Volume IX, No. VI November/December 2006 Mandy C. Leonard, Pharm.D., BCPS Assistant Director, Drug Information Service Editor Prophylaxis Against Human Papillomavirus Infections with Gardasil® Vaccine Meghan K. Lehmann, Pharm.D., BCPS by Jaime Anderson, Pharm.D. Drug Information Specialist Editor Introduction Dana L. Travis, R.Ph. T he recent development of two vac- HPV. Worldwide, the incidence of Drug Information Pharmacist cines targeting the prevention of hu- cervical cancer is estimated to be 10% Editor man papillomavirus (HPV) infection of cancers in women and is the second has created both anticipation and con- most common cause of death from David A. White, B.S., R.Ph. Restricted Drug Pharmacist troversy in the public and medical cancer in women after breast cancer. Associate Editor communities. Gardasil® (Merck and Approximately 80% of cervical can- Marcia J. Wyman, Pharm.D. Co., Inc.), approved by the Food and cers occur in less-developed coun- Drug Administration (FDA) on June 8, tries, where access to screening and Drug Information Pharmacist Associate Editor 2006, is a quadrivalent vaccine consist- treatment for HPV and cervical cancer 3 ing of recombinant HPV Types 6, 11, are limited. Amy T. Sekel, Pharm.D. 16, and 18.1 A second bivalent vaccine D rug Information Pharmacist Associate Editor containing recombinant HPV types 16 There are more than 100 types of In this Issue ® and 18, Cervarix (GlaxoSmithKline), HPV that have been identified, of 2 David Kvancz, M.S., R.Ph., FASHP is currently under investigation. which approximately 18 have been Chief Pharmacy Officer determined to be oncogenic.4 Of the Morton Goldman, Pharm.D., BCPS In the United States, the estimated oncogenic HPV types, HPV16 and Director, Pharmacotherapy Services prevalence of HPV infection is 20 to HPV18 account for about 50% and 40% in sexually active 20-year-old 20% of cervical cancers, respec- 3 In This Issue: women; the estimated lifetime risk for tively. It is believed that microtrauma • Gardasil® o ne or more genital HPV infections for or erosion of the overlying epithelial 3 • Medication Safety: Promethazine a ll women is at least 75%. Approxi- layers is a contributing factor allow- m ately 70% of these infections are ing viral particles to establish infec- c leared within 1 year, while 91% are tion in the basal epithelial cells.3 The c leared within 2 years. It is not well histologic precursor to squamous cell Drug Information Service understood or known whether this sug- cervical cancer is cervical intraepithe- (216) 444-6456, option #1 g ests the amount of viral matter present lial neoplasia (CIN), which has levels h as dropped below detectable levels or of progression from Stage 1 (low- Comprehensive information about i f the virus is completely eliminated.4 grade dysplasia) to Stage 2/3 medications, biologics, nutrients, (moderate to high-grade dysplasia). and drug therapy Human papillomaviruses infect the The histologic precursor for cervical stratified squamous epithelia of skin adenocarcinoma is adenocarcinoma in Formulary Information and mucous membranes, where they situ (AIS).5 The disease course from form benign lesions that have the po- HPV infection to development of Medication Inservices tential of progressing to invasive can- malignancy usually takes at least cers. Virtually all cases of cervical can- 10 years, with the risk of cervical can- cer result from sexual transmission of cer being highest in women over 40 years of age.3 A likely result of physiological proximity, Protocol 005, a double-blind, randomized, placebo-controlled, HPV also causes an estimated 35 to 50% of vulvar and vaginal multi-center Phase II trial conducted in women 16 to 23 years cancers. Additionally, HPV is the cause of genital warts old evaluated a vaccine for HPV type 16. Participants received (condyloma acuminata) which can be located in the cervico- 40 mcg (0.5 mL) intramuscular doses of the vaccine (n=768) vaginal, vulvar, and external genitalia areas but rarely pro- or placebo (n=765) at day 0, month 2, and month 6. Included gresses to cancer.5 The inclusion of recombinant HPV6 and were non-pregnant women who had no prior abnormal Papani- HPV11 in Gardasil® is targeted to protect against genital colaou (Pap) smears and had <5 male sex partners. Follow-up warts, as these two types of HPV account for approximately occurred at months 7 and 12, and every 6 months thereafter 90% of cases.6 until month 48. The primary outcome was persistent HPV type 16 infection, defined as having a cervical biopsy positive for Pharmacology CIN or cervical cancer with DNA probes yielding HPV type Gardasil® consists of highly purified virus-like particles 16, or being negative for HPV type 16 on day 0 and month 7 (VLPs) of the major capsid (L1) protein of HPV types 6, 11, with subsequent HPV type 16 DNA detected at two or more 16, and 18. The L1 proteins are produced by separate fermen- consecutive visits 4 or more months apart, or HPV type 16 tations in recombinant Saccaromyces cerevisiae and then self- DNA detected only in a sample collected at the last visit prior assembled into VLPs. These VLPs are released from the to being lost to follow-up. Any adverse events occurring S. cerevisiae cells by cell disruption and are further purified. within 14 days of being vaccinated or body temperatures The vaccine is then finalized by adsorbing the VLPs to an alu- >37.7C (100F) within 5 days of being vaccinated were also minum-containing adjuvant (amorphous aluminum hydroxy- analyzed. Median follow-up was 17.4 months. Forty-one cases phosphate sulfate).5,6 of HPV type 16 infections occurred in the placebo group of which 31 were persistent HPV type 16 infections without CIN, Clinical Studies of Gardasil® 9 were HPV type 16-related CIN (5=grade 1, 4=grade 2), and The approval of Gardasil® was guided largely by the over- 1 was an HPV type 16 positive patient lost to follow-up. In whelming evidence for efficacy determined in four separate the placebo group, the incidence of persistent HPV type 16 Phase II and III trials.1 The Phase II trials were termed Proto- infections was 3.8 per 100 woman-years at risk, whereas the col 005, which only evaluated a vaccine for HPV type 16, and incidence in the vaccine group was 0 per 100 woman-years at Protocol 007, which evaluated the quadrivalent vaccine for risk (95% CI 90-100; P<0.001). There were no significant HPV types 6, 11, 16, and 18.5,7,8 The FUTURE I (Females differences between the groups for adversities with injection United to Unilaterally Reduce Ecto/Endocervical Disease) and site pain being the most frequently reported adverse event. FUTURE II trials were Phase III studies which also evaluated The authors concluded that administration of a monovalent the quadrivalent vaccine.6,9 In all four trials, the primary HPV type 16 vaccine reduced the incidence of HPV type 16 analyses of efficacy were conducted in the per-protocol effi- infections and related CIN; however, a larger study was war- cacy (PPE) population, which consisted of those individuals ranted to determine if the vaccine prevents clinical disease. who had received the complete series of three vaccinations Also, a multivalent vaccine including other types of HPV within 1 year of study enrollment, did not deviate from the would be more beneficial.7 study protocol, and who were polymerase-chain reaction (PCR) negative for the relevant HPV types prior to the first Protocol 007, a double-blind, randomized, placebo-controlled, dose and through 1 month following the third dose.5 multi-center Phase II trial conducted in women 16 to 23 years Table 1: Combined Analyses of Efficacy of Gardasil® in the Per-Protocol Efficacy Population5 ® Population Gardasil Placebo % Efficacy Number of Number of (95% Confidence N N Cases Cases Interval) HPV type 16- or HPV18-Related CIN Stage 2/3 or AIS Combined Protocols 8487 0 8460 53 100 (92.89-100) HPV type 6-, 11-, 16-, or 18-Related CIN (stages 1, 2/3) or AIS Combined Protocols 7858 4 7861 83 95.2 (87.2-98.7) HPV type 6-, 11-, 16-, or 18-Related Genital Warts Combined Protocols 7897 1 7899 91 98.9 (93.7-100) CIN = Cervical Intraepithelial Neoplasia AIS = Adenocarcinoma in situ old evaluated the efficacy and safety of a quadrivalent cervical cancer, genital warts, VIN, VaIN, or vulvar/vaginal can- HPV vaccine against HPV types 6, 11, 16, and 18. Inclu- cer. The study was conducted in women 16 to 23 years old. The sion criteria were the same as in Protocol 005, except par- vaccine or placebo was administered at day 1, month 2, and ticipants were required to have had <4 male sex partners. month 6. Follow-up occurred at months 3 and 7, and then every After receiving 0.5 mL doses of vaccine (type 6=20 mcg, 6 months (total follow-up period not specified). After an average type 11=40 mcg, type 16=40 mcg, and type 18=20 mcg; of 17 months of follow-up the vaccine prevented 100% of HPV n=276) or placebo (n=275) at day 1, month 2, and month 6-, 11-, 16-, and 18-related CIN grades 1-3, genital warts, and 6, patients were followed-up at months 7 and 12, and then VIN/VaIN of any grade (95% CI 88-100). No cases of the com- every 6 months thereafter until month 36. Primary out- posite endpoint occurred in the vaccine group compared to come was the composite of persistent infection associated 40 cases in the placebo group.