Updated 9/14/2010

Midodrine Remains Approved and Available in the Marketplace

FDA intends to work with Shire, the generic manufacturers, and other organizations to discuss the data that are necessary to establish the efficacy of midodrine.

In an update posted on its website dated September 10, 2010, the U.S. Food and Drug Administration (FDA) stated that Shire (the sponsor of midodrine hydrochloride, marketed as ProAmatine; five generic drug manufacturers also make the medication) has requested a public hearing in response to FDA's proposal to withdraw midodrine. That hearing will provide an opportunity for the company to present the agency with data supporting the clinical benefit of the drug and for an advisory committee to review those data. The FDA intends to work with Shire, the generic manufacturers, and other organizations to discuss the data that are necessary to establish the efficacy of midodrine and will post this information in a public docket. Midodrine remains approved and available in the marketplace.

FDA noted that since it had notified the manufacturers of the proposed withdrawal of midodrine, the agency heard from professional organizations, doctors, and patients about their concern about losing access to midodrine. The Heart Rhythm Society wrote a letter (PDF, 110K) to the Director of the Center for Drug Evaluation and Research recommending that the FDA continue to allow prescription of midodrine hydrochloride to current and future patients with approved indications for the drug and work with the manufacturer to collect the missing information. The Society suggested that data from a subset of the 100,000 individuals who are currently taking the medication could be gathered, or collecting data from new recipients of midodrine hydrochloride.

The FDA stated that it has two goals with respect to midodrine:

• Obtain high quality data on the effectiveness of the medication and
• Maintain access for patients to the medication throughout this process

FDA stated that its previous announcement did not represent the actual withdrawal of the medication from the market, but rather a step in the regulatory process – a step that reflects both the regulatory requirement for manufacturers to verify the clinical benefit of accelerated approval products and the agency's position that more data about the benefits of midodrine would help doctors and patients understand who can benefit from the drug and how best to use it.

To reassure patients and their doctors, FDA has stated clearly that as the regulatory process moves forward, continued patient access to midodrine is a key agency priority. FDA believes that its approach will serve both of its goals — getting the necessary efficacy data and maintaining patient access to the medication while it does so.

Previous coverage of this issue remains below.

Society Urges FDA Not to Remove Midodrine Hydrochloride from Market

"...While it is regrettable that post market studies were not completed to comply with the requirement of drug approval, this decision to deny availability of this medication is estimated to negatively affect the care of approximately 100,000 patients who are currently receiving this drug... Cardiac electrophysiologists prescribe this drug because it has substantial effectiveness in the treatment of some patients who are seriously disabled by autonomic dysfunction and hypotension..." Read the Society’s letter to FDA (PDF, 110K) on the proposed removal of midodrine from the market Read the FDA press release Midodrine hydrochloride: FDA Proposes Withdrawal of Low Blood Pressure Drug (from Medwatch) On Friday, September 3 the New York Times published an article that the FDA stated that it will continue to allow midodrine to be sold in the United States. Read the NYT Article »

On August 16, 2010, the FDA proposed to withdraw approval for the drug midodrine hydrochloride because required post-approval studies have not been completed to verify the clinical benefits of the drug [learn more]. The drug, marketed as ProAmatine by Shire Development Inc. and as a generic by others (Apotex Corp., Impax Laboratories, Mylan Pharmaceuticals, Inc., Sandoz, Inc. and Upsher-Smith Laboratories, Inc.), is used to treat autonomic dysfunction with resultant hypotension and tachycardia.

The Society is concerned that removing midodrine hydrochloride from the market will harm patients, as there is no equivalent medication that can be substituted for it. The FDA has advised that patients who currently take this medication should not stop taking it and should consult their health care professional about other treatment options.

The FDA first approved Shire Pharmaceutical's ProAmatine in 1996 under the agency’s accelerated approval regulations for drugs that treat serious or life-threatening diseases. That accelerated approval allows drugs to be approved on clinical data that suggests a drug has benefits but requires manufacturers to conduct postmarketing clinical trials (often referred to as phase 4 trials) that verify and describe the clinical benefits, proving the product’s effectiveness. After the Shire Pharmaceutical ProAmatine decion, the FDA later approved midodrine hydrochloride, the generic form.

Responding to the FDA's proposed action, the Heart Rhythm Society wrote a letter (PDF, 110K) to the Director of the Center for Drug Evaluation and Research expressing our concerns. While the Society recognizes that that the required studies were not completed, removing this medication from the market — affecting those who now take it and preventing new patients beginning treatment — will harm patients. The Society made the point that there is no equivalent medication that can be substituted for midodrine hydrochloride.

In its letter, the Society recommends that the FDA:

• continue to allow prescription of midodrine hydrochloride to current and future patients with approved indications for the drug
• work with the manufacturer to collect the missing information. The Society suggest that ideally data from a subset of the 100,000 individuals who are currently taking the medication could be gathered. An alternative could be collecting data from new recipients of midodrine hydrochloride

The Heart Rhythm Society strongly encourages physicians and patients to contact the FDA expressing their own concerns about the proposed removal of midodrine mydrochloride from the market. Correspondence should be addressed to:

Janet Woodcock, MD
U.S Food and Drug Administration
Center for Drug Evaluation and Research
10903 New Hampshire Avenue
Silver Spring, MD 20993

The Society’s Health Policy staff will continue to monitor and report on this issue, and work with the FDA to resolve it.

FDA Action on Midodrine Hydrochloride (see also www.regulations.gov)

In August 2009 the FDA wrote to Shire and the holders of abbreviated new drug applications (ANDAs) for midodrine products, reiterating the Agency’s requirements regarding the postmarketing trials necessary to support efficacy. FDA stated that data should be derived from two randomized, double-blind, placebo-controlled trials, one to establish the effects of a single dose of midodrine on the symptoms of orthostatic hypotension and a second trial to establish the presence of symptomatic benefit after at least two weeks of treatment. The agency directed Shire and any ANDA holder intending to conduct phase 4 trials of midodrine to submit documentation of Institutional Review Board (IRB) approval and the proposed statistical analysis plans for both studies by February 12, 2010. FDA required 50 percent enrollment in both trials by April 12, 2010, and 100 percent enrollment by June 12, 2010, with any application holder conducting phase 4 trials expected to submit full study reports of the trials by October 12, 2010. Such trials were required to be successful at a conventional (p<0.05) level of statistical significance for FDA to conclude that midodrine effectively relieves symptoms of orthostatic hypotension.

No application holder has satisfied the requirements set forth in that letter; specifically, no application holder submitted documentation of IRB approval or statistical analysis plans for the two required studies on or before February 12, 2009, had 50 percent enrollment by April 12, 2010, or completed enrollment by June 12, 2010. FDA indicated that to its knowledge, the required studies are not currently being conducted. In light of this, FDA is exerting its authority under applicable provisions of the Federal Food, Drug, and Cosmetic Act and implementing regulations and thus proposing to withdraw approval of ProAmatine and midodrine hydrochloride.

Read the Society's letter to FDA (PDF, 110K) on the proposed removal of midodrine from the market