Gardasil

Jul 24, 2022

Generic name:  human papillomavirus quadrivalent  (types 6, 11, 16, and 18) vaccine, recombinant
Dosage form: injection, suspension
Drug class:  Viral vaccines

Indications and Usage for Gardasil

Girls and Women

Gardasil® is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine:

  • 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 the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:

  • 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

Boys and Men

Gardasil is indicated in boys and men 9 through 26 years of age for the prevention of the following diseases caused by HPV types included in the vaccine:

  • Anal cancer caused by HPV types 16 and 18
  • 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, and 18:

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

Limitations of Gardasil 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 should continue to undergo cervical cancer screening per standard of care. [See  Patient Counseling Information (17) .]

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

Gardasil 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. [See  Clinical Studies (14.4 ,  14.5) .]

Gardasil is not intended to be used for treatment of active external genital lesions; cervical, vulvar, vaginal, and anal cancers; CIN; VIN; VaIN; or AIN.

Gardasil has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. [See  Clinical Studies (14.4 ,  14.5) .]

Not all vulvar, vaginal, and anal cancers are caused by HPV, and Gardasil protects only against those vulvar, vaginal, and anal cancers caused by HPV 16 and 18.

Gardasil does not protect against genital diseases not caused by HPV.

Vaccination with Gardasil may not result in protection in all vaccine recipients.

Gardasil has not been demonstrated to prevent HPV-related CIN 2/3 or worse in women older than 26 years of age. [See  Clinical Studies (14.7) .]

Gardasil Dosage and Administration

Dosage

Gardasil should be administered intramuscularly as a 0.5-mL dose at the following schedule: 0, 2 months, 6 months. [See  Clinical Studies (14.8) .]

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 should not be diluted or mixed with other vaccines. After thorough agitation, Gardasil is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the product if particulates are present or if it appears discolored.

Gardasil should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.

Syncope has been reported following vaccination with Gardasil and may result in falling with injury; observation for 15 minutes after administration is recommended. [See  Warnings and Precautions (5.1) .]

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 the needle by twisting in a clockwise direction until the needle fits securely on the syringe. Administer the entire dose as per standard protocol.

Dosage Forms and Strengths

Gardasil 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.

Contraindications

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

Warnings and Precautions

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 vaccination with Gardasil. 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.

Managing Allergic Reactions

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

Adverse Reactions

Overall Summary of Adverse Reactions

Headache, fever, nausea, and dizziness; and local injection site reactions (pain, swelling, erythema, pruritus, and bruising) occurred after administration with Gardasil.

Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with Gardasil and may result in falling with injury; observation for 15 minutes after administration is recommended. [See  Warnings and Precautions (5.1) .]

Anaphylaxis has been reported following vaccination with Gardasil.

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.

Studies in Girls and Women (9 Through 45 Years of Age) and Boys and Men (9 Through 26 Years of Age)

In 7 clinical trials (5 Amorphous Aluminum Hydroxyphosphate Sulfate [AAHS]-controlled, 1 saline placebo-controlled, and 1 uncontrolled), 18,083 individuals were administered Gardasil or AAHS control or saline placebo on the day of enrollment, and approximately 2 and 6 months thereafter, and safety was evaluated using vaccination report cards (VRC)-aided surveillance for 14 days after each injection of Gardasil or AAHS control or saline placebo in these individuals. The individuals who were monitored using VRC-aided surveillance included 10,088 individuals 9 through 45 years of age at enrollment who received Gardasil and 7,995 individuals who received AAHS control or saline placebo. Few individuals (0.2%) discontinued due to adverse reactions. The race distribution of the 9- through 26-year-old girls and women in the safety population was as follows: 62.3% White; 17.6% Hispanic (Black and White); 6.8% Asian; 6.7% Other; 6.4% Black; and 0.3% American Indian. The race distribution of the 24- through 45-year-old women in the safety population of Study 6 was as follows: 20.6% White; 43.2% Hispanic (Black and White); 0.2% Other; 4.8% Black; 31.2% Asian; and 0.1% American Indian. The race distribution of the 9- through 26-year-old boys and men in the safety population was as follows: 42.0% White; 19.7% Hispanic (Black and White); 11.0% Asian; 11.2% Other; 15.9% Black; and 0.1% American Indian.

Common Injection-Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age

The injection site adverse reactions that were observed among recipients of Gardasil at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 1.

Adverse Reaction
(1 to 5 Days Postvaccination)
Gardasil
(N = 5088)
%
AAHS Control †
(N = 3470)
%
Saline Placebo
(N = 320)
%
Injection Site
Pain83.975.448.6
Swelling25.415.87.3
Erythema24.718.412.1
Pruritus3.22.80.6
Bruising2.83.21.6
* The injection-site adverse reactions that were observed among recipients of Gardasil were at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients. † AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Common Injection-Site Adverse Reactions in Boys and Men 9 Through 26 Years of Age

The injection site adverse reactions that were observed among recipients of Gardasil at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 2.

Adverse Reaction
(1 to 5 Days Postvaccination)
Gardasil
(N = 3093)
%
AAHS Control †
(N = 2029)
%
Saline Placebo
(N = 274)
%
Injection Site
Pain61.450.841.6
Erythema16.714.114.5
Swelling13.99.68.2
Hematoma1.00.33.3
* The injection-site adverse reactions that were observed among recipients of Gardasil were at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients. † AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Evaluation of Injection-Site Adverse Reactions by Dose in Girls and Women 9 Through 26 Years of Age

An analysis of injection-site adverse reactions in girls and women by dose is shown in Table 3. Of those girls and women who reported an injection-site reaction, 94.3% judged their injection-site adverse reaction to be mild or moderate in intensity.

Gardasil
(% occurrence)
AAHS Control *
(% occurrence)
Saline Placebo
(% occurrence)
Adverse ReactionPost-dose 1
N †  = 5011
Post-dose 2
N = 4924
Post-dose 3
N = 4818
Post-dose 1
N = 3410
Post-dose 2
N = 3351
Post-dose 3
N = 3295
Post-dose 1
N = 315
Post-dose 2
N = 301
Post-dose 3
N = 300
Pain63.460.762.757.047.849.633.720.327.3
Mild/Moderate62.559.761.256.647.348.933.320.327.0
Severe0.91.01.50.40.50.60.30.00.3
Swelling ‡ 10.212.815.18.27.57.64.43.03.3
Mild/Moderate9.611.914.28.17.27.34.43.03.3
Severe0.60.80.90.20.20.20.00.00.0
Erythema ‡ 9.212.114.79.88.48.97.35.35.7
Mild/Moderate9.011.714.39.58.48.87.35.35.7
Severe0.20.30.40.30.10.10.00.00.0
* AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † N = Number of individuals with follow-up ‡ Intensity of swelling and erythema was measured by size (inches): Mild = 0 to ≤1; Moderate = >1 to ≤2; Severe = >2.

Evaluation of Injection-Site Adverse Reactions by Dose in Boys and Men 9 Through 26 Years of Age

An analysis of injection-site adverse reactions in boys and men by dose is shown in Table 4. Of those boys and men who reported an injection-site reaction, 96.4% judged their injection-site adverse reaction to be mild or moderate in intensity.

Gardasil
(% occurrence)
AAHS Control *
(% occurrence)
Saline Placebo
(% occurrence)
Adverse ReactionPost-dose 1
N †  = 3003
Post-dose 2
N = 2898
Post-dose 3
N = 2826
Post-dose 1
N = 1950
Post-dose 2
N = 1854
Post-dose 3
N = 1799
Post-dose 1
N = 269
Post-dose 2
N = 263
Post-dose 3
N = 259
Pain44.736.934.438.428.225.827.520.516.2
Mild/Moderate44.536.434.137.928.225.527.520.216.2
Severe0.20.50.30.40.10.30.00.40.0
Swelling ‡ 5.66.67.75.64.54.14.81.53.5
Mild/Moderate5.36.27.15.44.54.04.81.53.1
Severe0.20.30.50.20.00.10.00.00.4
Erythema ‡ 7.28.08.78.36.35.77.15.75.0
Mild/Moderate6.87.78.38.06.25.67.15.75.0
Severe0.30.20.30.20.10.10.00.00.0
* AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † N = Number of individuals with follow-up ‡ Intensity of swelling and erythema was measured by size (inches): Mild = 0 to ≤1; Moderate = >1 to ≤2; Severe = >2.

Common Systemic Adverse Reactions in Girls and Women 9 Through 26 Years of Age

Headache was the most commonly reported systemic adverse reaction in both treatment groups (Gardasil = 28.2% and AAHS control or saline placebo = 28.4%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (Gardasil = 13.0% and AAHS control or saline placebo = 11.2%).

Adverse reactions that were observed among recipients of Gardasil, at a frequency of greater than or equal to 1.0% where the incidence in the Gardasil group was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 5.

Adverse Reactions
(1 to 15 Days Postvaccination)
Gardasil
(N = 5088)
%
AAHS Control †  or Saline Placebo
(N = 3790)
%
Pyrexia13.011.2
Nausea6.76.5
Dizziness4.03.7
Diarrhea3.63.5
Vomiting2.41.9
Cough2.01.5
Toothache1.51.4
Upper respiratory tract infection1.51.5
Malaise1.41.2
Arthralgia1.20.9
Insomnia1.20.9
Nasal congestion1.10.9
* The adverse reactions in this table are those that were observed among recipients of Gardasil at a frequency of at least 1.0% and greater than or equal to those observed among AAHS control or saline placebo recipients. † AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Common Systemic Adverse Reactions in Boys and Men 9 Through 26 Years of Age

Headache was the most commonly reported systemic adverse reaction in both treatment groups (Gardasil = 12.3% and AAHS control or saline placebo = 11.2%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (Gardasil = 8.3% and AAHS control or saline placebo = 6.5%).

Adverse reactions that were observed among recipients of Gardasil, at a frequency of greater than or equal to 1.0% where the incidence in the group that received Gardasil was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 6.

Adverse Reactions
(1 to 15 Days Postvaccination)
Gardasil
(N = 3093)
%
AAHS Control †  or Saline Placebo
(N = 2303)
%
Headache12.311.2
Pyrexia8.36.5
Oropharyngeal pain2.82.1
Diarrhea2.72.2
Nasopharyngitis2.62.6
Nausea2.01.0
Upper respiratory tract infection1.51.0
Abdominal pain upper1.41.4
Myalgia1.30.7
Dizziness1.20.9
Vomiting1.00.8
* The adverse reactions in this table are those that were observed among recipients of Gardasil at a frequency of at least 1.0% and greater than or equal to those observed among AAHS control or saline placebo recipients. † AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Evaluation of Fever by Dose in Girls and Women 9 Through 26 Years of Age

An analysis of fever in girls and women by dose is shown in Table 7.

Gardasil
(% occurrence)
AAHS Control *  or Saline Placebo
(% occurrence)
Temperature
(°F)
Postdose 1
N †  = 4945
Postdose 2
N = 4804
Postdose 3
N = 4671
Postdose 1
N = 3681
Postdose 2
N = 3564
Postdose 3
N = 3467
≥100 to <1023.74.14.43.13.83.6
≥1020.30.50.50.20.40.5
* AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † N = Number of individuals with follow-up

Evaluation of Fever by Dose in Boys and Men 9 Through 26 Years of Age

An analysis of fever in boys and men by dose is shown in Table 8.

Gardasil
(% occurrence)
AAHS Control *  or Saline Placebo
(% occurrence)
Temperature
(°F)
Postdose 1
N †  = 2972
Postdose 2
N = 2849
Postdose 3
N = 2792
Postdose 1
N = 2194
Postdose 2
N = 2079
Postdose 3
N = 2046
≥100 to <1022.42.52.32.12.21.6
≥1020.60.50.50.50.30.3
* AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † N = Number of individuals with follow-up

Serious Adverse Reactions in the Entire Study Population

Across the clinical studies, 258 individuals (Gardasil N = 128 or 0.8%; placebo N = 130 or 1.0%) out of 29,323 (Gardasil N = 15,706; AAHS control N = 13,023; or saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men) reported a serious systemic adverse reaction.

Of the entire study population (29,323 individuals), 0.04% of the reported serious systemic adverse reactions were judged to be vaccine related by the study investigator. The most frequently (frequency of 4 cases or greater with either Gardasil, AAHS control, saline placebo, or the total of all three) reported serious systemic adverse reactions, regardless of causality, were:

Headache [0.02% Gardasil (3 cases) vs. 0.02% AAHS control (2 cases)],
Gastroenteritis [0.02% Gardasil (3 cases) vs. 0.02% AAHS control (2 cases)],
Appendicitis [0.03% Gardasil (5 cases) vs. 0.01% AAHS control (1 case)],
Pelvic inflammatory disease [0.02% Gardasil (3 cases) vs. 0.03% AAHS control (4 cases)],
Urinary tract infection [0.01% Gardasil (2 cases) vs. 0.02% AAHS control (2 cases)],
Pneumonia [0.01% Gardasil (2 cases) vs. 0.02% AAHS control (2 cases)],
Pyelonephritis [0.01% Gardasil (2 cases) vs. 0.02% AAHS control (3 cases)],
Pulmonary embolism [0.01% Gardasil (2 cases) vs. 0.02% AAHS control (2 cases)].

One case (0.006% Gardasil; 0.0% AAHS control or saline placebo) of bronchospasm; and 2 cases (0.01% Gardasil; 0.0% AAHS control or saline placebo) of asthma were reported as serious systemic adverse reactions that occurred following any vaccination visit.

In addition, there was 1 individual in the clinical trials, in the group that received Gardasil, who reported two injection-site serious adverse reactions (injection-site pain and injection-site joint movement impairment).

Deaths in the Entire Study Population

Across the clinical studies, 40 deaths (Gardasil N = 21 or 0.1%; placebo N = 19 or 0.1%) were reported in 29,323 (Gardasil N = 15,706; AAHS control N = 13,023, saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men). The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (5 individuals who received Gardasil and 4 individuals who received AAHS control), followed by drug overdose/suicide (2 individuals who received Gardasil and 6 individuals who received AAHS control), gunshot wound (1 individual who received Gardasil and 3 individuals who received AAHS control), and pulmonary embolus/deep vein thrombosis (1 individual who received Gardasil and 1 individual who received AAHS control). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, 1 case of arrhythmia, 1 case of pulmonary tuberculosis, 1 case of hyperthyroidism, 1 case of post-operative pulmonary embolism and acute renal failure, 1 case of traumatic brain injury/cardiac arrest, 1 case of systemic lupus erythematosus, 1 case of cerebrovascular accident, 1 case of breast cancer, and 1 case of nasopharyngeal cancer in the group that received Gardasil; 1 case of asphyxia, 1 case of acute lymphocytic leukemia, 1 case of chemical poisoning, and 1 case of myocardial ischemia in the AAHS control group; and 1 case of medulloblastoma in the saline placebo group.

Systemic Autoimmune Disorders in Girls and Women 9 Through 26 Years of Age

In the clinical studies, 9- through 26-year-old girls and women were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received Gardasil or AAHS control or saline placebo are shown in Table 9. This population includes all girls and women who received at least one dose of Gardasil or AAHS control or saline placebo, and had safety data available.

ConditionsGardasil
(N = 10,706)
AAHS Control *  or Saline Placebo
(N = 9412)
n (%)n (%)
Arthralgia/Arthritis/Arthropathy † 120 (1.1)98 (1.0)
Autoimmune Thyroiditis4 (0.0)1 (0.0)
Celiac Disease10 (0.1)6 (0.1)
Diabetes Mellitus Insulin-dependent2 (0.0)2 (0.0)
Erythema Nodosum2 (0.0)4 (0.0)
Hyperthyroidism ‡ 27 (0.3)21 (0.2)
Hypothyroidism § 35 (0.3)38 (0.4)
Inflammatory Bowel Disease ¶ 7 (0.1)10 (0.1)
Multiple Sclerosis2 (0.0)4 (0.0)
Nephritis # 2 (0.0)5 (0.1)
Optic Neuritis2 (0.0)0 (0.0)
Pigmentation Disorder Þ 4 (0.0)3 (0.0)
Psoriasis ß 13 (0.1)15 (0.2)
Raynaud’s Phenomenon3 (0.0)4 (0.0)
Rheumatoid Arthritis à 6 (0.1)2 (0.0)
Scleroderma/Morphea2 (0.0)1 (0.0)
Stevens-Johnson Syndrome1 (0.0)0 (0.0)
Systemic Lupus Erythematosus1 (0.0)3 (0.0)
Uveitis3 (0.0)1 (0.0)
All Conditions245 (2.3)218 (2.3)
N = Number of individuals enrolled
n = Number of individuals with specific new Medical Conditions
NOTE: Although an individual may have had two or more new Medical Conditions, the individual is counted only once within a category. The same individual may appear in different categories.
* AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † Arthralgia/Arthritis/Arthropathy includes the following terms: Arthralgia, Arthritis, Arthritis reactive, and Arthropathy ‡ Hyperthyroidism includes the following terms: Basedow’s disease, Goiter, Toxic nodular goiter, and Hyperthyroidism § Hypothyroidism includes the following terms: Hypothyroidism and thyroiditis ¶ Inflammatory bowel disease includes the following terms: Colitis ulcerative, Crohn’s disease, and Inflammatory bowel disease # Nephritis includes the following terms: Nephritis, Glomerulonephritis minimal lesion, Glomerulonephritis proliferative Þ Pigmentation disorder includes the following terms: Pigmentation disorder, Skin depigmentation, and Vitiligo ß Psoriasis includes the following terms: Psoriasis, Pustular psoriasis, and Psoriatic arthropathy à Rheumatoid arthritis includes juvenile rheumatoid arthritis. One woman counted in the rheumatoid arthritis group reported rheumatoid arthritis as an adverse experience at Day 130.

Systemic Autoimmune Disorders in Boys and Men 9 Through 26 Years of Age

In the clinical studies, 9- through 26-year-old boys and men were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received Gardasil or AAHS control or saline placebo are shown in Table 10. This population includes all boys and men who received at least one dose of Gardasil or AAHS control or saline placebo, and had safety data available.

ConditionsGardasil
(N = 3093)
AAHS Control *  or Saline Placebo
(N = 2303)
n (%)n (%)
Alopecia Areata2 (0.1)0 (0.0)
Ankylosing Spondylitis1 (0.0)2 (0.1)
Arthralgia/Arthritis/Reactive Arthritis30 (1.0)17 (0.7)
Autoimmune Thrombocytopenia1 (0.0)0 (0.0)
Diabetes Mellitus Type 13 (0.1)2 (0.1)
Hyperthyroidism0 (0.0)1 (0.0)
Hypothyroidism † 3 (0.1)0 (0.0)
Inflammatory Bowel Disease ‡ 1 (0.0)2 (0.1)
Myocarditis1 (0.0)1 (0.0)
Proteinuria1 (0.0)0 (0.0)
Psoriasis0 (0.0)4 (0.2)
Skin Depigmentation1 (0.0)0 (0.0)
Vitiligo2 (0.1)5 (0.2)
All Conditions46 (1.5)34 (1.5)
N = Number of individuals who received at least one dose of either vaccine or placebo
n = Number of individuals with specific new Medical Conditions
NOTE: Although an individual may have had two or more new Medical Conditions, the individual is counted only once within a category. The same individual may appear in different categories.
* AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † Hypothyroidism includes the following terms: Hypothyroidism and Autoimmune thyroiditis ‡ Inflammatory bowel disease includes the following terms: Colitis ulcerative and Crohn’s disease

Safety in Concomitant Use with RECOMBIVAX HB® [hepatitis B vaccine (recombinant)] in Girls and Women 16 Through 23 Years of Age

The safety of Gardasil when administered concomitantly with RECOMBIVAX HB® [hepatitis B vaccine (recombinant)] was evaluated in an AAHS-controlled study of 1871 girls and women with a mean age of 20.4 years [see  Clinical Studies (14.10) ]. The race distribution of the study individuals was as follows: 61.6% White; 23.8% Other; 11.9% Black; 1.6% Hispanic (Black and White); 0.8% Asian; and 0.3% American Indian. The rates of systemic and injection-site adverse reactions were similar among girls and women who received concomitant vaccination as compared with those who received Gardasil or RECOMBIVAX HB [hepatitis B vaccine (recombinant)].

Safety in Concomitant Use 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)]

The safety of Gardasil 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 1040 boys and girls with a mean age of 12.6 years [see  Clinical Studies (14.11) ]. The race distribution of the study subjects was as follows: 77.7% White; 1.4% Multi-racial; 12.3% Black; 6.8% Hispanic (Black and White); 1.2% Asian; 0.4% American Indian, and 0.2% Indian.

There was an increase in injection-site swelling reported at the injection site for Gardasil (concomitant = 10.9%, non-concomitant = 6.9%) when Gardasil was administered concomitantly with Menactra and Adacel as compared to non-concomitant (separated by 1 month) vaccination. The majority of injection-site swelling adverse experiences were reported as being mild to moderate in intensity.

Safety in Women 27 Through 45 Years of Age

The adverse reaction profile in women 27 through 45 years of age was comparable to the profile seen in girls and women 9 through 26 years of age.

Postmarketing Experience

The following adverse events have been spontaneously reported during post-approval use of Gardasil. Because these events were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure.

Blood and lymphatic system disorders: Autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, lymphadenopathy.

Respiratory, thoracic and mediastinal disorders: Pulmonary embolus.

Gastrointestinal disorders: Nausea, pancreatitis, vomiting.

General disorders and administration site conditions: Asthenia, chills, death, fatigue, malaise.

Immune system disorders: Autoimmune diseases, hypersensitivity reactions including anaphylactic/anaphylactoid reactions, bronchospasm, and urticaria.

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.

Nervous system disorders: Acute disseminated encephalomyelitis, dizziness, Guillain-Barré syndrome, headache, motor neuron disease, paralysis, seizures, syncope (including syncope associated with tonic-clonic movements and other seizure-like activity) sometimes resulting in falling with injury, transverse myelitis.

Infections and infestations: cellulitis.

Vascular disorders: Deep venous thrombosis.

Drug Interactions

Use with RECOMBIVAX HB

Results from clinical studies indicate that Gardasil may be administered concomitantly (at a separate injection site) with RECOMBIVAX HB [hepatitis B vaccine (recombinant)] [see  Clinical Studies (14.10) ].

Use with Menactra and Adacel

Results from clinical studies indicate that Gardasil may be administered concomitantly (at a separate injection site) 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)] [see  Clinical Studies (14.11) ].

Use with Hormonal Contraceptives

In clinical studies of 16- through 26-year-old women, 13,912 (Gardasil N = 6952; AAHS control or saline placebo N = 6960) who had post-Month 7 follow-up used hormonal contraceptives for a total of 33,859 person-years (65.8% of the total follow-up time in the studies).

In one clinical study of 24- through 45-year-old women, 1357 (Gardasil N = 690; AAHS control N = 667) who had post-Month 7 follow-up used hormonal contraceptives for a total of 3400 person-years (31.5% of the total follow-up time in the study). Use of hormonal contraceptives or lack of use of hormonal contraceptives among study participants did not impair the immune response in the per protocol immunogenicity (PPI) population.

Use with Systemic Immunosuppressive Medications

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines [see  Use in Specific Populations (8.6) ].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B:

Reproduction studies have been performed in female rats at doses equivalent to the recommended human dose and have revealed no evidence of impaired female fertility or harm to the fetus due to Gardasil. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, Gardasil should be used during pregnancy only if clearly needed.

An evaluation of the effect of Gardasil on embryo-fetal, pre- and postweaning development was conducted using rats. One group of rats was administered Gardasil twice prior to gestation, during the period of organogenesis (gestation Day 6) and on lactation Day 7. A second group of pregnant rats was administered Gardasil during the period of organogenesis (gestation Day 6) and on lactation Day 7 only. Gardasil was administered at 0.5 mL/rat/occasion (120 mcg total protein which is equivalent to the recommended human dose) by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring.

Clinical Studies in Humans

In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of Gardasil. Women who were found to be pregnant before completion of a 3-dose regimen of Gardasil were instructed to defer completion of their vaccination regimen until resolution of the pregnancy.

Gardasil is not indicated for women 27 years of age or older. However, safety data in women 16 through 45 years of age was collected, and 3819 women (Gardasil N = 1894 vs. AAHS control or saline placebo N = 1925) reported at least 1 pregnancy each.

The overall proportions of pregnancies that resulted in an adverse outcome, defined as the combined numbers of spontaneous abortion, late fetal death, and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), were 22.6% (446/1973) in women who received Gardasil and 23.1% (460/1994) in women who received AAHS control or saline placebo.

Overall, 55 and 65 women in the group that received Gardasil or AAHS control or saline placebo, respectively (2.9% and 3.4% of all women who reported a pregnancy in the respective vaccination groups), experienced a serious adverse reaction during pregnancy. The most common events reported were conditions that can result in Caesarean section (e.g., failure of labor, malpresentation, cephalopelvic disproportion), premature onset of labor (e.g., threatened abortions, premature rupture of membranes), and pregnancy-related medical problems (e.g., pre-eclampsia, hyperemesis). The proportions of pregnant women who experienced such events were comparable between the groups receiving Gardasil and AAHS control or saline placebo.

There were 45 cases of congenital anomaly in pregnancies that occurred in women who received Gardasil and 34 cases of congenital anomaly in pregnancies that occurred in women who received AAHS control or saline placebo.

Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of Gardasil or AAHS control or saline placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received Gardasil compared to 1 case of congenital anomaly in the group that received AAHS control or saline placebo. The congenital anomalies seen in pregnancies with estimated onset within 30 days of vaccination included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, and club foot. Conversely, in pregnancies with onset more than 30 days following vaccination, 40 cases of congenital anomaly were observed in the group that received Gardasil compared with 33 cases of congenital anomaly in the group that received AAHS control or saline placebo.

Women who receive Gardasil during pregnancy are encouraged to contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

Nursing Mothers

Women 16 Through 45 Years of Age

It is not known whether Gardasil is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Gardasil is administered to a nursing woman.

Gardasil or AAHS control were given to a total of 1133 women (vaccine N = 582, AAHS control N = 551) during the relevant Phase 3 clinical studies.

Overall, 27 and 13 infants of women who received Gardasil or AAHS control, respectively (representing 4.6% and 2.4% of the total number of women who were breast-feeding during the period in which they received Gardasil or AAHS control, respectively), experienced a serious adverse reaction.

In a post-hoc analysis of clinical studies, a higher number of breast-feeding infants (n = 7) whose mothers received Gardasil had acute respiratory illnesses within 30 days post vaccination of the mother as compared to infants (n = 2) whose mothers received AAHS control.

Pediatric Use

Safety and effectiveness have not been established in pediatric patients below 9 years of age.

Geriatric Use

The safety and effectiveness of Gardasil have not been evaluated in a geriatric population, defined as individuals aged 65 years and over.

Immunocompromised Individuals

The immunologic response to Gardasil may be diminished in immunocompromised individuals [see  Drug Interactions (7.4) ].

Overdosage

There have been reports of administration of higher than recommended doses of Gardasil.

In general, the adverse event profile reported with overdose was comparable to recommended single doses of Gardasil.

Gardasil Description

Gardasil, Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant, is a non-infectious recombinant quadrivalent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate Sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer.

Gardasil is a sterile suspension for intramuscular administration. Each 0.5-mL dose contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg of HPV 18 L1 protein.

Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as Amorphous Aluminum Hydroxyphosphate Sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, <7 mcg yeast protein/dose, and water for injection. The product does not contain a preservative or antibiotics.

After thorough agitation, Gardasil is a white, cloudy liquid.

Gardasil – Clinical Pharmacology

Mechanism of Action

HPV only infects human beings. Animal studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines may involve the development of humoral immune responses. Human beings develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Gardasil has not been evaluated for the potential to cause carcinogenicity or genotoxicity.

Gardasil administered to female rats at a dose of 120 mcg total protein, which is equivalent to the recommended human dose, had no effects on mating performance, fertility, or embryonic/fetal survival.

The effect of Gardasil on male fertility has been studied in male rats at an intramuscular dose of 0.5 mL/rat/occasion (120 mcg total protein which is equivalent to the recommended human dose). One group of male rats was administered Gardasil once, 3 days prior to cohabitation, and a second group of male rats was administered Gardasil three times, at 6 weeks, 3 weeks, and 3 days prior to cohabitation. There were no treatment-related effects on reproductive performance including fertility, sperm count, and sperm motility. There were no treatment-related gross or histomorphologic and weight changes on the testes.

source :: https://www.drugs.com/pro/gardasil.html