Drug Updates

According to a meta-analysis published in JAMA, the anti–interleukin (IL)-12/23 agents ustekinumab and briakinumab and the anti–tumor necrosis-alpha (TNF-α) agents adalimumab, etanercept, and infliximab do not increase the rate of major adverse cardiovascular events (MACE).¹ Randomized, placebo-controlled, double-blind, monotherapy studies in patients with chronic plaque psoriasis were evaluated. More than 10,000 patients met the inclusion criteria in 22 randomized controlled trials. The primary outcome was a major adverse cardiovascular event, a composite endpoint of myocardial infarction (MI), cerebrovascular accident, or cardiovascular death during the placebo-controlled phase of the study in patients that received at least one dose of placebo or the study drug. All studies had at least a 12-week placebo-controlled phase, except for the infliximab studies, which had a 10-week placebo-controlled phase. The event rates were as follows: five of the 1,471 patients that received ustekinumab and five of the 1,428 patients that received briakinumab had an MI or stroke or died of heart-related causes, compared with none of the 1,474 patients given placebo. The investigators noted that the difference did not reach statistical significance. One of the 1,032 adalimumab-treated patients had an event, which was concluded to be “no difference” compared with placebo-treated patients. No patients that received etanercept (n=1,679) or infliximab (n=1,147) had a MACE. The briakinumab event rate was further scrutinized by the investigators, and the investigational studies were discontinued to further evaluate the potential mechanisms related to the MACE rates in these patients. Additionally, the manufacturer amended the open-label continuation trials to withdraw any patients with two or more predefined cardiovascular risk factors who had not experienced failure of prior anti–TNF-α therapies. The authors note that until further data are available, clinicians should use extra vigilance of cardiovascular risk factors when beginning anti–IL-12/23 therapies in patients with psoriasis.

Bisphosphonates (e.g., alendronate, etidronate, ibandronate, risedronate, risedronate delayed release, tiludronate), were evaluated on September 9, 2011 at a Food and Drug Administration (FDA) Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory meeting.^2,3 Bisphosphonate studies have shown that these agents have proven beneficial within the first three years of treatment in preventing osteoporosis fractures. However, when treatment is continued beyond five years, there does not appear to be a use benefit compared with using “no drug.” Additionally, women who have stopped taking bisphosphonates after five years of treatment seem to have a similar risk of fracture reduction and amount of increased bone density compared with women who continue to receive bisphosphonates. In regard to side effects such as unusual femur breaks, osteonecrosis of the jaw, or esophageal cancer, there is no conclusive evidence that bisphosphonates cause these effects. However, these serious but rare effects are difficult to study and cannot be ruled out as being caused by bisphosphonates. The long-term safety of bisphosphonates is still unclear due to conflicting study results. (See the October 2011 issue of Drug Safety Quarterly, available at www.rheumatology.org in the “Publications” menu, for more information.)

As also noted in the October 2011 Drug Safety Quarterly, Citalopram has recently been identified as causing dose-dependent QT interval prolongation.^4,5 Electrocardiogram changes can lead to the fatal arrhythmia called Torsade de Pointes. It is therefore recommended that this antidepressant no longer be prescribed at doses greater than 40 mg per day. Additionally, citalopram should not be used in patients with congenital long QT syndrome. Patients with congestive heart failure, bradyarrhythmias, or who are predisposed to hypokalemia or hypomagnesemia due to concomitant illness or drugs are at a higher risk of developing Torsade de Pointes. The citalopram drug label, including both brand and generic formulations, have been updated to include this warning. It is not clear whether these effects are seen with the S-enantiomer escitalopram.