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} Human papillomavirus (HPV) vaccine is commercially available in the US as 2 different vaccines containing virus-like particles (VLPs) of the major capsid proteins of HPV: a bivalent vaccine containing VLPs of HPV types 16 and 18 (HPV2; Cervarix) and a quadrivalent vaccine containing VLPs of HPV types 6, 11, 16, and 18 (HPV4; Gardasil).^{1 37} HPV vaccine is used to stimulate active immunity to the 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 Human Papillomavirus (HPV)

Human papillomavirus bivalent (types 16 and 18) vaccine, recombinant (HPV2; Cervarix): Prevention of cervical cancer, cervical intraepithelial neoplasia (CIN) grades 1, 2, or worse, and cervical adenocarcinoma in situ (AIS) in females 10 through 25 years of age.^{18 37}

Human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant (HPV4; Gardasil): Prevention of cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18 in females 9 through 26 years of age.^{1 8 11 12 13 17 18 20}

HPV4 (Gardasil): 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, and vaginal intraepithelial neoplasia (VaIN) grades 2 and 3 in females 9 through 26 years of age.^{1 8 11 12 13 17 18 20 32}

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 8 11 12 13 18 20 52}

Slideshow: Top Prevention Tips: Springtime Allergies

Genital HPV is the most common sexually transmitted infection in the US;^{4 8 14 19} 6.2 million individuals are infected with genital HPV in the US each year.⁸ Most genital HPV infections are asymptomatic and transient,^{4 7 8 14 19} but some high-risk HPV types may cause abnormal cells on the cervical lining that evolve into cancer.^{4 7 8 14 19}

USPHS Advisory Committee on Immunization Practices (ACIP), AAP, American Academy of Family Physicians (AAFP), and American College of Obstetricians and Gynecologists (ACOG) recommend that females 9 through 26 years of age receive a 3-dose series of HPV vaccine, unless contraindicated.^{8 15 18 19 28 50} (See Contraindications under Cautions.) For females 9 through 26 years of age, these experts state that either HPV2 (Cervarix) or HPV4 (Gardasil) is recommended for prevention of cervical precancers and cancers and HPV4 (Gardasil) is recommended for prevention of cervical, vaginal, and vulvar precancers and cancers and prevention of genital warts.^{18 50}

Experts suggest that use of HPV vaccine in males may provide direct health benefits to males and indirect health benefits to their female sexual partners.⁹ Males 9 through 26 years of age may receive HPV4 (Gardasil) to reduce their likelihood of acquiring genital warts.^{1 18 52} However, ACIP states that routine vaccination in males is not recommended.⁵²

Ideally, HPV vaccine should be administered before potential exposure to HPV occurs through sexual activity; however, age-appropriate individuals who are already sexually active should be vaccinated according to ACIP, AAP, AAFP, and ACOG guidelines.^{8 15 18 19 28 50 52}

May be used in age-appropriate females with or without prior exposure to HPV, equivocal or abnormal Papanicolaou (Pap) tests, positive HPV DNA tests (Hybrid Capture 2 [HC2] high-risk test), or genital warts.^{8 15 19}

There is no evidence that HPV vaccine has any beneficial effects on preexisting Pap test abnormalities or on preexisting HPV infection or genital warts (including those caused by HPV types represented in the vaccine).^{8 14 17} However, vaccination provides protection against infection with vaccine HPV types not already acquired.^{1 8 14 17 19}

Does not prevent infection or disease caused by HPV types not represented in the vaccine.^{1 8 12 17}

Does not provide protection against disease from vaccine and nonvaccine HPV types to which a woman has previously been exposed through sexual activity.^{1 17}

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; treatment of cervical, vulvar, or vaginal cancer; or treatment of precancerous genital lesions (i.e., CIN, VIN, VaIN).^{1 8 14 17}

Safety and efficacy of HPV2 not established in females <10 years of age or females ≥26 years of age.³⁷ However, clinical studies ongoing in women ≥26 years of age.^{28 43} Safety and efficacy of HPV2 (Cervarix) not established in males of any age.³⁷

Safety and efficacy of HPV4 (Gardasil) not established in females or males <9 years of age or ≥27 years of age.^{1 8} Safety and efficacy studies ongoing in females ≥27 years of age.^{8 28}

Human Papillomavirus Vaccine Dosage and Administration

Administration

IM Administration

Administer by IM injection.^{1 2 8 37}

Do not administer IV, sub-Q, or intradermally.^{1 2 37}

Shake vaccine well immediately prior to administration to provide a uniform, white, cloudy suspension.^{1 24 37} Discard vaccine if there are cracks in the vial or syringe or if it contains particulates, appears discolored, or cannot be resuspended with thorough agitation.^{1 24 37}

Administer IM in the deltoid region of the upper arm^{1 37} or in the anterolateral aspect of the upper thigh.¹ To ensure delivery of vaccine into the muscle, IM injections should be made at a 90° angle to the skin using a needle size that is appropriate for the individual’s age and body mass, thickness of adipose tissue and muscle at the injection site, and injection technique.²

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

Since syncope may occur following vaccination and may result in falling with injury, observe vaccinee for approximately 15 minutes after the dose.^{1 8 17 19 28 30 37 50 52} Syncope occurs most frequently in adolescents and young adults.^{8 30} (See Syncope under Cautions.)

Data not available to date regarding the interchangeability of HPV2 (Cervarix) and HPV4 (Gardasil).⁴⁵ ACIP recommends that the HPV vaccine used for the initial dose be used to complete the vaccination series, whenever possible.⁵⁰

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

HPV vaccine may be given simultaneously with other age-appropriate vaccines during the same health-care visit (using different syringes and different injection sites).^{8 45} (See Interactions.)

When multiple parenteral vaccines are administered during a single health-care visit, each vaccine should preferably be given at a different anatomic site.^{2 8} 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.²

Dosage

Pediatric Patients

Prevention of Disease Caused by Human Papillomavirus (HPV)

Females 10 through 18 Years of Age (HPV2; Cervarix)

IM

Primary immunization consists of a series of 3 doses.^{18 37} Each dose consists of the entire contents (0.5 mL) of the commercially available single-dose vial or prefilled syringe containing the vaccine.³⁷

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

ACIP, AAP, ACOG, and AAFP recommend that first dose be given at 11 or 12 years of age, second dose be given 1–2 months after first dose, and third dose be given 6 months after first dose (at least 24 weeks after first dose).^{18 28 50}

Initial dose may be given to females as young as 10 years of age at the discretion of the clinician.³⁷

Catch-up vaccination recommended for females 13 through 18 years of age who have not previously received the complete 3-dose series.^{15 18 28 50} Give second dose 1–2 months after first dose (at least 4 weeks 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).^{18 28 50}

Duration of immunity following the recommended 3-dose vaccination series and need for additional (booster) doses not determined.^{28 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 8 18 19} Each dose consists of the entire contents (0.5 mL) of the commercially available single-dose vial or prefilled syringe.¹

Manufacturer recommends that second and third doses be given at 2 and 6 months, respectively, after first dose.¹

ACIP, AAP, ACOG, and AAFP recommend that first dose be given at 11 or 12 years of age, second dose be given 1–2 months after first dose, and third dose be given 6 months after first dose (at least 24 weeks after first dose).^{8 18 19 28 50}

Initial dose may be given to females as young as 9 years of age at the discretion of the clinician.^{8 18 19 28 50}

Catch-up vaccination recommended for females 13 through 18 years of age who have not previously received the complete 3-dose series.^{8 18 19 28 50} Give second dose 1–2 months after first dose (at least 4 weeks 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).^{18 19 28 50}

Duration of immunity following the 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.)

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

IM

Primary immunization consists of a series of 3 doses.^{1 18 52} Each dose consists of the entire contents (0.5 mL) of the commercially available single-dose vial or prefilled syringe.¹

Manufacturer recommends that second and third doses be given at 2 and 6 months, respectively, after first dose.¹

Initial dose may be given to males as young as 9 years of age at the discretion of the clinician.^{1 18 52} First dose usually given at 11 or 12 years of age.¹⁸ Give second dose 1–2 months after first dose (at least 4 weeks 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).^{15 18 52}

Duration of immunity following the 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.)

Adults

Prevention of Disease Caused by Human Papillomavirus (HPV)

Females 19 through 25 Years of Age (HPV2; Cervarix)

IM

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

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

Catch-up vaccination recommended for females ≤25 years of age who are unvaccinated or incompletely vaccinated.^{15 28 50} Give second and third doses 1–2 and 6 months, respectively, after initial dose.^{15 28 50}

Duration of immunity following the recommended 3-dose vaccination series and need for additional (booster) doses not determined.^{28 37} (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 8 15 17 19} Each dose consists of the entire contents (0.5 mL) of the commercially available single-dose vial or prefilled syringe.¹

Give second and third doses 2 and 6 months, respectively, after initial dose.^{1 8 15 19}

Catch-up vaccination recommended for females ≤26 years of age who are unvaccinated or incompletely vaccinated.^{8 15 28 50} Give second and third doses 1–2 and 6 months, respectively, after initial dose.^{8 15 28 50}

If vaccine series is interrupted after the initial dose, give second vaccine dose as soon as possible (minimum 4 weeks after first dose) and give third doses at least 12 weeks after second dose.¹⁹ If only the third dose is delayed, administer as soon as possible (at least 24 weeks after first dose).¹⁹

Duration of immunity following the recommended 3-dose vaccination series and need for additional (booster) doses not determined.^{1 4 8 11 12 13 14 20 21 28} (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 52} Each dose consists of the entire contents (0.5 mL) of the 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

Duration of immunity following the 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 rubber plunger) contain dry natural latex; stopper on single-dose vial does not contain latex.³⁷ Some individuals may be hypersensitive to natural latex proteins.³⁷ Manufacturer states do not use prefilled syringes of HPV2 in latex-sensitive individuals.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.²

Syncope

Syncope, sometimes associated with falling and injury, has been reported in vaccinees who received HPV2 (Cervarix) or HPV4 (Gardasil).^{1 37} Syncope associated with tonic-clonic movements and other seizure-like activity also reported following HPV vaccination.^{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}

Because syncope has occurred, observe vaccinee for 15 minutes following vaccination.^{1 37}

Limitations of Vaccine Effectiveness

May not protect all vaccine recipients against HPV infection.^{1 8 15 17 37}

Vaccination with HPV vaccine does not substitute for routine cervical cancer screening.^{1 17 19 37} Vaccine recipients should continue to undergo cervical cancer screening (e.g., Pap tests) according to usual standards of care.^{1 37}

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}

Not used for treatment of active genital warts; treatment of cervical, vulvar, and vaginal cancers; or treatment of precancerous or dysplastic lesions (e.g., AIS, CIN, VIN, or VaIN).^{1 17}

May be used in patients who already have become infected with HPV (including HPV types represented in the vaccine).^{1 8 15} 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}

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.^{1 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.^{2 8}

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).^{2 8 50 52}

Individuals with Altered Immunocompetence

HPV vaccine 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 15 16 19 33 34} Consider possibility that the immune response to the vaccine and efficacy may be reduced in these individuals.^{1 8 15 28 34}

Although data are not available regarding safety, efficacy, and immunogenicity in individuals with HIV infection, ACIP, AAP, CDC, National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA), Pediatric Infectious Diseases Society, and other experts 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.^{33 34}

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.² 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.² If patient is receiving antihemophilia therapy, administer the IM vaccine shortly after a scheduled dose of such therapy.²

Improper Storage and Handling

Improper storage or handling of vaccines may result in loss of vaccine potency and reduced immune response in vaccinees.²

Do not administer HPV vaccine that has been mishandled or has not been stored at the recommended temperature.^{2 8 24 37} (See Storage under Stability.)

HPV4 (Gardasil) contains an aluminum adjuvant that may precipitate if the vaccine is exposed to freezing temperatures (≤0° C).²

Inspect all vaccines upon delivery and monitor during storage to ensure that the appropriate temperature is maintained.² If there are concerns about mishandling, contact the manufacturer or state or local health departments for guidance on whether the vaccine is usable.^{2 24}

Specific Populations

Pregnancy

Category B.^{1 37}

ACIP, AAFP, and ACOG state that HPV vaccine is not recommended for use in pregnant women.^{8 15 19 28 50} Manufacturer of HPV2 (Cervarix) states the vaccine is not recommended for women who are pregnant or planning to become pregnant during the 3-dose vaccination series.³⁷

Delay initiation of the 3-dose vaccine series until pregnancy is completed.^{8 19 28 50} If a woman is found to be pregnant after initiation of the series, defer any remaining doses until after completion of the pregnancy.^{8 50}

Pregnancy registry at 888-452-9622 (HPV2; Cervarix)³⁷ or 800-986-8999 (HPV4; Gardasil).^{1 8 19 50} Clinicians or vaccinees should report any exposure to the vaccine that occurs during pregnancy.^{1 8 28 37 50}

Lactation

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

ACIP, ACOG, and CDC state the vaccine may be used in nursing women.^{2 8 28 50} Manufacturers recommend caution.^{1 37}

Pediatric Use

HPV2 (Cervarix): Safety and efficacy not established in females <10 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): May be used in females 18 through 25 years of age.³⁷ Safety and efficacy not established in females ≥26 years of age or in males of any age.³⁷

HPV4 (Gardasil): May be used in females and males 18 through 26 years of age.¹ 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 10 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), 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 2 8 28 50 52} However, each parenteral vaccine should be administered using a different syringe and different injection site.⁸

Specific Drugs

Drug	Interaction	Comments
Estrogens or progestins	No evidence to date that hormonal contraceptives alter the immunologic response to HPV vaccine1 37
Hepatitis B (HepB) vaccine	Concomitant administration of the 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 the antibody response to either vaccine and did not increase the 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	Concomitant administration of HPV4 (Gardasil) and MCV4 (Menactra) (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 Tdap (Adacel).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
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 24} 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 24} (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, and vaginal 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}

• 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 17} 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 27 37}

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

• Advise the patient and/or patient’s parent or guardian that HPV2 is used only in females 10 through 25 years of age to protect against certain HPV-related diseases (e.g., cervical cancer and abnormal and precancerous cervical lesions) caused by HPV types 16 and 18.³⁷

• Advise patient and/or patient’s parent or guardian that HPV4 is used in females 9 through 26 years of age to protect against certain HPV-related diseases (e.g., cervical, vulvar, and vaginal cancers; abnormal and precancerous cervical, vaginal, and vulvar lesions) caused by HPV types 6, 11, 16, and 18 and in females and males 9 through 26 years of age to protect against genital warts caused by HPV types 6 and 11.^{1 17} The vaccine will not protect against disease due to HPV types not represented in the vaccine or against non-HPV-related cervical disease, viruses, or bacteria.^{1 17}

• Advise the patient and/or patient’s parent or guardian that HPV vaccine is not for treatment of active genital warts or treatment of cervical, vulvar, or vaginal cancers.^{1 17}

• 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 17}

• 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 17 19 27 37}

• Advise vaccine recipients to continue to practice behaviors that limit the risk of HPV exposure (e.g., 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 17 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 the dose.^{1 17 19 27 37}

• Advise patients that they should not receive HPV2 if they had a severe allergic reaction to any vaccine component.^{27 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 17 27}

• 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 17} 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 27 37}

• Importance of informing clinicians if the patient has a fever >37.8°C or a weakened immune system (e.g., genetic defect, HIV/AIDS).^{1 17}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.^{1 17 37}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 17 37} Advise vaccine recipients that HPV vaccine is not recommended for use in pregnant women^{1 8 17 19 27 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 the pregnancy registry at 888-452-9622 (HPV2; Cervarix) or at 800-986-8999 (HPV4; Gardasil).^{1 8 27 28 37 50}

• 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	Recombinant virus-like particle (VLP) of the major capsid (L1) protein of human papillomavirus (HPV) content: 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	Recombinant virus-like particle (VLP) of the major capsid (L1) protein of human papillomavirus (HPV) content: 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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.