Gardasil vaccine against human papillomavirus quadrivalent recombinant suspension for injection 1 dose syringe 0.5 ml No. 1

Instructions Gardasil vaccine against human papillomavirus quadrivalent recombinant suspension for injection 1 dose syringe 0.5 ml No. 1

Composition

active substance: papillomavirus (human types 6, 11, 16, 18).

One dose (0.5 ml) contains:

active ingredients: recombinant antigens: L1 protein of human papillomavirus in the following quantities: type 6 – 20 μg, type 11 – 40 μg, type 16 – 40 μg, type 18 – 20 μg;

excipients: aluminum in the form of aluminum hydroxyphosphate sulfate adjuvant, amorphous; sodium chloride; L-histidine; polysorbate 80; sodium borate; water for injections.

Dosage form

Suspension for injection.

Main physicochemical properties: white (due to the presence of alum in the composition) opaque suspension.

Pharmacotherapeutic group

The vaccine against human papillomavirus (types 6, 11, 16, 18) is quadrivalent. ATX code J07BM01.

Pharmacological properties

Immunological and biological properties.

Pharmacodynamics

Mechanism of action

Gardasil is an adjuvanted, non-infectious, recombinant quadrivalent vaccine made from highly purified virus-like particles (VLPs) of the major capsid protein (L1) of human papillomavirus (HPV) types 6, 11, 16, and 18.

L1 proteins are produced by separate fermentation in yeast cell culture (Saccharomyces cerevisiae CANADE 3C-5 (Strain 1895)) using recombinant DNA technology and form HPVs by self-assembly. HPVs for each type are purified and adsorbed onto amorphous aluminum hydroxyphosphate sulfate adjuvant (0.225 mg Al).

HPVs do not contain viral DNA, cannot infect cells, are not capable of reproduction, and cannot cause disease. HPV infects only humans, but animal studies with similar papillomaviruses suggest that the efficacy of L1 HPV vaccines is mediated by the development of a humoral immune response.

HPV 16 and HPV 18 have been identified as causing approximately 70% of cervical cancers and 75–80% of anal cancers; 80% of adenocarcinoma in situ (AIS); 45–70% of high-grade cervical intraepithelial neoplasia (CIN 2/3); 25% of low-grade cervical intraepithelial neoplasia (CIN 1); approximately 70% of high-grade vulvar intraepithelial neoplasia (VIN 2/3) and vaginal intraepithelial neoplasia (VaIN 2/3) and 80% of HPV-related high-grade anal intraepithelial neoplasia (AIN 2/3). HPV types 6 and 11 are responsible for approximately 90% of genital warts and 10% of low-grade cervical intraepithelial neoplasia (CIN 1). CIN 3 and AIS are considered the immediate precursors to invasive cervical cancer.

The term “precancerous lesions of the genital organs” refers to high-grade cervical intraepithelial neoplasia (CIN 2/3), high-grade vulvar intraepithelial neoplasia (VaIN 2/3), and high-grade vaginal intraepithelial neoplasia (VaIN 2/3).

The term “precancerous lesions of the anal canal” mentioned in the “Indications” section means high-grade anal intraepithelial neoplasia (AIN 2/3).

The indications for the vaccine are based on the demonstration of the efficacy of Gardasil in female patients aged 16 to 45 years and in male patients aged 16 to 26 years, as well as on the confirmation of the immunogenicity of Gardasil in girls and boys aged 9 to 15 years.

Clinical trials

Efficacy in female patients aged 16–26 years

The efficacy of Gardasil was evaluated in 4 placebo-controlled, double-blind, randomized phase II and III clinical trials involving 20,541 female patients aged 16 to 26 years who were administered the vaccine without prior screening for HPV infection.

Primary efficacy endpoints included: vulvar and vaginal lesions (genital warts, VIN, VaIN), CIN of any grade, and cervical cancer caused by HPV 6, 11, 16, or 18 (Protocol 013, FUTURE I); CIN 2/3, AIS, and cervical cancer caused by HPV 16 or 18 (Protocol 015, FUTURE II); persistent infection and disease caused by HPV 6, 11, 16, or 18 (Protocol 007); persistent infection caused by HPV 16 (Protocol 005).

Efficacy results are presented in a combined analysis of the study protocols. Efficacy against CIN 2/3 or AIS caused by HPV 16/18 is supported by data from Protocols 005 (type 16-related endpoints only), 007, 013, and 015. Efficacy for all other endpoints is based on Protocols 007, 013, and 015. Median follow-up was 4.0; 3.0; 3.0; and 3.0 years in Protocols 005, 007, 013, and 015, respectively. Median follow-up in the combined Protocols (005, 007, 013, and 015) was 3.6 years. The results of the individual studies support the results of the combined analysis. Gardasil was effective against disease caused by any of the four HPV types contained in the vaccine. After the end of the study, participants included in the two phase III studies (Protocol-013 and Protocol-015) were followed for a period of up to 4 years (mean 3.7 years).

Cervical intraepithelial dysplasia (CIN) grade 2/3 (moderately or highly differentiated dysplasia) and adenocarcinoma in situ (AIS) have been used in clinical trials as surrogate markers of cervical cancer.

In the long-term extension study, Protocol 015, 2,536 girls and women aged 16–23 years were followed up during the Gardasil vaccination period in the core study. In the protocol-defined efficacy population, no cases of HPV-related disease (severe CIN associated with HPV types 6, 11, 16, 18) were observed up to 14 years (median follow-up 11.9 years). In this study, long-term protection was statistically significant up to approximately 12 years.

Efficacy in women aged 24–45 years

The efficacy of Gardasil in women aged 24–45 years was evaluated in 1 placebo-controlled, double-blind, randomized, phase III clinical trial (Protocol 019, FUTURE III) involving 3,817 women enrolled and vaccinated without prescreening for HPV.

The primary efficacy endpoints included the combined incidence of persistent infection (within 6 months), genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancer caused by HPV 6, 11, 16, or 18, and caused by HPV 16 or 18. The median follow-up was 4.0 years.

In the long-term extension study under Protocol 019, 685 women aged 24-45 years were followed up during the Gardasil vaccination period in the main study. In the protocol-specified efficacy population, no cases of HPV-related diseases (CIN of any grade and condyloma acuminatum associated with HPV types 6, 11, 16, 18) were observed for 10.1 years (median follow-up period of 8.7 years).

Efficacy in women uninfected with relevant vaccine HPV types

The primary efficacy analysis was conducted in the per-protocol efficacy (PPE) population (i.e., all 3 vaccinations completed within 1 year, no major protocol violations, and no infection with relevant HPV types prior to dose 1 and through 1 month after dose 3 (Month 7). Efficacy was assessed starting at the Month 7 visit. Overall, 67% of participants were not infected with any of the 4 vaccine HPV types (negative PCR (polymerase chain reaction) and seronegative).

The efficacy of Gardasil against the incidence of combined persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancer caused by HPV 6, 11, 16, or 18 was 88.7% (95% confidence interval (CI): 78.1; 94.8).

The efficacy of Gardasil against the incidence of combined persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancer caused by HPV 16 or 18 was 84.7% (95% CI: 67.5; 93.7).

Efficacy in women with/without a history of infection or disease caused by HPV types 6, 11, 16, or 18

The full analysis population (also known as ITT) included patients (regardless of HPV status at Day 1) who received at least 1 dose of vaccine and whose case counting began on Day 1. This population was approximately similar to the general population of women in terms of incidence of HPV infection or disease at study entry.

The efficacy of Gardasil against the incidence of combined persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancer caused by HPV 6, 11, 16, or 18 was 47.2% (95% CI: 33.5; 58.2).

The efficacy of Gardasil against the incidence of combined persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancer caused by HPV 16 or 18 was 41.6% (95% CI: 24.3; 55.2).

In a retrospective analysis of individuals (who received at least one dose of vaccine) infected with a vaccine HPV type (seropositive) that was not detectable at the time of vaccination (negative PCR result), the efficacy of Gardasil in preventing disease caused by recurrence of the same HPV type was 100% (95% CI: 62.8-100.0; 0 vs. 12 cases [n=2572 from pooled studies in girls and women aged 16-26 years]) for CIN 2/3, VIN 2/3, VaIN 2/3, and genital warts caused by HPV 6, 11, 16, and 18 in girls and women aged 16-26 years. The efficacy was 68.2% (95% CI: 17.9, 89.5, 6 vs. 20 cases [n=832 from pooled studies in girls and women aged 16–26 years and women aged 27–45 years]) against persistent infection caused by HPV 16 and 18 in girls and women aged 16–45 years.

Efficacy in male patients aged 16 to 26 years

Efficacy was evaluated against HPV types 6, 11, 16, 18-related external condyloma acuminata, penile/perineal/perianal intraepithelial neoplasia grade 1/2/3, and persistent infection.

The efficacy of Gardasil was evaluated in a placebo-controlled, double-blind, randomized, phase III clinical trial (Protocol 020) in 4,055 male subjects aged 16 to 26 years who were vaccinated without prior screening for HPV infection. The median follow-up was 2.9 years.

In the Protocol 020 study, efficacy against anal intraepithelial neoplasia (grades 1/2/3) and anal cancer and intraanal persistent infection was evaluated in a subgroup of 598 men (Gardasil = 299; placebo = 299) who have sex with other men.

Efficacy in male patients with or without prior infection or disease caused by HPV types 6, 11, 16, or 18

The population for the full analysis included male patients, regardless of baseline HPV status at Day 1, who had received at least one vaccination and for whom the incidence of prior infection or disease was counted starting at Day 1. This population approximates the total male population with respect to the prevalence of HPV infection or disease at study entry.

The efficacy of Gardasil against HPV types 6, 11, 16, 18-related external condyloma acuminata was 68.1% (95% CI: 48.8–79.3).

The efficacy of Gardasil against HPV types 6, 11, 16, 18-related anal intraepithelial neoplasia of grade 2/3 and against HPV types 16 or 18-related anal intraepithelial neoplasia of grade 2/3 in homosexual men was 54.2% (95% CI: 18.0, 75.3; 18 cases out of 275 vs. 39 cases out of 276) and 57.5% (95% CI: -1.8, 83.9; 8 cases out of 275 vs. 19 cases out of 276), respectively.

Protection against severe HPV-related disease in male patients aged 16 to 26 years

The effect of Gardasil on the overall risk of genital warts was assessed after the first dose in 2,545 subjects enrolled in a Phase III efficacy study (Protocol 020). In male subjects who were negative for up to 14 of the most common HPV types, Gardasil reduced the incidence of genital warts caused by vaccine or non-vaccine HPV types by 81.5% (95% CI: 58.0–93.0). The full population analysis of vaccine efficacy was based on the overall incidence of genital warts, and the magnitude of the reduction was 59.3% (95% CI: 40.0–72.9), as Gardasil does not affect the course of infections or diseases that were present at the time of vaccination.

HIV-infected individuals

The safety and immunogenicity of the vaccine were evaluated in a study of 126 subjects aged 7 to 12 years infected with human immunodeficiency virus (HIV), of whom 96 subjects received Gardasil. Seroconversion to all four antigens was observed in more than 96% of subjects. SGT levels (geometric mean titer) were slightly lower than those observed in uninfected (HIV) subjects of the same age group in other studies. The clinical significance of the lower response is unknown. The safety profile is very similar to that in uninfected (HIV) subjects in other studies. Vaccination does not affect CD4% or plasma human immunodeficiency virus (HIV) RNA levels.

Immune response to Gardasil vaccine in a two-dose vaccination regimen in individuals aged 9–13 years

A clinical study showed that in girls who received 2 doses of HPV vaccine within 6 months, the antibody response to 4 HPV types 1 month after the last dose was no less effective than in young women who received 3 doses of vaccine within 6 months.

At Month 7, in the per-protocol group, the immune response in girls aged 9–13 years (n=241) who received 2 doses of Gardasil (at 0, 6 months) was non-inferior and nominally higher than the immune response in girls and women aged 16–26 years (n=246) who received 3 doses of Gardasil (at 0, 2, 6 months).

In this study, in girls aged 9–13 years, the immune response after the two-dose vaccine regimen was nominally lower than the response after the 3-dose vaccination (n=248 at 7 months; n=82 at 36 months). The clinical significance of these findings is unknown.

A retrospective analysis of data was performed at 120 months of follow-up in girls (2 doses, n=35; 3 doses, n=38) and women (3 doses, n=30). The odds ratios (girls who received 2 doses/women who received 3 doses) ranged from 0.99 to 2.02 for all 4 HPV types. The odds ratios (girls who received 2 doses/girls who received 3 doses) ranged from 1.10 to 2.82 for all 4 HPV types. The lower 95% CI of all odds ratios remained > 0.5 through 120 months.

The seropositivity rate in girls and women was > 95% for HPV 6, 11, and 16, and the seropositivity rate for HPV 18 was > 80% in girls who received 2 doses, > 90% in girls who received 3 doses, and > 60% in women who received 3 doses, in the Luminex-based competitive immunoassay.

Pharmacokinetics

Not applicable.

Indication

Gardasil vaccine is indicated for use in girls and women aged 9 to 45 years to prevent diseases caused by HPV types 6, 11, 16, 18, including cervical, vulvar, vaginal, and anal cancers; precancerous and dysplastic conditions; genital warts; and infections caused by human papillomavirus.

The Gardasil vaccine is indicated for the prevention of the following diseases:

cervical, vulvar, vaginal, and anal cancer caused by HPV types 16 and 18;

genital warts (Condyloma acuminata) caused by HPV types 6 and 11, and infections and subsequent precancerous or dysplastic conditions caused by HPV types 6, 11, 16 and 18;

cervical intraepithelial neoplasia grades 2 and 3 (CIN 2/3) and cervical adenocarcinoma in situ (AIS);

cervical intraepithelial neoplasia grade 1 (CIN 1);

vulvar intraepithelial neoplasia grades 2 and 3 (VIN 2/3);

vaginal intraepithelial neoplasia grades 2 and 3 (VaIN 2/3);

vulvar intraepithelial neoplasia grade 1 (VIN 1) and vaginal intraepithelial neoplasia grade 1 (VaIN 1);

anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.

Gardasil is also indicated for girls and women aged 9 to 26 years to prevent cervical intraepithelial neoplasia (CIN) associated with HPV types 31, 33, 52, and 58, or cervical adenocarcinoma in situ (AIS).

Gardasil is indicated for use in boys and men aged 9 to 26 years to prevent diseases and infections caused by HPV types 6, 11, 16, and 18:

anal cancer caused by HPV types 16 and 18;

Genital warts (Condyloma acuminata) caused by HPV types 6 and 11.

The vaccine is also indicated for the prevention of precancerous and dysplastic conditions caused by HPV types 6, 11, 16, and 18:

anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.

Contraindication

Hypersensitivity to the active substances or to any component of the vaccine, including severe allergic reactions to yeast (see section "Pharmacodynamics").

Individuals who develop symptoms suggestive of hypersensitivity following a dose of Gardasil should not receive a subsequent dose of the vaccine.

As with other vaccines, Gardasil should be postponed if the patient has an acute illness accompanied by fever. The presence of a mild infection, such as a minor upper respiratory tract infection or a low-grade fever, is not a contraindication to vaccination.

Special safety precautions

The vaccine is supplied ready-to-use; there is no need to dissolve or dilute it. The full recommended dosage should be used.

Shake well before use. To preserve the characteristics of the suspension, the bottle with the drug should be shaken well before use.

Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is present, the product should be disposed of in accordance with local requirements.

The pre-filled syringe with the vaccine is for single use only and for one person only. When using single-dose vials, each person is given the vaccine with a separate sterile syringe and needle.

Use of single-dose vaccine vials

Withdraw 0.5 ml of suspension from the single-dose vaccine vial using a sterile needle into a disposable syringe that does not contain preservatives, antiseptics, or detergents. The withdrawn vaccine should be administered immediately and the vial discarded.

Use of single-dose vaccine syringes

Inject the entire contents of the syringe.

Use of single-dose sterile pre-filled syringes complete with safety device

Use the enclosed needle to administer the vaccine. If you want to use a different one, make sure that the needle is securely attached to the syringe and that its length does not exceed 2.5 cm, which is a necessary condition for the correct operation of the safety device.

When injecting as above, push the plunger down firmly while holding the syringe and inject the entire dose. The needle guard will not engage unless the entire dose is injected. Withdraw the needle, release the plunger and allow the syringe to move upward until the entire needle is completely closed. To document the vaccination, peel off the label by pulling it slowly. Place the used syringe in a sharps container.

Interaction with other medicinal products and other types of interactions

Individuals who received immunoglobulin or blood products within 6 months prior to the first dose of vaccine were excluded from clinical trials.

Use with other vaccines

Concomitant administration of Gardasil (for injectable vaccines, at different sites) with hepatitis B vaccine (recombinant) did not affect the immune response to HPV types. Seroprotection rates (number of subjects achieving a seroprotective level of hepatitis B virus antibodies ≥ 10 mIU/mL) were unchanged (96.5% with concomitant vaccination and 97.5% with hepatitis B vaccine alone). Hepatitis B virus antibody geometric mean titers (GMTs) were lower with concomitant administration, but the clinical significance of this has not been established.

Gardasil can be administered concomitantly with a combined diphtheria (d) and tetanus (T) booster vaccine with pertussis [acellular component] (aP) and/or poliomyelitis [inactivated] (IPV) components (dTap, dT-IPV, dTap-IPV vaccines) without significant effect on the antibody response to either component of either vaccine. However, there was a trend toward lower HPV antibody titers in the group receiving multiple vaccines simultaneously. The clinical significance of this observation has not been established. These data are based on the results of a clinical trial in which the combined dTap-IPV vaccine and the first dose of Gardasil were administered concomitantly (see section 4.8).

Concomitant use of Gardasil with vaccines other than those listed above has not been studied.

Use with hormonal contraceptives

In clinical trials, 57.5% of female subjects aged 16–26 years and 31.2% of women aged 24–45 years who received Gardasil were using hormonal contraceptives at the time of vaccination. The use of hormonal contraceptives did not affect the quality of the immune response to Gardasil.

Application features

Tracking

To improve the traceability of biological medicinal products, it is necessary to clearly record the name and batch number of the medicinal product used.

The decision to vaccinate should be made taking into account the risk of prior HPV infection and the potential benefit of vaccination.

As with all injectable vaccines, emergency medical treatment should be readily available in case of anaphylactic reactions (which occur rarely) following vaccination. In the event of anaphylactic reactions, the individual should be under the supervision of a healthcare professional for at least 30 minutes after vaccination.

Syncope (fainting), sometimes accompanied by falling, may occur after or even before any vaccination, especially in adolescents, as a psychogenic response to the needle injection. This condition may sometimes be accompanied by several neurological signs, such as transient visual disturbances, paresthesias, and tonic-clonic movements of the limbs during the recovery period. Therefore, patients should be observed for 15 minutes after Gardasil administration. It is important to perform the procedure under conditions that avoid injury from fainting.

As with other vaccines, the use of Gardasil does not guarantee effectiveness in all vaccinees.

Gardasil provides protection only against diseases caused by HPV types 6, 11, 16 and 18, and to a lesser extent against diseases caused by related HPV types (see section “Immunological and biological properties”). Therefore, precautions against sexually transmitted diseases should be continued.

Gardasil is for prophylactic use only and does not affect active HPV infections or established clinical disease. Gardasil has not been shown to have a therapeutic effect and is therefore not indicated for the treatment of cervical cancer, high-grade dysplastic diseases of the cervix, vagina, and vulva, or genital warts. The vaccine is not indicated for the prevention of the progression of other lesions caused by HPV.

Gardasil is not indicated for the prevention of neoplasms resulting from vaccination against HPV types in patients infected with HPV types that were present at the time of vaccination (see section “Immunological and biological properties”).

When using Gardasil in adult women, the different prevalence of HPV types in different geographical areas should be taken into account.

The safety and immunogenicity of the vaccine have been evaluated in patients aged 7 to 12 years infected with human immunodeficiency virus (HIV) (see section “Immunological and biological properties”). In individuals with impaired immunological reactivity due to the use of immunosuppressants, a genetic defect or other reasons, the response to the vaccine may be absent.

This vaccine should be administered with caution to patients with thrombocytopenia or any bleeding disorders due to an increased risk of bleeding following intramuscular administration.

Long-term studies were conducted to determine the duration of the protective response (see section “Immunological and biological properties”).

There are no data on the safety, immunogenicity, or efficacy of switching during Gardasil vaccination to other vaccines that do not cover the same HPV types. Therefore, it is important to administer the same vaccine throughout the vaccination period for the established dosing schedule.

Sodium

This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially ‘sodium-free’.

Use during pregnancy or breastfeeding

Pregnancy.

Specific studies of the vaccine in pregnant women have not been conducted. During the clinical development program, at least one pregnancy was reported in 3,819 women (vaccine n=1,894, placebo n=1,925). There were no significant differences in the types of congenital anomalies or the number of pregnancies with an adverse outcome between those receiving Gardasil or placebo. These data on pregnant women (more than 1,000 exposures) indicate no malformations or toxicity to the fetus or newborn.

Data from the use of Gardasil during pregnancy have not indicated any safety concerns. However, these data are insufficient to recommend the use of Gardasil during pregnancy. Vaccination should be postponed until after the end of pregnancy.

Breast-feeding.

In breast-feeding women who received Gardasil or placebo during the vaccination period in clinical trials, the incidence of adverse reactions in mothers and breast-fed infants was comparable between the vaccine and placebo groups. In addition, the immunogenicity of the vaccine was comparable between breast-feeding and non-breast-feeding women during the vaccination period. Therefore, Gardasil can be used in women who are breastfeeding.

Fertility.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects on male fertility were observed in a rat study.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect on the ability to drive or operate other mechanisms have not been conducted.

Method of administration and doses

Method of application

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

The drug should not be administered intravenously. Subcutaneous and intradermal routes of administration have not been studied; these methods of administration are not recommended.

Dosage

Children aged 9 to 13 years inclusive

Gardasil can be administered in a two-dose regimen (0.5 ml: 0 and 6 months).

If the second dose is administered less than 6 months after the first, a third dose must be administered.

Alternatively, Gardasil can be administered in a three-dose schedule (0.5 mL: 0, 2, and 6 months). The second dose should be administered at least 1 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 administered within 1 year.

Children aged 14 and over and adults

Gardasil should be administered in a three-dose schedule (0.5 mL: 0, 2, and 6 months). The second dose should be administered at least 1 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 administered within 1 year.

Gardasil should be used according to official recommendations.

Individuals who have received the first dose of Gardasil are recommended to complete the full course of Gardasil vaccination.

The need for a booster dose has not been established.

Children

The safety and efficacy of Gardasil in children under 9 years of age have not been established; there are no data.

Elderly people

Studies of the effectiveness of the vaccine in people over 45 years of age have not been conducted, so its use in this category is not recommended.

Overdose

There have been reports of Gardasil vaccine administered at doses higher than recommended. Overall, the adverse reaction profile of overdose was comparable to that of the recommended single doses of Gardasil vaccine.

Side effects

In 7 clinical trials (6 placebo-controlled), participants received Gardasil or placebo on the day of study enrollment and then at approximately 2 and 6 months. A few subjects (0.2%) discontinued the study due to adverse reactions. Safety was assessed in all subjects (6 trials) and in a pre-specified subgroup (1 trial) by means of vaccination record records recorded for 14 days after each Gardasil or placebo injection. According to the subjects' vaccination records, 10,088 subjects received Gardasil (6,995 girls and women aged 9–45 years, 3,093 boys and men aged 9–26 years at study enrollment) and 7,995 subjects (5,692 girls and women and 2,303 boys and men) received placebo.

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

B. Adverse reaction table

Clinical Studies Table 1 presents vaccine-related adverse reactions that occurred in patients receiving Gardasil at an incidence of at least 1.0% and at a greater incidence than in the placebo group. Adverse reactions are classified according to the following frequency: 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), and rare (<1/10,000).

Post-marketing experience

Table 1 includes additional adverse reactions that have occurred spontaneously during post-marketing use of Gardasil worldwide. Because these reactions were reported voluntarily from an unknown number of individuals, it is not always possible to accurately estimate their frequency or establish a causal relationship to vaccine administration. As a result, the frequency of these adverse reactions is defined as “not known.”

Table 1. Adverse reactions following the administration of Gardasil vaccine from clinical trials and post-marketing surveillance

*Adverse reactions that have occurred during post-marketing use (frequency cannot be estimated from available data).

1During clinical trials, dizziness was the most common adverse reaction observed in women. In men, dizziness was not observed to be more common in the vaccine group compared to the placebo group.

In addition, in clinical trials, the following adverse reactions, which were determined by the investigator to be related to the vaccine or placebo, were observed at a frequency of less than 1%.

Respiratory, thoracic and mediastinal disorders: rare: bronchospasm.

Skin and subcutaneous tissue disorders: rare: urticaria.

Nine cases (0.06%) of urticaria were observed in the Gardasil group and 20 cases (0.15%) in the adjuvant placebo group.

In clinical trials in the safety study group, participants reported any new medical conditions that occurred during the follow-up period. Among 15,706 individuals who received Gardasil and 13,617 individuals who received placebo, 39 cases of nonspecific arthritis/arthropathy were identified (24 in the Gardasil group and 15 in the placebo group).

A clinical study in 843 healthy male and female adolescents aged 11 to 17 years, when the first dose of Gardasil was administered concomitantly with a combined (inactivated) diphtheria, tetanus, pertussis (acellular component) booster vaccine and (inactivated) polio vaccine, showed an increased incidence of injection site swelling and headache following concomitant administration.