The Role of Preservative Free Medica

tions in Glaucoma Treatment

Cynthia V Verzosa, MD, DPBO, MSc

Outline

I. Purpose of Treatment
II. Why Preservative Free?
III. Treatment Options
IV. Summary
Purpose of Treatment
Purpose of Treatment : What Guidelines Say

EGS Guidelines 2003

Preservation of visual function

adequate to the needs of the
individual with minimal or no side-
effects for the expected lifetime of
the patient without any disruption to
his or her normal activities at a
sustainable cost.

European Glaucoma Society.

Terminology and guidelines for glaucoma. 2003.
Purpose of Treatment : What Guidelines Say

APGC Guidelines 2016

The most appropriate medication:

1. Greatest chance of reaching target IOP

2. Best safety and tolerability profiles
3. Minimal inconvenience
4. Affordable
5. Maximal likelihood of Adherence

EMGT, AGIS, and OHTS studies show

that if IOP is lowered by 1 mm Hg,
The risk for visual field progression is
lowered by 10%
2016 Asia Pacific Glaucoma Guidelines.
Section 2.2 Medical Treatment p.38.
Purpose of Treatment : What Guidelines Say

Reference: European Glaucoma Society.

Terminology and guidelines for glaucoma. 4th ed. 2014
Purpose of Treatment : What Guidelines Say

EGS Guidelines 2014

EGS 2014 Guidelines:

The European Medicines Agency (EMEA)

… avoid use of preservatives in patients

who do not tolerate eyedrops with preser
vatives, in those on long term treatment,
or to use concentrations at the minimum le
vel consistent with satisfactory antimicrobi
al function…

Reference: European Glaucoma Society.

Terminology and guidelines for glaucoma. 4th ed. 2014
Purpose of Treatment : What Guidelines Say

Reference: European Glaucoma Society.

Terminology and guidelines for glaucoma. 4th ed. 2014
Continued Treatment is Important for Appropriate Management of Glaucoma

Treatment policy for primary open-angle glaucoma (broad definition)

Start
Start of
of
Treatment Interruption
Interruption
Treatment
of
of treatment
treatment
Favorable
Introduction Continuation

Usual deterioration of visual field due to aging

Visual field

Deterioration of visual field when

IOP is controlled properly

Visual field defect at a

level that interferes with
daily life Deterioration of
visual field due to
onset of glaucoma
(without treatment)
Poor
Age
5. EGS 4th Edition 2014 p. 131 9
Compliance vs Persistence

Compliance/Adherence - degree of conformity to recommen

ded timing, dosage, and frequency

Persistence – act of continuing the treatment for the prescrib

ed duration

Cramer JA, et al. Medication Compliance and Persistence: Terminology and Definitions.
Value in Health. 11:1, (2008);44-47. 10
Low Persistence rates in Glaucoma

1 year
YEAR Persistence Rate Country Participants Author Publication

2,440 subjects
1980 -1987 77% USA Glaucoma patients >65 yrs. Gurwitz JH, et al Am J Public Health 1993; 83:711-716
Newly prescribed drug
5,670 subjects
1994 - 2005 67% UK Glaucoma patients Owen CG, et al Eye 2009, 23: 1098-1110
Newly prescribed drug

33% LAT 28,741 subjects

1996 - 2002 19% other hypotensives USA Glaucoma Patients Reardon G, et al Am J Ophthalmol 2004; 137: S3-S12
Newly prescribed drug
2,001 subjects
1997 -1999 37%-70% UK POAG patients Zhou Z, et al Br J Ophthalmol 2004; 88: 1391-1394
Newly prescribed drug

39% LAT 1,474 subjects

1997 - 2002 USA POAG patients >20 yrs. Schwartz GF, et al Am J Ophthalmol 2004; 137: S13-S16
25% TIM Newly prescribed drug
11% LAT 6,271 subjects
2001 - 2004 9% BIM USA POAG patients >40 yrs Zimmerman TJ, et al J Ocul Phalmacol Ther 2009; 25: 145-152
5% TRV Newly prescribed drug

2005 32% USA 3,310 subjects Yeaw J, et al J Manag Care Pharm 2009; 15: 728-740
patients prescribed with PG

2005 - 2011 61% Japan 2,799 subjects Kashiwagi K, et al Jpn J Ophthalmol 2014; 58: 68-74
Newly prescribed drug

Schwartz Surv Ophthalmol 53:S57-S68, 2008

Persistence rates: Japan

Persistence Rate:
After 3 mon: 73.2%
After 6 mon: 68.1%
After 12 mon: 60.9%

~40%
Dropout
after the
1st year

[Participants] Enrolled in Social Insurance, newly diagnosed with prescription between 2005-2011: 2,799 subjects
[Method] By pursuing Medical Data. Observed: 3,6,12 months and 3 years

Kashiwagi K, et al, Jpn J Ophthalmol 2014; 58: 68-74

Persistence rate: USA

n =3,623 n = 1,677

Less than 40% remain on therapy after 1 year

4.Nordstorm Am J Ophthalmol 2005;140: 598–606. © 2005

13
Negative Effects of Ocular Adverse Effects

Broadway; European Ophthalmic Review, 2010;4(1):23-28 DOI

Reasons for Changing Medications for PGA mono patients

70%

61.0%
60%

N=118
50%

40%

30%

20.3%
20%

10%
5.9% 5.1%
3.4% 3.4%
0.8%
0%
Ocular Signs and Symptoms Lowering of IOP not sufficient Contraindication Systemic intolerability Progression Tachyphylaxis Others

% Patients

Hommer and Kimmich 2011 Switching patients from preserved

prostaglandin-analog monotherapy to preservative-free tafluprost
Why go preservative free?

17
1. Preservative Free Improves Adherence

14. Wolfram C, Stahlberg E, Pfeiffer N. Therapy adherence in glaucoma – The patient’s experience and
practice. P4,31. European Glaucoma Society. 12th EGS Congress. Prague, Czech Republic, 19-22 June
2016
18
2. Glaucoma and Ocular Surface Disease (OSD) go hand in hand

59% of Glaucoma patients reporte

d OSD symptoms

Tear film abnormalities

Reference: Leung et al. J Glaucoma 2008

Study description: Cross-sectional observational study of 101 glaucoma patients (202 eyes) with either POAG (78%) or OH (22%). Patient
demographics: 65% men, mean age 67 ± 12 years (36 to 90 years old). Patients completed Ocular Surface Disease Index (OSDI) questionnaire
and underwent evaluation by Schirmer test, corneal and conjunctival lissamine green staining, and tear break-up time.
3. Most of currently available PGAs contain BAK

Latanoprost Travoprost Bimatoprost Tafluprost

(Taflotan-S)

Source: Individual Package Inserts

Detergent Activity of BAK

BAK is a quaternary Ammonium molecule with Detergent Activity

Buron N, et al. Invest Ophthalmol Vis Sci. 2006;47:4221-30

Relationship of Number of BAK eye drops and OSD

80

70

60
% Patients with OSD

50

40 Normal
Abnormal

30

20

10

0
1 2 3 4

Number of BAK-containing Eye drops

Leung ; J Glaucoma 2008;17:354

BAK causes shrinkage of conjunctival cells

Control 0.01% BAK

Pisella PJ et al. Invest Ophthalmol Vis Sci. 2004;45:1360-8

Toxic Inflammatory Markers Increase with multiple treat
ments of preserved medications

70
* p < 0.001

60

50
HLA-DR expression (%)

* p < 0.03
NS
40

30

20

10

0
Control Non-preserved Preserved Multiple treatments

Baudouin C, et al. Ophthalmology. 2004;111:2186-92

Preservative Exposure and Surgical Outcomes in Glaucoma Patients

Boimer and Birt PESO Study 2013

4. Hyperemia is common in PGA Treatment

Standard photographs used to assess grades of conjunctival hyperemia

Parrish et al Am J Ophthalmol 2003; 135:688-703

Conjunctival Hyperemia with prostaglandins

80

70

60
% Patients

50

40

30

20

10

0
Latanoprost Bimatoprost Travoprost
(n=64) (n=137) (n=138)
Parrish et al Am J Ophthalmol 2003; 135:688-703
Treatment Options: Preservative Free Drops
Preservative free management

29
Preservative Free Eye Drops: Improves Subjective Symptoms

N = 9,658
Preservative Free Eye Drops: Improves Objective Symptoms

N = 9,658
Jaenen N, et al. Eur J Ophthalmol. 2007;17:341-9
Taflotan-S® vs BAK containing PGAs: Human conjunctival cells

o In vitro model
o 30-minute exposure to
• latanoprost (0.02% BAK)
• travoprost (0.015% BAK)
• bimatoprost (0.005% BAK)
• BAK alone (0.02%, 0.015%,
and 0.005%)
• preservative-free tafluprost
o Assessments
• membrane integrity
• pro-apoptotic effects
• oxidative stress
• cellular morphology

Brasnu E, et al. Curr Eye Res. 2008;33:303-12

 Tafluprost (Taflotan-S®) maintains better membrane integrity

In vitro study of effects of prostaglandin analogue formulations

on membrane integrity in human conjunctival cells

* Compared with Tafluprost PF.; PBS = phosphate-buffered saline.

Brasnu et al. 2008.
 Tafluprost (Taflotan-S®) : Less oxidative stress and apoptosis

In vitro study of effects of prostaglandin analogue formulations on

oxidative stress and apoptosis in human conjunctival cells

* Expressed as a ratio relative to control value.

†
p < 0.001 versus latanoprost and BAK, for both tests.
Brasnu et al. 2008.
Tafluprost (Taflotan-S®) :Less Cell Shrinkage

A BB
Human conjunctival cell line
visualized by fluorescent
staining.

Cell cytoskeleton: green

Nuclei: red

C D
A .Control
C D
B. Taflotan-S
C. latanoprost (0.02%BAK)
D. 0.02% BAK alone

Reproduced from Curr Eye Res, Vol. 33, Brasnu E et al.,

pages 303-12,  2008, Taylor & Francis.
Preserved and Unpreserved PGAs in Hyperemia
9 of 10 patients without Hyperemia when switched to
Taflotan-S®

Hyperaemia before and after switching from preserved prostaglandins to Taflotan

(N = 118)
P < 0.001
35.6%
Preserved No hyperaemia
PGAs Switch Mild hyperaemia

87.7% Moderate hyperaemia

Taflotan-S Severe hyperaemia

Preserved PGAs Taflotan-S (12 weeks)

Hommer A and Kimmich F. Clin Ophthalmol 2011; 5: 623-631

Tafluprost (Taflotan-S®): IOP-lowering you expect from a PGA

32% IOP lowering effect in treatment-naïve patients

Hommer et al. Curr Med Res Opin 2010

Effective IOP reduction in all subgroups

Tafluprost (Taflotan-S) lowered IOP in all patient subgroups

Change of IOP from baseline after 12 weeks of Taflotan-S treatment

Patients N Δ IOP (mmHg) * Δ IOP (%) P **

All patients 544 -4.1 -21.1 % < 0.001

Naïve patients 22 -7.1 -32.1 % < 0.001

Betablocker montherapy 110 -5.4 -25.6 % < 0.001

CAI monotherapy 57 -4.2 -21.9 % < 0.001

Prostaglandin monotherapy 118 -1.4 -8.7 % < 0.001

* IOP at final visit minus IOP at
baseline
** LOCF-analysis, t-test for paired
samples

Hommer A et al. Curr Med Res Opin 2010; 26: 1905-1913

Tafluprost (Taflotan-S®): IOP-lowering you expect from a PGA

Switching from preserved prostaglandin therapy to Taflotan-S resulted in effective IOP lowering
M e a n IO P ± S D ( m m H g )

* P < 0.001 Baseline PGAs

IOP before and after switching from
** P < 0.05 Taflotan final visit
preserved prostaglandins to Taflotan ***P = 0.252 (12 weeks)

22 IOP
20 * * ** **
* -1.4 mmHg
18
vs. preserved
16 PGA’s
14

12

10

8 Preserved PGAs Latanoprost Travoprost Bimatoprost

1 2 3 4
(N=118) (N=68) (N=32) (N=18)

Hommer A and Kimmich F. Clin Ophthalmol 2011; 5: 623-631

Tafluprost (Taflotan-S®): IOP-lowering you expect from a PGA

Effective glaucoma treatment with Taflotan-S

IOP at latanoprost baseline and after 12 weeks of Taflotan treatment

IO P (m m H g )

20

15 (N = 158)

10
All patients responded to
latanoprost at baseline.
5 Patients with at least two
ocular symptoms, or one
sign and one symptom,
during treatment with
0 latanoprost were switched to
Latanoprost
1 Taflotan-S
2 Taflotan.
(baseline) (12 weeks )

Uusitalo H et al. Acta Ophthalmol 2010; 88: 329-336

Taflotan-S with higher patient satisfaction
when switched from LAT

Increased patient satisfaction

Patients satisfied with drop comfort (N = 158)

79%
41% Taflotan-S
latanoprost Switch
51.6% 76.8%
Latanoprost Tafluprost

Latanoprost Taflotan-S (12 weeks)

Uusitalo H et al. Acta Ophthalmol 2010; 88: 329-336

Efficacy and Tolerability of Tafluprost (Taflotan-S®)

Study Purpose: Evaluation of efficacy, local tolerability and safety of

preservative-free Taflotan-S (tafluprost 0.0015%) in a natural setting

Study design
o Open-label, non-randomized, multicentre observational study over a
time-period of 6-12 weeks
o Number of patients: 2,123
o Study treatment was based on the decision of the physician:
o Naïve patients
o Change of medical treatment
• Monotherapy to monotherapy with preservative-free Taflotan
• Add-on of Taflotan to a monotherapy treatment regimen
• Substitution of drugs (non-fixed or fixed combinations)
Assessment of:
• Prior medical treatment and reasons for change
• IOP at baseline and 6-12 weeks
• Local tolerability
• Satisfaction with preservative-free Taflotan

Erb C et al. Adv Ther 2011; 28: 575-585, Erb DOG 2011
Results: Tafluprost (Taflotan-S) provided added IOP-lowering

In treatment-naïve patients and in patients switched from

other IOP-lowering medications

IOP-lowering with Taflotan treatment

Baseline
Taflotan final visit at 6-12 weeks
Naive patients Switch patients
41.1% Taflotan
*p < 0.001
final visit
Additional
IOP-lowering
after
switching
* * * * * up to
-3.6 mmHg

Beta-Blockers Alpha-Agonists CAI´s PGA´s

(N = 440) (N = 307) (N = 101) (N = 158) (N = 447)

Erb C et al. Adv Ther 2011; 28: 575-585, Erb DOG 2011
TAFLUPROST+TIMOLOL (TAPCOM-S): EFFICACY REVIEW

Diurnal IOP change from baseline after 3 months of Tafluprost+Timolol (Tapcom-S) treatment

Baseline IOP (mmHg)

25 – 26
23 – 24
22 – 23

24 – 25

29 – 30
27 – 28

28 – 29

30 – 31
26 – 27

≥ 31
<22
0
n=20 n=37 n=68 n=83 n=78 n=47 n=37 n=33 n=13 n=13 n=26

-2.5
IOP change (mmHg)

-5.0
28%
31%
-6.24 32%
-7.5 -6.52 31%
-7.42 -7.64 33%
35% 32%
-8.49 35%
-10.0 34%
-9.22 -9.10
-9.45
-10.03 38%
-11.36
-12.5
40%
Combined analysis of two phase III trials (Holló, et al 2014 and Pfeiffer et al 2014) -13.20
-13.0

Tafluprost+Timolol (Tapcom-S) achieves up to 40% IOP

reduction compared with baseline after 3 months
27. Holló G et al. Adv Ther 2014;31:932-944.
IOP REDUCTION SIMILAR TO OTHER FIXED DOSE PG + B
B

IOP change from baseline across 3 FDCs

PF Tafluprost/Timolol 28 Latanoprost/Timolol 29
Bimatoprost/Timolol 30

Baseline IOP (mmHg) Baseline IOP (mmHg) Baseline IOP (mmHg)

24-26 26-27 ≥ 26 24-26 25-27 26-30 23-26 24-26 24-26 27

0 0 0

IOP change from baseline (mmHg)

IOP change from baseline (mmHg)
-2 -2 -2
IOP change from baseline (mmHg)

-4 -4 -4

-6 -6 -6

  
range range
-8 range -8 range -8 range
7-9
7-9  7-9  7-9
7-9
range
range 
range range
range 8-9
7-8 range
8-10  8-10
8-10  8-10
-10 range -10 range -10
9-12

9-12 reduction
10
-12 -12 -12

*No comparable data available from Latanoprost/Timolol regulatory studies.

28. SmPC Taptiqom/Tapcom-S 29. SmPC Duotrav 30. EPAR Ganfort

IOP REDUCTION SIMILAR TO OTHER FIXED DOSE PG + B
B

The frequency of conjunctival/ ocular hyperemia associated with prostaglandins, as reported in the
Summaries of Product Characteristics, as a treatment-related adverse event:

Tafluprost+Timolol 31 Travoprost+Timolol 32 Bimatoprost+Timolol 33 Bimatoprost+Timolol 34

Single Dose single dose multidose

30% Hyperemia rate 30% Hyperemia rate 30% Hyperemia rate 30% Hyperemia rate

25% 25% 25% 25% 26%

20% 20% 20% 21% 20%

15% 15% 15% 15%

10% 10% 12% 10% 10%

5% 7% 5% 5% 5%

0% 0% 0% 0%

Frequency of hyperemia as an adverse event in the individual summary of product characteristics of Travoprost/Timolol, Bimatoprost/Timolol and PF
Tafluprost/Timolol . The rates are from separate studies, which may have used different grading scales for hyperemia.

Hyperemia associated with PF Tafluprost+Timolol is 7%

31. SmPC Tapcom-S/Taptiqom, 32. SmPC Duotrav, 33. SmPC Ganfort singleSanten,
dose, 34.data
SmPCon file
Ganfort
Summary

1. Glaucoma guidelines states the importance of PF treatment

2. Global low persistence rates
3. Why Preservative Free?
1. PF improves adherence
2. Glaucoma and OSD go hand in hand
3. Most of currently available treatment contain BAK
4. Hyperemia is common in Glaucoma

4. Treatment Options
1. Taflotan-S
• Improves ocular signs and symptoms vs preserved
• Lower hyperemia rate vs preserved
• 32% IOP lowering for naïve
• Further IOP lowering when switched from previous monotherapy
2. Tapcom-S
• As much as 40% IOP lowering
• 7% hyperemia rate vs. 26% rate of BIM PF

48
 What would you choose?

OLD: Effective but Toxic NEW: Effective but Non-Toxic

Questions
REFERENCES
1.Compliance and persistency in glaucoma follow-up treatment. Schwartz GF Curr Opin Ophthalmol. 2005 Apr; 16(2):114-21.
2.Schwartz Surv Ophthalmol 53:S57-S68, 2008
3.Kashiwagi K, et al, Jpn J Ophthalmol 2014; 58: 68-74
4.Nordstorm Am J Ophthalmol 2005;140: 598–606. © 2005
5.EGS 4th Edition 2014 p. 131
6.Kass MA Meltzer DW Gorden M et al. Compliance with topical pilocarpine treatment. Am J Ophthalmol. 1986 May 15;101(5):515-23.)
7.Muir K et al Arch Ophthalmol 2011; 129: 243-5
8.Robin AL, Covert D Ophthalmology. 2005 May; 112(5):863-8
9.Osterberg L, N Engl J Med. 2005 Aug 4; 353(5):487-97
10.Konstas et al Investigative Ophthalmology & Visual Science April 2009, Vol.50, 2477.
11.Bergman-Evans B Geriatr Nurs. 2006 May-Jun; 27(3):174-82; quiz 183
12.Eaddy M. How Patient Cost-Sharing Trends Affect Adherence and Outcomes Vol. 37 No.1 • January 2012 • P&T®
13.Zimmerman J Ocular Pharmacology and Therapeutics 2009
14.Wolfram C, Stahlberg E, Pfeiffer N. Therapy adherence in glaucoma – The patient’s experience and practice. P4,31. European Glaucoma Society. 12th EGS Congress. Prague, Czech Republic, 19-22
June 2016
15.EGS 4th Edition (Treatment Options.p152)
16.Leung, EW et al. J Glaucoma 2008;17:350–355
17. Ruangvaravate N. et al, Journal of Ocular Pharmacology and Therapeutics Volume 00, Number 00, 2018
18.Adapted from EU Medical Affairs, GLA-005-15 b, Date of preparation: January 2016
19.2016 Asia Pacific Glaucoma Guidelines p.33,34
20.Olthoff C et al. Ophthalmol 2005;112:953-961
21.Tapcom-S PH Package Insert 2018.
22.Holló G, et al. Adv Ther. 2014;31:932-944.
23.Tapcom Interview Form 2014.
24.Kuwayama Y. Journal of the Eye 2015;32:133-143
25.Pfeiffer N et al. Adv Ther 2014;31:1228-1246
26.Holló G et al. J Ocul Pharmacol Ther 2014; 30(6): 468-475
27.Holló G et al. Adv Ther 2014;31:932-944.
28.SmPC Taptiqom/Tapcom-S
29.SmPC Duotrav
30.EPAR Ganfort
31.SmPC Tapcom-S/Taptiqom
32.SmPC Duotrav,
33.SmPC Ganfort single dose
34.SmPC Ganfort