Switching Within Glaucoma Medication Class Simon K

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Switching within glaucoma medication class Simon K. Law

Jules Stein Eye Institute, University of California, Los Purpose of review Angeles, California, USA In the current medical care environment, switching within class is often demanded by Correspondence to Simon K. Law, MD, 100 Stein cost consideration, medical insurance coverage, or formulary restriction. With many Plaza #2-235, Jules Stein Eye Institute, Los Angeles, CA 90095, USA choices of drugs available within a glaucoma medication class, questions exist whether Tel: +1 310 794 1477; fax: +1 310 206 7773; switching within class is beneficial. The purpose of this article is to provide a e-mail: [email protected] clinical update on the feasibility of switching among the frequently used drugs within Current Opinion in Ophthalmology 2009, glaucoma medication class. 20:110–115 Recent findings Although efficacies of medications within a therapeutic class are similar and significant differences are generally not observed in clinical trials, response to medication often varies among individual patients in a clinical practice. Such variation may be secondary to differences in drug–receptor interactions, patient’s compliance and tolerability to medical treatment, or bioavailability of the medication in individual ocular condition. In addition, switching within class is often necessary to minimize the systemic or local adverse reactions from the active or inactive ingredients of the medication. Summary In addition to keeping up-to-date with the efficacy and safety profiles of drugs within each glaucoma medication class, clinicians should familiarize themselves with the different formulations available, preservative systems used, generics availability and compatibility, and the local insurance formulary restriction to deliver an effective glaucoma management.

Keywords class, glaucoma, medication, switch, therapy

Curr Opin Ophthalmol 20:110–115 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-8738

prostaglandin analogs for glaucoma management include Introduction latanoprost, travoprost, bimatoprost, and unoprostone. When the intraocular pressure (IOP) is not adequately The efficacies of latanoprost, travoprost, and bimatoprost controlled by one class of glaucoma medication or the are similar with IOP reduction of almost 30%; and dosed side-effect is not tolerable, the usual practice is to switch once daily, they have demonstrated superiority than to another class of glaucoma medication with a different timolol [1]. Unoprostone, however, is dosed twice daily mechanism of action. However, because there are many and with IOP reduction only comparable with betaxolol choices of drugs available within each glaucoma medi- but not timolol [2]. In a meta-analysis [1] of randomized cation class, switching within class is a reasonable con- clinical trials to estimate the IOP reduction achieved by sideration. In addition, switching within class is often the most frequently prescribed glaucoma drugs, includ- demanded by cost consideration, insurance coverage, or ing latanoprost, travoprost, and bimatoprost, IOP was formulary restriction, in the current medical care environ- reduced from baseline by 31–33% for the peak and ment. The purpose of this article is to provide a clinical 28–29% for the trough with topical prostaglandin analogs, update on the feasibility of switching within glaucoma and bimatoprost achieved the highest reduction of IOP at medication class with discussion focused on the fre- peak. There are studies showing that bimatoprost may be quently used drugs. slightly more effective than latanoprost and travoprost. For example, in a randomized, double-blinded crossover comparison [3] of bimatoprost and latanoprost, the Prostaglandin analogs 24-h diurnal IOP is statistically lower with bimatoprost Prostaglandin analogs are the most potent ocular hypo- than latanoprost. However, the difference was small tensive agent yet discovered. The primary mechanism of (0.5 mmHg) and may not be clinically meaningful. When action of prostaglandin analogs is believed to reduce IOP the three prostaglandin analogs were compared in a by increasing uveoscleral outflow, but they may have 12-week study [4], no statistical differences were effects on trabecular outflow also. Commercially available observed between them in mean IOP. Travoprost, which

1040-8738 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/ICU.0b013e32831d1fc7

has the highest affinity to PGF2a (FP) receptor, has been iris pigmentation and eyelash changes associated with shown to significantly reduce the IOP below baseline even unoprostone was lower than latanoprost, and probably 60 h after the last dose of a 2-week once-daily therapy [5]. other prostaglandin analogs [4,17–22]. However, similar study has not yet been conducted for bimatoprost and latanoprost and the three prostaglandin Travoprost is available both with and without benzalk- analogs are supposed to be dosed once daily. onium chloride (BAK) as preservative. The travoprost BAK-free solution uses sofZia as the preservative system, Although the efficacies of the three prostaglandin analogs and is the only prostaglandin analog that does not contain are similar in the study populations of clinical trials, BAK. It may be worth switching a patient who developed variable response to prostaglandin analogs in individual allergic reaction to prostaglandin analogs with BAK or has patients is occasionally observed in clinical practice. In a ocular surface disease associated with BAK to travoprost retrospective review [6] of more than 300 patients in a BAK-free solution. However, the rates of adverse events, health management organization that had switched all hyperemia, and discontinuation were not found to be patients from latanoprost to bimatoprost, approximately different between travoprost with or without BAK in 13% of patients had a further IOP reduction of more than phase 3 trial [23]. Careful monitoring for adverse 3 mmHg after switching from latanoprost to bimatoprost reactions is necessary after switching. compared with 5% of patients who had a more than 3 mmHg reduction while using latanoprost before the switch. Variation in patient’s response with bimatoprost b-Adrenergic antagonists was suggested to be a result of the interaction of bimato- Because timolol was noted to markedly reduce IOP in prost with a receptor for prostamides instead of the FP glaucoma patients in the 70s, several b-adrenergic receptor for prostaglandins. Cantor et al. [7] noted that the antagonists were marketed, which include timolol, levo- level of bimatoprost acid, which can bind to FP receptor, bunolol, metipranolol, carteolol, and betaxolol. Efficacies detected in aqueous from cataract patients was too low for a of IOP reduction among the b-adrenergic antagonists are significant IOP reduction effect. Studies [8,9] showed equivalent except for betaxolol, which most studies have that the in-vitro effect of bimatoprost on trabecular mesh- shown to be slightly less effective in reducing aqueous work was blocked by prostamide-selective antagonist. flow and decreasing IOP than timolol [24–26]. When However, other studies [10,11,12] found that the contrac- patients are switched from timolol to betaxolol or tility effect of bimatoprost on the human ciliary muscle was randomized to one versus the other, IOP is often about blocked by FP-receptor antagonist, and none of the com- 2 mmHg higher in the timolol-treated eyes. Therefore, if mercially available topical prostaglandin analogs had effect a stronger IOP reduction is needed in patients taking on IOP in FP-receptor-deficient mice. In addition, a betaxolol, switching to timolol may be considered. How- receptor specifically for bimatoprost has not yet been ever, betaxolol is the only selective b-adrenergic anta- identified, and its existence remains controversial. Another gonist available for topical ophthalmic use. It is often possible mechanism of variation in response to prostaglan- termed cardioselective because of its relative affinity for din analogs is single-nucleotide polymorphisms in the the b1 (cardiac) over the b2 (pulmonary) adrenergic FP-receptor gene. Although prostaglandin analogs are receptor. In patients who had mild pulmonary distress generally effective in reducing the IOP, low responders with other nonselective b-adrenergic antagonists, switch- or nonresponders to latanoprost were identified from 4 ing to betaxolol may provide a relief [27–30]. However, to 32% in different populations [13,14]. In healthy caution is advised because it certainly can provoke volunteers, who were low responders to latanoprost, single- bronchospasm [31,32]. Betaxolol is available in either a nucleotide polymorphisms in the FP-receptor gene corre- suspension form or solution form. The suspension form lated to lower transcriptional activity of the FP-receptor has longer half-life, is dosed once a day, and has a lower gene were identified [15,16]. On the basis of the notion overall systemic absorption. that patient’s response to medication varies individually, switching to another prostaglandin analogs may be justified Carteolol, unlike the other topical b-adrenergic if the IOP response to a prostaglandin analog is deemed antagonists, also demonstrates weak intrinsic sympatho- suboptimum. mimetic activity (ISA), causing an early transient agonist response. This ISA theoretically reduces bronchoconstric- Consideration of switching within the prostaglandin ana- tion and bradycardia, improves blood flow, and produces logs class is often based on the tolerability and compli- less alteration of the serum lipid profile [33,34]. However, ance. There are differences in the rates of local adverse the clinical significance is uncertain. reactions among the prostaglandin analogs. For example, significantly more conjunctival hyperemia and increased Timolol is available as maleate salt and hemihydrate eyelash growth were reported with bimatoprost and salt, which are considered to be different drugs, but travoprost than with latanoporst, but the incidence of their efficacies are equivalent and they can be used

interchangeably. Timolol maleate is also available in a gel- prevent IOP spikes after anterior segment laser. Brimo- forming solution as Timoptic XE (Merck & Co. Inc., West nidine is as effective as apraclonidine in preventing the Point, Pennsylvania, USA) as gellen gum gel-forming acute IOP spikes [40,41]. Apraclonidine is available as solution, or Timolol GFS (Alcon Laboratories Inc., Forth 1% in 0.1-ml dropperettes for a short-term administration Worth, Texas, USA) as xantham gum gel-forming solution. and concentrations of 0.5% in 5-ml bottles for long-term The gel formed with these two products increases the use. For chronic medical treatment, the current recom- contact time and bioavailability to achieve a longer action mendation is to instill 0.5% solution twice daily or three and they are approved for once-daily use. However, most times daily, although tachyphylaxis or loss of pressure- patients can achieve an adequate IOP reduction response lowering effect severely limits its long-term efﬁcacy. with the solution form of timolol in once-daily dosing Tachyphylaxis may occur after chronic use of brimoni- schedule [35,36]. The gel-forming preparation may have dine and the rate and duration it takes for this to occur are less systemic absorption. A study showed that the plasma uncertain, but the magnitude and frequency are certainly level of timolol and heart-rate effects from the gel-forming lower than apraclonidine. If tachyphylaxis occurs with preparation were lower than those from the solution apraclonidine, switching to brimonidine may resume the following 1 week of therapy [37]. IOP reduction effect.

Most available timolol solutions contain benzalkonium Brimonidine has higher ratio of a2-to-a1 activity than chloride 0.01% as a preservative, except Istalol (timolol apraclonidine and lower rate of local allergy rate than maleate 0.5%), which uses 0.005% benzalkonium chloride. apraclonidine [42,43]. However, brimonidine tartrate is a Preservative-free timolol dropperettes are available selective a2-agonist that is more lipophilic and has a from Merck & Co. The gel-forming formulations use higher rate of penetration across the blood–brain barrier benzododecinium bromide as preservative. Patients than apraclonidine and stronger sedative effect [44]. If on b-adrenergic antagonists who developed allergic the sedative effect with brimonidinen is intolerable, reaction to benzalkonium chloride may benefit from switching to apraclonidine may be considered. switching to preservative-free timolol dropperettes or gel-forming formulations of timolol. The major local reaction seen with apraclonidine and brimonidine use is an allergic conjunctivitis or periocular Although transient blurred vision following adminis- dermatitis. A mechanism for the high propensity of tration is a common adverse effect associated with topical apraclonidine to produce local allergy has been proposed. b-adrenergic antagonists, timolol gel-forming pre- It appears that bioactivation of the drug through oxidation parations may have additional blurring effect because occurs to a bis-iminoquinone, which conjugates with of the gel formed on ocular surface. Patients may also proteins to form immunologically active aproclonidine- report crusting of the lashes and foreign body sensation protein haptens. Brimonidine, on the other hand, has a with the gel-forming preparations, and may benefit from much lower oxidative potential, which may explain bri- switching to the solution form. In either case, patients monidine’s reduced tendency to produce local allergic should be instructed on the techniques of passive eyelid reactions [45]. It is possible that there is little cross- closure or active nasolacrimal occlusion to reduce systemic allergic reactivity between the immunologically drug- absorption [38]. protein haptens of apraclonidine and brimonidine. Several studies [46–48] have shown that patients that have allergic reactions to apraclonidine could be safely a-Adrenergic agonists treated with brimonidine. However, there are no data on Epinephrine or adrenaline is a nonselective a-adrenergic the safety of using apraclonidine in glaucoma patients agonist and b-adrenergic agonist. Dipivefrin is a prodrug with brimonidine allergy. Careful monitoring of the local of epinephrine that enhances local bioavailability and side-effects is required when switching from one reduces systemic side-effects. Systemic reactions are a2-agonist to another, especially if the patient is already common with epinephrine preparations and include sensitized to either one. tachycardia, hypertension, and arrhythmias. Cardiovas- cular side-effects are, for the most part, greatly reduced Brimonidine is marketed as brimonidine 0.2% solution with dipivefrin compared with epinephrine use. How- with BAK as the preservative and 0.15 and 0.1% as ever, because the a2-selective adrenergic agonists are Alphagan-P (Allergan Inc., Irvine, California, USA) with more potent and with fewer systemic side-effects, switch- purite as the preservative with the hope of reducing side- ing from dipivefrin to a2-selective adrenergic agonists effects associated with BAK. The manufacturer reports such as apraclonidine and brimonidine is recommended. an allergy rate of approximately 10–20% associated with brimonidine 0.15% with purite compared with 10–30% Apraclonidine and brimonidine have similar efficacy [39]. with brimonidine 0.2% with BAK [49]. However, the Apraclonidine was initially approved by the FDA to allergic reaction associated with brimonidine may be

caused by the immunologically active drug-protein zolamide may not have to be adjusted in patients with haptens instead of the preservatives. A patient known renal insufﬁciency [56]. For acute situations, where rapid to be allergic to brimonidine with BAK should discon- IOP lowering is desired, the longer onset of action seen tinue the medication instead of switching to brimonidine with methazolamide makes the drug less useful than with purite or vice versa. acetazolamide. But for long-term use, switching from acetazolamide to methazolamide is preferable.

Carbonic anhydrase inhibitors Systemic administration of CAIs is associated with a Carbonic anhydrase inhibitors (CAIs) are the only glau- higher rate of systemic side-effects than the topical coma medication class that has a topical preparation and formulation. However, in patients with ocular surface an oral and intravenous preparations for systemic admin- disease, an acute increase of IOP, patients who are on istration. Commercially available systemic CAIs include multiple topical medications or who require more reliable oral acetazolamide and methazolamide. Acetazolamide IOP control when awaiting glaucoma surgery, switching may also be administered intravenously. Topical CAIs from topical to oral CAIs temporally may be warranted. include dorzolaimde and brinzolamide. The two topical CAIs, dorzolamide and brinzolamide, are Systemic acetazolamide reduced aqueous flow in glau- similar in efficacy, but slightly different in tolerability. In coma patients more than topical dorzolamide as measured a study comparing the ocular comfort of TID-dosed by fluorophotometry [50]. Two proposed reasons may brinzolamide 1.0% and TID-dosed dorzolamide 2.0% account for the stronger effect of systemic CAIs. First, in patients with primary open angle glaucoma, complaints the metabolic acidosis induced by oral CAIs may inde- of ocular hyperemia and tearing were associated more pendently lower IOP [51]. The mechanism for this is with dorzolamide use and foreign-body sensation and unknown. Second, in addition to inhibition of carbonic blurred vision were more with brinzolamide use [57– anhydrase isozyme II, which is primarily responsible for 59]. The reduced hyperemia and tearing associated with aqueous humor production, there may be inhibition of brinzolamide may be secondary to the more neutral pH other isozymes that contribute to aqueous production [52]. than does dorzolamide, and the higher rate of blurred However, clinical trials did not observe a significant differ- vision may be related to the nature of the suspension of ence in regard to IOP reduction between the oral and brinzolamide. Switching between these two agents may topical forms [53,54]. It is important to note that the be based on tolerability. compliance to the regimen being studied and patient’s characteristics in clinical trials are often different from Dorzolamide is also available as generic, whereas brin- those of the general patient population in a clinical prac- zolamide is not. Patients who have IOP controlled on tice, and individual patients may have a stronger response brinzolamide may be switched to the generic dorzolamide with systemic CAIs. and still maintain similar pressure control.

Acetazolamide 250 mg and methazolamide 50 mg equiva- lently inhibit carbonic anhydrase. However, the greater Parasympathomimetics metabolic acidosis associated with acetazolamide can Parasympathomimetics have been supplanted by newer result in a slightly lower IOP than seen with methazola- medications that can be dosed less frequently and with mide. Because methazolamide is less bound to plasma fewer ocular and systemic side-effects. However, it protein, a relatively lower dose is needed to produce remains an important glaucoma medication class because therapeutic levels of carbonic anhydrase enzyme inhi- of its effectiveness in IOP reduction. Topical parasym- bition within the ciliary processes. Because of the exces- pathomimetics available in the United States include sive concentration of enzyme within the kidney, renal pilocarpine HCl, carbachol, and echothiophate iodide. effects of bicarbonate loss from carbonic anhydrase Other agents such as aceclidine, demecarium, physostig- inhibition may be avoided with a moderate dose of mine, and pilocarpine nitrate are either not available or methazolamide. Theoretically, methazolamide has other not used in the United States. pharmacological advantages over acetazolamide, such as better gastric absorption and easier access into ocular Pilocarpine is a direct-acting muscarinic drug, whereas tissue because of a more favorable partition coefﬁcient. carbachol is both a direct-acting muscarinic agonist and a It also has a longer duration of action (half-life equals 14 h direct-acting nicotinic agonist and has indirect agonist or approximately double the half-life of acetazolamide), activities. Echothiophate, on the other hand, is an indir- so that it can be administered twice daily [55]. Acetazo- ect, long-acting drug. The duration of action of IOP lamide is excreted as intact drug by the kidney, whereas reduction up to days with echothiophate is much longer methazolamide is metabolized by the liver (only 25% is than that with pilocarpine and carbachol, which lasts excreted by the kidney); therefore, the dosage of metha- for hours. Controlled-release pilocarpine aqueous gel

polymer contains 4% pilocarpine in a slow-release gel and 5 Gross JL, Peace JH, Smith SE, et al. Duration of IOP reduction with travoprost BAK-free solution. J Glaucoma 2008; 17:217–222. prolongs ocular duration to 18–24 h [60]. When used at This study showed the long duration of IOP reduction effect of travoprost. It may bedtime, much of the myopia and miosis will have stimulate interest to conduct similar study on other prostaglandin analogs. dissipated by the time the patient awakens and will 6 Law SK, Song J, Fang E, et al. Feasibility and efficacy of a mass switch from latanoprost to bimatoprost in glaucoma patients in a prepaid health main- remain relatively constant throughout the day. Another tenance organization. Ophthalmology 2005; 112:2123–2130. controlled-release pilocarpine polymer is the Ocusert that 7 Cantor LB, Hoop J, Wudunn D, et al. Levels of bimatoprost acid in the releases pilocarpine at either 20 or 40 mg/h with essen- aqueous humour after bimatoprost treatment of patients with cataract. Br J Ophthalmol 2007; 91:629–632. tially zero-order kinetics [61,62]. Switching from other Although a low level of bimatoprost acid was detectable in the aqueous humor, topical parasympathomimetics to the gel polymer of these authors argued that the level was too low to have a significant effect. pilocarpine or Ocusert is practical in younger glaucoma 8 Woodward DF, Krauss AH, Wang JW, et al. Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin-ethanolamides) in patients who visually benefit from the relatively constant the feline iris. Br J Pharmacol 2007; 150:342–352. This study showed that prostamide-selective antagonist blocked the effects of mild induced myopia, can tolerate the low-grade miosis, bimatoprost, but not of FP receptor agonist, implying the presence of a different and can readily adapt to placing and retaining the plastic receptor for bimatoprost than the FP receptor as for prostaglandins. ovoid disc in their conjunctival cul-de-sac [63,64]. How- 9 Wan Z, Woodward DF, Cornell CL, et al. Bimatoprost, prostamide activity, and conventional drainage. Invest Ophthalmol Vis Sci 2007; 48:4107–4115. ever, Ocusert is no longer manufactured and gel polymer This study showed that prostamide-selective antagonist blocked the in-vitro effect of pilocarpine is not readily available. of bimatoprost on trabecular meshwork. 10 Romano MR, Lograno MD. Evidence for the involvement of cannabinoid CB1 receptors in the bimatoprost-induced contractions on the human isolated ciliary muscle. Invest Ophthalmol Vis Sci 2007; 48:3677–3682. Conclusion This study showed that the bimatoprost-induced contractions on the human Drugs within a glaucoma medication class share similar isolated ciliary muscle was blocked by FP receptor antagonist, implying that mechanism of action and efficacy. Switching medication bimatoprost may exert its effect by interacting with FP receptor. 11 Ota T, Aihara M, Saeki T, et al. The effects of prostaglandin analogues on within class generally does not result in a clinically prostanoid EP1, EP2, and EP3 receptor-deficient mice. Invest Ophthalmol Vis significant difference in IOP reduction. However, Sci 2006; 47:3395–3399. response to medication varies among individual patients 12 Crowston JG, Lindsey JD, Morris CA, et al. Effect of bimatoprost on intraocular pressure in prostaglandin FP receptor knockout mice. Invest Ophthalmol and switching within a glaucoma medication class Vis Sci 2005; 46:4571–4577. occasionally provides a desirable response. More often, 13 Rossetti L, Gandolfi S, Traverso C, et al. An evaluation of the rate of switching within class is necessary to minimize the nonresponders to latanoprost therapy. J Glaucoma 2006; 15:238–243. systemic or local adverse reactions. Aside from being 14 Ikeda Y, Mori K, Ishibashi T, et al. Latanoprost nonresponders with open-angle glaucoma in the Japanese population. Jpn J Ophthalmol 2006; 50:153– knowledgeable with the efficacy and safety profile of 157. drugs, clinicians should also be familiar with the different 15 Sakurai M, Higashide T, Takahashi M, Sugiyama K. Association between formulations available, preservative systems used, gener- genetic polymorphisms of the prostaglandin F2alpha receptor gene and response to latanoprost. Ophthalmology 2007; 114:1039–1045. ics availability and compatibility, and the formulary restric- This study identified genetic polymorphisms of the receptor gene as a possible tion of local medical insurance to provide an effective cause of the variation of response to latanoprost. Similar genetic variation may explain the difference in response with other medications. glaucoma management. 16 Peng HB, Zahary MN, Tajudin LS, et al. A novel single nucleotide polymorph- ism, IVS2-97A>T, in the prostaglandin F2alpha receptor gene was identified among the Malaysian patients with glaucoma. Kobe J Med Sci 2007; 53:49– Acknowledgement 52. Author has no proprietary interest in the development or marketing of 17 Gandolfi S, Simmons ST, Sturm R, et al. Three-month comparison of bima- any of the products or devices mentioned in the study. toprost and latanoprost in patients with glaucoma and ocular hypertension. Adv Ther 2001; 18:110–121. 18 Netland PA, Landry T, Sullivan EK, et al. Travoprost compared with latano- References and recommended reading prost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol 2001; 132:472–484. Papers of particular interest, published within the annual period of review, have been highlighted as: 19 Noecker RS, Dirks MS, Choplin NT, et al., Bimatoprost/Latanoprost Study of special interest Group. A six-month randomized clinical trial comparing the intraocular pres- of outstanding interest sure-lowering efficacy of bimatoprost and lantanoprost in patients with ocular Additional references related to this topic can also be found in the Current hypertension or glaucoma. Am J Ophthalmol 2003; 135:55–63. World Literature section in this issue (p. 137). 20 Stewart WC, Kolker AE, Stewart JA, et al. Conjunctical hyperemia in healthy subjects after short-term dosing with latanoprost, bimatoprost, and travoprost. 1 van der Valk R, Webers CAB, Schouten JSAG, et al. 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