Pharmacology Watch

Tiotropium for Uncontrolled Asthma

In this issue: Tiotropium for uncontrolled asthma, sibutramine pulled from market, incidence and mortality data from WHI, FDA Actions.

Tiotropium for uncontrolled asthma

Tiotropium, a long-acting anticholinergic inhaler, is approved for treatment of chronic obstructive pulmonary disease. A new study suggests that it may also be effective for patients with asthma.

In a study of 210 adults with asthma with inadequate control with inhaled glucocorticoids, tiotropium was compared to doubling the dose of glucocorticoids, and was also compared to the addition of salmeterol, a long-acting beta agonist (LABA). Tiotropium was superior to doubling the dose of inhaled glucocorticoid as assessed by measuring the morning peak expiratory flow (PEF) (P < 0.001). It also improved evening PEF, asthma control days, and FEV1, as well as daily symptom scores. The addition of tiotropium was also non-inferior to the addition of salmeterol for all assessed outcomes and was superior to salmeterol in measures of prebronchodilator FEV1 (P = 0.003).

The authors conclude that tiotropium is superior to doubling the dose of glucocorticoid in patients with inadequately controlled asthma, and is equivalent to the addition of salmeterol in the same patient group (published online N Engl J Med Sept. 19, 2010). This study is important because it may result in options for patients with poorly controlled asthma beyond adding a LABA. Recently, asthma experts and the FDA have questioned the safety of LABA therapy (FDA Drug Safety Communication June 2, 2010), and a recent meta-analysis suggests that use of LABAs without concomitant inhaled corticosteroids increase the risk for intubation or death (Am J Med 2010;123:322-328).

Sibutramine pulled from market

Abbott Laboratories announced in October that it is withdrawing the weight-loss drug sibutramine (Meridia®) from the market. The move comes a month after the FDA finished a review of the drug and found that patients with cardiovascular disease or diabetes given sibutramine had a significantly higher rate of serious cardiovascular events compared to placebo. The drug was originally approved in 1997. In a news release, the FDA states "physicians are advised to stop prescribing Meridia to their patients and patients should stop taking this medication." The Wall Street Journal reports that while Meridia may be off the market, sibutramine is still available illegally in many weight-loss nutritional supplements, most of which are available via the Internet from oversee suppliers. The supplements are marketed as "all-natural" and their labels list only herbal ingredients. The FDA recently advised consumers that Slimming Beauty Bitter Orange Slimming Capsules contains sibutramine, and last year published a list of more than 50 other supplements containing the banned drug. For complete list of supplements containing sibutramine go to:

Incidence and mortality data from WHI

In 2002, the Women's Health Initiative (WHI) study was stopped early after 5.6 years when data showed that combination estrogen and progesterone therapy increased the risk of breast cancer. Mortality data had never been reported from WHI, however, and other studies have suggested that hormone therapy-associated breast cancers might have a more favorable prognosis than other breast cancers. A new analysis of WHI data dispels that notion.

The current study is a follow-up study of more than 16,000 women enrolled in WHI who were randomized to conjugated equine estrogen 0.65 mg per day plus medroxyprogesterone 2.5 mg per day (Prempro®) or placebo. Participants were followed for an average of 11 years with the main outcome measure being breast cancer incidence and breast cancer mortality. Women on hormone therapy had a higher rate of breast cancer compared to women on placebo (0.42% vs 0.34% per year; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = 0.004) and breast cancers in the hormone group were more likely to be node-positive (23.7% vs 16.2%; HR, 1.78; 95% CI, 1.23-2.58; P = 0.03). The death rate associated with breast cancer was higher in the hormone group (0.03% vs 0.01% per year; HR, 1.96; 95% CI, 1.00-4.04; P = 0.049), a finding that barely reached statistical significance because of the low number of cancers in either group.

The authors conclude that estrogen plus progesterone was associated with a higher breast cancer incidence, as well as cancers that were more commonly node-positive. Breast cancer mortality was also higher in the combined hormone group (JAMA 2010;304:1684-1692). An accompanying editorial points out that despite the borderline statistical significance of these findings it is likely that "the increase in breast cancer deaths due to hormone therapy has been underestimated in the current study." However, it is still unclear whether short courses of hormone therapy for relief of postmenopausal symptoms right after menopause may be safe and further research is needed "to determine whether lower doses or shorter durations of hormone therapy could alleviate menopausal symptoms without increasing cancer risk" (JAMA 2010;304:1719-1720).

FDA actions

The FDA has approved fingolimod, the first oral drug for the treatment of relapsing forms of multiple sclerosis. Fingolimod is a sphingosine 1-phosphate receptor modulator that is believed to reduce migration of lymphocytes into the central nervous system. Compared to interferon beta-1a, the annualized relapse rate was significantly lower with fingolimod. Patients need to be monitored for decreased heart rate and elevation of liver transaminases. Fingolimod is given as a once-daily 0.5 mg tablet. It is marketed by Novartis as Gilenya™.

As anticipated, the FDA has approved dabigatran to prevent strokes and blood clots in patients with atrial fibrillation. The drug is a direct thrombin inhibitor and is given orally twice a day. The approval was based on the RE-LY trial, which showed that dabigatran at 150 mg given twice a day was superior to warfarin for this indication. Unlike warfarin, dabigatran requires no monitoring. Dabigatran will be available in 75 mg and 150 mg capsules and will be marketed as Pradaxa® by Boehringer Ingelheim Pharmaceuticals.

The FDA has ordered a labeling change for bisphosphonates, warning of the risk of atypical femoral fractures. In March, the FDA announced an ongoing safety review of bisphosphonates and the occurrence of subtrochanteric and diaphyseal femoral fractures. The new warning is a result of that review and, while not acknowledging a direct link, the warning suggests that these fractures may be related to use of bisphosphonates for longer than 5 years. The agency further suggests that health care professionals consider periodic reevaluation of the need for continued bisphosphonate therapy in patients who have been on the drugs for more than 5 years. The labeling change will only affect bisphosphonates approved for osteoporosis, which include alendronate (Fosamax®), risedronate (Actonelsup®), ibandronate (Boniva®), and zoledronic acid (Reclast®).

The FDA has approved extended-release naltrexone to treat and prevent relapse of patients with opioid dependence who have undergone detoxification treatment. Extended-release naltrexone is administered by intramuscular injection once a month, and blocks opioid receptors in the brain. It was initially approved in 2006 to treat alcohol dependence. The drug is only approved for patients who have completed rehabilitation, otherwise it may trigger opioid withdrawal. The efficacy of naltrexone was shown in a 6-month placebo-controlled trial in which treated patients were more likely to stay in treatment and refrain from using illicit drugs. Extended-release naltrexone injection is marketed as Vivitrol® by Alkermes Inc.

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. Dr. Elliott reports no financial relationships to this field of study. Questions and comments, call: (404) 262-5468. E-mail: