Pharmacy Benefits Management Strategic Healthcare Group



Drug Class Review: Ophthalmic Prostaglandin Analogs

VHA Pharmacy Benefits Management Strategic Healthcare Group

and the Medical Advisory Panel

Prepared by: Kathryn Tortorice, Pharm.D., BCPS

Updated by: Berni Heron, Pharm.D., BCOP

Objectives

To review the efficacy, safety, and administration of currently available ophthalmic preparations of the prostaglandin analogs used in the management of glaucoma.

Table 1: Currently Available Ophthalmic Prostaglandin Analogs*1-4

|Generic Name |Trade name |Strength, package size |Manufacturer |

|Bimatoprost |Lumigan® |0.01%, 0.03%, |Allergan |

| | |2.5, 5, 7.5 ml | |

|Travoprost |Travatan Z® |0.004%, |Alcon |

| | |2.5, 5 ml | |

|Latanoprost |Xalatan® |0.005%, |Catalent, Pfizer |

| | |2.5 ml |Distributed by Pfizer, Pharmacia|

| | | |& Upjohn Co. |

|Latanoprost |Latanoprost Ophthalmic Solution |0.005%, 2.5 ml |Alcon, |

| | | |Distributed by Falcon |

* Unoprostone (Rescula®), which was included in the original drug class review, has since been discontinued and will not be included in this update.

Introduction5-10

Glaucoma can be described as a chronic ocular disorder characterized by the following features: progressive optic neuropathy (excavation of the optic nerve head and loss of visual field), with or without associated elevated intraocular pressure (IOP). Blindness results from the death of optic nerve ganglion and is irreversible. Historically, it was believed that increased intraocular pressure (IOP) was the sole cause of visual damage. However, it is now recognized that along with increased IOP many other factors such as retinal ischemia, and reduced or deregulated blood flow may contribute to the development and progression of glaucoma.

It is estimated that 2% of people in the U.S. over 40 years of age have glaucoma, affecting more than 2 million individuals. At least 25% of cases are undetected. Over 90% of cases are of the open-angle type, either primary open-angle or normal-tension glaucoma.6

Many factors influence the development of glaucoma. It is more prevalent in people over 40 and is more common in African Americans than Caucasians. In addition, a family history of glaucoma, and elevated IOP are risk factors for glaucoma development.5 The evidence for other risk factors such as diabetes mellitus, hypothyroidism, systemic hypertension and cardiovascular disease has been less consistent.

The goal in the treatment of glaucoma is to prevent a loss of vision. There are currently no proven direct treatments for the optic neuropathy of glaucoma. Instead, treatment is focused on lowering intraocular pressure, the one risk factor that can be modified. The publication of the Ocular Hypertension Treatment Study (OHTS) demonstrated that lowering IOP is useful in preventing Primary Open Angle Glaucoma (POAG) in certain populations, those at moderate or high risk such as African Americans, diabetics, etc. 8 The degree to which IOP should be lowered remains unclear. Ophthalmologists determine the optimal target IOP for their individual patients by considering risk factors that include level of current IOP elevation, visual acuity and optic nerve appearance. An initial target suggested by evidence from the Early Manifest Glaucoma Trial (EMGT) and Collaborative Initial Glaucoma Treatment Study (CIGTS) is > 25% reduction in IOP.

Pharmacologic therapies used in glaucoma control should prevent further loss of functional vision while avoiding an adverse impact on quality of life. Topically applied ocular preparations are usually the first step in the management of glaucoma. Currently there are five classes of medications that are used to lower eye pressure: topical cholinergic agonists, topical [beta]-adrenergic antagonists, topical adrenergic agonists, topical prostaglandin analogues, and topical and oral carbonic anhydrase inhibitors. Many of these drug classes are linked with adverse effects, poor patient acceptance and limited efficacy. This drug class review will focus on the topical prostaglandin analogues.

The original drug class review was completed in June, 2002. An update of this topic was completed in May, 2011. PubMed search terms for the update included: latanoprost, bimatoprost, travoprost. Limitations placed on the search included the dates of 11/02/2001 – 3/31/2011, clinical trials, meta-analyses, human species and English language. Randomized, comparative trials were the focus of this search. Fixed-combination products (e.g. latanoprost/timolol) were not included in the analysis. Studies that performed an interchange between products were also included in this review.

I. Pharmacology1-7, 11-17

These agents bind to specific receptors within the eye to lower intraocular pressure via increasing trabecular and/or uveoscleral outflow. This results in changes to either pressure-dependent or independent outflow, respectively. Additionally, it appears that a class effect of negligible diurnal variation in IOP control and lowering is true. A major difference between the prostaglandin agents may involve the receptors that are bound by each drug.7 Both latanoprost and travoprost are synthetic analogues of prostaglandin F2α and demonstrate affinity at the FP receptor.12 The binding of the FP receptor allows for an alteration in the collagen content of the ciliary muscle, reducing resistance in the uveoscleral pathway.13 Bimatoprost is a prostamide analogue. Prostamides are a naturally occurring substance, derived from anandamide a membrane lipid that act as potent ocular hypotensive agents.14,15 Bimatoprost does not have strong affinity for the FP receptor or any other known receptors. There have been recent reports that bimatoprost may also function as a prodrug with conversion in the cornea to a free acid form which binds at the FP receptors. 16, 17

Indications1-4

The prostaglandin analogs are all indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension.

Pharmacokinetics 1-4, 11, 15

The pharmacokinetic properties of the agents are reviewed in Table 2.

Table 2: Pharmacokinetics

|Variables |Bimatoprost |Latanoprost |Latanoprost generic |Travoprost |

|Cmax in aqueous |Within 10 min |2 hrs |2 hrs |Within 30 min |

|humor | | | | |

|Distribution |Plasma, approximately 88% |0.16 ± 0.02 L/kg; acid |0.16 ± 0.02 L/kg; acid |Plasma-in 1 hour then |

| |bound |measured in aqueous |measured in aqueous |rapidly eliminated |

| | |humor during first 4 |humor during first 4 | |

| | |hrs; plasma only during|hrs; plasma only during| |

| | |first hr |first hr | |

|Metabolism |N-deethylation and |Active acid via hepatic|Active acid via hepatic|Esterases in the cornea|

| |glucuronidation |β oxidation |β oxidation | |

|Elimination |67%-renal |Renal |Renal |Plasma levels |

| | | | |undetectable in 1 hour |

|Reduction in IOP |7-8mm Hg |6-8mm Hg |6-8 mm Hg |7-8 mm Hg |

NR- not reported

II. Clinical Efficacy

The Early Manifest Glaucoma Trial (EMGT) was the first large, randomized trial to study the effects of treatment vs. no treatment of early stage glaucoma. Although there is no set guideline for the optimal target IOP, the EMGT found that by lowering the IOP by ~ 25%, the rate of glaucoma progression can be reduced.8

At the time of initial writing, the standard agent used for comparison of IOP-lowering effects was timolol. The prostaglandin analogs have been measured against this standard. Evidence of their comparative effect is noted in Tables 3, 4 and 5. Unoprostone, a twice daily dosed docosanoid that did not demonstrate better IOP-lowering effects against timolol and was not included in the overall drug class review, has since been discontinued. There will be no further mention of unoprostone in this updated review. The products that will be the focus of this review include bimatoprost, latanoprost and travoprost.

Prostaglandin Analogs Versus Timolol

Latanoprost has been shown to be more effective or at least as effective as timolol twice daily in lowering the IOP of patients with primary open angle glaucoma (POAG) or ocular hypertension. These trials indicate an agent with once daily administration to be as effective or better than a twice-daily agent. Several meta-analysis have compared these studies. In the Hedman meta-analysis18, latanoprost treated patients had a mean reduction from baseline of 7.7+ 0.1 mm Hg in comparison to timolol treated patients with 6.5+ 0.1 mmHg. This was a statistically significant finding for latanoprost. It is also interesting to note that more latanoprost treated patients reached their target IOP than timolol treated patients. The meta-analysis by Zhang19, collaborated the findings as well as documented the increased adverse events of iris pigmentation and hyperemia in the latanoprost group. Additionally, a trial comparing once daily timolol gel to latanoprost demonstrated a superiority of latanoprost in IOP reduction over the 24 hour period measured.20 The benefits of latanoprost administration on circadian variation have also been documented.21,22 Table 3 reviews several trials of latanoprost and timolol.

Bimatoprost and travoprost given once daily have been compared to timolol dosed twice daily. Both agents showed an equal or superior efficacy to twice daily timolol. Table 4 reviews the bimatoprost trials, Table 5 the travoprost trials. In the Brandt trial23 it is interesting to note that the group of patients who received bimatoprost twice daily did not achieve a greater IOP lowering effect or better tolerability than the once daily group. In a report of the pooled results from two multicenter trials of bimatoprost,24 the IOP lowering effects of this agent were sustained over the six-month period. Additionally, there was little diurnal variation in pressure readings for the bimatoprost group. In the trials of travoprost there were a large percentage of African American patients with a range of 20.5-24.9% versus enrollments of 17-20% in the trials of latanoprost and bimatoprost.23, 24, 25 Of note is a finding that travoprost reduced the IOP more effectively in this population than in the other races, in comparison to latanoprost and timolol (mean IOP at 52 weeks of 17.2, 18.6 and 20.7 mmHg respectively). However, the study was not initially powered to detect this finding, the study was not collaborated by independent sources and further investigation must be performed to confirm the effect.

Table 3

Latanoprost once-daily monotherapy versus timolol

|Trial |Latanoprost |Timolol |Duration |N |Baseline |End Point | | |

| | | | | |IOP(SEM) |IOP(SEM) | | |

|Watson, 199627 |0.005% eve |0.5% BID |6 months |294 |26.2(0.3) |26.5(0.3) |17.1(0.2) |17.7(0.2) |

|Larsson, 200128 |0.005% eve |0.5% gel QD|1 month |27 |23.6(0.2) |24.0(0.3) |13.6(0.4) |15.2(0.4) |

|Alm, 199522 |0.005% morn or |0.5% BID |6 months |267 |25.1(0.5) |24.6(0.3) |17.1(0.4) |17.6(0.3) |

| |eve | | | | | | | |

|Camras, 199629 |0.005% eve |0.5% BID |6 months |268 |24.4(NR) |24.1(NR) |17.7(NR) |19.2(NR) |

Eve=evening, morn= morning, BID= twice daily, QD= once daily, L=latanoprost, T=timolol, IOP= intraocular pressure

All results are statistically significant in favor of latanoprost versus timolol

Table 4

Bimatoprost once daily monotherapy versus timolol

|Trial |Bimatoprost |Timolol |Duration |N |Baseline |End point | | |

| | | | | |IOP (SEM) |IOP (SEM) | | |

BID= twice daily, QD= once daily, B=bimatoprost, T=timolol, IOP= intraocular pressure

All results are statistically significant in favor of bimatoprost versus timolol

Table 5

Travoprost once daily monotherapy versus timolol

|Trial |Travoprost |Timolol |Duration |N |Baseline IOP|End point | | |

| | | | | | |IOP | | |

|Fellman, |0.0015% and 0.004%|0.5% BID |6 months |650 |27.1 |27.4 |19.9 |20.5 |

|200231 |QD | | | | | | | |

BID= twice daily, QD= once daily, TR=travoprost, TI=timolol, IOP= intraocular pressure

All results are statistically significant in favor of travoprost versus timolol

Randomized Comparative Trials of Prostaglandin Analogs

In a thirty-day comparison of bimatoprost and latanoprost to a vehicle placebo, DuBiner et al32, demonstrated that bimatoprost provided good diurnal control of IOP and was well tolerated by patients. The findings of this trial did not reach statistical significance (p=0.052). This is likely due to the small sample size of the trial (N=106, with N=21 in each treatment arm). There was no difference in adverse events or withdrawals between the treatment groups. A similar trial was conducted in 232 patients over a 3-month period.33 This trial demonstrated that target IOP of < 17 mm Hg were more often achieved in the bimatoprost group (p=0.029) as well as diurnal measurements at month 3 being lower in the bimatoprost group (p 20% reduction| |L, B greater ↓ IOP than t; |

| | |or absolute IOP | |L comparable to B; |

| | |< 20 mmHg) | |T comparable to t; |

| | | | |L ↓ hyperemia vs. B, T |

Key: POAG=Primary Open Angle Glaucoma; OAG=Open Angle Glaucoma; OH= Ocular Hypertension; L= latanoprost; B= bimatoprost; T= travoprost; t= timolol; IOP=intraocular pressure

Effect on PA’s on Circadian Intraocular Pressure

When comparing the effects of prostaglandin analogs, investigators have reported a variation of IOP-lowering effect. Noecker et al. noted that bimatoprost was significantly more effective than latanoprost at the hours of 0800, 1200 and 1600. Other comparative trials have focused only on the diurnal curve, not taking the nocturnal hours into consideration. Orzlesi, et al. studied the effects of each prostaglandin analog on circadian IOP in a crossover fashion. Each patient had baseline IOP values recorded at 0300, 0600, 0900, 1200, 1500, 1800, 2100 and 2400. After a washout period of one month, patients were randomly assigned to receive one of three PA’s. Again, 24-hour values were recorded, followed by another washout period, and switch to another PA. Their results indicate that there was no significant difference in mean change in IOP from baseline with either PA. Each prostaglandin analog had a significantly greater IOP-lowering effect during the diurnal hours vs. the nocturnal hours. Overall, concluding that not only did all 3 PA’s have similar IOP-lowering effects during the day, but also during the nighttime hours.48

In a randomized, parallel group design, Yildirim, et al. attempted to assess the IOP-lowering effects of all 3 PA’s in a newly diagnosed glaucoma population. Patients were admitted to an inpatient facility at baseline to record circadian tonometric curves at 0800, 1000, 1300, 1600, 2000, 2200 and 0300. They were then randomized to receive either bimatoprost, latanoprost or travoprost daily for 8 weeks. Again, patients were admitted to record their tonometric curves as described. The baseline values for all patients were not significantly different, except for the 0800 and 1000 hours. Patients assigned to receive travoprost had higher baseline IOP values. At the end of the 8 week period, the authors noted that there were significant reductions in the mean IOP among all treatment groups. Those receiving travoprost had a significantly greater reduction in mean IOP at hours 0800 and 1000. Possible limitations that may have impacted this finding include a higher baseline IOP value in the travoprost group, small numbers of patients and lack of crossover design.49

Table 8. Comparison of the Effects of Prostaglandin Analogs on Circadian IOP

|Variables |Mean IOP (± SD) |Reduction in |Reduction in |P value |

| |mm Hg |IOP (9a-9p) |IOP (12a-6a) | |

|Study |Population |Intervention |Duration |

|Yildirim, 2008; |OAG; |B vs. L vs. T; |8 wks |

|RT, PG, masked evaluator |Newly diagnosed; |1 drop each evening | |

| |Untreated | | |

|Conjunctival hyperemia |25-45% |NR |30-50% |

|DC due to hyperemia |0.5-3% |< 1% |0.5-3% |

|Ocular AE’s |1-10%; |5-15% |1-10% |

| |> 10% (eyelash growth, pruritus)| | |

|Non-Ocular AE’s |10% |4% |1-5% |

NR= not reported; AE’s= adverse events; DC= discontinuation

Table 10: Incidence of Adverse effects Reported in the Clinical Trial Setting

|Study |Adverse effect |Timolol (%) |Bimatoprost (%) |Latanoprost (%) |Travoprost (%) |

| |Iris pigment changes |0 | |5.2 |3.1 |

| |Eyelash changes |3.1 |** |25.8 |57.1 |

| |Systemic AE’s (htn) |4.5 |** |3.6 |6.5 |

| |DC due to AE |** |** |NR |NR |

|Gandolfi, 2001 |Hyperemia |** |36.1 |14.2s |** |

| |Iris pigment changes | | | | |

| |Eyelash changes |** |12.6 |4.4 |** |

| |DC due to AE |** |5 |4.4 | |

|Parrish, 2003 |Hyperemia |** |68.6 |47.1t |58 |

| |Eyelash changes | |2.9 |0 |0.7 |

| |Eye irritation |** |10.9 |6.6 |4.3 |

| |Blurred vision |** |3.6 |0 |1.4 |

| |Ocular AE’s |** |73.7 |53.7 |64.5u |

| |Systemic AE’s |** |18.2 |16.9 |16.7 |

| |DC due to AE |** |< 1 |0 |< 1 |

|Noecker, 2003 |Hyperemia |** |44.4 |20.6v |** |

| |Eyelash growth |** |10.5 |0v |** |

| |Ocular pruritus |** |9.8 |2.9w |** |

| |Ocular burning |** |5.3 |5.9 |** |

| |DC due to AE |** |4.5 |3.7 |** |

|Maul, 2007 |Hyperemia |** |** |12.2 |26.9 |

| |Discomfort |** |** |3.4 |3.2 |

| |Pruritis |** |** |2.0 |1.9 |

| |DC due to AE |** |** |2.9 |4.6 |

|Faridi, 2010 |Hyperemia |** |9 |4 |9 |

| |Allergy |** |2.5 |< 1 |< 1 |

| |Ocular irritation |** |3.2 |6 |4 |

| |DC due to AE |** |5.7 |0.8 |0.8 |

sp< 0.001; t p=0.001 between latanoprost and bimatoprost; up=0.003 among all 3 treatments; p ................
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