Papillomavirus (9-Valent) Vaccine (Human, Recombinant)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Intramuscular [preservative free]:

Gardasil 9: (0.5 mL) [contains polysorbate 80, yeast extract]

Suspension Prefilled Syringe, Intramuscular [preservative free]:

Gardasil 9: (0.5 mL) [contains polysorbate 80, yeast extract]

Pharmacology

Mechanism of Action

Contains inactive human papillomavirus (HPV) proteins (types 6 L1,11 L1, 16 L1, 18 L1, 31 L1, 33 L1, 45 L1, 52 L1, and 58 L1) which produce neutralizing antibodies to prevent cervical, vulvar, vaginal, and anal cancers, cervical adenocarcinoma, cervical, vaginal, vulvar, and anal neoplasia, and genital warts caused by HPV. Efficacy of HPV 9-valent vaccine against anogenital diseases related to the vaccine HPV types in humans is thought to be mediated by humoral immune responses induced by the vaccine, although the exact mechanism of protection is unknown.

Use: Labeled Indications

Prevention of human papillomavirus infection:

Females 9 to 45 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

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

Cervical intraepithelial neoplasia (CIN) grades 1, 2, and 3

Cervical adenocarcinoma in situ (AIS)

Vulvar intraepithelial neoplasia (VIN) grades 2 and 3

Vaginal intraepithelial neoplasia (VaIN) grades 2 and 3

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

Males 9 through 45 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

For the prevention of 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

The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination for females and males 11 to 12 years; for patients with any history of sexual abuse or assault, vaccination should be started at 9 years. Catch-up vaccination is recommended for all persons through age 26 years. Shared clinical decision-making regarding catch-up HPV vaccination is recommended for some adults 27 to 45 years of age (CDC/ACIP [Meites 2019]).

Contraindications

Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of this vaccine or human papillomavirus vaccine (recombinant) for types 6, 11, 16, 18

Dosage and Administration

Dosing: Adult

Immunization: IM:

Manufacturer's labeling: Adults ≤45 years of age: 3-dose series: 0.5 mL at 0, 2, and 6 months

CDC/ACIP recommended immunization schedule: Adults ≤26 years of age: Catch-up vaccination recommended in all persons ≤26 years of age if not previously vaccinated or completed the 3-dose series (typically administer first dose at age 11 to 12 years). Second and third doses may be given after age 26 years to complete a previously initiated series (CDC/ACIP [Markowitz 2014]; CDC/ACIP [Meites 2016]; CDC/ACIP [Meites 2019]). Note: Shared clinical decision-making regarding catch-up HPV vaccination is recommended for some adults 27 to 45 years of age (CDC/ACIP [Meites 2019]).

Have not received any doses: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months. There should be a 4-week minimum interval between the first and second dose; a 12-week minimum interval between the second and third dose; a 5-month minimum interval between the first and third dose.

Partially vaccinated, first dose before 15 years of age:

If 2 doses administered at least 5 months apart: no more doses needed

If only a single dose or if doses <5 months apart: IM: Administer one additional 0.5 mL dose

Partially vaccinated, first dose at 15 years of age or later: Complete 3-dose series: IM: There should be a 4-week minimum interval between the first and second dose; a 12-week minimum interval between the second and third dose; a 5-month minimum interval between the first and third dose.

Dosing: Pediatric

Note: Consult CDC/ACIP annual immunization schedules for additional information including specific detailed recommendations for catch-up scenarios and/or care of patients with high-risk conditions. According to ACIP, doses administered ≤4 days before minimum interval or age are considered valid; however, local or state mandates may supersede this timeframe (ACIP [Kroger 2017]).

Primary immunization: Children ≥9 years and Adolescents: IM: 0.5 mL per dose for 2 or 3 doses; see the following ACIP/CDC recommendations for number and timing of doses.

CDC/ACIP recommended immunization schedule: Routine vaccination at 11 to 12 years of age for all persons; may start as early as 9 years of age.

In a 2-dose schedule, minimum interval between first and second doses is 5 months.

In a 3-dose schedule, minimum interval between first and second doses is 4 weeks; the minimum interval between the second and third dose is 12 weeks; the minimum interval between first and third doses is 5 months (CDC/ACIP [Meites 2016]).

Non-immunocompromised patients and certain specified medical conditions: Asplenia, asthma, chronic granulomatous disease, chronic liver disease, chronic lung disease, chronic renal disease, central nervous system, anatomic barrier defects (eg, cochlear implant), complement deficiency, diabetes, heart disease, or sickle cell disease:

Children ≥9 years and Adolescents <15 years: 2-dose series: IM: 0.5 mL at 0, and 6 to 12 months. Administer first dose at age 11 to 12 years. For patients with any history of sexual abuse or assault, vaccination should be started at 9 years.

Adolescents ≥15 years: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months.

Immunocompromised patients: Including those with conditions that might reduce cell-mediated or humoral immunity, such as B lymphocyte antibody deficiencies, T lymphocyte complete or partial defects, HIV infection, malignant neoplasms, transplantation, autoimmune disease, or immunosuppressive therapy:

Children ≥9 years and Adolescents: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months.

Manufacturing labeling: May not reflect current practice:

Children ≥9 years and Adolescents <15 years:

2-dose series: IM: 0.5 mL per dose; administer the second dose at 6 to 12 months after initial dose. If the second dose is inadvertently administered earlier than 5 months after the first dose, then patient should be converted to a 3-dose series.

3-dose series: IM: 0.5 mL per dose; administer the second and third doses at 2 and 6 months after initial dose.

Adolescents ≥15 years: IM: 0.5 mL per dose for a total of 3 doses; administer the second and third doses at 2 and 6 months after initial dose.

Catch-up immunization: CDC/ACIP recommendations (Meites 2016; Meites 2019): Note: Do not restart the series. If doses have been given, begin the below schedule at the applicable dose number. Children ≥9 years and Adolescents: IM: 0.5 mL per dose for a total of 2 to 3 doses (See CDC/ACIP recommendations in Primary Immunization for 2-dose vs 3-dose schedule criteria):

First dose given on the elected date.

Second dose given at least 4 weeks after the first dose (for a 3-dose schedule) or 5 months after the first dose (for a 2-dose schedule).

Third dose (for a 3-dose schedule) given at least 12 weeks after the second dose and at least 5 months after the first dose.

Administration

IM: Shake suspension well before use. Do not use if discolored or if contains particulate matter, or if syringe is cracked. Inject the entire dose IM into the deltoid region of the upper arm or higher anterolateral thigh area. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (ACIP [Kroger 2017]). To prevent syncope related injuries, patients should be vaccinated while seated or lying down (ACIP [Kroger 2017]). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, and the administering person's name, title, and address be entered into the patient's permanent medical record.

For patients at risk of hemorrhage following intramuscular injection, the vaccine should be administered intramuscularly if, in the opinion of the physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, intramuscular vaccination can be scheduled shortly after such therapy is administered. A fine needle (23 gauge or smaller) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (ACIP [Kroger 2017]).

Storage

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

Administer as soon as possible after being removed from refrigeration. HPV 9-valent vaccine can be administered provided total (cumulative multiple excursion) time out of refrigeration (at temperatures between 8°C and 25°C) does not exceed 72 hours. Cumulative multiple excursions between 0°C and 2°C are also permitted as long as the total time between 0°C and 2°C does not exceed 72 hours. These are not, however, recommendations for storage.

Drug Interactions

Fingolimod: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting fingolimod. If vaccinated during fingolimod therapy, revaccinate 2 to 3 months after fingolimod discontinuation. Consider therapy modification

Immunosuppressants: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Exceptions: Cytarabine (Liposomal). Consider therapy modification

Siponimod: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Avoid administration of vaccines (inactivated) during treatment with siponimod and for 1 month after discontinuation due to potential decreased vaccine efficacy. Consider therapy modification

Venetoclax: May diminish the therapeutic effect of Vaccines (Inactivated). Monitor therapy

Adverse Reactions

To report suspected adverse reactions, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at (877) 888-4231 or VAERS at (800) 822-7967 or http://www.vaers.hhs.gov.

Frequency not always defined. Reported incidences are for individuals (females 9 to 26 years of age and males 9 to 15 years of age) who the vaccine is approved for use, unless otherwise specified by a specific population.

>10%:

Central nervous system: Headache (9% to 20%)

Local: Pain at injection site (63% to 90%), swelling at injection site (13% to 49%; swelling increased with successive doses and/or concomitant vaccines), erythema at injection site (7% to 42%; erythema increases with successive doses)

1% to 10%:

Cardiovascular: Syncope

Central nervous system: Dizziness (≤3%), fatigue (≤2%)

Gastrointestinal: Diarrhea (≤1%), upper abdominal pain (≤2%), nausea (1% to 4%)

Immunologic: Autoimmune disease (2%)

Local: Itching at injection site (4% to 8%), hematoma at injection site (1% to ≤5%), bruising at injection site (2%), induration at injection site (1% to ≤2%), bleeding at injection site (1%), injection site nodule (1%), injection site reaction (≤1%)

Neuromuscular & skeletal: Myalgia (≤1%)

Respiratory: Oropharyngeal pain (1% to 3%)

Miscellaneous: Fever (4% to ≤10%)

<1%, postmarketing, and/or case reports: Anaphylactoid reaction, hypersomnia, postural orthostatic tachycardia, pulmonary embolism, status asthmaticus, tonsillitis, upper respiratory tract infection, warm sensation at injection site

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid/hypersensitivity reactions: Immediate treatment (including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during vaccine use (ACIP [Kroger 2017]).
• Syncope: Syncope has been reported with use of injectable vaccines and may result in serious secondary injury (eg, skull fracture, cerebral hemorrhage); typically reported in adolescents and young adults and within 15 minutes after vaccination. Procedures should be in place to avoid injuries from falling and to restore cerebral perfusion if syncope occurs (ACIP [Kroger 2017]).

Disease-related concerns:

• Acute illness: The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and the etiology of the disease. Defer administration in patients with moderate or severe acute illness (with or without fever); vaccination should not be delayed for patients with mild acute illness (with or without fever) (ACIP [Kroger 2017]).
• Bleeding disorders: Use with caution in patients with a history of bleeding disorders (including thrombocytopenia); bleeding/hematoma may occur from IM administration; if the patient receives antihemophilia or other similar therapy, IM injection can be scheduled shortly after such therapy is administered (ACIP [Kroger 2017]).
• Human papillomavirus (HPV) infection: There is no evidence that individuals already infected with HPV will be protected; those already infected with 1 or more HPV types were protected from disease caused by the remaining HPV types. Not for the treatment of active disease; will not protect against diseases not caused by HPV vaccine types not included in the vaccine. Does not eliminate the necessity for recommended cervical or anal cancer screenings.

Concurrent drug therapy issues:

• Anticoagulant therapy: Use with caution in patients receiving anticoagulant therapy; bleeding/hematoma may occur from IM administration (ACIP [Kroger 2017]).
• Vaccines: In order to maximize vaccination rates, the ACIP recommends simultaneous administration of all age-appropriate vaccines (live or inactivated) for which a person is eligible at a single clinic visit, unless contraindications exist (ACIP [Kroger 2017]).

Special populations:

• Altered immunocompetence: Consider deferring immunization during periods of severe immunosuppression (eg, patients receiving chemo/radiation therapy or other immunosuppressive therapy [including high dose corticosteroids]); may have a reduced response to vaccination. In general, household and close contacts of persons with altered immunocompetence may receive all age-appropriate vaccines. Inactivated vaccines should be administered ≥2 weeks prior to planned immunosuppression when feasible; inactivated vaccines administered during chemotherapy should be readministered after immune competence is regained (ACIP [Kroger 2017]; IDSA [Rubin 2014]).

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.
• Previously vaccinated with Gardasil (quadrivalent): Safety and immunogenicity of Gardasil 9 were assessed in individuals who previously completed a 3-dose vaccination series with Gardasil (quadrivalent). Studies using a mixed regimen of HPV vaccines to assess interchangeability were not performed. Per the ACIP, if the provider does not have available or does not know the HPV product used previously, any gender appropriate product can be used to complete the series (CDC/ACIP [Petrosky 2015]).
• Yeast: Product may contain yeast.

Other warnings/precautions:

• Appropriate use: Use of this vaccine for specific medical and/or other indications (eg, immunocompromising conditions, hepatic or kidney disease, diabetes) is also addressed in the annual ACIP Recommended Immunization Schedules (refer to CDC schedule for detailed information). Specific recommendations for vaccination in immunocompromised patients with asplenia, cancer, HIV infection, cerebrospinal fluid leaks, cochlear implants, hematopoietic stem cell transplant (prior to or after), sickle cell disease, solid organ transplant (prior to or after), or those receiving immunosuppressive therapy for chronic conditions are available from the IDSA (Rubin 2014).
• Effective immunity: Vaccination may not result in effective immunity in all patients. Response depends upon multiple factors (eg, type of vaccine, age of patient) and may be improved by administering the vaccine at the recommended dose, route, and interval. Vaccines may not be effective if administered during periods of altered immune competence (ACIP [Kroger 2017]).
• Maximum efficacy: The entire series should be completed for maximum efficacy.

Monitoring Parameters

Screening for HPV is not required prior to vaccination. Monitor for anaphylaxis and syncope for 15 minutes following administration (ACIP [Kroger 2017]). If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion. Continue recommended anal cancer screening.

Females: Gynecologic screening exam, papillomavirus test; screening for cervical cancer should continue per current guidelines following vaccination

Pregnancy

Pregnancy Considerations

Based on available data, an increased risk of adverse pregnancy outcomes has not been observed following inadvertent use in pregnant women. Administration of the vaccine in pregnancy is not recommended. The vaccine series (or completion of the series) should be delayed until pregnancy is completed. Pregnancy testing is not required prior to administration of the vaccine (CDC/ACIP [Petrosky 2015]).

A registry has been established for women exposed to the Gardasil 9 HPV vaccine during pregnancy (1-800-986-8999).

Patient Education

What is this drug used for?

• It is used to prevent anal cancer, genital warts, and anal growths that may lead to cancer.
• It is used to prevent these health problems caused by HPV: Cervical cancer; vaginal or vulvar cancer; and cervical, vaginal, or vulvar growths that may lead to cancer.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Headache
• Nausea
• Diarrhea
• Sore throat
• Injection site pain or irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Skin infection
• Severe dizziness
• Passing out
• Trouble with motor activity
• Seizures
• Joint pain
• Enlarged lymph nodes
• Severe loss of strength and energy
• Confusion
• Chills
• Leg pain
• Shortness of breath
• Chest pain
• Muscle pain
• Muscle weakness
• Severe abdominal pain
• Bruising
• Bleeding
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.