Angela C. Kothe, OD, PhD
Director, Regulatory Affairs, Ophthalmic Drug Products
Alcon Research, Ltd.
6201 South Freeway
Forth Worth, TX 76134-2099

RE:  NDA #021994
       Travatan® Z (travoprost ophthalmic solution), 0.004%
       MACMIS# 18907

Dear Dr. Kothe:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a convention graphic (TRV124DT) for TRAVATAN Z® (travoprost ophthalmic solution) 0.004% (Travatan Z) submitted by Alcon Research, Ltd.  (Alcon) under cover of Form FDA 2253.  The convention graphic is misleading because it broadens the indication for Travatan Z and makes unsubstantiated superiority claims.  Therefore, the convention graphic misbrands Travatan Z in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C.  352(a).  Cf.  21 CFR 202.1 (e)(6)(i) & (ii). 

Background

According to the INDICATIONS AND USAGE section of the FDA-approved product labeling (PI)¹ for Travatan Z:

Travatan Z ophthalmic solution is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are intolerant of other intraocular pressure lowering medications or insufficiently responsive (failed to achieve target IOP determined after multiple measurements over time) to another intraocular pressure lowering medication. 

Travatan Z is associated with the following serious risks, as contained in the WARNINGS section of the PI (emphasis in original):

Prostaglandin analogues, including travoprost ophthalmic solution, 0.004% have been reported to cause changes to pigmented tissues.  The most frequently reported changes have been increased pigmentation of the iris and periorbital tissue (eyelid) and increased pigmentation and growth of eyelashes.  These changes may be permanent. 

Prostaglandin analogues, including travoprost ophthalmic solution, 0.004% may gradually change eye color, increasing the amount of brown pigmentation in the iris by increasing the number of melanosomes (pigment granules) in melanocytes.  The long term effects on the melanocytes and the consequences of potential injury to the melanocytes and/or deposition of pigment granules to other areas of the eye are currently unknown.  The change in iris color occurs slowly and may not be noticeable for months to years.  Patients should be informed of the possibility of iris color change. 

Eyelid skin darkening has been reported in association with the use of prostaglandin

analogues, including travoprost ophthalmic solution, 0.004%. 

Prostaglandin analogues, including travoprost ophthalmic solution, 0.004% may gradually change eyelashes in the treated eye; these changes include increased length, thickness, pigmentation, and/or number of lashes. 

Patients who are expected to receive treatment in only one eye should be informed about the potential for increased brown pigmentation of the iris, periorbital and/or eyelid tissue, and eyelashes in the treated eye and thus heterochromia between the eyes.  They should also be advised of the potential for a disparity between the eyes in length, thickness, and/or number of eyelashes. 

Pertinent Precautions in the PI include:

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products.  These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the epithelial surface. 

Travatan Z ophthalmic solution should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation. 

Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin F2α analogues.  These reports have mainly occurred in aphakic patients, pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors or macular edema.  Travatan Z should be used with caution in these patients. 

Travatan Z has not been evaluated for the treatment of angle closure, inflammatory or neovascular glaucoma. 

Broadening of Indication

The convention graphic is misleading because it suggests that Travatan Z is indicated for use in a broader range of conditions than has been demonstrated by substantial evidence or substantial clinical experience.  Specifically, the convention graphic includes the following claims (footnote and reference omitted):

•  “Drops over the next 18 years: 13,140”
•  “You’ll be managing your patients’ IOP for many years.”

These claims misleadingly suggest that Travatan Z is indicated for the treatment of any type of IOP, when this is not the case.  The indication for Travatan Z specifically limits the use of the drug for the treatment of elevated IOP in patients with open-angle glaucoma or ocular hypertension.  Additionally, the piece fails to present Travatan Z’s full approved indication, including the limitations to the indication regarding use only as a second-line therapy.  While we acknowledge that FDA approved Travatan Z for first-line therapy on August 31, 2010, this indication was not approved at the time this piece was initially used.  At the time of initial dissemination, Travatan Z was only indicated as a second-line therapy for the treatment of elevated IOP in patients with open-angle glaucoma or ocular hypertension who are intolerant of other intraocular pressure lowering medications or insufficiently responsive to another intraocular pressure lowering medication.  By omitting the drug product’s full indication and corresponding limitations, the convention graphic misleadingly implies that Travatan Z is indicated as first-line therapy for all types of IOP, when this was not the case at the time of initial dissemination. 

Unsubstantiated Superiority Claims

Promotional materials are misleading if they represent or suggest that a drug is safer or more effective than another drug when this has not been demonstrated by substantial evidence or substantial clinical experience.  The convention graphic claims:

•  “For patients you believe will benefit from BAK-free therapy, consider TRAVATAN Z ® Solution for today and tomorrow.”

This claim misleadingly implies that Travatan Z provides a safety benefit over other products because it does not contain benzalkonium chloride (BAK), when this is not the case.  Although the approval of Travatan Z was based on a bioequivalence trial comparing Travatan Z to Travatan (a product containing BAK), bioequivalence trials are not designed to assess superiority.  We are not aware of any substantial evidence or substantial clinical experience to support the claim that Travatan Z is safer than IOP lowering ophthalmic products that contain BAK.  If you have any evidence to support this claim, please submit it to FDA for review. 

Conclusion and Requested Action

For the reasons discussed above, the convention graphic misbrands Travatan Z in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a).  Cf. 21 CFR 202.1 (e)(6)(i) & (ii). 

DDMAC requests that Alcon immediately cease the dissemination of violative promotional materials for Travatan Z such as those described above.  Please submit a written response to this letter on or before October 26, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Travatan Z that contain violations such as those described above, and explaining your plan for discontinuing use of such violative 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 ID# 18907 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 Travatan Z comply with each applicable requirement of the Act and FDA implementing regulations. 

Sincerely,

Beth M. Carr, PharmD
Regulatory Review Officer
Division of Drug Marketing,
Advertising and Communications

________________________________________________________

¹  The approved PI submitted with the convention graphic and the version referred to within this letter is dated September 21, 2006.  In the most recent version of the PI approved August 31, 2010, Travatan Z’s Indication has been expanded to include approval for first-line therapy.  The current PI also includes additional changes to the Warnings and Precautions regarding use with contact lenses.