FDA Review Finds No Increased Cardiovascular Risk With Entacapone in Parkinson’s

Pauline Anderson

Disclosures

October 26, 2015

There is no clear evidence of an increased risk for myocardial infarction, stroke, or other cardiovascular events associated with the use of entacapone for the treatment of Parkinson's disease (PD), a safety review by the US Food and Drug Administration (FDA) has concluded.

As a result, recommendations for using entacapone (Comtan, Orion) and a combination product combining entacapone, carbidopa, and levodopa (Stalevo, Novartis) will remain the same in the drug labels, the FDA said in a press release.

In August 2010, the FDA announced that it would review clinical trial data suggesting that patients with PD taking Stalevo may be at a higher risk for cardiovascular events compared with those taking a combination of carbidopa and levodopa (Sinemet, Merck & Co).

STRIDE-PD

This possible safety issue was observed in a clinical trial called the Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) and in a meta-analysis that combined the cardiovascular-related findings from 15 clinical trials comparing Stalevo to carbidopa/levodopa.

Carbidopa and levodopa have been used extensively and have not been shown to have an increased cardiovascular risk. The FDA speculated that any increased risk may be due to entacapone.

Although the combination of carbidopa and levodopa has proven effective in treating PD, the addition of entacapone leads to a greater degree of improvement in some PD symptoms, the agency notes in its statement. These entacapone-containing products (Comtan and Stalevo) have been shown to be effective in treating symptoms of PD, such as muscle stiffness, tremors, spasms, and poor muscle control.

The FDA estimates that combination carbidopa/levodopa/entacapone (C/LE) products were prescribed to roughly 154,000 patients from the drug's approval in June 2003 to October 2009.

The entacapone single-ingredient product (Comtan) is always prescribed in conjunction with carbidopa and levodopa.

With its alert in 2010, the FDA required the Stalevo manufacturer, Novartis, to study the potential for cardiovascular risk with the entacapone component of the drug.

The FDA has now examined the results from this required study and from an additional study and concluded they do not show an increased risk for cardiovascular adverse events with entacapone.

The results observed in the original meta-analysis were driven by results of a single study (STRIDE-PD), which was not designed to assess cardiovascular risks, the press release notes.

"The FDA believes that the meta-analysis and STRIDE-PD results are chance findings and do not represent a true increase in risk due to entacapone."

Among other things, the trials in the meta-analysis were not specifically designed to evaluate the cardiovascular safety of C/LE, and 11 of these studies lasted for less than 6 months, which may not have been long enough to evaluate cardiovascular risk.

Notably, seven of the eight events in STRIDE-PD occurred after 6 months of treatment with C/LE. Also, most patients had pre-existing risk factors for cardiovascular disease.

In a move unrelated to STRIDE-PD, the FDA approved a revision to the labels for both C/LE and entacapone in February 2009 that explains the risk of developing intense urges — sexual and otherwise — along with melanoma.

In the event of any adverse events or side effects from these products, healthcare professionals and patients are encouraged to report them to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

  • Complete and submit the report online: www.fda.gov/MedWatch/report.

  • Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the preaddressed form, or submit by fax to 1-800-FDA-0178.

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