Droxidopa, a prodrug that is converted into norepinephrine, has been approved for the treatment of patients with neurogenic orthostatic hypotension, a rare, chronic, and often debilitating condition associated with Parkinson’s disease, multiple system atrophy, and pure autonomic failure, the Food and Drug Administration announced on Feb 18.
The approval is based on two clinical trials of people with NOH, who, over 2 weeks of treatment, reported improvements in dizziness, light-headedness, feeling faint, “or feeling as if they might black out,” compared with those taking a placebo, the FDA said in a statement announcing the approval. The most common adverse events reported by patients in the studies were headache, dizziness, nausea, hypertension, and fatigue.
The approval is an accelerated approval, which enables the FDA to approve a drug for a serious disease with few treatment options, based on data showing that the treatment has an effect on a clinical measure that is considered “reasonably likely” to predict longer-term benefit. In the case of droxidopa, approval was based on short-term relief of dizziness. The manufacturer, Chelsea Therapeutics, is required to conduct a postmarketing study to confirm the drug’s benefits.
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Droxidopa is “a synthetic catecholamine that is directly converted to norepinephrine (NE) via decarboxylation, resulting in increased levels of NE in the nervous system, both centrally and peripherally,” according to the company, which will market the drug under the trade name Northera.
“There are limited treatment options for people with NOH, and we are committed to helping make safe and effective treatments available,” Dr. Norman Stockbridge, director of the Division of Cardiovascular and Renal Drugs in the FDA’s Center for Drug Evaluation and Research, said in the statement. People with NOH “are often severely limited in their ability to perform routine daily activities that require walking or standing,” he added.
The prescribing information states that droxidopa is indicated for “the treatment of orthostatic dizziness, light-headedness, or the ‘feeling that you are about to black out’ in adult patients with symptomatic neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure [Parkinson’s disease (PD), multiple system atrophy, and pure autonomic failure], dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.”
The indications and usage statement also adds that effectiveness past 2 weeks “has not been established,” and that the “continued effectiveness of Northera should be assessed periodically.”
The prescribing information includes a boxed warning about the risk of supine hypertension, and recommends that supine blood pressure be monitored before and during treatment, and more often when doses are increased – and that elevating the head of the bed reduces the risk of supine hypertension.
At a meeting on Jan. 14, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 16 to 1 to recommend approval. In the FDA’s briefing documents filed prior to the meeting, the agency did not support approval of the drug, for reasons that included a lack of evidence indicating the drug had a durable effect, as well as safety issues.
Until the approval of droxidopa, the only drug approved for symptomatic NOH was midodrine, a vasoconstrictor that was approved in 1996. But midodrine may soon be off the market because postmarketing studies have failed to provide convincing evidence that treatment improves symptoms, according to the FDA’s briefing documents for the droxidopa panel meeting. Midodrine was approved on the basis of a surrogate endpoint – standing systolic blood pressure – which was considered “reasonably likely” to predict symptomatic benefit, but several postmarketing studies have failed to show that the drug is beneficial, despite its effect on increasing blood pressure.
NOH affects almost 300,000 people in the United States and European Union, according to Chelsea.
A statement on the approval issued by Chelsea said the company had a “preliminary” agreement with the FDA to conduct a postmarketing study to evaluate the clinical effects of droxidopa, which would be a multicenter, placebo-controlled, randomized study of about 1,400 patients enrolled over 6 years.
Steven S. Shayani, MD, FACC, FASNC 