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WASHINGTON -- The consumer watchdog group Public Citizen petitioned the FDA to add a black box warning to three classes of hypertension drugs, cautioning against their combined use.

The drugs -- angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren (Tekturna) -- are commonly used in combination to treat high blood pressure, but that studies have shown their combined use can cause kidney failure, hypotension, and hyperkalemia.

The watchdog group wrote FDA Commissioner Margaret Hamburg, MD, and Center for Drug Evaluation and Research Director Janet Woodcock, MD, to ask for a black box warning on the labels of all 18 ACE inhibitors and ARB medications, as well as aliskiren. The group also calls for a medication guide to be distributed to patients along with the drugs, and a "Dear Doctor" letter warning physicians of the dangers of the drugs' use in combination.

The FDA warned in April of aliskiren use with ACE inhibitors and ARBs, but Public Citizen called the current warning against combination therapy on the labels of aliskiren and five ACE inhibitors "wholly inadequate" and "dangerously insufficient."

While Public Citizen says the drugs in combination provide no clinical benefit, studies have shown the drugs lowered the risk of atrial fibrillation and reduced the size of enlarged heart chambers. But those studies are flawed, the group says.

"All trials were exceedingly small, with fewer than 100 patients on combination therapy in any one study," Public Citizen wrote in its petition. "The trials were also short term, ranging from four to 12 weeks, with one exception (one trial lasted 2.9 years). Therefore, almost all of the trials were not adequately powered to detect significant differences in rates of adverse events."

The watchdog group says the drug combination's benefit has been disproved in two large studies. Furthermore, a third trial studying the drugs in combination was stopped as a safety precaution after patients developed low blood pressure and kidney failure.

Results of the ONTARGET trial published in the New England Journal of Medicine showed combination-therapy subjects had higher rates of renal impairment and hypotension, Public Citizen said.

Patients on the combination permanently discontinued therapy because of hypotension (4.8%) at rates higher than those on telmisartan (Micardis, 2.7%) and ramipril (Altace, 1.7%) alone. Combination-therapy patients also stopped medication due to renal abnormalities at higher rates (1.1%) than those on either telmisartan (0.8%) or ramipril (0.7%).

"In fact, there is no patient population thus far studied in standardized trials in which ACE inhibitor/ARB combination therapy confers added clinical benefits," Public Citizen wrote in the petition. "By contrast, virtually all patient populations studied -- in both standardized and non-standardized trials -- incur added harms with combination therapy, including an increase in serious and life-threatening adverse effects."

The FDA has until early April 2013 to respond to the petition.

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