CERVARIX 20mcg / 20mcg suspension for injection in pre-filled syringe medication leaflet

Cervarix suspension for injection in pre-filled syringe

Cervarix suspension for injection in a vial

Cervarix suspension for injection in multidose container

Human Papillomavirus vaccine [Types 16, 18] (Recombinant, adjuvanted, adsorbed)

1 dose (0.5 ml) contains:

Human Papillomavirus1 type 16 L1 protein2,3,4 20 micrograms

Human Papillomavirus1 type 18 L1 protein2,3,4 20 micrograms1Human Papillomavirus = HPV2adjuvanted by AS04 containing:3-O-desacyl-4’- monophosphoryl lipid A (MPL)3 50 micrograms3adsorbed on aluminium hydroxide, hydrated (Al(OH)3) 0.5 milligrams Al3+ in total4L1 protein in the form of non-infectious virus-like particles (VLPs) produced by recombinant DNAtechnology using a Baculovirus expression system which uses Hi-5 Rix4446 cells derived from

Trichoplusia ni.

For the full list of excipients, see section 6.1.

Suspension for injection.

Turbid white suspension.

Cervarix is a vaccine for use from the age of 9 years for the prevention of premalignant ano-genitallesions (cervical, vulvar, vaginal and anal) and cervical and anal cancers causally related to certainoncogenic Human Papillomavirus (HPV) types. See sections 4.4 and 5.1 for important information onthe data that support this indication.

The use of Cervarix should be in accordance with official recommendations.

The vaccination schedule depends on the age of the subject.

Age at the time of the firstinjection Immunization and schedule9 to and including 14 years* Two doses each of 0.5 ml. The second dose givenbetween 5 and 13 months after the first dose

From 15 years and above Three doses each of 0.5 ml at 0, 1, 6 months**

*If the second vaccine dose is administered before the 5th month after the first dose, a third doseshould always be administered.

**If flexibility in the vaccination schedule is necessary, the second dose can be administered between1 month and 2.5 months after the first dose and the third dose between 5 and 12 months after the firstdose.

The need for a booster dose has not been established (see section 5.1).

It is recommended that subjects who receive a first dose of Cervarix complete the vaccination coursewith Cervarix (see section 4.4).

Paediatric population (children < 9 years of age)

Cervarix is not recommended for use in children below 9 years of age due to limited data on safetyand immunogenicity in this age-group.

Cervarix is for intramuscular injection in the deltoid region (see also sections 4.4 and 4.5).

Cervarix should under no circumstances be administered intravascularly or intradermally. No data areavailable on subcutaneous administration of Cervarix (see section 4.4).

If Cervarix is to be given at the same time as another injectable vaccine, the vaccines should always beadministered at different injection sites (see section 4.5).

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

As with all injectable vaccines, appropriate medical treatment and supervision should always bereadily available in case of a rare anaphylactic reaction following the administration of the vaccine.

Syncope (fainting) can occur following, or even before, any vaccination especially in adolescents asa psychogenic response to the needle injection. This can be accompanied by several neurologicalsigns such as transient visual disturbance, paraesthesia and tonic-clonic limb movements duringrecovery. It is important that procedures are in place to avoid injury from faints.

Administration of Cervarix should be postponed in subjects suffering from an acute severe febrileillness. However, the presence of a minor infection, such as a cold, is not a contraindication forimmunisation.

The vaccine should under no circumstances be administered intravascularly or intradermally.

No data are available on subcutaneous administration of Cervarix.

As with other vaccines administered intramuscularly, Cervarix should be given with caution toindividuals with thrombocytopenia or any coagulation disorder since bleeding may occur following anintramuscular administration to these subjects.

As with any vaccine, a protective immune response may not be elicited in all vaccinees.

Cervarix will only protect against diseases that are caused by HPV types 16 and 18 and to some extentagainst diseases caused by certain other oncogenic related HPV types (see section 5.1). Therefore,appropriate precautions against sexually transmitted diseases should continue to be used.

The vaccine is for prophylactic use only and has no effect on active HPV infections or establishedclinical disease. The vaccine has not been shown to have a therapeutic effect. The vaccine is thereforenot indicated for treatment of cervical cancer or cervical intraepithelial neoplasia (CIN). It is also notintended to prevent progression of other established HPV-related lesions or existing HPV infectionswith vaccine or non-vaccine types (see section 5.1 “Efficacy against HPV-16/18 in women withevidence of HPV-16 or HPV-18 infection at study entry.”).

Vaccination is not a substitute for routine cervical screening. Since no vaccine is 100% effective and

Cervarix will not provide protection against every HPV type, or against existing HPV infections,routine cervical screening remains critically important and should follow local recommendations.

Duration of protection has not fully been established. Timing and need of booster dose(s) has not beenestablished.

Except for asymptomatic human immunodeficiency virus (HIV) infected subjects for whomimmunogenicity data are available (see section 5.1), there are no data on the use of Cervarix insubjects with impaired immune responsiveness such as patients receiving immunosuppressivetreatment. As with other vaccines, an adequate immune response may not be elicited in theseindividuals.

There are no safety, immunogenicity or efficacy data to support interchangeability of Cervarix withother HPV vaccines.

This vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

In all clinical trials individuals who had received immunoglobulin or blood-derived products within 3months prior to the first vaccine dose were excluded.

Cervarix may be administered concomitantly with a combined booster vaccine containing diphtheria(d), tetanus (T) and pertussis [acellular] (pa) with or without inactivated poliomyelitis (IPV), (dTpa,dTpa-IPV vaccines), with no clinically relevant interference with antibody response to any of thecomponents of either vaccine. The sequential administration of combined dTpa-IPV followed by

Cervarix one month later tended to elicit lower anti-HPV-16 and anti-HPV-18 GMTs as compared to

Cervarix alone. The clinical relevance of this observation is not known.

Cervarix may also be administered concomitantly with meningococcal serogroups A, C, W-135, Ytetanus toxoid conjugate vaccine (MenACWY-TT); with combined hepatitis A (inactivated) andhepatitis B (rDNA) vaccine (Twinrix) or with hepatitis B (rDNA) vaccine (Engerix B).

Administration of Cervarix at the same time as Twinrix has shown no clinically relevant interferencein the antibody response to the HPV and hepatitis A antigens. Anti-HBs geometric mean antibodyconcentrations were significantly lower on co-administration, but the clinical relevance of thisobservation is not known since the seroprotection rates remain unaffected. The proportion of subjectsreaching anti-HBs ≥ 10mIU/ml was 98.3% for concomitant vaccination and 100% for Twinrix givenalone. Similar results were observed when Cervarix was given concomitantly with Engerix B with97.9% of subjects reaching anti-HBs ≥ 10mIU/ml compared to 100% for Engerix B given alone.

If Cervarix is to be given at the same time as another injectable vaccine, the vaccines should always beadministered at different injection sites.

Use with hormonal contraceptive

In clinical studies, approximately 60% of women who received Cervarix used hormonal contraceptives.

There is no evidence that the use of hormonal contraceptives has an impact on the efficacy of Cervarix.

See section 4.4.

Specific studies of the vaccine in pregnant women were not conducted. Data in pregnant womencollected as part of pregnancy registries, epidemiological studies and inadvertent exposure duringclinical trials are insufficient to conclude whether or not vaccination with Cervarix affects the risk ofadverse pregnancy outcomes including spontaneous abortion.

However, during the clinical development program, a total of 10,476 pregnancies were reportedincluding 5,387 in women who had received Cervarix. Overall, the proportions of pregnant subjectswho experienced specific outcomes (e.g., normal infant, abnormal infants including congenitalanomalies, premature birth, and spontaneous abortion) were similar between treatment groups.

Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy,embryonal/foetal development, parturition or post-natal development (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Cervarix during pregnancy. Womenwho are pregnant or trying to become pregnant, are advised to postpone or interrupt vaccination untilcompletion of pregnancy.

The effect on breast-fed infants of the administration of Cervarix to their mothers has not beenevaluated in clinical studies.

Cervarix should only be used during breast-feeding when the possible advantages outweigh thepossible risks.

No fertility data are available.

No studies on the effects on the ability to drive or use machines have been performed. However, someof the effects mentioned under section 4.8 “Undesirable effects” may temporarily affect the ability todrive or use machines.

In clinical studies that enrolled girls and women aged from 10 up to 72 years (of which 79.2% wereaged 10-25 years at the time of enrolment), Cervarix was administered to 16,142 females whilst13,811 females received control. These subjects were followed for serious adverse events over theentire study period. In a pre-defined subset of subjects (Cervarix = 8,130 versus control = 5,786),adverse events were followed for 30 days after each injection. In two clinical studies that enrolledmales aged 10 to 18 years, 2,617 males received Cervarix and were followed-up with active safetysurveillance.

The most common adverse reaction observed after vaccine administration was injection site painwhich occurred after 78% of all doses. The majority of these reactions were of mild to moderateseverity and were not long lasting.

Adverse reactions considered as being at least possibly related to vaccination have been categorised byfrequency.

Frequencies are reported as:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

System Organ Class Frequency Adverse reactions

Infections and infestations Uncommon Upper respiratory tract infection

Nervous system disorders Very common Headache

Uncommon Dizziness

Gastrointestinal disorders Common Gastrointestinal symptoms including nausea,vomiting, diarrhoea and abdominal pain

Skin and subcutaneous tissue Common Itching/pruritus, rash, urticariadisorders

Musculoskeletal and Very common Myalgiaconnective tissue disorders Common Arthralgia

General disorders and Very common Injection site reactions including pain, redness,administration site conditions swelling, fatigue

Common Fever (≥38°C)

Uncommon Other injection site reactions such asinduration, local paraesthesia

Blood and lymphatic system Not known* Lymphadenopathydisorders

Immune system disorders Not known* Allergic reactions (including anaphylactic andanaphylactoid reactions), angioedema

Nervous system disorders Not known* Syncope or vasovagal responses to injection,sometimes accompanied by tonic-clonicmovements (see section 4.4)

*Because these events were reported spontaneously, it is not possible to reliably estimate theirfrequency

In clinical trials a similar safety profile has been observed in subjects with prior or current HPVinfection as compared to subjects negative for oncogenic HPV DNA or seronegative for HPV-16 and

HPV-18 antibodies.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported.

Pharmacotherapeutic group: Vaccines, Papillomavirus vaccines, ATC code: J07BM02

Cervarix is an adjuvanted non-infectious recombinant vaccine prepared from the highly purified virus-like particles (VLPs) of the major capsid L1 protein of oncogenic HPV types 16 and 18. Since the

VLPs contain no viral DNA, they cannot infect cells, reproduce or cause disease. Animal studies haveshown that the efficacy of L1 VLP vaccines is largely mediated by the development of a humoralimmune response.

HPV-16 and HPV-18 are estimated to be responsible for approximately 70% of cervical cancers, 90%of anal cancers, 70% of HPV-related high grade vulvar and vaginal intraepithelial neoplasia and 78%of HPV related high-grade anal (AIN 2/3) intraepithelial neoplasia.

Other oncogenic HPV types can also cause ano-genital cancers (approximately 30%). HPV 45, -31and -33 are the 3 most common non-vaccine HPV types identified in squamous cervical carcinoma(12.1%) and adenocarcinoma (8.5%).

The term “premalignant ano-genital lesions” in section 4.1 corresponds to high-grade Cervical

Intraepithelial Neoplasia (CIN2/3), high-grade vulvar intraepithelial neoplasia (VIN2/3), high-gradevaginal intraepithelial neoplasia (VaIN2/3) and high-grade anal intraepithelial neoplasia (AIN 2/3).

Clinical studies

Clinical efficacy in women aged 15 to 25 years

The efficacy of Cervarix was assessed in two controlled, double-blind, randomised Phase II and IIIclinical trials that included a total of 19,778 women aged 15 to 25 years.

The phase II trial (study 001/007) enrolled only women who:

- Were tested negative for oncogenic HPV DNA of types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56,58, 59, 66 and 68

- Were seronegative for HPV-16 and HPV-18 and

- Had normal cytology

The primary efficacy endpoint was incident infection with HPV-16 and/or HPV-18. Twelve-monthpersistent infection was evaluated as additional efficacy endpoint.

The phase III trial (study 008) enrolled women without pre-screening for the presence of HPVinfection, i.e. regardless of baseline cytology and HPV serological and DNA status.

The primary efficacy endpoint was CIN2+ associated with HPV-16 and/or HPV-18 (HPV-16/18).

Cervical Intraepithelial Neoplasia (CIN) grade 2 and 3 (CIN2/3) and cervical adenocarcinoma in situ(AIS) were used in the clinical trials as surrogate markers for cervical cancer.

The secondary endpoints included 6- and 12-month persistent infection.

Persistent infection that lasts for at least 6 months has also been shown to be a relevant surrogatemarker for cervical cancer in women aged 15 to 25 years.

Prophylactic efficacy against HPV-16/18 infection in a population naïve to oncogenic HPV types

Women (N=1,113) were vaccinated in study 001 and evaluated for efficacy up to month 27. A subsetof women (N=776) vaccinated in study 001 was followed in study 007 up to 6.4 years (approximately77 months) after the first dose (mean follow-up of 5.9 years). There were five cases of 12-monthpersistent HPV-16/18 infection (4 HPV-16; 1 HPV-18) in the control group and one HPV-16 case inthe vaccine group in study 001. In study 007 the efficacy of Cervarix against 12-month persistent

HPV-16/18 infection was 100% (95% CI: 80.5; 100). There were sixteen cases of persistent HPV-16infection, and five cases of persistent HPV-18 infection, all in the control group.

In study HPV-023, subjects from the Brazilian cohort (N=437) of study 001/007 were followed up to amean of 8.9 years (standard deviation 0.4 years) after the first dose. At study completion, there wereno cases of infection or histopathological lesions associated with HPV-16 or HPV-18 in the vaccinegroup in study HPV-023. In the placebo group, there were 4 cases of 6-month persistent infection and1 case of 12-month persistent infection. The study was not powered to demonstrate a differencebetween the vaccine and the placebo group for these endpoints.

Prophylactic efficacy against HPV-16/18 in women naïve to HPV-16 and/or HPV-18

In study HPV-008, the primary analyses of efficacy were performed on the According to Protocolcohort (ATP cohort: including women who received 3 vaccine doses and were DNA negative andseronegative at month 0 and DNA negative at month 6 for the HPV type considered in the analysis).

This cohort included women with normal or low-grade cytology at baseline and excluded only womenwith high-grade cytology (0.5% of the total population). Case counting for the ATP cohort started onday 1 after the third dose of vaccine.

Overall, 74% of women enrolled were naïve to both HPV-16 and HPV-18 (i.e. DNA negative andseronegative at study entry).

Two analyses of study HPV-008 have been performed: an event-triggered analysis performed once atleast 36 CIN2+ cases associated with HPV-16/18 were accrued in the ATP cohort and an end-of studyanalysis.

Vaccine efficacy against the primary endpoint CIN2+at the end of study is presented in Table 1. In asupplemental analysis, the efficacy of Cervarix was evaluated against HPV-16/18-related CIN3+.

Table 1: Vaccine efficacy against high grade cervical lesions associated with HPV-16/18 (ATPcohort)

HPV-16/18 endpoint ATP cohort(1)

End of study analysis(3)

Cervarix Control % Efficacy (95% CI)(N = 7,338) (N = 7,305)n(2) n

CIN2+ 5 97 94.9% (87.7;98.4)

CIN3+ 2 24 91.7% (66.6;99.1)

N = number of subjects included in each groupn = number of cases(1) ATP: includes women who received 3 doses of vaccine, were DNA negative andseronegative at month 0 and DNA negative at month 6 to the relevant HPV type (HPV-16or HPV-18)(2) including 4 cases of CIN2+ and 2 cases of CIN3+ in which another oncogenic HPVtype was identified in the lesion, concomitantly with HPV-16 or HPV-18. These casesare excluded in the HPV type assignment analysis (see under Table).

(3) mean follow-up of 40 months post dose 3

At the event-triggered analysis the efficacy was 92.9% (96.1% CI: 79.9;98.3) against CIN2+ and 80%(96.1% CI: 0.3;98.1) against CIN3+. In addition, statistically significant vaccine efficacy against

CIN2+ associated with HPV-16 and HPV-18 individually was demonstrated.

Further investigation of the cases with multiple HPV types considered the HPV types detected by

Polymerase Chain Reaction (PCR) in at least one of the two preceding cytology samples, in additionto types detected in the lesion to distinguish the HPV type(s) most likely responsible to the lesion(HPV type assignment). This post-hoc analysis excluded cases (in the vaccine group and in the controlgroup) which were not considered to be causally associated with HPV-16 or HPV-18 infectionsacquired during the trial.

Based on the HPV type assignment post-hoc analysis, there was 1 CIN2+ case in the vaccine groupversus 92 cases in the control group (Efficacy 98.9% (95% CI: 93.8;100)) and no CIN3+ case in thevaccine group versus 22 cases in the control group (Efficacy 100% (95% CI: 81.8;100)) at the end ofstudy analysis.

In the event-triggered analysis, vaccine efficacy against CIN1 associated with HPV 16/18 observed inthe ATP cohort was 94.1% (96.1% CI: 83.4;98.5). Vaccine efficacy against CIN1+ associated with

HPV 16/18 observed in the ATP cohort was 91.7% (96.1% CI: 82.4;96.7). At the end of studyanalysis, vaccine efficacy against CIN1 associated with HPV 16/18 observed in the ATP cohort was92.8% (95% CI: 87.1;96.4).

At end of study analysis, there were 2 cases of VIN2+ or VaIN2+ in the vaccine group and 7 cases inthe control group in the ATP cohort associated with HPV-16 or HPV-18. The study was not poweredto demonstrate a difference between the vaccine and the control group for these endpoints.

Vaccine efficacy against virological endpoints (6-month and 12-month persistent infection) associatedwith HPV-16/18 observed in the ATP cohort at the end of study is presented in Table 2.

Table 2: Vaccine efficacy against virological endpoints associated with HPV-16/18 (ATP cohort)

HPV-16/18 endpoint ATP cohort(1)

End of study analysis(2)

Cervarix Control % Efficacy(N = 7,338) (N = 7,305) (95% CI)n/N n/N6-month persistent 35/7,182 588/7,137 94.3%infection (92.0;96.1)12-month persistent 26/7,082 354/7,038 92.9%infection (89.4;95.4)

N = number of subjects included in each groupn = number of cases(1) ATP: includes women who received 3 doses of vaccine, were DNA negative andseronegative at month 0 and DNA negative at month 6 to the relevant HPV type(HPV-16 or HPV-18)(2) mean follow-up of 40 months post dose 3

The efficacy results at the event-triggered analysis were 94.3% (96.1% CI: 91.5;96.3) against 6-monthpersistent infection and 91.4% (96.1% CI: 89.4;95.4) against 12-month persistent infection.

Efficacy against HPV-16/18 in women with evidence of HPV-16 or HPV-18 infection at study entry.

There was no evidence of protection from disease caused by the HPV types for which subjects were

HPV DNA positive at study entry. However, individuals already infected (HPV DNA positive) withone of the vaccine-related HPV types prior to vaccination were protected from clinical disease causedby the other vaccine HPV type.

Efficacy against HPV types 16 and 18 in women with and without prior infection or disease.

The Total Vaccinated Cohort (TVC) included all subjects who received at least one dose of thevaccine, irrespective of their HPV DNA status, cytology and serostatus at baseline. This cohortincluded women with or without current and/or prior HPV infection. Case counting for the TVCstarted on day 1 after the first dose.

The efficacy estimates are lower in the TVC as this cohort includes women with pre-existinginfections/lesions, which are not expected to be impacted by Cervarix.

The TVC may approximate to the general population of women in the age range of 15-25 years.

Vaccine efficacy against high grade cervical lesions associated with HPV-16/18 observed in TVC atend of study is presented in Table 3.

Table 3: Vaccine efficacy against high grade cervical lesions associated with HPV-16/18 (TVC)

HPV- TVC(1)16/18 End of study analysis(2)endpoint Cervarix Control % Efficacy (95% CI)(N = 8,694) (N = 8,708)n n

CIN2+ 90 228 60.7% (49.6;69.5)

CIN3+ 51 94 45.7% (22.9;62.2)

N = number of subjects included in each groupn = number of cases(1) TVC: includes all vaccinated subjects (who received at least one dose of vaccine)irrespective of HPV DNA status, cytology and serostatus at baseline. This cohort includeswomen with pre-existing infections/lesions(2) mean follow-up of 44 months post dose 1

Vaccine efficacy against virological endpoints (6-month and 12-month persistent infection) associatedwith HPV-16/18 observed in TVC at end of study is presented in Table 4.

Table 4: Vaccine efficacy against virological endpoints associated with HPV-16/18 (TVC)

HPV-16/18 TVC(1)endpoint End of study analysis(2)

Cervarix Control % Efficacy (95% CI)n/N n/N6-month persistent 504/8,863 1,227/8,870 60.9% (56.6;64.8)infection12-month persistent 335/8,648 767/8,671 57.5% (51.7;62.8)infection

N = number of subjects included in each groupn = number of cases(1) TVC: includes all vaccinated subjects (who received at least one dose of vaccine)irrespective of HPV DNA status, cytology and serostatus at baseline.(2) mean follow-up of 44 months post dose 1

Overall impact of the vaccine on cervical HPV disease burden

In study HPV-008, the incidence of high grade cervical lesions was compared between the placeboand vaccine group irrespective of the HPV DNA type in the lesion. In the TVC and TVC-naïvecohorts, the vaccine’s efficacy was demonstrated against high-grade cervical lesions at end of study(Table 5).

The TVC-naïve is a subset of the TVC that includes women with normal cytology, and who were HPV

DNA negative for 14 oncogenic HPV types and seronegative for HPV-16 and HPV-18 at baseline.

Table 5: Vaccine efficacy against high-grade cervical lesions irrespective of the HPV DNA type inthe lesion

End of study analysis(3)

Cervarix Control % Efficacy (95% CI)

N Cases N Cases

CIN2+

TVC-naïve(1) 5,466 61 5,452 172 64.9% (52.7;74.2)

TVC(2) 8,694 287 8,708 428 33.1% (22.2;42.6)

CIN3+

TVC-naïve(1) 5,466 3 5,452 44 93.2% (78.9;98.7)

TVC(2) 8,694 86 8,708 158 45.6% (28.8;58.7)

N = number of subjects included in each group(1) TVC naïve: includes all vaccinated subjects (who received at least onedose of vaccine) who had normal cytology, were HPV DNA negative for14 oncogenic HPV types and seronegative for HPV-16 and HPV-18 atbaseline.

(2) TVC: includes all vaccinated subjects (who received at least one dose ofvaccine) irrespective of HPV DNA status, cytology and serostatus atbaseline.

(3) mean follow-up of 44 months post dose 1

At the end of study analysis, Cervarix reduced definitive cervical therapy procedures (includes loopelectrosurgical excision procedure [LEEP], cold-knife Cone, and laser procedures) by 70.2% (95% CI:57.8;79.3) in TVC-naïve and 33.2% (95% CI: 20.8;43.7) in TVC.

Cross-protective efficacy

The cross-protective efficacy of Cervarix against histopathological and virological endpoints(persistent infection) has been evaluated in study HPV-008 for 12 non-vaccine oncogenic HPV types.

The study was not powered to assess efficacy against disease caused by individual HPV types. Theanalysis against the primary endpoint was confounded by multiple co-infections in the CIN2+ lesions.

Unlike histopathological endpoints, virological endpoints are less confounded by multiple infections.

HPV-31, 33 and 45 showed consistent cross-protection for 6-month persistent infection and CIN2+endpoints in all study cohorts.

End of study vaccine efficacy against 6-month persistent infection and CIN2+ associated withindividual non-vaccine oncogenic HPV types is presented in Table 6 (ATP cohort).

Table 6: Vaccine efficacy for non-vaccine oncogenic HPV types

ATP(1)

HPV type 6-month persistent infection CIN2+

Cervarix Control % Efficacy Cervari Control % Efficacy(95% CI) x (95% CI)n n n n

HPV-16 related types (A9 species)

HPV-31 58 247 76.8% 5 40 87.5%(69.0;82.9) (68.3;96.1)

HPV-33 65 117 44.8% 13 41 68.3%(24.6;59.9) (39.7;84.4)

HPV-35 67 56 -19.8% 3 8 62.5%(<0.0;17.2) (<0.0;93.6)

HPV-52 346 374 8.3% 24 33 27.6%(<0.0;21.0) (<0.0;59.1)

HPV-58 144 122 -18.3% 15 21 28.5%(<0.0;7.7) (<0.0;65.7)

HPV-18 related types (A7 species)

HPV-39 175 184 4.8% 4 16 74.9%(<0.0;23.1) (22.3;93.9)

HPV-45 24 90 73.6% 2 11 81.9%(58.1;83.9) (17.0;98.1)

HPV-59 73 68 -7.5% 1 5 80.0%(<0.0;23.8) (<0.0;99.6)

HPV-68 165 169 2.6% 11 15 26.8%(<0.0;21.9) (<0.0;69.6)

Other types

HPV-51 349 416 16.6% 21 46 54.4%(3.6;27.9) (22.0;74.2)

HPV-56 226 215 -5.3% 7 13 46.1%(<0.0;13.1) (<0.0;81.8)

HPV-66 211 215 2.3% 7 16 56.4%(<0.0;19.6) (<0.0;84.8)n= number of cases(1) ATP: includes women who received 3 doses of vaccine, were DNA negative at month 0 and atmonth 6 to the relevant HPV type.

The limits of the confidence interval around the vaccine efficacy were calculated. When the valuezero is included, i.e. when the lower limit of the CI is <0, the efficacy is not considered statisticallysignificant.

The efficacy against CIN3 was only demonstrated for HPV-31 and there was no evidence ofprotection against AIS for any of the HPV types.

Clinical efficacy in women aged 26 years and older

The efficacy of Cervarix was assessed in a double-blind, randomised Phase III clinical trial (HPV-015)that included a total of 5,778 women aged 26-72 years (median: 37.0 years). The study was conductedin North America, Latin America, Asia Pacific and Europe. Final analysis was performed at studyconclusion, 7 years after 1st vaccination.

The primary endpoint was a combination of a virological and a histopathological endpoint: HPV-16/18 related 6-month persistent infection and/or CIN1+. The primary analyses of efficacy wereperformed on the ATP cohort for efficacy and the TVC which included a subset of up to 15% ofwomen with a history of HPV-associated infection or disease (defined as two or more abnormalsmears in sequence, abnormal colposcopy, or biopsy or treatment of the cervix after abnormal smearor colposcopy findings). Inclusion of this subset allowed assessment of prophylactic efficacy in apopulation that is thought to reflect a real-world setting, as adult women are the age group generallytargeted for cervical screening.

Vaccine efficacy at study conclusion is summarised in the following table.

There is no evidence whether prevention of persistent infection that lasts for at least 6 months is arelevant surrogate marker for cervical cancer prevention in women aged 26 years and above.

Table 7 - Vaccine efficacy at study conclusion in study HPV-015

Endpoint ATP(1) TVC(2)

Cervarix Control % Efficacy Cervarix Control % Efficacyn/N n/N (96.2% CI) n/N n/N (96.2% CI)

HPV-16/186M PI 7/1,852 71/1,81 90.5% 93/2,768 209/2,778 56.8%and/or 8 (78.6; 96.5) (43.8; 67.0)

CIN1+6M PI 6/1,815 67/1,78 91.4% 74/2,762 180/2,775 60%6 (79.4; 97.1) (46.4; 70.4)

CIN2+ 1/1,852 6/1,818 83.7% 33/2,733 51/2,735 35.8%(<0.0; 99.7) (<0.0; 61.0)

ASC-US+ 3/1,852 47/1,81 93.8% 38/2,727 114/2,732 67.3%8 (79.9; 98.9) (51.4; 78.5)6M PI in 3/851 13/837 78% 42/1,211 65/1,192 38.7%subjects (15.0; 96.4) (6.3; 60.4)seropositive atbaselineonly

Cross protective efficacy

HPV-31 10/2,07 29/2,09 65.8% 51/2,762 71/2,775 29%6M PI 3 0 (24.9; 85.8) (<0.0; 52.5)

HPV-45 9/2,106 30/2,08 70.7% 22/2,762 60/2,775 63.9%6M PI 8 (34.2; 88.4) (38.6; 79.6)

HPV-31 5/2,117 23/2,12 78.4% 34/2,727 55/2,732 38.7%

ASC-US+ 7 (39.1; 94.1) (2.0; 62.3)

HPV-45 5/2,150 23/2,12 78.7% 13/2,727 38/2,732 66.1%

ASC-US+ 5 (40.1; 94.1) (32.7; 84.1)

N = number of subjects in each groupn = number of subjects reporting at least one event in each group6M PI = 6-month persistent infection

CI = Confidence Interval

ASC-US= Atypical Cells of Undetermined Significance (abnormal cytology)(1) 3 doses of vaccine, DNA negative and seronegative at month 0 (unless specified) and DNAnegative at month 6 for the relevant HPV type (HPV-16 and/or HPV-18)(2) at least one dose of vaccine, irrespective of HPV DNA and serostatus (unless specified) at month0. Includes 15% of subjects with previous history of HPV disease/infection

Efficacy against ≥ASC-US (abnormal cytology) associated with oncogenic non-vaccine types was37.2% (96.2% CI [21.3; 50.1]) (ATP).

Efficacy against CIN1+ irrespective of the HPV type detected in the lesion was 22.9% (96.2% CI [4.8;37.7]) (TVC).

There was no evidence of protection from disease caused by HPV in subjects aged 25 years and abovewho were DNA positive and/ or with abnormal cytology at study entry.

Immune response to Cervarix after the primary vaccination course

No minimal antibody level associated with protection against CIN of grade 2 or 3 or against persistentinfection associated with vaccine HPV types has been identified for HPV vaccines.

The antibody response to HPV-16 and HPV-18 was measured using a type-specific direct ELISA(version 2, MedImmune methodology, modified by GSK) which was shown to correlate with thepseudovirion-based neutralisation assay (PBNA).

The immunogenicity induced by three doses of Cervarix has been evaluated in 5,465 female subjectsfrom 9 to 55 years of age and over 800 male subjects aged 10 to 18 years.

In clinical trials, more than 99% of initially seronegative subjects had seroconverted to both HPVtypes 16 and 18 one month after the third dose. Vaccine-induced IgG Geometric Mean Titres (GMT)were well above titres observed in women previously infected but who cleared HPV infection (naturalinfection). Initially seropositive and seronegative subjects reached similar titres after vaccination.

Persistence of Immune Response to Cervarix

Study 001/007, which included women from 15 to 25 years of age at the time of vaccination,evaluated the immune response against HPV-16 and HPV-18 up to 76 months after administration ofthe first vaccine dose. In study 023 (a subset of study 001/007), the immune response continued to beevaluated up to 113 months. 92 subjects in the vaccine group had immunogenicity data at the [M107-

M113] interval after the first vaccine dose with a median follow-up of 8.9 years. Of these subjects,100% (95% CI: 96.1;100) remained seropositive for HPV-16 and HPV-18 in the ELISA assay.

Vaccine-induced IgG GMTs for both HPV-16 and HPV-18 peaked at month 7 and then declined toreach a plateau from month 18 up to the [M107-M113] interval with ELISA GMTs for both HPV-16and HPV-18 at least still 10-fold higher than the ELISA GMTs observed in women who cleared anatural HPV infection.

In study 008, immunogenicity up to month 48 was similar to the response observed in study 001. Asimilar kinetic profile was observed with the neutralising antibodies.

In another clinical trial (study 014) performed in women aged 15 to 55 years, all subjectsseroconverted to both HPV types 16 and 18 after the third dose (at month 7). The GMTs were,however, lower in women above 25 years. 470 subjects (142 aged 15-25 years, 172 aged 26-45 yearsand 156 aged 46-55 years) who completed study HPV-014 and received the 3-dose schedule werefollowed-up for up to 10 years in the extension study HPV-060. Ten years after administration of thefirst dose, 100% of subjects in the 15-25 years group, 99.2% in the 26-45 years group and 96.3% inthe 46-55 years group were still seropositive for HPV-16, and 99.2%, 93.7% and 83.8% for HPV-18,respectively. In all age groups, GMTs remained at least 5- to 32-fold for HPV-16 and 3- to 14-fold for

HPV-18 above those elicited in women who cleared a natural infection for both antigens.

Evidence of Anamnestic (Immune Memory) Response

In study 024 (a subset of study 001/007), a challenge dose of Cervarix was administered to 65 subjectsat a mean interval of 6.8 years after the administration of the first vaccine dose. An anamnestic immuneresponse to HPV-16 and HPV-18 (by ELISA) was observed one week and one month after the challengedose, GMTs one month after the challenge dose exceeded those observed one month after the primary3-dose vaccination.

Bridging the efficacy of Cervarix from young adult women to adolescents

In a pooled analysis (HPV-029,-30 & -48), 99.7% and 100% of females aged 9 years seroconverted to

HPV types 16 and 18, respectively after the third dose (at month 7) with GMTs at least 1.4-fold and2.4-fold higher as compared to females aged 10-14 years and 15 to 25 years, respectively.

In two clinical trials (HPV-012 & -013) performed in girls aged 10 to 14 years, all subjectsseroconverted to both HPV types 16 and 18 after the third dose (at month 7) with GMTs at least 2-foldhigher as compared to women aged 15 to 25 years.

In clinical trials (HPV-070 and HPV-048) performed in girls aged 9 to 14 years receiving a 2-doseschedule (0, 6 months or 0, 12 months) and young women aged 15-25 years receiving Cervarixaccording to the standard 0, 1, 6 months schedule, all subjects seroconverted to both HPV types 16 and18 one month after the second dose. The immune response after 2 doses in females aged 9 to 14 yearswas non-inferior to the response after 3 doses in women aged 15 to 25 years.

On the basis of these immunogenicity data, the efficacy of Cervarix is inferred from 9 to 14 years ofage.

Duration of the immune response in women aged 26 years and older

In the Phase III study (HPV-015) in women 26 years and older all subjects seroconverted one monthafter the third dose. At the 84-month time point, i.e. 78 months after completion of the full vaccinationcourse, 99.3% and 95.9% of initially seronegative women remained seropositive for anti-HPV-16 andanti-HPV-18 antibodies, respectively. All initially seropositive women remained seropositive for bothanti-HPV-16 and anti-HPV-18 antibodies. Antibody titers peaked at month 7 then gradually declinedup to month 18 and stabilized to reach a plateau up to month 84.

Immunogenicity in males aged 10 to 18 years

Immunogenicity in males was assessed in 2 clinical trials HPV-011 (N=173) and HPV-040 (N=556).

The data showed comparable immunogenicity in males and females. In study HPV-011, all subjectsseroconverted to both HPV-16 and 18 and GMT levels were non inferior to those observed in femalesaged 15 to 25 years in study HPV-012.

Bridging of clinical efficacy against anal lesions and cancers

No efficacy study against anal premalignant lesions has been conducted with Cervarix. However,studies conducted in girls aged 9 to 14 years (study HPV-071) and in women aged 18 to 45 years(study HPV-010) have consistently shown a higher immune response with Cervarix than with thecomparator for which efficacy data against anal premalignant lesions are conclusive and have shownprotection.

Immunogenicity in HIV infected women

Two clinical studies assessed safety and immunogenicity of Cervarix:

1. In study HPV-020, conducted in South Africa, 22 HIV uninfected and 42 HIV infectedsubjects (WHO clinical stage 1; ATP cohort for immunogenicity) received Cervarix.

2. Study HPV-019, a comparative study of Cervarix and quadrivalent HPV vaccine wasconducted in 289 (ATP cohort = 157) HIV uninfected and 257 (ATP cohort = 166) HIVinfected female subjects aged 15-25 years in Brazil, Estonia, India and Thailand.

At study entry, HIV infected subjects in both studies had to: be asymptomatic regardless of their priorclinical stage; have undetectable viral load (i.e., viral load < 400 copies/ml) for at least six months ifon antiretroviral therapy (ART) (HPV-020) or highly active antiretroviral therapy (HAART) for atleast one year (HPV-019); not be diagnosed with active tuberculosis (TB) or on TB therapy; in HPV-019 only - have a CD4 cell count > 350 cells/mm3.

In both studies, seroconversion at month 7 in HIV infected subjects receiving Cervarix was 100% forboth antigens in the ATP cohort. In HPV-019, seropositivity at month 24 after Cervarix vaccinationwas 100% for HPV-16 antibodies and >96% for HPV-18 antibodies with a Geometric Mean

Concentration (GMC) level more than 12 times higher than the response to natural HPV infection.

In both studies, the antibody GMCs in HIV infected subjects appeared lower than in the HIV negativesubjects (non-overlapping 95% confidence interval). In HPV-019, superiority of immune responses(neutralizing antibodies GMT ratios) to both HPV-16 and HPV-18 antigens was demonstrated with

Cervarix compared to quadrivalent HPV vaccine, at month 7 in HIV infected subjects. The clinicalrelevance of these observations is unknown. No clinical efficacy data exist about protection againstpersistent infection or precancerous lesions among HIV infected women.

The observed reactogenicity and safety profile of Cervarix in HIV infected women was in line with theknown safety profile in healthy subjects (see section 4.8).

Not applicable.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, acute and repeated dose toxicity, local tolerance, fertility, embryo-foetal and postnataltoxicity (up to the end of the lactation period).

Serological data suggest a transfer of anti-HPV-16 and anti-HPV-18 antibodies via the milk during thelactation period in rats. However, it is unknown whether vaccine-induced antibodies are excreted inhuman breast milk.

Sodium chloride (NaCl)

Sodium dihydrogen phosphate dihydrate (NaH2PO4.2 H2O)

Water for injections

For adjuvants, see section 2.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

5 years.

Cervarix should be administered as soon as possible after being removed from the refrigerator.

However, stability has been demonstrated when stored outside the refrigerator for up to 3 days attemperatures between 8°C and 25°C or for up to 1 day at temperatures between 25°C and 37°C. If notused at the end of this period the vaccine should be discarded.

After first opening, immediate use is recommended. If not used immediately, the vaccine should bestored in a refrigerator (2°C - 8°C). If not used within 6 hours it should be discarded.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage after first opening, see section 6.3.

Pre-filled syringe0.5 ml of suspension in a pre-filled syringe (type I glass) with a plunger stopper (butyl rubber) andwith a rubber tip cap. Pack sizes of 1 and 10, with or without needles.

Vial0.5 ml of suspension in a vial (type I glass) for 1 dose with a stopper (butyl rubber). Pack sizes of 1, 10and 100.

Multidose vial1 ml of suspension in a vial (type I glass) for 2 doses with a stopper (butyl rubber). Pack sizes of 1, 10and 100.

The tip cap and rubber plunger stopper of the pre-filled syringe and the stopper of the vial are madewith synthetic rubber.

Not all pack sizes may be marketed.

A fine white deposit with a clear colourless supernatant may be observed upon storage of the syringe.

This does not constitute a sign of deterioration.

The content of the syringe should be inspected visually both before and after shaking for any foreignparticulate matter and/or abnormal physical appearance prior to administration.

In the event of either being observed, discard the vaccine.

The vaccine should be well shaken before use.

Instructions for the pre-filled syringe

Luer Lock Adaptor

Hold the syringe by the barrel, not by theplunger.

Plunger Unscrew the syringe cap by twisting it

Barrel anticlockwise.

Cap

Needle hub

To attach the needle, connect the hub to the Luer

Lock Adaptor and rotate a quarter turnclockwise until you feel it lock.

Do not pull the syringe plunger out of the barrel.

If it happens, do not administer the vaccine.

Vial

A fine white deposit with a clear colourless supernatant may be observed upon storage of the vial. Thisdoes not constitute a sign of deterioration.

The content of the vial should be inspected visually both before and after shaking for any foreignparticulate matter and/or abnormal physical appearance prior to administration.

In the event of either being observed, discard the vaccine.

The vaccine should be well shaken before use.

A fine white deposit with a clear colourless supernatant may be observed upon storage of the vial. Thisdoes not constitute a sign of deterioration.

The content of the vial should be inspected visually both before and after shaking for any foreignparticulate matter and/or abnormal physical appearance prior to administration.

In the event of either being observed, discard the vaccine.

The vaccine should be well shaken before use.

When using a multidose vial, each 0.5 ml dose should be withdrawn using a sterile needle and syringe;precautions should be taken to avoid contamination of the contents.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

GlaxoSmithKline Biologicals SA.

Rue de l'Institut 89

B-1330 Rixensart, Belgium

EU/1/07/419/004

EU/1/07/419/005

EU/1/07/419/006

EU/1/07/419/007

EU/1/07/419/008

EU/1/07/419/009

Vial

EU/1/07/419/001

EU/1/07/419/002

EU/1/07/419/003

EU/1/07/419/010

EU/1/07/419/011

EU/1/07/419/012

Date of first authorisation: 20 September 2007.

Date of latest renewal: 17 September 2012.

DD/MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.