Silgard

Gardasil es una vacuna para su uso a partir de los 9 años para la prevención de:

- lesiones genitales premalignas (cervicales, vulvares y vaginales), lesiones anales premalignas, cánceres cervicales y cánceres anales causalmente relacionados con ciertos tipos de virus del papiloma humano (VPH) oncogénico

- verrugas genitales (condiloma acuminata) causalmente relacionadas con tipos específicos de VPH.

El uso de Gardasil debe estar de acuerdo con las recomendaciones oficiales.

Posología

Individuos de 9 a 13 años inclusive

Gardasil se puede administrar de acuerdo con un programa de 2 dosis (0,5 ml a las 0, 6 meses).

Si la segunda dosis de la vacuna se administra antes de los 6 meses posteriores a la primera dosis, siempre se debe administrar una tercera dosis.

Alternativamente, Gardasil se puede administrar de acuerdo con un programa de 3 dosis (0.5 ml a las 0, 2, 6 meses). La segunda dosis debe administrarse al menos un mes después de la primera dosis y la tercera dosis debe administrarse al menos 3 meses después de la segunda dosis. Las tres dosis deben administrarse dentro de un período de 1 año.

Individuos de 14 años de edad y mayores

Gardasil debe administrarse de acuerdo con un programa de 3 dosis (0,5 ml a los 0, 2 y 6 meses).

La segunda dosis debe administrarse al menos un mes después de la primera dosis y la tercera dosis debe administrarse al menos 3 meses después de la segunda dosis. Las tres dosis deben administrarse dentro de un período de 1 año.

El uso de Gardasil debe estar de acuerdo con las recomendaciones oficiales.

Población pediátrica

No se ha establecido la seguridad y eficacia de Gardasil en niños menores de 9 años. No hay datos disponibles.

Se recomienda que las personas que reciben una primera dosis de Gardasil completen el ciclo de vacunación con Gardasil.

No se ha establecido la necesidad de una dosis de refuerzo.

Método de administración

La vacuna debe administrarse mediante inyección intramuscular. El sitio preferido es el área deltoidea de la parte superior del brazo o en el área anterolateral superior del muslo.

Gardasil no debe inyectarse por vía intravascular. No se ha estudiado la administración subcutánea ni intradérmica. Estos métodos de administración no son recomendados.

Hipersensibilidad a los principios activos oa alguno de los excipientes.

Las personas que desarrollan síntomas indicativos de hipersensibilidad después de recibir una dosis de Gardasil no deben recibir dosis adicionales de Gardasil.

La administración de Gardasil debe posponerse en personas que padecen una enfermedad febril aguda grave. Sin embargo, la presencia de una infección menor, como una infección leve del tracto respiratorio superior o fiebre leve, no es una contraindicación para la inmunización.

La decisión de vacunar a un individuo debe tener en cuenta el riesgo de exposición previa al VPH y el beneficio potencial de la vacunación.

Al igual que con todas las vacunas inyectables, el tratamiento médico apropiado siempre debe estar disponible en caso de reacciones anafilácticas raras después de la administración de la vacuna.

El síncope (desmayo), a veces asociado con caídas, puede ocurrir después o incluso antes de cualquier vacunación, especialmente en adolescentes como respuesta psicógena a la inyección de la aguja. Esto puede ir acompañado de varios signos neurológicos, como alteraciones visuales transitorias, parestesia y movimientos de extremidades tónico-clónicas durante la recuperación. Por lo tanto, los vacunados deben observarse durante aproximadamente 15 minutos después de la administración de la vacuna. Es importante que existan procedimientos para evitar lesiones por desmayos.

Al igual que con cualquier vacuna, la vacunación con Gardasil puede no brindar protección a todos los receptores de la vacuna.

Gardasil solo protegerá contra enfermedades causadas por los tipos de VPH 6, 11, 16 y 18 y, en cierta medida, contra enfermedades causadas por ciertos tipos de VPH relacionados. Por lo tanto, se deben seguir tomando las precauciones adecuadas contra las enfermedades de transmisión sexual.

Gardasil es solo para uso profiláctico y no tiene ningún efecto sobre las infecciones activas por VPH o la enfermedad clínica establecida. No se ha demostrado que Gardasil tenga un efecto terapéutico. Por lo tanto, la vacuna no está indicada para el tratamiento del cáncer cervical, lesiones displásicas cervicales, vulvares y vaginales de alto grado o verrugas genitales. Tampoco está destinado a prevenir la progresión de otras lesiones establecidas relacionadas con el VPH.

Gardasil no previene las lesiones debidas a un tipo de vacuna contra el VPH en personas infectadas con ese tipo de VPH en el momento de la vacunación.

El uso de Gardasil en mujeres adultas debe tener en cuenta la variabilidad de la prevalencia del tipo de VPH en diferentes áreas geográficas.

La vacunación no es un sustituto del cribado cervical de rutina. Dado que ninguna vacuna es 100% efectiva y Gardasil no proporcionará protección contra todos los tipos de VPH, o contra las infecciones existentes por VPH, el cribado cervical de rutina sigue siendo de importancia crítica y debe seguir las recomendaciones locales.

La seguridad e inmunogenicidad de la vacuna se han evaluado en individuos de 7 a 12 años que se sabe que están infectados con el virus de la inmunodeficiencia humana (VIH). Las personas con capacidad de respuesta inmune deteriorada, debido al uso de una potente terapia inmunosupresora, un defecto genético u otras causas, pueden no responder a la vacuna.

Esta vacuna debe administrarse con precaución a personas con trombocitopenia o cualquier trastorno de la coagulación porque puede producirse sangrado después de una administración intramuscular en estos individuos.

Actualmente se están realizando estudios de seguimiento a largo plazo para determinar la duración de la protección..

No existen datos de seguridad, inmunogenicidad o eficacia para respaldar el cambio durante la vacunación con Gardasil a otras vacunas contra el VPH que no cubren los mismos tipos de VPH. Por lo tanto, es importante que se recete la misma vacuna para todo el régimen de dosis.

No se han realizado estudios sobre los efectos sobre la capacidad para conducir y utilizar máquinas.

A. Resumen del perfil de seguridad

En 7 ensayos clínicos (6 controlados con placebo), a los individuos se les administró Gardasil o placebo el día de la inscripción y aproximadamente 2 y 6 meses después. Pocos individuos (0.2%) descontinuaron debido a reacciones adversas. La seguridad se evaluó en toda la población de estudio (6 estudios) o en un subconjunto predefinido (un estudio) de la población de estudio utilizando la vigilancia asistida por la boleta de calificaciones (VRC) durante 14 días después de cada inyección de Gardasil o placebo. Las personas que fueron monitoreadas usando vigilancia asistida por VRC incluyeron 10,088 individuos (6,995 mujeres de 9 a 45 años de edad y 3,093 hombres de 9 a 26 años de edad al momento de la inscripción) que recibieron Gardasil y 7,995 individuos (5,692 mujeres y 2,303 hombres) que recibieron placebo.

Las reacciones adversas más comunes observadas fueron reacciones adversas en el lugar de la inyección (77.1% de los vacunados dentro de los 5 días posteriores a cualquier visita de vacunación) y dolor de cabeza (16.6% de los vacunados). Estas reacciones adversas generalmente fueron de intensidad leve o moderada.

B. Resumen tabulado de reacciones adversas

Ensayos clínicos

La Tabla 1 presenta reacciones adversas relacionadas con la vacuna que se observaron entre los receptores de Gardasil con una frecuencia de al menos 1.0% y también con una frecuencia mayor que la observada entre los receptores de placebo. Se clasifican bajo títulos de frecuencia utilizando la siguiente convención:

[Muy frecuentes (> 1/10); Frecuentes (> 1/100 a <1/10); Poco frecuentes (> 1 / 1,000 a <1/100); Raras (> 1 / 10,000 a <1 / 1,000)]

Experiencia posterior a la comercialización

La Tabla 1 también incluye eventos adversos adicionales que se han informado espontáneamente durante el uso posterior a la comercialización de Gardasil en todo el mundo. Debido a que estos eventos se informan voluntariamente de una población de tamaño incierto, no siempre es posible estimar de manera confiable su frecuencia o establecer una relación causal con la exposición a la vacuna. En consecuencia, la frecuencia de estos eventos adversos se califica como "no conocida".

Tabla 1: Eventos adversos después de la administración de Gardasil de ensayos clínicos y vigilancia posterior a la comercialización

Además, en ensayos clínicos, se observaron reacciones adversas que el investigador del estudio consideró relacionadas con la vacuna o el placebo a frecuencias inferiores al 1%:

Trastornos respiratorios, torácicos y mediastínicos:

Muy raros: broncoespasmo.

Trastornos de la piel y del tejido subcutáneo:

Raras: urticaria.

Se informaron nueve casos (0.06%) de urticaria en el grupo Gardasil y se observaron 20 casos (0.15%) en el grupo placebo que contiene adyuvante.

En los estudios clínicos, las personas en la población de seguridad informaron cualquier condición médica nueva durante el seguimiento. Entre 15.706 personas que recibieron Gardasil y 13.617 personas que recibieron placebo, se informaron 39 casos de artritis / artropatía no específica, 24 en el grupo Gardasil y 15 en el grupo placebo.

En un ensayo clínico de 843 adolescentes y mujeres sanos de 11 a 17 años de edad, la administración de la primera dosis de Gardasil concomitantemente con una vacuna combinada contra la difteria, el tétanos, la tos ferina [acelular, componente] y la poliomielitis [inactivada] mostró que había más inyección -hinchazón del sitio y dolor de cabeza informados después de la administración concomitante. Las diferencias observadas fueron <10% y en la mayoría de los sujetos, los eventos adversos se informaron como de intensidad leve a moderada.

Informe de sospechas de reacciones adversas

Informar sospechas de reacciones adversas después de la autorización del medicamento es importante. Permite un monitoreo continuo del equilibrio beneficio / riesgo del medicamento. Se solicita a los profesionales de la salud que informen sobre cualquier sospecha de reacciones adversas a través del Esquema de la Tarjeta Amarilla en www.mhra.gov.uk/yellowcard.

Ha habido informes de administración de dosis más altas que las recomendadas de Gardasil.

En general, el perfil de eventos adversos informado con sobredosis fue comparable a las dosis únicas recomendadas de Gardasil.

Pharmacotherapeutic group: Viral Vaccine, ATC code: J07BM01

Mechanism of Action

Gardasil is an adjuvanted non-infectious recombinant quadrivalent vaccine prepared from the highly purified virus-like particles (VLPs) of the major capsid L1 protein of HPV types 6, 11, 16 and 18. The VLPs contain no viral DNA, they cannot infect cells, reproduce or cause disease. HPV only infects humans, but animal studies with analogous papillomaviruses suggest that the efficacy of LI VLP vaccines is mediated by the development of a humoral immune response.

HPV 16 and HPV 18 are estimated to be responsible for 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 HPV related high-grade vulvar (VIN 2/3) and vaginal (VaIN 2/3) intraepithelial neoplasia and 80% of HPV related high-grade anal (AIN 2/3) intraepithelial neoplasia. HPV 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 have been accepted as immediate precursors of invasive cervical cancer.

The indication is based on the demonstration of efficacy of Gardasil in females 16 to 45 years of age and in males 16 to 26 years of age and on the demonstration of immunogenicity of Gardasil in 9- to 15-year old children and adolescents.

Clinical Studies

Efficacy in women 16 through 26 years

The efficacy of Gardasil in 16- through 26- year-old women was assessed in 4 placebo-controlled, double-blind, randomized Phase II and III clinical studies including a total of 20,541 women, who were enrolled and vaccinated without pre-screening for the presence of HPV infection.

The primary efficacy endpoints included HPV 6-, 11-, 16-, or 18-related vulvar and vaginal lesions (genital warts, VIN, VaIN) and CIN of any grade and cervical cancers (Protocol 013, FUTURE I), HPV 16- or 18-related CIN 2/3 and AIS and cervical cancers (Protocol 015, FUTURE II), HPV 6-, 11-, 16-, or 18-related persistent infection and disease (Protocol 007), and HPV 16-related persistent infection (Protocol 005). The primary analyses of efficacy, with respect to vaccine HPV types (HPV 6, 11, 16, and 18), were conducted in the per-protocol efficacy (PPE) population (i.e. all 3 vaccinations within 1 year of enrollment, no major protocol deviations and naïve to the relevant HPV type(s) prior to dose 1 and through 1 month Postdose 3 (Month 7)).

Efficacy results are presented for the combined analysis of study protocols. The efficacy for HPV 16/18 related CIN 2/3 or AIS is based on data from protocols 005 (16-related endpoints only), 007, 013, and 015. The efficacy for all other endpoints is based on protocols 007, 013, and 015. The median duration of follow-up for these studies was 4.0, 3.0, 3.0, and 3.0 years for Protocol 005, Protocol 007, Protocol 013, and Protocol 015, respectively. The median duration of follow-up for the combined protocols (005, 007, 013, and 015) was 3.6 years. Results of individual studies support the results from the combined analysis. Gardasil was efficacious against HPV disease caused by each of the four vaccine HPV types. At end of study, individuals enrolled in the two Phase-III studies (Protocol-013 and Protocol-015), were followed for up to 4 years (median 3.7 years).

Cervical Intraepithelial Neoplasia (CIN) Grade 2/3 (moderate to high-grade dysplasia) and adenocarcinoma in situ (AIS) were used in the clinical trials as a surrogate marker for cervical cancer.

In the long-term extension study of Protocol 015, 2,084 women 16-23 years old during vaccination with Gardasil in the base study were followed. In the PPE population no cases of HPV diseases (HPV types 6/11/16/18 related high grade CIN) were observed up to approximately 12 years. In this study, a durable protection was statistically demonstrated to approximately 10 years.

Efficacy in women naïve to the relevant vaccine HPV type(s)

Efficacy was measured starting after the Month 7 visit. Overall, 73% of women were naïve (PCR negative and seronegative) to all 4 HPV types at enrolment.

The efficacy results for relevant endpoints analysed at 2 years post-enrolment and at end of study (median duration of follow-up = 3.6 years) in the per-protocol population are presented in the Table 2.

In a supplemental analysis, the efficacy of Gardasil was evaluated against HPV 16/18-related CIN 3 and AIS.

Table 2: Analysis of efficacy of Gardasil against high grade cervical lesions in the PPE population

*Number of individuals with at least one follow-up visit after Month 7

**Based on virologic evidence, the first CIN 3 case in a patient chronically infected with HPV 52 is likely to be causally related to HPV 52. In only 1 of 11 specimens HPV 16 was found (at Month 32.5) and was not detected in tissue excised during LEEP (Loop Electro-Excision Procedure). In the second CIN 3 case observed in a patient infected with HPV 51 at Day 1 (in 2 of 9 specimens); HPV 16 was detected at a Month 51 biopsy (in 1 of 9 specimens) and HPV 56 was detected in 3 of 9 specimens at Month 52 in tissue excised during LEEP.

***Patients were followed for up to 4 years (median 3.6 years)

Note: Point estimates and confidence intervals are adjusted for person-time of follow-up.

At end of study and in the combined protocols,

- the efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related CIN 1 was 95.9 % (95% CI: 91.4, 98.4),

- the efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related CIN (1, 2, 3) or AIS was 96.0% (95% CI: 92.3, 98.2),

- the efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related VIN2/3 and VaIN 2/3 was 100% (95% CI: 67.2, 100) and 100% (95% CI: 55.4, 100), respectively,

- the efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related genital warts was 99.0% (95% CI: 96.2, 99.9).

In Protocol 012 the efficacy of Gardasil against the 6 month definition of persistent infection [samples positive on two or more consecutive visits 6 months apart (±1 month) or longer] related to HPV 16 was 98.7 % (95% CI: 95.1, 99.8) and 100.0% (95% CI: 93.2, 100.0) for HPV 18 respectively, after a follow-up of up to 4 years (mean of 3.6 years). For the 12 month definition of persistent infection, efficacy against HPV 16 was 100.0 % (95% CI: 93.9, 100.0) and 100.0 % (95% CI: 79.9, 100.0) for HPV 18 respectively.

Efficacy in women with evidence of HPV 6, 11, 16, or 18 infection or disease at day 1

There was no evidence of protection from disease caused by vaccine HPV types for which women were PCR positive at day 1. Women who were already infected with one or more vaccine-related HPV types prior to vaccination were protected from clinical disease caused by the remaining vaccine HPV types.

Efficacy in women with and without prior infection or disease due to HPV 6, 11, 16, or 18

The modified intention to treat (ITT) population included women regardless of baseline HPV status at Day 1, who received at least one vaccination and in whom case counting started at 1 month Postdose 1. This population approximates to the general population of women with respect to prevalence of HPV infection or disease at enrolment. The results are summarised in Table 3.

Table 3: Efficacy of Gardasil in high grade cervical lesions in the modified ITT-population including women regardless of baseline HPV status

*Number of individuals with at least one follow-up visit after 30 days after Day 1

**Percent efficacy is calculated from the combined protocols. The efficacy for HPV 16/18 related CIN 2/3 or AIS is based on data from protocols 005 (16-related endpoints only), 007, 013, and 015. Patients were followed for up to 4 years (median 3.6 years).

Note: point estimates and confidence intervals are adjusted for person-time of follow-up.

Efficacy against HPV 6-, 11-, 16-, 18-related VIN 2/3 was 73.3% (95% CI: 40.3, 89.4), against HPV 6-, 11-, 16-, 18-related VaIN 2/3 was 85.7% (95% CI: 37.6, 98.4), and against HPV 6-, 11-, 16-, 18-related genital warts was 80.3% (95% CI: 73.9, 85.3) in the combined protocols at end of study.

Overall 12% of the combined study population had an abnormal Pap test suggestive of CIN at Day 1. Among women with an abnormal Pap test at Day 1 who were naïve to the relevant vaccine HPV types at Day 1, efficacy of the vaccine remained high. Among women with an abnormal Pap test at Day 1 who were already infected with the relevant vaccine HPV types at Day 1, no vaccine efficacy was observed.

Protection Against the Overall Burden of Cervical HPV disease in 16- Through 26-Year-Old Women

The impact of Gardasil against the overall risk for cervical, HPV disease (i.e., disease caused by any HPV type) was evaluated starting 30 days after the first dose in 17,599 individuals enrolled in the two phase III efficacy trials (Protocols 013 and 015). Among women who were naïve to 14 common HPV types and had a negative Pap test at Day 1, administration of Gardasil reduced the incidence of CIN 2/3 or AIS caused by vaccine- or non-vaccine HPV types by 42.7% (95% CI: 23.7, 57.3) and of genital warts by 82.8% (95% CI: 74.3, 88.8) at end of study.

In the modified ITT population, the benefit of the vaccine with respect to the overall incidence of CIN 2/3 or AIS (caused by any HPV type) and of genital warts was much lower, with a reduction of 18.4% (95% CI: 7.0, 28.4) and 62.5% (95% CI: 54.0, 69.5), respectively, as Gardasil does not impact the course of infections or disease that are present at vaccination onset.

Impact on Definitive Cervical Therapy Procedures

The impact of Gardasil on rates of Definitive Cervical Therapy Procedures regardless of causal HPV types was evaluated in 18,150 individuals enrolled in Protocol 007, Protocols 013 and 015. In the HPV naïve population (naïve to 14 common HPV types and had a negative Pap test at Day 1), Gardasil reduced the proportion of women who experienced a definitive cervical therapy procedure (Loop Electro-Excision Procedure or Cold-Knife Conization) by 41.9% (95% CI: 27.7, 53.5) at end of study. In the ITT population the corresponding reduction was 23.9% (95% CI: 15.2, 31.7).

Cross-protective efficacy

The efficacy of Gardasil against CIN (any grade) and CIN 2/3 or AIS caused by 10 non-vaccine HPV types (HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) structurally related to HPV 16 or HPV 18 was evaluated in the combined Phase III efficacy database (N = 17,599) after a median follow-up of 3.7 years (at end of study). Efficacy against disease endpoints caused by pre-specified combinations of non-vaccine HPV types was measured. The studies were not powered to assess efficacy against disease caused by individual HPV types.

The primary analysis was done in type-specific populations that required women to be negative for the type being analyzed, but who could be positive for other HPV types (96% of the overall population). The primary time point analysis after 3 years did not reach statistical significance for all pre-specified endpoints. The final end-of-study results for the combined incidence of CIN 2/3 or AIS in this population after a median follow-up of 3.7 years are shown in Table 4. For composite endpoints, statistically significant efficacy against disease was demonstrated against HPV types phylogenetically related to HPV 16 (primarily HPV 31) whereas no statistically significant efficacy was observed for HPV types phylogenetically related to HPV 18 (including HPV 45). For the 10 individual HPV types, statistical significance was only reached for HPV 31.

Table 4: Results for CIN 2/3 or AIS in Type-Specific HPV-Naïve Individuals^†(end of study results)

Efficacy in women 24 through 45 years

The efficacy of Gardasil in 24- through 45-year-old women was assessed in 1 placebo-controlled, double-blind, randomized Phase III clinical study (Protocol 019, FUTURE III) including a total of 3,817 women, who were enrolled and vaccinated without pre-screening for the presence of HPV infection.

The primary efficacy endpoints included the combined incidence of HPV 6-, 11-, 16- or 18-related and the combined incidence of HPV 16- or HPV 18-related persistent infection (6 month definition), genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancers. The median duration of follow-up for this study was 4.0 years.

In the long-term extension study of Protocol 019, 685 women 24-45 years old during vaccination with Gardasil in the base study were followed. In the PPE population, no cases of HPV diseases (HPV types 6/11/16/18 related CIN any grade and Genital Warts) were observed through 10.2 years (median follow-up of 9.2 years).

Efficacy in women naïve to the relevant vaccine HPV type(s)

The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population (i.e. all 3 vaccinations within 1 year of enrolment, no major protocol deviations and naïve to the relevant HPV type(s) prior to dose 1 and through 1 month Postdose 3 (Month 7)). Efficacy was measured starting after the Month 7 visit. Overall, 67% of individuals were naïve (PCR negative and seronegative) to all 4 HPV types at enrolment.

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

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

Efficacy in women with and without prior infection or disease due to HPV 6, 11, 16, or 18

The Full Analysis Set population (also known as the ITT population) included women regardless of baseline HPV status at Day 1, who received at least one vaccination and in whom case counting started at Day 1. This population approximates to the general population of women with respect to prevalence of HPV infection or disease at enrolment.

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

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

Efficacy in women (16 to 45 years) with evidence of a prior infection with a vaccine HPV type (seropositive) that was no longer detectable at vaccination onset (PCR negative)

In post hoc analyses of individuals (who received at least one vaccination) with evidence of a prior infection with a vaccine HPV type (seropositive) no longer detectable (PCR negative) at vaccination onset, the efficacy of Gardasil to prevent conditions due to the recurrence of the same HPV type was 100% (95% CI: 62.8, 100.0; 0 vs. 12 cases [n = 2572 from pooled studies in young women]) against HPV 6-, 11-, 16-, and 18-related CIN 2/3, VIN 2/3, VaIN 2/3, and genital warts in women 16 to 26 years. Efficacy was 68.2% (95% CI: 17.9, 89.5; 6 vs. 20 cases [n= 832 from studies in young and adult women combined]) against HPV 16- and 18-related persistent infection in women 16 to 45 years.

Efficacy in men 16 through 26 years

Efficacy was evaluated against HPV 6-, 11-, 16-, 18-related external genital warts, penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3, and persistent infection.

The efficacy of Gardasil in 16- through 26-year-old men was assessed in 1 placebo-controlled, double-blind, randomized Phase III clinical study (Protocol 020) including a total of 4,055 men who were enrolled and vaccinated without pre-screening for the presence of HPV infection. The median duration of follow-up was 2.9 years.

In a subset of 598 men (GARDASIL = 299; placebo = 299) in Protocol 020 who self-identified as having sex with men (MSM) efficacy against anal intraepithelial neoplasia (AIN grades 1/2/3) and anal cancer, and intra-anal persistent infection was evaluated.

MSM are at higher risk of anal HPV infection compared to the general population; the absolute benefit of vaccination in terms of prevention of anal cancer in the general population is expected to be very low.

Efficacy in Men naïve to the relevant vaccine HPV types

The primary analyses of efficacy, with respect to vaccine HPV types (HPV 6, 11, 16, 18), were conducted in the per-protocol efficacy (PPE) population (i.e. all 3 vaccinations within 1 year of enrolment, no major protocol deviations and naïve to the relevant HPV type(s) prior to dose 1 and through 1 month Postdose 3 (Month 7)). Efficacy was measured starting after the Month 7 visit. Overall, 83% of men (87% of heterosexual subjects and 61% of MSM subjects) were naïve (PCR negative and seronegative) to all 4 HPV types at enrolment.

Anal Intraepithelial Neoplasia (AIN) Grade 2/3 (moderate to high-grade dysplasia) was used in the clinical trials as a surrogate marker for anal cancer.

The efficacy results for relevant endpoints analysed at end of study (median duration of follow-up 2.4 years) in the per-protocol population are presented in the Table 5. Efficacy against PIN grades 1/2/3 was not demonstrated.

Table 5: Efficacy of Gardasil against external genital lesions in the PPE* population of 16-26 year old men

At end of study analysis for anal lesions in the MSM population (median duration of follow-up was 2.15 years), the preventive effect against HPV 6-, 11-, 16-, 18-related AIN 2/3 was 74.9% (95 % CI: 8.8, 95.4; 3/194 versus 13/208) and against HPV 16- or 18-related AIN 2/3 86.6% (95 % CI: 0.0, 99.7; 1/194 versus 8/208).

The duration of protection against anal cancer is currently unknown. In the long-term extension study of Protocol 020, 918 men 16-26 years old during vaccination with Gardasil in the base study were followed. In the PPE population, no cases of HPV types 6/11 related genital warts, HPV 6/11/16/18 external genital lesions or HPV 6/11/16/18 high grade AIN in MSM were observed through 9.6 years (median follow-up of 8.5 years).

Efficacy in men with or without prior infection or disease due to HPV 6, 11, 16, or 18

The Full Analysis Set population included men regardless of baseline HPV status at Day 1, who received at least one vaccination and in whom case counting started at Day 1. This population approximates to the general population of men with respect to prevalence of HPV infection or disease at enrolment.

The efficacy of GARDASIL again

No aplica.

Los estudios de toxicidad de dosis única y dosis repetidas y tolerancia local no revelaron riesgos especiales para los humanos.

Gardasil indujo respuestas de anticuerpos específicos contra los tipos 6, 11, 16 y 18 de VPH en ratas preñadas, después de una o múltiples inyecciones intramusculares. Los anticuerpos contra los cuatro tipos de VPH fueron transferidos a la descendencia durante la gestación y posiblemente durante la lactancia. No hubo efectos relacionados con el tratamiento sobre los signos del desarrollo, el comportamiento, el rendimiento reproductivo o la fertilidad de la descendencia.

GARDASIL administrado a ratas macho a la dosis humana completa (proteína total de 120 mcg) no tuvo efectos sobre el rendimiento reproductivo, incluida la fertilidad, el recuento de espermatozoides y la motilidad de los espermatozoides, y no hubo cambios brutos o histomorfológicos relacionados con la vacuna en los testículos y ningún efecto sobre los testículos. pesos.

En ausencia de estudios de compatibilidad, este medicamento no debe mezclarse con otros medicamentos.

Gardasil, suspensión inyectable :

- Gardasil puede aparecer como un líquido transparente con un precipitado blanco antes de la agitación.

- Agite bien antes de usar para hacer una suspensión. Después de una agitación completa, es un líquido blanco y turbio.

- Inspeccione la suspensión visualmente para detectar partículas y decoloración antes de la administración. Deseche la vacuna si hay partículas y / o si parece descolorida.

- Retirar la dosis de 0,5 ml de vacuna del vial de dosis única con una aguja y jeringa estériles.

- Inyecte inmediatamente usando la ruta intramuscular (IM), preferiblemente en el área deltoidea de la parte superior del brazo o en el área anterolateral superior del muslo.

- La vacuna debe usarse como se suministra. Se debe usar la dosis completa recomendada de la vacuna.

Cualquier vacuna no utilizada o material de desecho debe eliminarse de acuerdo con los requisitos locales.

Gardasil, suspensión inyectable en una jeringa precargada :

- Gardasil puede aparecer como un líquido transparente con un precipitado blanco antes de la agitación.

- Agite bien antes de usar, la jeringa precargada, para hacer una suspensión. Después de una agitación completa, es un líquido blanco y turbio.

- Inspeccione la suspensión visualmente para detectar partículas y decoloración antes de la administración. Deseche la vacuna si hay partículas y / o si parece descolorida.

- Se proporcionan dos agujas de diferentes longitudes en el paquete, elija la aguja adecuada para garantizar una administración intramuscular (IM) dependiendo del tamaño y peso de su paciente.

- Conecte la aguja girándola en el sentido de las agujas del reloj hasta que la aguja se ajuste firmemente a la jeringa. Administre la dosis completa según el protocolo estándar.

- Inyecte inmediatamente usando la ruta intramuscular (IM), preferiblemente en el área deltoidea de la parte superior del brazo o en el área anterolateral superior del muslo.

- La vacuna debe usarse como se suministra. Se debe usar la dosis completa recomendada de la vacuna.

Cualquier vacuna no utilizada o material de desecho debe eliminarse de acuerdo con los requisitos locales.