section 4.5 - coadministration with meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate vaccine (MenACWY-TT);

Section 4.8 Reporting details amended due to pack split (removal of UK details).

No submission to agency so date of revision is not amended.

Section 1: Vial and multidose container presentations added
Section 4.4: 'against HPV-16/18' added to 'see section 5.1' cross reference
Section 4.8: UK adverse event reporting details updated
Section 5.1: Formatting changes to table, commas added
Section 6.3: Shelf life changed from 4 to 5 years. Paragraph on multidose vial added
Section 6.4: Line on multidose vial added
Section 6.5: Text on prefilled syringe and multidose vial added. Heading of 'vial' added for the text that was previously there.
Section 6.6: Subheading 'pre-filled syringe' added. instructions for administration by pre-filled syringe added. Paragraphs on instructions for use of vial and multidose vial added.
Section 8: MA numbers for prefilled syringe, vial and multidose vial added

Description of change to SPC:

Section 4.6  - updated to reflect recently available data

Update section 4.4 to delete the sentence “The decision to vaccinate an individual woman should take into account her risk for previous HPV exposure and her potential benefit from vaccination”  in line with changes requested by the CHMP

Section 4.8 has been updated with the addition of HPRA details for adverse reporting.

4.2       Posology and method of administration

Updated to introduce a 2 dose schedule for vaccinees aged 9 to 14 years, with specific instructions regarding the factors requiring a third dose, i.e. administration in vaccinees from 15 years and older and in all vaccinees where the second vaccine dose is administered before the 5^th month after the first dose.

5.1       Pharmacodynamic properties

Updated to describe the updated seroconversion and immune response data report in clinical trials, which justified the changes to the Posology described above.

Package leaflet

3.         How Cervarix is given

Under the sub-heading ‘How much is given’, the description is changed in-line with the Posology updates in the SPC.

4.1          Therapeutic indications

Updated the indication to include vulvar and vaginal lesions, grouped with cervical legions under the term genital lesions, to read:

Cervarix is a vaccine for use from the age of 9 years for the prevention of premalignant genital (cervical, vulvar and vaginal) lesions and cervical cancer causally related to certain oncogenic Human Papillomavirus (HPV) types. See sections 4.4 and 5.1 for important information on the data that support this indication.

5.1          Pharmacodynamic properties

Mechanism of action

Updated the statement regarding the effects HPV-16 and HPV-18 is responsible for to include ‘HPV-related high grade vulvar and vaginal intraepithelial neoplasia’, to read:

HPV-16 and HPV-18 are estimated to be responsible for approximately 70% of cervical cancers and 70% of HPV-related high grade vulvar and vaginal intraepithelial neoplasia. Other oncogenic HPV types can also cause cervical cancer (approximately 30%). HPV 45, -31 and -33 are the 3 most common non-vaccine HPV types identified in squamous cervical carcinoma (12.1%) and adenocarcinoma (8.5%).

Updated the term of ‘premalignant cervical lesions’ to ‘premalignant genital lesions’ and changed it’s definition to include ‘high-grade vulvar intraepithelial neoplasia (VIN2/3) and high-grade vaginal intraepithelial neoplasia (VaIN2/3)’, to read:

The term “premalignant genital lesions” in section 4.1 corresponds to high-grade Cervical Intraepithelial Neoplasia (CIN2/3), high-grade vulvar intraepithelial neoplasia (VIN2/3) and high-grade vaginal intraepithelial neoplasia (VaIN2/3).

Clinical studies

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

Added the following paragraph:

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

SPC UPDATE

Editorial changes to sections 2, 4.3, 4.4, 4.5, 4.7, 4.8, 5.2, 6.3, 6.5 and 6.6

3.         Pharmaceutical Form

Removed the statement regarding the appearance of the product upon storage, i.e.;

Upon storage, a fine white deposit with a clear colourless supernatant may be observed.

4.2          Posology and method of administration

The Posology statement has been updated to specify 3 separate doses, i.e.;

The recommended vaccination consists of 3 separate 0.5 ml doses administered according to the schedule:  0, 1, 6 months.

4.6          Fertility, pregnancy and lactation

Added the subheadings ‘Pregnancy’, ‘Breast-feeding’ and ‘Fertility’.

Under the subheading ‘Pregnancy’ regarding the specific studies of the vaccine in pregnant women, changed the total number of pregnancies reported from 3,993 to 10,476, and the number of pregnancies reported in women who received Cervarix from 2,009 to 5,387.

Added the following statement regarding ‘Fertility’:

No fertility data are available.

5.1          Pharmacodynamic properties

Under ‘Clinical studies’ added two subheadings ‘Clinical efficacy in women aged 15 to 25 years’ and ‘Clinical efficacy in women aged 26 years and older’.

Added the following updated under the new subheading ‘Clinical efficacy in women aged 26 years and older’ further to the interim analysis of the clinical trial HPV-015

The efficacy of Cervarix was assessed in a double-blind, randomised Phase III clinical trial (HPV-015) that included a total of 5777 women aged 26 years and older. The study was conducted in North America, Latin America, Asia Pacific and Europe, and allowed women with previous history of HPV disease/infection to be enrolled. An interim analysis was performed when all subjects had completed the month 48 study visit.

The primary analyses of efficacy were performed on the ATP cohort for efficacy and the TVC.

Vaccine efficacy against 6 month persistent infection with HPV-16/18 (relevant surrogate marker for cervical cancer) is summarised in the following table.

Table 7: Vaccine efficacy against 6M PI with HPV 16/18 in ATP and TVC

Vaccine efficacy against 6-month persistent infection was 79.1% (97.7% CI [27.6; 95.9]) for HPV-31 and 76.9% (97.7% CI [18.5; 95.6]) for HPV-45 in the ATP cohort (3 doses of vaccine, DNA negative at months 0 and 6 for the relevant HPV type).

Vaccine efficacy against 6-month persistent infection was 23.2% (97.7% CI [-23.3; 52.5]) for HPV-31 and 67.7% (97.7% CI [35.9; 84.9]) for HPV-45 in the TVC.

Added the new subheading ‘Immunogenicity in women aged 26 years and older’, with the following information:

In the Phase III study (HPV-015) in women 26 years and older, at the 48-month time point, i.e. 42 months after completion of the full vaccination course, 100% and 99.4% of initially seronegative women remained seropositive for anti-HPV-16 and anti-HPV-18 antibodies, respectively. All initially seropositive women remained seropositive for both anti-HPV-16 and anti-HPV-18 antibodies. Antibody titers peaked at month 7 then gradually declined up to month 18 and stabilized to reach a plateau up to month 48.

5.1          Pharmacodynamic properties

Up-dated regarding Final Analysis of Efficacy study HPV-008, to include end-of study data.

4.5          Interaction with other medicinal products and other forms of interaction

Updated to include the statement that Cervarix can be administered concomittantly with a combined hepatitis A (inactivated) and hepatitis B (rDNA) vaccine (Twinrix) or with hepatitis B (rDNA) vaccine (Engerix B), with specific inclusion of the ‘Twinrix’ and ‘Engerix B’ product names

5.1          Pharmacodynamic properties

Under the subheading ‘Persistence of Immune Response to Cervarix’ updated the data regarding study 023, including the update that:

Vaccine-induced IgG GMTs for both HPV-16 and HPV-18 peaked at month 7 and then declined to reach a plateau from month 18 up to the [M95-M101] interval with ELISA GMTs for both HPV-16 and HPV-18 at least still 10-fold higher [previously 11-fold higher] than the ELISA GMTs observed in women who cleared a natural HPV infection.

Previous to the approval of V0018, this was ‘11-fold higher’

4.1        Therapeutic indications

·         Removed specific reference to HPV types 16 and 18, using the term ‘certain oncogenic’ HPV types

·         Added reference to section 4.4 of the SPC for more information

·         Added statement that:

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

 

4.2        Posology and method of administration

·         Added the following instruction regarding the use of a flexible schedule when necessary:

If flexibility in the vaccination schedule is necessary, the second dose can be administered between 1 month and 2.5 months after the first dose and the third dose between 5 and 12 months after the first dose.

·         Added subheadings ‘Posology’, ‘Paediatric population’ and ‘Method of administration’

 

4.4        Special warnings and precautions for use

·         The following was added:

The decision to vaccinate an individual woman should take into account her risk for previous HPV exposure and her potential benefit from vaccination.

·         Extended the precaution that Cervarix only protects against diseases caused by HPV types 16 and 18 and certain other oncogenic related HPV types and added that;

… appropriate precautions against sexually transmitted diseases should continue to be used.

·         Added warnings that Cervarix is for prophylactic use only and has no effect on active HPV infections or established clinical disease and that routine cervical screening remains critically important and should follow local recommendations.

 

4.6        Fertility, pregnancy and lactation

·         Added ‘Fertility’ to the heading of this section

·         Updated the numbers of pregnancies reported during the clinical development program from a total of 1,737 to 3,993 pregnancies, and of those in women who had received Cervarix from 870 to 2,009

 

4.8        Undesirable effects

·         Moved the following side effect to the top of the list of undesirable effects reported in clinical trials, with no change to the frequency or actual undesirable effect:

Infections and infestations:

Uncommon: upper respiratory tract infection

 

5.1        Pharmacodynamic properties

·         Under the subheading Mechanism of action, added that Cervarix is an adjuvanted vaccine and qualified the statement that HPV-16 and HPV-18 are estimated to be responsible for approximately 70% of cervical cancers. Added the statement that:

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

·         Under the subheading Mechanism of action , added the definition:

The term “premalignant cervical lesions” in section 4.1 corresponds to high-grade Cervical Intraepithelial Neoplasia (CIN2/3).

·         Under the subheading Clinical studies:

Referring to the phase III trial (study 008), extended the primary efficacy end points from CIN2 to include CIN2/3 or AIS, adding the statement that:

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.

Added the satatement that the secondary endpoints included 6-month persistent infection in addition to the previously approved 12-month persistent infection, explaining that:

Persistent infection that lasts for at least 6 months has also been shown to be a relevant surrogate marker for cervical cancer.

Deleted the following statements:

o    Cervical Intraepithelial Neoplasia (CIN) grade 2 and 3 was used in the clinical trials as a surrogate marker for cervical cancer.

o    The term “premalignant cervical lesions” in section 4.1 corresponds to high-grade Cervical Intraepithelial Neoplasia (CIN 2/3).

·         Updated the subheading ‘Prophylactic efficacy in women naïve to HPV-16 and/or HPV-18’ to specify efficacy against HPV-16/18, i.e.:

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

·         Under the updated heading Prophylactic efficacy against HPV-16/18 in women naïve to HPV-16 and/or HPV-18, updated all the efficacy data in line with the updated results from study HPV008

·         Replaced the previous subheading ‘Prophylactic efficacy in women with current or prior infection’ with two new subheadings ‘Efficacy against HPV-16/18 in women with evidence of HPV-16 or HPV-18 infection at study entry’ and ‘Efficacy against HPV types 16 and 18 in women with and without prior infection or disease’, and updated the data in line with the updated results from study HPV008

·         Added the subheading ‘Overall impact of the vaccine on cervical HPV disease burden’, and updated the data in line with the updated results from study HPV008

·         Added the subheading ‘Cross-protective efficacy’ and updated data regarding cross-protection and vaccine efficacy against 6-months persistent infection.

·         Under the subheading ‘Immunogenicity’ added the following three new subheadings:

‘Immune response to Cervarix after the primary vaccination course’

‘Persistence of Immune Response to Cervarix’

·         …under which the statement regarding immunogenicity observed in study 008 was updated to refer to immunogenicity data ‘up to 36 months’ as opposed to ‘up to 7 months’

‘Evidence of Anamnestic (Immune Memory) Response’

·         …under which a statement was added regarding the results of study 024 in which a challenge dose administered to 65 subject at a mean interval of 6.5 years after administration of the first vaccine dose resulted in an anamnestic immune response to HPV-16 and HPV-18

 

 

5.1          Pharmacodynamic properties

Under Clinical studies and the sub-heading Prophylactic efficacy in women with current or prior infection:

Added the acronym (PBNA) for pseudovirion-based neutralisation assay.

Updated the information regarding study 001/007 further to data from the month-12 of Study HPV-023, from:

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 post dose 1.

Vaccine-induced IgG Geometric Mean Titres (GMT) for both HPV-16 and HPV-18 peaked at month 7 and then declined to reach a plateau from month 18 up to the end of the follow-up (month 76). At the end of the follow-up period, GMTs for both HPV-16 and HPV-18 were still at least 11-fold higher than titres observed in women previously infected but who cleared HPV infection and >98% of the women were still seropositive for both antigens.

to:

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 of the first vaccine dose. In study 023 (a subset of study 001/007), the immune response continued to be evaluated up to 88 months. 111 subjects in the vaccine group had immunogenicity data at the [M83-M88] interval after the first vaccine dose with a median follow-up of 7 years. Of these subjects, 100% (95% CI: 96.7;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 to reach a plateau from month 18 up to the [M83-M88] interval with ELISA GMTs for both HPV-16 and HPV-18 at least still 11-fold higher than the ELISA GMTs observed in women who cleared a natural HPV infection.

6.6          Special precautions for disposal and other handling

Removed diagram of needle and instruction in point 2 to ‘see picture’

Cervarix suspension for injection in pre-filled syringe

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

Updates to SPC and Package Leaflet following the Commission Decision (approval) of 23/11/2009 of variations V0012 and V0013

SPC UPDATES

Section 4.4 Special warnings and precautions for use

Updated to include the following additional warning regarding occurrence of syncope:

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

Section 4.5 Interaction with other medicinal products and other forms of interaction

Updated to add the following statement regarding the co-administration of Cervarix and HAB vaccine (Twinrix):

Cervarix may be administered concomitantly with a combined hepatitis A (inactivated) and hepatitis B (rDNA) vaccine (HAB vaccine).

Administration of Cervarix at the same time as Twinrix (HAB vaccine) has shown no clinically relevant interference in the antibody response to the HPV and hepatitis A antigens. Anti-HBs geometric mean antibody titers were lower on co-administration, but the clinical significance of this observation is not known since the seroprotection rates remain unaffected. The proportion of subjects reaching anti-HBs ≥ 10mIU/ml was 98.3% for concomitant vaccination and 100% for Twinrix alone.

Section 4.8 Undesirable effects

Updated to include the categorization ‘clinical trials’ for the existing undesirable effects and to add the following listing of undesirable effects, as reported through post-marketing surveillance.

Post marketing surveillance

Because these events were reported spontaneously, it is not possible to reliably estimate their frequency.

Blood and lymphatic system disorders

Lymphadenopathy

Immune system disorders

Allergic reactions (including anaphylactic and anaphylactoid reactions), angioedema

Nervous system disorders

Syncope or vasovagal responses to injection, sometimes accompanied by tonic-clonic movements (see section 4.4)

Section 6.6 Special precautions for disposal and other handling

Updated to include the following instructions for administration of the vaccine:

Instructions for administration of the vaccine presented in pre-filled syringe

1.       Holding the syringe barrel in one hand (avoid holding the syringe plunger), unscrew the syringe cap by twisting it anticlockwise.

2.       To attach the needle to the syringe, twist the needle clockwise into the syringe until you feel it lock. (see picture)

3.       Remove the needle protector, which on occasion can be a little stiff.

4.       Administer the vaccine.

Cervarix suspension for injection in pre-filled syringe (EU/1/07/419/004)

Updates due to V0006 (co-administration with other vaccines (dTpa and dTpa-IPV)
Canges in red 

SPC

Section 4.5, Interaction with other medicinal products and other forms of interaction

Under the subheading ‘Use with other vaccines’ the instruction was updated from:

Data have not been generated on the concomitant administration of Cervarix and other vaccines.

to:

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 the components 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 significance of this observation is not known.

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