Full Prescribing Info
Contents
Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine.
Description
Each 0.5-mL dose contains approximately: Human papillomavirus (HPV) type 6 L1 protein 20 mcg, HPV type 11 L1 protein 40 mcg, HPV type 16 L1 protein 40 mcg, HPV type 18 L1 protein 20 mcg.
L1 protein in the form of virus-like particles produced in yeast cells (Saccharomyces cerevisiae) CANADE 3C-5 (Strain 1895) by recombinant DNA technology and adsorbed on amorphous aluminum hydroxyphosphate sulphate adjuvant (225 mcg AI).
Gardasil also contains the following excipients: Sodium chloride, L-histidine, polysorbate 80, sodium borate and water for injections.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Gardasil is a non-infectious recombinant quadrivalent vaccine prepared from the highly purified virus-like particles (VLPs) at the major capsid L1 protein of HPV types 6, 11, 16 and 18. The VLPs contain no viral DNA, they cannot infect cells, reproduce or cause disease. HPV only infects humans, but animal studies with analogous papillomaviruses suggest that the efficacy of L1 VLP vaccines is mediated by the development of a humoral immune response.
Of the HPV types in the vaccine, HPV 16 and 18 are responsible for approximately 70% of high-grade cervical dysplasia (CIN 2/3) and adenocarcinoma in situ (AIS) cases, and approximately 70% of high-grade vulvar dysplasia (VIN 2/3) cases in young premenopausal females. HPV 16 and 18 are also responsible for a majority of high-grade squamous vaginal lesions (VaIN 2/3). Other HPV types not contained in the vaccine are responsible for 20-30% of remaining cases of CIN 2/3, VIN 2/3 and VaIN 2/3. CIN 3 is an accepted immediate precursor of invasive cervical cancer. VIN 3 is an important risk factor for the development of vulvar cancer in young premenopausal females infected with carcinogenic HPV types.
HPV 6 and 11 are responsible for approximately 90% of genital warts cases.
HPV 6, 11, 16 and 18 are responsible for 35-50% of CIN 1 or low-grade cervical dysplasia.
Clinical Studies: The efficacy of Gardasil was assessed in 4 placebo-controlled, double-blind, randomized phase II and III clinical studies including a total of 20,541 16- to 26-year old women, who were enrolled and vaccinated without pre-screening for the presence of HPV infection.
The primary efficacy endpoints induded HPV 6-, 11-, 16- or 18-related vulvar and vaginal lesions (genital warts, VIN, VaIN) and CIN of any grade (Protocol 013, Future I), HPV 16- or 18-related CIN 2/3 and AIS (Protocol 015, Future II) HPV 6-, 11-, 16- or 18-related persistent infection (Protocol 007), and HPV 16-related persistent infection (Protocol 005).
Cervical intraepithelial neoplasia (CIN) grade 2/3 (moderate- to high-grade dysplasia) was used in the clinical trials as a surrogate marker for cervical cancer.
Prophylactic Efficacy: The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population (n=all 3 vaccinations within 1 year of enrollment, no major protocol deviations and naive to the relevant HPV type(s) prior to dose 1 and through 1 month post-dose 3 (month 7). Efficacy was measured starting after the month 7 visit. Overall, 73% of subjects were naive (PCR negative and seronegative) to all 4 HPV types at enrollment.
Efficacy in Subjects Naive to the Relevant Vaccine HPV Type(s): The efficacy results for relevant endpoints in the per-protocol population are presented in Table 1. (See Table 1.)


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The efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related CIN (1, 2, 3) or AIS was 100% (97.5% CI: 87.4, 100) in Protocol 013 where it was the primary endpoint and 95.2% (95% CI: 87.2, 98.7) in the combined protocols.
The efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related CIN 1 was 100% (95% CI: 84.1, 100) in Protocol 013 and in the combined analysis, it was 93.1% (95% CI: 81.4, 98.2).
In the integrated analysis (Protocols 007, 013, 015), the efficacy of Gardasil against high-grade HPV 6-, 11-, 16- or 18-related vulvar lesions (VIN 2/3) was 100% (95% CI: 41.4, 100). Vaccine efficacy against high-grade vaginal lesions (VaIN 2/3) did not reach statistical significance. Altogether, there were 8 cases 1 VIN 2/3 and 5 cases of VaIN 2/3, all occurred in the placebo group.
On the basis of 12-month definition of persistent infection (ie, at least 2 positive specimens over a minimum interval of 12 months), the efficacy against persistent HPV 16 infection was 93.3% (95% CI: 79.1, 98.7) in Protocol 005. In Protocol 007, the efficacy of Gardasil against persistent HPV 16 or HPV 18 infection was 100% (95% CI: 43.3, 100). There were 6 cases of persistent HPV 16 infection, and 2 cases of persistent HPV 18 infection, all in the placebo group.
Efficacy in Subjects With Current or Prior Infection: There was no evidence of protection from disease caused by HPV types for which subjects were PCR positive and/or seropositive at baseline. However, individuals who were already infected with ≥1 vaccine-related HPV types prior to vaccination were protected from clinical disease caused by the remaining vaccine HPV types.
In the modified intention-to-treat (ITT) population, defined as women who received at least 1 vaccination regardless of baseline HPV status at day 1 with case counting starting at 1 month post-dose 1, the results are summarized in Table 2. This population approximates to the general population of women with respect to prevalence of HPV infection and disease at enrollment. (See Table 2.)


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The efficacy of Gardasil against HPV 6-, 11-, 18-related CIN (1, 2, 3) or AIS was 46.4% (95% CI: 35.2, 55.7) in this same population.
Overall, 12% of the combined study population had an abnormal Pap test suggestive of CIN at day 1. Among subjects with an abnormal Pap test at day 1 who were naive to the relevant vaccine HPV types at day 1, efficacy of Gardasil remained high. Among subjects with an abnormal Pap test at day 1 who were already infected with the relevant vaccine HPV types at day 1, no vaccine efficacy was observed.
Immunogenicity: Assays to Measure Immune Response: No minimum antibody level associated with protection has been identified for HPV vaccines.
The immunogenicity of Gardasil was assessed in 8915 (Gardasil n=4666; placebo n=4249) women 18-26 years and 3400 female (Gardasil n=1471; placebo n=583) and male (Gardasil n=1071: placebo n=275) adolescents 9-17 years.
Type-specific immunoassays, competitive Luminex-based immunoassay (cLIA), with type-specific standards were used to assess immunogenicity to each vaccine type. This assay measures antibodies against neutralizing epitopes for each HPV type.
Immune Responses to Gardasil: Overall, 99.9%, 99.8%, 99.8% and 99.6% of individuals who received Gardasil became anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 seropositive, respectively, by 1 month post-dose 3 across all age groups tested. Gardasil induced high anti-HPV Geometric Mean Titres (GMTs) 1 month post-dose 3 in all age group tested.
Anti-HPV levels in placebo subjects who had cleared an HPV infection (seropositive and PCR negative) were substantially lower than those induced by the vaccine. Furthermore, anti-HPV levels in vaccinated subjects remained higher during the long-term follow-up of the phase III studies.
Bridging the Efficacy of Gardasil to Young Adult Women to Young Adolescents: A clinical study (Protocol 016) compared the immunogenicity of Gardasil in 10- to 15-year-old boys and girls to those in 16- to 23-year old adolescent and young women. In the vaccine group, 99.1-100% became seropositive to all vaccine serotypes by 1 month post-dose 3.
Table 3 compares the 1 month post-dose 3 anti-HPV 6, 11, 16 and 18 GMTs in 9- to 15-year old boys and girls with those in 16- to 26-year old young women. (See Table 3.)


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Anti-HPV responses at month 7 among 9- to 15-year old girls and boys were non-inferior to anti-HPV responses in 16- to 26-year old young women for whom efficacy was established in the phase III studies. Immunogenicity was related to age and month 7 anti-HPV levels were significantly higher younger individuals <12 years than in those above that age.
On the basis of this immunogenicity bridging, the efficacy of Gardasil in 9- to 15-year old girls is inferred.
Immunogenicity and safety of Gardasil have been demonstrated in 9- to 15-year old boys. Protective efficacy has not been evaluated in males.
Persistence: In Protocol 007, peak anti-HPV 6, 11, 16, 18 GMTs were observed at month 7. The GMTs declined through month 24 and then stabilized until at least month 60. The observation period is currently limited to 2 years in the phase III trials of young women and 18 months in trials of adolescents. The exact duration of immunity following a 3-dose series has not been established.
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 addition, a subset of vaccinated individuals who received a challenge dose of Gardasil 5 years after the onset of vaccination, exhibited a rapid and strong anamnestic response that exceeded the anti-HPV GMTs observed 1 month post-dose 3.
Pharmacokinetics: Evaluation of pharmacokinetic studies is not required for vaccines.
Toxicology: Preclinical Safety Data: Single-dose and repeated-dose toxicity, and local tolerance studies revealed no special hazard to humans.
Gardasil induced specific antibody responses against HPV types 6, 11, 16 and 18 in pregnant rats, following 1 or multiple IM injections. Antibodies against all 4 HPV types were transferred to the offspring during gestation and possibly during lactation. There were no treatment-related effects on development signs, behavior, reproductive performance or fertility of the offspring.
Indications/Uses
Gardasil is a vaccine for the prevention of high-grade cervical dysplasia (CIN 2/3), cervical carcinoma, high-grade vulvar dysplastic lesions (VIN 2/3) and external genital warts (condyloma acuminata) causally related to human papillomavirus (HPV) types 6, 11, 16 and 18.
The indications are based on the demonstration of efficacy of Gardasil in adult females 16-26 years and on the demonstration of immunogenicity of Gardasil in 9- to 15-year old children and adolescents. Protective efficacy has not been evaluated in males (see Pharmacology under Actions). The use of Gardasil should be in accordance with official recommendations.
Dosage/Direction for Use
The primary vaccination series consists of 3 separate 0.5-mL doses administered according to the following schedule: 0, 2, 6 months.
If an alternate vaccination schedule is necessary, the 2nd dose should be administered at least 1 month after the 1st dose and the 3rd dose should be administered at least 3 months after the 2nd dose. All 3 doses should be given within a 1-year period.
The need for a booster dose has not been established.
Children: Gardasil is not recommended for use in children <9 years due to insufficient data on immunogenicity, safety and efficacy (see Pharmacology under Actions).
Administration: Gardasil should be administered by IM injection. The preferred site is the deltoid area of the upper arm or in the higher anterolateral area of the thigh.
Gardasil must not be injected intravascularly. SC and intradermal administration have not been studied, and therefore, are not recommended (see Cautions for Usage for disposal and other handling).
Overdosage
There have been reports of administration of higher than recommended doses of Gardasil. In general, the adverse event profile reported with overdose was comparable to recommended single doses of Gardasil.
Contraindications
Hypersensitivity to quadrivalent human papillomavirus (types 6, 11, 16, 18) or to any other excipients of Gardasil.
Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of Gardasil should not receive further doses of Gardasil.
Administration of Gardasil should be postponed in subjects suffering from an acute severe febrile illness. However, the presence of a minor infection eg, a mild upper respiratory tract infection or low-grade fever, is not a contraindication of immunization.
Special Precautions
As with all injectable vaccines, appropriate medical treatment should always be readily available in case of rare anaphylactic reactions following the administration of Gardasil.
As with any vaccine, vaccination with Gardasil may not result in protection in all vaccine recipients. Also, Gardasil will only protect against diseases that are caused by HPV types 6, 11, 16 and 18. Therefore, appropriate precautions against sexually transmitted diseases should continue to be used.
Gardasil has not been shown to have a therapeutic effect. It is therefore not indicated for treatment of cervical cancer, high-grade cervical, vulvar and vaginal dysplastic lesions or genital warts. It is also not intended to prevent progression of other established HPV-related lesions.
Vaccination is not a substitute for routine cervical screening. Since no vaccine is 100% effective and Gardasil will not provide protection against non-vaccine HPV types, or against existing HPV infections, routine cervical screening remains critically important and should follow local recommendations.
There are no data on the use of Gardasil in subjects with impaired immune responsiveness. Individuals with impaired immune responsiveness, whether due to the use of potent immunosuppressive therapy, a genetic defect, human immunodeficiency virus (HIV) infection or other causes, may not respond to Gardasil.
Gardasil should be given with caution to individuals with thrombocytopenia or any coagulation disorder because bleeding may occur following an IM administration in these individuals.
The duration of protection is currently unknown. Sustained protective efficacy has been observed for 4.5 years after completion of the 3-dose series. Longer-term follow-up studies are ongoing (see Pharmacology under Actions).
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
Use in pregnancy & lactation: Specific studies of Gardasil in pregnant women were not conducted. However, during the prelicensure clinical development program, 2266 women (vaccine=1115 vs placebo=1151) reported at least 1 pregnancy. Overall, the proportions of pregnancies with an adverse outcome were comparable in subjects who received Gardasil and subjects who received 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. Conversely, in pregnancies with onset >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 type of anomalies observed were consistent with those generally observed in pregnancies in women aged 16-26 years.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development (see Toxicology under Actions).
The data on Gardasil administered during pregnancy did not indicate any safety signal. However, these data are insufficient to recommend use of Gardasil during pregnancy.
Vaccination should, therefore, be postponed until after completion of pregnancy.
A total of 995 breastfeeding mothers were given Gardasil or placebo during the vaccination period of the clinical trials. The rates of adverse reactions in the mother and the breastfed infant were comparable between the vaccination and the placebo groups. In addition, vaccine immunogenicity was comparable among breastfeeding mothers and women who did not breastfeed during Gardasil administration.
Gardasil can be given to breastfeeding women.
Use In Pregnancy & Lactation
Specific studies of Gardasil in pregnant women were not conducted. However, during the prelicensure clinical development program, 2266 women (vaccine=1115 vs placebo=1151) reported at least 1 pregnancy. Overall, the proportions of pregnancies with an adverse outcome were comparable in subjects who received Gardasil and subjects who received 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. Conversely, in pregnancies with onset >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 type of anomalies observed were consistent with those generally observed in pregnancies in women aged 16-26 years.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development (see Toxicology under Actions).
The data on Gardasil administered during pregnancy did not indicate any safety signal. However, these data are insufficient to recommend use of Gardasil during pregnancy.
Vaccination should, therefore, be postponed until after completion of pregnancy.
A total of 995 breastfeeding mothers were given Gardasil or placebo during the vaccination period of the clinical trials. The rates of adverse reactions in the mother and the breastfed infant were comparable between the vaccination and the placebo groups. In addition, vaccine immunogenicity was comparable among breastfeeding mothers and women who did not breastfeed during Gardasil administration.
Gardasil can be given to breastfeeding women.
Adverse Reactions
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 (0.2%) discontinued due to adverse reactions. Safety was evaluated in either the entire study population (4 studies) or in a predefined subset (1 study) of the study population 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 6160 subjects (5088 females 9-26 years and 1072 males 9-15 years at enrollment) who received Gardasil and 4064 subjects who received placebo.
The following vaccine-related adverse reactions were observed among recipients of Gardasil at a frequency of at least 1% and also at a greater frequency than observed among placebo recipients. They are ranked under headings of frequency using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports.
General Disorders and Administration Site Conditions: Very Common: Pyrexia. At the Injection Site: Erythema, pain, swelling. Common: At the Injection Site: Bleeding, pruritus.
In addition, in clinical trials, adverse reactions that were judged to be vaccine- or placebo-related by the study investigator were observed at frequencies <1%.
Respiratory, Thoracic and Mediastinal Disorders: Very Rare: Bronchospasm.
Skin and Subcutaneous Tissue Disorder: Rare: Urticaria. Seven cases (0.06%) of urticaria were reported in the Gardasil group and 17 cases (0.18%) were seen in the adjuvant-containing placebo group.
In the clinical studies, subjects in the Safety Population reported any new medical conditions during the follow-up of up to 4 years. Among 11,813 subjects who received Gardasil and 9701 subjects who received placebo, there were 8 cases of nonspecific arthritis reported, 6 in the Gardasil group and 2 in the placebo group.
Drug Interactions
In all clinical trials, individuals who had received immunoglobulin or blood-derived products during the 6 months prior to the 1st vaccine dose were excluded.
Use with Other Vaccines: Administration of Gardasil at the same time (but, for injected vaccines, at a different injection site) as hepatitis B (recombinant) vaccine did not interfere with the immune response to the HPV types. The seroprotection rates (proportion of subjects reaching seroprotective level anti-HBs >10 mIU/mL) were unaffected (96.5% for concomitant vaccination and 97.5% for hepatitis B vaccine only). Anti-HBs geometric mean antibody titres were lower on co-administration but the clinical significance of this observation is not known.
The concomitant administration of Gardasil with vaccines other than hepatitis B (recombinant) vaccine has not been studied.
Use with Hormonal Contraceptives: In clinical studies, 57.5% of women (age 16-26 years) who received Gardasil used hormonal contraceptives. Use of hormonal contraceptives did not appear to affect the immune response to Gardasil.
Incompatibilities: In the absence of compatibility studies, Gardasil must not be mixed with other medicinal products.
Caution For Usage
Special Precautions for Disposal and Other Handling: Gardasil should be used as supplied; no dilution or reconstitution is necessary. The full recommended dose of Gardasil should be used.
Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of Gardasil.
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.
Single-Dose Vial Use: Withdraw the 0.5 mL dose of vaccine from the single-dose 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.
Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
Pre-Filled Syringe Use: Note: Use one of the enclosed needles for administration. Two detachable labels containing details of the batch number, expiry date and product name are provided.
Instructions for Using the Pre-Filled Single-dose Syringes Pre-Assembled without Needle Guard (Safety) Device: Hold the syringe barrel and attach the needle by twisting in clockwise direction, until the needle fits securely on the syringe.
Storage
Store in a refrigerator (2°-8°C). Do not freeze. Keep the vial or pre-filled syringe in the outer carton to protect from light.
ATC Classification
J07BM01 - papillomavirus (human types 6, 11, 16, 18) ; Belongs to the class of papillomavirus vaccines.
Presentation/Packing
Pre-filled syringe 0.5 mL x 1's.
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