Which molecules for metabolic
Krzysztof
hypertension and why
Place of diuretics
Diuretics are the second most commonly prescribed class of antihypertensive
agents (after angiotensin-converting enzyme [ACE] inhibitors), and have been
in widespread clinical usage for more than half a century.30-32 This, along with
their proven ability to reduce the risk of cardiovascular events, means that
diuretics are one of the important classes of antihypertensive agents.2,13,33-35
Furthermore, diuretics (especially thiazide-like agents) are an important part
of many dual or triple antihypertensive therapy combinations used for the
management of patients with cardiovascular risk factors, hard-to-control BP
and/or resistant hypertension.2,33-35
Thiazide diuretics reduce BP by increasing urinary sodium and water losses.
This is particularly relevant for patients with diabetes or obesity, who often
have hypervolemia. Thus, although beneficial for the majority of patients
with hypertension, the mechanism of action of diuretics means that they
are particularly suited for, and recommended in, certain patient subgroups,
including patients with diabetes and/or obesity, as well as black patients and
those aged >65 years.2,13,33 These groups are not mutually exclusive, and it is
their common features (including salt sensitivity and salt-related fluid retention)
that likely contribute to the therapeutic benefit of diuretic-based therapy.
Within the overall class, diuretics are a heterogenous group of agents. The most
common types of diuretic agents are thiazide-type (eg, hydrochlorothiazide
[HCTZ]), thiazide-like (eg, indapamide, chlorthalione), loop (eg, furosemide) and
potassium-sparing (eg, amiloride, eplerenone). Thiazide, and especially thiazide-
like diuretics, are the agents most recommended in current guidelines.2,13,33-35
Some guidelines specifically recommend thiazide-like diuretics over thiazide-
type diuretics due to the available body of evidence in cardiovascular event
prevention.2,10,13,33-35
Why do the latest guidelines
recommend thiazide-like diuretics such
as indapamide?
Major guidelines recommendations for specific antihypertensive drug classes are
based on proven BP-lowering activity, and the ability of treatment with these
agents to effectively reduce cardiovascular events in placebo-controlled clinical
trials Table I .2,10,13,33-35 Diuretics are among the classes of agents fulfilling these
requirements, along with ACE inhibitors, angiotensin receptor blockers, calcium
channel blockers (CCBs), and β-blockers.2,10,13,33,34 Thiazide-like diuretics such
as indapamide have specific roles in the secondary prevention of stroke and in
patients with metabolic hypertension.2,13,33,34
In addition to lifestyle modifications (especially weight reduction in patients with
obesity), first-line treatment for patients with hypertension and diabetes mellitus,
particularly those with concomitant renal disease, is a renin-angiotensin system
(RAAS) inhibitor. However, patients with diabetes and/or obesity also tend to
retain fluid, increasing the risk of progression to heart failure or further renal
dysfunction.36
For most patients with hypertension, including those with diabetes, it is
recommended that pharmacological treatment is initiated with a dual-therapy
Prof.
Narkiewicz
Medical University
of Gdansk, Poland
SPC (ideally a RAAS blocker with a diuretic or CCB), stepping up to a triple therapy
SPC including a RAAS inhibitor + CCB + diuretic if required to achieve BP control.13
Including a diuretic in the SPC would be preferable for patients with metabolic
hypertension because this group of patients will benefit from the volume control
and/or natriuresis associated with diuretic therapy (Table I).
In the European hypertension guidelines, target SBP in patients with diabetes is
130 mm Hg (and not <120 mm Hg) in those aged 18 to 65 years and 130–140 in
those aged ≥65 years; target DBP in all patients with hypertension and diabetes
is 70 to 79 mm Hg.13
Guideline-based treatment strategies are based on cardiovascular risk,10,13,35
and the presence of diabetes in patients with hypertension places them
in the “high risk” or “very high risk” category in terms of recommended
antihypertensive treatment strategy.13 European guidelines also highlight the
importance of achieving BP control within 3 months of treatment initiation
in patients with grade ≥2 hypertension.13 The latest diabetes treatment
guidelines state that antihypertensive treatment should include drug classes
that have been specifically shown to reduce cardiovascular risk in patients with
hypertension and diabetes, including ACE inhibitors, thiazide-like diuretics or
dihydropyridine CCBs.37
Specificity of indapamide
Indapamide is a non-thiazide indoline derivative with a dual mechanism of
action. In addition to increasing urinary excretion of sodium and water by
inhibiting sodium reabsorption in the cortical diluting tubule of the nephron,
indapamide also lowers SBP via a calcium antagonist-like vasorelaxant effect.38
Indapamide is a lipid-soluble molecule that is rapidly absorbed and shows
excellent bioavailability after oral administration.39 The drug binds to plasma
proteins and selectively accumulates in vascular smooth muscle, meaning it
has a prolonged plasma half-life.39
For patients with normal renal function, thiazide-like diuretics such as
indapamide have greater antihypertensive potency than the thiazide-type
diuretic HCTZ.40 For example, meta-analysis data showed that reductions in
SBP with indapamide were 54% greater than those with HCTZ.40 In addition,
treatment with indapamide was associated with significant reductions in
cardiovascular event rates in large, randomized, controlled clinical trials,41-44
whereas no such data exist for low-dose HCTZ alone.
Indapamide-containing regimens have been shown to have a number of
beneficial effects that could contribute to cardiovascular risk reduction beyond
control of BP. These include:
• improved perfusion in the microcirculation;45
• improved endothelial function;46
• improved metabolic parameters (including blood glucose, cholesterol and uric
acid levels);47,48
• decreased oxidative stress;49
• inhibition of carbonic anhydrase;50
• reduction in the left ventricular mass index;51
• greater creatinine clearance than HCTZ for comparable reductions in BP;52
• stronger antiplatelet effect than HCTZ.53
1
 Table I. Guideline-based recommendations for antihypertensive therapy with diuretics in patients with hypertension,
including those with co-existing metabolic risk factors

Guidelines, year General recommendations Specific suggestions

Hypertension

ISH, 202010 Thiazide-like diuretics preferred • Treatment of hypertension in patients with diabetes should include
an RAAS inhibitor, plus a CCB and/or a thiazide-like diuretic

NICE UK, 201935 Diuretics suitable for first-line • Thiazide-like diuretics specifically recommended for patients
therapy (thiazide-like agents aged >55 years and those of African or Caribbean descent
preferred)
• Triple therapy should include a thiazide-like diuretic
ESC/ESH, 201813 Diuretics suitable for first-line • Drug treatment regimens should be simplified by the use of an
therapy regimens SPC including an ARB or ACEi combined with a diuretic or CCB
(for most patients)
• Thiazide and thiazide-like diuretics are less effective in patients
with reduced renal function

ACC/AHA, 20172 Diuretics suitable for first-line • Secondary stroke prevention regimens should include a thiazide
therapy regimens diuretic
• A thiazide-like agent should be used to maximize diuretic therapy
in resistant hypertension
Diuretics suitable for initial and • Longer-acting, thiazide-like diuretics preferred
Canada, 201734 ongoing antihypertensive therapy,
alone or as part of a SPC • Diuretics useful for hypertensive patients with uncomplicated
diabetes mellitus

• Diuretic/ACEi combination suggested for pts with previous

stroke or TIA

Latin America, 201733
Diuretics suitable for the • Slow-release indapamide specifically recommended for the pre-
initiation and maintenance of vention of recurrent stroke (possibly in combination with an ACEi)
antihypertensive therapy, alone
or in combination with other
• Use of an SPC containing an ACEi or ARB plus CCB or diuretics
antihypertensives; thiazide-like
preferred in those with moderate or high CV risk, and in pts with
agents preferred
Grade 2 hypertension
• Diuretics should be part of a triple therapy prescription

Diabetes
ESC/EASD, 201984 Antihypertensive treatment in • BP control often requires multiple drug therapy
patients with diabetes should be
initiated with the combination of
a RAAS blocker plus a CCB or
thiazide/thiazide-like diuretic

Antihypertensive treatment in
ADA, 201937 patients with diabetes should • Dual therapy should be started as first-line treatment (two
include agents from drug classes agents or an SPC)
that have been shown to reduce
• Treatment with multiple antihypertensive agents is usually
cardiovascular events (including
required to achieve BP targets
thiazide-like diuretics)

ACC, American College of Cardiology; ACEi, angiotensin converting enzyme inhibitor; ADA, American Diabetes Association; AHA, American Heart Association; ARB, an-
giotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; CV, cardiovascular; EASD, European Association for the Study of Diabetes; ESC, European
Society of Cardiology; ESH, European Society of Hypertension; ESC, European Society of Cardiology; HF, heart failure, ISH, International Society of Hypertension; NICE,
National Institutes for Health and Care Excellence; RAAS, renin-angiotensin system; SPC, single-pill combination; TIA, transient ischemic attack.

2. Whelton PK et al. J Am Coll Cardiol. 2018;71:2199-2269.
10. Unger T et al. J Hypertens. 2020;38:982-1004.
13. Williams B et al. Eur Heart J. 2018;39:3021-3104
30. Kantor ED et al. JAMA. 2015;314:1818-1831.
31. Roush GC et al. Am J Hypertens. 2016;29:1130-1137.
32. Moser M et al. Arch Intern Med. 2009;169:1851-1856.
33. Task Force of the Latin American Society of
Hypertension. J Hypertens. 2017;35:1529-1545.
34. Nerenberg KA et al. Can J Cardiol. 2018;34:506-525
35. N ational Institute for Health and Care Excellence.
Available at: https://www.nice.org.uk/guidance/ng136/
resources/hypertension-in-adults-diagnosis-and-
management-pdf-66141722710213. Accessed 24 Apr
2019.
36. Bahtiyar G et al. Curr Diab Rep. 2016;16:116.
37. A merican Diabetes Association. Diabetes Care.
2019;42:S1-S193.
38. W aeber B et al. Expert Opin Pharmacother.
2012;13:1515-1526.
39. Caruso FS et al. Am Heart J. 1983;106:212-220.
40. Roush GC et al. Hypertension. 2015;65:1041-1046.
41. PATS Collaborating Group. Chin Med J (Engl).
1995;108:710-717.
42. P R O G R E S S C o l l a b o r a t i v e G r o u p . L a n c e t .
2001;358:1033-1041.
43. Beckett NS et al. N Engl J Med. 2008;358:1887-1898
44. Chalmers J et al. Hypertension. 2014;63:259-264.
45. Debbabi H et al. Am J Hypertens. 2010;23:1136-1143.
46. Thuillez C et al. J Hum Hypertens. 2005;19 Suppl
1:S21-25.
47. Karpov YA. Clin Drug Investig. 2017;37:207-217. This
study was not conducted in line with the EU indication of
perindopril 10/indapamide 2.5, to be approved by local
RA.
48. Farsang C et al. Blood Press. 2013;22 Suppl 1:3-10.
49. Vergely C et al. Mol Cell Biochem. 1998;178:151-155.
50. Bataillard A et al. Clin Pharmacokinet. 1999;37 Suppl
1:7-12.
51. Carey PA et al. Am J Cardiol. 1996;77:17b-19b.
52. Madkour H et al. Am J Cardiol. 1996;77:23b-25b.
53. Rendu F et al. J Cardiovasc Pharmacol. 1993;22 Suppl
6:S57-63.
COMPOSITION* : COVERSYL PLUS 4 mg/1.25 mg tablets: Perindopril tertbutylamine 4 mg -
Indapamide 1.25 mg. Contains lactose as excipient. INDICATIONS* : Essential hypertension
in patients whose blood pressure is not adequately controlled on perindopril alone. DOSAGE
and ADMINISTRATION* : One tablet per day preferably in the morning and before a meal.
Elderly: can be treated if renal function is normal and after considering blood pressure
responses. Renal impairment: Frequent monitoring of creatinine and potassium is required.
Creatinine clearance (CrCl) > 60 mL/min: no dosage modification. CrCl 30-60 mL/min: one
tablet. CrCl<30 mL/min: treatment contraindicated. CONTRAINDICATIONS* : Hypersensitivity
to the active substances, any other ACE inhibitor, any other sulfonamides, or to any of the
excipients. History of angioedema (Quincke’s edema) associated with previous ACE inhibitor
therapy (see warnings section). Hereditary/ idiopathic angioedema. Concomitant use with
aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60
ml/ min/1.73 m²). Concomitant use with sacubitril/valsartan. Extracorporeal treatments.
Significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney.
Hypokalemia. Severe renal impairment (CrCl <30 mL/min). Hepatic encephalopathy. Severe
hepatic impairment. Medicine inadvisable in combination with non-antiarrhythmic agents
causing torsades de pointes (see interaction section). Second and third trimesters of pregnancy
and lactation (see fertility, pregnancy, and breastfeeding section). Due to the lack of sufficient
therapeutic experience, should not be used in dialysis patients and patients with untreated
decompensated heart failure. WARNINGS*: Special warnings: Lithium, potassium-sparing
diuretics and potassium salts; dual blockade of the renin-angiotensin-aldosterone system
(RAAS) through the combined use of ACE-inhibitors, ARB or Aliskiren: not recommended
because of increased risk of hypotension, hyperkalaemia and decreased renal function
(including acute renal failure). In patients with diabetic nephropathy when associated with
ARB: should not be used. Neutropenia/ agranulocytosis, thrombocytopenia and anemia:
extreme caution in patients with collagen vascular disease, immunosuppressant therapy,
treated with allopurinol or procainamide, periodic monitoring of white blood cell counts
advised. Increased risk of hypotension and renal insufficiency when used in patients with
bilatreal renal artery stenosis or stenosis of the artery to a single functioning kidney.
Hypersensitivity/ angioedema, intestinal angioedema: stop treatment and monitor until
complete resolution of symptoms. Angioedema associated with laryngeal oedema may be
fatal. Combination with sacubitril/valsartan (contraindicated due to the increased risk of
angioedema). Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus):
patients may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with
or without respiratory impairment). Anaphylactoid reactions during desensitisation: isolated
life-threatening anaphylactoid reactions during treatment with hymenoptera (e.g. bees, wasps)
venom. Coversyl PLUS should be used with caution in allergic patients treated with
desensitisation and avoided in those undergoing venom immunotherapy. These reactions
could be prevented by temporary withdrawal of ACE inhibitor for at least 24 hours before
desensitisation. Anaphylactoid reactions during LDL apheresis with dextran sulphate: rarely
patients have experienced life-threatening anaphylactoid reactions. Temporarily withhold
treatment prior to each apheresis. Anaphylactoid reactions during dialysis with high-flux
membranes: consider use of a different type of membrane or a different class of
antihypertensive agent. Primary aldosteronism: use is not recommended. Pregnancy: stop
treatment and change to alternative therapy if appropriate. Hepatic encephalopathy: stop
treatment. Photosensitivity: stop treatment. Renal failure: stop treatment in case of functional
renal insufficiency without pre-existing apparent renal lesions and possibly restart at a low
dose or with one constituent only. Monitoring of potassium and creatinine, after two weeks of
treatment and then every two months during therapeutic stability period. If bilateral renal artery
stenosis or a single functioning kidney: not recommended. Precautions for use: Hepatic
failure: stop treatment if jaundice or marked elevations of hepatic enzymes. Rarely, ACE
inhibitors have been associated with a syndrome that starts with cholestatic jaundice and
progresses to fulminant hepatic necrosis and (sometimes) death. Functional renal insufficiency:
treatment should be stopped and possibly restarted at a low dose or with one constituent only;
frequent monitoring of potassium and creatinine. Renovascular hypertension: start treatment
at hospital; monitor renal function and potassium. Risk of arterial hypotension, and/or renal
insufficiency in the case of water and electrolyte depletions in patients with low blood pressure,
renal artery stenosis, congestive heart failure or cirrhosis with edema and ascites: start
treatment at low dose and increase progressively. Sudden hypotension if pre-existing sodium
depletion (in particular if renal artery stenosis): re-establish blood volume and pressure, restart
treatment at a reduced dose or with only one of the constituents. Severe cardiac insufficiency
(grade IV): start treatment under medical supervision with reduced initial dose. Aortic or mitral
valve stenosis/hypertrophic cardiomyopathy: use with caution if obstruction in the outflow tract
of the left ventricle. Atherosclerosis: start treatment at low dose in patients with ischemic heart
disease or cerebral circulatory insufficiency. Dry cough. Potassium levels: regular monitoring.
Hyperkalemia: frequent monitoring of blood potassium if renal insufficiency, worsening of renal
function, age (>70 years), diabetes mellitus: treatment should be started under medical
supervision with a reduced initial dose, dehydration, acute cardiac decompensation, metabolic
acidosis, and concomitant use of potassium-sparing diuretics and potassium salts; can cause
serious, sometimes fatal arrhythmias. Hypokalemia: high risk for elderly and/or malnourished
subjects , cirrhotic patients with edema and ascites, coronary and heart failure patients, long
QT interval; more frequent monitoring necessary in all cases; may favor the onset of torsades
de pointes, which may be fatal. Sodium levels: test before treatment starts; more frequent
monitoring in elderly and cirrhotic patients, hyponatraemia with hypovolaemia may be
responsible of dehydration and orthostatic hypotension. Concomitant loss of chloride ions may
lead to secondary compensatory metabolic alkalosis (slight incidence and degree).
Hypercalcemia: stop treatment before investigating parathyroid function. Hyperuricemia:
increased tendency to gout attacks. Anesthesia: treatment stop is recommended one day
before surgery. Hereditary problems of galactose intolerance, total lactase deficiency or
glucose-galactose malabsorption: should not be administered. Diabetics: monitor blood
glucose in the case of hypokalemia. Black people: higher incidence of angioedema and
apparently less effective in lowering blood pressure than in non-blacks. Children and
adolescents: efficacy and tolerability not established. Athletes: may cause positive doping test.
Acute myopia and secondary angle-closure glaucoma: discontinue drug intake as rapidly as
possible. Prompt medical or surgical treatments may need to be considered if the intraocular
pressure remains uncontrolled. INTERACTIONS* : Contra-indicated: Aliskiren (in diabetic
or impaired renal patients), extracorporeal treatments, sacubitril/ valsartan. Not
recommended: Aliskiren (in other patients), lithium, potassium-sparing diuretics, concomitant
therapy with ACE inhibitor and angiotensin-receptor blocker, estramustine, co-trimoxazole,
potassium salts. Special care: Baclofen, nonsteroidal anti-inflammatory medicinal products
(including aspirin ≥3g/day), antidiabetic agents, torsades de pointes−inducing drugs,
potassium-lowering drugs, non-potassium-sparing diuretics, digitalis preparation, allopurinol,
racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus). Some care:
Imipramine-like antidepressants (tricyclics), neuroleptics, antihypertensive agents and
vasodilatators, allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids
or procainamide or tetracosactide, anesthetic drugs, gliptins, sympathomimetics, gold,
metformin, iodinated contrast media, calcium (salts), ciclosporin tacrolimus. FERTILITY,
PREGNANCY AND BREASTFEEDING* Not recommended during the first trimester of
pregnancy. Contraindicated during the second and third trimesters of pregnancy
and lactation. DRIVE & USE MACHINES* : May be impaired due to low blood pressure that
may occur in some patients. UNDESIRABLE EFFECTS* : Common: Hypersensitivity reactions
(mainly dermatological in subjects with a predisposition to allergic and asthmatic reactions),
paresthesia, headache, asthenia, dizziness, vertigo, vision impairment, tinnitus, hypotension,
cough, dyspnea, constipation, nausea, vomiting, abdominal pain, dysgeusia, dyspepsia,
diarrhea, rash, pruritus, rash maculopapular, muscle cramps. Uncommon: Eosinophilia,
hypoglycaemia, hyperkalaemia, hyponatremia, mood altered, sleep disorder, somnolence,
syncope, palpitations, tachycardia, vasculitis, bronchospasm, dry mouth, angioedema,
urticaria, purpura, hyperhidrosis, photosensitivity reaction, pemphigoid, arthralgia, myalgia,
renal insufficiency, erectile dysfunction, chest pain, malaise, oedema peripheral, pyrexia,
blood urea increased, blood creatinine increased, fall. Rare: Psoriasis aggravation, fatigue,
blood bilirubin increased, hepatic enzyme increased. Very rare: Thrombocytopenia,
leukopenia, neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia, hypercalcaemia,
confusion, stroke possibly secondary to excessive hypotension in high-risk patients, arrhythmia
(including bradycardia, ventricular tachycardia, atrial fibrillation), angina pectoris and
myocardial infarction, (secondary to hypotension in high-risk patients), eosinophilic pneumonia,
rhinitis, pancreatitis, hepatitis, hepatic function abnormal, erythema multiforme, toxic
epidermal necrolysis, Stevens-Johnson syndrome, renal failure acute haemoglobin decreased
and haematocrit decreased. Not known: potassium depletion with hypokalemia particularly
serious in certain high-risk populations, myopia, vision blurred, torsades de pointes
(potentially fatal), hepatic encephalopathy (in the case of hepatic insufficiency), possible
worsening of pre-existing acute disseminated lupus erythematosus, ECG QT prolonged,
blood glucose and blood uric acid increased, Raynaud’s phenomenon. Cases of SIADH
have been reported with other ACE inhibitors. OVERDOSE*. PROPERTIES* : Coversyl PLUS
is a combination of perindopril tertbutylamine salt, an angiotensin converting enzyme inhibitor,
and indapamide, a sulfonamide, pharmacologically related to thiazide diuretics with a dose-
dependent antihypertensive effect on diastolic and systolic arterial pressure whilst supine or
standing. PRESENTATION*: Pack of 30 tablets. 091019
COMPOSITION:* Coversyl PLUS 5 mg/1.25 mg tablets: Perindopril arginine 5 mg -
Indapamide 1.25 mg. Coversyl PLUS 10 mg/2.5 mg tablets: Perindopril arginine 10 mg -
Indapamide 2.5 mg. Contains lactose as excipient. INDICATIONS:* Coversyl PLUS
5/1.25: Essential hypertension in patients whose blood pressure is not adequately controlled
on perindopril alone. Coversyl PLUS 10/2.5: Substitution therapy for treatment of essential
hypertension in patients already controlled with perindopril and indapamide given concurrently
at the same dose level. DOSAGE and ADMINISTRATION:* One tablet per day preferably
in the morning and before a meal. Elderly: Coversyl PLUS 5/1.25 & 10/2.5: can be treated
if renal function is normal and after considering blood pressure responses. Coversyl PLUS
10/2.5: plasma creatinine must be adjusted in relation to age, weight, and sex. Renal
impairment: Frequent monitoring of creatinine and potassium is required. Creatinine
clearance (CrCl) >60 mL/min: no dosage modification. CrCl<30 mL/min: treatment
contraindicated. CONTRAINDICATIONS:* Hypersensitivity to perindopril or any other ACE
inhibitor, to indapamide or any other sulfonamides or to any of the excipients. History of
angioedema (Quincke’s edema) associated with previous ACE inhibitor therapy. Hereditary/
idiopathic angioedema. Concomitant use with aliskiren- containing products in patients with
diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73m2). Concomitant use with
sacubitril/valsartan (see WARNINGS* and INTERACTIONS*), extracorporeal treatments
leading to contact of blood with negatively charged surfaces (see INTERACTIONS*),
significant bilateral renal artery stenosis or stenosis of the artery to a single functioning
kidney (see WARNINGS*). Hypokalemia. Severe renal impairment (CrCl <30 mL/min) for
Coversyl PLUS 5/1.25. Moderate to severe renal impairment (CrCl <60 mL/min) for
Coversyl PLUS 10/2.5. Hepatic encephalopathy. Severe hepatic impairment. Medicine
inadvisable in combination with non-antiarrhythmic agents causing torsades de pointes (see
interaction section). Second and third trimesters of pregnancy and lactation (see fertility,
3
pregnancy, and breastfeeding section). Due to the lack of sufficient therapeutic experience,
should not be used in dialysis patients and patients with untreated decompensated heart
failure. WARNINGS:* Special warnings: Lithium, potassium-sparing diuretics and potassium
salts; dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the
combined use of ACE-inhibitors, ARB or Aliskiren: not recommended because of increased
risk of hypotension, hyperkalaemia and decreased renal function (including acute renal
failure). In patients with diabetic nephropathy when associated with ARB: should not be
used. Neutropenia/agranulocytosis, thrombocytopenia and anemia: extreme caution in
patients with collagen vascular disease, immunosuppressant therapy, treated with allopurinol
or procainamide, periodic monitoring of white blood cell counts advised. Renovascular
hypertension: increased risk of hypotension and renal insufficiency in patients with bilateral
renal artery stenosis or stenosis of the artery to a single functioning kidney. Diuretics may be
a contributory factor. Loss of renal function may occur (minor changes in serum creatinine)
even in patients with unilateral renal artery stenosis. Hypersensitivity/angioedema, intestinal
angioedema: stop treatment and monitor until complete resolution of symptoms. Angioedema
associated with laryngeal oedema may be fatal. Concomitant use of mTOR inhibitors (e.g.
sirolimus, everolimus, temsirolimus): patients may be at increased risk for angioedema (e.g.
swelling of the airways or tongue, with or without respiratory impairment). Combination with
sacubitril/valsartan (contraindicated due to the increased risk of angioedema). Sacubitril/
valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy.
Sacubitril/valsartan must not be initiated until 36 hours after the last dose of Coversyl
PLUS. Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE inhibitors may
also increase the risk of angioedema. Anaphylactoid reactions during desensitisation:
isolated life-threatening anaphylactoid reactions during treatment with hymenoptera (e.g.
bees, wasps) venom. Coversyl PLUS should be used with caution in allergic patients treated
with desensitisation and avoided in those undergoing venom immunotherapy. These reactions
could be prevented by temporary withdrawal of ACE inhibitor for at least 24 hours before
desensitisation. Anaphylactoid reactions during LDL apheresis with dextran sulphate: rarely
patients have experienced life-threatening anaphylactoid reactions. Temporarily withhold
treatment prior to each apheresis. Anaphylactoid reactions during dialysis with high-flux
membranes: consider use of a different type of membrane or a different class of
antihypertensive agent. Primary aldosteronism: Use not recommended in patients with
primary hyperaldosteronism (not responding to drugs acting through inhibition of the renin-
angiotensin system). Pregnancy: stop treatment and change to alternative therapy if
appropriate. Hepatic encephalopathy: stop treatment. Photosensitivity: stop treatment.
Renal failure: stop treatment in case of functional renal insufficiency without pre-existing
apparent renal lesions and possibly restart at a low dose or with one constituent only.
Monitoring of potassium and creatinine, after two weeks of treatment and then every two
months during therapeutic stability period. If bilateral renal artery stenosis or a single
functioning kidney: not recommended. Precautions for use: Hepatic failure: stop treatment
if jaundice or marked elevations of hepatic enzymes. Rarely, ACE inhibitors have been
associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant
hepatic necrosis and (sometimes) death. Functional renal insufficiency: treatment should
be stopped and possibly restarted at a low dose or with one constituent only; frequent
monitoring of potassium and creatinine. Renovascular hypertension: start treatment at
hospital; monitor renal function and potassium. Risk of arterial hypotension, and/or renal
insufficiency in the case of water and electrolyte depletions in patients with low blood
pressure, renal artery stenosis, congestive heart failure or cirrhosis with edema and ascites:
start treatment at low dose and increase progressively. Sudden hypotension if pre-existing
sodium depletion (in particular if renal artery stenosis): re-establish blood volume and
pressure, restart treatment at a reduced dose or with only one of the constituents. Severe
cardiac insufficiency (grade IV) start treatment under medical supervision with reduced initial
dose. Aortic or mitral valve stenosis/hypertrophic cardiomyopathy: use with caution if
obstruction in the outflow tract of the left ventricle. Atherosclerosis: start treatment at low
dose in patients with ischemic heart disease or cerebral circulatory insufficiency. Dry cough.
Potassium levels: regular monitoring. Hyperkalemia: frequent monitoring of blood
potassium if renal insufficiency, worsening of renal function, age (>70 years), diabetes
mellitus: treatment should be started under medical supervision with a reduced initial dose,
dehydration, acute cardiac decompensation, metabolic acidosis, and concomitant use of
potassium-sparing diuretics and potassium salts; can cause serious, sometimes fatal
arrhythmias. Hypokalemia: high risk for elderly and/or malnourished subjects, cirrhotic
patients with edema and ascites, coronary and heart failure patients, long QT interval; more
frequent monitoring necessary in all cases ; may favor the onset of torsades de pointes, which
may be fatal. Sodium levels: test before treatment starts; more frequent monitoring in elderly
and cirrhotic patients, hyponatremia with hypovolaemia may be responsible of dehydration
and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary
compensatory metabolic alkalosis (slight incidence and degree). Hypercalcemia: stop
treatment before investigating parathyroid function. Hyperuricemia: increased tendency to
gout attacks. Anesthesia: treatment stop is recommended one day before surgery.
Hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose
malabsorption: should not be administered. Coversyl PLUS is essentially “sodium-free” (less
than 1mmol sodium (23mg) per tablet). Diabetics: monitor blood glucose in the case of
hypokalemia. Black people: higher incidence of angioedema and apparently less effective in
lowering blood pressure than in non blacks. Children and adolescents: efficacy and tolerability
not established. Athletes: may cause positive doping test. Acute myopia and secondary
angle-closure glaucoma: discontinue drug intake as rapidly as possible. Prompt medical or
surgical treatments may need to be considered if the intraocular pressure remains
uncontrolled. INTERACTIONS:* Contra-indicated: Aliskiren (in diabetic or impaired renal
patients), Extracorporeal treatments, Sacubitril/valsartan. Not recommended: Aliskiren (in
other patients), lithium, potassium-sparing diuretics, concomitant therapy with ACE inhibitor
and angiotensin-receptor blocker, Estramustine, Co-trimoxazole (trimethoprim/
sulfamethoxazole), potassium salts. Special care: Baclofen, nonsteroidal anti-inflammatory
medicinal products (including aspirin ≥ 3g/day), antidiabetic agents, torsades de pointes-
inducing drugs, potassium-lowering drugs, non-potassium-sparing diuretics, potassium-
sparing diuretics, digitalis preparation, racecadotril, mTOR inhibitors (e.g. sirolimus,
everolimus, temsirolimus) and allopurinol. Some care: Imipramine-like antidepressants
(tricyclics), neuroleptics, antihypertensive agents and vasodilatators, allopurinol, cytostatic or
immunosuppressive agents, systemic corticosteroids or procainamide or tetracosactide,
anesthetic drugs, gliptins, sympathomimetics, gold, metformin, iodinated contrast media,
calcium (salts), ciclosporin, tacrolimus. FERTILITY, PREGNANCY AND BREASTFEEDING:*
Not recommended during the first trimester of pregnancy. Contraindicated during the second
and third trimesters of pregnancy and lactation. DRIVE & USE MACHINES:* May be
impaired due to low blood pressure that may occur in some patients. UNDESIRABLE
EFFECTS:* Common: Hypersensitivity reactions (mainly dermatological in subjects with a
predisposition to allergic and asthmatic reactions), dizziness, headache, parasthesia,
dysgeusia, vision impairment, vertigo, tinnitus, hypotension whether orthostatic or not,
cough, dyspnoea, abdominal pain, constipation, diarrhoea, dyspepsia, nausea, vomiting,
pruritus, rash, rash maculopapular, muscle cramps, asthenia. Uncommon: Eosinophilia,
hypoglycaemia, hyperkalaemia, hyponatremia, mood altered, sleep disorder, somnolence,
syncope, palpitations, tachycardia, vasculitis, bronchospasm, dry mouth, urticaria,
angioedema, purpura, hyperhidrosis, photosensitivity reaction, pemphigoid, arthralgia,
myalgia, renal insufficiency, erectile dysfunction, chest pain, malaise, oedema peripheral,
pyrexia, blood urea increased, blood creatinine increased, fall. Rare: Psoriasis aggravation,
fatigue, blood bilirubin increased, hepatic enzyme increased. Very rare: Rhinitis,
agranulocytosis, aplastic anemia, pancytopenia, leukopenia, neutropenia, hemolytic anemia,
thrombocytopenia, hypercalcaemia, stroke possibly secondary to excessive hypotension in
high-risk patients, confusion, arrhythmia (including bradycardia, ventricular tachycardia,
atrial fibrillation), angina pectoris and myocardial infarction, (secondary to hypotension in
high-risk patients), eosinophilic pneumonia, pancreatitis, hepatitis, hepatic function
abnormal, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome,
renal failure acute, haemoglobin decreased and haematocrit decreased. Not known:
Potassium depletion with hypokalemia particularly serious in certain high-risk populations,
hepatic encephalopathy (in the case of hepatic insufficiency), myopia, vision blurred, torsades
de pointes (potentially fatal), possible worsening of pre-existing acute disseminated lupus
erythematosus, blood glucose and blood uric acid increased, ECG QT prolonged, Raynaud’s
phenomenon. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) can be
considered as a very rare but possible complication associated with ACE inhibitor therapy.
OVERDOSE*. PROPERTIES:* Coversyl PLUS is a combination of perindopril arginine
salt, an angiotensin converting enzyme inhibitor, and indapamide, a sulfonamide,
pharmacologically related to thiazide diuretics with a dose-dependent antihypertensive effect
on diastolic and systolic arterial pressure whilst supine or standing. PRESENTATION:*
Coversyl PLUS 5/1.25: Pack of 30 film-coated tablets. Coversyl PLUS 10/2.5: Pack of
30 film-coated tablets. 191119
* For complete information, please refer to the Summary of Product Characteristics for
your country. Please refer to full prescribing information before prescribing. For Healthcare
Professionals only.
SERVIER MALAYSIA SDN BHD (199701036026) -(451526-M)
1301, Level 13, Uptown 2, No. 2, Jalan SS21/37, Damansara Uptown,
47400 Petaling Jaya, Selangor Darul Ehsan, Malaysia.
Tel: 603 - 7726 3866 Fax: 603 - 7725 1049 www.servier.com