Active Ingredients: Human Papillomavirus Vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed)
Gardasil, suspension for injection
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
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01.0 NAME OF THE MEDICINAL PRODUCT
GARDASIL INJECTABLE SUSPENSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 dose (0.5 ml) contains approximately:
Human Papillomavirus1 type 6 L1 protein 20 mcg
Human Papillomavirus1 type 11 L1 protein 40 mcg
Human Papillomavirus1 type 16 L1 protein 40 mcg
Human Papillomavirus1 type 18 L1 protein 20 mcg
1 Human Papillomavirus = HPV.
2 L1 protein in the form of virus-like particles produced by yeast cells (Saccharomycescerevisiae CANADE 3C-5 (Strain 1895)) by recombinant DNA technology.
3 adsorbed on amorphous aluminum hydroxyphosphate sulfate adjuvant (0.225 milligrams of Al).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Suspension for injection.
Before shaking, Gardasil may appear as a clear liquid with a white precipitate. After being thoroughly stirred, it appears as a white, opalescent liquid.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Gardasil is a vaccine indicated for use from 9 years of age for the prevention of:
- precancerous genital lesions (of the cervix, vulva and vagina), precancerous anal lesions, cervical cancers and anal cancers caused by various oncogenic types of Human Papillomavirus (HPV)
- genital lesions (condyloma acuminata) caused by specific types of HPV
See sections 4.4 and 5.1 for important information regarding supportive data for therapeutic indications.
The use of Gardasil must be established in accordance with official recommendations.
04.2 Posology and method of administration
Dosage
Individuals from 9 to 13 years of age inclusive
Gardasil can be administered according to a 2 dose schedule (0.5 ml at 0.6 months) (see section 5.1).
If the second dose of vaccine is given earlier than 6 months after the first dose, a third dose should always be given.
Alternatively Gardasil can be administered according to a 3 dose schedule (0.5 ml at 0, 2, 6 months).
The second dose should be administered at least one month after the first dose and the third dose at least 3 months after the second dose. All three doses should be administered within a 1 year period.
Individuals aged 14 and over
Gardasil should be administered according to a 3 dose schedule (0.5 ml at 0, 2, 6 months).
The second dose should be given at least one month after the first dose and the third dose should be given at least 3 months after the second dose. All three doses should be administered within the 1 year period.
The use of Gardasil must be in accordance with official recommendations.
Pediatric population:
The safety and efficacy of Gardasil in children aged less than 9 years have not been established. No data are available (see section 5.1).
It is recommended that individuals receiving a first dose of Gardasil complete the vaccination course with Gardasil (see section 4.4).
The need for a booster dose has not been established.
Method of administration
The vaccine should be administered by intramuscular injection. The preferred site is the deltoid region of the upper arm or the superior anterolateral area of the thigh.
Gardasil must not be injected intravascularly. Subcutaneous and intradermal administration have not been studied. These methods of administration are not recommended (see section 6.6).
04.3 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 additional doses of Gardasil.
Administration of Gardasil should be postponed in individuals suffering from acute severe febrile illness. However, the presence of a minor infection, such as a mild upper respiratory tract infection or a mild fever, is not a contraindication to immunization.
04.4 Special warnings and appropriate precautions for use
The decision to vaccinate a subject must take into account the risk of previous HPV exposure and the potential benefit of vaccination.
As with all injectable vaccines, adequate medical treatment should always be readily available in case of a rare anaphylactic reaction following the administration of the vaccine.
Syncope (fainting) may occur following, or even before, any vaccination especially in adolescents as a psychogenic response to needle injection. This phenomenon can be accompanied by various neurological disorders such as transient visual disturbances, paraesthesia and tonic movements. -clonic limbs during the recovery phase Therefore, vaccinated subjects should be kept under observation for approximately 15 minutes following the administration of the vaccine.
It is important that adequate procedures are in place to avoid injuries caused by fainting.
As with any other vaccine, vaccination with Gardasil may not ensure the protection of all vaccinated individuals.
Gardasil will only protect against diseases caused by HPV types 6, 11, 16 and 18, and to a limited extent from diseases caused by some related HPV types (see section 5.1). Therefore, appropriate precautions against sexually transmitted diseases must continue to be followed.
Gardasil is indicated for prophylactic use only and has no effect on active infections or established clinical HPV disease. Gardasil was not shown to have a therapeutic effect. The vaccine is therefore not indicated for the treatment of cervical cancer, high-grade dysplastic lesions of the cervix, vulva and vagina, or genital warts. The vaccine is also not indicated to prevent the progression of other existing lesions related to Human Papillomavirus.
Gardasil does not prevent injury due to a vaccine HPV type in individuals infected with the same HPV type at the time of vaccination (see section 5.1).
For the use of Gardasil in adult women, the variability of the prevalence of HPV types in different geographical areas must be taken into account.
Vaccination does not replace routine cervical screening. Since no vaccine is 100% effective and since Gardasil does not protect against all types of HPV or pre-existing HPV infections, routine cervical screening remains critical and should be done in accordance with local recommendations.
The safety and immunogenicity of the vaccine were evaluated in individuals with known Human Immunodeficiency Virus (HIV) infection aged 7 to 12 years (see section 5.1). People with a reduced immune response, due to the use of strong immunosuppressive therapy, a genetic defect or other causes, may not respond to the vaccine.
This vaccine should be administered with caution to individuals with thrombocytopenia or any other coagulation disorder as bleeding may occur in these individuals following intramuscular administration.
Long-term extension studies are currently underway to determine the duration of protection (see section 5.1).
There are no safety, immunogenicity or efficacy data to support the interchangeability of Gardasil with other HPV vaccines.
04.5 Interactions with other medicinal products and other forms of interaction
In all clinical studies, subjects who had received immunoglobulins or human blood products within 6 months prior to the first vaccine dose were excluded.
Use with other vaccines
Concomitant administration (however, at different injection sites for injectable vaccines) of Gardasil with hepatitis B (recombinant) vaccine does not interfere with the immune response to HPV types. seroprotective anti-HBs level ≥ 10 mIU / ml) were not affected (96.5% for concomitant vaccination and 97.5% for hepatitis B vaccine administered alone).
Geometric mean anti-HBs antibody titers were reduced on co-administration, however the clinical significance of this observation has not been established.
Gardasil can be administered concomitantly with a combined booster vaccine containing diphtheria (d) and tetanus (T) together with pertussis [acellular component] (ap) and / or [inactivated] poliomyelitis (IPV) (dTap vaccines, dT-IPV, dTap-IPV) without interfering in any way with the immune response to the different components of each vaccine. However, a lower trend in anti-HPV GMT levels was observed in the group of patients who received co-administration.
The clinical significance of this observation is unknown. These data are based on results observed in a clinical study conducted by administering a combination dTap-IPV vaccine concomitantly with the first dose of Gardasil (see section 4.8).
Co-administration of Gardasil with vaccines other than those mentioned above has not been studied.
Use with hormonal contraceptives
In clinical trials, 57.5% of women aged 16 to 26 and 31.2% of women aged 24 to 45 who received Gardasil were using hormonal contraceptives during the period of vaccination. The use of hormonal contraceptives does not appear to have affected the immune response to Gardasil.
04.6 Pregnancy and lactation
Pregnancy
No specific vaccine studies have been performed in pregnant women. During the clinical development program, 3,819 women (of whom 1,894 received the vaccine and 1,925 the placebo) developed at least one pregnancy. No significant differences were reported in the type of abnormalities or in the proportion of unsuccessful pregnancies in women who received Gardasil and those who received placebo. These data on pregnant women (more than 1,000 affected cases) indicate no malformation or fetus / neonatal toxicity.
Data on administration of Gardasil during pregnancy have not provided any reports regarding the safety of use. However, such data are insufficient to recommend the use of Gardasil during pregnancy. Vaccination should therefore be postponed until completion of pregnancy.
Feeding time
In nursing mothers who received Gardasil or placebo during the vaccination period of the clinical trials, the incidence of adverse reactions in mothers and infants was comparable between the vaccine and placebo group. Furthermore, the immunogenicity of the vaccine was comparable between lactating mothers and women who were not lactating during vaccine administration.
Therefore Gardasil can be used during breastfeeding.
Fertility
Animal studies show no direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). No effect on male fertility was observed in rats (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
04.8 Undesirable effects
A. Summary of the safety profile
In 7 clinical trials (including 6 placebo-controlled), enrolled individuals received either Gardasil or placebo on the day of enrollment and approximately 2 and 6 months after enrollment. Few individuals (0.2%) discontinued the trial due to adverse reactions. Safety was assessed, both for the whole study population (6 studies) and for a predefined subgroup of the study population (1 study), based on vaccination card surveillance (VRC - vaccination report card), within 14 days following each injection of Gardasil or placebo. Individuals who were monitored on the basis of surveillance via the VRC vaccination card included 10,088 individuals who received Gardasil (including 6,995 females aged 9 to 45 years and 3,093 males aged 9 to 26 years, at time of enrollment) and 7,995 individuals who received placebo (5,692 females and 2,303 males).
The most common adverse reactions observed were those at the injection site (77.1% of the vaccinated within 5 days after each vaccination session) and headache (16.6% of the vaccinated). These adverse reactions were generally mild or moderate in intensity.
B. Summary table of adverse reactions
Clinical studies
Table 1 presents the vaccine-related adverse reactions that were observed in subjects who received Gardasil with a frequency of at least 1.0%, and also with a higher frequency than that observed in subjects who received placebo. The reactions were grouped by frequency according to the following convention:
[Very Common (≥ 1/10); Common (≥ 1/100 to
Post-marketing experience
Table 1 also includes additional adverse events that have been spontaneously reported during post-marketing use of Gardasil worldwide. As these events have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate. their frequency or establish a causal relationship with vaccine exposure. Consequently, the frequency of these adverse events is defined as "not known".
Table 1: Adverse Events Following Administration of Gardasil During Studies clinical and post-marketing surveillance
* Post-Marketing Adverse Events (frequency cannot be estimated from the available data)
1 In clinical trials, dizziness was observed as a common adverse reaction in women. In males, dizziness was not observed more frequently in vaccinated subjects than in subjects who received placebo.
In addition, adverse reactions that were considered vaccine or placebo related by investigators were observed in clinical trials with a frequency of less than 1%:
Respiratory, thoracic and mediastinal disorders
Very rare: bronchospasm.
Skin and subcutaneous tissue disorders
Rare: hives.
Nine cases (0.06%) of urticaria were reported in the Gardasil group and 20 cases (0.15%) were observed in the adjuvant-containing placebo group.
During the clinical trials, individuals in the population assessed for safety in use reported any new medical conditions during the follow-up period.Among the 15,706 individuals who received Gardasil and 13,617 individuals who received placebo, 39 cases of non-specific arthritis / arthropathy were reported, including 24 in the Gardasil group and 15 in the placebo group.
In a clinical study involving 843 healthy adolescents (males and females) aged 11-17 years, the administration of the first dose of Gardasil concomitantly with a combined diphtheria, tetanus, pertussis [acellular component] booster vaccine ] and [inactivated] poliomyelitis, showed that injection site swelling and headache were reported more frequently following co-administration. The observed differences were
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. .
04.9 Overdose
There have been reports of administration of higher than recommended doses of Gardasil.
In general, the adverse event profile reported in the event of overdose was comparable to that of the single recommended doses of Gardasil.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Viral vaccine, ATC code: J07BM01
Mechanism of action
Gardasil is a recombinant non-infectious adjuvanted quadrivalent vaccine prepared from highly purified virus-like particles (VLPs) from the L1 major capsid protein of HPV types 6, 11, 16 and 18.
VLPs do not contain viral DNA, cannot infect cells, reproduce or cause disease.
HPV only infects humans, but animal studies with similar papillomaviruses suggest that the efficacy of L1 VLP vaccines is mediated by the development of a humoral-type immune response. HPV 16 and HPV 18 are estimated to be responsible for approximately 70% of cervical cancers and 75-80% of anal cancers; of 80% of adenocarcinoma in situ (AIS); of 45-70% of high grade intraepithelial neoplasms of the cervix (CIN 2/3); 25% of low grade intraepithelial neoplasms of the cervix (CIN 1); approximately 70% of high grade HPV related intraepithelial neoplasms of the vulva (VIN 2/3) and vagina (VaIN 2/3 ) and 80% of HPV-related high grade anal intraepithelial neoplasms (AIN 2/3).
HPV 6 and 11 are responsible for approximately 90% of genital warts and 10% of low grade cervical intraepithelial neoplasms (CIN 1). CIN 3 and AIS have been considered as direct precursors of invasive neck cancer of the uterus.
The term "precancerous genital lesions" reported in section 4.1 identifies high grade intraepithelial neoplasia of the cervix (CIN 2/3), high grade intraepithelial neoplasia of the vulva (VIN 2/3) and intraepithelial neoplasia of high grade of the vagina (VaIN 2/3).
The term "anal precancerous lesions" reported in section 4.1 corresponds to high grade anal intraepithelial neoplasia (AIN 2/3).
The indication is based on the demonstration of efficacy of Gardasil in women aged 16 to 45 years and men aged 16 to 26 years, and on the demonstration of the immunogenicity of Gardasil in children and adolescents aged 9 to 15 years.
Clinical studies
Efficacy in women aged 16 to 26 years
The efficacy of Gardasil in women aged 16 to 26 years was evaluated in 4 randomized, double-blind, placebo-controlled Phase II and III clinical trials which included a total of 20,541 women who were enrolled and vaccinated. without pre-screening for the presence of an HPV infection.
Primary efficacy endpoints included lesions of the vulva and vagina (genital warts, VIN, VaIN) and any grade CIN and cervical cancers related to HPV types 6, 11, 16 or 18 (Protocol 013 , FUTURE I), CIN 2/3 and "adenocarcinoma in situ (AIS) and cervical cancers related to" HPV types 16 or 18 (Protocol 015, FUTURE II), persistent infection and related diseases HPV types 6, 11, 16, or 18 (Protocol 007); and persistent infection related to HPV type 16 (Protocol 005).
Efficacy results are presented based on the combined analysis of the different study protocols. Efficacy for HPV 16/18 related CIN 2/3 or AIS is based on data extracted from protocols 005 (Type 16 related endpoints only) , 007, 013 and 015. Efficacy for all other endpoints is based on protocols 007, 013 and 015. The median duration of the follow-up period for these studies in protocols 005, 007, 013 and 015 was 4, 3, 3, and 3 years, respectively. The median duration of follow-up for the combined protocols (005, 007, 013, and 015) was 3.6 years. The results of the individual studies support the results of the combined analyzes. Gardasil was shown to be effective against HPV diseases caused by each of the four HPV types contained in the vaccine. At the end of the 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).
Grade 2/3 cervical intraepithelial neoplasia (CIN) (moderate to severe dysplasia) and adenocarcinoma in situ (AIS) have been used in clinical trials as a surrogate clinical marker for cervical cancer.
Efficacy in women naïve to the HPV types contained in the vaccine
The primary efficacy analyzes, with respect to the HPV types contained in the vaccine (HPV 6, 11, 16, and 18), were performed in the population per protocol (PPE Per-protocol Efficacy) (e.g. all 3 vaccinations within 1 year of enrollment, no major deviation from study protocol and naïve to relevant HPV types before dose 1 and up to 1 month after dose 3 (Month 7) Efficacy was measured from visit to month 7. Overall, 73% of women were naïve (PCR negative and seronegative) for all 4 HPV types.
Table 2 presents the efficacy results on the related endpoints analyzed at 2 years from enrollment and at the end of the study (median duration of follow-up = 3.6 years) in the population per protocol.
In a supplementary analysis, the efficacy of Gardasil was evaluated against HPV 16/18 related CIN 3 and AIS.
Table 2: Efficacy Analysis of Gardasil Against High-Grade Cervical Injuries in the PPE Population
* Number of individuals with at least one follow-up visit after the 7th month
** based on virological evidence, the first case of CIN 3 in a chronically infected patient with HPV 52 is likely to be causally related to HPV 52. Only 1 of the 11 samples was found to have HPV 16 (at month 32.5 ) and was not detected in tissue collected and examined during the Loop Electro-Excision Procedure (LEEP). In the second case of CIN 3 observed in a patient infected with HPV 51 on day 1 (in 2 of 9 samples), HPV 16 was found in a biopsy at Month 51 (in 1 of 9 samples) and HPV 56 was was detected in 3 of 9 samples at Month 52 on tissue collected and examined during LEEP.
*** Patients were followed up for up to 4 years (median 3.6 years)
Note: Percentage values and confidence intervals were normalized with respect to the follow-up time per person.
At the end of the 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 CIN or AIS related at HPV 6, 11, 16, 18, was 96.0% (95% CI: 92.3-98.2), the efficacy of Gardasil against VIN2 / 3 and VaIN 2/3 related to HPV 6, 11, 16, 18, 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 towards 6-month definition of persistent infection [positive samples on two or more consecutive visits 6 months (± 1 month) or more apart] was 98.7% (95 % CI: 95.1-99.8) for HPV 16 and 100.0% (95% CI: 93.2-100.0) for HPV 18, after a follow-up of up to 4 years (mean value of 3.6 years). For the 12-month definition of persistent infection, efficacy was 100.0% (95% CI: 93.9-100.0) against HPV 16 and 100.0% (95 % CI: 79.9-100.0) versus HPV 18.
Efficacy in women with evidence of HPV 6, 11, 16 or 18 infection or disease, on day 1 There was no evidence of protection from disease caused by the HPV types contained in the vaccine for which the women were PCR positive at day 1. Women who were already infected with one or more types of HPV contained in the vaccine before vaccination were found to be protected from the clinical disease caused by the other HPV types contained in the vaccine.
Efficacy in women with and without HPV 6, 11, 16 or 18 infection or disease
The population intention to treat modified (ITT) included women who had received at least one vaccination, regardless of baseline HPV status on day 1 and for whom case counts started from 1 month after dose 1. This population is similar to the general female population relative to the prevalence of HPV infection or disease at enrollment. The results are shown in Table 3.
Table 3: Efficacy of Gardasil against high-grade cervical lesions in the population Modified ITT that included women regardless of baseline HPV status
* Number of individuals with at least one follow-up visit after 30 days from Day 1
** The percentage of efficacy is calculated based on the combined protocols. Efficacy for HPV 16/18 related CIN 2/3 or AIS is based on data extracted from protocols 005 (type 16 related endpoints only), 007, 013 and 015. Patients were followed for up to 4 years (median 3.6 years).
Note: Percentage values and confidence intervals were normalized with respect to the follow-up time per person.
The efficacy against HPV 6, 11, 16, 18-related VIN 2/3 was 73.3% (95% CI: 40.3-89.4), against HPV 6-related VaIN 2/3, 11, 16, 18, was 85.7% (95% CI: 37.6- 98.4), and against HPV 6, 11, 16, 18-related genital warts, it was 80, 3% (95% CI: 73.9-85.3) in the combined protocols at the end of the study.
Overall, 12% of the combined study population had an abnormal Pap smear indicative of CIN on day 1. In the "setting of women with abnormal Pap smears on day 1 who were naïve to the HPV types contained in the vaccine on day 1, l" vaccine efficacy remained high. Vaccine efficacy was not observed in women with abnormal Pap smears on day 1 who were already infected with the HPV types contained in the vaccine.
Protection against the overall impact of HPV cervical pathologies in young women aged between 16 and 26 years
The impact of Gardasil on the overall risk of HPV cervical disease (eg diseases caused by any type of HPV) was assessed starting 30 days after the first dose in 17,599 individuals enrolled in the two studies. of phase III efficacy (Protocols 013 and 015). Among women who were naïve to the 14 common types of HPV and who had a negative Pap smear on Day 1, administration of Gardasil reduced the incidence of CIN 2/3 or AIS related to HPV types contained or not in the vaccine. 42.7% (95% CI: 23.7-57.3) and the incidence of genital warts 82.8% (95% CI: 74.3-88.8) at the end of the 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 type of HPV) and genital warts was much lower, with a reduction of 18.4% (95% CI), respectively. : 7.0-28.4) and 62.5% (95% CI: 54.0-69.5), since Gardasil has no influence on the course of the infection or diseases already present at the start of vaccination.
Impact on conclusive cervical therapeutic procedures
The impact of Gardasil on the rate of use of conclusive cervical therapeutic procedures, regardless of the types of HPV that caused the infection, was evaluated in 18,150 individuals enrolled in Protocols 007, 013 and 015. In the HPV-naïve population (understood as naïve to the 14 most common HPV types and with negative Pap smears on day 1), Gardasil reduced the percentage of women who experienced a conclusive cervical therapeutic procedure (Loop Electro-Excision Procedure) by 41.9% (95% CI: 27.7--53.5) at the end of the study. In the ITT population, the corresponding reduction was 23.9% (95% CI: 15.2--31.7).
Effectiveness on cross-protection
The efficacy of Gardasil against CIN (any grade) and CIN 2/3 or AIS caused by 10 types of HPV not contained in the vaccine (HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) , structurally related to HPV 16 or HPV 18, was evaluated based on pooled Phase III efficacy data (N = 17,599) after a median follow-up of 3.7 years (at the end of the study). Efficacy was evaluated against endpoints such as diseases caused by HPV types not contained in the vaccine in prespecified combinations. Studies were not designed to evaluate efficacy against diseases caused by single HPV types.
The primary analysis was performed in type-specific populations, ie women who were seronegative to the type of HPV analyzed but who could be seropositive for other types of HPV (96% of the total population). After 3 years, at the first time interval, the "Primary analysis did not reach statistical significance for all pre-specified endpoints. The final results at the end of the study on 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 compound endpoints, statistically significant efficacy against pathologies HPV has been demonstrated against phylogenetically related HPV types to HPV 16 (especially HPV 31), while "non-statistically significant efficacy was observed for phylogenetically related HPV types to HPV 18 (including HPV 45). Relative to the 10 single types. of HPV, statistical significance was obtained only for HPV 31.
Table 4: Results for CIN 2/3 or AIS in individuals † naïve to specific HPV types (results at the end of the study)
Efficacy in women aged 24 to 45 years
The efficacy of Gardasil in women 24 to 45 years of age was evaluated in a Phase III, randomized, double-blind, placebo-controlled clinical trial (Protocol 019, FUTURE III), which included a total of 3,817 women who they were enrolled and vaccinated without pre-screening for the presence of "HPV infection."
Primary efficacy endpoints included the combined incidence of persistent infection (6-month definition), genital warts, vulva and vaginal lesions, all grade CIN, AIS, and cervical cancers related to HPV types. 6, 11, 16, or 18, and related to HPV types 16 or 18. The median duration of follow-up for this study was 4.0 years.
Efficacy in women naïve to the HPV types contained in the vaccine
Primary efficacy analyzes were performed in the per-protocol (PPE) population (i.e. all 3 vaccinations within 1 year of enrollment, no major deviation from study protocol, and naïve to relevant HPV types prior to dose 1 and up to 1 month after dose 3 (Month 7)). Efficacy was measured from visit to month 7. Overall, 67% of women were naïve (PCR negative and seronegative) for all 4 types of HPV at enrollment. The efficacy of Gardasil against the combined incidence of persistent infection, genital warts, vulva and vaginal lesions, all grade CIN, AIS, and cervical cancers related to HPV type 6 , 11, 16, or 18, was 88.7% (95% CI: 78.1 - 94.8).
The efficacy of Gardasil against the combined incidence of persistent infection, genital warts, lesions of the vulva and vagina, any grade CIN, AIS, and cervical cancers related to HPV types 16 or 18 was of "84.7% (95% CI: 67.5 - 93.7).
Efficacy in women with and without HPV infection or disease 6, 11, 16 or 18 The population under analysis full set (also known as the ITT population) included women who had received at least one vaccination, regardless of baseline HPV status on day 1, and for whom case counts started from day 1. This population is similar to the general female population compared the prevalence of HPV infection or disease at enrollment.
The efficacy of Gardasil against the combined incidence of persistent infection, genital warts, lesions of the vulva and vagina, any grade CIN, AIS, and cervical cancer related to HPV types 6, 11, 16 or 18 , was 47.2% (95% CI: 33.5 - 58.2).
The efficacy of Gardasil against the combined incidence of persistent infection, genital warts, lesions of the vulva and vagina, any grade CIN, AIS, and cervical cancers related to HPV types 16 or 18, was of 41.6% (95% CI: 24.3 - 55.2).
Efficacy in women (16 to 45 years) with evidence of previous infection with a type of vaccine (seropositive) HPV that was no longer detectable at the start of vaccination (PCR negative)
In post hoc analyzes of subjects (who received at least one dose of vaccine) with evidence of previous infection with a vaccine type (seropositive) that was no longer detectable (PCR negative) at the start of vaccination, the efficacy of Gardasil in the prevention of conditions due to recurrence of the same type of HPV was 100% (95% CI: 62.8 - 100.0; 0 vs. 12 cases [n = 2,572 subjects from the combined studies conducted in young women]) in comparisons of CIN 2/3, VIN 2/3, VaIN 2/3 and genital warts related to HPV 6, 11, 16 and 18 in women aged 16 to 26 years. The efficacy was 68.2% (95% CI: 17.9 - 89.5; 6 vs. 20 cases [n = 832 subjects from studies conducted in young and adult women combined]) against persistent infections related to HPV 16 and 18 in women aged 16 to 45 years.
Efficacy in men aged 16 to 26 years
Efficacy was evaluated against external genital warts, penile / perineal / perianal intraepithelial neoplasia (PIN) grade 1/2/3, and persistent infection related to HPV types 6, 11, 16, 18.
The efficacy of Gardasil in men aged 16 to 26 years was evaluated in 1 randomized, double-blind, placebo-controlled Phase III clinical study (Protocol 020), which included a total of 4,055 men who were enrolled and vaccinated without pre-screening for HPV infection Median duration of follow-up was 2.9 years.
Efficacy against anal intraepithelial neoplasia (AIN grades 1/2/3) and anal cancer, and persistent intra-anal infection, was evaluated in a subgroup of 598 men (GARDASIL = 299; placebo = 299), belonging to to Protocol 020, who have self-reported having sexual intercourse with other men (MSM population).
The MSM population has a higher risk of anal HPV infection than the general population; an absolute benefit of vaccination in terms of anal cancer prevention in the general population is assumed to be very low.
HIV infection was an exclusion criterion (see also section 4.4).
Efficacy in vaccine-naïve men with HPV types
The primary efficacy analyzes, with respect to the HPV types contained in the vaccine (HPV 6, 11, 16, 18), were performed in the population per protocol (PPE - i.e. all 3 vaccinations within 1 year of enrollment, no deviation highest by study protocol and naïve to relevant HPV types before dose 1 and up to 1 month after dose 3 (Month 7)). Efficacy was measured starting at visit at month 7. Overall l " 83% of men (87% of heterosexual subjects and 61% of subjects belonging to the MSM population) were naïve (PCR negative and seronegative) for all 4 HPV types at the time of enrollment.
Grade 2/3 anal intraepithelial neoplasia (AIN) (moderate to severe dysplasia) has been used in clinical trials as a surrogate clinical marker for anal cancer.
The efficacy results for the relevant endpoints analyzed at the end of the study (median duration of followup = 2.4 years) in the population per protocol are presented in Table 5. The efficacy against grade 1/2/3 PIN was not demonstrated.
Table 5: Efficacy of Gardasil against external genital lesions in the PPE * population of men aged 16 to 26 years
* Subjects included in the PPE population received all 3 vaccinations within 1 year of enrollment, had no major deviation from the study protocol, and were naïve to relevant HPV types before dose 1 and up to 1 month after dose 3 (Month 7).
At the end of the study analysis with respect to anal lesions in the MSM population (median duration of follow-up 2.15 years), the preventive effect against AIN 2/3 related to HPV types 6, 11, 16, 18 is status was 74.9% (95% CI: 8.8 - 95.4; 3/194 cases vs 13/208) and against AIN 2/3 related to HPV types 16 or 18 was 86.6% ( 95% CI: 0.0 - 99.7; 1/194 cases vs 8/208).
The duration of protection against anal cancer is currently unknown. In the Protocol 020 long-term extension study for 16-26-year-old men, in the per-protocol population of men vaccinated with Gardasil in the base study, no cases of HPV disease (HPV 6/11 related genital warts, external genital lesions HPV 6/11/16/18 and AIN of any grade from HPV 6/11/16/18 in the MSM population) has been observed up to approximately 6 years.
Efficacy in men with or without previous HPV 6, 11, 16, or 18 infection or disease
The population under analysis full set (also known as the ITT population) included men who had received at least one vaccination, regardless of baseline HPV status on day 1, and for whom case counts started from day 1. This population is similar to the adult male general population with respect to the prevalence of HPV infection or disease at enrollment.
The efficacy of Gardasil against HPV 6, 11, 16, 18 external genital warts was 68.1% (95% CI: 48.8 - 79.3).
The efficacy of Gardasil against HPV 6, 11, 16 or 18 and HPV 16 and 18-related AIN 2/3 in the MSM substudy was 54.2%, respectively (95% CI: 18.0 - 75 , 3; 18/275 cases vs 39/276 cases) and 57.5% (95% CI: -1.8 - 83.9; 8/275 cases vs 19/276 cases).
Protection against the overall impact of HPV diseases in men aged 16 to 26 years
The impact of Gardasil on the overall risk of external genital injury was assessed after the first dose in 2,545 subjects enrolled in the Phase III efficacy study (Protocol 020). Among men who were naïve to the 14 common types of HPV, administration of Gardasil reduced the incidence of external genital lesions related to HPV types contained or not in the vaccine by 81.5% (95% CI: 58.0 - 93.0).
In the population under analysis full set (FAS) the vaccine benefit compared to the overall incidence of external genital lesions (EGL) was lower, with a reduction of 59.3% (95% CI: 40.0 - 72.9), since Gardasil has no influence on the course of the infection or diseases already present at the start of vaccination.
Impact on biopsies and conclusive therapeutic procedures
The impact of Gardasil on the rate of biopsies performed and EGL treatments regardless of HPV types was evaluated in 2,545 individuals enrolled in Protocol 020. In the HPVnaïve population (naïve to the 14 common HPV types) Gardasil reduced the percentage of men who had a biopsy of 54.2% (95% CI: 28.3 - 71.4) and the percentage of those who were treated 47.7% (95% CI: 18.4 - 67.1) at the end of the study. In the FAS population, the corresponding reduction was 45.7% (95% CI: 29.0 - 58.7) and 38.1% (95% CI: 19.4 - 52.6 ).
Immunogenicity
Test to measure the immune response
A minimum antibody level associated with protection has not been identified for HPV vaccines. Gardasil immunogenicity was evaluated in 20,132 girls and women aged 9 to 26 years (Gardasil n = 10,723; placebo n = 9,409), in 5,417 boys and men aged 9 to 26 years (Gardasil n = 3,109; placebo n = 2,308), and in 3,819 women aged between 24 and 45 years (Gardasil n = 1,911; placebo n = 1,908).
To evaluate immunogenicity to each type contained in the vaccine, type-specific immunoassays were used, in particular the competitive assay based on Luminex technology (cLIA) with type-specific standards. This assay measures antibodies against a single neutralizing epitope for each specific type of HPV.
Immune responses to Gardasil at 1 month post dose 3
In clinical studies conducted in women aged 16 to 26 years, 99.8%, 99.8%, 99.8%, and 99.5% of individuals who received Gardasil were shown to be seropositive, respectively. anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18, within 1 month after dose 3. In the clinical study in women aged 24 to 45 years, 98.4% , 98.1%, 98.8%, and 97.4% of individuals who received Gardasil showed seropositivity to anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18, respectively, by 1 month after dose 3. In clinical studies in men aged 16 to 26 years, 98.9%, 99.2%, 98.8%, and 97.4% of individuals who received Gardasil became seropositive for HPV 6, HPV 11, HPV 16 and HPV 18, respectively, 1 month after dose 3. Gardasil induced a "high geometric mean of anti-HPV antibody titers (GMTs) 1 month after dose 3 in all age groups evaluated .
As expected for women aged 24 to 45 years (Protocol 019) the antibody titers were lower than that observed in young women aged 16 to 26 years. Anti-HPV levels in individuals in the placebo group who passed an HPV infection (seropositive and PCR negative) were substantially lower than vaccine-induced levels.
Furthermore, anti-HPV levels (GMTs) in vaccinated individuals remained at or above the serum cut-off value during follow up long-term Phase III studies (refer to section on Persistence of the Gardasil immune response in clinical studies).
"Bridging" of efficacy of Gardasil between women and girls
A clinical study (Protocol 016) compared the immunogenicity of Gardasil in girls aged 10-15 years with that observed in women aged 16-23. 100% showed seropositivity to all serotypes contained in the vaccine within 1 month from dose 3.
Table 6 provides a comparison of the anti HPV 6, 11, 16 and 18 GMTs observed 1 month after dose 3 in girls aged 9 to 15 years versus those observed in women aged 16 to 26 years.
Table 6: Immunogenicity bridging between 9-15 year old girls and 16-26 year old women (per-protocol population) based on titers measured by the cLIA method
Anti-HPV responses at month 7 in 9-15 year old girls were not lower than anti-HPV responses in 16-26 year old women for whom efficacy was defined in phase III studies Immunogenicity was age-related and at Month 7 anti-HPV levels were significantly higher in younger individuals less than 12 years of age compared to older ones.
On the basis of this immunogenicity bridging, the efficacy of Gardasil in girls between the ages of 9 and 15 is extrapolated.
"Bridging" of Gardasil efficacy between men and boys
Three clinical studies (Protocols 016, 018 and 020) were used to compare the immunogenicity of Gardasil in boys aged 9 to 15 versus men aged 16 to 26. In the vaccinated group, since 97, 4 to 99.9% showed seropositivity to all serotypes contained in the vaccine within 1 month from dose 3.
Table 7 compares anti-HPV GMTs 6, 11, 16, and 18, in boys 9 to 15 years old versus those in men 16 to 26 years old 1 month after dose 3.
Table 7: Immunogenicity bridging between 9-15 year old boys and older men between 16 and 26 years (per-protocol population) based on titers measured by the cLIA method
GMT - mean geometric titer in mMU / ml (mMU = milli-Merck units)
The anti-HPV responses at month 7 for boys aged 9 to 15 were not lower than the anti-HPV responses observed in men aged 16 to 26 for which efficacy was established in Phase III studies. Immunogenicity was age-related and anti-HPV levels at month 7 were significantly higher in younger individuals.
On the basis of this immunogenicity bridging, the efficacy of Gardasil in children aged between 9 and 15 years is deduced.
Persistence of the Gardasil immune response in clinical studies
For women aged 16 to 26 years, the longest immunogenicity follow-up was in Protocol 007 where anti-HPV 6, anti-HPV 11, anti-HPV 16, anti-HPV 18 GMTs were observed. , at month 7. GMTs decreased through Month 24 and then stabilized until at least Month 60. The exact duration of immunity following a 3-dose schedule has not been established.
In the phase III studies in women 16 to 26 years of age, at the end of the study, 90%, 95%, 98%, and 60% of individuals who received Gardasil in the per-protocol population assessed for immunogenicity were respectively anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti HPV 18 seropositive with the cLIA test.
In the phase III study in women aged 24 to 45, after a median follow-up of 4.0 years, 91.5%, 92.0%, 97.4%, and 47.9% of individuals who received Gardasil in the per-protocol population assessed for immunogenicity were anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti HPV 18 seropositive with the cLIA test, respectively.
Men vaccinated with Gardasil at 16-26 years of age in the Protocol 020 base study will be followed for up to 10 years in the extension study. Depending on the type of HPV, 48-97% and 82-100% of subjects were found to be seropositive with the cLIA and IgG LIA tests 6 years after vaccination, respectively.
In longer-term follow-up in women aged 16 to 45 and in men aged 16 to 26, subjects who were seronegative for anti-HPV 6, anti-HPV 11, anti-HPV 16 , anti-HPV 18, measured with the cLIA test, at the end of the study, were still protected against the clinical manifestations of the disease.
Evidence of anamnestic responses (immune memory)
Evidence of an anamnestic response was observed in vaccinated women who were seropositive to relevant HPV types prior to vaccination. Additionally, a subgroup of vaccinated women who received an additional dose of Gardasil 5 years after the start of the vaccination course. , showed a rapid and strong anamnestic response with anti-HPV GMTs levels higher than those observed one month after dose 3.
HIV-infected subjects
An academic study documenting the safety and immunogenicity of Gardasil was conducted in 126 HIV-infected subjects aged 7 to 12 years (including 96 vaccinated with Gardasil). Seroconversion to all four antigens occurred in more than 96% of subjects. The GMTs were slightly lower than reported in other studies in subjects of the same age without HIV infection. The clinical relevance of the minor response is unknown. The safety profile was similar. to that of HIV-free subjects in other studies.The levels of CD4 or HIV RNA measured in plasma were not affected by vaccination.
Immune response to Gardasil using a 2-dose schedule in subjects 9 to 13 years of age
A clinical study showed that among girls who received 2 doses of HPV vaccine 6 months apart, antibody responses to 4 types of HPV one month after the last dose were not lower than the responses observed among young women. who received 3 doses of the vaccine within 6 months.
At month 7, in the per protocol population, the immune response in girls 9 to 13 years of age (n = 241) who received 2 doses of Gardasil (at 0.6 months) was non-lower and numerically higher than the response in women 16 to 26 years of age (n = 246) who had received 3 doses of Gardasil (at 0, 2, 6 months).
At 36-month follow-up, the GMTs in girls (2 doses, n = 86) remained no less than the GMTs in women (3 doses, n = 86) for all 4 HPV types.
In the same study, in girls 9 to 13 years of age, the immune response after a 2-dose schedule was numerically lower than a 3-dose schedule (n = 248 at month 7; n = 82 at month 36) . The clinical relevance of these observations is unknown.
The duration of protection of a 2-dose schedule of Gardasil has not been established.
05.2 "Pharmacokinetic properties
Not applicable.
05.3 Preclinical safety data
Single and repeated dose toxicity studies and local tolerance studies did not reveal any particular risk for humans.
Gardasil induced specific antibody responses against HPV types 6, 11, 16 and 18 in pregnant rats following single or multiple intramuscular injections. Antibodies to all four HPV types were transmitted to offspring during gestation and possibly during lactation. There were no treatment-related effects on developmental parameters, behavior, reproductive capacity, or fertility of the offspring.
Administration of Gardasil to male rats at the full human dose (120 μg of total protein) had no effect on reproductive capacity, including fertility, sperm count and motility, and no obvious changes were observed in the testes. vaccine-related histomorphologies, nor effects on testicular weight.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium chloride
L-histidine
Polysorbate 80
Sodium borate
Water for injections
For the adjuvant, see section 2.
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other products.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C).
Do not freeze. Keep the vial in the outer carton to protect it from light.
06.5 Nature of the immediate packaging and contents of the package
0.5 ml suspension in a vial (glass) with a stopper (chlorobutyl elastomer coated with FluroTec or Teflon) and a flip-off plastic cap (aluminum seal), in packs of 1, 10 or 20 doses.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
The vaccine should be used as supplied; no dilution or reconstitution is required.
The full recommended dose of the vaccine should be administered.
Shake well before use. Careful shaking is required immediately before use to keep the vaccine in suspension.
Medicinal products to be administered parenterally should be visually inspected for the presence of particulate matter and discolouration prior to administration.
Do not use the vaccine in the presence of particulates or if the color appears to be altered.
Use of the single-dose vial
Withdraw the 0.5 ml dose of vaccine from the single-dose vial using a sterile needle and a syringe free of preservatives, disinfectants and detergents. Once the single-dose vial has been punctured, the vaccine should be withdrawn and used promptly, and the vial should be discarded.
Disposal
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Sanofi Pasteur MSD SNC, 162 avenue Jean Jaurès, 69007 Lyon, France
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/06/357/001
037311014
EU / 1/06/357/002
037311026
EU / 1/06/357/018
037311180
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 20 September 2006
Date of most recent renewal: 22 September 2011
10.0 DATE OF REVISION OF THE TEXT
June 2014
