Combination Therapy for Glaucoma Management (1).pptx

Combination therapy for
Glaucoma Management

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Glaucoma
Indian Scenario
12 million
people
affected
1.2 million
people blind
from the
disease
>90% of cases
remain
undiagnosed
Second Leading Cause of Irreversible Blindness Globally

E u r o p e a n G l a u c o m a S o c i e t y , 1 9 9 8
Algorithm
IOP >21 mm of Hg
If No cardiac or Pulmonary Problem
Beta Blocker
IOP Controlled Failure
Alternate Mono-therapy
Failure
Combination
Failure
Surgery
Continue Treatment
IOP Controlled

S u r v e y o f O p h t h a l m o l o g y ; 2 0 0 3 V o l . 4 8 ( 1 ) : S 1 - S 3
Glaucoma: Treatment Goal
 The goal of glaucoma treatment is to preserve the visual
field of patients and prevent the loss of visual function
associated with the disease

IOP Control
 First-line treatment – mono-therapy with a single agent
 If IOP reduction is inadequate, treatment switched to
 alternative mono-therapy
 combined with a second agent

IOP Elevation Drives Treatment
7

J A M A O p h t h a l m o l . 2 0 1 5 ; 1 3 3 ( 7 ) : 7 5 5 - 7 6 1
Rationale
 Prostaglandin analogues and β-blockers lower IOP by increasing
aqueous humor uveoscleral outflow and decreasing aqueous
humor production, respectively.
 However, even with their use, the IOP of many patients is not
adequately controlled because of adverse effects and/or
nonresponse
 Indeed, as indicated in the Ocular Hypertension Treatment
Study, a number of patients required 2 or more medications to
reach their target IOPs

Evidences
 Need to add medications under circumstances
such as diminished IOP control with time or
disease progression in spite of pressure control
9

Multiple medications may be problem
 Persistence with a fixed-dose glaucoma medication was
better than with two or more separate bottles, and
supports the idea that adding medication bottles reduces
persistence with glaucoma medication
 Thus, the use of fixed-combination formulations can
simplify regimens and positively contribute to patient
persistence.
10

K l i n M o n b l A u g e n h e i l k d . 2 0 1 3 F e b ; 2 3 0 ( 2 ) : 1 3 3 -
4 0
Advantages of Fixed dose Combinations
 Provide adequate 24-hour IOP control
 Patient Compliance
 Applied less frequently which may improve
adherence
 Lower amount of toxic preservatives
 May eliminate the risk of a "washout”

E x p e r t O p i n i o n o n D r u g S a f e t y ; V o l u m e 1 9 , 2 0 2 0 - I s s u e
1 1
Selecting the right FDC
12
Tolerability
Adherence
Efficacy
Optimizes safety, long-term tolerability and 24-hour IOP efficacy while
considering patient adherence

Rho Kinase Inhibitors
&
Beta blockers
An Emerging therapy in Glaucoma Management
Presenting…….

Ripasudil
 Ripasudil, a derivative of fasudil, a rho-associated protein
kinase inhibitor or ROCK inhibitor (ROCK) used for the
treatment of glaucoma and ocular hypertension

Ripasudil - Role in Glaucoma
Decrease AH
outflow resistance
Neuroprotection
of RGCs
Increase Ocular
Blood Flow

Space narrow
Space widen
Distribute IOP induced
stress across the entire
trabecular lamellae
system
Before
After
Ripasudil – Mechanism of action

Decrease AH Outflow Resistance
By altering cellular components of the TM & Schlemm’s
canal ROCK inhibitors decrease resistance in the TM
outflow pathway & promote reduction of IOP

Neuroprotection of RGCs
ROCK pathway inhibition has shown to
enhance axonal regeneration & increases
ocular blood flow
In POAG, it is widely thought that the initial
site of neuronal injury is the RGC axon
Primary OAG: POAG

Beta Blockers
 Topical beta-blockers reduce the intraocular pressure (IOP)
by blockade of sympathetic nerve endings in the ciliary
epithelium causing a fall in aqueous humor production
19

Timolol
 Used to treat increased pressure inside the eye such as in
ocular hypertension and glaucoma
 First beta blocker approved for topical use in treatment of
glaucoma in the United States (1978)
 Reduces intraocular pressure (IOP) 18–34% below baseline
within first few treatments
20

Timolol
 Decrease aqueous production
 No effect on outflow
 Max IOP reduction of 20-30% (Peak effect 2 hours)
 Once to twice daily (OD to BID) dosing
21

22
Ripasudil
Increases AH outflow
Timolol
Decreases AH production

Ripasudil
Decreases Episcleral
Venous Pressure

24
Ripasudil
Increases AH outflow
Ripasudil
Decreases Episcleral
Venous Pressure
Timolol
Decreases AH
production

Clinical Studies

J O p h t h a l m o l . 2 0 1 7 ; 2 0 1 7 : 7 0 7 9 6 4 5 .
Additive Efficacy
 Additive IOP-lowering effect by was seen with ripasudil through
increment of conventional outflow and with timolol through
suppressing the aqueous humor production
 Combination of ripasudil with timolol prolonged the duration of IOP-
lowering effects compared with single instillation of each agent
 Thus, ripasudil showed additional maximum IOP-lowering effect or
prolongation of IOP-lowering effect in combination with timolol
26

C l i n O p h t h a l m o l . 2 0 2 0 ; 1 4 : 1 2 2 9 – 1 2 3 6 .
Additive Efficacy
 56-day, multicenter, randomized, placebo controlled,
double-masked, at 29 Japanese clinical centers
27
Reductions in IOP at trough and peak levels from baseline

Additive Efficacy
 Reductions in IOP at trough and peak levels from baseline in each week are
shown ripasudil – timolol study, the mean IOP reductions from baseline in
the ripasudil and placebo groups were −2.4 and −1.5 mm Hg before
instillation (9 AM) for a difference of 0.9mmHg and −2.9 and −1.3 mm Hg at
2 hours after instillation (11 AM) for a difference of 1.6mmHg
Conclusion
 The mean IOP reductions from baseline at trough and peak (2
hours after instillation) levels were −2.4 and −2.9mmHg (additive
effect – 0.9 -1.6mmHg)
28

J A M A O p h t h a l m o l . 2 0 1 5 ; 1 3 3 ( 7 ) : 7 5 5 - 7 6 1
Safety
29
• Addition of ripasudil to
timolol did not increase the
incidence of conjunctival
hyperemia
• Furthermore, conjunctival
hyperemia was mild and
resolved before the next
instillation

Composition
 Ripasudil 0.4%
 Timolol 0.5%

Indications
 Primary Open Angle
 Ocular Hypertension
 Secondary Glaucoma

Dosage
 One drop twice a day
33

Benefits
 Lowers IOP by cytoskeletal restructuring of the TM &
decreases AH production
 Reduces Episcleral venous pressure
 Higher & prolong IOP control
 Prevents the death of RGCs & enhancing blood flow to
optic nerve

Combination Therapy for Glaucoma Management (1).pptx

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