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Combined Therapy of Pilocarpine or Latanoprost with Timolol Versus Latanoprost Monotherapy
SURVEY OF OPHTHALMOLOGY VOLUME 47 • SUPPLEMENT 1 • AUGUST 2002
Combined Therapy of Pilocarpine or Latanoprost with Timolol Versus Latanoprost Monotherapy Michael Diestelhorst, MD,1 Jean-Philippe Nordmann, MD,2 and Carol B. Toris, PhD3 1
Department of Ophthalmology, University of Cologne, Cologne, Germany; 2Department of Ophthalmology, Quinze-Vingts Hospital, Paris, France; 3Department of Ophthalmology, University of Nebraska Medical Center, Omaha, Nebraska, USA Abstract. Adjunctive intraocular pressure (IOP)-lowering therapy is widely used today, as one-third of all patients being treated for glaucoma need additional therapy to reach and maintain healthy IOPs. Timolol, latanoprost, and pilocarpine are three potent drugs that have been used in combination to reduce IOP. Timolol reduces the production rate of aqueous humor to achieve the IOP decrease. Latanoprost and pilocarpine both affect aqueous outflow, although by different mechanisms. The IOP efficacy of combined therapy with timolol and pilocarpine compared with timolol and latanoprost or with latanoprost alone has been investigated in three multicenter, randomized, clinical trials in Europe. This is a review of those published trials. In 2 of the 3 studies, the additional IOP lowering effect of latanoprost 0.005% administered once daily was compared with pilocarpine 2% administered 3 times daily in patients with primary open-angle glaucoma (POAG) or ocular hypertension currently on monotherapy with timolol 0.5% twice daily. These 6-month studies found that the timolol and latanoprost combination reduced IOP more and was better tolerated with fewer side-effects than the timolol and pilocarpine combination. At 6 months, there was no evidence of long-term drift in IOP with timolol and latanoprost. This combined therapy provides an effective and safe option for lowering IOP in glaucoma patients. These results suggest that the timolol/latanoprost combination is preferable to the timolol/pilocarpine combination not only with regard to side effects but also to the magnitude of IOP reduction. Two of the 3 studies compared latanoprost monotherapy with timolol and pilocarpine combined therapy in patients with POAG, various other glaucomas, or ocular hypertension. Treatment was for 6 weeks or 6 months. In both studies, latanoprost was more effective and better tolerated than the combination of timolol and pilocarpine. These results suggest that latanoprost alone should be tried before the addition of pilocarpine to timolol therapy is considered. The convenience of daily administration of a single drop of latanoprost versus multiple drops of timolol and pilocarpine should improve patient compliance. (Surv Ophthalmol 47(Suppl 1):S155–S161, 2002. © 2002 by Elsevier Science Inc. All rights reserved.) Key words. glaucoma • intraocular pressure • latanoprost pilocarpine • prostaglandin analog • timolol
Until recently, -adrenergic antagonists, in general, and timolol, in particular, have been the drugs of choice to treat glaucoma and elevated intraocular pressure (IOP). They work by decreasing the production rate of ocular aqueous humor.6,12,13,29,38 In many patients, topical -antagonists alone are inef-
fective or insufficient in lowering IOP. Recently prostaglandin F2-analogs have been added to the therapeutic armamentarium of glaucoma patients. Latanoprost has been compared favorably with timolol, in large multicenter trials over a period of years.1,2,9–11,23,35–37,39 It reduces IOP predominantly by
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increasing the uveoscleral drainage of aqueous humor.17,24,33,34,40 Its effects on outflow along with timolol’s effects on inflow would be expected to provide potent IOP-lowering additivity. In theory and in practice, these drugs together reduce IOP more than each drug alone. Treatment with latanoprost 0.005% and timolol 0.5% is currently the most commonly used combination therapy. The IOP-lowering effect of this combination is reported to be in the range of 13% to 37% from baseline.3,5,20,22,28 Pilocarpine, a cholinergic agonist, is an outflow drug and, like latanoprost, would be expected to be additive to the inflow drug, timolol. Pilocarpine has been used for glaucoma therapy for decades and frequently is used as “add on” therapy. Miotic treatment causes contraction of the ciliary muscle, which pulls on the scleral spur and reduces the resistance in the trabecular meshwork. This increases aqueous humor outflow through the pressure-dependent pathway and thus reduces IOP.4 Studies of a fixed combination of timolol and pilocarpine found the combination to be more efficacious than either drug alone.26,31 It has been established that either latanoprost or pilocarpine combine well with timolol to improve the IOP effect needed in some patients whose IOPs are uncontrolled on other medications. From a clinical perspective, it may be of interest to know which of these combinations is the most effective. It has been noted that latanoprost given alone may be as efficacious as latanoprost in combination with other glaucoma medications.16 Following is a brief summary of 3 published multicenter clinical trials comparing the efficacy of combining timolol, with either latanoprost or pilocarpine or substituting combined therapy with latanoprost alone in reducing IOP. All studies reported that IRB approval was obtained from each center and informed consent was received from each patient, and there was no discussion regarding compliance.
Timolol Plus Pilocarpine Combined Therapy Versus Latanoprost Monotherapy A multicenter, randomized, observer-masked, 6-week trial of 237 patients was conducted in France and Sweden.25 Patients had primary open-angle glaucoma (POAG), exfoliation glaucoma, pigmentary glaucoma, mixed glaucoma, or ocular hypertension. At the prestudy visit, patients had an IOP of at least 22 mm Hg while on treatment with topical -adrenergic antagonists as monotherapy or in combination with other glaucoma medications. They were switched to timolol 0.5% twice daily if needed and treated for a 21-day run-in period. Patients were randomized to one of two 6-week parallel treatment groups. One group was switched from timolol to latanoprost
DIESTELHORST ET AL
0.005% once-daily in the evening and a second group received a fixed combination of timolol/pilocarpine twice daily. Statistical comparisons between and within groups were done using an analysis of covariance (ANCOVA). At 6 weeks of treatment, the mean diurnal IOP from measurements taken at 8 or 9 am, 12 noon, and 4 pm was significantly (p 0.001) decreased from baseline (timolol monotherapy) in both groups. Switching from timolol to latanoprost reduced the 8 am IOP by 21%. Switching from timolol to the timolol/pilocarpine fixed combination reduced the 8 am IOP by 23%. The mean diurnal IOP decrease from baseline was 22% in the latanoprost group and 20% in the fixed-combination group. This difference in IOP reduction between groups was not significant (p 0.24). Results are summarized in Table 1. Side effects, including blurred vision, decreased visual acuity, decreased twilight vision, and headache, were statistically significantly more frequent in the timolol/pilocarpine treatment group than the latanoprost group (p 0.001). Side effects caused 10 patients to drop out of the timolol/pilocarpine group and 2 patients to drop out of the latanoprost group (Table 2). There was no significant difference in occurrence of conjunctival hyperemia, corneal punctate erosions, or dizziness between the two groups. No cells and flare were reported for any patient during the study. It was concluded that latanoprost monotherapy was at least as effective as therapy with the fixed combination of timolol and pilocarpine in reducing mean diurnal IOP in patients not adequately controlled on topical -adrenergic antagonists. Latanoprost was better tolerated than timolol/pilocarpine.
Combined Therapies of Timolol Plus Latanoprost Versus Timolol Plus Pilocarpine A 6-month, multicenter, randomized, open-label study14 in Germany included patients with POAG and IOPs greater than 22 mm Hg, or ocular hypertension and IOPs greater than 26 mm Hg, on timolol 0.5% given twice daily. They were assigned to one of two treatment groups. In addition to the timolol, one group was treated with latanoprost 0.005% once daily in the evening and another group was treated with pilocarpine 2% three times daily. Diurnal IOPs were determined from measurements taken at 10 am, 2 pm and 4 pm. An analysis of covariance was used to compared diurnal IOPs within and between groups. The major findings in the study were that the diurnal IOP was reduced by 24% with the addition of latanoprost to timolol therapy and by 21% with the addition of pilocarpine. These IOP reductions in both groups were significant (p 0.001, Table 1).
25
POAG or pseudoexfoliation glaucoma uncontrolled on -adrenergic antagonists, run-in for 14 to 28 days with timolol 0.5%, bid
Bucci, et al7 45 37 46
49 50
104
121
49
75
95
119
121
102
118
Number Completed
added latanoprost 0.005%, qd, 6 months added piolocarpine 2%, tid, 6 months Switched to latanoprost 0.005%, qd, 6 months
added pilocarpine 2%, tid, 6 months added latanoprost 0.005%, qd, 6 months
switched to latanoprost 0.005%, QD, 6 weeks switched to timololpilocarpine bid, fixed combination, 6 weeks
Drugs and Treatment Regimen
0900, 1200, and 1600 hours
1000, 1400, and 1600 hours
0800 or 0900, 1200, and 1600 hours
Measurement Times
21.8
22.2
21.8
23.3
23.0
24.8
24.7
Baseline (Timolol Only)
16.3
18.0
15.7
17.8
18.5
19.2
19.4
Added/ Changed Therapy
25
19
28
24
21
23
21
% IOP Reduction from Baseline
BID twice-daily; IOP intraocular pressure; OHT ocular hypertension; POAG primary open-angle glaucoma; QD once daily; TID three times daily.
POAG or OHT, uncontrolled on timolol 0.5%, bid
POAG, various other glaucomas or OHT, uncontrolled on -adrenergic antagonists, run-in for 21 day with timolol 0.5%, bid
Subjects
Diestelhorst, et al14
Nordmann, et al
Study
Number Enrolled
Mean Diurnal IOP
Studies Comparing the IOP Effects of Combined Therapy of Timolol Plus Pilocarpine, Timolol Plus Latanoprost or Latanoprost Alone
TABLE 1
TIMOLOL COMBINED THERAPY VS. LANTANOPROST MONOTHERAPY S157
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DIESTELHORST ET AL TABLE 2
Medical Reasons for Withdrawal from Three Published Clinical Studies7,14,25 Comparing Treatment of Timolol and Pilocarpine With Timolol and Latanoprost and/or Latanoprost Alone Study Group
Reason Miosis Visual disturbance Blurred vision/eye pain Ocular discomfort Myopia Conjunctivitis/blepharitis Visual field defect Increased IOP Photopsia Cataract Dizziness Headache Vertigo Glomerulonephritis Unspecific malaise Acute dyspnea Conjunctival hyperemia with ocular discomfort
Timolol Pilocarpine Three studies7,14,25 n 219 16 11 14 3 2 2 1 1 1 1 1 9 2 1
Timolol Latanoprost Two studies7,14 n 153
Latanoprost Two studies7,25 n 152
1
2
1
1 1 3
1
1
Numbers listed for each adverse event indicate total number of reported occurrences for that group.
The 0.8 mm Hg difference between groups was significant (p 0.04) with the latanoprost group having the lower mean diurnal IOP. Thirty-eight patients in the latanoprost group and 106 patients in the pilocarpine group reported ocular adverse events. This difference between groups was significant (p 0.001). The total number of ocular adverse events reported was twice as many for the pilocarpine as the latanoprost group with 185 and 60 events, respectively (p 0.001). The authors reported that the most common adverse event in the latanoprost group was conjunctival hyperemia and in the pilocarpine group was miosis. The number of patients withdrawing from the study due to adverse events are listed in Table 2. The authors concluded that the addition of latanoprost to timolol therapy more effectively lowered IOP and was better tolerated than the addition of pilocarpine.
Latanoprost Monotherapy Versus Combined Therapies of Timolol Plus Latanoprost or Timolol Plus Pilocarpine A multicenter observer-masked randomized trial of patients in Italy enrolled 148 patients with POAG or pseudo-exfoliation glaucoma uncontrolled on topical -adrenergic antagonists.7 The specific IOP enrollment criteria were not reported. If necessary, patients were switched to timolol 0.5% twice daily
for a run-in period of 2 to 4 weeks. Patients were then assigned to one of three groups: one group received add-on therapy of latanoprost 0.005% once daily in the evening, another received add-on therapy of pilocarpine 2% three times daily, and the third group switched from timolol to latanoprost 0.005% once daily. Analysis of covariance was used to compare differences in diurnal IOP between treatments and reductions in IOP within treatments. The 6-month diurnal IOPs in the different treatment groups are summarized in Table 1. Adding pilocarpine to timolol treatment reduced diurnal IOP by 19%. Adding latanoprost to timolol treatment reduced diurnal IOP by 28%. Switching from timolol to latanoprost reduced diurnal IOP by 25%. The mean IOP reductions in all groups were statistically significant. The addition of latanoprost to timolol therapy achieved a significantly (p 0.001) greater IOP reduction than the addition of pilocarpine. Latanoprost alone produced a significantly (p 0.004) greater IOP decrease when compared with the pilocarpine/timolol combination and a similar decrease compared with the latanoprost/ timolol combination. At 6 months, 128 patients completed the study. More patients withdrew from the timolol plus pilocarpine group (12) than from the other two groups (4 each, Table 2). Ocular adverse events included blurred vision, eye pain, and reduced vision in the
TIMOLOL COMBINED THERAPY VS. LANTANOPROST MONOTHERAPY
timolol plus pilocarpine group; conjunctival hyperemia in all groups; conjunctivitis in both groups treated with latanoprost and increased IOP in the timolol plus latanoprost group. The investigators concluded that adding latanoprost to timolol therapy more effectively reduced IOP than adding pilocarpine to timolol therapy and it was better tolerated. Switching from timolol to latanoprost monotherapy was almost as effective as adding latanoprost to timolol therapy.
Discussion The studies summarized in this review were all in agreement that treating patients with a combination of timolol and latanoprost is preferable to the combination of timolol and pilocarpine in terms of IOP efficacy and ocular tolerability. Treatment with latanoprost alone is at least as effective as timolol plus pilocarpine and nearly as effective as timolol plus latanoprost. Since the discovery of the IOP-lowering effect of pilocarpine more than 140 years ago, parasympathomimetic agents have been a major cornerstone in the conservative management of POAG. For decades, the drug of first choice for the treatment of POAG was pilocarpine. The short duration of action of pilocarpine in the anterior segment of the eye indicates that three to four times daily application is necessary to control IOP. The most common dose is 2% four times daily. In heavily pigmented eyes, a higher concentration of 4% is necessary to render sufficient control of IOP. The preparation or formulation of pilocarpine affects considerably its retention time in the eye. Side effects are serious enough to significantly affect compliance. Headache, miosis, shifting myopia, ciliary spasm, brow ache, increased salivation, profuse perspiration, nausea, vomiting, bronchohypertension, pulmonary edema, systemic hypertension, bradycardia, abdominal pain, and diarrhea have been reported by patients. Cholinergic agonists, like pilocarpine, are not used as much today as they have been in the past because of the high percentage of ocular and systemic side effects, the inconvenience of frequent applications necessary to achieve a constant IOP reduction, and because of more therapeutic options on the market. Within the past 25 years, many highly effective ocular hypotensive drugs have been developed and approved for clinical use. Among others, these include -adrenergic antagonists and prostaglandin analogs. Timolol is the most often prescribed of the -blockers. It is usually given at a dose of 0.5% once or twice daily. Although effective at reducing IOP during the day, it does not work well at night.32 Its ocular adverse effects, although rare, include burning,
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stinging, conjunctival hyperemia, conjunctivitis, blepharitis, anesthetic effect, and dry eye. Systemic adverse effects occur but also are rare. These include headache, weakness, nausea, diarrhea, depression, cardiovascular and respiratory difficulties. In general, it is well tolerated by most patients. Latanoprost was one of the first topical prostaglandin F2 analogs to be approved for treatment of elevated IOP. It is effective at a dose of 0.005% once daily in the evening. Recently it was approved as firstline treatment in Europe. Because its ocular hypotensive mechanism of action is an increase in uveoscleral outflow,33 latanoprost and other prostaglandin analogs can produce a substantial additional reduction in IOP when added to treatment regimens consisting of topical or systemic ocular hypotensive agents that work by other mechanisms. Unlike timolol,32 latanoprost is as effective at night as during the day.27 Reducing IOP at night potentially has the added advantage of reducing glaucomatous damage during sleep when ocular perfusion pressure may be reduced secondarily to decreased systemic blood pressure.19 Because of its mechanism of action, latanoprost potentially can reduce IOP below episcleral venous pressure, unlike medications that increase outflow facility, like pilocarpine.21 This, along with its more favorable effect on ocular perfusion pressure, presents a potential advantage in normal-tension glaucoma, which may require very low IOPs for adequate control.15,18 Its proven ocular side effects include iris color darkening, eyelash changes, and mild conjunctival hyperemia.8 It is not known to have systemic side effects because of its low concentration and short half-life in the blood.30 Despite the general effectiveness of pilocarpine, timolol, and latanoprost, there are patients whose IOPs remain uncontrolled on monotherapy. Studies of the efficacy and tolerability of combinations of these drugs concluded that therapy with a combination of timolol and latanoprost is preferable to the combination of timolol and pilocarpine when considering number of times per day of administration and side effects. However, before additional therapy is tried on a patient uncontrolled on other medications, it may be advantageous to first switch to latanoprost monotherapy, which is administered once daily and is nearly as effective as combined therapy.
Method of Literature Search The references cited here were found via a literature search of Medline with use of various combinations of the words timolol, pilocarpine, latanoprost, additivity, clinical trials and glaucoma therapy. All languages were included in the search. The search was conducted in January 2002.
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References 1. Alm A: Comparative phase III clinical trial of latanoprost and timolol in patients with elevated intraocular pressure, in Samuelsson B, Ramwell PW, Paoletti R, et al (eds): Advances in Prostaglandin, Thromboxane, and Leukotriene Research. New York, Raven Press, Ltd, 1995, pp 527–32 2. Alm A, Camras CB, Watson PG: Phase III latanoprost studies in Scandinavia, the United Kingdom and the United States. Surv Ophthalmol 41:S105–S110, 1997 3. Alm A, Widengård I, Kjellgren D, et al: Latanoprost administered once daily caused a maintained reduction of intraocular pressure in glaucoma patients treated concomitantly with timolol. Br J Ophthalmol 79:12–6, 1995 4. Bill A, Wålinder P-E: The effects of pilocarpine on the dynamics of aqueous humor in a primate (Macaca irus). Invest Ophthalmol 5:170–5, 1966 5. Bron AM, Denis P, Nordmann J-P, et al: Additive IOP-reducing effect of latanoprost in patients insufficiently controlled on timolol. Acta Ophthalmol 79:289–93, 2001 6. Brubaker RF, Nagataki S, Bourne WM: Effect of chronically administered timolol on aqueous humor flow in patients with glaucoma. Ophthalmology 89:280–3, 1982 7. Bucci MG, the Italian Latanoprost Study Group: Intraocular pressure-lowering effects of latanoprost monotherapy versus latanoprost or pilocarpine in combination with timolol: a randomized, observer-masked multicenter study in patients with open-angle glaucoma. J Glaucoma 8:24–30, 1999 8. Camras CB: Safety and side-effects of latanoprost, in Weinreb RN, Kitazawa Y, Krieglstein GK (eds): Glaucoma in the 21st Century. London, Mosby International Limited, 2000, pp 201–11 9. Camras CB, Alm A, Watson PG, et al: Latanoprost, a prostaglandin analog, for glaucoma therapy: efficacy and safety after one year of treatment in 198 patients. Ophthalmology 103:1916–24, 1996 10. Camras CB, the United States Latanoprost Study Group: Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma. A six-month, masked, multicenter trial in the United States. Ophthalmology 103: 138–47, 1996 11. Camras CB, Wax MB, Ritch R, et al: Latanoprost treatment for glaucoma: effects of treating for 1 year and of switching from timolol. Am J Ophthalmol 126:390–9, 1998 12. Coakes RL, Brubaker RF: The mechanism of timolol in lowering intraocular pressure. In the normal eye. Arch Ophthalmol 96:2045–8, 1978 13. Dailey BA, Brubaker RF, Bourne WM: The effects of timolol maleate and acetazolamide on the rate of aqueous formation in normal human subjects. Am J Ophthalmol 93:232–7, 1982 14. Diestelhorst M, German Latanoprost Study Group: The additive intraocular pressure-lowering effect of latanoprost 0.005% once daily and pilocarpine 2% t.i.d. in patients with open-angle glaucoma or ocular hypertension. A 6-month, randomized, multicenter study. Graefes Arch Clin Exp Ophthalmol 238:433–9, 2000 15. Drance SM, Crichton A, Mills RP: Comparison of the effect of latanoprost 0.005% and timolol 0.5% on the calculated ocular perfusion pressure in patients with normal-tension glaucoma. Am J Ophthalmol 125:585–92, 1998 16. Emmerich K-H: Comparison of latanoprost monotherapy to dorzolamide combined with timolol in patients with glaucoma and ocular hypertension. A 3-month randomised study. Graefes Arch Clin Exp Ophthalmol 238:19–23, 2000 17. Gabelt BT, Kaufman PL: Prostaglandin F2a increases uveoscleral outflow in the cynomolgus monkey. Exp Eye Res 49: 389–402, 1989 18. Greve EL, Rulo AH, Drance SM, et al: Reduced intraocular pressure and increased ocular perfusion pressure in normal tension glaucoma: a review of short-term studies with three dose regimens of latanoprost treatment. Surv Ophthalmol 41:S89–S92, 1997 19. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WLM:
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Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 117: 603–24, 1994 Hoyng PFJ, Rulo A, Greve EL, et al: The additive intraocular pressure-lowering effect of latanoprost in combined therapy with other ocular hypotensive agents. Surv Ophthalmol 41: S93–S98, 1997 Kaufman PL, Crawford KS: Aqueous humor dynamics: how PGF2a lowers intraocular pressure, in Bito LZ, Stjernschantz J (eds): The Ocular Effects of Prostaglandins and Other Eicosanoids. New York, Alan R. Liss, Inc, 1989, pp 387–416 Larsson L-I: The effect on diurnal intraocular pressure of the fixed combination of latanoprost 0.005% and timolol 0.5% in patients with ocular hypertension. Acta Ophthalmol 79:125–8, 2001 Mishima HK, Masuda K, Kitazawa Y, et al: A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension. A 12 week study. Arch Ophthalmol 114:929–32, 1996 Nilsson SFE, Samuelsson M, Bill A, Stjernschantz J: Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2a-1-isopropylester in the cynomolgus monkey. Exp Eye Res 48:707–16, 1989 Nordmann J-P, Söderström M, Rouland J-F, et al: Comparison of the intraocular pressure lowering effect of latanoprost and a fixed combination of timolol-pilocarpine eye drops in patients insufficiently controlled with b adrenergic antagonists. Br J Ophthalmol 84:181–5, 2000 Puustjärvi TJ, Repo LP, The Scandinavian Timpilo Study Group: Timolol-pilocarpine fixed-ratio combinations in the treatment of chronic open angle glaucoma. A controlled multicenter study of 48 weeks. Arch Ophthalmol 110:1725–9, 1992 Rácz P, Ruzsonyi MR, Nagy ZT, et al: Around-the-clock intraocular pressure reduction with once-daily application of latanoprost by itself or in combination with timolol. Arch Ophthalmol 114:268–73, 1996 Rulo AH, Greve EL, Hoyng PF: Additive effect of latanoprost, a prostaglandin F2a analogue, and timolol in patients with elevated intraocular pressure. Br J Ophthalmol 78:899–902, 1994 Schenker HI, Yablonski ME, Podos SM, Linder L: Fluorophotometric study of epinephrine and timolol in human subjects. Arch Ophthalmol 99:1212–6, 1981 Sjöquist B, Stjernschantz J: Ocular and systemic pharmacokinetics of latanoprost in humans. Surv Ophthalmol 47(Suppl 1):S6-S12, 2002 Sturm A, Vogel R, Binkowitz B, The Timolol-Pilocarpine Clinical Study Groups: A fixed combination of timolol and pilocarpine: double-masked comparisons with timolol and with pilocarpine. J Glaucoma 1:7–13, 1992 Topper JE, Brubaker RF: Effects of timolol, epinephrine, and acetazolamide on aqueous flow during sleep. Invest Ophthalmol Vis Sci 26:1315–9, 1985 Toris CB, Camras CB, Yablonski ME: Effects of PhXA41, a new prostaglandin F2a analog, on aqueous humor dynamics in human eyes. Ophthalmology 100:1297–304, 1993 Toris CB, Camras CB, Yablonski ME, Brubaker RF: Effects of exogenous prostaglandins on aqueous humor dynamics and blood-aqueous barrier function. Surv Ophthalmol 41:S69– S75, 1997 Watson P, Stjernschantz J, the Latanoprost Study Group: A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. Ophthalmology 103:126–37, 1996 Watson PG, Stjernschantz J, UK Latanoprost Study Group: Intraocular pressure (IOP) reducing effect and side-effects of latanoprost and timolol. A six-month double-masked comparison. Ophthalmology 101:80, 1994 Watson PG, the Latanoprost Study Group: Latanoprost. Two years’ experience of its use in the United Kingdom. Ophthalmology 105:82–7, 1998 Yablonski ME, Zimmerman TJ, Waltman SR, Becker B: A fluorophotometric study of the effect of topical timolol on aqueous humor dynamics. Exp Eye Res 27:135–42, 1978 Zhang WY, Po ALW, Dua HS, Azuara-Blanco A: Meta-analy-
TIMOLOL COMBINED THERAPY VS. LANTANOPROST MONOTHERAPY sis of randomised controlled trials comparing latanoprost with timolol in the treatment of patients with open angle glaucoma or ocular hypertension. Br J Ophthalmol 85:983–90, 2001 40. Ziai N, Dolan JW, Kacere RD, Brubaker RF: The effects on aqueous dynamics of PhXA41, a new prostaglandin F2a analogue, after topical application in normal and ocular hypertensive human eyes. Arch Ophthalmol 111:1351–8, 1993
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The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: Michael Diestelhorst, MD, Department of Ophthalmology, University of Cologne, Joseph-Stelzmann-str 9, Cologne 50931 Germany. Email: [email protected].
Combined Therapy of Pilocarpine or Latanoprost with Timolol Versus Latanoprost Monotherapy Michael Diestelhorst, MD,1 Jean-Philippe Nordmann, MD,2 and Carol B. Toris, PhD3 1
Department of Ophthalmology, University of Cologne, Cologne, Germany; 2Department of Ophthalmology, Quinze-Vingts Hospital, Paris, France; 3Department of Ophthalmology, University of Nebraska Medical Center, Omaha, Nebraska, USA Abstract. Adjunctive intraocular pressure (IOP)-lowering therapy is widely used today, as one-third of all patients being treated for glaucoma need additional therapy to reach and maintain healthy IOPs. Timolol, latanoprost, and pilocarpine are three potent drugs that have been used in combination to reduce IOP. Timolol reduces the production rate of aqueous humor to achieve the IOP decrease. Latanoprost and pilocarpine both affect aqueous outflow, although by different mechanisms. The IOP efficacy of combined therapy with timolol and pilocarpine compared with timolol and latanoprost or with latanoprost alone has been investigated in three multicenter, randomized, clinical trials in Europe. This is a review of those published trials. In 2 of the 3 studies, the additional IOP lowering effect of latanoprost 0.005% administered once daily was compared with pilocarpine 2% administered 3 times daily in patients with primary open-angle glaucoma (POAG) or ocular hypertension currently on monotherapy with timolol 0.5% twice daily. These 6-month studies found that the timolol and latanoprost combination reduced IOP more and was better tolerated with fewer side-effects than the timolol and pilocarpine combination. At 6 months, there was no evidence of long-term drift in IOP with timolol and latanoprost. This combined therapy provides an effective and safe option for lowering IOP in glaucoma patients. These results suggest that the timolol/latanoprost combination is preferable to the timolol/pilocarpine combination not only with regard to side effects but also to the magnitude of IOP reduction. Two of the 3 studies compared latanoprost monotherapy with timolol and pilocarpine combined therapy in patients with POAG, various other glaucomas, or ocular hypertension. Treatment was for 6 weeks or 6 months. In both studies, latanoprost was more effective and better tolerated than the combination of timolol and pilocarpine. These results suggest that latanoprost alone should be tried before the addition of pilocarpine to timolol therapy is considered. The convenience of daily administration of a single drop of latanoprost versus multiple drops of timolol and pilocarpine should improve patient compliance. (Surv Ophthalmol 47(Suppl 1):S155–S161, 2002. © 2002 by Elsevier Science Inc. All rights reserved.) Key words. glaucoma • intraocular pressure • latanoprost pilocarpine • prostaglandin analog • timolol
Until recently, -adrenergic antagonists, in general, and timolol, in particular, have been the drugs of choice to treat glaucoma and elevated intraocular pressure (IOP). They work by decreasing the production rate of ocular aqueous humor.6,12,13,29,38 In many patients, topical -antagonists alone are inef-
fective or insufficient in lowering IOP. Recently prostaglandin F2-analogs have been added to the therapeutic armamentarium of glaucoma patients. Latanoprost has been compared favorably with timolol, in large multicenter trials over a period of years.1,2,9–11,23,35–37,39 It reduces IOP predominantly by
S155 © 2002 by Elsevier Science Inc. All rights reserved.
0039-6257/02/$–see front matter PII S0039-6257(02)00329-6
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increasing the uveoscleral drainage of aqueous humor.17,24,33,34,40 Its effects on outflow along with timolol’s effects on inflow would be expected to provide potent IOP-lowering additivity. In theory and in practice, these drugs together reduce IOP more than each drug alone. Treatment with latanoprost 0.005% and timolol 0.5% is currently the most commonly used combination therapy. The IOP-lowering effect of this combination is reported to be in the range of 13% to 37% from baseline.3,5,20,22,28 Pilocarpine, a cholinergic agonist, is an outflow drug and, like latanoprost, would be expected to be additive to the inflow drug, timolol. Pilocarpine has been used for glaucoma therapy for decades and frequently is used as “add on” therapy. Miotic treatment causes contraction of the ciliary muscle, which pulls on the scleral spur and reduces the resistance in the trabecular meshwork. This increases aqueous humor outflow through the pressure-dependent pathway and thus reduces IOP.4 Studies of a fixed combination of timolol and pilocarpine found the combination to be more efficacious than either drug alone.26,31 It has been established that either latanoprost or pilocarpine combine well with timolol to improve the IOP effect needed in some patients whose IOPs are uncontrolled on other medications. From a clinical perspective, it may be of interest to know which of these combinations is the most effective. It has been noted that latanoprost given alone may be as efficacious as latanoprost in combination with other glaucoma medications.16 Following is a brief summary of 3 published multicenter clinical trials comparing the efficacy of combining timolol, with either latanoprost or pilocarpine or substituting combined therapy with latanoprost alone in reducing IOP. All studies reported that IRB approval was obtained from each center and informed consent was received from each patient, and there was no discussion regarding compliance.
Timolol Plus Pilocarpine Combined Therapy Versus Latanoprost Monotherapy A multicenter, randomized, observer-masked, 6-week trial of 237 patients was conducted in France and Sweden.25 Patients had primary open-angle glaucoma (POAG), exfoliation glaucoma, pigmentary glaucoma, mixed glaucoma, or ocular hypertension. At the prestudy visit, patients had an IOP of at least 22 mm Hg while on treatment with topical -adrenergic antagonists as monotherapy or in combination with other glaucoma medications. They were switched to timolol 0.5% twice daily if needed and treated for a 21-day run-in period. Patients were randomized to one of two 6-week parallel treatment groups. One group was switched from timolol to latanoprost
DIESTELHORST ET AL
0.005% once-daily in the evening and a second group received a fixed combination of timolol/pilocarpine twice daily. Statistical comparisons between and within groups were done using an analysis of covariance (ANCOVA). At 6 weeks of treatment, the mean diurnal IOP from measurements taken at 8 or 9 am, 12 noon, and 4 pm was significantly (p 0.001) decreased from baseline (timolol monotherapy) in both groups. Switching from timolol to latanoprost reduced the 8 am IOP by 21%. Switching from timolol to the timolol/pilocarpine fixed combination reduced the 8 am IOP by 23%. The mean diurnal IOP decrease from baseline was 22% in the latanoprost group and 20% in the fixed-combination group. This difference in IOP reduction between groups was not significant (p 0.24). Results are summarized in Table 1. Side effects, including blurred vision, decreased visual acuity, decreased twilight vision, and headache, were statistically significantly more frequent in the timolol/pilocarpine treatment group than the latanoprost group (p 0.001). Side effects caused 10 patients to drop out of the timolol/pilocarpine group and 2 patients to drop out of the latanoprost group (Table 2). There was no significant difference in occurrence of conjunctival hyperemia, corneal punctate erosions, or dizziness between the two groups. No cells and flare were reported for any patient during the study. It was concluded that latanoprost monotherapy was at least as effective as therapy with the fixed combination of timolol and pilocarpine in reducing mean diurnal IOP in patients not adequately controlled on topical -adrenergic antagonists. Latanoprost was better tolerated than timolol/pilocarpine.
Combined Therapies of Timolol Plus Latanoprost Versus Timolol Plus Pilocarpine A 6-month, multicenter, randomized, open-label study14 in Germany included patients with POAG and IOPs greater than 22 mm Hg, or ocular hypertension and IOPs greater than 26 mm Hg, on timolol 0.5% given twice daily. They were assigned to one of two treatment groups. In addition to the timolol, one group was treated with latanoprost 0.005% once daily in the evening and another group was treated with pilocarpine 2% three times daily. Diurnal IOPs were determined from measurements taken at 10 am, 2 pm and 4 pm. An analysis of covariance was used to compared diurnal IOPs within and between groups. The major findings in the study were that the diurnal IOP was reduced by 24% with the addition of latanoprost to timolol therapy and by 21% with the addition of pilocarpine. These IOP reductions in both groups were significant (p 0.001, Table 1).
25
POAG or pseudoexfoliation glaucoma uncontrolled on -adrenergic antagonists, run-in for 14 to 28 days with timolol 0.5%, bid
Bucci, et al7 45 37 46
49 50
104
121
49
75
95
119
121
102
118
Number Completed
added latanoprost 0.005%, qd, 6 months added piolocarpine 2%, tid, 6 months Switched to latanoprost 0.005%, qd, 6 months
added pilocarpine 2%, tid, 6 months added latanoprost 0.005%, qd, 6 months
switched to latanoprost 0.005%, QD, 6 weeks switched to timololpilocarpine bid, fixed combination, 6 weeks
Drugs and Treatment Regimen
0900, 1200, and 1600 hours
1000, 1400, and 1600 hours
0800 or 0900, 1200, and 1600 hours
Measurement Times
21.8
22.2
21.8
23.3
23.0
24.8
24.7
Baseline (Timolol Only)
16.3
18.0
15.7
17.8
18.5
19.2
19.4
Added/ Changed Therapy
25
19
28
24
21
23
21
% IOP Reduction from Baseline
BID twice-daily; IOP intraocular pressure; OHT ocular hypertension; POAG primary open-angle glaucoma; QD once daily; TID three times daily.
POAG or OHT, uncontrolled on timolol 0.5%, bid
POAG, various other glaucomas or OHT, uncontrolled on -adrenergic antagonists, run-in for 21 day with timolol 0.5%, bid
Subjects
Diestelhorst, et al14
Nordmann, et al
Study
Number Enrolled
Mean Diurnal IOP
Studies Comparing the IOP Effects of Combined Therapy of Timolol Plus Pilocarpine, Timolol Plus Latanoprost or Latanoprost Alone
TABLE 1
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Medical Reasons for Withdrawal from Three Published Clinical Studies7,14,25 Comparing Treatment of Timolol and Pilocarpine With Timolol and Latanoprost and/or Latanoprost Alone Study Group
Reason Miosis Visual disturbance Blurred vision/eye pain Ocular discomfort Myopia Conjunctivitis/blepharitis Visual field defect Increased IOP Photopsia Cataract Dizziness Headache Vertigo Glomerulonephritis Unspecific malaise Acute dyspnea Conjunctival hyperemia with ocular discomfort
Timolol Pilocarpine Three studies7,14,25 n 219 16 11 14 3 2 2 1 1 1 1 1 9 2 1
Timolol Latanoprost Two studies7,14 n 153
Latanoprost Two studies7,25 n 152
1
2
1
1 1 3
1
1
Numbers listed for each adverse event indicate total number of reported occurrences for that group.
The 0.8 mm Hg difference between groups was significant (p 0.04) with the latanoprost group having the lower mean diurnal IOP. Thirty-eight patients in the latanoprost group and 106 patients in the pilocarpine group reported ocular adverse events. This difference between groups was significant (p 0.001). The total number of ocular adverse events reported was twice as many for the pilocarpine as the latanoprost group with 185 and 60 events, respectively (p 0.001). The authors reported that the most common adverse event in the latanoprost group was conjunctival hyperemia and in the pilocarpine group was miosis. The number of patients withdrawing from the study due to adverse events are listed in Table 2. The authors concluded that the addition of latanoprost to timolol therapy more effectively lowered IOP and was better tolerated than the addition of pilocarpine.
Latanoprost Monotherapy Versus Combined Therapies of Timolol Plus Latanoprost or Timolol Plus Pilocarpine A multicenter observer-masked randomized trial of patients in Italy enrolled 148 patients with POAG or pseudo-exfoliation glaucoma uncontrolled on topical -adrenergic antagonists.7 The specific IOP enrollment criteria were not reported. If necessary, patients were switched to timolol 0.5% twice daily
for a run-in period of 2 to 4 weeks. Patients were then assigned to one of three groups: one group received add-on therapy of latanoprost 0.005% once daily in the evening, another received add-on therapy of pilocarpine 2% three times daily, and the third group switched from timolol to latanoprost 0.005% once daily. Analysis of covariance was used to compare differences in diurnal IOP between treatments and reductions in IOP within treatments. The 6-month diurnal IOPs in the different treatment groups are summarized in Table 1. Adding pilocarpine to timolol treatment reduced diurnal IOP by 19%. Adding latanoprost to timolol treatment reduced diurnal IOP by 28%. Switching from timolol to latanoprost reduced diurnal IOP by 25%. The mean IOP reductions in all groups were statistically significant. The addition of latanoprost to timolol therapy achieved a significantly (p 0.001) greater IOP reduction than the addition of pilocarpine. Latanoprost alone produced a significantly (p 0.004) greater IOP decrease when compared with the pilocarpine/timolol combination and a similar decrease compared with the latanoprost/ timolol combination. At 6 months, 128 patients completed the study. More patients withdrew from the timolol plus pilocarpine group (12) than from the other two groups (4 each, Table 2). Ocular adverse events included blurred vision, eye pain, and reduced vision in the
TIMOLOL COMBINED THERAPY VS. LANTANOPROST MONOTHERAPY
timolol plus pilocarpine group; conjunctival hyperemia in all groups; conjunctivitis in both groups treated with latanoprost and increased IOP in the timolol plus latanoprost group. The investigators concluded that adding latanoprost to timolol therapy more effectively reduced IOP than adding pilocarpine to timolol therapy and it was better tolerated. Switching from timolol to latanoprost monotherapy was almost as effective as adding latanoprost to timolol therapy.
Discussion The studies summarized in this review were all in agreement that treating patients with a combination of timolol and latanoprost is preferable to the combination of timolol and pilocarpine in terms of IOP efficacy and ocular tolerability. Treatment with latanoprost alone is at least as effective as timolol plus pilocarpine and nearly as effective as timolol plus latanoprost. Since the discovery of the IOP-lowering effect of pilocarpine more than 140 years ago, parasympathomimetic agents have been a major cornerstone in the conservative management of POAG. For decades, the drug of first choice for the treatment of POAG was pilocarpine. The short duration of action of pilocarpine in the anterior segment of the eye indicates that three to four times daily application is necessary to control IOP. The most common dose is 2% four times daily. In heavily pigmented eyes, a higher concentration of 4% is necessary to render sufficient control of IOP. The preparation or formulation of pilocarpine affects considerably its retention time in the eye. Side effects are serious enough to significantly affect compliance. Headache, miosis, shifting myopia, ciliary spasm, brow ache, increased salivation, profuse perspiration, nausea, vomiting, bronchohypertension, pulmonary edema, systemic hypertension, bradycardia, abdominal pain, and diarrhea have been reported by patients. Cholinergic agonists, like pilocarpine, are not used as much today as they have been in the past because of the high percentage of ocular and systemic side effects, the inconvenience of frequent applications necessary to achieve a constant IOP reduction, and because of more therapeutic options on the market. Within the past 25 years, many highly effective ocular hypotensive drugs have been developed and approved for clinical use. Among others, these include -adrenergic antagonists and prostaglandin analogs. Timolol is the most often prescribed of the -blockers. It is usually given at a dose of 0.5% once or twice daily. Although effective at reducing IOP during the day, it does not work well at night.32 Its ocular adverse effects, although rare, include burning,
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stinging, conjunctival hyperemia, conjunctivitis, blepharitis, anesthetic effect, and dry eye. Systemic adverse effects occur but also are rare. These include headache, weakness, nausea, diarrhea, depression, cardiovascular and respiratory difficulties. In general, it is well tolerated by most patients. Latanoprost was one of the first topical prostaglandin F2 analogs to be approved for treatment of elevated IOP. It is effective at a dose of 0.005% once daily in the evening. Recently it was approved as firstline treatment in Europe. Because its ocular hypotensive mechanism of action is an increase in uveoscleral outflow,33 latanoprost and other prostaglandin analogs can produce a substantial additional reduction in IOP when added to treatment regimens consisting of topical or systemic ocular hypotensive agents that work by other mechanisms. Unlike timolol,32 latanoprost is as effective at night as during the day.27 Reducing IOP at night potentially has the added advantage of reducing glaucomatous damage during sleep when ocular perfusion pressure may be reduced secondarily to decreased systemic blood pressure.19 Because of its mechanism of action, latanoprost potentially can reduce IOP below episcleral venous pressure, unlike medications that increase outflow facility, like pilocarpine.21 This, along with its more favorable effect on ocular perfusion pressure, presents a potential advantage in normal-tension glaucoma, which may require very low IOPs for adequate control.15,18 Its proven ocular side effects include iris color darkening, eyelash changes, and mild conjunctival hyperemia.8 It is not known to have systemic side effects because of its low concentration and short half-life in the blood.30 Despite the general effectiveness of pilocarpine, timolol, and latanoprost, there are patients whose IOPs remain uncontrolled on monotherapy. Studies of the efficacy and tolerability of combinations of these drugs concluded that therapy with a combination of timolol and latanoprost is preferable to the combination of timolol and pilocarpine when considering number of times per day of administration and side effects. However, before additional therapy is tried on a patient uncontrolled on other medications, it may be advantageous to first switch to latanoprost monotherapy, which is administered once daily and is nearly as effective as combined therapy.
Method of Literature Search The references cited here were found via a literature search of Medline with use of various combinations of the words timolol, pilocarpine, latanoprost, additivity, clinical trials and glaucoma therapy. All languages were included in the search. The search was conducted in January 2002.
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The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: Michael Diestelhorst, MD, Department of Ophthalmology, University of Cologne, Joseph-Stelzmann-str 9, Cologne 50931 Germany. Email: [email protected].