Pharmacology Watch: FDA Issues Black Box’ Warning Based on WHI Study

Pharmacology Watch

The FDA has mandated a "Black Box" warning for all estrogen and estrogen/progestin products for use by postmenopausal women. The new warnings are based on analysis of data from the Women’s Health Initiative (WHI) study that was published July 2002. The box warning emphasizes that these drugs have been associated with increased risks for heart disease, heart attacks, strokes, and breast cancer and that they are not approved for heart disease prevention. Wyeth Pharmaceuticals, the manufacturer of Premarin, Prempro, and Premphase, products that were used in the WHI study, are also required to change their indications to: treatment of severe vasomotor symptoms, vulvar and vaginal atrophy associated with menopause, prevention of postmenopausal osteoporosis, and should only be used when the benefit clearly outweighs the risk. The labeling will also be required to include consideration of other therapies for the atrophy and osteoporosis indications, and to recommend use of the lowest dose for the shortest duration possible. While Wyeth’s products are the focus of this initial press release and FDA action, all estrogen products will be subject to new labeling. The FDA is also recommending future research to answer questions regarding the risks of lower-dose estrogen products and if other types of estrogens and progestins are associated with lower risk of CVD and breast cancer. The complete press release can be viewed at

ALLHAT: Thiazide for Hypertension Treatment

Thiazide diuretics should be considered first-line therapy for hypertension, according to the authors of the ALLHAT study published in December. In a finding that surprised nearly everyone (especially the sponsors of the study) in patients with hypertension and at least one other cardiovascular risk factor, the diuretic chlorthalidone was associated with better cardiovascular outcomes at less cost and with equal tolerability compared to a calcium channel blocker or an ACE inhibitor. ALLHAT enrolled more than 33,000 patients from 623 centers in the United States, Canada, and the US Virgin Islands. Patients were randomized to the calcium channel blocker amlodipine, the angiotensin-converting enzyme inhibitor lisinopril, or chlorthalidone. Mean follow-up was 4.9 years with the primary outcome being combined fatal CHD or nonfatal MI. Secondary outcomes included all-cause mortality, stroke, combined CHD, and combined cardiovascular disease (CVD). The 6-year rate of the primary outcome and all-cause mortality was virtually identical for all 3 drugs. Chlorthalidone was superior to amlodipine in preventing heart failure (10.2% vs 7.7%, RR, 1.38, 95% CI, 1.25-1.52) and was superior to lisinopril for lowering blood pressure and in 6-year rates of combined cardiovascular disease including stroke (6.3% vs 5.6%) and heart failure (8.7% vs 7.7%). With improved cardiovascular outcomes, lower cost, and equal tolerability, the study concludes that thiazide-type diuretics are superior in preventing one or more forms of CVD and that they should be the preferred agent in antihypertensive therapy, and should be included in all multidrug regimens (JAMA. 2002;288:2981-2997). An accompanying editorial calls ALLHAT "one of the most important trials of antihypertensive therapy" and suggests that national guidelines should be changed to emphasize use of thiazide diuretics as initial therapy (JAMA. 2002;288:3039-3042).

Candesartan Effective Against Migraines

The angiotensin II receptor blocker candesartan is effective in preventing migraine headaches, according to a new study. Norwegian researchers looked at 60 patients age 18-65 with 2-6 migraines per month. Patients were randomized in a double-blind placebo-controlled crossover study with the main outcome being number of days with headache. Secondary outcomes included use of pain medications and triptans, hours with headache, headache severity, and days lost from work. During the 12-week study, the mean number of days with headache was 18.5 with placebo vs 13.6 with candesartan (P = .001) in the intention to treat analysis (n = 57). Patients were considered a candesartan responder if they noted a reduction of 50% or more of days with headache (18 of 57 patients, 31.6%) or days with migraine (23 of 57 patients, 40.4%). Although this represented a minority of patients, those who did respond benefited from effective migraine prophylaxis. Candesartan’s tolerability profile was comparable with placebo (JAMA. 2003;289:65-69).

Cough! No Cold Relief from Echinacea

Echinacea offers no benefit in treating the common cold according to a study from the University of Wisconsin. A total of 148 college students with recent onset colds were randomized to an encapsulated mixture of unrefined Echinacea (E purpurea herb and root and E angustifolia root) 6 times a day on the first day of illness and 3 times a day on the subsequent days up to a total of 10 days. The main outcome was the severity and duration of self-reported symptoms of URI. No statistically significant differences were detected between Echinacea and placebo groups for any of the measured outcomes, which included trajectories of severity over time or mean cold duration. No significant side effects were noted with Echinacea. The study concludes that no detectable benefit or harm could be found with Echinacea treatment for the common cold (Ann Intern Med. 2002;137:939-946).

COX-2 Inhibitors and GI Benefits Could Be Overrated

Could the GI benefits of COX-2 inhibitors be overrated? A new study suggests that the COX-2 inhibitor celecoxib is no safer than a combination of diclofenac plus omeprazole with regard to ulcer risk in patients with a history of peptic ulcer disease and arthritis. Researchers from Hong Kong recruited patients with arthritis and NSAID-related bleeding ulcers. After their ulcers had healed, 287 patients who were negative for Helicobacter pylori, were randomly assigned to receive celecoxib 200 mg twice a day plus placebo, or diclofenac 75 mg twice a day plus 20 mg of omeprazole for 6 months. Recurrent bleeding ulcer occurred in 7 patients receiving celecoxib and 9 receiving diclofenac/omeprazole (4.9% vs 6.4%). Renal adverse events including hypertension, peripheral edema, and renal failure occurred in 24.3% of patients receiving celecoxib and 30.8% of those receiving diclofenac/omeprazole. The authors suggest that neither regimen offered effective protection against recurrent ulcer complications or renal adverse effects (N Engl J Med. 2002;347:2104- 2110).

FDA Actions

Pfizer’s new anti-migraine drug, eletriptan (Relpax) has been approved by the FDA for marketing. The drug that is available in 20-mg and 40-mg tablets has been shown to be effective in aborting migraine headaches within 2 hours. The company is marketing a 80-mg tablet in Europe, but the FDA refused to approve the higher dose due to an increase in adverse events.

Montelukast (Singulair), Merck’s leukotriene inhibitor, has been approved by the FDA for the treatment of seasonal allergic rhinitis. The drug has been on the market since 1998 for the treatment of asthma in adults and children. This new indication is the first for a leukotriene inhibitor, and creates a new, nonantihistamine treatment modality for this indication. Montelukast was approved for symptoms of seasonal allergic rhinitis in adults and children aged 2 years and older. It is available in 10 mg strength for adults, and a chewable 4 mg or 5 mg strength for children.