Download Fixed Combinations – Concept of Use

issue 3
2 010
Inside this
issue:
Special Focus:
What’s New:
Clinical Issues:
Practical Tips:
Quality Use of Fixed
Combinations
Mechanisms of
Action of Fixed
Combinations
Fixed Combinations in
Treatment Algorithms and
Guidelines
Fixed Combinations
and Patient’s
Perspective
PAGE 2
PAGE 5
PAGE 9
PAGE 10
LEARNING OBJECTIVES
•Special Focus: Action of components,
limitations and additivity, effects and
side effects, cost issues.
•What’s New: Mechanisms of action,
patient case study, choice of combination products
•Clinical Issues: Fixed combinations
in the treatment algorithm, reference in
guidelines.
Practical Tips: Patient perspective:
factors influencing adherence, quality of
life, costs.
TARGET AUDIENCE
This educational activity is aimed at
general ophthalmologists, glaucoma
specialists and ophthalmo­logy residents.
EDITORIAL BOARD
Clive Migdal MD, FRCS, FRCOphth
Western Eye Hospital, London, UK.
Main topic issue No 3:
Fixed Combinations –
Concept of Use
Glaucoma Now is a continuing medical education publication.
Distributed worldwide to approximately 40,000 ophthalmologists,
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Glaucoma Now is in the process of gaining accreditation for
Continuing Medical Education (CME) by the European Accreditation Council for Continuing Medical Accreditation.
Ivan Goldberg MD, FRANZCO, FRACS
Sydney Eye Hospital, Sydney, NSW,
Australia.
Remo Susanna MD, Professor and
Head of Department of Ophthalmology,
University of São Paulo, Brazil.
Glaucoma Now – No3. www.glaucomanow.com
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1
Special Focus:
Quality Use of Fixed Combinations
Francisco Javier Goñi MD, PhD1. Mercè Guarro MD2
1. Chief of the Integrated Dept of Ophthalmology, Hospitals of Granollers, Mollet and Sant Celoni. Co-director of
Barcelona Glaucoma Centre-IOB-USP
2. Coordinator of the Integrated Dept of Ophthalmology, Hospitals of Granollers, Mollet and Sant Celoni
Core Concepts
• Beta blockers (BBs) and alpha agonists (AAs) reduce aqueous formation
by decreasing the rate of movement
of water to the ciliary non-pigmented
epithelial (NPE) aqueous surface.
• Carbonic
anhydrase
inhibitors
(CAIs) reduce aqueous production
by decreasing bicarbonate formation,
thus preventing sodium and water
movement from the non pigmented
epithelial cells.
• Prostaglandin analogs (PGAs) increase uveoscleral outflow of aqueous. While all other PGAs activate the
FP receptor, bimatoprost seems to act
through a variant of this receptor.
Action of components
Mechanism of action: Ocular hypotensive FDCs are products that include
two active agents in the same bottle.
All currently available FDCs include
timolol – a nonselective beta-blocker at
the concentration of 5 mg per ml (0.5%).
The other drug is a PGA, including bimatoprost, latanoprost or travoprost;
the alpha-agonist brimonidine, a CAI,
(brinzolamide or dorzolamide),; or the
cholinergic agent pilocarpine at 2% or
4% concentrations (1).
Although mechanisms of action of
these drugs are different, all of them
reduce IOP either by reducing aqueous
production (AP) or by facilitating aqueous outflow (AO). (3,4,5).
CAIs reversibly bind to the almost
ubiquitous enzyme carbonic anhydrase
II, hindering it from catalyzing its reaction (6). This reduces the production of
bicarbonate and consequently aqueous
humor formation.
PGAs increase uveoscleral outflow,
the alternative route for aqueous outflow,
and can be classified as AO facilitators
(8). Among the different PGAs available as fixed combinations, latanoprost
2
• PGAs are the most potent hypotensive drugs available, reducing IOP up
to 31-33% from baseline.
• PGAs reduce IOP for at least 24
hours, consistently flattening the circadian curve better than CAIs, AAs or
BBs.
• Fixed dose combinations (FDCs)
have advantages such as reduced
preservative exposure, wash out effects and drug interactions.
• The non inferiority design of studies
comparing FDCs with individual components might limit the evidence.
• Cost effectiveness studies differ
greatly in methodology and in selected outcomes measures, making interdrug comparison difficult.
and travoprost activate the FP receptor.
FP activation alters second messenger
signaling, stimulating intracellular production of pro-metalloproteinase. These
convert to metalloproteinase outside the
cell, and degrade collagen fibres, making
the ciliary extracellular matrix more porous and facilitating passage of aqueous.
Bimatoprost could act through a variant
of the FP receptor (9)
Finally, cholinergic agents like pilocarpine stimulate ciliary muscle contraction, thus stretching and opening the
trabecular meshwork (10). This facilitates aqueous passage through the conventional pathway. Cholinergics do not
block the effect of PGAs, as might be expected from their respective mechanisms
of action (11)
Beyond these hypotensive effects,
there may be IOP-independent actions
for some agents: improvement in ocular hemodynamics by dorzolamide (12),
or retinal neuroprotection with brimonidine (13). Further studies are needed
to confirm the true added value of these
compounds in glaucoma management.
Efficacy: Efficacy varies between drugs;
it is the amount of IOP reduction from
an untreated baseline, expressed as a
percentage and/or absolute values, depending on the design and methodology
of studies for that particular drug.
According to a meta-analysis (14),
PGAs are the most powerful hypotensive drugs currently available, reducing
IOP as much as 31–33% from baseline.
Theoretically, FDCs containing PGA
(PGAFDC) should be the most effective
two-drug combination, as they bring together an AP reducer plus an AO facilitator. When latanoprost/timolol FDC
once daily was compared with dorzolamide/timolol FDC bid there were no
statistically significant differences in IOP
reduction (15,16). Conversely, travoprost/timolol FDC once daily compared
with dorzolamide/timolol bid demonstrated statistical significance favouring
the PGAFDC, although the mean IOP
differences between both FDCs was less
than 1 mmHg (17).
Studies comparing the efficacy of the
different PGAFDCs, report statistically
significant differences, in favour of bimatoprost/timolol FDC for IOP reduction, compared with latanoprost/timolol
FDC (18) and travoprost/timolol FDC
(19). While these differences are quantitatively small, even small amounts of
IOP lowering could be relevant. A measurable direct relationship between IOP
reduction and decreased risk of glaucoma progression has been estimated (20,
21). The clinical relevance for visual field
preservation remains to be determined
through adequately designed studies.
Also relevant is the duration of a
drug´s hypotensive effect. As monotherapy, PGAs show a sustained IOP
reduction lasting at least 24 hours, consistently flattening the day and night
IOP curve, superior to BBs or CAIs
(22). Non-PGAFDCs, like dorzolamide/timolol FDC bid, have 24 hour
IOP control comparable with latanoprost monotherapy daily and better
than brimonidine monotherapy tid (23).
Glaucoma Now – No3. www.glaucomanow.com
Similarly, dorzolamide/timolol FDC
bid performed equally to latanoprost/
timolol FDC daily. (24). One study
has compared 24 hour-IOP efficacy of
two different PGAFDCs. Travoprost/
timolol FDC qd showed statistically
significant differences in 24 hour IOP
lowering at some individual time points
ahead of latanoprost/timolol FDC qd
(25). With PGAFDCs, both morning
and evening instillation are effective, but
evening dosing might yield statistically
significant better 24-hour IOP control
(25-27).
Limitations/additivity: FDCs have
advantages and disadvantages. Benefits include: lower risk of a washout
effect, less preservative-induced ocular
damage and drug interactions, and increased compliance. (28,29) Regarding
PGAFDC efficacy, concerns arise when
studies are analyzed in depth. A recent
meta-analysis (30), which included studies investigating the IOP lowering effect
of PGA combined with BB therapy, has
reported that differences in efficacy may
relate to study design limitations such as
the concept of non-inferiority of FDCs
compared with the concomitant combination of their separate components
as well as different dosing schedules
(morning versus evening). Concomitant
but separate use of timolol 0.5% bid and
latanoprost daily appears to reduce IOP
better than the FDC. However, morning dosing with latanoprost/timolol
FDC obtained only IOP data up to 8
hours after administration thus underestimating the peak effect of the PGA
component.
Regarding non-PGAFDC efficacy,
analysis of non-inferiority with the same
dosing schedules for fixed and non-fixed
treatment regimens (31-32), has shown
comparable treatment arms for trough
and peak effects; however, they evaluated only two time points, before and
after drug instillation.
A danger with FDCs is the simultaneous use of two of them: all include
timolol (33), which would be doubledosed use in this way. A limitation is
inability to adjust the concentration or
timing of each component to individual
patient requirements (34).
Switching from timolol 0.5% bid to
latanoprost/timolol FDC qd, results in
a pooled change of –2.8 mmHg (30),
or a range of change from –1.9 to –3.3
mmHg when switching from timolol
0.5% bid to travoprost/timolol FDC qd
(35). Clinical equivalence studies estimate that switching from timolol 0.5%
bid to dorzolamide/timolol FDC bid
(36) or to brimonidine/timolol FDC bid
(31) reduces IOP between 4.2 and 5.4
and between 4.4 and 5.3 mmHg respectively. Similarly, brinzolamide/timolol
FDC has demonstrated equivalent efficacy to dorzolamide/timolol FDC (37).
Recently, a study compared a threedrug, non-PGA non-FDC (timolol
0.5%, dorzolamide 2% and brimonidine
0.2%) with dorzolamide/timolol FDC
(38); the multi-drug FDC lowered mean
IOP more effectively from baseline
throughout the six-month follow-up.
Side effects: Several studies have reported a similar safety profile when different FDCs are compared with their
separate components (36,31,39,40,41).
As all FDCs include timolol, a specific cardiopulmonary history including
asthma or bradyarrhythmias must be excluded (42).
All PGA-FDCs have a reduced rate
and severity of conjunctival hyperemia
compared with each of the PGAs used
alone (41, 43, 44). Similarly, the incidence
of conjunctival allergy-like reaction
from AAs, is lower for the brimonidine/
timolol FDC bid than in monotherapy
with brimonidine tid (45,46). Over the
long term, latanoprost/timolol FDC is
safe and effective over five years; more
than two third of patients treated with
this FDC, did not show increased iris
pigmentation.(48)
Cost-effectiveness (CE): Some studies have addressed cost issues of glaucoma medical treatment with FDCs.
Travoprost monotherapy was compared
with a fixed combination of latanoprost/
timolol as first-line therapies for ocular hypertension or glaucoma. (49). The
authors estimated a reduction around
half of the mean daily costs in favor of
travoprost. These results do not support FDCs as a cost-effective first-line
therapy, compared with PGA monotherapy. Travoprost/timolol FDC was
shown to compare favorably with latanoprost/timolol FDC through an algorithmic approach that converted IOP
data into visual field progression (50).
Two European studies have analyzed
the efficacy and cost implications comparing the three PGA-FDCs (51) with
two non-PGA-FDCs (52). The authors
reported brimonidine/timolol FDC bid
Glaucoma Now – No3. www.glaucomanow.com
to be more cost-effective than dorzolamide/timolol bid, and bimatoprost/
timolol FDC the most effective and least
costly PGA-FDC in most of the evaluated countries. However, CE analyses of
glaucoma management has limitations:
some patient concerns such as life expectancy or disease stage, outcome measures selected, as well as differences in
design and methodology. Such factors
significantly influence results.
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4
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Glaucoma Now – No3. www.glaucomanow.com
What’s New
Mechanisms of Action of Fixed Combinations
Stephen J Best FRANZCO
Consultant Ophthalmologist at the Auckland District Health Board. He is also Senior Clinical Lecturer at the Ophthalmology
Department of the University of Auckland, New Zealand.
Core Concepts
• Medications from the same pharmacological group should not be
used in combination
• Therapeutic agents should act
synergistically e.g. a drug that increases uveoscleral outflow should
be combined with one that decreases aqueous inflow
• When initiating a combination
therapy, attention needs to be given
to the patient’s medical history
• Prostaglandin monotherapies are
considered best clinical practice and
should be the basis for combination
therapies
• Fixed combinations may have the
benefit of increased patient compliance and less exposure to preservative, potentially improving patients’
quality of life
Introduction
The major risk factor for glaucoma is
elevated intraocular pressure.
The only proven effective strategy
for treating glaucoma is reducing intraocular pressure.
In most clinical situations, significant reduction of intraocular pressure
is achieved by the application of topical
medication.
The ideal treatment would be a single
agent that is well tolerated, administered once daily with excellent efficacy.
However in some routine cases adequate reduction of the intraocular
pressure towards the desired target
pressure can only be achieved with the
use of more than one agent.
The options of combination therapy
are discussed centred on a typical glaucoma case history scenario.
Case Study:
JT, a 56 year old Caucasian with no
family history of glaucoma, was referred by his optometrist. He was sys-
temically well on no medications. His
unaided visual acuity was 6/6 OU.
His intra-ocular pressures (IOP) were
32 mmHg OD and 28 mmHg OS (CCT
554nm and 557nm) and he had open
angles on gonioscopy without pigment
dispersion or pseudo-exfoliation.
The right optic disc had an inferior
focal thinning of the neuro-retinal rim,
and there was corresponding superior
arcuate visual field loss.
The diagnosis was primary open angle
glaucoma. A target intraocular pressure
of 14–16 mmHg was suggested. Best
clinical practice is to use a topical prostaglandin analogue as initial therapy.
These agents are used once daily, and
have minimal side effects (initial hyperemia, eyelashes longer, darker, thicker,
and possible iris darkening long term.)
Daily treatment, often at night-time is
presumed to improve compliance, as well
reduce exposure to topical preservatives.
A therapeutic trial of Gtt latanoprost at
night time (1 drop) to the right eye was
initiated.
6 weeks later the respective IOP
meaurements were 26 mmHg OD and
27 mmHg OS.
To reach target IOP, medical therapy
needed to be changed: what are the options available? To switch within the
same class of ocular hypotensive (prostaglandin) or to add an additional agent
from another class?
We switched “within same class of
drug” to of Gtt brimatoprost, (1 drop) at
bedtime only for the right eye.
8 weeks later IOP were 22 OD and
26 OS. As target IOP had not yet been
reached, additional therapy is required.
The clinical photos of the Humphrey
Visual fields are depicted on page 6 (figure 1) and 7 (figure 2). The optic disc photographs are shown on page 8 (figure 3).
This case history illustrates a common
scenario in medical treatment of glaucoma: one hypotensive agent results in
insufficient IOP lowering. While there
are several options available, the treat-
Glaucoma Now – No3. www.glaucomanow.com
ing physician must tailor treatment to
the individual accounting for multiple
factors, including concurrent systemic
medical conditions.
When more than one topical ocular
hypotensive agent is commonly required in glaucoma management, what
are the options?
Two agents can be combined together
into one solution (“Fixed Combination”), or the two agents can be instilled
simultaneously but separately (“Unfixed
Combination”).
All currently available fixed combination medications use timolol as the second agent
Timolol + DorzolamideCosopt®
MSD
Timolol + Latanoprost Xalacom ® Pfizer
Timolol + Travoprost Duotrav® Alcon
Timolol + Bimatoprost Ganfort® Allergan
Timolol + Brimonidine Combigan ® Allergan
Timolol + Pilocarpine Only available in a
few countries
Add-on topical therapies fall into three
categories:
a) Beta blockers;
b) Alpha agonists;
c) Carbonic anhydrase inhibitors.
Each of these medications has its own
potential side effects and precautions;
in particular topical beta blockers may
exacerbate asthma/reactive airways disease, heart disease, and have other central nervous system side effects. Attention must be given to the patient’s past
medical history.
Topical alpha analogues are contraindicated in children, and their use may
be limited by local allergic reactions.
Topical carbonic anhydrase inhibitors have little systemic side effects (occasional after-taste), but may cause local
discomfort.
When a medication is added to an
ongoing regimen, there are multiple options.
The following overview lists advantages and disadvantages of fixed combination therapy with un-fixed combined
therapy1:
5
Major advantages
1) Presumed improved compliance
with reduced total daily instillation
frequency;
2) Reduced exposure to topical preservatives;
3) Avoidance of the need to wait at least
five minutes between drops from different bottles;
4) Reduced local side effects (especially
hyperemia) when timolol is combined with brimonidine and any of
the prostaglandin agents;
5) All this contributes to improved
quality of life, an important often
neglected factor in the treatment of
glaucoma patients
Major disadvantages
1) No avoidance of possible systemic
and local side effects of component
agents;
2) No avoidance of possible tachyphylaxis (especially with topical beta
blockers);
3) The additive hypotensive effect may
not meet target IOP;
4) The two agents might be slightly
more effective if used in an unfixed
combination (little evidence).
Implementing a combination
therapy
General Principles
Medications from the same pharmacological group should not be used in
combination: There is a variably additive
effect across all pharmacological groups
of ocular hypotensive agents, which requires any combination to be tested for
each patient. No patient should use a
fixed combination unless they have been
shown to have inadequate IOP reduction
from each agent alone, and to have an
additive effect from both together.
Adherence
Even though we cannot measure accurately true compliance in everyday treatment situations as opposed to carefully
crafted randomized double masked trials, we suspect it to be reduced. Indirect
measurements of drug purchased from
the pharmacy demonstrate that even
with single daily dosage regimen the adherence was found to be as low as 50%2 .
These findings were confirmed by
another study group that additionally
found adherence further decreased if 2
medications were applied (32%)3.
6
Table 2.2 of the SEAGIG guidelines outlines the mechanisms of action of the different drug classes (reproduced with permission)5
Mechanism of action
Increase in aqueous outflow
Decrease in aqueous inflow
Drug class
PGAs
Increase uveoscheral outflow
Cholinergics
Increase trabecular outflow
β-Blockers
α2 -adrenergic agonists
CAIs
Side Effects
Fixed combination therapy brimonidine
+ timolol appears to have a reduced in-
Preparations
Latanoprost
Travoprost
Bimatoprost
Unoprostone
Pilocarpine
Carbachol
β1-Non-selective
Timolol
Levoburolol
Carteolol
β1-Selective
Betaxolol
Brimodininen
Apracloridine
Systemic
Acetazolamide
Methazolamide
Dichlorphenamide
Topical
Dorzolamide
Brinzolamide
cidence of allergic reaction compared
with unfixed combined therapy. Initial
reports of this phenomena were anec-
Figure 1: Case study – Humphrey Visual Field Test 24-2, right eye.
Central 24-2 Threshold Test
Fixation Monitor: Gaze/Bind Spot
Stimulus: II, White
Pupil Diameter: 7.9 mm
Date:03-29-201
Fixation Target: Central
Background: 31.5 ASB
Visual Acuity: 20/25
Time: 9:17 AM
Fixation Losses: 2/16
Strategy: SITA-Standard
RX: +5.50 DS DC X
Age: 59
False POS Errors: 0 %
False NEG Errors: 3 %
Test Duration: 05:50
Fovea: OFF
GHT
Outside normal limits
MD
–4.25 dB P <0.5 %
PSD 6.37 dB P <0.5 %
Total
Pattern
Deviation
Deviation
Glaucoma Now – No3. www.glaucomanow.com
Figure 2: Case study – Humphrey Visual Field Test 24-2, left eye.
Central 24-2 Threshold Test
Fixation Monitor: Gaze/Bind Spot
Stimulus: II, White
Pupil Diameter: 4.1 mm
Date:03-29-201
Fixation Target: Central
Background: 31.5 ASB
Visual Acuity: 20/25
Time: 9:24 AM
Fixation Losses: 5/14 xx
Strategy: SITA-Standard
RX: +5.50 DS DC X
Age: 59
False POS Errors: 0 %
False NEG Errors: 0 %
Test Duration: 04:51
Fovea: OFF
and reflect differing methodologies for
the studies..1
Having considered all above points
the case history continued as follows:
This patient was keen to keep therapy
simple, so after further discussion treatment with a fixed combination prostaglandin analogue + timolol with evening
dosing was prescribed.
After instilling Gtt travoprost/timolol
fixed combination ( 1 drop ) at night in
the right eye for 8 weeks, IOP were right
17 mmHg on the right and 21 mmHg
on the left. Subsequently both eyes were
treated with the same medication.
What is the best adjunctive
therapy?
***Low Test Reliability***
GHT
Within normal limits
MD
–0.73 dB
PSD 1.53 dB
Total
Pattern
Deviation
Deviation
dotal, but have been confirmed in 2008
by Motolko.4
Similarly the fixed prostaglandin +
timolol preparations also appear to have
a reduced incidence of hyperaemia.1
Theories of best treatment options
Perhaps the unfixed combination of a
prostaglandin analogue at night-time
(to reduce nocturnal IOP) and day time
agents that reduce aqueous production,
might control IOP more effectively.
However this increases the complexity
of drug dosing with the risk of reduced
compliance.
Time of administration:
Studies suggest that night-time dosing
of fixed combinations of PGA is more
effective than morning dosing for lowering IOP. However this effect night
reflect the time of measurement of IOP
Within the EGS 2008 guidelines, the table on page 139 (reproduced with permission) outlines the additive effects of drug combinations.6
Current Drug
α2 agonists
β-blockers
Topical CAIs
Cholinergic
Prostaglandin/
Prostamides
Drug Combinations- Additive Effect
Additional Drug
α2 agonists β-blockers Topical Cholinergic
CAIs
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Glaucoma Now – No3. www.glaucomanow.com
+/–
Prostaglandin/
Prostamide
+
+
+
+/–
Additive medical decisions must be individualized to minimize side effects
and maximize compliance.
When one topical medication is combined with a second, the rationale underpinning the choice of drugs is based
on the knowledge of the mechanism of
actions. It would make sense to combine
a drug, that increases aqueous outflow
by increased uveoscleral outflow, (prostaglandin analogue) with a second drug
that decreases aqueous inflow (a beta
Blocker). Drugs of the same class would
not be expected to have an additive or
synergistic effect when used as a combined preparation. Another alternative is
the combination of two drugs that both
decrease aqueous inflow; the two available options representing this therapeutic
approach combines a beta blocker either
an alpha adrenergic agonist (Combigan),
or with a carbonic anhydrase inhibitor
(Cosopt).
Conclusion
The use of a typical glaucoma case history scenario provided the framework
for discussion of the available options of
combination therapy for reduction of intraocular pressure.
One of the main principles is the concomitant use of therapeutic agents that
act synergistically to reduce intraocular
pressure.
There are potential benefits from
combination therapy that need to be
balanced by the convenience of single
agents as opposed to multiple agents,
and must be tailored to the individual
patient circumstances in order to achieve
the desired target intraocular pressure.
7
Figure 3: Case study – Optic disc photographs (OD above, OS below).
References
1 Tabet, R et al : A review of additivity of Prostaglandin Analogues : Fixed and unfixed combinations. Survey of Ophthalmology; 53 Supplement
1, Nov 2008.
2 Rait,
LJ&Adena,AA
Persistency
rates
for prostaglandin and other hypotensive
eyedrops:population-based study using pharmacy claims data. CEO 2007; 35: 602–611.
3 Patel SC, Spaeth GL. Compliance in patients
prescribed eye drops for glaucoma. Ophthalmic
Surg 1995; 26: 234–236.
4 Motolko M, Curr Med Res Opin 2008; 24(9):
2663–2667.
5South East Asia Glaucoma Interest Group:
Asia Pacific Glaucoma Guidelines. Second Edition, 2008.
6 European Glaucoma Society: Terminology
and Guidelines for Glaucoma. Second Edition
2003.
8
Glaucoma Now – No3. www.glaucomanow.com
Clinical Issues:
Fixed Combinations in Treatment Algorithms and
Guidelines
Alessandro Bagnis1, Marina Papadia1, Carlo Enrico Traverso1
1 Centro di Ricerca Clinica e Laboratorio per il Glaucoma e la Cornea, Clinica Oculistica Di.N.O.G., University of Genova, Genova, Italy.
Core Concepts
• Glaucoma treatment should be
started with a topical monotherapy
• If the first choice monotherapy is
not effective or tolerable, a switch
to a different monotherapy is to be
considered
• If the first choice monotherapy is
effective, but does not yield target
IOP, an adjunctive therapy is to be
considered
• When two or more actives are neccessary a fixed combination should
be considered.
• Fixed combinations may offer several advantages, such as improved
efficacy and tolerability – through
less exposure to preservatives – as
well as improved patient compliance
and quality of life.
There’s a general consensus to start glaucoma medical therapy with one topical intraocular pressure (IOP) lowering
medication. If the first choice monotherapy alone is not effective to reduce
IOP or is not tolerated, it is preferable
to switch to another molecule that is
initiated as monotherapy. Adjunctive
therapy should be considered whenever a
monotherapy does not reach target IOP
or the target must be lowered as the disease is progressing (1,2) (Fig.1). Usually
fixed-combinations are not ideal as a first
choice product, unless an large reduction
in IOP is needed quickly.
In such cases, fixed-combination drug
preparations may have advantages if
compared with two separate instillations
of the same agents (1) (Fig.1).
Improved compliance. Compliance
with any given medical therapy in glaucoma, like other chronic diseases, is better when regimens are simple rather than
complex (3). In most patients it is not recommended to use more than two drugs
in two separate bottles or to add more
than one single drug to a fixed-combination. Besides complexity, the higher costs
from more bottles seem to promote noncompliance and reduce persistence (4).
Reduced daily amount of exposure
to preservatives and side effects: There
may be a direct correlation between the
presence of preservatives and the surface
symptoms provoked by anti-glaucoma
therapy (5); reducing such exposure
could improve the patient’s comfort
and thus compliance. Long-term use of
topical drugs may be detrimental as a
dose- and time-dependent consequence
to benzalkonium chloride exposure (5).
Such changes may reduce the success rate
of subsequent filtration surgery (6). Although no definitive data exist, at least
some of the currently available fixed
combination have shown a better safety
profile and tolerability when compared
with the same molecules used separately
(1,7).
Possibly more efficacy. Several openlabel replacement studies have suggested
an additional IOP lowering effect when
switching from dorzolamide and a betablocker to the fixed-combination dorzolamide/timolol, but no definitive data
is available (7). Increased compliance
and elimination of the dilution effect if
drops are instilled from different bottles
without sufficient time between, could
explain such fixed-combination benefit.
A substantial proportion of patients on
a multiple drops regimen wait less than
3 minutes before instilling the second
medication. The dilution effect occurs
when patients consecutively instill multiple eye drops too closely, so that the
first drop is washed away by the second
drop before the first can achieve maximal ocular penetration and thus efficacy
(8)
Possible cost savings. The cost of a
fixed combination is not necessarily less
1st CHOICE
MONOTHERAPY
NOT effective and/or
not tolerated
Effective, well
tolerated
Change
monotherapy
TARGET IOP NOT
REACHED
Add a 2nd drug
Add a 2nd drug in a
FIXED COMBINATION
Figure 1. Treatment algorithm of OAG. Fixed combinations are a viable
option when monotherapy fails in reaching the target IOP (1,2).
Glaucoma Now – No3. www.glaucomanow.com
9
than the cost of the single components.
However, fixed combinations reduce the
number of purchased bottles, which may
reduce costs for patients whose prescription drug coverage requires a co-payment
for each prescription filled.
Quality of life. The goal of glaucoma
treatment is to maintain the patient’s visual function and related quality of life
(1). Besides the functional loss and having the diagnosis of a potentially blinding disease, other factors alone or in
combination may affect patients’ quality
of life: inconvenience of the treatment,
side effects and therapy costs. By reducing drops and bottles without losing efficacy, fixed combinations represent an
important tool in order to maintain a
good quality of life, which is one of the
most important aspects for patients.
Conclusions
When two or more active molecules are
necessary to obtain an adequate IOP,
fixed-dose combination eye drops may
offer advantages for patients, while
maintaining at least the same effect on
IOP than separate instillation of the
same two products. Reducing the number of daily drops may improve compliance and quality of life, save costs and
reduce detrimental effects to the ocular
surface.
References
1. Treatment principles and options. In: European Glaucoma Society, Terminology and Guidelines for Glaucoma (3rd ed.), DOGMA Srl, Savona, Italy; 2008. p. 117–169
2. Medical treatment. In: South East Asia Glaucoma Interest Group, Asia Pacific Glaucoma
Guidelines (2nd ed.), SEAGIG, Sydney, Australia;
2008. p. 25–28.
3. Olthoff CM, Schouten JS, Van de Brne BW,
Webers CA. Non compliance with ocular hypothensive treatment in patients with glaucoma or
ocular hypertension: an evidence-based review.
Ophthalmology. 2005;112(6):953–961.
4.Soumerai SB, Pierre-Jacques M, Zhang F, et
al. Cost-related medication nonadherence among
elderly and disabled Medicare beneficiaries: a
national survey 1 year before the Medicare drug
benefit. Arch Intern Med. 2006;166:1829–35.
5. Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the
good, the bad and the ugly. Prog Retin Eye Res.
2010;29(4):312–34. Epub 2010 Mar 17.
6. Baudouin C . Side effects of antiglaucomatous
drugs on the ocular surface. Curr Opin Ophthalmol 1996;7(2):80–6
7. Higginbothan EJ. Considerations in glaucoma
therapy: fixed combinations vs their component
medications. Clin Ophthalmol. 2010;4:1–9.
8.Sleath B, Robin AL, Covert D, et al. Patient-reported behavior and problems in using glaucoma
medications. Ophthalmology. 2006;113:431–436.
Practical Tips:
Fixed Combinations and Patient’s Perspective
Vital P. Costa, MD
Director, Glaucoma Service, University of Campinas, Brazil, Professor of Ophthalmology, University of Campinas, Brazil
Core concepts
• Glaucoma is an asymptomatic
disease and motivating patients to
adhere to treatment is a well known
issue
• Studies have shown that only
about 50% of patients adhere to
monotherapy and even less patients
adhere to a therapy scheme including to 2 medications; as a consequence this has a negative effect
on drug efficacy and treatment success
• In combination therapy use of
multiple agents can lead to washout effects and increase exposure
to toxic effects of preservatives
• Use of fixed combinations decreases such issues and ultimately
have a positive effect on patients’
quality of life.
10
Glaucoma is a chronic, asymptomatic
disease that requires long-term, potentially costly treatment. Medical treatment often causes side effects, with no
subjective improvement in visual function. Unsurprisingly, non-adherence is
so frequent among our patients. One additional factor increasing non-adherence
rates is the frequent need for more than
one medication to control their intraocular pressure (IOP). Among the patients
on medications in the Ocular Hypertension Treatment Study, 40 % required 2
or more medications to obtain a mean
IOP reduction of 20 %1. When IOP
reduction is greater, such as in the Collaborative Initial Glaucoma Treatment
Study, where patients achieved a mean
IOP reduction of 40 %, 75 % of those in
the medical treatment group were using
2 or more agents2.
One of the most important factors
associated with non-adherence is the
medical regimen. Patel & Spaeth3 demonstrated that while 49 % of patients using one medication for the treatment of
glaucoma were compliant, only 32 % of
those using two medications were. The
more medications we prescribe for one
patient, the higher the chances of nonadherence.
Using multiple agents can also lead
to an undesirable “washout effect”. Although we ask patients to wait at least 5
minutes between dosing different medications, few of them actually do. If a patient waits only 30 seconds between dosing medications, up to 45 % of the first
medication can be washed out by the
second4. The time interval between doses
has also been found to affect IOP reduction significantly. In a small study, the
mean IOP decreases were 17.2 % when
2 different topical eye medications were
Glaucoma Now – No3. www.glaucomanow.com
instilled at the same time, 24.5 % when
they were instilled 2 minutes apart, and
27.3 % when the interval between drops
was 5 minutes5.
Recently, interest has increased concerning ocular surface disease in glaucoma patients on medical treatment.
Several medications increase toxic effects to the ocular surface, which may be
secondary to eye drop preservatives (especially benzalkonium chloride, BAK)6.
In terms of efficacy, most randomized, clinical trials that compared fixed
with unfixed combinations showed better IOP control with the latter. While
randomized, controlled trials are the
best way to assess efficacy and safety of
medications, they do not provide insight
into the impact on adherence, since all
patients are closely monitored and encouraged to use their medications correctly. “Real-world” studies, in which
glaucoma patients are switched from
unfixed to fixed-combination therapy,
demonstrate further reductions in IOP,
probably as a consequence of increased
adherence to therapy7,8.
In conclusion, fixed combinations
may increase adherence and improve the
patient’s quality of life by decreasing the
number of instillations required per day
and by reducing the toxic effects induced
by preservatives. Finally, they may even
improve the IOP reduction compared
Problems with multiple mediactions
used separately and simultaneously
Increased number of instillations per day
Fixed combinations
Negative impact on quality of life
Less negative impact on quality of life
Negative impact on adherence and
efficacy
Less negative impact on adherence and
efficacy
Ocular surface side-effects (BAK)
Reduced ocular surface side-effects
Wash-out between drugs
No need for wash-out
Decreased number of instillations per day
with unfixed combinations, especially
in non-adherent patients. These benefits
have encouraged some ophthalmologists to use fixed combinations as first
line therapy. We do not recommend this
approach: patients should be started on
monotherapy, with other medications
being substituted or added in a stepwise
fashion as needed to achieve target IOP.
Before using a fixed combination, the
ophthalmologist needs to confirm the
efficacy and safety of each of its constituent compounds for the individual
patient.
tial Glaucoma Treatment Study comparing initial
treatment randomized to medications or surgery.
Ophthalmology 2001; 108:1943–53.
References
7. Arend K-O, Raber T. Observational study results in glaucoma patients undergoing a regimen replacement to fixed combination travoprost
0.004%/timolol 0.5% in Germany. J Ocular Pharmacol Therapeut. 2008; 24:414-420.
1. Kass MA, Heuer DK, Higginbotham EJ, et al.
The Ocular Hypertension Treatment Study: a
randomized trial determines that topical ocular
hypotensive medication delays or prevents the
onset of primary open-angle glaucoma. Arch
Ophthalmol. 2002; 120:701–713.
2. Lichter PR, Musch DC, Gillespie BW, Guire KE,
Janz NK, Wren PA, Mills RP; CIGTS Study Group.
Interim clinical outcomes in the Collaborative Ini-
Glaucoma Now – No3. www.glaucomanow.com
3. Patel SC, Spaeth GL. Compliance in patients
prescribed eye drops for glaucoma. Ophthalmic
Surg. 1995; 26:234–236.
4. Chrai SS, Makoid MC, Eriksen SP, Robinson
JR. Drop size and initial dosing frequency problems of topically applied ophthalmic drugs. J
Pharm Sci. 1974; 63:333–338.
5. Serle J, Toor A, Fahim M, et al. The effect of
varying dosing intervals on the efficacy of intraocular pressure lowering drugs. Invest. Ophthalmol
Vis Sci. 2004;45: ARVO E-Abstract 974.
6. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma 2008;17:350–5.
8. Choudhri S, Wand M, Shields MB. A comparison of dorzolamide-timolol combination versus
the concomitant drugs. Am J Ophthalmol. 2000;
130:832–3.
11
CME credits can be obtained via the questions on the website very soon.
The process of obtaining CME accreditation for the journal is currently ongoing.
STATEMENT OF NEED AND
PROGRAM DESCRIPTION
Recent months and years have seen
significant advances in our understanding of glaucoma. Much has been
learned, not only about damage mechanisms and pathogenesis, but also about
diagnosis and management. Treatment
options – both medical and surgical –
continue to expand. This program will
review this new knowledge with an emphasis on incorporating recent insights
into day-to-day practice.
discussed or suggested in this activity
should not be used by clinicians without
evaluation of their patient’s conditions
and possible contraindications or dangers in use, applicable manufacturer’s
product information, and comparison
with recommendations of other authorities.
CONTRIBUTORS
•
DATE OF ORIGINAL RELEASE
October 2010. Approved for a period of
12 months
DISCLAIMER
Participants have an implied responsibility to use newly acquired information to
enhance patient outcomes and professional development. The information
presented in this activity is not meant
to serve as a guideline for patient
care. Any procedures, medications, or
other courses of diagnosis or treatment
12
•
•
Francisco Goñi is co-director of
Barcelona Glaucoma Centre-IOBUSP. He is also chief of the Integrated Department of Ophthalmology
at the Hospital of Granollers, Mollet
and Sant Celoni. Mercè Guarro is
his specialist co-worker.
Stephen Best is Consultant Ophthalmologist at the Auckland District
Health Board. He is also Senior
Clinical Lecturer at the Ophthalmology Department of the University of
Auckland, New Zealand.
Carlo Enrico Traverso is Professor
of Ophthalmology at the Centro di
Ricerca Clinica e Laboratorio per il
Glaucoma e la Cornea, Clinica Oculista Di.N.O.G at the University of
Genova, Genova, Italy. Alessandro
Bagnis and Marina Papadia are his
specialist co-workers.
•
Vital P. Costa is Director of Glaucoma Services and Professor of
Ophthalmology at the University of
Campinas, Brazil
DISCLOSURE STATEMENT
EDITORIAL BOARD
Clive Migdal serves on the Faculty and
Advisory Boards of the following companies: Alcon, Allergan, Merck, Pfizer and
Santen.
Ivan Goldberg serves on the Faculty
and Advisory Boards of the following
companies: Alcon, Allergan, Merck and
Pfizer.
Remo Susanna serves on the Faculty
and Advisory Boards of the following
companies: Alcon, Allergan, Merck and
Pfizer.
Glaucoma Now – No3. www.glaucomanow.com