Dnuo EvnluATIoN
`
`Drugs & Aging 1996 Nov; 9 (5): 363-378
`1 | 7y2nxt96lm r'r -q363/508,m/0
`
`O Adis ln?ernolionol Limiteo All rlghts reserved
`
`Latanoprost
`A Review of its Pharmacological Properties, Clinical Efficacy
`and Tolerability in the Management of Primary Open-Angle
`Glaucoma 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 of
`Ophthalmology, 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"mfelilet
`Casey Eye lnstitute, Oregon Health Sciences University, Portland, Oregon, USA; B. Frisfiiim, Department
`of Ophthalmology, Link6ping University, Link(ping, Sweden; K.A. McClellaz, Department of Clinical
`Ophthalmology 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.
`
`,3U
`, 365
`. 366
`. 366
`. 366
`. 368
`. 368
`368
`. 368
`. 368
`. 369
`. 370
`, 370
`. 371
`. 37r
`. 371
`. 373
`. 373
`. 373
`, 373
`
`. 374
`
`Conlents
`
`Summory
`l. Overview of Gloucomo ond Oculor Hypertension
`2. Phormocodynomic Properties
`2.1 Mechonism of Action
`2.2 Oculor Etfects
`2,3 Generol Phormocology
`3. Phormocokinetic Properties
`3.1 Corneol Permeobility . .
`3,2 Systemic Absorption
`3.3 Metobolism ond Excretion .
`4. Clinicol Evoluotion
`4.1 Dose-Ronging Studies
`4.2 Comporotive Studies .
`4.3 Combinotion Theropy
`5. Tolerobility
`5.1 Conjunctivol Hyperoemio
`5,2 lridiol Pigmentotion
`5.3 Other Oculor Adverse Events
`5.4 Systernic Adverse Events .
`Dosoge ond Administrotion .
`Ploce of Lotonoprost in the Monogement of Prirnory Open-Angle Gloucomo
`ond Oculor Hypertension
`
`6 7
`
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`

`354
`
`Surnmary
`Synopsis
`
`Phormocodynomic
`Properlies
`
`Phormqcokinelic
`Properties
`
`Clinicol Evqluo?ion
`
`Patel €t Spencer
`
`Latanoprost is an ester prodrug analogue of prostaglandin Fzawhich effectively
`reduces intraocular pressure (lOP) by increasing uveoscleral outflow rather than
`altering conventiorul (trabeculo-canalicular) aqueous outflow. The lOP-lowering
`effect 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 twice
`daily in the treatment of patients with primary open-angle glaucoma or ocular
`hypertension. A number of studies also demonstrate that latanoprost enhances
`IOP-lowering effects when applied in combination with other antiglaucoma
`agents.
`Latanoprost is well tolerated with flo, or barely detectable, conjunctival
`hyperaemia, 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-lowering
`agent 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 suitably
`poise latanoprost for a prominent position in the management of patients with
`primary open-angle glaucoma and ocular hypertension.
`Latanoprost is an ester prodrug analogue of prostaglandin Fza with high selectivity
`for the FP subtype of prostanoid receptors. Unlike contemporary antiglaucorna
`agents, latanoprost reduces intraocular pressure (IOP) by increasing uveoscleral
`outflow, with linle or no alteration of conventional (trabeculo-canalicular) aqueous
`outflow and no effects on retinal vasculature or perrneability of the blood-aqueous
`barrier.
`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 24
`hours. Long term (6 months) application of latanoprost is not associated with
`morphological alterations to the ciliary muscle or trabecular meshwork, according to
`animal data. Furthermore, other body systems (brain, cardiovascular, respiratory)
`do not appear to be significantly affected by latanoprost at concentrations up to
`l0-fold greater than those used clinically for topical application.
`Latanoprost is more Iipophilic than its parent prostaglandin and therefore better
`able to penetrate the cornea. After uptake by the cornea, latanoprost is cornpletely
`hydrolysed; 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 after
`topical administration, the acid of latanoprost was then released from the cornea
`into the anterior eye. The drug had an elimination half-life of 3 to 4 hours from
`the 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 excreted
`primarily 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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`
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`
`

`

`latanoprost: A Review
`
`355
`
`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, multicentre
`studies 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. At
`clinically effective doses, no or a barely detectable increase in conjunctival
`hyperaemia was noted in at least gOVo of latanoprost or timolol recipients. In
`contrast 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 ocular
`hypertension. If used in combination with other topical antiglaucoma agents, the
`drugs should be instilled at least 5 minutes apart.
`
`Tolerobility
`
`Dosoge ond
`Administrolion
`
`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-angle
`glaucoma (POAG) and ocular hypertension.ls-el
`Latanoprost is the R component of an approxi-
`mately equimolar R/S epimeric mixture initially
`identified 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 pharmacological
`properties, clinical efficacy and tolerability of top-
`ically applied latanoprost for the treatment of
`POAG and ocular hypertension.
`
`I. Overview of Gloucomo
`ond Oculor Hyperlension
`
`The terrn glaucorna encompasses a group of
`diseases that share all or some of the following
`pathophysiological features: elevated intraocular
`pressure (IOP), excavation of the optic nerve head,
`and loss of visual field (see Lesarl r4l). Glaucoma is
`
`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.
`
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`

`Patel I Spencu
`
`Table l. Classification of glaucoma[l4]
`
`Primary glaucoma
`Open-angle
`Angle closure
`
`Secondary glaucoma
`Open-angle
`
`Angle closure
`
`Congenital glaucoma
`
`with pupillary block
`without pupillary block
`
`pretrabecular
`trabecular
`post-trElbecular
`with pupillary block
`without 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 for
`a detailed classificationl I 4l;.
`Briefly, POAG, which is diagnosed in =90Vo of
`patients 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 inhibited
`drainage of aqueous humour because of chronic
`low-grade partial obstruction of either the trabecu-
`lar meshwork or Schlemm's canal (fig. 27.tt4l In
`from 25 to
`patients with POAG the IOP can rang€
`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 of
`IOP 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 of
`visual 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
`
`corticosteroid use and ethnicity (particularly
`Americans 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 affinity
`for this receptor is considerably higher than that
`for other prostanoid receptors.[2t] Latanoprost, like
`its 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 to
`Schlemm's canal (i.e. conventional or trabeculo-
`canalicular route) and via uveoscleral outflow
`through the ciliary muscle, suprachoroidal space
`and the scl era.176,271 The difference in the outflow
`rates between the 2 routes is marked: uveoscleral
`outflow occurs at0.2 to 0.5 pl/min, compared with
`1.5 to 1.8 pl/min via the conventional route.[l4l
`The process by which latanoprost produces an
`IoP-lowering effect (i.e. increasing uveoscleral
`outflow) is novel compared with that of existing
`nonprostaglandin agents used to treat glaucolrls,
`which act by increasing aqueous hurnour outflow
`via the trabecular meshwork or by inhibiting
`aqueous humour production.[28] The basis for
`the 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 fully
`elucidated. 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
`
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`

`Latanoprost: A Review
`
`367
`
`days of twice daily application with latanoprost
`0.006Vo in volunteers.t2sl Latanoprost 0.0O6Vo
`twice daily for 5 days increased tonographic out-
`flow facility (by 24 to 30Vo) in I study (n = 20
`patients/20 volunteers)t30t but not in another study
`of 22 volunteers adrninistered the same dosage
`regimep.[25] Latanoprost did not affect fluoro-
`photornetric outflow facility,lz5l which was repre-
`sented by the ratio of pharmacologically induced
`changes in aqueous flow : changes in IOP. At doses
`that effectively reduced IOP, latanoprost also did
`not affect retinal vasculature[31] or permeability of
`the blood-aqueous barrier - as indicated by rnini-
`mal effects on the rate of entry and polarisation of
`fluorescein 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 humans
`with normotension or ocular hypertension have
`shown significant decreases in IOP (by 22 to 25Vo)
`after 5 to 8 days of treatment with latanoprost
`0.006Vo twice daily.l2s'301 Maximal decreases in
`IOP occurred within the first 2 days of initiating
`latanoprost 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 20
`to 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 the
`high lipophilicity of the prodrug and consequent
`corneal trapping of the de-esterified drug (see sec-
`tion 3. I ).
`
`cana!
`humour flow
`
`,..-.r-i€
`ift===
`
`lris
`
`Posterior
`
`b
`
`Trabecular
`meshwork
`
`Anterior chamber
`Posterior chamber
`
`Cornea
`lris
`
`Conjunctiva
`
`Schlemm's
`canal
`
`Ciliary
`body
`
`Suspensory
`ligaments
`
`Vitreous body
`
`Optic
`
`I
`Extraocular
`muscle
`
`Optic stalk
`
`Fig. 2- Anatomical features of the human eye under normal condiiions (a) and in primary open-angle glaucoma (b). ln the normal
`eye, 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-angle
`glaucoma, lhe eye appears anatomically normal but the llow of aqueous humour is obstrucled at the trabeqJlar meshwork or
`Schlemm's canal, resulling in elevated inlraocular pressure.
`
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`Drugs & Aging 1996 Nov; 9 (5)
`
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`
`

`

`358
`
`Patel €t Spencn
`
`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 ciliary
`muscle 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 (for
`review 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 cynomolgus
`rnonkeys. t20;
`
`2,3 Generol Phormocology
`
`In cynomolgus monkeys, intravenous doses of
`latanoprost (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, stroke
`volume, 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 blood
`flow 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. Radioactivity
`was determined by liquid scintillation counting
`and high performance liquid chrornatography with
`on-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
`
`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 volunteers
`who 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, latanoprost
`undergoes 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-hydroxyprostaglandin
`dehydrogenase. 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 6
`hours 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
`
`,nol Limited. All rights reserved.
`
`Drugs & Aging 1996 Nov; 9 (5)
`
`Micro Labs Exhibit 1045-6
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`

`

`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
`No. of
`Reference
`Treatment
`patients (duration; wk)
`
`Mean diumal intraocular pressure (mm Hg)
`[percentage change from baseline]
`baseline time atter treatment initiation (wk)
`24
`16.5" [J28] 17.9e11221 17.3" [J251
`17 .Oa lJ28l 18.3a p22l
`17 .8a [J2s]
`16.4a lJ29l 17 .Oa tJ26l
`17 .4a p24J
`24.8a [16]
`n.8a f4
`23.8a [t2l
`16.8 [J32]
`18.1 lJ27l
`
`23.O
`23.6
`23.0
`23.4
`24.8
`
`24.9
`23.4
`24.1
`23.9
`23.e
`23.8
`25.7
`18.2e
`
`20.4 tJ13l 19.4 [J17]'
`18.3 [J24] 1e.1 [J21]'
`17.8 tJ26l 17.6 [JZe1't
`21 .s tJsl
`22s Il7)
`18.2d 1!Zt7
`n.2d tJffil
`fi st llzzl
`
`12
`
`15.7 [J371"
`18.0 [J281
`
`Atm er at.l3sl
`
`15
`1 s
`1 5
`1s
`Atm er 61.1501 25
`2s
`coakes et at.ts2l p
`11
`12
`10
`50 totalc
`
`Lusky s1 6;.tssl
`
`Nagasubramanian 20
`et al.lsl
`
`LO.OO350/" bid (4)
`L O.OO5% bid (4)
`L 0.011 5olo bid (4)
`P (4)
`L 0.006% onb 1te;
`L 0.006% bidb (12)
`L 0.00125"/o on (2)
`L O.OO25% on (2\
`L O.OO5% on (2)
`P (2)
`L 0.0015% bid (3)
`L 0.00s% od (3)
`L 0.005% od (3)
`after L 0.001 5% bid (3)
`L 0.001s% bid (3)
`after L 0.005% od (3)
`L 0.006% od (2)
`
`17.2s
`
`24.8
`
`19.1, IJ26I
`
`16.2 [J35]"' 1 5.9 [J36]"'
`
`L 0.006% bid (2)
`25.0
`1 9
`17.8 [J29].., 18.0 [J28]"',
`25.3
`24.0 tJsl
`10
`23.6[J7]
`P (21
`L 0.006% on (5 days) 25.4
`Rdcz er at.l36l 9
`19h [J25J"
`25.2
`6
`23.sh [u]
`P (5 days)
`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.
`
`4.1 Dose-Ronging Studies
`
`4. Clinicol Evoluotion
`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 with
`POAG 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-lowering
`values 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 least
`to measure IOP.
`as effective as a twice daily dose without any
`
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`
`Drugs & Aging 1996 Nov; 9 (O
`
`Micro Labs Exhibit 1045-7
`
`

`

`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) throughout
`the 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 significantly
`more effective than timolol at 12 and l8 weeks
`(fig. 4).ts8l Latanoprost applied in the evening
`produced 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\
`
`10
`
`E
`oo
`
`EC
`
`L
`(u ,-.
`EE
`Ee
`7=_=E 20
`
`kxoltrE;e
`
`ooE0
`
`)cE
`
`30
`
`tr Latanoprost om
`I Latanoprost on x 3mo
`then om x 3mo
`I Latanoprost om x 3mo
`then 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 showing
`percentage reductions in intraocular pressure 6tt97 $tsol or 6ls7-ssl months'treatmenl wiih eiiher latanoplost 0.005% once daily
`or 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.
`
`(l Adis lnternotionol Limited All rights reserved
`
`Drugs & Aging 1996 Nov; 9 (5)
`
`Micro Labs Exhibit 1045-8
`
`

`

`Latanoprost: A Review
`
`377
`
`25
`
`6-
`E20E
`
`oE
`
`oc
`
`t
`
` ls
`
`(U3 10
`
`o(
`
`Us
`
`5
`
`212
`
`18
`Duration of treatment (wk)
`
`26
`
`Fig. 4. lntraocular pressure response profiles with latanoprost
`and timolol. Comparative profiles of intraocular pressure re-
`sponse (9am measurements) to latanoprost 0.005% (once
`daily) and timolol 0.5% (twice daily) over 6 months'treatment
`in
`patients 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 hyperaemia
`was 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 with
`time (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 of
`hyperaemia was mild. A comparison of maximum
`hyperaemia scores at baseline and at 6 months in 2
`studies showed that, in at least 90Vo of patients,
`
`tension;,t57-5el Watson et al.t581 noted that timolol
`produced greater reductions in IOP in men (9.0
`vs 7.lmm Hg in women; p < 0.01) and in patients
`with POAG (9.4 v.r 7.lmm Hg in patients with
`ocular hypertension; p < 0.01). Iris colour did not
`affect the IoP-lowering effect of timolol or of
`latanoprost in 2 studies,[s7'5el whereas a third
`study noted that patients with hazel eyes had a
`better response than those with blue- or green-grey
`eyes (9.3 v.r 8.0mm Hg reduction in IOP with
`latanoprost; p = 0.006).t581
`
`4.3 Combinotion Theropy
`
`Six clinical studies (n S 50 patients per study)
`have examined the effects of topical latanoprost
`applied in cornbination with other topical or oral
`antiglaucoma agents (table III). Monotherapy
`was 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 the
`monotherapy period, there was a trend towards a
`greater reduction of IOP with latanoprost than with
`dipivefrine, pilocarpine or timolol (although the
`statistical significance of this was not stated). At
`the end of the combination therapy period, IOP had
`decreased even further (relative to baseline) than
`after monotherapy (table III). Thus, these data
`show 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 prototypical
`agent, PGF2q- I -isopropyl ester, was associated
`with initial increases in IOP, photophobia, ocular
`irritation 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 well
`tolerated in 4 pivotal phase III clinical studies com-
`paring latanoprost with timolol.ls6-sel
`
`nol Limiled. All rights reserved
`
`Drugs & Aging ]996 Nov; 9 (5)
`
`Micro Labs Exhibit 1045-9
`
`

`

`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
`No. o, Treaunent and
`Reference
`palients duration (wk)
`(study design)
`
`Mean diumal intraocular pressure (mm Hg)
`[percentage reduction lrom baseline]
`baseline time after treatment initiation (wk)
`2412
`
`Dipivefrine (D) combination
`Atm er 31.te0F (NS)
`
`Watson et at.l61F (r, sm, sc;
`
`Timolol (T) combination
`Alm et 31.t5ol (r, dm, mc)
`
`Rulo et al.lsl (r, sm, sc)
`
`22 totat L 0.005o/o od (2)
`D 0.1 y. bad (2)
`t+ Db (e)
`o+tb(z)
`L 0.0060/o bid (1)
`D 0.1% bid (1)
`L+ Dc (1)
`D+Lc(1)
`
`10
`10
`10
`10
`
`25
`
`25
`
`I
`10
`9
`10
`
`L 0.0060/. on +
`T O.5% b.d (12)
`L 0.0060/o bid +
`T O.5o/o bid (12)
`L 0.006o/o bid (1)
`T o.s% bid (1 )
`L+T(l)d
`T+L(1)d
`
`L 0.0O60/o bid (1)
`P 2Yo rid (1)
`L+ P (1)e
`P + L (1)e
`
`12.4 [J361
`14.s [J33l
`
`16.8 [J32] 1 s.7 [J371',
`
`18.1 ll27l 18.0 lJ28I
`
`19.3
`
`22.3
`
`24.7
`26.3
`
`16.9 [J32]
`1e.1 lL27)
`
`24.8
`
`24.9
`
`28.5
`24.2
`
`19.6 [J31]'
`18.3 [J24]'
`
`25.1
`23.8
`
`19.1 [J24J"
`20.4 [J14J"
`
`14.8 [J23]
`18.4 tJ14
`
`14.7 tJ40l
`13.8 [J48]
`
`17.0 [J4o]
`15.7 tJ3sl
`
`17.6 [J3Ol.,
`17.7 lL26l"
`
`Pilocarpine (P) combination
`Fristrom & Nilssonlsz) (r sm, sc) 10
`10
`10
`9
`
`Acetazolamide (A) combination
`(r, dm, mc)
`Rulo
`
`"1 ";.t62la
`
`1g.Se
`
`16.9 tJ 14J"
`
`20.8 tTl.3I
`
`24 total A250mg bid +
`L 0.005o/o oot (e)
`A 250m9 bid + PBO (2) 19.5s
`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 of
`htanopost 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 of
`latanoprost 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 ol
`latanoprosl 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 ol
`latanoprosl 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 daiy
`intheevening; PBO=placebo; r=randomised;sc=singlecentre; sm=singlemask;lid=3timesdaily; J=decrease; 1=increase;'p<0.01
`vs baseline value and compaEtor gKrup (Alm et al.lgl;; " p < O.OOI r4s placebo combinalion (Rulo et al.l62f or baseline value (Fdstr6m &
`Nilssonlsl).
`
`@ Adis lnternotionol Limited. All rights reserued
`
`Dru$ & Aging 1996 Nov; 9 (5)
`
`Micro Labs Exhibit 1045-10
`
`

`

`Latanoprost: A Review
`
`373
`
`there was no or a barely detectable increase in
`hyperaemia with both latanoprost and timolol
`(fie s).
`
`5.2 lridiol Pigmentotion
`
`Topical latanoprost therapy (0.005Vo applied
`once daily) was associated with increased iridial
`pigmentation in 3 to l}Vo of patients after 3 to 4.5
`months' continuous treatment in randomised
`double-masked rnulticentre stud1.t.l57-sel The
`increase in iridial pigmentation occurred only
`in patients whose eyes were already of mixed col-
`ours (i.e. green-brown or blue/grey-brownl.[57'581
`However, freckles and naevi in the iris were unaf-
`fected; i.e. they did not change shape or colour
`during 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, although
`stimulation of melanin synthesis rather than pro-
`liferation of melanocytes is thought to be a key
`component.t5T-5el Long term follow-up studies are
`required to establish whether or not this increased
`pigmentation is an irreversible effect.
`
`5.3 Other Oculor Adverse Events
`
`Latanoprost 0.0O5Vo once daily was a