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The Official Scientific Journal of Delhi Ophthalmological Society
Difluprednate: An Overview
Charu Mithal, Shilpa Singh, Sonali Gupta, Sandeep Mithal
Department of Ophthalmology, L.L.R.M. Medical College, Meerut, Uttar Pradesh, India
Corresponding Author:
Dr. Sonali Gupta
E-Mail : sonali1286@yahoo.com
Published Online: 25-SEP-2013
DOI: http://dx.doi.org/10.7869/djo.2012.63
Abstract
The mainstay in the treatment of ocular inflammation, either post-surgical or endogenous, is the use of steroids. While these agents effectively address inflammation, they are not without their risks, including ocular hypertension and acceleration of cataract formation. The most notorious culprits are the strong steroids, such as prednisolone acetate and betamethasone. This review aims to cover the biochemistry and drug development of difluprednate, a novel synthetic strong steroid emulsion. In vivo pharmacokinetics as well as ocular distribution and metabolism are discussed, followed by a comprehensive summary of phase I, II, and III clinical trials evaluating safety and efficacy in patients suffering from postoperative inflammation, posterior segment inflammation or anterior uveitis.
Controlling and preventing inflammation is the most important concern of the ophthalmologist in achieving optimal results following surgery. Surgical manipulation of anterior segment structures triggers the release of arachidonic acid from cell membranes, leading to the production of prostaglandins and leukotrienes. These inflammatory mediators, in turn, lead to cellular reaction and protein leakage. Although often self limited, untreated inflammation can lead to complications such as pain, discomfort, photophobia, corneal edema, synechiae, glaucoma, and cystoid macular edema.[1,2] Even though some ocular surgeries, such as phacoemulsification, do not generally result in significant inflammation, there are still, a portion of patients that will experience some form of postoperative inflammation, which can potentially lead to sight-threatening issues such as cystoid macular edema.

As such, the majority of physicians employ a prophylactic regimen of anti-inflammatory medications in the perioperative period. Because of their broad anti-inflammatory activity, corticosteroids are typically the cornerstone of these treatment regimens. These agents are continued until the anterior chamber (AC) reaction has resolved and the blood–aqueous barrier has been reestablished.[3] Currently, the most widely prescribed strong topical corticosteroid is prednisolone acetate 1%. While it controls inflammation effectively, it has not been shown to consistently address postoperative pain and discomfort in a large clinical trial.[4] In June 2008 difluprednate ophthalmic emulsion 0.05% was approved by the US Food and Drug Administration (FDA) for the treatment of inflammation and pain associated with ocular surgery the first strong ophthalmic steroid approved by the FDA since 1973. Difluprednate is the first ophthalmic steroid developed in the past 35 years with high potency, a favorable safety profile, and the ability to reduce postoperative pain.

Indications and Usage

Difluprednate ophthalmic emulsion 0.05%, a topical corticosteroid, is indicated for the treatment of inflammation and pain associated with ocular surgery (only FDA approved indication).

Dosage and Administration

It is prescribed in a twice daily (BID) or 4 times daily (QID) dosage depending upon the severity of inflammation.

Dosage Strengths

Difluprednate 0.05% as a sterile preserved emulsion for topical ophthalmic administration.

Pharmacology and Drug Development

Difluprednate (difluoroprednisolone butyrate acetate, or DFBA) is a synthetic difluorinated prednisolone derivative. Originally developed for dermatologic applications, the molecule derives its potency from fluorination at the C6 and C9 positions.[5] Its anti-inflammatory activity is further augmented by replacing the 17-hydroxyl group with butyrate, while its lipophilicity and hence corneal penetration  is enhanced by substituting the 21-hydroxyl group with acetate6 (Figure 1).

Pharmacokinetics

Once instilled, difluprednate emulsion is rapidly deacetylated in the aqueous humor to difluoroprednisolone butyrate (DFB), the drug’s active metabolite, which has a similar corticosteroid activity profile.[7] Endogenous tissue esterases then metabolize DFB to the inert metabolite hydroxyfluoroprednisolone butyrate (HFB), which limits systemic exposure to the active compound.[8]



Drug Dose Uniformity

The drug is formulated as an emulsion to avoid the potential problems associated with a suspension like flocculation, caking, and poor redispersibility, all of which can lead to dosing errors during administration. Difluprednate ophthalmic emulsion demonstrates excellent and consistent dose uniformity compared with the suspensions, suggesting that the clinical use of difluprednate may produce more predictable efficacy and safety.

Large Randomized Clinical and Comparative Trials

Post Operative Inflammation

A phase 3 multicenter randomized double-masked parallel group comparative noninferiority trial conducted in Japan assessed the safety and efficacy of 0.05% difluprednate to 0.1% betamethasone for the treatment of postoperative inflammation following cataract or vitreous surgery.[9] At the completion of the study period, postoperative inflammation was similarly reduced in both groups, verifying the study’s noninferiority hypothesis (P < 0.01). Analysis of secondary endpoints revealed no differences between difluprednate and betamethasone in either AC flare or total sign score, except for day 7 when the difluprednate arm showed a statistically significant improvement in total sign score, including hyperemia, chemosis, and keratic precipitates.

The difluprednate group also showed a statistically significant improvement compared to the betamethasone group in subjective symptoms, including pain, photophobia, foreign body sensation, and blurred vision at all time points after the initiation of therapy. A few patients in each group experienced elevated intraocular pressure (IOP), all of which resolved spontaneously or with the addition of a topical agent. This study verified that difluprednate was at least as effective as betamethasone in treating postoperative inflammation, and that it had a favourable safety profile. As early as day 3, there was a mean decrease in grade of AC cell, with an 87% reduction in AC cell count in the difluprednate groups versus only a 30% reduction in the placebo groups. Difluprednate also reduced pain as early as day 3, with 38.2% of the bid patients (P = 0.012) and 45.3% of the four times daily patients (P < 0.0001) claiming to be pain and discomfort free, versus 24.8% of patients in the placebo group. On day 3, patients randomized to difluprednate had a substantial reduction in photophobia from baseline (p = 0.0041 in the BID group, p < 0.0001 in the QID group), while scores for placebo-treated patients worsened. This multicenter randomized trial once again demonstated the safety and efficacy of difluprednate emulsion. More important, however, was the finding that the signs and symptoms seen following ocular surgery were effectively treated with twice-daily dosing. Less frequent dosing may engender better patient compliance and reduce total steroid exposure.

Anterior Uveitis

In a phase 3 noninferiority study conducted in Japan, difluprednate 0.05% was compared to betamethasone 0.1% in patients with endogenous anterior uveitis.[10] At day 14, improvement in AC cell scores were comparable between both treatments, corroborating the study’s noninferiority hypothesis. However, difluprednate produced a substantially more rapid improvement, by day 7 more patients in the difluprednate group had AC cell scores of 1 or lower (P = 0.0298). Similar findings were noted when examining secondary efficacy measures such as AC flare score (P < 0.05) and total sign score (P = 0.035).

The incidence of elevated IOP was equal between the two groups, and resolved with or without medical treatment. None of the patients in the difluprednate arm withdrew from the study due to symptom aggravation, compared to 3 patients in the betamethasone group. The safety and efficiacy of difluprednate ophthalmic emulsion 0.05% was further evaluated in an open-label phase 3 trial of 19 patients with severe refractory endogenous anterior uveitis (<50 cells per high-powered field in the anterior chamber).[11] These patients had not responded to previous treatment with betamethasone 0.1%, even when given at a frequency greater than the recommended qid dosing specified on its label; most had been dosed between 8 and 12 times per day. Difluprednate 0.05% dosed qid demonstrated a statistically significant improvement in mean AC cell score from baseline [4.0 ± 0.0 (mean ± standard deviation)] to day 14 (1.3 ± 0.8) (P < 0.0001) in the 18 patients who completed the study. Significant improvements from baseline were also observed on day 3 (P < 0.0001) and day 7 (P < 0.0001). In 13 of the 18 patients (72.2%), the AC cell score had improved to 1 or less by day 14, with 2 patients reaching 0. Significant improvement from baseline in AC flare, total sign and total symptom scores were noted at days 3, 7, and 14 (P < 0.0002 at all measures).In all patients, difluprednate was well tolerated, with only 2 participants experiencing IOP elevation, both controlled with topical beta blocker. Most recently, a multicenter randomized double-masked trial compared the efficacy and safety of difluprednate 0.05% dosed qid to prednisolone acetate 1% dosed 8 times daily.[12] At day 14, the mean cell grade reduction was 2.1 in the difluprednate arm, compared to 1.9 in the prednisolone acetate group, confirming the noninferiority of difluprednate qid to prednisolone 8 times daily. A prospective multicenter, double-masked, randomized, contralateral-eye trial was conducted in 63 patients (126 eyes). We found that the administration of difluprednate in a pulse-dosing fashion provided better vision and less corneal edema (measured via pachymetry) on day 1 when compared with prednisolone. Also in the difluprednate arm, there was significantly less endothelial cell loss at day 30, with a difference of 180 cells between the two groups. This was interesting, since it shows that a pulse dosing regimen may help to preserve endothelial cells, and that a more potent steroid may have an added effect. In addition, OCT measurements revealed thinner retinas at days 15 and 30 in the difluprednate group. By day 15, the mean retinal thickness in the eyes treated with difluprednate was 7.74 µm less than the prednisolone treated eyes (P = 0.011).





Difluprednate : Efficacy in Posterior Segment

In a recently published preclinical study by Tajika et al, a single instillation of radiolabeled difluprednate resulted in detectable posterior segment levels (anterior retina/choroid = 273 ngeq/g; posterior retina/choroid = 59 ngeq/g), suggesting that topical administration may have possible effectiveness in the posterior segment.[13] The study also demonstrated that the glucocorticoid binding affinity for the active metabolite of difluprednate was 56 times stronger than prednisolone. The greater binding affinity may be attributed to the unique molecular structure of difluprednate. While no large studies have specifically explored the use of difluprednate in retinal disease, two small case control studies published by Nakano et al demonstrated potential utility. In the first, difluprednate was compared with a sub-tenons injection of triamciniolone and was found to have similar effects at reducing retinal thickness in patients with refractory diabetic macular edema (DME).[14] In the second, difluprednate was compared with betamethasone in treating diffuse DME prior to vitrectomy, and difluprednate was found to reduce retinal thickness and improve visual acuity (VA) more effectively than betamethasone after 1 month of treatment.[15] While these studies must be interpreted cautiously, due to their size and design, they provide interesting hypotheses. Nonetheless, given difluprednate’s high potency and strong affinity for the glucocorticoid receptor, there may be a place for this topical steroid in treating posterior segment disease with an inflammatory component.

Safety & Tolerability

Extensive clinical testing has demonstrated that difluprednate 0.05% emulsion causes an elevation in IOP in a small minority of patients. This increase resolved in all patients after stopping the medication or with topical pressure-lowering drops. Compared with betamethasone dosed at equal frequency, the incidence of IOP elevation was essentially equal between the two groups[9,10,16] indicating an acceptable safety level. Difluprednate ophthalmic emulsion does not contain benzalkonium chloride (BAK), and instead uses sorbic acid as a preservative. Sorbic acid causes little damage and irritation to the ocular surface and is recommended for use in sensitive eyes.[17]

Use In Specific Populations

Pregnancy

Pregnancy Category C: Difluprednate has been shown to be embryotoxic (decrease in embryonic body weight and a delay in embryonic ossification) and teratogenic (cleft palate and skeletal) anomalies when administered subcutaneously to rabbits and rats during organogenesis.

It is difficult to extrapolate these doses of difluprednate to maximum daily human doses of difluprednate, since it is administered topically with minimal systemic absorption, and difluprednate blood levels were not measured in the reproductive animal studies. However, since use of difluprednate during human pregnancy has not been evaluated and cannot rule out the possibility of harm, difluprednate should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

Nursing Mothers

It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when difluprednate is administered to a nursing woman.

Pediatric use

Safety and effectiveness in pediatric patients has not been established.

Geriatric use

No overall differences in safety or effectiveness have been observed between elderly and younger patients

Contraindications

The use of difluprednate, as with other ophthalmic corticosteroids, is contraindicated in most active viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal disease of ocular structures.

References
  1. Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv Ophthalmol 1992; 37:73–116.
  2. Miyake K, Maekubo K, Miyake Y, et al. Pupillary fibrin membrane; a frequent early complication after posterior chamber lens implantation in Japan. Ophthalmol 1989; 96:1228–33.
  3. Sanders DR, Kraff M. Steroidal and nonsteroidal anti-inflammatory agents. Effect on postsurgical inflammation and blood–aqueous humor barrier breakdown. Arch Ophthalmol 1984; 102(10):1453–6.
  4. Korenfeld M. Difluprednate: changing the landscape of ocular pharmacology. Expert Rev Ophthamol 2008; 3(6):619–25.
  5. Bikowski J. The position not the presence of the halogen in corticosteroids influences potency and side effects. J Drugs Dermatol 2006; 5(2):125–30.
  6. Yamaguchi M, Yasueda S, Isowaki A, et al. Formulation of an ophthalmic lipid emulsion containing an anti-inflammatory steroidal drug, difluprednate. Int J Pharmaceutics 2005; 301:121–8.
  7. Fujino A, Ohtu S, Shibata K, et al. Studies on the metabolic fate of difluprednate (DFBA): Metabolism in rats and rabbits after subcutaneous administration. Pharmacometrics 1985; 29:713–23.
  8. Tajika T, Shirasaki Y, Kimura M, et al. Ocular distribution and metabolism after instillation of difluprednate ophthalmic emulsion in rabbits. The 2007 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO). Poster B744, Program 2654. Fort Lauderdale, FL, USA, 6–10 May 2007.
  9. Ohji M, Tano Y, Hida T, et al. Efficacy and safety results of a phase III study of difluprednate ophthalmic emulsion 0.05% in postoperative inflammation. The 2007 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO). Poster B807, Program 3903. Fort Lauderdale, FL, USA, 6–10 May 2007.
  10. Ohno S, Mochizuki M, Usui M, et al. A phase III noninferiority study of difluprednate ophthalmic emulsion 0.05% in the treatment of anterior uveitis. The 2007 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO). Poster B808, Program 3904. Fort Lauderdale, FL, USA, 6–10 May 2007.
  11. Mochizuki M, Ohno S, Usui M, et al. A phase III open-label clinical study of difluprednate ophthalmic emulsion 0.05% in the treatment of severe refractory anterior uveitis. The 2007 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO). Poster B809, Program 3905. Fort Lauderdale, FL, USA, 6–10 May 2007.
  12. Sirion Therapeutics, Inc., Tampa, FL. A phase III multicenter, randomized, double-masked study of the safety and efficacy of difluprednate 0.05% ophthalmic emulsion compared to prednisolone acetate 1% ophthalmic suspension in the treatment of endogenous anterior uveitis. Dec 2008. Data on file.
  13. Tajika T, Isowaki A, Sakaki H. Ocular distribution of difluprednate ophthalmic emulsion 0.05% in rabbits. J Ocul Pharmacol Ther. 2011; 27(1):43–9.
  14. Nakano S, Yamamoto T, Kirii E, Abe S, Yamashita H. Steroid eye drop treatment (difluprednate ophthalmic emulsion) is effective in reducing refractory diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 2010; 248(6):805–10.
  15. Nakano Goto S, Yamamoto T, Kirii E, Abe S, Yamashita H. Treatment of diffuse diabetic macular oedema using steroid eye drops. Acta Ophthalmol. 2012; 90(7):628-32.
  16. Senju Pharmaceutical Co., Ltd., Osaka, Japan. Phase IIb clinical study of difluprednate 0.05% vs betamethasone 0.1% in the treatment of postoperative inflammation. Apr 2004. Data on file.
  17. Abelson MB, Washburn S. The downside of tear preservatives. Rev Ophthalmol 2002; 9:102–6.
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Mithal C, Singh S, Gupta S, Mithal SDifluprednate: An Overview.DJO 2013;23:165-168
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Mithal C, Singh S, Gupta S, Mithal SDifluprednate: An Overview.DJO [serial online] 2013[cited 2017 Oct 23];23:165-168. Available from: http://www.djo.org.in/articles/23/3/difluprednate-an-overview.html
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