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    Papillomavirus Vaccines

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant vaccine
    Used for immunization against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58
    Only for prophylaxis; not for HPV treatment

    COMMON BRAND NAMES

    Gardasil 9

    HOW SUPPLIED

    Gardasil 9 Intramuscular Inj Susp

    DOSAGE & INDICATIONS

    For human papillomavirus (HPV) infection prophylaxis.
    Intramuscular dosage
    Adults 18 through 26 years of age

    0.5 mL IM for 3 doses. For routine vaccination, ACIP recommends administering the first dose at age 11 or 12 years, or any time between 13 and 26 years if not previously vaccinated. The CDC recommends vaccination for 1) females through 26 years of age and males through 21 years of age who have not already been vaccinated or who have not completed the 3-dose series, and 2) any male through age 26 who has had sexual contact with other men or with a compromised immune system (including HIV), if they did not get HPV vaccine when they were younger. However, any male age 22 through 26 years may receive the vaccine. If any recipient reaches age 27 years before the 3-dose series is complete, the second and/or third doses may be administered after 26 years of age to complete the series. The FDA-approved schedule is to administer the first dose at an elected date, the second dose 2 months after that, and the third dose 6 months after the first dose.

    Adolescents 15 to 17 years of age

    0.5 mL IM for 3 doses. For routine vaccination, ACIP recommends administering the first dose at age 11 or 12 years, or any time between 13 and 26 years if not previously vaccinated. Administer the second dose 1 to 2 months after the first and the third dose 6 months after the first. The FDA-approved schedule is to administer the first dose at an elected date, the second dose 2 months after that, and the third dose 6 months after the first.

    Children and Adolescents 9 to 14 years of age

    0.5 mL IM for 2 or 3 doses. ACIP recommends routine vaccination with 2 doses if series is initiated before age 15. Administer at age 9 for children with any history of sexual abuse or assault; vaccination may be administered starting at age 9, even in the absence of a high risk condition. For routine vaccination, administer the first dose at age 11 or 12, or any time between age 13 and 26 if not previously vaccinated. For the 2 dose regimen, give the second dose 6 to 12 months (minimum 5 months) after the first. Patients who are HIV positive or immunosuppressed for other reasons should receive 3 doses. For the 3 dose regimen, ACIP recommends giving the second dose 1 to 2 months after the first and giving the third dose 6 months after the first. The FDA-approved 3-dose regimen administers the first dose at an elected date, the second dose 2 months after that, and the third dose 6 months after the first.

    MAXIMUM DOSAGE

    Adults

    > 26 years: Safety and efficacy not established.
    18 to 26 years: 0.5 mL IM.

    Geriatric

    Safety and efficacy not established.

    Adolescents

    13 to 17 years: 0.5 mL IM.

    Children

    9 years and older: 0.5 mL IM.
    8 years and younger: Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    Neonates

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: According to U.S. federal laws, the health care provider must record in the patient's permanent record the manufacturer, lot number, administration date, and the name and address of the person administering the vaccine.
    Inform the patient, parent, guardian, or responsible adult of the benefits and risks of the vaccine. Provide the Vaccine Information Statements from the manufacturer to the recipient or guardian before each immunization. The action is required by the National Childhood Vaccine Injury Act of 1986.
    If a human papillomavirus (HPV) vaccine has been previously given, question the patient, parent, or guardian about any symptoms or signs of an adverse reaction.
    Complete a Vaccine Adverse Event Reporting System (VAERS) report form if adverse events have been identified. The reporting of events is required by the National Childhood Vaccine Injury Act of 1986. The toll-free number for VAERS is 1—800—822—7967. Also, report an adverse event to the manufacturer. Depending on the adverse reaction, a subsequent dose may be contraindicated 
    Health care professionals administering vaccines should take appropriate precautions to prevent allergic reactions in vaccine recipients. The health care professional should have immediate availability of epinephrine (1:1000) injection and other agents used in the treatment of severe anaphylaxis in the event of a serious allergic reaction.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Following vigorous shaking, the vaccine is a cloudy white suspension. If discoloration or visible particulate matter are present, discard the vaccine dose.
    Do not mix with any other vaccine or product in the same syringe.

    Intramuscular Administration

    Use the vaccine as supplied; no dilution or reconstitution is necessary.
    Both the prefilled syringe and single-dose vial require vigorous shaking prior to administration to ensure a homogenous white suspension; DO NOT administer if the vaccine cannot be re-suspended.
    Single-dose vial: Using a sterile needle and syringe, withdraw the 0.5 mL dose and administer immediately.
    Prefilled syringe: Attach a sterile needle by twisting in a clockwise direction. Administer entire dose contained within the syringe.
    Prior to administration, clean skin over the injection site with a suitable cleansing agent.
    The preferred injection site is the deltoid muscle of the upper arm or the higher anterolateral area of the thigh. Do NOT inject into the gluteal area or other areas where there may be a major nerve trunk.
    Aspirate before injecting the dose to avoid injecting the vaccine into a blood vessel. If blood appears in the syringe, remove the needle and discard the vaccine. Use a new dose to try again.
    Carefully observe patients for approximately 15 minutes after administration of the vaccine; syncope may occur.
    Storage of unopened vials/syringes: Store refrigerated at 2—8 degrees C (36 to 46 degrees F); do not freeze. Administer as soon as possible after being removed from refrigeration. Total time (cumulative multiple excursions) outside of refrigeration [temperatures 8—25 degrees C (46 to 77 degrees F)] must not exceed 72 hours. Cumulative multiple excursions between 0—2 degrees C (32 to 36 degrees F) are also permitted if total time does not exceed 72 hours.

    STORAGE

    Gardasil 9:
    - Do not freeze
    - Protect from light
    - Store between 36 to 46 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Yeast hypersensitivity

    Human papillomavirus (HPV) 9-valent vaccine is contraindicated for use in patients with a severe allergic reaction to yeast (yeast hypersensitivity), as the vaccine components are recombinantly produced in brewers yeast, Saccharomyces cerevisiae. In addition, administration must be avoided in patients who have experienced a hypersensitivity reaction to a previous dose of the vaccine or to Gardasil quadrivalent. With any biologic product, the prescriber or health care professional should take precautions to prevent allergic reactions. The health care professional should have immediate availability of epinephrine (1:1000) injection and other agents used in the treatment of severe anaphylaxis in the event of a serious allergic reaction. Prior to administration, inform the parent, guardian, or responsible adult of the benefits and risks of the vaccine, and provide the Vaccine Information Statement, accessible at the Centers for Disease Control and Prevention (CDC) website. These actions are required by the National Childhood Vaccine Injury Act of 1986. If a dose of human papillomavirus 9-valent vaccine has been previously given, question the parent or guardian about previous adverse reactions that may preclude further administration. Report all adverse reactions to the Vaccine Adverse Event Reporting System (VAERS), as well as the manufacturer. The toll-free number for VAERS is 1—800—822—7967. Educate the responsible adult(s) to promptly report any adverse reaction after vaccine administration to a health care provider.

    Anticoagulant therapy, coagulopathy, hemophilia, thrombocytopenia, vitamin K deficiency

    The human papillomavirus 9-valent vaccine is indicated for intramuscular administration. Therefore, the vaccine should be given cautiously to patients receiving anticoagulant therapy. Also, patients with thrombocytopenia, vitamin K deficiency, a coagulopathy (e.g., hemophilia), or other bleeding disorders should be monitored closely for bleeding at the IM injection site. Steps to avoid hematoma are recommended.

    Syncope

    Injectable vaccines, including human papillomavirus 9-valent vaccine, have been associated with episodes of syncope and fainting. These events may be accompanied by transient tonic-clonic limb movements and other seizure-like activities. Prior to administration, ensure procedures are in place to prevent falls and restore cerebral perfusion. Monitor vaccine recipients for 15 minutes after administration of the dose. If syncope occurs, place the patient in a supine or Trendelenburg position to restore cerebral perfusion.

    Agammaglobulinemia, human immunodeficiency virus (HIV) infection, hypogammaglobulinemia, immunosuppression, neoplastic disease, radiation therapy, severe combined immunodeficiency (SCID)

    Patients with significant immunosuppression may not have an adequate antibody response to human papillomavirus 9-valent vaccine. Immunosuppressed persons may include patients with human immunodeficiency virus (HIV) infection; severe combined immunodeficiency (SCID); hypogammaglobulinemia; agammaglobulinemia; altered immune states due to generalized neoplastic disease; or an immune system compromised by radiation therapy or drug therapy (e.g., chemotherapy or corticosteroid therapy with greater than physiologic doses). Short-term (< 2 weeks) corticosteroid therapy or intra-articular, bursal, or tendon injections with corticosteroids should not be immunosuppressive.

    Fever

    The decision to administer or to delay vaccination with the human papillomavirus 9-valent vaccine because of current or recent febrile illness depends on the severity of symptoms and on the etiology of the disease. The Advisory Committee on Immunization Practices recommends that vaccinations be delayed during the course of a moderate or severe acute febrile illness and administered after the acute phase of illness has resolved. All vaccines can be given to persons with minor illnesses such as diarrhea, mild upper-respiratory infection with or without low-grade fever, or other low-grade febrile illness.

    Children, infants, neonates

    Safety and efficacy of the human papillomavirus 9-valent vaccine have not been established in neonates, infants, nor children younger than 9 years of age.

    Pregnancy

    No adequate and well controlled studies have been conducted in pregnant women. It is unknown whether this vaccine can cause fetal harm or affect reproductive capacity. If a woman is found to be pregnant after initiating the vaccination series, delay the remainder of the 2- or 3-dose regimen until after completion of the pregnancy. In clinical trials, women were tested for pregnancy before each dose; if pregnancy was detected, completion of the regimen was deferred until pregnancy resolution. During a five year pregnancy registry there were 1,640 pregnancies with known outcomes. Rates of miscarriage (6.8%; 111/1,640) and major birth defects (2.4%; 37/1,527) were consistent with pregnancy outcomes observed in the general population. Two post-marketing studies included 1,740 pregnancies and found no suggestion of increased risk in the rate of assessed outcomes with vaccine administration during pregnancy. The manufacturer recommends administration during pregnancy only if clearly needed. Vaccinees and health care providers are encouraged to report any vaccine exposure during pregnancy by calling 1-800-986-8999.

    Breast-feeding

    Data are limited regarding use of the human papillomavirus 9-valent vaccine during breast-feeding and its excretion in human milk is unknown. The manufacturer recommends caution when administering to nursing women; however, according the Advisory Committee on Immunization Practices (ACIP), vaccines administered to a lactating woman do not affect the safety of breast-feeding. In addition, breast-feeding does not adversely affect immunization and is not a contraindication for any inactivated recombinant vaccine. In fact, limited data suggest breast-feeding may enhance the immune response to certain antigens. Also, no serious adverse events in a breast-fed infant have been associated with the use of an inactivated recombinant vaccine. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    myelitis / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    Guillain-Barre syndrome / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    muscle paralysis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    edema / Delayed / 0-49.0
    erythema / Early / 0-42.3
    hematoma / Early / 0.9-4.8
    bleeding / Early / 1.0-1.0
    acute disseminated encephalomyelitis / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 0-90.3
    headache / Early / 7.3-19.6
    fever / Early / 1.0-8.9
    pruritus / Rapid / 4.0-7.7
    nausea / Early / 1.0-4.4
    dizziness / Early / 0.7-3.0
    fatigue / Early / 1.4-2.3
    abdominal pain / Early / 0.7-1.7
    diarrhea / Early / 0.3-1.2
    influenza / Delayed / 1.2-1.2
    myalgia / Early / 0.7-1.0
    malaise / Early / Incidence not known
    syncope / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    arthralgia / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    chills / Rapid / Incidence not known
    asthenia / Delayed / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Human Papillomavirus 9-Valent Vaccine products.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate and well controlled studies have been conducted in pregnant women. It is unknown whether this vaccine can cause fetal harm or affect reproductive capacity. If a woman is found to be pregnant after initiating the vaccination series, delay the remainder of the 2- or 3-dose regimen until after completion of the pregnancy. In clinical trials, women were tested for pregnancy before each dose; if pregnancy was detected, completion of the regimen was deferred until pregnancy resolution. During a five year pregnancy registry there were 1,640 pregnancies with known outcomes. Rates of miscarriage (6.8%; 111/1,640) and major birth defects (2.4%; 37/1,527) were consistent with pregnancy outcomes observed in the general population. Two post-marketing studies included 1,740 pregnancies and found no suggestion of increased risk in the rate of assessed outcomes with vaccine administration during pregnancy. The manufacturer recommends administration during pregnancy only if clearly needed. Vaccinees and health care providers are encouraged to report any vaccine exposure during pregnancy by calling 1-800-986-8999.

    Data are limited regarding use of the human papillomavirus 9-valent vaccine during breast-feeding and its excretion in human milk is unknown. The manufacturer recommends caution when administering to nursing women; however, according the Advisory Committee on Immunization Practices (ACIP), vaccines administered to a lactating woman do not affect the safety of breast-feeding. In addition, breast-feeding does not adversely affect immunization and is not a contraindication for any inactivated recombinant vaccine. In fact, limited data suggest breast-feeding may enhance the immune response to certain antigens. Also, no serious adverse events in a breast-fed infant have been associated with the use of an inactivated recombinant vaccine. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    The human papillomavirus (HPV) only infects humans. An infection from this virus can cause squamous cell cervical cancer and cervical adenocarcinoma and their precursor lesions, which are cervical intraepithelial neoplasia (CIN) 1, 2, and 3 and adenocarcinoma in situ (AIS), respectively. HPV also causes anal cancer, vulvar cancer, vaginal cancer, and genital warts (condyloma acuminata), which are growths of the cervicovaginal, vulvar, and the external genitalia that rarely progress to cancer. The HPV 6, 11, 16, and 18 types cause 35—50% of all CIN 1, VIN 1, and VaIN 1 cases and 90% of genital wart cases. Further, the HPV 16 and 18 types cause approximately 70% of cervical cancer, AIS, CIN 3, VIN 2/3, and VaIN 2/3 cases and 50% of CIN 2 cases.
     
    The exact mechanism by which the HPV 9-valent vaccine protects against type-specific HPV infection and sequela is unknown. Receipt of the HPV 9-valent vaccine is thought to result in a humoral immune response directed against HPV-L1 capsid proteins. The vaccine contains recombinant L1 protein, which is the major antigenic protein of the capsid of HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. These L1 proteins are produced in brewers yeast (i.e., Saccharomyces cerevisiae), purified, and adsorbed on an aluminum-containing adjuvant (amorphous aluminium hydroxyphosphate sulfate or AAHS).
     
    The HPV 9-valent vaccine series elicited detectable antibody concentrations against those HPV types contained within the vaccine; however, the minimum anti-HPV titer needed to confer protective efficacy has not been determined. To evaluate efficacy against HPV types 31, 33, 45, 52, and 58, the vaccine was administered to 7,099 girls and women age 16 to 26 years. In this study primary efficacy was determined based on a composite clinical endpoint of cervical, vulvar, vaginal cancers and neoplasia. An analysis of the data starting 7 months post-dose found the vaccine to be effective in preventing HPV type 31-, 33-, 45-, 52-, and 58-related persistent infections and diseases, as observed through a reduction in the incidence of Pap test abnormalities, cervical and external genital biopsy, and definitive therapy. For HPV 6, 11, 16, and 18, immunogenicity was determined by comparing the vaccine induced geometric mean titers (GMTs) with those induced by the HPV quadrivalent vaccine (Gardasil quadrivalent). At 7 months post-dose, Gardasil 9 was found to be non-inferior to Gardasil quadrivalent, with 99.7% of girls and women (age 9—26 years) becoming seropositive for each of the 4 HPV types. Results from these two studies were subsequently used to infer vaccine efficacy in boys and girls age 9 to 15 years. This was accomplished through a non-inferiority comparison of the GMTs in boys and girl age 9 to 15 years with those observed in females age 16 to 26 years.
     
    One study evaluated the immune response to Gardasil 9 in 921 girls and women (ages 12 to 26 years) who had recently received (within a 1 year period) 3 Gardasil quadrivalent injections. Data from this study found the anti-HPV 31, 33, 45, 52, and 58 GMTs induced by Gardasil 9 to be 25—63% of those that were observed in Gardasil 9 recipients who had not previously received Gardasil quadrivalent. The clinical relevance if these results are unknown. Efficacy of Gardasil 9 in preventing infections/diseases from HPV types 31, 33, 45, 52, and 58 in individuals previously vaccinated with Gardasil quadrivalent has not been evaluated.
     
    The duration of immunity after vaccination with the Gardasil 9 series has not been established. Peak anti-HPV GMTs are observed at month 7; however despite the decline after month 7, a similar proportion of vaccine recipients remain seropositive to each vaccine HPV type at month 24.

    PHARMACOKINETICS

    The human papillomavirus 9-valent vaccine is administered intramuscularly. Vaccination does not ensure immunity. Distrubution, metabolism, and excretion of the vaccine have not been defined.
     
    Pooled data from clinical trials found >= 99.5% of vaccine recipients became seropositive for each of the 9 human papillomavirus (HPV) types contained within the vaccine by month 7. Peak anti-HPV geometric mean titers (GMTs) are observed at month 7; however despite the decline after month 7, a similar proportion of vaccine recipients remain seropositive to each vaccine HPV type at month 24. The duration of immunity has not been established.