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   Table of Contents      
ORIGINAL ARTICLE
Year : 2007  |  Volume : 55  |  Issue : 2  |  Page : 127-131

A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan® in comparison with generic Latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension


1 Medical Research Foundation, Sankara Nethralaya, Chennai, India
2 Medical Research Division, Pfizer Ltd., Mumbai, India

Date of Submission17-May-2006
Date of Acceptance07-Dec-2006

Correspondence Address:
Arun Narayanaswamy
Glaucoma Services, Sankara Nethralaya, Medical Research Foundation, 18, College Road, Chennai - 600 006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0301-4738.30707

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  Abstract 

Aim: To compare the efficacy and tolerability of Xalatan® with generic latanoprost (Latoprost) in subjects with primary open angle glaucoma (POAG) or ocular hypertension (OH).
Materials and Methods:
This was a single-center, randomized, open label, crossover, two period comparative study. At the baseline visit, subjects were randomized to two groups. Group A received Xalatan® for weeks 1-12 followed by Latoprost for weeks 13-24. Group B received Latoprost for weeks 1-12 followed by Xalatan® for weeks 13-24.
Results: 30 subjects were recruited, 12 in Group A and 18 in Group B. In subjects administered Xalatan®, intraocular pressure (IOP) showed a greater decrease ( P <0.001) from 23.64 ± 3.13 mmHg at baseline to 14.29 ± 1.61 mmHg at week 12 (fall of 9.35 ± 3.55 mmHg, 38.66% ± 10.29) than that seen in the Latoprost group (22.74 ± 2.47 mmHg to 16.98 ± 2.49 mmHg, fall of 5.76 ± 1.41 mmHg; 25.42% ± 5.98). In period 2 when subjects were crossed over to Xalatan® from Latoprost, there was a further fall from 16.98 ± 2.49 mmHg to 16.09 ± 1.49 at week 24 (fall of 0.89 ± 1.59 mmHg; 4.3% ± 8.76). However, when subjects were crossed over to Latoprost from Xalatan®, the IOP rose from 14.29 ± 1.61 mmHg to 15.36 ± 1.71 mmHg at week 24 (8.86% ± 17.76). There was no significant difference in incidence of conjunctival hyperemia or any other adverse events in both the groups.
Conclusion: The magnitude of IOP lowering in patients with POAG and OH with Xalatan® and Latoprost is different. In our study, the IOP lowering with Xalatan® was higher than that with Latoprost.

Keywords: Intraocular pressure, Latoprost, ocular hypertension, primary open angle glaucoma, Xalatan ®


How to cite this article:
Narayanaswamy A, Neog A, Baskaran M, George R, Lingam V, Desai C, Rajadhyaksha V. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan® in comparison with generic Latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension. Indian J Ophthalmol 2007;55:127-31

How to cite this URL:
Narayanaswamy A, Neog A, Baskaran M, George R, Lingam V, Desai C, Rajadhyaksha V. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan® in comparison with generic Latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension. Indian J Ophthalmol [serial online] 2007 [cited 2019 May 23];55:127-31. Available from: http://www.ijo.in/text.asp?2007/55/2/127/30707

Summary of ophthalmic adverse events

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Summary of ophthalmic adverse events

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Summary of intraocular pressure (in mm Hg) of
study eye(s) at week 12


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Summary of intraocular pressure (in mm Hg) of
study eye(s) at week 12


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Summary of intraocular pressure level at visit 4
(week 12) and end of treatment visit (week 24)


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Summary of intraocular pressure level at visit 4
(week 12) and end of treatment visit (week 24)


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Demographic characteristics

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Demographic characteristics

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Several recent studies have reported the value of reducing intraocular pressure (IOP) as treatment for primary open angle glaucoma (POAG).[1],[2] Currently there are five major classes of medications that are used to lower the IOP: beta adrenergic antagonists, adrenergic agonists, parasympathomimetics, prostaglandin analogues, and carbonic anhydrase inhibitors.[1],[2],[3],[4],[5]

Prostaglandin analogues are fast becoming the mainstay of therapy for subjects with glaucoma.[4] Latanoprost, the first prostaglandin to become commercially available, offers certain advantages over other medications for the treatment of glaucoma or ocular hypertension (OH).[6],[7],[8] Clinical studies have shown that latanoprost reduces IOP by 20-36% with minimal side effects.[9],[10],[11],[12],[13] Xalatan® (latanoprost 50 mg/mL) has been commercially available since 1996 and 1997 in the USA and most European countries, respectively, and is used in around 65 countries worldwide including India.[14] In addition to Xalatan®, generic versions of latanoprost are available in the Indian market. While generic latanoprost may be chemically equivalent to Xalatan®, there is no available information on their therapeutic or clinical equivalence. The aim of this pilot study was to compare the efficacy and tolerability of Xalatan® with generic latanoprost in subjects with POAG or OH.


  Materials and Methods Top


To detect a difference in IOP of 1.5 mm Hg between the changes in IOP from baseline produced by the two treatments, with an alpha of 5% and power of 80% it was calculated to have 64 subjects. The between groups standard deviation was estimated to be 3 mmHg. The study team decided to enroll 30 subjects only for this pilot study.

Inclusion criteria were subjects with 18 years of age or older with unilateral or bilateral POAG or OH and IOP greater than 22 mmHg (9:00 hours ± 1 hour reading). Subjects without previous glaucoma treatment were included in the study, those on treatment with topical beta-antagonists at screening were eligible only after a medication free period (wash out) of at least 21 days prior to baseline.

Exclusion criteria were closed or slit like anterior chamber angle, history of acute angle closure, current use of contact lenses, history of argon laser trabeculoplasty within 3 months prior to screening (the unlasered eye could be enrolled in the study) or of any ocular filtering surgical intervention (the un operated eye could be enrolled in the study), ocular surgery or ocular inflammation/infection in either eye within 3 months prior to screening or best corrected visual acuity £ 20/200.

This was a single-center, prospective, randomized, open label, blinded end point (PROBE) crossover, and two-period comparative study. After obtaining approval from the institutional review board, a signed informed consent was obtained from all subjects before enrollment in the study. The study was performed according to the declaration of Helsinki and the international conference on harmonization of technical requirements for registration of pharmaceuticals for human use good clinical practice guidelines. This study proposed to include 30 subjects (15 subjects in each group). There were six study visits. At the baseline visit, subjects fulfilling eligibility criteria were randomized to group A or group B in a 1:1 ratio using block randomization. Subjects in group A received Xalatan® for weeks 1-12 followed by Latoprost for weeks 13-24 while subjects in group B received Latoprost for weeks 1-12 followed by Xalatan® for weeks 13-24.

The study medication for both groups (provided by Pfizer) was dispensed during visit 1/baseline visit and collected back after, the first treatment period, during visit 4. At Visit 4 (week 12), subjects crossed over to the other arm of the study and received study medication for treatment period 2. An end of treatment (EOT) visit occurred at week 24 ± 7 days where all the study medication for treatment period 2 was collected. Subjects were instructed to instill one drop of study medication in the affected eye(s) every evening at approximately 20:00 hours and to use the dropper bottles within 4 weeks of opening.

IOP was measured with a Goldmann applanation tonometer at specified times. For all patients, at the baseline visit, week 12, and week 24 visit, IOP measurements were taken at 9:00 hours, 13:00 hours, and 17:00 hours. A deviation of (1 hour was accepted. At visits 2, 3, 5, and 6, the IOP measurements were taken at 9:00 hours (21 hour). At each visit, two IOP measurements in each eye, alternating between eyes and starting with the right eye were taken. The mean of the two measurements was used in the statistical analyses. If the difference in the two readings for an eye was more than 2 mmHg, a third reading was taken and an average of the three readings was taken as the reading for that eye. In those subjects where both eyes qualified to be included in the study, the mean IOP of the two eyes was taken for analysis. Post randomization IOP readings were recorded by a masked evaluator who was an independent ophthalmologist blinded to the study treatment. At visit 4 and EOT visit, the date and time of administration of the last eye drop before the visit was recorded.

Slit lamp examinations were performed to examine conjunctiva, palpebra, bulbi, cornea, iris, lens for opacities or other changes, anterior vitreous/vitreous membrane and anterior chamber with special emphasis on cells and flare. Gonioscopy was performed on all subjects. Post-dilatation lens opacities classification system was used to grade lens changes in the lens and a detailed retinal and optic disc examination was performed. The skin and margins of upper and lower lids were examined and best-corrected visual acuity was tested. Automated visual field testing (Humphrey Perimetry, Carl Zeiss Inc. using the Swedish Interactive Threshold Algorithm Program) were performed at the screening visit (gonioscopy and automated visual field testing were not required, if they had been performed within past 12 months and 3 months, respectively), visit 4 and EOT visit. Photographs of the eye(s) were taken at the baseline visit and visits 2, 4, 5, and EOT visit, prior to tonometry and prior to any drops being dispensed in the eye. The study photographs were compared with standard photographs by an independent panel of two ophthalmologists who remained blinded to study treatment and study visits. The standard photographs depicted conjunctival hyperemia of grades 0, 1, 2, and 3 where 0 signified none or trace, 1 mild, 2 moderate, and 3 severe. A scale ranging from 0 to 3 units in 1 unit increment was used to assess ocular hyperemia by comparison of the subject photographs with standard photographs. For subject assessment of hyperemia, at each visit, the subject was asked whether they or anyone else have noticed any redness in their eye(s) since the last visit and if so, to what extent they were bothered by such redness using four possible responses (Not at all, a small amount, a moderate amount, a great amount).

Adverse events were monitored throughout the study. In case of an adverse event the investigator was required to assess the relationship of the study treatment and report the outcome.

Xalatan® marketed by Pfizer Ophthalmics and Latoprost marketed by Sun Pharmaceuticals, India (hereinafter also referred to as generic latanoprost) were used in this study.

The primary efficacy endpoint was the change in IOP from the start to end of each study period and the secondary end point was the percentage change in IOP from start to end of each study period. Efficacy analyses were based on study eye(s). The primary null hypothesis was that the mean change in IOP from the start to end of each treatment period for both the drugs was equal. Unpaired t- test was used for differences between two groups while paired t- test was used to detect amongst group differences. For nominal data, Chi square test was used. The mixed effects model used change/percent change in IOP for both periods as responses with sequence, period, and treatment considered fixed effects and subject within sequence considered a random effect and baseline IOP as a covariate. Estimates of adjusted mean differences (Test-Reference) and corresponding 95% CIs were estimated from this model. A P value of < 0.05 was considered as significant.


  Results Top


About 41 subjects were screened in this study. Eleven subjects were excluded and 30 were assigned to study treatment. Twelve subjects were recruited in group A and 18 in group B. One subject from Group A discontinued from the study due to uncontrollable IOP level in non-study eye. Demographic characteristics are summarised in [Table - 1]. The two treatment sequence groups appeared to be balanced at baseline with respect to sex, race, and age.

[Table - 2][Table - 3] show the mean IOP and number of patients achieving a particular target IOP at various follow-up visits. The IOP levels decreased for all subjects following treatment with study medication in both treatment groups. All subjects in group A had their IOP levels below 18 mm Hg at week 24 while all subjects in group B had their IOP levels below 21 mm Hg at week 24.

At the start of period 1, the mean baseline IOP was 23.64 ± 3.13 mm Hg in group A and 22.74 ± 2.57 mm Hg in group B. There was no statistically significant difference between these values ( P = 0.399).

At the end of period 1 (day 0 to week 12), the IOP level fell from 23.64 ± 3.13 mm Hg to 14.29 ± 1.61 mm Hg (fall of 9.35 ± 3.55 mm Hg, % change 38.66 ± 10.29) in group A and from 22.74 ± 2.47 mm Hg to 16.98 ± 2.49 mm Hg in group B (fall of 5.76 ± 1.41 mm Hg, reduction of 25.42% ± 5.98). The actual fall and percent reduction in IOP in group A was significantly better than group B ( P <0.001).

In period 2 (week 12 to week 24), when subjects were crossed over to Xalatan® from Latoprost, there was a further fall from 16.98 ± 2.49 mm Hg to 16.09 ± 1.49 mm Hg at week 24 (fall of 0.89 ± 1.59 mm Hg, 4.3% ± 8.76). On the other hand, when subjects were crossed over to Latoprost from Xalatan®, the IOP rose from 14.29 ± 1.61 mm Hg to 15.36 ± 1.71 mm Hg at week 24 (rise of 1.08 ± 2.59 mm Hg, 8.86% ± 17.76). The actual change ( P = 0.017) from week 12 to week 24 (EOT visit) and the percentage change ( P = 0.013) were statistically significant. The difference in IOP at the end of period 2 between the two groups was not statistically significant ( P = 0.236).

In group A, 9 subjects (out of 11) had >30 % decrease in their IOP levels at week 12 following administration of Xalatan®. In comparison, only three subjects (out of 18) in group B had their IOP level lowered by >30 % following administration of Latoprost. Four subjects (out of 11) in group A had >40% decrease in IOP level following administration of Xalatan® while no subjects in group B had >40% decrease in the IOP level at visit 4 (week 12). After crossing over to Latoprost in group A, 8 subjects (out of 11) had <0% reduction in IOP levels (i.e., had an increase in IOP) while 12 (out of 18) subjects after being crossed over to Xalatan® in group B had <25% reduction in IOP level at week 24 (EOT Visit). No person in this group reported an increase in IOP after being transferred to Xalatan®. The percentage reduction in IOP is summarized in [Figure - 1].

Eight ophthalmic adverse events were reported at the end of week 12 by subjects receiving Xalatan® in group A and 16 ophthalmic adverse events were reported by subjects receiving Latoprost. When subjects were crossed over to Latoprost in group A, a further 11 adverse events were reported at the end of week 24 whereas when subjects were crossed over to Xalatan® in group B, 6 adverse events were reported. The ophthalmic adverse events are summarized in [Table - 4].

At the end of week 12 among those receiving Xalatan® (group A) no subjects complained of ocular irritation while five out of 18 subjects receiving Latoprost (group B) reported ocular irritation ( P =0.15). When the subjects were crossed over to Latoprost in group A, two incidences of irritation were reported whereas when subjects were crossed over to Xalatan® from Latoprost, one incidence of irritation was reported which was not considered treatment-related by the investigator. The incidence of conjunctival hyperemia based on photographs as assessed by independent ophthalmologists was similar in both treatment groups. No other significant ocular complaints were reported from either group.


  Discussion Top


Previous studies have shown that in subjects with OH or open-angle glaucoma, a single drop of Xalatan® 0.005% solution administered topically once daily reduced diurnal IOP by 22-39% over 1-12 months' treatment in well-controlled trials.[9],[10],[11],[12],[13] Efficacy was maintained during treatment periods of up to 2 years.

Our study showed that treatment with Xalatan® reduced the IOP by > 35% at the end of visit 4, which was maintained till EOT visit. Findings in our study are consistent with those of a recent study carried out in India, which showed similar results with 35% reduction in IOP amongst subjects who completed the study duration of 12 weeks.[15] In this study, the effect of drug was evident at the first visit and was constant during the study period. It is known that action of latanoprost starts within the first 2 weeks, maximizes within first 6 weeks, and stabilizes thereafter without short or longterm drift.[12]

The high percentage reduction in IOP is also similar to the previous Indian study in which a 25% reduction from baseline was obtained in 83.1%; a 30% reduction in 76.1%.[15]

Our results showed that Xalatan® reduced the IOP significantly more than Latoprost at the end of week 12. An issue of clinical relevance is also the further decrease in IOP when subjects receiving Latoprost were crossed to Xalatan® and increase in IOP when subjects receiving Xalatan® were crossed over to Latoprost.

Latanoprost is generally well tolerated and induces minimal systemic adverse events. In well controlled, 6-month trials, the most commonly occurring drug-related ocular events in latanoprost recipients were mild to moderate conjunctival hyperemia.[13] Similar results were obtained in this study. There were three incidences of conjunctival hyperemia in both groups at the end of week 12.

Chemical analysis of samples has revealed that as compared to Xalatan®, Latoprost has higher levels of particulate matter, which could potentially cause greater ocular irritation.[15] Since latanoprost is a prodrug, the higher pH of Latoprost could also potentially affect stability as well as release of active drug in the eye. This may possibly explain the higher incidence of ocular irritation seen in the group receiving generic latanoprost as compared to the group receiving Xalatan®.

Concerns about ophthalmic agents not being therapeutically equivalent have been raised in the past. Weir et al . have reported that three of the five brands of generic Ciprofloxacin eye drops that they tested had a significant proportion of sub-optimal drug concentration.[16] Cantor has raised concerns about use of generic antiglaucoma medications compared to clinically evaluated branded drugs.[17] Studies in the past have demonstrated inequivalence of the generic drug with the branded prednisolone,[18] diclofenac sodium ophthalmic solution and ketorolac.[19],[20] Use of generic diclofenac was associated with high incidence of corneal melting and superficial punctate keratopathy.[20] Similar concerns have been raised with use of generic versions of timolol gel forming solution.[20] Retention time on the ocular surface, inactive ingredients and preservative concentrations differed between the branded and generic version of timolol gel forming solution.[20] On the basis of this, it has been proposed that other considerations such as particle size and other properties of a suspension must be evaluated with respect to generic equivalence.[20]

Our study substantiates these findings. On one hand, we found generic latanoprost to be not as effective as Xalatan® in lowering IOP. On the other hand, adverse events in patients receiving the generic formulation were more that those receiving Xalatan® though it did not reach statistical significance. Since the pathophysiology of glaucoma is quite complex and bioavailability of a drug may be altered due to pH, excipients, vehicle and other constituents of the generic product, substitution of a patient well controlled on Xalatan® to other generic drugs should be evaluated with great caution.

The unequal numbers of subjects in the two groups is the limitation of the study, which arose mainly because of block randomization. However any bias/difference was probably offset by the crossover design of the study. Since there was no washout period limited inferences could be drawn on the safety and tolerability especially in the second phase. While the study had adequate power to detect the difference of 1.5 mm Hg in IOP between the two groups, it was not powered enough to detect a significant difference in safety.

Our results cannot be attributed to bias. The baseline characteristics of both groups were similar. Although the study was not blinded, it was observer masked and hence, evaluators of IOP did not know the exact group to which patients may have been randomized to, reducing any chance of bias.

While we can make some conclusions on one generic version of latanoprost used in the study, we are not in a position to comment on other generic versions available in Indian market at this stage.


  Conclusion Top


Xalatan® lowers IOP significantly more than generic latanoprost with low incidence of conjunctival hyperemia and ocular irritation. Chemical equivalence may not necessarily translate into clinical/therapeutic equivalence and would need to be kept in mind before deciding on the desired therapeutic agent.


  Acknowledgement Top


Pfizer Ltd., Mumbai provided financial assistance to the study.

 
  References Top

1.
Magnitude and causes of visual impairment. Fact sheet no. 282, November 2004. [cited on 2006 Feb 8]. Available from: http://www.who.int/mediacentre/factsheets/fs282/en/.  Back to cited text no. 1
    
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Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M, et al . Reduction of intraocular pressure and glaucoma progression: Results from the early manifest glaucoma trial . Arch Ophthalmol 2002;120:1268-79.  Back to cited text no. 2
    
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The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators. Am J Opthalmol 2000;130:429-40.  Back to cited text no. 3
    
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Medeiros FA, Weinreb RN. Medical backgrounders: Glaucoma. Drugs Today 2002;38:563-70.  Back to cited text no. 4
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Fechtner RD. Glaucoma therapeutics. ANZ Glaucoma Club 2003. p. 6-9.  Back to cited text no. 5
    
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Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a new prostaglandin F2a analogue on aqueous humour dynamics in human eyes. Ophthalmology 1993;100:1297-304.  Back to cited text no. 6
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Ziai N, Dolan JW, Kacere RD, Brubaker RF. The effects on aqueous dynamics of PhXA41, a new prostaglandin F2 alpha analogue, after topical application in normal and ocular hypertensive human eyes. Arch Ophthalmol 1993;111:1351-8.  Back to cited text no. 7
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Hylton C, Robin AL. Update on prostaglandin analogues. Curr Opin Ophthalmol 2003;14:65-9.  Back to cited text no. 8
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Villumsen J, Alm A. PhXA34-a prostaglandin F2 alpha analogue. Effect on intraocular pressure in patients with ocular hypertension. Br J Ophthalmol 1992;76:214-7.  Back to cited text no. 9
    
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Camras CB, Schumer RA, Marks A, Lustgarten JS, Serle JB, Stjernschantz J, et al. Intraocular pressure reduction with Ph XA34, a new prostaglandin analogue in patients with ocular hypertension. Arch Ophthalmol 1992;110:1733-8.  Back to cited text no. 10
    
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Stjernschantz J, Alm A. Latanoprost as a new horizon in the medical management of glaucoma. Curr Opin Ophthalmol 1996;7:11-7.  Back to cited text no. 11
[PUBMED]    
12.
Camras CB. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: A six-month masked, multicenter trial in the United States. The United States Latanoprost Study Group. Ophthalmology 1996;103:138-47.  Back to cited text no. 12
    
13.
Watson PG. Latanoprost. Two years' experience of its use in the United Kingdom. Latanoprost Study Group. Ophthalmology 1998;105:82-7.  Back to cited text no. 13
    
14.
Data on File, Pfizer Ltd., India.   Back to cited text no. 14
    
15.
Thomas R, Parikh R, Sood D, Vijaya L, Chandra S, Sood N, et al . Efficacy and safety of latanoprost for Glaucoma treatment: A three month multicentric study in India. Indian J Ophthalmol 2005;53:23-30.  Back to cited text no. 15
    
16.
Weir RE, Zaidi FH, Charteris DG, Bunce C, Soltani M, Lovering AM. Variability in the content of Indian generic ciprofloxacin eye drops. Br J Ophthalmol 2005;89:1094-6.  Back to cited text no. 16
    
17.
Canter LB. Ophthalmic generic drug approval process: Implications for efficacy and safety . J Glaucoma 1997;6:344-9.  Back to cited text no. 17
    
18.
Fiscella RG, Jensen M, Van Dyck G. Prednisolone suspension substitution. Arch Ophthalmol 1998;116:703.  Back to cited text no. 18
    
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Garbe D. True extent of NSAID problems now becoming clearer. Ocul Surg News 2000;2:43-4.  Back to cited text no. 19
    
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Fiscella RG, Gaynes BI, Jensen M. Equivalence of generic and brand name ophthalmic products. Am J Health System 2001;58:616-7.  Back to cited text no. 20
    


    Figures

  [Figure - 1]
 
 
    Tables

  [Table - 1], [Table - 2], [Table - 3], [Table - 4]


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