Silgard - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 dose (0.5 ml) contains approximately:

Human Papillomavirus1 Type 6 L1 protein2,3     20 micrograms

Human Papillomavirus1 Type 11 L1 protein2,3    40 micrograms

Human Papillomavirus1 Type 16 L1 protein2,3    40 micrograms

Human Papillomavirus1 Type 18 L1 protein2,3    20 micrograms.

• 1Human Papillomavirus = HPV.

• 2L1 protein in the form of virus-like particles produced in yeast cells (Saccharomyces cerevisiae CANADE 3C-5 (Strain 1895)) by recombinant DNA technology.

• 3adsorbed on amorphous aluminium hydroxyphosphate sulphate adjuvant (0.225 milligram­s Al).

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Silgard, suspension for injection.

Silgard, suspension for injection in a pre-filled sy

Prior to agitation, Silgard may appear as a clear liquid with a white precipitate. After thorough agitation, it is a white, cloudy liquid.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Silgard is a vaccine for use from the age of 9 years for the prevention of:

• – premalignant genital lesions (cervical, vulvar and vaginal), premalignant anal lesions, cervical cancers and anal cancers causally related to certain oncogenic Human Papillomavirus (HPV) types

• – genital warts (condyloma acuminata) causally related to specific HPV types.

See sections 4.4 and 5.1 for important information on the data that support this indication.

se of Silgard should be in accordance with official recommendations.

4.2 Posology and method of administration

Posology

Individuals 9 to and including 13 years of age

Silgard can be administered according to a 2-dose schedule (0.5 ml at 0, 6 months) (see section 5.1).

If the second vaccine dose is administered earlier than 6 months after the first dose, a third dose should always be administered.

Alternatively, Silgard can be administered according to a 3-dose (0.5 ml at 0, 2, 6 months) schedule. The second dose should be administered at least one month after the first dose and the third dose should be administered at least 3 months after the second dose. All three doses should be given within a 1-year period.

Individuals 14 years of age and older

Silgard should be administered according to a 3-dose (0.5 ml at 0, 2, 6 months) schedule.

The second dose should be administered at least one month after the first dose and the third dose should be administered at least 3 months after the second dose. All three doses should be given withi a 1-year period.

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

Paediatric population

The safety and efficacy of Silgard in children below 9 years of age have not been established. No data are available (see section 5.1).

It is recommended that individuals who receive a first dose of Silgard complete the vaccination course with Silgard (see section 4.4).

The need for a booster dose has not been established.

Method of administration

The vaccine should be administered by intramuscular inj the upper arm or in the higher anterolateral area of the th

Silgard must not be injected intravascularly. Neither subcutaneous nor intradermal administration has been studied. These methods of administration are not recommended (see section 6.6).

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients.

Individuals who develop s should not receive further doses of Silgard.

Administration of Silgard should be postponed in individuals suffering from an acute severe febrile illness. However, the presence of a minor infection, such as a mild upper respiratory tract infection or low-grade fever, is not a contraindication for immunisation.

As with all injectable vaccines, appropriate medical treatment should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine.

Syncope (fainting), sometimes associated with falling, 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. Therefore, vaccinees should be observed for approximately 15 minutes after vaccine administration. It is important that procedures are in place to avoid injury from faints.

As with any vaccine, vaccination with Silgard may not result in protection in all vaccine recipients.

Silgard will only protect against diseases that are caused by HPV types 6, 11, 16 and 18 and to a limited extent against diseases caused by certain related HPV types (see section 5.1). Therefore, appropriate precautions against sexually transmitted diseases should continue to be used.

Silgard is for prophylactic use only and has no effect on active HPV infections or established clinical disease. Silgard has not been shown to have a therapeutic effect. The vaccine is therefore not indicated for treatment of cervical cancer, high-grade cervical, vulvar, and vaginal dysplastic lesions or genital warts. It is also not intended to prevent progression of other established HPV-related lesions.

Silgard does not prevent lesions due to a vaccine HPV type in individuals infected with that HPV at the time of vaccination (see section 5.1).

The use of Silgard in adult women should take into consideration the variability of HPV type prevalence in different geographical areas.

Vaccination is not a substitute for routine cervical screening. Since no vaccine is 100% effective and Silgard will not provide protection against every HPV type, or against existing HPV infections, routine cervical screening remains critically important and should follow local recommendations.

Safety and immunogenicity of the vaccine have been assessed in individuals aged from 7 to 12 years who are known to be infected with human immunodeficiency virus (HIV) (see section 5.1).

Individuals with impaired immune responsiveness, due to either the use of potent immunosuppressive therapy, a genetic defect, or other causes, may not respond to the vaccine.

This vaccine should be given with caution to individuals with thrombocytopaenia or any coagulation disorder because bleeding may occur following an intramuscular administration in these individuals.

Long-term follow-up studies are currently ongoing to determine the duration of protection (see section 5.1).

There are no safety, immunogenicity or efficacy data to support change during vaccination with Silgard to other HPV vaccines which do not cover the same HPV types. Therefore, it is important that the same vaccine should be prescribed for the whole dose regimen.

4.5 Interaction with other medicinal products and other forms of interaction

In all clinical trials, individuals who had received immunoglobulin or blood-derived products during the 6 months prior to the first vaccine dose were excluded.

♦

Use with other vaccines

Administration of Silgard at the same time (but, for injected vaccines, at a different injection site) as hepatitis B (recombinant) vaccine did not interfere with the immune response to the HPV types. The Seroprotection rates (proportion of individuals reaching seroprotective level anti-HBs >10 mIU/ml) were unaffected (96.5% for concomitant vaccination and 97.5% for hepatitis B vaccine only). Anti-HBs geometric mean antibody titres were lower on co-administration, but the clinical significance of this observation is not known.

Silgard may be administered concomitantly with a combined booster vaccine containing diphtheria (d) and tetanus (T) with either pertussis [acellular, component] (ap) and/or poliomyelitis [inactivated] (IPV) (dTap, dT-IPV, dTap-IPV vaccines) with no significant interference with antibody response to any of the components of either vaccine. However, a trend of lower anti-HPV GMTs was observed in the concomitant group. The clinical significance of this observation is not known. This is based on the results from a clinical trial in which a combined dTap-IPV vaccine was administered concomitantly with the first dose of Silgard (see section 4.8).

The concomitant administration of Silgard with vaccines other than the ones above has not been studied.

Use with hormonal contraceptives

In clinical studies, 57.5% of women aged 16 to 26 years and 31.2% of women aged 24 to 45 years who received Silgard used hormonal contraceptives during the vaccination period. Use of hormonal contraceptives did not appear to affect the immune response to Silgard.

4.6 Fertility, pregnancy and lactation

Pregnancy

Specific studies of the vaccine in pregnant women were not conducted. During the clinical development program, 3,819 women (vaccine = 1,894 vs. placebo = 1,925) reported at least one pregnancy. There were no significant differences in types of anomalies or proportion of pregnancies with an adverse outcome in Silgard and placebo treated individuals. These data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity.

The data on Silgard administered during pregnancy did not indicate an data are insufficient to recommend use of Silgard during pregnancy. V until completion of pregnancy.

Breast-feeding

In breast-feeding mothers given Silgard or placebo during the vaccination period of the clinical trials the rates of adverse reactions in the mother and the breast-fed infant were comparable between the vaccination and the placebo groups. In addition, vaccine immunogenicity was comparable among breast-feeding mothers and women who did not breast-feed during the vaccine administration.

Therefore Silgard can be used during b

eding.

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). No effects on male fertility were observed in rats (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

• A. Summary of the safety profile

In 7 clinical trials (6 placebo-controlled), individuals were administered Silgard or placebo on the day of enrolment and approximately 2 and 6 months thereafter. Few individuals (0.2%) discontinued due to adverse reactions. Safety was evaluated in either the entire study population (6 studies) or in a predefined subset (one study) of the study population using vaccination report card (VRC)-aided surveillance for 14 days after each injection of Silgard or placebo. The individuals who were monitored using VRC-aided surveillance included 10,088 individuals (6,995 females 9 to 45 years of age and 3,093 males 9 to 26 years of age at enrolment) who received Silgard and 7,995 individuals (5,692 females and 2,303 males) who received placebo.

The most common adverse reactions observed were injection-site adverse reactions (77.1% of vaccinees within 5 days following any vaccination visit) and headache (16.6% of the vaccinees). These adverse reactions usually were mild or moderate in intensity.

• B. Tabulated summary of adverse reactions

Table 1 presents vaccine-related adverse reactions which were observed among recipients of Silgard at a frequency of at least 1.0% and also at a greater frequency than observed among placebo recipients.

They are ranked under headings of frequency using the following convention: [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)]

Table 1 also includes additional adverse events which have been spontaneously reported duri post-marketing use of Silgard worldwide. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Consequently, the frequency of these adverse events is qualified as „not known“.

Table 1: Adverse Events Following Administration of Silgard from Clinical Trials and Post-Marketing Surveillance

Post-Marketing adverse events (frequency cannot be estimated from the available data).

1During clinical trials, dizziness was observed as a common adverse reaction in females. In males, dizziness was not observed at a greater frequency in vaccine recipients than in placebo recipients.

In addition, in clinical trials adverse reactions that were judged to be vaccine- or placebo-related by the study investigator were observed at frequencies lower than 1%:

Respiratory, thoracic and mediastinal disorders: Very rare: bronchospasm.

Skin and subcutaneous tissue disorders:

Rare: urticaria.

Nine cases (0.06%) of urticaria were reported in the Silgard group and 20 cases (0.15%) were seen in the adjuvant-containing placebo group.

In the clinical studies, individuals in the Safety Population reported any new medical conditions during the follow-up. Among 15,706 individuals who received Silgard and 13,617 individuals who received placebo, there were 39 cases of non-specific arthritis/arthro­pathy reported, 24 in the Silgard group and 15 in the placebo group.

In a clinical trial of 843 healthy adolescent males and females 11–17 years of age, administration of the first dose of Silgard concomitantly with a combined diphtheria, tetanus, pertussis [acellular,

component] and poliomyelitis [inactivated] booster vaccine showed that there was more injection-site swelling and headache reported following concomitant administration. The differences observed were < 10% and in the majority of subjects, the adverse events were reported as mild to moderate in intensity.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is import allows continued monitoring of the benefit/risk balance of the medicinal product. Healthca e professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

5.  PHARMACOLOGICAL PROPERTIES

5.1  Pharmacodynamic properties

• v 1

  Table 7 compares the 1 month Postdose 3 anti-HPV 6, 11, 16, and 18 GMTs in 9– to 15-year-old boys with those in 16– to 26-year-old men.

  Table 7: Immunogenicity bridging between 9– to 15-year-old boys and 16– to 26-year-old men (per-

  otocol population) based on titres as measured by cLIA

  	9– to 15-Year-Old Boys		16– to 26-Year-Old Men
  	n	GMT (95% CI)	n	GMT (95% CI)
  HPV 6	884	1038 (964, 1117)	1093	448 (419, 479)
  HPV 11	885	1387 (1299, 1481)	1093	624 (588, 662)
  HPV 16	882	6057 (5601, 6549)	1136	2403 (2243, 2575)
  HPV 18	887	1357 (1249, 1475)	1175	403 (375, 433)

  GMT- Geometric mean titre in mMU/ml (mMU = milli-Merck units)

  Anti-HPV responses at Month 7 among 9– to 15-year-old boys were non-inferior to anti-HPV responses in 16– to 26-year-old men for whom efficacy was established in the Phase III studies. Immunogenicity was related to age and Month 7 anti-HPV levels were significantly higher in younger individuals.

  On the basis of this immunogenicity bridging, the efficacy of Silgard in 9– to 15-year-old boys is inferred.

  In the long-term extension study of Protocol 018, 326 boys 9–15 years old during vaccination with Silgard in the base study, were followed. In the PPE population, no cases of HPV diseases (HPV typ 6/11/16/18 related External Genital Lesions) were observed through 10.6 years (median follow-up of 9.9 years).

  Persistence of Immune Response of Silgard

  A subset of individuals enrolled in the Phase III studies was followed up for a long-term period for safety, immunogenicity and effectiveness. Total IgG Luminex Immunoassay (IgG LIA) was used to assess the persistence of immune response in addition to cLIA.

  In all populations (women 9–45 years, men 9–26 years), peak anti-HPv 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs cLIA were observed at Month 7. Afterwards, the GMTs declined through Month 24 – 48 and then generally stabilized. The exact duration of immunity following a 3-dose series has not been established and is currently being studied.

  Girls and boys vaccinated with Silgard at 9–15 years of age in Protocol 018 base study were followed up in an extension study. Depending on HPV type, 60–96% and 78–98% of subjects were seropositive by cLIA and IgG LIA respectively 10 years after vaccination (see Table 8).

  Table 8: Long-term immunogenicity data (per-protocol population) based on percentage of seropositive subjects as measured by cLIA and IgG LIA (Protocol 018) at 10 years, in girls and boys 9–15 years of age

  	cLIa		IgG LIA
  	n <	% of seropositive subjects	n	% of seropositive subjects
  HPV 6	409 V	89%	430	93%
  HPV 11	409	89%	430	90%
  HPV 16	403	96%	426	98%
  HPV 18	o 408	60%	429	78%

  Women vaccinated with Silgard at 16–23 years of age in Protocol 015 base study will be followed up

  to 14 years in an extension study. Nine years after vaccination, 94%, 96%, 99% and 60% were anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 seropositive in the cLIA, respectively, and 98%, 96%, 100% and 91% were anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 seropositive in the IgG LIA, respectively.

  Women vaccinated with Silgard at 24–45 years of age in Protocol 019 base study were followed up in an extension study. Ten years after vaccination, 79%, 85%, 94%, and 36% were anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 seropositive in the cLIA, respectively, and 86%, 79%, 100% and 83% were anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 seropositive in the IgG LIA, respectively.

  Men vaccinated with Silgard at 16–26 years of age in Protocol 020 base study were followed up in an extension study. Ten years after vaccination, 79%, 80%, 95% and 40% were anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 seropositive in the cLIA, respectively, and 92%, 92%, 100% and 92% were anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 seropositive in the IgG

  LIA, respectively.

  In these studies, individuals who were seronegative for anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 in the cLIA were still protected against clinical disease after a follow-up of 9 years for 16–23 year-old women, 10 years for 24–45 year-old women, and 10 years for 16–26 year-old men.

  Evidence of Anamnestic (Immune Memory) Response

  
  

  Evidence of an anamnestic response was seen in vaccinated women who were seropositive to relevant HPV type(s) prior to vaccination. In addition, a subset of vaccinated women who received a challenge dose of Silgard 5 years after the onset of vaccination, exhibited a rapid and strong anamnestic res that exceeded the anti-HPV GMTs observed 1 month Postdose 3.

  HIV-infected subjects

  An academic study documenting safety and immunogenicity of Silgard has been pe 126 HIV infected subjects aged from 7 to 12 years (of which 96 received Silgard). Sersion to all four antigens occurred in more than ninety-six percent of the subjects. The GMTs were somewhat lower than those reported in non-HIV infected subjects of the same age in other studies. The clinical relevance of the lower response is unknown. The safety profile was similar to non-HIV infected subjects in other studies. The CD4% or plasma HIV RNA was not affected by vaccination.

  Immune Responses to Silgard using a 2-dose schedule in individuals 9–13 years of age

  A clinical trial showed that among girls who received 2 doses of HPV vaccine 6 months apart, antibody responses to the 4 HPV types, one month after the last dose were non-inferior to those among young women who received 3 doses of the vaccine within 6 months.

  At Month 7, in the Per Protocol population, the immune response in girls aged 9–13 years (n = 241) who received 2 doses of Silgard (at 0, 6 months) was non-inferior and numerically higher to the immune response in women aged 16–26 years (n = 246) who received 3 doses of Silgard (at 0, 2, 6 months).

  
  

  At 36 month follow-up, the GMT in girls (2 doses, n = 86) remained non-inferior to the GMT in women (3 doses, n = 86) for all 4 HPV types.

  In the same study, in girls aged 9–13 years, the immune response after a 2-dose schedule was numerically lower than after a 3-dose schedule (n = 248 at Month 7; n = 82 at Month 36). The clinical relevance of these findings is unknown. A subset of the study participants from the 2-dose group (n=50) were followed 5-years post-vaccination (Month 60 Postdose 1). Among the girls receiving 2 doses of the vaccine, 96%, 100%, 100%, and 84% remained seropositive to anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18, respectively, in the cLIA.

  Duration of protection of a 2-dose schedule of Silgard has not been established.

  armacokinetic properties

  ot applicable.

5.3 Preclinical safety data

Single-dose and repeated-dose toxicity and local tolerance studies revealed no special hazards to humans.

Silgard induced specific antibody responses against HPV types 6, 11, 16, and 18 in pregnant rats, following one or multiple intramuscular injections. Antibodies against all four HPV types were transferred to the offspring during gestation and possibly during lactation. There were no treatment-related effects on developmental signs, behaviour, reproductive performance, or fertility of the offspring.

Silgard administered to male rats at the full human dose (120 mcg total protein) had no effects on reproductive performance including fertility, sperm count, and sperm motility, and there were no vaccine-related gross or histomorphologic changes on the testes and no effects on testes weights.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

products

Store in a refrigerator (2°C – 8°C)

Data from stability studies demonstrate that the vaccine components are stable for 72 hours when stored at temperatures from 8°C to 42°C. At the end of this period Silgard should be used or discarded. These data are intended to guide healthcare professionals in case of temporary temperature excursion only.

Silgard suspension for injection in a pre-filled syringe

ore in a refrigerator (2°C – 8°C)

Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light.

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

Data from stability studies demonstrate that the vaccine components are stable for 72 hours when stored at temperatures from 8°C to 42°C. At the end of this period Silgard should be used or discarded. These data are intended to guide healthcare professionals in case of temporary temperature excursion only.

6.5 Nature and contents of container

Silgard, suspension for injection: 0.5 ml suspension in a vial (glass) with stopper (FluroTec-coated or Teflon-coated chlorobutyl elastomer) and flip-off plastic cap (aluminium crimp band) in a pack size of 1, 10 or 20.

Silgard, suspension for injection in a pre-filled syringe:

0.5 ml suspension in a pre-filled syringe (glass) with plunger stopper (siliconized FluroTec-coated bromobutyl elastomer or non-coated chlorobutyl elastomer) and a tip cap (bromobutyl) without needle or with one or two needle(s) – pack size of 1, 10 or 20.

Not all pack sizes are marketed.

6.6 Special precautions for disposal and other handling

Silgard, suspension for injection:

• • Silgard may appear as a clear liquid with a white precipitate prior to agitation.
• • Shake well before use to make a suspension. After thorough agitation, it is a white, cloudy

liquid.

• • Inspect the suspension visually for particulate matter and discolouration prior to administration.

Discard the vaccine if particulates are present and/or if it appears discoloured.

• • Withdraw the 0.5 ml dose of vaccine from the single-dose vial using a sterile needle and syringe.
• • Inject immediately using the intramuscular (IM) route, preferably in the deltoid area of the

upper arm or in the higher anterolateral area of the thigh.

• • The vaccine should be used as supplied. The full recommended dose of the vaccine should be

used.

Any unused vaccine or waste material should be disposed of in accordance with local requirements.

Silgard, suspension for injection in a pre-filled syringe:

• • Silgard may appear as a clear liquid with a white precipitate prior to agitation.
• • Shake well before use, the pre-filled syringe, to make a suspension. After thorough agitation, it

a white, cloudy liquid.

Inspect the suspension visually for particulate matter and discolouration prior to administration.

Discard the vaccine if particulates are present and/or if it appears discoloured.

Two needles of different lengths are provided in the pack, choose the appropriate needle to

ensure an intramuscular (IM) administration depending on your patient’s size and weight.

• • Attach the needle by twisting in a clockwise direction until the needle fits securely on the

syringe. Administer the entire dose as per standard protocol.

• • Inject immediately using the intramuscular (IM) route, preferably in the deltoid area of the

7. MARKETING AUTHORISATION HOLDER

^>0

8. MARKETING AUTHORISATION NUMBER(S)

Silgard, suspension for injection:

EU/1/06/358/001

EU/1/06/358/002

EU/1/06/358/018

Silgard, suspension for injection in a pre-filled syringe:

EU/1/06/358/003

EU/1/06/358/004

EU/1/06/358/005

EU/1/06/358/006

EU/1/06/358/007

EU/1/06/358/008

EU/1/06/358/019

EU/1/06/358/020

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 September 2006

Date of latest renewal: 20 July 2011