FDA proposes withdrawal of marketing approval for midodrine hydrochloride

In mid August, FDA issued a “Proposal to Withdraw Marketing Approval and Notice of Opportunity for a Hearing” to the companies that manufacture midodrine hydrochloride (ProAmatine, Shire Development Inc., and generics by Apotex Corp., Impax Laboratories Inc., Mylan Pharmaceuticals, Sandoz Inc., and Upsher-Smith Laboratories). Midodrine, a vasopressor used to lower blood pressure, was granted accelerated marketing approval in 1996 because the agency deemed it to be an important drug to treat a serious or life-threatening condition. However, such accelerated approvals by FDA require that manufacturers verify a drug’s clinical benefit to patients by conducting post-approval studies.

“We’ve worked continuously with the drug companies to obtain additional data showing the drug’s clinical benefits to patients,” said Norman Stockbridge, MD, director of the Division of Cardiovascular and Renal Drugs in FDA’s Center for Drug Evaluation and Research. “Since the companies have not been able to provide evidence to confirm the drug’s benefit, the FDA is pursuing a withdrawal of the product.” 

Such evidence confirming midodrine’s benefit would likely have to come from the evaluation of a terminal end point in clinical trials, for example, showing that midodrine use improved a patient’s ability to perform activities of daily living, and not a surrogate end point such as a beneficial effect on blood pressure. Midodrine has been principally studied in patients with orthostatic hypotension (a condition in which patients are unable to maintain blood pressure in the upright position and, thus, become dizzy or faint when they stand up), and on average, clinical trials have found it to significantly increase both supine and sitting blood pressure by approximately 16/8 to 20/10 mmHg, respectively. While Shire stated it has completed the required post-marketing trials, according to a press release on the company’s website, FDA “viewed these trials as inconclusive and required that additional trials be conducted for ProAmatine to maintain its marketing authorization.” 

According to representatives at Shire Development Inc., the company has elected to withdraw the product effective September 30, 2010. In the meantime, FDA is working with manufacturers to develop an expanded-access program to allow patients who currently receive the midodrine, on a case-by-case basis, to continue to receive it.

According to figures from FDA, about 100,000 patients in the United States filled a prescription for either a brand or generic form of midodrine in 2009.