Clinical Applications and Tolerability 12-Month Safety

12-Month Safety Results
„
Clinical Applications and
Tolerability
„
„
Paul J. Harasymowycz, MD
MD,
FRCSC, DABO
„
Brimonidine/timolol combination was safe and well
tolerated
No unexpected adverse events
No clinically relevant differences between treatments
in VF, c:d, BP, HR, labs
Improved tolerability compared with brimonidine 0.2%
TID
– Lower incidence of treatment-related adverse events (53.0%
vs 62.8%; P = .006) and discontinuations for adverse events
(14.3% vs 30.4%; P < .001) with the fixed combination than
with brimonidine monotherapy
April 2008 Chicago
Brimonidine and timolol monotherapies are approved for first line therapy.
Sherwood et al. Arch Ophthalmol.
Ophthalmol. 2006.
Treatment-Related Adverse
Events
Serious Adverse Events
Two patients with treatment-related
serious adverse events (timolol)
40
Fixed Brimonidine/Timolol BID (n = 385)
Percentage
e of patients
„
– Respiratory distress secondary to
emphysema
– Nausea, sweating, and tachycardia
„
Four deaths unrelated to treatment
Brimonidine 0.2% TID (n = 382)
35
*P ≤ .03 vs brimonidine 0.2% TID
**P ≤ .02 vs timolol 0.5% BID
Timolol 0.5% BID (n = 392)
30
25
20
15
*
**
10
*
*
*
**
*
**
5
*
0
Conjunctival
hyperemia
– Two in brimonidine group and 1 each in
brimonidine/timolol and timolol groups
„
Ocular
stinging
Eye
pruritus
Conjunctival
Allergic
follicles
conjunctivitis
Oral dryness and adverse events related to conjunctival allergy/inflammation
significantly less common with fixed brimonidine/timolol than with brimonidine
Sherwood et al. Arch Ophthalmol.
Ophthalmol. 2006.
Sherwood et al. Arch Ophthalmol.
Ophthalmol. 2006.
Theory of Adrenergic Effects on Cell
Size and Intercellular Space
„
Study suggests lower allergy rate with
COMBIGAN™ opthalmic solution than
with brimonidine monotherapy
py
– COMBIGAN™ (brimonidine
tartrate/timolol maleate ophthalmic
solution) 0.2%/0.5% phase 3 study
„
Adrenergic agents reduce cell size, expand intercellular spaces and
allow greater migration of “pro-inflammatory mediators” to
subconjunctival tissues
Inflammatory Mediators
The area between
cells was 4X
greater for cells
treated with
adrenergic agonists
Conjunctiva
al
Epithelial Cellls
COMBIGAN™ Allergy Rate
„
Oral
dryness
Ocular Allergy
Sherwood et al. Arch Ophthalmol.
Ophthalmol. 2006.
Results from experiments using cultured human
cells of the outflow pathway.
The clinical significance is unknown.
Alvarado. Arch Ophthalmol. 2007;
Butler et al. Arch Ophthalmol. 1995.
1
Timolol may reduce the space between conjunctival epithelial
cells, thereby reducing migration of “pro-inflammatory
mediators”
Inflammatory Mediators
„
Adrenergic effects
blocked by timolol
Conjunctival
Epithelial Cells
COMBIGAN™ and Cosopt ®
Tolerability and Comfort
Percentage of patie
ents with
rating of moderate o
or severe
Theory of Adrenergic Effects on Cell
Size and Intercellular Space
COMBIGAN™(brimonidine tartrate/timolol
40%
maleate ophthalmic solution) 0.2%/0.5% (n = 85)
Cosopt® (dorzolamide hydrochloride-timolol
30%
l t ophthalmic
hth l i solution)
l ti ) (n
( = 86)
maleate
20%
10%
0%
Results from experiments using cultured
human cells of the outflow pathway.
The clinical significance is unknown.
Reduced Ocular Allergy
P = .0149
1Nixon
P = .0047
and Hollander.
2AAO,
2007. Data on file, Allergan, Inc.
1.97
*P < .0001 vs Cosopt®
1.5
1.0
n = 30
0.43
Percentage of subjects rating
omfortable
treatment as most co
30–40 Seconds After Drop Instillation
2.0
*
Unusual taste
Ocular Comfort: COMBIGAN™ (brimonidine
tartrate/timolol maleate ophthalmic solution)
0.2%/0.5% and Cosopt® (dorzolamide hydrochloridetimolol maleate ophthalmic solution)
30–40 Seconds After Drop Instillation
Mean ocular discomfo
ort score
Burning
P = .0001
Alvarado. Arch Ophthalmol.
Ophthalmol. 2007.
Ocular Discomfort: COMBIGAN™ (brimonidine
tartrate/timolol maleate ophthalmic solution)
0.2%/0.5% and Cosopt® (dorzolamide hydrochloridetimolol maleate ophthalmic solution)
0.5
Stinging
80%
*
80%
*P < .0001 vs Cosopt®
60%
n = 30
40%
20%
10%
10%
0%
0.0
COMBIGAN™
COMBIGAN™
Cosopt®
Cosopt®
Chan et al. J Ocul Pharmacol Ther.
Ther. 2007.
Dorzolamide/Timolol Combination versus
Concomitant Administration of Brimonidine and
Timolol
Treatments equally
comfortable
Chan et al. J Ocul Pharmacol Ther.
Ther. 2007.
COSOPT versus
Alphagan + Timolol bid
Six-Month Comparison of Efficacy and Tolerability
„
Conclusions:
– The efficacy of the
dorzolamide/timolol
combination and the
concomitant
administration of
brimonidine and timolol
were comparable.
– The incidence of drugrelated adverse
experiences and the
incidence of
discontinuations caused
by drug-related adverse
experiences
were2003;110:615–624
Ophthalmology
similar between groups.
2
Dorzolamide/Timolol Combination versus
Concomitant Administration of Brimonidine
and Timolol
Case Presentation
„
„
„
„
„
64 yo female with migraines
Mother blind from glaucoma
CCT 536/521; Tmax=
Tmax 25; SLT OU
Treated with Xalatan + Cosopt x 18
months
On mini DTC IOP fluctuating
between17- 19 OD and 17-20 OS
(alternating times)
3
Case Presentation
„
„
„
„
Pt told that a trip to the OR (NPGS) will be
necessary to control her glaucoma
Admits to poor compliance using Cosopt
every 2-3 days because of burning
sensation and dygeusia
Switched to Combigan bid OU; comfortable
Fup 2 months: IOP 14 OU
4