Released by FDA: 9/22/00.  Posted by FDA:  9/25/00

David Garbe
Director, Scientific Information and Medical Complance
Allergan, Inc. 
2525 DuPont Drive TL-1L
P0 Box 19534 
Irvine, CA 92623-9534

RE:   NDA 20-613 
        Alphagan (brimonidine tartrate ophthalmic solution) 0.2% 
        MACMIS ID # 8412

Dear Mr. Garbe:

This letter is in reference to Allergan. Inc.’s (Allergan) promotional campaign for Alphagan.  We refer to your dissemination of promotional materials¹ that suggest or imply that Alphagan is safer than beta-blockers for lowering intraocular pressure.  The Division of Drug Marketing, Advertising and Communications (DDMAC) has reviewed these promotional materials and has concluded that they are false or misleading under the Federal Food, Drug. and Cosmetic Act and its implementing regulations.  We have identified many examples in your promotional campaign in footnote #1.   However, this is not an exhaustive listing.   Our specific objections follow:

Misleading Claims of Superior Safety

1. In the headline of the sales aid ( RX9478 ) and journal ad (SIMC99-369)., you claim that one can “steer clear of first-line risks” by mak[ing]  ALPHAGAN your first line choice."  On the second page of’ the sales aid, you similarly claim that one can "minimize first-line concerns” by “mak[ing] Alphagan your first-line choice” (emphasis added).
   
   
2. Further, in your brochure titled “Steer clear of’ first-line risks” identified :is RX9478,  you also claim one may “minimize first-line concerns by making Alphagan your first- line choice” (emphasis added).  Additionally, many of your promotional materials have the tagline, “The safe course to long-term efficacy” (emphasis added).
   
   
3. Also in your brochure titled “Have you asked your glaucoma patients Are you feeling your best?”  you make numerous inferences that Alphagan does not have risks like topical beta-blockers, and that Alphagan is a “safer alternative.”
   
   
4. On the clipboard, you list numerous physical limitations a patient may have: 1. “irregular heartbeat,”  2. “Difficulty breathing, consistent coughing, recent difficulty in smoking cigarettes,”  3.  “Not able to exercise,”  4. “Depression,  weepiness, lability,”  5. “Generally not feeling well,"  6. ‘“Tired, yawning,”  7. “Balance problems or dizziness,’  8, “Contusion.” 9. “Falling,”  10. “Changes in sexual desire or performance.” and 11 “Having a problem with other medications.”  You imply these limitations related to beta-blockers can be avoided with Alphagan.
   
   
5. Similarly, in your brochure titled “Avoid the risks of topical beta-blocker side effects” identified as 7831X,  you suggest that because 19% of patients with glaucoma take systemic anti-hypertensive beta-blockers, topical beta-blockers should typically he avoided in these patients.  You follow this claim with the statement that the efficacy of timolol was significantly reduced by concomitant systemic beta-blocker administration, but that systemic beta-blocker therapy had no influence on the efficacy of Alphagan.   Again, you imply that. Alphagan is safer and inure effective than timolol.
   
   
6. In the patient brochure titled “For glaucoma patients using intraocular pressure- lowering eve drops Are you feeling your best?” you make the following statements:

Your intraocular pressure (IOP) lowering eyedrops “may also he time cause of some unwanted side effects—especially if you’re using a topical beta-blocker.’

“You may he experiencing breathing difficulties, an irregular heartbeat, or a reduction in exercise tolerance,”

“You may have fallen recently,  felt dizzy or faint, and at times seemed confused, even depressed. or unusually sad.”

"You may also have noticed a recent change in sexual desire or performance."

Again, you imply that Alphagan is the safer alternative: because not only does it not cause any of the above side effects, but Alphagan’s side effects “are usually not severe enough to cause you to stop using Alphagan.”

All of’ these promotional materials arc misleading because they state or suggest that Alphagan is a safer alternative to topical beta-blockers.   However, none of these claims are supported by substantial evidence.  Your multi-center head-to-head comparative trials with timolol 0.5% conducted to demonstrate the safety and efficacy of’ Alphagan identified the safety concerns discussed below.

Fair Balance

Further, these materials are also misleading because they lack fair balance because you have not adequately presented the safety concerns associated with the use of Alphagan (emphasis added).  For instance, you fail to present with similar prominence as your claims for Alphagan that “patients who engage in hazardous activities should be cautioned of’ the potential for a decrease in mental alertness.” and that “Alphagan may cause fatigue and/or drowsiness in some patients.  Further, the PI for Alphagan includes the side effects of dizziness, depression,  hypertension,  anxiety, palpitations,  and syncope.  These side effects arc not prominently conveyed.

Misleading Data

In the sales aid RX9535, you claim that in clinical studies², the “First-line mean peak IOP reduction (26.3%) comparable to timolol (24.4%) at the end of year 1 (N = 837).”  Your claim is misleading because you omitted material facts.  You claim that Alphagan is as effective as timolol at lowering IOP at the end of One year, but fail to present that in this extended study, 44% of the patients treated with Aiphagan dropped out of the study (59 patients withdrew because of ocular allergy experienced with brimonidine therapy versus 1 patient with timolol while only 22% of the timolol patients dropped out.

Further, you claim that new 4-year data in 31 patients demonstrate that Alphagan has sustained first-line IOP reduction comparable to timolol. This claim is misleading because it lacks adequate substantiation.  It is also inconsistent with the precautions section of the PI that states “during the studies there was a loss of effect in some patients” and “the IOP lowering efficacy observed with Alphagan Ophthalmic Solution during the first month of therapy may not always reflect the long-term level of IOP reduction.”

Requested Actions

In order to address these objections, we request that you immediately cease the dissemination of these violative promotional materials and all similar promotional materials that contain the same or similar messages.

You should respond in writing to us regarding this issue by October 6, 2000.  Your response should include Allergan’s intent to comply with the above request, the date that it ceased disseminating these and any other violative promotional materials with the same or similar messages, and a list of the discontinued materials.

Ii you have questions, please contact me by facsimile at (301) 594-6771 , or by written at the Division of Drug Marketing. Advertising, and Communications,  HFD-42; Room 17B-20; 5600 Fishers Lane, Rockville, MD 20857.  We remind you that only written communications are considered official.

In all future correspondence regarding this matter, please refer to MACMIS # 8412 and NDA 20-613.

Sincerely.

Warren F. Rumble 
Regulatory Review Officer 
Division of Drug Marketing,
  Advertising and Communications

_____________________________________________________

1. Patient brochure titled "For glaucoma patients using intraocular pressure-reducing eye drops.  Are you feeling your best!’’ 
   Fold-out brochure and diskette tilled. “I have you asked your glaucoma patients. Are you feeling your best?” 
   Sales aid RX9478
   Mailer 7831X
   Cup to disk ratio card RX9414
   Advertisement titled “Steer clear of first-line risks”  SIMC99-369
   Exhibit poster titled  “Steer clear of beta-blocker risks” SIMC99-371 
   Clipboard titled,  “Are your patients feeling their best!” 
   Telephone message pad RN9246
   
   
2. L. Jay Katz and the Brimonidine Study Group. ‘‘Brimonidine Tartrate 0.2% , Twice Daily vs Timolol 0.5% Twice Daily: 1-Year Results in Glaucoma Patients.  American Journal of Ophthalmology.  January 1999.