DRUG EVALUATION

Drugs & Aging 2 (6): 473-486, 1992 I 170-229X/92/001 1-0473/$07.00/0 © Adis International Limited. All rights reserved. DRAl143

Ocular Diclofenac

A Review of its Pharmacology and Clinical Use in Cataract Surgery, and Potential in Other Inflammatory Ocular Conditions Karen L. Goa and Paul Chrisp Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by: M. Araie, Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan; W. Behrens-Baumann, Augenklinik und Poliklinik, Georg-August-Universitat G6ttingen, G6ttingen, Federal Republic of Germany; P. Bhattacherjee, Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky, USA; L. Bonomi, Istituto di Clinica Oculistica, Universita degli Studi di Verona, Verona, Italy; H. Ertiirk, Department of Ophthalmology, Uludag University Faculty of Medicine, Bursa, Turkey; F.T. Fraunfelder, Casey Eye Institute, Oregon Health Sciences University School of Medicine, Portland, Oregon, USA; K. Nishi, Nishi Eye Hospital, Osaka, Japan; O. Nishi, Nishi Eye Hospital, Osaka, Japan; c.l. Phillips, Ophthalmology Unit, University of Edinburgh Department of Surgery, Edinburgh, Scotland; C.D. Quentin, Augenklinik und Poliklinik, Georg-August-Universitat G6ttingen, G6ttingen, Federal Republic of Germany; M.D. Trousdale, Doheny Eye Institute, Los Angeles, California, USA.

Contents 474 475 475 476 476 476 477 478 478 478 479 479 480 480 480

482 484 484 484

Summary I. Pharmacodynamic Properties 1.1 Role of Arachidonic Acid Metabolites in Ocular Inflammation 1.2 Effects of Dic10fenac on Arachidonic Acid Metabolism 1.3 Effects on In Vivo Models of Ocular Inflammation 1.4 Inhibition of Blood-Aqueous Barrier Breakdown in Patients with Cataracts 1.5 Effects on Leucocyte Accuinulation 1.6 Other Effects 2. Pharmacokinetic Properties 2.1 Absorption and Distribution 2.2 Metabolism and Excretion 3. Clinical Use in Cataract Surgery 3.1 Inhibition of Surgically Induced Miosis During and After Cataract Extraction 3.2 Pre- and Postoperative Prophylaxis of Cystoid Macular Oedema 3.3 Effects on Postoperative Inflammation and Intraocular Pressure 4. Potential Use in Other Ocular Conditions 5. Tolerability 6. Dosage and Administration 7. Place of Ocular Dic10fenac in Therapy

Drugs & Aging 2 (6) 1992

474

Summary Synopsis Diclofenac sodium is a potent nonsteroidal anti-inflammatory drug with analgesic activity. When instilled as a topical 0.1% solution in a limited number of patients undergoing cataract surgery, diclofenac limits surgically induced miosis, reduces signs of ocular inflammation, does not cause elevations in intraocular pressure, and reduces the occurrence and severity of cystoid macular oedema. Preliminary findings suggest a niche for topical diclofenac in other ocular inflammatory conditions such as iritis, episcleritis and conjunctivitis, although its efficacy in these areas awaits confirmation. The drug appears well tolerated, apart from a transient burning sensation after instillation in some patients. Ocular diclofenac thus appears well suited as a local anti-inflammatory adjunct to cataract surgery, and may be useful in some other inflammatory ocular conditions.

Pharmacodynamic Properties Tissue injury causes breakdown of phospholipids to arachidonic acid which is converted either to prostaglandins by cyclo-oxygenase, or to hydroxy acids and leukotrienes by 5-lipoxygenase. Prostaglandins have been detected in rabbit eyes following trauma, and leukotrienes in ocular tissue of patients with inflammatory eye conditions. Diclofenac sodium (the salt of diclofenac referred to exclusively in this review) is a potent inhibitor of prostaglandin synthesis (i.e. it acts mainly through cyclo-oxygenase inhibition), as shown in various animal models, in vitro and when administered systemically in vivo. Although the in vitro effects of diclofenac on prostaglandin synthesis in eye tissue have not been documented, the drug attenuated the increases in intraocular pressure (lOP) and aqueous humour protein levels induced by various traumas when instilled in rabbit eyes in vivo, but had an equivocal effect on surgically induced miosis. Leucocyte accumulation in rabbit eyes induced by a synthetic chemotactic agent was reduced by ocular diclofenac 0.064%. Ocular diclofenac inhibits breakdown of the blood-aqueous barrier in elderly patients, and in patients undergoing cataract surgery, possibly more effectively than the commonly used topical prednisolone.

Pharmacokinetic Properties The pharmacokinetic profile of topically applied diclofenac is incomplete. Concentrations of diclofenac were highest in the cornea and conjunctiva of rabbit eye after instillation of eyedrops, and subsided within I hour. In patients with cataracts, diclofenac penetrates into aqueous humour, with mean peak concentrations of about 130 mgfL achieved within I hour of eyedrop instillation. Diclofenac is highly bound to plasma proteins (~ 99.5%). The drug is metabolised after oral administration principally to 4-hydroxy-diclofenac, and has a mean elimination half-life of I to 2 hours. Pharmacokinetics of diclofenac are largely unaffected by age, or renal or hepatic impairment.

Clinical Use and Tolerability Although relatively few trials have investigated the efficacy of ocular diclofenac as an adjunct to cataract surgery, most studies were well-designed. Diclofenac 0.1 % ophthalmic solution instilled 2 to 4 times daily after cataract surgery relieved signs of ocular inflammation to a similar extent as dexamethasone 0.1 % in an identical regimen, with less tendency to induce elevated lOP. lOP elevation was similar following treatment with diclofenac 0.1 % or indomethacin 1%. Diclofenac 0.1 % was at least as effective in relieving inflammation as prednisolone 1%. Preoperative instillation of diclofenac 0.1 % attenuated surgically induced miosis, a clinically important effect which facilitates successful surgery, and was superior to placebo, routine medications (cyclopentolate I %, phenylephrine 10%), and indomethacin 1%. Diclofenac 0.1% in a multiple dose pre- and postoperative regimen for 6 months decreased the incidence and severity of cystoid macular oedema to a significantly greater extent than placebo.

475

Ocular Diclofenac: A Review

Limited evidence suggests that ocular diclofenac ameliorates symptoms and signs of iritis/ iridocyclitis, and may have a potential role in some forms of episcleritis and conjunctivitis, and in reducing inflammation caused by laser trabeculoplasty. Ocular diclofenac appears well tolerated, although few published data are available. Slight transient burning in the eye has been experienced by some patients, and blurred vision, hypersensitivity reactions and keratitis punctata have been reported rarely.

Dosage and Administration The recommended regimen for preoperative use of diclofenac 0.1 % eyedrops in patients undergoing cataract surgery is I drop up to 5 times during the 3 hours before surgery. For postoperative use, I drop should be instilled 3 times during the day after surgery, then 1 drop 3 to 5 times daily. In other indications 1 drop 4 to 5 times daily is advocated.

Diclofenac (fig. 1) is a nonsteroidal anti-inflammatory drug (NSAID) and analgesic which inhibits prostaglandin synthesis (throughout this review, diclofenac refers only to the sodium salt of the drug). Recent interest has centred on the applicability of diclofenac eyedrops in inflammatory ocular conditions, with particular emphasis on its use following cataract surgery and intraocular lens implantation. This review is devoted exclusively to this area of research, rather than to the drug's well established systemic efficacy in rheumatic disease, discussed elsewhere (Todd & Sorkin 1988).

1. Pharmacodynamic Properties 1.1 Role of Arachidonic Acid Metabolites in Ocular Inflammation In the past 2 decades since the work of Eakins et al. (1972) and others, it has become apparent that prostaglandins play a significant role in the ocular response to injury. Damage to the iris and conjunctiva in animals promotes prostaglandin synthesis, leading to intraocular inflammation, elevated intraocular pressure (lOP) and miosis (Mishima et al. 1985). The following discussion is drawn from the recent review by Bhattacherjee (1989), to which readers are referred for additional details. Activation of phospholipase A2 following tissue injury breaks down cell membrane phospholipids to arachidonic acid. This is then converted either

to prostaglandins by cyclo-oxygenase, or to hydroxy acids and leukotrienes by 5-lipoxygenase, which is found in uveal tissue. Prostaglandins formed via cyclo-oxygenase activity in the aqueous humour are derived, for the most part, from the iris-ciliary body. According to experiments conducted in rabbits, prostaglandins are present in the eye following various types of injury when inflammatory reactions are maximal (BhattacheIjee 1975; Eakins et al. 1972; Yamuchi et al. 1979). The correlation between the prostaglandin level and the severity of inflammation has not been investigated. Leukotriene B4 and peptido-Ieukotrienes, products of the 5-lipoxygenase pathway, have been observed in the conjunctiva of patients with chronic conjunctivitis, and are present in the aqueous humour of patients with uveitis (Abelson 1984; Parker et al. 1986). Several ocular structures in animal models in vivo have been shown to synthesise these

Fig. 1. Chemical structure of didofenac sodium.

Drugs & Aging 2 (6) 1992

476

Table I. Effects of ocular diclofenac (D) on the integrity of the blood-aqueous barrier in patients after cataract surgery, as assessed in fluorophotometric studies

Reference

Study design

Mean age (years)

Araie et al. (1983)

NO

65 73 70

Kraff et al. (1990)

r, dm, pg, ic

74.5 70.5 71.2 70.0

No. of treated eyes

13 10 10

30

34 29 31

Dosage and duration

R R + 00.1% R + F 0.1% (3, 2, 1, 0.5h preop; postop qid x 6d) 00.01% 00.05% 00.1% Pr 1% (1 drop q6h/24h preop and qO.5h x 4.~h preop; postop q6h x

Fluorescein leakage8 % diff(oP-UNOP) week 1

week 3

49 t 62t 57t 280

21t 27t

0.039 0.017" 0.014"

39 93

21d)

a

(hr- 1)

K'in represents the apparent transfer coefficient of fluorescein from the plasma into the anterior chamber; % diff(OP-UNOP) = median percentage difference in fluorescein leakage into the eye in the operated vs the unoperated eye. Abbreviations and symbols: d = days; dm = double-masked; F = flurbiprofen; h = hours; ic = intraindividual control (operated vs unoperated eye); NO = no data given; pg = parallel groups; Pr = prednisolone; q112h = every half hour; q6h = every 6 hours; qid = 4 times daily; r = randomised; R = routine postoperative medications (antibiotics, betamethasone 0.1%, atropine 1%); "p < 0.005 vs control; t p < 0.05 vs prednisolone.

compounds. Injection ofleukotriene B4 into rabbit eye promotes a chemotactic response characterised by leucocyte accumulation (Bhattacherjee et al. 1989). Other compounds, such as eicosanoids and products of the cytochrome P450 pathway of arachidonic acid metabolism, may contribute to the' inflammatory response but this has yet to be convincingly demonstrated (see review by Bhattacherjee et al. 1989). 1.2 Effects of Diclofenac on Arachidonic Acid Metabolism Diclofenac has proven to be a potent in vitro inhibitor of cyclo-oxygenase in animal seminal vesicles (Ku et al. 1975, 1985), cerebral cortex

(Krupp et al. 1976), and polymorphonuclear cells and macrophages (Ku et al. 1985). Although the drug displays some activity in vitro and ex vivo against 5- and 15-lipoxygenase in rats (Ku et al. 1985, 1986), the contribution of this effect to the overall mechanism of anti-inflammatory action is not clear. Diclofenac 0.1 % ophthalmic solution reduced levels of prostaglandin E2 and prostaglandin F,,, in rabbits subjected to extracapsular eye surgery (unpublished data on file, Ciba Vision). Levels of prostaglandins were decreased in vivo by diclofenac in rabbit renal medulla (Oliw et al. 1978) and in the gastric mucosa of rats and pigs (Kobayashi et al. 1985; Rainsford & Willis 1982). Diclofenac thus reduces prostaglandin activity mainly, if not completely, by inhibition of cyclooxygenase.

477

Ocular Dic1ofenac: A Review

1.3 EtTects on In Vivo Models of Ocular Inflammation

prevented miosis when applied before paracentesis (Bonomi et a1. 1987a).

Surgery involving the anterior segment of the eye, such as cataract removal and lens implantation, is associated with protein influx into the aqueous humour due to breakdown of the bloodaqueous barrier (section 1.4), increases in lOP and miosis resistant to atropine. These detrimental changes are mediated in part by prostaglandins, although other vasoactive factors and neurogenic mechanisms may be involved. Application of diclofenac 0.0 I to 0.1 % solution to rabbit eyes significantly attenuated the increases in lOP induced by alkali (sodium hydroxide) or paracentesis, and the rise in aqueous humour protein and fluorescein levels provoked by paracentesis, sesame oil or arachidonic acid 5% (Agata et a1. 1983; Rowland et a1. 1986; van Haeringen et a1. 1982, 1983a,b). The anti-inflammatory etTect of 0.01% solutions of diclofenac, flurbiprofen and indomethacin persisted for 6 hours after instillation in rabbit eyes, as assessed by aqueous humour protein and fluorescein levels (van Haeringen et a1. 1982b); inflammation produced by the intravitreous injection of canine serum and application of tinctura capsici was also ameliorated (Agata et a1. 1983). The drug either had no etTect on miosis induced by paracentesis (Rowland et a1. 1986), or ~ 300 ~§

I

E" 200 -;~ g !Ii 250 CIl

~

u

8 150

I

'6 c: 100 CIl'(j)

g> ~ 50 ~o

I

I

I

I

I

I

I

fJ...,

, "

"

'

I/

"

"

"

".

£~ -2g+------.----,-------, o 2 3 Time (weeks)

Fig. 2. Percentage median differences in fluorescein concentration in operated vs unoperated eyes of 124 patients undergoing cataract surgery who received topical prednisolone 1% (e), or didofenac 0.01% (0), 0.05% (0), or 0.1% (f'» [after Kraff et al. 1990).

1.4 Inhibition of Blood-Aqueous Barrier Breakdown in Patients with Cataracts Breakdown of the blood-aqueous barrier is measurable by fluorophotometric study of fluorescein entry from blood to aqueous humour. Diclofenac 0.01 to 0.1% eyedrops reduced the leakage of orally administered fluorescein into the anterior chamber of the eye compared with controls (routine medication with topical antibiotics, steroids and atropine, or vs the untreated eye) in elderly patients who had undergone cataract surgery (table I). These etTects were similar to those of another topically applied NSAID, flurbiprofen 0.1 % (Araie et a1. 1983), but were superior to those of the topical corticosteroid prednisolone 1%, at both 1 and 3 weeks post-treatment (fig. 2) [KratT et a1. 1990]. Fewer diclofenac (50 to 69%) than prednisolone (93%) recipients showed> 40% increases in fluorescein leakage in the operated vs control eye (KratT et a1. 1990). 1.5 EtTects on Leucocyte Accumulation Topical application of diclofenac 0.064% to rabbit eyes reduced leucocyte accumulation induced by N-formyl-methionyl-leucyl-phenylalanine (NFor-Met-Leu-Phe) [Rowland et a1. 1986]. Diclofenac 25 to 100 mg/L was also shown to inhibit human polymorphonuclear leucocyte chemokinetic activity elicited in vitro by human serum and N-For-Met-Leu-Phe (Perianin et a1. 1985), and to prevent inflammation-induced leucocyte migration into implanted polyester sponges in rats when administered orally at doses of 2 to 10 mg/kg (Ku et a1. 1985). These findings are in accord with the observations of Srinivasan and Kulkarni (1981) who reported that other topically applied NSAIDs (flurbiprofen 0.01 %, indomethacin 0.5% and aspirin 0.5%) inhibited the appearance of poly morpho-

478

nuclear leucocytes in tear fluid of rabbits subjected to corneal de-epithialisation.

Drugs & Aging 2 (6) 1992

capillaries) therefore appears to be negligible. Data in this section are derived from the review of Todd and Sorkin (1988) unless otherwise indicated.

1.6 Other Effects 2.1 Absorption and Distribution Diclofenac 0.1 % and flurbiprofen 0.03% eyedrops did not exacerbate acute herpes keratitis in rabbits, whereas application of prednisolone 1% prolonged the period of viral shedding (Trousdale et al. 1989). Wound healing of corneal epithelium in rabbits was delayed by diclofenac 0.1 %, prednisolone I % and flurbiprofen 0.03% compared with placebo, but there was no difference among the 4 treatment groups in indices of toxicity to the cornea. Iritis was significantly decreased in the diclofenac compared with the placebo and prednisolone groups on days I and 2 (Hersh et al. 1990). These data do not support the suggestion that topical NSAIDs may be less likely than corticosteroids to delay wound healing, although the authors conceded that tOO- study may not have been ideally structured to detect such a difference. Diclofenac in concentrations of 0.5 to 30 mgfL suppressed the in vitro proliferation and fibrous metaplasia of human lens epithelial cells (Nishi & Nishi 1991), prompting the investigators to postulate that this effect may represent an additional mechanism of action for diclofenac in preventing inflammation after cataract surgery.

2. Pharmacokinetic Properties Relatively little information is available to date on the pharmacokinetic profile of ocular diclofenac. A brief overview is thus provided of diclofenac pharmacokinetics after oral and intravenous administration. However, the relevance of these data to ocular instillation is questionable, as plasma concentrations following ophthalmic application of 3 to 16 drops of diclofenac 0.1 % solution in 16 patients were below the detection limits of the gasliquid chromatographic assay « 5 ng/g) [unpublished data on file, Ciba-Geigy]. The amount of an instilled dose of diclofenac solution which reaches the systemic circulation (through drainage into the nasal mucosa or absorption from oropharyngeal

Orally administered diclofenac is almost totally absorbed, but undergoes first-pass metabolism resulting in 60% of the dose reaching the systemic circulation as unchanged drug. When applied topically to skin as a gel, diclofenac is absorbed percutaneously. Peak plasma diclofenac concentrations are achieved within IO to 30 minutes after administration in oral (solution), rectal or intramuscular form. No saturation of distribution or metabolic processes occurs at therapeutic dosages. Concomitant oral administration of aspirin in therapeutic doses significantly reduces plasma diclofenac concentrations. 20 minutes after instillation of 50~1 of 0.1 % diclofenac in rabbit eye (Agata et al. 1984), drug concentrations were highest in the cornea (13.63 ~gf g), conjunctiva (12.98), extraocular muscle (4.64) and anterior sclera (3.77). Small quantities of diclofenac were also measurable in plasma and liver (both 0.02 ~g/g at I hour). Although diclofenac concentrations subsided rapidly within I hour, they remained highest in these ocular tissues, together with the iris and aqueous humour. The lowest concentrations of diclofenac were in the vitreous humour and lens, and the drug was cleared from all ocular tissues after 6 hours (unpublished data on file, Ciba-Geigy). More importantly, penetration of diclofenac 0.1 % eyedrops into aqueous humour has also been demonstrated in 46 patients administered either of 2 formulations of the drug (Voltaren Ophthalmic®; Dispersa Naclof®) prior to cataract surgery. Diclofenac concentrations in aqueous humour ranged from 30 to 426 (mean approximately 130) mg/L, and appeared to reach a peak at I hour, according to this brief abstract (Vickers et al. 1990). Four drops of either of these 2 formulations, given 20 minutes apart, yielded aqueous humour concentrations below the assay sensitivity limit of 5 mgf L in a majority of 25 patients undergoing cataract

Ocular Diclofenac: A Review

surgery (unpublished data on file, Ciba-Geigy). One drop every lO minutes to a maximum of 8 drops, however, resulted in a mean aqueous humour concentration of 126.8 mg/L (range 30 to 426 mg/L) in 34 patients receiving the Voltaren Ophthalmic® formulation, and of 134.1 mg/L (34 to 311 mg/L) in 33 others given Dispersa Naclof® (unpublished data on file, Ciba-Geigy). A peak at 1 hour was again evident. Quentin (1991) reported mean concentrations in aqueous humour of 131. 7 ng/g when diclofenac 0.1 % eyedrops were given 5 times preoperatively, compared with 65.5 ng/g when 3 drops were given preoperatively, and 13.4 ng/g after 5 drops were instilled the night before surgery. Application of 3 to 16 drops of diclofenac 0.1 % ophthalmic solution in 16 patients resulted in a mean aqueous humour concentration of 96.6 ng/g (range < 5 to 430 ng/g, representing large interindividual variation) [unpublished data on file, CibaGeigy]. Similarly, concentrations ranged between < 5 and 574 ng/g (mean 131.8 ng/g) in 9 other patients after 5 drops of diclofenac 0.1 %, and between 15 and 361 ng/g (mean 116.8 ng/g) in 5 more given 6 drops (unpublished data on file, CibaGeigy). Diclofenac concentrations after systemic administration in rats are highest in blood, liver, bile, kidney, heart and lung. The drug penetrates into synovial fluid and persists at the inflammatory site in arthritic patients. Binding of diclofenac to human serum proteins, mainly albumin, is high (~ 99.5%). 2.2 Metabolism and Excretion Metabolism, and subsequent urinary and biliary excretion of glucuronide and sulphate conjugates, represents the main route of elimination of diclofenac. The principal metabolite, 4'-hydroxy diclofenac, has approximately 3% of the activity of diclofenac in animal models of arthritic inflammation, and comprises 20 to 30% of the dose recoverable in urine. A further lO to 20% is accounted for by 4 other inactive metabolites, and 5 to lO% by conjugates of unchanged diclofenac. The mean elimination half-life of diclofenac after

479

oral administration in healthy volunteers is about 1 to 2 hours, but this is extended to 25 to 30 hours when all metabolites are included. The pharmacokinetic properties of orally administered diclofenac appear to be largely unaffected by increasing age, renal function or hepatic impairment, with the possible exception of elevated plasma diclofenac concentrations in elderly vs younger patients. This is unlikely to be of any clinical significance, however.

3. Clinical Use in Cataract Surgery Cataract is defined as any opacity in the crystalline lens of the eye. Cataract is responsible for almost half of the blindness in the world's population (WHO 1989). The prevalence of cataract is estimated as 12% overall among Americans aged 50 to 85 (Framingham Eye Study 1980), but the prevalence increases lO-fold in the elderly aged ~ 75 years (46%) versus that in persons aged 50 to 65 years (4.6%) [Kini et al. 1978; Klein & Klein 1982]. Less developed nations have a higher prevalence of cataract - in some areas of India this approaches 70% in those aged> 70 years (Chatterjee et al. 1982). Factors other than age also thought to contribute to cataract development include: • long term exposure to sunlight (UVB radiation) [Italian-American Cataract Study Group 1991]; • low education (Italian-American Cataract Study Group 1991); • oral corticosteroid use (Italian-American Cataract Study Group 1991; Leske et al. 1991) • diabetes (Ederer et al. 1981; Leske et al. 1991) • other factors such as diet and smoking (Leske et al. 1991) Nonetheless, the majority of cataracts are agerelated (Dawson & Schwab 1981). Surgical removal of the opacity is the only currently effective treatment for cataract. However, the trauma to the eye associated with surgery produces undesirable inflammation (section l.l), treatable with topical steroids and, more recently, topical NSAIDs. The development of a topical formulation of di-

480

clofenac for use in ocular inflammation followed the observation that orally administered diclofenac exerted a beneficial effect on postoperative inflammation in patients undergoing cataract extraction (Ronen et al. 1985). Diclofenac as an ophthalmic solution has now been examined, in limited but usually well-designed trials, as an adjunct to cataract surgery for ameliorating postoperative inflammation, as pre- and postoperative prophylaxis of cystoid macular oedema, and for prevention of miosis. Its use in some other inflammatory ocular conditions unrelated to cataract surgery is also undergoing preliminary assessment (section 4). 3.1 Inhibition of Surgically Induced Miosis During and After Cataract Extraction Maintenance of mydriasis is necessary to facilitate intraocular surgery, although this is not consistently achievable despite the preoperative use of mydriatic drugs such as atropine. Instillation of diclofenac 0.1 % eyedrops (1 drop every 15 or 30 min X 4; 3 times daily x 2 days; or 1 drop at 120, 60 and 15 min) prior to cataract surgery (with or without intraocular lens implantation) prevented miosis to a significantly greater extent than did placebo, or routine medications (cyclopentolate 1%, phenylephrine 10%) [table II]. Mean pupil diameters achieved after instillation of diclofenac were greater than those obtained with indomethacin immediately prior to lens implantation (Dimitrakos et al. 1992). At this time, 50% of pupils treated with diclofenac had a diameter greater than 6mm, compared with 20% of those in the control and indomethacin groups. An unpublished trial by Condon and Watson reported that pupil diameter decreased by more than 2mm in 1 of 42 diclofenac recipients (a reduction from 9 to 7mm) versus 7 of 35 in a placebo group (unpublished data on file, Ciba-Geigy). Moreover, the rate of pupil constriction was 0.015 mm/min in the patients given diclofenac, compared with 0.032 mm/min with placebo (p < 0.05). This effect may be clinically relevant since cataract extraction operations are of relatively short duration. The prevention of miosis afforded by diclofenac persisted throughout the first

Drugs & Aging 2 (6) 1992

postoperative day (Bonomi et al. 1987b). Maintenance of mydriasis and prevention of miosis arising through trauma during surgery greatly facilitates operative procedures (Drews & Katsev 1989; Duffin et al. 1982; Erturk et al. 1991). 3.2 Pre- and Postoperative Prophylaxis of Cystoid Macular Oedema Sustained ocular inflammation is thought to be the cause of extravasation from retinal vessels which results in cystoid macular oedema following cataract surgery. This condition may be assessed by fluorescence angiography, and is graded from 0 (absent) to III (severe) [Behrens-Baumann et al. 1989; Miyake 1978]. Prophylactic instillation of diclofenac 0.1 % eyedrops (2 drops 5 times) preoperatively, then postoperatively (1 drop 5 times daily till discharge, then 1 drop 3 times daily for 6 months), reduced the occurrence of cystoid macular oedema compared with placebo (p = 0.03) in 112 patients in a well designed trial (Quentin et al. 1989). Inflammatory symptoms resolved and visual acuity improved faster in diclofenac recipients. Furthermore, the percentage of patients with more severe grades of cystoid macular oedema (grade III) was less in the diclofenac group on the day of discharge, and at 6 weeks and 6 months after surgery (fig. 3). In a shorter term study, no instances of cystoid macular oedema developed in 46 patients treated with either topical diclofenac 0.1 % or dexamethasone 0.1 % for 60 days (Ilic et al. 1984), although the period of follow-up may have been too short to detect such an occurrence. These preliminary results perhaps warrant further investigation of diclofenac in the prophylaxis of cystoid macular oedema. 3.3 Effects on Postoperative Inflammation and Intraocular Pressure Compared with placebo in double-masked trials, diclofenac 0.1 % [I drop 4 times daily for 16 days (Vickers et al. 1991), or 1 drop 3 times daily for 60 days then once daily for a further 30 days (Oth-

20 20

dm, pc, r, pg

pc, r, pg

dm, r, pg

dm, r, pg

dm, r, pg

Bonomi et al. (1987b)

Oimitrakos et al. (1992)

Ertiirk et al. (1991)

Fabian et al. (1991)

Unpublished data on file, Ciba· Geigy 00.1% P 1 drop q30 min X 4 preop

NOc

13.99%tb 27.81%

-3.05" -3.95

at cortex aspiration

-0.34" -0.72

-0.42" -0.94

-4.06

-3.09

-1.18' -2.51

-3.17" -4.00

-3.09'

day 1 postop

end surgery

-1.69'

-3.21

-3.06

-2.22"

before implant -1.83 -1.54

day 2 postop -2.02 -2.14

day 7 postop

Mean difference (from preoperative values) in pupil diameter (mm)

O>P

O>P

O>R

0;;'1; O>R

O>P

Efficacy

a Aged 36 to 81 years. b Percentage reduction in pupil surface area, assessed by computer-assisted microscopic photograph comparisons. c 'Most patients were over 70 years old.' Abbreviations and symbols: dm = double-masked; I = indomethacin; NO = no data given; P = placebo, pc = placebo-controlled; pg = parallel group; qx min = every x minutes; r = randomised; R = routine medications only (cyclopentolate 1%. phenylephrine 5 or 10% ± tropicamide 0.5%; control group); tid = 3 times daily; • p < 0.05, •• P < 0.01, t p < 0.0001, between-group differences; 0 ;;. indicates tendency towards superior effect for 0; 0 > indicates significantly superior effect for O.

42 35

00.1% P 1 drop q15 min X 4 preop

00.1% tid X 2 days preop R

00.1% 1 drop 120,60 and 15 min preop I 1% 1 drop 120, 60 and 15 min preop R

00.1% P 1 drop q15 min x 4 preop

Dosage regimen

NOs

64.3

30 20 20

62.4

NO

70 69.5

Mean age (years)

35

21

26

26

No. of pts

Study design

Effects of ocular diclofenac (D) in preventing surgically induced miosis in patients undergoing cataract surgery

Reference

Table II.

.j:o

00

~

iii'



n

(t> :::t r.>

".0"

0(') c:: iii .., 10

Drugs & Aging 2 (6) 1992

482

o o

Olclolenac

n = 57

Grade Grade Grade • Grade

0 I II III

n = 53

n = 57

Placebo

n = 55

n = 47

Discharge

6 weeks postoperatively

n

in suppressing postoperative inflammation, as assessed by laser cell and flare meter and slit lamp examination, in 30 patients (Roberts 1992) [table III]. Another study revealed that diclofenac 0. 1% (n = 37) was superior to prednisolone 1% (n = 40) based on anterior chamber fluorophotometry, although there were no significant differences in terms of clinical signs of inflammation (Alpar 1992) [table III]. Diclofenac when applied in these regimens thus reduced inflammation and prevented elevations in lOP induced by cataract surgery.

4. Potential Use in Other Ocular Conditions

= 55

6 months postoperativl!1y

Fig. 3. Severity of cystoid macular oedema in patients undergoing cataract surgery who received ocular diclofenac 0.1 % or placebo for 6 months (after Quentin et al. 1989).

enin-Girard et al. 1992)] after cataract surgery, significantly reduced the severity of anterior chamber inflammation. Visual acuity was unaffected by dic10fenac (Othenin-Girard et al. 1992). lOP was not significantly different between 2 groups of 46 patients given either placebo or diclofenac 0.1 % (every 6 hours for 3 doses on the preceding day and 4 doses at 90, 60, 30 and 15 min prior to cataract removal, then every 6 hours until 72 hours after the operation) [Strelow et al. 1992]. Diclofenac 0.1 % instilled for I day preoperatively and 2 to 4 times daily for up to 60 days postoperatively alleviated signs of ocular inflammation to a similar extent as dexamethasone 0. 1% in an identical regimen, but tended to be superior to the steroid with respect to postoperative increases in lOP (table III). Preoperative instillation of diclofenac 0.1 % (1 drop every 10 minutes for 6 doses) also minimised postsurgical rises in lOP. Diclofenac 0.1 % and indomethacin I % had similar effects, and both were of greater benefit than mydriatics alone in attenuating the rise in lOP at 2 and 24 hours postoperatively (table III; fig 4). Diclofenac 0. 1% was equivalent to prednisolone 1%

Diclofenac was equivalent to dexamethasone (for up to 4 weeks; dosage not stated) in relieving symptoms and signs of iritis or iridocyclitis in 34 eyes (31 patients), but was less satisfactory than the steroid in promoting healing (4 vs 10 eyes healed; p < 0.016) [Quentin & Behrens-Baumann 1987)]. Small noncomparative trials of between 4 and 40 days' duration have indicated good efficacy of diclofenac 0. 1% in the treatment of patients with episcleritis (n = 30), limbal corneal ulcer (n = 9) and allergic conjunctivitis and/or conjunctivitis phlyctenulosa (n = II) [van Husen 1986]. All patients were clinically healed or had resolution of 20

o

o

Control Indomethacin Diclofenac

Oi I

.sE 10 Cl.

Q

0~~~LJ~--~~2~hL-L-~~2~4~h~ Before

surgery

~

Postoperatively

Fig. 4. Intraocular pressure (lOP) in 33 patients undergoing cataract surgery treated postoperatively with diclofenac 0.1%. or indomethacin I %. compared with control (after Pillunat et al. 1987).

483

Ocular Diclofenac: A Review

Table III. Comparative trials of ocular diclofenac (D) versus other topical anti-inflammatory agents in the treatment of postoperative inflammation after cataract removal

Effects on indices of inflammation

Study design

No. of pts Age (procedure) (mean, years)

Dosage regimen

Alpar (1992)

dm, r, pg

NO

00.1% Pr 1% (frequency not stated)

0> Pr

llic et al. (1984)

dm, r, pg

76.2 77.3

00.1% Oex 0.1%8

0 .... Oex

Pillunat et al. (1987)

sm, r, pg

37 40 (cataract extraction + lens implant) 46 (cataract extraction + lens implant) 11 11

72 71

00.1% 11% 1 drop q10 min x 6 preop Mydriatics only (not defined) 00.1% Pr 1% 1 drop qid x 1w, then bid x 3w

Reference

Roberts (1992) NO

11 (cataract extraction) 50 (cataract extraction)

75

NO

anterior corneal chamber oedema inflammation

visual acuity

Efficacy lOP (mmHg)

0> Pr

Oex

~

0

0 .... Oex

o~

Oex

t 2.2' t 2.19' at

0 .... Oex

0 .... 1> M

2h

t 9.8 0 .... Pr

0 .... Pr

D== Pr

0 .... Pr

Patients were treated for 1 day preoperatively with either diclofenac 0.1% (n = 22) or placebo (n = 24), then postoperatively each group was split into 2 groups (Le. a total of 4 groups) which received either diclofenac or dexamethasone 2 to 4 times daily for up to 60 days. Abbreviations and symbols: bid = twice daily; dm = double-masked; Oex = dexamethasone, I = indomethacin; lOP = intraocular pressure; M = mydriatics only; NO = no data given; pg = parallel group; Pr = prednisolone; q10 min = every. 10 minutes; qid = 4 times daily; r = randomised; sm = single-masked; w = weeks; • p < 0.05 compared mydriatics; .... indicates equivalent efficacy; > indicates significantly superior efficacy; ~ indicates tendency for superior efficacy. a

their symptoms, with the exception of 2 patients with episcleritis and one with conjunctivitis who showed some improvement, and 1 patient with episcleritis which worsened. Data from a 4-week randomised double-masked comparative trial in 56 patients aged 11 to 89 years with chronic conjunctivitis support the efficacy of diclofenac 0.1 % 4 times daily in this condition, showing an equiva-

lent effect to dexamethasone 0.1 % 4 times daily in ameliorating symptoms (Stodtmeister & Marquardt 1986). However, no placebo control was included in this study. Finally, topical diclofenac 4 times daily successfully reduced inflammation within about 3 days in patients with inflamed eyes after laser trabeculoplasty (Mermoud et al. I 992a,b).

484

5. Tolerability From the limited published data available, diclofenac instilled in the eye appears well tolerated. Most investigators who discussed the tolerability of the drug reported no adverse events (Bonomi et al. 1987a; Ertiik et al. 1991; Quentin & BehrensBaumann 1987). A slight transient burning sensation has been experienced by a few patients (Ilic et al. 1984; Stodtmeister & Marquardt 1986; van Husen 1986); blurred vision, hypersensitivity reactions and keratitis punctata have occurred rarely (unpublished data on file, Dispersa AG).

6. Dosage and Administration For preoperative use, 1 drop of diclofenac 0.1 % solution may be instilled in the affected eye up to 5 times during the 3 hours prior to surgery. The recommended postoperative regimen is 1 drop instilled 3 times after surgery, then 1 drop 3 to 5 times daily. In other nonsurgical indications, 1 drop of diclofenac 0.1 % instilled 4 to 5 times daily, depending on disease severity, is advised. Topical diclofenac, like other NSAIDs, is contraindicated in patients allergic or sensitive to aspirin or other NSAIDs. Patients with blurred vision should not drive or operate machinery, and soft contact lenses should not be worn during treatment. Diclofenac 0.1 % has been administered concomitantly with timolol 0.5% without adversely affecting the lowering effect of the ,B-blocker on lOP in healthy volunteers (Castillo Laguarta et al. 1991):

7. Place of Ocular Diclofenac in Therapy As the world's population ages, cataract will become an even more common problem facing clinicians and surgeons. In the absence of proven pharmacotherapeutic management, surgery.is currently the only viable option. Identification of effective pharmacological methods of treating or preventing acute inflammatory processes associated with surgical extraction of cataract constitutes an import-

Drugs & Aging 2 (6) 1992

ant goal of pre- and postoperative management. Topical corticosteroids are currently employed in this setting, but possible detriments of their use include induction of ocular hypertension, delayed wound healing and increased risk of infection. NSAIDs have more recently become a focal point in the search for an alternative anti-inflammatory adjunct to cataract surgery. The activity of this class of drugs in inhibiting prostaglandin synthesis underlies the rationale for their use in attenuating the ocular inflammatory processes thought to be at least partly mediated by prostaglandins. Diclofenac, a potent NSAID, has displayed equivalent efficacy (when formulated as a 0.1 % solution) to dexamethasone 0:1% solution in attenuating signs of ocular inflammation, and was at least as effective as prednisolone 1%. The drug was similar to indomethacin 1% but tended to be superior to dexamethasone 0.1 % in preventing elevations in lOP following cataract surgery. The occurrence and severity of cystoid macular oedema is lessened with prophylactic instillation of diclofenac (compared with placebo), and the drug appears to prevent surgically induced miosis to a greater degree than placebo, mydriatics alone, or indomethacin 1%. Maintenance of mydriasis facilitates surgical procedures such as extracapsular extraction and posterior chamber intraocular lens implantation (Ertiirk et al. 1991). Other ocular inflammatory conditions in which diclofenac appears effective according to very preliminary findings are iritis or iridocyclitis, episcleritis, limbal corneal ulcer, conjunctivitis and inflammation after laser trabeculoplasty. Diclofenac eyedrops appear to be well tolerated from the limited data available, with a transient localised burning sensation reported by some patients. Ocular diclofenac, with its potent anti-inflammatory effects and apparently good tolerability, therefore appear well suited as an adjunct to cataract surgery, and holds promise in several other inflammatory ocular conditions.

References Abelson MB. Lipoxygenase products in ocular inflammation. Investigative Ophthalmology and Visual Science 25 (Suppl.): 42, 1984

Ocular Dic1ofenac: A Review

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Correspondence: Paul Chrisp, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand.

Ocular diclofenac. A review of its pharmacology and clinical use in cataract surgery, and potential in other inflammatory ocular conditions.

Diclofenac sodium is a potent nonsteroidal anti-inflammatory drug with analgesic activity. When instilled as a topical 0.1% solution in a limited numb...
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