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Uveitis is a condition in which part of the uveal tract, which includes the iris, ciliary body, and choroid, becomes inflamed. Jabs et al,1 with the Standardization of Uveitis Nomenclature Working Group, helped eye care professionals to work toward accurate terminology for the types of uveitis. Specifically, the location where the inflammation occurs determines the diagnosis as anterior uveitis, posterior uveitis, or intermediate uveitis.
Anterior uveitis is reportedly the most prevalent form of uveitis, and much of it is said to be idiopathic.2-4 The severity of anterior uveitis is graded proportionate to the degree of cells and flare observed in the anterior chamber. Depending on the structures involved, it may be subcategorized as iritis, iridocyclitis, or anterior cyclitis. Anterior uveitis is characterized by acute pain, redness, tearing, and sensitivity to light.5
Treatment and management of anterior uveitis centers on reducing pain and inflammation. Pain is managed by paralyzing the ciliary muscle with cyclopegic agents, and inflammation is typically managed with topical corticosteroids. The prolonged administration of topical steroids can produce certain adverse events, most notably elevated intraocular pressure (IOP) and cataract development. However, these adverse events are correlated to dosage and thus can be predicted.
The proper dosage for a drug is determined by how fast a patient’s body can metabolize or eliminate the drug molecules. The therapeutic index of a drug is the ratio of toxic concentration to effective concentration; the wider the therapeutic index of a given medication, the safer it is when properly prescribed.
This article summarizes adverse events reported in the literature associated with the use of difluprednate ophthalmic emulsion 0.05% (Durezol; Alcon) in the clinical management of anterior uveitis. It illustrates how overdosing of this drug can result in acute toxic events and how the use of correct dosing strategies can avoid these events.
A high dosage of steroids is the preferred method of treatment for uveitis during its acute phase, with emphasis that the drug be tapered off in a gradual and sustained manner.6 The longer a steroid is used, the greater the chance for occurrence of adverse events.7,8
Prolonged administration of topical steroids for the treatment of uveitis is associated with adverse effects such as increased IOP. This association has been documented extensively in the literature in patients with uveitis. Herbert et al found a positive correlation between administration of steroid for treatment of uveitis and elevations in IOP.9 Sijssens et al, in a case series including 42 pediatric patients with uveitis, reported that prolonged use of steroids had the effect of raising IOP.10 Takahashi et al estimated the proportion of steroid-induced glaucoma in patients with uveitis to be 8.9%.11
There is thus general agreement that steroid use can entail adverse effects, including but not limited to IOP spikes that can lead to glaucoma, steroid-induced cataract (specifically posterior subcapsular cataract), delayed wound healing, and suppressed immune response leading to opportunistic infections or exacerbation or prolongation of existing infections. Because of this last effect, steroids are often used in combination with an antibiotic.
Difluprednate ophthalmic emulsion, 0.05%, approved by the US Food and Drug Administration (FDA) in 2008, is a topical antiinflammatory corticosteroid, initially indicated for the treatment of inflammation and pain after ocular surgery (Figure 1).12 Its indications were extended in 2012 to include the treatment of endogenous anterior uveitis.12
Difluprednate was the first strong ophthalmic steroid approved by the FDA since 1973 with high potency, a favorable safety profile, and the ability to mitigate postoperative pain, according to Jamal and Callanan.13 Writing in 2009, those authors called difluprednate “a welcome addition to the ophthalmologist’s armamentarium” and noted that untreated inflammation can lead to complications such as corneal edema, cystoid macular edema, glaucoma, and subsequent visual field loss.13
The new drug was indeed welcome for several reasons. First, the approved formulation contains no benzalkonium chloride preservative, using instead sorbic acid, a better preservative for sensitive eyes.13 Second, it is formulated as an emulsion, and emulsions allow drugs with traditionally low solubility to dissolve in the oil phase, increasing bioavailability.14 Third, the emulsion eliminates the need to shake the bottle, allowing administration of a consistent dosage of drug in each drop.15
The efficacy and safety of difluprednate ophthalmic emulsion to suppress signs of inflammation in patients after cataract surgery was evaluated by Korenfeld et al in a phase 3 clinical trial.16 These investigators found that 0.05% difluprednate emulsion, given twice or four times a day, was effective against ocular inflammatory responses and reduced pain rapidly and effectively (Figure 1). No serious ocular adverse events were noted (Table). Compared with those receiving placebo, the difluprednate-treated groups had reduced signs of inflammation. IOP elevation (Figure 2) was similar to that seen with betamethasone sodium phosphate 0.1% treatment for mild inflammation, and better than with betamethasone for severe inflammation.
CAUTION FOR A STRONG MEDICINE
Korenfeld et al cautioned against applying difluprednate in the same manner of dosing as other less potent ophthalmic steroids: that is, treating difluprednate as on par with other steroids and prescribing a similar dosage without realizing that difluprednate is far more potent.16 They noted that, dosed too aggressively, difluprednate could delay the process of healing because of its tendency to inhibit edema, leukocyte migration, fibrin deposition, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation.
In light of this caution expressed by the authors of the multicenter phase 3 trial of difluprednate, it may not be surprising that the drug is known by those involved in the field to be associated with acute events arising from overdosage. It appears that eye care professionals keep prescribing this drug in an excessive manner. This may be due to earlier schooling and literature, based on earlier steroid formulations, advising to treat uveitis aggressively until two grades of improvement is noted. Practitioners may think of difluprednate as analogous to prednisolone acetate 1% (Pred Forte; Allergan, and other generics), when its potency is actually closer to that of betamethasone (multiple manufacturers).
The increased potency of difluprednate is due to the dual fluorination of the molecule, which improves tissue penetration. Halogenation (in this case fluorination at the C-6 and C-9 positions) of topical corticosteroids has been associated with both higher potency and greater potential for adverse reactions. The degree of impact on potency correlates directly with the structural position of the halogenation and the type of halogen atom used. Maximum augmentation of potency occurs through replacement of hydrogen at C-9 with fluorine, and lesser potentiation with fluorination at C-6.
ADVERSE EVENTS IN THE LITERATURE
Administering difluprednate in excess of four times per day (or every 6 hours) and/or giving it for more than 14 days consecutively before tapering down predisposes patients to acute toxic adverse effects. These effects were taken into account in the labeling of difluprednate when the FDA first approved the drug for ophthalmic use. In the evidence-based studies reported below, the above guidelines were exceeded.
Slabaugh et al evaluated the efficacy of difluprednate in a retrospective case study of 14 patients younger than 18 years who were affected by noninfectious uveitis and needed to be observed or followed for 6 months or more.17 Patients were assessed for adverse effects including IOP elevation and development of cataract. Diagnoses included anterior uveitis and idiopathic chronic anterior and intermediate uveitis associated with juvenile idiopathic arthritis. The patients were treated for a mean 27 (range 4-63) weeks with administration of difluprednate four times daily. The final follow-up included 26 eyes. Acute events in the form of significant IOP elevations were observed in approximately 50% of patients. These IOP elevations were 10 mm Hg or greater from baseline measurements and 24 mm Hg or greater absolute. There was a statistically significant difference in cumulative drop load between those who developed clinically significant increase in IOP and those who did not. This retrospective study emphasizes that when difluprednate is prescribed for prolonged periods it is associated with acute adverse events and stresses the need for eye care professionals to avoid such use.
Kurz et al documented the case of a 9-year-old boy with pars planitis treated with difluprednate for 1 year.18 The steroid was initially dosed twice daily for 3 weeks, stopped for 6 weeks, then restarted at every 2 hours for 3 weeks and tapered to four times daily and subsequently two times daily over the course of 2 months. This dosage was then continued for 8 months. The condition was complicated by the advent of IOP increase to 38 mm Hg after about 6 months of treatment. Additional complications noted included the development of cataract within 3 weeks of the commence of treatment. It is significant to note that the child’s IOP returned to normal within 10 days after discontinuation of difluprednate, suggesting the role of the medication as the cause of this acute event.
Birnbaum et al conducted a longitudinal study of 27 patients (46 eyes) treated with difluprednate between November 2008 and October 2010.19 Before being switched to difluprednate, 17 of these patients were given branded prednisolone acetate 1%, eight used generic prednisolone acetate 1%, and two were not using any topical steroid. All of those who were treated with branded or generic prednisolone were switched to difluprednate due to exhibiting persistent anterior chamber inflammation in at least one eye. The authors noted an increase of 15 mm Hg or more in 11 patients, four of whom were children. Initial IOP increase was noted at a mean 4.9 weeks, with peak elevation at 9.6 weeks. Duration of treatment ranged from 1 to 46 weeks, well beyond the FDA label dosage guidelines. All patients experienced a decrease in IOP after discontinuation of difluprednate.
These results show that over-dosage of difluprednate can lead to significant increases in IOP, perhaps especially in children. More important, the increase in IOP was observed even in patients who were not previously considered to be responders to other steroids such as prednisolone acetate. The fact that the increase in IOP was rapid (mean 4.9 weeks) makes it clear that this overdosage has acute implications and stresses the importance of consistent monitoring of IOP.
All the studies mentioned share one common factor that has clinical implications. In all of the studies, no doubts were expressed about the efficacy of difluprednate drops, especially in regard to its role in combating intraocular inflammation. However, treatment was maintained for extended periods of time, well beyond the recommended 2-week period, and significant rises in IOP resulted. This underscores the importance of not exceeding the recommended dosage of difluprednate.
Meehan et al described the case of a 49-year-old black man with traumatic anterior uveitis that was not responding to treatment with prednisolone acetate 1% treatment.20 Difluprednate 0.05% was substituted for the other steroid in an effort to better control the inflammation. The medication was administered every 2 hours for the first 3 days (ie, three times the recommended dosage frequency) and tapered down to four times daily for 2 weeks. At 2-week follow-up, IOP had increased from 9 mm Hg to 48 mm Hg. The patient was given timolol maleate 0.5%, dorzolamide 2%, and bimatoprost 0.03% in the office, which brought the IOP down to 7 mm Hg. Difluprednate was discontinued and was substituted with alternative prescriptions. Two weeks later, all symptoms had subsided. From this case report, it is logical to conclude that the cause of IOP elevation was the overdosage of difluprednate, in this case in the frequency of dosing rather than duration.
MORE LIKE IT
Smith et al conducted a randomized trial to assess the efficacy and safety of difluprednate emulsion 0.05% for the management of inflammation and pain after cataract extraction.21 The medication was initiated 24 hours before surgery; patients (N = 121) were randomly assigned (2:1) to drug or placebo, one drop twice daily for 16 days, with a tapering period of 14 days. Clinical signs of inflammation within the anterior chamber, ocular pain or discomfort, IOP, and adverse events were assessed. A significant proportion of patients treated with difluprednate were relieved of ocular pain and discomfort, compared with those taking placebo. The study authors also found a low incidence (< 0.03%) of an adverse event defined as IOP of 21 mm Hg or IOP increase of 10 mm Hg or more from baseline. This incidence of IOP elevation was similar to that for prednisolone acetate. None of the patients receiving placebo experienced elevated IOP.
In contrast with the other studies and case reports cited, this study thus shows that when difluprednate is administered in accordance to recommended guidelines it is not only effective but also has a safety profile similar to those of more established topical steroid options.
This literature review serves to remind us of the maxim “Do no harm,” which is universal to the medical profession. Topical steroids in general have a tendency to lead to adverse events such as increases in IOP. Difluprednate is a highly potent steroidal antiinflammatory drug indicated for treatment of anterior uveitis. Overdosage of this medication should be discouraged, as it is likely to increase the risk of an acute adverse event.
Clinicians must operate within the recommended guidelines for therapeutic use of drugs, especially when they are prescribing a very potent steroidal antiinflammatory such as difluprednate to individuals with anterior uveitis. Close, continual monitoring of patients for inflammatory response and IOP spikes during treatment is required of the practitioner. As the studies cited above show, overdosage of difluprednate is happening, and acute adverse events are produced as a direct result. When adverse events involving difluprednate are reported, one should pay close attention to how often and how frequently it was dosed, and thus whether it was overdosed. n
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2. Chang JH, McCluskey PJ, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol. 2005;50(4):364-388.
3. Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. Ophthalmology. 2004;111(3):491-500.
4. McCannel CA, Holland GN, Helm CJ, et al. Causes of uveitis in the general practice of ophthalmology. UCLA Community-Based Uveitis Study Group. Am J Ophthalmol. 1996;121(1):35-46.
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11. Takahashi T, Ohtani S, Miyata K, et al. A clinical evaluation of uveitis-associated secondary glaucoma. Jpn J Ophthalmol. 2002:46(5):556-562.
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14. Del Rosso JQ. Topical corticosteroids: examining pharmacologic properties. The Dermatologist. 2006;14(2):86.
15. Karpecki P. New anti-infective and anti-inflammatory medications and trends. Contact Lens Spectrum. 2009;24(12):20-22.
16. Korenfeld MS, Silverstein SM, Cooke DL, et al; the Difluprednate Ophthalmic Emulsion 0.05% (Durezol) Study Group. Difluprednate ophthalmic emulsion 0.05% for postoperative inflammation and pain. J Cataract Refract Surg. 2009;35(1):26-34.
17. Slabaugh MA, Herlihy E, Ongchin S, van Gelder RN. Efficacy and potential complications of difluprednate use for pediatric uveitis. Am J Ophthalmol. 2012;153(5):932-938.
18. Kurz PA, Chheda LV, Kurz DE. Effects of twice-daily topical difluprednate 0.05% emulsion in a child with pars planitis. Ocul Immunol Inflamm. 2011;19(1):84-85.
19. Birnbaum AD, Jiang Y, Tessler HH, Goldstein DA. (January 01, 2011). Elevation of intraocular pressure in patients with uveitis treated with topical difluprednate. Arch Ophthalmol. 2011;129(5):667-668.
20. Meehan K, Vollmer L, Sowka J. Intraocular pressure elevation from topical difluprednate use. Optometry. 2010;81(12):658-662.
21. Smith S, Lorenz D, Peace J, et al. Difluprednate ophthalmic emulsion 0.05% (Durezol) administered two times daily for managing ocular inflammation and pain following cataract surgery. Clin Ophthalmol. 2010;4:983-991.
David Gutowski, OD
• in the process of joining a private practice in New Mexico
• Financial disclosure: none acknowledged
Agustin L. Gonzalez, OD
• Optometric glaucoma specialist and therapeutic optometrist in practice at Eye & Vision in Richardson, Texas
• Financial disclosure: consultant to Allergan, Shire, and Valeant