36
DRUG EVALUATION
Perindopril Arginine: Advantages over the Currently
Available Perindopril-tert-butylamine
Supanimit Teekachunhatean
Department of Pharmacology, Faculty of Medicine, Chiang Mai University,
Chiang Mai 50200, Thailand
Abstract
The angiotensin-converting enzyme (ACE) inhibitor perindopril has been
demonstrated to be an effective treatment in all stages of the cardiovascular continuum.
The currently available perindopril is a salt of tert-butylamine which has a shelf life of
approximately 2 years in countries with a temperate climate. Because of instability of
perindopril-tert-butylamine in countries with high temperature and relative humidity,
this salt requires special PVC/aluminum blister packs overwrapped with a watertight
bag containing a desiccant. Substitution of perindopril-tert-butylamine with perindopril
arginine causes the increase in drug stability and shelf life (from 2 to 3 years) of the new
arginine salt, therefore facilitates the use of a simplified packaging in the form of a high
density polyethylene (HDPE) canister all over the world irrespective of the climate
zones. Because the molecular weight of perindopril arginine is approximately 25%
greater than that of perindopril-tert-butylamine, thus the dosage of perindopril arginine
need to be changed accordingly. To achieve equivalent plasma concentrations of
perindoprilat, a dosage of perindopril-ter-butylamine 4-8 mg is substituted by
perindopril arginine 5-10 mg. Perindopril arginine is bioequivalent and produces the
similar antihypertensive efficacy to perindopril-tert-butylamine, but causes fewer
treatment-related adverse events. Therefore, perindopril arginine should exert better
benefits in the same way as demonstrated in clinical trials performed by using
perindopril-tert-butylamine. Consequently, perindopril arginine has been accepted to be
an effective treatment in the same indications as those of the tert-butylamine salt.
Furthermore, in the study comparing an overall preference for the canister containing
perindopril arginine versus that for the blister pack containing perindopril-tertbutylamine, the canister receives a higher preference than the blister pack. In
conclusion, the new perindopril arginine is more beneficial than perindopril-tertbutylamine in terms of better drug stability, longer shelf life, fewer treatment-related
adverse events, and higher patients’ preference.
Keywords : Perindopril, perindopril arginine, perindopril-tert-butylamine
Address correspondence and reprint requests to: Supanimit Teekachunhatean M.D., Ph.D., Department of
Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Thai J Pharmacol; Vol 30: No 2, 2008
37
Perindopril Arginine: 5F/=3F 9<9: 0'4/1. Perindopril-tert-butylamine
$'39:2$F'# 2'N%%O#'
$89 783N
50200
7#3<./
Perindopril angiotensin-converting enzyme (ACE) inhibitor <:H = D5&
; <{ 5 836G 5; < 8GD G 5 cardiovascular continuum perindopril @=D5;=C .$.1988 D =G 5 tert-butylamine b%5 ?&
<$9 $; << shelf life <3 2 C ;=?&<$ 839; <
D:5 @ 5 watertight bag = 8 PVC/aluminum blister packs ; <:=:D %5<
5 =5>? perindopril-tert-butylamine perindopril arginine b%5
5= :=5 shelf life 2 3 C ; <@:N?&>
893c6H; high density polyethylene (HDPE) canister >8:9 9 $ %5
5 perindopril arginine D@ 8 = perindopril-tert-butylamine N%5 25% 5D
D5: 53D G 5 perindopril (= ?) ; <>GGG 5 perindoprilat = %5 5G perindopril arginine G 5-10 mg ; perindopril-tertbutylamine G 4-8 mg @ D5D $%&;:5= perindopril arginine bioequivalence ; <
lHm = perindopril-tert-butylamine ;= 836>= %5<:56: H6
&> = 5D <6 %5>& perindopril arginine %5=<>
$5 $%&5 perindopril-tert-butylamine 8D perindopril arginine
%5> =G =5D perindopril-tert-butylamine D $%&
%5 G 5 perindopril arginine 8 canister perindopril-tert-butylamine 8 blister pack = 893c6; canister > %5 :5= blister pack :8
perindopril arginine G > = perindopril-tert-butylamine 5G 5= shelf life = 836>= %5<:56: H6& = ; <> %5 :5=
7;";7#> : Perindopril, perindopril arginine, perindopril-tert-butylamine
38
';
Perindopril angiotensin-converting
enzyme (ACE) inhibitor dicarboxyl
group 56< 5:5 8
D<:H = D5&; <
{ 5 836G 5; < 1v6 % 5 @ D = 5
; = <$ D5D perindopril  8 = G 5 tertbutylamine b%5 ? &<$ 9 $; < (temperate climate)
< shelf life <3 2 C ;=?&
<$G D : H6
(relative humidity, RH) :5 P
5G 5 (drug stability) 8D
@& t 93c6
perindopril tert-butylamine perindopril arginine b%5 shelf life ; <
5 G 5 G%D :<
G:=5; <?&
&=//DE5/6 perindopril
5:G 5 renin-angiotensin
system D7,8 renin @ ; 5
angiotensinogen angiotensin I 5
D angiotensin converting enzyme (ACE) <
angiotensin I angiotensin II b%5
mediator = := =5
> < = vasoconstriction, aldosterone secretion, oxidative stress,
= endothelial dysfunction, cardio-
vascular remodeling, < plasminogen
activator inhibitor-1 (PAI-1), :=5:
thrombosis ; <=5 atherosclerosis Perindopril7-10 8= ACE
inhibitors D5@5G 5 ACE @
< angiotensin II 5 :=5
arterioles ; < venules G D5 5 aldosterone adrenal cortex
D perindopril 5 D5: G 5 bradykinin @< bradykinin =5 G%D @>:= = nitric
oxide ; < prostacyclin b%5 mediators @
G %5 :8 G 5
angiotensin-bradykinin perindopril
5 ;>G : 5 angiotensin
II 5 =>G5
!"#$%&'(")*5/6 perindopril
Perindopril8-10 prodrug N
b%> =5?; <= bioavailability =
75-95% = 5>? 5Nb%
5 ; <=G:= = perindopril
<3 20-50% <N hepatic esterase ; 5 perindoprilat b%5
active metabolite lHm59: (=
%5E G 5 ; 5= 1-2
5) D5D :N perindoprilat
>9 30 5< ; <N%5
<:5:8 >9 3-7 5
>= <= = oral bioavailability
Thai J Pharmacol; Vol 30: No 2, 2008
G 5 perindopril ;= oral bioavailability
G 5 perindoprilat ><3 35% 5D
5l&ƒ%5;<@<=5
= D5 perindopril ; < perindoprilat
D5 metabolites G 5NG5>
GG 5 perindoprilat &3<
biphasic elimination pharmacokinetics
= =5;=%5<3 3-10
5 ; <=5 5=%5<3 30120 5 ( 5 dissociation ACE
=D >= G5) @5G 5> = 5 G
5 D ; 5 (metabolic
clearance) G 5 perindopril 5 5>
@5 = 5 =58;5
Perindopril onset of action = G5 ACE inhibitors = 5 <3 8 5%5
<? lHm D 5 ACE : 5 :8 5 < perindopril-tert-butylamine G 8 mg D5 (single oral dose)
= 5>? 5 :N D 5> N% 5
70% 3 24 5 5<9
:=5 perindopril = trough to peak ratio
:5:8 (<3 75-100%) ACE inhibitors 811 5D < <D5 %5<:H = 8 24 5
5/6 perindopril 2' cardiovascular
continuum
39
Cardiovascular disease continuum12
N%5 @G 5<; <
:5 (=
, :5) ; < t>
coronary artery disease, myocardial
infarction (MI) stroke, cardiac
remodeling, congestive heart failure (CHF),
; <: @
N%58 $%&5 ::8= perindopril <:H
= 8GD G 5 cardiovascular continuum
=5=
The Action in Diabetes and Vascular
disease: preterAx and diamicroN MR
Controlled Evaluation (ADVANCE) - BP
lowering intervention1 $%&<:H
G 5 fixed combination G 5 perindopril/
indapamide (Per/Ind) = { 5 836
G 5 macrovascular ; < microvascular events
2 >=@%5N%5
< = ; <G 5
@ 5> = D5D
ADVANCE trial >;:5=: Per/Ind
;= 2 :5
= major vascular events (9%) D5
all-cause death (14%) ; < cardiovascular
death (18%) =5:@P The Anglo-Scandinavian Cardiac
Outcomes Trial v Blood Pressure Lowering
Arm (ASCOT-BPLA)2 $%&
40
:5;:5= amlodipine/
perindopril = :5=
endpoints =5F =5:@P (= fatal
; < non-fatal stroke, total cardiovascular
events ; < procedures, all-cause mortality,
; < new-onset diabetes) atenolol/bendroflumethiazide =
The EURopean trial On reduction of
cardiac events with Perindopril in stable
coronary Artery disease (EUROPA)3 $%&;:5= : perindopril
=&4 chronic
stable coronary artery disease :5
= G 5 cardiovascular death,
nonfatal MI, ; < resuscitated cardiac arrest
> =5:@PN%5 20% The Perindopril pROtection aGainst
REcurrent Stroke Study (PROGRESS)4 $%&;:5= perindopril-based
regimen << 4 C < stroke = :5=
recurrent stroke > =5:@PN%5
28% ; <5:N :5= major vascular events (b%5>;= G 5
stroke, heart attack, ; < cardiovascular death)
>N%5 26% The Perindopril and Remodeling in
Elderly with Acute Myocardial Infarction
(PREAMI) study5 $%&;:5= perindopril << 1 C :5 8b%5 9< AMI (;=
left ventricular function ) :5= G 5 death, hospitalization heart failure, ; < cardiac remodeling > =5
:@PN%5 22% The Perindopril in Elderly People
with Chronic Heart Failure (PEP-CHF) study6
$%& heart failure 8
>70 C b%5 echocardiogram =5D
= diastolic dysfunction ;=$
substantial LV systolic dysfunction valve disease $%&=5C;;:5
= perindopril 8 36 G 5 ;>=> 5; = 5 5 heart failure (unplanned heart
failure related hospitalization) > =5
:@PN%5 37% :=P=:N ; <
= perindopril > D5D =
>= %5<:56 >= 8= ACE inhibitors >;= > ;5 b%5
>=8;5; <> 5
58 =5>? $%&5
<< = perindopril 836
G 5 > , @, ; <N $%&= G5@9,13
N>0 9:<1#7176)#15/6 perindopriltert-butylamine
5G 5 N%55
G 5= <5 9
Thai J Pharmacol; Vol 30: No 2, 2008
; <8 G%D<=5
; <?& := shelf life G 5
N%5<< ?&b%5lHm
59:> 5@=3c6@
> N = 3G 5 active substance
>= ; 5>= 5% ; <
; 5D 5>=: &14 %5
:9 9 $ = 5= D oxygen ;:5:=5 ; < 839 
:=5 H = 5G 5>
<5G 5:5
@>G 5G 5=5G 54
G 5 8@ = D5 D
The International Conference on
Harmonization of Technical Requirements
for Registration of Pharmaceuticals for
Human Use (ICH) >@ ICH guidelines
:@ : 5 G 5 15,16
> @ :9 8 3 9 ; < RH :@<= climatic zones >
4 :9 b% 5> : 8 < =5<$:9 9 $G>
;= < zone16 >5 1 %5 climatic
zone IV :9 :@$%&
5G 5:9<=5 (accelerated aging
studies)
5 active substance ; 5 ? &9 : 9 839; < RH :5 (climatic zones III ; <
IV)17v20 b% 5 ; 5 5 = ƒ<=5 active substance 41
excipients b%5:=5 = 3G 5 active
substance @83 &3<5<
(= = active substance
; < < ) ; 5>21 5>=
D degradation products G%D 9
:9 5 = :8G 5 >= %5
<:56 =5= ; 5G 5
tetracycline 9:9 839; < RH
:5 >= 5@ ; 55
; <9 = D (:G 5 5 = D@ G ) ;= degradation
product(s) 5@ & = > 22,23
= $%&5G 5
> :@ P G%D = 5 D5 D
: 5 9t6G 5 =8 93c659:
> <$= 5F ; <N :=5
<> D5 ? &
9: 9 ;= 5 5 D World
Health Organization (WHO) b% 5 ?5 ?
:@ P5 = %5;<@$%&
5G 59:9 climate zone
IV :@ = 5; = 24
Perindopril @=D5;=C .$.
1988 = G 5 tert-butylamine25
5GD (crystallization
phase) :N;: 5 > 5= =5>? $%&5
climatic zones III ; < IV = perindopril-
42
tert-butylamine @ 5? &8
9 3 c6 $& { 5 ; 59 : 9 5 = D 5 D <$ :9 9 $ = climatic zones I ; < II @= perindopril-tert-butylamine 8 = PVC/aluminum blister packs :=<$
:9 = climatic zones III ; <
IV @ 5 watertight bag = 8
PVC/aluminum blister packs ; <:=:
D %5<5G 517
$%&5G 5 ICH
guidelines ;:5= ; 5G 5
perindopril <= 5? & 5 > 2 <17 1. :9 RH : 5 @ hydrolysis G 5 ester := 5 diacid
metabolite b%5:Nb%5
> 2. :9 839= G5:5 @
5:55 8 G 5 ; 5>
=5; (cyclization) :=5 )69: 1 G 5 climatic zones ; < =5G 5<$ climatic zones ;=5F
(; 5Telejko E17)
@ H
839
RH
=5G 5<$
Zone I
<
< 20.5°C
45% Canada, Poland, Russia, ; < UK
Zone II
<; <D 20.5v24°C 60% Australia, China, France, Spain, ; <
USA
Zone III
; <;5
> 24°C
35% Botswana ; < Jordan
Zone IV
; <D
> 24°C
75% Brazil, India, Singapore, Taiwan,
<$>
RH N%5 D: H6 (relative humidity)
)69: 2 5G 5 nonsalified perindopril, perindopril-tert-butylamine ; <
perindopril arginine ?&>GB B 3 839 100°C 2 (; 5 Telejko E17)
3 = 5?& (%)
Nonsalified
PerindoprilPerindopril
perindopril
tert-butylamine
arginine
GB, 100°C, 2 < 1%
100%
100%
GB, 100°C, 2 < 1%
< 1%
100%
Thai J Pharmacol; Vol 30: No 2, 2008
lactam-type compounds ; <:8>
degradation product = Y31
%5 ; 55 5: 5
> = 5; :N{ 5> G 5 (salification) D5D
@ : @ nonsalified
perindopril ; < perindopril =
tert-butylamine ?&>9<B 3
8 3 9 100°C 2
= nonsalified
perindopril D 5 ; 5> Y31 = 5: 36
G3< perindopril-tert-butylamine >= ; 5F = 5>? @$%&9<B = perindopriltert-butylamine ?:N ; 5>
Y31 >= (5 2) D5D H>=
8 3 9 : 5 @ tert-butylamine < %5 ;= perindopril b%5 < ; 5> Y31 > $%&
5 =;:5= perindopril =G 5
tert-butylamine :5= :P:
5 B893c617
G =G5 <?=
 P 55 G 5 perindopril-tertbutylamine := 5 : = bioavailability
G 5D 5 perindopril
; < perindoprilat
D 5 < @ <:H 5 5> 5D
%5 > t G 5
perindopril ;= b%55
G%D b%5<> = < G N>
43
7176)#15/6 perindopril arginine
tG 5
@ : >= : N<
(nonvolatile alternatives) perindopril = G 5 arginine
5 = tert-butylamine
= 5N%5 100% : D5
9<B ; <9<B 3 8 3 9 100°C 2 17 (5 2)
D ; perindopril-tertbutylamine perindopril arginine 5
H ;  P 8 9 3 c6 8= 5 ; <
b b :@ <$ :9
9 $> climatic zones III ; <
IV D5 D $% &5 G 5? perindopril arginine 8 high density
polyethylene (HDPE) canister :D
? perindopril-tertbutylamine 8 aluminum/PVC blister
packs 9 climatic zone IV (40°C/75%
RH) << 6 = perindopril arginine ; 5>
degradation products 5 0.82% ;=
perindopril-tert-butylamine ; 5
N%5 8.74% $%&5 =::8=
perindopril arginine 8 HDPE canister
5 = perindopril-tertbutylamine 8 blister
packs17
D perindopril
arginine 5 shelf life >N%5 50%
= 2 C 3 C >=G%D =
44
)69: 3 ::= (ratio) G 5 pharmacokinetic parameters :@ perindopril ; < perindoprilat
(=; ) 5< perindopril arginine (10 mg) perindopril-tertbutylamine (8 mg) (D5) : :: $:8G9 @ 36 (; 5
Telejko E17)
Parameter
::=G 5 perindopril arginine / perindopril-tert-butylamine (90% CI)
Perindopril
Perindoprilat
AUCt
96.00% (92%, 100%)
96.55% (92%, 108%)
Cmax
98.23% (88%, 109%)
92.17% (87%, 97%)
CI, confidence intervals; AUCt, area under the plasma concentration-time curve; Cmax, maximum plasma concentration
839?&17
Bioequivalence 5/6 perindopril arginine
9< 9<# perindopril-tert-butylamine
5 perindopril arginine D@
8 = perindopril-tert-butylamine N%5
25% (542.680 441.615)
5D D5: 53D G 5
perindopril (= ?) = %5 5
G perindopril arginine 5 mg
; perindopril-tert-butylamine 4 mg ; <
perindopril arginine 10 mg ; perindopriltert-butylamine 8 mg17,26
> $% & bioequivalence G 5
perindopril D 5: 5 17,26 :: :8G9 @ 36 8E 31.3 ± 9.6
C ; < body mass index E 23.3 ± 1.7 kg/m2
$% &D ; open-label, randomized,
two-period, crossover, pharmacokinetic study
:8= =5 :: 2 8= ;= <
8= > < immediate-release
perindopril (D 5 ) arginine (10
mg) tert-butylamine (2 × 4 mg) =5
=5%5 5D 8 (washout period)
;= < 8= <N : < = 5: D5 ; D5 D
:: <> pharmacokinetic
parameters b% 5>; = maximum
plasma concentration (Cmax), time at
maximum plasma concentration (tmax), area
under the plasma concentrationvtime curve
(AUCt), ; < half-life (t½) D5
cardiovascular parameters b%5>;=
blood pressure (BP) ; < heart rate, D5
G 5 5= 5= ; < <<F
=5 120 5 5 $%&D
5 :: 3-5 5
> < D5 :8 =5 ; < electrocardiogram (ECG),
BP, heart rate, ; < laboratory parameters
Thai J Pharmacol; Vol 30: No 2, 2008
Bioequivalence G 5 perindopril D5: 5>
3 perindopril arginine/ perindopril-tert-butylamine AUC t ratios b%5=
= 96% (95% confidence interval (CI),
92v100%) :@ AUC G 5 perindopril ; <
96.55% (95% CI, 92v108%) :@ AUC G 5
perindoprilat (5 3) = CIs =
= 5 > = D 5: 5 bioequivalence = (80v125%)17,26
% 5 D 5 : 5 5 pharmacokinetic parameters F 5
D 5 <: H >=; = 5 ; <>= :@ P 5 = ; 5
laboratory parameters ; < ECG parameters
0 )O * = . CU 6 , " 6 7* % 2 $F
perindopril arginine
$%& bioequivalence =G5
>% (acceptability profile)
G 5D5: 5> = 2/36 (5.56%) 836>= %5<:56: H6
&=5> perindopril arginine
G3< 6/36 (16.67%) 836
>= %5<:56: H6&=5
> perindopril-tert-butylamine G 5 =;:5= acceptability profile G 5
perindopril arginine > >= perindopriltert-butylamine17 %5 836>= %5<:56
45
(= $&<, = , Influenza-like
illness, > ) ? %55
>$%&5 G 5 perindopril3,4
D : > perindopril arginine = G 5@ (2.8%)17
?> &3<$%&= D5= perindopril = >
= ACE inhibitors 13
71CU6C/2%)./2$F perindopril arginine
>$%& %5 G 5
@ 120 perindopril 8 simplified HDPE
canister blister pack17 8= =5 $
; <P5 8 60v70 C (50%) ; < 8
= 70 C (50%) b%5><
$ 6 9: 3 $ 6 <$
Australia D5D 8 ><<
= =5 %5 $%&
= 69% %5 (overall
preference) = 8 9 3 c6 ; canister
(perindopril arginine 5 ; < 10 mg)
31% ( p < 0.01) = 893c6
; blister pack (perindopril-tert-butyl-amine
4 ; < 8 mg) :=<;5=8=5F
= canister <; %5 :5=
; blister pack 8= :<
(78% 13%), > =5:<:
(68% 24%), ?&5=(62% 17%) ; <B 5= (50% 46
27%) <?5 ==<:=5 =
= = 5:@ :
(compliance) E < = 5 5 :5 8
)69:4 ;=5<=5 perindopril arginine perindopril-tert-butylamine
(; 5 Telejko E17)
G Perindopril
Perindopril-tertarginine
butylamine
D@ 8
542.680
441.615
G
5v10 mg/
4v8 mg/
5G 5 (35 5?&
100%
<1%
9<B 3 839 100°C 2 )
5G 5 (::=G 5 degradation product G%D
0.82%
8.74%
: 9 climatic zone IV << 6
)
:836>= %5<:56: H6& (n =
5.56%
16.67%
36)
Shelf life
3 C
2 C
"O
;=5<=5 perindopril D5: 5;:5>5 4 D5D
:8>= ACE inhibitor perindopril arginine 5 ; < shelf life
G%D =5>? D@ 8 ;=5<=5 perindopril D5
: 5 @@ 5 G (=
?) @ perindopril arginine 5 mg ; perindopril-tert-butylamine 4 mg ; <
@ perindopril arginine 10 mg ;
perindopril-tert-butylamine 8 mg D5D $% &5 pharmacokinetics ;:5= perindopril arginine bioequivalence =
perindopril-tert-butylamine 5 D < 6 % 5 > perindopril-tertbutylamine $%&5 GP=
: : 8 % 5 : N@ perindopril arginine > 8D G =5DG 5
perindopril arginine <$ G%D <>%5 8N%5 :5,
heart failure, ; < stable coronary artery
disease17,27 D 5G%DG 5
perindopril arginine 5@:N
Thai J Pharmacol; Vol 30: No 2, 2008
893c6; HDPE canister >8
:9 9 $ b%5 %5 G 5=
893c6; canister =<:=5 = =5:@: G%D
/"/F6/6
1. ADVANCE Collaborative Group. Effects of
a fixed combination of perindopril and
indapamide on macrovascular and microvascular outcomes in patients with type 2
diabetes mellitus (the ADVANCE trial): a
randomised
controlled
trial.
Lancet
2007;370:829-40.
2. The ASCOT Investigators. Prevention of
cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding
bendroflumethiazine as required, in the
Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm (ASCOTBPLA): a multicentre randomised controlled
trial. Lancet 2005;366:895-906.
3. Fox KM, European trial on reduction of
cardiac events with perindopril in stable
coronary artery disease investigators.
Efficacy of perindopril in reduction of
cardiovascular events among patients with
stable coronary artery disease: randomised,
double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet
2003;362:782-8.
4. PROGRESS Collaborative Group. Randomised trial of a perindopril-based bloodpressure-lowering regimen among 6,105
individuals with previous stroke or transient
ischaemic attack. Lancet 2001;358:1033-41.
5. The PREAMI Investigators. Effects of
angiotensin-converting enzyme inhibition
with perindopril on left ventricular
remodeling and clinical outcomes. Arch
Intern Med 2006;166:659-66.
6. Cleland JG, Tendera M, Adamus J,
Freemantle N, Polonski L, Taylor J; PEPCHF Investigators. The perindopril in elderly
people with chronic heart failure (PEP-CHF)
study. Eur Heart J 2006; 27:2338-45.
7. Benowitz NL. Antihypertensive agents. In:
Katzung BG, editor. Basic & clinical
pharmacology. 8th ed. New York: The
McGraw-Hill Companies, Inc; 2001. p.15580.
8. Jackson EK. Renin and angiotensin. In:
Hardman JG, Limbird LE, Gilman AG,
47
editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 10th ed. New
York: The McGraw-Hill Companies, Inc;
2001. p.809-42.
9. Ferrari R. Angiotensin-converting enzyme
inhibition in cardiovascular disease: evidence
with perindopril. Expert Rev Cardiovascular
Ther 2005;3(1):15-29.
10. Alfakih K, Hall AS. Perindopril. Expert Opin
Pharmacother 2006;7(1):63-71.
11. Physicians’ Desk Reference, 55th ed. Montvale,
NJ: Medical Economics Company, 2001.
12. Dzau V, Braunwald E. Resolved and
unresolved issues in the prevention and
treatment of coronary artery disease: a
workshop consensus statement. Am Heart J
1991;121:1244-63.
13. Yoshinaga K, Saruta T, Abe K, et al. Clinical
evaluation of monotherapy with perindopril,
an ACE inhibitor, in the treatment of
essential hypertension: double-blind parallel
comparison with enalapril. J Clin Ther
Medicines 1997;13:4259-97.
14. Telejko E. Stability of tablets and efficiency
and safety of drug use in various situations.
Farmacja Polska 2006;62:381-88.
15. ICH Steering Committee. Quality guidelines. Available from http://www. ich.org/
cache/compo/363-272-1.html. [accessed 14
June 2008]
16. Dietz R, Feilner K, Gerst F, Grimm W. Drug
stability testing. Classification of countries
according to climatic zone. Drugs made in
Germany 1993;36:99-103.
17. Telejko E. Perindopril arginine: benefits of a
new salt of the ACE inhibitor perindopril.
Current Medical Research and Opinion 2007;
23: 953-60.
18. Al Omari MM, Abdelah MK, Badwan AA,
Jaber AM. Effect of the drug-matrix on the
stability of enalapril maleate in tablet
formulations. J Pharm Biomed Anal
2001;25:893-902.
19. Reynolds JM, Rogers DH. Adjusting
dissolution specifications for the variability
induced by storage conditions. J Biopharm
Stat 2000;10:425-31.
20. Stanisz B. Kinetics of degradation of
quinapril hydrochloride in tablets. Pharmazie
2003;58:249-51.
21. Risha PG, Vervaet C, Vergote G, et al. Drug
formulations intended for the global market
should be tested for stability under tropical
climatic conditions. Eur J Clin Pharmacol
2003;59:135-41.
22. Wu Y, Fassihi R. Stability of metronidazole,
tetracycline HCl and famotidine alone and in
combination. Int J Pharm 2005;290:1-13.
48
23. Mohamad H, Aiache JM, Renoux R, et al.
Study on the biopharmaceutical stability of
medicines IV. Application to tetracycline
hydrochloride capsules. In vivo study. STP
Pharm 1987;3:407-11.
24. Nazerali H, Muchemwa T, Hogerzeil HV.
Stability of Essential Medicines in Tropical
Climates: Zimbabwe. WHO/ DAP/94.16.
Geneva, Switzerland: WHO 1996.
25. Medenica M, Ivanovic D, Maskovic M,
Jancic B, Malenovic A. Evaluation of
impurities level of perindopril tertbutylamine in tablets. J Pharm Biomed Anal
2007;44:1087-94.
26. Health Canada 's Summary Basis of Decision.
COVERSYL®.
Available
from
http://www.hc-sc.gc.ca/dhp
mps/prodpharma/sbd-smd/phase1-decision/drug med/sbd_
smd_2006_coversyl_092251-eng.php#1.
[accessed 14 June 2008]
27. Servier
Canada
Inc.
COVERSYL®:
perindopril arginine 2.5 mg, 5 mg, and 10 mg
tablets (Product Monograph Part III).
Available from http://www.hc-sc.gc.ca/dhpmps/alt_formats/hpfbdgpsa/pdf/prodpharma/
pm_mp_2005_coversyl_092251_partiiieng.pdf. [accessed 14 June 2008]