Pharmacology Watch

HPV Vaccine Now Recommended for Males

In this issue: New recommendations for HPV vaccine; guidelines for treatment of essential tremor; updates on smoking cessation drugs; and FDA actions.

HPV vaccine and anal cancer risk

The human papillomavirus (HPV) vaccine is routinely administered to adolescent girls; now the CDC's Advisory Committee on Immunization Practices is recommending the vaccine for 11- and 12-year-old boys as well. The vaccine has been approved for use in both adolescent girls and boys to protect them against HPV but has been somewhat underutilized in girls and rarely used in boys. HPV causes genital warts and cervical cancer in women and the vaccine effectively reduces the rate of both. The vaccine is generally recommended for 11 and 12 year olds when they get other routine vaccines, and before they become sexually active. Although the vaccine is approved for boys, the CDC had not made a recommendation on routine use until now. After evaluating data on efficacy in males, the committee felt that the vaccine could protect boys against genital warts, as well as throat and anal cancer caused by HPV, and could help prevent spread of the virus to girls.

In related news, a new study shows the HPV vaccine is effective in preventing anal intraepithelial neoplasia in men who have sex with men. In a double-blind study of 602 men (ages 16-26) who have sex with men, half were randomized to the quadravalent HPV vaccine and half to placebo. The vaccine reduced the risk of anal intraepithelial neoplasia caused by the four subgroups of HPV covered by the vaccine (HPV-6, 11, 16, and 18) by half in the intention-to-treat population and by 77% in the per-protocol population. Anal intraepithelial neoplasia caused by HPV of any type was reduced by 25.7% and 54.9%, respectively. Rates of anal intraepithelial neoplasia per 100 person years were 17.5 in the placebo group and 13 in the vaccine group in the intention-to-treat, and 8.9% placebo vs 4.0% vaccine in the per-protocol population. The rate of grade 2 or 3 anal intraepithelial neoplasia related to HPV subtypes covered by the vaccine was reduced by 54.2% (intention-to-treat) and 74.9% (per-protocol). The vaccine was well tolerated. The authors conclude that the HPV vaccine reduced the rate of anal intraepithelial neoplasia in men who have sex with men and may help reduce the risk of anal cancer (N Engl J Med 2011;365:1576-1585).

Treatment of essential tremor

The American Academy of Neurology has published its updated guideline for the treatment of essential tremor. Propranolol and primidone remain first options with a Level A recommendation (established as effective). Alprazolam, atenolol, gabapentin as monotherapy, sotalol, and topiramate are graded as Level B (probably effective), while nadolol, nimodipine, clonazepam, botulinum toxin a, deep brain stimulation, and thalamotomy remain as level C (possibly effective). There is not enough evidence to make a recommendation for gamma knife therapy. The new guideline also states that there is insufficient evidence to support or refute the use of pregabalin, zonisamide, or clozipine. Levetiracetam and 3,4 diaminopyridine are ineffective and flunarizine is probably ineffective. The guideline was published online in Neurology October 19, 2011 (doi: 10.1212/WNL.0b013e318236f0fd).

Chantix and neuropsychiatric side effects

There is good news for the smoking cessation drug varenicline (Chantix). Following concern about neuropsychiatric side effects, the FDA sponsored two epidemiologic studies that evaluated the risk of neuropsychiatric hospitalizations associated with the drug. Neither study found a difference in risk of neuropsychiatric hospitalization between varenicline and nicotine replacement therapy, although hospitalization was the only endpoint evaluated and they did not rule out an increased risk of other neuropsychiatric events. While reassuring, the FDA is recommending that health care professionals and patients continue to follow the recommendations previously established and monitor for neuropsychiatric symptoms when prescribing or using varenicline. The manufacturer is conducting a large safety study of the drug to assess neuropsychiatric adverse effects but the results will not be available until 2017 (www.fda.gov/Drugs/DrugSafety/). In related news, the inexpensive partial nicotine agonist cytisine is an effective adjunct to smoking cessation, according to a new study in the New England Journal of Medicine. Cytisine is extracted from the seeds of Cysisus laborinum L. (Golden Rain acacia) and has been available worldwide for years, particularly in Eastern Europe, where it can be purchased for $6-$15 per course. Researchers randomized 740 smokers to cytisine or matching placebo for 25 days along with counseling. The rate of sustained 12 months abstinence was 8.4% in the cytisine group compared with 2.4% in the placebo group (P = 0.01). GI side effects were slightly more prevalent in the treatment group. The authors conclude that cytisine was more effective than placebo for smoking cessation and may be "an affordable treatment to advance smoking cessation globally" (N Engl J Med 2011;365:1193-1200).

FDA Actions

The FDA is continuing to review the association of oral contraceptives and thrombotic risk, particularly oral contraceptives containing drospirenone. On October 27, the FDA issued a preliminary Drug Safety Communication, with the full report due out in early December. Reviewing the records of Kaiser Permanente members in California and state Medicaid programs in Tennessee and Washington, which included 835,826 women receiving contraceptive prescriptions from 2001-2007, an increased risk of venous thromboembolism (VTE), deep venous thrombosis, and pulmonary embolism was noted with several contraceptives, with low estrogen hormonal contraceptives as a reference. Products containing drospirenone had relative risk of VTE of 1.74 (95% confidence interval [CI] 1.42-2.14). The norelgestromin/ethinyl estradiol transdermal patch was associated with relative risk of 1.55 (95% CI 1.17-2.07) and etonogestrel/estradiol vaginal ring was associated with a relative risk of 1.56 (95% CI 1.02-2.37). The risk was higher in younger users than older women (www.FDA.gov./DRUGS/DrugSafety/ucm277346.htm).

The FDA has approved the first generic olanzapine (Zyprexa) to treat schizophrenia and bipolar disorder. The generic carries the same warnings as the brand regarding increased risk of death in elderly people with psychosis or dementia. Generic olanzapine will be available from several manufacturers as tablets and orally disintegrating tabs.

The FDA has announced that drotrecogin alfa (Xigris) is being withdrawn from the market by Eli Lilly & Co. The withdrawal is based on the results of the recently completed PROWESS-SHOCK trial in which drotrecogin alfa failed to show a survival benefit in patients with severe sepsis and septic shock. The FDA is recommending that the drug should be stopped in any patients currently being treated and should not be initiated in new patients. All remaining product should be returned to the supplier.

The FDA has approved tadalafil (Cialis) for the treatment of benign prostatic hyperplasia (BPH)either alone or when it occurs along with erectile dysfunction (ED). The drug was approved in 2003 for treatment of ED. The approval was based on two trials in which men taking tadalafil 5 mg daily experienced significant improvements in BPH symptoms compared with those taking placebo. A third study in which men had both BPH and ED, tadalafil 5 mg daily improved both symptoms of BPH and ED compared to placebo. Tadalafil should not be used in patients taking nitrates or in combination with alpha blockers for the treatment of BPH.

The FDA has approved a combination of sitagliptin and simvastatin for the treatment of adults with type 2 diabetes and hypercholesterolemia. This represents the first combination drug for treating these two conditions. The fixed dose combination is available in three strengths: 100 mg sitagliptin/10 mg simvastatin, 100 mg/20 mg, and 100 mg/40 mg. The approval was based on "substantial experience with both sitagliptin and simvastatin" and is a "convenience combination," according to the FDA. Sitagliptin/simvastatin will be marketed as Juvisync by MSD International GmbH Clonmel in Tipperary, Ireland.


This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5404. E-mail: neill.kimball@ahcmedia.com.