FDA approves droxidopa for neurogenic orthostatic hypotension

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.

http://www.ecardiologynews.com/single-view/fda-approves-droxidopa-for-neurogenic-orthostatic-hypotension/138cf2a757264c256e82661ba60a3859.html

 

 

 

Moderate exercise reduces female stroke risk

SAN DIEGO – Moderate exercise significantly reduced the risk of stroke in women and seemed to offset much but not all of the increased stroke risk in postmenopausal women on hormone therapy, a large retrospective study found.

A self-reported history of moderate-to-strenuous physical activity in the prior 3 years was associated with a roughly 20%-30% lower risk for stroke in an analysis of data on 133,479 women in the California Teachers Study who had been followed every 4-5 years since 1995 by questionnaire, Sophia S. Wang, Ph.D., and her associates reported.

They linked the data set with hospitalization data during 1996-2010 to identify 2,416 ischemic strokes and 710 hemorrhagic strokes in the cohort that were validated by a review of medical records.

The strongest reduction in stroke risk was seen in women who reported moderate physical activity such as brisk walking, recreational tennis, golf, volleyball, or cycling on level streets. Women who reported in 1995-1996 questionnaires that they had engaged in moderate activity in the prior 3 years were 12%-22% less likely to develop a stroke, depending on the amount of activity each week, compared with inactive women who reported less than a half-hour per week of moderate activity.

“You don’t have to climb a mountain” to gain the stroke-reducing benefits of exercise, Dr. Wang said in an interview at the International Stroke Conference. And the fact that people tend to overreport how much they exercise when surveyed makes the findings “particularly robust,” she said.

Indeed, reports of strenuous activity were not significantly associated with lower stroke risk. Strenuous activity included swimming laps, aerobics, running, calisthenics, jogging, basketball, racquetball, or cycling on hills. Risk levels ranged from an increase of 3% to a reduction of 18% with strenuous activity, compared with inactive women.

Because most women who exercised strenuously also reported moderate activity, the investigators combined those two activity categories and again found approximately a 20% reduction in stroke risk that clearly was being driven by the benefits of moderate activity, said Dr. Wang of Beckman Research Institute at the City of Hope, Duarte, Calif. Stroke risk reductions ranged from 15%-23% in the combined activity analysis for the 1995-1996 surveys.

Surveyed again in 2005-2006, women who reported moderate or strenuous activity in the prior 3 years were 12%-20% less likely to develop a stroke, compared with inactive women, she said at the meeting, sponsored by the American Heart Association.

More than 5 hours of activity wasn’t more beneficial than fewer hours, she added. Stroke reduction benefits seemed greatest with 3.5-5 hours of activity per week, which was associated with a 23% risk reduction in the earlier survey and a 29% reduction in the later survey. With more than 5 hours, the risk reduction was 17% and 27%, respectively.

In inactive postmenopausal women, current hormone use was associated with a 59% higher risk for stroke and former hormone use was associated with a 16% increased risk, compared with postmenopausal women who didn’t use hormones, Dr. Wang said. However, the elevated stroke risk with hormone use fell in women who exercised, compared with those who didn’t.

In current hormone users, stroke risk was 37% higher in women who reported 0.51-3.5 hours of moderate or strenuous activity per week and 29% higher in women who reported more than 3.5 hours of activity per week, compared with non-hormone users. In former hormone users, stroke risk was 15% higher in those who reported 0.51-3.5 hours of activity per week and 5% higher in those who exercised more than 3.5 hours per week, compared with non-hormone users.

Because of smaller numbers of women in the subset analyses of postmenopausal hormone use, these differences between groups did not reach statistical significance, Dr. Wang said.

She and her associates plan further studies related to these findings, including whether or not activity levels may help prevent stroke in women who’ve already had a stroke, she said.

Dr. Wang and her colleagues reported having no financial disclosures. The National Institute of Neurological Disorders and Stroke funded the study.

http://www.ecardiologynews.com/single-view/moderate-exercise-reduces-female-stroke-risk/e98ae0e5d5e6180cf80efe5de44a9e8c.html

Picture courtesy of heart.arizona.edu