Dnuo EvnluATIoN Drugs & Aging 1996 Nov; 9 (5): 363-3781 | 7y2nxt96lm r'r -q363/508,m/0

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LatanoprostA Review of its Pharmacological Properties, Clinical Efficacyand Tolerability in the Management of Primary Open-AngleGlaucoma and Ocular Hypertension

Sanjay S. Patel andCaroline M. Spancer

Adis Intemational Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:A. Alm, Department of Ophthalmology, University Hospital, Uppsala, Sweden; LZ. Bito, Department ofOphthalmology, College of Physicians and Sulgeons of Columbia University, New York, New York, USA;R.E Brubaket , Departmmt of Oph thalmology, The Mayo Clinic, Rodrester, Minnesota, US A; F,T. har"mfeliletCasey Eye lnstitute, Oregon Health Sciences University, Portland, Oregon, USA; B. Frisfiiim, Departmentof Ophthalmology, Link6ping University, Link(ping, Sweden; K.A. McClellaz, Department of ClinicalOphthalmology and Eye Health, Sydney Eye Hospitd, The University of Sydney, Sydney, New South Wales,Australia; H.K. Mishima, Department of Ophthalmology, Hiroshima University School of Medicine,Hiroshima, |apan; S.Nagasubtamanian, Glaucoma Unit, Moorfields Eye Hospital, London, England.

Conlents

Summoryl. Overview of Gloucomo ond Oculor Hypertension2. Phormocodynomic Properties

2.1 Mechonism of Action2.2 Oculor Etfects2,3 Generol Phormocology

3. Phormocokinetic Properties3.1 Corneol Permeobility . .

3,2 Systemic Absorption3.3 Metobolism ond Excretion .

4. Clinicol Evoluotion4.1 Dose-Ronging Studies4.2 Comporotive Studies .

4.3 Combinotion Theropy5. Tolerobility

5.1 Conjunctivol Hyperoemio5,2 lridiol Pigmentotion5.3 Other Oculor Adverse Events5.4 Systernic Adverse Events .

Dosoge ond Administrotion .

Ploce of Lotonoprost in the Monogement of Prirnory Open-Angle Gloucomoond Oculor Hypertension

,3U, 365. 366. 366. 366. 368. 368

368. 368. 368. 369. 370, 370. 371

. 37r

. 371

. 373

. 373

. 373, 373

. 374

67

354 Patel €t Spencer

SurnmarySynopsis

PhormocodynomicProperlies

PhormqcokinelicProperties

Clinicol Evqluo?ion

Latanoprost is an ester prodrug analogue of prostaglandin Fzawhich effectivelyreduces intraocular pressure (lOP) by increasing uveoscleral outflow rather thanaltering conventiorul (trabeculo-canalicular) aqueous outflow. The lOP-loweringeffect of latanoprost lasts for 20 to 24 hours after a single dose, which allows a

single daily dosage regimen.Data from 4 randomised double-masked multicentre studies indicate that a

once daily dose of topical latanoprost 0.005Vo is as effective as timolol 0,5V0 twicedaily in the treatment of patients with primary open-angle glaucoma or ocularhypertension. A number of studies also demonstrate that latanoprost enhancesIOP-lowering effects when applied in combination with other antiglaucomaagents.

Latanoprost is well tolerated with flo, or barely detectable, conjunctivalhyperaemia, and, unlike timolol, is not associated with systemic adverse efficts.However 3 to l}Vo of patients treated with latanoprost 0.005V0 have shown in-creased iris pigmentation after 3 to 4.5 months'treatment.

In summary, the available data show that latanoprost is a potent loP-loweringagent with a number of positive features including a single daily dosage regimen,

a novel mechanism of action that enhances the lOP-lowering effict of contem-porary agents, and a lack of systemic adverse effects. These properties suitablypoise latanoprost for a prominent position in the management of patients withprimary open-angle glaucoma and ocular hypertension.

Latanoprost is an ester prodrug analogue of prostaglandin Fza with high selectivityfor the FP subtype of prostanoid receptors. Unlike contemporary antiglaucornaagents, latanoprost reduces intraocular pressure (IOP) by increasing uveoscleraloutflow, with linle or no alteration of conventional (trabeculo-canalicular) aqueous

outflow and no effects on retinal vasculature or perrneability of the blood-aqueousbarrier.

The reduction in IOP produced by latanoprost is dose-dependent. The IOP-lowering effects after a single dose of latanoprost 0.006Vo last for up to 20 to 24hours. Long term (6 months) application of latanoprost is not associated withmorphological alterations to the ciliary muscle or trabecular meshwork, according toanimal data. Furthermore, other body systems (brain, cardiovascular, respiratory)do not appear to be significantly affected by latanoprost at concentrations up tol0-fold greater than those used clinically for topical application.

Latanoprost is more Iipophilic than its parent prostaglandin and therefore betterable to penetrate the cornea. After uptake by the cornea, latanoprost is cornpletelyhydrolysed; the drug does not seem to be metabolised by other means in the eye.

In monkeys, the highest drug concentrations were observed in the cornea aftertopical administration, the acid of latanoprost was then released from the corneainto the anterior eye. The drug had an elimination half-life of 3 to 4 hours fromthe eye tissues.

Drug that is systemically absorbed has a short plasma elimination half-life.The major metabolic pathway is by p-oxidation and the metabolites are excretedprimarily via the kidneys. Recovery of radiolabelled drug appears to be complete.

Dose-ranging studies show that a once daily topical dose of latanoprost (optimal con-centration of 0.005 or 0.006Vo) effectively produces a decrease in IOP in patients

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latanoprost: A Review 355

Tolerobility

with primary open-angle glaucoma or ocular hypertension. Single daily applica-tion of latanoprost is at least as effective as a twice daily dose.

Three of 4long term (3 or 6 months) randomised, double-masked, multicentrestudies indicated that once daily latanoprost 0.005Vo was more effective than

timolol 0.57o twice daily in reducing IOP. A number of clinical studies have also

shown that latanoprost applied in combination with other antiglaucoma agents

produces enhanced IOP-lowering effects.

Data from phase trI clinical studies indicate that topical latanoprost 0.005 Vo onca

daily application is, overall, as well tolerated as timolol 0.5Vo twice daily. Atclinically effective doses, no or a barely detectable increase in conjunctivalhyperaemia was noted in at least gOVo of latanoprost or timolol recipients. Incontrast to timolol, latanoprost is not associated with systemic adverse effects.

On the other hand, increased iridial pigmentation has been noted in 3 to l0%o

of patients after 3 to 4.5 months'continuous treatrnent with latanoprost O.OOSVo.

It occurred only in patients with mixed colouririses (green-brown or bluelgrey-brown); freckles or naevi in the iris were not affected.

Once-daily topical instillation of latanoprost 0.005Vo is the recommended dosage

regimen for the treatment of patients with primary open-angle glaucoma or ocularhypertension. If used in combination with other topical antiglaucoma agents, the

drugs should be instilled at least 5 minutes apart.

Dosoge ondAdministrolion

Latanoprost (fig. 1) is one of a number of ration-ally designed ester prodrug analogues of prosta-

glandin Fzo eGF2q;lt-+l that have been investigated

as potential treatments for primary open-angleglaucoma (POAG) and ocular hypertension.ls-el

Latanoprost is the R component of an approxi-mately equimolar R/S epimeric mixture initiallyidentified as PhXA3 4.lr) The epimeric mixture was

originally evaluated for the treatment of POAG and

ocular hypertension,[10-l2l but later displaced in fa-

vour of latanoprosl.l I'l 3 I

This review describes the pharmacologicalproperties, clinical efficacy and tolerability of top-ically applied latanoprost for the treatment ofPOAG and ocular hypertension.

I. Overview of Gloucomoond Oculor Hyperlension

The terrn glaucorna encompasses a group ofdiseases that share all or some of the followingpathophysiological features: elevated intraocularpressure (IOP), excavation of the optic nerve head,

and loss of visual field (see Lesarl r4l). Glaucoma is

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a chronic disorder that, in the majority of patients,

results frorn an imbalance between aqueous humour

Latanoprost

Prostaglandin F.,.

Fig. 1. Structural formulae of prostaglandin F26 dnd latanoprost.

Drugs & Aging 1996 Nov; 9 (5)

Table l. Classification of glaucoma[l4]

Primary glaucoma

Open-angle

Angle closure

Secondary glaucoma

Open-angle

Angle closure

Congenital glaucoma

with pupillary blockwithout pupillary block

pretrabecular

trabecularpost-trElbecular

with pupillary blockwithout pupillary block

production and outflow from the anterior segrnent

of the eye (see Lesarll4l). Broadly, glaucoma can be

divided into open-angle, angle closure and primary,

secondary and congenital glaucoma (see table I fora detailed classificationl I 4l;.

Briefly, POAG, which is diagnosed in =90Vo ofpatients with primary glaucolrs, is bilateral and

insidious in onset (visual acuity remains normal

until the late stage of the disease).[14'ls] It is prob-

ably, at least partly, a consequence of inhibiteddrainage of aqueous humour because of chronic

low-grade partial obstruction of either the trabecu-

lar meshwork or Schlemm's canal (fig. 27.tt4l In

patients with POAG the IOP can rang€ from 25 to

45mm Hg, whereas in healthy eyes normal IOP

is maintained between l0 and 2lmm Hg.tl4'l6l IOP

is usually similar in both eyes but shows consider-

able circadian variation.[l4l Chronic elevation ofIOP may cause optic nerve ischaemia and conse-

quent progressive loss of vision.ll4l

Patients with ocular hypertension have elevated

IOP but normal visual fields and optic discs; this

contrasts with patients with normal-tension

glaucoma (present in > l5Vo of patients) in whom

IOP is normal (<21mm Hg) but there is loss ofvisual field and the optic disc is cupped.ll4'lsl

Ocular hypertension is often regarded as a pre-

glaucoma stage.llzl

Key factors that predispose individuals to

developing glaucoma (for review see Quiglerttsl;include high IOP, family history of glaucoffio,

age>40 yeirs, systemic vascular disease, high degree

of myopia, diabetes, long term topical or systemic

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Patel I Spencu

corticosteroid use and ethnicity (particularlyAmericans of African heritage, Russians, Scandi-

navians and the Irish).114'lel

2. Pholmocodynomic ProPerlies

2.1 Mechonism of Action

Latanoprost is a highly selective agonist of the

FP subtype of prostanoid receptors;|201 its affinityfor this receptor is considerably higher than that

for other prostanoid receptors.[2t] Latanoprost, likeits congeners,[22-241lowers IOP by increasing uveo-

scleral outflow, with little or no effect on the con-

ventional aqueous outflow facility.lzst In the nor-

mal eye (fig, 2), outflow of aqueous humour occurs

by filtration through the trabecular meshwork toSchlemm's canal (i.e. conventional or trabeculo-canalicular route) and via uveoscleral outflowthrough the ciliary muscle, suprachoroidal space

and the scl era.176,271 The difference in the outflowrates between the 2 routes is marked: uveoscleral

outflow occurs at0.2 to 0.5 pl/min, compared with1.5 to 1.8 pl/min via the conventional route.[l4l

The process by which latanoprost produces an

IoP-lowering effect (i.e. increasing uveoscleraloutflow) is novel compared with that of existingnonprostaglandin agents used to treat glaucolrls,which act by increasing aqueous hurnour outflowvia the trabecular meshwork or by inhibitingaqueous humour production.[28] The basis forthe precise mechanism of action by which prosta-

glandins decrease IOP remains unclear at present

(see review by Camra5l2el; and the precise pro-

stanoid receptor(s) involved has not been fullyelucidated. Nevertheless, the FP subtype of pro-

stanoid receptors appears to be important as evi-dent from the IOP-lowering effect of latanoprost(section 4).

2.2 Oculor Effects

Most ocular effects of latanoprost in hurnans

parallel those seen with its congeners .1zsl As pre-

viously stated, latanoprost produces an increase

in uveoscleral outflow; an increase from 0.39 (at

baseline) to 0.87 pl/min (p < 0.05) occurred after 8

Drugs & Aging 1996 Nov; 9 (5)

Latanoprost: A Review

days of twice daily application with latanoprost0.006Vo in volunteers.t2sl Latanoprost 0.0O6Vo

twice daily for 5 days increased tonographic out-flow facility (by 24 to 30Vo) in I study (n = 20patients/20 volunteers)t30t but not in another studyof 22 volunteers adrninistered the same dosageregimep.[25] Latanoprost did not affect fluoro-photornetric outflow facility,lz5l which was repre-sented by the ratio of pharmacologically inducedchanges in aqueous flow : changes in IOP. At doses

that effectively reduced IOP, latanoprost also didnot affect retinal vasculature[31] or permeability ofthe blood-aqueous barrier - as indicated by rnini-mal effects on the rate of entry and polarisation offluorescein or aqueous flare intensity.t30l

Latanoprost, like PGFza- I -isopropyl esterls'81 and

PhXA3 4,u21lowered IOP without altering aqueous

flow in volunteers and patients.[2s'30] Placebo-

controlled (contralateral eye) studies in humanswith normotension or ocular hypertension haveshown significant decreases in IOP (by 22 to 25Vo)

after 5 to 8 days of treatment with latanoprost0.006Vo twice daily.l2s'301 Maximal decreases inIOP occurred within the first 2 days of initiatinglatanoprost treatment (as is also the case with pilo-carpinelzzll in patients with POAG or ocular hyper-tension .132'381 The IOP-lowering effect was inde-pendent of the time of application of the agent.[3e'401

Reductions in IOP with latanoprost can last for 20to 24 hours after a single dose '134'36,41I the reason

for this sustained effect is not adequately under-stood, although it can be explained, in part, by thehigh lipophilicity of the prodrug and consequentcorneal trapping of the de-esterified drug (see sec-tion 3. I ).

Anterior chamberCornea

Posterior chamberlris

Conjunctiva

Schlemm'scanal

IExtraocular

muscle

Optic stalk

Fig. 2- Anatomical features of the human eye under normal condiiions (a) and in primary open-angle glaucoma (b). ln the normaleye, aqueous humour (secreted into the posterior chambeo enters the anterior cfiamber through the pupil. ln the anterior chambe(it passes through the trabecular meshwork inlo Schlemm's canal and lrom there inlo the \renous system. ln primary open-angleglaucoma, lhe eye appears anatomically normal but the llow of aqueous humour is obstrucled at the trabeqJlar meshwork orSchlemm's canal, resulling in elevated inlraocular pressure.

cana! ,..-.r-i€ lris

humour flow ift=== Posterior

Ciliary Suspensorybody ligaments

Vitreous bodyOptic

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367

b Trabecularmeshwork

358

Preliminary data from studies in animals in-dicated that long term apPlication of latanoprost(10 pgleye once daily for 6 months) was not asso-

ciated with morphological alterations in the ciliarymuscle or trabecular meshwork.l42l In contrast,previous studies with PGF2, (administered to

cynomolgus monkeys once or twice daily for <8

days) have indicated morphological changes to the

tissues involved with aqueous inflow/outflow (forreview see Ltitjen-Drecoll & Kaufmanta3l). Vitre-ous concentrations of latanoprost (up to l0 mg/L)did not affect the electroretinogram of rabbit eyes

in vitro,l44l and ocular blood flow wEIS unaffected

by intravenous doses of latanoprost in cynomolgusrnonkeys. t20;

2,3 Generol Phormocology

In cynomolgus monkeys, intravenous doses oflatanoprost (up to 1O-fold greater than those used

topically in clinical practice) did not produce sig-

nificant changes in cardiovascular parameters(blood pressure, cardiac output, heart rate, strokevolume, cardiac work and coronary blood flow) or

respiratory parameters (respiration rate and intra-thoracic inspiratory-expiratory pressure differ-ences).Jzol These doses also had no effect on bloodflow to the brain or splanchnic beds.l2ol

3. Phormocokinelic Properlies

Pharmacokinetic data pertaining to topical and

intravenous latanoprost have been generated using

tritium-labelled samples of the drug. Radioactivitywas determined by liquid scintillation countingand high performance liquid chrornatography withon-line radioactivity detection .145'461

3,1 Corneol Permeobility

Esterified prodrugs of prostaglandins, such as

latanoprost, are more lipophilic than the parent

drug and are therefore better able to penetrate

the cornea.l4T'481 After topical administration of[3H]latanoprost to the monkey eye, the drug was

shown to penetrate the cornea; the cornea showed

the highest concentration of radioactivity (0.6ng

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Patel €t Spencn

equivalents lmg tissue). The cornea then appeared

to release radioactivity to the anterior parts of the

eye. Peak concentrations of radioactivity in the

iris, anterior chamber and ciliary body were ob-

served t hour postdose with an elimination half-life from the eye tissues of 3 to 4 hours.l4el

3.2 Systemic Absorption

Drugs applied topically to the eye can enter the

systemic circulation via drainage through the

nasolacrimal duct and absorption from the naso-

pharyngeal mucosa.lsol In 4 healthy volunteerswho received [3H]latanoprost, maximum plasma

concentrations (Cr.*) of 0.6 and l2.51tg equiva-

lents/L were observed after topical (3pg) and intra-venous (2lOpg) administration, respectively.146l

Time to Cr.* (15 minutes) was independent of the

route of admi nistration.l46l

Latanoprost was 90Vo bound to plasma proteins

in the first few minutes after intravenous adminis-tration, although this decreased over time (60Vo 2

hours postdose).t+6t

3.3 Metobolism ond Excretion

Once partitioned into the cornea, latanoprostundergoes l00%o ester hydrolysis,t4s l probably

mostly in the corneal epithelium.l4el Latanoprost does

not appear to be subject to further ocular meta-

bolism, and, unlike other related phenyl analogues,

it is not a substrate for l5-hydroxyprostaglandindehydrogenase. t45l

Initial (tvrd and terrninal (tvril plasma elimina-tion half-lives of total radioactivity were 6.6 and

69 minutes, respectively, after 4 healthy volunteers

received a 2l01tg intravenous dose of [3H]-latanopys5l.la6l Radioactivity in plasma samples

was undetectable t hours after intravenous and 6hours after topical (3pg) doses .1461 In monkeys,

the main systemic metabolic pathway was by p-

oxidation in the liver.t2ol In humans, excretion oc-

curred primarily via the kidneys (88Vo and 97Vc

recovery of urinary radioactivity after topical and

intravenous doses, respectively), with some faecal

excretion (15 and l6Vo, respectively;.1+61

Drugs & Aging 1996 Nov; 9 (5)

Latanoprost: A Review 369

Table ll. Topical latanoprost (L) treatment in patients with primary open-angle glaucoma or ocular hyperlension: randomised double-masked

dose-ranging andor placebo-conttolled studies

Reference No. of Treatment Mean diumal intraocular pressure (mm Hg)

patients (duration; wk) [percentage change from baseline]

baseline time atter treatment initiation (wk)

24 12

Atm er at.l3sl 15 LO.OO350/" bid (4) 23.O 16.5" [J28] 17.9e11221 17.3" [J251

1 s L O.OO5% bid (4) 23.6 17 .Oa lJ28l 18.3a p22l 17 .8a [J2s]1 5 L 0.011 5olo bid (4) 23.0 16.4a lJ29l 17 .Oa tJ26l 17 .4a p24J

1s P (4) 23.4 n.8a f4 24.8a [16] 23.8a [t2lAtm er 61.1501 25 L 0.006% onb 1te; 24.8

2s L 0.006% bidb (12) 24.9

coakes et at.ts2l p L 0.00125"/o on (2) 23.4 20.4 tJ13l 19.4 [J17]'11 L O.OO25% on (2\ 24.1 18.3 [J24] 1e.1 [J21]'12 L O.OO5% on (2) 23.9 17.8 tJ26l 17.6 [JZe1't10 P (2) 23.e 21 .s tJsl 22s Il7)

Lusky s1 6;.tssl 50 totalc L 0.0015% bid (3) 23.8

L 0.00s% od (3) 25.7

L 0.005% od (3) 18.2e

after L 0.001 5% bid (3)

L 0.001s% bid (3) 17.2s

after L 0.005% od (3)

Nagasubramanian 20 L 0.006% od (2) 24.8 16.2 [J35]"' 1 5.9 [J36]"'et al.lsl

1 9 L 0.006% bid (2) 25.0 17.8 [J29].., 18.0 [J28]"',10 P (21 25.3 24.0 tJsl 23.6[J7]

Rdcz er at.l36l 9 L 0.006% on (5 days) 25.4 19h [J25J"6 P (5 days) 25.2 23.sh [u]

a Data rellect changes based on nlues al 8am and not mean diumal values.

b Topical timolol 0.5of twice daily and latanoprost treatmenl were applied concomitantly in all patients.

c Crossover study design.

d Measured value at swk after inithting treatmenl.

e Mean intraocular pressure betore latanoprost 0.0o5o/. administration.

I Measured value at 3wk afrercrossover.

g Mean intraocular pressure belore latanopost 0.0015% administration.

h Measured value at 5 days after initiating treatrnent.

Abbreviationsardsyrnbors.'bkl=twicedaily; od=oncedaily; on=oncedaityintheevening(night); P=placebo; T=timolol; J=decrease;1=increase;'p<O.O5vsplacebo;"p<0.01 rGcomparatorgroup(Almetal.lsl;6rbaselinevalue(R6czetal.tq); "'p<O.OO1 vsplacebo;t p = 0.045 tzs L 0.001250/o group.

4. Clinicol Evoluotion 4.1 Dose-Ronging Studies

A number of studies have evaluated topical la- Dose-ranging studies (n S 60 patients per study)

tanoprost for the treatment of patients with POAG generally showed that latanoprost, at concentrations

or ocular hypertension. The patient population in ranging from 0.00125 to 0.01157o, effectively pro-

these studies comprised a mix of those with either duced significant decreases in IOP compared withPOAG or ocular hypertension. Diurnal IOP was placebo (table II). The reduction in IOP was dose

defined as the mean IOP over the day based on dependent,tal'5r-s3l and the optimal IOP-loweringvalues obtained at 8 or 9am, l2 noon or lpm and 4 concentration was 0.005 or O.N6%.or 5pm. Goldmann applanation tonometry was used A once daily dose of latanoprost was at leastto measure IOP. as effective as a twice daily dose without any

16.8 [J32] 15.7 [J371"18.1 lJ27l 18.0 [J281

18.2d 1!Zt7n.2d tJffilfi st llzzl

19.1, IJ26I

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370 Patel & Spencu

diminution in the IOP-lowering effect for up to 3

months (table II). The reason for this paradoxical

but consistent and beneficial observation is unclear

at present.

4,2 Comporotive Studies

Four long term (3 or 6 months) randomised,

double-masked, multicentre studies (total n = 1013

patients) have compared the efficacy of latanoprost(0.005Vo single daily application) versus tirnolol(0.5Vo twice daily) in patients with IOP >20mm

Hg.ts6-sel Three trials measured diurnal IOP.l57-5el

the remaining trial measured IOP at garn only.ts6t

Both agents reduced IOPfrom baseline by 27 to35Vo

(latanoprost) and l9 to 33Vo (timolol) throughoutthe treatment periods (fig. 3).t56-5el In 3 of these

studies, Iatanoprost produced a greater decrease in

mean IOP than timolol at 3 or 6 months (p <

0.001).t56'sz'5el Although the fourth study did not

find the difference between the treatments sig-

nificant at 6 months, latanoprost was significantlymore effective than timolol at 12 and l8 weeks

(fig. 4).ts8l Latanoprost applied in the eveningproduced a significantly better response than

morning application (p < 0.0011.ts21

Whereas the IOP-lowering effect of latano-prost was unaffected by variables such as gender,

age, race or diagnosis (POAG vs ocular hyper-

Alm et al.tszl Watson et al.[sa] Camras et a!.lsel Mishima et al.tsel

\o,s\,t\,sn\ o"^t',d s,$l,tto \,.,s\--$o\

E 10

ooECL

(u ,-.EEEe7=_=E 20kxoltrE;eooE0)cE 30

tr Latanoprost om

I Latanoprost on x 3mothen om x 3mo

I Latanoprost om x 3mothen on x 3mo

I Latanoprost on

E Timolol bid

Fig. 3. Comparative efficacy ol latanoprost and timolol. Data {rom 4 randomised double-masked multicentre studies showingpercentage reductions in intraocular pressure 6tt97 $tsol or 6ls7-ssl months'treatmenl wiih eiiher latanoplost 0.005% once dailyor timolol 0.5% twice daily in evaluable patients with primary open-angle glaucoma or ocular hypertension. All reduciions were

significant ys baseline. Abfevhtions: bid = twice daily; om = once daily in lhe morning; on = once daily in the evening; ' p < 0.001

vs timolol.

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Latanoprost: A Review 377

tension;,t57-5el Watson et al.t581 noted that timololproduced greater reductions in IOP in men (9.0vs 7.lmm Hg in women; p < 0.01) and in patients

with POAG (9.4 v.r 7.lmm Hg in patients withocular hypertension; p < 0.01). Iris colour did notaffect the IoP-lowering effect of timolol or oflatanoprost in 2 studies,[s7'5el whereas a thirdstudy noted that patients with hazel eyes had abetter response than those with blue- or green-grey

eyes (9.3 v.r 8.0mm Hg reduction in IOP withlatanoprost; p = 0.006).t581

4.3 Combinotion Theropy

Six clinical studies (n S 50 patients per study)have examined the effects of topical latanoprostapplied in cornbination with other topical or oralantiglaucoma agents (table III). Monotherapywas administered for about 1 or 2 weeks and was

followed by combination therapy for the same re-spective time frames (table III). At the end of themonotherapy period, there was a trend towards a

greater reduction of IOP with latanoprost than withdipivefrine, pilocarpine or timolol (although thestatistical significance of this was not stated). Atthe end of the combination therapy period, IOP had

decreased even further (relative to baseline) thanafter monotherapy (table III). Thus, these datashow that latanoprost can be administered in com-bination with other antiglaucoma agents to pro-duce enhanced lowering of IOP.

5. Tolerobility

Previous investigations of topical prostaglandin

analogues have identified agents with unaccept-able adverse effects .l't,e,22,63-6sl The prototypicalagent, PGF2q- I -isopropyl ester, was associatedwith initial increases in IOP, photophobia, ocularirritation and conjunctival hyperaemia.l5'61 Al-though latanoprost, which is also an isopropyl ester(fig. 1), has been associated with some of these

adverse effects, it is better tolerated than its analo-gous predecessors. Overall, latanoprost was welltolerated in 4 pivotal phase III clinical studies com-paring latanoprost with timolol.ls6-sel

nol Limiled. All rights reserved

25

212 18 26

Duration of treatment (wk)

Fig. 4. lntraocular pressure response profiles with latanoprostand timolol. Comparative profiles of intraocular pressure re-sponse (9am measurements) to latanoprost 0.005% (oncedaily) and timolol 0.5% (twice daily) over 6 months'treatment inpatients with primary open-angle glaucoma or ocular hyper-tension (n = 268).ts8l Symbols: ',p .0.05; " p .0.02 vstimolol.

5. I Conjunctivol Hyperoemio

Barely detectable, or no, conjunctival hyperaemiawas noted among patients treated with topical la-

tanOprOSt adminiStered alOnel I 3'30'32-36,38,41,5 1,55.57-591

or in combination with dipivefrinel6ol or timo-161.1331 Hyperaemia was graded using visual ana-

logue scales or by comparisons with standard

baseline photographs; scores were defined by an

arbitrary scale ranging from 0 to 3 with 0 corre-

sponding to no hyperaemia and 3 to severe hyper-

aemla.

The mean hyperaemia score with latanoprost

treatment, based on maximal hyperaemia observed

during the day,was predominantly <0.5.ts7-5el

The incidence of conjunctival hyperaemia was

most pronounced within the first 2 days of initiat-ing latanoprost therapy, and diminished withtime (after 2 to 4 weeks).134'lsl Although the inci-dence of hyperaemia was greater with latanoprost

than with timolol (p < 0.001),1581 the degree ofhyperaemia was mild. A comparison of maximumhyperaemia scores at baseline and at 6 months in 2studies showed that, in at least 90Vo of patients,

6-E20E

o

E lsoct(U

3 10o(U

s5

Drugs & Aging ]996 Nov; 9 (5)

372 Patel E Spencer

Table lll. Clinical studies evaluating the efficacy of topical latanoprost (L) applied in combination with oihertopical or oral (acehzolamide)antiglaucoma agenls in patients with primary open-angle glaucoma or ocular hypertension

Reference No. o, Treaunent and Mean diumal intraocular pressure (mm Hg)(study design) palients duration (wk) [percentage reduction lrom baseline]

baseline time after treatment initiation (wk)

2412

Dipivefrine (D) combinationAtm er 31.te0F (NS) 22 totat L 0.005o/o od (2) 19.3

D 0.1 y. bad (2) 22.3

t+ Db (e)

o+tb(z)Watson et at.l61F (r, sm, sc; 10 L 0.0060/o bid (1) 24.7 16.9 [J32]

10 D 0.1% bid (1) 26.3 1e.1 lL27)

10 L+ Dc (1)

10 D+Lc(1)

Timolol (T) combinationAlm et 31.t5ol (r, dm, mc) 25 L 0.0060/. on + 24.8

T O.5% b.d (12)

25 L 0.0060/o bid + 24.9

T O.5o/o bid (12)

Rulo et al.lsl (r, sm, sc) I L 0.006o/o bid (1) 28.5 19.6 [J31]'10 T o.s% bid (1 ) 24.2 18.3 [J24]'

9 L+T(l)d10 T+L(1)d

Pilocarpine (P) combination

Fristrom & Nilssonlsz) (r sm, sc) 10 L 0.0O60/o bid (1) 25.1 19.1 [J24J"10 P 2Yo rid (1) 23.8 20.4 [J14J"10 L+ P (1)e

9 P + L (1)e

Acetazolamide (A) combinationRulo

"1 ";.t62la (r, dm, mc) 24 total A250mg bid + 1g.Se

L 0.005o/o oot (e)

A 250m9 bid + PBO (2) 19.5s

14.8 [J23]

18.4 tJ14

14.7 tJ40l

13.8 [J48]

17.0 [J4o]

15.7 tJ3sl

17.6 [J3Ol.,

17.7 lL26l"

16.9 tJ 14J"

20.8 tTl.3I

12.4 [J361

14.s [J33l

16.8 [J32] 1 s.7 [J371',

18.1 ll27l 18.0 lJ28I

a Preliminary data presented as an abstract.

b L + D: dipivelrine was added to latanopK,st therapy after 2wk monotherapy with latranoprost; vice v€rsa lor the D + L group. Doses ofhtanopost and dipivefrine used during combination therapy were the same as those used indivilually lor rmnotherapy.

c L + D: dipivefrine was added to latanoprost lh€rapy after lwk monotherapy with htanoprost; vice \rersa lor the D + L group. DosBs oflatanoprost and dipivetrine used during combination therapy were the same as lhose used indivi.Jually lor nonotherapy.

d L + T timolol was added to latanopiost therapy after l wk monotherapy with latanoprost; vice versa for the T + L grcup. Doses ollatanoprosl and timolol used dudng combinalion therapy were the same as those used individually lor monotherapy.

e L + P: pilocarpine was added to latanoprost therapy after l wk monotherapy whh latanoprost; vice versa lor the P + L group. Doses ollatanoprosl and pilocarpine used during combinalion lherapy were the same as those used individually lor rnonotherapy.

f Latanopost was added lo curent treatment with orally administered acetazolamide.

g Mean intraocular pressure betore addition of latianoprost or placebo to acelazolamide therapy.

Abbreiations andsynbols: bil = twice daily; dm = double-mask; mc = multicentre; NS = study design not stat€d; od = once daily; on = once daiyintheevening; PBO=placebo; r=randomised;sc=singlecentre; sm=singlemask;lid=3timesdaily; J=decrease; 1=increase;'p<0.01vs baseline value and compaEtor gKrup (Alm et al.lgl;; " p < O.OOI r4s placebo combinalion (Rulo et al.l62f or baseline value (Fdstr6m &Nilssonlsl).

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Latanoprost: A Review 373

there was no or a barely detectable increase inhyperaemia with both latanoprost and timolol(fie s).

5.2 lridiol Pigmentotion

Topical latanoprost therapy (0.005Vo appliedonce daily) was associated with increased iridialpigmentation in 3 to l}Vo of patients after 3 to 4.5

months' continuous treatment in randomiseddouble-masked rnulticentre stud1.t.l57-sel The

increase in iridial pigmentation occurred onlyin patients whose eyes were already of mixed col-ours (i.e. green-brown or blue/grey-brownl.[57'581However, freckles and naevi in the iris were unaf-fected; i.e. they did not change shape or colourduring treatment. [ 57-5e]

No other pharmacological agent has been re-

ported to produce changes in iris pigmentation.lssl

The precise mechanisrn of this effect with latano-prost is not adequately understood, althoughstimulation of melanin synthesis rather than pro-

liferation of melanocytes is thought to be a keycomponent.t5T-5el Long term follow-up studies are

required to establish whether or not this increasedpigmentation is an irreversible effect.

5.3 Other Oculor Adverse Events

Latanoprost 0.0O5Vo once daily was as welltolerated as timolol 0.5 Vo twice daily with respectto other ocular adverse events: of the 3 phase IIIstudies to perform a statistical analysis, none re-ported a significant difference in the ocular ad-

verse events between the 2 groups throughout the 6

months of treatment.lsT'sel These events includedpunctate keratopathy, dry eye sensation, blurredvision, excessive tearing, ocular or eyelid discom-fort, burning, stinging, itching and foreign bodysensations.l5T-5el

Although a few cells in the anterior chamberand slight flare were detected rarely,l35's+'s6'581

neither latanoprost nor timolol caused significantinfiltration of cells into the anterior charnber orsignificant changes in aqueous flare intensity orpupillary diametsl.[57-5el Changes in aqueous hu-mour protein concentrations after either Ia-

nol Limited. All rights reserved.

tanoprostll3'30's3l or timolslts3l ffeatment were notsignificantly different from those at baseline. Visualacuity or refraction were not affected by latano-prost or timolsl.tsT-sel Worsening of the visual fieldor significant changes in laboratory tests (haema-

tology, clinical chemistry or urinalysis) after la-

tanoprost therapy have not been reported either.Latanoprost, like PhXA34, has not been associatedwith elevation of IOP.

5.4 Systemic Adverse Events

Topical latanoprost had little effect on heart rate

or systemic blood pressure in patients.[33-35'56-5el

In contrast, topically applied timolol resulted inreduced mean heart rate (by 3 to 4 beats/min; p <

0.05 vr pretreatment)l'7'sel and mean systolicblood pressure in one study (by 3mm Hg; p < 0.05vs baseline at 3 monthslsell but not in another.ts7l

A number of other systemic adverse events such as

upper respiratory tract infection, musculoskeletalpain, eczemalallergy were reported with both treat-ments, but these effects did not appear to be relatedto the drugs.

Respiratory function, heart rate and systolic and

diastolic blood pressures were not adversely af-fected in patients with asthma who received 2 to20ttg (total doses) of latanoprost.l66)

6. Dosoge ond Administrolion

Latanoprost 0.O05Vo is the recommended con-centration for once daily topical (eye) instillationin patients with POAG or ocular hypertension. Itcan be used in combination with other topicalophthalmic agents to reduce IOB although the drugs

must be instilled at least 5 minutes apart.

7. Plqce of Lolonoprosl in theMonogement of Pdmory Open-AngleGlqucomo ond Oculor Hyperlension

Although glaucoma can develop at any age,l67'6al

it is most common in the elderly population (up

to lU%o of persons aged >75 years).[l6.6el It is

estimated that glaucoma may remain undetected inup to 507o of individuals.lT0l Once the diagnosis of

Drugs & Aging 1996 Nov; 9 (5)

Patel €t Spencer

BD

Alm et al. tszl

glaucoma has been confirmed, topical drug ther-apy is usually the first-line option; the aim of thistreatment is preservation of visual function bymanaged control of IOP.I l6'2E,71 I At present, topicalp-adrenergic antagonists (e.g. timolol, carteolol) are

the agents of first choice for the management ofPOAG and ocular hypertension,l l6'28'721 with topi-cal adrenergic agonists [e.g. epinephrine (adrenaline)

and dipivefrinel and parasympathomimetic agents(e.g. pilocarpine, carbachol) as second-line agent5.l72l

Oral carbonic anhydrase inhibitors (e.g. acetazol-amide) and systernic hyperosmolar agents (e.g.

O Adis lnternotionol Limited. All rights reserved.

I Latanoprost

Timolol

BD MiId

Watson et al. tssl

mannitol) are also used for the treatment of glau-coma, though the latter type are used only for acute

treatment.l | 6'2E,721 Recently, topically active uno-prostonel65.73l (a PGFza derivative) and dorzol-amidett4l (a topical carbonic anhydrase inhibitor)have been approved for clinical use .1721

Patients refractory to topical drug therapy orwho are persistently poorly compliant require la-ser therapy (trabeculoplasty) or surgical interven-tion (trabeculectomy).f 16'71'721 In most patientswith POAG or ocular hypertension, the prognosisis good; progression to blindness is rare with early

Flg. 5. Degree of increase in conjunctival hyperaemia with topical latanoprost or limolol treatment in palienis with primary open-angleglaucoma or ocular hypertension. Percentage of patients with an increase in maximum conjunctival hyperaemia versus baselineexamination after 6 months'treatment wilh latanoprost 0.005% once daily (n = 175Js7) n = 138t$l) or timolol 0.5% iwice daily (n =821sz1n = 131l5El). Abbteviations: BD = barely detec{able increase; MM = mild to moderale increase; Nl = no inciease.

Drugs & Aging 1996 Nov; 9 (5)

374

A60soC.o(uCL

ociz

40

Latanoprost: A Review 375

diagnosis, adequate and closely monitored drugtreatment, and good patient compliance.llal

In recent years, this traditional approach to the

management of glaucoma has been re-examined

because conventional treatment addresses justone (elevated IOP) of the several risk factors, al-

though it is the only risk factor amenable to treat-

ment.lte'7s'761 More importantly, adequate controlof IOP may not necessarily confer a protectiveeffect against underlying pathological processes,

since there is no long term proof of a cause and

effect relationship. t72'7sl Preliminary data indicatethat glaucoma may also be associated with elevated

levels of excitatory amino acids (such as gluta-rnate) in the eye.lle)

Latanoprost is an effective IOP-lowering agentwith a clinical profile that compares favourablywith that of other antiglaucoma agents (section 4).

The beneficial effect of latanoprost is evident at

considerably lower concentrations (0.005 or0.006Vo) than those required with other topicalagents (e.g . 0.25 to ZVo for p-adrenergic antago-

nists, 0.5 to ZVo for adrenergic agonists, and 0.03to 4Vo for parasympathomimetic agents). Althoughcomparative clinical data are limited at present,

further (long term) studies comparing latanoprostmonotherapy with other established and more re-cently introduced antiglaucoma agents should en-

able consolidation of its place among these agents.

Four large multicentre studies (n > 180 per study)have already shown that latanoprost comparesfavourably with timolol.

A major advantage of latanoprost is its longduration of action, which means that it can be ad-

ministered as a single daily dose. In contrast, mostestablished topical antiglaucoma agents requireat least twice daily application, although a newforrnulation of timolol has been developed thatcan be administered once daily. Another advantage

of latanoprost is its novel mechanism of action(section 2) which means that combination therapyallows more effective control of IOP. Neverthe-less, studies of latanoprost administered in combi-nation with other new agents (e.9. dorzolamide) are

awaited.

O Adis lnternotionol Limited All rights reserved,

Despite the pharmacological advantages and

favourable clinical profile of latanoprost, some un-certainty has been expressed about the long term

effects of topi c al pros tagl and i ns . l7 s'1 7 ) S pec i fi c al I y,

these are the long term effects of chronic increases

in uveoscleral outflow, effects on chorioretinal cir-culation or episcleral venous pressure and, moreimportantly, the overall effect on the glaucomatousproces s.I7s,77l Comparative long term studiesshould help address some of these concerns.

The selectivity of latanoprost has resulted ina marked improvement in tolerability over that ofits antecedents (see AlmtT8l and otherstle-9t I for an

overview of the historical development of prosta-glandins as IoP-lowering agents). It is as well tol-erated as tirnolol, despite its unusual and uncom-mon effect of increasing iris pigmentation inselected populations during long term (6 months)studies (section 5.2). Although latanoprost, likeall other topically applied ophthalmic drugs, isabsorbed into the systemic circulation (section 3),even long term application of this agent has not

been associated with adverse systemic effects. Thismay be due, in part, to the extremely small arnountof active agent applied to the eye and to its very

effective renal excretion. This profile sharplycontrasts with that of topical p-adrenergic antago-nists (which can precipitate respiratory and/orcardiovascular complications and cause mentaland physical lethargy and erectile dysfunction), ad-

renergic agonists (which can induce tachycardiaand allergic reactions, mydriasis and pigmented

corneal and conjunctival deposits), parasympatho-

mimetic agents (which can cause pupillary miosis,reduced vision and myopia) or carbonic anhydraseinhibitors (which can cause paraesthesia, uretero-lithiasis, mental and physical lethargy and erectiled Ysfuncti on ) .l

t 6'28'7 2' 8 2'83 I

In conclusion, latanoprost is a potent IOP-lowering agent with key favourable features: a

single daily dosage regimen that produces a highlyeffective IOP reduction around-the-clock; a novelmechanisrn of action that facilitates enhanced IOP-lowering effects in combination with other agents;

and a tolerability profile that is likely to be superior

Drugs & Aging .l996

Nov; 9 (5)

375

to that of timolol with regard to systemic adverse

effects. Thus, although the long term effects oflatanoprost are unknown, the available data forthis drug point towards its prominence in the man-

agement of patients with POAG and ocular hyper-

tenston.

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58. Watson P, Stjernsch'antz J, the Latanoprost Study Group. A six-month, randomized, double-masked study comparinglatanoprost with timolol in open-angle glaucoma and ocularhypertension. Ophthalmology 1996 Jzrn; 103 (l): 126-37

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