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    Papillomavirus Vaccines

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant vaccine
    Used for immunization against HPV types 6, 11, 16, and 18
    Only for prophylaxis; not for HPV treatment

    COMMON BRAND NAMES

    Gardasil

    HOW SUPPLIED

    Gardasil Intramuscular Inj Susp

    DOSAGE & INDICATIONS

    For human papillomavirus (HPV) infection prophylaxis.
    For HPV infection prophylaxis in adult females outside of FDA-approved populations†.
    Intramuscular dosage
    Female Adults aged 27 to 45 years†

    There is some evidence that HPV vaccination outside of FDA-approved populations may be effective at preventing HPV infection and related genital disease in female adults. In a randomized clinical trial, 4 of 1,615 4vHPV vaccine recipients (3-dose series of 0.5 mL IM at 0, 2, and 6 months) had infection of at least 6 months duration and cervical and external genital disease related to HPV 6, 11, 16, and 18 after series completion vs. 41 of 1,607 placebo recipients. However, routine vaccination is not recommended by the CDC, as the expected population-level impact of HPV vaccination in this female age group is lower than that for younger females, as mid-adult women may have already had vaccine type infection thus lowering the percent of incident infection and resulting disease that could be prevented.

    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 dose.

    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 years to 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, ACIP recommends giving 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 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.

    MAXIMUM DOSAGE

    Adults

    > 26 years: Safety and efficacy not established.
    18—26 years: 0.5 mL/dose IM.

    Geriatric

    Safety and efficacy not established.

    Adolescents

    0.5 mL/dose IM.

    Children

    >= 9 years: 0.5 mL/dose IM.
    < 9 years: 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.
    Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine.
    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 region of the upper arm or in 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.
    Carefully observe patients for approximately 15 minutes after administration of the vaccine; syncope may occur.
    Storage of unopened vials: 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. The vaccine can remain outside of refrigeration at temperatures up to 25 degrees C (77 degrees F) for a total cumulative time of not more than 72 hours.

    STORAGE

    Gardasil:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from freezing
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Yeast hypersensitivity

    Human papillomavirus (HPV) quadrivalent 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. 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 quadrivalent 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 quadrivalent 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 quadrivalent 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 quadrivalent 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 quadrivalent vaccine have not been established in neonates, infants, nor children < 9 years of age.

    Pregnancy

    The human papillomavirus quadrivalent vaccine is rated FDA pregnancy risk category B. No adequate and well controlled studies have been conducted in pregnant women, and 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, the remainder of the 3-dose regimen should be delayed until after completion of the pregnancy. In clinical trials, women were tested for pregnancy before each dose. Completion of a pregnant woman's vaccination regimen was deferred until pregnancy resolution. Overall 1,973 women were exposed to the vaccine during pregnancy, with 22.6% (n = 446/1,973) experiencing an adverse outcome (i.e., spontaneous abortion, late fetal death, congenital anomaly). This rate was less than in women who received the placebo control 23.1% (n = 460/1,994). For congenital anomalies specifically, 45 cases occurred in recipients of the vaccine compared to 34 cases with the placebo control. The majority of these cases had an onset of greater than 30 days post-dose (40 cases vaccine, 33 cases placebo control). The anomalies that occurred with an estimated onset within 30 days of vaccination (n= 5) included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, and club foot. The manufacturer recommends administration of the vaccine during pregnancy only if clearly needed. Vaccinees and health care providers are encouraged to report any exposure to the vaccine during pregnancy by calling 1—877—888—4231 or 1—800—822—7967.

    Breast-feeding

    Data are limited regarding use of the human papillomavirus quadrivalent vaccine during breast-feeding and its excretion in human milk is unknown. During clinical studies, a total of 582 infants were breast-fed during the period in which their mothers were vaccinated. Of those infants, 4.6% (n = 27) experiencing a serious adverse reactions, with 7 of these reactions (acute respiratory illness) occurring within 30 days of the maternal vaccination. 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

    pulmonary embolism / Delayed / 0-0.1
    anaphylactic shock / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    uveitis / Delayed / Incidence not known
    muscle paralysis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    Guillain-Barre syndrome / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known

    Moderate

    edema / Delayed / 13.9-25.4
    erythema / Early / 16.7-24.7
    hematoma / Early / 1.0-2.8
    lymphadenopathy / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    hypothyroidism / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    psoriasis / Delayed / Incidence not known
    hyperthyroidism / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    acute disseminated encephalomyelitis / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 0-83.9
    headache / Early / 12.3-28.2
    fever / Early / 8.3-13.0
    nausea / Early / 2.0-6.7
    dizziness / Early / 4.0-4.0
    diarrhea / Early / 2.7-3.6
    pruritus / Rapid / 3.2-3.2
    pharyngitis / Delayed / 2.6-2.6
    vomiting / Early / 1.0-2.4
    cough / Delayed / 2.0-2.0
    infection / Delayed / 0-1.5
    dental pain / Delayed / 1.5-1.5
    abdominal pain / Early / 1.4-1.4
    myalgia / Early / 1.3-1.3
    insomnia / Early / 1.2-1.2
    nasal congestion / Early / 1.1-1.1
    arthralgia / Delayed / 1.1-1.1
    urticaria / Rapid / Incidence not known
    malaise / Early / Incidence not known
    purpura / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    fatigue / Early / Incidence not known
    skin hypopigmentation / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    syncope / Early / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Human Papillomavirus Quadrivalent Vaccine products.

    PREGNANCY AND LACTATION

    Pregnancy

    The human papillomavirus quadrivalent vaccine is rated FDA pregnancy risk category B. No adequate and well controlled studies have been conducted in pregnant women, and 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, the remainder of the 3-dose regimen should be delayed until after completion of the pregnancy. In clinical trials, women were tested for pregnancy before each dose. Completion of a pregnant woman's vaccination regimen was deferred until pregnancy resolution. Overall 1,973 women were exposed to the vaccine during pregnancy, with 22.6% (n = 446/1,973) experiencing an adverse outcome (i.e., spontaneous abortion, late fetal death, congenital anomaly). This rate was less than in women who received the placebo control 23.1% (n = 460/1,994). For congenital anomalies specifically, 45 cases occurred in recipients of the vaccine compared to 34 cases with the placebo control. The majority of these cases had an onset of greater than 30 days post-dose (40 cases vaccine, 33 cases placebo control). The anomalies that occurred with an estimated onset within 30 days of vaccination (n= 5) included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, and club foot. The manufacturer recommends administration of the vaccine during pregnancy only if clearly needed. Vaccinees and health care providers are encouraged to report any exposure to the vaccine during pregnancy by calling 1—877—888—4231 or 1—800—822—7967.

    Data are limited regarding use of the human papillomavirus quadrivalent vaccine during breast-feeding and its excretion in human milk is unknown. During clinical studies, a total of 582 infants were breast-fed during the period in which their mothers were vaccinated. Of those infants, 4.6% (n = 27) experiencing a serious adverse reactions, with 7 of these reactions (acute respiratory illness) occurring within 30 days of the maternal vaccination. 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 quadrivalent vaccine protects against type-specific HPV infection and sequela is unknown. Receipt of the HPV quadrivalent 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, and 18. 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).
     
    Efficacy of the 3-dose HPV quadrivalent vaccine series was established through 6 clinical studies involving a total of 28,413 vaccine recipients (20,541 females ages 16—26 years; 4055 males ages 16—26; 3817 women ages 25—45 years). The percentage of study participants who were naive to all 4 vaccine HPV types at baseline include 73% of females ages 16—26 years, 83% of males ages 16—26 years, and 67% of women ages 24—45 years. Data from these studies found the vaccine to be more than 93% efficacious in preventing cervical and genital diseases associated with HPV type 6, 11, 16 and 18 in females aged 16—26 years who were HPV naive at baseline. In HPV naive women aged 24—45 years, the vaccine was found to be 80.5% (95% CI: 68.3, 88.6) effective in preventing persistent infection, 85.8% (95% CI: 52.4, 97.3) effective in preventing cervical intraepithelial neoplasia (any grade), and 87.6% (95% CI: 7.3, 99.7) effective in preventing genital warts. The vaccine was also effective in HPV naive males (age 16—26 years) in reducing anal intraepithelial neoplasia related to all 4 HPV types and genital warts related to HPV type 6 and 11. However, evident to suggest vaccine efficacy in individuals previously exposed to HPV type 6, 11, 16 or 18 is not available. In addition, the vaccine was not found to provide cross-protection against HPV types not contained within the vaccine, nor was it found to protect against genital diseases not related to HPV.
     
    The long-term protection of the HPV quadrivalent vaccine continues to be studied. Two extension studies have reported data regarding the long-term protection of the HPV quadrivalent vaccine against HPV-related disease. In a trial including 1902 females 16—23 years of age who completed the 3-dose vaccination series, the median follow-up from initial vaccination was 6.7 years (2.8—8.4 years). No cases of HPV 6-, 11-, 16-, or 18-related CIN, AIS, cervical cancer, vulvar cancer, or vaginal cancer were observed over a total of 5765 person-years at risk. In an extension of a Phase 3 study, including 246 girls and 168 boys who completed the HPV quadrivalent vaccine series, the mean follow-up from the first dose of vaccine was 7.2 years (0.5—8.5 years). No cases of persistent infection of at least 12 months’ duration and no cases of HPV 6-, 11-, 16-, or 18-related CIN, AIS, VIN, VaIN, cervical cancer, vulvar cancer, vaginal cancer, or genital lesions were observed over a total 1105 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.
     
    Inoculation with the HPV quadrivalent vaccine elicited detectable antibody concentrations to HPV type 6, 11, 16, and 18. Most vaccine recipients (> 97%) are seropositive for all 4 HPV types at 1 month after the third dose; however, the minimum anti-HPV titer that confers protective efficacy has not been determined. After the 3-doses vaccine series, geometric mean titers for anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 peaked at month 7, declined through month 24, and stabilized through month 36 at levels above baseline; titers at month 60 were similar to those observed at month 24 for all 4 HPV types. The interim reports of 2 extension studies included analysis of type-specific anti-HPV antibody titers at 9 years postdose 1 for girls and women 16 through 23 years of age and at 8 years postdose 1 for boys and girls 9 through 15 years of age at enrollment. The proportions of seropositive subjects ranged from 88.4% to 94.4% for anti-HPV 6, from 89.1% to 95.5% for anti-HPV 11, from 96.8% to 99.1% for anti-HPV 16, and from 60.0% to 64.1% for anti-HPV 18.

    PHARMACOKINETICS

    The human papillomavirus (HPV) quadrivalent vaccine is administered intramuscularly. Vaccination does not ensure immunity. Distrubution, metabolism, and excretion of the vaccine have not been defined.
     
    During clinical trials, immunogenicity of the HPV quadrivalent vaccine was evaluated in 12,634 females (age 9 to 45 years) and 3,109 males (age 9 to 45 years). Immunity was determine by measuring geometric mean titers for each of the 4 HPV type, and determining the percentage of vaccine recipients who were seropositive for antibodies against those HPV types. Overall, a seropositive immune response was observed in more than 99% of females (age 16 to 26 years), more than 97% of women (age 27 to 45 years), and more than 97% of males (age 16 to 26 years). In all three groups, immunity was assessed 1 month after the third vaccine dose. Geometric mean titer peak at month 7, declined through month 24, then stabilize through month 36 at levels above baseline; titers at month 60 are similar to those observed at month 24 for all 4 HPV types. The interim reports of 2 extension studies included analysis of type-specific anti-HPV antibody titers at 9 years post-dose 1 for girls and women 16 through 23 years of age and at 8 years post-dose 1 for boys and girls 9 through 15 years of age at enrollment. The proportions of seropositive subjects ranged from 88.4% to 94.4% for anti-HPV 6, from 89.1% to 95.5% for anti-HPV 11, from 96.8% to 99.1% for anti-HPV 16, and from 60.0% to 64.1% for anti-HPV 18.