130pm2RealiniFixedCombinationAgents

8/14/2019 130pm2RealiniFixedCombinationAgents

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Fixed Combination Therapy

Tony Realini, MD, MPH

West Virginia University



• Historical combos

• Modern combos

– Cosopt

– Combigan

– Cosopt PF

– Simbrinza



Traditional Stepped Algorithm

Medications

Trabeculoplasty

Surgery



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.



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



Wouldn’t it be nice if two

medications were combined in the

same bottle?



Fixed Combinations: Advantages

• Easier regimen • Fewer bottles

• Fewer drops

• Easier regimen

•

Better compliance?




• 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




• Easier regimen


• Eliminates the washout

effect

• Minimizes exposure to

excipient ingredients

• Do patients really wait

5-10 minutes between

drops?

• Do we really tell themto?




• Easier regimen


• 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



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




• 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




• 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.



The rule of fixed combinations

Side effects are always additive

but efficacy never is



Fixed Combos of Historical Interest

• Epinephrine-pilocarpine

• Timolol – pilocarpine

•

Betaxolol – pilocarpine (never marketed)



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



Cosopt



Cosopt Safety

• All the systemic beta-blocker effects

– Cardiopulmonary

– Lethargy

– Impotence

• All the topical CAI topical effects

– Stinging

– Bad taste



Combigan



Combigan

= Baseline

= Brimonidine/timolol fixed combination

= Brimonidine and timolol concomitantly dosed



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



Simbrinza

14

16

18

20

22

24

26

28

8AM 10AM 3PM 5PM

m m H

g Baseline

Brinzolamide

Brimonidine

Fixed Combo



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



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)



Where do fixed combinations fit

in the treatment algorithm?



We start with a prostaglandin



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



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



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!



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



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

130pm2RealiniFixedCombinationAgents

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