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
I patie is with type II diabetes.

Peas see Impo Safety nfonnation on ge 1

ower pressure withou losing control
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):

p- 0.6~
10 p~ 0.001
I
~
....
8 7.2 7.2 .s'" 186 185.6
':l<
~
(J
6
e
(l)
185

<"
.0
iii
Ql
184

:I: "0 183

c:
III
4 J::
U 181.7
II> 182
:E E
2 ...C1i.
:I
181
m
0
...
iii
{2
180

179
BASELINE MONTH 5 t 01
N=433 BASELINE MONTH 51

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 II>- Metoprolol tartrate demonstrated

significant increase in HbA 1c (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:
COREG CR has eft t
110
on triglycerides or weiig t

In GEMINI, patients taking COREG"

No Change in Weight 1.2

p= 0.36

I I
:J 21'1]
I P=0?8
Ci 100
98.2 97.2
~
Cl
.s
200
190
I I ~
...
.c:
95
90

'"
180
168.3 Cl
'iii 85
<II
"0
'':
170
160
159.4 ~
,.,
"0
80

,.,
<II
0 150 0
cc
75
70
0> 1~0 c
~ ro 65
130 <II
c :E 60
ro 120
<II ~tJ
:E 110
100 SC
~
01
BASELINE MONTH 51 BASELINE MONTH 5 f

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

... Metoprolol tartrate demonstrated ... Metoprolol tartrate demonstrated

significant elevation in triglycerides significant weight gain from baseline
(change from baseline 13.2%; (change from baseline 1.2 kg;
P<O.0001)1.2 P<O.0001)1.2

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.

COR
'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
conlrOI.)C! tf,al .lAMA 200~;2922227-2236. 2. Data 011 file (/55), (ii 61. arn (1158), GiaxoSmlthKlire.
(carvedilol phosphate)
Extended-release Capsules
I o,wer pressure wi hou losing control
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 tolerated 1

... 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

I P<O.005, changes from

baseline vs placebo.

§ Systolic blood pressure.

0
II Diastolic blood pressure.

-2

c;
JO
E
-4 .. Maintains significant
.§.

a. -6 BP reductions
Cll
.S
'<:"
Cl
-8 throughout the
u'"
..:= -10 entire 24 hours 3
<:
-12
''""
~
-14

.., Provides BP control

in a dose-dependent
-16
-15.3 t
Peak DBP" manner3

CORG C . BP reductions at trough 2

DOSE SBP DBP P<O.OOl, changes from

(mmHg) (mmHg) baseline vs placebo 4

20 mg -2.8

40 mg -5.2

80 mg -8.4~ -7.4~

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 .. 1 11

-AACE Hypertension Task Force

Level of Grade'
Evidence·
--­

ACE Inhibitor or ARB as first- or second-line agent

1 A
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 BP= Blood Pressuro

action) for the be cial effects of TPR= Total Peripheral Re~isl£lnce
Beta blockade in hyperte as
not been established. CO=. Cardiac Outpul
 ONCE-A-DAY

Card ioprotective 5

I CA Coreg® (carve i 0) red ce all...cau e mortali y

1r.

Post-MI LV pa "e by 23% (95°/0 C ,2 % '040 0/or,2

All-cause mortality was 15% in

Fatal or Nonfatal Reinfarction U 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
...Across the
cardiovascular continuum
": COR G reduc,ed ortality in sy p oma'c HF
------­
•

17%
RISK REDUCTION
19%
RISK REDUCTION
67%
RISK REDUCTION
34% In t . CO ~G group 14S'~ in e COREG group o qql n ttl. 0
...0% It the. .e1oprc I Irtml " Ollp 17. t 8 melopr I tar rme roup 2.5 u In 18 m Jopr I
95 95 u Ct, gc,\;, to 32.' 9"' CI, 38 ~ lJ H~,fl
:::.0 p= 11006

Extrapolation from the survival curves suggested that COREG

extended median survival by 1.4 years 4
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

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
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-to­
ilead 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.

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 I Te 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
ONCE-A-DAY

C R e

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 press ure wrthout losing control
11
 C · A once-a-day
beta-blocker wit out aU I e
No adverse effect on metabolic profile: HbA 1 c'
total cholesterol, triglycerides, HDL and weight 1
to Low incidence of adverse events that most cone
physicians: fatigue, erectile dysfunction, and dizziness 2
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 plans t4

'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