Glaucoma Therapy: The Glaucoma Therapy: The “Art” of Medical “Art” of Medical Management Management

J. James J. James Thimons,O.D.,FAAOThimons,O.D.,FAAO

Medical Director, Medical Director, Ophthalmic Consultants Ophthalmic Consultants

of CTof CT

                                                                                                     

                                 

The Role of IOP The Role of IOP Management in Management in

GlaucomaGlaucoma

PEAK Effect with Evening DosePEAK Effect with Evening DoseOnce daily drug:Once daily drug:• Peak effectPeak effect (8 mm Hg) at 12-14 hrs (8 mm Hg) at 12-14 hrs

post dosepost dose• Trough effectTrough effect (2 mm Hg) at 22-24 (2 mm Hg) at 22-24

hrs hrs post dosepost dose

3

Courtesy of David B. Yan, M.D., F.R.C.S.(C)

0

1

2

3

4

5

6

7

8

9

0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400

IOP

Re

du

ctio

n (

mm

Hg)

Time of Day (hr)

Office hours

Trough

2:00

am

4:00

am

6:00

am

12:00

pm

8:00

am

10:00

am

2:00

pm

4:00

pm

6:00

pm

8:00

pm

12:00

am

10:00

pm

Time of Day (hr) Dose

IOP VariabilityIOP Variability

Highest (peak) IOP may commonly occur Highest (peak) IOP may commonly occur outside of usual clinic office hoursoutside of usual clinic office hours1,21,2

In spite of achieving target IOP during In spite of achieving target IOP during office hours patients may experience:office hours patients may experience:– ““damaging”/above target IOPs at other times damaging”/above target IOPs at other times

of the dayof the day– disease progressiondisease progression

Are we missing IOP spikes, peak, Are we missing IOP spikes, peak, damaging IOP, IOPs at other times of damaging IOP, IOPs at other times of dayday33??

1. Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204.2. Mosaed S, et al. Am J Ophthalmol. 2005; 139(2): 320–324.3. Hughes E, et al. J of Glaucoma 2003; 12: 232-236.

4

PURPOSE:PURPOSE: To determine the relationship between office To determine the relationship between office IOP and peak IOPIOP and peak IOP

METHODS (Study One)METHODS (Study One)11:: 42 patients with OAG42 patients with OAG Treated with 3 different IOP lowering eye drops Treated with 3 different IOP lowering eye drops 24 hr IOP values obtained in sitting position with 24 hr IOP values obtained in sitting position with

Goldmann applanation tomography at 3 hr intervalsGoldmann applanation tomography at 3 hr intervalsMETHODS (Study Two)METHODS (Study Two)22:: 103 patients with OAG (including 35 untreated)103 patients with OAG (including 35 untreated) 24 hr IOP values obtained at 2 hr intervals using a 24 hr IOP values obtained at 2 hr intervals using a

pneumatometer, in sitting and supine positions during pneumatometer, in sitting and supine positions during the diurnal/wake period and in the supine position the diurnal/wake period and in the supine position during the nocturnal/sleep periodduring the nocturnal/sleep period

5

Peak IOP Outside Office Hours

1.Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204.2.Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320-324.

Peak IOP Outside Office Peak IOP Outside Office HoursHours

• 67% of peak 67% of peak IOP occurs IOP occurs outside office outside office hourshours22

6

Times at which maximum and Times at which maximum and minimum IOP occurred in a 24-hr minimum IOP occurred in a 24-hr

periodperiod11::

Time of maximum IOP in 24-hourTime of minimum IOP in 24-hour

8

Num

ber o

f eye

s

2819

10

40

30

20

10

03am-6am

9am-12pm

3pm-6pm

9pm-12am

2010 12

23

1.Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204.2.Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320-324.

Study 1Study 2

IOP is Higher at NightIOP is Higher at Night Higher nocturnal supine IOP than diurnal sitting IOP Higher nocturnal supine IOP than diurnal sitting IOP

(healthy and OAG)(healthy and OAG) Supine IOP higher than sitting IOP, regardless of time of daySupine IOP higher than sitting IOP, regardless of time of day

7

Habitual IOP of healthy eyes

IOP

(m

m H

g)

Habitual IOP of glaucomatous eyes

3:3

0 A

M

3:3

0 P

M

5:3

0 P

M7

:30

PM

9:3

0 P

M1

1:3

0 P

M1

:30

AM

5:3

0 A

M7

:30

AM

9:3

0 A

M

11

:30

AM

1:3

0 P

M

252423222120191817161514

26

Clock Time

n=24

Nocturnal

Supine

Nocturnal

Supine

Diurnal SittingDiurnal Sitting

Diurnal SittingDiurnal SittingNocturnal

Supine

Nocturnal

Supine

Diurnal SittingDiurnal Sitting

Diurnal SittingDiurnal Sitting

Clock Time

1:3

0 P

M

IOP

(m

m

Hg

)

252423222120191817161514

26

3:3

0 A

M

3:3

0 P

M

5:3

0 P

M

7:3

0 P

M

9:3

0 P

M1

1:3

0 P

M

1:3

0 A

M

5:3

0 A

M7

:30

AM

9:3

0 A

M

11

:30

AM

n=24

Liu JH et al. Invest Ophthalmol Vis Sci. 2003; 44: 1586-1590.

*Error bars = SEM*Error bars = SEM

Diurnal Fluctuations in IOP: Diurnal Fluctuations in IOP: Independent Risk Factor?Independent Risk Factor?

8

Asrani S, et al. J Glaucoma 2000; 9: 134-142.

PURPOSE: To study the risk associated with diurnal IOP variations in patients with OAG

METHODS:• 64 patients with OAG and IOP below 25 mm Hg (over 5 year

follow-up)• Patients successfully performed tonometry with a self-tonometer

5 times a day for 5 days• Baseline status and time to progression of visual field loss

identified from clinical charts• Level and variability of diurnal IOP characterized and risk of

progression analyzed using a nonparametric time-to-event model

9

0

1

2

3

4

5

6

Diurnal IOP range

3.1 mm Hg

Diurnal IOP range

5.4 mm Hg

1.0

5.76

Rela

tive

risk

of d

isea

se

prog

ress

ion

with

in 5

yea

rs

Hazard ratio between higher quartile and lower quartile for “Range in Home IOP” was 5.7

Hazard ratio between higher quartile and lower quartile for “Range in Home IOP” was 5.7

Diurnal Fluctuations Correlate with Visual Field Progression

Asrani S, et al. J Glaucoma 2000; 9: 134-142.

Patients on More ThanPatients on More ThanOne IOP-Lowering MedicationOne IOP-Lowering Medication

Source: Verispan’s PDDA, MAT Nov 2006.Source: Verispan’s PDDA, MAT Nov 2006.

69.8%

24.4%

5.6%

0.2%

1 Medication

2 Medications

3 Medications

4 Medications

Pathways to lower Intraocular Pathways to lower Intraocular PressurePressure

InflowInflow– Alpha 2- Alpha 2-

agonistsagonists– B1 blockersB1 blockers– CAICAI

Outflow Outflow – Alpha 2–Alpha 2–

agonistsagonists– CholinergicsCholinergics– Prostaglandins/ Prostaglandins/

ProstamindesProstamindes

Beta-blockersBeta-blockers 30 year history of successfully lowering 30 year history of successfully lowering

IOPIOP

Reduces aqueous humor formationReduces aqueous humor formation

Adrenergic agonistsAdrenergic agonists

Lowers IOP 22-28%Lowers IOP 22-28%

Ocularly well toleratedOcularly well tolerated

Beta BlockersBeta Blockers

Beta receptor in the ciliary body epitheliumBeta receptor in the ciliary body epithelium

Beta 1 receptors >> Beta 2 receptors in the Beta 1 receptors >> Beta 2 receptors in the eyeeye

Beta receptors stimulate productions of Beta receptors stimulate productions of aqueous.aqueous.

Beta blockers suppress aqueous productionBeta blockers suppress aqueous production

Beta-blockersBeta-blockers Timolol maleate – Timoptic, Timoptic Timolol maleate – Timoptic, Timoptic

XE (1/2, 1/4 %)XE (1/2, 1/4 %) Carteolol – Ocupress 1% (Intrinsic Carteolol – Ocupress 1% (Intrinsic

sympathomimetic activity)sympathomimetic activity) Levobunolol – Betagan ½%Levobunolol – Betagan ½% Timolol hemihydrate – Betimol ¼, ½%Timolol hemihydrate – Betimol ¼, ½% Istalol ¼,1/2% - QD dosing indicationIstalol ¼,1/2% - QD dosing indication Betaxolol ¼% - cardioselective, safer?Betaxolol ¼% - cardioselective, safer?

SystemicSystemic

BradycardiaBradycardia Congestive heart failureCongestive heart failure Exacerbation of heart blockExacerbation of heart block BronchospasmBronchospasm Mood changeMood change Impotence Impotence Lipid profileLipid profile

ContraindicationsContraindications

AsthmaAsthma Severs COPDSevers COPD CHFCHF Heart blockHeart block Myasthenia gravisMyasthenia gravis Diabetes Diabetes

Lama study (AJO 11/02)Lama study (AJO 11/02) Conclusions:Conclusions:

– ...identifies no scientific studies ...identifies no scientific studies supporting the development of supporting the development of worsening claudication, depression, worsening claudication, depression, hypoglycemia,sexual dysfunction or hypoglycemia,sexual dysfunction or impaired neuromuscular transmissionimpaired neuromuscular transmission

– Recommends careful medical history Recommends careful medical history and checking pulse rate and rhythmand checking pulse rate and rhythm

So?So?

TimololTimolol

Equally effective in Equally effective in AA’s and WhitesAA’s and Whites

IOP decrease 30-60 IOP decrease 30-60 minmin

Long term drift Long term drift – 47% decrease at 1 47% decrease at 1

wk wk – 25% at 1 yr 25% at 1 yr

Carteolol (ocupress)Carteolol (ocupress)

Intrinsic Intrinsic sympathomimetic sympathomimetic activityactivity

Less likely to Less likely to

increase systemic increase systemic lipid profilelipid profile

Ocular Side EffectsOcular Side Effects

Punctate keratopathyPunctate keratopathy

Corneal anesthesia ( Watch for DESx)Corneal anesthesia ( Watch for DESx)

BlepharoconjunctititisBlepharoconjunctititis

Brimonidine 0.1% AlphaganBrimonidine 0.1% Alphaganalpha-2 alpha-2

Decrease aqueous productionDecrease aqueous production Also increase uveoscleral outflow Also increase uveoscleral outflow

(small amount)(small amount) Not as effective as timolol but Not as effective as timolol but

closeclose May be neuroprotectiveMay be neuroprotective More effective than or More effective than or

dorzolamide?dorzolamide? Can cause mild mydriasisCan cause mild mydriasis Comes in 0.1%, 0.15%, 0.2%Comes in 0.1%, 0.15%, 0.2%

Brimonidine:Brimonidine:Dual Mechanism of IOP LoweringDual Mechanism of IOP Lowering

Enhances Enhances uveoscleral uveoscleral outflowoutflow

Suppresses Suppresses aqueous aqueous humor humor production production (inflow)(inflow)

Toris et al. 1995 and 1999. Toris et al. 1995 and 1999.

Brimonidine Formulation Brimonidine Formulation ComparisonComparison

ALPHAGANALPHAGAN®® P P ALPHAGANALPHAGAN®®

ConcentratioConcentration of n of BrimonidineBrimonidine

0.1%0.1% 0.15%0.15% 0.2%0.2%

pHpH 7.77.7 7.27.2 6.3-6.56.3-6.5

PreservativePreservative PURITEPURITE®® BAKBAK

Viscosity Viscosity agentagent

CarboxymethylcellulCarboxymethylcelluloseose Polyvinyl alcoholPolyvinyl alcohol

ElectrolytesElectrolytes

Potassium chloride, Potassium chloride, calcium chloride calcium chloride

dihydrate, dihydrate, magnesium chloride magnesium chloride

hexahydratehexahydrate

––

Side effectsSide effects

10-30% dry mouth10-30% dry mouth 10% allergy rate10% allergy rate Avoid with MAO Avoid with MAO

inhibitorsinhibitors Alphagan P 0.1%Alphagan P 0.1%

– Better toleratedBetter tolerated

Mean IOP at Peak (10 Mean IOP at Peak (10 amam))

Katz.Katz. J Glaucoma J Glaucoma. 2002.. 2002.

Brimonidine-PURITE® 0.15% (N = 372)

Brimonidine 0.2%* (N = 376)

16

18

20

22

24

26

28

30

0 2 4 6 8 10 12Months of treatment

*Original ALPHAGAN*Original ALPHAGAN®®

Me

an

IOP

(m

m H

g)

Mean IOP at Trough (8 Mean IOP at Trough (8 amam))

Katz.Katz. J Glaucoma J Glaucoma. 2002.. 2002.

16

18

20

22

24

26

28

30

0 2 4 6 8 10 12

Months of treatment

Brimonidine-PURITE® 0.15% (N = 372)

Brimonidine 0.2%* (N = 376)

*Original ALPHAGAN*Original ALPHAGAN®®

Me

an

IOP

(m

m H

g)

Alpha Agonists-side effectsAlpha Agonists-side effects

Ocular-Ocular-– dermatitis, dermatitis, – lid retraction, lid retraction, – conjunctival conjunctival

blanching, blanching, – allergic reactionsallergic reactions

Systemic Systemic – dry mouth, dry mouth, – dry eyedry eye– lethargy, lethargy, – apnea in apnea in

children,children,– hypotensionhypotension

ContraindicationContraindication

ChildrenChildren

MAO inhibitorsMAO inhibitors

Nocturnal Efficacy: Nocturnal Efficacy: Brimonidine MonotherapyBrimonidine Monotherapy

Liu JH, et al. Ophthalmology 2010; 117: 2075–2079.

29

PURPOSE: To investigate the effect of brimonidine monotherapy on IOP during the nocturnal/sleep period

DESIGN: Prospective, open-label studyMETHODS: • Baseline data of 24 hr IOP in untreated patients collected in a

sleep laboratory• Measurements of IOP taken using a pneumatonometer every 2 hrs

in sitting and supine positions during the 16 hr diurnal period and in supine position during the 8 hr nocturnal period

• Patients treated afterward with brimonidine 0.1% 3 times per day for 4 weeks, and 24 hr IOP data were collected under the same laboratory conditions

PURPOSE: To investigate the effect of brimonidine monotherapy on IOP during the nocturnal/sleep period

DESIGN: Prospective, open-label studyMETHODS: • Baseline data of 24 hr IOP in untreated patients collected in a

sleep laboratory• Measurements of IOP taken using a pneumatonometer every 2 hrs

in sitting and supine positions during the 16 hr diurnal period and in supine position during the 8 hr nocturnal period

• Patients treated afterward with brimonidine 0.1% 3 times per day for 4 weeks, and 24 hr IOP data were collected under the same laboratory conditions

02468

101214161820222426283.

30PM

5.30

PM

7.30

PM

9.30

PM

11.3

0PM

1.30

AM

3.30

AM

5.30

AM

7.30

AM

9.30

AM

11.3

0AM

1.30

PM

BaselineBrimonidine

30

NOCTURNAL/SLEEP

DIURNAL/WAKE

DIURNAL/WAKE

Hab

itual

IOP

(mm

Hg)

Clock Time

brimonidine

brimonidine

brimonidine

Brimonidine Efficacy During Nocturnal Period

Liu JH, et al. Ophthalmology 2010; 117: 2075–2079.

Error bars = SEMN = 15Error bars = SEMN = 15

Glaucoma & PregnancyGlaucoma & Pregnancy

BJO 2009; JD Ho: BJO 2009; JD Ho: 244 pregnant women treated for 244 pregnant women treated for

glaucoma analyzed for birth weightglaucoma analyzed for birth weight 1,952 age matched controls1,952 age matched controls No significant difference between No significant difference between

women on BB’s vs: no Txwomen on BB’s vs: no Tx Herndon, L: D/C Brimonodine several Herndon, L: D/C Brimonodine several

weeks before d/t risk of apnea weeks before d/t risk of apnea

COMBIGAN™COMBIGAN™(Brimonidine Tartrate/Timolol (Brimonidine Tartrate/Timolol Maleate Ophthalmic Solution) Maleate Ophthalmic Solution)

0.2%/0.5%0.2%/0.5%

Diurnal Mean IOP at Month 12Diurnal Mean IOP at Month 12

0

4

8

12

16

20

Brimonidine (n = 382)***

Timolol (n = 392)***

Fixed brimonidine/timolol (n = 385)

*P < .001 vs timolol

Mea

n I

OP

(m

m H

g)

8 AM 10 AM 3 PM 5 PM

**P < .001 vs brimonidine

Dose all treatments

Dose brimonidine

Sherwood et al. Sherwood et al. Arch OphthalmolArch Ophthalmol. 2006.. 2006.

*****

**

***

Statistical significance does not necessarily correlate to clinical significance. ***Brimonidine and timolol monotherapies are approved for first line therapy.

Treatment-Related Adverse EventsTreatment-Related Adverse Events

***

* ****

***

*

0

5

10

15

20

25

30

35

40Fixed Brimonidine/Timolol BID (n = 385)

Brimonidine 0.2% TID (n = 382)***

Timolol 0.5% BID (n = 392)***

* P ≤ .03 vs brimonidine 0.2% TID** P ≤ .02 vs timolol 0.5% BID

Sherwood et al. Sherwood et al. Arch OphthalmolArch Ophthalmol. 2006.. 2006.

Conjunctivalhyperemia

Ocularstinging

Eyepruritus

Allergicconjunctivitis

Conjunctivalfollicles

Oraldryness

Per

cen

tag

e o

f p

atie

nts

***Brimonidine and timolol monotherapies are approved for first line therapy.

15.2 15.3

21.9

0

4

8

12

16

20

24

0 1 2 3

COMBIGAN™ in Adjunctive Therapy COMBIGAN™ in Adjunctive Therapy With a PGA: Mean IOPWith a PGA: Mean IOPM

ean

IO

P (

mm

Hg

)

Month

-6.9 mm Hg(29%)

Added to a PGA baseline

* *

*P < .0001 vs baseline

COMBIGAN™(brimonidine tartrate/timolol maleate

ophthalmic solution) 0.2%/0.5% + PGA (n = 37)

11Nixon and Hollander. Nixon and Hollander. 22AAO, 2007. Data on file, Allergan, Inc.AAO, 2007. Data on file, Allergan, Inc.

COMBIGAN™ and COMBIGAN™ and CosoptCosopt®®

Randomized, investigator-masked, 3-month, parallel Randomized, investigator-masked, 3-month, parallel comparison comparison

Pooled data from 2 studies at 10 sites with identical Pooled data from 2 studies at 10 sites with identical protocols (Canada)protocols (Canada)

Patients with OAG/OHT requiring additional IOP Patients with OAG/OHT requiring additional IOP lowering lowering

Two subgroups Two subgroups – Monotherapy: COMBIGAN™(brimonidine tartrate/timolol maleate Monotherapy: COMBIGAN™(brimonidine tartrate/timolol maleate

ophthalmic solution) 0.2%/0.5% (n = 54) and ophthalmic solution) 0.2%/0.5% (n = 54) and CosoptCosopt®® (dorzolamide (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 47) hydrochloride-timolol maleate ophthalmic solution) (n = 47)

– Adjunctive: COMBIGAN™ added to PGA (n = 37) and Adjunctive: COMBIGAN™ added to PGA (n = 37) and CosoptCosopt®® added to PGA (n = 42) added to PGA (n = 42)

IOP 2 hours after morning doseIOP 2 hours after morning dose Visits at baseline, 1 month, and 3 monthsVisits at baseline, 1 month, and 3 months

PGA = prostaglandin analoguePGA = prostaglandin analogue 11Nixon and Hollander. AAO. 2007; Nixon and Hollander. AAO. 2007; 22Data on file, Allergan, Inc.Data on file, Allergan, Inc.

COMBIGAN™ and COMBIGAN™ and CosoptCosopt®® as as Monotherapy: Mean IOPMonotherapy: Mean IOP

Mean IOP reductions from baseline at month 3 were 7.7 mm Hg Mean IOP reductions from baseline at month 3 were 7.7 mm Hg with COMBIGAN™ and 6.7 mm Hg with with COMBIGAN™ and 6.7 mm Hg with CosoptCosopt®® ( (PP = .040) = .040)

Mea

n I

OP

(m

m H

g)

23.6

16.3 17.223.0

15.8 15.6

0

4

8

12

16

20

24

0 1 2 3Month

*

*P = 0.04 (mean change from baseline)Cosopt® (dorzolamide hydrochloride-timolol maleate

ophthalmic solution) (n = 47)

COMBIGAN™ (brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% (n = 54)

11Nixon and Hollander. AAO. 2007; Nixon and Hollander. AAO. 2007; 22Data on file, Allergan, Inc.Data on file, Allergan, Inc.

COMBIGAN™ and COMBIGAN™ and CosoptCosopt ®®

Tolerability and ComfortTolerability and Comfort

Per

cen

tag

e o

f p

atie

nts

wit

h

rati

ng

of

mo

der

ate

or

seve

re

0%

10%

20%

30%

40%

Stinging Burning Unusual taste

COMBIGAN™(brimonidine tartrate/timolol

maleate ophthalmic solution) 0.2%/0.5% (n = 85)

Cosopt® (dorzolamide hydrochloride-timolol

maleate ophthalmic solution) (n = 86)

P = .0001 P = .0149 P = .0047

11Nixon and Hollander. Nixon and Hollander. 22AAO, 2007. Data on file, Allergan, Inc.AAO, 2007. Data on file, Allergan, Inc.

Carbonic Anhydrase InhibitorsCarbonic Anhydrase Inhibitors

4 types of isoenzymes4 types of isoenzymes I erythrocytes and corneal epitheliumI erythrocytes and corneal epithelium II non pigmented ciliary body II non pigmented ciliary body

epithelium , iris retinas lensepithelium , iris retinas lens III skeletal muscleIII skeletal muscle IV kidneyIV kidney

Carbonic Anhydrase InhibitorsCarbonic Anhydrase Inhibitors

Aqueous humor formation depends Aqueous humor formation depends on secretion of bicarbonate from the on secretion of bicarbonate from the ciliary processes when bicarbonate is ciliary processes when bicarbonate is formed, it tied with sodium and water formed, it tied with sodium and water followsfollows

Similar process in CSF production Similar process in CSF production and in kidney and in kidney

CAICAI

DorzolamideDorzolamide 2%2% BrinzolamideBrinzolamide 1%1% AcetazolamideAcetazolamide 125, 250, 125, 250,

500mg sequels500mg sequels Methazolamide Methazolamide 25, 50 mg25, 50 mg

Systemic Side Effects Oral UseSystemic Side Effects Oral Use Malaise and fatigue Malaise and fatigue Weight lossWeight loss AnorexiaAnorexia Loss of libidoLoss of libido Depression Depression Sulfa allergiesSulfa allergies Sickle cellSickle cell Marked kidney/liver Marked kidney/liver Low potassiumLow potassium Low sodium levelLow sodium level Transient myopiaTransient myopia

– Swelling of CBSwelling of CB

Pregnancy Category CPregnancy Category C ParesthesiaParesthesia TinitusTinitus NauseaNausea Taste alterationsTaste alterations Metabolic acidosisMetabolic acidosis

Contraindications to Oral Therapy Contraindications to Oral Therapy

Sulfa allergiesSulfa allergies Sickle cellSickle cell Marked kidney/liver Marked kidney/liver Low potassiumLow potassium Low sodium levelLow sodium level Pregnancy Category CPregnancy Category C Metabolic acidosisMetabolic acidosis

CAIs make wonderful partnersCAIs make wonderful partners Feldman, et al 2006 –Feldman, et al 2006 – 1.5-1.8 mm lower IOP as compared 1.5-1.8 mm lower IOP as compared

to brimonidine 0.15% when added to to brimonidine 0.15% when added to travaprosttravaprost

This significance was present at all This significance was present at all time pointstime points

BID dosingBID dosing

Companion study #2Companion study #2 When compared to brimonidine 2% When compared to brimonidine 2%

adding them to Travaprost...adding them to Travaprost... IOP lowered by 13% w/ brimonidineIOP lowered by 13% w/ brimonidine IOP lowered by 23% w/ brinzolamideIOP lowered by 23% w/ brinzolamide

Brinzolamide as an Brinzolamide as an Adjunct to LatanoprostAdjunct to Latanoprost

Shoji N, et al. Cur Med Res Opin 2005; 21: 503-507.

46

PURPOSE: To evaluate the IOP lowering effect of brinzolamide (1.0%) as an adjunctive therapy to latanoprost (0.005%) in patients with open-angle glaucoma or ocular hypertension

METHODS: • 14 patients with open-angle glaucoma or ocular hypertension who

had been using latanoprost for more than 6 months were initiated on adjunctive brinzolamide therapy

• IOP values at 1, 2 and 3 months compared with baseline (beginning of adjunctive therapy)

• Incidence of adverse events examined

PURPOSE: To evaluate the IOP lowering effect of brinzolamide (1.0%) as an adjunctive therapy to latanoprost (0.005%) in patients with open-angle glaucoma or ocular hypertension

METHODS: • 14 patients with open-angle glaucoma or ocular hypertension who

had been using latanoprost for more than 6 months were initiated on adjunctive brinzolamide therapy

• IOP values at 1, 2 and 3 months compared with baseline (beginning of adjunctive therapy)

• Incidence of adverse events examined

47

Brinzolamide as an Adjunct to Latanoprost

Shoji N, et al. Cur Med Res Opin 2005; 21: 503-507.

21.1 ± 4.816.9 ± 4.5 16.6 ± 4.0 15.9 ± 3.1

0

5

10

15

20

25

30

Baseline 1 Month 2 Months 3 Months

IOP

(mm

Hg)

** P < 0.01 (Wilcoxon signed ranked test)

** ****

Adjunctive therapy lowered IOP by an additional Adjunctive therapy lowered IOP by an additional 5.2 mm Hg after 3 months5.2 mm Hg after 3 months

02468

101214161820222426

3.30

PM

5.30

PM

7.30

PM

9.30

PM

11.3

0PM

1.30

AM

3.30

AM

5.30

AM

7.30

AM

9.30

AM

11.3

0AM

1.30

PM

latanoprostlatanoprost + brinzolamidelatanoprost + timolol

48

Brinzolamide or Timolol: Adjunct to Latanoprost in an Open-Label Study

Liu JH, et al. Ophthalmology 2009; 116(3): 449-54.

N=26Error bars = SEMN=26Error bars = SEM

Clock Time

Hab

itual

IOP

(mm

Hg)

DIURNAL/WAKEDIURNAL/WAKE DIURNAL/WAKEDIURNAL/WAKENOCTURNAL/SLEEPNOCTURNAL/SLEEP

ProstaglandinsProstaglandins/Prostamides/Prostamides

Uveal seleral outflowUveal seleral outflow Affects many properties with the Affects many properties with the 1955-Ambache described irin which 1955-Ambache described irin which

medicated ocular response to medicated ocular response to inflammationinflammation

Naturally synthesized by trabecular Naturally synthesized by trabecular endothelial cells/ciliary muscle cellsendothelial cells/ciliary muscle cells

May have only minor inflammatoryMay have only minor inflammatory Regulatory effects Regulatory effects

ProstaglandinsProstaglandins/Prostamides/Prostamides

Different receptor sites DP,EP,IPDifferent receptor sites DP,EP,IP Prostaglandins E and F most effective Prostaglandins E and F most effective

in lowering IOPin lowering IOP They seem to facilitate aqueous They seem to facilitate aqueous

outflow via the uvealscleral pathwayoutflow via the uvealscleral pathway

Latanoprost 0.005%Latanoprost 0.005% XalatanXalatan– Prostaglandin F 2a analogueProstaglandin F 2a analogue– Prodrug Prodrug

Travoprost 0.004% Travoprost 0.004% TravatanTravatan– Prostaglandin F 2a analogueProstaglandin F 2a analogue– ProdrugProdrug

Brimatoprost 0.03%Brimatoprost 0.03% LumiganLumigan– Synthetic prostamide analogSynthetic prostamide analog– Not a prodrugNot a prodrug

Tafluprost ZioptanTafluprost Zioptan

- Non-preserved unit dose- Non-preserved unit dose

XLT Study – Parrish, Palmberg, et al.XLT Study – Parrish, Palmberg, et al.(AJO, May 2003, Vol. 135, No.5)(AJO, May 2003, Vol. 135, No.5)

Multicenter study to compare IOP Multicenter study to compare IOP lowering efficacy of Bimatoprost vs lowering efficacy of Bimatoprost vs Latanoprost vs TravaprostLatanoprost vs Travaprost

Also compared safety profiles of the 3 Also compared safety profiles of the 3 drugsdrugs

Conclusions: All 3 drugs were Conclusions: All 3 drugs were comparable in their ability to lower IOP at comparable in their ability to lower IOP at all time periods.all time periods.– Latanoprost exhibited greater ocular Latanoprost exhibited greater ocular

tolerabilitytolerability

PGAs: IOP-Lowering EffectsPGAs: IOP-Lowering EffectsPURPOSE:PURPOSE: To compare the IOP-lowering effect and safety of To compare the IOP-lowering effect and safety of

latanoprost, bimatoprost, and travoprostlatanoprost, bimatoprost, and travoprostMETHODS:METHODS: 12-week, randomized, parallel-group study conducted at 12-week, randomized, parallel-group study conducted at

45 45 US sites US sites

Previously treated patients with OAG or OH and an IOP ≥ Previously treated patients with OAG or OH and an IOP ≥ 23 mm Hg in one or both eyes after washout23 mm Hg in one or both eyes after washout

Received either latanoprost (0.005%), bimatoprost Received either latanoprost (0.005%), bimatoprost (0.03%), or travoprost (0.004%) once daily in the evening (0.03%), or travoprost (0.004%) once daily in the evening

At baseline and after 6 and 12 weeks of therapy, masked At baseline and after 6 and 12 weeks of therapy, masked evaluators measured IOP in triplicate at 8:00 AM, noon, evaluators measured IOP in triplicate at 8:00 AM, noon, 4:00 PM, and 8:00 PM. The primary efficacy outcome 4:00 PM, and 8:00 PM. The primary efficacy outcome measure was change between baseline and week 12 in measure was change between baseline and week 12 in the 8:00 AM IOPthe 8:00 AM IOP

57Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703.

Primary OutcomePrimary Outcome

58

8 A.M. IOP reduction (mm Hg) from baseline 8 A.M. IOP reduction (mm Hg) from baseline to week 12:to week 12:

Latanoprost: 8.6 ± 3.7Latanoprost: 8.6 ± 3.7 Travoprost: 7.9 ± 3.4Travoprost: 7.9 ± 3.4 Bimatoprost: 8.7 ± 3.8Bimatoprost: 8.7 ± 3.8

Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703.

59

Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703.

Adverse EffectsLatanoprost Latanoprost

(n=136)(n=136)Bimatoprost Bimatoprost

(n=137)(n=137)Travoprost Travoprost (n=138)(n=138)

nn No. eventsNo. events nn No. eventsNo. events nn No. No. eventsevents

hyperemiahyperemia 6464 7171 9494 110110 8080 9090

Eye irritationEye irritation 99 1010 1515 1616 66 66

Vision blurredVision blurred 00 00 55 55 22 22

Eye painEye pain 22 22 11 11 44 44

Growth of Growth of lasheslashes

00 00 44 44 11 11

Skin Skin discolorationdiscoloration

22 22 44 44 44 44

Dry eyeDry eye 22 22 33 33 22 22

Visual acuity Visual acuity reducedreduced

22 22 22 33 33 33

PruritusPruritus 00 00 00 00 33 33

Look at their failure rate:Look at their failure rate: Percent of pxs who didn’t reach their Percent of pxs who didn’t reach their

target IOPtarget IOP– Latanoprost – 14%Latanoprost – 14%– Bimatoprost- 6%Bimatoprost- 6%– Travaprost – 8%Travaprost – 8%

Adverse EffectsAdverse Effects

Changes to pigmented tissuesChanges to pigmented tissues– Iris pigmentation starts at pupil and spreads Iris pigmentation starts at pupil and spreads

concentricallyconcentrically– Long thick lashesLong thick lashes– Periobital pigment changesPeriobital pigment changes

Caution with macular edema, iris/uveitis, Caution with macular edema, iris/uveitis, keratitiskeratitis

Caution with renal/hepatic dysfunctionCaution with renal/hepatic dysfunction Pregnancy category CPregnancy category C

Prostaglandin Side EffectsProstaglandin Side Effects Iris pigmentationIris pigmentation

– Is it reversible?Is it reversible?– Is it pre-cancerous?Is it pre-cancerous?

Xalatan – 6.7% @ 6mthsXalatan – 6.7% @ 6mths 16% @ 12mths 16% @ 12mths

Travatan – 3% @ 12 mthsTravatan – 3% @ 12 mths Lumigan – 1.9% @ 12mthsLumigan – 1.9% @ 12mths

Other Prostaglandin side effectsOther Prostaglandin side effects CMECME UveitisUveitis Reactivation of HSKReactivation of HSK HypertrichosisHypertrichosis Periorbital skin darkeningPeriorbital skin darkening

One must take into consideration the One must take into consideration the benefits of low IOP with the risks of the benefits of low IOP with the risks of the side effectsside effects

TravatanTravatan(Travoprost 0.004%)(Travoprost 0.004%)

Lowers IOP 30-33% Lowers IOP 30-33% Contraindicated in pregnant womanContraindicated in pregnant woman Excellent responder rated in black Excellent responder rated in black

ptspts No CMENo CME

Responder rates in all patientsResponder rates in all patients

56.3% for IOP 17 mm Hg for travatan56.3% for IOP 17 mm Hg for travatan 49% for xalatan49% for xalatan 39% for timolol39% for timolol

PGAs: Effects on Circadian PGAs: Effects on Circadian IOPIOP

66

PURPOSE: To compare 24 hr reduction in IOP with latanoprost, travoprost and bimatoprost in patients with OAG and ocular hypertension (OH)

DESIGN: Randomized, double-masked, crossover studyPARTICIPANTS: 24 OAG and 20 OH patientsMETHODS: • Patients treated with randomized cross-over sequence of

latanoprost, travoprost and bimatoprost for 1 month each, with 30 day washout in between

• 24 hr tonometric curves were recorded at baseline (prior to each treatment) and after each treatment period in seated and supine positions

• Baseline and post-treatment IOP measured at 3:00, 6:00, 9:00 AM and noon and 3:00, 6:00, 9:00 PM and midnight

Orzalesi N, et al. Ophthalmology 2006; 113: 239-246.

Bimatoprost and Travoprost:Bimatoprost and Travoprost:12-Week Study12-Week Study

Parrish et al. Am J Ophthalmol. 2003.

Baseline mean IOP comparable between groupsBaseline mean IOP comparable between groups

Travoprost: 25.5, 23.8, 22.8, 22.0Travoprost: 25.5, 23.8, 22.8, 22.0 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg)Bimatoprost: 25.7, 23.8, 22.8, 22.3 Bimatoprost: 25.7, 23.8, 22.8, 22.3 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg)

8 AM 12 PM 4 PM 8 PM

Time of Day

Mea

n I

OP

(m

m H

g)

0

4

8

12

16

20

24

Travoprost (n = 138)Bimatoprost (n = 136)

Mean IOP at Week 12

Travoprost AppearsTravoprost Appears Consistent Peak to Trough Consistent Peak to Trough

Peak-to-trough loss:Peak-to-trough loss:• Bimatoprost = 38%Bimatoprost = 38%• Latanoprost = 26%Latanoprost = 26%• Travoprost = 14%Travoprost = 14%

68

60%% o

f pea

k IO

P re

ducti

on(@

12

hr)

Time

65%

70%75%

80%

85%90%95%

100%

9:00am

3:00pm

9:00pm

12 hours post dose = peak IOP reduction 24 hours post dose = trough IOP reduction

TravoprostLatanoprostBimatoprost

Orzalesi N, et al. Ophthalmology 2006; 113: 239-246.

69

Effect of Travoprost on Diurnal and Nocturnal IOP

Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133.

PURPOSE: To assess the diurnal and nocturnal persistence of IOP reduction after omission of up to two doses of once-daily topical travoprost in patients with OAG or OH

DESIGN AND METHODS:• Prospective, open-label study• 20 patients underwent 24 hr IOP monitoring at baseline prior to

treatment and after 4 weeks or more of travoprost treatment

Effect of Travoprost on Diurnal Effect of Travoprost on Diurnal and Nocturnal IOPand Nocturnal IOP

Measured in the usual Measured in the usual “habitual position” of the “habitual position” of the patients during those time patients during those time periodsperiods

– Diurnal period – sittingDiurnal period – sitting– Nocturnal period – supineNocturnal period – supine

70

Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133.

NOCTURNAL/SLEEP

DIURNAL/WAKEDIURNAL/WAKE28

26

24

22

20

18

16

14

3:30

PM

5:30

PM

7:30

PM

9:30

PM

11:3

0 PM

1:30

AM

3:30

AM

5:30

AM

7:30

AM

9:30

AM

11:3

0 AM

1:30

PM

Hab

itual

IOP

(mm

Hg)

Clock TimeBaseline “On Treatment”

Error bars = SEMError bars = SEM

Bimatoprost and Travoprost:Bimatoprost and Travoprost:6-Month Safety Results6-Month Safety Results

Both medications were well toleratedBoth medications were well tolerated Most common adverse event: ocular rednessMost common adverse event: ocular redness

– 16 patients (20.8%) in the bimatoprost group and 12 16 patients (20.8%) in the bimatoprost group and 12 patients (14.8%) in the travoprost group (patients (14.8%) in the travoprost group (PP = .326) = .326)

Ocular itching reported for 7.4% of travoprost Ocular itching reported for 7.4% of travoprost patients and 2.3% of bimatoprost patients (patients and 2.3% of bimatoprost patients (PP = .278)= .278)

Treatment-related adverse events leading to Treatment-related adverse events leading to patient discontinuations patient discontinuations – 8 patients in the travoprost group exited early: 4 for lack 8 patients in the travoprost group exited early: 4 for lack

of efficacy, 2 for ocular redness and lid erythema, 1 for of efficacy, 2 for ocular redness and lid erythema, 1 for ocular dryness and itching, and 1 for allergic symptoms ocular dryness and itching, and 1 for allergic symptoms

– 2 patients in the bimatoprost group exited early: 1 for 2 patients in the bimatoprost group exited early: 1 for blurry visionblurry visionand 1 for ocular redness and lid erythemaand 1 for ocular redness and lid erythema

Cantor et al. Br J Ophthalmol. In press.

Bimatoprost Bimatoprost (Lumigan 0.03%)(Lumigan 0.03%)

Lowers IOP 30-33%Lowers IOP 30-33% Favorable lowering of IOP with Favorable lowering of IOP with

lumigan vs xalatanlumigan vs xalatan Side effectsSide effects 15-45% hyperemia15-45% hyperemia 15% ocular pruritis15% ocular pruritis 45% Eyelash growth45% Eyelash growth CME rare CME rare

Bimatoprost and TimololBimatoprost and Timolol12-Month Study12-Month Study

Higginbotham et al. Arch Ophthalmol. 2002.

Bimatoprost QD (n = 474) Timolol BID (n = 241)

*P < .010 vs timolol

Target IOP (mm Hg)

Per

cen

tag

e o

f P

atie

nts

Rea

chin

g T

arg

et

IOP

at

10 A

M,

Mo

nth

12

≤

Target Pressures at Month 12

≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤

**

*

*

*

*

**

*

25

9

16

26

37

47

61

69

712

21

31

47

58

69

77

85

0

10

20

30

40

50

60

70

80

90

12 13 14 15 16 17 18 19 20

Additional Intraocular Pressure Lowering (mm Hg)

-2

-2.5

-3.9-4.5

-4-3.5

-3-2.5

-2-1.5

-1-0.5

0

Alpha Agonist Beta-blocker TCAI

74

Additive IOP-Lowering Effect

O’Connor DJ, et al. Am J Ophthalmol. 2002; 133(6): 836-7.

N=25N=25

N=25N=25N=23N=23

Nocturnal Efficacy: Nocturnal Efficacy: Timolol vs. LatanoprostTimolol vs. Latanoprost

PURPOSE: PURPOSE: To compare the nocturnal effects of once-To compare the nocturnal effects of once-daily timolol and latanoprost on IOP daily timolol and latanoprost on IOP

DESIGN: DESIGN: Prospective, open-label, crossover studyProspective, open-label, crossover studyMETHODS: METHODS: 18 patients received topical treatments with timolol 18 patients received topical treatments with timolol

(0.5%), latanoprost (0.005%), and no IOP-lowering (0.5%), latanoprost (0.005%), and no IOP-lowering medication, for at least 4 weeksmedication, for at least 4 weeks

At the end of each treatment period, the patient was At the end of each treatment period, the patient was housed in a sleep laboratory for 24 hrs and IOP was housed in a sleep laboratory for 24 hrs and IOP was measured every 2 hrs using a pneumotonometermeasured every 2 hrs using a pneumotonometer

Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395.

75

Clock Time

Hab

itual

IOP

(mm

Hg)

Sitting Supine Sitting

76

Timolol: Nocturnal IOP

Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395.

02468

10121416182022242628

3.30

PM

5.30

PM

7.30

PM

9.30

PM

11.3

0PM

1.30

AM

3.30

AM

5.30

AM

7.30

AM

9.30

AM

11.3

0AM

1.30

PM

No treatment

TimololN=18Error bars = SEMN=18Error bars = SEM

Can There be Too much Can There be Too much Prostaglandin?Prostaglandin?

Alverado, J; Oct 2009 UCSFAlverado, J; Oct 2009 UCSF Laboratory Analysis of Effect of SLT on Trabecular OutflowLaboratory Analysis of Effect of SLT on Trabecular Outflow SCE’s were exposed to six different IOP lowering drugs and SCE’s were exposed to six different IOP lowering drugs and

SLT/TME’sSLT/TME’s The junction assembly/dissassembly was monitored by The junction assembly/dissassembly was monitored by

confocal flourescent time lapse microscopyconfocal flourescent time lapse microscopy Latanaprost, bimatoprost & Travaprost shared a common Latanaprost, bimatoprost & Travaprost shared a common

mechanism of action with SLTmechanism of action with SLT– Widening of the paracellular pathwaysWidening of the paracellular pathways– Induction of intercellular junction dissassemblyInduction of intercellular junction dissassembly– Decreased transepithelial flow across SCE’sDecreased transepithelial flow across SCE’s

Clinical impact: TME’s play a critical role in regulating SCE’sClinical impact: TME’s play a critical role in regulating SCE’s Non-Competing IOP agents may improve IOP spot SLTNon-Competing IOP agents may improve IOP spot SLT

CholinergicsCholinergics

Cholinergics are bound by melanin and Cholinergics are bound by melanin and may need a high concentration to affect may need a high concentration to affect darker iridesdarker irides

Anticholinesterases have similar effects to Anticholinesterases have similar effects to cholinergicscholinergics

These medications facilitate outflow via These medications facilitate outflow via the trabecular meshworkthe trabecular meshwork

Echothiophate iodine may prolong the Echothiophate iodine may prolong the effects of succinylcholineeffects of succinylcholine

CholinergicsCholinergics

Generally contraindicated in Generally contraindicated in synechial angle closure, neovascular synechial angle closure, neovascular glaucomaglaucoma

Uveitic glaucoma, retinal detachment Uveitic glaucoma, retinal detachment of peripheral breaksof peripheral breaks

Pilocarpine pregnancy category CPilocarpine pregnancy category C Anticholinesterases contraindicated Anticholinesterases contraindicated

in pregnant womenin pregnant women

CholingegicsCholingegics

CholinergicsCholinergics– Pilocarpine HCLPilocarpine HCL 0.25%-10%0.25%-10%– Pilocarpine nitrated Pilocarpine nitrated 1%, 2%, 4%1%, 2%, 4%– Pilocarpine ocuserts Pilocarpine ocuserts 20%, 40%20%, 40%

Cholinesterase InhibitCholinesterase Inhibit– EchothiophateEchothiophate 0.03%, 0.06% 0.03%, 0.06%

0.125%0.125%– DemecariumDemecarium 0.125%, 0.25%0.125%, 0.25%

MixedMixed– CarbacholCarbachol 0.75%,1.5%, 2.25%, 0.75%,1.5%, 2.25%,

3.%3.%

PilocarpinePilocarpine

Low concentrations deepen chamberLow concentrations deepen chamber High concentrations may cause High concentrations may cause

pupillary blockpupillary block Increase axial length of the lens, Increase axial length of the lens,

shallows ACshallows AC Induce myopiaInduce myopia Decrease uveosclearl outflowDecrease uveosclearl outflow

Pilocarpine Pilocarpine

Cilary block (malignant) glaucoma is Cilary block (malignant) glaucoma is worsened with miotisworsened with miotis

Increase permeability of blood aqueous Increase permeability of blood aqueous barrierbarrier

Increase post-op inflammationIncrease post-op inflammation Need higher concentration in pigmented Need higher concentration in pigmented

iridesirides Max effect occurs in 2 hours last 8 hours; Max effect occurs in 2 hours last 8 hours;

12-15 hr still 14-15% reduction in IOP12-15 hr still 14-15% reduction in IOP

Pilo toxicity-WetPilo toxicity-Wet

SalivationSalivation LacrimationLacrimation SweatingSweating Vomiting/diarrheaVomiting/diarrhea Pulmonary edema/deathPulmonary edema/death Makes Parkinsons disease worse Makes Parkinsons disease worse

– (more acetylcholine than dopamine)(more acetylcholine than dopamine) 10 ml 1% pilocarpine, 100mg is dangerous10 ml 1% pilocarpine, 100mg is dangerous

Ocular Side EffectsOcular Side Effects

Conj Conj hyperemia/folliclehyperemia/follicle

MiosisMiosis Brow achesBrow aches EpitheliopathyEpitheliopathy MyopiaMyopia Shallowing of the Shallowing of the

ACAC IritisIritis

Pupillary cystsPupillary cysts

Lens opacitiesLens opacities

Retinal detachmentRetinal detachment

Pemphigoid type Pemphigoid type reactionreaction

Systemic side effectsSystemic side effects

DiarrheaDiarrhea BradycardiaBradycardia TearingTearing SalivationSalivation NauseaNausea DiaphoresisDiaphoresis Cramps Cramps