DDMAC To Cornerstone: Zyflo CR Promotions Need Current Safety Labeling

An FDA advertising violation letter for Cornerstone Therapeutics' asthma therapy Zyflo CR should serve to remind industry that providing outdated safety labeling with promotions is a sure way to draw the agency's regulatory scrutiny.

A Zyflo CR (zileuton extended-release) webpage and visual aid disseminated by Cornerstone in November included labeling from 2007 that did not reflect an August 2009 safety update for the leukotriene synthesis inhibitor. The revised labeling added a new precaution stating that neuropsychiatric events have been reported in adults and adolescents taking zileuton, as have post-marketing adverse events such as sleep disorders and behavior changes.

FDA requested the labeling changes for Zyflo and Zyflo CR, as well as two leukotriene receptor antagonists, Merck's Singulair (montelukast) and AstraZeneca's Accolate (zafirlukast), in June 2009 following a review of data on suicidality, mood and behavioral adverse events from the drugs' placebo-controlled clinical trials (¹ (Also see "Singulair Safety Division Of Labor: In Search For Suicide Data, Merck Will Scan Studies While FDA Tackles Post-marketing Reports" - Pink Sheet, 22 Jun, 2009.)).

"Cornerstone committed in writing on Aug. 26, 2009, to immediately revise all its promotional materials to include the new information from the PI related to neuropsychiatric events," DDMAC states in a June 22 "untitled" letter. "We are very concerned that you are continuing to use outdated product labeling that omits this important risk information, despite your commitment."

The visual aid was presented to a DDMAC representative by a Cornerstone rep at the American College of Chest Physicians annual meeting in November, marking another example of FDA's efforts to crack down on promotional violations at medical meetings and trade shows (² (Also see "DDMAC's Latest Exhibit Hall Citation Is Vectibix; Firms Try Multiple Ways To Avoid FDA At Trade Shows" - Pink Sheet, 26 May, 2010.)).

The agency is also asking physicians to report instances of off-label drug promotion made during continuing medical education classes, an initiative similar to its "Bad Ad" program for promotional claims made by sales reps in private conversations with doctors (³ (Also see ""Bad CME" Program May Be Developed By FDA" - Pink Sheet, 25 Jun, 2010.)).

Cornerstone's failure to include current product labeling is further magnified by the Zyflo CR webpage's complete omission of risk information. The page's link to the outdated label is insufficient to mitigate the absence of risk information, DDMAC says. "For promotional materials to be truthful and non-misleading, they must contain risk information in each part as necessary to qualify any effectiveness or safety claims made in that part."

Proper presentation of risk information also is lacking for the visual aid. The front contains claims about Zyflo's mechanism of action and information on contraindications, but fails to include information on warnings, precautions, drug interactions and common adverse events.

Additional risk information is printed on the back. However, from a practical matter this is not accessible to the viewer because there is an adhesive strip on the back enabling it to be secured to a flat surface. "Presenting the risk information in this manner is not sufficient to ensure that claims in each part of the visual aid are truthful and non-misleading," the letter states.

FDA also has objections related to the presentation of the benefit information, noting that the ad overstates Zyflo's efficacy in a couple of ways.

The visual aid suggests that zileuton's mechanism of action in stopping leukotriene synthesis makes it a superior asthma treatment to leukotriene receptor antagonists, which only block one of several receptors in the target cell. "We are not aware of substantial evidence or substantial clinical experience to support the implication that Zyflo CR is superior in efficacy to LTRAs due to its place of action in the leukotriene cascade," DDMAC says.

The back side of the visual aid states that Zyflo CR can be prescribed early in treatment of chronic asthma and is included "as early as step 3" in the National Heart, Lung and Blood Institute guidelines for asthma diagnosis and management. This claim, DDMAC says, is misleading because the NHLBI guidelines also caution that zileuton is a less desirable option than LTRAs due to limited efficacy data and the need for liver function tests.

- Sue Sutter ( ⁴ [email protected] )