GARDASIL 9: Package Insert and Label Information (Page 2 of 5)

6.2 Post-Marketing Experience

There is limited post-marketing experience following administration of GARDASIL 9. However, the post-marketing safety experience with GARDASIL is relevant to GARDASIL 9 since the vaccines are manufactured similarly and contain the same antigens from HPV types 6, 11, 16, and 18. 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. The following adverse experiences have been spontaneously reported during post-approval use of GARDASIL and may also be seen in post-marketing experience with GARDASIL 9:

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.

7 DRUG INTERACTIONS

7.1 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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 Corp., a subsidiary of Merck & Co., Inc., at 1-800-986-8999.

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There are 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.

In one developmental toxicity study, 0.5 mL of a vaccine formulation containing between 1 and 1.5 –fold of each of the 9 HPV antigen types was administered to female rats prior to mating and during gestation. In another study, animals were administered a single human dose (0.5 mL) of GARDASIL 9 prior to mating, during gestation and during lactation. These animal studies revealed no evidence of harm to the fetus due to GARDASIL 9 [see Data].

Data

Human Data

In pre-licensure clinical studies of GARDASIL 9, women underwent pregnancy testing immediately prior to administration of each dose of GARDASIL 9 or control vaccine (GARDASIL). (Data from GARDASIL are relevant to GARDASIL 9 because both vaccines are manufactured using the same process and have overlapping compositions.) Subjects who were determined to be pregnant were instructed to defer vaccination until the end of their pregnancy. Despite this pregnancy screening regimen, some subjects were vaccinated very early in pregnancy before human chorionic gonadotropin (HCG) was detectable. An analysis was conducted to evaluate pregnancy outcomes for pregnancies with onset within 30 days before or after vaccination with GARDASIL 9 or GARDASIL. Among such pregnancies, there were 62 and 55 with known outcomes (excluding ectopic pregnancies and elective terminations) for GARDASIL 9 and GARDASIL, respectively, including 44 and 48 live births, respectively. The rates of pregnancies that resulted in a miscarriage were 27.4% (17/62) and 12.7% (7/55) in subjects who received GARDASIL 9 or GARDASIL, respectively. The rates of live births with major birth defects were 0% (0/44) and 2.1% (1/48) in subjects who received GARDASIL 9 or GARDASIL, respectively.

A five-year pregnancy registry enrolled 2,942 women who were inadvertently exposed to GARDASIL within one month prior to the last menstrual period (LMP) or at any time during pregnancy, 2,566 of whom were prospectively followed. After excluding elective terminations (n=107), ectopic pregnancies (n=5) and those lost to follow-up (n=814), there were 1,640 pregnancies with known outcomes. Rates of miscarriage and major birth defects were 6.8% of pregnancies (111/1,640) and 2.4% of live born infants (37/1,527), respectively. These rates of assessed outcomes in the prospective population were consistent with estimated background rates.

In two post-marketing studies of GARDASIL (one conducted in the U.S., and the other in Nordic countries), pregnancy outcomes among subjects who received GARDASIL during pregnancy were evaluated retrospectively. Among the 1,740 pregnancies included in the U.S. study database, outcomes were available to assess the rates of major birth defects and miscarriage. Among the 499 pregnancies included in the Nordic study database, outcomes were available to assess the rates of major birth defects. In both studies, rates of assessed outcomes did not suggest an increased risk with the administration of GARDASIL during pregnancy.

Animal Data

Developmental toxicity studies were conducted in female rats. In one study, animals were administered 0.5 mL of a vaccine formulation containing between 1 and 1.5 –fold of each of the 9 HPV antigen types 5 and 2 weeks prior to mating, and on gestation day 6. In a second study, animals were administered a single human dose (0.5 mL of GARDASIL 9) 5 and 2 weeks prior to mating, on gestation day 6, and on lactation day 7. No adverse effects on pre- and post-weaning development were observed. There were no vaccine-related fetal malformations or variations.

8.2 Lactation

Risk Summary

Available data are not sufficient to assess the effects of GARDASIL 9 on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered 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. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

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

8.5 Geriatric Use

The safety and effectiveness of GARDASIL 9 have not been evaluated in a geriatric population, defined as individuals aged 65 years and over.

8.6 Immunocompromised Individuals

The immunologic response to GARDASIL 9 may be diminished in immunocompromised individuals [see Drug Interactions (7.1)].

11 DESCRIPTION

GARDASIL 9, Human Papillomavirus 9-valent Vaccine, Recombinant, is a non-infectious recombinant 9-valent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The L1 proteins are produced by separate fermentations using 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 or AAHS). The 9-valent 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 9 is a sterile suspension for intramuscular administration. Each 0.5-mL dose contains approximately 30 mcg of HPV Type 6 L1 protein, 40 mcg of HPV Type 11 L1 protein, 60 mcg of HPV Type 16 L1 protein, 40 mcg of HPV Type 18 L1 protein, 20 mcg of HPV Type 31 L1 protein, 20 mcg of HPV Type 33 L1 protein, 20 mcg of HPV Type 45 L1 protein, 20 mcg of HPV Type 52 L1 protein, and 20 mcg of HPV Type 58 L1 protein.

Each 0.5-mL dose of the vaccine also contains approximately 500 mcg of aluminum (provided as AAHS), 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, and water for injection. The product does not contain a preservative or antibiotics.

After thorough agitation, GARDASIL 9 is a white, cloudy liquid.

12 CLINICAL PHARMACOLOGY

12.1 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. Efficacy of GARDASIL 9 against anogenital diseases related to the vaccine HPV types in human beings is thought to be mediated by humoral immune responses induced by the vaccine, although the exact mechanism of protection is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

GARDASIL 9 has not been evaluated for the potential to cause carcinogenicity, genotoxicity or impairment of male fertility. GARDASIL 9 administered to female rats had no effects on fertility [see Pregnancy (8.1)].

14 CLINICAL STUDIES

In these studies, seropositive is defined as anti-HPV titer greater than or equal to the pre-specified serostatus cutoff for a given HPV type. Seronegative is defined as anti-HPV titer less than the pre-specified serostatus cutoff for a given HPV type. The serostatus cutoff is the antibody titer level above the assay’s lower limit of quantification that reliably distinguishes sera samples classified by clinical likelihood of HPV infection and positive or negative status by previous versions of competitive Luminex Immunoassay (cLIA). The lower limits of quantification and serostatus cutoffs for each of the 9 vaccine HPV types are shown in Table 5 below. PCR positive is defined as DNA detected for a given HPV type. PCR negative is defined as DNA not detected for a given HPV type. The lower limit of detection for the multiplexed HPV PCR assays ranged from 5 to 34 copies per test across the 9 vaccine HPV types.

Table 5: Competitive Luminex Immunoassay (cLIA) Limits of Quantification and Serostatus Cutoffs for GARDASIL 9 HPV Types
HPV Type cLIA Lower Limit of Quantification (mMU */mL) cLIA Serostatus Cutoff(mMU */mL)
*
mMU=milli-Merck Units
HPV 6 16 30
HPV 11 6 16
HPV 16 12 20
HPV 18 8 24
HPV 31 4 10
HPV 33 4 8
HPV 45 3 8
HPV 52 3 8
HPV 58 4 8

14.1 Efficacy and Effectiveness Data for GARDASIL

Efficacy and effectiveness of GARDASIL are relevant to GARDASIL 9 since the vaccines are manufactured similarly and contain four of the same HPV L1 VLPs.

Individuals 16 through 26 Years of Age

Efficacy of GARDASIL was assessed in five AAHS-controlled, double-blind, randomized clinical trials evaluating 24,596 individuals 16 through 26 years of age (20,541 girls and women and 4,055 boys and men). The results of these trials are shown in Table 6 below.

Table 6: Analysis of Efficacy of GARDASIL in the PPE * Population for Vaccine HPV Types
Disease Endpoints GARDASIL AAHS Control % Efficacy (95% CI)
N Number of cases N Number of cases
N=Number of individuals with at least one follow-up visit after Month 7
CI=Confidence Interval
Note 1: Point estimates and confidence intervals are adjusted for person-time of follow-up.
Note 2: Table 6 does not include cases due to HPV types not covered by the vaccine.
AAHS = Amorphous Aluminum Hydroxyphosphate Sulfate, CIN = Cervical Intraepithelial Neoplasia, VIN = Vulvar Intraepithelial Neoplasia, VaIN=Vaginal Intraepithelial Neoplasia, PIN=Penile Intraepithelial Neoplasia, AIN=Anal Intraepithelial Neoplasia, AIS=Adenocarcinoma In Situ
*
The PPE population consisted of individuals who received all three vaccinations within one 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 who remained PCR negative to the relevant HPV type(s) through one month post-dose 3 (Month 7).
Analyses of the combined trials were prospectively planned and included the use of similar study entry criteria.
16- through 26-Year-Old Girls and Women
HPV 16- or 18-related CIN 2/3 or AIS 8493 2 8464 112 98.2 (93.5, 99.8)
HPV 16- or 18-related VIN 2/3 7772 0 7744 10 100.0 (55.5, 100.0)
HPV 16- or 18-related VaIN 2/3 7772 0 7744 9 100.0 (49.5, 100.0)
HPV 6-, 11-, 16-, or 18-related CIN (CIN 1, CIN 2/3) or AIS 7864 9 7865 225 96.0 (92.3, 98.2)
HPV 6-, 11-, 16-, or 18-related Genital Warts 7900 2 7902 193 99.0 (96.2, 99.9)
HPV 6- and 11-related Genital Warts 6932 2 6856 189 99.0 (96.2, 99.9)
16- through 26-Year-Old Boys and Men
External Genital Lesions HPV 6-, 11-, 16-, or 18-related
External Genital Lesions 1394 3 1404 32 90.6 (70.1, 98.2)
Condyloma 1394 3 1404 28 89.3 (65.3, 97.9)
PIN 1/2/3 1394 0 1404 4 100.0 (-52.1, 100.0)
HPV 6-, 11-, 16-, or 18-related Endpoint
AIN 1/2/3 194 5 208 24 77.5 (39.6, 93.3)
AIN 2/3 194 3 208 13 74.9 (8.8, 95.4)
AIN 1Condyloma AcuminatumNon-acuminate 194194194 404 208208208 16611 73.0 (16.3, 93.4)100.0 (8.2, 100.0)60.4 (-33.5, 90.8)

In an extension study in females 16 through 26 years of age at enrollment, prophylactic efficacy of GARDASIL through Month 60 against overall cervical and genital disease related to HPV 6, 11, 16, and 18 was 100% (95% CI: 12.3%, 100%) compared to AAHS control.

An extension study in girls and women 16 through 23 years of age used national healthcare 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. An interim analysis of the per-protocol effectiveness population included 1,902 subjects who completed the GARDASIL vaccination series within one year, were naïve to the relevant HPV type through 1 month post-dose 3, had no protocol violations, and had follow-up data available. The median follow-up from the first dose of vaccine was 6.7 years with a range of 2.8 to 8.4 years. At the time of interim analysis, no cases of HPV 6-, 11-, 16-, or 18-related CIN (any grade), AIS, cervical cancer, vulvar cancer, or vaginal cancer were observed over a total of 5,765 person-years at risk.

Girls and Boys 9 through 15 Years of Age

An extension study of 614 girls and 565 boys 9 through 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. An interim analysis of the per-protocol effectiveness population included 246 girls and 168 boys who completed the GARDASIL vaccination series within one year, were seronegative to the relevant HPV type at initiation of the vaccination series, and had not initiated sexual activity prior to receiving the third dose of GARDASIL. The median follow-up from the first dose of vaccine was 7.2 years with a range of 0.5 to 8.5 years. At the time of interim analysis, 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 were 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.

Women 27 through 45 Years of Age

A clinical trial evaluated efficacy of GARDASIL in 3,253 women 27 through 45 years of age, based on a combined endpoint of 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. These women were randomized 1:1 to receive either GARDASIL or AAHS control. The efficacy estimate for the combined endpoint was driven primarily by prevention of persistent infection. No statistically significant efficacy was demonstrated for GARDASIL in prevention of cervical intraepithelial neoplasia grades 2 and 3 (CIN 2/3), adenocarcinoma in situ (AIS) or cervical cancer related to HPV types 16 and 18.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2019. All Rights Reserved.