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  • CLASSES

    Papillomavirus Vaccines

    DEA CLASS

    Rx

    DESCRIPTION

    Non-infectious recombinant vaccine
    Used to prevent HPV infection and associated diseases caused by HPV types 16 and 18
    Only for prophylaxis; not a treatment for HPV infection

    COMMON BRAND NAMES

    Cervarix

    DOSAGE & INDICATIONS

    For human papillomavirus (HPV) infection prophylaxis.
    Intramuscular dosage
    Female Adults, Adolescents, and Children aged 9 to 25 years

    0.5 mL IM for 3 doses. ACIP recommends the vaccine to be administered at age 9 years to children with any history of sexual abuse or assault. For routine vaccination, administer the first dose at age 11 to 12 years or any time between 13 and 26 years, if not previously vaccinated. Administer the second dose 4 to 8 weeks after the first, and the third dose 24 weeks after the first dose and 16 weeks (minimum interval of 12 weeks) after the second dose. The FDA-approved schedule is to administer the first dose at an elected date, the second dose 1 month after that, and the third dose 6 months after the first dose.

    MAXIMUM DOSAGE

    Adults

    > 25 years: Safety and efficacy not established.
    18—25 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. After thorough agitation, the vaccine is a homogenous, turbid, 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. A fine, white deposit with a clear, colorless supernatant may be observed in a vaccine that has been stored. The fine, white deposit is normal and is not a sign of deterioration.
    Prior to administration, clean skin over the injection site with a suitable cleansing agent.
    Attach a sterile needle to the  prefilled syringe by twisting in a clockwise direction. Administer entire dose contained within the syringe.
    The preferred administration site is the deltoid region of the upper arm. 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. Discard if the vaccine has been frozen.

    STORAGE

    Cervarix:
    - Discard if product has been frozen
    - Do not freeze
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

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

    The human papillomavirus bivalent 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.

    Children, geriatric, infants, neonates

    The human papillomavirus (HPV) bivalent vaccine, like other HPV vaccines, is not recommended for use in geriatric patients, nor is it approved for use in neonates, infants, or children less than 9 years of age. The vaccine is only recommended for use by individuals 9—25 years of age.

    Latex hypersensitivity

     Human papillomavirus bivalent vaccine is contraindicated for use by patients with severe allergic reactions such as anaphylaxis to any component of the vaccine. Patients who have latex hypersensitivity may be inappropriate candidates for the vaccine as the tip caps of the prefilled syringes may contain natural rubber latex. Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of the vaccine should not receive further doses. 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.

    Fever

    The decision to administer or to delay vaccination with the human papillomavirus bivalent 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.

    Pregnancy

    The human papillomavirus bivalent 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. During clinical trials, a total of 7,276 pregnancies were reported (3,696 in the vaccine group and 3,580 in the control group). The majority of women in both groups gave birth to normal infants; however, 11% of the vaccine recipients and 10.8% of patients in the control group experienced spontaneous abortions. Among women who had their last menstrual period (LMP) within 30 days before or 45 days after a vaccine dose, 13.6% of 396 women had a spontaneous abortion whereas 9.6% of 365 control recipients had the outcome. A post-hoc analysis of pregnancy data with known outcomes found that compared with the control group (n = 33/338), exposure to 1 dose of the vaccine (n = 46/326) between 45 days prior to and 35 days after the LMP had a relative risk for spontaneous abortion of 1.55 (95% CI: 0.95, 2.54); if exposed to 2 vaccine doses (n = 8/71) during this time, the relative risk was 1.21 (95% CI: 0.27, 7.33). In a retrospective, observational cohort study, pregnancy data from women exposed to >= 1 vaccine doses between 45 days prior to and 35 days after the LMP (close exposure) was compare with those exposed between 18 months and 120 days prior to the LMP (remote exposure). The hazard ratio for spontaneous abortion for the close exposure group (n = 23/207) was 1.26 (95% CI: 0.77, 2.09) when compared against the remote exposure cohort (n = 56/632).

    Breast-feeding

    Data are limited regarding use of the human papillomavirus bivalent vaccine during breast-feeding and its excretion in human milk is unknown. The manufacturer recommends caution when administering to nursing women; however according to 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.

    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 bivalent 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.

    Syncope

    Injectable vaccines, including human papillomavirus bivalent vaccine, have been associated with episodes of syncope and fainting. These events may be accompanied by transient tonic-clonic limb movements and seizure-like activities. Prior to administration of the vaccine, 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.

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    myelitis / Delayed / 0-1.0
    lupus-like symptoms / Delayed / 0-1.0
    optic neuritis / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0

    Moderate

    erythema / Early / 48.4-48.4
    edema / Delayed / 44.3-44.3
    thrombocytopenia / Delayed / 0-1.0
    psoriasis / Delayed / 0-1.0
    hyperthyroidism / Delayed / 0-1.0
    diabetes mellitus / Delayed / 0-1.0
    hypothyroidism / Delayed / 0-1.0
    lymphadenopathy / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 0-91.9
    fatigue / Early / 54.6-54.6
    headache / Early / 0-53.4
    myalgia / Early / 48.8-48.8
    nausea / Early / 27.9-27.9
    abdominal pain / Early / 27.9-27.9
    diarrhea / Early / 27.9-27.9
    vomiting / Early / 27.9-27.9
    arthralgia / Delayed / 20.7-20.7
    fever / Early / 12.9-12.9
    rash / Early / 9.5-9.5
    urticaria / Rapid / 7.2-7.2
    pharyngitis / Delayed / 1.4-3.7
    influenza / Delayed / 3.1-3.1
    dizziness / Early / 2.2-2.2
    infection / Delayed / 0-2.0
    dysmenorrhea / Delayed / 1.9-1.9
    pruritus / Rapid / 1.3-1.3
    back pain / Delayed / 1.1-1.1
    syncope / Early / Incidence not known

    DRUG INTERACTIONS

    Ocrelizumab: (Moderate) Administer all non-live vaccines at least 2 weeks before ocrelizumab initiation, whenever possible. Ocrelizumab may interfere with the effectiveness of non-live virus vaccines. Attenuated antibody responses to tetanus toxoid-containing vaccine, pneumococcal polysaccharide and pneumococcal conjugate vaccines, and seasonal influenza vaccine were observed in patients exposed to ocrelizumab at the time of vaccination during an open-label study. Infants born to mothers exposed to ocrelizumab during pregnancy may receive non-live vaccines as indicated before B-cell recovery; however, consider assessing the immune response to the vaccine. ACIP recommends that patients receiving any vaccination during immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated a minimum of 3 months after discontinuation of therapy. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination.

    PREGNANCY AND LACTATION

    Pregnancy

    The human papillomavirus bivalent 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. During clinical trials, a total of 7,276 pregnancies were reported (3,696 in the vaccine group and 3,580 in the control group). The majority of women in both groups gave birth to normal infants; however, 11% of the vaccine recipients and 10.8% of patients in the control group experienced spontaneous abortions. Among women who had their last menstrual period (LMP) within 30 days before or 45 days after a vaccine dose, 13.6% of 396 women had a spontaneous abortion whereas 9.6% of 365 control recipients had the outcome. A post-hoc analysis of pregnancy data with known outcomes found that compared with the control group (n = 33/338), exposure to 1 dose of the vaccine (n = 46/326) between 45 days prior to and 35 days after the LMP had a relative risk for spontaneous abortion of 1.55 (95% CI: 0.95, 2.54); if exposed to 2 vaccine doses (n = 8/71) during this time, the relative risk was 1.21 (95% CI: 0.27, 7.33). In a retrospective, observational cohort study, pregnancy data from women exposed to >= 1 vaccine doses between 45 days prior to and 35 days after the LMP (close exposure) was compare with those exposed between 18 months and 120 days prior to the LMP (remote exposure). The hazard ratio for spontaneous abortion for the close exposure group (n = 23/207) was 1.26 (95% CI: 0.77, 2.09) when compared against the remote exposure cohort (n = 56/632).

    Data are limited regarding use of the human papillomavirus bivalent vaccine during breast-feeding and its excretion in human milk is unknown. The manufacturer recommends caution when administering to nursing women; however according to 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.

    MECHANISM OF ACTION

    The human papillomavirus (HPV) only infects humans. An infection from this virus can cause squamous cell cervical cancer, 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 bivalent vaccine protects against type-specific HPV infection and sequela is unknown. Receipt of the HPV bivalent vaccine may cause development of IgG neutralizing antibodies directed against HPV-L1 capsid proteins. The vaccine contains recombinant L1 protein, which is the major antigenic protein of the capsid of HPV types 16 and 18. These L1 proteins are produced using a recombinant Baculovirus expression vector in Trichoplusia ni insect cells. The proteins are then purified and assembled into an adjuvant system composed of 3-O-desacyl-4-monophosphoryl lipid A (MPL) adsorbed to aluminum hydroxide.
     
    Efficacy of the 3-dose HPV bivalent vaccine series was evaluated in 2 clinical studies involving a total of 19,778 females, age 15—25 years. The first study enrolled females who were negative for oncogenic HPV DNA types 16 and 18 in cervical samples and seronegative for HPV 16 and 18 antibodies at the time of vaccination. Results from this study found efficacy against CIN 2/3 or AIS associated with HPV-16 or HPV-18 to be 100% (98.67% CI: 28.4, 100). Efficacy against 12-month persistent infection with HPV-16 or HPV-18 was also 100% (98.67% CI: 74.4, 100). The second study enrolled females regardless of baseline HPV DNA status, serostatus, or cytology. In this study, the vaccine was effective against CIN 1/2/3 or AIS associated with HPV-16 or HPV-18 (91.7% (96.1% CI: 82.4, 96.7). Efficacy against 12-month persistent infection with HPV-16 or HPV-18 was 91.4% (96.1% CI: 89.4, 95.4). However, no definitive evidence for vaccine-induced protection against HPV 16- or HPV 18-associated precancerous lesions or AIS was found among women who were HPV DNA positive regardless of serostatus at baseline.
     
    Inoculation with the HPV bivalent vaccine elicited detectable antibody concentrations to HPV type 16 and 18. Most patients (> 98%) were seropositive for both HPV 16 and HPV 18 at all timepoints during clinical trials; however, the minimum anti-HPV titer that confers protective efficacy has not been determined. After the 3-dose vaccine series, geometric mean titers for both anti-HPV 16 and anti-HPV18 peaked at month 7 and reached a plateau that was sustained from month 18 up to month 76. The duration of immunity after a complete schedule of immunization has not been established.

    PHARMACOKINETICS

    The human papillomavirus (HPV) bivalent vaccine is administered intramuscularly. Vaccination does not ensure immunity. Distrubution, metabolism, and excretion of the vaccine have not been defined.
     
    Immunogenicity of the vaccine was assessed in women 15—25 years of age who received the recommended schedule of 3 doses (baseline, 1 month later, and then 5 months later). Vaccine-induced geometric mean titers for both HPV 16 and HPV 18 peaked at month 7 and reached a plateau that was sustained up to month 76. Over this time period, more than 98% of patients were seropositive for both HPV types.