Gardasil, suspension for injection in a pre-filled syringe.

Human Papillomavirus Vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed).

1 dose (0.5 ml) contains approximately:

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 (225 micrograms Al).

For a full list of excipients, see section 6.1.

Suspension for injection in a pre-filled syringe.

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

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

- premalignant genital lesions (cervical, vulvar and vaginal) and cervical cancer 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.

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

Posology

The primary vaccination series consists of 3 separate 0.5 ml doses administered according to the following schedule: 0, 2, 6 months.

If an alternate vaccination schedule is necessary, 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.

The need for a booster dose has not been established.

It is recommended that individuals who receive a first dose of Gardasil complete the 3-dose vaccination course with Gardasil (see section 4.4).

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

Method of administration

The vaccine should be administered by intramuscular injection. The preferred site is the deltoid area of the upper arm or in the higher anterolateral area of the thigh.

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

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

Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of Gardasil should not receive further doses of Gardasil.

Administration of Gardasil 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.

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

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) may follow any vaccination, especially in adolescents and young adults. Syncope, sometimes associated with falling and/or tonic-clonic movements, has occurred after vaccination with Gardasil (See section 4.8). Therefore, vaccinees should be carefully observed for approximately 15 minutes after administration of Gardasil.

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

Gardasil 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.

Gardasil is for prophylactic use only and has no effect on active HPV infections or established clinical disease. Gardasil 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.

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

The use of Gardasil in adult women should take into consideration the variability of HPV type preva lence in different geographical areas.

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

There are no data on the use of Gardasil in individuals with impaired immune responsiveness. Individuals with impaired immune responsiveness, whether due to the use of potent immunosuppressive therapy, a genetic defect, Human Immunodeficiency Virus (HIV) infection, 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.

The duration of protection is currently unknown. Sustained protective efficacy has been observed for 4.5 years after completion of the 3-dose series. Longer term follow-up studies are ongoing (see section 5.1).

There are no safety, immunogenicity or efficacy data to support interchangeability of Gardasil with other HPV vaccines.

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 Gardasil 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.

Gardasil 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 Gardasil. (see section 4.8).

The concomitant administration of Gardasil 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 Gardasil used hormonal contraceptives during the vaccination period. Use of hormonal contraceptives did not appear to affect the immune response to Gardasil.

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 Gardasil and placebo treated individuals. These data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity.

The data on Gardasil administered during pregnancy did not indicate any safety signal. However, these data are insufficient to recommend use of Gardasil during pregnancy. Vaccination should be postponed until completion of pregnancy.

Breastfeeding

In breastfeeding mothers given Gardasil or placebo during the vaccination period of the clinical trials the rates of adverse reactions in the mother and the breastfed infant were comparable between the vaccination and the placebo groups. In addition, vaccine immunogenicity was comparable among breastfeeding mothers and women who did not breastfeed during the vaccine administration.

Therefore Gardasil can be used during breast-feeding.

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).

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

A. Summary of the safety profile

In 7 clinical trials (6 placebo-controlled), individuals were administered Gardasil or placebo on the day of enrollment and approximately 2 and 6 months thereafter. Few individuals (0.2%) discontinued due to adverse reactions. Safety was eva luated 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 Gardasil 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 enrollment) who received Gardasil 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

Clinical Trials

Table 1 presents vaccine-related adverse reactions which were observed among recipients of Gardasil 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)]

Post-Marketing Experience

Table 1 also includes additional adverse events which have been spontaneously reported during the post-marketing use of Gardasil 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 Gardasil from Clinical Trials and Post-Marketing Surveillance

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