1. Name Of The Medicinal Product
Cervarix suspension for injection in pre-filled syringe
Human Papillomavirus vaccine [Types 16, 18] (Recombinant, adjuvanted, adsorbed)
2. Qualitative And Quantitative Composition
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For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Suspension for injection in pre-filled syringe.
Turbid white suspension. Upon storage, a fine white deposit with a clear colourless supernatant may be observed.
4. Clinical Particulars
4.1 Therapeutic Indications
Cervarix is a vaccine for the prevention of premalignant cervical 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.
The indication is based on the demonstration of efficacy in women aged 15-25 years following vaccination with Cervarix and on the immunogenicity of the vaccine in girls and women aged 10-25 years.
The use of Cervarix should be in accordance with official recommendations.
4.2 Posology And Method Of Administration
Posology
The recommended vaccination schedule is 0, 1, 6 months.
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.
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 3-dose vaccination course with Cervarix (see section 4.4).
Paediatric population
Cervarix is not recommended for use in girls below 10 years of age due to lack of data on safety and immunogenicity in this age-group.
Method of administration
Cervarix is for intramuscular injection in the deltoid region (see also sections 4.4 and 4.5).
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients.
Administration of Cervarix should be postponed in subjects suffering from an acute severe febrile illness. However, the presence of a minor infection, such as a cold, is not a contraindication for immunisation.
4.4 Special Warnings And Precautions For Use
The decision to vaccinate an individual woman should take into account her risk for previous HPV exposure and her potential benefit from vaccination.
As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine.
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.
Cervarix 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 to individuals with thrombocytopenia or any coagulation disorder since bleeding may occur following an intramuscular 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 extent against 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.
Cervarix is for prophylactic use only and has no effect on active HPV infections or established clinical disease. Cervarix has not been shown to have a therapeutic effect. The vaccine is therefore not indicated for treatment of cervical cancer or cervical intraepithelial neoplasia (CIN). It is also not intended to prevent progression of other established HPV-related lesions or existing HPV infections with vaccine or non-vaccine types (see section 5.1 “Efficacy in women with evidence 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 been established.
There are no data on the use of Cervarix in subjects with impaired immune responsiveness such as HIV infected patients or patients receiving immunosuppressive treatment. As with other vaccines, an adequate immune response may not be elicited in these individuals.
There are no safety, immunogenicity or efficacy data to support interchangeability of Cervarix with other HPV vaccines.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
In all clinical trials individuals who had received immunoglobulin or blood products within 3 months prior to the first vaccine dose were excluded.
Use with other vaccines
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 relevance of this observation is not known.
Cervarix may be administered concomitantly with a combined hepatitis A (inactivated) and hepatitis 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 interference in the antibody response to the HPV and hepatitis A antigens. Anti-HBs geometric mean antibody concentrations were significantly lower on co-administration, but the clinical relevance of this observation is not known since the seroprotection rates remain unaffected. The proportion of subjects reaching anti-HBs
If Cervarix is to be given at the same time as another injectable vaccine, the vaccines should always be administered at different injection sites.
Use with hormonal contraceptive
In clinical efficacy 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.
Use with systemic immunosuppressive medicinal products
As with other vaccines it may be expected that, in patients receiving immunosuppressive treatment, an adequate response may not be elicited.
4.6 Pregnancy And Lactation
Specific studies of the vaccine in pregnant women were not conducted. However, during the clinical development program, a total of 3,993 pregnancies were reported including 2,009 in women who had received Cervarix. Overall, the proportions of pregnant subjects who experienced specific outcomes (e.g., normal infant, abnormal infants including congenital anomalies, 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).
These data are insufficient to recommend use of Cervarix during pregnancy.
Vaccination should, therefore, be postponed until after completion of pregnancy.
The effect on breast-fed infants of the administration of Cervarix to their mothers has not been evaluated in clinical studies.
Cervarix should only be used during breast-feeding when the possible advantages outweigh the possible risks.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive or use machines have been performed.
4.8 Undesirable Effects
Clinical trials
In clinical studies that enrolled girls and women aged from 10 up to 72 years (of which 79.2% were aged 10-25 years at the time of enrolment), Cervarix was administered to 16,142 subjects whilst 13,811 subjects received control. These subjects were followed for serious adverse events over the entire 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.
The most common adverse reaction observed after vaccine administration was injection site pain which occurred after 78% of all doses. The majority of these reactions were of mild to moderate severity and were not long lasting.
Adverse reactions considered as being at least possibly related to vaccination have been categorised by frequency.
Frequencies are reported as:
Very common (
Common (
Uncommon (
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 disorders:
Common: itching/pruritus, rash, urticaria
Musculoskeletal and connective tissue disorders:
Very common: myalgia
Common: arthralgia
General disorders and administration site conditions:
Very common: injection site reactions including pain, redness, swelling; fatigue
Common: fever (
Uncommon: other injection site reactions such as induration, local paraesthesia
A similar safety profile has been observed in subjects with prior or current HPV infection as compared to subjects negative for oncogenic HPV DNA or seronegative for HPV-16 and HPV-18 antibodies.
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)
4.9 Overdose
No case of overdose has been reported.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmaco-therapeutic group: Papillomavirus vaccines, ATC code: J07BM02
Mechanism of action
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 have shown that the efficacy of L1 VLP vaccines is largely mediated by the development of a humoral immune response.
HPV-16 and HPV-18 are estimated to be responsible for approximately 70% of cervical cancers. 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%).
The term “premalignant cervical lesions” in section 4.1 corresponds to high-grade Cervical Intraepithelial Neoplasia (CIN2/3).
Clinical studies
The efficacy of Cervarix was assessed in two controlled, double-blind, randomised Phase II and III clinical 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-month persistent infection was evaluated as additional efficacy endpoint.
The phase III trial (study 008) enrolled women without pre-screening for the presence of HPV infection, i.e. regardless of baseline cytology and HPV serological and DNA status.
The primary efficacy endpoint was CIN2+ (CIN2/3 or AIS) 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 surrogate marker for cervical cancer.
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 subset of women (N=776) vaccinated in study 001 was followed in study 007 up to 6.4 years (approximately 77 months) after the first dose (mean follow-up of 5.9 years). There were five cases of 12-month persistent HPV-16/18 infection (4 HPV-16; 1 HPV-18) in the control group and one HPV-16 case in the 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-16 infection, and five cases of persistent HPV-18 infection, all in the control group.
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 Protocol cohort (ATP cohort: including women who received 3 vaccine doses and were DNA negative and seronegative 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 women with high-grade cytology (0.5% of the total population). Case counting for the ATP cohort started on day 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 and seronegative at study entry).
The mean follow-up for women included in study HPV-008 was approximately 39 months post dose 1 in TVC and 35 months post dose 3 in the ATP cohort.
Vaccine efficacy against the primary endpoint CIN2/3 or AIS is presented in Table 1. In a supplemental analysis, the efficacy of Cervarix was evaluated against HPV-16/18-related CIN3 or AIS.
Table 1: Vaccine efficacy against high grade cervical lesions associated with HPV-16/18 (ATP cohort)
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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 addition to 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 control group) which were not considered to be causally associated with HPV-16 or HPV-18 infections acquired during the trial.
Based on the HPV type assignment post-hoc analysis, there were 1 CIN2/3 or AIS case in the vaccine group versus 53 cases in the control group (Efficacy 98.1% (96.1% CI: 88.4; 100)) and 0 CIN3 or AIS cases in the vaccine group versus 8 cases in the control group (Efficacy 100% (96.1% CI: 36.4; 100)).
In addition, statistically significant vaccine efficacy against CIN2/3 or AIS associated with HPV-16 and HPV-18 individually was demonstrated.
Vaccine efficacy against CIN1 associated with HPV 16/18 observed in the ATP cohort was 94.1% (96.1% CI: 83.4;98.5). Vaccine efficacy against CIN1/2/3 or AIS associated with HPV 16/18 observed in the ATP cohort was 91.7% (96.1% CI: 82.4;96.7).
Vaccine efficacy against virological endpoints (6-month and 12-month persistent infection) associated with HPV-16/18 observed in the ATP cohort is presented in Table 2.
Table 2: Vaccine efficacy against virological endpoints associated with HPV-16/18 (ATP cohort)
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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) with one of the vaccine-related HPV types prior to vaccination were protected from clinical disease caused by 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 the vaccine, irrespective of their HPV DNA status, cytology and serostatus at baseline. This cohort included women with or without current and/or prior HPV infection. Case counting for the TVC started on day 1 after the first dose.
The efficacy estimates are lower in the TVC as this cohort includes women with pre-existing infections/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 is presented in Table 3.
Table 3: Vaccine efficacy against high grade cervical lesions associated with HPV-16/18 (TVC)
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Vaccine efficacy against virological endpoints (6-month and 12-month persistent infection) associated with HPV-16/18 observed in TVC is presented in Table 4.
Table 4: Vaccine efficacy against virological endpoints associated with HPV-16/18 (TVC)
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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 placebo and vaccine group irrespective of the HPV DNA type in the lesion. In the TVC and TVC-naïve cohorts, the vaccine's efficacy was demonstrated against high-grade cervical lesions (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 in the lesion
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Cervarix reduced definitive cervical therapy procedures (includes loop electrosurgical excision procedure [LEEP], cold-knife Cone, and laser procedures) by 68.8% (96.1% CI: 50.0;81.2) in TVC naïve and by 24.7% (96.1% CI: 7.4;38.9) 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. The analysis 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.
Only HPV-31 showed consistent cross-protection for all endpoints (6m and 12m persistent infection, CIN2/3 or AIS) and all study cohorts. Vaccine efficacy against 6 months persistent infection has also been shown for HPV-33 and HPV-45 in all study cohorts.
Vaccine efficacy against 6-month persistent infection and CIN2/3 or AIS associated with individual non-vaccine oncogenic HPV types is presented in Table 6 (ATP cohort).
Table 6: Vaccine efficacy for non-vaccine oncogenic HPV types
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