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.

GARDASIL is a vaccine indicated in girls and women 9-26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types 6, 11, 16, and 18:

· Cervical cancer

· Genital warts (condyloma acuminata) and the following precancerous or dysplastic lesions:

· 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 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

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. Subcutaneous and intradermal administration have not been studied, and therefore are not recommended.

The prefilled syringe is for single use only and should not be used for more than 1 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. Do not use the product if particulates are present or if it appears discolored.

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.

Inject the entire contents of the syringe.

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

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

No. 4045 GARDASIL is supplied as a carton of one 0.5-mL single-dose vial, NDC 0006-4045-00.
No. 4045 GARDASIL is supplied as a carton of ten 0.5-mL single-dose vials, NDC 0006-4045-41.

No. 4109 GARDASIL is supplied as a carton of one 0.5-mL single-dose prefilled Luer Lock syringe, preassembled with UltraSafe Passive† delivery system. A one-inch, 25-gauge needle is provided separately in the package. NDC 0006-4109-31.

No. 4109 GARDASIL is supplied as a carton of six 0.5-mL single-dose prefilled Luer Lock syringes, preassembled with UltraSafe Passive† delivery system. One-inch, 25-gauge needles are provided separately in the package. NDC 0006-4109-06.

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

In 5 clinical trials (4 placebo-controlled), subjects were administered GARDASIL or placebo on the day of enrollment, and approximately 2 and 6 months thereafter. Few subjects (0.1%) discontinued due to adverse experiences. In all except 1 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 subjects who were monitored using VRC-aided surveillance included 5088 girls and women 9 through 26 years of age at enrollment who received GARDASIL and 3790 girls and women who received placebo.

The vaccine-related adverse experiences that were observed among female 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 Table 6.

Table 6
Vaccine-related Injection-site and Systemic Adverse Experiences*

*The vaccine-related adverse experiences that were observed among recipients of GARDASIL were at a frequency of at least 1.0% and also at a greater frequency than that observed among placebo recipients.

All-cause systemic adverse experiences for female subjects 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 Table 7.

Table 7
All-cause Common Systemic Adverse Experiences

Evaluation of Injection-site Adverse Experiences by Dose

An analysis of injection-site adverse experiences in female subjects by dose is shown in Table 8. Overall, 94.3% of subjects who received GARDASIL judged their injection-site adverse experience to be mild or moderate in intensity.

Table 8
Postdose Evaluation of Injection-site Adverse Experiences

Evaluation of Fever by Dose

An analysis of fever in girls and women by dose is shown in Table 9.

Table 9
Postdose Evaluation of Fever

Serious Adverse Experiences

A total of 102 subjects out of 21,464 total subjects (9- to 26-year-old girls and women and 9- to 15-year-old boys) who received both GARDASIL and placebo reported a serious adverse experience on Day 1-15 following any vaccination visit during the clinical trials for GARDASIL. The most frequently reported serious adverse experiences for GARDASIL compared to placebo and regardless of causality were:

headache                           (0.03% GARDASIL vs. 0.02% Placebo),
gastroenteritis                     (0.03% GARDASIL vs. 0.01% Placebo),
appendicitis                        (0.02% GARDASIL vs. 0.01% Placebo),
pelvic inflammatory disease (0.02% GARDASIL vs. 0.01% Placebo).

One case of bronchospasm and 2 cases of asthma were reported as serious adverse experiences that occurred during Day 1-15 of any vaccination visit.

Across the clinical studies, 17 deaths were reported in 21,464 male and female subjects. The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (4 subjects who received GARDASIL and 3 placebo subjects), followed by overdose/suicide (1 subject who received GARDASIL and 2 subjects who received placebo), and pulmonary embolus/deep vein thrombosis (1 subject who received GARDASIL and 1 placebo subject). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, and 1 case of arrhythmia in the group that received GARDASIL, and 1 case of asphyxia in the placebo group.

In the clinical studies, subjects were evaluated for new medical conditions that occurred over the course of up to 4 years of follow up. The number of subjects who received both GARDASIL and placebo and developed a new medical condition potentially indicative of a systemic immune disorder is shown in Table 10.

Table 10
Summary of Subjects Who Reported an Incident Condition Potentially Indicative of Systemic Autoimmune Disorder After Enrollment in Clinical Trials of GARDASIL

Safety in Concomitant Use with Other Vaccines

The safety of GARDASIL when administered concomitantly with hepatitis B vaccine (recombinant) was evaluated in a placebo-controlled study. There were no statistically significant higher rates in systemic or injection-site adverse experiences among subjects who received concomitant vaccination compared with those who received GARDASIL or hepatitis B vaccine alone.

The US Department of Health and Human Services has established a Vaccine Adverse Event Reporting System (VAERS) to accept 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.

Use with Other Vaccines

Results from clinical studies indicate that GARDASIL may be administered concomitantly (at a separate injection site) with hepatitis B vaccine (recombinant) (see CLINICAL PHARMACOLOGY, Studies with Other Vaccines). Co-administration of GARDASIL with other vaccines has not been studied.

In clinical studies, 13,293 subjects (vaccine = 6644; placebo = 6649) who had post-Month 7 follow-up used hormonal contraceptives for a total of 17,597 person-years (65.1% of the total follow-up time in the study for these subjects). Use of hormonal contraceptives or lack of use of hormonal contraceptives among study participants did not alter vaccine efficacy in the PPE population.

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

No information provided.

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 genital warts; cervical cancer; CIN, VIN, or VaIN.

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

GARDASIL has not been shown to protect against diseases due to non-vaccine 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.

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.

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 PRECAUTIONS, Drug Interactions).

As with other intramuscular injections, GARDASIL should not be given to individuals with bleeding disorders such as hemophilia or thrombocytopenia, or to persons on anticoagulant therapy unless the potential benefits clearly outweigh the risk of administration. If the decision is made to administer GARDASIL to such persons, it should be given with steps to avoid the risk of hematoma following the injection.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

Pregnancy

Pregnancy Category B:

Reproduction studies have been performed in female rats at doses up to 300 times the human dose (on a mg/kg basis) and have revealed no evidence of impaired female fertility or harm to the fetus due to GARDASIL. However, it is not known whether GARDASIL can cause fetal harm when administered to a pregnant woman or if it can affect reproductive capacity. GARDASIL should be given to a pregnant woman only if clearly needed. An evaluation of the effect of GARDASIL on embryo-fetal, pre- and postweaning development was conducted using rats. One group of rats was administered GARDASIL twice prior to gestation, during the period of organogenesis (gestation day 6) and on lactation day 7. A second group of pregnant rats was administered GARDASIL during the period of organogenesis (gestation day 6) and on lactation day 7 only. GARDASIL was administered at 0.5 mL/rat/occasion (approximately 300-fold excess relative to the projected human dose on a mg/kg basis) by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring. The effect of GARDASIL on male fertility has not been studied.

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.

During clinical trials, 2266 women (vaccine = 1115 vs. placebo = 1151) reported at least 1 pregnancy each. Overall, the proportions of pregnancies with an adverse outcome were comparable in subjects who received GARDASIL and subjects who received placebo. Overall, 40 and 41 subjects in the group that received GARDASIL or placebo, respectively (3.6% and 3.6% of all subjects 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 subjects who experienced such events were comparable between the vaccination groups.

There were 15 cases of congenital anomaly in pregnancies that occurred in subjects who received GARDASIL and 16 cases of congenital anomaly in pregnancies that occurred in subjects who received placebo.

Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of GARDASIL or 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 0 cases of congenital anomaly in the group that received placebo. The congenital anomalies seen in pregnancies with estimated onset within 30 days of vaccination included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia and club foot. Conversely, in pregnancies with onset more than 30 days following vaccination, 10 cases of congenital anomaly were observed in the group that received GARDASIL compared with 16 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 to 26 years.

Pregnancy Registry for GARDASIL

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

Lactation

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

Because many drugs are excreted in human milk, caution should be exercised when GARDASIL is administered to a nursing woman.

A total of 995 nursing mothers (vaccine = 500, placebo = 495) were given GARDASIL or placebo during the vaccination period of the clinical trials. GMTs in nursing and non-nursing mothers were as follows:

The GMTs in nursing mothers were 595.9 (95% CI: 522.5, 679.5) for anti-HPV 6, 864.3 (95% CI: 754.0, 990.8) for anti-HPV 11, 3056.9 (95% CI: 2594.4, 3601.8) for anti-HPV 16, and 527.2 (95% CI: 450.9, 616.5) for anti-HPV 18. The GMTs for women who did not nurse during vaccine administration were 540.1 (95% CI: 523.5, 557.2) for anti-HPV 6, 746.3 (95% CI: 720.4, 773.3) for anti-HPV 11, 2290.8 (95% CI: 2180.7, 2406.3) for anti-HPV 16, and 456.0 (95% CI: 438.4, 474.3) for anti-HPV 18.

Overall, 17 and 9 infants of subjects who received GARDASIL or placebo, respectively (representing 3.4% and 1.8% of the total number of subjects 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-feeding infants (n = 6) whose mothers received GARDASIL had acute respiratory illnesses within 30 days post-vaccination of the mother as compared to infants (n = 2) whose mothers received placebo. In these studies, the rates of other adverse experiences in the mother and the nursing infant were comparable between vaccination groups.

Pediatric Use

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

Geriatric Use

The safety and efficacy of GARDASIL have not been evaluated in adults above the age of 26 years.

No information provided.

Hypersensitivity to the active substances or to any of the excipients of the vaccine.

Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of GARDASIL should not receive further doses of GARDASIL.

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.

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.

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 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.

Overall, 73% of subjects were naïve (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 naïve (PCR negative and seronegative) to the remaining 3 types.

In subjects who were naïve (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 naïve (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 was efficacious against HPV disease caused by each of the 4 vaccine HPV types.

In a pre-defined analysis, the efficacy of GARDASIL against HPV 16/18-related disease was 100% (95% CI: 87.9%, 100.0%) for CIN 3 or AIS and 100% (95% CI: 55.5%, 100.0%) for VIN 2/3 or VaIN 2/3. The efficacy of GARDASIL against HPV 6-, 11-, 16-, and 18-related VIN 1 or VaIN 1 was 100% (95% CI: 75.8%, 100.0%). These analyses were conducted in the PPE population that 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).

GARDASIL is a prophylactic vaccine.

There was no clear evidence of protection from disease caused by HPV types for which subjects were PCR positive and/or seropositive at baseline.

Individuals who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from clinical disease caused by the remaining vaccine HPV types.

The general population of young American women 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. The clinical trials population approximated the general population of American women with respect to prevalence of HPV infection and disease at enrollment. 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 2. Impact was measured starting 1 month Postdose 1. Prophylactic efficacy denotes the vaccines 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 2
General Population Impact for Vaccine HPV Types

GARDASIL does not prevent infection with the HPV types not contained in the vaccine. Cases of disease due to non-vaccine types were observed among recipients of GARDASIL and placebo in Phase II and Phase III efficacy studies.

Among cases of CIN 2/3 or AIS caused by vaccine or non-vaccine HPV types in subjects in the general population who received GARDASIL, 79% occurred in subjects who had an abnormal Pap test at Day 1 and/or who were positive (PCR positive and/or seropositive) to HPV 6, 11, 16, and/or 18 at Day 1.

An interim analysis of the general population impact for GARDASIL was performed from studies 007, 013, and 015 that had a median duration of follow-up of 1.9 years. GARDASIL reduced the overall rate of CIN 2/3 or AIS caused by vaccine or non-vaccine HPV types by 12.2% (95% CI: -3.2%, 25.3%), compared with placebo.

An analysis of overall population impact for the HPV 16 L1 VLP vaccine was conducted from study 005 that had a median duration of follow-up of 3.9 years. The HPV 16 L1 VLP vaccine reduced the overall incidence of CIN 2/3 caused by vaccine or non-vaccine HPV types by 32.7% (95% CI: -34.7%, 67.3%) through a median duration of follow-up of 1.9 years (fixed case analysis) and by 45.3% (95% CI: 10.9%, 67.1%), through a median duration of follow-up of 3.9 years (end of study).

GARDASIL reduced the incidence of definitive therapy (e.g., loop electrosurgical excision procedure, laser conization, cold knife conization) by 16.5% (95% CI: 2.9%, 28.2%), and surgery to excise external genital lesions by 26.5% (95% CI: 3.6%, 44.2%), compared with placebo for all HPV-related diseases. These analyses were performed in the general population of women which includes women regardless of baseline HPV PCR status or serostatus. GARDASIL has not been shown to protect against the diseases caused by all HPV types and will not treat existing disease caused by the HPV types contained in the vaccine. The overall efficacy of GARDASIL, described above, will depend on the baseline prevalence of HPV infection related to vaccine types in the population vaccinated and the incidence of HPV infection due to types not included in the vaccine.

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

The immunogenicity of GARDASIL was assessed in 8915 women (GARDASIL N = 4666; placebo N = 4249) 18 to 26 years of age and female adolescents 9 to 17 years of age (GARDASIL N = 1471; placebo N = 583).

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.

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.

Overall, 99.8%, 99.8%, 99.8%, and 99.5% of girls and women 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. Anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs peaked at Month 7. GMTs declined through Month 24 and then stabilized through Month 36 at levels above baseline (Table 3). The duration of immunity following a complete schedule of immunization with GARDASIL has not been established.

Table 3
Summary of Anti-HPV cLIA Geometric Mean Titers in the PPI* Population

Table 4 compares anti-HPV GMTs 1 month Postdose 3 among subjects who received Dose 2 between Month 1 and Month 3 and subjects who received Dose 3 between Month 4 and Month 8 (Table 4).

Bridging the Efficacy of GARDASIL from Young Adult Women to Adolescent Girls

A clinical study compared anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs in 10- to 15-year-old girls with responses in 16- to 23-year-old adolescent and young adult women. Among subjects who received GARDASIL, 99.1 to 100% became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive by 1 month Postdose 3.

Table 5 compares the 1 month Postdose 3 anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs in 9- to 15-year-old girls with those in 16- to 26-year-old adolescent and young adult women.

Table 5
Immunogenicity Bridging Between 9- to 15-year-old Female Adolescents and 16- to 26-year-old Adult Women

Anti-HPV responses 1 month Postdose 3 among 9- to 15-year-old girls were non-inferior to anti-HPV responses in 16- to 26-year-old adolescent and young adult women in the combined database of immunogenicity studies for GARDASIL.

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

The safety and immunogenicity of co-administration of GARDASIL with hepatitis B vaccine (recombinant) (same visit, injections at separate sites) were evaluated in a randomized study of 1871 women aged 16 to 24 years at enrollment. Immune response to both hepatitis B vaccine (recombinant) and GARDASIL was non-inferior whether they were administered at the same visit or at a different visit.

Information for the Patient, Parent, or Guardian

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.

The health care provider should provide the vaccine information required to be given with each vaccination to the patient, parent, or guardian.

The health care provider should inform the patient, parent, or guardian of the benefits and risks associated with vaccination. For risks associated with vaccination, see PRECAUTIONS and ADVERSE REACTIONS.

GARDASIL is not recommended for use in pregnant women.

The health care provider should inform the patient, parent, or guardian of the importance of completing the immunization series unless contraindicated.

Patients, parents, or guardians should be instructed to report any adverse reactions to their health care provider.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

HUMAN PAPILLOMAVIRUS VACCINE - INJECTION

COMMON BRAND NAME(S): Gardasil

USES: This medication is a vaccine used to prevent cervical cancer, genital warts, and abnormal tissue growth in the vagina/cervix that can lead to cancer in women. These conditions are commonly caused by certain types of human papillomavirus (HPV). Vaccines work by increasing the body's natural defense (immunity) against the virus.

This medication does not protect against all types of HPV, only the types in the vaccine. It is used to prevent the diseases and will not treat active cervical cancer, genital warts, or other diseases caused by the types of HPV in the vaccine.

HOW TO USE: Read the Patient Information Leaflet available from your health care provider before being given this vaccine. If you have any questions, consult your doctor or pharmacist.

This vaccine is given by injection into the muscle of the thigh or upper arm by a health care professional. This vaccine must not be injected directly into a vein.

Before using, shake the medication well. It should be a white, cloudy liquid after shaking. Check the product visually for particles or discoloration. If either is present, do not use the liquid.

This vaccine is given as 3 separate doses. The second dose should be given 2 months after the first dose, and the third dose should be given 6 months after the first dose. The vaccination schedule should be followed closely for the vaccine to be most effective.

SIDE EFFECTS: Redness, itching, swelling, bruising, and pain at the injection site may occur. Fever may also occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these rare but very serious side effects occur: joint pain/swelling.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before receiving this medication, tell your doctor or pharmacist if you are allergic to it; or to other vaccines; or if you have any other allergies.

Before receiving this vaccination, tell your doctor or pharmacist your medical history, especially of: immune system problems (e.g., HIV infection), bleeding disorders (e.g., hemophilia, thrombocytopenia), current fever/illness.

This vaccine is not recommended for use during pregnancy. Consult your doctor for more details.

It is not known if this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before receiving this vaccination, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: "blood thinners" (e.g., warfarin), cancer chemotherapy, corticosteroids (e.g., prednisone, dexamethasone), drugs that weaken the immune system (e.g., cyclosporine, tacrolimus).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: Overdose with this vaccine is highly unlikely. If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center.

NOTES: As with any vaccine, this vaccine may not fully protect everyone who receives it.

Getting this vaccine does not replace cervical cancer screening. Continue to have regular obstetrician/gynecologist checkups.

MISSED DOSE: If you miss a dose in the vaccination schedule, contact your doctor immediately.

STORAGE: Store refrigerated between 36-46 degrees F (2-8 degrees C) away from light. Do not freeze. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.