Post on 04-Jun-2018
transcript
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 1/33
Fixed Combination Therapy
Tony Realini, MD, MPH
West Virginia University
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 2/33
• Historical combos
• Modern combos
– Cosopt
– Combigan
– Cosopt PF
– Simbrinza
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 3/33
Traditional Stepped Algorithm
Medications
Trabeculoplasty
Surgery
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 4/33
The Bias In Our Algorithm
• Bias toward medication
– Drugs do not work as well as we think they do
– Patients do not adhere to medical therapy
– Many “adherent” patients miss their eye with the
drop
• Bias against surgery
–Surgery does have risks but they are overrated
– CIGTS and TVT had high complication rates but most
were self-limited and did not pose a threat to vision
Heuer D. AGS Subspecialty Day Lecture. AAO 2011.
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 5/33
The need for multiple medications
26%
42%
0
510
15
20
25
3035
40
45
>1 med >2 meds
P
e r c e n t o f S u b j e c t
s
OHTS 2
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 6/33
Wouldn’t it be nice if two
medications were combined in the
same bottle?
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 7/33
Fixed Combinations: Advantages
• Easier regimen • Fewer bottles
• Fewer drops
• Easier regimen
•
Better compliance?
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 8/33
Fixed Combinations: Advantages
• Easier regimen
• Possibly less expensive
• One co-pay instead of
two
• Only if patient has
prescription drugbenefit
• Two generics may be
cheaper than one
branded fixed
combination
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 9/33
Fixed Combinations: Advantages
• Easier regimen
• Possibly less expensive
• Eliminates the washout
effect
• Minimizes exposure to
excipient ingredients
• Do patients really wait
5-10 minutes between
drops?
• Do we really tell themto?
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 10/33
Fixed Combinations: Advantages
• Easier regimen
• Possibly less expensive
• Eliminates the washout
effect
• Minimizes exposure to
excipient ingredients
• Some have acidic pH
– The stinging might
disincentivize dosing
•Some have BAC – This may aggravate
ocular surface disease
– 40-50% of glaucoma
patients have coincidentocular surface disease
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 11/33
Fixed Combinations: Disadvantages
• Cannot separately
adjust dosing of
constituents
• Not every patient needs
BID beta-blockers
• All fixed combinations
containing a beta-blocker require dosing
twice daily
• This is beta-blocker
overdose for some
patients
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 12/33
Fixed Combinations: Disadvantages
• Cannot separatelyadjust dosing ofconstituents
•
Cannot adjustconcentration of eitherconstituent
• All fixed combinationsthat contain timololhave the 0.5%concentration
• Many patients can becontrolled using timolol0.25%
•
This is also beta-blockeroverdose for somepatients
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 13/33
Fixed Combinations: Disadvantages
• Cannot separately
adjust dosing of
constituents
• Cannot adjustconcentration of either
constituent
• Might be more
expensive than two
generics
• Depends on
prescription drug
benefit…and whether
the fixed combination ison the plan’s formulary.
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 14/33
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 15/33
The rule of fixed combinations
Side effects are always additive
but efficacy never is
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 16/33
Fixed Combos of Historical Interest
• Epinephrine-pilocarpine
• Timolol – pilocarpine
•
Betaxolol – pilocarpine (never marketed)
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 17/33
Modern Fixed Combos (US)
• Cosopt (timolol-dorzolamide)
– Dosed twice daily
– Available with BAC and preservative-free
• Combigan (timolol-brimonidine)
– Dosed twice daily
• Simbrinza (brinzolamide-brimonidine)
– Dosed three times daily
– BID studies ongoing in Europe
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 18/33
Cosopt
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 19/33
Cosopt
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 20/33
Cosopt Safety
• All the systemic beta-blocker effects
– Cardiopulmonary
– Lethargy
– Impotence
• All the topical CAI topical effects
– Stinging
– Bad taste
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 21/33
Combigan
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 22/33
Combigan
= Baseline
= Brimonidine/timolol fixed combination
= Brimonidine and timolol concomitantly dosed
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 23/33
Combigan Safety
• All the systemic beta-blocker effects
• All the brimonidine systemic effects
– Lethargy (contraindicated in young kids)
– Medication interactions (MOA inhibitors)
• Oddly, a 3-fold lower allergy rate than
brimonidine alone
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 24/33
Simbrinza
14
16
18
20
22
24
26
28
8AM 10AM 3PM 5PM
m m H
g Baseline
Brinzolamide
Brimonidine
Fixed Combo
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 25/33
Simbrinza Safety
• No beta-blocker side effects
– The only beta-blocker free fixed combination
• All the brimonidine safety issues
– Allergy issues
– Lethargy (esp. in young kids)
• All the brinzolamide issues
– Blurred vision(suspension)
– Bad taste
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 26/33
Fixed Combos Outside the US
• PGA + Beta-Blocker
– Xalacom (latanoprost + timolol)
– DuoTrav (travoprost + timolol)
– Ganfort (bimatoprost + timolol)
• CAI + Beta-Blocker
– Azarga (brinzolamide + timolol)
• CAI + Beta-Blocker + Adrenergic Agonist
– Krytanek (brinzolamide + brimonidine + timolol)
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 27/33
Where do fixed combinations fit
in the treatment algorithm?
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 28/33
We start with a prostaglandin
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 29/33
Options for First Adjunct to PGA
• Beta-blocker
– Typically adds only 1-1.5 mmHg to PGA
• CAI
– My preference (dosed bid)
– Adds 2.5-4 mmHg to PGA
• Brimonidine
–Adds 2-4 mmHg to PGA
• SLT
– May be slightly less effective in eyes on PGA
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 30/33
Options for Adjunct to PGA + CAI
• Timolol
– PGA + Cosopt
– But beta-blockers still add little to PGAs
• Brimonidine
– PGA + Simbrinza
• SLT
– I suggest this as first adjunct and push harder for
second adjunct
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 31/33
My Path to MMT
• PGA first
• Add CAI (but suggest SLT)
– I use CAIs BID as adjunctive therapy
• SLT• Add brimonidine (PGA + Simbrinza)
– I’ll use Simbrinza BID as adjunctive therapy
– Soon I’ll likely start using Simbrinza as first adjunct
• Add timolol versus surgery
– Timolol is now 4th line!
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 32/33
BAC-Free MMT
• Zioptan
– Tafluprost preservative-free PGA
– In single-dose vials
– Useful in patients who run out of drug
• Cosopt PF
• Alphagan P
– Branded drug is Purite preserved (no BAK)
• SLT
8/14/2019 130pm2RealiniFixedCombinationAgents
http://slidepdf.com/reader/full/130pm2realinifixedcombinationagents 33/33
Summary
• Many glaucoma patients are on multiple meds
• Fixed combinations have pros and cons
• They are generally equally safe and effective
as concomitant dosing
• We now have a beta-blocker-free combination
•
Their place in the treatment algorithm is notentirely clear