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

Pronunciation

(pap ih LO ma VYE rus typs six e LEV en SIX teen AYE teen vak SEEN YU man ree KOM be nant)

Index Terms

  • 4-Valent HPV
  • 4vHPV
  • HPV Vaccine (Quadrivalent)
  • HPV4
  • Human Papillomavirus Vaccine (Quadrivalent)
  • Quadrivalent Human Papillomavirus Vaccine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, suspension [preservative free]:

Gardasil: HPV 6 L1 protein 20 mcg, HPV 11 L1 protein 40 mcg, HPV 16 L1 protein 40 mcg, and HPV 18 L1 protein 20 mcg per 0.5 mL (0.5 mL) [contains aluminum, polysorbate 80; manufactured using S. cerevisiae (baker's yeast)]

Brand Names: U.S.

  • Gardasil

Pharmacologic Category

  • Vaccine
  • Vaccine, Inactivated (Viral)

Pharmacology

Contains inactive human papillomavirus (HPV) proteins HPV 6 L1, HPV 11 L1, HPV 16 L1, and HPV 18 L1 which produce neutralizing antibodies to prevent cervical cancer, cervical adenocarcinoma, cervical, vaginal and vulvar neoplasia, and genital warts caused by HPV. The vaccine has not been shown to provide cross-protective efficacy to HPV types not contained in the vaccine. Immunogenicity has been measured by the percentage of persons who became seropositive for antibodies contained in the vaccine; the minimum anti-HPV antibody concentration needed to protect against disease has not been determined. The population benefit to vaccination is influenced by the prevalence of HPV within the geographic area and subject characteristics (eg, lifetime sexual partners).

Efficacy: Vaccination with 4vHPV reduced the incidence of CIN 2/3 and AIS by 98% to 100% in several randomized clinical trials. Efficacy against vulvar or vaginal intraepithelial neoplasia grades 2/3 was 100%. Against HPV 6- and 11-related genital warts, 4vHPV vaccination reduced incidence in women by 99% in several clinical trials. In men and boys, 4vHPV vaccination reduced the incidence of the following end points: external genital warts , 89% penile intraepithelial neoplasia of any severity, 100%; anal intraepithelial neoplasia (AIN) of any severity, 78% (CDC/ACIP [Markowitz 2014]).

Onset of Action

Peak seroconversion was observed 1 month following the last dose of vaccine

Duration of Action

Not well defined; at least 8 years

Use: Labeled Indications

Prevention of human papillomavirus infection:

US labeling:

Females 9 to 26 years of age:

For the prevention of the following diseases: Cervical, vulvar, vaginal, and anal cancer caused by HPV types 16 and 18; genital warts (condyloma acuminatum) caused by HPV types 6 and 11;

For the prevention of the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18: Cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ; CIN grade 1; vulvar intraepithelial neoplasia grade 2 and 3; vaginal intraepithelial neoplasia grade 2 and 3; and anal intraepithelial neoplasia grades 1, 2, and 3.

Males 9 through 26 years of age:

For the prevention of the following diseases: Anal cancer caused by HPV types 16 and 18; genital warts (condyloma acuminata) caused by HPV types 6 and 11;

For the prevention of anal intraepithelial neoplasia grades 1, 2, and 3 caused by HPV types 6, 11, 16, and 18.

Limitations of use: Does not provide protection against vaccine HPV types to which a person has already been previously exposed, or HPV types not contained in the vaccine; does not prevent CIN grade 2/3 or worse in women >26 years of age. Not intended for the treatment of active external genital lesions or cervical, vulvar, vaginal, and anal cancers.

Canadian labeling:

Females ≥9 years and ≤26 years of age: Prevention of anal cancer caused by HPV types 16 and 18; anal intraepithelial neoplasia caused by HPV types 6, 11, 16, and 18

Females ≥9 years and ≤45 years of age: Prevention of cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; cervical adenocarcinoma in situ, vulvar, vaginal, or cervical intraepithelial neoplasia caused by HPV types 6, 11, 16, and 18

Males ≥9 years and ≤26 years of age: Prevention of anal cancer caused by HPV types 16 and 18; anal intraepithelial neoplasia caused by HPV types 6, 11, 16, and 18; genital warts caused by HPV types 6 and 11

The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination for females and males 11 to 12 years of age; for patients with any history of sexual abuse or assault, vaccination should be started at 9 years of age. Catch-up vaccination is recommended for females 13 to 26 years of age and males 13 to 21 years of age. Vaccination for males 22 through 26 years of age is recommended if immunocompromised (including HIV) and for men who have sex with men and may be considered for any other male in this age group (CDC/ACIP [Markowitz 2014]; ACIP [Robinson 2016]).

Contraindications

Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or a previous dose of the vaccine

Dosing: Adult

Immunization regimen:

US labeling: IM: Adults ≤26 years: 0.5 mL per dose for a total of 3 doses; administer the second and third doses at 2 and 6 months after initial dose

Canadian labeling: IM: Adults ≤45 years: 0.5 mL per dose for a total of 3 doses; administer the second and third doses at 2 and 6 months after initial dose

CDC/ACIP recommended immunization schedule: 0.5 mL per dose for a total of 3 doses; administer the second and third doses at 1 to 2 and 6 months after initial dose. There should be a 4-week minimum interval between the first and second dose; a 12-weeks minimum interval (16 weeks preferred) between the second and third dose; a 24-week minimum interval between the first and third dose. Begin series in females ≤26 years or males ≤21 years if not previously vaccinated or completed the 3-dose series (typically administer first dose at age 11 to 12 years). Vaccination for males 22 through 26 years of age is recommended if immunocompromised (including HIV) and for men who have sex with men and may be considered for any other male in this age group. Second and third doses may be given after age 26 years to complete a previously initiated series. The HPV vaccine series should be completed with the same product whenever possible (ACIP [Kim 2016]; CDC/ACIP [Markowitz 2014]).

Dosing: Pediatric

Immunization: IM:

US labeling: Children ≥9 years and Adolescents: 0.5 mL per dose for a total of 3 doses; administer the second and third doses at 2 and 6 months after initial dose

Canadian labeling: Children ≥9 years and Adolescents: 0.5 mL per dose for a total of 3 doses; administer the second and third doses at 2 and 6 months after initial dose

CDC/ACIP recommended immunization schedule: 0.5 mL per dose for a total of 3 doses; administer the second and third doses at 1 to 2 and 6 months after initial dose. There should be a 4-week minimum interval between the first and second dose; a 12-weeks minimum interval (16 weeks preferred) between the second and third dose; a 24-week minimum interval between the first and third dose. Typically, administer first dose at age 11 to 12 years; for patients with any history of sexual abuse or assault, vaccination should be started at 9 years of age; begin series in adolescents (≥13 years) if not previously vaccinated or who have not completed the 3-dose series (CDC/ACIP [Markowitz 2014]; ACIP [Robinson 2016]).

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Administration

Shake suspension well before use. Inject the entire dose IM into the deltoid region of the upper arm or higher anterolateral thigh area. To prevent syncope related injuries, adolescents and adults should be vaccinated while seated or lying down (NCIRD/ACIP 2011). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, and the administering person's name, title, and address be entered into the patient's permanent medical record.

For patients at risk of hemorrhage following intramuscular injection, the vaccine should be administered intramuscularly if, in the opinion of the physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, intramuscular vaccination can be scheduled shortly after such therapy is administered. A fine needle (23 gauge or smaller) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (NCIRD/ACIP 2011).

Compatibility

Do not mix with other vaccines or injections. Separate needles and syringes should be used for each injection.

Storage

Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect from light. Administer as soon as possible after removing it from refrigeration; can be out of refrigeration (at temperatures at or below 25°C [77°F]) for a total time of not more than 72 hours.

Drug Interactions

Belimumab: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Patients should receive inactivated vaccines prior to initiation of belimumab therapy whenever possible, due to the risk for an impaired response to the vaccine during belimumab therapy. Consider therapy modification

Fingolimod: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting fingolimod. If vaccinated during fingolimod therapy, revaccinate 2 to 3 months after fingolimod discontinuation. Consider therapy modification

Immunosuppressants: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Exceptions: Cytarabine (Liposomal). Consider therapy modification

Venetoclax: May diminish the therapeutic effect of Vaccines (Inactivated). Monitor therapy

Adverse Reactions

All serious adverse reactions must be reported to the U.S. Department of Health and Human Services (DHHS) Vaccine Adverse Event Reporting System (VAERS) 1-800-822-7967 or online at https://vaers.hhs.gov/esub/index. In Canada, adverse reactions may be reported to local provincial/territorial health agencies or to the Vaccine Safety Section at Public Health Agency of Canada (1-866-844-0018).

>10%:

Central nervous system: Headache (12% to 28%), fever (8% to 13%)

Local: Injection site: Pain (61% to 84%), erythema (17% to 25%), swelling (14% to 25%)

1% to 10%:

Central nervous system: Dizziness (1% to 4%), malaise (1%), insomnia (1%)

Gastrointestinal: Nausea (2% to 7%), diarrhea (3% to 4%), vomiting (1% to 2%), toothache (2%)

Local: Injection site: Bruising (3%), pruritus (3%), hematoma (1%)

Neuromuscular & skeletal: Arthralgia (1%), myalgia (≤1%)

Respiratory: Pharyngolaryngeal pain (3%), cough (2%), nasal congestion (1%)

<1% (Limited to important or life-threatening): Acute disseminated encephalomyelitis, alopecia areata, anaphylactic/anaphylactoid reaction, appendicitis, arrhythmia, arthritis, asthma, autoimmune hemolytic anemia and other autoimmune diseases, bronchospasm, cellulitis, cerebrovascular accident, chills, DVT, fatigue, gastroenteritis, Guillain-Barré syndrome, hypersensitivity reaction, hyper-/hypothyroidism, injection site joint movement impairment, ITP, JIA, lymphadenopathy, motor neuron disease, pancreatitis, paralysis, pelvic inflammatory disease, pulmonary embolus, RA, renal failure (acute), seizure, sepsis, syncope (may result in falls with injury or be associated with tonic-clonic movements), transverse myelitis, urticaria, weakness

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid/hypersensitivity reactions: Immediate treatment (including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during vaccine use (NCIRD/ACIP 2011).

• Syncope: Syncope has been reported with use of injectable vaccines and may result in serious secondary injury (eg, skull fracture, cerebral hemorrhage); typically reported in adolescents and young adults and within 15 minutes after vaccination. Procedures should be in place to avoid injuries from falling and to restore cerebral perfusion if syncope occurs (NCIRD/ACIP 2011).

Disease-related concerns:

• Acute illness: The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and the etiology of the disease. Consider deferring administration in patients with moderate or severe acute illness (with or without fever); vaccination should not be delayed for patients with mild acute illness (with or without fever) (CDC/ACIP [Markowitz 2014]; NCIRD/ACIP 2011).

• Bleeding disorders: Use with caution in patients with a history of bleeding disorders (including thrombocytopenia) and/or patients on anticoagulant therapy; bleeding/hematoma may occur from IM administration; if the patient receives antihemophilia or other similar therapy, IM injection can be scheduled shortly after such therapy is administered (NCIRD/ACIP 2011).

• Human papillomavirus (HPV) infection: There is no evidence that individuals already infected with HPV will be protected; those already infected with 1 or more HPV types were protected from disease in the remaining HPV types. Not for the treatment of active disease; will not protect against diseases not caused by HPV vaccine types 6, 11, 16, and 18.

Concurrent drug therapy issues:

• Vaccines: In order to maximize vaccination rates, the ACIP recommends simultaneous administration (ie, >1 vaccine on the same day at different anatomic sites) of all age-appropriate vaccines (live or inactivated) for which a person is eligible at a single clinic visit, unless contraindications exist (NCIRD/ACIP 2011).

Special populations:

• Altered immunocompetence: May be administered to those who are immunosuppressed (CDC/ACIP [Markowitz 2014]). Use with caution in severely immunocompromised patients (eg, patients receiving chemo/radiation therapy or other immunosuppressive therapy [including high dose corticosteroids]); may have a reduced response to vaccination (CDC/ACIP [Markowitz 2014]; NCIRD/ACIP 2011). In general, household and close contacts of persons with altered immunocompetence may receive all age-appropriate vaccines (IDSA [Rubin 2014]; NCIRD/ACIP 2011); inactivated vaccines should be administered ≥2 weeks prior to planned immunosuppression when feasible (IDSA [Rubin 2014]).

• Pregnancy: Not recommended for use during pregnancy.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

• Yeast: Product may contain yeast.

Other warnings/precautions:

• Appropriate use: Use of this vaccine for specific medical and/or other indications (eg, immunocompromising conditions, hepatic or kidney disease, diabetes) is also addressed in the ACIP Adult Recommended Immunization Schedule (ACIP [Kim 2016]). Specific recommendations for use of this vaccine in immunocompromised patients with asplenia, cancer, HIV infection, cerebrospinal fluid leaks, cochlear implants, hematopoietic stem cell transplant (prior to or after), sickle cell disease, solid organ transplant (prior to or after), or those receiving immunosuppressive therapy for chronic conditions are available from the IDSA (Rubin 2014).

• Effective immunity: Vaccination may not result in effective immunity in all patients. Response depends upon multiple factors (eg, type of vaccine, age of patient) and may be improved by administering the vaccine at the recommended dose, route, and interval. Vaccines may not be effective if administered during periods of altered immune competence (NCIRD/ACIP 2011).

• Maximum efficacy: The entire 3-dose regimen should be completed for maximum efficacy.

Monitoring Parameters

Screening for HPV is not required prior to vaccination. Monitor for syncope for 15 minutes following administration (NCIRD/ACIP 2011). If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion.

Females: Gynecologic screening exam, papillomavirus test; screening for cervical cancer should continue per current guidelines following vaccination

Pregnancy Risk Factor

B

Pregnancy Considerations

Teratogenic effects were not observed in animal reproduction studies. In clinical trials, women who were found to be pregnant before the completion of the 3-dose regimen were instructed to defer any remaining dose until pregnancy resolution. Pregnancies detected within 30 days of vaccination had a higher rate of congenital anomalies (pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, club foot) than the placebo group. Pregnancies with onset beyond 30 days of vaccination had a rate of congenital anomalies consistent with the general population. Overall, the types of teratogenic events were the same as those generally observed for this age group. Administration of the vaccine in pregnancy is not recommended; until additional information is available, the vaccine series (or completion of the series) should be delayed until pregnancy is completed. Pregnancy testing is not required prior to administration of the vaccine (CDC/ACIP [Petrosky 2015]).

A registry has been established for women exposed to the HPV vaccine during pregnancy (1-877-888-4231).

Patient Education

• Discuss specific use of vaccine and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or injection site pain or irritation. Have patient report immediately to prescriber severe dizziness, passing out, seizures, or difficulty with motor activity (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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