h 3 c c h 3 s n combigan n c h 3 · 2017-04-24 · alone. combigan® has a rapid onset of action...

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COMBIGAN ® Eye Drops PI v5.0 ccdsv3.1 1 of 15 COMBIGAN ® Eye Drops NAME OF THE MEDICINE The active constituents of COMBIGAN ® eye drops are brimonidine tartrate and timolol maleate. O N N S N O N H H 3 C CH 3 CH 3 H OH HO HO O O (structure of brimonidine tartrate) (structure of timolol maleate) CAS Registry No. 79570-19-7 CAS Registry No. 26921-17-5 Brimonidine tartrate is an alpha-2 selective adrenergic receptor agonist for ophthalmic use. Brimonidine tartrate is a white to off-white, pale yellow powder and is water soluble (34 mg/mL). In solution, brimonidine tartrate has a clear, greenish-yellow colour. Chemical name: 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate Molecular weight: 442.24 as the tartrate salt Empirical formula: C11H10BrN5.C4H6O6 Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. It is a white to off-white crystalline powder which is soluble in water, alcohol and practically insoluble in ether. Chemical name: (S)-1-(tert-butylamino)-3- [(4-morpholino-1,2,5-thiadiazol-3-yl) oxy] - 2-propanol maleate(1:1) (salt) Molecular weight: 432.50 as the maleate salt Empirical formula: C13H24N4O3S.C4H4O4 DESCRIPTION COMBIGAN ® is a combination eye drop containing brimonidine tartrate and timolol maleate. COMBIGAN ® is a sterile ophthalmic solution. Each mL of COMBIGAN ® solution contains: ACTIVES: brimonidine tartrate 2.0 mg (equivalent to 1.32 mg as brimonidine free base) and 6.8 mg of timolol maleate (equivalent to 5.0 mg of timolol) PRESERVATIVE: benzalkonium chloride 0.05 mg INACTIVES: dibasic sodium phosphate heptahydrate, monobasic sodium phosphate monohydrate, hydrochloric acid or sodium hydroxide, purified water. PHARMACOLOGY Pharmacodynamics Mechanism of Action COMBIGAN ® consists of two active substances: brimonidine tartrate and timolol maleate. These two components decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound administered alone. COMBIGAN ® has a rapid onset of action with peak effect at 2 hours post dosing. NH Br N N N HN C C COOH H HO OH COOH H

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COMBIGAN® Eye Drops PI v5.0 – ccdsv3.1

1 of 15

COMBIGAN® Eye Drops

NAME OF THE MEDICINE

The active constituents of COMBIGAN® eye drops are brimonidine tartrate and timolol maleate.

O

N

NS

NO

NH

H3CCH3

CH3

HOH

HO

HOO

O

(structure of brimonidine tartrate) (structure of timolol maleate)

CAS Registry No. 79570-19-7 CAS Registry No. 26921-17-5

Brimonidine tartrate is an alpha-2 selective adrenergic receptor agonist for ophthalmic use.

Brimonidine tartrate is a white to off-white, pale yellow powder and is water soluble (34 mg/mL). In

solution, brimonidine tartrate has a clear, greenish-yellow colour.

Chemical name: 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate

Molecular weight: 442.24 as the tartrate salt

Empirical formula: C11H10BrN5.C4H6O6

Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. It is a white to off-white

crystalline powder which is soluble in water, alcohol and practically insoluble in ether.

Chemical name: (S)-1-(tert-butylamino)-3- [(4-morpholino-1,2,5-thiadiazol-3-yl) oxy] - 2-propanol

maleate(1:1) (salt)

Molecular weight: 432.50 as the maleate salt

Empirical formula: C13H24N4O3S.C4H4O4

DESCRIPTION

COMBIGAN® is a combination eye drop containing brimonidine tartrate and timolol maleate.

COMBIGAN® is a sterile ophthalmic solution. Each mL of COMBIGAN® solution contains:

ACTIVES: brimonidine tartrate 2.0 mg (equivalent to 1.32 mg as brimonidine free base) and 6.8 mg of

timolol maleate (equivalent to 5.0 mg of timolol)

PRESERVATIVE: benzalkonium chloride 0.05 mg

INACTIVES: dibasic sodium phosphate heptahydrate, monobasic sodium phosphate monohydrate,

hydrochloric acid or sodium hydroxide, purified water.

PHARMACOLOGY

Pharmacodynamics

Mechanism of Action

COMBIGAN® consists of two active substances: brimonidine tartrate and timolol maleate. These two

components decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and

the combined effect results in additional IOP reduction compared to either compound administered

alone. COMBIGAN® has a rapid onset of action with peak effect at 2 hours post dosing.

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0 aR aL m 180 aA s 180 aA a arc cp fill}b/OA{np0 cw -2 dv mv aL 0 aR aL m 180 aA s 180 arc 0 cw -2 dv rlineto cp fill}b/SA{aF m lW m/aL x aL 1 aR s m np 0 p mv rad 0 p l gs cm sm st gr}b/CA{aF lW m/aL x aL 1 aR s m 2 dv rad dp m o dp m s dp 0 le{pppp pp}{sqrt at 2 m np rad 0 rad 180 6 -1 r s 180 6 -1 r s arc gs cm sm st gr cpt e at ro}ie}b/AA{np rad 0 rad 180 180 6 -1 r a arc gs cm sm st gr}b/RA{lW m/w x np rad w p mv w w p l rad w n p mv w w n p l w 2 m dp p mv 0 0 pl w 2 m dp n p l st}b/HA{lW m/w x np 0 0 p mv w 2 m dp p l w 2 m w p l rad w p l rad w n p l w 2 m w n p l w 2 m dp n p l cp st}b/Ar1{gs 5 1 r 3 ix 3 ix xl 3 -1 r s 3 1 r e s o o at ro dp m e dp m a sqrt/rad x[{2.25 SA DA}{1.5 SA DA}{1SA DA}{cw 5 m sl 3.375 SA DA}{cw 5 m sl 2.25 SA DA}{cw 5 m sl 1.5 SA DA}{270 CA DA}{180 CA DA}{120 CA DA}{90 CA DA}{3 RA}{3 HA}{1 -1 sc 270 CA DA}{1 -1 sc 180 CA DA}{1 -1 sc 120 CA DA}{1 -1 sc 90 CA DA}{6RA}{6 HA}{dL 2.25 SA DA}{dL 1.5 SA DA}{dL 1 SA DA}{2.25 SA OA}{1.5 SA OA}{1 SA OA}{1 -1 sc 2.25 SA OA}{1 -1 sc 1.5 SA OA}{1 -1 sc 1 SA OA}{270 CA OA}{180 CA OA}{120 CA OA}{90 CA OA}{1 -1 sc 270 CA OA}{1-1 sc 180 CA OA}{1 -1 sc 120 CA OA}{1 -1 sc 90 CA OA}{1 -1 sc 270 AA}{1 -1 sc 180 AA}{1 -1 sc 120 AA}{1 -1 sc 90 AA}]e g exec gr}b/ac{arcto 4{pp}repeat}b/pA 32 d/rO{4 lW m}b/Ac{0 0 px dp m py dp m a sqrt 0 360 arc cm sm gs sg fill grst}b/OrA{py px at ro px dp m py dp m a sqrt dp rev{neg}if sc}b/Ov{OrA 1 0.4 sc 0 0 1 0 360 arc cm sm gs sg fill gr st}b/Asc{OrA 1 27 dv dp sc}b/LB{9 -6 mv 21 -10 27 -8 27 0 cv 27 8 21 10 9 6 cv -3 2 -3 -2 9 -6 cv cp}b/DLB{0 0 mv -4.8 4.8 l-8 8 -9.6 12 -9.6 16.8 cv -9.6 21.6 -8 24.6 -4.8 25.8 cv -1.6 27 1.6 27 4.8 25.8 cv 8 24.6 9.6 21.6 9.6 16.8 cv 9.6 12 8 8 4.8 4.8 cv cp}b/ZLB{LB}b/Ar{dp 39 lt{Ar1}{gs 5 1 r o o xl 3 -1 r e s 3 1 r s e o 0 lt o 0 lt ne/rev xdp 0 lt{1 -1 sc neg}if/py x dp 0 lt{-1 1 sc neg}if/px x np[{py 16 div dup 2 S lt{pp 2 S}if/lp x lp 0 p mv 0 0 p l 0 py p l lp py p l px lp s 0 p mv px 0 p l px py p l px lp s py p l cm sm st}{py 16 div dup 2 S lt{pp 2 S}if/lp x lp 0 p mv 0 0 0 py lp ac0 py 2 dv lp neg o lp ac 0 py 2 dv 0 py lp ac 0 py lp py lp ac px lp s 0 p mv px 0 px py lp ac px py 2 dv px lp a o lp ac px py 2 dv px py lp ac px py px lp s py lp ac cm sm st}{py dp 2 dv py 180 pA s 180 pA a arc st np px py s py 2 dvpy pA dp neg arcn st}{0 0 p mv 0 py p l px py p l px 0 p l cp cm sm st}{px lW 2 dv a lW -2 dv p mv rO dp rlineto px lW 2 dv a rO a py lW 2 dv a rO a p l rO lW -2 dv a py lW 2 dv a rO a p l lW -2 dv py lW 2 dv a p l 0 py p l px py p l px 0 p l cp fill0 0 p mv 0 py p l px py p l px 0 p l cp cm sm st}{0 rO p mv 0 py px py rO ac px py px 0 rO ac px 0 0 0 rO ac 0 0 0 py rO ac cp cm sm st}{rO py p mv rO rO xl 0 py px py rO ac px py px 0 rO ac px 0 0 0 rO ac rO neg dp xl px py 0 py rO accp fill 0 rO p mv 0 py px py rO ac px py px 0 rO ac px 0 0 0 rO ac 0 0 0 py rO ac cp st}{1.0 Ac}{0.5 Ac}{1.0 Ov}{0.5 Ov}{Asc LB gs 1 sg fill gr cm sm st}{Asc LB gs 0.5 sg fill gr cm sm st}{Asc LB gs 0.5 sg fill gr gs cm sm st grnp -1 -1 sc LB gs 1 sg fill gr cm sm st}{Asc LB gs 0.5 sg fill gr gs cm sm st gr np -0.4 -0.4 sc LB gs 1 sg fill gr cm sm st}{Asc LB gs 1 sg fill gr gs cm sm st gr np -0.4 -0.4 dp sc LB gs 0.5 sg fill gr cm sm st}{Asc DLB -1 -1 sc DLB gs 1 sg fill grgs cm sm st gr np 90 ro DLB -1 -1 sc DLB gs 0.5 sg fill gr cm sm st}{Asc gs -1 -1 sc ZLB gs 1 sg fill gr cm sm st gr gs 0.3 1 sc 0 0 12 0 360 arc gs 0.5 sg fill gr cm sm st gr ZLB gs 1 sg fill gr cm sm st}{Asc gs -1 -1 sc ZLB gs 0.5 sgfill gr cm sm st gr gs 0.3 1 sc 0 0 12 0 360 arc gs 1 sg fill gr cm sm st gr ZLB gs 0.5 sg fill gr cm sm st}{0 0 p mv px py p l cm sm st}{gs bW 0 ne{bW}{5 lW m}ie sl 0 0 p mv px py p l cm sm st gr}{gs dL 0 0 p mv px py p l cm sm st gr}{OrA 1 16 dv dp sc0 1 p mv 0 0 1 0 1 ac 8 0 8 -1 1 ac 8 0 16 0 1 ac 16 0 16 1 1 ac cm sm st}]e 39 s g exec gr}ie}b/Cr{0 360 np arc st}b/DS{np p mv p l st}b/DD{gs dL DS gr}b/DB{gs 12 OB bW 0 ne{bW}{2 bd m}ie sl np 0 0 p mv 0 p l st gr}b/ap{e 3 ix ae 2 ix a}b/PT{8 OB 1 sc 0 bd p 0 0 p 3 -1 r s 3 1 r e s e 0 0 p mv 1 0 p l 0 0 p ap mv 1 0 p ap l e n e n 0 0 p ap mv 1 0 p ap l pp pp}b/DT{gs np PT cm sm st gr}b/Bd{[{pp}{[{DS}{DD}{gs 12 OB np bW 0 ne{bW 2 dv/bd x}if dp nH dv dp 3 -1 ro 2 dv s{dp bd p mv bd n p l}for st gr}{gs 12 OB 1 sc np bW 0 ne{bW 2 dv/bd x}if 1 1 nH 1 s{nH dv dp bd m wF m o o p mv n p l}for cm sm st gr}{pp}{DB}{gs 12 OB np 0 lW 2 dv o o n p mv p l bW 0 ne{bW 2 dv}{bd}ie wF m o o p l n p lcp fill gr}{pp}{gs 12 OB/bL x bW 0 ne{bW 2 dv/bd x}if np 0 0 p mv bL bd 4 m dv round 2 o o lt{e}if pp cvi/nSq x bL nSq 2 m dv dp sc nSq{.135 .667 .865 .667 1 0 rcurveto .135 -.667 .865 -.667 1 0 rcurveto}repeat cm sm st gr}]o 1 g 1 s g e 2 4 gi al pp5 -1 r exec}{al pp 8 ix 1 eq{DD}{DS}ie 5 -1 r 2 eq{DB}{DS}ie pp}{2 4 gi al pp DT}]o 0 g g exec}b/CS{p mv p l cw lW cW 2 m a sl sp sl}b/cB{12 OB 0 0 p mv 0 p l cm sm cw bW 0 ne{bW}{bd 2 m}ie cW 2 m a sl sp sl}b/CW{12 OB 1 sc cW lW 2 dva 0 o p mv 0 e n p l bW 0 ne{bW 2 dv}{bd}ie wF m cW a 1 o n p l 1 e p l cp cm sm}b/CB{np[{[{CS}{CS}{cB}{CW}{pp}{cB}{CW}{pp}{cB}]o 1 g 1 s g e 2 4 gi al pp 5 -1 r exec}{al pp p mv p l CS pp pp}{2 4 gi al pp PT cm sm cw cW 2 m sl sp sl}]o0 g 1 s g exec clip}b/Ct{bs rot g bs rot g gs o CB CB 1 setgray clippath fill 0 setgray Bd gr}b/wD 18 dict d/WI{wx dx ne{wy dy s wx dx s dv/m1 x wy m1 wx m s/b1 x}if lx ex ne{ly ey s lx ex s dv/m2 x ly m2 lx m s/b2 x wx dx ne{b2 b1 s m1 m2 s dv}{wx}iedp m2 m b2 a}{ex n dp m1 m b1 a}ie}b/WW{gs wD begin bs e g 2 4 gi al pp o o xl 4 -1 r 3 -1 r s/wx x s/wy x bs e g 2 4 gi al pp 4 -1 r 3 -1 r s/lx x s/ly x 0 bW 2 dv wF m o o wy wx at mt ro tr/dy x/dx x ly lx at mt ro tr n/ey x n/ex x np wxwy p mv WI p l ex n/ex x ey n/ey x dx n/dx x dy n/dy x lx ly p l WI p l cp fill end gr}b/In{px dx ne{py dy s px dx s dv/m1 x py m1 px m s/b1 x}if lx 0 ne{ly lx dv/m2 x ly ey s m2 lx ex s m s/b2 x px dx ne{b2 b1 s m1 m2 s dv}{px}iedp m2 m b2 a}{ex n dp m1 m b1 a}ie}b/BW{wD begin bs e g/wb x bs e g/bb x wb 4 g/cX x wb 5 g/cY x bb 4 g cX eq bb 5 g cY eq and{bb 2 g bb 3 g}{bb 4 g bb 5 g}ie cY s/ly x cX s/lx x/wx wb 2 g cX s d/wy wb 3 g cY s d 0 bW 2 dv ly lx at mt ro tr/ey x/ex x0 bW 2 dv wF m wy wx at mt ro tr/dy x/dx x 0 lW 2 dv wy wx at mt ro tr wy a/py x wx a/px x gs cX cY xl np px py p mv In p l lx ex s ly ey s p l ex n/ex x ey n/ey x dx n/dx x dy n/dy x wx 2 m px s/px x wy 2 m py s/py x lx ex s ly ey s p lIn p l px py p l cp fill gr end}b/Db{bs{dp type[]type eq{dp 0 g 2 eq{gs dp 1 g 1 eq{dL}if 6 4 gi al pp DS gr}{dp 0 g 3 eq{2 4 gi al pp DT}{pp}ie}ie}{pp}ie}forall}b/I{counttomark dp 1 gt{2 1 rot{-1 r}for}{pp}ie}b/DSt{o/iX x dp/iY x o/cXx dp/cY x np p mv counttomark{bs e g 2 4 gi al pp o cX ne o cY ne or{4 1 r 4 1 r}if pp pp o/cX x dp/cY x o iX eq o iY eq and{pp pp cp}{p l}ie}repeat pp st}b/SP{gs/sf x/lW x/bW x/cW x count 9 ge 7 ix 192837465 eq and{ 7 -1 r pp6 -2 r o o xl 7 -1 r s e 7 -1 r s e 5 -1 r dv neg e 5 -1 r dv neg e sc neg e neg e xl}{xl pp pp}ifelse 1 1 S dv dp sc cm currentmatrix pp lW sl 4.0 setmiterlimit np}b end209 102 86 275 40 80 20 20 chemdict begin SP 26 /N 0 d/B{bs N rot put/N N 1 a d}b/bs e array d[1 1 2691 5926 2352 6183]B[1 1 2691 5926 2552 5525]B[2 0 2352 6183 2352 6608 2403 6208 2403 6579 ]B[1 1 3080 6300 3088 6608]B[1 1 2352 6608 2720 6820]B[1 1 2552 5525 2128 5525]B[2 0 2720 6820 2720 7245 2771 6849 2771 7216 ]B[1 1 2720 7245 3088 7458]B[2 0 3088 7458 3456 7245 3088 7399 3405 7216 ]B[1 1 3456 7245 3456 6820]B[2 0 3456 6820 3088 6608 3405 6849 3088 6666 ]B[1 1 2720 6820 3088 6608]B[1 1 3456 7245 3824 7458]B[2 0 3824 7458 4192 7245 3824 7399 4141 7216 ]B[1 1 4192 7245 4192 6820]B[2 0 4192 6820 3824 6608 4141 6849 3824 6666 ]B[1 1 3456 6820 3824 6608]B[1 1 2128 5525 2005 5926]B[1 1 2352 6183 2005 5926]B[1 1 5300 6160 5300 6585]B[1 1 5300 6585 5300 7010]B[1 1 5300 6585 5800 6580]B[1 1 5300 6585 5020 6580]B[1 1 5300 6160 5620 6160]B[1 1 5300 6160 5300 5735]B[1 1 5300 6160 4875 6160]B[0 1 5 17 18 2 4 11 10 16 15 14 13 12 9 I 2352 6183 DSt [3 I 3088 6608 DSt [6 I 7 8 3456 7245 DSt [19 24 I 20 5300 7010 DSt [21 22 I 5800 6580 DSt [23 25 I 5620 6160 DSt Db gr end

NH

Br

N

N

N

HNC

C

COOH

HHO

OH

COOH

H

COMBIGAN® Eye Drops PI v5.0 – ccdsv3.1

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Brimonidine tartrate

Brimonidine tartrate is an alpha-2 adrenergic agonist that is approximately 1000-fold more selective

for the alpha-2 adrenoreceptor than the alpha-1 adrenergic receptor. Affinity at human alpha-1 and

alpha-2 adrenoreceptors are ~2000 nM and ~2 nM, respectively. This selectivity results in no

mydriasis and the absence of vasoconstriction in microvessels associated with human retinal

xenografts.

Topical administration of brimonidine solution decreases intraocular pressure (IOP) in humans. When

used as directed, brimonidine eye drops have the action of reducing elevated IOP with minimal effect

on cardiovascular parameters.

Brimonidine has a rapid onset of action, with the peak ocular hypotensive effect occurring at two hours

post-dosing. The duration of effect is 12 hours or greater.

Fluorophotometric studies in animals and humans suggest that brimonidine solution has a dual

mechanism of action. Brimonidine lowers IOP by reducing aqueous humor production and enhancing

uveoscleral outflow.

Timolol

Timolol maleate is a nonselective beta-adrenergic receptor blocking agent that does not have

significant intrinsic sympathomimetic, direct myocardial depressant or local anaesthetic (membrane

stabilising) activity. Timolol maleate combines reversibly with a part of the cell membrane, the beta-

adrenergic receptor, and thus inhibits the usual biological response that would occur with stimulation

of that receptor. The specific competitive antagonism blocks stimulation of the beta-adrenergic

receptors by catecholamines having beta-adrenergic stimulating (agonist) activity, whether these

originate from an endogenous or exogenous source. Reversal of this blockade can be accomplished by

increasing the concentration of the agonist, which will restore the usual biological response.

The precise mechanism of action of timolol in lowering intraocular pressure is not clearly established

at this time, although a fluorescein study and tonography studies indicate that its predominant action

may be related to reduced aqueous formation. However, in some studies a slight increase in outflow

facility was also observed.

Pharmacokinetics

Absorption

Combigan

Plasma brimonidine and timolol concentrations were determined in a crossover study comparing the

monotherapy treatments to COMBIGAN® treatment in healthy subjects. There were no statistically

significant differences in brimonidine or timolol AUC between COMBIGAN® and the respective

monotherapy treatments. Mean plasma Cmax values for brimonidine and timolol following dosing with

COMBIGAN® were 0.0327 and 0.406 ng/mL respectively.

Studies in healthy subjects and patients revealed that compared to monotherapy with brimonidine or

timolol, there was a tendency for reduced systemic exposure to both brimonidine and timolol

following treatment with COMBIGAN®. The absorption of timolol was delayed following

combination treatment compared to monotherapy (2.4 vs 1.4 hours). Following treatment with

combination eye drops, the systemic concentrations of brimonidine and timolol were significantly

higher in females and elderly patients.

COMBIGAN® Eye Drops PI v5.0 – ccdsv3.1

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Brimonidine tartrate

After ocular administration of a 0.2% solution twice daily in normal healthy subjects for 10 days,

plasma concentrations were measured as (mean) Cmax 0.06 ng/mL. Plasma concentrations peaked

within 1 to 4 hours and declined with a systemic half-life of approximately 3 hours.

Timolol

After ocular administration of a 0.25% eye drop to humans, peak timolol concentration in the aqueous

humor was 1.56 µg/mL at 1 hour post dose. The half-life of timolol in plasma is about 7 hours.

Metabolism

Brimonidine is metabolized primarily by the liver while Timolol is partially metabolised by the liver

Excretion

Urinary excretion is the major route of elimination of Brimonidine and its metabolites. Approximately

87% of the radioactivity following an orally-administered radioactive dose was eliminated within 120

hours, with 74% found in the urine.

Timolol and its metabolites are excreted by the kidney. Timolol is not extensively bound to plasma.

CLINICAL TRIALS

Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the

greater the likelihood of optic nerve damage and visual field loss. Brimonidine has the action of

lowering intraocular pressure with minimal effect on cardiovascular and pulmonary parameters.

The efficacy of COMBIGAN® was demonstrated in 4 multicentre, randomised, double-masked

parallel group studies.

Study 1 compared twice daily COMBIGAN® eye drops to twice daily TIMOPTOL® (timolol 0.5%) or

twice daily ALPHAGAN® (brimonidine tartrate 0.2%). A total of 589 patients were enrolled.

Study 2 compared twice daily COMBIGAN® eye drops compared to twice daily TIMOPTOL®

(timolol 0.5%) and twice daily ALPHAGAN® (brimonidine tartrate 0.2%) administered adjunctively.

A total of 371 patients were enrolled.

Table 1: Mean IOP (mm Hg) at Baseline and Mean Change from Baseline at each Scheduled

Visit (ITT and LOCF) for Study 1 and Study 2 Study 1 Study 2

Timepoint COMBIGAN

®

(BID)

(N=196)

Brimonidine

tartrate (BID)

(N = 202)

Timolol (BID)

(N = 191) COMBIGAN

®

(BID)

(N = 188)

Adjunctive

(BID)

(N = 183)

Baseline Hour 0 24.8 24.5

(-0.10, 0.81)

24.8

(-0.49, 0.44)

25.0 25.0

(-0.41, 0.68)

Hour 2 22.2 21.7

(-0.13, 1.03)

21.7

(-0.12, 1.05)

22.6 22.4

(-0.31, 0.81)

Week 12 Hour 0 -4.3 -2.7 a

(-2.18, -0.79)

-3.9

(-1.06, 0.34)

-4.9 -4.9

(-0.60, 0.79)

Hour 2 -5.0 -4.0 a

(-1.64, -0.13)

-3.0 b

(-2.73, -1.19)

-5.3 -5.3

(-0.66, 0.61) a p < 0.05 for COMBIGAN® vs brimonidine tartrate b p < 0.05 for COMBIGAN® vs timolol (95% CI)

COMBIGAN® Eye Drops PI v5.0 – ccdsv3.1

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In Study 1, there were no statistically significant differences in the mean values of Hour 0 and Hour 2

at baseline between the 3 groups. The mean decreases from baseline IOP were statistically significant

within each treatment group at each follow-up timepoint (p < 0.001). The mean decrease from

baseline IOP was statistically significantly greater with COMBIGAN® than with brimonidine tartrate

at Hour 0 and 2 at all follow-up visits (p ≤ 0.022). At the primary timepoint of Hour 0, Week 12, a

difference of 1.49 mm Hg from baseline IOP favouring COMBIGAN® over brimonidine tartrate was

seen. This can be considered to be a clinically significant difference. There was no statistically

significant difference in the mean decrease from baseline IOP between COMBIGAN® and timolol at

Hour 0 at any follow-up visit (p ≥ 0.055), however the mean decreases from baseline IOP for

COMBIGAN® were always numerically superior at Hour 0 at all visits.

The mean decrease from baseline IOP was statistically significantly greater with COMBIGAN® than

with timolol at hour 2 at all follow-up visits (p < 0.001). Clinically significant differences of at least

1.5 mm Hg in mean change from baseline IOP favouring COMBIGAN® over timolol were seen at

hour 2 at all follow-up visits.

In Study 2, the mean values of Hour 0 and Hour 2 at baseline were similar between the 2 groups, with

no significant differences. Mean changes from baseline IOP at Weeks 2, 6 and 12 ranged from -4.4 to

-5.3 mm Hg in both treatment groups. At Week 12 the mean change from baseline in Hour 0 IOP

(primary efficacy endpoint) was -4.9 mm Hg for both groups. The upper limit of the 95% CI for the

difference in the COMBIGAN® minus the adjunctive groups was below 1.5 mm Hg, the criterion for

non-inferiority, demonstrating that the COMBIGAN® group was non-inferior to the adjunctive group.

The mean decreases from baseline IOP at both Hour 0 and Hour 2 were also statistically significant at

all follow-up visits within each treatment group (p < 0.001). Thus non-inferiority of the

COMBIGAN® group compared with the adjunctive group was demonstrated at all timepoints.

Studies 3 and 4 compared twice daily COMBIGAN® with that of twice daily TIMOPTOL® (timolol

0.5%) or ALPHAGAN® (brimonidine tartrate 0.2%) three times daily administered for 12 months in

patients with glaucoma or ocular hypertension. A total of 1159 patients were enrolled.

Table 2: Mean IOP (mm Hg) at Baseline and Mean Change from Baseline at each Scheduled

Visit (ITT and LOCF) for Study 3 and Study 4

Study 3 Study 4

Timepoint COMBIGAN®

(BID)

(N = 192)

Brimonidine

tartrate (TID)

(N = 186)

Timolol (BID)

(N = 195)

COMBIGAN®

(BID)

(N = 193)

Brimonidine

tartrate

(TID)

(N = 196)

Timolol (BID)

(N = 197)

Baseline Hour 0 24.5 24.7

(-0.73, 0.31)

25.1a

(-1.08, -0.05)

24.9 25.0

(-0.64, 0.42)

24.8

(-0.42, 0.63)

Hour 2 22.8 23.2

(-1.03, 0.19)

23.5a

(-1.22, -0.01)

23.7 23.7

(-0.56, 0.62)

23.6

(-0.44, 0.74)

Hour 7 21.6 22.0

(-1.04, 0.29)

22.6a

(-1.56, -0.24)

22.6 23.0

(-1.07, 0.14)

22.4

(-0.47, 0.75)

Hour 9 21.4 21.9

(-1.17, 0.15)

22.5a

(-1.68, -0.37)

22.2 22.5

(-0.98, 0.25)

22.3

(-0.77, 0.45)

Month 12 Hour 0 -6.0 -3.4b

(-3.32, -1.91)

-5.2c

(-1.72, -0.37)

-6.1 -3.2a

(-3.59, -2.17)

-5.5

(-1.31, 0.10)

Hour 2 -6.9 -5.0b

(-2.57, -1.19)

-4.8c

(-3.00, -1.73)

-7.5 -5.0a

(-3.12, -1.73)

-5.3b

(-2.88, -1.49)

Hour 7 -4.7 -2.2b -3.8c -5.1 -3.2a -4.1b

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(-3.21, -1.75) (-2.07, -0.81) (-2.54, -1.30) (-1.67, -0.43)

Hour 9 -4.1 -4.4

(-0.36, 0.98)

-3.6c

(-1.62, -0.44)

-4.7 -4.1

(-1.23, 0.07)

-4.1

(-1.22, 0.08) a = Combination mean IOP at baseline statistically significantly lower than timolol (p ≤ 0.046) b = Combination mean decrease in IOP from baseline statistically significantly greater than brimonidine tartrate (p < 0.001). c = Combination mean decrease in IOP from baseline statistically significantly greater than timolol (p ≤ 0.026).

(95% CI)

In Study 3, the mean decrease from baseline diurnal IOP was statistically significantly greater with

COMBIGAN® than with brimonidine tartrate at Hours 0, 2, and 7 at all follow-up visits (p < 0.001).

In addition, clinically significant differences of more than 1.5 mm Hg in mean change from baseline

IOP favouring COMBIGAN® over brimonidine tartrate were seen at Hours 0, 2 and 7 at all follow-up

visits. There was no statistically significant difference in the mean decrease from baseline IOP

between COMBIGAN® and brimonidine tartrate at Hour 9 at any follow-up visit (p ≥ 0.339).

The mean decrease from baseline diurnal IOP was statistically significantly greater with

COMBIGAN® than with timolol at Hours 0, 2, 7 and 9 at all follow-up visits (p ≤ 0.026). In addition,

clinically significant differences of more than 1.5 mm Hg in mean change from baseline IOP favouring

COMBIGAN® over timolol were seen at Hours 0, 2, 7 and 9 (Week 2, Months 6 and 12), at Hours 0, 2

and 7 (Month 3), at Hours 2 and 7 (Week 6) and at Hour 2 (Month 9).

In Study 4, the mean decrease from baseline diurnal IOP was statistically significantly greater with

COMBIGAN® than with brimonidine tartrate at Hours 0, 2 and 7 at all follow-up visits (except Month

9, Hour 7, when IOP was not measured) (p < 0.001). In addition, clinically significant differences of

more than 1.5 mm Hg in mean change from baseline IOP favouring COMBIGAN® over brimonidine

tartrate were seen at Hours 0, 2 and 7 at all follow-up visits. There was no statistically significant

difference in the mean decrease from baseline IOP between COMBIGAN® and brimonidine tartrate at

Hour 9 at any follow-up visit (p ≥ 0.082).

The mean decrease from baseline diurnal IOP was statistically significantly greater with

COMBIGAN® than with timolol at hours 0, 2 and 7 at all follow-up visits (except Hour 0 at Month 12)

and at Hour 9 at Week 2, Week 6 and Month 3 (p ≤ 0.046). In addition, clinically significant

differences of more than 1.5 mm Hg in mean change from baseline favouring COMBIGAN® over

timolol were seen at Hours 0, 2 and 7 (Week 2); at Hours 2 and 7 (Week 6, Months 6 and 12) and at

Hour 2 (Months 3 and 9).

Over 12 weeks of study treatments, approximately 10% of patients on combination treatment reached

and maintained an IOP of ≤ 18 mm Hg, compared to 5.4% with brimonidine alone (p = 0.077 vs

combination) and 9.4% with timolol alone (p = 0.779). Similarly, the number of patients achieving

target IOP of ≤ 18 mm Hg was similar in the combination and adjunctive treatment groups (6.9% and

9.3% with combination and adjunctive treatments, respectively, p = 0.402). However, over 12 months

of treatment, the number of patients achieving and maintaining target IOP (≤ 18 mm Hg) was

significantly greater in the combination group (10% - 13%) compared to the brimonidine group (1.5%)

in both Study 3 and Study 4. Combination treatment was significantly superior to timolol (13.5% vs

5.6%) in Study 3 only.

INDICATIONS

COMBIGAN® eye drops are indicated for the reduction of elevated intraocular pressure for treatment

of open angle glaucoma and/or ocular hypertension, in patients not adequately responding to

monotherapy.

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CONTRAINDICATIONS

COMBIGAN® eye drops are contraindicated in patients with hypersensitivity to any component of this

medication, in patients receiving monoamine oxidase (MAO) inhibitor therapy, in patients with

bronchospasm, bronchial asthma or patients with a history of bronchial asthma, or severe chronic

obstructive pulmonary disease, in patients with sinus bradycardia, sick sinus syndrome, sino-atrial

nodal block, second or third degree atrioventricular block not controlled with a pacemaker, overt

cardiac failure or cardiogenic shock.

Patients who have been receiving MAO inhibitor therapy should wait 14 days after discontinuation

before commencing therapy.

COMBIGAN® eye drops are also contraindicated in neonates and infants ie, children under the age of

2 years.

PRECAUTIONS

Like other topically applied ophthalmic agents, COMBIGAN® may be absorbed systemically. No

enhancement of the systemic absorption of the individual active substances has been observed.

Due to the beta-adrenergic component, timolol, the same types of cardiovascular and pulmonary

adverse reactions as seen with systemic beta-blockers may occur.

Caution should be exercised in treating patients with severe or unstable and uncontrolled

cardiovascular disease (e.g., coronary heart disease, Prinzmetal’s angina and cardiac failure) and

hypotension. Cardiac failure should be adequately controlled before beginning therapy. Sympathetic

stimulation may be essential for support of the circulation in individuals with diminished myocardial

contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe

failure. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure

and have their pulse rates checked. In patients without a history of cardiac failure, continued

depression of the myocardium with beta-blocking agents over a period of time can, in some cases lead

to cardiac failure. At first sign or symptom of cardiac failure, COMBIGAN® should be discontinued.

Cardiac and respiratory reactions, including death due to bronchospasm in patients with asthma, and

rarely, death in association with cardiac failure have been reported following administration of timolol

maleate.

Due to its negative effect on conduction time, beta-blockers should only be given with caution to

patients with first degree heart block.

COMBIGAN® eye drops have not been studied in patients with hepatic or renal impairment; caution

should be used in treating such patients. In patients with severe renal impairment on dialysis, treatment

with timolol has been associated with pronounced hypotension.

COMBIGAN® eye drops should be used with caution in patients with depression, cerebral or coronary

insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans.

Patients should be advised that if they develop an intercurrent ocular condition (e.g. trauma, ocular

surgery or infection) or any ocular reactions, particularly conjunctivitis and lid reactions, they should

immediately seek their doctor’s advice concerning the continued use of the product.

Beta-blockers may also mask the clinical signs of hyperthyroidism (eg, tachycardia) and cause

worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension.

Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt

withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.

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Patients who are already receiving a beta-adrenergic blocking agent orally and who are given timolol

should be observed for a potential additive effect either on the intraocular pressure or on the known

systemic effects of beta-blockade. The use of two topical beta-adrenergic blocking agents is not

recommended.

COMBIGAN® should not be used alone in the treatment of acute angle-closure glaucoma.

Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated

with caution.

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g.

timolol, acetazolamide) after filtration procedure.

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction

to a variety of allergens may be more reactive to repeated accidental, diagnostic or therapeutic

challenge with such allergens and may be unresponsive to the usual dose of adrenaline used to treat

anaphylactic reactions.

Beta-adrenergic blocking agents should be administered with caution in patients subject to

spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) who are

receiving insulin or oral hypoglycaemic agents as beta-blockers may mask the signs and symptoms (eg

tachycardia) of acute hypoglycaemia.

Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically

mediated reflex stimuli. This may augment the risk of general anaesthesia in surgical procedures. In

patients undergoing elective surgery, it may be necessary to gradually withdraw the beta-adrenergic

receptor blocking agents. If necessary during surgery, the effects of beta-adrenergic blocking agents

may be reversed by sufficient doses of adrenergic agonists.

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain

myasthenic symptoms (e.g. diplopia, ptosis, and generalised weakness). Timolol has been reported

rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these

agents should be used with caution in patients with cerebrovascular insufficiency. If signs or

symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with

COMBIGAN® , alternate therapy should be considered.

Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or

moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial

asthma or a history of bronchial asthma, in which timolol is contraindicated [see Contraindications])

should, in general, not receive products containing beta-blockers, including COMBIGAN®; however,

if COMBIGAN® is deemed necessary in such patients, it should be administered with caution.

Delayed ocular hypersensitivity reactions have been reported with brimonidine tartrate ophthalmic

solution 0.2%, with some reported to be associated with an increase in IOP.

Children 2 years of age and above, especially those weighing ≤ 20 kg, should be treated with caution

and closely monitored due to the high incidence and severity of somnolence.

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Information for Patients

The preservative in COMBIGAN® eye drops, benzalkonium chloride, may be absorbed by and cause

discolouration of soft contact lenses. Patients wearing soft contact lenses should be instructed to

remove contact lenses prior to administration of the solution and wait at least 15 minutes after using

COMBIGAN® eye drops before reinserting soft contact lenses.

Patients should be instructed that allowing the tip of the dispensing container to contact the eye or

surrounding structures can cause injury and/or contamination of eye drops. Serious damage to the eye

and subsequent loss of vision may result from using contaminated solution.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No study has been conducted to investigate the carcinogenicity, mutagenicity or effects on fertility of

COMBIGAN®. The following information is based on studies with timolol maleate or brimonidine

tartrate alone.

In a two-year study of timolol maleate in rats, there was a statistically significant increase in the

incidence of adrenal pheochromocytomas in male rats dosed orally at 300 mg/kg/day, but not at 100

mg/kg/day (approximately 1000 times the maximum recommended ophthalmic dose in humans on a

“mg/m2” basis). In a long term study in mice, there were statistically significant increases in the

incidence of benign and malignant pulmonary tumours, benign uterine polyps and mammary

adenocarcinomas in female mice dosed orally at 500 mg/kg/day, but not at 50 mg/kg/day

(approximately 300 times the maximum recommended ophthalmic dose in humans on a “mg/m2”

basis). In a subsequent study in female mice, in which post-mortem examinations were limited to the

uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumours was

again observed at 500 mg/kg/day. The increased occurrence of mammary adenocarcinomas in female

mice was associated with elevations in serum prolactin. An increased incidence of mammary

adenocarcinomas in rodents has been associated with administration of several other therapeutic agents

that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumours

has been established in humans. In adult women who received oral treatment with timolol maleate at

doses up to 60 mg (the maximum recommended human oral dosage), there were no clinically

meaningful changes in serum prolactin.

No compound-related carcinogenic effects of brimonidine were observed in a 21-month study in mice

or a 2-year study in rats at oral doses up to 2.5 and 1 mg/kg/day (as the free base), respectively, with

plasma concentrations of brimonidine at least 150 times those expected in humans dosed

therapeutically.

Both in vitro and in vivo studies (Ames test, neoplastic cell transformation assay, cytogenetic assay

and micronucleus test in mice) showed no genotoxicity of timolol. Negative results were also observed

for brimonidine in assays for chromosomal damage (Chinese hamster cells in vitro, in vivo bone

marrow cytogenetic assay and a dominant lethal assay). In gene mutation assays with S. typhimurium

and E. coli, brimonidine gave a positive response in one S. typhimurium strain without metabolic

activation, but gave negative results in other tester strains.

Reproductive toxicity studies of timolol in rats showed no adverse effects on male or female fertility at

oral doses up to 100 mg/kg/day. A study of brimonidine in rats also did not reveal significant effects

on fertility at oral doses of up to 0.66 mg/kg/day.

Use in Pregnancy (Category C)

There are no adequate data on the use of COMBIGAN® eye drops in pregnant women.

Timolol was not teratogenic in mice, rats or rabbits at oral doses up to 50 mg/kg/day (over 300 times

the maximum recommended clinical dose on a “mg/m2” basis), although delayed fetal ossification was

COMBIGAN® Eye Drops PI v5.0 – ccdsv3.1

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observed at this dose in rats tAt higher doses, there were increases in resorptions and fetal variations

(14 ribs and hypoplastic sternebrae) in mice (1000 mg/kg/day), increased resorptions in rabbits (≥ 90

mg/kg/day), and a decreased number of caudal vertebral bodies and arches as well as an increase in

hypoplastic sternebrae in rats (500 mg/kg/day).

Epidemiological studies suggest that owing to their pharmacological effects beta-blockers may reduce

placental perfusion, which may result in intrauterine growth retardation, premature delivery, or fetal

death. In addition, undesirable effects (e.g. bradycardia and hypoglycaemia) may occur in the fetus and

the neonate. There is also an increased risk of cardiac and pulmonary complications in a neonate that

has been exposed to a beta-blocker.

Brimonidine was not teratogenic in rats or rabbits. However, the drug crosses the placenta and enters

fetal circulation in rats. At exposures of about 580 times that maximally anticipated in humans (based

on AUC), brimonidine was associated with both maternal and embryofetal toxicity (increased early

resorptions/post-implantation losses and decreased pup viability and body weights) in rats. Evidence

for maternal and embryofetal toxicity (abortions) of brimonidine was also observed in rabbits at

exposures about 37 times that maximally anticipated in humans.

COMBIGAN® should not be used during pregnancy unless the expected therapeutic benefit clearly

outweighs the potential risk to the fetus.

Use in Lactation

It is not known whether brimonidine is excreted in human milk. In lactating rats, levels of the drug in

milk were up to 12 times higher than those in maternal plasma; and in a peri- and postnatal study in

rats, brimonidine was associated with decreased pup viability and pup weights during lactation at

maternal plasma exposures of about 55 times greater than those expected in humans.

Timolol is excreted in human milk following oral and ophthalmic administration and there is potential

for serious adverse reactions from timolol in breastfed infants.

Therefore, a decision should be made whether to discontinue breastfeeding or to discontinue

COMBIGAN® eye drops, taking into account the importance of COMBIGAN® eye drops to the

mother.

Paediatric Use

Safety and effectiveness in paediatric patients have not been established. During post-marketing

surveillance, apnea , bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor,

respiratory depression, and somnolence have been reported in neonates, infants and children

receiving brimonidine either for congenital glaucoma or by accidental ingestion. See also

Contraindications.

Effects on Ability to Drive and Use Machines

As with other similar medications, COMBIGAN® eye drops can potentially cause fatigue and/or

drowsiness in some patients. Patients who engage in hazardous activities requiring mental alertness,

including driving and operating machinery, should be cautioned of the potential for a decrease in

mental alertness. COMBIGAN® may also cause transient blurred vision or visual disturbances. The

patient should wait until these symptoms have cleared before driving or using machinery.

INTERACTIONS WITH OTHER MEDICINES

Although specific drug interaction studies have not been conducted with COMBIGAN® eye drops, the

possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates,

sedatives, or anesthetics) should be considered. There is potential for additive effects resulting in

hypotension, and/or marked bradycardia when eye drops with timolol are administered concomitantly

COMBIGAN® Eye Drops PI v5.0 – ccdsv3.1

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with oral calcium channel blockers, digitalis glycosides,guanethidine, anti-arrhythmics, or

parasympathomimetics.

Caution should be used in the coadministration of beta-adrenergic blocking agents, such as

COMBIGAN® , and oral or intravenous calcium antagonists because of possible atrioventricular

conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac

function, coadministration should be avoided.

Patients who are receiving a beta-adrenergic blocking agent orally and COMBIGAN® should be

observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure.

Because COMBIGAN® may reduce blood pressure, caution in using concomitant drugs such as anti-

hypertensives and/or cardiac glycosides is advised.

Caution is advised when initiating or changing the dose of a concomitant systemic agent (irrespective

of pharmaceutical form) which may interact with -adrenergic agonists or interfere with their activity

i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin).

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-

blockers. No data on the level of circulating catecholamines after COMBIGAN® eye drops are

instilled are available. Caution, however, is advised in patients taking tricyclic antidepressants which

can affect the metabolism and uptake of circulating amines.

As brimonidine tartrate is metabolised primarily by the liver, most likely by cytochrome P450 and

aldehyde oxidase, COMBIGAN® eye drops may affect the metabolism of other drugs that utilise the

cytochrome P450 pathway.

Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during

combined treatment with CY2D6 inhibitors (eg quinidine, selective serotonin reuptake inhibitors) and

timolol, possibly because quinidine inhibits the metabolism of timolol via the P450 enzyme, CYP2D6.

Although timolol used alone has little or no effect on pupil size, mydriasis resulting from concomitant

therapy with timolol and epinephrine has been reported occasionally.

Close observation of the patient is recommended when a beta-blocker is administered to patients

receiving catecholamine-depleting drugs such as reserpine because of possible additive effects and the

production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or

postural hypotension.

Concomitant use of a beta blocker with anesthetic drugs may attenuate compensatory tachycardia and

increase the risk of hypotension. The anesthetist must therefore be informed if the patient is taking

COMBIGAN®.

ADVERSE EFFECTS

Based on 12 month clinical trial data, the most commonly reported adverse drug reactions in the

combination group were conjunctival hyperaemia (approximately 17% of patients) and burning

sensation in the eye (approximately 11% of patients). The majority of cases were mild and led to

discontinuation rates of only 3.4% and 0.5% respectively. The most common adverse events in the

brimonidine group were conjunctival hyperaemia (approximately 23% of patients), eye pruritus

(approximately 12% of patients) and allergic conjunctivitis (approximately 10% of patients), leading to

discontinuation in 8.9%, 4.5%, and 7.6% respectively. The most common adverse events in the timolol

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group were burning sensation in the eye (approximately 13% of patients) and conjunctival hyperaemia

(approximately 8% of patients), leading to discontinuation in 1% and 0.5% respectively.

In the 12 month studies, discontinuations due to adverse events occurred in 14.3% of patients in the

combination group compared with 30.6% in the brimonidine group and 5.1% in the timolol group.

Over 85% of patients in each treatment group showed no change in visual acuity, defined as less than a

2-line difference from baseline. An improvement in visual acuity of 2 lines or more was reported for

0.3% of patients in the combination group, and 0.1% each in the brimonidine and timolol groups. A

worsening of visual acuity of 2 lines or more was reported for 9.4% of patients in the combination

group, 9.2% in the brimonidine group, and 12.2% of patients in the timolol group.

Overall, approximately 95% of patients in each treatment group showed a < 5 dB change in mean

deviation of the visual fields from baseline. Improvement in visual fields (increase of > 5 dB) was

reported for 0.9% of patients in the timolol group, 0.6% in the combination group, and 0% in the

brimonidine group. Worsening of visual fields of ≥ 5 dB was reported for 3.4% of patients in the

combination group, 4.6% of patients in the brimonidine group, and 3.4% of patients in the timolol

group.

Greater than 96% of patients in each treatment group showed a minimal change (between > -0.2 and

<+0.2) from baseline in Cup/Disc ratio. Worsening of ≥ +0.2 was reported for 2.1% of patients in the

combination group, 0.8% of patients in the brimonidine group, and 2.1% of patients in the timolol

group.

The following adverse drug reactions were reported during clinical trials with COMBIGAN(R) eye

drops:

Eye disorders:

Very common (>1/10): conjunctival hyperaemia, burning sensation.

Common (>1/100, <1/10): stinging sensation in the eye, eye pruritus, eyelid oedema, eyelid pruritus,

eyelid erythema, allergic conjunctivitis, conjunctival folliculosis, visual disturbance, blepharitis,

epiphora, corneal erosion, superficial punctate keratitis, eye dryness, eye discharge, eye pain, eye

irritation, foreign body sensation.

Uncommon (>1/1000, <1/100): visual acuity worsened, conjunctival oedema, follicular conjunctivitis,

conjunctivitis, vitreous floater, asthenopia, photophobia, papillary hypertrophy, eyelid pain, abnormal

vision, conjunctival blanching, corneal oedema, corneal infiltrates, vitreous detachment.

Psychiatric disorders:

Common (>1/100, <1/10): depression

Nervous system disorders:

Common (>1/100, <1/10): somnolence, headache

Uncommon (>1/1000, <1/100): dizziness, syncope

Cardiac disorders:

Uncommon (>1/1000, <1/100): congestive heart failure, palpitations, bradycardia

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Vascular disorders:

Common (>1/100, <1/10): hypertension

Uncommon (>1/1000, <1/100): hypotension

Respiratory, thoracic and mediastinal disorders:

Uncommon (>1/1000, <1/100): rhinitis, nasal dryness

Gastrointestinal disorders:

Common (>1/100, <1/10): oral dryness

Uncommon (>1/1000, <1/100): taste perversion, diarrhoea, nausea

Immune system disorders:

Uncommon (>1/1000, <1/100): allergic contact dermatitis

General disorders and administration site conditions:

Common (>1/100, <1/10): asthenic conditions

Investigations:

Common (>1/100, <1/10): LFTs abnormal

Additional adverse events that have been seen with one of the components and may potentially occur

also with COMBIGAN® eye drops are as follows:

Brimonidine tartrate

Eye disorders: Blurring, ocular allergic reaction, corneal staining, conjunctival discharge, conjunctival

papillae, iritis, iridiocyclitis (anterior uveitis), miosis.

Immune system disorders: Hypersensitivity, Skin reaction (including erythema, face edema, pruritus

rash), vasodilitation

Psychiatric disorders: Insomnia

Cardiac disorders: Palpitations/arrhythmias, tachycardia

Vascular disorders: Syncope

Respiratory, thoracic and mediastinal disorders: Upper respiratory symptoms, nasal dryness

Gastrointestinal disorders: Gastrointestinal symptoms, taste perversion

Systemic effects: Fatigue/drowsiness, and systemic allergic reaction

Timolol

Immune system disorders: Signs and symptoms of systemic allergic reactions, including anaphylaxis,

angioedema, pruritus, urticaria, generalised and localized rash; systemic lupus erythematosus.

Endocrine disorders: Masked symptoms of hypoglycemia in diabetes patients (see Precautions).

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Nervous system/ Psychiatric disorders: Cerebral ischemia, cerebral vascular accident, increase in signs

and symptoms of myasthenia gravis, insomnia, nightmares, behavioural changes and psychic

disturbances including confusion, hallucinations, anxiety, disorientation, nervousness, memory loss,

fatigue and paraesthesia.

Eye disorders: Choroidal detachment following filtration surgery (see Precautions), conjunctivitis,

cystoid macular edema, decreased corneal sensitivity, pseudopemphigoid, ptosis, refractive changes,

blepharoptosis, diplopia, keratitis.

Ear and labyrinth disorders: Tinnitus.

Cardiac disorders: Arrhythmia, cardiac arrest, cardiac failure, claudication, cold hands and feet, heart

block, palpitation, pulmonary oedema, Raynaud’s phenomenon, worsening of angina pectoris, oedema,

chest pain, congestive heart failure and atrioventricular block.

Vascular disorders: Syncope

Respiratory, thoracic and mediastinal disorders: Bronchospasm (predominantly in patients with pre-

existing bronchospastic disease), respiratory failure, exacerbation of asthma, dyspnoea, cough, upper

respiratory infection, nasal congestion.

Gastrointestinal disorders: Anorexia, abdominal pain, dyspepsia, dysgeusia, vomiting

Skin and subcutaneous tissue disorders: Alopecia, exacerbation of psoriasis, psoriasiform rash and

skin rash.

Renal and urinary disorders: Peyronie’s disease, retroperitoneal fibrosis.

Musculoskeletal and connective tissue disorders: Myalgia

Other: Decreased libido, sexual dysfunction

Post Marketing Experience

Symptoms of bradycardia, hypotension, hypothermia, hypotonia and apnea have been reported (rarely)

in neonates receiving brimonidine(see also Contraindications).The following adverse reactions have

been identified during post-marketing use of COMBIGAN® in clinical practice.

Eye disorders: Vision blurred, visual acuity reducedSkin and subcutaneous tissue disorders: Erythema

facial

DOSAGE AND ADMINISTRATION

The recommended dose is one drop of COMBIGAN® in the affected eye(s) twice daily, approximately

12 hours apart.

In order to minimise systemic absorption of COMBIGAN® eye drops, apply pressure to the tear duct

immediately following administration of the drug.

As with all eye drops containing benzalkonium chloride as a preservative, there is potential for

incompatibility with other topical ophthalmic medications. If more than one topical ophthalmic drug is

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to be used, other eye drops should not be used within five to ten minutes of using COMBIGAN® eye

drops.

To avoid contamination of the solution, keep container tightly closed. Do not touch dropper tip to any

surface. Discard contents 4 weeks after opening the bottle. Contents are sterile if seal is intact.

OVERDOSAGE

There is limited data available with regard to overdose with COMBIGAN® eye drops.

Brimonidine tartrate

Ophthalmic overdose

In those cases received, the events reported have been generally those already listed as adverse

reactions., Symptoms of brimonidine tartrate overdose such as hypotension, bradycardia, hypothermia,

coma, hypotonia, lethargy, pallor, respiratory depression, somnolence and apnoea have been reported

in neonates, infants and children receiving brimondine tartrate ophthalmic solution as part of medical

treatment of congenital glaucoma or by accidental ingestion. Please see Paediatric Use.

Systemic overdose resulting from accidental ingestion

Accidental human adult ingestion of brimonidine tartrate 0.2% has resulted in a hypotensive

episode followed by rebound hypertension.

Oral overdoses of other alpha 2 agonists have been reported to cause symptoms such as

hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnea,

hypotonia, hypothermia, respiratory depression and seizure.

Timolol

Symptoms of systemic timolol overdose are dizziness, headache, shortness of breath,

bradycardia, hypotension, bronchospasm and cardiac arrest. A study of patients showed that

timolol did not dialyse readily.

If overdose occurs treatment should be symptomatic and supportive; a patent airway should

be maintained. Contact the Australian Poisons Information Centre (telephone 13 11 26) for

advice on overdose management.

PRESENTATION AND STORAGE CONDITIONS

COMBIGAN® (brimonidine tartrate 0.2% and timolol 0.5%) ophthalmic sterile solution is supplied in

white opaque plastic dropper bottles.

Eye drops: 5 mL

Storage: Store below 25° C. Protect from light.

AUST R 97690

NAME AND ADDRESS OF THE SPONSOR

Allergan Australia Pty Ltd

810 Pacific Highway

Gordon NSW 2072

A.B.N. 85 000 612 831

COMBIGAN® Eye Drops PI v5.0 – ccdsv3.1

15 of 15

POISON SCHEDULE OF THE MEDICINE

Prescription Only Medicine, S4

DATE OF FIRST INCLUSION IN THE ARTG

17 December 2004

DATE OF MOST RECENT AMENDMENT

31 March 2017

® Marks owned by Allergan, Inc