Bundesinstitut für Arzneimittel und Medizinprodukte

Decentralised Procedure

RMS Public Assessment Report

Latanoprost Malcosa 0,005% Xalaprost 0,005% Laxatan 0,005% Pharmecol 0.005%

DE/H/1999/001/DC DE/H/2281/001/DC DE/H/2282/001/DC DE/H/2382/001/DC

Applicant: Malcosa Ltd.

Reference Member State DE Date of this report: 06.12.2010

The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/30

CONTENTS

ADMINISTRATIVE INFORMATION ...... 3 I. RECOMMENDATION ...... 4 II. EXECUTIVE SUMMARY...... 4 II.1 Problem statement...... 4 II.2 About the product ...... 4 II.3 General comments on the submitted dossier ...... 5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles..6 III. SCIENTIFIC OVERVIEW AND DISCUSSION ...... 6 III.1 Quality aspects...... 6 III.2 Nonclinical aspects ...... 7 III.3 Clinical aspects ...... 7 IV. BENEFIT RISK ASSESSMENT ...... 30 V. Package Leaflet (PL)/Assessment of User Testing ...... 30

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ADMINISTRATIVE INFORMATION

a) Latanoprost Malcosa 0,005% Proposed name of the medicinal b) Xalaprost 0,005% product in the RMS c) Laxatan 0,005% d) Pharmecol 0.005%

INN (or common name) of the active Latanoprost substance(s):

Pharmaco-therapeutic group S01EE01 (ATC Code):

Pharmaceutical form(s) and Eye drops, solution, 50 microgram/ml strength(s): a) DE/H/1999/001/DC Reference Number for the b) DE/H/2281/001/DC Decentralised Procedure c) DE/H/2282/001/DC d) DE/H/2382/001/DC Reference Member State: DE a) BG, CY, EL, ES, IT, PL, PT, RO b) BG, CZ, HU, PL, RO, SK Member States concerned: c) AT, UK d) BG Malcosa Ltd. Acropolis Tower, 66 Acropolis avenue Applicant (name and address) 2012 Strovolos - Nicosia Cyprus Malcosa Ltd. Names and addresses of Acropolis Tower, 66 Acropolis avenue manufacturers responsible for batch release in the EEA 2012 Strovolos - Nicosia Cyprus

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A) RECOMMENDATION

Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMS on quality, safety and efficacy, the RMS considers that the application for Latanoprost Malcosa 0,005%, in the treatment of

Reduction of elevated intraocular pressure in patients with open angle glaucoma and ocular hypertension, is approvable as satisfactory responses are given and the applicant committed to perform a number of post authorisation follow- up measures.

EXECUTIVE SUMMARY a.1 Problem statement The submitted documentation is in accordance with a "generic application". The application refers to an essential similar original product granted for more than 10 years in the Community according to Directive 2001/83/EC Article 10(1). This mutual recognition application concerns a generic version of Latanoprost. Latanoprost Eye drops solution of 0.005% is registered in most of the European countries under the brand name of Xalatan® by Pfizer. The data protection period is already expired and reference has been made to the non-clinical and clinical documentation of the reference product. The Marketing Authorization for Xalatan 0.005% eye drops solution was first granted for the UK market on December 16, 1996. ® The product Latanoprost was developed as a generic alternative to Xalatan ophthalmic solution (Latanoprost 50μg/ml, Pfizer) with minor changes in the composition (see confidential ANNEX). The product is supplied as a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolarity of approximately 270mOsmol/kg. Each millilitre of Latanoprost finished product contains 50 micrograms of Latanoprost. Benzalkonium chloride, 0.02 % is added as a preservative. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous and water for injection. The present Product License application is therefore submitted under Directive 2001/83/EC, Article 10.1 (a) (iii) in cross-reference to the pharmaco-toxicological and clinical data supporting the brand leader Xalatan® ophthalmic solution 50 μg/ml

a.2 About the product The active substance latanoprost, a prostaglandin F2analogue, is a selective prostanoid FP receptor agonist which reduces the intraocular pressure by increasing the outflow of aqueous humour. Reduction of the intraocular pressure in man starts about three to four hours after administration and maximum effect is reached after eight to twelve hours. Pressure reduction is maintained for at least 24 hours.

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Latanoprost Malcosa is indicated in the treatment of elevated intraocular pressure in patients with open angle glaucoma and ocular hypertension. The recommended therapy is one eye drop in the affected eye(s) once daily. Optimal effect is obtained if Xalatan is administered in the evening. A possible risk management strategy is not yet established, but will be developed by the company.

a.3 General comments on the submitted dossier Legal basis: The application of Latanoprost Malcosa is submitted under Directive 2001/83/EC, Article 10.1 (a) (iii) in cross-reference to the pharmaco-toxicological and clinical data supporting the originator Xalatan® ophthalmic solution 50 μg/ml. The type of marketing authorisation application incl. reference to legal basis of the application is appropriate. The Reference medicinal product XALATAN 0,005% Colirio en solución PFIZER, S.A has been authorized for the Spainish market on 23/12/1997 under the Marketing authorisation number: 61.756. The SmPC of the originator is also used for Latanoprost Malcosa. Essential Similarity: Eye drops solutions of the Reference products from the Korean and the Dutch market and the Latanoprost Malcosa have been compared with respect to the physicochemical parameters.

Samples tested were as follows: Product Strength Country Lot No / Expiry Xalatan® Eye drops solution Korea ND0115 / 03/2009 0.005% Xalatan® Eye drops solution Holland NH0379 / 08/2009 0.005% Latanoprost Malcosa Eye drops solution 7001/ 02/2007 0.005%

The results obtained for the assay of Latanoprost in the three formulations under comparison were well within the ±5% limit of the labeled claim. In addition, comparisons of the impurity profile that Xalatan has a relative high percentage of 5,6 trans-Latanoprost but more or less the same profile on the rest of the impurities.

Conclusion The comparison of all the above described tests adequately supports the pharmaceutical equivalence of the Latanoprost Malcosa 0.005% Eye drops solution and Xalatan 0.005% Eye drops solution (composition of Latanoprost Malcosa - see confidential part). The applicant summaried the grounds and evidence used for demonstrating that the constituents of Latanoprost Malcosa have a well- established use with an acceptable level of safety and efficacy.

Risk management plan: A qualified person responsible for pharmacovigilance activities (QPRP) has been appointed by the applicant to ensure permanent and continous availability for pharmacovigilance activities. A system is in place to ensure the surveillance of Latanoprost Malcosa worldwide. Indication and posology: The proposed indication and posology is in line with the SmPC of the originator.

Paediatric indication: A paediatric development could not be recommended at the moment, because the originator has also no paediatric indication.

5/30 a.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. The Qualified Person of., the manufacturer located in the EEA and responsible for batch release, declares that the active substance manufacturer operates in compliance with the detailed guidelines on good manufacturing practice for starting materials.

The drug product is manufactured as a sterile ophthalmic solution. The manufacture of the formulation and primary packaging takes place at A copy of the GMP certificate has been provided. Additionally a copy of the GMP certificate issued by the competent Polish Inspection Service, dated 12.05.2008, has been provided. The Main Pharmaceutical Inspector states that the manufacturing conditions for Latanoprost 0.005% eye drops at the manufacturing site , comply with the requirements of Good Manufacturing Practice. The RMS has accepted this copy as certification that acceptable standards of GMP are in place at this site outside the Community.

Secondary packaging takes place at Batch release is performed by The RMS has accepted copies of the current manufacturer authorisation and the GMP certificate issued by inspection services of the competent authority of as certification that acceptable standards of GMP are in place at these sites within the Community.

SCIENTIFIC OVERVIEW AND DISCUSSION a.5 Quality aspects

Drug substance Latanoprost is an analogue of prostaglandin F2α. The active substance is not described in a compendial monograph. The active substance is manufactured by An ASMF has been submitted by the ASM. The batch results comply with the specification of the active substance. The stability studies were carried out at – 20°C (long-term) and at 5°C as well as at 25°C (accelerated). The data indicate that the active substance is stable for 36 months when stored at – 20°C. There are no major objections concerning the quality of the drug substance. However, there are a some points for clarification, including points to clarification to the restricted part of the Active Substance Master File, which should be resolved prior approval.

Drug Product The drug product is a colourless sterile solution which contains 50 µg latanoprost per millilitre solution. The eye drops are preserved with benzalkonium chloride and supplied in a multidose container (LDPE bottles with LDPE dropper insert and HDPE screw cap). The choice of the composition, and the container closure system have been adequately been explained. The manufacturing process consists of manufacture of the aqueous solution, sterile filtration and aseptic filling into the container closure system. The container closure system is pre-sterilized by gamma-irradiation before being supplied to the drug product manufacturer. All excipients are controlled by compendial monographs. The product specifications have been provided. The test methods are described. The results of batch analysis comply with the specifications. The stability data at 5°C (long-term stability) and at 25°C/60% RH (accelerated stability) adequately support the proposed shelf-life of 36 months, if the drug product is stored and transported under refrigeration at 2-8°C. The in-use stability data are sufficient for granting an in-use shelf-life of 4 weeks, if stored in the refrigerator. There are no major objections concerning the quality of the drug product. However, there are a number of points for clarification, which should to be resolved prior approval.

6/30 a.6 Nonclinical aspects

Pharmacological, pharmacokinetic and toxicological properties of latanoprost are well known. As latanoprost is a widely used, well-known active substance, the applicant did not provide additional studies and none are required.

The provided non-clinical overview on the preclinical pharmacology, pharmacokinetics and toxicology of latanoprost is adequate and considered sufficient to support the application.

All excipients including the used preservative benzalkonium chloride are well known and the qualitative and quantitative composition of Latanoprost Malcosa 0.005% eye drops is identical to the reference product Xalatan 0.005% eye drops solution.

There are no objections for approval of Latanoprost Malcosa 0.005% eye drops from a non-clinical point of view.

a.7 Clinical aspects

Generic applications The clinical overview on the clinical pharmacology, efficacy and safety has been considered as adequate. The claimed indication is in line with the SmPC of the approved innovator product Xalatan®. The application contains an adequate review of published clinical data. However, no clinical study was conducted to demonstrate therapeutic equivalence. The lack of clinical studies can only be accepted in this special case with regard to no differences between composition of originator and test product. Eye drops solutions of the Reference product from the Korean and Dutch market, as well as Latanoprost Malcosa have been compared with respect to their physicochemical parameters. Latanoprost Malcosa has the same quantitative composition, the same pharmaceutical form as the reference medicinal product, and all physicochemical properties are identical. Therefore, essential similarity is demonstrated by pharmaceutical equivalence. Based on these data it can be assumed that Latanoprost Malcosa will induce the same extent and duration of IOP reduction in patients during long-term therapy and will exhibit the same level of safety as demonstrated for the originator Xalatan®. Therefore, further clinical data are not required.

The SmPC is in line with the original product.

Pharmacokinetics Latanoprost has been determined by HPLC with on-line radioactivity detection. The maximum concentration of latanoprost acid in aqueous humor averaged 32.6±20.6 ng/ml (~10-7M) and was detected approximately 2.5 hours after administration. The elimination half-life of latanoprost acid from the aqueous humor was 2.8 hours. The concentration 24 hours after administration was 0.2 ng/ml or lower (Sjoquist and Sternschantz 2002). 2.5.3.2.1. Systemic pharmacokinetics after intravenous and topical administration on the eye following intravenous infusion for 15 minutes, the radioactivity was rapidly cleared from the blood and plasma. The initial phase half-lives of total radioactivity were 11±13 minutes in blood and 14±10 minutes in plasma, close to the half-life (t1/2) 16.6±0.9 minutes calculated for latanoprost acid. The AUC for latanoprost acid was 7.15±0.79 ng·h/ml, the plasma clearance (Clp) 0.40±0.04 L/h·kg, and the volume of distribution (V) 0.16±0.02 L/kg. After topical administration t1/2 for latanoprost acid was 17 minutes, AUC 34 pg·h/ml, Clp 0.88 L/h · kg, and the volume of distribution (V) 0.36 L/kg. The maximum concentration in plasma (Cmax) was 53 pg/ml (~10-10M) after 5 minutes (Tmax). The plasma concentrations of latanoprost acid could be monitored during the first 40 minutes after topical administration. Latanoprost was completely hydrolyzed in plasma. The only significant radioactive component in plasma during the first hour after administration had a retention time in the HPLC system corresponding to the latanoprost acid. The systemic bioavailability of latanoprost acid was 45% after topical application on the eye (Sjoquist and Sternschantz 2002).

7/30 Maximum plasma concentrations during chronic treatment The concentrations of latanoprost acid in plasma of the patients that had been treated with latanoprost eye drops continuously for at least 1 year were very low. In five out of 10 patients, the concentrations were below the detection limit (<30 pg/ml). In the other five patients, the maximum concentration was 45.6±15.5 pg/ml 5–15 minutes after administration of latanoprost (Sjoquist and Sternschantz 2002).

Metabolites in urine and feces In the mass balance study it was found that the major part of the radioactivity administered was recovered in urine both after intravenous and topical administration. The excretion in urine was nearly completed during the first 24 hours after administration. No latanoprost or latanoprost acid was found in the first urine samples collected after intravenous administration in any of the volunteers. Metabolites more polar than latanoprost acid were present in every urine sample. There was no obvious difference in the metabolic pattern after intravenous and topical administration. However, quantitatively the most polar metabolites constituted a greater share of the radioactivity profile after intravenous compared to topical administration. The least polar metabolite had a retention time equivalent to 1,2-dinor latanoprost acid. The 1,2,3,4-tetranor latanoprost acid has a structure that easily forms a ä-lactone, namely, an internal ester between the carboxylic acid moiety and the hydroxyl group on carbon 5 (equal to carbon 9 in latanoprost acid). There is an equilibrium between the acid and the lactone. The major metabolites in human urine after topical administration chromatographed as 1,2-dinor latanoprost acid and 1,2,3,4-tetranor latanoprost acid in equilibration with its corresponding ä-lactone. The â-oxidation metabolites, 1,2-dinor latanoprost acid and 1,2,3,4-tetranor latanoprost acid, accounted for about 42% of radioactivity in the metabolic profile after intravenous administration and for 66% after topical administration. To investigate if the more polar metabolites were glucuronic acid or sulphate conjugates, urine samples collected 0–2 hours after the end of the intravenous infusion of latanoprost, were incubated with glucuronidase and sulfatase. These experiments indicated the presence of a glucuronide conjugate of 1,2-dinor latanoprost acid, and in addition at least one unknown glucuronide conjugate. No further changes in the chromatographic profile were observed after incubation with arylsulfatase. Possible polar metabolites could be formed through hydroxylation and conjugation in the ù-chain in combination with â-oxidation in the á-chain of latanoprost acid. About 15% of the total radioactivity administered was excreted in feces mainly during day 2 and 3 after a single ocular administration. In the feces samples collected after intravenous administration and topical administration two major metabolites appeared. One of these metabolites was judged to correspond to 1,2-dinor latanoprost acid. The 1,2-dinor latanoprost acid metabolite accounted for about 45–60% of the radioactivity after intravenous administration, and 7–23% after topical administration. In addition, another prominent very polar metabolite was present. This metabolite remained unidentified (Sjoquist and Sternschantz 2002).

Pharmacodynamics

Mechanism of action Latanoprost is an ester prodrug analogue of prostaglandin F2á with a high selectivity for the FP subtype of prostanoid receptors.Latanoprost is believed to reduce the intraocular pressure by increasing the outflow of aqueous humor. Studies in animals and man suggest that the main mechanism of action is increased uveoscleral outflow (PDR 2003).

Ocular effects Effects on intraocular pressure Latanoprost, like PGF2á-1-isopropyl ester (Kerstetter et al 1988, Villumsen and Alm 1989) and PhXA34 (Alm and Villumsen 1991), lowered intraocular pressure without altering aqueous flow in volunteers and patients (Toris et al 1993, Ziai et al 1993). In healthy volunteers or patients with ocular hypertension or open-angle glaucoma, intraocular pressure reductions were maximal within 8 to 12 hours after a single topical dose of latanoprost (0.005 or 0.006%), and intraocular pressure remained below pretreatment levels for at least 24 hours (Hotehama and Mishima 1993, Racz et al 1993 and 1996, Mishima et al 1997, Larsson 2001a). Placebo-controlled (contralateral eye) studies in humans with normotension or ocular hypertension have shown significant decreased in intraocular pressure (by 22 to 25%) after 5 to 8 days of treatment with latanoprost 0.006% daily (Toris et al 1993, Ziai et al

8/30 1993). Maximal decreases in intraocular pressure occurred within the first 2 days of initiating latanoprost treatment in patients with primary open-angle glaucoma or ocular hypertension (Alm et al 1993, Fristrom and Nilsson 1993, Nagasubramanian et al 1993, Racz et al 1993, Rulo et al 1994). The intraocular pressure-lowering effect was independent of the time of application of the agent (Racz et al 1996). Reductions in intraocular pressure with latanoprost can last for 20 to 24 hours after a single dose (Nagasubramanian et al 1993, Racz et al 1993, Hotehama et al 1993). The reason for this sustained effect is not adequately understood, although it can be explained, in part, by the high lipophilicity of the prodrug and consequent corneal trapping of the de-esterified drug (Patel and Spencer 1996). Buguet et al (1994) measured intraocular pressure hourly during 24 hours in 12 young and 12 older healthy white adults and demonstrated that intraocular pressure followed a circadian rhythm with a nocturnal peak value (acrophase) (Buguet et al 1994). During 24-hour intraocular pressure measurements, latanoprost showed similar efficacy during daytime and night-time hours and circadian fluctuations were minimal (Racz et al 1993 and 1996, Mishima et al 1997, Konstas et al 1999, Larsson 2001a). Larsson (2001a) performed a randomized, double-masked placebo-controlled cross-over study in 20 healthy volunteers to measure the effect on intraocular pressure over 24 hours after single-dose administration of latanoprost 0.005%. The author concluded that latanoprost applied as a single dose reduced intraocular pressure over 24 hours in healthy subjects compared with placebo. The intraocular pressure reduction was still present, however, less pronounced, 48 hours after drug application (Larsson 2001a). Larsson (2001b) conducted a randomized, open, crossover single-center study to compare the effect on intraocular pressure over 24 hours after 4 weeks of treatment with latanoprost 0.005% and timolol gel 0.5%. The authors concluded that latanoprost reduced mean 24- hour intraocular pressure, mean daytime intraocular pressure, and mean nighttime intraocular pressure statistically significantly more than timolol. Also, latanoprost reduced intraocular pressure more effectively at every measured time point over the 24 hours compared with timolol gel (Larsson 2001b). Orzalesi et al (2003) performed a 1-month crossover study to compare the circadian intraocular pressure reductions induced by latanoprost, brimonidine tartrate, and a fixed combination of timolol maleate and dorzolamide hydrochloride in patients with primary open-angle glaucoma or ocular hypertension. The authors concluded that latanoprost and the fixed combination of timolol and dorzolamide led to similar circadian reductions in intraocular pressure, whereas brimonidine was less effective, particularly during the night (Orzalesi et al 2003). Intraocular pressure reductions were greatest when latanoprost was administered once rather than twice daily (Nagasubramanian et al 1993, Alm et al 1995a, Linden and Alm 1997); the reason for this is not entirely clear but may be related to a loss of some of the effect due to development of receptor subsensitivity (Linden and Alm 1998). Larsson et al (2002) reviewed four studies evaluating the efficacy of latanoprost during both day and night to assess the effects of latanoprost on circadian intraocular pressure. The studies reviewed clearly demonstrated that topical administration of latanoprost 0.005% once daily provided a steady reduction of the intraocular pressure during both day and night. Given as a single dose to healthy volunteers, latanoprost resulted in a sustained effect with a significant intraocular pressure reduction over 24 hours, and the reduction was still present, however less pronounced, even after 48 hours. Latanoprost administered once daily for 4 weeks to patients with glaucoma or ocular hypertension was more effective in reducing the intraocular pressure over 24 hours than timolol gel solution 0.5% once daily, timolol aqueous solution 0.5% twice daily, or dorzolamide 2% three times daily. Latanoprost applied once daily thus provided a better effect on the intraocular pressure together with a stable and sustained intraocular pressure reduction during both day and night (Larsson et al 2002). Following discontinuation of latanoprost after treatment for 6 to 12 months, intraocular pressure is restored to pretreatment levels after a few (>2) weeks (Linden et al 1997).

Pharmacodynamic drug interactions At least 50% of patients are treated with more than 1 ocular hypotensive medication. Thus, the determination of the additive effects on intraocular pressure of glaucoma medications will help to define optimum treatment regimens. Kashiwagi and Tsukahara (2003) performed a prospective and observer masked clinical trial to investigate the effects of a non-steroidal anti-inflammatory drug ophthalmic solution on latanoprost induced intraocular pressure reduction using 13 normal volunteers. The authors concluded that non-steroidal anti-inflammatory drug ophthalmic solution may interfere with intraocular pressure reduction by latanoprost ophthalmic solution in normal volunteers and that it should be taken into account when treating patients with glaucoma using latanoprost ophthalmic

9/30 solution (Kashiwagi and Tsukahara 2003). Chiba et al (2006) investigated the effects of a non- steroidal anti-inflammatory drug ophthalmic solution on latanoprost induced intraocular pressure reduction in glaucoma patients. Examination was conducted on 16 eyes of 16 glaucoma patients who had been given only latanoprost for at least 6 weeks. The non-steroidal anti-inflammatory drug ophthalmic solution, sodium 2-amino-3-(4-bromobenzoyl) phenylacetate sesquihydrate, was additionally given for 12 weeks into one eye (non-steroidal anti-inflammatory drug group), while sodium hyaluronic acid ophthalmic solution was administered into the other eye (control group) in a double masked fashion. The authors concluded that non-steroidal anti-inflammatory drug ophthalmic solution may partly affect intraocular pressure reduction by latanoprost (Chiba et al 2006).

Clinical efficacy OPEN-ANGLE GLAUCOMA OR OCULAR HYPERTENSION Open studies Camras et al (1996a) determined the efficacy and safety of latanoprost during 1 year of treatment. After baseline measurements, 0.005% latanoprost was topically applied once daily for 12 months in patients from Scandinavia, the United Kingdom, and the United States who had elevated intraocular pressure. Diagnoses included ocular hypertension, chronic open-angle glaucoma, exfoliation syndrome, and pigment dispersion syndrome. Treatment was masked for the first 6 months and open- label during the second 6 months. The results of the study demonstrated that of the 272 patients initially enrolled, withdrawals were due to inadequate intraocular pressure control (1%), increased iris pigmentation (5%), other ocular problems (3%), systemic medical problems (3%), and nonmedical reasons (14%). Latanoprost significantly (P < 0.0001) reduced diumal intraocular pressure from 25.3 ± 3.0 mmHg (mean ± standard deviation) at baseline to 17.4 ± 2.7 mmHg (32% reduction) at 12 months in the 198 patients who completed 1 year of treatment. The intraocular pressure reduction was maintained at a consistent level throughout the 12 months without evidence of drift, and was not affected by sex, age, race, or eye color. Overall, latanoprost caused a possible or definite increase in iris pigmentation in 12% of the 272 patients, all of whom had multicolored irides at baseline. One half of these patients with increased pigmentation withdrew before completing 1 year of therapy. Visual field, optic disc cupping, visual acuity, refractive error, conjunctival hyperemia, aqueous flare, anterior chamber cellular response, lens examination, blood pressure, heart rate, blood tests, and urinalysis were not appreciably altered. The authors concluded that latanoprost safely and effectively reduces intraocular pressure for 1 year in patients of diverse nationalities, providing further evidence for its usefulness in chronic glaucoma therapy (Camras et al 1996a). Ravi et al (2005) conducted a prospective, non-randomized, open-label multicentric trial to evaluate the short-term efficacy and safety of 0.005% topical latanoprost in Indian eyes. One hundred and fifty patients with ocular hypertension, primary open-angle glaucoma, pseudoexfoliation or pigmentary glaucoma were enrollaed at four centers. Each center contributed at least 20 patients. Following baseline measurements, 0.005% latanoprost was applied topically once daily in the evening for three months. Patients were examined at 2, 6 and 12 weeks. The primary outcome measure was mean intraocular pressure reduction. The mean diurnal variation of intraocular pressure (difference between highest and lowest intraocular pressure) at baseline and at 12-weeks was compared. According to the results of the study, one hundred and thirty of 150 enrolled patients completed the study. One randomly selected eye of each patient was included for analysis. At three months, latanoprost reduced the mean intraocular pressure from 24.9 (±3.16) mm Hg at baseline to 16.10(±2.7) mm Hg, a reduction of 35.25%. 83% had a reduction in intraocular pressure of >25%. The intraocular pressure reduction was maintained throughout the study period, and was not affected by gender or age of the patient. One eye did not show any response to the drug. Daytime diurnal variation of intraocular pressure was reduced from 4.5 to 2.9 mm Hg. Twenty patients had conjunctival hyperemia. Six patients had side effects requiring withdrawal from the study. The authors concluded that in this short-term multicentric study, latanoprost effectively reduced intraocular pressure and stabilised the diurnal curve in Indian eyes. There were no clinically significant or systemic adverse effects (Ravi et al 2005). Baudouin et al (2006) conducted a multicentric open study to assess the changes in intraocular pressure and ophthalmic symptoms with the Glaucoma Symptom Scale in patients suffering from open-angle glaucoma or ocular hypertension after 3 months of treatment with latanoprost. Adult patients suffering from open-angle glaucoma or simple ocular hypertension (naive or previously treated with monotherapy) and needing a change or initiation of anti-glaucomatous treatment were enrolled. One drop of latanoprost 0.005% was instilled every evening for 12 weeks in each affected eye. Efficacy

10/30 was assessed by the variation in intraocular pressure and ophthalmic symptomatology at the end of treatment. Prognosis factors associated with a relative intraocular pressure reduction of at least 30% were sought (using a logistic regression model). According to the results of the study, a total of 920 patients suffering from open-angle glaucoma (54%) or ocular hypertension (44%), either previously treated (69%) or naive (31%), were included. The male/female ratio was 0.78 and the mean age was 63+/-13 years. At inclusion, the mean intraocular pressure was 22.1+/-3.8 mmHg. After treatment, intraocular pressure was significantly decreased by 5.1+/-4 mmHg, corresponding to a 22% reduction. Intraocular pressure reduction was 7.1+/-4 mmHg, corresponding to 29% in naive patients and 4.2+/-4 mmHg, corresponding to 19% in previously treated patients. A relative intraocular pressure reduction of at least 30% was reached by 47% of naive patients and 21% of previously treated patients. In previously treated patients, a relative intraocular pressure reduction of at least 30% had a greater chance of being reached in men with previous ophthalmic history and high intraocular pressure at inclusion (above 21 mmHg). Intraocular pressure reduction was similar in patients with open-angle glaucoma and ocular hypertension. A significant improvement in ophthalmic symptoms was observed after treatment in previously treated patients. A total of 7% of the patients presented an adverse event affecting the visual system: eye irritation (2%), eye pain (2%), or eye hyperemia (1%). Compliance was good for 94% of the patients. The authors concluded that latanoprost given as first or second-line treatment at the recommended dose effectively decreases intraocular pressure in patients with open- angle glaucoma or ocular hypertension. This treatment also improves visual and nonvisual symptoms in previously treated patients and presents a good safety profile (Baudouin et al 2006).

Concentration and administration considerations Concentration A prospective, randomised, double-masked and placebo-controlled trial of twice daily latanoprost did not reveal any difference in effectiveness between 0.003% or 0.012% concentrations over a 30-day period (Alm et al 1993). Another report did not reveal a difference in response between latanoprost 0.005% given as a single drop versus 3 drops in the evening, but the statistical power of the study was not stated (Linden and Alm 1997). Independent direct comparisons of once daily 0.005% versus twice daily 0.0015% concentrations also found the once daily application of the higher concentration (0.005%) to have a statistically significant greater effect on lowering intraocular pressure (Diestelhorst et al 1997, Lusky et al 1997). A single dose of 0.0025, 0.005 or 0.010% provided a dose-dependent intraocular pressure lowering from baseline over a 24-hour period (Hotehama et al 1993). The higher doses (0.005 and 0.010%) produced statistically significant reductions from 4 to 24 hours. Fristrom and Nilsson (1997) compared the intraocular pressure reducing effect of latanoprost 0.005% and 0.001%. The authors concluded that latanoprost 0.005% was more effective than latanoprost 0.001% in reducing intraocular pressure. Even the lower concentration was surprisingly effective (Fristrom and Nilsson 1997).

Administration: Once versus twice daily A single dose has been shown to be effective in lowering intraocular pressure (Hotehama and Mishima 1993, Hotehama et al 1993, Linden and Alm 1998), but the drug activity is reported to peak on day 2 of usage (Nagasubramanian et al 1993, Racz et al 1993) and persist for up to 2 weeks after discontinuation from long term use (Linden et al 1997). A 2-week, placebo-controlled study found greater effectiveness of the 0.006% concentration given once versus twice daily (Nagasubramanian et al 1993). Another direct comparison found greater intraocular pressure reduction with once nightly administration in 18 healthy volunteers (Linden and Alm 1997). A 3-month, multicentre additivity study with timolol found a statistically lower intraocular pressure in the once nightly group (37%, n = 23) versus the twice daily group (28%, n = 25) (Alm et al 1995b). A study specifically designed to address this issue used a randomised, double-masked design with 40 healthy volunteers. Intraocular pressure was measured on 4 different days (3 times per day) during the 17-day period. On day 2, there was a 3.3 and 3.4 mm Hg drop in intraocular pressure for once and twice daily usage, respectively (not significantly different), but by day 15 this had changed to 3.3 mm Hg for once daily, and 2.7 mm Hg for twice daily (p<0.001). This difference was significant for every time-point throughout the day (08.00, 12.00, 16.00h) (Linden and Alm 1998). The majority of direct comparison studies support the conclusion that once daily use of latanoprost is more efficacious than twice daily use (Nagasubramanian et al 1993, Alm et al 1995b, Linden and Alm

11/30 1997 and 1998). Once daily administration has also been shown to produce good control of intraocular pressure without appreciable fluctuation in 24-hour studies (Racz et al 1993 and 1996).

Administration: Morning versus night Does the time of day affect the activity of latanoprost? A direct comparison of morning versus evening administration, which included a crossover and comparison with timolol, but did not include a placebo control, found evening dose administration more effective, 36% (n = 96) reduction versus 31% (n = 89). Both before and after the crossover, the group taking latanoprost in the evening had a significantly lower intraocular pressure than the timolol control group, whereas there was no difference between latanoprost in the morning and timolol twice daily. It has been suggested that the apparent difference in efficacy of the morning and evening times is the result of peak and trough sampling times (Alm et al 1995a), but an around-the-clock study found minimal circadian fluctuation of effectiveness (Racz et al 1996). Although the direct comparison indicates that once nightly application of latanoprost provides the greatest intraocular pressure lowering effect, an open label study did not reveal a difference between morning or evening usage (n = 98) (Camras et al 1998). Konstas et al (1999) compared the 24-hour diurnal ocular hypotensive efficacy of two dosing regimens of latanoprost, once daily (8 AM or 10 PM), vs timolol, twice daily. This study indicated that both latanoprost and timolol are effective in lowering intraocular pressure throughout a 24-hour period; however, latanoprost is most effective in the 12-hour to 24-hour period after administration (Konstas et al 1999).

Latanoprost vs placebo Liu et al (1999) performed a 14-day randomized, double-masked, parallel-group study comparing topical latanoprost with placebo, followed by a 10-week, one-armed, open-labelled latanoprost treatment study to determine the efficacy and safety of latanoprost 50 micrograms/ml in Chinese patients with primary open-angle glaucoma and ocular hypertension. Intraocular pressure, visual function, ocular manifestations and miscellaneous adverse effects were evaluated at baseline, and days 1, 7, 14, 15, week 6 and week 12 visits. Twenty-six eligible patients were enrolled in the study. The authors concluded that topical latanoprost is effective in reducing intraocular pressure for patients with primary open-angle glaucoma and ocular hypertension. The pressure-lowering effect lasts for at least 24 hours after 1 drop instillation and no drift of effect is noted during this 12-week study. Conjunctival hyperemia was the most common side-effect, which was mild in degree and recovered after discontinuation of the medication (Liu et al 1999).

Latanoprost vs other topical pressure-lowering agents The following table presents an overview of the prospective, randomized clinical trials comparing the intraocular pressure-lowering efficacy of topical latanoprost monotherapy with other topical pressure- lowering agents in patients with open-angle glaucoma or ocular hypertension (Perry et al 2003).

Table Summary of prospective, randomized clinical trials comparing the intraocular pressure-lowering efficacy of topical latanoprost (L) monotherapy with other topical pressure-lowering agents in patients with open-angle glaucoma or ocular hypertension

(Perry et al 2003) Reference No. of Treatment regimen IOP (mm Hg; mean) evaluated pts

baseline reduction from baseline (%) Compared with timolol (T) Alm et al (1995a) 89 L 0.005% od am x 24.8 8.6 (35)*†† (db) 3mo then pm x 3mo 94 L 0.005% od am x 25.5 7.8 (31)* 3mo then pm x 3mo 84 T 0.5% bid x 6mo 24.6 6.7 (27)*

12/30 Aquino and Lat- 28 L 0.005% od x 3mo 29.3 11.1 (39)**† Luna (1999) (db) 29 T 0.5% bid x 3mo 29.3 9.1 (32)** Camras et al 118 L 0.005% od x 6mo 25 6.7 (27)†† (1996b) (db) 130 T 0.5% bid x 6mo 25 4.6 (20) Mishima et al d L 0.005% od x 3mo e 6.2 (27)†† (1996) (db) 80 23.1 d T 0.5% bid am x 3mo e 4.4 (19) 83 23.1 Watson et al (1996) 86 L 0.005% od x 6mo 25.2 8.5 (34)** (db) 79 T 0.5% bid x 6mo 25.4 8.3 (33) ** Compared with dorzolamide (D) O’ Donoghue 109 L 0.005% od x 3mo 27.2 8.5 (31)†† (2000)(nb, mc) 107 D 2% tid x 3mo 27.2 5.6 (21) Compared with brimonidine (BR) Camras (2002) (nb, Tot: 152 L 0.005% od x 6mo 24.5 5.7 (23)†† mc) BR 0.2% bid x 6mo 24.8 3.3 (13) DuBiner et al d L 0.005% od x 3mo e 6.5 (27) (2001a) (db, mc) 61 24.1 d BR 0.2% bid x 3mo e 6.8 (28) 64 24.5 Kampik et al (2002) 187 L 0.005% od x 6mo 25.1 7.1 (28)**†† (nb, mc) 192 BR 0.2% bid x 6mo 24.9 5.2 (21)** Stewart et al (2001) Tot: 33 L 0.005% od x 6w 19.8 4.4 (22)**†† (db, co, mc) BR 0.2% bid x 6w 19.8 2.2 (11)** Compared with bimatoprost (B) DuBiner et al 22 L 0.005% od x 1mo e 7.6 (30)** (2001b) (db, mc) 25.2 21 B 0.3% od x 1mo e 8 (31)** 25.6 21 PL od x 1mo e 1.7 (7) 25.8 Gandolfi et al 113 L 0.005% od x 3mo e 7.8 (30)** (2001) (sb, mc) 25.7 119 B 0.3% od x 3mo e 8.2 (32)** 25.7 Walters et al (2001) 38 L 0.005% od x 1mo e 7.5 (32) (sb, mc) 23.6 38 B 0.3% od x 1mo e 8.2 (34) 24.1 Compared with travoprost (TR) Netland et al (2001) 193 L 0.005% od x 12mo e 7.5 (28) (db, mc) 26.9 202 TR 0.0015% od x e 7.0 (27) 12mo 26.4 197 TR 0.004% od x 12mo e 7.1 (26) 26.8 Compared with unoprostone (U) Aung et al (2001) d L 0.005% od x 1mo 22.3 61 (27)**† (db, co) Tot: 56 U 0.12% bid x 1mo 23.2 4.2 (18) **

13/30 Jampel et al (2002) 84 L 0.005% od x 8w 25.3 7.2 (28)†† (nb, mc) 81 U 0.15% bid x 8w 25.5 3.9 (15) Saito et al (2001) 26 L 0.005% od x 6w 22.9 6(26)*† (nb) 26 U 0.12% bid od x 6w 22.7 3.3 (15)* Susanna et al (2001) d L 0.005% od x 2 mo 24.1 6.7 (28)**†† db) 52 d U 0.12% bid x 2mo 24.1 3.4 (14)** 53 a Patients were either treatment-naive or had withdrawn from other pressure-lowering therapy (with no more than 2 other agents) prior to the trial; the percentage of treatment-naïve versus previously treated pts was not provided except where indicated. b L was administered as a single drop to the eye in the evening unless otherwise specified. c IOP was calculated from the mean of 2 or 3 measurements taken between 8am and 5pm (unless otherwise indicated). d Percentage of treatment-naïve pts was 47 and 46% of L and T groups (Mishima et al 1996), 77% of all pts (Aung et al 2001), 14 and 15% of L and U recipients (Susanna et al 2001), and 48 and 39% of L and BR recipients (DuBiner et al 2001a). e Measured in the morning before drug application (trough) (Mishima et al 1996), between 9 and 11am (DuBiner et al 2001a), and at 8am (DuBiner et al 2001b, Gandolfi et al 2001, Netland et al 2001). bid = twice daily; co = crossover; db = double-blind; mc = multicentre; mo = months; nb = nonblind; od = once daily; PL = placebo; pts = patients; sb = single-blind (investigator masked); Tot = total number of † †† pts; w = weeks; * p < 0.05, ** p < 0.001 vs baseline; p < 0.05, p < 0.001 vs comparator drug.

Table Results of prospective, randomized clinical trials comparing the intraocular pressure-lowering efficacy of topical latanoprost monotherapy versus combination therapy with topical timolol (T) and dorzolamide (D) or pilocarpine (P) in patients with elevated intraocular pressure despite previous timolol therapy (Perry et al 2003) Reference No. of Treatment regimen IOP (mm Hg; mean) evaluated pts

baseline reduction from baseline (%) Compared with T + D Italian Multicentric 80 L 0.005% od x 3mo 23.5 6.1 (26)*† Study (2000) (nb) 75 T 0.5% bid + D 2% 23.0 4.7 (21)* bid x 3mo Emmerich (2000) (nb, 85 L 0.005% od x 3mo 22.2 4.5 (20)* mc) 90 T 0.5% bid + D 2% 23.0 5.2 (23)*† bid x 3mo Garcia Sanchez (2000) 77 L 0.005% od x 3mo 23.0 5.2 (23)*† (nb, mc) 79 T 0.5% bid + D 2% 23.7 4.0 (17)* bid x 3mo Honrubia et al (2002) 113 L 0.005% od x 3mo 23.2 4.3 (19)* (nb, mc) 113 T 0.5% bid + D 2% 23.1 4.0 (17)* bid x 3mo Polo et al (2001) (mc, 18 L 0.005% od x 3mo 22.1 5.0 (23)* nb) 17 T 0.5% bid + D 2% 22.4 3.4 (18)* bid x 3mo Compared with T + P Bucci (1999) (sb, mc) 46 L 0.005% od x 6mo d e 21.5 5.5 (25)*†

14/30 37 T 0.05% bid + P 2% d 4.2 (19)* tid x 6mo 22.3 45 T 0.05% bid + L d 6.1 (28)* 0.005% od x 6mo 21.5 Nordman et al (2000) 102 L 0.005% od x 6w 24.3 5.4 (22)* (sb, mc) 95 f 24.2 4.9 (20)* T 0.5% + P 2% bid x 6w Compared with â-blocker plus other agents g 348 L 0.005% od x 6mo 17.8 0.26 Pillunat et al (2003) (nb, mc) 114 â-blocker plus other 17.6 0.37 h agents

Adjunctive therapy with one or more other agents Adjunctive therapy for the management of glaucoma is commonly used. Unfixed combinations of the prostaglandin analog latanoprost and other glaucoma medications have been demonstrated to effectively lower intraocular pressure. The range of reported additional reductions in intraocular pressure compared to a monotherapy baseline is as follows: latanoprost-timolol (13-37%), latanoprost- pilocarpine 2% (7-14%), latanoprost and carbonic anhydrase inhibitors (15-24.1%), and latanoprost and dipivefrin (15-28%) (Higginbotham et al 2002a). DesMarchais et al (2000) report the clinical experience with latanoprost when added to one or two other glaucoma medications. Review of the charts of 53 patients with open-angle glaucoma whose intraocular pressure was uncontrolled with one or two glaucoma medications and who had latanoprost added as a second or third drug. Patients whose intraocular pressure decreased by 3 mm Hg or more were considered to be responders. The results of the study demonstrated that the shortest length of follow-up was 2.3 months (median 5.8 months). Latanoprost was given as a second medication to 35 patients, of whom 22 (63%) responded, with a mean intraocular pressure reduction of 6.1 mm Hg (standard deviation [SD] 2.73 mm Hg) (28.7% [SD 12.10%]). Of the 18 patients to whom latanoprost was given as a third medication, 10 (56%) responded, with a mean intraocular pressure reduction of 6.3 mm Hg (SD 3.86 mm Hg) (24.5% [SD 10.12%]). The authors concluded that latanoprost provides additional intraocular pressure reduction in some patients with open-angle glaucoma when added to one or two other glaucoma medications (DesMarchais et al 2000). Bayer et al (2002) performed a prospective case series to assess the efficacy of latanoprost as additive therapy in patients with open-angle glaucoma and an intraocular pressure deemed to be too high on maximum tolerated medical therapy. Consecutive patients with open-angle glaucoma, presenting to the Gulhane Military Medical Hospital Ophthalmology Clinic from May 1999 to September 2000 were enrolled. The effect of latanoprost on intraocular pressure was followed during a period of 12 months. The criterion for success was defined as having an intraocular pressure reduction of at least 20% from baseline or a final intraocular pressure of less than 22 mm Hg. Several clinical pretreatment variables (age, gender, ocular laterality, type of glaucoma, number of antiglaucomatous medications at study entry, pretreatment intraocular pressure) were analyzed for a significant effect on the efficacy of latanoprost additive therapy. The main outcome measure was intraocular pressure. According to the results of the study, sixty-five eyes of 35 patients were included. The mean baseline intraocular pressure +/- SD was 23.3 +/- 2.0 mm Hg. Two patients (5.71%) developed ocular allergy in the first month requiring cessation of latanoprost. In the remaining 61 eyes of 33 patients, intraocular pressure was significantly reduced compared with baseline measurements with a mean intraocular pressure reduction of 6.1 +/- 1.8 (26.1%), 6.0 +/- 2.2 (25.3%) and 5.5 +/- 2.4 (23.2%) mm Hg at the 1-, 3- and 6-month follow-up controls, respectively (p < 0.001). Successful outcome was obtained in 50 (76.9%), 46 (70.7%) and 38 (58.4%) of 65 eyes at the 1-, 3- and 6-month visits, respectively. During the period from 6 to 12 months, 28 eyes underwent either a combined procedure (cataract extraction + intraocular lens implantation + trabeculectomy; 8 eyes) or only trabeculectomy (20 eyes) because of uncontrolled intraocular pressure; 4 eyes underwent the combined procedure because of visually significant cataract, and 8 eyes were lost to follow-up. Sixteen out of 21 eyes followed for more than 12 months with the same medications continued to have a successful outcome, and the mean intraocular pressure of 18.8 +/- 3.7 mm Hg was significantly different from baseline (p < 0.001). None of the pretreatment variables was a significant prognostic

15/30 factor for failure of latanoprost additive therapy. This study supports the use of latanoprost additive therapy in patients with elevated intraocular pressure already receiving maximum-tolerated medical therapy (Bayer et al 2002). Sodhi et al (2003) conducted a double-blind, randomised, controlled trial to evaluate the efficacy and safety of brimonidine, dorzolamide and latanoprost as an adjunctive therapy in patients with primary open angle glaucoma. A total of 200 males and 72 females with primary open angle glaucoma uncontrolled with previous glaucoma therapy were randomly allocated to receive topical brimonidine 0.2% b.d. (n = 90), topical dorzolamide 2% b.d. (n=91) or topical latanoprost 0.005% o.d. (n = 91).

ANGLE-CLOSURE GLAUCOMA Aung et al (2000) conducted a randomized, double-masked two-center clinical trial to compare the intraocular pressure-reducing effect and side effects of 0.005% latanoprost once daily to 0.5% timolol twice daily in patients with primary chronic angle closure glaucoma. Thirty-two Asian patients with chronic angle closure glaucoma, defined as glaucomatous optic neuropathy with a compatible visual field defect and at least 6 clock hours of synechial angle closure on gonioscopy were recruited. All patients had previous peripheral iridotomy (PI) with intraocular pressure >21 mmHg after PI and were thereafter controlled (intraocular pressure <22 mmHg) with one or two pressure-reducing drugs. After a washout period, the patients were randomized to a 2-week treatment period with either placebo in the morning and 0.005% latanoprost in the evening or 0.5% timolol twice daily. The main outcome measure was the short-term intraocular pressure reduction of latanoprost and timolol in patients with chronic angle closure glaucoma. Intraocular pressure was measured at baseline, and after 2, 7, and 14 days of treatment. In addition, the short-term ocular and systemic adverse events of the two drugs were evaluated. According to the results of the study, thirty patients completed the study. Two patients in the timolol group were withdrawn because of inadequate intraocular pressure control. Compared with baseline, the intraocular pressure after 2 weeks of treatment was statistically significantly reduced by 8.8 ± 1.1 mmHg (mean ± SEM, P < 0.001) in the latanoprost group, and by 5.7 ± 0.9 mmHg (P < 0.001) in the timolol group. The difference in intraocular pressure reduction between the two treatment groups was 3.1 ± 1.5 mm Hg in favour of latanoprost (P = 0.04). The main ocular adverse events reported in both treatment groups were conjunctival hyperemia and discomfort. The authors concluded that in this preliminary study, a significantly greater intraocular pressure reduction was achieved with 0.005% latanoprost once daily compared with 0.5% timolol twice daily in patients with chronic angle closure glaucoma. The results suggest that latanoprost may be a therapeutic choice for the medical treatment of primary chronic angle closure glaucoma (Aung et al 2000). Hung et al (2000) tested the effectiveness of latanoprost in cases of residual primary angle-closure glaucoma. Twenty-six eyes of 26 primary angle-closure glaucoma patients with persistently elevated intraocular pressure after iridectomy, despite treatment with conventional intraocular pressure lowering drugs (beta blockers and pilocarpine) were included. Latanoprost 0.005%, one drop daily, was added adjunctively to all eyes. Measurement of intraocular pressure at baseline and after the start of treatment with latanoprost indicated a significant intraocular pressure reduction. The intraocular pressure decreased by about 21% (p < 0.005) during the first 3 months, and showed a reduction of about 36% at the end of 1 year. At the 1-year follow up, the intraocular pressure was well controlled (below 20 mmHg) in all eyes. The authors concluded that, in combination with beta blockade and pilocarpine, latanoprost can ameliorate residual primary angle-closure glaucoma after iridectomy and could potentially forestall the need for further therapeutic intervention (Hung et al 2000). Chew et al (2002) reviewed the above two independent, prospective trials conducted to assess the efficacy of latanoprost in reducing intraocular pressure in patients with primary angle-closure glaucoma. The first study was a 2-week, randomized, double-masked comparison of latanoprost treatment and timolol treatment in patients with primary angle-closure glaucoma. Patients were randomized to one of two parallel treatment groups, receiving either placebo in the morning and latanoprost 0.005% in the evening, or timolol 0.5% twice daily. The mean intraocular pressure reduction in latanoprost group was 8.8 ± 1.1 mm Hg (mean ± SEM, p < 0.001; 34.2%) from a mean baseline intraocular pressure of 25.7 ± 0.9 mm Hg, and the corresponding figures for the timolol group were 5.7 ± 0.9 mm Hg (p < 0.001; 22.6%) from a mean baseline intraocular pressure of 25.2 ± 1.1 mm Hg. A significantly greater intraocular pressure reduction of 3.1 ± 1.5 mm Hg (95% confidence interval: 0.1 to 6.0) was achieved in the latanoprost group compared to the timolol treatment group (p = 0.04). In the second study, latanoprost 0.005% once a day was added adjunctively to primary angle-closure glaucoma patients with persistently elevated intraocular pressure after iridectomy, despite treatment with beta-blockers and pilocarpine. The intraocular pressure

16/30 decreased by about 21% during the first 3 months, and showed a reduction of about 36% at the end of 1 year. At the 1-year follow-up, intraocular pressure was <20 mm Hg in all eyes. In both studies, latanoprost was well tolerated with few adverse events. The authors concluded that latanoprost is effective in reducing intraocular pressure in patients with primary angle-closure glaucoma (Chew et al 2002). The same authors conducted later (2004) a randomized, double-masked, multicenter 12-week study to demonstrate that the intraocular pressure-reducing effect of latanoprost once daily is at least as good as that of timolol twice daily in patients with chronic angle-closure glaucoma. In all, 137 patients with unilateral or bilateral chronic angle-closure glaucoma were treated with latanoprost, and 138 were treated with timolol. Patients received either latanoprost (9 pm) and a placebo (9 am) or timolol (both 9 am and 9 pm). Intraocular pressure was measured at 9 am and 5 pm at baseline and weeks 2, 6, and 12. The difference between groups in daily intraocular pressure (average of 9 am and 5 pm measures) reduction was the primary outcome. Secondary outcomes included differences between groups in intraocular pressure reductions at 9 am and 5 pm, and in proportions of patients reaching specified daily intraocular pressure levels. The results of the study demonstrated that using repeated measures (analysis of covariance: intent to treat), mean changes from baseline in daily intraocular pressure levels during 12 weeks were -8.2 mmHg and -5.2 mmHg for latanoprost- and timolol-treated patients, respectively (difference: -3.0 mmHg [95% confidence interval: -4.0, -2.1], P<0.001). Greater reductions in intraocular pressure levels at both 9 am and 5 pm were found in latanoprost-treated patients (P<0.001 for both), and greater proportions of patients receiving latanoprost reached prespecified target daily intraocular pressure levels (P<0.001 for all 3 target levels tested). Both drugs were well tolerated. The authors concluded that latanoprost administered once daily provides significantly greater intraocular pressure reduction in chronic angle-closure glaucoma patients than does timolol instilled twice daily (Chew et al 2004). Sihota et al (2004) performed a prospective, randomized, crossover study of 60 eyes of 30 patients with chronic primary angle-closure glaucoma after laser iridotomy to compare latanoprost and timolol maleate as primary therapy in 60 eyes with chronic primary angle-closure glaucoma after a laser iridotomy. Patients were randomized to 2 groups: those taking latanoprost once daily or those taking timolol twice daily. Three months after treatment with the first drug, the second drug was substituted. The circadian rhythm of intraocular pressure was recorded before the start of therapy, at 3 months, and at 7 months. The fourth month was the washout period for the first drug. The results of the study revealed that the mean baseline intraocular pressure was 23.5 +/- 2.1 mm Hg, which decreased by 8.2 +/- 2.0 mm Hg with latanoprost (P<.001) and by 6.1 +/- 1.7 mm Hg with timolol (P =.01). The decrease in intraocular pressure was greater for patients taking latanoprost (P<.001). Latanoprost was significantly more effective in eyes having morning and afternoon peaks of intraocular pressure. A total of 43 eyes (72%) of patients taking latanoprost and 26 (43%) on timolol achieved a reduction of more than 30% from baseline intraocular pressure. The authors concluded that there were greater mean and peak intraocular pressure reductions achieved with 0.005% latanoprost once daily compared with 0.5% timolol twice daily (Sihota et al 2004). Sakai et al (2005) To compare the efficacy, adverse effects, and patient compliance of latanoprost monotherapy with unfixed combination therapy with 0.5% timolol maleate and 1% dorzolamide in the treatment of chronic primary angle-closure glaucoma, 36 Japanese patients with chronic primary angle-closure glaucoma following laser iridotomy were treated for 12 weeks with instillation of latanoprost alone or with unfixed combination therapy of 0.5% timolol maleate and 1% dorzolamide hydrochloride. After 12 weeks of treatment, latanoprost reduced intraocular pressure from 22.2 +/- 2.0 mmHg to 14.8 +/- 1.9 mmHg (33% reduction); timolol maleate and dorzolamide hydrochloride also reduced intraocular pressure from 22.5 +/- 2.2 mmHg to 17.1 +/- 2.7 mmHg (24% reduction). Latanoprost monotherapy significantly lowered intraocular pressure compared with unfixed combination therapy of 0.5% timolol maleate and 1% dorzolamide hydrochloride. Furthermore, a systemic adverse effect of bradycardia was not observed in the latanoprost monotherapy group. Concerning compliance, no significant difference was observed between the two groups. The authors concluded latanoprost monotherapy is more effective than unfixed combination therapy with 0.5% timolol maleate and 1% dorzolamide in the treatment of chronic primary angle- closure glaucoma following relief of pupillary block in Japanese patients (Sakai et al 2005).

OTHER TYPES OF GLAUCOMA Normal-tension glaucoma Normal-tension glaucoma was previously thought to be pressure insensitive, as medical treatment hardly reduced intraocular pressure and it did not prevent visual field loss. In the last decade, however,

17/30 evidence has shown that the treatment of normal-tension glaucoma by lowering intraocular pressure can slow the deterioration of visual fields, hence the glaucomatous process. It was shown that a reduction of intraocular pressure of at least 30% is needed to induce a favorable alteration in the course of normal-tension glaucoma. New agents, such as prostaglandin analogs, the alpha(2)- adrenoceptor agonist brimonidine, and carbonic anhydrase inhibitors, have become available and may be of use in the treatment of normal-tension glaucoma. Monotherapy with prostaglandin analogs may meet the target of a reduction of intraocular pressure with 30%, but combination therapy will be needed in many cases (Hoyng and Kitazawa 2002). Kjellgren et al (1995) performed a double masked randomized study to assess the efficacy of latanoprost compared to placebo. Latanoprost was given topically to 20 patients with normal pressure glaucoma. Either latanoprost 0.006% or placebo (vehicle) was administered twice a day for 14 days. The results of the study revealed that latanoprost caused a statistically significant (p < 0.001) reduction in intraocular pressure from a diurnal baseline level of 16.8 to 14.3 mmHg, as measured on day 14. Latanoprost was well tolerated (Kjellgren et al 1995). Rulo et al (1996) conducted a randomized, double-masked, placebo-controlled cross-over study was performed in 30 patients with normal-tension glaucoma to evaluate the intraocular pressure-reducing potential and side effects of latanoprost in this patient group. 29 patients completed the study. During three periods of 3 weeks each, patients received, in a random order, 50 micrograms/ml latanoprost once daily, 15 micrograms/ml latanoprost twice daily, and placebo. The authors concluded that both latanoprost regimens significantly reduce intraocular pressure in patients with normal-tension glaucoma, but 50 micrograms/ml latanoprost once daily is more effective in reducing intraocular pressure than 15 micrograms/ml latanoprost twice daily. Lowering the concentration did not result in an improved side effects profile. Latanoprost is more effective at higher intraocular pressure levels (Rulo et al 1996). Tamada et al (2001) performed a study on 31 patients with mainly normal-tension glaucoma and treated the patients with once-daily latanoprost for 8 weeks. They found a 3.2 mm Hg reduction of intraocular pressure (19.9%) and observed a correlation between the initial intraocular pressure level and the magnitude of the fall in intraocular pressure. Like Rulo et al (1996) they found that the higher the baseline intraocular pressure the greater was the intraocular pressure reduction (Tamada et al 2001). Drance et al (1998) conducted a three-center, double-masked, randomized, crossover study with 36 patients to compare the calculated mean ocular perfusion pressure at the end of 3 weeks' treatment with latanoprost 0.005% once daily or timolol 0.5% twice daily in normal- tension glaucoma patients. The authors concluded that because ocular perfusion pressure may be important in some glaucomatous patients, latanoprost appears to affect ocular perfusion pressure more favourably than timolol does in patients with normal-tension glaucoma (Drance et al 1998). Liu et al (2002b) performed a randomized, open-label, crossover study to evaluate and compare the effects of latanoprost 0.005% once daily and brimonidine tartrate 0.2% twice daily in 28 patients with normal- tension glaucoma with progressive visual field defects/optic disc excavation, new disc hemorrhage, or field defects that threatened fixation. The authors concluded that both latanoprost and brimonidine reduce intraocular pressure in normal-tension glaucoma patients. Brimonidine has a peak intraocular pressure-lowering effect equal to that of latanoprost but produces a higher mean diurnal intraocular pressure than does latanoprost because of its shorter effect. Latanoprost might favourably alter optic disc blood perfusion by increasing ocular perfusion pressure (Liu et al 2002b). Ang et al (2004) determined the long term effect of latanoprost on the intraocular pressure of patients with normal tension glaucoma. Newly diagnosed patients with normal tension glaucoma were recruited into the study and had their baseline intraocular pressures measured hourly between 8 am and 5 pm using a handheld electronic Tonopen. Patients with fixation threatening field defects were placed immediately into the treatment group while those with non-fixation threatening field defects were randomised into either the treatment group or the control group (no treatment). Treatment consisted of once daily topical latanoprost 0.005%. After a minimum period of 6 months, the patients underwent a second period of intraocular pressure phasing. The authors concluded that latanoprost had a sustained hypotensive effect in eyes with normal tension glaucoma and 41% of treated patients achieved a reasonable response. However, in the majority of eyes with normal tension glaucoma, latanoprost monotherapy may be insufficient in producing a desirable 30% reduction in intraocular pressure (Ang et al 2004). Tomita et al (2004) conducted an open-label, randomized, study to compare the longitudinal effects of treatment on intraocular pressure and visual field performance in Japanese normal-tension glaucoma between latanoprost and timolol. A total of 62 normal-tension glaucoma patients were prospectively, consecutively enrolled. All study subjects were randomly assigned to 0.005% latanoprost instillation once daily in the morning or 0.5% timolol instillation twice daily for a

18/30 prospective 3-year follow-up, and underwent a routine ocular examination every month. Automated perimetry was performed every 6 months using Humphrey field analysers. Stereophotographs of optic discs were also obtained every 6 months. The authors concluded that both latanoprost and timolol single treatments reduced intraocular pressure by 13-15% at their trough effects for 3 years in Japanese normal-tension glaucoma patients; both showed similar effects on visual field performance (Tomita et al 2004). Oh and Park (2005) evaluated the intraocular pressure-lowering efficacy of latanoprost in normal-tension glaucoma. In this study, one-hundred and seventeen eyes of 63 normal- tension glaucoma patients treated with 0.005% latanoprost once a day were enrolled in this study. Of these, 85 eyes of 47 patients were treated for 12 months. Mean intraocular pressures were analyzed, and the mean intraocular pressure reductions from the untreated baseline were assessed after two weeks and after 1, 3, 6, 9, and 12 months of treatment. The results of the study demonstrated that the mean untreated baseline intraocular pressure was 15.0 +/- 2.7 mmHg. After two weeks of latanoprost treatment, the mean intraocular pressure reduction from the baseline value was 2.6 +/- 0.2 mmHg (17.3%, p<0.05), and after 6 and 12 months, the reduction was 2.4 +/- 0.2 mmHg (16.0%, p<0.05) and 2.4 +/- 0.2 mmHg (16.0%, p<0.05), respectively. Patients with a baseline intraocular pressure of > or = 15 mmHg achieved significantly higher intraocular pressure reductions than those with a baseline intraocular pressure of <15 mmHg at all follow-ups (p<0.05). The authors concluded that latanoprost was found to be well tolerated and to significantly reduce intraocular pressure in normal-tension glaucoma patients (Oh and Park 2005). Dirks et al (2006) performed a multicenter, randomized, double-blind clinical trial to compare the intraocular pressure-lowering efficacy and safety of topical bimatoprost 0.03% with that of latanoprost 0.005% for the treatment of patients with normal-tension glaucoma. Overall mean reduction in intraocular pressure after 3 mo of treatment was 3.4 mm Hg (19.9% rpar; with bimatoprost and 2.3 mm Hg (14.6%) with latanoprost (P=.035). No significant between-group differences were observed in incidence of adverse events, clinical success, or demographic variables. Bimatoprost was found to be more effective than latanoprost in lowering intraocular pressure in the patient with normal-tension glaucoma. Both drugs were efficacious and well tolerated (Dirks et al 2006).

Pigmentary glaucoma Mastropasqua et al (1999) performed a prospective, randomized, double-masked, clinical study to compare the efficacy and side effects and the effect on aqueous humor dynamics of 0.005% latanoprost applied topically once daily with 0.5% timolol given twice daily for 12 months to patients with pigmentary glaucoma. Thirty-six patients affected with bilateral pigmentary glaucoma controlled with no more than a single hypotensive medication were enrolled in the study. The sample population was randomly divided into 2 age- and gender-matched groups each of 18 patients. Group 1 received 0.005% latanoprost eyedrops once daily and the vehicle (placebo) once daily; group 2 was assigned to timolol 0.5% eyedrops twice daily. Diurnal curves of intraocular pressure were performed on the baseline day and after 0.5, 3, 6, and 12 months of treatment. The intraocular pressure measurements were performed at 8:00 AM, 12:00 noon, 4:00 PM, and 8:00 PM. Outflow facility ("C") was measured on the baseline day and on the last day of the study with a Schiotz electronic tonometer. A two-tailed Student's t test for paired or unpaired data was used for statistical evaluation of differences between treatment and baseline values or between the latanoprost and timolol group. Diurnal intraocular pressure measurements were compared hour by hour. Mean values of the two eyes intraocular pressure and "C" were used for analysis. The results of the study revealed that compared with baseline measurements, both latanoprost and timolol caused a significant (P < 0.001) reduction of intraocular pressure at each hour of diurnal curve throughout the duration of therapy. Reduction of intraocular pressure was 6.0 ± 4.5 and 5.9 ± 4.6 with latanoprost and 4.8 ± 3.0 and 4.6 ± 3.1 with timolol after 6 and 12 months, respectively. Comparison of mean diurnal measurements with latanoprost and timolol showed a statistical significant (P < 0.001) difference at 3, 6, and 12 months. Mean "C" was found to be significantly enhanced (+30%) only in the latanoprost-treated group compared with the baseline (P = 0.017). Mean conjunctival hyperemia was graded at 0.3 in latanoprost-treated eyes and 0.2 in timolol-treated eyes. A remarkable change in iris colour was observed in both eyes of 1 of the 18 patients treated with latanoprost and none of the 18 patients who received timolol. Darkening of the peripheral iris stroma was suspected in two patients treated with latanoprost. In the timolol group, heart rate was significantly reduced from 72 ± 9 at baseline to 67 ± 10 beats per minute at 12 months. The authors concluded that although further studies may need to confirm these data on a larger sample and to evaluate the side effect of increased iris pigmentation on long-term follow-up, in patients with

19/30 pigmentary glaucoma, 0.005% latanoprost taken once daily was well tolerated and more effective in reducing intraocular pressure than 0.5% timolol taken twice daily (Mastropasqua et al 1999).

Exfoliation glaucoma Konstas et al (2001) compared the 24 hour efficacy of latanoprost 0.005% given every evening with that of pilocarpine 4% given four times daily as third-line therapy in patients with exfoliation glaucoma receiving timolol 0.5% and dorzolamide 2% each given twice daily. 30 patients with exfoliation glaucoma not adequately controlled on timolol maleate 0.5% and dorzolamide 2% were enrolled. Each patient underwent a baseline 24 hour intraocular pressure curve testing at 06:00, 10:00, 14:00, 18:00, 22:00 and 02:00 hours. Patients were randomised to receive either latanoprost 0.005% or pilocarpine 4% for a minimum of 8 weeks and were then crossed over to the opposite therapy. Diurnal curve testing was repeated at the end of each treatment. The results of the study demonstrated a significant decrease from baseline in intraocular pressure at each timepoint for both study medicines (p < 0.016). Latanoprost provided better intraocular pressure control than pilocarpine at daytime measuresments (17.4 vs 19.7 mmHg at 06:00 hours, p < 0.001; 17.8 vs 19.1 mmHg at 10:00 hours, p = 0.04). However, pilocarpine reduced the pressure more than latanoprost at 22:00 hours (18.4 vs 19.5 mmHg, p = 0.016). Overall, the diurnal intraocular pressure was reduced from a baseline of 21.5 ± 3.7 mmHg to 18.8 ± 3.1 mmHg on pilocarpine and to 18.0 ± 3.0 mmHg on latanoprost (p = 0.06). In addition, mean peak pressure was similar between pilocarpine (21.0 ± 2.9 mmHg) and latanoprost (20.5 ± 3.8 mmHg) (p = 0.20). Side-effects were similar with the exception of blurred vision, which was only found with pilocarpine (10%). Compliance was more difficult with pilocarpine. The authors concluded that in exfoliation glaucoma, as a third-line adjunctive therapy added to timolol and dorzolamide, latanoprost and pilocarpine have similar diurnal efficacy. However, latanoprost provides a greater morning pressure reduction (Konstas et al 2001). The same authors in a subsequent study (2003) evaluated the safety and efficacy of the timolol/dorzolamide fixed combination vs latanoprost 0.005% in exfoliation glaucoma patients. 65 newly diagnosed exfoliation glaucoma patients were randomized in an observer-masked fashion to either the timolol/dorzolamide twice daily or latanoprost daily treatment for 2 months and then crossed these over to the other treatment. According to the results of the study, a total of fifty-four patients completed the study. After 2 months of chronic dosing, the morning intraocular pressure (10:00) was reduced from a baseline of 31.2+/-6.5 mmHg to 18.1+/-3.0 with the fixed combination and to 18.9+/-4.1 mmHg with latanoprost (P = 0.21). Six patients were discontinued early from both treatment periods owing to inadequate intraocular pressure control and two others were discontinued from latanoprost treatment only. The fixed combination showed a significantly greater incidence of taste perversion (P < 0.001) and stinging upon instillation (P = 0.036), while latanoprost showed a trend for increased conjunctival injection (P = 0.056). However, five patients demonstrated either bradycardia or asthmatic symptoms with initiation of the fixed combination therapy. One patient on latanoprost complained of dizziness. Patient preference was generally given to latanoprost (63 vs 20.3%) mainly because of its once daily dosing (P < 0001). The authors concluded that both latanoprost and the timolol/dorzolamide fixed combination are efficacious in the treatment of newly diagnosed exfoliation glaucoma (Konstas et al 2003). Konstas et al (2004) conducted a 3-month prospective, single-masked, active-controlled, parallel comparison performed in six centres in Greece to compare the diurnal intraocular pressure efficacy and safety of timolol vs latanoprost in subjects with exfoliation glaucoma. Subjects were randomized in a 1 : 1 ratio to either latanoprost in the evening (2000 hours) and placebo in the morning (0800 hours), or timolol twice daily (0800 and 2000 hours). In all, 103 subjects completed the study. The results of the study revealed that after 3 months of chronic dosing, the latanoprost group exhibited a trend to a greater diurnal intraocular pressure reduction from an untreated baseline (24.9+/-3.2-17.4+/-2.9) compared with timolol (24.7+/-2.8-18.3+/-1.9 mmHg) (P=0.07). Latanoprost showed a significantly greater intraocular pressure reduction at 0800 hours (-8.5 vs -6.0 mm Hg for timolol, P<0.0001) whereas no difference was observed between the two medications at 1000, 1400, and 2000 hours after a Bonferroni Correction. In addition, latanoprost demonstrated a narrower range of diurnal intraocular pressure (2.4) than timolol (3.2 mmHg)(P=0.0017). Safety was similar between groups, except there was more conjunctival hyperaemia with latanoprost (n=8) than timolol (n=1)(P=0.01). The authors concluded that latanoprost provides a statistically lower 08:00-hour intraocular pressure and better range of intraocular pressure than timolol in the treatment of exfoliation glaucoma (Konstas et al 2004). Parmaksiz et al (2006) conducted a randomized, prospective, investigator-masked study with 50 pseudoexfoliation glaucoma patients to compare the intraocular pressure lowering effect and safety of

20/30 latanoprost, travoprost given every evening, and the fixed combination dorzolamide + timolol given twice daily in pseudoexfoliation glaucoma. Patients were assigned to one of three groups: travoprost 0.004%, fixed combination of dorzolamide 2%+timolol 0.5%, or latanoprost 0.005% for 6 months. At baseline and 0.5, 1, 2, 3, 4, 5, and 6 months of therapy, intraocular pressure (8 am, 10 am, 4 pm), blood pressures, and pulse rates were measured, and ophthalmologic examination was performed. The side effects were recorded at each visit. According to the results of the study, forty-two of the 50 patients initially enrolled completed this study. Withdrawn patients included one (latanoprost) for lack of efficacy, five (three travoprost, one latanoprost, one fixed combination dorzolamide + timolol) for adverse events, and two (one latanoprost, one fixed combination dorzolamide + timolol) for loss of follow-up. Each of the three drugs considerably reduced the intraocular pressure in pseudoexfoliation glaucoma cases throughout the 6 months. Mean intraocular pressure reduction at 6 months was -9.3+/- 2.9 mmHg in the travoprost group, -8.2+/-1.2 mmHg in the latanoprost group, and 11.5+/-3.3 mmHg in the fixed combination dorzolamide + timolol group. Comparing the groups, fixed combination dorzolamide + timolol is more effective than latanoprost and travoprost in lowering intraocular pressure (p<0.05). There was no difference between travoprost and latanoprost. The most common treatment-related adverse event was conjunctival hyperemia. Intensity of ocular hyperemia was greater in the travoprost group compared with the latanoprost and fixed combination dorzolamide + timolol groups (p<0.05). There were no significant effects on systemic safety parameters. The authors concluded that fixed combination dorzolamide + timolol is more effective in reducing intraocular pressure than latanoprost and travoprost. Latanoprost and travoprost had similar ocular hypotensive effects in patients with pseudoexfoliation glaucoma. All three drugs were well tolerated; there were fewer ocular side effects attributable in the latanoprost group (Parmaksiz et al 2006).

OTHER USES Latanoprost is also an effective and safe drug for the: Prevention of post-operative increase in intraocular pressure after cataract surgery (Scherer et al 1998, Miyake et al 1999, Arici et al 2006). Prevention of ocular hypertension after phacoemulsification and intraocular lens implantation (Lai et al 2000 and 2001). Reduction of intraocular pressure rise following neodymium: Yag laser iridotomy (Liu et al 2002c). Treatment of steroid-induced ocular hypertension after excimer laser photorefractive keratectomy (Vetrugno et al 2000). Treatment of Meniere’s disease (Rask-Andersen et al 2005).

LONG TERM STUDIES Watson et al (1998) a randomized, 6-month double-masked parallel group, multicenter study comparing latanoprost with timolol followed by an 18-month open-label, multicenter study in which all patients were treated with latanoprost to assess the efficacy and safety of latanoprost in the long- term treatment of glaucoma. In total, 277 patients were treated with latanoprost for up to 24 months. For the first 6 months of treatment, latanoprost (0.005%) administered once daily was compared with timolol (0.5%) administered twice daily. Patients then received latanoprost (once daily) for an 18- month follow-up period regardless of their initial treatment. Intraocular pressure was measured over the 24-month treatment period, and any ocular-systemic symptoms or adverse events were evaluated. The results of the study revealed that latanoprost significantly reduced (P < 0.001) intraocular pressure by approximately 8 mmHg from pretreatment values, and this reduction was maintained over the 24- month treatment period with no sign of upward drift. Latanoprost is apparently free of any systemic side effect. The most significant ocular side effect with latanoprost was an increase in iris pigmentation, which occurred in 51 patients. The authors concluded that latanoprost, administered once daily, is effective and well tolerated for the long-term treatment of patients with open-angle glaucoma or ocular hypertension (Watson et al 1998). Alm and Widengard (2000) conducted a randomized, parallel group, double-masked, multicenter comparison between latanoprost and timolol in patients with open angle glaucoma or ocular hypertension, followed by an open-label 18-month extension during which all patients were treated with latanoprost to assess efficacy and side effects of latanoprost during two years of treatment. The results of the study revealed that latanoprost caused a marked and sustained reduction of the intraocular pressure. Intraocular pressure was reduced from baseline levels 25.1±3.5 mm Hg (mean±SD) in 183 patients initially randomized to treatment with

21/30 latanoprost to 17.4±2.9 mm Hg (n=66) after 24 months of treatment. For patients initially randomized to treatment with timolol the corresponding figures were 24.3±2.3 mm Hg (n=72) and 17.4±2.6 (n=41) mm Hg after 18 months of treatment with latanoprost. Two patients were withdrawn because of uncontrolled intraocular pressure and 11 patients required additional timolol treatment to maintain an adequate intraocular pressure control. Patients initially treated with timolol and switched to latanoprost had a further reduction of the intraocular pressure of 1.0 mm Hg after 6 months of treatment with latanoprost (p<0.005). 46 patients were withdrawn from the study, mostly due to increased iris pigmentation or an iris colour with known high risk of developing increased pigmentation. 22 patients developed increased pigmentation of the iris. The follow-up revealed no previously unknown ocular or systemic side effects. The authors concluded that once daily applications of latanoprost cause a marked and sustained reduction of the intraocular pressure. The only clinically significant side effect noted was the increased pigmentation of the iris, most frequently seen in irides with a mixture of brown and blue/grey or green colours. No systemic side effect was observed (Alm and Widengard 2000). Costagliola et al (2002) performed an unmasked prospective study on 76 glaucomatous patients (145 eyes) to assess the efficacy and side effects of 0.005% latanoprost once daily during 3 years of treatment in glaucomatous patients in whom intraocular pressure was not adequately controlled by beta-blockers twice daily. Patients were treated with 0.005% latanoprost at bedtime, after a 21-day wash-out period from beta-blockers. Intraocular pressure measurement and visual field examination were recorded over the follow-up period. The results of the study revealed that latanoprost significantly reduced intraocular pressure from 26.5+/-6.6 mmHg (mean +/- SD) to 17.4+/-2.7 mmHg after 36 months of treatment in 48 patients (63.1%), who completed the trial. Twenty-eight patients (36.8%) discontinued the therapy. In 12 patients (15.8%) the treatment did not obtain a satisfactory target intraocular pressure. In two subjects (2.6%), despite the intraocular pressure reduction, visual field damage progressed. The remaining 10 patients (13.1%) discontinued the treatment because of the following side effects: microfollicular conjunctivitis (seven cases); severe oedema of conjunctiva and eyelids (one case); corneal punctate erosion (one case); cystoid macular oedema (one case). No flare or pigmentary changes of iris and eyelash were observed. The authors concluded that latanoprost 0.005% once daily significantly reduces intraocular pressure in the majority of glaucomatous patients uncontrolled by beta-blockers. The reduction of intraocular pressure was statistically significant during 3 years of follow-up, confirming the clinical efficacy of this compound. The ocular side effects requiring cessation of therapy were mainly allergic reactions. The most severe adverse effects were one case of corneal punctate erosion and one case of cystoid macular oedema in a pseudophakic patient (Costagliola et al 2002). Hedman et al (2002) reviewed the effects of long-term treatment with latanoprost on the intraocular pressure in open-angle glaucoma or ocular hypertensive patients during long-term. A total of 532 patients treated with 0.005% latanoprost were enrolled, including 493 and 113 patients treated for 6 and 24 months, respectively. Mean intraocular pressure was analyzed with the analysis of variance technique. The risk of treatment failure was analyzed with survival analysis technique. After 2 weeks of latanoprost treatment, the mean intraocular pressure was reduced 8.2 (32%) and 8.9 (34%) mm Hg in the subgroups of patients treated for 6 and 24 months, respectively. The change in mean intraocular pressure during 2 years of latanoprost treatment was not statistically significant (p = 0.15). Patients with primary open-angle glaucoma or ocular hypertension showed an 86% and 97% chance of receiving a sufficient intraocular pressure reduction with latanoprost (p < 0.01), respectively. The initial mean intraocular pressure reduction was maintained throughout the 2 years of treatment (Hedman et al 2002). Bayer et al (2004) evaluated the long-term follow-up of patients who were changed to latanoprost from previous glaucoma therapies. Primary open-angle, exfoliative or chronic angle-closure glaucoma, or ocular hypertensive patients who switched to latanoprost therapy with a 2-year follow-up, were evaluated for efficacy, safety, and continuance of therapy. The results of the study revealed that in 1,571 patients, the intraocular pressure across all treatment groups of 21.3 +/- 4.1 was reduced to 17.6 +/- 3.2 mm Hg after switching to latanoprost. Latanoprost reduced the intraocular pressure from previous monotherapies, including nonselective beta-adrenergic blockers, topical carbonic anhydrase inhibitors, alpha-adrenergic agonists and pilocarpine (p < 0.0001) and adjunctive therapies, including the fixed combinations of dorzolamide and timolol, pilocarpine and timolol, and pilocarpine and metipranolol, and the unfixed combination of dorzolamide and timolol and dorzolamide and clonidine (p < 0.0028). Latanoprost further reduced the intraocular pressure across all diagnostic groups (p < 0.0001). The most common ocular adverse event was ocular irritation (n = 25; 1.6%), which was also the most common reason given for patients who discontinued latanoprost because of an adverse event (n = 20; 1.3%). The authors concluded that the

22/30 mean intraocular pressure was maintained at an acceptable level throughout the 2-year follow-up period on latanoprost. Latanoprost generally provides further reduction of intraocular pressure when switched from previous mono- and adjunctive therapies, with a low rate of side effects and discontinuations (Bayer et al 2004).

EFFICACY IN CHILDREN There are three peer-reviewed publications involving the use of latanoprost in the treatment of pediatric patients with glaucoma. One of these case series involved children with a wide variety of glaucoma diagnoses (Enyedi et al 1999), while the other two dealt with Sturge-Weber associated glaucoma (Yang et al 1998, Altuna et al 1999). Enyedi and Freedman (2002) evaluated the efficacy and safety of latanoprost in children from the three above peer-reviewed publications involving the use of this drug in the treatment of pediatric patients with glaucoma. Most of the patients in these studies showed disappointingly little intraocular pressure effect from this drug, but some children, particularly older children and those with juvenile-onset open-angle glaucoma, do have a significant ocular hypotensive effect with latanoprost. Systemic and ocular side effects in children on latanoprost are infrequent and mild (Enyedi and Freedman 2002). Urban et al (2004) evaluated the effect of latanoprost in 14 children aged 12-18 years (mean 15 years): 10 patients with glaucoma juvenile (I group); 2 patients with secondary glaucoma because of uveitis recidivans and 2 patients with aniridia and albinismus (II group). In the I group the average intraocular pressure decrement was 9 mmHg or 36.5% (range 29-44%). In the II group the average intraocular pressure decrement was 6.5 mmHg or 23.5% (range 11-33%). In one child with aniridia after one year of treatment intraocular pressure rose again to 26 mmHg and antiglaucomatous surgery was necessary. Ocular side effects in children of latanoprost are mild (Urban et al 2004).

Clinical safety

The relative systemic safety of glaucoma medications is presented in the next table (Camras et al 1999). Table Relative systemic safety of glaucoma medications (ranked in order of systemic safety with 1 = safest and 8 = least safe) (Camras et al 1999) 1. Latanoprost 2. Miotics 3. Dipivefrine = apraclonidine = topical carbonic anhydrase inhibitors 4. Epinephrine (adrenaline) = apraclonidine = topical carbonic anhydrase inhibitors 5. Brimonidine = betaxolol 6. Nonselective â-blockers 7. Timolol – dorzolamide 8.Oral carbonic anhydrase inhibitors = indicates greater than or equal to.

Alm et al (2004) conducted a 3-year, open-label, uncontrolled, prospective trial with a 2-year extension phase to evaluate the 5-year safety and efficacy of adjunctive 0.005% latanoprost once daily. Patients with primary open-angle or exfoliation glaucoma who completed the 3-year trial could enter the 2-year extension phase. High-resolution color photographs of irides were taken at baseline and at 14 subsequent visits. Photographs were assessed for change in iris pigmentation compared with baseline. Intraocular pressures and adverse events were recorded. The main outcome measure was the development and progression of increased iris pigmentation over 5 years. Of the 519 original patients, 380 enrolled in the extension phase with approximately 89% having an eye color known to be susceptible to color change. The results of the study revealed that after 5 years, most patients had no increase in iris pigmentation, but certain colored irides exhibited notably greater susceptibility than others. For those whose irides did change, onset occurred during the first 8 months in 74% and during the first 24 months in 94%. No patient developed an increase in pigmentation after month 36; the rate of progression decreased over time. Adverse event profiles were similar for patients with and without increased pigmentation. The overall mean intraocular pressure reduction from baseline of 25% was

23/30 sustained with no need for change in intraocular pressure-lowering treatment in 70% of the eyes. The authors concluded that latanoprost therapy is safe and well tolerated for long-term treatment of open- angle glaucoma (Alm et al 2004).

SIDE/ADVERSE EFFECTS Ocular effects The relative frequency / severity of ocular side effects of current topical glaucoma medications is presented in the next table (Camras et al 1999).

Table Relative frequency / severity of ocular side effects of current topical glaucoma medications (Camras et al 1999) Low Medium High Latanoprost á-Agonists Cholinergic agonists Unprostone Topical carbonic anhydrase inhibitors â-Antagonists Brimatoprost Travoprost

Inoue et al (2006) prospectively investigated adverse reactions induced by latanoprost such as eyelid pigmentation, iridial pigmentation, or hypertrichosis. One hundred and one Japanese glaucoma or ocular hypertension patients were included. Iridial, eyelid, and eyelash photographs were taken before and at 6 months after latanoprost treatment. Increased eyelid pigmentation, iridial pigmentation, eyelash pigmentation, vellus hair of the lid, and hypertrichosis were assessed from these photographs. The correlation between the incidence of these adverse reactions and the time of instillation, type of glaucoma, sex, age, or concomitantly used eye drops, and the overlap of these were evaluated. The results of the study revealed increased pigmentation of the eyelid in 6 cases(5.9%), of the iris in 32 cases (31.7%), of the eyelashes in 29 cases (28.7%), vellus hair of the lid in 38 cases(37.6%), and hypertrichosis in 51 cases(50.5%). Pigmentation of the eyelid was more frequently observed in patients who used latanoprost concomitantly (16.7%) than in those who did not use anti-glaucomatous eye drops before latanoprost treatment (1.6%), or in those treated with latanoprost who had switched from other anti-glaucomatous eye drops (6.3%) (p= 0.03). The authors concluded that the incidence of adverse reactions caused by latanoprost was higher in the eyelashes and iris than in the eyelid (Inoue et al 2006).

Conjunctival hyperaemia In direct comparisons with timolol, the latanoprost group had a nearly identical adverse effect profile despite having 2- to 4- fold as much benzalkonium chloride exposure in its vehicle (Eisenberg and Camras 1999). The large, independent 6-month multicentre trials reported very mild increases in hyperaemia (Alm et al 1995a, Camras et al 1996b, Watson et al 1996), but only 1 reported a statistically significant increase (Watson et al 1996). All of the cases reported were mild. An unmasked comparison did reveal a very small but statistically significant increase in hyperaemia in the group changing from timolol to latanoprost. The degree of hyperaemia reported was also mild and not clinically important (Camras et al 1998).

Iris pigmentation Darkening of the irides occurs with prolonged use of latanoprost. This colour change has been reported to occur as early as 2 months after beginning treatment, and predominantly in irides of mixed colour (green-brown, blue-grey, yellow-brown) (Eisenberg and Camras 1999). In one study, 10 of 27 (37%) green-brown irides showed possible colour change, as did 2 of 7 yellow-brown (295) and 4 of 35 (11%) blue/grey-brown irides (Camras et al 1996a). In another study, iris hyperpigmentation incidence was observed in 42.8% of 140 open-angle glaucoma patients on 0.005% latanoprost, especially after continual use for around 7 months (Chou et al 2005). No study has found a serious consequence of this colour change, nor any evidence that iris nevi are affected. Histological examinations of iris specimens from human eyes treated with latanoprost have failed to detect a difference from controls by light and elections microscopy (Eisenberg and Camras 1999). Latanoprost induced increased melanogenesis in the iridial melanocytes in 12, 23 and 11% of patients in the USA, United Kingdom (UK) and Scandinavia, respectively, during one year of treatment. The highest incidence of induced pigmentation was seen in green-brown, yellow-brown and blue/grey-brown eyes, in that order. The relatively high

24/30 proportion of patients with green-brown eyes in the UK explains the larger number of affected patients in this country. Typically, a concentric increase of the iris pigmentation appeared after six months (range: 3-17) and was judged to be noticeable by the patient in about 2/3 of the cases. Irides, homogeneously blue, grey, green or brown, were seldom affected. Naevi or freckles on iris, conjunctiva, or eye lids were not affected. It is intriguing that many patients with mixed eye colour, particularly the blue-brown eyes, have not developed increased pigmentation even during two years of treatment (Wistrand et al 1997). This could be due to a relatively slow melanogenesis or to refractory melanocytes in these individuals (Wistrand et al 1997, Grierson et al 1999). Darkening of the irises was not seen in one report of 317 Japanese patients with glaucoma and predominantly brown eyes who received latanoprost for approximately 4 months (Demitsu et al 2001). However, it has been observed in many other randomized studies, as well as reported in several case reports. Pfeiffer et al (2001) determined whether 3 months of topical latanoprost treatment caused proliferative or degenerative effects on the peripheral iris of patients with glaucoma. Seventeen patients requiring filtering surgery for primary open-angle glaucoma or pseudoexfoliation glaucoma were randomized to receive topical latanoprost for 3 months (n = 8) or alternative medication (n = 9) before surgery. A trabeculectomy and a peripheral iridectomy specimen were obtained from each patient during surgery. The tissue was subjected to histological and immunohistochemical evaluation using 2 cell cycle markers: proliferating cell nuclear antigen and nuclear-associated protein (Ki-67). The authors concluded that short-term treatment with latanoprost does not produce morphological changes or cellular proliferation changes in the iris (Pfeiffer et al 2001). Albert et al (2004) examined the histopathologic features of iridectomy specimens from patients undergoing glaucoma surgery and to compare histologic abnormalities in a group of patients with a history of latanoprost therapy with those in a group of patients who had no history of prostaglandin therapy (controls). Iridectomy specimens and patient history forms were submitted to the central Latanoprost Pathology Center. These were independently examined by 3 ophthalmic pathologists in a masked fashion. Specimens were evaluated for malignant, premalignant, and other changes including differences in levels of pigmentation, degrees of cellularity, inflammation, vascular abnormalities, and changes in the iris pigment epithelium. Specimens were received from 449 patients with a history of latanoprost treatment and 142 patients who had no history of treatment with latanoprost or other prostaglandin analogues. The authors concluded that latanoprost-induced eye color changes are due to an increased amount of melanin within the iris stromal melanocytes. The increased numbers of freckles may be a focal manifestation of this effect (Albert et al 2004). Arranz-Marquez et al (2004) conducted a prospective, observer-masked study on 14 eyes treated with latanoprost and 8 untreated control eyes to assess the histologic aspects of irises subjected to extended latanoprost treatment. Iris biopsies of eyes treated with latanoprost were analyzed (all had a photographically documented increase in iris pigmentation) plus control eyes (untreated with prostanoids) using optical microscopy. The main outcome measure was the morphologic characteristics of the irises. The authors concluded that chronic therapy with latanoprost appears to induce more changes in the iris than a simple increase in the melanin content of the melanocytes (Arranz-Marquez et al 2004). Hara (2001) evaluated the incidence of the increased iris pigmentation in Japanese with topical latanoprost. One hundred and twelve patients who had homogeneous brown irises were studied. Age of the patients was 23 to 80(average 63.8 ± 10.4) and follow-up periods were 6 to 12 (10.3 ± 1.4) months. Slit lamp examination was carefully performed before use and at every month after use of latanoprost. Photographs were taken when necessary. The Kaplan-Meier life table method was used to evaluate the incidence of the increased iris pigmentation. According to the results of the study, iris pigment increase was observed in 47 patients. The incidence of the increased iris pigmentation was calculated as 10.1% at 3 months, 26.4% at 6 months, 50.1% at 9 months and 51.6% at 12 months after use. Pigmentation progressed as a granular concentric or sunrise pattern or a subtype of these. Some pigmentation occurred at one month after use, and progressed monthly. No patients noted their own iris colour change, but were told by their relatives. Iris colour changes of brown iris were considered to be less strong than in the hazel (green or blue/gray or yellow combined with brown) eye (Hara 2001). Chiba et al (2001) investigated the incidence of iridial pigmentation induced by latanoprost ophthalmic solution in Japanese glaucoma patients by a prospective and observer-masked study. Sixty-nine eyes of 69 glaucoma patients were included. Patients who had undergone intraocular surgery, laser trabeculoplasty, and laser iridotomy within 12 months before enrollment, and patients with history of uveitis and any changes in antiglaucoma drugs within 6 months before enrollment were excluded. Iridial photographs were taken by one examiner under the same conditions at 1, 3, and 6 months after the initiation of latanoprost treatment. Three glaucoma specialists, masked of patient information,

25/30 independently assessed the iridial pigmentation. Cases with iridial pigmentation diagnosed by three specialists were categorized as showing a definite increase in iridial pigmentation. The authors concluded that the incidence of iridial pigmentation by latanoprost ophthalmic solution in Japanese patients was higher than previously reported values in pigmented races (Chiba et al 2001). The same authors, more recently (2004) conducted a 12-month prospective study on the occurrence of latanoprost-induced iridial pigmentation and eyelash change in Japanese patients with glaucoma. Seventy-five patients (75 eyes) were enrolled in the study. Photographs of the iris and eyelashes were taken under identical conditions before and after treatment. Three glaucoma specialists assessed the iridial pigmentation/eyelash change independently with no knowledge of patient data. The effects of age, sex, concomitant medication, and type of glaucoma on iridial pigmentation/eyelash change were investigated, and intraocular pressure reduction and iridocorneal angle pigmentation before and after latanoprost treatment were compared between patients with iridial pigmentation/eyelash change and patients without these changes. The authors concluded that iridial pigmentation and eyelash change occurred at a high frequency in long-term treatment with latanoprost in Japanese glaucoma patients (Chiba et al 2004). Latanoprost-Induced Iris Pigmentation Study Group (2006) performed a cohort study to prospectively determine the incidence of a latanoprost-induced increase in iris pigmentation in Japanese brown iris eyes by identifying changes in iris pigmentation on a series of iris color photographs. 104 patients (104 eyes) with primary open-angle glaucoma or normal-tension glaucoma who began treatment with latanoprost eye drops for the first time were prospectively and consecutively enrolled. None of the enrolled patients had a history of previous intraocular surgery or laser surgery. The authors concluded that latanoprost instillation for at least 1 year induced increased iris pigmentation in approximately 50% of the treated Japanese eyes, which is a considerably higher percentage than that reported in Caucasians (Latanoprost-Induced Iris Pigmentation Study Group 2006). After cessation of latanoprost, no change of the induced pigmentation has been seen in patients followed for two years, and there have been no signs of dispersion of pigment into the anterior chamber (Wistrand et al 1997). Camras et al (2000) determined the effect on iris colour of discontinuing latanoprost treatment in a patient with pronounced iris colour darkening, and to assess the possible role of sympathetic innervation. In a patient demonstrating pronounced iris colour darkening in both eyes after treatment with latanoprost for 6 months, magnified iris colour photographs were taken at 3- to 6-month intervals for 5 years after discontinuation of latanoprost treatment. Pupillary testing for sympathetic insufficiency was performed with cocaine 10% or hydroxyamphetamine 1%. The results of the study revealed that the iris colour did not appreciably change after discontinuing latanoprost. The cocaine-induced increase in pupillary diameter was considerably greater for the control subject than for the patient who demonstrated the latanoprost- induced colour change. The authors concluded that latanoprost-induced iris colour darkening does not appreciably change for several years after discontinuing treatment. Some eyes that show latanoprost- induced darkening may have relative ocular sympathetic insufficiency (Camras et al 2000).

Review Stjernschantz et al (2002) surveyed the available preclinical and clinical data on prostaglandin-induced iris pigmentation and assessed the phenomenon from a clinical perspective. Most of the data have been obtained with latanoprost, and it appears that there is a predisposition to latanoprost-induced iris pigmentation in individuals with hazel or heterochromic eye colour. As latanoprost and travoprost are selective agonists for the prostaglandin F(2alpha) receptor, it is likely that the phenomenon is mediated by this receptor. Several studies indicate that latanoprost stimulates melanogenesis in iridial melanocytes, and transcription of the tyrosinase gene is upregulated. The safety aspects of latanoprost- induced iris pigmentation have been addressed in histopathologic studies, and no evidence of harmful consequences of the side effect has been found. Although a final assessment of the clinical significance of prostaglandin-induced iris pigmentation currently is impossible to make, it appears that the only clear-cut disadvantage is a potential heterochromia between the eyes in unilaterally treated patients because the heterochromia is likely to be permanent, or very slowly reversible (Stjernschantz et al 2002).

Hypertrichosis and hyperpigmentation of the eyelashes

26/30 Contradictory reports have previously been published concerning the hypertrichotic effect of prostaglandins. However, latanoprost exerts a hypertrichotic effect at least on the eye lashes, and this phenomenon is relatively consistent. Stjernschantz (2001) studied the receptor pharmacology of the hypertrichotic effect of prostaglandins using a mouse model in which the fur is shaved and the regrowth of the fur during local treatment with selective prostanoid receptor agonists is studied. The hypertrichotic effect seems to be mediated primarily by the FP receptor. However, at the cellular level the mechanism in the hair follicle remains unknown and a proliferative effect of latanoprost on fibroblasts or keratinocytes for example has not been found. A possibility is that latanoprost activates follicular melanocytes, which in turn regulate the proliferation of keratinocytes in the hair follicle (Stjernschantz 2001). There has been a case report (Wand 1997) and a case series report (Johnstone 1997) noting an increase in both number of lashes and pigmentation of the lashes in patients treated unilaterally with latanoprost. This had been noted in only 1 of the longer comparison studies of latanoprost versus timolol (Alm et al 1995a) and was not reported in the others (Camras et al 1996b, Watson et al 1996). Elgin et al (2006) compared the eyelash lengthening effect of latanoprost in adults and children with glaucoma. Twenty eyes of 13 men and 7 women (mean age: 54.9, range 42-69 years) with primary open-angle glaucoma and 20 eyes of 9 boys and 11 girls (mean age: 10.7, range 6- 16 years) with glaucoma were included in this prospective study. The authors concluded that the differences in mean eyelash lengths at baseline and at the sixth month of latanoprost therapy were statistically significant in both adults and children (p=0.000). The mean of the difference of the eyelash length in children was higher than in adults but the result was not statistically significant (p=0.678) (Elgin et al 2006).

Review Johnstone and Albert (2002) reviewed prostaglandin-induced hair growth. The results of this analysis demonstrated that latanoprost, used clinically in the treatment of glaucoma, induces growth of lashes and ancillary hairs around the eyelids. Manifestations include greater thickness and length of lashes, additional lash rows, conversion of vellus to terminal hairs in canthal areas as well as in regions adjacent to lash rows. In conjunction with increased growth, increased pigmentation occurs. Vellus hairs of the lower eyelids also undergo increased growth and pigmentation. Brief latanoprost therapy for 2-17 days (3-25.5 microg total dosage) induced findings comparable to chronic therapy in five patients. Latanoprost reversed alopecia of the eyelashes in one patient. Correlation with laboratory studies suggests that initiation and completion of latanoprost hair growth effects occur very early in anagen and the likely target is the dermal papilla (Johnstone and Albert 2002).

Cystoid macular oedema and uveitis There are several reports of cystoid macular oedema or iritis temporally associated with latanoprost use, most involving eyes that have undergone incisional surgery and/or have other risk factors for inflammation (Rowe et al 1997, Gaddie and Bennett 1998, Wardrop and Wishart 1998, Avakian et al 1998, Ayyala et al 1998, Callanan et al 1998, Fechtner et al 1998, Heier et al 1998, Reis et al 1998, Lima et al 2000, Tokunaga et al 2002, Jager and Jonas 2003, Watanabe et al 2003). A retrospective, uncontrolled case series found prevalences of cystoid macular oedema and anterior uveitis of 2 and 6%, respectively, in 94 patients during an 11-month period (Warwar et al 1998). This degree of cystoid macular oedema and uveitis was not seen in the primary long term studies (Alm et al 1995a, Camras et al 1996a and b, Watson et al 1996, Camras et al 1998) or in 63 patients receiving latanoprost followed for 2 years (Watson et al 1998). After extended use for 6 to 12 months, no change in aqueous flare, as determined by a sensitive laser flare-cell metre, was found upon discontinuation of latanoprost use. The authors concluded that this result demonstrated a lack of alteration of the blood-aqueous barrier (Linden et al 1997). A study specifically designed to address postoperative inflammation and angiographic cystoid macular oedema found statistically more flare by laser flare cell metre and more perifoveal leakage by fluoroscein angiography at several time-points post cataract surgery in the groups using fluorometholone with or without latanoprost (Miyake et al 1999). Moroi et al (1999) performed a retrospective observational case series to identify coexisting ocular diagnoses in a case series of eyes that developed cystoid macular edema associated with latanoprost therapy. Seven eyes of seven patients who developed cystoid macular edema possibly associated with latanoprost treatment were studied. The authors concluded that in this case series of pseudophakic, aphakic, or phakic eyes, the temporal relationships between the use of latanoprost and developing cystoid macular edema, and the resolution of cystoid macular edema following cessation of the drug, suggest an association

27/30 between latanoprost and cystoid macular edema. In all cases, coexisting ocular conditions associated with an altered blood-retinal barrier were present (Moroi et al 1999). Yeh and Ramanathan (2002) evaluated the association between latanoprost and clinically significant cystoid macular edema in patients after uneventful phacoemulsification with intraocular lens implantation. One hundred forty- five consecutive patients (162 eyes) who had phacoemulsification from July 1999 to December 2000 were retrospectively reviewed to determine which patients developed cystoid macular edema. The authors concluded that this retrospective study shows a clinical association between latanoprost use and postoperative cystoid macular edema after uneventful phacoemulsification. Given the absence of other coexisting risk factors for cystoid macular edema, this series suggests latanoprost is a significant etiologic factor for the development of postoperative cystoid macular edema (Yeh and Ramanathan 2002). On the other hand, Furuichi et al (2001) studied prospectively using optical coherence tomography whether topical latanoprost induces retinal disorders, such as cystoid macular edema, in patients with glaucoma and a normally functioning blood-ocular barrier. Sixty-eight eyes of 38 patients with glaucoma and no history of intraocular surgery, uveitis, or laser trabeculoplasty were studied. The authors concluded that it is unlikely that topical latanoprost induces retinal disorders, such as cystoid macular edema, in glaucomatous eyes with a normally functioning blood-ocular barrier (Furuichi et al 2001). Wand et al (2001) determined the magnitude of the association between latanoprost use and cystoid macular edema in high-risk aphakic or pseudophakic eyes. In a referral glaucoma practice, 40 consecutive patients with glaucoma uncontrolled on maximally tolerated medications without latanoprost were studied. The authors concluded that approximately 5% of high-risk eyes treated with latanoprost developed clinically symptomatic and angiographically documented cystoid macular edema. The temporal relationship between initiation of treatment and the decreased vision in these 2 cases suggests but does not establish a causal relationship between cystoid macular edema and latanoprost (Wand et al 2001).

Multicenter, randomized, double-masked, clinical trials performed in over 1,000 patients have failed to demonstrate a difference in the occurrence of aqueous flare or an anterior chamber cellular response in eyes treated with latanoprost or timolol. Very sensitive techniques used to assess small changes in the blood–aqueous barrier, including fluorophotometry and laser-flare meters, failed to detect an effect of latanoprost in several controlled studies in normotensive volunteers and in glaucoma patients treated for as long as 1 year (Schumer et al 2002). However, reports have described uveitis occurring in eyes treated with latanoprost (Fechtner et al 1998, Warwar et al 1998, Smith et al 1999, Sacca et al 2001). Many of these eyes exhibited a very mild cellular response with minimal evidence for a cause and effect relationship. With few exceptions, eyes were not rechallenged, and none were rechallenged repeatedly with proper controls. Nevertheless, four select patients with predisposing risk factors exhibited a rather compelling history for a causal relationship (Fechtner et al 1998). In a controlled clinical trial, latanoprost applied four times daily for 2 weeks produced transient photophobia, mild flare, and/or a few cells in 15 of 28 volunteers. In general, these symptoms and signs resolved in the first few days of treatment despite continued excessive dosing at four times the daily recommended dose. This study demonstrates that latanoprost applied in excessive doses produces statistically significant, low grade, transient inflammation in some eyes (Linden and Alm 2001). It must be noted that the results from two clinical trials reviewed by Miyake and Ibaraki (2002) suggest that the preservative rather than the active ingredient (prostaglandins) is the causative factor for cystoid macular edema (Miyake and Ibaraki 2002).

Herpes simplex keratitis reactivation Three reports describe five patients who purportedly developed reactivation of herpes simplex keratitis when treated with latanoprost (Wand et al 1999, Dios-Castro and Maquet-Dusart 2000, Ekatomatis 2001). In general, these patients had a history of previous episodes of herpes simplex keratitis, viral cultures were not obtained to confirm the diagnoses, and the eyes were not rechallenged. Pseudodendrites, which may be mistaken for herpes simplex keratitis, have been reported with the use of latanoprost, beta-blockers, anti-virals, contact lens solutions, and other topically applied medications. Other medications used in glaucoma therapy, including beta-blockers and epinephrine, have been reported to reactivate herpes simplex keratitis (Schumer et al 2002). Herpetic dermatitis of the periocular skin purportedly developed in two patients treated with latanoprost (Morales et al 2001). However, the patients were not rechallenged to establish a causal relationship (Schumer et al 2002).

28/30 Corneal effects Lass et al (2001) performed a double-masked, randomized, prospective, multicenter clinical trial to compare the long-term effects on corneal endothelial cell density and corneal thickness of latanoprost and the fixed combination latanoprost-timolol to timolol. Three hundred sixty-nine subjects with bilateral ocular hypertension or open-angle glaucoma who had a baseline central corneal endothelial cell density of at least 1500 cells/mm(2), central corneal thickness of less than 0.68 mm, no corneal pathologic condition on slit-lamp examination, and intraocular pressure of less than 22 mmHg after a 3-week run-in on timolol, 0.5%, once daily were included. Subjects were randomly assigned to treatment with latanoprost 0.005% (n = 127), fixed-combination latanoprost 0.005%-timolol 0.5% (n = 116), or timolol 0.5% (n = 126) one drop, once daily in the morning for 1 year. All subjects were treated in both eyes. Specular microscopy and ultrasonic pachymetry were performed before treatment, and after 6 and 12 months of treatment. The main outcome measure was mean percent change in central endothelial cell density and central corneal thickness after 1 year of treatment. The authors concluded that latanoprost and fixed combination latanoprost-timolol are equivalent to timolol regarding long-term corneal effects after 1 year of treatment (Lass et al 2001). Marchini et al (2003) performed a prospective, controlled, open trial to assess the effects of 0.005% latanoprost on the anterior segment geometry and ciliary body thickness using ultrasound biomicroscopy. Intraocular pressure, refraction, visual acuity, and pupil size were also evaluated. Thirty patients with untreated ocular hypertension or primary open-angle glaucoma (mean age: 59.3 +/- 9.9 years) were recruited. The authors concluded that the increase of ciliary body thickness, which was measured in vivo by ultrasound biomicroscopy and associated with the intraocular pressure-lowering effect, indirectly supports the mechanism of uveoscleral outflow enhancement induced by latanoprost. These data are in agreement with the biochemical hypothesis of the passage of the aqueous flow through the extracellular spaces of the ciliary muscle (Marchini et al 2003).

Other ocular adverse events A low frequency of adverse effects such as tearing, itching, burning, punctate epitheliopathy and headache have been reported in multiple studies. It is not clear whether these adverse effects are due to latanoprost, the vehicle (benzalkonium chloride) or chance. Large masked studies comparing timolol and latanoprost found an equal occurrence of these adverse effects in each group (Eisenberg and Camras 1999). The following other ocular adverse effects have also been associated with latanoprost use: bilateral optic disc oedema (Stewart et al 1999, Aslanides 2000). blurred vision and trichomegaly (Woo and Franzco 2001). choroidal detachment (Marques-Pereira and Katz 2001). choroidal effusion (Sakai et al 2002, Alimgil and Benian 2002). allergic contact dermatitis (Jerstad and Warshaw 2002, Lai et al 2006). iris cyst development simulating an iris melanoma (Sodhi 2003, Browning et al 2003, Lai et al 2003). corneal neovascularization (Orhan et al 2003). bullous keratopathy after argon laser iridotomy (Takahashi et al 2003). lash ptosis (Casson and Selva 2005).

Systemic adverse effects There have been 14 reports of latanoprost-induced hypertension, 12 reports of edema (peripheral and facial), 5 reports of dyspnea, 6 reports of asthma exacerbation, 4 reports of tachycardia, 7 reports of chest pain/angina pectoris, 1 reported myocardial infarction, and 2 reported cerebral vascular accidents (Peak and Sutton 1998).

Other systemic adverse effects The following other systemic adverse effects have also been associated with latanoprost use: exacerbation of angina (Mitra et al 2001). toxic epidermal necrolysis (Florez et al 2005).

OVERDOSAGE

29/30 Apart from ocular irritation and conjunctival or episcleral hyperemia, the ocular effects of latanoprost administered at high doses are not known. Intravenous administration of large doses of latanoprost in monkeys has been associated with transient bronchoconstriction; however, in 11 patients with bronchial asthma treated with latanoprost, bronchoconstriction was not induced. Intravenous infusion of up to 3 ìg/kg in healthy volunteers produced mean plasma concentrations 200 times higher than during clinical treatment and no adverse reactions were observed. Intravenous dosages of 5.5 to 10 ìg/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea and sweating (PDR 2003). If latanoprost is accidentally ingested the following information may be useful: one bottle contains 125 micrograms latanoprost. More than 90% is metabolised during the first pass through the liver. Intravenous infusion of 3 micrograms/kg in healthy volunteers induced no symptoms, but a dose of 5.5-10 micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. In monkeys, latanoprost has been infused intravenously in doses up to 500 micrograms/kg without major effects on the cardiovascular system. If overdosage with latanoprost occurs, treatment should be symptomatic (Medicines Compendium 2006).

Pharmacovigilance system The AR of the PhV-System is submitted.

BENEFIT RISK ASSESSMENT The benefit-risk-relation is considered positive. Approval is recommended.

PACKAGE LEAFLET (PL)/ASSESSMENT OF USER TESTING This readability test was carried out in order to fulfil the legal requirements of EU legislation Article 59 (3) and 61 (1) of Directive 2001/83 as amended by Directive 2004/27/EC which states that consultation with target groups is necessary to ensure that the package leaflet of a medicinal product is legible, clear and easy to use. The User Test was commissioned by (The Sponsor). The test was carried out by (The Tester). The Package Leaflet (PL) tested in the User test report refers to the medicinal product Latanoprost Malcosa, eye drops 50 microgram/ml. The questions were designed to cover the parts of the leaflet where a clear understanding by the patient is necessary in order for the patient to take the medication correctly and safely. The questions were balanced between general and product specific issues. The number of general questions was one and the number of specific questions was twenty. Questions have been classed as important/less important. The number of less important questions was two and the number of important questions was nineteen.

Results

Understanding: 100% of the test questions were dealt with successfully with no difficulty understanding. Locating: 97.5% of the test questions were dealt with successfully with no difficulty in locating the information. For 2.5% of the test questions, slight difficulty was experienced locating the information.

Conclusion The criterion for a successful test was fulfilled (>90%) and therefore the test was deemed to be successful. The test scored extremely well therefore no suggestions for improvement are necessary.

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