AD W 0 I

CI ic da demon.r-+........+....-~ CCl~rEG C TI'

C~REG C controls hy e ensio (carvedHol phosphate)without affecting metabo ic arame e -. Extended-release Capsules

patie is with type II diabetes.

ower pressure withou losing control Peas see Impo Safety nfonnation on ge 1

I

ONCE-A-DAY

COREG CR has no adverse effects on HbA1c or total cholesterol

Uncontrolleit Hypertension

~ 46 years old ~ One or more of the following comorbid conditions: ~CAD

~ Type 2 Diabetes ~ Dyslipidemia

~@D.COREG CR 20 mg OD

In GEMINI*, patients taking Coreg® (carvedilol):

10

8 ':l< ~

(J 6<".0 :I: c: 4 III II>

:E 2

0

p- 0.6~

I 7.2 7.2

BASELINE MONTH 5 t

HbAl c did not c:hanl.1i'" IrlJrn baseline (mean [:80] cnangt:!: U.U2 iJ !±O.l)4%); 95% el, -0.00 b to O.10uhJ; P=O.65}.

Metoprolol tartrate demonstrated

p~ 0.001

~ .... '" 186 185.6.s e 185 (l)

184iii Ql

"0 183 J:: U 181.7182E :I... 181C1i. m

180iii... {2 179

01 N=433 BASELINE MONTH 51

II>- Metoprolol tartrate demonstrated significant increase in HbA1c (change no effect on total cholesterol (P=0.5)1.2 from baseline 0.15%; P<0.001)1

The effects of carvedilol and metoprolol tartrate on clinical outcomes have not been compared in long-term clinical trials in

patients with hypertension and type 2 diabetes. In the GEMINI study, metoprolol succinate-which is the generic name of Toprol-Xl' (a registered trademark of the AstraZeneca group of companies) extended-release tablets-was not studied.

Please see Important Safety Information on page 11. 2:

(carvedilol phosphate) Extended-release Capsules

losing control

COREG CR has 110 eft t on triglycerides or weiig t

In GEMINI, patients taking COREG"

COREG CR is indicated for the management of essential hypertension. COREG CR can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

'A randol\].iled. double-blind, parallel-group trial (The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Companson in Hypertensives IGEMINIJ) compared the effects of carvedllol and metoprolol tartrate on glycemiC control. The 1235 participants (COREG n=498, 'Iletoprolol tartrate n=737) were aged 36 to 85 years with hypertension (> 130/80 mmNg) and type 2 diabetes mellitus (glycosylaled hemoglobin [HbAlcI, 6.5%-8.5%) and were receiving renin-angiotensin system (RAS) blockers. Patients were followed for up to 35 weeks.

'Month 5 represents the maintenance penod after randomization,

References: 1.8akns Gl. Fonseca V. Kalholi RE, GL ,lor loo Gfl'I'I~II~veslll;l ors. Mel<UJooliC errc<:ls 01 carvedllol vs et II ol(J' in patients with type 2 dlirlJ tes me Illrs 3JId 11\'pSl1e'lsJ~n; a r I du:nizcd COR conlrOI.)C! tf,al .lAMA 200~;2922227-2236. 2. Data 011 file (/55), (ii 61. arn (1158), GiaxoSmlthKlire.

I o,wer pressure wi hou

I P=0?821'1]:J 200

Cl 190 ~

.s 180'" 170<II "0 '': 160<II 0,., 150 0> 1~0

~ 130 cro 120 <II

110:E 100 ~

01 BASELINE MONTH 51

... Metoprolol tartrate demonstrated significant elevation in triglycerides (change from baseline 13.2%; P<O.0001)1.2

II 168.3159.4

... Metoprolol tartrate demonstrated significant weight gain from baseline (change from baseline 1.2 kg; P<O.0001)1.2

No Change in Weight1 .2

p= 0.36

I I98.2Ci 100 97.2

~ 95... .c: 90 'iii Cl

85 ~ ,., 80 "0 75 cc 0

70 c ro 65<II :E 60

~tJ

SC

BASELINE MONTH 5 f

Wclgh1 did not a nge from baseline (mean Change: 0,' kg: P-O.J6).

Low incidence of beta-blocker adverse events that concern physicians

r e beta bloc e olerabirty co ce ns: atigue, erecti e io ',a d d"zzi as "'

Incidence With COR EO CR in Hypertensiont1

ADVERSE EVENT PLACEBO CORE CR (N=84)

FATIGUE 4%

ERECTILE DYSFUNCTION 0%

orZZINESS 1% 2%

.. All dose strengths were generally well tolerated1

... Other adverse events occurring more frequently with COREG CR than with placebo (incidence>1%) included: nasopharyngitis (4%), nausea (2%), peripheral edema (2%)2

'Survey of 287 physicians, Ilcluding cardioloqlsts (n=41), electrophysiologlsts (n=40), i'1terventional cardiologists (n=40), Internal ne> (n (1), f3 Iy practice/general practice (n. 74). and others (n=21). Physicians were asked to "Please Indicate the 3 most concerning lolerablilt\llSSUeS OClaled WI!

Il-blockers that have been ~xperienced by patients In yotJr practice.'

tOouble-blind, randomized. parallel-group study that compared the BP 8ffects ot COREG CR and placebo In patients using ambulatory blOOd pressure monitoring (ABPM). The study included 338 patients with essential hypertension (Sitting diastoliC blood pressure [DBPj ~90 and ~109 mmHq) who were randomized to receive 20, 40, or 80 mg of CORf'iG CR or placebo for 6 weeks.

Please see Important Safety Infonmation on page 11.

CO' G C provided i ifi ant peak bl,o'Q,d essure (BP) reducti ns1,3

0

-2 c; JO -4E .§. a. -6 Cll

.S -8 Cl '" <:

..:= -10'" u <: -12'" ~'"

-14

-16 Peak DBP"

CORG C . BP reductions at trough2

DOSE SBP DBP (mmHg) (mmHg)

-15.3t

20 mg -2.8

40 mg -5.2 80 mg -8.4~ -7.4~

I P<O.005, changes from

baseline vs placebo.

§ Systolic blood pressure.

II Diastolic blood pressure.

.. Maintains significant BP reductions throughout the entire 24 hours3

.., Provides BP control in a dose-dependent manner3

P<O.OOl, changes from baseline vs placebo4

OOREG CR placebO-subtracted reductions from a double-blind. rar:1domlzed, parallel·group study that compared the BP effects of COREG OR and placebo in patients using ABPM. The study Included 338 patients with essential hypertension (sitting DBP ,,90 and ,,109 mmHg) who were randDmli:ed to receive 20, 40, or 80 mg 00 of COREG OR or placebo for 6 weeks. Mean sitting SBP and DBP al baseline were 150 mmHg and 99 mmHg, fespecNvely. The primary endpoint was change In mean 24-hotJr DBP by ABPM. Placebo· subtracted mean changes in mean 24-hour SBP/OBP measured by ABPM were -6.1/-4.0 mmHg, -9.4/·7.6 mmHg. and -11.8/-9.2 mmHg for 20 mg, 40 mg, and 80 mg, respectively. Peak and trough BP were measured as average of hours 3· 7 and 20·24, respectrvely.2

References: 1, Data on fite (#81), (#82), and (#77), GlaxoSl1lllhKI·ne. 2, Prescribing r"lormalion for COREG CR. GlaxoS rtIIKIJOO. j, Weber MA, Sica DA. Tarka EA, Iyergar M, Fleck R. Bakris til Controlled· re:p.asp. f.arvedilol ill he tr tmenl of esse'llial h 'petleflSilln Am J CardIa!. 2006,98(snppl):32 -38l 4. Wp.bec MA. Bakris Gl. Taf1<a EA, 'Iyengar M, FI'eck R, Sica lJ Efficacy Of a once·dally [armulatloll of carverlilol lor the treatment of hypel1ension J Clln Hypertens. 2006;8840.849

Lower pressure withou 10 ing cant I

According to the American Association of Clinical Endocrinolo ists

Guidelines for treat' nt of hyperte • n in patients with diabetes1

Because the major adverse effects of {3-blockers may be mediated by peripheral vasoconstriction.. drugs that block both a- and {3-receptors (such as carvedi/o/) may prove to be particularly beneficial .. 11 1

-AACE Hypertension Task Force

Level of Evidence·

Grade'

--­

AACE Inhibitor or ARB as first- or second-line agent 1

Thiazide diuretic as first- or second-line agent (in low dosage with adequate potassium replacement or sparing) 1 A

~-blocker (preferably drugs that block both a- and 13-receptors) as second- or third-line agent 1 A

CCB (preferably nondihydropyridine) as secondo, third-, or fourth-line agent 1 A

'Level of evidence and grade are determined by the Amencan Association of Clinical Endocnnologists, wtlich reviews and grades Clinical !l\'iden~ in iIOCordance with established criteria. (See: The American Association of Cllnlca ndocrinologists protocol for standardized production of clinical, guidelines. Endocr Pracl. 2004;10:353-361.)

Reference: 1. AACE Hypel1cnslon Task Force. American IIssoclation of 'Clinical EndocTinologists Medical GUidelines ,tOI GI It<II Pradlc:e lor lire diag I~nad I $Ulmelll or hypenension Endocr Pract. 2006:12:193-222. 2. Egan BM, Basiie J. Gillilan RJ. Cohen jD Cardioprotecllofl'l e I I beta blocker th fO,DY J elm Hyper!lHIs 2005;7 09-416

6

Comprehensive vasodilating SNS blockade f3- ockade wit I p oved B 0 Row

Selective Beta-1 Bl'ockade Comprehensive Vasodilating Blockade1

~ Beta-1 blockade reduces heart rate

tThe basis (mecl'.a sm of action) for the be cial effects of Beta blockade in hyperte as not been established.

BP= Blood Pressuro

TPR= Total Peripheral Re~isl£lnce

CO=. Cardiac Outpul

ONCE-A-DAY

Card ioprotective 5

1r. Coreg® (carve i 0) red ce all ...cau e mortali y Post-MI LV pa "e by 23% (95°/0 C ,2% '0400/or,2

I CA

All-cause mortality was 15% in Fatal or Nonfatal ReinfarctionU the placebo group and 12% in the

COREG group1

% II> Added cardioprotection on top of current standard therapies in Post-MI LVDt

PATIENT TYPE STARTING DOSE

POST-MI LVD

Please see Indications Statements and Important Safety Information on pages 10 and 11.

'Carvedtlol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) was a double-blind study comparing COREG and placebo in 1959 plUl nls with a recent MI (within 21 days) and left ventricular ejection fraction (LVEF) .-;40%, with (47%) or without (53%) symptoms of HF. Patients given COREG rec.1 d 6.25 mg BID, titrated as tolerated to 25 I11g BID. Entry cnteria inclUded a systolic BP >90 mmHg. a sitting heart rate >60 beats/minute. and no contraindlcations \0 Il-blocker use.

, Support for the use of COREG CR for the treatment of mild-to-severe HF and Post-MI LVD is based on the equivalence of pharmacok,netlc and pharmacodynamic UJ,-blockadej parameters between COREG CR and COREG.

'ACE inhibitors or angiotensin II receptor blockers (97%). aspirin (85%). dluret1cs (34%), lipid-lowering agents (23%). and anticoagulants (20%); 47% were revascularized.

'Starling dose: 20 m9 00. Uptitrate to 40 m9 00 after 3-10 days as tolerated The maximum/target dose is 80 mg 00. If clinically indicated. start at 10 m9 00 and/or uptitrate more slowly. Patients should be malntalOed on lower doses If higher doses are not tolerated. No dosing alteration needed when slarted after IV or oral iI-blocker MI treatment.

8

•

9"' CI, 38 ~ lJ H~,fl

p= 11006

67% RISK REDUCTION

o qql n ttl. 0 2.5 u In 18 m Jopr I

19% RISK REDUCTION

14S'~ in e COREG group 17. t 8 melopr I tar rme roup

95 u Ct, gc,\;, to 32.' :::.0

ortality in sy p oma'c HF ------­

": COR G reduc,ed

17% RISK REDUCTION

34% In t . CO ~G group ...0% It the. .e1oprc I Irtml " Ollp

95

Extrapolation from the survival curves suggested that COREG extended median survival by 1.4 years4

...Across the cardiovascular continuum

References: 1,1re CAPRICORN I ve 'galors E eel of carwllllol on olJleome aIle. ,"'{O(;iIroi Ir1 a'ction II) PJtle!1ts wi h 3ft-ven rleli f dysflll'\C!lon: UN! CAPRICORN r~n~omised I. L'J'",el 200Ul57J385-1390. 2. F'reseriiJlnli Inlonn~li n lor COREG Cll GI~xoS ~ lin 3. [lara 011 file (g66) and (#78), GIsxOSl1llIRKlil18 4. Pnoll7­\'/1I50n PA. Swenberg K_ Icli!nd JG~, et al. lor tile COMET IIIvb'!;[llfalors. Comparison of c.lIF'o'edliol af)U m loprol cllrtk~J oulcolnes 'II p~1iefll~ v!itluh~nir. rt a ITe I~ tile

r..edllal r Metoprolal European Trial (COMET!' randCnUsed conlnllled triol Lancet. 2003;362:7-13 5_ Tor·)·Pl!der en C. Poo - san PA, Swedberg K, at ai, forlhe COMET In~llSlJjJalllt'$. ~fi1ecl~ or metoprolol an a"Mllllol on cami,e-speci!lc morJa'lty and Il'lDrbi~ll,!, In palienls v"llh I;l']rome hem f Illre-OOMET Am Hem J. 2005:149:370-376. Lower p ess ra wi hoo 10 ing COil r 6. Toprol-XL· Pr ~rRiI11l111In·mallon. Wlm ngm ,Oe Asl neca LP: 2007

In a separate, crossover study of patients with HF or Post-MI LVD receiving COREG CR, the most common adverse events were dizziness (3%) and headache (2%)~3

20% cardiovascular death risk reduction (29% in the COREG group, 35% in the metoprolol tartrate group; 95% CI, 10% to 30%; P=0.0004)5

Carvedilol Metoprolol European Trial (COMET) was a dou 'ind, ~ bllllZed, roup loal comparing COREG with metoprolol tartr;;lte In 3029 pallents with chronic HF (NYHA Class II-IV) followed for approxim 5 years. 'PATIENT TYPE STARTING DOSE COMET compared carvedilol (target dose: 25 m9 BID) to metoprolol tartrate (targel dose: 50 Ing BID). It is not known whether this formulation of H ART FAILURE' metoprolol at any dose or this low dose of metoprololln any formulalton has any effect on survival or hospitalization In patients wllll HF. Metoprolol tartrate is not Indicated in the Uniled Stales for HF. COMET did not compare carvedilol to metoprolol succlnale (Toprol-XL-). The efficacy of carvedildl versus metoprolol succinate in HF has not been established In a head-to­ilead outcomes study. The target dose of metoprolol succinate in HF IS 200 ~ 00." Thus. thiS tnill extends the time over which carvediloJ manilests benafi g SI)

'n HF, but It IS not evidenoe that carvedilollmproves outcrnne CtL'et' the formlJlatj~ of metoprolol ( oprol-XL ) with benefits in HF.

·Nonrandomlz.ed, crossover study of 174 patients with mild-to-!ilevere HF or aSYlllptol"latlc Post-MI LV lilat compared tho pllarrT1flL"Oknnic profil~ 01 COREG and CORt::G CR. Patients received COREG (3.125, 6.25,12.5, or 25 mg twice dally) for 2 weeks and then the eqUivalent dose of COREG CR (10. 20, 40. or 00 mg CIlcedaily) for 2 weeks.

'Start ng dose: 10 mg 00 for 2 weeks. Uptltration to 20, 40, and 80 mg 00 should occur over successive intervals of at least 2 weeks, based on olera ,I.

The maximum/target dose is 80 mg 00. Patients should be 'I11all'llarned on lower doses If higher doses are not tolerated.

ONCE-A-DAY

eC R

Indications

Hypertension

COREG CR is indicated for the management of essential hypertension. COREG CR can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

Post-M I Left entric lar Dysfunction (l:.VD)

COREG CR is indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of an MI and have a left ventricular ejection fraction (LVEF) -:;40% (with or without symptomatic heart failure [HF]).

Mila-to-Severe F

COREG CR is indicated for the treatment of mild-to-severe HF of ischemic or cardiomyopathic origin, usually in addition to diuretics, angiotensin-converting enzyme (ACE) inhibitor, and digitalis, to increase survival and, also, to reduce the risk of hospitalization.

Please see Important Safety Information on page 11.

o

Important Safety Information Patients taking COREG CR or Coreg®

(carvedilol) should avoid abrupt cessation

of therapy. Following abrupt cessation of

therapy with certain ~-blocking agents,

exacerbation of angina pectoris and, in

some cases, MI and ventricular

arrhythmias have occurred. The dosage

should be reduced gradually over a 1- to

2-week period and the patient should be

carefully monitored.

COREG CR and COREG are

contraindicated in patients with bronchial

asth ma or related bronchospastic

conditions, second- or third-degree

AV block, sick sinus syndrome, or severe

bradycardia (unless a permanent

pacemaker is in place), in patients with

cardiogenic shock or decompensated

heart failure (HF) requiring the use of

intravenous inotropic therapy (such

patients should first be weaned from

intravenous therapy before initiating

COREG CR or COREG), in patients with

clinically manifest hepatic impairment,

and in patients who are hypersensitive

to any component of this product.

Like other I)-blockers, COREG CR and

COREG should be used with caution in

patients with peripheral vascular disease,

thyrotoxicosis or who are undergoing

major surgery. Caution should also be

used in diabetic patients as I)-blockers

may mask some of the manifestations of

hypoglycemia, particularly tachycardia.

Worsening HF or fluid retention may occur

during uptitration of COREG CR or COREG.

The most common side effects reported

in the controlled trials in HF (reported

in ~1 0% of patients [both the mild-to­

moderate and the severe populations

studied] and more frequently on COREG)

were dizziness, fatigue, weight increase,

hypotension, and bradycardia. Worsening

HF symptoms were also reported, but

with equal or greater frequency in

placebo-treated patients.

The most common side effects reported

with COREG in the CAPRICORN trial were

consistent with the profile of the drug in

the US HF trials and the COPERNICUS

trial, as well as the health status of

patients. The only additional adverse

events reported in >3% of patients and

more frequently on COREG in CAPRICORN

were dyspnea, lung edema, and anemia.

The most common side effects in

hypenension trials with carvedilol were

nasopharyngitis (COREG CR) and

dizziness and fatigue (COREG) and were

generally mild.

Lower pressure wrthout losing control

11

C · A once-a-day beta-blocker wit out aU eI

No adverse effect on metabolic profile: HbA1c' total cholesterol, triglycerides, HDL and weight1

to Low incidence of adverse events that most cone physicians: fatigue, erectile dysfunction, and dizziness2

Significant BP reductions throughout the entire 24 hours3

PATIENTS WITH HIYPERTENSION*

STARTI G DOSE

UPT TRATION DOS

MAX MUM TARGET DOSE

COREG CR is covered on 89% o~ tiered commercial managed care planst4

'Starting dose: 20 mg 00. Uptilrale to 40 rng 00 after 1 10 2 weeks. as needed for BP control. The ma~nnum/largel doso IS 80 rng QO, if required.

hier 2 coverago = 54%, Tier 3 coverage = 35%

Relerences: 1. Data on hie (#~5), (#56), allD (#58), GlaxoSmithKlll1e 2 Oata all file (#81). (#S2.), !l1ld ('77). GlaroSnllU Xlln 3. bilr M;\ SI 011, T I;a E! 1'fEl1'III r M, 1llCl: R, Bakns GL. Controlled-release carvedllol in the Ireil"lme!1! of essenllalllypenensloll. Am J Cardio/. 2005,98(s'JIIPI).32L-38L. 4. MI!(1IlJ1~dl, US~, orJ'lllI f'j CempllS£, NI:J~ be' 2007, Employer. HMO, HMO-Medicaid, HMO-Medicare. flSurer. MedJcal GrOl,r, PllM. POS. PPO, S1[t M!lIJic:aid Of anllatioll .IDes. N (1,840)

COREG CR should be taken as a whole capsule in the morning with food. It should. not be crushed, chewed, or taken in divided doses.

Please see complete Prescribing Information provided. COREG (carvedilol phosphate) Extended-release Capsules

GtaxoSmtthKline COHc~;GIL"'o Lower pressl.J re wirthoullosing control