Active ingredients: Human Papillomavirus 9-valent vaccine (Recombinant, adsorbed)
Gardasil 9 suspension for injection in pre-filled syringe
Why is Gardasil 9 used? What is it for?
Gardasil 9 is a vaccine indicated for children and adolescents from 9 years of age and for adults. Vaccination with Gardasil 9 is indicated for protection against diseases caused by Human Papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 45, 52, and 58.
These conditions include pre-cancerous and cancerous lesions of the female genitalia (cervix, vulva and vagina), pre-cancerous and cancerous lesions of the anus and genital warts in males and females.
Gardasil 9 has been studied in males and females between the ages of 9 and 26.
Gardasil 9 protects against the types of HPV that are responsible for most cases of these diseases.
Gardasil 9 is indicated to prevent these diseases. The vaccine is not used to treat HPV-related diseases. Gardasil 9 has no effect in people who already have a persistent infection or disease associated with one of the HPV types contained in the vaccine. However, in individuals who have already been infected with one or more types of HPV contained in the vaccine, Gardasil 9 may still protect against diseases associated with the other HPV types contained in the vaccine.
Gardasil 9 cannot cause HPV related diseases.
When a person is vaccinated with Gardasil 9, the immune system (the body's natural defense system) stimulates the production of antibodies against the 9 types of HPV in the vaccine, which help protect against diseases caused by these viruses.
If you or your child receive a first dose of Gardasil 9, the vaccination course with Gardasil 9 must be completed.
If you or your child have already received an HPV vaccine, ask your doctor if Gardasil 9 is suitable for you.
Gardasil 9 must be used in accordance with official guidelines.
Contraindications When Gardasil should not be used 9
You should not receive Gardasil 9 if you or the child:
- you are allergic to one of the active substances or to any of the other ingredients of this vaccine (listed as "other ingredients" in section 6);
- you have developed an allergic reaction after receiving a dose of Gardasil or Silgard (HPV types 6,11,16 and 18) or Gardasil 9.
Precautions for use What you need to know before you take Gardasil 9
Talk to your doctor or nurse if you or your child:
- you have a bleeding disorder (a disease that involves more than normal bleeding), such as haemophilia;
- you have a weakened immune system, for example due to a genetic defect, HIV infection, or medicines that affect the immune system;
- you have a disease with a high fever. However, a mild fever or an "upper respiratory infection (for example a cold) does not in itself constitute a reason to postpone the vaccination.
Fainting, sometimes accompanied by falls, may occur (especially in adolescents) following any needle injection. Therefore, tell your doctor or nurse if you fainted from a previous injection.
As with all vaccines, Gardasil 9 may not fully protect all vaccinated individuals.
Gardasil 9 will not protect against any type of Human Papillomavirus. Therefore the use of appropriate precautions against sexually transmitted diseases should be maintained.
Vaccination does not replace routine cervical control. If you are a woman, you will need to continue to follow your doctor's instructions regarding cervical smear / Pap tests and preventive and protective measures.
What other important information do you or the child need to know about Gardasil 9
The duration of the protection conferred is not currently known. Longer-term studies are ongoing to determine whether a booster dose is needed.
Interactions Which drugs or foods can modify the effect of Gardasil 9
Tell your doctor or pharmacist if you or the child are taking, have recently taken or might take any other medicines, including non-prescription medicines.
Gardasil 9 can be given together with a combined booster vaccine containing diphtheria (d) and tetanus (T) along with pertussis [acellular component] (ap) and / or [inactivated] poliomyelitis (IPV) (dTap vaccines, dT-IPV, dTap-IPV), at separate injection sites (in another part of the body, for example the other arm or leg) during the same vaccination session.
Gardasil 9 may not have an optimal effect when used together with medicines that suppress the immune system.
Hormonal contraceptives (eg the pill) do not reduce the protection conferred by Gardasil 9.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant or are planning to have a baby, or if you are breast-feeding, ask your doctor for advice before receiving this vaccine.
Gardasil 9 can be given to women who are breastfeeding or planning to breastfeed.
Driving and using machines
Gardasil 9 may slightly and temporarily affect the ability to drive or use machines (see section 4 "Possible side effects").
Gardasil 9 contains sodium chloride
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, ie essentially "sodium free".
Dose, Method and Time of Administration How to use Gardasil 9: Posology
Gardasil 9 is given by injection by your doctor. You or the child will receive 3 doses of the vaccine.
First injection: on the established date.
Second injection: preferably 2 months after the first injection.
Third injection: preferably 6 months after the first injection.
If an alternative vaccination schedule is required, 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 a 1 year period. Ask your doctor for more information on this.
Subjects receiving the vaccine must complete the 3-dose vaccination course; otherwise the person receiving the vaccine may not be fully protected.
Gardasil 9 will be given by injection through the skin into the muscle (preferably the arm or thigh muscle).
Overdose What to do if you have taken too much Gardasil 9
If a dose of Gardasil 9 is not given:
If you miss one of the scheduled injections, your doctor will decide when to give you the missing dose. It is important that you follow the instructions of your doctor or nurse regarding subsequent vaccination sessions for administering the remaining doses. If you forget to go to the doctor at the appointed time, or are unable to go, ask your doctor for advice. given Gardasil 9 as the first dose, the next two doses to complete the 3-dose vaccination course should be Gardasil 9 and not another HPV vaccine.
If you have any further questions on the use of this vaccine, ask your doctor or pharmacist.
Side Effects What are the side effects of Gardasil 9
Like all vaccines, this vaccine can cause side effects, although not everybody gets them.
The following side effects may be observed after using Gardasil 9:
Very common (may affect more than 1 in 10 people): side effects seen at the injection site (pain, swelling, redness) and headache.
Common (may affect up to 1 in 10 people): side effects seen at the injection site (bruising and itching), fever, tiredness, dizziness and nausea.
When Gardasil 9 was given with a combined diphtheria, tetanus, pertussis [acellular component] and poliomyelitis [inactivated] booster vaccine during the same vaccination session, more swelling at the injection site was reported.
The following side effects have been reported after receiving GARDASIL or SILGARD and may also occur after administration of Gardasil 9:
Fainting, sometimes accompanied by shaking or stiffening, has been reported. Although fainting episodes are not common, vaccinated individuals should be observed for 15 minutes following the administration of the HPV vaccine.
Allergic reactions have been reported. Some of these reactions have been severe. Symptoms may include difficulty in breathing, fatigue in breathing, wheezing, hives and / or rash.
As with other vaccines, side effects have been reported during widespread use of the vaccine which include: enlarged lymph nodes (neck, armpits, groin); (muscle weakness, abnormal sensations, tingling in the arms, legs and upper part of the body, or confusion (Guillain-Barré syndrome, acute disseminated encephalomyelitis); vomiting, joint pain, muscle aches, unusual tiredness and weakness, chills, general feeling of discomfort, bleeding or bruising more easily than normal, and infection of the skin at the injection site.
Reporting of side effects
If you or the child get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep the vaccine out of the sight and reach of children.
Do not use this vaccine after the expiry date which is stated on the syringe label and outer carton after EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2 ° C - 8 ° C). Do not freeze. Store the syringe in the outer case to protect it from light.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Gardasil contains 9
The active ingredients are: highly purified non-infectious proteins for each type of Human Papillomavirus (6, 11, 16, 18, 31, 33, 45, 52 and 58).
1dose (0.5 ml) contains approximately:
Human Papillomavirus1 type 6 L1 protein 30 micrograms
Human Papillomavirus1 type 11 L1 protein 40 micrograms
Human Papillomavirus1 type 16 L1 protein 60 micrograms
Human Papillomavirus1 type 18 L1 protein 40 micrograms
Human Papillomavirus1 type 31 L1 protein 20 micrograms
Human Papillomavirus1 type 33 L1 protein 20 micrograms
Human Papillomavirus1 type 45 L1 protein 20 micrograms
Human Papillomavirus1 type 52 L1 protein 20 micrograms
Human Papillomavirus1 type 58 L1 protein 20 micrograms
1 Human Papillomavirus = HPV.
2 L1 protein in the form of virus-like particles produced by yeast cells (Saccharomyces cerevisiae CANADE 3C-5 (Strain 1895)) by recombinant DNA technology.
3 adsorbed on amorphous aluminum hydroxyphosphate sulfate adjuvant (0.5 milligrams of Al).
Amorphous aluminum hydroxyphosphate sulfate is present in this vaccine as an adjuvant. Adjuvants are used to enhance the immune response of vaccines.
The other ingredients present in the vaccine suspension are: sodium chloride, L-histidine, polysorbate 80, sodium borate and water for injections.
What Gardasil 9 looks like and contents of the pack
1 dose of Gardasil 9 suspension for injection contains 0.5 ml.
Before shaking, Gardasil 9 appears as a clear liquid with a white precipitate. After careful stirring, it appears as an opalescent white liquid.
Gardasil 9 is available in packs of 1 or 10 pre-filled syringes.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
GARDASIL 9 SUSPENSION FOR INJECTION IN PRE-FILLED SYRINGE
▼ Medicinal product subject to additional monitoring. This will allow quick identification of new security information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 dose (0.5 ml) contains approximately:
Human Papillomavirus1 type 6 L1 protein 30 mcg
Human Papillomavirus1 type 11 L1 protein 40 mcg
Human Papillomavirus1 type 16 L1 protein 60 mcg
Human Papillomavirus1 type 18 L1 protein 40 mcg.
Human Papillomavirus1 type 31 L1 protein 20 mcg
Human Papillomavirus1 type 33 L1 protein 20 mcg
Human Papillomavirus1 type 45 L1 protein 20 mcg
Human Papillomavirus1 type 52 L1 protein 20 mcg.
Human Papillomavirus1 type 58 L1 protein 20 mcg.
1 Human Papillomavirus = HPV.
2 L1 protein in the form of virus-like particles produced by yeast cells (Saccharomyces cerevisiae CANADE 3C-5 (Strain 1895)) by recombinant DNA technology.
& isup3; Adsorbed on amorphous aluminum hydroxyphosphate sulfate adjuvant (0.5 milligrams of Al).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Suspension for injection in pre-filled syringe.
Clear liquid with white precipitate.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Gardasil 9 is indicated for the active immunization of individuals from 9 years of age against the following HPV diseases:
• Precancerous lesions and tumors affecting the cervix, vulva, vagina and anus caused by the HPV subtypes contained in the vaccine.
• Genital warts (Condyloma acuminata) caused by specific types of HPV.
See sections 4.4 and 5.1 for important information on data supporting these therapeutic indications.
The use of Gardasil 9 must be established in accordance with official recommendations.
04.2 Posology and method of administration
Dosage
The primary vaccination course consists of the separate administration of 3 doses of 0.5 ml, according to the following schedule: 0, 2, 6 months.
If an alternative vaccination schedule is required, 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 a 1 year period.
The need for a booster dose has not been established.
It is recommended that subjects receiving a first dose of Gardasil 9 complete the 3-dose vaccination course with Gardasil 9 (see section 4.4).
For Gardasil 9, no studies have been performed using mixed (interchangeable) regimens of HPV vaccines.
Subjects previously vaccinated with a 3-dose regimen of quadrivalent HPV types 6, 11, 16 and 18 (Gardasil or Silgard) vaccine, hereafter referred to as qHPV vaccine, may receive 3 doses of Gardasil 9 (see section 5.1).
Pediatric population (children less than 9 years of age)
The safety and efficacy of Gardasil 9 in children aged less than 9 years have not been established. There are no data available (see section 5.1).
Female population aged 27 or over
The safety and efficacy of Gardasil 9 in women aged 27 years and older have not been studied (see section 5.1).
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 9 must not be injected intravascularly, subcutaneously or intradermally. The vaccine should not be mixed in the same syringe with other vaccines or solution.
For instructions on handling the vaccine before use, see section 6.6.
04.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Subjects with hypersensitivity after a previous administration of Gardasil 9 or Gardasil / Silgard should not receive additional doses of Gardasil 9.
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 and supervision should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine.
Syncope (fainting) may occur, sometimes associated with falling, 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 disturbances of vision. , paraesthesia and tonic-clonic movements of the limbs during the recovery phase Therefore, vaccinated subjects should be kept under observation for approximately 15 minutes after vaccination.It is important that procedures are in place to avoid injuries caused by fainting.
Vaccination should be postponed in subjects suffering from acute severe febrile illness. However, the presence of a minor infection, such as a mild upper respiratory tract infection or low fever, is not a contraindication to immunization.
As with any other vaccine, vaccination with Gardasil 9 may not ensure the protection of all vaccinated individuals.
The vaccine will only protect against diseases caused by the HPV types covered by the vaccine (see section 5.1). Therefore, appropriate precautions against sexually transmitted diseases must continue to be followed.
The vaccine is indicated for prophylactic use only and has no effect on active HPV infections or established clinical pathologies. The vaccine has not been 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 (HPV).
Gardasil 9 does not prevent injury due to one of the HPV types contained in the vaccine in individuals infected with the same HPV type at the time of vaccination (see section 5.1).
Vaccination does not replace traditional cervical screening. Since no vaccine is 100% effective and Gardasil 9 does not protect against any type of HPV, nor against HPV infections present at the time of vaccination, traditional neck screening "uterus retains critical importance and should be performed in accordance with local recommendations.
There are no data on the use of Gardasil 9 in subjects with a reduced immune response. The safety and immunogenicity of the qHPV vaccine have been evaluated in individuals aged 7 to 12 years with known Human Immunodeficiency Virus (HIV) infection. ) (see section 5.1).
People with a reduced immune response, due to the use of strong immunosuppressive therapy, a genetic defect, Human Immunodeficiency Virus (HIV) infection, 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 follow-up 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 9 with bivalent or quadrivalent HPV vaccines.
04.5 Interactions with other medicinal products and other forms of interaction
The safety and immunogenicity in subjects who received immunoglobulin or blood-derived products in the 3 months prior to vaccination have not been studied in clinical studies.
Use with other vaccines
Gardasil 9 can be administered concomitantly with a combined booster vaccine containing diphtheria (d) and tetanus (T) together with pertussis [acellular component] (ap) and / or [inactivated] lapoliomyelitis (IPV) (dTap vaccines, dT-IPV, dTap-IPV) with no significant interference with the antibody response of either vaccine. These data are based on results observed in a clinical study in which the dTap-IPV combination vaccine was administered concomitantly with the first dose of Gardasil 9 (see section 4.8).
Use with hormonal contraceptives
In clinical trials, 60.2% of women aged 16 to 26 who received Gardasil 9 were using hormonal contraceptives during the vaccination period. The use of hormonal contraceptives did not appear to affect specific immune responses to Gardasil 9.
04.6 Pregnancy and lactation
Pregnancy
A large number of studies of Gardasil 9 in pregnant women (more than 1,000 affected cases) do not indicate any malformation or fetal / neonatal toxicity (see section 5.1).
Animal studies do not indicate reproductive toxicity (see section 5.3).
However, these data are considered insufficient to recommend the use of Gardasil 9 during pregnancy. Vaccination should therefore be postponed until completion of pregnancy (see section 5.1).
Feeding time
Gardasil 9 can be used during breastfeeding.
A total of 92 women were breastfeeding during the vaccination period of the clinical studies with Gradasil 9. In the studies, the immunogenicity of the vaccine was similar between breastfeeding mothers and non-breastfeeding women. the adverse reaction profile for women who were breastfeeding was similar to that for women in the general clinical trial population.No serious adverse reactions were reported in infants who were breastfed during the vaccination period.
Fertility
There are no data on the effects of Gardasil 9 on human fertility. Studies in animals do not show harmful effects on fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
Gardasil 9 has no or negligible influence on the ability to drive or use machines. However, some of the effects mentioned in section 4.8 "Undesirable Effects" may temporarily affect the ability to drive or use machines.
04.8 Undesirable effects
A. Summary of the safety profile
Over the course of 7 clinical trials, subjects received Gardasil 9 on the day of enrollment and approximately 2 and 6 months thereafter. Safety was assessed by surveillance with vaccination card support (VRC - vaccination report card), in the 14 days following each Gardasil injection 9. A total of 15,776 subjects (of which 10,495 subjects aged 16 to 26 and 5,281 adolescents aged 9 to 15 years, at the time of enrollment) had received Gardasil 9. Few subjects (0.1%) discontinued dosing due to adverse reactions.
The most common adverse reactions observed with Gardasil 9 were related to injection site (84.8% of vaccinated within 5 days after each vaccination session) and headache (13.2% of vaccinated within 15 days after each vaccination session) ). These adverse reactions were generally mild or moderate in intensity.
B. Summary table of adverse reactions
Clinical studies
Adverse reactions, which were considered to be possibly related to vaccination, were divided by frequency.
Frequencies are reported as:
• Very common (≥1 / 10)
• Common (≥1 / 100 y
Table 1: Adverse reactions observed following administration of Gardasil 9, with a frequency of at least 1.0% in clinical studies
In a clinical study involving 1,053 healthy adolescents aged 11 to 15 years, administration of the first dose of Gardasil 9 at the same time as the booster dose of a combined diphtheria, tetanus, pertussis [acellular component] and poliomyelitis vaccine [inactivated] showed an increase in injection site reactions (swelling, erythema), headache and pyrexia. The observed differences were
Post-marketing experience
The following adverse reactions were spontaneously reported during the use of the qHPV vaccine following its authorization and could also be observed during post-marketing experience with Gardasil 9. Post-marketing safety experience with qHPV vaccine is correlated. to Gardasil 9, since vaccines contain L1 HPV proteins of 4 of the same HPV types.
Since these adverse reactions were reported voluntarily from a population of undefined size, it is not possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure for all events.
Infections and infestations: Cellulitis at the injection site
Blood and lymphatic system disorders: Idiopathic thrombocytopenic purpura, lymphadenopathy.
Immune system disorders: Hypersensitivity reactions including anaphylactic / anaphylactoid reactions.
Nervous system disorders: Acute disseminated encephalopathy, Guillan-Barré syndrome, syncope sometimes accompanied by tonic / clonic movements.
Gastrointestinal disorders: Vomiting.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.
General disorders and administration site conditions: Asthenia, chills, malaise.
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
No cases of overdose have been reported.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Vaccines, Papillomavirus vaccines, ATC code: J07BM03
Mechanism of action
Gardasil 9 is a non-infectious adjuvanted recombinant 9-valent vaccine. It is prepared from highly purified virus-like particles (VLPs) of the major capsid protein L1 from the 4 types of Human Papillomavirus (HPV) (6, 11, 16 and 18), present in the Gardasil or Silgard qHPV vaccine, and from the 5 additional types of HPV. Uses the same amorphous aluminum hydroxyphosphate sulfate adjuvant used for the qHPV vaccine. VLPs cannot infect cells, reproduce or cause disease. The efficacy of L1 VLP vaccines is thought to be mediated by the development of a humoral-like immune response.
Epidemiological studies suggest that Gardasil 9 protects against different types of HPV responsible for approximately: 90% of cervical cancers, more than 95% of adenocarcinomas in situ (AIS), 75-85% of high cervical grade (CIN 2/3), 85-90% of HPV-related vulvar cancers, 90-95% of HPV-related high-grade vulvar intraepithelial neoplasms (VIN 2/3), 80 -85% of HPV-related vaginal cancers, 75-85% of HPV-related high grade vaginal intraepithelial neoplasms (VaIN 2/3), 90-95% of HPV-related anal cancers, 85-90 % of HPV-related high-grade anal intraepithelial neoplasms (AIN 2/3) and 90% of genital warts.
The indication of Gardasil 9 is based on:
• the non-inferior immunogenicity between Gardasil 9 and the qHPV vaccine for HPV Types 6, 11, 16 and 18 in girls and women aged 9 to 26 years; consequently, it can be inferred that the efficacy for Gardasil 9 against persistent infection and diseases related to HPV types 6, 11, 16, or 18, it is comparable to that of the qHPV vaccine.
• the demonstration of efficacy against persistent infection and diseases related to HPV Types 31, 33, 45, 52 and 58 in girls and women aged 16 to 26, and
• the demonstration of no less immunogenicity against the nine types of HPV contained in Gardasil 9, in boys and girls between the ages of 9 and 15 and men between the ages of 16 and 26, compared to girls and women of age between 16 and 26 years.
Clinical trials for the qHPV vaccine
Efficacy in women and men aged 16 to 26 years
Efficacy was evaluated in 6 randomized, double-blind, placebo-controlled Phase II and III clinical trials involving 28,413 subjects (20,541 girls and women aged 16 to 26 years, 4,055 boys and men aged between 16 and 26 years) The qHPV vaccine has been shown to be effective in reducing the incidence of CIN (any grade, including CIN 2/3); AIS, genital warts; VIN 2/3; and VaIN 2/3 for vaccine against HPV types 6,11,16 or 18 in those girls and women who tested negative on PCR and seronegative at baseline (Table 2). The qHPV vaccine was effective in reducing the incidence of genital warts related to HPV types 6 and 11 in boys and men who were PCR negative and seronegative at baseline. Efficacy against penile / perineal intraepithelial neoplasia (PIN) Grade 1/2/3 / perianal or penile / perineal / perianal cancer has not been demonstrated due to too few cases to reach statistical significance (Table 2). The qHPV vaccine was effective in reducing the incidence of anal intraepithelial neoplasms (AIN) grades 2 and 3 related to HPV vaccine types 6, 11, 16, and 18 in PCR-negative and seronegative boys and men at baseline (Table 2 ).
Table 2: Analysis of qHPV Vaccine Efficacy in the PPE Population * for Vaccine Against Different Types of HPV
* The PPE population consisted of individuals who had received all 3 vaccinations within 1 year of enrollment, who had no significant deviations from the study protocol, and were naïve (PCR negative and seronegative) for the HPV types in question (Types 6, 11, 16, and 18) before dose 1 and up to 1 month after dose 3 (Month 7).
† The analyzes of the pooled studies were planned prospectively and included the use of similar inclusion criteria.
N = number of people with at least 1 follow-up visit after Month 7.
CI = Confidence Interval.
Efficacy in women aged 24 to 45 years
The efficacy of qHPV vaccine in women 24 to 45 years of age was evaluated in a randomized, double-blind, placebo-controlled Phase III clinical trial (Protocol 019, FUTURE III), which included a total of 3,817 women.
In the PPE population, the efficacy of qHPV vaccine 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 the qHPV vaccine against the combined incidence of persistent infection, genital warts, lesions of the vulva and vaginal, CIN of any grade, AIS, and cervical cancers related to HPV types 16 or 18 was 84.7% (95% CI: 67.5, 93.7).
Long-term efficacy studies
A subset of subjects is currently being followed up 10 to 14 years after qHPV vaccination for safety, immunogenicity, and protection against clinical disease related to HPV types 6/11/16/18.
Persistence of the antibody response was observed for 8 years in adolescents aged 9 to 15 years at the time of vaccination; for 9 years in women aged 16-23 at the time of vaccination; for 6 years in men aged 16 to 23 at the time of vaccination, and in women aged 24 to 45 at the time of vaccination.
Clinical protection was observed in all subjects (including those found to be seronegative for anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18): no cases of HPV disease were observed after a follow-up. up of about 6.9 years in girls between the ages of 9 and 15 at the time of vaccination; 6.5 years in males between the ages of 9 and 15 at the time of vaccination; 8 years in women aged 16 to 23 years at the time of vaccination; 6 years in men aged 16 to 26 at the time of vaccination and in women aged 24 to 45 at the time of vaccination.
Efficacy in HIV infected subjects
A study documenting the safety and immunogenicity of the qHPV vaccine was performed on 126 HIV-infected subjects aged 7 to 12 years with a baseline CD4 rate ≥ 15 and at least 3 months of highly active antiretroviral therapy ( HAART) for subjects with percentage of CD4 antigens occurred in more than 96% of subjects. The Geometric Means of Titers (GMTs) were slightly lower than those reported in other studies of non-HIV infected subjects of the same age. Clinical relevance of the lower response is unknown. The safety profile was similar to that in non-HIV infected subjects reported in other studies. The percentage of CD4 or plasma HIV RNA was not affected by vaccination.
Clinical studies of Gardasil 9
The efficacy and / or immunogenicity of Gardasil 9 was evaluated in seven clinical studies. Clinical trials evaluating the efficacy of Gardasil 9 versus placebo were not acceptable because HPV vaccination is recommended and implemented in many countries for protection against HPV infection and disease. Therefore, the pivotal clinical trial (Protocol 001) evaluated the efficacy of Gardasil 9, using the qHPV vaccine as a comparator.
Efficacy against HPV types 6, 11, 16, and 18 was first assessed with a bridging strategy demonstrating similar immunogenicity (as measured by Geometric Mean Titers (GMT)) of Gardasil 9 versus qHPV vaccine ( Protocol 001 and GDS01C / Protocol 009).
In the pivotal Protocol 001 study, the efficacy of Gardasil 9 against HPV types 31, 33, 45, 52, and 58 was evaluated against the qHPV vaccine in women aged 16 to 26 years (N = 14,204: 7,099 Gardasil 9 recipients; 7,105 qHPV vaccine recipients).
Protocol 002 assessed the immunogenicity of Gardasil 9 in girls and boys aged 9 to 15 and women aged 16 to 26 (N = 3,066: 1,932 girls; 666 boys; and 468 women receiving Garsadil 9) .
Protocol 003 evaluated the immunogenicity of Gardasil 9 in men aged 16 to 26 and in women aged 16 to 26 (1,103 heterosexual men [HM]; 313 men who had sex with men [MSM] , and women receiving Gardasil 9).
Protocols 005 and 007 evaluated administration of Gardasil 9 concomitantly with routinely recommended vaccines in girls and boys 11 to 15 years of age (N = 2,295).
In Protocol 006 they evaluated the administration of Gardasil 9 to girls and women aged 12 to 26 years previously vaccinated with the qHPV vaccine (N = 921; 615 who received Gardasil 9 and 306 who received placebo).
The GDS01C / Protocol 009 evaluated the immunogenicity of Gardasil 9 in girls 9 to 15 years of age (N = 600; 300 receiving Gardasil 9 and 300 receiving qHPV vaccine).
Studies supporting the efficacy of Gardasil 9 against HPV types 6, 11, 16, 18
Comparative efficacy studies between Gardasil 9 and the qHPV vaccine, against the different types of HPV 6, 11, 16 and 18 were conducted in a population of women aged 16 to 26 from protocol 001 and girls aged between 9 and 15 years from GDS01C / Protocol 009.
A "statistical analysis of non-inferiority was performed at Month 7 and compared the antibody titers cLIA GMT anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 between subjects vaccinated with Gardasil 9 and subjects vaccinated with Gardasil. Immune responses, as measured by GMT, for Gardasil 9 were not inferior to immune responses for Gardasil (Table 3). In clinical trials 99.6-100% of subjects who received Gardasil 9 became seropositive for antibodies against all 9 vaccine types by month 7 in all groups tested.
Table 3: Comparison of immune responses (measured by cLIA) between Gardasil 9 and qHPV vaccine for HPV types 6, 11, 16, and 18 in the PPI * population including girls and women aged 9 to 26 years.
* The PPI population consisted of subjects who received all three vaccinations within the designated day intervals, showed no major deviations from the study protocol, showed predefined criteria for the intervals between sessions at Month 6 and Month 7, were naïve (PCR negative and seronegative) for the HPV types concerned (Types 6, 11, 16, and 18) before dose 1 and in girls and women aged 16 to 26 years, PCR negative (s) for the HPV type (s) in question up to 1 month after dose 3 (Month 7).
§MMU = milli-Merck units.
¶Value-p
CI = Confidence Interval.
GMT = Geometric Mean of Stocks.
cLIA = Competitive Luminex Immunoassay.
N = Number of randomized subjects from the respective vaccination group who received at least one injection.
n = number of subjects who contributed to the analysis.
Studies supporting the efficacy of Gardasil 9 against HPV types 31, 33, 45, 52, and 58 The efficacy of Gardasil 9 was evaluated in women aged 16 to 26 years, in a clinical study comparing it with - active, double-blind, randomized control (Protocol 001), which included a total of 14,204 women (Gardasil 9 = 7,099; qHPV vaccine = 7,105). Subjects were followed up to Month 54 with a mean follow-up duration of 40 months. Gardasil 9 was effective in preventing persistent infection and HPV-related diseases 31-, 33-, 45-, 52-, and 58 (Table 4). Gardasil 9 also reduced the incidence of Pap smear abnormalities, cervical and external genital procedures (eg biopsies), and definitive cervical therapeutic procedures related to HPV 31, 33, 45, 52, and 58 (Table 4).
Table 4: Analysis of the efficacy of Gardasil 9 against HPV types 31, 33, 45, 52, and 58 in the PPE population ‡ including women aged 16 to 26 years.
‡ The PPE population consisted of subjects who had received all 3 vaccinations within 1 year of enrollment, had no major deviations from the study protocol, and were naïve (PCR negative and seronegative) for the HPV types in question ( types 31, 33, 45, 52, and 58) prior to dose 1, and which remained PCR negative for the HPV types in question 1 month after dose 3 (Month 7).
N = Number of subjects randomized to the respective vaccination group who received at least one injection.
n = number of individuals who contributed to the analysis. § Persistent infection detected in samples after two or more consecutive visits 6 months apart (visit windows ± 1).
¶ Persistent infection detected in samples after two or more consecutive visits 6 months apart (visit windows ± 1).
#Papanicolaou test.
CI = Confidence Interval.
ASC-US = Atypical squamous cells of uncertain significance.
HR = High Risk.
* Number of individuals with at least one follow-up visit after Month 7.
** Subjects followed up to 54 months after dose 1 (median 4 years).
α No cases of cervical cancer, VIN2 / 3, vulvar and vaginal cancer diagnosed in the PPE population.
† Electrosurgical loop excision procedure (LEEP) or conization.
Evaluation of the additional efficacy of Gardasil 9 against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58
Since the efficacy of Gardasil 9 could not be evaluated against placebo, the following exploratory analyzes were conducted.Evaluation of the efficacy of Gardasil 9 against high-grade cervical diseases caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in PPE The efficacy of Gardasil 9 against CIN 2 and above, related HPV type 6, 11, 16, 18, 31, 33, 45, 52, and 58 compared to qHPV vaccine was 94.4% (95% CI 78.8, 99.0) with 2 / 5,952 cases against 36 / 5.947 cases. The efficacy of Gardasil 9 against CIN 3 related to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 compared to the qHPV vaccine was 100% (95% CI 46.3; 100 , 0) with 0 / 5.952 cases against 8 / 5.947.
Impact of Gardasil 9 on cervical biopsy and conclusive therapy related to HPV type 6, 11, 16, 18, 31, 33, 45, 52, and 58 in PPE The efficacy of Gardasil 9 against HPV-related cervical biopsy of type 6, 11, 16, 18, 31, 33, 45, 52, and 58 compared to the qHPV vaccine was 95.9% (95% CI 92.7, 97.9), with 11/6016 cases against 262/6018. The efficacy of Gardasil 9 against conclusive cervical therapy (including electrosurgical loop excision procedure (LEEP) or conization) related to HPV type 6, 11, 16, 18, 31, 33, 45, 52 , and 58 compared to the qHPV vaccine was 90.7% (95% CI 76.3; 97.0) with 4/6016 cases versus 43/6018.
Immunogenicity The minimum anti-HPV titer, which confers protective efficacy has not been determined. Type-specific immunoassays with type-specific standards were used to assess immunogenicity to each HPV type contained in the vaccine. These tests measure antibodies against neutralizing epitopes for each HPV type. The scales for these tests are unique to each type. each HPV type; therefore, type comparisons and other tests are not appropriate. Immune response to Gardasil 9 at month 7 in all clinical studies Immunogenicity was measured by the percentage of individuals seropositive for antibodies against the vaccine for the type of relevant HPV, and from the geometric mean of the titers (GMT). Gardasil 9 induced robust anti-HPV 6, anti-HPV 11, anti-HPV 16, anti-HPV 18, anti-HPV 31, anti-HPV 33, anti-HPV 45, anti-HPV 52 and anti-HPV immune responses 58 measured at Month 7 (Table 5). In clinical trials, 99.6-100% of individuals who received Gardasil 9, by month 7 became HIV positive for antibodies against all 9 vaccine types in all groups tested. GMTs were higher in girls and boys than in women aged 16 to 26, and higher in boys than in girls and women.
Table 5: Summary of month 7, of the geometric mean of the titers measured with cLIA Anti-HPV in the PPI population *
* The PPI population consisted of subjects who received all three vaccinations within a set day interval, showed no major deviations from the study protocol, showed predefined criteria for the intervals between sessions at Month 6 and Month 7, were naïve (PCR negative and seronegative) for the HPV types concerned (Types 6, 11, 16, and 18) before dose 1 and in girls and women aged 16 to 26 years and who were PCR negative for the HPV types in question (Types 6, 11, 16, and 18) at 1 month after dose 3 (Month 7).
§MMU = milli-Merck units.
cLIA = Competitive Luminex Immunoassay.
CI = Confidence Interval.
GMT = Geometric Mean of Stocks.
N = Number of randomized subjects from the respective vaccination group who received at least one injection.
n = number of subjects who contributed to the analysis.
Anti-HPV responses at month 7 in girls / boys 9-15 years of age were comparable to anti-HPV responses in women 16-26 years of age in the combined Gardasil 9 immunogenicity study database. such immunogenicity bridging, the efficacy of Gardasil 9 in boys and girls aged 9 to 15 years is inferred.
Anti-HPV GMT antibodies at month 7 in heterosexual (HM) boys and men aged 16 to 26 years were comparable to anti-HPV GMT antibodies in girls and women aged 16 to 26 years. High immunogenicity was observed in men who have had sexual intercourse with men (MSM) between the ages of 16 and 26, although less than that of HMs, similar to the qHPV vaccine. These results support the efficacy of Gardasil 9 in the male population.
No studies have been conducted in women over 26 years of age. The efficacy of Gardasil 9 for the 4 original types in women aged 27 to 45 years is expected based on the high efficacy of the qHPV vaccine in women aged 16 to 45 and the comparable immunogenicity of Gardasil 9 and the qHPV vaccine in girls and women aged 9 to 26 years.
Persistence of the immune response to Gardasil 9 The persistence of the antibody response following a complete vaccination program with Gardasil 9 is being studied in a subset of subjects who will be followed for at least 10 years after vaccination to evaluate safety, "immunogenicity and efficacy." In adolescents aged 9 to 15 years, persistence of the antibody response has been demonstrated for at least 3 years; depending on the type of HPV, 93-99% of the subjects were HIV positive. In women aged 16 to 26 years, persistence of the antibody response has been demonstrated for at least 3.5 years; depending on the type of HPV, 78-98% of the subjects were HIV positive. Efficacy was maintained in all subjects until the end of the study, regardless of seropositive status, for any type of HPV vaccine.
Administration of Gardasil 9 to individuals previously vaccinated with the qHPV vaccine
Protocol 006 evaluated the immunogenicity of Gardasil 9 in 921 girls and women (aged 12 to 26 years) who had previously been vaccinated with the qHPV vaccine. For subjects vaccinated with Gardasil 9 after receiving 3 doses of the vaccine qHPV, a 3-dose regimen was administered with an interval of at least 12 months between the completion of vaccination with the qHPV vaccine and the initiation of vaccination with Gardasil 9, (the time interval of 12 to 36 months). per protocol, seropositivity for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 at month 7, ranged from 98.3 to 100%, in subjects who received Gardasil 9. The GMTs for HPV types 6, 11, 16, 18, were higher than in the population that had not previously received the qHPV vaccine in other studies, while the GMTs for HPV types 31, 33, 45, 52, and 58 were lower. The clinical significance of this observational study is unknown.
Pregnancy
No specific studies have been performed on Gardasil 9 in pregnant women. QHPV vaccine was used as an active control during the clinical development program for Gardasil 9.
During the Gardasil 9 clinical development program, 2,586 women (including 1,347 in the Gardasil 9 recipient group vs. 1,239 in the qHPV vaccine recipient group) experienced at least one pregnancy. The type of abnormalities or proportion of adverse pregnancies in subjects who received Gardasil 9 or the qHPV vaccine were comparable and in agreement with those reported by the general population.
05.2 "Pharmacokinetic properties
Not applicable.
05.3 Preclinical safety data
Single-dose and repeat-dose toxicity studies in rats and local tolerance studies did not reveal any particular risk for humans.
Administration of Gardasil 9 to female rats had no effect on reproductive capacity, fertility, or embryonic / fetal development.
Administration of Gardasil 9 to female rats had no effect on the development, behavior, reproductive capacity or fertility of the offspring. Antibodies against all 9 HPV types were transmitted to offspring during gestation and lactation.
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 pre-filled syringe in the outer carton to protect it from light.
Gardasil 9 should be administered as soon as possible, after being removed from the refrigerator.
Stability data indicate that the vaccine components remain stable for a period of 72 hours if the vaccine is stored at temperatures between 8 ° C and 25 ° C or between 0 ° C and 2 ° C. At the end of this time Gardasil 9 must be used or disposed of. This data is a guide for healthcare professionals only in the event of a temporary temperature excursion.
06.5 Nature of the immediate packaging and contents of the package
0.5 ml suspension in pre-filled syringe (glass) with plunger stopper (siliconised FluroTec-coated bromobutyl elastomer) and cap (synthetic mixture of isoprene and bromobutyl), with 2 needles in packs of 1 to 10.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
• Prior to shaking, Gardasil 9 may appear as a clear liquid with a white precipitate.
• Shake well before use until a suspension is formed. After careful stirring, a white opalescent liquid is obtained.
• Prior to administration, the suspension should be visually inspected for the presence of particles and discolouration. Dispose of the vaccine in the presence of particles and / or if the color appears discolored.
• 2 needles of different lengths are provided in the package, choose the appropriate needle to ensure intramuscular (IM) administration based on the size and weight of the patient.
• Insert the needle by turning it clockwise until it is firmly attached to the syringe. Administer the entire dose as per protocol.
• Immediately inject intramuscularly (IM), preferably in the deltoid region of the upper arm or the upper anterolateral area of the thigh.
• The vaccine should be used as directed. The full recommended vaccine dose should be used.
• Thorough shaking immediately before use is required to keep the vaccine in suspension.
Any unused material 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 / 1/15/1007/002
700017940
EU / 1/15/1007/003
700017953
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: DD month YYYY
