Latanoprost Administered Once Daily Caused a Maintained Reduction Ofintraocularpressure in Glaucoma Patients Treated Concomitantly with Timolol 13

12 Britishj7ournalofOphthalmology 1995; 79: 12-16

Latanoprost administered once daily caused a

maintained reduction ofintraocular pressure in Br J Ophthalmol: first published as 10.1136/bjo.79.1.12 on 1 January 1995. Downloaded from glaucoma patients treated concomitantly with timolol

Albert Alm, Ingmar Widengard, Daniel Kjellgren, Mats Soderstrom, Bjorn Fristrom, Anders Heijl, Johan Stjerschantz

Abstract In a first dose finding study with twice daily The long term effects of two dose regimens of administrations of latanoprost, ocular hyperten- latanoprost (PhXA41) administered to eyes sive eyes were treated for 4 weeks.5 There was no concomitantly treated with timolol which had significant difference between the three concen- not adequately been controlied by timolol trations of latanoprost eye drops used; 0 0035%, alone were compared. A total of50 patients, 17 0 006%, and 0-0115%, and all were significantly with primary open angle glaucoma and 33 with better than placebo. The initial response, on the capsular glaucoma, were recruited from five second day of treatment, was good with a 31- clinics. All had glaucomatous visual field 38% reduction of the IOP, but after 1 week of defects and an intraocular pressure (IOP) of at treatment there was some diminution of effect least 22 mm Hg despite treatment with 0*5% and after 4 weeks the IOP reduction was between timolol twice daily. Patients were randomised 19 and 22% for the three concentrations of to two treatment groups. In one group 0.006% latanoprost used. A partial diminution in the latanoprost was given twice daily, in the other IOP effect was also observed by Camras et al after group placebo was given at 8 am and latano- 5 days of treatment twice daily with 0-01% prost at 8 pm for 3 months, with concomitant latanoprost, but not with 0003%. Fristrom and timolol treatment in both groups. Average Nilsson also noted some reduction of the IOP daytime IOP (mean (SD)) at baseline (on effect with 0-006% latanoprost given twice daily timolol alone) and after 4 and 12 weeks' treat- for 1 week, similar to that observed for 2% ment was 24*8 (3.6), 16-8 (4.3), and 15*7 (2.4) pilocarpine administered three times daily.9 mm Hg respectively with once daily applica- They also found that the effect on IOP of tion of latanoprost and 24-9 (2.9), 18*1 (3.0), latanoprost and pilocarpine was at least partially and 18-0 (3.6) mm Hg respectively with latano- additive.9 Both drugs act on outflow; latanoprost prost twice daily. No clinically significant side has no effect on aqueous flow.'68 Thus one effects were observed during treatment. would expect latanoprost and an aqueous flow causes a marked and sustained suppressor to be a better combination. The effect http://bjo.bmj.com/ Department of Latanoprost Ophthalmology, IOP reduction in eyes which are also being on IOP of prostaglandin F20-isopropylester University Hospital, treated with timolol. Latanoprost given once (PGF20-IE) has previously been found to be Uppsala, Sweden daily is at least as effective and probably additive to that of timolol'"" and a direct com- A Alm I Widengard superior to a twice daily dose regimen parison ofthe additivity of latanoprost to timolol (BrJ Ophthalmol 1995; 79: 12-16) 0 5% twice daily and pilocarpine 2% three times Department of daily suggested that pretreatment with pilocar- Ophthalmology, 12 on September 30, 2021 by guest. Protected copyright. University Hospital, pine reduced the effect oflatanoprost on IOP. Umea, Sweden Several previous studies have demonstrated that The present study was designed to evaluate D Kjellgren the phenyl substituted prostaglandin F2a the effect oflatanoprost administered either once Department of analogue, 13,14-dihydro-17-phenyl-18, 19, or twice daily in addition to timolol. Treatment Ophthalmology, 20-trinor-prostaglandin F2a-isopropylester was given for 3 months to be able to detect any University Hospital, (latanoprost, PhXA41) and its epimeric mixture long term diminution in the effect of the drug on Huddinge, Sweden PhXA34 reduce significantly the intraocular IOP. M Soderstrom pressure (IOP) in normal, ocular hypertensive, Department of or glaucomatous eyes."18 The present study was Ophthalmology, to more on and methods University Hospital, undertaken obtain information dose Patients Linkoping, Sweden regimen, long term effect, and additivity to a 13 B Fristrom adrenergic antagonist, timolol. SUBJECT SELECTION Latanoprost has a long duration of effect on The study was performed as a five centre, Department of Ophthalmology, IOP, but whether it should be administered once randomised, parallel, double masked study of University Hospital, of twice daily is unclear. In two dose finding latanoprost, 0-006%, given either once, in the Malmo, Sweden studies with the epimeric mixture PhXA34 a evening, or twice daily for 12 weeks. Patients of A Heijl duration ofat least 24 hours was observed but the either sex over the age of 60, with primary open Pharmacia Ophthalmics, effect 24 hours after the dose was less pro- angle glaucoma (POAG) or capsular glaucoma, Uppsala, Sweden nounced than that seen at 12 hours after the in whom the IOP was not adequately controlled J Stjerschantz dose.' 2 Such an attenuation of the effect was not despite 0-5% timolol twice daily were included. Correspondence to: Albert Alm, MD, Department observed in a study on hospitalised patients Inadequate IOP control was defined as an IOP of of Ophthalmology, University treated with latanoprost,7 and in one dose at least 22 mm Hg on two occasions taken at an Hospital, S-751 85 Uppsala, Sweden. regimen study administration of 0-006% latano- interval of at least 1 hour at the pre-inclusion Accepted for publication prost once daily was at least as effective as twice examination. Ten patients were recruited from 10 August 1994 daily.4 each centre, five per treatment group. Patients Latanoprost administered once daily caused a maintained reduction ofintraocularpressure in glaucoma patients treated concomitantly with timolol 13

Table I Examination schedule

Day O Day 14 Day 28 Week 12 Br J Ophthalmol: first published as 10.1136/bjo.79.1.12 on 1 January 1995. Downloaded from Pre-inclusion Week 6 Week 8 Week 10 Investigational event within I month 8 12 4 4 8 12 4 4 pm 4 pm 4 pm 8 12 4 Ocular examination * * Symptomatology * * * * * * * ** * * * * * Visual acuity * * * * Biomicroscopy * * ** * * * * * * * * * * Photography * * * * * * * Hyperaemia grading * * * * * ** ** * * * lop * * ** * **** *

with a history of severe ocular trauma, severe STATISTICAL ANALYSIS AND EVALUATION OF ocular inflammation within the past 3 months, or EFFECT intraocular surgery within the last 6 months were Diurnal IOP was defined as the mean IOP over excluded. Exclusion criteria also included the day based on the values obtained at 8 am, 12 known contraindications to adrenergic noon, and 4 pm. Owing to differences in baseline blockers, a history of acute angle closure IOP between patients, baseline IOP was used as glaucoma, a history of significant dry eyes, and a covariate in statistical analysis of the IOP wearing contact lenses. The study protocols were reduction. The difference in IOP reduction reviewed and approved by the National Board of between treatment groups at week 12 at 4 pm was Health and Welfare and by the appropriate local analysed by two way analysis of covariance with review boards. Written informed consent was treatment group and centre as factors and base- obtained from all subjects. line IOP as covariate. Maximal hyperaemia was defined as the highest score from the three measurements during the day. Change in maxi- EXAMINATION SCHEDULE AND PROCEDURES mal hyperaemia at week 12 within treatment A pre-inclusion examination was performed groups was tested with the sign test. Comparison within 1 month before the study. We obtained a of change in maximal hyperaemia at week 12 medical and ophthalmic history including between treatment groups was performed with information on ocular symptoms. In addition to Wilcoxon rank sum test. The X2 test was used to IOP determinations the initial examination compare the number of patients who responded included measurement of refractive error and positively to latanoprost in the two groups. Snellen visual acuity, a slit-lamp evaluation of the anterior segment, ophthalmoscopic examination of the optic nerve, and a visual field if one Results had not been performed within the last 6 Of the 50 patients who entered 48 were able to months. complete the study. The two patients who with- The examination schedule is presented in drew were in the group which administered Table 1. The patients visited the clinic three times latanoprost once daily. One patient developed a http://bjo.bmj.com/ on the baseline day and 4 and 12 weeks after keratitis after 4 weeks' treatment and one with- initiation of treatment but only once daily for drew after 6 weeks and 4 days' treatment owing examinations after 2, 6, 8, and 10 weeks' treat- to difficulties in distinguishing between the ment. The degree of conjunctival hyperaemia dropper bottles. was graded in the treated eye by comparison with Oral 1 blocking agents were used by one

four standard photographs corresponding to no patient in the twice daily group compared with on September 30, 2021 by guest. Protected copyright. hyperaemia, mild, moderate, and severe hyper- seven patients in the once daily group. Otherwise aemia respectively. A photograph was taken of there were no major differences between treat- the anterior segment of the eye which was later ment groups with respect to demographic or evaluated in a masked manner. clinical data (Table 2). The patients were randomised to two treat- The mean diurnal IOPs at baseline and weeks ment groups. Each patient was provided with 4 and 12 for the two groups are presented in one bottle of 0-5% timolol (Blocadren, MSD) Table 3, and the IOPs measured at 4 pm at and two identical bottles, one labelled morning baseline and at 2 week intervals for 12 weeks are and one evening. For group A both bottles shown in Figure 1. After 4 weeks' treatment the contained 0-006% latanoprost, for group B the mean diurnal IOP was reduced by 8O0 mm Hg in morning bottle contained vehicle and the evening bottle 0-006% latanoprost. Timolol was Table 2 Demographic and clinical characteristics always administered first with 5 minutes Once Twice between eye drops. The first dose of latanoprost daily daily All or vehicle was given in the evening, about 8 pm, Age ofthe baseline day (day 0). Patients were instruc- Mean 74 0 72-6 73-3 ted to administer the drops in the morning at Range 60-84 63-87 60-87 Sex (M/F) 6/19 9/16 15/35 8 am and in the evening at 8 pm throughout the Iris colour study. Twenty patients were treated with timolol Blue/green 21 20 41 in both eyes Brown 3 1 4 before entering the study. These Grey 1 4 5 patients continued with timolol treatment in the Diagnosis eye POAG 8 9 17 fellow also during the study. Capsular glaucoma 17 16 33 One patient had been on timolol for only 2 Family history ofOH or glaucoma 1 1 8 19 weeks before entering the study, six patients Use oforal 1B blockers 1 7 8 between 1 and 4 months, and the remaining 43 POAG=primary open angle glaucoma. patients, at least 6 months. OH=ocular hypertension. 14 Alm, Widengdrd, Kjellgren, Soderstrom, Fristrom, Heijl, Stjerschantz

Table 3 Mean (SD) diurnal IOP (mm Hg) at baseline, 3' - Severe week 4, and week 12

Treatment Baseline Week 4 Week 12 Br J Ophthalmol: first published as 10.1136/bjo.79.1.12 on 1 January 1995. Downloaded from Once daily 24-8 (3 6) 16-8 (4 3) 15-7 (2-4) 2 - Moderate Twice daily 24-9 (2 9) 18-1(3 0) 18-0(3 6) G) p Values for test between 0 treatments 0-15 <0-01 1 - Mild the once daily group and by 6-8 mm Hg in the twice daily group which corresponds to 32 and 27% of baseline diurnal IOP, respectively. After Baseline 4 12 12 weeks' treatment the corresponding figures Week were 9d1 mm Hg (37%) and 6-9 mm Hg (28%) Figure 2 Maximum hyperaemia scores on baseline day and respectively, with a statistically significant after4 and 12 weeks' on 0-006% latanoprost once daily (a) or difference in IOP between the two groups twice daily (A). (Means (SEM).) (p

to timolol. Latanoprost was given to patients none of these studies were designed to detect a with inadequate IOP control, and thus placebo small change in aqueous flow and the possibility

was not used and timolol was not washed out that latanoprost causes an increase of aqueous Br J Ophthalmol: first published as 10.1136/bjo.79.1.12 on 1 January 1995. Downloaded from before adding latanoprost. Most patients had flow of, for example, 10% for 8 to 12 hours been on timolol for at least 6 months and some cannot be excluded. were taking oral fi blockers. Consequently, the The other possibility, is a development of a effect on IOP of timolol alone at the start of the moderate degree of receptor tolerance. One study is not known. Comparison of the two dose argument in favour ofthis explanation is that the regimens can be made but it is not possible to difference between the two dose regimens is not calculate the combined effect of the two drugs. seen until after a few days of treatment. In fact, The results, however, are clear; latanoprost Nagasubramanian et al found that 0-006% causes a marked and significant reduction ofIOP latanoprost given twice daily was significantly in patients who are using timolol, which has been superior to the same dose given once daily on the previously shown for PGF2a-IE.' " The magni- second day of the study but significantly inferior tude of the effect in the present study is better after 14 days of treatment.4 Thus, the observed than in a previous study where 0'006% latano- phenomenon that latanoprost given once daily prost was given twice daily for 1 month in seems to be superior to the same dose given twice otherwise untreated eyes.5 The results support daily may be based on development of some the assumption that because of their different degree of receptor tolerance. Continued treat- mechanisms of action the effects of timolol and ment after the first 2 weeks does not result in latanoprost are completely additive.6 further loss ofeffect. The present study also demonstrates that In the present study a small but statistically 0-006% latanoprost given once daily seems to significant reduction in IOP also occurred in the be superior to twice daily administrations. contralateral eye. A drug related effect in the Nagasubramanian et al made the same observa- fellow eye cannot be expected with latanoprost as tion after 2 weeks oftreatment with the same two the dose given is very small and latanoprost is dose regimens.4 As the results of two indepen- rapidly metabolised with a half life in plasma of dent studies are the same it is unlikely that this is only about 10 minutes. 19 Some of the fellow eyes due to chance variation. Alternative explanations were being treated with timolol, but these eyes for this unusual response should be considered did not differ from untreated fellow eyes with such as a dual effect of latanoprost on aqueous respect to change in IOP during the study. humour dynamics or the development of a Improved compliance during the study cannot moderate degree ofreceptor tolerance. explain the contralateral effect which was small Latanoprost was administered in the evening and of no clinical significance. It perhaps is to the once daily group and IOP was determined explained by a regression towards the mean since 12-20 hours later, whereas IOP determinations a lower limit for IOP was part of the inclusion were made 4-8 hours after the dose in the twice criteria and the IOP of the two eyes tend to vary

daily group. Thus one obvious possibility is that in concert.20 http://bjo.bmj.com/ latanoprost affects aqueous humour dynamics in Side effects were minimal in the present study. more than one way, a short duration effect - less One patient interrupted the study owing to a than 12 hours - which would increase IOP and a keratitis that was judged as non-drug related. long duration IOP reducing effect. In early Flare was not observed in either group, and studies with PGF20-IE an initial increase in IOP previous studies with various techniques have was observed, presumably due to intraocular found no significant effect of latanoprost on the vasodilatation.'3 An intraocular vasodilatation blood-aqueous barrier.8 A slight increase in on September 30, 2021 by guest. Protected copyright. and an increased episcleral venous pressure conjunctival injection was noted, but was not lasting for 8 hours is, however, an unlikely clinically significant. There was no increase in explanation to the difference between the two ocular symptoms and no change in visual acuity, dose regimens. Latanoprost, unlike PGF2,-IE, or refraction. Thus there is a large difference in has only a slight effect on intraocular blood side effects between the phenyl substituted flow.'4 No dual effect on aqueous outflow has analogue latanoprost and its mother compound been observed for either PGF2a or latanoprost in PGF2a-IE, which caused marked conjunctival monkeys; both increase uveoscleral flow with- hyperaemia and ocular irritation in large doses.'3 out measurable effect on conventional out- In conclusion 0-006% latanoprost given once flow.' '7 A short duration increase of aqueous daily causes marked reduction of the IOP in flow could explain the observed results, but patients being treated with timolol concomi- previous studies both using PGF2,a-IE and tantly, and administration once daily is not only latanoprost have failed to demonstrate any effect adequate but probably superior to twice daily. on aqueous flow in the human eye.6"11 In those Thus these results support the view that latano- studies latanoprost was given alone and in the prost may become a valuable addition to the present study latanoprost was added to eyes with treatment of glaucoma. timolol suppressed aqueous flow, and the effect of latanoprost on aqueous flow in timolol treated eyes has not been determined. However, an AA is a consultant to Pharmacia Ophthalmics AB. Johan Stiemschantz is employed by Pharmacia Ophthahnics AB. The increase of suppressed aqueous flow by latano- authors do not have commercial or proprietary interest in latanoprost cannot explain the observation that the prost eye drops. The results have been presented in part at the AAO meeting in Dallas, Texas, 8-12 November 1992, and at the same difference between the two dose regimens ARVO meeting in Sarasota, Florida, 2-7 May 1993. was found in eyes not treated with timolol,4 and Financial support was provided by Pharmacia Ophthalmics. Ziai et Anders Marsk, MS assisted with study design and regulatory al found that latanoprost had no effect on affairs and Thomas Kaponen, MS, of Pharmacia Ophthalmics non-stimulated aqueous flow at night.8 Still, assisted with the statistical analysis. 16 Alm, Widengdrd, Kjellgren, Soderstrom, Fristrom, Heijl, Stjerschantz

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