Consumer medicine information

Cervarix

Human papillomavirus vaccine, recombinant

BRAND INFORMATION

Brand name

Cervarix

Active ingredient

Human papillomavirus vaccine, recombinant

Schedule

What is in this leaflet?

Please read this leaflet carefully before you use CERVARIX.

This leaflet answers some common questions about CERVARIX. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Sometimes new risks are found even when a medicine has been used for many years. Your doctor has weighed the expected benefits of you taking CERVARIX against the risks this medicine could have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What is CERVARIX used for?

CERVARIX is a vaccine used in females from 10 to 45 years of age to prevent early stage cervical cancers (pre-cancerous lesions), pap smear abnormalities and cervical cancer caused by human papillomaviruses (HPV) types 16 and 18.

HPV is a very common virus which affects humans. More than 100 types of HPV have been identified, most of which are harmless. About 30 types are spread through sexual contact, of which some types can cause visible genital warts, while others can cause cervical cancer and other genital cancers. HPV 16 and 18 belong to the group of HPVs that cause cervical cancer and other genital cancers.

When a person is given the vaccine, the immune system (the body’s natural defence system) will make antibodies against HPV. These antibodies are expected to protect against disease caused by HPV.

As with all vaccines, CERVARIX may not completely protect all people who are vaccinated against the human papillomavirus infections it is intended to prevent.

If you are already infected with HPV at initiation of the vaccination course, CERVARIX is not expected to induce regression of the lesions and may not be able to protect you against the disease progression.

As cervical cancer can be caused by HPV types not included in the vaccine and as CERVARIX is not expected to induce regression of any lesions if you are already infected with HPV types 16 and 18 at the start of the vaccination course, it is important to continue to consult your doctor for regular cervical screening.

Before you take CERVARIX

Do not take if:

You must not takeCERVARIX if:

if you have previously had any allergic reaction to human papillomavirus vaccines, or any ingredient contained in CERVARIX. The active substances and other ingredients in CERVARIX are listed at the end of the leaflet. Signs of an allergic reaction may include itchy skin rash, shortness of breath and swelling of the face or tongue.
if you are already pregnant or trying to become pregnant. If you become pregnant after commencing the course of vaccination then further doses should be postponed until after completion of the pregnancy. Women trying to become pregnant should postpone vaccination until completion of pregnancy.
if you have a severe infection with a high temperature. It might be necessary to postpone the vaccination until recovery. A minor infection such as a cold should not be a problem, but talk to your doctor first.
the expiry date (EXP) printed on the pack has passed.
the packaging is torn or shows signs of tampering.
take special care with CERVARIX if you have a bleeding problem or bruise easily.

Fainting can occur following, or even before, any needle injection, therefore tell the doctor or nurse if you have fainted with a previous injection.

Tell your doctor if:

You must tell your doctor if:

you are allergic to foods, dyes, preservatives or any other medicines.
you are taking any other medicines, including medicines you buy without a prescription.
you are breastfeeding, pregnant or trying to become pregnant.

How CERVARIX is given

The total number of injections you will receive depends on your age at the time of the first injection. Each injection is given on a separate visit. You will be informed by the doctor or nurse when you should come back for subsequent injections.

If you are between 10 and 14 years old:

CERVARIX can be administered according to the following 2-dose or 3-dose schedule:

2-dose schedule:
Second injection: given between 5 and 13 months after the first injection.

3-dose schedule:
Second injection: 1 month after the first injection.
Third injection: 6 months after the first injection.

If you are 15 to 45 years old:

CERVARIX is administered according to the 3-dose schedule above.

It is important that you follow the instructions of your doctor or nurse regarding return visits. If you forget to go back to your doctor at the scheduled time, ask your doctor for advice.

If you do not finish the complete vaccination course you may not get the best response to vaccination.

The doctor will give CERVARIX as an injection into the muscle.

The vaccine should never be given into a vein.

While you are receiving CERVARIX

Things you must do:

Keep your visits with the doctor or clinic. It is important CERVARIX doses are given at the correct times. This will ensure the best effect of the vaccine in protecting you (or your child) against cervical cancer and cervical abnormalities.

Things to be careful of:

Be careful driving or operating machinery until you know how CERVARIX affects you. CERVARIX should not normally interfere with your ability to drive a car or operate machinery. But in some people vaccination can cause dizziness or lightheadedness. Make sure you know how you react to CERVARIX before you drive a car or operate machinery, or do anything that could be dangerous if you are dizzy or lightheaded.

What are the side-effects?

Check with your doctor as soon as possible if you think you or your child are experiencing any side effects or allergic reactions due to taking CERVARIX, even if the problem is not listed below.

Like other medicines, CERVARIX can cause some side-effects. If they occur, they are most likely to be minor and temporary. However, some may be serious and need medical attention.

You or your child may feel:

pain or discomfort at the injection site

or you or your child may see some:

redness or swelling at the injection site.

However, these effects usually clear up within a few days.

Other side effects that occurred during clinical trials with CERVARIX were as follows:

Very common (side effects which may occur in more than 1 per 10 doses of vaccine):
- headache
- aching muscles, muscle tenderness or weakness, not caused by exercise
- fatigue
Common (side effects which may occur in less than 1 per 10 but more than 1 per 100 doses of vaccine):
- gastrointestinal including nausea, vomiting, diarrhoea, and abdominal pain
- itching, red skin rash, hives
- joint pain
- fever (≥37.5°C -≤38°C)
Uncommon (side effects which may occur in less than 1 per 100 but more than 1 per 1,000 doses of vaccine):
- upper respiratory tract infection
- swollen glands in the neck, armpit or groin
- dizziness
- other injection site reactions including hard lump, loss of feeling, especially pain, during a medical procedure, itching
- flu-like symptoms, such as high temperature, sore throat, runny nose, cough and chills
Rare (side effects which may occur in less than 1 per 1,000 but more than 1 per 10,000 doses of vaccine):
- spinning sensation
- muscular weakness
- generally feeling unwell

Following rare side effects (these may occur with up to 1 in 1,000 doses of the vaccine) have been reported:

allergic reactions. These can be recognised by:
- itchy rash of the hands and feet
- swelling of the eyes and face
- difficulty in breathing or swallowing
- sudden drop in blood pressure and loss of consciousness
fainting sometimes accompanied by shaking or stiffness.

If you or your child gets any of these symptoms you should contact a doctor urgently.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

This is not a complete list of all possible side-effects. Others may occur in some people and there may be some side-effects not yet known.

Tell your doctor or pharmacist if you notice any side effects from your medicine which are not mentioned here.

Do not be alarmed by this list of possible side-effects. You may not experience any of them.

How do I store CERVARIX?

CERVARIX is usually stored at the doctor’s clinic or surgery, or at the pharmacy. But if you need to store CERVARIX always:

Keep CERVARIX in a refrigerator stored between +2°C and +8°C. Do not store it in the bathroom, or leave it in the car. Avoid exposing the vaccine to sunlight. HEAT CAN DESTROY THE VACCINE.
Keep the vaccine out of the reach of children.
Keep CERVARIX in the original pack until it is time for it to be given.

Ask your pharmacist what to do with any left over CERVARIX that has expired or has not been used.

Product description

What CERVARIX looks like

CERVARIX is a turbid white suspension for injection.

CERVARIX is available in pre-filled syringes with or without needles in packs of 1 and 10.

Not all pack sizes may be marketed.

Ingredients

CERVARIX contains the active ingredients HPV-16 L1 protein and HPV-18 L1 protein.

CERVARIX also contains 3-O-desacyl-4’- monophosphoryl lipid A (MPL), aluminium hydroxide hydrate, sodium chloride, monobasic sodium phosphate and water for injections.

Supplier:

Your CERVARIX is supplied by:

GlaxoSmithKline Australia Pty Ltd
Level 4, 436 Johnston Street
Abbotsford, Victoria 3067
Australia

Where to go for further information

Pharmaceutical companies are not in a position to give people an individual diagnosis or medical advice. Your doctor or pharmacist is the best person to give you advice on the treatment of your condition.

The information provided applies only to: CERVARIX

CERVARIX: AUST R 126114

This leaflet was prepared on 10 January 2020.

Version 7

Trade marks are owned by or licensed to the GSK group of companies.

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Cervarix

Active ingredient

Human papillomavirus vaccine, recombinant

Schedule

1 Name of Medicine

Human papillomavirus vaccine types 16 and 18 (recombinant, AS04 adjuvanted).

2 Qualitative and Quantitative Composition

Cervarix contains recombinant C-terminally truncated L1 proteins from human papillomavirus (HPV) type 16 and type 18 each assembled as virus-like particles (VLPs). The HPV-16 and HPV-18 L1 antigens are prepared by recombinant DNA technology using a Baculovirus expression system in Trichoplusia ni cells.
HPV-16 and HPV-18 L1 antigens in Cervarix are adjuvanted with AS04. This AS04 adjuvant system comprises aluminium hydroxide hydrate (Al(OH)₃) and 3-O-desacyl-4'- monophosphoryl lipid A (MPL). The MPL within AS04 enhances the initiation of the immune response through the activation of innate immunity, leading to an improved cellular and humoral adaptive immune response.
Each 0.5 mL dose of Cervarix contains 20 microgram each of HPV-16 L1 and HPV-18 L1 proteins, 0.5 milligram of Al(OH)₃ and 50 microgram of MPL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Suspension for injection.
Cervarix is presented as a turbid white suspension. Upon storage, a fine white deposit with a clear colourless supernatant can be observed. This does not constitute a sign of deterioration.

4 Clinical Particulars

4.1 Therapeutic Indications

Cervarix is indicated in females from 10 to 45 years of age for the prevention of persistent infection, premalignant cervical lesions and cervical cancer caused by human papillomavirus types 16 and 18. Immunogenicity studies have been conducted in females aged 10 to 14 years and 26 to 45 years to link efficacy in females aged 15 to 25 years to other populations (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Dosage.

The vaccination schedule depends on the age of the subject (see Table 1).

The necessity for a booster dose has yet to be established (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Method of administration.

Cervarix is for intramuscular injection in the deltoid region (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The content of the syringe should be inspected visually both before and after shaking for any foreign particulate 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.

Hold the syringe by the barrel, not by the plunger.
Unscrew the syringe cap by twisting it anticlockwise.
To attach the needle, connect the hub to the Luer Lock Adaptor and rotate a quarter turn clockwise until you feel it lock.
Do not pull the syringe plunger out of the barrel. If it happens, do not administer the vaccine.

4.3 Contraindications

Cervarix should not be administered to subjects with known hypersensitivity to any component of the vaccine (see Section 2 Qualitative and Quantitative Composition).

4.4 Special Warnings and Precautions for Use

As with other vaccines, the administration of Cervarix should be postponed in subjects suffering from acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination.
It is good clinical practice to precede vaccination by a review of the medical history (especially with regard to previous vaccination and possible occurrence of undesirable events) and a clinical examination.
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 as a psychogenic response to the needle injection. It is important that procedures are in place to avoid injury from faints.
As for 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.
Cervarix should under no circumstances be administered intravascularly or intradermally.
No data are available on subcutaneous administration of Cervarix.
As with any vaccine, a protective immune response may not be elicited in all vaccinees.
Cervarix is a prophylactic vaccine. Cervarix is not intended to be a treatment for persistent infection or for HPV-related lesions present at the time of vaccination. Cervarix is not intended to prevent progression of established HPV-related lesions present at the time of vaccination.
HPV-16 and HPV-18 are not responsible for all cervical cancers (See Section 5.1 Pharmacodynamic Properties, Clinical trials). Other oncogenic HPV types can also cause cervical cancer. HPV infections and related clinical outcomes due to these other oncogenic types may not be prevented by vaccination.
Vaccination is primary prevention and is not a substitute for regular cytological screening (secondary prevention) or for precautions against exposure to HPV and sexually transmitted diseases.
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. For these individuals an adequate immune response may not be elicited.
Duration of protection has not been established. Limited data support protective efficacy for 6.4 years after the first dose. Long-term studies are ongoing to establish the duration of protection.

Use in the elderly.

No data available.

Paediatric use.

See Section 4.4 Special Warnings and Precautions for Use.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Use with other vaccines.

Cervarix can be given concomitantly with any of the following vaccines: reduced antigen diphtheria-tetanus-acellular pertussis vaccine (dTpa), inactivated poliovirus vaccine (IPV), the combined dTpa-IPV vaccine, hepatitis A (inactivated) vaccine (HepA), hepatitis B (rDNA) vaccine (HepB) and the combined HepA-HepB vaccine.
Administration of Cervarix at the same time as Twinrix (combined HepA-HepB 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 ≥ 10 mIU/mL was 98.3% for concomitant vaccination and 100% for Twinrix alone.
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 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 medications.

As with other vaccines, it may be expected that in patients receiving immunosuppressive treatment, an adequate response may not be elicited.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility was not affected in female rats given double the clinical dose of Cervarix by intramuscular administration 30 days prior to mating.
(Category B2)
No adverse effects on embryofetal development, parturition or postnatal development were observed in pregnant rats that received double the clinical dose of vaccine on 4 occasions during gestation.
Specific studies of Cervarix in pregnant women have not been conducted.
Data in pregnant women collected as part of pregnancy registries, epidemiological studies and inadvertent exposure during clinical trials are insufficient to conclude whether or not vaccination with Cervarix affects the risk of adverse pregnancy outcomes including spontaneous abortion.
During the clinical development program, a total of 10,476 pregnancies were reported including 5,387 in women exposed to Cervarix.
Women who are pregnant or trying to become pregnant are advised to postpone vaccination until completion of pregnancy.
Cervarix should only be used during breast-feeding when the possible advantages outweigh the possible risks.
The effect on breastfed infants of the administration of Cervarix to their mothers has not been evaluated in clinical studies.
Serological data suggest a transfer of anti-HPV-16 and anti-HPV-18 antibodies via the milk during the lactation period in rats. However, it is unknown whether vaccine-induced antibodies are excreted in human breast milk.

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 Adverse Effects (Undesirable Effects)

In total, approximately 45,000 doses of Cervarix were administered to approximately 16,000 subjects aged 10 - 68 years. These subjects were followed to assess the safety of the vaccine.
Adverse reactions occurring after vaccination during these studies were reported. The most common 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.
Table 2 summarises data from seven pivotal studies for solicited local and general symptoms reported during a 7-day follow-up period after vaccination.
Data generated on the 2-dose schedule for Cervarix administered as a 0, 5-13 month in the 9-14 years age group provides a similar safety profile to that observed in 15-25 years age group having received a standard 3-dose schedule (0, 1, 6 months).

Other events.

Other adverse reactions considered as being at least possibly related to vaccination have been categorised by frequency.
Frequencies are reported as: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to ≤ 1/100); Rare (≥ 1/10,000 to ≤ 1/1,000); Very rare (< 1/10,000).

Infections and infestations.

Uncommon: upper respiratory tract infection.

Blood and lymphatic system disorders.

Uncommon: lymphadenopathy.

Nervous system disorders.

Very common: headache. Uncommon: dizziness.

Gastrointestinal disorders.

Common: gastrointestinal including nausea, vomiting, diarrhoea and abdominal pain.

Skin and subcutaneous tissue disorders.

Common: itching/pruritus, rash, urticaria.

Musculoskeletal and connective tissue and bone disorders.

Very common: myalgia. Common: arthralgia.

General disorders and administration site conditions.

Very common: injection site reactions including pain, redness, swelling, fatigue. Common: fever (≥ 38°C). Uncommon: other injection site reactions such as induration, local paraesthesia.

Postmarketing data.

Immune system disorders.

Rare: allergic reactions (including anaphylactic and anaphylactoid reactions), angioedema.

Nervous system disorders.

Rare: syncope or vasovagal responses to injection, sometimes accompanied by tonic-clonic movements.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No case of overdose has been reported.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Cervarix is a recombinant vaccine prepared from VLPs of the major L1 protein of HPV types 16 and 18. Since VLPs contain no viral DNA, they cannot infect cells or reproduce. Animal studies suggest that the efficacy of VLPs is largely mediated by the development of a humoral immune response and cell-mediated immunity.
Transudation of anti-HPV IgG antibodies from the serum to the cervical mucosa is thought to be the primary mechanism of protection against persistent oncogenic HPV infection, the necessary cause of cervical cancer.
Cervarix is adjuvanted with AS04. In clinical trials Cervarix adjuvanted with AS04 compared to the same antigens adjuvanted with aluminium hydroxide hydrate alone showed:
significantly higher antibody titres at least 2 fold higher (at all time points analysed up to 4 years after first dose);
significantly higher functional antibody titres (analysed up to 4 years after first dose);
B cell memory frequency approximately 2 fold higher (at all time points analysed up to 2 years after first dose).
Epidemiological evidence confirms that persistent infection with oncogenic (high-risk) HPV types is the primary cause of cervical cancer and most precursor lesions. Persistent infection with at least one oncogenic HPV type is a necessary causal factor for pre-cancerous high-grade cervical epithelial abnormalities, for example, cervical intraepithelial neoplasia (CIN).
Invasive cervical cancer includes squamous cervical carcinoma (84%) and adenocarcinoma (16% up to 20% in developed countries with screening programs).
HPV-16 and HPV-18 are responsible for approximately 70% of cervical cancers across all regions worldwide.
Other oncogenic HPV types (HPV-31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) can also cause cervical cancer. The 5 most common types identified in cervical cancer are HPV-16, 18, 33, 45 and 31.

Evidence of anamnestic (immune memory) response.

The administration of a challenge dose after a mean of 6.8 years following the first vaccination elicited an anamnestic immune response to HPV-16 and HPV-18 (by ELISA and pseudovirion-based neutralising assay) at day 7. One month after the challenge dose, GMTs exceeded those observed one month after the primary vaccination course.

Clinical trials.

Vaccine efficacy.

Clinical efficacy in women aged 15 to 25 years. The efficacy of Cervarix was assessed in 2 controlled, double-blind, randomised phase II and III clinical studies (HPV-001/007 and HPV-008) that included a total of 19,778 women aged 15 to 25 years.
Clinical trial HPV-001/007 was a study conducted in North America and Latin America. Study HPV-023 followed-up subjects from the Brazilian cohort of study 001/007. Study entry criteria were: negative for oncogenic HPV DNA (HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) in cervical samples, seronegative for HPV-16 and HPV-18 antibodies and normal cytology. These characteristics are representative of a population presumed naïve to oncogenic HPV types prior to vaccination.
Clinical trial HPV-008 is an on-going study conducted in North America, Latin America, Europe, Asia Pacific and Australia. Pre-vaccination samples were collected for oncogenic HPV DNA (HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) testing and serum testing for HPV-16 and HPV-18 antibodies. Women were vaccinated regardless of baseline cytology and HPV serological and DNA status. These characteristics are representative of a population which includes women with or without evidence of past and/or current HPV infection.
Subjects initially infected with a particular HPV type were not eligible for the efficacy assessment of that type.
The primary endpoints in study HPV-001/007 are incident HPV-16 and/or HPV-18 infections.
The primary endpoint in study HPV-008 is HPV-16 or HPV-18 related CIN2+.
In both studies, the following endpoints were evaluated:
CIN2+ (cervical intraepithelial neoplasia grade 2 and higher grade lesions);
CIN1+ (cervical intraepithelial neoplasia grade 1 and higher grade lesions);
Cytological abnormalities including atypical squamous cells of undetermined significance (ASC-US), low grade squamous intraepithelial lesions (LSIL), high grade squamous intraepithelial lesions (HSIL) and ASC-US of suspected high grade (ASC-H);
12 month persistent infection (i.e. at least 2 positive specimens for the same HPV type over a minimum interval of 10 months);
6 month persistent infection (i.e. at least 2 positive specimens for the same HPV type over a minimum interval of 5 months).
In study HPV-008, the following endpoints were also evaluated:
CIN3+ (cervical intraepithelial neoplasia grade 3 and higher grade lesions);
VIN1+ (vulvar intraepithelial neoplasia grade 1 and higher grade lesions);
VaIN1+ (vaginal intraepithelial neoplasia grade 1 and higher grade lesions).
Cervical intraepithelial neoplasia (CIN) grade 2 and 3 (CIN2+) was used in the clinical trials as a surrogate marker for cervical cancer. Persistent infection that lasts for at least 6 months has also been shown to be a relevant surrogate marker for cervical cancer. Although CIN1 is not a surrogate marker for cervical cancer, these lesions require medical follow-up.

1. Studies HPV-001/007/023. Vaccine efficacy against HPV-16/18 in women naïve to oncogenic HPV types.

Efficacy results for the endpoints associated with HPV-16 and/or HPV-18 (HPV-16/18) observed in study HPV-001/007 through 6.4 years after the first vaccine dose are presented in Table 3.

In summary, sustained efficacy of the vaccine was demonstrated against HPV-16 and/or HPV-18 persistent infections, as well as against cytological abnormalities and histopathological lesions.
In study HPV-023, subjects (N=437) were followed-up to 9.4 years (approximately 113 months) after dose one. There were no new cases of infection or histopathological lesions associated with HPV-16/18 in the vaccine group. In the placebo group, there were 4 cases of 6-month persistent infection, 1 case of 12-month persistent infection and 1 case of CIN1+ associated with HPV-16/18.
In the descriptive combined analysis of studies HPV-001/007/023, efficacy against HPV-16/18 incident and 6-month persistent infection was 91.0% (95% CI: 80.2; 96.5) and 96.8% (95% CI: 80.4; 99.9), respectively.
Despite evidence of continuous exposure to HPV infections as observed in the control group, there is no evidence of waning protection in vaccinated women.

2. Study HPV-008. Vaccine efficacy in women with/ without evidence of past and/or current HPV infection.

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 naïve to the respective HPV type at month 0 and month 6) and the Total Vaccinated Cohort-1 (TVC-1 cohort: including women who received at least one vaccine dose and were naïve to the respective HPV type at month 0). Both cohorts included women with normal or low-grade cytology at baseline and excluded only women with high-grade cytology (0.5%).
In addition, analyses of efficacy were performed on the broader Total Vaccinated Cohort (TVC) which included all vaccinated women. The TVC approximates a general population of women, including those who are sexually active, and may have previous or current HPV infection, cytological abnormalities or precancerous cervical lesions. The TVC-naïve cohort includes women with no evidence of previous or current HPV infection and no cytological abnormalities, and approximates to a population of young women before sexual debut. See Table 4.

For the three Total Vaccinated Cohorts, case counting began the day after first vaccination. For the According to Protocol cohort, case counting began the day after the third vaccination.
In study HPV-008, approximately 26% of women had evidence of current and/or prior HPV-16/18 infection and less than 1% of women were HPV DNA positive for both HPV-16 and HPV-18 types at baseline. An event triggered analysis of study HPV-008 was performed when at least 36 CIN2+ cases associated with HPV-16/18 were accrued in the ATP cohort. The mean follow-up was approximately 39 months post dose one.
End of study analysis was performed at the end of the 4-year follow-up period (i.e. 48 months post dose one) and included all subjects from the Total Vaccinated Cohort (TVC).
Vaccine efficacy against CIN3+, CIN2+ and CIN1+ associated with HPV-16/18 are provided in Table 5.

At the event triggered analysis the efficacy against HPV types 16/18 for the ATP cohort was 92.9% (96.1% CI: 79.9; 98.3) against CIN2+ and 80% (96.1% CI: 0.3; 98.1) against CIN3+. The efficacy against HPV types 16/18 for the TVC-naïve cohort was 98.4% (90.4; 100) against CIN2+ and 100% (64.7; 100) against CIN3+.
Further investigation identified that several CIN3+, CIN2+ and CIN1+ cases had multiple oncogenic HPV types in the lesion. In order to distinguish between the HPV type(s) most likely to be responsible for a lesion, from the HPV type(s) only temporally associated, an HPV type assignment was applied (exploratory analysis). The HPV type assignment considered the HPV types detected by Polymerase Chain Reaction (PCR) in at least one of the two preceding cytologic samples, in addition to types detected in the lesion. Based on this HPV type assignment, the 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 (see Table 6).

At the event-triggered analysis the efficacy for the ATP cohort for the HPV type assignment was 98.1% (96.1% CI: 88.4; 100) against CIN2+ and 100% (96.1% CI: 36.4; 100) against CIN3+.
In addition, statistically significant vaccine efficacy against CIN2+ and CIN1+ associated with HPV-16 and HPV-18 individually was demonstrated for both the ATP and TVC-1 cohorts (see Table 7).

Statistically significant efficacy against virological and cytological endpoints associated with HPV16/18 was demonstrated (see Table 8).

At the event triggered analysis the efficacy for the ATP cohort for the HPV type assignment was 94.3% (96.1% CI: 91.5; 96.3) against 6 month persistent infection, 91.4% (96.1% CI: 86.1; 95.0) against 12 month persistent infection and 89.0% (96.1% CI: 84.9; 92.1) for cytological abnormalities.
At the event triggered analysis, statistically significant vaccine efficacy against VIN1+ or VaIN1+ associated with HPV-16/18 was observed in the ATP cohort 80.0% (96.1% CI: 0.3; 98.1), and in the TVC-1 cohort 83.2% (96.1% CI: 20.2; 98.4). At the end of study analysis, vaccine efficacy against VIN1+ or VaIN1+ associated with HPV-16/18 was 75.1% (95% CI: 22.9; 94.0) in the ATP cohort and 77.7% (95% CI: 32.4; 94.5) in the TVC-1 cohort.
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 with one of the vaccine-related HPV types prior to vaccination were protected from clinical disease caused by the other vaccine HPV type.
Prophylactic efficacy against oncogenic HPV genotypes other than HPV-16 and HPV-18. HPV-16 and HPV-18 are not responsible for all cervical cancers. Other oncogenic HPV types can also cause cervical cancer. Of these, HPV-45, HPV-31, HPV-33, HPV-52 and HPV-58 are the next most prevalent types worldwide. Study HPV-008 assessed persistent infection with the following oncogenic HPV types by PCR; HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 as a secondary endpoint. Recent studies have shown a strong association between persistent infection with oncogenic HPV and high grade abnormalities (CIN2/ CIN3).
High levels of vaccine efficacy for both the virological and histopathological endpoints were also seen for oncogenic HPV types other than HPV-16 and HPV-18. The vaccine efficacy results for the various cohorts studied for the three most prevalent oncogenic HPV types after HPV types 16 and 18 are provided in Table 9.

At the event triggered analysis, statistically significant vaccine efficacy against 6-month persistent infection was observed for HPV types 31, 33 and 45 in the ATP cohort and for HPV types 31, 33, 45 and 51 in the TVC-1 cohort. Statistically significant vaccine efficacy against CIN2+ was observed for HPV types 31, 51 and 58 in the ATP cohort and for HPV types 31, 33, 35 and 51 in the TVC-1 cohort.
At the end of study analysis, statistically significant vaccine efficacy was observed for HPV types 31, 33, 45 and 51 for both 6 month persistent infection and CIN2+ in the ATP and TVC-1 cohorts. For CIN2+, statistically significant vaccine efficacy was observed for HPV type 39 in the ATP cohort and HPV type 66 in the TVC-1 cohort.
The results for vaccine efficacy against the virological and histopathological endpoints were statistically significant for oncogenic HPV types including HPV-16/18, in HPV DNA negative subjects, regardless of initial serostatus, in the ATP cohort and are provided in Table 10.

Overall impact of the vaccine on HPV disease burden. The overall vaccine efficacy irrespective of HPV DNA in lesions and stratified by baseline HPV DNA status and serostatus was evaluated in study HPV-008 (see Table 11).
In the TVC and TVC-naïve cohorts, vaccine efficacy against CIN3+, CIN2+ and CIN1+ was demonstrated (see Table 11). The impact of Cervarix on reduction of local cervical therapy (Loop Electro-Excision Procedure, Cone, Knife or Laser) was also demonstrated in the same cohorts.
The TVC-naïve cohort is a subset of the TVC that includes women with normal cytology, and who were HPV DNA negative for 14 oncogenic HPV types (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68) and seronegative for HPV-16 and HPV-18 at baseline.

At the end of study analysis, Cervarix reduced definitive cervical therapy procedures (includes loop electrosurgical 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.
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 5777 women aged 26 years and older. The study was conducted in North America, Latin America, Asia Pacific (including Australia) 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 objectives of HPV-015 were to demonstrate vaccine efficacy in the prevention of:
(1) persistent infection (6-month definition) with HPV-16 or HPV-18 (by polymerase chain reaction [PCR]); and/or
(2) histopathologically confirmed cervical intraepithelial neoplasia (CIN)1+ (defined as CIN1, CIN2, CIN3, adenocarcinoma in situ [AIS] or invasive cervical cancer) associated with HPV-16 or HPV-18 cervical infection detected by PCR within the lesional component of the cervical tissue specimen, overall and stratified according to initial HPV-16 or HPV-18 serostatus detected by enzyme-linked immunosorbent assay (ELISA).
If efficacy was demonstrated, the primary objectives were assessed sequentially using the HPV type assignment algorithm (HPV TAA), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA):
The HPV type assignment algorithm (HPV TAA) was developed to detect the causally associated types in case multiple HPV types were detected in the lesions. The following rules applied.
If more than one HPV type was found in a lesion, the presence of HPV types in the two immediately preceding cytology samples were to be evaluated:
The HPV types present in both the lesion and in at least one of the two immediately preceding cytology samples were considered to be associated with that lesion.
In case none of the HPV types present in the lesion was found in any of the two immediately preceding cytology samples, then the HPV types present in the lesion was considered to be associated with that lesion.
If only a single HPV type was found in a lesion, then this type was considered to be associated with the lesion.
Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type by PCR in cervical samples at two consecutive evaluations over approximately a 6-month interval.
CIN1+ is defined as CIN1, CIN2, CIN3, AIS or invasive cervical cancer.
Vaccine efficacy against the combined primary endpoint (6 month persistent infection and/or CIN1+) associated with HPV-16/18 is summarised in Table 12.

Vaccine efficacy at the 48 month time point 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.
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.

Immunogenicity.

The antibody response to HPV-16 and HPV-18 was measured using a type specific ELISA which was shown to correlate with neutralisation assays (including pseudovirion-based neutralising assay developed by the US National Cancer Institute). Due to the high efficacy of the vaccine, it has not been possible to establish minimum anti-HPV-16 and anti-HPV-18 antibody levels that protect against clinical disease caused by HPV-16 and/or 18.
The immunogenicity induced by three doses of Cervarix has been evaluated in 5,303 female subjects from 10 to 55 years of age.
In clinical trials, 99% of initially seronegative subjects had seroconverted to both HPV type 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 (natural infection). Initially seropositive and seronegative subjects reached similar titres after vaccination.
Immunogenicity in women aged 15 to 25 years. The immune response against HPV-16 and HPV-18 was evaluated up to 76 months after first vaccination in study HPV-001/007 in women aged 15 to 25 years at the time of vaccination. In study HPV-023, this immune response continued to be evaluated up to 9.4 years (113 months) after first vaccination in a subset of the population from study HPV-001/007.
In study HPV-023, ≥ 96.7% of women were seropositive for both HPV-16 and HPV-18 by ELISA or by pseudovirion-based neutralising assay (PBNA) up to 9.4 years after first vaccination.
Immunogenicity results by ELISA from studies HPV-001/007/023 are presented in Figures 1 and 2.

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 with no substantial decline up to the end of the follow-up period (month 113). At (month 113), 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 (natural infection) and 100% of the women were seropositive by ELISA for both antigens.
A similar kinetic profile was observed with the neutralising antibodies.
In study HPV-008, immunogenicity up to month 36 was similar to the response observed in study HPV-001/007.
Bridging the efficacy of Cervarix demonstrated in 15 to 25 year olds to other age groups. In two clinical trials (HPV-012 and HPV-013) performed in girls aged 10 to 14 years, all subjects seroconverted to both HPV type 16 and 18 after the third dose (at month 7) with GMTs at least 2-fold higher compared to women aged 15 to 25 years.
In study HPV-014 performed in women aged 26 to 55 years (N = 362), after vaccination, 100% of initially seronegative subjects had seroconverted to both HPV-16 and HPV-18 antigens in all age groups after the third dose (at month 7). The GMTs were lower in this population compared to women aged 15 to 25 years. However, all subjects remained seropositive for HPV-16 and all subjects except one remained seropositive for HPV-18 throughout the follow-up phase (up to month 48) maintaining antibody levels at an order of magnitude above those encountered after natural infection.
On the basis of immunogenicity data observed in females aged 10 to 14 years and aged 26 to 45 years, the efficacy of Cervarix is inferred from 10 to 45 years.
Two dose schedule in girls 9-14 years of age. In a clinical trial (HPV-070) immune response in girls aged 9 to 14 years receiving a 2-dose schedule (0, 6 months or 0, 12 months) was compared with immune response after 3 doses (0, 1, 6 months) in women aged 15 to 25 years.
After Dose 1 (Day 0), the trial protocol allowed some flexibility in the administration of the 2nd dose of the vaccine (180 ± 30 days in 0, 6 months group and 365 ± 60 days in 0, 12 months group). The 2nd and 3rd doses in the 3-dose (0, 1, 6 months) group could be administered at 21-90 days and 180 ± 30 days respectively.
All subjects seroconverted to both HPV types 16 and 18 one month after the completion of respective schedule. The immune response after 2 doses in females aged 9 to 14 years was demonstrated to be non-inferior to the immune response after 3 doses in women aged 15 to 25 years.
The efficacy of 2-dose Cervarix is inferred on the basis of immunogenicity data observed in girls vaccinated from age 9 to 14 years. Immunological correlates of efficacy have not been established.
Immunogenicity in seropositive women. The vaccination of women who were initially seropositive for HPV-16 or HPV-18 or both types has shown that the presence of anti-HPV-16 and/or anti-HPV-18 antibodies from natural infection does not affect the immune response to the HPV-16/18 vaccine.
Immunogenicity in males. To date, the vaccine has not been evaluated in males.

5.2 Pharmacokinetic Properties

Not relevant to vaccines.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of Cervarix has not been investigated. The adjuvant substance MPL has been tested for genotoxicity in a series of in vitro assays (bacterial mutation and chromosomal aberration) and an in vivo rat micronucleus test. Under the condition of these assays, MPL did not cause genetic damage.

Carcinogenicity.

The carcinogenic potential of Cervarix has not been investigated.

6 Pharmaceutical Particulars

6.1 List of Excipients

Cervarix also contains sodium chloride (NaCl) 4.4 mg, monobasic sodium phosphate (NaH₂PO₄.2 H₂O) 624 microgram and water for injection as excipients. Cervarix does not contain a preservative.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Cervarix must be stored at 2°C to 8°C. Do not freeze, discard if vaccine has been frozen. The vaccine should be stored in the original package in order to protect from light.
Cervarix should be administered as soon as possible after being removed from refrigeration. Cervarix can be kept out of refrigeration at temperatures at or below 25°C, for a total time of not more than 72 hours or at temperatures between 25°C and 37°C, for a total time of not more than 24 hours.

6.5 Nature and Contents of Container

Cervarix is presented as 0.5 mL of suspension in a pre-filled syringe (type I glass) with a plunger stopper (rubber butyl rubber) and with a rubber tip cap with or without needles in pack sizes of 1 and 10.
The tip cap and rubber plunger stopper of the pre-filled syringe are not made with natural rubber latex.
Not all pack sizes and container types may be distributed in Australia.

6.6 Special Precautions for Disposal

Cervarix syringes are for single use in a single patient only.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

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Cervarix

Human papillomavirus vaccine, recombinant

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