Gardasil · 4.4 Special warnings and precautions for use · 1

HOS-094438 · has-adverse-reaction-information · PDF-Seite 5

Summary of the safety profile In 7 clinical trials (6 placebo-controlled), individuals were administered Gardasil 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 5 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 enrolment) 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. 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 System Organ Class Frequency Adverse Events Infections and infestations Not known Injection-site cellulitis * Blood and lymphatic system Not known Idiopathic thrombocytopenic purpura*, disorders lymphadenopathy* Immune system disorders

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HOS-094434 · has-contraindication-information · PDF-Seite 3

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.

HOS-094433 · has-indication-information · PDF-Seite 2

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

HOS-094436 · has-interaction-information · PDF-Seite 4

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. 4 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.

HOS-094437 · has-pregnancy-information · PDF-Seite 5

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 1,000 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. Breast-feeding In breast-feeding mothers given Gardasil 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, 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).

HOS-094435 · has-warning-information · PDF-Seite 3

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. 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), 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 3 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 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 prevalence 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. Safety and immunogenicity of the vaccin

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