An Update on Bimatoprost (Lumigan®) in Glaucoma Therapy

DRUG PROFILE

An update on bimatoprost (Lumigan®) in glaucoma therapy

Robert J Noecker, MD†1 The prostamide bimatoprost (Lumigan®, Allergan Inc.) has been proven highly effective as and Melissa L Earl, MPH2 monotherapy, adjunctive, and replacement therapy for lowering intraocular pressure (IOP) †1Department of and providing good diurnal control of IOP in patients with open-angle glaucoma and Ophthalmology, University of Arizona, Tucson, Arizona ocular hypertension. Target pressure results from large, randomized, multicenter clinical 85711, USA. trials comparing bimatoprost with timolol, latanoprost (Xalatan®, Pharmacia & Upjohn), [email protected] travoprost (Travatan®, Alcon laboratories), fixed combination timolol/dorzolamide 2 Director, Innovative Medical (Cosopt®, Merck Inc.) or latanoprost and timolol gel have been analyzed. In each of the & Epidemiologic Data Solutions (IMEDS), analyses, patients were more likely to achieve low target pressures with bimatoprost than 12625 Frederick St. with the other medications. Patients on bimatoprost therapy achieve low IOP levels that Suite I-5 334 Moreno Valley, are maintained throughout the day and night, and long-term trials have shown that the CA 92553, USA Tel.: +1 909 786 0403 efficacy of bimatoprost is sustained. Bimatoprost has been proven to be safe and well Fax: +1 909 786 0439 tolerated in postmarketing surveillance and, as a once-daily drug, allows for patient [email protected] convenience resulting in better treatment compliance. Bimatoprost may be the most effective medication available for protecting the visual field in patients with glaucoma or ocular hypertension.

Overview of glaucoma available. Physicians are now targeting greater The American Academy of Ophthalmology IOP reductions and lower IOP levels for their (AAO) defines glaucoma as “a multifactorial patients than thought necessary in years past. optic neuropathy in which there is a characteris- It has been suggested by the AAO that, for tic acquired loss of retinal ganglion cells and patients with mild damage (optic disc cupping atrophy of the optic nerve” [1]. but no visual field loss), the initial target pres- The disease is characterized by progressive reti- sure should be 20 to 30% lower than baseline, nal ganglion cell (RGC) loss, gradual optic disk while for patients with advanced damage the cupping, and associated visual field deficits. Ele- target pressure should be a reduction of 40% vated intraocular pressure (IOP) is not currently or more from baseline. included in the definition, but it is still listed as Studies have shown that low pressures are an important contributing factor. It is a com- beneficial in preserving the visual field in glau- mon disease occurring worldwide [2], and coma patients, even in patients with IOP in the remains a leading cause of blindness [3]. normal range. In a study by Mao and col- Several other risk factors for the development leagues, pressures less than 17 mmHg protected of glaucoma have been identified including; the optic nerve from damage in patients with advanced age, African ancestry, a family history early primary OAG, while pressures over of glaucoma, severe myopia, and ocular trauma. 21 mmHg resulted in optic disc cupping and/or In many cases, the immediate causes of damage visual field loss [4]. In advanced glaucoma, pres- and death of retinal ganglion cells in glaucoma sures substantially lower than 17 mmHg may be are unknown. Lowering IOP is presently the required to prevent deterioration of the visual Keywords: bimatoprost, glaucoma, only proven treatment modality for halting the field. The Advanced Glaucoma Intervention intraocular pressure, ocular progression of glaucomatous damage in open- Study (AGIS) investigators reported that after hypertension, open-angle angle glaucoma (OAG), and normal tension surgery to reduce IOP in advanced glaucoma, glaucoma glaucoma (NTG). eyes with IOP less than 14 mmHg had less visual field loss than those with IOP higher than Rationale for lowering & stabilizing IOP 17.5 mmHg, suggesting that very low target The paradigm for the management of glau- pressures are beneficial for these patients [5]. coma has evolved considerably in recent years Similarly, reducing IOP to low target levels Future Drugs Ltd as new evidence from clinical trials has become decreases the risk of glaucomatous progression

2004 © Future Drugs Ltd ISSN 1475-0708 http://www.future-drugs.com Therapy (2004) 1(1), 31–41 31 DRUG PROFILE – Noecker & Earl

in patients with NTG. A 1998 study by the Col- and expected lifespan, and the presence of other laborative Normal Tension Glaucoma Study risk factors for glaucoma such as family history Group reported that a 30% IOP reduction in and race [14,15]. patients with NTG had a significantly favorable effect on visual field stability [6]. Pharmacological approaches to IOP lowering Reducing IOP also decreases the risk of the The medications available for reducing IOP in development of glaucoma in patients with ocular glaucoma patients include topical β-adrenergic hypertension (OHT) – defined as elevated IOP antagonists (e.g., timolol, betaxolol), carbonic but no evidence of optic disc damage or visual anhydrase inhibitors (e.g., dorzolamide [Tru- field loss. A controlled trial involving 1636 sopt®, Merck & Co.], brinzolamide [Azopt®, patients with OHT (IOP between 24 and Alcon Laboratories]), cholinergics (e.g., pilo- 32 mmHg in the most impaired eye) conclu- carpine), α-adrenergic agonists (e.g., brimonidine sively demonstrated that lowering IOP by 20% [Alphagan®P, Allergan Inc.]), prostaglandins (or to no more than 24 mmHg) halves the risk of (e.g., latanoprost [Xalatan®, Pharmacia & the development of OAG [7]. In the accompany- Upjohn], travoprost [Travatan®, Alcon laborato- ing editorial [8], it is concluded that lowering IOP ries]), and the prostamide bimatoprost (Lumi- helps preserve visual function in OAG, NTG, gan®, Allergan Inc). In choosing among these and OHT, and for patients with each of these medications, both efficacy and safety/tolerability diagnoses, a 3 mmHg reduction in IOP roughly issues should be considered. Except for β-block- corresponds to a 50% reduction in the risk of the ers, which have been associated with rare but seri- development or progression of glaucoma. ous cardiopulmonary events [16], the ocular Achieving a low target pressure at a single time hypotensive agents commonly used seem to be point is insufficient to prevent the progression of systemically safe and are generally well tolerated. glaucomatous damage as it is likely that even The most appropriate medication, therefore, will transient elevations of IOP can cause damage to often be the one that is most efficacious in the optic nerve. Therefore, for the best protec- lowering and stabilizing IOP. tion of the visual field of glaucoma and OHT In evaluating the IOP-lowering efficacy of a patients, low pressures must be sustained medication, it is important to consider both through 24 h. IOP normally fluctuates through- mean IOP lowering and reliability of the medi- out the day and night in a circadian rhythm [9], cation in helping patients achieve target pres- and pressure peaks can occur at any time during sures. Further, the mechanism of IOP lowering the day or night [10–12]. may also be a key consideration in evaluating Glaucoma patients typically have larger diur- drug efficacy. The elevated IOP in glaucoma is nal variations in IOP compared with normal caused by impaired aqueous outflow [17]. A med- subjects. Large diurnal IOP fluctuations are a ication that lowers IOP by decreasing aqueous clinical concern, because they have been associ- production does not treat the physiological ated both with an increased risk of the develop- pathology in glaucoma, and it might cause addi- ment of glaucoma and an increased risk of tional damage to the outflow channels [18]. Con- glaucomatous progression. In concurrence with versely, a medication that increases tonographic earlier studies, Asrani and colleagues demon- outflow facility (trabecular meshwork ouflow) strated that large diurnal IOP fluctuations are a corrects the deficit that leads to elevated IOP. A risk factor for visual field loss in glaucoma inde- medication that enhances outflow facility may pendent of the level of IOP [13]. Thus, treatment also be preferred for therapy, as it could be best that prevents fluctuations in IOP should able to dampen pressure spikes and provide flat improve the prognosis of glaucoma patients. diurnal IOP curves [19,20]. Although other treatment strategies may even- Among the ocular hypotensive medications tually be used for glaucoma patients, such as that are currently available, bimatoprost stands neuroprotection, the current goal of glaucoma out for its IOP-lowering efficacy. therapy is to lower and stabilize IOP. In clinical practice, many physicians set a target pressure for Background on bimatoprost their patients to achieve on long-term therapy. Bimatoprost is a synthetic prostamide analog Factors that should be considered in setting an that reduces IOP by increasing aqueous humor appropriate target pressure include the IOP level outflow through a dual mechanism of action, at which optic nerve damage occurred, the rate improving both pressure-dependent (presumed and extent of glaucomatous damage, patient age trabecular, via Schlemm’s canal and the episcleral

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veins) and pressure-independent (presumed uve- addressing this question, though this data is not oscleral, ciliary muscle) outflow pathways [19]. yet published in peer reviewed literature. Cantor Once-daily (q.d.) bimatoprost has proven to be and colleagues reported that low levels of the free a powerful ocular hypotensive agent that pro- acid hydrolysis product were detected in the aque- vides large mean IOP reductions in clinical trials ous humor of cataract patients in a presentation at [21–25]. Moreover, it has been shown to control the American Glaucoma Society Meeting in IOP throughout the day, maintaining a flat March of 2004 (CA, USA). In addition, these diurnal curve [26]. same authors also presented evidence on the The cellular mechanism of action of bimato- hydrolysis of bimatoprost and latanoprost to their prost is less well understood. It has been reported free acids in the aqueous humor of cataract to have no meaningful affinity for receptors that patients at the European Glaucoma Society Meet- are known to be involved in IOP regulation, ing in May of 2004. Both of these studies were including adrenergic, dopaminergic, cholinergic, consistent with low levels of the free acid of cannabinoid, and prostaglandin receptors [27]. It bimatoprost in the aqueous humor following sin- has also been confirmed that bimatoprost does gle dose administration in eyes scheduled for cata- not bind to prostaglandin F2α (FP) receptors at ract surgery. Furthermore, the systemic levels of physiological (sub-µmolar) concentrations [28]. bimatoprost and its metabolic degradation prod- However, bimatoprost demonstrates inherent ucts have been monitored after clinical dosing, activity in the cat iris sphincter isolated prepara- and the potential C-1 acid metabolite of bimato- tion [27]. Bimatoprost is not a prodrug in this prost was not detected in the blood of patients model system as it does not need to be metabo- who were treated with once- or twice-daily (b.i.d) lized in order to cause iris constriction. Together, bimatoprost for up to 1 year (quantification by the results of radioligand binding assays and bio- validated liquid chromatography tandem mass assays suggest that the actions of the drug are spectrometry, limit of detection = 50 pg/mL) [32]. mediated through novel receptors that have not These results strongly suggest that bimatoprost is yet been identified [27]. Importantly, a recent not a prodrug, but rather, bimatoprost itself is the study showed that bimatoprost and the prostag- active moiety in human eyes. landin latanoprost produce additive IOP lowering in glaucomatous monkey eyes [29]. These Update on clinical studies of results strongly suggest that bimatoprost and the bimatoprost prostaglandins activate different receptors and Results of clinical studies to date have demon- have distinct cellular mechanisms of action. strated that bimatoprost is highly effective as The possibility that bimatoprost might be monotherapy, adjunctive, and replacement ther- metabolized to compounds with activity at pros- apy for glaucoma and OHT patients. It has con- taglandin receptors has been extensively sistently lowered IOP throughout the day and investigated [30], although differences in drug night and provided flat diurnal and circadian metabolism between species make it difficult to IOP curves. Most patients achieved low target extrapolate these results to humans. Conflicting pressures on bimatoprost therapy with efficacy results have been obtained in studies of the met- sustained over long-term use and found to be abolic stability of bimatoprost in homogenates of generally well tolerated systemically. human ocular tissue. In one study using homogenates of iris–ciliary body obtained from Comparison of bimatoprost with timolol healthy donor eyes within 4 h post-mortem, The object of a 2-year, double-blind, comparison there was no measurable conversion of bimato- of bimatoprost with timolol was to determine prost to the free acid metabolite in human iris– long-term efficacy in patients treated with bimat- ciliary body homogenates, suggesting that it is oprost q.d (n = 167), bimatoprost b.i.d not a prodrug in human eyes [27]. In contrast, a (n = 131), and timolol b.i.d (n = 81) [33]. Patients preliminary report using homogenates of iris–cil- who were given the q.d regimen of bimatoprost iary body as well as cornea and sclera from had significantly greater mean reduction from human donor eyes within 15 h post-mortem baseline in IOP. Bimatoprost q.d provided signif- suggested that bimatoprost could be hydrolyzed icantly lower mean IOP compared with timolol to a free acid metabolite [31]. b.i.d at every time of the day on each study visit The results of these in vitro metabolism studies (p ≤ 0.001). At 10 am (peak timolol effect) at might reflect the situation in patients in vivo. month 24, the mean reduction in IOP from base- There have been several recent presentations line in the bimatoprost q.d group was 7.8 mmHg www.future-drugs.com 33 DRUG PROFILE – Noecker & Earl

compared with 4.6 mmHg in the timolol group progression in more glaucoma and OHT (p < 0.001). Patients treated with bimatoprost patients than does latanoprost. A decrease in IOP q.d sustained significantly lower mean IOP than of 15–20% from baseline is frequently used to timolol-treated patients at every follow-up visit define a clinically relevant response to a glau- throughout the 2-year study period (p ≤ 0.006). coma medication [34–36] and, in the present study, At 10 am at month 24, a significantly greater the responder rate at 6 months was statistically proportion of bimatoprost q.d than timolol significantly higher in the bimatoprost group patients achieved target pressures of less than or than the latanoprost group at all times measured equal to 13–18 mmHg (p ≤ 0.010). Mean reduc- regardless of whether a therapeutically relevant tion from baseline IOP with bimatoprost b.i.d response was defined as a 15 or 20% IOP was not significantly different from that with decrease. The results of this study were consistent timolol at month 24 at 10 am. The IOP lowering with those of earlier trials in which bimatoprost provided by bimatoprost in this study is consist- was more effective than latanoprost in lowering ent with other earlier trials [21,22,25] and confirm IOP at all time points and statistically superior in that bimatoprost q.d is superior to timolol in achieving low target pressures [24,37]. IOP lowering. Further, these findings demon- In a study by Parrish and colleagues [38], the strate the IOP lowering provided by bimatoprost IOP lowering efficacy of latanoprost was com- is sustained with long-term use. pared with that of bimatoprost and travoprost. In this large scale 12-week clinical study, there Comparison of bimatoprost with latanoprost were no significant among-group differences A 6-month, multi-center, randomized, investiga- in mean IOP but it was concluded that all were tor-masked trial compared q.d bimatoprost with potent IOP-lowering treatments. The reason q.d latanoprost as monotherapy for patients with for the failure of this study to find differences glaucoma or OHT [23]. Mean IOP at baseline in efficacy between bimatoprost and either was comparable between treatment groups at latanoprost and travoprost is unclear, but may 8 am and 4 pm; at 12 pm mean baseline IOP be due to selection biases in the patient popu- was significantly higher for bimatoprost lation selected for the Parrish study. For (24.0 mmHg) than for latanoprost instance, approximately half of the patients in (23.3 mmHg; p = 0.028). Bimatoprost lowered the Parrish study were previously treated with mean IOP statistically significantly more than a prostaglandin analogue and the data pre- latanoprost at all time points throughout the 6 sented suggests that the study may have been months of this study. At every measurement biased to select patients responsive to prostag- throughout the study, mean changes from base- landins. Detailed examination of these data is line IOP were significantly greater with bimato- difficult, however, because results of responder prost than with latanoprost (p ≤ 0.025). By the analyses and achievement of target pressures end of the study, mean changes from baseline were not published. were 1.2–2.2 mmHg greater with bimatoprost than with latanoprost (p < 0.004). At month 6, Bimatoprost in nonresponders to the mean decrease from baseline IOP was latanoprost 1.5 mmHg greater with bimatoprost than with The prevalence of nonresponders to latano- latanoprost at 8 am (p < 0.001), 2.2 mmHg prost monotherapy in human glaucomas is not greater at 12 pm (p < 0.001), and 1.2 mmHg presently defined. Approximately 1% of sub- greater at 4 pm (p < 0.004). More patients jects enrolled in two major clinical trials and achieved low target pressures at all times of the treated with latanoprost monotherapy were day in the bimatoprost group than the latano- withdrawn because of uncontrolled IOP [39–41]. prost group. IOPs less than or equal to To test the efficacy of bimatoprost in patients 20 mmHg were achieved in 82.0–91.0% of nonresponsive to latanoprost, 15 patients with patients treated with bimatoprost compared with a history of lack of response (≤10%) to latano- 68.4–79.4% of patients treated with latanoprost. prost after 6–8 weeks of treatment were IOPs less than or equal to 15 mmHg were enrolled in a randomized, investigator-masked, achieved by 20.3–36.1% of patients treated with crossover study [41]. One eye of each subject bimatoprost compared with 17.6–25.0% of was randomly selected for treatment with either patients treated with latanoprost. The target bimatoprost or latanoprost for 30 days fol- pressure analysis in this study suggests that lowed by a 30-day washout and then crossover bimatoprost may reduce the risk of disease to the other drug for 30 days of treatment. The

34 Therapy (2004) 1(1) Lumigan® – DRUG PROFILE

other eye was treated with preserved artificial comparably lowered IOP, but bimatoprost was tears. Once switched to bimatoprost, 13 of the more likely than travoprost to allow achievement 15 nonresponders showed a decrease in IOP of every target pressure from 12 to 19 mmHg at less than or equal to 20%. No IOP changes month 3. At 3 months, the mean IOP reduction were detected in the other untreated eye. It has from baseline was 8.4 mmHg (34%) in the been postulated that prostamides to not acti- bimatoprost group and 7.9 mmHg (30%) in the vate the same receptors as prostaglandins [27,41]. travoprost group. A second trial compared The lack of response to latanoprost, a prodrug, bimatoprost with travoprost in 26 patients with may also involve poor deesterification of the glaucoma or OHT for 6 months with compara- prodrug to the pharmacologically active free ble results [45]. After 6 months of therapy, both fatty acid. A 2-month, open-label trial where treatments provided significant mean reductions bimatoprost (alone or in combination with from baseline IOP at every time point other drugs at the physician’s discretion) was (p ≤ 0.007). Mean IOP reductions ranged from used as a replacement for latanoprost for 1283 7.4 to 8.8 mmHg (34–36%) with bimatoprost patients. In this study, bimatoprost provided a and from 4.6 to 7.2 mmHg (19–29%) with tra- mean decrease in IOP of 3.4 mmHg after 2 voprost (p ≤ 0.057) after 6 months of treatment. months of therapy [42]. The percentage of Again, more patients achieved low target pres- patients achieving a target pressure of less than sures with bimatoprost than with travoprost at or equal to 18 mmHg doubled from 33–66% each time point and larger mean IOP reductions. (p < 0.001). Moreover, the percentage of These results are being further evaluated in patients achieving a target pressure of less than larger, ongoing clinical trials. or equal to 14 mmHg increased from 6% at baseline to 26% by month 2 and those achiev- Bimatoprost in replacement of ing a target pressure less than or equal to timolol/latanoprost 15 mmHg increased from 11% at baseline to When IOP is not adequately controlled with 36% by month 2 (p < 0.001). A subgroup anal- monotherapy, the physician may choose to add ysis showed comparable improvements in IOP another medication to the patient’s regimen or to control regardless of the previous treatment replace the regimen with one that is more effica- regimen of whether bimatoprost was used alone cious. The efficacy of bimatoprost monotherapy or in combination with other medications. as replacement therapy was evaluated in a 4- Another open-label trial of bimatoprost in 21 month, open-label, multicenter, crossover evalu- patients not responsive (<3 mmHg IOP reduc- ation of 83 patients with glaucoma or OHT [46]. tion) to latanoprost after 3 weeks of treatment Patients were treated with dual therapy with saw an additional mean IOP reduction of latanoprost and timolol gel-forming solution for 3.5 mmHg after 8 weeks of treatment with 60 days. At day 60, patients were switched to bimatoprost [43]. Taken together, these studies bimatoprost monotherapy for an additional 60 indicate that bimatoprost helps many more days. The mean IOP at 8 am was comparable patients reach low target pressures when used as between day 60 (17.9 mmHg with a replacement for latanoprost in a variety of timolol/latanoprost dual therapy) and day 120 treatment regimens. (18.6 mmHg with bimatoprost monotherapy; p = 0.084). The majority of patients (50/83, Comparison of bimatoprost with travoprost 60.2%) achieved IOP lowering with bimato- Travoprost has been shown to be more effective prost monotherapy that was the same or better in black patients than in white patients, while than that achieved with timolol/latanoprost bimatoprost has been shown to be equally effec- therapy, and 76.3% of patients (61/80) were at tive. An investigator-masked, parallel-design trial least as satisfied with bimatoprost monotherapy compared bimatoprost with travoprost in Afri- as with dual timolol/latanoprost therapy. can Americans with glaucoma or OHT [44]. After Patients were as likely to be clinically successful a washout, patients were assigned to bimatoprost with bimatoprost monotherapy as with dual q.d (n = 16) or travoprost q.d (n = 15) for 3 timolol/latanoprost therapy (65/79, 82.3% with months. Study visits were at baseline and at bimatoprost compared with 68/82, 82.9% with months 1, 2, and 3. Primary outcome measures dual timolol/latanoprost; p > 0.999). These were the percentage of patients who achieved findings indicate that in most patients, bimato- selected target pressures and the mean reduction prost monotherapy controls IOP as effectively as in IOP from baseline at month 3. Both drugs dual timolol/latanoprost therapy. www.future-drugs.com 35 DRUG PROFILE – Noecker & Earl

Comparison of bimatoprost with bimatoprost, timolol gel-forming solution, and timolol/dorzolamide latanoprost to provide 24-hour IOP control Bimatoprost was compared with fixed combina- [26]. After washout, patients with OAG or OHT tion timolol/dorzolamide in a 3-month, rand- were randomly assigned treatment to receive omized, controlled trial in 177 glaucoma or bimatoprost 0.03% q.d (n = 38), or latanoprost OHT patients who had inadequate IOP control 0.005% q.d (n = 38) between 7 and 9 pm, or after at least 2 weeks on timolol monotherapy timolol gel 0.5% q.d (n = 39) between 7 and [47]. Patients were randomly assigned to treat- 9 am for 1 month. The primary outcome meas- ment with bimatoprost monotherapy q.d ure was circadian IOP, measured at eight time (n = 90) or timolol/dorzolamide fixed combina- points over the course of 24 h beginning at tion b.i.d (n = 87). Bimatoprost lowered mean 8 am on day 28. In the overall analysis of circa- IOP 6.8 mmHg to 7.6 mmHg from baseline at dian IOP, the mean IOP was significantly lower 8 am measurements, whereas combined timolol with bimatoprost or latanoprost than with and dorzolamide lowered mean IOP 4.4– timolol gel (p < 0.001). At 10 am (peak drug 5.0 mmHg from baseline (p < 0.001). At the 3- effect) on day 28, the mean IOP reduction month visit, patients had better diurnal IOP from baseline was significantly greater with control with bimatoprost than with combined bimatoprost (9.3 mmHg, 40.3%) than with timolol and dorzolamide. At 8 am, the percent- timolol gel (7.1 mmHg, 31.1%; p = 0.024) or ages of patients achieving IOPs of less than or latanoprost (7.4 mmHg, 33.3%; p = 0.022). equal to 13–16 mmHg were more than twice as The results of this trial indicate that q.d bimat- great for bimatoprost than for timolol/dorzola- oprost or latanoprost provides significantly bet- mide (all p ≤ 0.008). These results indicate that ter 24 h IOP control than timolol gel in bimatoprost consistently provides significantly patients with glaucoma or OHT. greater IOP lowering than combined timolol and dorzolamide. Bimatoprost as adjunctive therapy Because bimatoprost lowers IOP by increasing Comparison of bimatoprost with timolol aqueous outflow through both pressure-sensitive & pilocarpine (trabecular) and pressure-insensitive (uveoscle- A 3-month, masked study assessed the effect of ral) pathways [19], bimatoprost might be changing 32 patients from concomitant timolol expected to show additive efficacy with β-block- 0.5% b.i.d and pilocarpine 2% TID to bimato- ers, which reduce IOP by lowering the rate of prost 0.03% q.d on ocular blood flow and IOP in aqueous humor formation. The efficacy of primary chronic angle closure glaucoma [48]. IOP bimatoprost as an adjunct to topical β-blockers and pulsatile ocular blood flow were recorded was investigated in a 3-month, multicenter, dou- before and after starting bimatoprost and were fol- ble-masked, randomized, vehicle-controlled, lowed up every 4 weeks. Bimatoprost provided sta- parallel-group clinical trial with study extension tistically significant (p < 0.05) mean IOP reduction for the active medication to 1 year [49]. Patients from 19.3 ± 6.6 to 13.5 ± 4.5 mmHg (30.5%) and uncontrolled on topical β-blockers were given there was improvement from 858 ± 260 to adjunctive bimatoprost q.d (n = 93), bimato- 1261 ± 321 µL/min (46.8%) in mean pulsatile prost b.i.d (n = 97), or vehicle b.i.d (n = 95) for ocular blood flow (p < 0.05). Bimatoprost 3 months. During this 3-month initial treatment improved ocular blood flow and provided a better period, adjunctive bimatoprost provided clini- diurnal IOP control than concomitant cally and statistically significant greater IOP low- timolol/pilocarpine. The improvement of ocular ering than vehicle. Mean IOP was 3.3 to blood flow with bimatoprost may be useful as it is 4.5 mmHg lower with bimatoprost/β-blocker possible that improving ocular blood flow may q.d than with vehicle/β-blocker at all measure- improve visual outcomes in patients with glau- ments. In the study extension, patients who were coma. However, this mechanism is still the subject continued on adjunctive bimatoprost q.d of debate and definitive clinical trials are needed to showed sustained IOP lowering throughout 1 conclusively demonstrate the relationship between year of treatment. At the hour 0 measurement, blood flow and improving visual outcomes. adjunctive bimatoprost q.d consistently provided more than 30% additional IOP lowering Circadian IOP control with bimatoprost from the β-blocker treated baseline. These A 1-month, randomized, multicenter, investi- results showed that bimatoprost has outstanding gator-masked trial compared the ability of efficacy as an adjunct to β-blockers.

36 Therapy (2004) 1(1) Lumigan® – DRUG PROFILE

No controlled studies of bimatoprost used peak hyperemia (day 1), mean severity scores adjunctively with prostaglandin therapy have yet ranged from low mild-to-moderate and by day 28 been reported. had returned to near-baseline levels (in the trace range of the scale). The difference between day 28 Postmarketing surveillance and baseline hyperemia levels was statistically sig- A 2-month, open-label, noncomparative surveil- nificant (p = 0.002) only in the conjunctival ves- lance trial was undertaken to evaluate the safety sel bed (mean score near trace). Incidence analysis and efficacy of bimatoprost for the treatment of revealed that treatment-related hyperemia was glaucoma and OHT in clinical practices predominantly trace, mild, or mild-to-moderate. throughout the USA and Puerto Rico [50]. There Moderate-to-severe or severe hyperemia was lim- were 6767 patients enrolled at 1439 clinical sites. ited to a few eyes and only at days 1 through 3 to Physicians prescribed bimatoprost as mono- 5. No statistically or clinically significant changes therapy for newly diagnosed patients (n = 1946, occurred in corneal fluorescein staining. Consist- 28.8%), as an adjunct to one or more other med- ent with other clinical studies, in an earlier 1-year ications (n = 2640, 39.0%), or as a replacement comparison of bimatoprost with timolol, mean for another medication (n = 2117, 31.3%). conjunctival hyperemia scores were in the trace Bimatoprost treatment provided significant IOP range by the 2-week follow-up visit. Hyperemia reductions in all three groups of patients. For levels continued to decrease after 4 weeks, and by newly diagnosed patients, the mean IOP reduc- 6 months no further patients discontinued partic- tion after 2 months of bimatoprost monotherapy ipation because of hyperemia [25]. In this study, was 7.9 mmHg (30.7%, p < 0.001). For patients mean conjunctival hyperemia scores were who had bimatoprost added to ongoing treat- between trace and mild at day 14 and were trace ment regimens, the mean additional IOP reduc- at day 28. The majority of patients reported they tion with bimatoprost was 5.0 mmHg (21.3%, were not troubled by their ocular redness, and p < 0.001). For patients who were given bimato- investigators did not believe it warranted discon- prost in replacement of another medication, the tinuation of therapy. These findings, together mean IOP reduction from baseline on the previ- with the failure of previous studies to show an ous therapy was 4.2 mmHg (18.6%, p < 0.001). association between hyperemia and intraocular Patients were also significantly more likely to inflammation, suggest that this hyperemia is not achieve low target pressures after 2 months of clinically significant. Bimatoprost is an extremely bimatoprost therapy (p < 0.001). effective drug that lowers IOP to the level needed These trials suggest that bimatoprost is very for long-term preservation of visual function, a effective when used in clinical practice for the capability that far outweighs the occurrence of treatment of glaucoma and OHT. Substantial short-term hyperemia. IOP reductions can be anticipated, regardless of Increased iris pigmentation occurs with low whether bimatoprost is used alone or adjunctively incidence (1–2% of patients after 1 year of treat- with other medications. ment) in patients treated with bimatoprost. Patients should be warned about the possibility Safety & tolerability of increased pigmentation of the eyelashes and Bimatoprost has been proven to be safe and well periorbital tissue. Cystoid macular edema has tolerated with a high rate of study completion in occurred with low incidence. clinical trials [21,23–25,37,47,51,52]. The most commonly reported side effect of bimatoprost therapy Regulatory affairs is trace or mild hyperemia, which may occur in Bimatoprost (Lumigan®, Allergan Inc.) ophthal- approximately 14% of patients [33]. A 28-day, mic solution 0.03%, is currently available in the open-label study evaluated the onset and progres- USA, the UK, Germany, and Italy. It has sion of hyperemia associated with bimatoprost received approval for marketing in the European once daily in 39 patients with OAG and OHT Union and in six Latin American countries. [53]. Current glaucoma medication was either replaced with or augmented by bimatoprost. Pre- Conclusion vious users of bimatoprost were excluded. Mean Bimatoprost has been demonstrated to be hyperemia scale scores for each of the three vessel clearly superior to timolol and has consistently beds (ciliary, conjunctival, episcleral) peaked one provided approximately 1 mmHg greater mean day after the first installation of bimatoprost and IOP lowering than latanoprost in clinical tri- consistently decreased throughout the study. At als. The greater mean IOP lowering with www.future-drugs.com 37 DRUG PROFILE – Noecker & Earl

bimatoprost reflects a significant difference in effective than travoprost. It will be important to the percentage of patients that reached target compare travoprost, arguably the most efficacious pressures. Bimatoprost has consistently allowed of the prostaglandins, with bimatoprost in large, more patients to reach the low target pressures head-to-head trials to confirm this. that best protect the visual field. Bimatoprost The mechanism of action of a selected med- provides low, stable IOP throughout the day ication should also be considered when choos- and night, and the efficacy is sustained with ing ocular hypotensive regimens. Different long-term use. It can be concluded that bimat- classes of medications lower IOP by different oprost is very effective in both monotherapy mechanisms, such as decreasing aqueous pro- and adjunctive therapy. No safety concerns duction, increasing trabecular meshwork aque- have arisen in postmarketing surveillance. ous outflow, or increasing uveoscleral outflow. Bimatoprost has proven to be a valuable agent Reports have suggested that medications that for glaucoma therapy. lower IOP by increasing trabecular outflow (pressure-sensitive outflow) may provide more Expert opinion stable control of IOP [20]. Mechanism of Today, a goal of therapy is to reduce IOP to a action should also be considered when select- target level sufficiently low to halt glaucomatous ing adjunctive agents because agents with progression and preserve the visual field. Physi- complementary mechanisms or dual mecha- cians have been selecting lower IOP targets for nisms of action may provide greater additive their patients than in years past. The prosta- IOP lowering. mides and prostaglandins lower IOP more effec- Further studies investigating the adjunctive tively than medications that were previously use of bimatoprost are also needed. Bimatoprost available. It is now possible for physicians to has been shown to provide substantial addi- achieve 30% or greater IOP lowering in most tional IOP lowering with used adjunctively with patients with a single medication. β-blockers [49]. Additive IOP lowering with Bimatoprost and the prostaglandins share a bimatoprost and the prostaglandins might also similar profile of side effects. Therefore, the be predicted because choice of therapy will often be made on the • The drug classes have different cellular basis of efficacy. There are several factors to mechanisms of action consider in evaluating efficacy of these drugs. Until the relative effectiveness of medications • IOP lowering with these medications has been in preserving retinal ganglion cells and the vis- shown to be additive in a primate model of ual field can be determined, the measures of glaucoma [29] efficacy must involve IOP. The mean IOP low- Patient convenience and compliance are also ering of a drug should be considered, as well as important factors in selecting an ocular hypo- the likelihood that patients achieve low target tensive regimen. Whenever possible, it is pref- pressures on the drug. Another consideration erable to control IOP with a single medication should be the reliability of patient response: rather than multiple medications, because there may be a relatively high rate of nonre- every medication added to the regimen has side sponders to latanoprost, particularly among effects, and each added medication increases newly diagnosed (treatment naïve) patients [54]. the costs of treatment. Furthermore, multiple It may also be necessary to consider the race of medications may increase the patient’s exposure the patient. to benzalkonium chloride (BAK), a common Recent clinical trials have suggested that β- preservative. BAK may accumulate in ocular blockers are more effective in Caucasian than in tissues for a lengthy period of time and at high African-American patients [25,55]. This does not concentrations, promote cellular damage in a seem to be true for the prostaglandins or bimato- dose-dependent manner [56]. Moreover, prost. Travoprost, however, has been shown to be patients are more likely to be compliant with less effective in Caucasians than in African-Ameri- their once-a-day monotherapeutic regimen can patients, while bimatoprost is equally effective than with multiple medications given in multi- in Caucasian and African-American patients ple doses. The stability of the medications var- [25,44,55]. Comparison of results from separate trials ies, furthermore, and this may influence the suggests that travoprost and bimatoprost may be convenience of their use. Latanoprost has to be similarly effective in African-American patients, protected from light until opened, when it can while in Caucasian patients, bimatoprost is more be stored at temperatures up to 25°C for up to

38 Therapy (2004) 1(1) Lumigan® – DRUG PROFILE

Highlights experiencing a change in IOP [46], and bimatoprost monotherapy is as effective or more effec- • Glaucoma is a multifactorial optic neuropathy characterized by the loss of tive than timolol/dorzolamide fixed retinal ganglion cells. combination treatment [47]. • Although elevated intraocular pressure (IOP) is only considered to be a risk A final factor that might influence treatment factor in glaucoma, lowering IOP remains the only proven method of decisions is cost. Treatment with either latano- preserving the visual field in patients with the disease. prost or travoprost treatment may cost approxi- • Bimatoprost (Lumigan®, Allergan Inc.), a prostamide, is not a prodrug and is inactive at prostaglandin receptors. mately 30% more than treatment with • Bimatoprost has been proven to provide highly effective IOP lowering in bimatoprost [58]. many patients. • Numerous studies have demonstrated that bimatoprost provides greater Outlook IOP lowering than that provided by latanoprost (Xalatan®, Pharmacia & As our understanding of the pathophysiology of Upjohn). glaucoma continues to evolve, so too will our • Bimatoprost is very effective as both monotherapy and adjunctive therapy. ability to treat and, perhaps one day, prevent this • No safety concerns have arisen in postmarketing surveillance. disease. Neuroprotection, or the ability to pre- • Bimatoprost is a convenient, once-daily medication that requires no serve the function of the retinal ganglion cells, refrigeration. These attributes may promote enhanced patient compliance. may become an important part of the treatment • Bimatoprost has proven to be a valuable agent for glaucoma therapy. of glaucoma in the future. Currently, however, the available data present a compelling argument 6 weeks. Patients should be cautioned that that the preservation of the visual field in glau- exposure of the medication container to sun- coma is best accomplished through early and light or high temperatures causes degradation aggressive IOP-lowering and this is unlikely to of the drug [57]. Travoprost does not require change in the immediate future. refrigeration if stored at or below 25°C. Bimat- oprost is also stable, and it can be stored at Disclaimer room temperatures up to 25°C. Most patients Neither author has any proprietary interest in can be switched from timolol/latanoprost dual bimatoprost, Allergan, or any pharmacologic therapy to bimatoprost monotherapy without agent discussed in this review.

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