Gardasil 9

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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Gardasil 9 Generic Name & Formulations

    Legal Class

    Rx

    General Description

    9-valent human papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 45, 52, and 58 vaccine; recombinant; aluminum adsorbed, susp for IM inj; preservative-free.

    Pharmacological Class

    HPV.

    How Supplied

    Single-dose vials—10; Prefilled syringes (w. tip caps)—10

    Storage

    • Store refrigerated at 2°C to 8°C (36 to 46°F). Do not freeze. Protect from light. 

    • Once Gardasil 9 is removed from refrigeration, administer as soon as possible. Can administer provided total (cumulative multiple excursion) time out of refrigeration (at temperatures between 8°C and 25°C) does not exceed 72 hours. Cumulative multiple excursions between 0°C and 2°C are also permitted as long as the total time between 0°C and 2°C does not exceed 72 hours. These are not, however, recommendations for storage.

    Manufacturer

    Merck & Co., Inc.

    Generic Availability

    NO

    Mechanism of Action

    The efficacy of Gardasil 9 against anogenital diseases related to the vaccine HPV types in humans is thought to be mediated by humoral immune responses induced by the vaccine, although the exact mechanism of protection is unknown.

    Gardasil 9 Indications

    Indications

    In females 9–45yrs old, to prevent cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58; genital warts caused by HPV types 6 and 11; cervical intraepithelial neoplasia (CIN) grades 2 and 3 and cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grade 1, vulvar intraepithelial neoplasia (VIN) grades 2 and 3, vaginal intraepithelial neoplasia (VaIN) grades 2 and 3, and anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. In males 9–45yrs old, to prevent anal, oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58; genital warts caused by HPV types 6 and 11; and anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

    Limitations of Use

    Vaccination does not eliminate the necessity to undergo screening for cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers as recommended. Not for protection against disease from HPV types through exposure to sexual activity or diseases due to HPV types other than 6, 11, 16, 18, 31, 33, 45, 52, and 58. Not for treating external genital lesions; cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers; CIN; VIN; VaIN; or AIN. May not protect all vaccine recipients.

    Gardasil 9 Dosage and Administration

    Adults and Children

    Give by IM inj in deltoid or upper thigh. Each dose is 0.5mL. <9yrs: not established. 9–14yrs: 2-dose regimen: give 1st dose at elected date, 2nd dose 6–12mos after the 1st dose (if the 2nd dose is given earlier than 5mos after the 1st dose, administer a 3rd dose at least 4mos after the 2nd dose). Or, 9–45yrs: 3-dose regimen: give 1st dose at elected date, 2nd dose 2mos after the 1st dose, and 3rd dose 6mos after the 1st dose. Monitor patients for 15mins after administration.

    Administration

    • Do not dilute or mix with other vaccines.

    • Shake well immediately before use.

    • Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the product if particulates are present or if it appears discolored.

    • Administer intramuscularly in the deltoid or anterolateral area of the thigh.

    • Observe patients for 15 minutes after administration.

    Gardasil 9 Contraindications

    Contraindications

    Yeast allergy.

    Gardasil 9 Boxed Warnings

    Not Applicable

    Gardasil 9 Warnings/Precautions

    Warnings/Precautions

    Immunocompromised. Have treatment available to manage anaphylactic reactions. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Syncope

    • Syncope may develop after vaccination, sometimes resulting in falling. Observe patients for 15 minutes after administration.

    • Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported after administration. These movements are usually transient and typically respond to maintaining a supine or Trendelenburg position.

    Managing Allergic Reactions 

    • Appropriate medical treatment and supervision must be readily available in case of anaphylactic reactions following the administration.

    Pregnancy Considerations

    Pregnancy Exposure Registry

    • There is a pregnancy exposure registry to monitor pregnancy outcomes in women exposed to Gardasil 9 during pregnancy. To enroll in or obtain information about the registry, call Merck Sharp & Dohme LLC at 1-800-986-8999.

    Risk Summary

    • No adequate and well-controlled studies of Gardasil 9 in pregnant women.

    • Available human data do not demonstrate vaccine-associated increase in risk of major birth defects and miscarriages when Gardasil 9 is administered during pregnancy.

    Nursing Mother Considerations

    Risk Summary

    • Available data are not sufficient to assess the effects on the breastfed infant or on milk production/excretion.

    • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Gardasil 9 and any potential adverse effects on the breastfed child from Gardasil 9 or from the underlying maternal condition.

    Pediatric Considerations

    • The safety and efficacy have not been established in patients younger than 9 years of age.

    Geriatric Considerations

    • The safety and efficacy have not been established in patients 65 years of age and older.

    Other Considerations for Specific Populations

    Immunocompromised Individuals 

    • The immunologic response to Gardasil 9 may be diminished in this patient population.

    Gardasil 9 Pharmacokinetics

    See Literature

    Gardasil 9 Interactions

    Interactions

    Immunosuppressants: may get suboptimal response.

    Gardasil 9 Adverse Reactions

    Adverse Reactions

    Inj site reactions (eg, swelling, erythema, pain), headache; post-administration syncope (may be associated with tonic-clonic movements and other seizure-like activity).

    Gardasil 9 Clinical Trials

    Clinical Trials

    Efficacy and Effectiveness Data for Gardasil

    Individuals 16 through 26 Years of Age

    • Five AAHS-controlled, double-blind, randomized clinical trials included 24,596 patients 16 to 26 years of age; of which 20,541 were girls and women, and 4,055 were boys and men.

    • The efficacy of Gardasil for vaccine HPV types among girls and women were as followed:

      • HPV 16- or 18-related CIN 2/3 or AIS: 98.2% (95% CI, 93.5-99.8)

      • HPV 16- or 18-related VIN 2/3: 100% (95% CI, 55.5-100.0)

      • HPV 16- or 18-related VaIN 2/3: 100% (95% CI, 49.5-100.0)

      • HPV 6-, 11-, 16-, or 18-related CIN (CIN 1, CIN 2/3) or AIS: 96.0% (95% CI, 92.3-98.2)

      • HPV 6-, 11-, 16-, or 18-related Genital Warts: 99.0% (95% CI, 96.2-99.9)

      • HPV 6- and 11-related Genital Warts: 99.0% (95% CI, 96.2-99.9)

    • The efficacy of Gardasil for vaccine HPV types among boys and men were as followed:

      • External genital lesions HPV 6-, 11-, 16-, or 18-related

        • External genital lesions: 90.6% (95% CI, 70.1-98.2)

        • Condyloma: 89.3% (95% CI, 65.3-97.9)

        • PIN 1/2/3: 100.0% (95% CI, -52.1, 100.0)

      • HPV 6-, 11-, 16-, or 18-related endpoint

        • AIN 1/2/3: 77.5% (95% CI, 39.6-93.3)

        • AIN 2/3: 74.9% (95% CI, 8.8-95.4)

        • AIN 1: 73.0% (95% CI, 16.3-93.4)

        • Condyloma acuminatum: 100% (95% CI, 8.2-100.0)

        • Non-acuminate: 60.4% (95% CI, -33.5, 90.8)

    • In an extension study of females 16 to 26 years of age, the vaccine efficacy of Gardasil 9 was 100% (95% CI, 12.3-100) against overall cervical and genital disease related to HPV 6, 11, 16, and 18 through Month 60 compared with AAHS control.

    • An extension study of girls and women 16 to 23 years of age used in health care registries in Denmark, Iceland, Norway and Sweden to monitor endpoint cases of HPV 6-, 11-, 16-, or 18-related CIN (any grade), AIS, cervical cancer, vulvar cancer, or vaginal cancer among 2,650 girls and women 16 through 23 years of age at enrollment who were randomized to vaccination with Gardasil. At interim analysis, there were no cases of HPV 6-, 11-, 16- or 18-related CIN (any grade), AIS, cervical cancer, vulvar cancer, or vaginal cancer observed over a total of 5765 person-years at risk.

    Girls and Boys 9 through 15 Years of Age

    • An extension study of 614 girls and 565 boys 9 to 15 years of age at enrollment who were randomized to vaccination with GARDASIL actively followed subjects for endpoint cases of HPV 6-, 11-, 16-, or 18-related persistent infection, CIN (any grade), AIS, VIN, VaIN, cervical cancer, vulvar cancer, vaginal cancer, and external genital lesions from the initiation of sexual activity or age 16 onwards.

    • At the time of interim analysis, there were no cases of persistent infection of at least 12 months’ duration and no cases of HPV 6-, 11-, 16-, or 18-related CIN (any grade), AIS, VIN, VaIN, cervical cancer, vulvar cancer, vaginal cancer, or external genital lesions observed over a total 1,105 person-years at risk.

    • There were 4 cases of HPV 6-, 11-, 16-, or 18-related persistent infection of at least 6 months’ duration, including 3 cases related to HPV 16 and 1 case related to HPV 6, none of which persisted to 12 months’ duration.

    Individuals 27 through 45 Years of Age

    • The clinical trial evaluated the efficacy of Gardasil in 3253 women 27 to 45 years of age. The combined endpoints included HPV 6-, 11-, 16- or 18-related persistent infection, genital warts, vulvar and vaginal dysplastic lesions of any grade, CIN of any grade, AIS, and cervical cancer. Patients were randomly assigned 1:1 to receive either Gardasil or AAHS control. The trial was conducted in 2 phases: a base study and a long-term study extension.

    • The per-protocol efficacy (PPE) population received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, were naïve (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16 and 18) prior to dose 1 and remained PCR negative to the relevant HPV type(s) through one month post-dose 3 (Month 7). 

    • In the base study:

      • The vaccine efficacy was 87.7%  (95% CI, 75.4%-94.6%) for Gardasil against the combined incidence of HPV 6-, 11-, 16-, and 18-related persistent infection, genital warts, VIN, VaIN, vulvar cancer, vaginal cancer, cervical dysplasia (any grade CIN), AIS and cervical cancer in the PPE population.

      • The vaccine efficacy was 95.0% (95% CI, 68.7%-99.9%) for Gardasil against combined incidence of HPV 6-, 11-, 16-, and 18-related genital warts or cervical dysplasia in the PPE population.

    • In the long-term extension study:

      • There were no cases of HPV  6-, 11-, 16-, or 18- related CIN (any grade) or genital warts observed in the PPE population.

     

    Clinical Trials for Gardasil 9

    Efficacy – HPV Types 31, 33, 45, 52 and 58 in Girls and Women 16 through 26 Years of Age

    • Study 1 – The active comparator-controlled, double-blind, randomized trial compared the efficacy of Gardasil 9 to Gardasil in 14,204 girls and women 16 to 26 years of age, who were enrolled and vaccinated without prescreening for the presence of HPV infection. 

    • The primary efficacy evaluation was conducted in the PPE population based on a composite clinical endpoint of HPV 31-, 33-, 45-, 52-, and 58-related cervical cancer, vulvar cancer, vaginal cancer, CIN 2/3 or AIS, VIN 2/3, and VaIN 2/3. Efficacy for all endpoints was measured starting after the Month 7 visit.

    • Gardasil 9 prevented HPV 31-, 33-, 45-, 52-, and 58-related persistent infection and disease and also reduced the incidence of HPV 31-, 33-, 45-, 52-, and 58-related Pap test abnormalities, cervical and external genital biopsy, and definitive therapy.

    • In the PPE population, the vaccine efficacy of Gardasil 9 for the disease endpoints are as followed:

      • HPV 31-, 33-, 45-, 52-, 58-related CIN 2/3, AIS, Cervical Cancer, VIN 2/3, VaIN 2/3, Vulvar Cancer, and Vaginal Cancer: 96.7% (95% CI, 80.9-99.8)

      • HPV 31-, 33-, 45-, 52-, 58-related CIN 1: 98.6% (95% CI, 92.4-99.9)

      • HPV 31-, 33-, 45-, 52-, 58-related CIN 2/3 or AIS: 96.3% (95% CI, 79.5-99.8)

      • HPV 31-, 33-, 45-, 52-, 58-related Vulvar or Vaginal Disease: 93.8% (95% CI, 61.5-99.7)

      • HPV 31-, 33-, 45-, 52-, 58-related Persistent Infection ≥6 Months: 96.2% (95% CI, 94.4-97.5)

      • HPV 31-, 33-, 45-, 52-, 58-related Persistent Infection ≥12 Months: 96.1% (95% CI, 93.7-97.9)

      • HPV 31-, 33-, 45-, 52-, 58-related ASC-US HR-HPV Positive or Worse Pap Abnormality: 92.6% (95% CI, 89.7-94.8)

      • HPV 31-, 33-, 45-, 52-, 58-related Biopsy: 96.9% (95% CI, 93.6-98.6)

      • HPV 31-, 33-, 45-, 52-, 58-related Definitive Therapy: 87.5% (95% CI, 65.7-96.0)

     

    Effectiveness in Prevention of HPV-Related Oropharyngeal and Other Head and Neck Cancers

    • The effectiveness of Gardasil 9 against oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58, is based on the effectiveness of Gardasil and Gardasil 9 to prevent anogenital disease caused by HPV types covered by the vaccine.

     

    Immunogenicity of a 3-Dose Regimen

    Studies Supporting the Effectiveness of Gardasil 9 against HPV Types 6, 11, 16, and 18

    • The efficacy of Gardasil 9 against persistent infection and disease related to HPV Types 6, 11, 16, or 18 was inferred from non-inferiority comparisons in Study 1 (16- through 26-year-old girls and women) and Study 3 (9- through 15-year-old girls) of GMTs following vaccination with Gardasil 9 with those following vaccination with Gardasil.

    • The primary analyses were conducted in the per-protocol population, which included subjects who received all three vaccinations within one year of enrollment, did not have major deviations from the study protocol, and were HPV-naïve. 

    • Anti-HPV 6, 11, 16 and 18 GMTs at Month 7 for Gardasil 9 among girls 9 through 15 years of age and young women 16 through 26 years of age were non-inferior to those among the corresponding populations for Gardasil. At least 99.7% of individuals included in the analyses for each HPV type became seropositive by Month 7.

    Study Supporting the Effectiveness of Gardasil 9 against Vaccine HPV Types in 9- through 15-Year Old Girls and Boys

    • The efficacy of Gardasil 9 against persistent infection and disease related to vaccine HPV types in 9- through 15-year-old girls and boys was inferred from non-inferiority comparison conducted in the PPI population in Study 2 of GMTs following vaccination with Gardasil 9 among 9- through 15-year-old girls and boys with those among 16- through 26-year-old girls and women.

    • Anti-HPV GMTs at Month 7 among 9- through 15-year-old girls and boys were non-inferior to anti-HPV GMTs among 16- through 26-year-old girls and women. 

    Study Supporting the Effectiveness of Gardasil 9 against Vaccine HPV Types in 16- through 26-Year Old Boys and Men

    • The efficacy of Gardasil 9 against persistent infection and disease related to vaccine HPV types in 16- through 26-year-old boys and men was inferred from non-inferiority comparison conducted in the PPI population in Study 7 of GMTs following vaccination with Gardasil 9 among 16- through 26-year-old HM with those among 16- through 26-year-old girls and women.

    • Anti-HPV GMTs at Month 7 among 16- through 26-year-old HM were non-inferior to anti-HPV GMTs among 16- through 26-year-old girls and women.

    Study Supporting the Effectiveness of Gardasil 9 against Vaccine HPV Types in 27- through 45-Year Old Women

    • The efficacy of Gardasil 9 against persistent infection and disease related to vaccine HPV types in 27- through 45-year-old women was supported by immunobridging comparisons conducted in the PPI population in Study 9.

    • The GMT ratios of anti-HPV responses at Month 7 among 27- through 45-year-old women relative to anti-HPV responses among 16- through 26-year-old girls and women met the success criteria of having the lower bound of the 95% CI of the GMT ratios greater than 0.50 for HPV 16, 18, 31, 33, 45, 52, and 58.

    Immune Response to Gardasil 9 across All Clinical Trials

    • Across all clinical trials at Month 7, the anti-HPV GMTs among 9- through 15- year-old girls and boys and 16- through 26-year-old boys and men were comparable to anti-HPV responses among 16- through 26-year-old girls and women in the combined database of immunogenicity studies for Gardasil 9. 

    Persistence of Immune Response to Gardasil 9

    • Following a 3-dose schedule of vaccination with Gardasil 9, the duration of immunity has not been established.

    • Peak anti-HPV GMTs for each vaccine HPV type occurred at Month 7.

    • Proportions of individuals who remained seropositive to each vaccine HPV type at Month 24 were similar to the corresponding seropositive proportions at Month 7.

    Administration of Gardasil 9 to Individuals Previously Vaccinated with Gardasil

    • Study 4 evaluated the immunogenicity of 3 doses of Gardasil 9 in 921 girls and women (12 through 26 years of age) who had previously been vaccinated with 3 doses of Gardasil.

    • Seropositivity to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in the per protocol population ranged from 98.3 to 100% by Month 7 in individuals who received Gardasil 9.

    • The anti-HPV 31, 33, 45, 52 and 58 GMTs for the population previously vaccinated with Gardasil were 25-63% of the GMTs in the combined populations from Studies 1, 2, 3, and 5, who had not previously received Gardasil, although the clinical relevance of these differences is unknown.

    Concomitant Use of Hormonal Contraceptives

    • Among 7,269 female recipients of Gardasil 9 (16 through 26 years of age), 60.2% used hormonal contraceptives during the vaccination period of clinical studies 1 and 2. Use of hormonal contraceptives did not appear to affect the type specific immune responses to Gardasil 9.

    Immune Responses to Gardasil 9 Using a 2-Dose Regimen in Individuals 9 through 14 Years of Age 

    • The efficacy of Gardasil 9 against persistent infection and disease related to vaccine HPV types in 9- through 14-year-old girls and boys who received a 2-dose regimen was inferred from non-inferiority comparison conducted in the PPI population in Study 8 of GMTs following vaccination with Gardasil 9 among 9- through 14-year-old girls and boys who received a 2-dose regimen (at 0, 6 months or 0, 12 months) with those among 16- through 26-year-old girls and women who received a 3-dose regimen (at 0, 2, 6 months).

    • Anti-HPV GMTs at one month after the last dose among 9- through 14-year-old girls and boys who received 2 doses of Gardasil 9 were non-inferior to anti-HPV GMTs among 16- through 26- year-old girls and women who received 3 doses of Gardasil 9.

    • One month following the last dose of the assigned regimen, between 97.9% and 100% of subjects across all groups became seropositive for antibodies against the 9 vaccine HPV types. 

    • In the same study, in girls and boys 9 through 14 years old, GMTs at one month after the last vaccine dose were numerically lower for some vaccine types after a 2-dose schedule than in girls 9 through 14 years old after a 3-dose schedule (HPV types 18, 31, 45, and 52 after 0, 6 months and HPV type 45 after 0, 12 months). The clinical relevance of these findings is unknown. Duration of immunity of a 2-dose schedule of Gardasil 9 has not been established.

    Studies with Menactra and Adacel 

    • Study 5 evaluated the safety and immunogenicity of concomitant administration of Gardasil 9 with Menactra and Adacel in 1237 boys and girls 11 through 15 years of age at enrollment.

    • The antibody response to any of the vaccines were not affected with the concomitant administration of Gardasil 9 with Menactra and Adacel.

    Gardasil 9 Note

    Notes

    Register pregnant patients exposed to Gardasil 9 by calling (800) 986-8999.

    Gardasil 9 Patient Counseling

    Patient Counseling

    Inform the patient, parent, or guardian: 

    • Vaccination does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening. Women who receive Gardasil 9 should continue to undergo cervical cancer screening per standard of care. 

    • Recipients of Gardasil 9 should not discontinue anal cancer screening if it has been recommended by a health care provider. 

    • Gardasil 9 has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a person has previously been exposed through sexual activity. 

    • Since syncope has been reported following HPV vaccination sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. 

    • Vaccine information is required to be given with each vaccination to the patient, parent, or guardian. 

    • Provide information regarding benefits and risks associated with vaccination. 

    • Safety and effectiveness of Gardasil 9 have not been established in pregnant women. A pregnancy registry is available. Women exposed to Gardasil 9 around the time of conception or during pregnancy are encouraged to register by calling 1-800-986-8999.

    • It is important to complete the full vaccination series unless contraindicated. 

    • Report any adverse reactions to their health care provider. 

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