GARDASIL 9SIDE EFFECTS
- Generic Name: human papillomavirus 9-valent vaccine, recombinant sterile suspension for intramuscular administratio
- Brand Name: Gardasil 9
- Drug Class: Vaccines, Inactivated, Viral
SIDE EFFECTS
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 VRCaided 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 | |
| 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 |
| 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 |
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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 9 N=7071 |
GARDASIL N=7078 |
GARDASIL 9 N=299 |
GARDASIL N=300 |
|
| 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 | 0.2 | 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 |
| 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 |
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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
| GARDASIL 9 | |
| 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 |
| 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). *Unsolicited adverse reactions reported by ≥1% of individuals N=number of subjects vaccinated with safety follow-up †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 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 |
|
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 Placebo N=305 |
|
| 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) |
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| 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 |
| The data for GARDASIL 9 and saline placebo are from Study 4 (NCT01047345). *Unsolicited adverse reactions reported by ≥1% of individuals N=number of subjects vaccinated with safety follow-up †For oral temperature: number of subjects with temperature data GARDASIL 9 N=604; Saline Placebo N=304 |
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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.
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 nonconcomitant 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.
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 n 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.
SRC: NLM .