In partnership with the

Evaluation of Generic versus Original

Prostaglandin Analogues in the Treatment
of Glaucoma
A Systematic Review and Meta-Analysis
Alvilda T. Steensberg, MBBS,1 Olivia O. Müllertz, BSc Pharm,1 Gianni Virgili, MD,2
Augusto Azuara-Blanco, MD, PhD,3 Miriam Kolko, MD, PhD1,4

Topic: An evaluation of the efficacy and tolerability of generic prostaglandin analogues (PGAs) compared
with their original counterpart.
Clinical Relevance: This systematic review was initiated to enlighten ophthalmologists and patients in the
use of original and generic ophthalmic solutions.
Methods: A literature search was conducted on PubMed, EMBASE, MEDLINE, Clinicaltrials.gov, and the
World Health Organization International Clinical Trials Registry Platform, along with a manual search, from the
marketing of the first PGA, latanoprost, in 1995 to the present. Randomized controlled trials comparing an original
PGA with its generic counterpart were included. The last literature search was conducted in June 2019. Risk of
bias was assessed by 2 independent reviewers using the Cochrane Handbook for Systematic Reviews Tool. The
primary outcome was reduction of intraocular pressure (IOP) from baseline. Secondary outcomes included
tolerability, ocular surface health, quality of life, disease progression, and cost-effectiveness. Meta-analysis of the
primary outcome was planned.
Results: Of 385 screened articles, 6 were included in a broad characterization and in the meta-analysis. A
total of 619 patients were enrolled. The duration of the studies ranged from 3 to 16 weeks. Meta-analysis of all 6
studies denied any clinically significant difference in efficacy, and the 95% confidence interval included nil (
0.50
to 0.04 mmHg). The evidence was of moderate certainty because of unclear or high risk of bias in all studies.
There were no reported differences in tolerability.
Conclusions: Trials comparing original and generic PGAs did not show a clinically significant difference in
IOP-lowering effect or tolerability. However, the quality of the trials is suboptimal. Overall, there is uncertainty, and
further research is needed to confirm equivalence. Ophthalmology Glaucoma 2020;3:51-59 ª 2019 by the
American Academy of Ophthalmology

Supplemental material available at www.ophthalmologyglaucoma.org.

On a global scale, 36 million people are estimated to be
blind, and glaucoma is the second leading cause of irre-
versible vision loss.1,2 No cure exists, but treatments that
lower intraocular pressure (IOP) are known to reduce the
rate of disease progression in most cases.3 The IOP is a
balance between the production of aqueous humor and the
uveoscleral outflow and outflow through the trabecular
meshwork. The most common treatment strategy is
eyedrops that reduce the production of aqueous humor or
increase outflow. Among the existing anti-glaucomatous
eyedrops, the far most frequently used class of topical
glaucomatous drugs, with this effect, are prostaglandin an-
alogues (PGAs). The first PGA used for glaucoma, latano-
prost 0.005%, received approval from the European
Medicines Evaluation Agency and the US Food and Drug
Administration as a first-line drug in patients with
open-angle glaucoma (OAG) or ocular hypertension
(OHT).4 The PGAs latanoprost, travoprost, bimatoprost, and
tafluprost are all used in the treatment of glaucoma, both as
original brand-name drugs and as generic formulaions.5
Generic drugs do not need clinical trials but can be
approved by regulators with the use of bioavailability tests.
The market cost of generic medications is often reduced,
and in some countries the pharmacist is obliged to inform
the patient of the cheapest alternative to the prescribed drug.
In the United Kingdom, generic latanoprost is recommended
as first-line medical treatment for OHT and OAG. An
alternative/generic is valued as having the same active
ingredient, same dose, and same indication as the originally
marketed drug. No claims are made to the excipients in the

 2019 by the American Academy of Ophthalmology https://doi.org/10.1016/j.ogla.2019.10.002 51

Published by Elsevier Inc. ISSN 2589-4196/19
 Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020
eye drop formulation or packaging.6,7 Emerging studies and
case reports have found significant differences in physical
and chemical properties among original PGAs and generic
products.8-10 Because the efficacy and side effects of
eyedrops can be dependent on excipients in the formulation,
pH, buffer capacity, and viscosity, concerns have been
raised on the effectiveness and tolerability of generic
eyedrops.11 This study concerns the effectiveness of original
and generic PGAs when treating patients of all ages
diagnosed with OAG and OHT.
Why Is This Systematic Review Important?
The increasing number of generic eyedrops on the market is
of great socioeconomic relevance. However, patients and
ophthalmologists have raised concern regarding the effec-
tiveness, tolerability, and safety of generic eyedrops. Sparse
information is found in the literature on this matter. The
studies that do exist have not been assessed for bias, and the
results are not clear. To our knowledge, there has not been a
systematic review of the evidence pertaining to the efficacy
of original PGAs compared with its generic counterpart.
Methods
The systematic review protocol was registered at PROSPERO In-
ternational Prospective Register of Systematic Reviews (https://
www.crd.york.ac.uk/prospero, Registration No.
CRD42019125147). This article adheres to the PRISMA state-
ment12 checklist for the preferred reporting of systematic reviews
and meta-analysis.
Eligibility Criteria
This systematic review focused on studies that investigated the
IOP-lowering effect of original PGA and its generic counterparts
when treating individuals of all ages diagnosed with OAG or OHT.
All PGAs in the treatment of OAG and OHT were included. These
are latanoprost, travoprost, bimatoprost, and tafluprost, with no
restriction to the final follow-up time. Nonrandomized studies of
intervention and cost analysis were excluded, and records not
written in Danish, English, or German were also excluded.
Search Method
Three databases (PubMed, EMBASE, and MEDLINE) were
searched for randomized controlled trials (RCTs) from the
marketing of the first PGA (latanoprost) in 1995 to the present
date. The following search terms were used to retrieve relevant
studies: ((glaucoma (Title/Abstract) OR ocular hypertension
(Title/Abstract) OR oht (Title/Abstract)) and generic*). More-
over, clinicaltrials.gov (www.clinicaltrials.gov) and World
Health Organization International Clinical Trials Registry Plat-
form were sought for any ongoing or finalized clinical trials that
have published results. Then, a manual search was performed by
checking the reference lists of the RCTs. For further details
regarding the search strategy, see Supplementary 1 (available at
www.ophthalmologyglaucoma.org).
Two reviewers (ATS and OOM) independently completed the
literature search of all databases and screened references of all
included studies. The main search was conducted in March 2019,
with a follow-up search in June 2019. A flow chart illustrating the
article search process is presented in Figure 1.
52
Study Selection
The abstracts of the records were read by 2 independent review au-
thors (ATS and OOM) and classified as “relevant,” possibly rele-
vant,” or “not relevant.” All relevant or possibly relevant articles
were read full length and further divided into “include” or “exclude.”
After any disagreements, a third author was asked to arbitrate.
Data Collection and Extraction
The following data were extracted from each of the studies: (1) name
of the first author, (2) year of publication, (3) trial design, (4) par-
ticipants, (5) intervention, (6) comparison, (7) outcomes (described
later), (8) study setting, and (9) timeframe for follow-up. The primary
outcome was change of IOP from baseline. Secondary outcomes
included patient preference, any measures of quality of life, cost-
effectiveness, and tolerability or side effects, when reported.
Risk of Bias Assessment
The quality of each included RCT was evaluated individually by the
2 independent review authors. The Cochrane Handbook for Sys-
tematic Reviews Tool was used to assess the risk of bias regarding
selection bias, performance bias, detection bias, attrition bias, se-
lective outcome reporting bias, and other sources of bias. All studies
were divided into “high risk,” “low risk,” or “unknown risk” based
on risk of bias. After any disagreements, a third author was asked to
arbitrate. If insufficient data were presented to assess the risk of bias,
contact was taken to the authors. For crossover studies, another type
of bias was considered, the risk of carry-over effect, that is, the effect
of the drug used in the first period extends to the second period and
influences IOP measured after treatment with the second drug.
Although a washout period would be ideal, it was considered
potentially unethical in noninferiority studies and accepted as low
risk in studies in which IOP was measured at least 3 to 5 weeks after
treatment initiation.13 Moreover, average IOP will be considered a
stable condition at medium term, so there was no concern
regarding period effect in crossover studies. Also, regarding
allocation concealment in crossover studies, in which each patient
receives both brand and generic treatment with PGAs, and only the
period order is randomized if no carry-over effects were suspected,
as was the case in all included studies, selection bias was unlikely to
happen, and this bias domain was judged as “low risk.”
Data Synthesis
A meta-analysis was planned for the primary outcome change of
IOP from baseline to final follow-up, per protocol, using a random
effect (DerSimonian and Laird) inverse variance meta-analysis to
pool data. A difference of 2 mmHg or more was considered post
hoc to be clinically significant for the primary outcome. The effect
of each study was investigated on the pooled estimate using a
leave-1-out technique. The principal summary measures were
presented as mean difference (MD) and standard error (SE).
To deal with crossover studies and when data were missing for
the primary outcome (change in IOP from baseline), recommen-
dations given in the Cochrane Handbook were followed.14 When
estimates of the MDs between treatment groups were not
available, these were computed from group means to obtain MDs
between crossover phases and then between treatments. When
SEs of the difference were not available, they were extracted
with the following strategy: back-calculation using P values and
the correspondent values of the t distribution; when group standard
deviations (SDs), but not P values were available, a correlation of
0.8 between crossover phases was assumed, also conducting a
sensitivity analysis with 0.5 correlation; when neither P values nor
 Steensberg et al 
Generic vs Original Prostaglandin Analogues
Figure 1. Article search process.
group SDs were available, the SEs were imputed using the median
SE of each treatment group in other studies.
To investigate the precision of this meta-analysis and assess the
risk of bias regarding different thresholds for the clinically mean-
ingful difference between brand and generic PGAs, the optimal
information size (OIS) was computed following Guyatt et al.15 The
secondary outcomes were narratively described, and a summary of
how the secondary outcomes were reported in the studies. The
results of these findings were reported in Table 1.
Results
Study Characteristics
By using the initial search strategy, 385 articles were identified,
and 379 articles were excluded because of irrelevance or study
design. Six studies were included in this systematic review and in
the meta-analysis.16-21 Descriptions of participants, follow-up time,
and outcome measures are presented in Table 2. All studies
evaluated OAG and OHT, and 2 studies evaluated normal-
tension glaucoma.
Risk of Bias in Included Studies
A risk of bias assessment was performed for all RCTs included
in this systematic review as per methodology described in the
Cochrane Handbook for Systematic Reviews of Interventions.
The findings are outlined in Figure 2 divided into proportion of
low, high, and unknown risk of bias. For sequence generation, 4
studies were of low risk and 2 studies were of unknown risk of
bias. For allocation concealment, 4 studies were of low risk and
2 studies were of unknown risk of bias. For blinding of
participants and personnel, 3 studies were of low risk and 3
studies were of unknown risk of bias. For blinding of
53
54

Table 1. Number of Reported Adverse Events, Number of Patients Reporting Adverse Events, and Ocular Surface Disease Index Score for the Included Studies

Slit-Lamp Examination
Reported AE No. of Patients with AE OSDI Score TBUT (Mean Decrease, Seconds ± SD) (% of Conjunctival Hyperemia)

Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020

Original Generic Original Generic Original Generic Original Generic Original Generic
Diagourtas 2018 e e e e 2 Lataz: 4 0.47  0.85 Lataz: 0.72  1.21 Xalaprost: 1.03 e e
Xalaprost: 7  0.79
Golan 2015 12 21 e e e e e e e e
Allaire 2012 e e 5 2 18% 15%
Narayanaswamy 2007 14 27 e e e e e e NR NR
Digiuni 2013 e e 5 8 e e e e e e
Kim 2018 NR NR NR NR e e e e e e

AE ¼ adverse event; NR ¼ not reported; OSDI ¼ Ocular Surface Disease Index; TBUT ¼ tear break-up time.

Table 2. Overview of Details of Included Studies

Participants; Original PGA Follow-up Primary Sources of

Author Year Design Glaucoma Subtype (Manufacturer) Generic PGA (Manufacturer) (wks) Outcome Secondary Outcome Funding/COI
Diagourtas 2018 RCT 60; OAG or OHT Xalatan (Pfizer Inc, 1. Lataz (Rafarm Pharmaceuticals, 16 Mean DIOP TBUT, OSDI NR/NR
New York, NY) Korinthou, Greece) questionnaire
2. Xalaprost (Cooper
Pharmaceuticals, Greece)
Golan 2015 RCT, CO 19; OAG, OHT, Xalatan (Pfizer Inc) Glautan (Unipharm, Tel Aviv, 4 Mean DIOP AE NR/NR
or NTG Israel)
Allaire 2012 RCT 257; POAG or OHT Xalatan (Pfizer Inc) Latanoprost 0.005% (Bausch & 6 Mean DIOP Subjective: AE NR/Employees of
Lomb, Berlin, Germany) Objective: slit-lamp Bausch & Lomb
examination
Narayanaswamy RCT, CO 29; OAG or OHT Xalatan (Pfizer Inc) Latoprost (Sun Pharmaceuticals, 12 Mean DIOP Subjective: AE Pfizer Ltd./NR
2007 Mumbai, India) Objective: slit-lamp
examination
Digiuni 2013 RCT 184; OAG or OHT Xalatan (Pfizer Inc) 0,005% Latanoprost (Galaxia, Alfa 12 Mean DIOP Local AE PH&T/(Charlotte,
Intes srl, Italy) Systemic AE NC)/NR
Kim RCT, CO 70; OAG, OHT, Travatan Z (Alcon Inc, Travoprost (Sandoz Inc, Canada, 3 Mean DIOP AE Department of
2018 or NTG Geneva, Switzerland) Boucherville, Quebec, Canada) Surgery at University
of Sherbrook/NR

AE ¼ adverse event; DIOP ¼ change in IOP from baseline to final visit; CO ¼ cross-over; COI ¼ conflicts of interest; NR ¼ not reported; NTG ¼ normal-tension glaucoma; POAG ¼ primary open-angle
glaucoma; OAG ¼ open-angle glaucoma; Obj ¼ Objective; OHT ¼ ocular hypertension; OSDI ¼ Ocular Surface Disease Index; RCT ¼ randomized controlled trial; Subj ¼ Subjective; TBUT ¼ tear break-
up time.
 Steensberg et al 
Generic vs Original Prostaglandin Analogues
Figure 2. Proportion of low, high, and unknown risk of bias.
outcome assessment, 1 study was of low risk and 5 studies were
of unknown risk of bias. For incomplete outcome data, 4 studies
were of low risk and 2 studies were of unknown risk of bias.
For selective reporting, 6 studies were of unknown risk of
bias. All of the 3 crossover studies were at low risk, because
they used a sufficiently long period of treatment before
collecting outcomes (3e5 weeks). Bias domains of greater
concern were insufficient details on masking of outcome
assessors in 5 of 6 studies and insufficient details on
prespecified reporting of outcomes, particularly adverse
effects. A detailed risk of bias assessment is shown in
Supplement 2 (available at www.ophthalmologyglaucoma.org).
Effect of Intervention/Meta-Analysis
Table 3 presents baseline and final IOP values for each study.
Figure 3 presents the meta-analysis results for the primary
outcome: the change in IOP from baseline to final visit. The
pooled estimate for latanoprost (
0.24 mmHg; 95% confidence
interval [CI],
0.58 to 0.11 mmHg; I2, 39.5%) was nearly
identical to the effect measured by Kim et al,18 the single study
on travoprost (
0.24 mmHg; 95% CI,
0.75 to 0.27 mmHg).
The 95% CI including all 6 studies excluded a clinically
meaningful difference and included nil (
0.23 mmHg; 95%
CI,
0.50 to 0.04 mmHg; I2, 24%). Table 4 presents the
results of leave-1-out sensitivity analyses. The exclusion of the
study by Narayanaswamy et al,19 which showed only partial
overlapping with other studies and a significant difference
favoring original PGAs, reduced heterogeneity from 24% to
nil. I2 remained between 21% and 40% after exclusion of any
other study. The exclusion of the studies by Diagourtas et al17
and Digiuni et al13 made the 95% CI of the pooled estimate
approach nominal statistical significance, but the overall
interpretation of the results did not change. A sensitivity
analysis using a moderate correlation (0.5 rather than 0.8) for
SE imputation in the study by Kim et al18 did not change the
meta-analytic estimate (
0.231 mmHg), whereas 95% CIs
widened to a small extent (from
0.50/0.04 to
0.52/0.06).
The OIS criterion was used to further assess the precision of our
estimates using different thresholds for a clinically meaningful
difference. Given a median SD of 2 mmHg and 2.5 mmHg in the
brand and generic groups, respectively, at final follow-up, a trial
with a sample size of 717 was found, such that the total size of this
meta-analysis would have 84% power to detect a difference of 0.5
mmHg between groups at an alpha of 0.05 and a power of
approximately 100% to detect a difference of 1 mmHg. Thus, it is
believed that the OIS criterion is largely met by this meta-analysis,
and we did not downgrade the certainty of evidence for
imprecision.
Tolerability
An overview of adverse events and tolerability outcomes is pre-
sented in Table 1. No significant differences in the number of
patients with local adverse events were found by Allaire et al16
(chi-square test) and Digiuni et al13 (Fisher exact test).
Diagourtas et al17 found no significant difference in tear break-
up time (TBUT) calculated by a KruskaleWallis test.
Narayanaswamy et al19 found similar hyperemia between the 2
treatment groups when performing a visual comparison by a slit-
lamp examination. Digiuni et al13 and Kim et al18 suggested that
the tolerability of the groups was similar. By using a
questionnaire, Golan et al20 and Narayanaswamy et al19 found a
greater incidence of local adverse events when treating with
generics latanoprost than with Xalatan (Pfizer, New York, NY).
However, Golan et al20 did not evaluate this difference as
significant (P ¼ 0.06), calculated by a McNemar test for which
P < 0.05 was considered statistically significant.
Discussion
The meta-analysis, including all 6 studies, suggests no
clinically significant difference regarding efficacy between
the generic and original PGAs (0.23 mmHg, CI,
0.50 to
0.04 mmHg). The quality of this evidence was moderate
because most studies had at least 1 domain of low or unclear
55
 Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020

No.

127

29
20

20

19

91

70
risk of bias. The data manipulation and imputation of the
primary outcome measures may have had limitations
regarding the strength of the evidence; nonetheless, standard

7.0 (NR)
5.4 (NR)

6.2 (NR)

5.1 (NR)
7.5 (1.0)

7.0 (1.0)

7.3 (2.6)
DIOP
Cochrane methods were used for this purpose and suggest
that such manipulation caused little risk of bias. There were
no significant differences in adverse events. This evidence
was of low quality because of risk of bias issues and the

15.6 (NR)

17.2 (NR)
Final IOP

16.4 (2.3)
15.8 (1.5)

16.1 (1.4)

16.4 (2.7)

18.4 (3.5)
heterogeneity in reporting adverse events, which led us to
conduct a qualitative synthesis. It is believed that variability
in study follow-up is a minor limitation in this review,
because treatment duration was sufficient to establish the

(19.00e27.50)y
full treatment effect of PGAs.13
Baseline IOP
Mean (SD),

21.1 (NR)

23.1 (2.7)
23.3 (1.3)

23.1 (1.5)

24.5 (1.7)

22.8 (1.9)
Generic PGA

mmHg

The matter of generic medications is based on a risk/

DIOP ¼ change in IOP from baseline to final visit; IOP ¼ intraocular pressure; NR ¼ not reported; PGA ¼ prostaglandin analogue; SD ¼ standard deviation.
benefit scale, in which the risks are toxicology and adverse
23.50*
events and the benefits are lower costs and consistent
compliance.22 When a drug loses its data exclusivity, other
pharmaceutical fabricants are able to formulate a generic
Pharmaceuticals, Athens, Greece)

version of that drug. This generic drug does not need

0.005% Latanoprost (Galaxia, Alfa
1. Lataz (Rafarm Pharmaceuticals,
Table 3. Baseline and Final Intraocular Pressure Values for Each Study

Latoprost (Sun Pharmaceuticals)

years of clinical trials but can be marketed on the basis of

Latanoprost 0.005% (Bausch &
Glautan (Unipharm, Tel Aviv,
Name (Manufacturer)

bioavailability tests. Because there are no means of

Lomb, Berlin, Germany)

Intes srl, Casoria, Italy)

measuring bioavailability when treating with eyedrops,

Travoprost (Sandoz Inc)

bioequivalence cannot be determined. Generic eyedrops

Karinthou, Greece)
2. Xalaprost (Cooper

are marketed on the basis of chemical tests that ensure

comparability of the generic drug to the original reference
product.7 Because there are fewer tests, the cost of
development is less and therefore cheaper for the patient.
Israel)

As for this economic benefit, many patients choose the

generic alternative before the original.23 The downside to
the generic alternative is that there are no regulations
No.

130
19

29

70
20

93

stating that the inactive ingredients should be consistent,

so the possibility of different degrees of adverse events is
likely to occur.22 However, this study provides no
6.4 (NR)

8.0 (NR)

8.1 (NR)
6.4 (NR)
7.5 (2.8)
7.3 (1.0)
DIOP

evidence of difference in efficacy and tolerability between

the generic and the original PGA. By enlightening the
prescriber about the use of generic PGAs, this can be
12.3 (NR)

16.8 (NR)

18.2 (NR)
Final IOP

14.3 (1.8)
15.8 (1.2)

16.5 (2.3)

economically beneficial for both the patient and the

healthcare system.
The IOP-lowering effect of PGAs is reliant on both
intrinsic and extrinsic factors, the extrinsic being patient
Original PGA

compliance and the intrinsic being the stability and chemical

(21.88e28.63)y
Baseline IOP
Mean (SD),

properties of the ophthalmologic solution. In recent years,

18.8 (NR)
23.1 (1.6)

24.4 (1.8)

23.1 (2.7)
22.8 (1.8)
mmHg

studies have investigated the physical properties of the plastic

container and the chemical properties of the formulation in
26.25*

various generic PGAs and compared these with those of the

original formulation.8,10,24-29 Drop size should also be
considered because this will determine the actual amount
Name (Manufacturer)

of drug available for administration. Multiple studies

Xalatan (Pfizer Inc)

Xalatan (Pfizer Inc)

Xalatan (Pfizer Inc)

Xalatan (Pfizer Inc)

Xalatan (Pfizer Inc)

show significant variations regarding these properties.8,24

(Alcon Inc)

Differences in concentrations of latanoprost, osmolality,

Travatan Z

pH, and total drop per container have also been

suggested.8,24,28 When evaluating the physical and chemical
properties of generic and brand-name travoprost, variations
were found among drug concentration, osmolality, pH, mean
drop size, and volume per container.10 Because of the results
Interquartile interval.
Narayanaswamy 2007

of these studies and clinical experience, ophthalmologists

Diagourtas 2018

have raised concerns regarding the efficacy and safety of the

Digiuni 2012
Allaire 2012

use of generic eyedrops. The pH and osmolarity have an

Golan 2015

Kim 2018

*Median.

impact on the comfort when installing the drop. When using

an eye drop with pH ranging far from that of the ocular tear
film (pH ¼ 7.4) and if hypo- or hyperosmolar, discomfort
y

56
 Steensberg et al 
Generic vs Original Prostaglandin Analogues

Figure 3. Meta-analysis of the effect of prostaglandin analogue (PGA) original compared with the generic. CI ¼ confidence interval; ES ¼ effect size.

can occur.24 In this systematic review, it is reported that is often achieved 3 to 5 weeks from commencement of
neither of the studies found a significant difference in regard treatment.13
to tolerability between the original and generic PGAs. This The articles included in this systematic review all use
suggests that the pH and osmolarity are within limits of change in IOP from baseline as a measure of the efficacy,
discomfort. which made it possible to perform a meta-analysis. A lack of
Studies included in this systematic review have some consensus and variability in outcomes and methods to use
limitations. Because relatively many of these have problems when comparing effectiveness of glaucoma interventions
with their methodology and the sample size was relatively have been observed.30,31 To address this issue, inspiration
small, the question regarding efficacy and tolerability for can be drawn from the Core Outcome Measures in
brand-name PGA and their generics is still open. It is Effectiveness Trials initiative, a way of identifying the
important to remember that the generic latanoprost drugs important core outcomes of interest to the patient,
that are compared in this meta-analysis are different drugs clinician, and other stakeholders.30-32 There is also a need
from different brands and may have different ingredients. for a standardized set of core outcomes when comparing the
Finally, the studies vary regarding follow-up time. It is tolerability and safety of eyedrops, because it is difficult to
assumed that the maximum effect is achieved at all the final compare the varying types of outcome measures. An
IOP measurements because maximum IOP-lowering effect example of this could be measurements of TBUT and a
standardized way to report subjective adverse events, for
Table 4. Results of Leave-1-Out Sensitivity Analyses example, the Ocular Surface Disease Index questionnaire.
In conclusion, although the physical and chemical dif-
P Value ferences might indicate a possible influence on the clinical
Excluded Study MD (95% CI) I2 for Effect efficacy and safety, this systematic review found no evi-
All studies
0.23 (
0.50 to 0.04) 24.4% 0.251 dence of difference between generic and original formula-
Diagourtas 2018
0.30 (
0.60 to 0.0) 22.4% 0.049 tions of ophthalmic PGAs regarding efficacy. Both generic
Golan 2015
0.20 (
0.54 to 0.13) 35.6% 0.231 and original PGAs were well tolerated. This evidence is of
Allaire 2012
0.23 (
0.56 to 0.09) 39.5% 0.158 moderate quality, but a small number of studies were
Narayanaswamy 2007
0.14 (
0.39 to 0.11) 0% 0.263 available, and more randomized trials comparing other
Digiuni 2012
0.30 (
0.59 to 0.0) 21% 0.044
generic PGAs with original formulations would be useful to
Kim 2018
0.24 (
0.58 to 0.11) 39.5% 0.176
further investigate the robustness and generalizability of
these findings. Concerning tolerability and safety, it would
CI ¼ confidence interval; MD ¼ mean difference. be valuable with a set of core outcomes based on

57
 Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020
standardized methods and patient-reported outcomes in
future studies, for example, the Ocular Surface Disease In-
dex questionnaire and measurement of TBUT.
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 Steensberg et al 
Generic vs Original Prostaglandin Analogues

Footnotes and Financial Disclosures

Originally received: June 13, 2019.
Final revision: October 8, 2019.
Accepted: October 22, 2019.
Available online: November 1, 2019. Manuscript no. 2019-95.
1 Data collection: Steensberg, Müllertz, Virgili, Azuara-Blanco, Kolko
Department of Drug Design and Pharmacology, University of Copenha-
gen, Copenhagen, Denmark.
2 Kolko
Department of Neurosciences, Psychology, Drug Research and Child
Health, University of Firenze and AOU, Careggi, Italy.
3
Centre for Public Health, Queen’s University Belfast, Belfast, United
Kingdom.
4
Department of Ophthalmology, Copenhagen University Hospital, Rig-
shospitalet e Glostrup, Glostrup, Denmark.
Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials
discussed in this article.
HUMAN SUBJECTS: No human subjects were included in this study. No
Institutional Review Board approval was required. All research adhered to
the tenets of the Declaration of Helsinki. The requirement for informed
consent was waived because of the retrospective nature of the study.
No animal subjects were used in this study.
Author Contributions:
Conception and design: Steensberg, Müllertz, Azuara-Blanco, Kolko
Analysis and interpretation: Steensberg, Müllertz, Virgili, Azuara-Blanco,
Obtained funding: Not applicable
Overall responsibility: Steensberg, Müllertz, Virgili, Azuara-Blanco, Kolko
Abbreviations and Acronyms:
CI ¼ confidence interval; IOP ¼ intraocular pressure; MD ¼ mean dif-
ference; OAG ¼ open-angle glaucoma; OHT ¼ ocular hypertension;
OIS ¼ optimal information size; PGA ¼ prostaglandin analogue;
RCT ¼ randomized controlled trial; SD ¼ standard deviation;
SE ¼ standard error.
Correspondence:
Alvilda T. Steensberg, MBBS, Department of Drug Design and Pharma-
cology, University of Copenhagen, Universitetsparken 2, 2100 Kbh,
Denmark. E-mail: alvilda.steensberg@gmail.com.

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