Vicente Anido Jr., Ph.D. 
President and Chief Executive Officer
ISTA Pharmaceuticals
15295 Alton Parkway
Irvine, CA 92618

RE:  NDA #021664
       Bromday^TM (bromfenac ophthalmic solution) 0.09%
       MACMIS #20150

Dear Dr. Anido:

As part of its monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S.  Food and Drug Administration (FDA) has reviewed a representative flyer (BQD657-2/11) (flyer) for Bromday^TM (bromfenac ophthalmic solution) 0.09% (Bromday) submitted by ISTA Pharmaceuticals (ISTA) under cover of Form FDA-2253.  The flyer is false or misleading because it omits important risk information and material facts.  Thus, the flyer misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & 321(n).  Cf. 21 CFR 202.1(e)(3)(i) and 202.1(e)(5).  These violations are concerning from a public health perspective because they suggest that Bromday is safer than has been demonstrated. 

Background

Below is the indication and summary of the most serious and most common risks associated with the use of Bromday.¹

Bromday is indicated for the treatment of postoperative inflammation and reduction of ocular pain in patients who have undergone cataract surgery. 

The FDA-approved product labeling (PI) for Bromday contains Warnings and Precautions regarding: sulfite allergic reactions, slowed or delayed healing, potential for cross-sensitivity, increased bleeding time, keratitis and corneal reactions, and contact lens wear. 

In addition, the most commonly reported adverse reactions for Bromday were abnormal sensation in eye, conjunctival hyperemia, and eye irritation (including burning/stinging). 

Prior Communications with DDMAC

ISTA submitted a Supplemental New Drug Application (sNDA) for XibromTM (bromfenac ophthalmic solution) 0.09% (Xibrom) to FDA that proposed a product with the same formulation as Xibrom, but with the proprietary name Bromday, and with a change to the dosing regimen to once-a-day (QD) dosing beginning one day prior to surgery, continuing on the day of surgery, and for 14 days after surgery.  This sNDA was approved by FDA on October 16, 2010. 

DDMAC has expressed concerns regarding ISTA’s promotional materials in a previous letter.  On March 10, 2010, DDMAC sent ISTA a Warning Letter for a Xibrom professional sales aid that, among other violations, omitted important risk information and other material facts.  DDMAC is concerned that ISTA is continuing to promote this product in a similarly violative manner. 

Omission of Risk Information

The flyer makes claims regarding the use of Bromday in cataract surgery.  Although it discloses the most common adverse reactions associated with the use of Bromday, it fails to reveal any of the warnings and precautions for the drug.  The flyer omits the serious and important Warnings and Precautions regarding the potential for anaphylactic and life- threatening allergic reactions to sodium sulfite, slowed or delayed healing, potential for cross-sensitivity reactions, increased bleeding time, and possible sight-threatening keratitis and corneal reactions.  Furthermore, it fails to communicate the Warning and Precaution that Bromday should not be administered while wearing contact lenses.  By omitting these important risks associated with the use of the drug, the flyer misleadingly suggests that Bromday is safer than has been demonstrated.  We note the inclusion of the statement, “Please see full prescribing information on reverse” at the bottom of the flyer; however, this does not mitigate the misleading omission of important risk information. 

Omission of Material Facts

The flyer is misleading because it fails to reveal important dosing limitations that are material to the safe use of the drug.  Specifically, the flyer claims that Bromday is, “The FIRST and ONLY QD ophthalmic NSAID for use in cataract surgery” and “QD Bromday^TM Replaces XIBROMTM” (emphasis in original).  While the flyer discloses that Bromday is dosed once daily, it fails to communicate that Bromday should be applied beginning 1 day prior to cataract surgery, continued on the day of surgery, and through the first 14 days of the postoperative period.  This omission is particularly concerning in light of the claim that Bromday is the replacement for Xibrom, which suggests that Bromday has the same dosing regimen that was previously approved for Xibrom, when this is not the case.  In fact, the PI for Xibrom indicated that the drug should be applied two times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period.  Furthermore, this omission of important dosing information is concerning because, according to the Warnings and Precautions section of the current PI for Bromday, use of topical NSAIDS more than 24 hours prior to surgery or use beyond 14 days post surgery may increase patient risk for the occurrence and severity of corneal adverse events. 

Conclusion and Requested Action

For the reasons discussed above, the flyer misbrands Bromday in violation of the Act, 21 U.S.C. 352(a) & 321(n).  Cf. 21 CFR 202.1(e)(3)(i) and 202.1(e)(5). 

DDMAC requests that ISTA immediately cease the dissemination of violative promotional materials for Bromday such as those described above.  Please submit a written response to this letter on or before July 27, 2011, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Bromday 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 and repeated, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages (corrective) about the issues discussed in this letter to the audience(s) that received the violative promotional materials.  In order to clearly identify the violative promotional piece(s) and/or activity and focus on the corrective message(s), DDMAC recommends that corrective piece(s) include a description of the violative promotional piece(s) and/or activity, include a summary of the violative message(s), provide information to correct each of the violative message(s), and be free of promotional claims and presentations.  To the extent possible, corrective messaging should be distributed using the same media, and generally for the same duration of time and with the same frequency that the violative promotional material was disseminated. 

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, or facsimile at 301-847-8444.  In all future correspondence regarding this matter, please refer to MACMIS #20150 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 Bromday 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,
 

Thomas W.  Abrams, RPh, MBA
Director
Division of Drug Marketing,
Advertising, and Communications

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1 This information is for background purposes only and does not necessarily represent the risk information that should be included in the promotional piece cited in this letter.