexual debut; and (2) the general study population of individuals regardless of baseline HPV status, some of whom had HPV-related disease at vaccination onset.

In both populations, GARDASIL^® reduced the proportions of individuals who experienced a Pap test abnormality suggestive of CIN, a colposcopic biopsy, a definitive cervical therapy procedure (Loop Electro-Excision Procedure or Cold-Knife Conization), a vulvar or vaginal biopsy, or a definitive excisional procedure of the vagina or vulva (Table 19).

Table 19 - Impact of GARDASIL^® on Rates of Pap Test Abnormalities and Cervical, Vulvar, and Vaginal Procedures in 16- Through 26-Year-Old Girls and Women

In addition, administration of GARDASIL^® to an HPV naïve population of 16- through 26-year-old individuals reduced the incidence of HPV 16-related and HPV 18-related Pap abnormalities (ASC-US HR positive, LSIL, or worse) by 92.4% (95% CI: 83.7%, 97.0%) and 96.9% (95% CI: 81.6%, 99.9%) in the FUTURE I study. These results should not be interpreted as a reason to reduce or eliminate Pap smear testing.

Immunogenicity

Assays to Measure Immune Response

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

No minimum anti-HPV 6, 11, 16, 18 antibodies level that protects against clinical disease caused by the HPV types has been established. This was partly due to the few disease cases in naïve individuals (PCR negative and seronegative) to vaccine HPV types, at baseline, in the group that received GARDASIL^®.

The immunogenicity of GARDASIL^® was assessed in 23,951, 9- through 45-year-old girls and women (GARDASIL^® N = 12,634; placebo N = 11,317) and 5417, 9- through 26-year-old boys and men (GARDASIL^® N = 3109; placebo N = 2308).

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

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

Immune Response to GARDASIL^®

In clinical studies in 16- through 26-year-old girls and women, 99.8%, 99.8%, 99.8%, and 99.4% who received GARDASIL^® became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month Postdose 3 across all age groups tested.

In clinical studies in 27- through 45-year-old women, 98.2%, 97.9%, 98.6%, and 97.1% who received GARDASIL^® became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested.

In clinical studies in 16- through 26-year-old in boys and men, 98.9%, 99.2%, 98.8%, and 97.4% who received GARDASIL^® became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested.

Across all populations, anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs peaked at month 7 (Table 20 and Table 21). GMTs declined through month 24 and then stabilized

through month 36 at levels above baseline. Tables 22 and 23 display the persistence of anti-HPV cLIA geometric mean titers by gender and age group. The duration of immunity following a complete schedule of immunization with GARDASIL^® has not been established.

Table 20 - Summary of Month 7Anti-HPV cLIA Geometric Mean Titers in the PPI* Population of 9- Through 45-Year-Old Girls and Women

Table 21 - Summary of Month 7 Anti-HPV cLIA Geometric Mean Titers in the PPI* Population of Boys and Men

Table 22 - Persistence of Anti-HPV cLIA Geometric Mean Titers in 9- Through 45-Year-Old Girls and Women

Table 23 - Persistence of Anti-HPV cLIA Geometric Mean Titers in 9- Through 26-Year-Old Boys and Men

Tables 20 and 21 display the Month 7 immunogenicity data for girls and women and boys and men. Anti-HPV responses 1 month postdose 3 among 9- through 15-year-old adolescent girls were non-inferior to anti-HPV responses in 16- through 26-year-old girls and women in the combined database of immunogenicity studies for GARDASIL^®. Anti-HPV responses 1 month postdose 3 among 9- through 15-year-old adolescent boys were non-inferior to anti-HPV responses in 16- through 26-year-old boys and men in Protocol 020.

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

Persistence of the Immune Response to GARDASIL^®

The duration of immunity following a complete schedule of immunization with GARDASIL^® has not been established. After peaking at Month 7, anti-GMTs for all HPV types decreased through Month 24 and then stabilized at levels above baseline.

In Protocol 007, peak anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs were observed at Month 7. The GMTs decreased through Month 24 and then stabilized until at least Month 60 (see Figure 2).

Figure 2 - Persistence of Anti-HPV Responses Following a 3-dose Regimen of GARDASIL^®

Persistence of Anti-HPV 11 Responses

Persistence of Anti-HPV 6 Responses

Persistence of Anti-HPV 16 Responses Persistence of Anti-HPV 18 Responses

Evidence of Anamnestic (Immune Memory) Response

Evidence of an anamnestic response was seen in vaccinated individuals who were seropositive to relevant HPV type(s) prior to vaccination.

In a study to evaluate the capacity to induce immune memory, individuals who received a 3-dose primary series of vaccine were given a challenge dose of GARDASIL^® 5 years after the onset of vaccination. These individuals exhibited a rapid and strong anamnestic response that exceeded the anti-HPV GMTs observed 1 month Postdose 3 (Month 7). The GMTs 1 week post-challenge dose were 0.9-, 2.2-, 1.2-, and 1.4-fold higher than the Postdose 3 GMTs for types 6, 11, 16, and 18, respectively (Table 24). The GMTs 1 month post-challenge dose were 1.3-, 4.2-, 1.5-, and 1.7-fold higher than the Postdose 3 GMTs for types 6, 11, 16, and 18 respectively (Table 24). At 1 week post-challenge dose, 87.2%, 94.9%, 86.4% and 95.2% of individuals had anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs higher than those detected at Month 60.

In addition, a subset of individuals that received a 3-dose primary series of vaccine became nominally anti-HPV 18 seronegative by Month 60. Although these individuals were nominally anti-HPV 18 seronegative, no cases of HPV 18-related disease were detected among these individuals. They also showed immune memory: when these individuals were given a challenge dose of GARDASIL^® (at Month 60), 93% and 97% became anti-HPV 18 seropositive by 1 week and 1 month post-challenge, respectively; 73% had anti-HPV 18 levels at 1 month post-challenge that were higher than their Month 7 (1 month Postdose 3) anti-HPV 18 level.

Table 24 - Comparison of HPV Antibody Responses At Month 7, Month 60, 1 Week Post-challenge Dose, and 1 Month Post-challenge Dose for GARDASIL^® in The Extension Per-protocol Population*

Persistence of Immune Response in Phase III Studies of 9- Through 45-Year-Old Girls and Women for GARDASIL^®

Anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositivity was highest at Month 7, and then declined at persistence time points. At Month 48, anti-HPV seropositivity was highest among 9- through 15-year-olds and lowest among 35- through 45-year-olds for HPV types 6, 11, and 18. Anti-HPV 16 seropositivity was comparable at Month 24 in the 18- through 26-year-olds as compared to the 9- through 17-year-olds.

The decline in the percent seropositivity for anti-HPV 18 responses was greater than the decline in the percent seropositivity for anti-HPV 6, anti-HPV 11, and anti-HPV 16 responses. Despite this decline, the efficacy of the vaccine remained high, across all age groups. In the PPE population of the FUTURE I and FUTURE II studies, efficacy against HPV 18-related CIN 2/3 or AIS was 100.0% (95% CI: 86.6%, 100.0%) and efficacy against HPV 18-related CIN (any grade) or AIS was 98.4% (95% CI: 90.6%, 100.0%). In the PPE population of the FUTURE III study, efficacy against HPV 18-related persistent infection or cervical, vulvar, and vaginal disease was 100.0% (95% CI: 67.4%, 100.0%).

Persistence of Immune Response in Phase III Studies of 9- Through 26-Year-Old Boys and Men for GARDASIL^®

Anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositivity was highest at Month 7, and then generally declined at persistence time points. At Month 36, anti-HPV seropositivity was highest among 9- through 15-year-olds and lowest among 16- through 26-year-olds.

The decline in the percent seropositivity for anti-HPV 18 responses was greater than the decline in the percent seropositivity for anti-HPV 6, anti-HPV 11, and anti-HPV 16 responses. Despite this decline, the efficacy of the vaccine remained high, across all age groups.

Schedule Flexibility

All individuals evaluated in the PPE populations of the Phase II and III studies received the 3-dose regimen of GARDASIL^® within a 1-year period, regardless of the interval between doses. An analysis of immune response data suggests that flexibility of ±1 month for Dose 2 (i.e., Month 1 to Month 3 in the vaccination regimen) and flexibility of ±2 months for Dose 3 (i.e., Month 4 to Month 8 in the vaccination regimen) do not substantially impact the immune responses to GARDASIL^® (see DOSAGE AND ADMINISTRATION).

Immune Responses to GARDASIL^® using a 2-dose schedule

A clinical trial showed that, at Month 7, the immune response in girls aged 9-13 years (n=259) who received 2 doses of GARDASIL^® (at 0, 6 months) was not inferior to the immune response in women aged 16-26 years (n=310) who received 3 doses of GARDASIL^® (at 0, 2, 6 months). The administration of the second dose at intervals other than 6 or 12 months after the first dose has not been formally evaluated.

Duration of protection of a 2-dose schedule of GARDASIL^® has not been established.

Studies with Other Vaccines

Studies with RECOMBIVAX HB^® [hepatitis B vaccine (recombinant)] The safety and immunogenicity of co-administration of GARDASIL^® with RECOMBIVAX HB^® [hepatitis B vaccine (recombinant)] (same visit, injections at separate sites) were evaluated in a randomized study of 1871 women aged 16 through 24 years at enrollment. Immune response and safety profile to both RECOMBIVAX HB^® [hepatitis B vaccine (recombinant)] and GARDASIL^® were similar whether they were administered at the same visit or at a different visit.

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

The safety and immunogenicity of co-administration of GARDASIL^® with Menactra* [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel* [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis

Vaccine Adsorbed (Tdap)] (same visit, injections at separate sites) were evaluated in a randomized study of 1040 boys and girls 11 through 17 years of age at enrollment. Concomitant administration of GARDASIL^® with Menactra* [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel* [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] does not interfere with the antibody response to any of the components of any of the vaccines. In addition, the safety profile was generally similar (See DRUG INTERACTIONS, Drug-Drug Interactions, Use with Other Vaccines).

TOXICOLOGY

ANIMAL TOXICOLOGY

Acute and Subacute Toxicity

Single-dose (acute) toxicity studies in mice and rats showed no evidence of toxicity. The doses administered were 56 µg total protein for mice which corresponds to approximately 1200-fold the projected human dose and 112 µg total protein for rats which corresponds to approximately 300-fold the projected human dose.

A three-dose (subacute) toxicity study in mice showed a mixed inflammatory response at the injection site and hyperplasia in the draining lymph nodes but no significant changes in the tissues as assessed by histomorphologic examinations. The dose administered for mice was 56 µg total protein which corresponds to approximately 1450-fold excess relative to the projected human dose.

Local Tolerance

An intramuscular irritation (local tolerance) study in rabbits showed that the vaccine caused very slight to moderate irritation at the injection site. The irritation was similar to or slightly greater than the AAHS adjuvant placebo control as assessed by histomorphologic examinations. The dose administered for rabbits ranged from 120 to 280 µg total protein which corresponds to approximately 20- to 40-fold excess relative to the projected human dose.

Carcinogenesis and Mutagenesis

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

Reproductive Toxicology

GARDASIL^® administered to female rats at a dose of 120 µg total protein, which corresponds to approximately 300-fold excess relative to the projected human dose, had no effects on mating performance, fertility, or embryonic/fetal survival.

GARDASIL^® administered to male rats at a dose of 120 µg total protein, which corresponds to approximately 200-fold excess relative to the projected human dose, had no effects on reproductive performance including fertility, sperm count, and sperm motility, and there were no vaccine-related gross or histomorphologic changes on the testes and no effects on testes weights.

Developmental Toxicology

GARDASIL^® administered to female rats at a dose of 120 µg total protein, which corresponds to approximately 300-fold excess relative to the projected human dose, showed no evidence of developmental toxicity as assessed by embryonic/fetal survival, fetal body weight, and fetal external, visceral, coronal, or skeletal morphology. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring.

Antibodies against all 4 HPV serotypes were transferred to the offspring during gestation and possibly during lactation. The passively transferred antibodies remained up to postnatal day 77, when they were last measured.

REFERENCES

1. 1. Walboomers JMM, Jacobs MV, Manos M, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-19.
2. 2.

   Muñoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al..

   Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348 (6):518-27.

3. 3. Bosch FX, Lorincz A, Munoz N et al. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244-65.
4. 4. Franco EL, Harper DM. Vaccination against human papillomavirus infection: a new paradigm in cervical cancer control. Vaccine 2005;23:2388-94.
5. 5.

   IARC Monograph on the Evaluation of Carcinogenic Risks to Humans: Human

   Papillomaviruses, 2005;90.

6. 6. American Cancer Society. Cancer facts and figures 2005.
7. 7.

   Joura E. Epidemiology, diagnosis, and treatment of Vulvar Intraepithelial Neoplasia. Curr

   Opin Obstet Gynecol 2002;14: 39-43.

8. 8. Dodge JA, Eltabbakh GH, Mount SL, Walker RP, Morgan A. Clinical features and risk of recurrence among patients with Vaginal Intraepithelial Neoplasia. Gynecol Oncol 2001;83:363-69.
9. 9. Koutsky LA. Epidemiology of genital HPV infection. Am J Med 1997;102: 3-8.
10. 10. Health Canada. It's Your Health: Human Papillomavirus (HPV). September 2004.
11. 11. Sellors JW, Mahony JB, Kaczorowski J, Lytwyn A, Bangura H, Chong S, et al. Prevalence and predictors of human papillomavirus infection in women in Ontario, Canada. CMAJ 2000;163(5):503-8.
12. 12. Health Canada. Cervical Cancer Screening in Canada: 1998 Surveillance Report.
13. 13.

    Kliewer, E, Demers, A, Elliott, L, and Bristow, R. E. Poster From 24 th International

    Papillomavirus Conference and Clinical Workshop.Beijing.Nov 3-9,2007. - Twenty Year Trends (1985-2004) in the Incidence and Prevalence of Anogenital Warts in Manitoba, Canada: Preliminary Results. Incidence/Prevalence.

14. 14.

    National Advisory Committee on Immunization (NACI). An Advisory Committee

    Statement (ACS): Statement on Human Papillomavirus Vaccine. Canada Communicable Disease Report 2007;33(ACS-2):1-32.

15. 15.

    Duarte-Franco E and Franco EL. Women's Health Surveillance Report: Cancer of the

    Uterine Cervix, 2003.

16. 16.

    Saslow D, Runowicz CD, Solomon D, Mosciki AB, Smith RA, Eyre HJ, et al. American

    Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 2002;52:342-62.

17. 17. Canadian Cancer Society. Canadian Cancer Statistics 2005.
18. 18. Marrett LD. Cancer incidence in young adults in Canada: Preliminary results of a cancer surveillance project. Chronic Dis Can 2002;23(2):58-64.
19. 19.

    Maw RD, Reitano M, Roy M. An international survey of patients with genital warts:

    perceptions regarding treatment and impact on lifestyle. Int J STD AIDS 1998;9:571-8.

20. 20. Munk C, Svare EI, Poll P, Bock JE, Kjaer S. History of genital warts in 10,838 women 20 to 29 years of age from the general population: risk factors and association with Papanicolaou smear history. Sex Transm Dis 1997;24(10):567-72.
21. 21. PHLS Communicable Disease Surveillance Centre. Sexually transmitted infections quarterly report: anogenital warts and HSV infection in England and Wales. CDR Weekly 2001;11(35).
22. 22.

    Kliewer, E., Demers, A., Elliott, L., Lotocki, R., Musto, G. Twenty Year Trends (1985-

    2004) in the Incidence and Prevalence of Anogenital Warts in Manitoba. Cancer Care in Manitoba, 2008.

23. 23.

    Marra F., Ogilvie, G., Colley L., Kliewer E., A Marra, C. Epidemiology and Costs

    Associated with Genital Warts in Canada. www.sti.bmj.com. Consulted on 7 January 2009.

24. 24.

    Butler JRG., Kliewer EV., Demers AA., Musto G., Lotocki R., et al. The Cost of Treating

    Anogenital Warts in Manitoba, Canada. Poster presented at the 24th International Papillomavirus Conference, Beijing, China, November 3-9, 2007.

25. 25. Clifford GM, Smith JS, Plummer M, Munoz M. Fransceschi. Human Papillomavirus Types in Cervical Cancer Worldwide: A Meta-analysis. Br. J Cancer 2003 (88):63-73.
26. 26. von Krogh G, Lacey CJN, Gross G, Barrasso R, Schneider A. European course on HPV associated pathology: guidelines for primary care physicians for the diagnosis and management of anogenital warts ; Sex Transm Inf 2000;(76):162-68.
27. 27. Daling JR, Madeleine MM, Schwartz SM, Shera KA, Carter JJ, McKnight B, et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Pathol 2002;84:263-70.
28. 28. Bernard HU, Bosch FX, Campo MS, Cuzick J, Gissmann L, Koutsky LA, et al. Studies of cancer in humans. IARC Monographs on the evaluation of carcinogenic risks to humans. 1995:87-130.
29. 29.

    Moore RA, Fornika DJ, Moravan V, Amirabbasi-Biek M, Kollar A, Towers L, St. Germain

    L, Brisson M, Matisic J, Ogilvie G and Brooks-Wilson AR. HPV Type Distribution in North America - A Population-Based Study of 5000 British Columbia Women. [Abstract]. 23rd International Papillomavirus Conference and Clinical Workshop 2006;P-367.

30. 30.

    Jansen KU, Rosolowsky M, Schultz LD, Markus HZ, Cook JC, Donnelly JJ, et al.

    Vaccination with yeast-expressed cottontail rabbit papillomavirus (CRPV) virus-like particles protects rabbits from CRPV-induced papilloma formation. Vaccine 1995;13(16):1509-14.

31. 31. Suzich JA, Ghim SJ, Palmer-Hill FJ, White WI, Tamura JK, Bell JA, et al. Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas. Proc Natl Acad Sci U S A 1995;92:11553-7.
32. 32. Lowe RS, Brown DR, Bryan JT, Cook JC, George HA, Hofmann KJ, et al. Human papillomavirus type 11 (HPV-11) neutralizing antibodies in the serum and genital mucosal secretions of African green monkeys immunized with HPV-11 virus-like particles expressed in yeast. J Infect Dis 1997;176:1141-5.
33. 33.

    Benedet JL, Odicino F, Maisonneuve P, Beller U, Creasman WT, Heintz APM, et al.

    Carcinoma of the cervix uteri. Int J of Gynecol and Obstet 2003;83(Suppl 1):41-78.

34. 34. Sellors JW, Karwalajtys TL, Kaczorowski J, et al. Incidence, clearance and predictors of human papillomavirus infection in women. CMAJ 2003;168(4):421-5.
35. 35.

    Public Health Agency of Canada. What Everyone Should Know About Human

    Papillomavirus (HPV): Questions And Answers. Accessible online. Dec 1, 2005.

36. 36. Akom E, Venne S. Human Papillomavirus (HPV) Infection. Literature survey an expert consultation from a public health perspective – dimensions and nature of the HPV infection, prevention and public health impact. Institut National de Santé Publique du Québec 2002;374(2nd Quarter): I-152.
37. 37. Dobson SR, McNeil S, Dionne M, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women. JAMA 2013; 309(17): 1793-1802.