17 Flach Final 11/9/01 11:23 AM Page 205
`
`CORNEAL MELTS ASSOCIATED WITH TOPICALLY APPLIED NONSTEROIDAL
`ANTI-INFLAMMMATORY DRUGS*
`
`BY Allan J. Flach, MD
`
`ABSTRACT
`
`Purpose: Topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to prevent miosis during
`cataract surgery, to treat ocular allergies, to prevent excessive postoperative inflammation following cataract surgery, and
`to treat cystoid macular edema following cataract surgery. They have also been used to control pain and photophobia fol-
`lowing radial keratotomy and excimer laser photorefractive keratectomy. During August of 1999, severe complications fol-
`lowing topical NSAID use, including corneal melting, were reported by members of the American Society of Cataract and
`Refractive Surgery (ASCRS) responding to a survey distributed in letters from ASCRS to its members. The purpose of
`this report is to review 11 cases of corneal melting in patients treated with topical NSAIDs, with special attention to the
`observed toxicity and its relationship to dose and duration of treatment, coexistent disease and therapies, and the indica-
`tion for treatment. The goal of this study is to identify factors useful in minimizing the occurrence of corneal toxicity.
`
`Methods: The medical records and/or histories of 11 patients with corneal melting associated with the use of topical
`NSAIDs are reviewed, with special attention to the indication for treatment, the dose and duration of treatment, and
`coexistent diseases and medical treatments. In addition, the relationship between NSAID treatment and surgery and
`between NSAID treatment and onset and extent of corneal toxicity are described.
`
`Results: Each of the 11 patients appeared to suffer severe corneal toxicity following the topical use of 0.5% diclofenac
`ophthalmic solution. Generic diclofenac (Falcon) (Alcon Laboratories, Inc, Fort Worth, Texas) was associated with 7 and
`Voltaren (Ciba Vision, Atlanta, Georgia) with 4 of these cases. Duration of treatment prior to corneal melting varied from
`6 days to 17 months. Associated ocular and systemic diseases and their respective treatments complicate the analysis of
`these cases. In addition, the indication for treatment with topical NSAIDs was frequently unclear.
`
`Conclusions: The inconsistent and variable dose-toxicity relationships suggest that coexistent factors other than a sim-
`ple drug toxicity are implicated, if not causative, in NSAID-associated corneal melting. These cases demonstrate the
`importance of making a clinical diagnosis before treatment and of following the clinical course of patients carefully dur-
`ing treatment.
`
`Tr Am Ophth Soc 2001;99:205-212
`
`INTRODUCTION
`
`Topically applied nonsteroidal anti-inflammatory drugs
`(NSAIDs) are frequently used to prevent miosis during
`cataract surgery, to treat ocular allergies, to prevent exces-
`sive postoperative inflammation, and to treat cystoid mac-
`ular edema following cataract surgery. These agents have
`also been used to control pain and photophobia following
`radial keratotomy and excimer laser photorefractive kera-
`tectomy.1,2 During August of 1999, severe complications
`following topical NSAID use, including corneal melting,
`
`*From the Department of Veteran Affairs, San Francisco, and the
`Department of Ophthalmology, University of California, San Francisco,
`School of Medicine. Supported by a Merit Review grant from the
`Department of Veterans Affairs, San Francisco; a grant from That Man
`May See, Inc; and a departmental core grant from the National
`Institutes of Health, Department of Ophthalmology, University of
`California, San Francisco, School of Medicine.
`
`were reported by members of the American Society of
`Cataract and Refractive Surgery (ASCRS) responding to a
`survey distributed in letters from ASCRS to its mem-
`bers.3,4 This led to a recall of Falcon, a generic form of
`diclofenac ophthalmic solution (Alcon Laboratories, Inc,
`Fort Worth, Texas).5 Some have concluded that the avail-
`ability of generic diclofenac was the sole reason that
`corneal toxicity was observed.6 However, the potential
`importance of completing a careful review of all of these
`reported cases before concluding that an isolated drug
`toxicity explains the appearance of these severe corneal
`toxicities has been recently emphasized.7 The purpose of
`this report is not to substitute itself for a complete analy-
`sis of the cases of corneal melting, but only to provide an
`interim review of 11 cases of corneal melting in patients
`treated with topical NSAIDs, with special attention to the
`observed corneal toxicity and its relationship to dose and
`duration of treatment, coexistent diseases and therapies,
`
`Tr. Am. Ophth. Soc. Vol. 99, 2001
`
`205
`
`SENJU EXHIBIT 2058
`INNOPHARMA v. SENJU
`IPR2015-00903
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`Flach
`
`and indication for treatment. The goal of this report is to
`help identify factors potentially useful in minimizing the
`occurrence of corneal toxicity while we await a more thor-
`ough examination of the factors associated with these tox-
`icities.
`
`METHODS
`
`The medical records and histories of 11 patients with
`corneal melting associated with the use of topical NSAIDs
`were reviewed, with special attention to the indication for
`treatment, the dose and duration of treatment, and coex-
`istent diseases and medical therapies. These 11 cases con-
`sist of 5 published cases,8 3 cases reported as a poster pres-
`entation,9 and 3 cases from the author’s referral practice.
`Seven cases mentioned at the 104th Annual Meeting of
`the American Academy of Ophthalmology (AAO) are also
`included.6
`
`RESULTS
`
`Each of the 11 patients presented with severe corneal tox-
`icity and a history of treatment with 0.5% diclofenac oph-
`thalmic solution. Generic diclofenac (Falcon) was associ-
`ated with 7 and Voltaren (Ciba Vision Corporation,
`Atlanta, Georgia) was associated with 4 of these cases. A
`summary of the 11 cases is provided in Table I. A brief
`description of each case follows:
`
`CASE 1
`A 76-year-old woman with a history of dry eye (Schirmer
`test results, 2 mm and 5 mm) developed a red, painful eye
`
`3 months following cataract surgery. She was treated with
`Falcon for 10 days, and after a corneal infiltrate with 80%
`tissue loss was observed, she eventually perforated.
`Culture revealed group B streptococcus.
`
`CASE 2
`A 66-year-old woman with a history of dry eyes was treat-
`ed with Voltaren and apraclonidine hydrochloride
`(Iopidine) (Alcon Laboratories, Inc) following cataract
`surgery. After 4 days of treatment, she complained of a
`foreign body sensation in the eye. The eye was red and
`photophobic, and she stated that the Voltaren burned
`more upon instillation. She was told to refrigerate the
`Voltaren to reduce the burning sensation and to continue
`treatment. She presented 29 days after surgery with 50%
`tissue loss. She had reduced values on the Schirmer test.
`
`CASE 3
`A 77-year-old man was treated with Voltaren and
`tobramycin-dexamethasone drops (TobraDex) (Alcon
`Laboratories, Inc) following cataract surgery. Although he
`had normal examination results 1 week after surgery, he
`presented with corneal perforation in the area of surgery
`18 days after surgery. He had reduced values on Schirmer
`tests (12 mm and 8 mm) and diminished corneal sensation.
`
`CASE 4
`A 71-year-old diabetic man with systemic hypertension
`was treated with Falcon and 1% prednisolone given 6
`times daily following cataract surgery. He experienced dis-
`comfort and hyperemia on postoperative day 7, and he
`noted decreased vision on postoperative day 9.
`Perforation occurred on postoperative day 11.
`
`TABLE I. SUMMARY OF CASES
`
`CASE(AGE/SEX)
`
`TREATMENT
`DURATION
`
`CORNEAL
`PERFORATION
`
`1. 76 F
`2. 66 F
`
`3. 77 M
`
`4. 71 M
`5. 79 M
`
`6 27 M
`7. 47 F
`8. 80 M
`
`9. 65 F
`10. 71 F
`11. 77 F
`
`10 days
`29 days
`
`18 days
`
`11 days
`17 days
`
`5 days (6 hr)
`4 days
`10 mo
`7 mo
`5 mo
`5 days
`14 days
`
`Yes
`No (keratitis)
`
`Yes
`
`Yes
`Yes
`
`Yes
`No (descemetocele)
`No (descemetocele)
`No (descemetocele)
`No (keratitis)
`No (keratitis)
`Yes
`
`NSAID, nonsteroidal anti-inflammatory drug; NP, not performed.
`
`NSAID
`(REGIMEN)
`
`Falcon (QID)
`Voltaren (QID)
`
`Voltaren (QID)
`
`(Falcon) (QID)
`Falcon (QID)
`
`Falcon (QID)
`Falcon (QID)
`Voltaren (QID)
`Falcon (QID)
`Voltaren (QID)
`Voltaren (TID)
`Falcon (6/day)
`
`OTHER
`MEDICATIONS
`
`INDICATION FOR TREATMENT
`(CULTURED ORGANISM)
`
`Tears
`Glaucoma medications,
`tears
`Dexamethasone,
`tobramycin, tears
`Prednisolone
`Glaucoma medications,
`prednisolone
`Rimexolone, Ciloxan
`Corticosteroid
`None
`None
`Flarex, Alcaine
`Econopred, Ciloxan
`Polymixin B sulfate,
`neomycin,
`dexamethasone
`
`Unknown (streptococci)
`Unknown (NP)
`
`Postsurgery
`Inflammation (NP)
`Unknown (no growth)
`Unknown (NP)
`
`Unknown (NP)
`Unknown (NP)
`Unknown (NP)
`Unknown (NP)
`Corneal abrasion? (NP)
`Dellen? (NP)
`Unknown (NP)
`
`206
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`17 Flach Final 11/9/01 11:23 AM Page 207
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`Corneal Melts Associated With Topically Applied Nonsteroidal Anti-InfLammmatory Drugs
`
`CASE 5
`A 79-year-old man underwent argon laser trabeculoplasty
`and was treated with 1% prednisolone with good results.
`His eye became painful and developed an anterior cham-
`ber reaction 3 weeks following surgery. Falcon was added
`to a regimen of brimonidine tartrate ophthalmic solution
`(Alphagan) (Allergan, Inc, Irvine, California), dorzo-
`lamide
`(Trusopt)
`(Merck & Co, West Point,
`Pennsylvania), timolol maleate (Timoptic) (Merck & Co),
`and latanoprost (Xalatan) (Pharmacia Corp, Kalamazoo,
`Michigan). Increased pain, photophobia, and hyperemia
`developed over 2 weeks, and he presented with 99% tis-
`sue loss and a descemetocele 17 days after initiation of
`treatment with Falcon.
`
`CASE 6
`A 27-year-old man presented 5 days following excimer
`laser surgery complaining of pain. No corneal thinning
`was observed on examination. He was using rimexolone
`(Vexol) (Alcon Laboratories, Inc), ciprofloxacin (Ciloxan)
`(Alcon Laboratories, Inc), and Falcon ophthalmic med-
`ications. Falcon was discontinued, but he continued to use
`rimexolone and ciprofloxacin. He returned in 6 hours with
`a corneal perforation.
`
`CASE 7
`A 47-year-old woman with a history of radial keratotomy
`20 years previously returned for excimer laser surgery.
`She received postoperative treatment with Falcon, fluo-
`rometholone acetate (Flarex) (Alcon Laboratories, Inc),
`and ciprofloxacin. She returned on postoperative day 4
`complaining of pain. Her medical regimen was discontin-
`ued, and cephazolin and tobramycin eye drops were pre-
`scribed. The cornea continued to melt, and a topical cor-
`ticosteroid was added to the regimen. She required a pen-
`etrating keratoplasty 5 months later.
`
`CASE 8
`An 80-year-old man developed cystoid macular edema 5
`months after cataract surgery. He was treated with
`Voltaren for 10 months without toxic effects. Falcon was
`substituted, and after 7 months he presented with pain.
`Corneal thinning was observed, and a descemetocele was
`noted after 48 hours.
`
`fluorometholone, and a bandage contact lens for 2 weeks.
`Voltaren was discontinued, after which she developed bul-
`lous keratopathy. Despite intermittent debridement, epi-
`lation, and treatment with Voltaren and Flarex, her cornea
`continued to exhibit a superficial punctate keratitis. She
`eventually underwent a penetrating keratoplasty with
`good results.
`
`CASE 10
`A 71-year-old woman was treated with Voltaren, pred-
`nisolone acetate (Econopred) (Alcon Laboratories, Inc),
`and ciprofloxacin following cataract surgery. She present-
`ed on postoperative day 5 with ocular pain, and a dellen
`was observed during examination. Voltaren was discontin-
`ued, and goniosol hydroxypropyl methylcellulose (Ciba
`Vision) was added to the Econopred treatment. Following
`a poor response to patching, she underwent conjunctival
`grafting with good results.
`
`CASE 11
`A 77-year-old woman with an eye that had been irritated
`for many months following a complicated cataract surgery
`presented with increased pain and redness in that eye and
`an associated “injection of the upper tarsus” of unknown
`origin. She was treated with Voltaren every 4 hours. She
`returned in 2 weeks using Falcon and a steroid-antibiotic
`eye drop. She eventually suffered corneal melt with cen-
`tral perforation.
`
`OTHER CASES
`In addition to these 11 cases, corneal melting in 7
`“healthy, asymptomatic eyes” following refractive or
`cataract surgery in patients treated with Falcon were
`reported at the 104th Annual Meeting of the AAO.6
`Although detailed clinical descriptions were not provided
`for these cases, at least 2 of the patients were said to have
`a history of punctal plug insertion, which suggested clini-
`cally significant dry eyes. In addition, it was noted that all
`7 cases had occurred in one practice, while the nation’s
`“top 15 presribers of Voltaren” have yet to report a severe
`case of corneal toxicity with use of topical NSAIDs. The
`speaker concluded that use of Falcon was the cause of all
`of the cases of corneal melting observed.
`
`DISCUSSION
`
`CASE 9
`A 65-year-old woman with trichiasis and a history of
`cataract surgery 3 years previously underwent a YAG cap-
`sulotomy during which she suffered a corneal abrasion.
`After treatment with Voltaren without patching, she
`developed a recurrent corneal erosion. She was treated
`with
`intermittent patching, Voltaren, proparacaine
`hydrochloride (Alcaine) (Alcon Laboratories, Inc),
`
`Corneal complications related to topical NSAID use are
`uncommon. Superficial punctate keratitis, corneal infil-
`trates, and epithelial defects have been reported following
`the use of these anti-inflammatory agents.10-13 These find-
`ings are not surprising, because most topically applied
`medications, particularly those with preservatives, are
`associated with potential corneal toxicity.14,15 However, the
`
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`Flach
`
`reports of corneal melting associated with topical NSAID
`treatment are surprising and of great interest. Because
`both infectious and noninfectious corneal melting disor-
`ders have many different causes, careful examination of
`patients is important before a drug toxicity is identified as
`the cause in all of these cases.16
`Generic diclofenac (Falcon) may be the sole reason
`that corneal melting occurred in 2000. Unfortunately, this
`conclusion is supported only by anecdotal presentations
`that include a minimum of data with limited analysis and
`little or no discussion or consideration of complicating fac-
`tors and alternative explanations.6 The 7 cases of corneal
`melts in Falcon-treated patients that were presented at
`the AAO annual meeting6 are difficult to discuss because
`the associated environmental factors and clinical descrip-
`tions were not provided. Furthermore, it appears that
`potentially important coexistent ocular disease was largely
`ignored during the review of these cases. For example, 2
`patients requiring punctal plugs were included as
`“healthy, asymptomatic patients,” ignoring the fact that
`patients with Sjögren’s syndrome can develop sterile
`corneal ulcerations and perforations without any medical
`treatment or surgical procedure.17 In addition, patients
`with mild and clinically insignificant keratitis sicca have
`developed severe penetrating and perforating ulcers fol-
`lowing cataract surgery without any associated medical
`treatments.18 Finally, it is impressive that there appears to
`be an unbalanced geographic distribution of these cases of
`corneal melting. An asymmetric distribution of an
`observed drug toxicity can reflect production or manufac-
`turing problems in a specific lot of drug.19 Therefore, it is
`of paramount importance to complete a careful review of
`all of the reported cases of corneal toxicity before con-
`cluding that an isolated drug toxicity explains the appear-
`ance of these severe corneal toxicities.7
`This review of 11 cases of corneal toxicity observed in
`patients using topically applied diclofenac does not pro-
`vide compelling evidence of an isolated drug toxicity. The
`potential causes of acute corneal melting suggest that
`many cases are unrelated to medical treatment, as sum-
`marized in Table II.20 There is little evidence that these
`potential causes were carefully excluded from these 11
`cases. A clinical diagnosis and therefore an indication for
`anti-inflammatory treatment were lacking in 8 of 11 cases.
`It is particularly impressive how seldom an infectious
`cause was ruled out despite the presence of an uncom-
`fortable red eye of uncertain origin (9 of 11 patients).
`Three patients (cases 1, 2, and 3) had dry eyes. A deficient
`tear film has been associated with corneal melting11,17,18 In
`addition, abnormal tear production may contribute to
`enhanced corneal toxicity from topical therapy, particular-
`ly if preservatives are present. Therefore, coexistent dis-
`eases may have contributed to any or all of the observed
`
`208
`
`corneal melting in this small series of 11 cases.
`Coexistent local and systemic medical treatments
`complicate the analysis of these cases of corneal toxicity.
`For more than 2 decades, corticosteroids have been rec-
`ognized as a cause of corneal toxicity. In fact, 25 cases of
`corneal perforation reminiscent of these cases of corneal
`melting have been reported by a single observer.21
`Therefore, the use of corticosteroids by 8 of 11 of these
`patients may be important. In further support of this pos-
`sibility, it is of note that in case 7, a descemetocele formed
`despite discontinuation of Falcon and during use of only a
`corticosteroid. In addition, patient 5, who eventually per-
`forated, was using not only a corticosteroid but also mul-
`tiple medications, some of which predispose to dry eye
`(hydrochlorothiazide and timolol) and others that have
`significant potential for inducing corneal toxicity (dorzo-
`lamide, timolol, brimonidine, and latanoprost).
`A touchstone for the determination of pharmacologic
`toxic disease has been proposed.22 I advocate use of the
`following Koch-type postulates for a toxic etiology:
`• The clinical signs of toxicity must be reproducible in
`experimental animals.
`• The toxic dose-response may show normal scatter of
`random distribution, but no patient must get toxic
`effects from doses differing by several orders of mag-
`nitude.
`• Cessation of dosage should be followed by a decrease
`in toxicity.
`The corneal toxicity reported in these 11 cases does
`not fulfill these criteria.
`Corneal melting has not been reproduced in experi-
`mental animals with use of topically applied, commercially
`available, brand-name NSAIDs. To the contrary, well-
`designed laboratory studies suggest that these topically
`administered NSAIDs may be beneficial in protecting ani-
`mals from corneal melting.20 In addition, carefully
`
`TABLE II: POTENTIAL CAUSES OF ACUTE CORNEAL MELTING
`
`Herpes simplex keratitis
`Mooren’s ulcer
`Rheumatoid arthritis
`Bacterial keratitis
`Keratoconjunctivitis sicca
`Erythema multiforme
`Alkali burn
`Anterior-segment dysgenesis
`Herpes zoster
`Neuroparalytic keratitis
`Wound melt/keratoplasty
`Pemphigoid
`Rosacea keratitis
`Thermal burn
`Vernal keratoconjunctivitis
`
`Information from Kenyon.20
`
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`
`Corneal Melts Associated With Topically Applied Nonsteroidal Anti-InfLammmatory Drugs
`
`controlled, prospective, double-masked, randomized clini-
`cal studies in hundreds of patients indicate that topically
`applied brand-name NSAIDs appear safe for use in
`patients.1,2 Therefore, it is unlikely that there is something
`distinctive about the diclofenac molecule that predisposes to
`severe corneal toxicity. It remains to be seen how carefully
`the generic NSAID Falcon has been tested for the potential
`of inducing a corneal melt in experimental animals.
`An incredibly inconsistent dose-toxicity relationship
`exists within the group of 11 cases described here. In case
`8, for example, the patient was treated with Voltaren for
`10 months and Falcon for 7 months for cystoid macular
`edema following cataract surgery without apparent toxici-
`ty. Then, for unexplained reasons, the patient developed
`corneal thinning with descemetocele formation over 48
`hours while using Falcon. This history of prolonged expo-
`sure without corneal toxicity followed by an acute corneal
`melt is not typical of an isolated drug toxicity.
`Patient 9 was referred to the author as a possible case
`of NSAID-induced corneal melt. This case clearly demon-
`strates how resistant a cornea can be to the potential
`corneal toxicity of Voltaren. The patient was treated for
`various indications, including corneal abrasion, recurrent
`corneal erosion, and bullous keratopathy with Voltaren
`therapy. Despite concurrent treatment with Flarex and
`Alcaine, with and without patching, bandage contact lens
`application, and intermittent debridement, no significant
`thinning of the cornea was noted during 5 months of treat-
`ment. This is remarkable. The coexistent corneal treat-
`ments could have in and of themselves caused consider-
`able corneal damage, but little was observed.
`Finally, in case 6, the patient had a normal corneal
`examination 5 days after excimer surgery only to have per-
`foration 6 hours later while using Falcon. It is difficult to
`find any drug or chemical toxicity reported within the lit-
`erature with such a rapid course. Therefore, a comparison
`of cases 6, 8, and 9 makes clear an unusual inconsistency
`of observed corneal toxicity with topically administered
`diclofenac. This is unlike an isolated drug toxicity.
`Case 10 demonstrates the importance of careful post-
`operative examinations. This patient was referred to the
`author because she was unhappy despite a good visual
`outcome. She believed that she had suffered an “eye melt-
`ing” due to Voltaren use. Five days following cataract sur-
`gery, she had a painful eye and was treated with Voltaren
`and Econopred. She was carefully examined, and a dellen
`was recognized and appropriately treated. Fortunately,
`the patient was not simply treated aggressively for a resist-
`ant postoperative inflammatory response without benefit
`of an examination. It is likely that the careful follow-up
`care that she received helped her to avoid severe corneal
`damage related to an improperly treated dellen. It is iron-
`ic that the patient ignored the extensive diagnostic and
`
`therapeutic efforts of her surgeon and the resultant excel-
`lent visual outcome, but instead gravitated toward a
`potential toxicologic explanation that was at the time pop-
`ularized in the tabloids and debated on the Internet.
`Overall, this review of 11 cases of corneal toxicity
`observed in patients using topically applied diclofenac
`reveals an inconsistent and variable dose-toxicity relation-
`ship. Furthermore, all of the cases are complicated by
`coexistent diseases and medical therapies. This makes it
`difficult to establish a definitive diagnosis for the observed
`corneal melting. These cases underscore the importance
`of making a clinical diagnosis before initiating nonspecific
`anti-inflammatory treatment and the need for careful fol-
`low-up of patients after surgical procedures.
`While we await a definitive analysis of all the report-
`ed cases of corneal melting associated with topical NSAID
`use, it seems prudent to keep in mind an admonishment
`from Sir William Osler concerning the potential toxicity of
`medications, quoted by Dr Fred Wilson II in his
`American Ophthalmological Society thesis:23
`
`In the fight which we have to wage incessantly against igno-
`rance and quackery among the masses and follies of all sorts
`among the classes, diagnosis, not drugging, is our chief
`weapon of offence. Lack of systematic personal training in
`the methods of the recognition of disease leads to the mis-
`application of remedies, to long courses of treatment when
`treatment is useless, and so directly to that lack of confi-
`dence in our methods which is apt to place us in the eyes of
`the public on a level with empirics and quacks.
`
`CONCLUSIONS
`
`The inconsistent and variable dose-toxicity relationships
`reflected in these 11 cases of corneal melting in patients
`using topical diclofenac suggest that coexistent factors
`other than a simple drug toxicity are implicated, if not
`causative, in these toxicities. Concurrent ocular and sys-
`temic disease in many of these patients, as well as their
`use of medications including corticosteroids, complicates
`this analysis. The occurrence of corneal melting can be
`minimized by attempting to make a definitive diagnosis
`before initiating anti-inflammatory treatment and by care-
`ful follow-up examinations of patients after surgery.
`
`REFERENCES
`
`2.
`
`1.
`
`Flach AJ. Cyclo-oxygenase inhibitors in ophthalmology. Surv
`Ophthalmol 1992;36:259-284.
`Flach AJ. Duane’s Foundations of Clinical Ophthalmology. 2nd ed.
`Philadelphia, Pa: JB Lippincott; 1994;1-32.
`3. NSAID Adverse Reaction Report. (Press release): American
`Society of Cataract and Refractive Surgery, Aug 3, 1999.
`4. NSAID Update. (Press release): American Society of Cataract and
`Refractive Surgery, American Society of Ophthalmic
`Administrators, Aug 11, 1999.
`
`209
`
`Page 5 of 8
`
`

`
`17 Flach Final 11/9/01 11:23 AM Page 210
`
`Flach
`
`5.
`
`7.
`
`8.
`
`Rosenthal KJ. ASCRS inquiry of NSAID problem leads to drug
`recall. Ophthalmol Times 1999;Nov 15.
`6. Gayton JL. Primary management problems symposium:
`Complications of NSAIDs. Presented at the 104th Annual Meeting
`of the American Academy of Ophthalmology, Oct 24, 2000.
`Flach AJ. Topically applied nonsteroidal anti-inflammatory drugs
`and corneal problems: An interim review and comment.
`Ophthalmology 2000;107:1224-1226.
`Lin JC, Rapuano CJ, Laibson PR, et al. Corneal melting associated
`with use of topical nonsteroidal anti-inflammatory drugs after ocu-
`lar surgery. Arch Ophthalmol 2000;118:1129-1132.
`Apte RS, Hargrave SL, June JC, et al. Matrix metalloproteinases
`and post-operative corneal melts. Scientific Poster 231. Presented
`at the 104th Annual Meeting of the American Academy of
`Ophthalmology, Oct 24, 2000.
`10. Gills JP. Voltaren associated with medication keratitis. (Letter) J
`Cataract Refract Surg 1994;20:110.
`11. Sher NA, Krueger RR, Teal R. Role of topical corticosteroids and
`nonsteroidal anti-inflammatory drugs in the etiology of stromal
`infiltrates after excimer photorefractive keratectomy. J Refract
`Corneal Surg 1994;10:587-588.
`12. Probst LEV, Machat JJ. Corneal subepithelial infiltrates following
`photorefractive keratectomy. (Letter) J Cataract Refract Surg
`1996;22:281.
`13. Shimazaki J, Saito H, Yang HY, et al. Persistent epithelial defect
`following penetrating keratoplasty: An adverse effect of diclofenac
`eyedrops. Cornea 1995;14:623-627.
`14. Wilson FM. Adverse external ocular effects of topical ophthalmic
`medications. Surv Ophthalmol 1979;24:57-88.
`15. Burstein NL. Corneal cytotoxicity of topically applied drugs, vehi-
`cles and preservatives. Surv Ophthalmol 1980;25:15-30.
`16. Donzis PB, Mondino BJ. Management of noninfectious corneal
`ulcers. Surv Ophthalmol 1987;32:94-110.
`17. Pfister RR, Marphy GE. Corneal ulceration and perforation asso-
`ciated with Sjögren’s syndrome. Arch Ophthalmol 1980;98:89-94.
`18. Radtke N, Meyers S, Kaufman HE. Sterile corneal ulcers after
`cataract surgery in keratoconjunctivitis sicca. Arch Ophthalmol
`1978;96:51-52.
`19. O’Day DM. Value of a centralized surveillance system during a
`national
`epidemic
`of
`endophthalmitis. Ophthalmology
`1985;92:309-315.
`20. Kenyon KR. Inflammatory mechanisms in corneal ulceration.
`Trans Am Ophthalmol Soc 1985;83:610-663.
`21. Thygeson P. Controversies in Ophthalmology. Philadelphia, Pa:
`WB Saunders; 1977;450-469.
`22. Potts AM. Tobacco amblyopia. Surv Ophthalmol 1973;17:313-339.
`23. Wilson FM. Adverse external ocular effects of topical ophthalmic
`therapy: An epidemiologic, laboratory, and clinical study. Trans Am
`Ophthalmol Soc 1983;81:854-965.
`
`9.
`
`DISCUSSION
`
`DR MICHAEL A. LEMP. Dr Flach has called our attention,
`by way of a retrospective series of 11 patients, to the con-
`temporary vexing problem of keratolysis associated with
`the use of non-steroidal anti-inflammatory topical med-
`ications. He points out the compounding variables in
`these cases and suggests that co-existing factors rather
`than a simple drug toxicity are implicated.
`Indeed, the conditions associated with these, and
`other previously recorded cases include cataract surgery,
`dry eye in a significant number of these patients,
`
`210
`
`autoimmune disease and co-existent bacterial ulcers in
`some of these patients. Both the brand (Voltaren)
`diclofenac and the generic brand have been implicated,
`about 60% of the cases having been treated with the
`generic brand.1
`Corneal melting or keratolysis in the absence of treat-
`ment with NSAIDs, occurs in the association with autoim-
`mune disease, keratoconjunctivitis sicca, diabetes and
`steroid use (which occurred in a number of these
`patients). Recently analysis of tissue removed from a
`patient suffering a corneal melt associated with NSAID
`use suggests that this keratolysis was mediated by matrix
`metalloproteinases (MMPs). MMP is a family of degrada-
`tive enzymes. They degrade collagen I, II, III, V, VII, in
`addition to basement membrane, laminin, and proteogly-
`cans. In a case report by O’Brien et al, MMP8 was iden-
`tified.2 The source of this is thought to be neutrophils and
`epithelium; this enzyme degrades collagens I, II and III.
`In addition, MMP2 and MMP9 have been identified after
`refractive surgery and in patients with keratoconjunctivi-
`tis sicca.3
`It seems likely that possible triggers of MMPs
`include: keratoconjunctivitis sicca, ocular surface disease,
`bacterial infections, NSAIDs, preservatives in topical
`medications, and surgery. In a predisposed ocular sur-
`face, the use of NSAIDs may substantially increase the
`risk of a clinically significant episode of keratolysis.
`
`REFERENCES
`
`1. Lin JC, Rapuano CJ, Laibson PR, et al. Corneal melting associated
`with use of topical non-steroidal anti-inflammatory drugs after ocu-
`lar surgery. Arch Ophthalmol 2000;118(8):1129-1132.
`2. O’Brien TP, Li QJ, Sauerburger F, et al. The role of matrix metal-
`loproteinases in ulcerative keratolysis associated with perioperative
`diclofenac use. Ophthalmol 2001;108: 656-659
`3. Sack RA, Sathe S, Bialon A. Gelatinases, origins, and associated
`proteins in normal and dry eye tear fluids. Invest Ophth Vis Sci
`2001;42(4)(Supple); S263
`
`[Editor’s note] DR OLIVER SHINE discussed the paper he
`co-authored that analyzed 140 patients with corneal toxic-
`ity associated with the use of NSAID’s, and the problem
`of multiple events and underlying diseases which could
`affect the cornea in these patients. DR TAYLOR ASBURY
`mentioned that Dr Philips Thygeson was one of the first
`physicians to describe corneal melting associated with the
`use of topical medicines (corticosteroids).
`
`DR ALLAN J. FLACH. First I want to thank Dr Michael
`Lemp for agreeing to discuss my paper and also Drs Tuck
`Asbury and Oliver Shine for their interest and comments.
`Dr Asbury reminds us that it was Dr Philips Thygeson
`who first emphasized the dangers of corneal melts associ-
`ated with corticosteroids and that he was elected to the
`
`Page 6 of 8
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`17 Flach Final 11/9/01 11:23 AM Page 211
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`Corneal Melts Associated With Topically Applied Nonsteroidal Anti-InfLammmatory Drugs
`
`AOS in 1936. I would like to add that Dr Thygeson, while
`not physically as active as he would like to be, is still intel-
`lectually active at 97 years of age. Although he must lift
`himself from his bed with block and tackle, he continues
`to have many interests including the history of American
`Indians of the southwestern United States. In fact, I
`recently sent him an article concerning Geronomo as
`reflected in the writings of Edgar Rice Burroughs.
`One of my greatest fears is to prepare to present a
`paper and submit a copy of the manuscript, only to have a
`similar paper appear in print just prior to my presentation.
`Today my greatest fear has been fully realized. Not only
`1 but 3 papers have been recently published on corneal
`melts associated with topical NSAIDs.1,2,3 Dr Lemp has
`mentioned one of them and Dr Shine is a co-author on
`another.1,2 Fortunately, my paper is reasonably consistent
`with all 3 of them in terms of its observations and conclu-
`sions. Dr Lemp has summarized the results of O’Brien et
`al’s case study of 1 case in which the matrix metallopro-
`teinases (MMPs) may have been implicated in the
`observed corneal melting reported in a patient using top-
`ical NSAIDs.1 This report compliments a poster presen-
`tation provided by Apte et al at the 104th Annual Meeting
`of the American Academy of Ophthalmology on this same
`subject as is mentioned within the text of my presenta-
`tion.4 While both paper and poster share the common
`suggestion that the observed corneal melts are consistent
`with enhanced MMP activity, both presentations