Pharmacology Update

Human Papillomavirus Quadrivalent Recombinant Vaccine (Gardasil®)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD . Dr. Elliot is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The FDA has extended the approval for the Human Papillomavirus Quadrivalent Recombinant Vaccine to include the prevention of vaginal and vulvar cancer. The vaccine, originally approved in 2006, is already approved for the prevention of cervical cancer and genital warts.

Indications

The HPV vaccine is indicated in girls and women ages 9-26 years for the prevention of cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18 and genital warts caused by HPV types 6, 11, 16, and 18. It is also indicated for precancerous or dysplastic lesions caused by types 6, 11, 16, and 18. These include cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ; cervical intraepithelial neoplasia grade 1; vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3; and vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3.1

Dosage

The recommended vaccination schedule is 0.5 mL intramuscularly at 0, 2, and 6 months.

Potential Advantages

After two years of additional follow-up, the vaccine appears to be 100% effective in preventing HPV-related precancerous vulvar and vaginal lesions in patients who were seronegative after vaccination.2,3

Potential Disadvantages

The rate of anaphylaxis may be higher with the HPV vaccine than other vaccines used in a similar age group.4

Comments

HPV vaccine was approved in 2006 and was intended for use in females ages 9-26 years to prevent infections caused by various viruses that are the most common cause of cervical cancer and genital warts. Based on additional follow-up data, the FDA determined that there was sufficient evidence to extend the indication for the vaccine to prevent vulva and vaginal cancer. In women who were HPV16- or HPV18-seronegative after completion of the series of vaccinations, the vaccine (n = 7811) was 100% (95% confidence interval [CI], 72%-100%) effective vs placebo (n = 7785) against VIN2-3 or VaIN2-3. For females who were seronegative at day 1, efficacy was 97% (95% CI, 79%-100%). In an intent-to-treat analysis, where women could have been infected at baseline, the efficacy was 71% (95% CI, 37-88%). The vaccine has been reported to reduce the incidence of HPV16/18-related cervical precancers and cervical cancers.5 Vaccination may also reduce oral cancers as approximately 90% are HPV16-positive.6 While the rate may be higher than other vaccines, such as the MMR, hepatitis B, and conjugated meningococcal vaccines, anaphylaxis is still considered to be rare. The estimated rate is 2.6 per 100,000 dose, similar to the varicella vaccine, and very rare by WHO categorization (< 1 in 10,000).

Clinical Implications

HPV vaccine is currently recommended by the CDC's Advisory Committee on Immunization Practices as routine 3-dose vaccination of girls ages 11 and 12 as well as girls and women ages 13-26 years who have not yet been vaccinated or who have not received all 3 doses. The FDA and the CDC summarized the safety of the vaccine in July 2008 and stated that the vaccine continues to be safe and effective, and its benefit outweighs its risk.7 The expanded indication further strengthens the benefit of the vaccine.

References

1. Gardasil Product Information. Whitehouse Station, NJ: Merck & Co., Inc.; September 2008.

2. FDA. Available at: www.fda.gov/bbs/topics/NEWS/2008/NEW01885.html. Accessed Oct. 3, 2008.

3. Joura EA, 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;369:1693-1702.

4. Botherton JM, et al. Anaphylaxis following quadrivalent human papillomavirus vaccination. CMAJ 2008;179:525-533.

5. Ault KA; The Future II Study Group. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: A combined analysis of four randomised clinical trials. Lancet 2007;369:1861-1868.

6. Gillison ML. Human papillomavirus-related diseases: Oropharynx cancers and potential implications for adolescent HPV vaccination. J Adolesc Health 2008;43(4 Suppl):S52-S60.

7. FDA. Available at: www.fda.gov/cber/safety/gardasil071408.htm. Accessed Oct. 3, 2008.