Human Papillomavirus Vaccine

Class: Vaccines
ATC Class: J07BF01
VA Class: IM100
Brands: Cervarix, Gardasil

Introduction

Inactivated (recombinant) virus vaccine.1 4 5 10 11 12 37 Commercially available in US as a bivalent and a quadrivalent vaccine containing virus-like particles (VLPs) of the major capsid (L1) proteins of certain human papillomavirus (HPV) types.1 37 Human papillomavirus bivalent (types 16 and 18) vaccine, recombinant (HPV2; Cervarix) contains VLPs of HPV types 16 and 18;37 human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant (HPV4; Gardasil) contains VLPs of HPV types 6, 11, 16, and 18.1 Used to stimulate active immunity to HPV serotypes represented in the vaccine.1 4 5 10 11 12 37 Other HPV vaccines are being investigated or may be available in other countries.4 5 6 10 12 14

Uses for Human Papillomavirus Vaccine

Prevention of Disease Caused by HPV

HPV2 (Cervarix): Prevention of cervical cancer, cervical intraepithelial neoplasia (CIN) grades 1, 2, or worse, and cervical adenocarcinoma in situ (AIS) caused by HPV types 16 and 18 in females 9 through 25 years of age.37

HPV4 (Gardasil): Prevention of cervical, vulvar, vaginal, and anal cancer caused by HPV types 16 and 18 in females 9 through 26 years of age.1 Also used for prevention of precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18, including CIN grades 1 and 2/3, cervical AIS, vulvar intraepithelial neoplasia (VIN) grades 2 and 3, vaginal intraepithelial neoplasia (VaIN) grades 2 and 3, and anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 in females 9 through 26 years of age.1

HPV4 (Gardasil): Prevention of anal cancer caused by HPV types 16 and 18 and prevention of precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18, including AIN grades 1, 2, and 3, in males 9 through 26 years of age.1

HPV4 (Gardasil): Prevention of genital warts (condyloma acuminata) caused by HPV types 6 and 11 in females and males 9 through 26 years of age.1

Anogenital HPV is the most common sexually transmitted infection in US;8 14 19 105 166 approximately 20 million individuals already infected and 6.2 million more become infected each year.8 166 Most HPV infections are asymptomatic and resolve spontaneously within 1–2 years,7 8 14 19 but some low-risk HPV types cause anogenital warts (condyloma acuminata) and some high-risk HPV types are associated with persistent anogenital infections, dysplastic lesions, and development of cervical and other anogenital cancers (e.g., penile, vulvar, vaginal, anal).7 8 14 19 105 166 HPV types 6 and 11 cause about 90% of all cases of genital warts and HPV types 16 and 18 cause about 70% of all cases of cervical and anogenital cancer in females and about 70% of all cases of anal cancer in males.7 14 166

Slideshow: HealthQuiz: Basics About Stroke Signs and Symptoms

USPHS Advisory Committee on Immunization Practices (ACIP), AAP, and others recommend routine vaccination against HPV in all females 9 through 26 years of age using a 3-dose series of HPV vaccine.7 8 19 28 50 199 200 These experts state either HPV2 (Cervarix) or HPV4 (Gardasil) can be used for routine vaccination in these females.50 200

ACIP, AAP, and others recommend routine vaccination against HPV in all males 9 through 21 years of age using a 3-dose series of HPV4 (Gardasil).19 56 199 200 These experts also recommend vaccination with a 3-dose series of HPV4 for previously unvaccinated males 22 through 26 years of age who have sex with men or are immunocompromised, including those with HIV infection.19 56 200 HPV4 also may be used in other previously unvaccinated males 22 through 26 years of age who desire protection against HPV.19 56 200

Ideally, administer HPV vaccine before potential exposure to HPV occurs through sexual activity; however, age-appropriate individuals who are sexually active should still be vaccinated since vaccination may provide protection against infection with vaccine HPV types not already acquired.1 8 19 28 50 56

Prevaccination testing or screening for HPV DNA or HPV antibody not needed and not recommended.8 50 HPV vaccine may be used in age-appropriate individuals with or without prior exposure to HPV and in women with equivocal or abnormal Papanicolaou (Pap) tests, positive HPV DNA tests (Hybrid Capture 2 [HC2] high-risk test), or genital warts.8 19 200

Does not prevent infection or disease caused by HPV types not represented in the vaccine.1 8 12

Does not provide protection against disease from vaccine and nonvaccine HPV types to which an individual has previously been exposed through sexual activity.1 37

Not all vulvar and vaginal cancers are caused by HPV; HPV vaccine protects only against those vulvar and vaginal cancers caused by HPV types 16 and 18.1

Not used for treatment of active genital warts and not used for treatment of precancerous or dysplastic lesions (e.g., AIN, CIN, VIN, VaIN) or cervical, vulvar, vaginal, or anal cancer.1 8 14

HPV2 (Cervarix): Safety and efficacy not established in females <9 years of age or ≥26 years of age.37 Safety and efficacy not established in males of any age.37

HPV4 (Gardasil): Safety and efficacy not established in females or males <9 years of age or ≥27 years of age.1 8 Available data to date have not shown HPV4 to be effective for prevention of HPV-related CIN 2/3 or worse in females ≥27 years of age.1 55

Human Papillomavirus Vaccine Dosage and Administration

Administration

IM Administration

Administer by IM injection.1 37

Do not administer IV, sub-Q, or intradermally.1 37

Administer IM in deltoid region of upper arm1 37 or anterolateral aspect of upper thigh.1

To ensure delivery of vaccine into muscle, make IM injections at a 90° angle to the skin using a needle length appropriate for the individual’s age and body mass, thickness of adipose tissue and muscle at injection site, and injection technique.134

Shake well immediately prior to administration to provide a uniform, white, cloudy suspension.1 37 Discard if vaccine contains particulates, appears discolored, or cannot be resuspended with thorough agitation.1 37

Do not dilute; do not mix with any other vaccine or solution.1 37

Syncope (vasovagal or vasodepressor reaction; fainting) may occur following vaccination;1 37 134 may be accompanied by transient neurologic signs (e.g., visual disturbance, paresthesia, tonic-clonic limb movements).37 134 Occurs most frequently in adolescents and young adults.134 Have procedures in place to avoid falling injury and restore cerebral perfusion following syncope.134 Syncope and secondary injuries may be averted if vaccinees sit or lie down during and for 15 minutes after vaccination.134 If syncope occurs, observe patient until symptoms resolve.134 (See Syncope under Cautions.)

May be given simultaneously with other age-appropriate vaccines.8 19 134 (See Interactions.) When multiple vaccines are administered during a single health-care visit, each parenteral vaccine should be given with a different syringe and at different anatomic sites.134 Injection sites should be separated by at least 1 inch (if anatomically feasible) to allow appropriate attribution of any local adverse effects that may occur.134

Dosage

Data not available regarding interchangeability of HPV2 (Cervarix) and HPV4 (Gardasil).45 50 105 Although ACIP and AAP recommend that the HPV vaccine used for the initial dose be used to complete the vaccination series whenever feasible, either HPV vaccine can be used to complete the series in females if the HPV vaccine previously administered is unknown or not available.50 105

If interruptions occur resulting in an interval between doses longer than recommended, there is no need to start the vaccination series over.8 50 105

Pediatric Patients

Prevention of Disease Caused by HPV
Females 9 through 18 Years of Age (HPV2; Cervarix)
IM

Primary immunization consists of a series of 3 doses.37 199 Each dose consists of entire contents (0.5 mL) of commercially available single-dose prefilled syringe.37

Manufacturer states give second and third dose 1 and 6 months, respectively, after first dose.37

ACIP, AAP, and others recommend giving first dose at 11 through 12 years of age, second dose 1–2 months after first dose, and third dose 6 months after first dose (at least 12 weeks after second dose and at least 24 weeks after first dose).28 50 199 200

Initial dose may be given to females as young as 9 years of age at the discretion of the clinician.19 37 50 199

Catch-up vaccination recommended for adolescent females 13 through 18 years of age who have not previously received the complete 3-dose series.28 50 199 200 Give second dose 1–2 months after first dose and give third dose 6 months after first dose (at least 12 weeks after second dose and at least 24 weeks after first dose).50 199

Duration of immunity following recommended 3-dose vaccination series and need for additional (booster) doses not determined.8 19 37 (See Duration of Immunity under Cautions.)

Females 9 through 18 Years of Age (HPV4; Gardasil)
IM

Primary immunization consists of a series of 3 doses.1 199 Each dose consists of entire contents (0.5 mL) of commercially available single-dose vial or prefilled syringe.1

Manufacturer states give second and third doses 2 and 6 months, respectively, after first dose.1

ACIP, AAP, and others recommend giving first dose at 11 through 12 years of age, second dose 1–2 months after first dose, and third dose 6 months after first dose (at least 12 weeks after second dose and at least 24 weeks after first dose).8 19 50 199

Initial dose may be given to females as young as 9 years of age at the discretion of the clinician.1 8 19 50 199

Catch-up vaccination recommended for adolescent females 13 through 18 years of age who have not previously received the complete 3-dose series.8 19 50 199 200 Give second dose 1–2 months after first dose and give third dose 6 months after first dose (at least 12 weeks after second dose and at least 24 weeks after first dose).50 199

Duration of immunity following recommended 3-dose vaccination series and need for additional (booster) doses not determined.1 4 11 12 13 14 19 20 21 (See Duration of Immunity under Cautions.)

Males 9 through 18 Years of Age (HPV4; Gardasil)
IM

Primary immunization consists of a series of 3 doses.1 56 199 Each dose consists of entire contents (0.5 mL) of commercially available single-dose vial or prefilled syringe.1

Manufacturer states give second and third doses at 2 and 6 months, respectively, after first dose.1

ACIP, AAP, and others recommend giving first dose at 11 through 12 years of age, second dose 1–2 months after first dose, and third dose 6 months after first dose (at least 12 weeks after second dose and at least 24 weeks after first dose).19 199

Initial dose may be given to males as young as 9 years of age at the discretion of the clinician.1 19 56 199

Catch-up vaccination recommended for adolescent males 13 through 18 years of age who have not previously received the complete 3-dose series.19 56 199 200 Give second dose 1–2 months after first dose and give third dose 6 months after first dose (at least 12 weeks after second dose and at least 24 weeks after first dose).19 199 200

Duration of immunity following recommended 3-dose vaccination series and need for additional (booster) doses not determined.1 4 11 12 13 14 19 20 21 (See Duration of Immunity under Cautions.)

Adults

Prevention of Disease Caused by HPV
Females 19 through 25 Years of Age (HPV2; Cervarix)
IM

Primary immunization consists of a series of 3 doses.37 200 Each dose consists of entire contents (0.5 mL) of commercially available single-dose vial or prefilled syringe.37

Manufacturer states give second and third doses at 1 and 6 months, respectively, after first dose.37

Catch-up vaccination recommended for females 19 through 25 years of age who are unvaccinated or incompletely vaccinated.19 50 200 Give second dose 1–2 months after first dose and give third dose 6 months after first dose (at least 12 weeks after second dose and at least 24 weeks after first dose).19 50 200

Duration of immunity following the recommended 3-dose vaccination series and need for additional (booster) doses not determined.8 19 (See Duration of Immunity under Cautions.)

Females 19 Through 26 Years of Age (HPV4; Gardasil)
IM

Primary immunization consists of a series of 3 doses.1 200 Each dose consists of entire contents (0.5 mL) of commercially available single-dose vial or prefilled syringe.1

Manufacturer states give second and third doses at 2 and 6 months, respectively, after first dose.1

Catch-up vaccination recommended for females 19 through 26 years of age who are unvaccinated or incompletely vaccinated.8 50 200 Give second dose 1–2 months after first dose and give third dose 6 months after first dose (at least 12 weeks after second dose and at least 24 weeks after first dose).50 200

Duration of immunity following recommended 3-dose vaccination series and need for additional (booster) doses not determined.1 4 8 11 12 13 14 20 21 (See Duration of Immunity under Cautions.)

Males 19 through 26 Years of Age (HPV4; Gardasil)
IM

Primary immunization consists of a series of 3 doses.1 56 200 Each dose consists of entire contents (0.5 mL) of commercially available single-dose vial or prefilled syringe.1

Manufacturer states give second and third doses 2 and 6 months, respectively, after initial dose.1

Catch-up vaccination recommended for males 19 through 21 years of age who are unvaccinated or incompletely vaccinated.56 199 200 Give second dose 1–2 months after first dose and give third dose 6 months after first dose (at least 24 weeks after first dose).200

Catch-up vaccination also recommended for males 22 through 26 years of age who are unvaccinated or incompletely vaccinated and have sex with men or are immunocompromised (including HIV-infected).56 200 Give second dose 1–2 months after first dose and give third dose 6 months after first dose (at least 24 weeks after first dose).200

Duration of immunity following recommended 3-dose vaccination series and need for additional (booster) doses not determined.1 4 11 12 13 14 20 21 (See Duration of Immunity under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations.1 37

Renal Impairment

No specific dosage recommendations.1 37

Geriatric Patients

Safety and efficacy not established in females or males ≥65 years of age.1 37

Cautions for Human Papillomavirus Vaccine

Contraindications

  • HPV2 (Cervarix): History of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine.37

  • HPV4 (Gardasil): Hypersensitivity to any vaccine component (including severe allergic reactions to yeast).1 8 19 Hypersensitivity to a previous dose.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylactic/anaphylactoid reactions, bronchospasm, urticaria, angioedema, generalized rash, erythema multiforme) reported.1 29 35 36 37

Most reported cases of anaphylaxis occurred following the first dose in the HPV vaccination series.36 In an Australian vaccination program in adolescents and women 12–26 years of age, the rate of anaphylaxis following HPV vaccination was 2.6 cases per 100,000 doses.36

The cause of hypersensitivity reactions following administration of HPV vaccine is unclear.35 36 When sensitivity tests were performed in individuals who had suspected anaphylaxis following a dose of HPV vaccine, skin prick or intradermal tests using the vaccine, yeast, or polysorbate 80 generally were negative.29 35 However, at least one patient had a positive intradermal test that was consistent with IgE-mediated hypersensitivity.35

Appropriate medical treatment and supervision must be available in case an anaphylactic reaction occurs following the administration of the vaccine.1 37

Yeast Allergy

HPV4 (Gardasil) is manufactured using Saccharomyces cerevisiae (yeast);1 each dose contains <7 mcg of yeast protein.1

Data from the Vaccine Adverse Event Reporting System (VAERS) indicate that recombinant yeast-derived vaccines pose a minimal risk for anaphylactic reactions in individuals with a history of allergic reactions to yeast.8 23

Latex Sensitivity

HPV2 (Cervarix): Some packaging components of prefilled single-dose syringes (i.e., tip cap and/or rubber plunger) contain dry natural latex.37 Some individuals may be hypersensitive to natural latex proteins.37

ACIP states that vaccines supplied in vials or syringes containing dry natural rubber or natural rubber latex may be administered to individuals with latex allergies other than anaphylactic allergies (e.g., history of contact allergy to latex gloves), but should not be used in those with a history of severe (anaphylactic) allergy to latex unless the benefits of vaccination outweigh the risk of a potential allergic reaction.134 Contact-type allergy is the most common type of latex sensitivity.134

Syncope

Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity reported following vaccination with HPV2 (Cervarix) or HPV4 (Gardasil).1 37 Tonic-clonic movements are transient and typically respond to restoration of cerebral perfusion by maintaining vaccinee in a supine or Trendelenburg position.1 37

Syncope also reported with other vaccines; occurs most frequently in adolescents and young adults.134

Observe vaccinee for 15 minutes following vaccination;1 37 have procedures in place to avoid falling injury and restore cerebral perfusion if syncope occurs.1 37 134 (See Administration under Dosage and Administration.)

Limitations of Vaccine Effectiveness

May not protect all vaccine recipients against HPV infection.1 8 37

Vaccination with HPV vaccine does not substitute for routine cervical cancer screening.1 19 37 Female recipients should continue to undergo cervical cancer screening (e.g., Pap tests) according to usual standards of care.1 37

Male and female recipients of HPV vaccine should continue anal cancer screening if recommended by health-care professional.1

HPV vaccine does not provide protection against disease due to HPV types not contained in the vaccine and does not provide protection from vaccine and non-vaccine HPV types an individual previously has been exposed to through sexual activity.1 37

May be used in patients who already have become infected with HPV (including HPV types represented in the vaccine).1 8 Although the vaccine will not provide any beneficial effects in regard to preexisting HPV infections, it will provide protection against the vaccine HPV types that the vaccinee has not already acquired.1 8 19

Not used for treatment of active genital warts.1

Not used for treatment of precancerous or dysplastic lesions (e.g., AIN, CIN, VIN, VaIN) and not used for treatment of cervical, vulvar, vaginal, or anal cancer.1

Duration of Immunity

Duration of immunity following the 3-dose vaccination series of HPV2 (Cervarix) or HPV4 (Gardasil) not determined.1 37

Data to date suggest that HPV2 induces anti-HPV antibody levels against HPV types 16 and 18 that are maintained for at least 6 years.37 51

Data to date suggest that HPV4 induces anti-HPV antibody levels against HPV types 6, 11, 16, and 18 that are maintained for at least 5 years.19 20 22

Concomitant Illness

A decision to administer or delay vaccination in an individual with a current or recent acute illness depends on the severity of symptoms and etiology of the illness.8 134

ACIP states that HPV vaccine may be administered to age-appropriate individuals with minor acute illnesses such as diarrhea or mild upper respiratory tract infection (with or without fever), but recommends deferring vaccination in those with moderate or severe acute illness (with or without fever).8 50 134

Individuals with Altered Immunocompetence

May be administered to individuals immunosuppressed as a result of disease (e.g., congenital immunodeficiency, HIV infection, hematologic or generalized malignancy) or immunosuppressive therapy.8 9 16 19 105 155 156 200 Consider possibility that the immune response to the vaccine and efficacy may be reduced in these individuals.1 8 9 37 105 156 200

Although data not available regarding safety, efficacy, and immunogenicity in individuals with HIV infection, ACIP, AAP, CDC, and others state that recommendations regarding use of HPV vaccine in HIV-infected individuals are the same as those for individuals who are not infected with HIV.155 156 HIV-infected individuals 9 through 26 years of age should receive the usually recommended 3-dose HPV vaccination series,19 56 200 preferably with HPV4 (Gardasil).19

Individuals with Bleeding Disorders

ACIP states that vaccines may be given IM to individuals who have bleeding disorders or are receiving anticoagulant therapy if a clinician familiar with the patient’s bleeding risk determines that the vaccine can be administered with reasonable safety.134 In these cases, use a fine needle (23 gauge) to administer the vaccine and apply firm pressure to the injection site (without rubbing) for ≥2 minutes.134 If patient is receiving therapy for hemophilia, administer the IM vaccine shortly after a scheduled dose of such therapy.134

Advise individual and/or their family about the risk of hematoma from IM injections.134

Improper Storage and Handling

Improper storage or handling of vaccines may reduce vaccine potency resulting in reduced or inadequate immune response in vaccinees.134

Inspect all vaccines upon delivery and monitor during storage to ensure that the appropriate temperature is maintained.134 (See Storage under Stability.)

Do not administer HPV vaccine that has been mishandled or has not been stored at the recommended temperature.8 37 134

If there are concerns about mishandling, contact the manufacturer or state or local immunization or health departments for guidance on whether the vaccine is usable.134

Specific Populations

Pregnancy

Category B.1 37

Manufacturers of HPV2 (Cervarix) and HPV4 (Gardasil) state use during pregnancy only when clearly needed.1 37

ACIP, AAP, ACOG, and others state HPV vaccine is not recommended for use in pregnant women.8 19 28 50 105 200

Although pregnancy testing not needed before initiation of the 3-dose HPV vaccine series,19 50 105 question sexually active individuals about the possibility of pregnancy.19 105 Delay initiation of the vaccine series until pregnancy is completed.8 19 28 50 If a woman is found to be pregnant after series initiated, defer any remaining doses until after completion of the pregnancy.8 50 105 200

Report any exposure to the vaccine that occurs during pregnancy to pregnancy registry at 888-452-9622 (HPV2; Cervarix)37 or manufacturer at 877-888-4231 (HPV4; Gardasil).60

Lactation

Not known whether HPV vaccine is distributed into milk.1 37

Manufacturers recommend the vaccines be used with caution in nursing women.1 37

ACIP, AAP, ACOG, and others state the vaccine may be used in nursing women.8 28 50 134

Pediatric Use

HPV2 (Cervarix): Safety and efficacy not established in females <9 years of age or in males of any age.37

HPV4 (Gardasil): Safety and efficacy not established in females or males <9 years of age.1 8

Adults 18 through 64 Years of Age

HPV2 (Cervarix): Safety and efficacy not established in females ≥26 years of age or in males of any age.37

HPV4 (Gardasil): Safety and efficacy not established in females or males ≥27 years of age.1

Geriatric Use

Safety and efficacy not established in females or males ≥65 years of age.1 37

Common Adverse Effects

HPV2 (Cervarix) in females 9 through 25 years of age: Injection site reactions (pain, redness, swelling), fatigue, headache, myalgia, GI symptoms, arthralgia.37 42

HPV4 (Gardasil) in females 9 through 26 years of age: Injection site reactions (pain, swelling, erythema, pruritus, bruising),1 8 20 21 headache,1 fever,1 8 21 nausea,1 8 dizziness,1 8 diarrhea,1 vomiting.1

HPV4 (Gardasil) in males 9 through 26 years of age: Injection site reactions (pain, erythema, swelling, hematoma), headache, fever, pharyngolaryngeal pain, diarrhea, nasopharyngitis, nausea.1

Interactions for Human Papillomavirus Vaccine

Other Vaccines

Although specific studies may not be available evaluating concurrent administration with each antigen, simultaneous administration of HPV vaccine with other age-appropriate vaccines, including live virus vaccines, toxoids, or inactivated or recombinant vaccines, during the same health-care visit is not expected to affect immunologic responses or adverse reactions to any of the preparations.1 8 28 50 134 Immunization against HPV can be integrated with immunization against diphtheria, tetanus, pertussis, hepatitis B, influenza, meningococcal disease, pneumococcal disease, poliovirus, measles, mumps, rubella, and varicella.8 105 134 Each parenteral vaccine should be administered using a different syringe and different injection site.8 134

Specific Drugs

Drug

Interaction

Comments

Estrogens or progestins

No evidence to date that hormonal contraceptives alter immunologic response to HPV vaccine1 37

Hepatitis B (HepB) vaccine

Concomitant administration of 3-dose vaccination series of HPV4 (Gardasil) and HepB vaccine (Recombivax HB) (at different injection sites) during the same health-care visits in women 16–24 years of age did not decrease antibody response to either vaccine and did not increase incidence of clinically important adverse effects compared with administration during separate visits1 8 25

May be administered concomitantly (using different syringes and different injection sites)1 8

Immunosuppressive agents (e.g., alkylating agents, antimetabolites, corticosteroids, radiation)

Potential for decreased antibody response to vaccines1

Meningococcal vaccine

MCV4 (Menactra): Concomitant administration with HPV4 (Gardasil) (at different injection sites) in adolescents 10–17 years of age did not decrease antibody response to either vaccine compared with administration during separate visits (1 month apart); subjects also received Tdap (Adacel);1 53 safety profiles were similar except for increased incidence of swelling at HPV4 injection site when all 3 vaccines administered concomitantly1 53

MCV4 (Menveo): Concurrent administration with HPV4 (Gardasil) and Tdap (Boostrix) in adolescents 11 through 18 years of age did not interfere with immune response to meningococcal antigens;152 systemic adverse reactions were more frequent in those receiving HPV4, Tdap, and MCV4 concomitantly compared with those receiving MCV4 alone152

May be administered concomitantly (using different syringes and different injection sites)1 8 53

Tetanus toxoid and reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap)

Concomitant administration of HPV4 (Gardasil) and Tdap (Adacel) (at different injection sites) in adolescents 10–17 years of age did not decrease the antibody response to either vaccine compared with administration during separate visits (1 month apart); subjects also received MCV4 (Menactra).1 53 Safety profiles were similar except for an increased incidence of swelling observed at HPV4 injection site when all 3 vaccines administered concomitantly1 53

May be administered concomitantly (using different syringes and different injection sites)1 8 53

Stability

Storage

Parenteral

Suspension, for IM Use (HPV2; Cervarix)

2–8°C.37 Protect from freezing;37 discard if exposed to freezing temperatures.37 (See Improper Storage and Handling under Cautions.)

A fine, white deposit with a clear, colorless supernatant may be observed during storage; not considered a sign of deterioration.37

Does not contain thimerosal or any other preservative.37

Suspension, for IM Use (HPV4; Gardasil)

2–8°C.1 8 Should be administered as soon as possible after removal from refrigeration, but can be kept at temperatures ≤25°C for up to 72 hours.1 Protect from light and freezing.1 8 (See Improper Storage and Handling under Cautions.)

Does not contain thimerosal or any other preservatives or antibiotics.1 8

Actions

  • HPV2 (Cervarix) is a suspension of VLPs of the major capsid proteins of 2 HPV types (types 16, 18) that commonly infect humans.37 The VLPs are replicated separately using recombinant DNA technology in Trichoplusia ni insect cells; purified using chromatographic and filtration methods; and adsorbed onto an aluminum-containing adjuvant system (AS04).37

  • HPV4 (Gardasil) is a suspension of the VLPs of the major capsid proteins of 4 HPV types (types 6, 11, 16, 18) that commonly infect humans.1 4 6 8 11 12 14 The VLPs are prepared separately using recombinant DNA technology in Saccharomyces cerevisiae; purified by a series of chemical and physical methods; and adsorbed onto preformed aluminum-containing adjuvant (amorphous aluminum hydroxyphosphate sulfate).1 4 5 10 14

  • HPV vaccine VLPs are structurally indiscernible from native HPV virions and stimulate active immunity to the HPV types represented in the vaccine.4 5 12 14 The VLPs do not contain DNA and are noninfectious.4 5 12 14

  • Vaccination with a 3-dose series of HPV2 can prevent disease caused by HPV types 16 and 18, including cervical cancer and precancerous genital lesions.37

  • Vaccination with a 3-dose series of HPV4 can prevent diseases caused by HPV types 6, 11, 16, and 18, including genital warts caused by HPV types 6 and 11; cervical, vulvar, vaginal, and anal cancer caused by HPV types 16 and 18; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18.1 4 5 12 14 20 21

  • HPV types 6 and 11 cause about 90% of all cases of genital warts and HPV types 16 and 18 cause about 70% of all cases of cervical cancer, AIS, CIN 3, VIN 2/3, and VaIN 2/3 and 50% of all cases of CIN 2.4 7 11 12 13 14 19 20 HPV-related cancers in males (including anal, penile, oropharyngeal) are predominantly caused by HPV type 16.56

  • Data from studies evaluating HPV2 in females 15 through 25 years of age indicate that >98% of vaccine recipients developed antibodies to HPV types 16 and 18; mean antibody titers peaked 1 month following the third vaccine dose and then declined to a level that was maintained for up to 76 months after study initiation.37 38 39 Another study indicates 99.5% of females 15 through 25 years of age who were seronegative at baseline were seropositive for anti-HPV-16 and anti-HPV-18 antibodies at 1 month following the third vaccine dose.37 48

  • Data from studies evaluating HPV4 indicate that 99.4–99.9% of female vaccine recipients and 97.4–99.9% of male vaccine recipients 9 through 26 years of age develop antibodies to HPV types 6, 11, 16, and 18 by 1 month following the third dose of vaccine.1 In clinical trials, mean antibody titers of anti-HPV 6, 11, 16, and 18 peaked in vaccinees at 1 month following the third vaccine dose.1

  • Minimum antibody titers that provide protection against infection with HPV types 6, 11, 16, and 18 not established to date.1 37 38 43

Advice to Patients

  • Prior to administration of each vaccine dose, provide copy of manufacturer’s patient information to the patient and/or patient’s parent or guardian.1 37 Also provide a copy of the appropriate CDC Vaccine Information Statement (VIS) to the patient or patient’s legal representative (VISs are available at ).1 37 57 58

  • Advise patient and/or patient’s parent or guardian of the risks and benefits of vaccination with HPV2 or HPV4.1 37

  • Advise patient and/or patient’s parent or guardian that HPV vaccine does not provide protection against disease from vaccine and nonvaccine HPV types that an individual has previously been exposed to through sexual activity.1 37

  • Advise patient and/or patient’s parent or guardian that vaccination with HPV vaccine does not substitute for routine cervical cancer screening.1 37 Vaccine recipients should continue to receive routine cervical cancer screening (e.g., Pap tests) according to the usual standards of care.1 8 14 19 37

  • Advise vaccine recipients not to discontinue anal cancer screening if it has been recommended by a health-care provider.1

  • Advise vaccine recipients to continue to practice behaviors that limit the risk of HPV exposure (e.g., sexual abstinence, monogamy, limited number of sexual partners, use of condoms).7 8 14 19 28

  • Importance of completing the 3-dose vaccination series of HPV vaccine, unless contraindicated.1 37

  • Advise patient and/or patient’s parent or guardian that fainting, sometimes resulting in falling with injury, has been reported following vaccination with HPV vaccine and the patient should be observed for 15 minutes after administration.1 19 37

  • Advise patients that they should not receive HPV2 if they had a severe allergic reaction to any vaccine component.37

  • Advise patient they should not receive HPV4 if they have had a life-threatening allergic reaction to a previous dose or to yeast or any other vaccine component.1

  • Importance of contacting clinicians if a hypersensitivity reaction (difficulty breathing, wheezing, hives, rash, swollen glands [neck, armpit, or groin], joint pain, weakness, chest pain) occurs following a vaccine dose.1 Clinicians or individuals can report any adverse reactions that occur following vaccination to the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or .1 37

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.1 37

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 37 Advise vaccine recipients that HPV vaccine is not recommended for use in pregnant women1 8 19 28 37 or women who plan on becoming pregnant during the 3-dose vaccination series.37 If any exposure to HPV vaccine occurs during pregnancy, vaccinees and their clinicians are encouraged to contact pregnancy registry at 888-452-9622 (HPV2; Cervarix)37 or manufacturer at 877-888-4231 (HPV4; Gardasil).60

  • Importance of informing patients of other important precautionary information.1 37 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injectable suspension, for IM use

20 mcg of HPV type 16 L1 and 20 mcg of HPV type 18 L1 protein per 0.5 mL

Cervarix

GlaxoSmithKline

Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Quadrivalent

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injectable suspension, for IM use

20 mcg of HPV type 6 L1, 40 mcg of HPV type 11 L1, 40 mcg of HPV type 16 L1, and 20 mcg of HPV type 18 L1 protein per 0.5 mL

Gardasil

Merck

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 28, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Merck & Co. Gardasil (human papillomavirus quadrivalent [types 6, 11, 16, 18] vaccine recombinant) prescribing information. Whitehouse Station, NJ; 2013 Mar.

4. Siddiqui MA, Perry CM. Human papillomavirus quadrivalent (types 6, 11, 16, 18) recombinant vaccine (Gardasil). Drugs. 2006; 66:1263-71. [PubMed 16827602]

5. Villa LL, Costa RL, Petta CA et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005; 6:271-8. [PubMed 15863374]

6. Schmiedeskamp MR, Kockler DR. Human papillomavirus vaccines. Ann Pharmacother. 2006 Jul; 40:1344-52.

7. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Morb Mortal Wkly Rep. 2010; 59(No. RR-12):1-110. [PubMed 20075837]

8. Centers for Disease Control and Prevention. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007; 56 (RR-2):1-24.

9. Centers for Disease Control and Prevention. HPV vaccine information for clinicians- factsheet. 2012Jul. From CDC website . Accessed 2013 Jan 11.

10. Reinis M. Technology evaluation: HPV vaccine (quadrivalent), Aventis Pasteur MSD/CSL. Curr Opin Mol Ther. 2004; 6:206-11. [PubMed 15195933]

11. Villa LL, Ault KA, Giuliano AR et al. Immunologic responses following administration of a vaccine targeting human papillomavirus types 6, 11, 16, and 18. Vaccine. 2006; 24:5571-83. [PubMed 16753240]

12. Ault KA. Vaccines for the prevention of human papillomavirus and associated gynecologic diseases: a review. Obstet Gynecol Surv. 2006; 61:26-31S.

13. Anon. A human papillomavirus vaccine. Med Lett Drugs Ther. 2006; 48:65-6. [PubMed 16977280]

14. Dunne EF, Markowitz LE. Genital human papillomavirus infection. Clin Infect Dis. 2006; 43:624-9. [PubMed 16886157]

16. Merck & Co. Whitehouse Station, NJ: Personal communication.

19. American Academy of Pediatrics. Policy statement: HPV vaccine recommendatoins. Pediatrics. 2012; 129:602-5. [PubMed 22371460]

20. FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007; 356:1915 -27. [PubMed 17494925]

21. Garland SM, Hernandez-Avila M, Wheeler CM et al for the FUTURE 1 Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007; 356:1928-43. [PubMed 17494926]

22. Villa LL, Costa RLR, Petta CA et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer. 2006; 95:1459-66. [PubMed 17117182]

23. DiMiceli L, Pool V, Kelso JM et al. Vaccination of yeast sensitive individuals: review of safety data in the US vaccine adverse event reporting system (VAERS). Vaccine. 2006; 24:703-7. [PubMed 16154669]

25. Wheeler CM, Bautista OM, Tomassini JE et al. Safety and immunogenicity of co-administered quadrivalent human papillomavirus (HPV)-6/11/16/18 L1 virus-like particle (VLP) and hepatitis B (HBV) vaccines. Vaccine. 2008; 26:686-96. [PubMed 18164106]

28. American College of Obstetricians and Gynecologists Committee on Adolescent Health Care. Committee opinion No. 467: human papillomavirus vaccination. Obstet Gynecol. 2010; 116:800-3. [PubMed 20733476]

29. Brotherton JM, Gold MS, Kemp AS et al. Anaphylaxis following quadrivalent human papillomavirus vaccination. CMAJ. 2008; 179:525-33. [PubMed 18762618]

30. Centers for Disease Control and Prevention. Syncope after vaccination—United States, January 2005–July 2007. MMWR Morb Mortal Wkly Rep. 2008; 57:457-60. [PubMed 18451756]

31. Giuliano AR, Lazcano-Ponce E, Villa L et al. Impact of baseline covariates on the immunogenicity of a quadrivalent (types 6, 11, 16, and 18) human papillomavirus virus-like-particle vaccine. J Infect Dis. 2007; 196:1153-62. [PubMed 17955433]

32. Joura EA, Leodolter S, Hernandez-Avila M et al. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet. 2007; 369:1693-702. [PubMed 17512854]

35. Kang LW, Crawford N, Tang ML et al. Hypersensitivity reactions to human papillomavirus vaccine in Australian schoolgirls: retrospective cohort study. BMJ. 2008; 337:a2642. [PubMed 19050332]

36. Halsey NA. The human papillomavirus vaccine and risk of anaphylaxis. CMAJ. 2008; 179:509-10. [PubMed 18762617]

37. GlaxoSmithKline. Cervarix (human papillomavirus bivalent [types 16 and 18] vaccine, recombinant) prescribing information. Research Triangle Park, NC; 2012 Aug.

38. Harper DM, Franco EL, Wheeler C et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004 Nov 13-19; 364:1757-65.

39. Harper DM, Franco EL, Wheeler CM et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006; 367:1247-55. [PubMed 16631880]

40. Paavonen J, Naud P, Salmerón J et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009; 374:301-14. [PubMed 19586656]

41. Pedersen C, Petaja T, Strauss G et al. Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant. J Adolesc Health. 2007; 40:564-71. [PubMed 17531764]

42. Descamps D, Hardt K, Spiessens B et al. Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials. Hum Vaccin. 2009; 5:332-40. [PubMed 19221517]

43. Keam SJ, Harper DM. Human papillomavirus types 16 and 18 vaccine (recombinant, AS04 adjuvanted, adsorbed) [Cervarix]. Drugs. 2008; 68:359-72. [PubMed 18257611]

45. Markowitz L. Recommendations for bivalent HPV vaccine and HPV vaccines in females. Talk presented at: Advisory Committee on Immunization Practices Meeting; Oct 21, 2009; Atlanta, GA. From CDC website. Accessed Nov 5, 2009.

48. Paavonen J, Jenkins D, Bosch FX et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007; 369:2161-70. [PubMed 17602732]

49. Giuliano AR, Palefsky JM, Goldstone S et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med. 2011; 364:401-11. [PubMed 21288094]

50. Centers for Disease Control and Prevention (CDC). FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2010; 59:626-9. [PubMed 20508593]

51. The GlaxoSmithKline Vaccine HPV-007 Study Group. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet. 2009; :.

53. Reisinger KS, Block SL, Collins-Ogle M et al. Safety, tolerability, and immunogenicity of Gardasil given concomitantly with Menactra and Adacel. Pediatrics. 2010; 125:1142-51. [PubMed 20439595]

54. Palefsky JM, Giuliano AR, Goldstone S et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med. 2011; 365:1576-85. [PubMed 22029979]

55. Munoz N, Manalastas R, Pitisuttithum P et al. Safety, immonogenicity, and efficacy of quadrivalent human papilomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial. ,Lancet. 2009; 373:1949-57. [PubMed 19493565]

56. Centers for Disease Control and Prevention (CDC). Recommendations on the use of quadrivalent human papillomavirus vaccine in males- Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011; 60:1705-8. [PubMed 22189893]

57. Centers for Disease Control and Prevention. HPV vaccine (Cervarix) vaccine information statement (interim). 2011 May 3. From CDC website (). Accessed 2013 Jan 21.

58. Centers for Disease Control and Prevention. HPV vaccine (Gardasil) vaccine information statement (interim). 2013 May 17. From CDC website (). Accessed 2013 May 28.

59. US National Institutes of Health. Clinical trials database. Accessed 2013 Mar 19.

60. Merck & Co. Gardasil pregnancy registry. From Merck website. Accessed 2013 May 28.

105. American Academy of Pediatrics. 2012 Red Book. Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.

134. National Center for Immunization and Respiratory Diseases. General recommendations on immunization --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011; 60:1-64.

152. Novartis Vaccines and Diagnostics, Inc. Menveo (meningococcal [Groups A, C, Y and W-135] oligosaccharide diphtheria CRM197 conjugate vaccine) prescribing information. Cambridge, MA; 2011 Mar.

155. Kaplan JE, Benson C, Holmes KH et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009; 58:1-207; quiz CE1-4.

156. Mofenson LM, Brady MT, Danner SP et al. Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR Recomm Rep. 2009; 58:1-166. [PubMed 19730409]

166. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 12th ed. Washington DC: Public Health Foundation; 2012. Available at CDC website.

199. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) recommended immunization schedules for persons aged 0 through 18 years–United States, 2013. Updates may be available at CDC website.

200. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) recommended immunization schedule for adults aged 19 years and older–United States, 2013. Updates may be available at CDC website.

Hide
(web1)