FDA Sends Warning Letter to Allergan Regarding Acular Advertisement

ROCKVILLE, Md., May 30, 2007 - The Food and Drug Administration today posted on its website a warning letter sent to Allergan, Inc. regarding a professional journal advertisement for Acular LS. The letter is below.



DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Food and Drug Administration
Rockville, MD 20857

TRANSMITTED BY FACSIMILE

David E.I. Pyott
President and Chief Executive Officer
Allergan, Inc.
PO Box 19534
Irvine, CA 92623-9534

RE: NDA #21-528
ACULAR LS® (ketorolac tromethamine ophthalmic solution) 0.4%
MACMIS #15238
WARNING LETTER

Dear Mr. Pyott:
The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a
professional journal advertisement (ad) (4961273) for ACULAR LS® (ketorolac tromethamine
ophthalmic solution) (Acular LS) submitted by Allergan, Inc. (Allergan) under cover of Form FDA
2253. The journal ad is false or misleading because it broadens the indication, presents
unsubstantiated superiority claims, and omits important risk information for Acular LS. Thus, the
journal ad misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21
U.S.C. §§ 352(n) & 321(n), and FDA implementing regulations. See 21 C.F.R §§ 202.1(e)(5)(i) &
(iii); (6)(i) & (ii). These violations are concerning from a public health perspective because they
suggest that Acular LS is safer or more effective than has been demonstrated, and they encourage the
use of Acular LS in circumstances other than those for which the drug has been shown to be safe and
effective.

Background
According to the Indications and Usage section of the FDA approved product labeling (PI):
ACULAR LS ophthalmic solution is indicated for the reduction of ocular pain and
burning/stinging following corneal refractive surgery.

The PI also explains that Acular LS is associated with several risks. It states (in pertinent part):

WARNINGS
There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives,
and other nonsteroidal anti-inflammatory agents. Therefore, caution should be used when
treating individuals who have previously exhibited sensitivities to these drugs.
With some nonsteroidal anti-inflammatory drugs there exists the potential for increased
bleeding time due to interference with thrombocyte aggregation. There have been reports that
ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular
tissues (including hyphemas) in conjunction with ocular surgery.

PRECAUTIONS
General: All topical nonsteroidal anti-inflammatory drugs (NSAIDs), including ketorolac
tromethamine ophthalmic solution, may slow or delay healing. Topical corticosteroids are also
known to slow or delay healing. Concomitant use of topical NSAIDS and topical steroids may
increase the potential for healing problems.

Use of topical NSAIDs may result in keratitis. In some susceptible patients, continued use of
topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal
ulceration or corneal perforation. These events may be sight threatening. Patients with
evidence of corneal epithelial breakdown should immediately discontinue use of topical
NSAIDs and should be closely monitored for corneal health.

Postmarketing experience with topical NSAIDs suggests that patients with complicated ocular
surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface
diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short
period of time may be at increased risk for corneal adverse events which may become sight
threatening. Topical NSAIDs should be used with caution in these patients.

Postmarketing experience with topical NSAIDs also suggests that use 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.

It is recommended that ACULAR LS ophthalmic solution be used with caution in patients with
known bleeding tendencies or who are receiving other medications, which may prolong
bleeding time.

ADVERSE REACTIONS
The most frequently reported adverse reactions for ACULAR LS ophthalmic solution occurring
in approximately 1 to 5% of the overall study population were conjunctival hyperemia, corneal
infiltrates, headache, ocular edema and ocular pain.

The most frequent adverse events reported with the use of ketorolac tromethamine ophthalmic
solutions have been transient stinging and burning on instillation. These events were reported
by 20% - 40% of patients participating in these other clinical trials.

DOSAGE AND ADMINISTRATION
The recommended dose of ACULAR LS ophthalmic solution is one drop four times a day in
the operated eye as needed for pain and burning/stinging for up to 4 days following corneal
refractive surgery.

Broadening of Indication
The journal ad is false or misleading because it suggests that Acular LS is effective in a broader range
of patients and conditions than has been demonstrated by substantial evidence or substantial clinical
experience; in fact, it suggests that Acular LS is effective for an entirely new use. Specifically, the
journal ad presents data intended to show a favorable result in a study of patients undergoing
phacoemulsification, who received either Acular LS or Nevanac (nepafenac ophthalmic suspension)
0.1% 4 times daily for 2 days preoperatively plus 4 drops in the 90 minutes prior to surgery. This data
includes a bar graph comparing the mean aqueous concentrations of Acular LS with the prodrug and
active molecules of Nevanac—amfenac (active molecule) and nepafenac (prodrug molecule). Acular
LS is depicted as having a greater mean aqueous concentration (1079 ng/mL) than nepafenac (588
ng/mL) and amfenac (365 ng/mL). The headline for the journal ad states (emphasis original):
“ACULAR LS®: Outstanding Ocular PENETRATION”

The graph is accompanied by the following claims (emphasis original):
    • “In this study, ACULAR LS® achieved nearly 3-times greater penetration in patients than
the active metabolite of Nevanac™1 (clinical significance unknown)”
    • “In the same study, ACULAR LS® reduced prostaglandins below detectability in 62% of
treated eyes vs 18% with Nevanac™ (N = 82)1”

This presentation is false or misleading for several reasons. First, its emphasis on the “mean aqueous
concentrations” and “penetration” “achieved” with Acular LS in the study described above suggests
that Acular LS is effective for use in patients undergoing phacoemulsification, when this is not
supported by substantial evidence or substantial clinical experience. Acular LS is not approved for any
use in patients undergoing phacoemulsification. Acular LS is only approved for corneal refractive
surgery, which does not involve phacoemulsification.2 The inclusion below these statements of the
approved indication for Acular LS does not mitigate this misleading presentation.

1 Amico LM, Bucci FA Jr, Waterbury D. Aqueous PGE2 inhibition of ketorolac 0.4% vs. nepafenac 0.1% in patients
undergoing phacoemulsification. Poster presented at: Annual Meeting of the Association for Research in Vision and
Ophthalmology: April 30-May 4, 2006; Fort Lauderdale, Fla.
2 Phacoemulsification and corneal refractive surgery are two distinct and separate ocular surgeries. Corneal refractive
surgery is an elective procedure performed on a healthy eye. Either a laser or a surgical blade is used to reshape the cornea
and, therefore, change the refractive error. The eyeball itself is not penetrated. Phacoemulsification is a surgical procedure
in which a cataract causing decreased visual acuity is removed. An incision is made into the eye and a machine using highfrequencyultrasonic waves emulsifies and removes the lens. Usually, an artificial intraocular lens is placed into the eye to
provide the refractive power which the natural lens previously provided.


We also note that the data cited in support of this presentation do not constitute substantial evidence or
substantial clinical experience supporting use in patients undergoing phacoemulsification. The
abstract1 cited describes a study that measured prostaglandin levels but did not evaluate the reduction
of ocular inflammation in patients. Reduced prostaglandin levels have not been shown to correlate
with clinical efficacy for reducing ocular inflammation. Furthermore, the study measured mean
aqueous drug concentrations and drug penetration but did not evaluate any clinical endpoints, such as
ocular pain or burning/stinging. Despite the journal ad's emphasis on "mean aqueous concentrations"
and "penetration" "achieved," mean aqueous drug concentrations and penetration have not been shown
to correlate with clinical efficacy.

Second, the claim “In the same study, ACULAR LS® reduced prostaglandins below detectability…”
implies that Acular LS is effective for treating inflammation, when this is not supported by substantial
evidence or substantial clinical experience. Acular LS is not approved to treat inflammation associated
with any ocular surgery. Furthermore, as noted above, reduced prostaglandin levels have not been
shown to correlate with clinical efficacy for reducing ocular inflammation.

Third, this presentation implies that Acular LS is safe and effective when used 4 times daily for 2 days
preoperatively along with 4 drops in the 90 minutes prior to surgery, when this is not supported by
substantial evidence or substantial clinical experience. Acular LS is only approved for use following
surgery. Specifically, Acular LS is approved for the reduction of ocular pain and burning/stinging
following corneal refractive surgery. In addition, the PI for Acular LS includes a precaution
concerning the use of Acular LS more than 24 hours prior to surgery because postmarketing
experience with topical NSAIDs suggests that such use may increase patient risk for the occurrence
and severity of corneal adverse events.

Fourth, the comparison to Nevanac further misleadingly implies that Acular LS is approved for use in
cataract surgery as Nevanac is. Nevanac is indicated for the treatment of pain and inflammation
associated with cataract surgery, but Acular LS is indicated only for use as needed postoperatively for
the reduction of ocular pain and burning/stinging following corneal refractive surgery. Cataract
surgery and corneal refractive surgery are two distinct and separate ocular surgeries.

Finally, the claim “#1 Choice Among Ophthalmologists” adds to the misleading impression that
Acular LS is approved for phacoemulsification. This claim, in the context of the totality of the
presentation describing the use of Acular LS versus Nevanac in phacoemulsification discussed above,
misleadingly suggests that Acular LS is an effective “choice” for use in phacoemulsification, when this
is not supported by substantial evidence or substantial clinical experience.

Unsubstantiated Superiority Claims
The journal ad misleadingly suggests that Acular LS is superior to Nevanac for use in
phacoemulsification, a use consistent with Nevanac’s indication for cataract surgery, when this has not
been demonstrated by substantial evidence or substantial clinical experience. Indeed, as noted above,
Acular LS is not indicated for use in phacoemulsification. Specifically, the journal ad presents data
comparing the mean aqueous concentrations, penetration, and prostaglandin levels of patients treated
with Acular LS to patients treated with Nevanac. The phrase "clinical significance unknown" next to
the statement that Acular LS "achieved nearly 3-times greater penetration in patients than the active
metabolite of Nevanac" (emphasis original) does not mitigate this misleading presentation. As noted
above, these measurements have not been shown to correlate with clinical efficacy. Therefore, the
data1 cited in support of this presentation do not constitute substantial evidence or substantial clinical
experience that Acular LS is superior to Nevanac for any purpose.

Omission of Risk Information
Promotional materials are misleading if they fail to reveal facts that are material in light of the
representations made or with respect to the consequences that may result from the use of the drug as
recommended or suggested in the materials. The journal ad contains information from the Acular LS
PI regarding the contraindication, one of the precautions, and the less common adverse events.
However, the ad fails to communicate several important risks associated with the use of Acular LS.
The ad omits important warnings associated with Acular LS therapy regarding the potential for cross
sensitivity reactions, potential for increased bleeding times, and increased bleeding of ocular tissues. It
also omits information from the Precautions section of the PI regarding the risk of keratitis and the
increased risk for corneal adverse events associated with certain concomitant disease states or
conditions and factors such as duration of treatment. Finally, the journal ad omits the more common
adverse reactions, including transient burning/stinging upon instillation. By omitting the most serious
risks and common risks associated with the drug, the journal ad misleadingly suggests that Acular LS
is safer than has been demonstrated.

Conclusion and Requested Action
For the reasons discussed above, the journal ad misbrands Acular LS in violation of the Act, 21 U.S.C.
§§352(n) & 321(n), and FDA implementing regulations. See 21 C.F.R §§202.1(e)(5)(i) & (iii); (6)(i)
& (ii).

DDMAC requests that Allergan immediately cease the dissemination of violative promotional
materials for Acular LS such as those described above. Please submit a written response to this letter
on or before June 11, 2007, stating whether you intend to comply with this request, listing all violative
promotional materials for Acular LS the same as or similar to those described above, and explaining
your plan for discontinuing use of such 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 audience(s) 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,
or facsimile at 301-796-9878. In all future correspondence regarding this matter, please refer to
MACMIS #15238 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 Acular LS 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 Abrams, R.Ph. M.B.A.
Director
Division of Drug Marketing,
Advertising and Communications
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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/
---------------------
Thomas Abrams
5/25/2007 11:46:23 AM

Posted: May 2007


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