Trans. aphtha I. Soc. U.K. (1981) 101,27

Clobetasone butyrate eye drops Effect on ocular inflammation and intraocular pressure

J. WILLIAMSON·, L. A. EILONt, AND S. R. WALKERt:t:

From The ·Southern General Hospital. Glasgow. and the tGlaxo Group Research Limited. Greenford. Middlesex

Summary

Clobetasone butyrate eye drops comprise a new steroid preparation which has been investigated in two comparable, double-blind, multicentre clinical trials in patients with ocular inflammation. One study compared clobetasone butyrate with betamethasone phosphate eye drops (205 patients) and the other study compared corresponding preparations containing neomycin (169 patients). There was no difference between the responses to cIobetasone butyrate and betamethasone. An excellent or good response was obtained in 73 per cent of patients treated with c1obetasone butyrate, 75 per cent with betamethasone, 69 per cent with cIobetasone butyrate formulated with neomycin, and 76 per cent with betamethasone formulated with neomycin.

Patients who were known to react with a rise of intraocular pressure (lOP) to steroids were treated with clobeta­sone butyrate eye drops in one eye and either prednisolone eye drops (6 patients) or hydrocortisone eye drops (4 patients) in the other eye. The doses were continued for 6 weeks, or less if the lOP rose more than 10 mm Hg in one eye. All patients experienced a greater intraocular pressure rise in the eye treated with prednisolone or hydro­cortisone. The mean changes in lOP were 9 mm Hg for prednisolone compared to 2 mm Hg for cIobetasone butyrate (P<0.05 Wilcoxon signed ranks test) and 16 mm Hg for hydrocortisone compared to 2 mm Hg for c1obetasone butyrate.

A new steroid eye preparation containing c1obetasone butyrate has been undergoing clinical evaluation. There have been several reports of its anti-inflammatory activity in the treatment of various ocular diseases: anterior uveitis (Dunne and Travers, I979); postopera­tive inflammation (Ramsell, Bartholomew, and Walker, 1980); allergic conjunctivitis (Frankland and Walker, in press); episcIeritis (Lloyd-Jones, Tokarewicl, and Watson, in press).

This paper reports on two large multicentre studies in which the anti-inflammatory efficacy of c1obetasone butyrate eye drops with and without neomycin has been compared to that of betamethasone with and without neomycin respectively. The effect of c1obetasone butyrate on intraocular pressure has also been investiga­ted in patients who are known to react to steroid preparations with a raised intraocular pressure and this has been compared with the effect of hydrocortisone and prednisolone eye drops.

Address for reprints: Dr. J. Williamson, MD, FRCS, Department of Ophthalmology, Southern General Hospital, Glasgow, GS 1 4TF

:j:Present Address: Centre for Medicines Research, 12, Whitehall, London, SWIA 2DY

Patients and methods Anti-inflammatory studies Two multicentre, between-patient studies were carried out; one to compare eye drops containing clobetasone butyrate (0.1 per cent) with those containing betamethasone sodium phosphate (0.1 per cent) and the other to compare the corresponding perparations with added neomycin sulphate (0.5 per cent). Patients were selected who required steroid (or steroid with anti-infective) eye drops for inflammatory ocular conditions. Patients receiving other topical or systemic steroid therapy (except oral contraceptives) were excluded.

Patients were randomly allocated to one of the prepara­tions. The usual dosage was two drops instilled four times a day but this was altered by the ophthalmologist depending on the severity of the disease. At the first visit the inflammation was recorded as mild, moderate, or severe, and the intra­ocular pressure was measured. The return visits were made at I or 2-weekly intervals when the ophthalmologist assessed the response to treatment as excellent, good, satisfactory, or poor, and again intraocular pressure was measured.

Intraocular pressure studies Two double-blind, within-patient studies were carried out. Patients were selected who were known to have elevated lOP after 4 to 6 weeks administration of betamethasone eye drops. These patients instilled two drops into the eye four times a day; clobetasone butyrate (0.1 per cent) into one eye and prednisolone (0.5 per cent) or hydrocortisone (1.0 per cent)

28 Transactions oj the Ophthalmological Society oj the United Kingdom

into the other eye. They returned to the clinic at I or 2-weekly intervals and at each visit lOP was measured by applanation tonometry. The treatment was stopped after 6 week\>pr earlier ir the pressure in one or both eyes had risen by more than 10 mm Hg.

Results A I1ti-inJlammalory studies 205 patients took part in the trial comparing cIobeta­sone butyrate with betamethasone eye drops and 169 patients in the comparison of the drops containing neomycin. Table I gives details of the patients. The groups were well matched with respect to age, sex, and initial severity of the inflammation; most patients' inflammation was assessed as mild or moderate. The majority of patients had postoperative inflammation (after cataract surgery) (Table II). The mean'period of treatment was 29 and 28 days for cIobetasone butyrate and betamethasone drops respectively, and 25 and 28 days for clobetasone butyrate with neomycin and beta­methasone with neomycin.

After treatment with cIobetasone butyrate, 73 per

Table I Anti-inflammatory studies: Patient details

Eye drops CB B CB+N B+N

No. o/patients: 103 102 81 88

Sex Male 52 46 30 32 Female 50 55 50 55 Unrecorded I I I I

Age (yrs) Average 61 60 63 63 Range 6-95 8-91 10-95 18-87

Initial Mild 45 42 30 28 assessment Moderate 39 45 38 41

Severe 16 13 13 16 Unrecorded 2 2 0 3

Key: CB : clobetasone butyrate eye drops B : betamethasone phosphate eye drops CB+N : clobetasone butyrate with neomycin eye drops B+ N : betamethasone phosphate with neomycin eye drops

Table II A nti-injlammatory studies: Type 0/ disease

Eye drops Diagnosis

CB B , CB+N B+N

Postoperative inflammation 63 60 53 59 Squamous blepharitis 4 7 9 5 Anterior uveitis 13 14 2 6 Vernal conjunctivitis 4 7 2 I Episcleritis 7 3 0 3 Other 12 11 15 14

Total 103 102 81 88

cent of patients had an excellent or good response to treatment, 75 per cent with betamethasone, 69 per cent with clobetasone butyrate with neomycin , and 76 per cent with betamethasone with neomycin (Table III). The responses were similar if the results were analysed after 7 days treatment. Also, no difference between the steroid treatments could be detected when the results were analysed according to the different diseases.

Table III A nti-inf/ammatory studies: Assessment at last visit

Eye drops

Assessment CB B CB+N B+N

Per Per Per Per No. cent No. cent No. cent No. cent

---Excellent 52 50 42 41 26 32 40 45 Good 24 23 35 34 30 37 27 31 Satisractory 19 18 19 19 16 20 15 17 Poor 8 8 6 6 9 11 6 7

Inc[l~ases of more than 6 mm Hg in lOP were observed in several patients during the course of the studies (Table IV). Only "three patients experienced an intraocular pressure rise of over 6 mm Hg during treat­ment with clobetasone butyrate (with or without neomycin) whereas thirteen patients showed such an increase during treatment with betamethasone (with or without neomycin).

Table IV Anti-inflammatory studies: Intraocular pressure rises

Rise in Pressure Eye drops

(mm Hg) CB B CB+N B+N

6 4 0 3 2 7 and over 3 10 0 3

Intraocular pressure studies Six patients (48 to 62 years) received c1obetasone butyrate drops in one eye and prednisolone in the other eye. In each patient a greater rise in lOP was observed in the eye receiving prednisolone (statistically signifi­cant; Wilcoxon matched pairs signed ranks test: P<0.05). The change in pressure ranged from 5 to 11 mm Hg (mean 9 mm Hg) for the eyes treated with prednisolone and from -1 to 6 mm Hg (mean 2 mm Hg) for the eyes treated with cIobetasone butyrate (Table V).

A further four patients (61-74 years) received cIobeta­sone butyrate drops in one eye and hydrocortisone in the other. As with prednisolone drops, each patient experienced a greater increase of lOP in the eye receiv­ing hydrocortisone. The change in pressure with hydro­cortisone ranged from 11 to 20 mm Hg (mean

Table V Intraocular pressure trials: Results

Duration of CB Comparative steroid

Patient No.

treatment Rise in lOP Steroid

(wks) (mm Hg) -----

I 4 3 Pred. 2 5 3 Pred. 3 2 2 Pred. 4 3 0 Pred. 5 4 6 Pred. 6 6 -I Pred.

I 4 4 Hyd. 2 4 -1 Hyd. 3 2 -I Hyd. 4 6 4 Hyd.

CB -c1obetasone butyrate eye drops Pred.-prednisolone eye drops Hyd.-hydrocortisone eye drops

Rise in lOP (mm Hg)

8 II 10 5

II 7

20 II 19 14

16 m m Hg) and with clobetasone butyrate from -1 to 4 mm Hg (mean 2 mm Hg).

Conclusion The anti-inflammatory studies showed that clobetasone butyrate eye drops with or without neomycin were as effective in the treatment of ocular inflammation as beta-

References

DUNNE, J . A., and TRAVERS, J. P. (1979) Brit. J. Ophthal .• 63, 762 FRANKLAND, A. W., and WALKER, S. R. c/in. Allergy. In press

Clobetasone butyrate eye drops 29

methasone with or without neomycin respectively. Significantly more patients in these studies reacted with an intraocular pressure rise to betamethasone than to c1obetasone butyrate. This property of c1obetasone butyrate has been investigated in specifically designed studies with patients who are known to experience a rise in lOP with ocular steroid treatment. Clobetasone butyrate has been shown to have a lower propensity to raise lOP than dexamethasone (Dunne and Travers, 1979) and betamethasone (Ramsell and others. 1980). We have shown that c1obetasone butyrate also has less potential to raise lOP than prednisolone or hydrocorti­sone. Thus, c1obetasone butyrate eye drops may be con­sidered to be a safer steroid therapy, being as effective as betamethasone drops with a lower potential to raise intraocular pressure.

We should like to thank the following ophthalmologists who took part in the multicentre anti -inflammatory studies and who kindly allowed their results to be presented: Dr. R. S. Bartholomew, Edinburgh; Mr. P. M. Drummond, Lincoln: Mr. J . Dunne, Manchester ; Mr. R. P. Ellis, Plymouth: Mr. H. Hardy, Ipswich; Mr. K. Jordan, Cambridge; Mr. J. L. Kennerley Bankes, London; Miss V. Mohan, Birmingham: Mrs. A. Morrison, Liverpool; Mr. A. Rahman, Birmingham; Mr. T. G. RamselJ, Birkenhead; Mr. A. Richards, Reading ; Mr. C. J. Tallents, Kidderminster.

We should also like to thank Miss J. M. Scheidegger for secretarial assistance.

LLOYD-JONES, D .. TOKAREWICZ, A., .and WATSON, P. G. Brit. J . Ophthal. In press RAMSELL, T. G .. BARTHOLOMEW, R. S., and WALKER, S. R. (1980) Ibid .. 64,43