GARDASIL 9: Package Insert and Label Information

GARDASIL 9- human papillomavirus type 6 l1 capsid protein antigen, human papillomavirus type 11 l1 capsid protein antigen, human papillomavirus type 16 l1 capsid protein antigen, human papillomavirus type 18 l1 capsid protein antigen, human papillomavirus type 31 l1 capsid protein antigen, human papillomavirus type 33 l1 capsid protein antigen, human papillomavirus type 45 l1 capsid protein antigen, human papillomavirus type 52 l1 capsid protein antigen and human papillomavirus type 58 l1 capsid protein antigen injection, suspension
A-S Medication Solutions

1 INDICATIONS AND USAGE

1.1 Girls and Women

GARDASIL® 9 is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases:

  • Cervical, vulvar, vaginal, and anal cancer caused by Human Papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58
  • Genital warts (condyloma acuminata) caused by HPV types 6 and 11

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:

  • Cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ (AIS)
  • Cervical intraepithelial neoplasia (CIN) grade 1
  • Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
  • Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
  • Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3

1.2 Boys and Men

GARDASIL 9 is indicated in boys and men 9 through 26 years of age for the prevention of the following diseases:

  • Anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58
  • Genital warts (condyloma acuminata) caused by HPV types 6 and 11

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:

  • Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3

1.3 Limitations of Use and Effectiveness

The health care provider should inform the patient, parent, or guardian that 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. [See Patient Counseling Information (17).]

Recipients of GARDASIL 9 should not discontinue anal cancer screening if it has been recommended by a health care provider [see Patient Counseling Information (17)].

GARDASIL 9 has not been demonstrated to provide protection against disease from vaccine HPV types to which a person has previously been exposed through sexual activity.

GARDASIL 9 has not been demonstrated to protect against diseases due to HPV types other than 6, 11, 16, 18, 31, 33, 45, 52, and 58.

GARDASIL 9 is not a treatment for external genital lesions; cervical, vulvar, vaginal, and anal cancers; CIN; VIN; VaIN; or AIN.

Not all vulvar, vaginal, and anal cancers are caused by HPV, and GARDASIL 9 protects only against those vulvar, vaginal, and anal cancers caused by HPV 16, 18, 31, 33, 45, 52, and 58.

GARDASIL 9 does not protect against genital diseases not caused by HPV.

Vaccination with GARDASIL 9 may not result in protection in all vaccine recipients.

Safety and effectiveness of GARDASIL 9 have not been assessed in individuals older than 26 years of age.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

Each dose of GARDASIL 9 is 0.5-mL.

Administer GARDASIL 9 as follows:

Age Regimen Schedule
*
If the second dose is administered earlier than 5 months after the first dose, administer a third dose at least 4 months after the second dose. [See Clinical Studies (14.2 and 14.5).]
9 through 14 years 2-dose 0, 6 to 12 months *
3-dose 0, 2, 6 months
15 through 26 years 3-dose 0, 2, 6 months

2.2 Method of Administration

For intramuscular use only.

Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. GARDASIL 9 should not be diluted or mixed with other vaccines. After thorough agitation, GARDASIL 9 is a white, cloudy liquid. Parenteral drug products should be inspected visually 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 GARDASIL 9 intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.

Observe patients for 15 minutes after administration [see Warnings and Precautions (5)].

Single-Dose Vial Use

Withdraw the 0.5-mL dose of vaccine from the single-dose vial using a sterile needle and syringe and use promptly.

Prefilled Syringe Use

This package does not contain a needle. Shake well before use. Attach a needle by twisting in a clockwise direction until the needle fits securely on the syringe. Administer the entire dose as per standard protocol.

2.3 Administration of GARDASIL 9 in Individuals Who Have Been Previously Vaccinated with GARDASIL®

Safety and immunogenicity were assessed in individuals who completed a three-dose vaccination series with GARDASIL 9 and had previously completed a three-dose vaccination series with GARDASIL [see Adverse Reactions (6.1) and Clinical Studies (14.4)]. Studies using a mixed regimen of HPV vaccines to assess interchangeability were not performed for GARDASIL 9.

3 DOSAGE FORMS AND STRENGTHS

GARDASIL 9 is a suspension for intramuscular administration available in 0.5-mL single-dose vials and prefilled syringes. See Description (11) for the complete listing of ingredients.

4 CONTRAINDICATIONS

Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of GARDASIL 9 or GARDASIL [see Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Syncope

Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following HPV vaccination. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position.

5.2 Managing Allergic Reactions

Appropriate medical treatment and supervision must be readily available in case of anaphylactic reactions following the administration of GARDASIL 9.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

The safety of GARDASIL 9 was evaluated in seven clinical studies that included 15,703 individuals who received at least one dose of GARDASIL 9 and had safety follow-up. Study 1 and Study 3 also included 7,378 individuals who received at least one dose of GARDASIL as a control and had safety follow-up. The vaccines were administered on the day of enrollment and the subsequent doses administered approximately two and six months thereafter. Safety was evaluated using vaccination report card (VRC)-aided surveillance for 14 days after each injection of GARDASIL 9 or GARDASIL.

The individuals who were monitored using VRC-aided surveillance included 9,097 girls and women 16 through 26 years of age, 1,394 boys and men 16 through 26 years of age, and 5,212 girls and boys 9 through 15 years of age (3,436 girls and 1,776 boys) at enrollment who received GARDASIL 9; and 7,078 girls and women 16 through 26 years of age and 300 girls 9 through 15 years of age at enrollment who received GARDASIL. The race distribution of the integrated safety population for GARDASIL 9 was similar between girls and women 16 through 26 years of age (56.8% White; 25.2% Other Races or Multiracial; 14.1% Asian; 3.9% Black), girls and boys 9 through 15 years of age (62.0% White; 19.2% Other Races or Multiracial; 13.5% Asian; 5.4% Black), and boys and men 16 through 26 years of age (62.1% White; 22.6% Other Races or Multiracial; 9.8% Asian; 5.5% Black). The safety of GARDASIL 9 was compared directly to the safety of GARDASIL in two studies (Study 1 and Study 3) for which the overall race distribution of the GARDASIL cohorts (57.0% White; 26.3% Other Races or Multiracial; 13.6% Asian; 3.2% Black) was similar to that of the GARDASIL 9 cohorts.

Injection-Site and Systemic Adverse Reactions

Injection-site reactions (pain, swelling, and erythema) and oral temperature were solicited using VRC-aided surveillance for five days after each injection of GARDASIL 9 during the clinical studies. The rates and severity of these solicited adverse reactions that occurred within five days following each dose of GARDASIL 9 compared with GARDASIL in Study 1 (girls and women 16 through 26 years of age) and Study 3 (girls 9 through 15 years of age) are presented in Table 1. Among subjects who received GARDASIL 9, the rates of injection-site pain were approximately equal across the three reporting time periods. Rates of injection-site swelling and injection-site erythema increased following each successive dose of GARDASIL 9. Recipients of GARDASIL 9 had numerically higher rates of injection-site reactions compared with recipients of GARDASIL.

Table 1: Rates (%) and Severity of Solicited Injection-Site and Systemic Adverse Reactions Occurring within Five Days of Each Vaccination with GARDASIL 9 Compared with GARDASIL (Studies 1 and 3)
GARDASIL 9 GARDASIL
Post-dose 1 Post-dose 2 Post-dose 3 Post any dose Post-dose 1 Post-dose 2 Post-dose 3 Post any dose
The data for girls and women 16 through 26 years of age are from Study 1 (NCT00543543), and the data for girls 9 through 15 years of age are from Study 3 (NCT01304498).
N=number of subjects vaccinated with safety follow-up
n=number of subjects with temperature data
Pain, Any=mild, moderate, severe or unknown intensity
Pain, Severe=incapacitating with inability to work or do usual activity
Swelling, Any=any size or size unknown
Swelling, Severe=maximum size greater than 2 inches
Erythema, Any=any size or size unknown
Erythema, Severe=maximum size greater than 2 inches
Girls and Women 16 through 26 Years of Age
Injection-Site Adverse Reactions N=7069 N=6997 N=6909 N=7071 N=7076 N=6992 N=6909 N=7078
Pain, Any 70.7 73.5 71.6 89.9 58.2 62.2 62.6 83.5
Pain, Severe 0.7 1.7 2.6 4.3 0.4 1.0 1.7 2.6
Swelling, Any 12.5 23.3 28.3 40.0 9.3 14.6 18.7 28.8
Swelling, Severe 0.6 1.5 2.5 3.8 0.3 0.5 1.0 1.5
Erythema, Any 10.6 18.0 22.6 34.0 8.1 12.9 15.6 25.6
Erythema, Severe 0.2 0.5 1.1 1.6 0.2 0.2 0.4 0.8
Systemic Adverse Reactions n=6995 n=6913 n=6743 n=7022 n=7003 n=6914 n=6725 n=7024
Temperature ≥100°F 1.7 2.6 2.7 6.0 1.7 2.4 2.5 5.9
Temperature ≥102°F 0.3 0.3 0.4 1.0 0.2 0.3 0.3 0.8
Girls 9 through 15 Years of Age
Injection-Site Adverse Reactions N=300 N=297 N=296 N=299 N=299 N=299 N=294 N=300
Pain, Any 71.7 71.0 74.3 89.3 66.2 66.2 69.4 88.3
Pain, Severe 0.7 2.0 3.0 5.7 0.7 1.3 1.7 3.3
Swelling, Any 14.0 23.9 36.1 47.8 10.4 17.7 25.2 36.0
Swelling, Severe 0.3 2.4 3.7 6.0 0.7 2.7 4.1 6.3
Erythema, Any 7.0 15.5 21.3 34.1 9.7 14.4 18.4 29.3
Erythema, Severe 0 0.3 1.4 1.7 0 0.3 1.7 2.0
Systemic Adverse Reactions n=300 n=294 n=295 n=299 n=299 n=297 n=291 n=300
Temperature ≥100°F 2.3 1.7 3.0 6.7 1.7 1.7 0 3.3
Temperature ≥102°F 0 0.3 1.0 1.3 0.3 0.3 0 0.7

Unsolicited injection-site and systemic adverse reactions (assessed as vaccine-related by the investigator) observed among recipients of either GARDASIL 9 or GARDASIL in Studies 1 and 3 at a frequency of at least 1% are shown in Table 2. Few individuals discontinued study participation due to adverse experiences after receiving either vaccine (GARDASIL 9 = 0.1% vs. GARDASIL <0.1%).

Table 2: Rates (%) of Unsolicited Injection-Site and Systemic Adverse Reactions Occurring among ≥1.0% of Individuals after Any Vaccination with GARDASIL 9 Compared with GARDASIL (Studies 1 and 3)
Girls and Women 16 through 26 Years of Age Girls 9 through 15 Years of Age
GARDASIL 9N=7071 GARDASILN=7078 GARDASIL 9N=299 GARDASILN=300
The data for girls and women 16 through 26 years of age are from Study 1 (NCT00543543), and the data for girls 9 through 15 years of age are from Study 3 (NCT01304498).
N=number of subjects vaccinated with safety follow-up
Injection-Site Adverse Reactions (1 to 5 Days Post-Vaccination, Any Dose)
Pruritus 5.5 4.0 4.0 2.7
Bruising 1.9 1.9 0 0
Hematoma 0.9 0.6 3.7 4.7
Mass 1.3 0.6 0 0
Hemorrhage 1.0 0.7 1.0 2.0
Induration 0.8 0.2 2.0 1.0
Warmth 0.8 0.5 0.7 1.7
Reaction 0.6 0.6 0.3 1.0
Systemic Adverse Reactions (1 to 15 Days Post-Vaccination, Any Dose)
Headache 14.6 13.7 11.4 11.3
Pyrexia 5.0 4.3 5.0 2.7
Nausea 4.4 3.7 3.0 3.7
Dizziness 3.0 2.8 0.7 0.7
Fatigue 2.3 2.1 0 2.7
Diarrhea 1.2 1.0 0.3 0
Oropharyngeal pain 1.0 0.6 2.7 0.7
Myalgia 1.0 0.7 0.7 0.7
Abdominal pain, upper 0.7 0.8 1.7 1.3
Upper respiratory tract infection 0.1 0.1 0.3 1.0

In an uncontrolled clinical trial with 639 boys and 1,878 girls 9 through 15 years of age (Study 2), the rates and severity of solicited adverse reactions following each dose of GARDASIL 9 were similar between boys and girls. Rates of solicited and unsolicited injection-site and systemic adverse reactions in boys 9 through 15 years of age were similar to those among girls 9 through 15 years of age. Solicited and unsolicited adverse reactions reported by boys in this study are shown in Table 3.

In another uncontrolled clinical trial with 1,394 boys and men and 1,075 girls and women 16 through 26 years of age (Study 7), the rates of solicited and unsolicited adverse reactions following each dose of GARDASIL 9 among girls and women 16 through 26 years of age were similar to those reported in Study 1. Rates of solicited and unsolicited adverse reactions reported by boys and men 16 through 26 years of age in this study are shown in Table 3.

Table 3: Rates (%) of Solicited and Unsolicited * Injection-Site and Systemic Adverse Reactions among Boys 9 through 15 Years of Age and among Boys and Men 16 through 26 Years of Age Who Received GARDASIL 9 (Studies 2 and 7)
GARDASIL 9
The data for GARDASIL 9 boys 9 through 15 years of age are from Study 2 (NCT00943722). The data for boys and men 16 through 26 years of age for GARDASIL 9 are from Study 7 (NCT01651949).
N=number of subjects vaccinated with safety follow-up
Pain, Any=mild, moderate, severe or unknown intensity
Pain, Severe=incapacitating with inability to work or do usual activity
Swelling, Any=any size or size unknown
Swelling, Severe=maximum size greater than 2 inches
Erythema, Any=any size or size unknown
Erythema, Severe=maximum size greater than 2 inches
*
Unsolicited adverse reactions reported by ≥1% of individuals
For oral temperature: number of subjects with temperature data for boys 9 through 15 years of age N=637; for boys and men 16 through 26 years of age N=1,386
Boys and Men 16 through 26 Years of Age N=1394
Solicited Adverse Reactions (1-5 Days Post-Vaccination, Any Dose)
Injection-Site Pain, Any 63.4
Injection-Site Pain, Severe 0.6
Injection-Site Erythema, Any 20.7
Injection-Site Erythema, Severe 0.4
Injection-Site Swelling, Any 20.2
Injection-Site Swelling, Severe 1.1
Oral Temperature ≥100.0°F 4.4
Oral Temperature ≥102°F 0.6
Unsolicited Injection-Site Adverse Reactions (1-5 Days Post-Vaccination, Any Dose)
Injection-Site Hypersensitivity 1.0
Injection-Site Pruritus 1.0
Unsolicited Systemic Adverse Reactions (1-15 Days Post-Vaccination, Any Dose)
Headache 7.3
Pyrexia 2.4
Fatigue 1.4
Dizziness 1.1
Nausea 1.0
Boys 9 through 15 Years of Age N=639
Solicited Adverse Reactions (1-5 Days Post-Vaccination, Any Dose)
Injection-Site Pain, Any 71.5
Injection-Site Pain, Severe 0.5
Injection-Site Erythema, Any 24.9
Injection-Site Erythema, Severe 1.9
Injection-Site Swelling, Any 26.9
Injection-Site Swelling, Severe 5.2
Oral Temperature ≥100.0°F 10.4
Oral Temperature ≥102°F 1.4
Unsolicited Injection-Site Adverse Reactions (1-5 Days Post-Vaccination, Any Dose)
Injection-Site Hematoma 1.3
Injection-Site Induration 1.1
Unsolicited Systemic Adverse Reactions (1-15 Days Post-Vaccination, Any Dose)
Headache 9.4
Pyrexia 8.9
Nausea 1.3

Serious Adverse Events in Clinical Studies

Serious adverse events were collected throughout the entire study period (range one month to 48 months post-last dose) for the seven clinical studies for GARDASIL 9. Out of the 15,705 individuals who were administered GARDASIL 9 and had safety follow-up, 354 reported a serious adverse event; representing 2.3% of the population. As a comparison, of the 7,378 individuals who were administered GARDASIL and had safety follow-up, 185 reported a serious adverse event; representing 2.5% of the population. Four GARDASIL 9 recipients each reported at least one serious adverse event that was determined to be vaccine-related. The vaccine-related serious adverse reactions were pyrexia, allergy to vaccine, asthmatic crisis, and headache.

Deaths in the Entire Study Population

Across the clinical studies, ten deaths occurred (five each in the GARDASIL 9 and GARDASIL groups); none were assessed as vaccine-related. Causes of death in the GARDASIL 9 group included one automobile accident, one suicide, one case of acute lymphocytic leukemia, one case of hypovolemic septic shock, and one unexplained sudden death 678 days following the last dose of GARDASIL 9. Causes of death in the GARDASIL control group included one automobile accident, one airplane crash, one cerebral hemorrhage, one gunshot wound, and one stomach adenocarcinoma.

Systemic Autoimmune Disorders

In all of the clinical trials with GARDASIL 9 subjects were evaluated for new medical conditions potentially indicative of a systemic autoimmune disorder. In total, 2.2% (351/15,703) of GARDASIL 9 recipients and 3.3% (240/7,378) of GARDASIL recipients reported new medical conditions potentially indicative of systemic autoimmune disorders, which were similar to rates reported following GARDASIL, AAHS control, or saline placebo in historical clinical trials.

Clinical Trials Experience for GARDASIL 9 in Individuals Who Have Been Previously Vaccinated with GARDASIL

A clinical study (Study 4) evaluated the safety of GARDASIL 9 in 12- through 26-year-old girls and women who had previously been vaccinated with three doses of GARDASIL. The time interval between the last injection of GARDASIL and the first injection of GARDASIL 9 ranged from approximately 12 to 36 months. Individuals were administered GARDASIL 9 or saline placebo and safety was evaluated using VRC-aided surveillance for 14 days after each injection of GARDASIL 9 or saline placebo in these individuals. The individuals who were monitored included 608 individuals who received GARDASIL 9 and 305 individuals who received saline placebo. Few (0.5%) individuals who received GARDASIL 9 discontinued due to adverse reactions. The vaccine-related adverse experiences that were observed among recipients of GARDASIL 9 at a frequency of at least 1.0% and also at a greater frequency than that observed among saline placebo recipients are shown in Table 4. Overall the safety profile was similar between individuals vaccinated with GARDASIL 9 who were previously vaccinated with GARDASIL and those who were naïve to HPV vaccination with the exception of numerically higher rates of injection-site swelling and erythema among individuals who were previously vaccinated with GARDASIL (Tables 1 and 4).

Table 4: Rates (%) of Solicited and Unsolicited * Injection-Site and Systemic Adverse Reactions among Individuals Previously Vaccinated with GARDASIL Who Received GARDASIL 9 or Saline Placebo (Girls and Women 12 through 26 Years of Age) (Study 4)
GARDASIL 9 N=608 Saline PlaceboN=305
The data for GARDASIL 9 and saline placebo are from Study 4 (NCT01047345).
N=number of subjects vaccinated with safety follow-up
*
Unsolicited adverse reactions reported by ≥1% of individuals
For oral temperature: number of subjects with temperature data GARDASIL 9 N=604; Saline Placebo N=304
Solicited Adverse Reactions (1-5 Days Post-Vaccination, Any Dose)
Injection-Site Pain 90.3 38.0
Injection-Site Erythema 42.3 8.5
Injection-Site Swelling 49.0 5.9
Oral Temperature ≥100.0°F 6.5 3.0
Unsolicited Injection-Site Adverse Reactions (1-5 Days Post-Vaccination, Any Dose)
Injection-Site Pruritus 7.7 1.3
Injection-Site Hematoma 4.8 2.3
Injection-Site Reaction 1.3 0.3
Injection-Site Mass 1.2 0.7
Unsolicited Systemic Adverse Reactions (1-15 Days Post-Vaccination, Any Dose)
Headache 19.6 18.0
Pyrexia 5.1 1.6
Nausea 3.9 2.0
Dizziness 3.0 1.6
Abdominal pain, upper 1.5 0.7
Influenza 1.2 1.0

Safety in Concomitant Use with Menactra and Adacel

In Study 5, the safety of GARDASIL 9 when administered concomitantly with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] was evaluated in a randomized study of 1,241 boys (n = 620) and girls (n = 621) with a mean age of 12.2 years [see Clinical Studies (14.6)].

Of the 1,237 boys and girls vaccinated, 1,220 had safety follow-up for injection-site adverse reactions. The rates of injection-site adverse reactions were similar between the concomitant group and non-concomitant group (vaccination with GARDASIL 9 separated from vaccination with Menactra and Adacel by 1 month) with the exception of an increased rate of swelling reported at the injection site for GARDASIL 9 in the concomitant group (14.4%) compared to the non-concomitant group (9.4%). The majority of injection-site swelling adverse reactions were reported as being mild to moderate in intensity.

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