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Cornerstone Therapeutics, Inc. 6/22/10

   

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
  Silver Spring, MD 20993


TRANSMITTED BY FACSIMILE


Brian Dickson, Chief Medical Officer
Cornerstone Therapeutics, Inc.
1255 Crescent Green Drive, Suite 250
Cary, NC 27518


RE: NDA # 022052
Zyflo CR® (zileuton) extended-release tablets
MACMIS # 18747

 


Dear Dr. Dickson:


The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a web page1 and visual aid (CTZ1339A0709) for Zyflo CR® (zileuton) extended-release tablets (Zyflo CR) submitted by Cornerstone Therapeutics, Inc. (Cornerstone) under cover of Form FDA-2253. The visual aid was also obtained at the American College of Chest Physicians Annual Meeting in November 2009. The web page is false or misleading because it presents efficacy claims for Zyflo CR but omits risk information associated with the product. The visual aid is false or misleading because it omits important information about the risks associated with use of Zyflo CR, makes unsubstantiated superiority claims, and omits material facts. Thus, the promotional pieces misbrand the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & (n); 321(n). See 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i), (ii) & (viii). In addition, the visual aid and web page were disseminated with an outdated version of the FDA-approved product labeling (PI) for Zyflo CR, in violation of 21 CFR 201.100(d). These violations are concerning from a public health perspective because they suggest that Zyflo CR is safer than has been demonstrated by substantial evidence or substantial clinical experience.


Background


The INDICATIONS AND USAGE section of the PI for Zyflo CR2 states the following:


ZYFLO CR is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.


ZYFLO CR is not indicated for use in the reversal of bronchospasm in acute asthma attacks. Therapy with ZYFLO CR can be continued during acute exacerbations of asthma.


The PI for Zyflo CR includes contraindications regarding its use in patients with active liver disease or transaminase elevations greater than or equal to three times the upper limit of normal (≥3XULN) or a history of allergic reaction to zileuton or any ingredients of Zyflo CR. The PI also contains warnings and precautions regarding hepatotoxicity and neuropsychiatric events.


In addition to the Contraindications and Warnings and Precautions associated with Zyflo CR, according to the drug interactions section of the PI, co-administration of Zyflo CR with theophylline, warfarin, and/or propanolol warrants close monitoring and dosage adjustments of the co-administered drug. The most common adverse reactions for Zyflo CR that occurred at an incidence ≥5% were sinusitis, nausea, and pharyngolaryngeal pain.


Omission of Risk Information – Web Page


Promotional materials are misleading if they fail to reveal material facts in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials. Although the web page presents information about the use of Zyflo CR in the treatment of asthma, it entirely omits risk information for Zyflo CR, including the Contraindications, Warnings and Precautions, and the most frequently reported adverse events from the PI. As a result, the web page misleadingly suggests that Zyflo CR is safer than has been demonstrated by substantial evidence or substantial clinical experience. Although the web page includes a link to prescribing information for Zyflo CR, this is not sufficient to mitigate the misleading omission of risk information from the web page. For promotional materials to be truthful and nonmisleading, they must contain risk information in each part as necessary to qualify any effectiveness or safety claims made in that part. We further note that the link to the prescribing information provided on the web page leads to an outdated version of the PI, which fails to include information about neuropsychiatric events that may occur with Zyflo CR.


Omission and Minimization of Risk Information – Visual Aid


Promotional materials are misleading if they fail to reveal material facts in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials. The front side of the visual aid presents the headline, “ZYFLO CR® IS DESIGNED TO PREVENT THE FORMATION OF LEUKOTRIENES” (emphasis original) followed by a diagram entitled, “The 5-lipoxygenase (5-LO) inflammatory pathway” and other claims about Zyflo CR. However, this presentation fails to adequately communicate important risk information associated with Zyflo CR’s use. Although it includes information regarding the contraindications for Zyflo CR, it fails to include other risk information for Zyflo CR, including warnings and precautions regarding hepatotoxicity and neuropsychiatric events, drug interactions, and the most common adverse reactions.


We acknowledge that some additional risk information is printed on the back of the visual aid. However, as a practical matter, the risk information printed on the back of the piece is not visible or even accessible to the viewer since the back of the visual aid contains an adhesive strip at the top of the page designed to be adhered to a flat surface. Once the visual aid is adhered to a flat surface, the information on the back is not accessible. 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. As a result, the piece misleadingly suggests that Zyflo CR is safer than has been demonstrated by substantial evidence or substantial clinical experience.


Unsubstantiated Superiority Claim


The visual aid suggests Zyflo CR is superior to leukotriene receptor antagonists (LTRAs) for the treatment of asthma when this has not been demonstrated by substantial evidence or substantial clinical experience. Specifically, the front side of the proposed visual aid contains a headline claim the “ZYFLO CR® IS DESIGNED TO PREVENT THE FORMATION OF LEUKOTRIENES.” This is followed by a presentation of the leukotriene cascade. This presentation highlights Zyflo CR working at the top of the pathway at the level of the arachidonic acid formation, and contrasts this with the LTRAs, which are displayed working at the bottom of the pathway at the level of the CYSLT1 receptor. The presentation includes text indicating that “ZYFLO CR® inhibits leukotriene synthesis” while “LTRAs primarily block one receptor.” The presentation is followed by the claim, “ZYFLO CR® is the only FDA-approved leukotriene synthesis inhibitor.” The totality of this comparative presentation misleadingly suggests that Zyflo CR is superior to LTRAs because its unique drug class works by stopping leukotriene synthesis, whereas LTRAs 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.


Omission of Material Fact – Visual Aid


Promotional materials are misleading if they fail to reveal facts that are material in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials. The back side of the visual aid presents the headline, “PRESCRIBE ZYFLO CR EARLY IN THE TREATMENT OF CHRONIC ASTHMA” (emphasis original) along with the claim, “Included as early as Step 3 in the NHLBI guidelines.”3


This claim omits material facts regarding the use of Zyflo CR. While the National Heart, Lung, and Blood Institute (NHLBI) guidelines for the management of asthma recommend zileuton at step 3 for persistent asthma, the guidelines explicitly caution that "A 5-lipoxygenase inhibitor (zileuton) is an alternative treatment option that is a less desirable than LTRAs due to more limited efficacy data and the need for liver function monitoring." The visual aid misleadingly fails to disclose this important context for the prominent early treatment claim.

 

Use of Outdated Product Labeling


The web page and visual aid were disseminated with an outdated version of the PI, in violation of 21 CFR 201.100(d). The most current version of the FDA-approved PI is dated August 21, 2009. Nonetheless, on November 9, 2009, a Cornerstone representative at the American College of Chest Physicians Annual Meeting provided the visual aid to a DDMAC representative with a PI dated May 2007. As stated above, the website http://www.zyflocr.com (last accessed April 29, 2010) links to the same 2007 outdated version of the PI. We note that, following the August 21, 2009 PI revision, Cornerstone committed in writing on August 26, 2009, to immediately revise all its promotional materials to include the new information from the PI related to Neuropsychiatric Events. We are very concerned that you are continuing to use outdated product labeling that omits this important risk information, despite your commitment.


Conclusion and Requested Action


For the reasons discussed above, these pieces misbrand Zyflo CR in violation of the Act, 21 U.S.C. 352(a) & (n); 321(n). See 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i), (ii) & (viii). The visual aid and webpage were also disseminated with an outdated version of the FDA approved PI for Zyflo CR, in violation of 21 CFR 201.100(d).


DDMAC requests that Cornerstone immediately cease the dissemination of violative promotional materials for Zyflo CR such as those described above. Please submit a written response to this letter on or before July 6, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Zyflo CR that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Because the violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audiences that received the violative promotional materials.


Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS# 18747 in addition to the NDA number. We remind you that only written communications are considered official.


The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Zyflo CR comply with each applicable requirement of the Act and FDA implementing regulations.


Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.

Sincerely,
{See appended electronic signature page}
Thomas W. Abrams, R.Ph., M.B.A.
Director
Division of Drug Marketing,
Advertising, and Communications

 

1Zyflo CR webpage, at http:www.zyflocr.com. (last accessed on April 29, 2010)
2 The most current version of the FDA-approved PI for Zyflo CR was approved on August 21, 2009, and is the version referred to in this letter.

3Guidelines for the Diagnosis and Management of Asthma. July 2007. National Heart, Lung, and Blood Institute Website. http://www.nhlbi.nih.gov/guidelines/asthma.

 

Application Type/Number Submission Type/Number Submitter Name Product Name
NDA-22052 ORIG-1 CORNERSTONE THERAPEUTICS INC ZYFLO XR (ZILEUTON) ENTENDED RELEASE TABS

 


This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

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/s/
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THOMAS W ABRAMS
06/22/2010