1. Name Of The Medicinal Product
Gardasil,
Human Papillomavirus Vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed).
2. Qualitative And Quantitative Composition
1 dose (0.5 ml) contains approximately:
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1Human Papillomavirus = HPV.
2L1 protein in the form of virus-like particles produced in yeast cells (Saccharomyces cerevisiae CANADE 3C-5 (Strain 1895)) by recombinant DNA technology.
3adsorbed on amorphous aluminium hydroxyphosphate sulphate adjuvant (225 micrograms Al).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Suspension for injection in a pre-filled syringe.
Prior to agitation, Gardasil may appear as a clear liquid with a white precipitate. After thorough agitation, it is a white, cloudy liquid.
4. Clinical Particulars
4.1 Therapeutic Indications
Gardasil is a vaccine for use from the age of 9 years for the prevention of:
– premalignant genital lesions (cervical, vulvar and vaginal) and cervical cancer causally related to certain oncogenic Human Papillomavirus (HPV) types
– genital warts (condyloma acuminata) causally related to specific HPV types.
See sections 4.4 and 5.1 for important information on the data that support this indication.
The use of Gardasil should be in accordance with official recommendations.
4.2 Posology And Method Of Administration
Posology
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 second dose should be administered at least one 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.
The need for a booster dose has not been established.
It is recommended that individuals who receive a first dose of Gardasil complete the 3-dose vaccination course with Gardasil (see section 4.4).
Paediatric population: The safety and efficacy of Gardasil in children below 9 years of age have not been established. No data are available (see section 5.1).
Method of administration
The vaccine should be administered by intramuscular 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. Neither subcutaneous nor intradermal administration has been studied. These methods of administration are not recommended (see section 6.6).
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients.
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 individuals suffering from an acute severe febrile illness. However, the presence of a minor infection, such as a mild upper respiratory tract infection or low-grade fever, is not a contraindication for immunisation.
4.4 Special Warnings And Precautions For Use
The decision to vaccinate an individual should take into account the risk for previous HPV exposure and potential benefit from vaccination.
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 and/or tonic-clonic movements, has occurred after vaccination with Gardasil (See section 4.8). Therefore, vaccinees should be carefully observed for approximately 15 minutes after administration of Gardasil.
As with any vaccine, vaccination with Gardasil may not result in protection in all vaccine recipients.
Gardasil will only protect against diseases that are caused by HPV types 6, 11, 16 and 18 and to a limited extent against diseases caused by certain related HPV types (See section 5.1). Therefore, appropriate precautions against sexually transmitted diseases should continue to be used.
Gardasil is for prophylactic use only and has no effect on active HPV infections or established clinical disease. Gardasil has not been shown to have a therapeutic effect. The vaccine 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.
Gardasil does not prevent lesions due to a vaccine HPV type in individuals infected with that HPV type at the time of vaccination (see section 5.1).
The use of Gardasil in adult women should take into consideration the variability of HPV type prevalence in different geographical areas.
Vaccination is not a substitute for routine cervical screening. Since no vaccine is 100% effective and Gardasil will not provide protection against every HPV type, 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 individuals 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 the vaccine.
This vaccine should be given with caution to individuals with thrombocytopaenia or any coagulation disorder because bleeding may occur following an intramuscular 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 section 5.1).
There are no safety, immunogenicity or efficacy data to support interchangeability of Gardasil with other HPV vaccines.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
In all clinical trials, individuals who had received immunoglobulin or blood-derived products during the 6 months prior to the first 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 individuals 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.
Gardasil may be administered concomitantly with a combined booster vaccine containing diphtheria (d) and tetanus (T) with either pertussis [acellular, component] (ap) and/or poliomyelitis [inactivated] (IPV) (dTap, dT-IPV, dTap-IPV vaccines) with no significant interference with antibody response to any of the components of either vaccine. However, a trend of lower anti-HPV GMTs was observed in the concomitant group. The clinical significance of this observation is not known. This is based on the results from a clinical trial in which a combined dTap-IPV vaccine was administered concomitantly with the first dose of Gardasil. (see section 4.8).
The concomitant administration of Gardasil with vaccines other than the ones above has not been studied.
Use with hormonal contraceptives
In clinical studies, 57.5% of women aged 16 to 26 years and 31.2% of women aged 24 to 45 years who received Gardasil used hormonal contraceptives during the vaccination period. Use of hormonal contraceptives did not appear to affect the immune response to Gardasil.
4.6 Pregnancy And Lactation
Pregnancy
Specific studies of the vaccine in pregnant women were not conducted. During the clinical development program, 3,819 women (vaccine = 1,894 vs. placebo = 1,925) reported at least one pregnancy. There were no significant differences in types of anomalies or proportion of pregnancies with an adverse outcome in Gardasil and placebo treated individuals. These data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity.
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 be postponed until completion of pregnancy.
Breastfeeding
In breastfeeding mothers 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 the vaccine administration.
Therefore Gardasil can be used during breast-feeding.
Fertility
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). No effects on male fertility were observed in rats (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable Effects
A. Summary of the safety profile
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. Few individuals (0.2%) discontinued due to adverse reactions. Safety was evaluated in either the entire study population (6 studies) or in a predefined subset (one study) of the study population 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 (6,995 females 9 to 45 years of age and 3,093 males 9 to 26 years of age at enrollment) who received Gardasil and 7,995 individuals (5,692 females and 2,303 males) who received placebo.
The most common adverse reactions observed were injection-site adverse reactions (77.1% of vaccinees within 5 days following any vaccination visit) and headache (16.6% of the vaccinees). These adverse reactions usually were mild or moderate in intensity.
B. Tabulated summary of adverse reactions
Clinical Trials
Table 1 presents vaccine-related adverse reactions which were observed among recipients of Gardasil at a frequency of at least 1.0% and also at a greater frequency than observed among placebo recipients. They are ranked under headings of frequency using the following convention:
[Very Common (
Post-Marketing Experience
Table 1 also includes additional adverse events which have been spontaneously reported during the post-marketing use of Gardasil worldwide. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Consequently, the frequency of these adverse events is qualified as "not known".
Table 1: Adverse Events Following Administration of Gardasil from Clinical Trials and Post-Marketing Surveillance
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In addition, in clinical trials adverse reactions that were judged to be vaccine- or placebo-related by the study investigator were observed at frequencies lower than 1%:
Respiratory, thoracic and mediastinal disorders:
Very rare: bronchospasm.
Skin and subcutaneous tissue disorders:
Rare: urticaria.
Nine cases (0.06%) of urticaria were reported in the Gardasil group and 20 cases (0.15%) were seen in the adjuvant-containing placebo group.
In the clinical studies, individuals in the Safety Population reported any new medical conditions during the follow-up. Among 15,706 individuals who received Gardasil and 13,617 individuals who received placebo, there were 39 cases of non-specific arthritis/arthropathy reported, 24 in the Gardasil group and 15 in the placebo group.
In a clinical trial of 843 healthy adolescent males and females 11-17 years of age, administration of the first dose of Gardasil concomitantly with a combined diphtheria, tetanus, pertussis [acellular, component] and poliomyelitis [inactivated] booster vaccine showed that there was more injection-site swelling and headache reported following concomitant administration. The differences observed were < 10% and in the majority of subjects, the adverse events were reported as mild to moderate in intensity.
4.9 Overdose
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Viral Vaccine, ATC code: J07BM01
Mechanism of Action
Gardasil is an adjuvanted 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 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 LI VLP vaccines is mediated by the development of a humoral immune response.
HPV 16 and HPV 18 are estimated to be responsible for approximately 70% of cervical cancers; 80% of adenocarcinoma in situ (AIS); 45-70% of high-grade cervical intraepithelial neoplasia (CIN 2/3); 25% of low grade cervical intraepithelial neoplasia (CIN 1); approximately 70% of HPV related high-grade vulvar (VIN 2/3) and vaginal (VaIN 2/3) intraepithelial neoplasia. HPV 6 and 11 are responsible for approximately 90% of genital warts and 10% of low grade cervical intraepithelial neoplasia (CIN 1). CIN 3 and AIS have been accepted as immediate precursors of invasive cervical cancer.
The term "premalignant genital lesions" in section 4.1 corresponds to high-grade cervical intraepithelial neoplasia (CIN 2/3), high-grade vulvar intraepithelial neoplasia (VIN 2/3) and high-grade vaginal intraepithelial neoplasia (VaIN 2/3).
The indication is based on the demonstration of efficacy of Gardasil in females 16 to 45 years of age and in males 16 to 26 years of age and on the demonstration of immunogenicity of Gardasil in 9- to 15-year old children and adolescents.
Clinical Studies
Efficacy in women 16 through 26 years
The efficacy of Gardasil in 16- through 26- year-old women was assessed in 4 placebo-controlled, double-blind, randomized Phase II and III clinical studies including a total of 20,541 women, who were enrolled and vaccinated without pre-screening for the presence of HPV infection.
The primary efficacy endpoints included HPV 6-, 11-, 16-, or 18-related vulvar and vaginal lesions (genital warts, VIN, VaIN) and CIN of any grade and cervical cancers (Protocol 013, FUTURE I), HPV 16- or 18-related CIN 2/3 and AIS and cervical cancers (Protocol 015, FUTURE II), HPV 6-, 11-, 16-, or 18-related persistent infection and disease (Protocol 007), and HPV 16-related persistent infection (Protocol 005).
Efficacy results are presented for the combined analysis of study protocols. The efficacy for HPV 16/18 related CIN 2/3 or AIS is based on data from protocols 005 (16-related endpoints only), 007, 013, and 015. The efficacy for all other endpoints is based on protocols 007, 013, and 015. The median duration of follow-up for these studies was 4.0, 3.0, 3.0, and 3.0 years for Protocol 005, Protocol 007, Protocol 013, and Protocol 015, respectively. The median duration of follow-up for the combined protocols (005, 007, 013, and 015) was 3.6 years. Results of individual studies support the results from the combined analysis. Gardasil was efficacious against HPV disease caused by each of the four vaccine HPV types. At end of study, individuals enrolled in the two Phase-III studies (Protocol-013 and Protocol-015), were followed for up to 4 years (median 3.7 years).
Cervical Intraepithelial Neoplasia (CIN) Grade 2/3 (moderate to high-grade dysplasia) and adenocarcinoma in situ (AIS) were used in the clinical trials as a surrogate marker for cervical cancer.
Efficacy in women naïve to the relevant vaccine HPV type(s)
The primary analyses of efficacy, with respect to vaccine HPV types (HPV 6, 11, 16, and 18), were conducted in the per-protocol efficacy (PPE) population (i.e. all 3 vaccinations within 1 year of enrollment, no major protocol deviations and naïve to the relevant HPV type(s) prior to dose 1 and through 1 month Postdose 3 (Month 7)). Efficacy was measured starting after the Month 7 visit. Overall, 73% of women were naïve (PCR negative and seronegative) to all 4 HPV types at enrollment.
The efficacy results for relevant endpoints analysed at 2 years post-enrollment and at end of study (median duration of follow-up = 3.6 years) in the per-protocol population are presented in the Table 2.
In a supplemental analysis, the efficacy of Gardasil was evaluated against HPV 16/18-related CIN 3 and AIS.
Table 2: Analysis of efficacy of Gardasil against high grade cervical lesions in the PPE population
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*Number of individuals with at least one follow-up visit after Month 7
**Based on virologic evidence, the first CIN 3 case in a patient chronically infected with HPV 52 is likely to be causally related to HPV 52. In only 1 of 11 specimens HPV 16 was found (at Month 32.5) and was not detected in tissue excised during LEEP (Loop Electro-Excision Procedure). In the second CIN 3 case observed in a patient infected with HPV 51 at Day 1 (in 2 of 9 specimens); HPV 16 was detected at a Month 51 biopsy (in 1 of 9 specimens) and HPV 56 was detected in 3 of 9 specimens at Month 52 in tissue excised during LEEP.
***Patients were followed for up to 4 years (median 3.6 years)
Note: Point estimates and confidence intervals are adjusted for person-time of follow-up.
At end of study and in the combined protocols,
the efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related CIN 1 was 95.9 % (95% CI: 91.4, 98.4),
the efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related CIN (1, 2, 3) or AIS was 96.0% (95% CI: 92.3, 98.2),
the efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related VIN2/3 and VaIN 2/3 was 100% (95% CI: 67.2, 100) and 100% (95% CI: 55.4, 100), respectively.
The efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related genital warts was 99.0% (95% CI: 96.2, 99.9).
In Protocol 012 the efficacy of Gardasil against the 6 month definition of persistent infection [samples positive on two or more consecutive visits 6 months apart (±1 month) or longer] related to HPV 16 was 98.7 % (95% CI: 95.1, 99.8) and 100.0% (95% CI: 93.2, 100.0) for HPV 18 respectively, after a follow-up of up to 4 years (mean of 3.6 years). For the 12 month definition of persistent infection, efficacy against HPV 16 was 100.0 % (95% CI: 93.9, 100.0) and 100.0 % (95% CI: 79.9, 100.0) for HPV 18 respectively.
Efficacy in women with evidence of HPV 6, 11, 16, or 18 infection or disease at day 1
There was no evidence of protection from disease caused by vaccine HPV types for which women were PCR positive at day 1. Women 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.
Efficacy in women with and without prior infection or disease due to HPV 6, 11, 16, or 18
The modified intention to treat (ITT) population included women regardless of baseline HPV status at Day 1, who received at least one vaccination and in whom case counting started at 1 month Postdose 1. This population approximates to the general population of women with respect to prevalence of HPV infection or disease at enrollment. The results are summarised in Table 3.
Table 3: Efficacy of Gardasil in high grade cervical lesions in the modified ITT-population including women regardless of baseline HPV status
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*Number of individuals with at least one follow-up visit after 30 days after Day 1
**Percent efficacy is calculated from the combined protocols. The efficacy for HPV 16/18 related CIN 2/3 or AIS is based on data from protocols 005 (16-related endpoints only), 007, 013, and 015. Patients were followed for up to 4 years (median 3.6 years).
Note: point estimates and confidence intervals are adjusted for person-time of follow-up.
Efficacy against HPV 6-, 11-, 16-, 18-related VIN 2/3 was 73.3% (95% CI: 40.3, 89.4), against HPV 6-, 11-, 16-, 18-related VaIN 2/3 was 85.7% (95% CI: 37.6, 98.4), and against HPV 6-, 11-, 16-, 18-related genital warts was 80.3% (95% CI: 73.9, 85.3) in the combined protocols at end of study.
Overall 12% of the combined study population had an abnormal Pap test suggestive of CIN at Day 1. Among women with an abnormal Pap test at Day 1 who were naïve to the relevant vaccine HPV types at Day 1, efficacy of the vaccine remained high. Among women 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.
Protection Against the Overall Burden of Cervical HPV disease in 16- Through 26-Year-Old Women
The impact of Gardasil against the overall risk for cervical, HPV disease (i.e., disease caused by any HPV type) was evaluated starting 30 days after the first dose in 17,599 individuals enrolled in the two phase III efficacy trials (Protocols 013 and 015). Among women who were naïve to 14 common HPV types and had a negative Pap test at Day 1, administration of Gardasil reduced the incidence of CIN 2/3 or AIS caused by vaccine- or non-vaccine HPV types by 42.7% (95% CI: 23.7, 57.3) and of genital warts by 82.8% (95% CI: 74.3, 88.8) at end of study.
In the modified ITT population, the benefit of the vaccine with respect to the overall incidence of CIN 2/3 or AIS (caused by any HPV type) and of genital warts was much lower, with a reduction of 18.4% (95% CI: 7.0, 28.4) and 62.5% (95% CI: 54.0, 69.5), respectively, as Gardasil does not impact the course of infections or disease that are present at vaccination onset.
Impact on Definitive Cervical Therapy Procedures
The impact of Gardasil on rates of Definitive Cervical Therapy Procedures regardless of causal HPV types was evaluated in 18,150 individuals enrolled in Protocol 007, Protocols 013 and 015. In the HPV naïve population (naïve to 14 common HPV types and had a negative Pap test at Day 1), Gardasil reduced the proportion of women who experienced a definitive cervical therapy procedure (Loop Electro-Excision Procedure or Cold-Knife Conization) by 41.9% (95% CI: 27.7, 53.5) at end of study. In the ITT population the corresponding reduction was 23.9% (95% CI: 15.2, 31.7).
Cross-protective efficacy
The efficacy of Gardasil against CIN (any grade) and CIN 2/3 or AIS caused by 10 non-vaccine HPV types (HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) structurally related to HPV 16 or HPV 18 was evaluated in the combined Phase III efficacy database (N = 17,599) after a median follow-up of 3.7 years (at end of study). Efficacy against disease endpoints caused by pre-specified combinations of non-vaccine HPV types was measured. The studies were not powered to assess efficacy against disease caused by individual HPV types.
The primary analysis was done in type-specific populations that required women to be negative for the type being analyzed, but who could be positive for other HPV types (96% of the overall population). The primary time point analysis after 3 years did not reach statistical significance for all pre-specified endpoints. The final end-of-study results for the combined incidence of CIN 2/3 or AIS in this population after a median follow-up of 3.7 years are shown in Table 4. For composite endpoints, statistically significant efficacy against disease was demonstrated against HPV types phylogenetically related to HPV 16 (primarily HPV 31) whereas no statistically significant efficacy was observed for HPV types phylogenetically related to HPV 18 (including HPV 45). For the 10 individual HPV types, statistical significance was only reached for HPV 31.
Table 4: Results for CIN 2/3 or AIS in Type-Specific HPV-Naïve Individuals† (end of study results)
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