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Healio
ByMonte S. Dirks, MD
February 15, 2006
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Safety of Topical NSAIDs

ByMonte S. Dirks, MD

Although efficacy is a primary issue with all drugs, it represents only part of a physician’s concerns when considering the use of a new medication. Safety is an overwhelming factor, especially with the nonsteroidal anti-inflammatory drugs where a disparity exists between the tolerability of topical and systemic formulations.

Can a topical application of an NSAID have systemic effects? This issue was evaluated extensively with bromfenac solution.

Data from a phase 1 double-blind pharmacokinetic and safety trial assessed the effects of bromfenac solution on plasma levels in 14 patients. Two concentrations were tested; a 0.09% solution equivalent to the commerical formulation of Xibrom (ISTA Pharmaceuticals, Inc.) and a 0.2% solution, which is more than twice the concentration of Xibrom. Two drops of each solution were instilled four times a day, representing twice the commercial dosage. Each solution was administered for 28 days, which is twice the duration of the labeled treatment. Following the treatment period, plasma drug concentrations for groups were shown to be below the level of quantitation (50 µg/mL), indicating that the topical application of bromfenac is not likely to produce systemic effects.

Systemic effects of oral NSAIDs

Monte S. Dirks, MD

When discussing safety issues with NSAIDs, it is essential to distinguish between topical and oral agents. The greater tissue penetration achieved with oral NSAIDs is balanced by the increased risk of serious systemic effects. A good example is oral diclofenac, which is associated with gastrointestinal perforations, ulcerations and bleeding.

I have used oral ketorolac following glaucoma surgery and found that this agent works well for patients with severe pain secondary to choroidal effusion. As with diclofenac, potentially serious gastrointestinal side effects can occur; however, this agent is also highly hepatoxic and was withdrawn from the market in France and Germany. Between 1990 and 1993, 143 deaths were attributed to the use of this agent. Oral ketorolac is still available in the United States, albeit with a black box warning that limits its use to 5 days.

An oral form of bromfenac was also associated with hepatoxicity, including acute hepatic failures, when used outside the labeled dosage. Although the death rate was not as high as with ketorolac, in 1998, the manufacturer voluntarily withdrew this formulation from the United States, where bromfenac is now available only as a topical agent.

Reference

A phase 3 clinical trial of bromfenac in postoperative cataract patients assessed the effect of treatment on liver function. This analysis included 497 patients with no liver conditions; of these, 340 were treated with bromfenac and the remainder received placebo. At the end of the trial, no significant differences in liver function tests were found between the bromfenac and placebo groups and no patients graded more than 1 on the WHO Common Toxicity Criteria scale of grade 1 to grade 4.

Two phase 3 trials assessed the incidence of adverse ocular effects that occurred during treatment with bromfenac (Figure). The results showed a minimal incidence of adverse events in both the bromfenac and placebo groups, and the reported events were those that would be expected 1 day following cataract surgery. Importantly, only 1.4% of patients treated with bromfenac reported burning and stinging following instillation. In addition, cystoid macular edema was reported by only 1.4% of patients in the bromfenac group compared to 4.7% of patients who received a placebo (P<.05). As an investigator in this study, I was impressed by the postoperative comfort reported by patients treated with bromfenac.

Figure: Common Ocular Adverse Events Associated with NSAIDs
Figure

Data from U.S. Clinical Trials show an advantageous safety profile for bromfenac.

(Figure courtesy of Monte S. Dirks, MD)

Ocular side effects are not unique to bromfenac. A retrospective study of 16 patients with adverse corneal events identified severe keratopathy, ulceration, perforations and corneal or scleral melts during treatment with ophthalmic ketorolac or brand (Voltaren) or generic diclofenac sodium. Nathan G. Congdon, MD, MPH, and colleagues examined the medical records of 129 patients who experienced corneal complications following treatment with topical ophthalmic NSAIDs. Most confirmed cases occurred with generic diclofenac. Toxicity associated with brand diclofenac (Voltaren) and ketorolac tended to involve an ocular comorbidity or a high total dose of NSAID, whereas severe adverse events occurred at lower doses in routine postoperative settings with generic diclofenac. A third study suggested that corneal complications associated with NSAIDs, including keratitis, ulceration and perforation, may be more likely to occur in patients with risk factors such as the presence of systemic and ocular conditions that predispose the patient to rosacea and pre-existing epithelial keratopathy.

Japanese data on topical bromfenac

Despite the phase 3 efficacy and safety data and favorable physician ratings, experience with bromfenac in the United States is limited, as this medication was approved in 2005. However, since 2000, an identical formulation of bromfenac (Bronuck, Senju Pharmaceuticals) has been available in Japan, where the efficacy and safety of this agent has been clearly established.

Between 2000 and 2004, bromfenac was used in more than 6 million patients in Japan with no reports of serious systemic events. Serious ocular events were reported in 13 patients (0.0000023%) and included corneal erosions, ulcers and perforations, conjunctival disorders and one anterior capsule contraction. These events are similar to those expected with most topical NSAIDs; however, the frequency was much lower than with the generic agents available in the United States.

Other uses of topical NSAIDs

Monte S. Dirks, MD

With the excellent penetration of the newer agents into the vitreous and retina, the use of topical NSAIDs may prove beneficial in cystoid macular edema. Bromfenac has compared favorably to ketorolac and nepafenac for the prevention of CME, and to ketorolac for the treatment of CME. Topical NSAIDs have been shown to be useful in alleviating pain following PRK and I believe that these agents would provide effective pain control following any type of refractive surgery.

I have used bromfenac in patients with traumatic loss of corneal epithelium, including those with corneal ulceration or herpes zoster, and found that it provides excellent pain control in these patients. NSAIDs may be useful following selective laser trebeculoplasty (SLT). In my practice, SLT has completely replaced argon laser trabeculoplasty (ALT) in the treatment of glaucoma. These are two different procedures and SLT does not induce as much inflammation as ALT. In fact, we rely on the inflammation that occurs with SLT to induce macrophages and other immune cells to expedite the recovery of trabecular meshwork.

Many practitioners do not use steroids following SLT because these agents suppress the inflammation needed to achieve the desired results. Ketorolac is often used post-SLT; however, the best anti-inflammatory agent in this setting is still in question. We are planning to investigate bromfenac for this use; it is efficacious and will likely control postoperative pain in our patients with results similar to those seen with other NSAIDs.

Reference

  • Data on file, ISTA Pharmaceuticals, Inc.

The Pharmaceutical Affairs Law in Japan mandates post-marketing safety programs to continuously monitor drug safety and efficacy. The Bromfenac Post-Marketing Safety Report, filed with the Minister of Health, Labour and Welfare in 2005, presented safety data from 3,425 patients treated with bromfenac between 2000 and 2004. No serious drug-related systemic adverse events were reported. Importantly, the patients surveyed ranged from infants to geriatric patients, and included 39 patients who had liver disease before starting treatment. In view of these findings, I believe bromfenac has established a favorable safety profile.

After bromfenac was approved in the United States in March 2005, 400 physicians were invited to participate in the Xibrom First Experience Trial. Each physician placed at least 10 patients on bromfenac and was asked to rate the general experience with bromfenac compared to other topical NSAIDs. To date, 225 physicians have reported experiences with 2,604 patients, with the majority indicating that they were satisfied with bromfenac.

References

  • Data on file, ISTA Pharmaceuticals, Inc.
  • Shiffman ML, Donnenfeld ED, Holland EJ, Grillone LR. Investigation of liver toxicity following topical treatment with Xibrom 0.1%, an NSAID for post-cataract surgery inflammation. Paper presented at: annual meeting of the American Society of Cataract and Refractive Surgery; April 15-19, 2005; Washington, D.C.
  • Donnenfeld ED, Holland EJ, Steward R, Grillone LR for the Xibrom Study Group (2005). Topical Xibrom 0.1% Investigational NSAID to decrease inflammation after cataract surgery [abstract]. 2005 American Society for Cataract and Congress on Ophthalmic Practice Management, and Clinical & Surgical Staff Program. April 18, 2005. Washington D.C.
  • Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology. 2001. 108(5):936-944.
  • Congdon NG, Schein OD, von Kulajta P, Lubomski LH, Gilbert D, Katz J. Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs. J Cataract Refract Surg. 2001;27:622-631.
  • Luchs JI, Guidera AC, Udell IJ. Keratitis, ulceration and perforation associated with topical nonsteroidal anti-inflammatory drugs. Presented at the Third International Symposium on Ocular Pharmacology and Pharmaceutics-ISOPP; Feb. 10-13, 2000; Lisbon, Portugal.
  • Data on file, ISTA Pharmaceuticals, Inc.
  • Kitao N, Shimoji H, Fukuda M. Post-Marketing Surveillance of Bromfenac Sodium (Bronuck®) Ophthalmic Solution-Use-Result Surveillance. Atarashii Granka 2005;22:1299-1308.
  • Survey finds new NSAID meets or exceeds expectations. Ophthalmology Times. Nov. 15, 2005.

Discussion

David F. Chang, MD: What has been your experience with NSAID-related complications?

Deepinder K. Dhaliwal, MD: The nonsteroidal agents are a wonderful adjunct to the treatment of a variety of ocular disorders. However, it is important to remember that we have seen corneal melting with these agents. In fact, I have a patient who developed a corneal perforation while on bromfenac. The caveat is that she never should have been on a nonsteroidal agent because she had Stevens-Johnsons syndrome and a severely compromised ocular surface. Unfortunately, after 2 weeks of twice-daily dosing with bromfenac, she presented to the UPMC Eye Center with a corneal perforation. Although a potent NSAID with twice-daily dosing is a valuable therapeutic option, it does not mean that it should be used in compromised eyes. It is critically important that in patients with rheumatoid arthritis, Stevens-Johnsons syndrome or other conditions that can lead to compromised eyes, nonsteroidal agents not be used on the ocular surface. Avoiding use in these patients will help prevent corneal melting and subsequent perforation.

Barry A. Schechter, MD: I agree that if there is a previous history or a possibility of perforation or corneal thinning, then NSAIDs should be avoided. However, I did a study about the concomitant use of ketorolac and cyclosporine in severely compromised dry eye patients, and they did extremely well. I had some patients on this regimen for up to 1 year. The use of cyclosporine may allow for concomitant use of a nonsteroidal agent.

Dhaliwal: If a nonsteroidal agent is used in compromised eyes, close follow-up is critical, and patients should be seen a few days or a week later.

Chang: Do we understand the mechanism of corneal melts that have been reported with NSAIDs?

Schechter: I believe that it is mediated by T cells in many cases.

Dhaliwal: The mechanism is not entirely known and there are various hypotheses. There is promotion of collagenase activity, and if this activity is predominantly T-cell mediated, then use of cyclosporine with a nonsteroidal may provide a significant benefit.

Chang: There is also a theory that NSAIDs potentiate matrix metalloproteinases, which are enzymes that digest collagen. Are there categories of eye surgical patients for whom you would definitely not recommend a topical NSAID?

Schechter: Patients with rheumatoid arthritis or Stevens-Johnson syndrome should definitely not be treated with an NSAID. However, I would like to stress again that NSAIDs can be highly beneficial in patients with dry eye.

Monte S. Dirks, MD: Over time, topical steroids will increase IOP in many patients with open-angle glaucoma. In patients who need chronic anti-inflammatory therapy, it is better to use a potent NSAID that needs to be instilled only twice a day than to use a steroid and risk increased IOP.

Schechter: The nepafenac package insert states that there is a 5% to 10% chance of a drug-related rise in IOP. Can you explain that?

Dirks: Increased IOP is likely caused by the inhibition of the trabecular meshwork. A 5% to 10% chance is not nearly as bad as the 90% risk in increased IOP associated with prednisolone acetate.

Chang: The epidemic of corneal melts that occurred several years ago was eventually attributed to the vehicle in the generic diclofenac preparation. Nevertheless, topical NSAIDs are potent drugs and can certainly compromise ocular surfaces. Another situation to be wary of is the use of topical NSAIDs in post-zoster neurotrophic cornea patients because NSAIDs will further blunt corneal sensation. I have also seen melts in patients with combined cataract-pterygium surgery — another clinical situation in which patients have abnormal surface protection and compromised corneal healing. Are there other situations in which you would be concerned with the use of topical steroids postoperatively?

Schechter: I think that whenever there is an infection the etiology of the infection poses a concern. Steroids should not be used if there is a possibility of a polymicrobial infection. This is the reason that I use nonsteroidal agents in corneal ulcer patients. These agents provide significant pain control, and although there is some anti-inflammatory effect, there is no reason to be concerned about these cases.

Dhaliwal: Dr. Dirks, you mentioned that you use nonsteroidal agents in patients with corneal abrasions and corneal ulcers. Can you describe your approach and how often you monitor the patients?

Dirks: I use NSAIDs primarily for pain control in these patients, although they may also have some degree of anterior chamber inflammation. The patients are observed on a daily basis. Most re-epithelialize within a few days and at that point in time the NSAID is discontinued.

Dhaliwal: Do you use a bandage contact lens in patients with abrasions?

Dirks: I use a bandage contact lens in patients with large abrasions. However, NSAIDs are potent enough as analgesics to provide effective pain control for patients with 3-mm or 4-mm abrasions who do not otherwise need a bandage lens.

Chang: What do you do when you have a post-herpetic patient who needs a surgical procedure? Do you treat with steroids?

William B. Trattler, MD: I am comfortable using topical steroids following cataract surgery in patients whose eyes are not inflamed and who have a history of a herpetic corneal infection, but have not had a recent recurrence. Of course, there is always a small chance of recurrence in any patient.

Dhaliwal: Do you administer an oral anti-viral prophylaxis in these patients?

Trattler: Yes. There are some clinicians who think anti-viral prophylaxis can be used to prepare patients with a previous history of herpes simplex virus for refractive surgery. I typically avoid refractive surgery in these patients because of the significant risk.

Dirks: The risks of a melt in a neurotrophic cornea are increased in patients with herpes zoster or recurrent simplex. What has been your approach to pain management in these patients?

Dhaliwal: I think that following up with patients on a daily basis is critically important. Clinicians must closely evaluate patients to ensure that they are healing properly and that the cornea is not melting. This is the key to the proper use of any powerful agent. NSAIDs are appropriate when a corneal abrasion develops in a healthy person because the patient has the capacity to heal the cornea in a timely fashion. Conversely, NSAIDs would not be appropriate for the treatment of a sterile melt in the center of the cornea in a patient with rheumatoid arthritis.

Chang: Corneal melts, although dramatic, are rare. The more common scenario is a patient who, after taking an NSAID for several weeks, returns with significant punctuate keratitis. Frequently, the topical NSAID is causing the problem. With twice-daily dosing of bromfenac it will be interesting to see if reducing the frequency of instillation by half will make this occurrence less common.

Schechter: Because many of our cataract patients are older and have advanced dry eye, their ocular surface is compromised at the time of cataract surgery. I have seen several patients who are sensitive to the 5% povidone-iodine that we place in the cul-de-sac and, without the concomitant use of an NSAID, these patients often return with an irritated conjunctiva, sometimes with conjunctival abrasions. Addressing compromised ocular surfaces at the outset with topical cyclosporine or punctal occlusion as necessary would avoid some of these issues.

References

  • Schechter BA, Wittpenn J. Evaluation of ketorolac 0.4% (ACULAR LS) during the induction phase of cyclosporin therapy to improve patient comfort. Presented at the annual meeting of ARVO; May 1-5, 2005; Fort Lauderdale, Fla.
  • Gerometta R, Podos SM, Candia OA, et al. Steroid-induced ocular hypertension in normal cattle. Arch Ophthalmol. 2004;122:1492-1497.
  • Kim T. Corneal melting linked to use of topical NSAIDS. OSN. 2005(suppl);10-12.