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{{Short description|High blood pressure medication}}
{{drugbox
{{Drugbox
| IUPAC_name ='H''-indole-2-carboxylic acid
| Verifiedfields = changed
| image = Perindopril.svg
| verifiedrevid = 464199140
| width = 180
| IUPAC_name = (2''S'',3''aS'',7''aS'')-1-[(2''S'')-2-<nowiki/>{[(2''S'')-1-ethoxy-1-oxopentan-2-yl]amino}propanoyl]-octahydro-1''H''-indole-2-carboxylic acid
| CAS_number = 107133-36-8
| image = Perindopril 2.svg
| width = 222

<!--Clinical data-->
| tradename = Coversyl, Coversum, Aceon
| Drugs.com = {{drugs.com|monograph|aceon}}
| routes_of_administration = [[Oral administration|By mouth]]

| legal_CA = Rx-only
| legal_CA_comment = <ref>{{cite web | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00418 | title=Regulatory Decision Summary for APO-Perindopril Arginine | website=[[Health Canada]] | date=23 October 2014 }}</ref>
| legal_UK = POM
| legal_US = Rx-only

<!--Pharmacokinetic data-->
| bioavailability = 24%
| protein_bound = 20%
| metabolism = Kidney
| elimination_half-life = 1–17 hours for perindoprilat (active metabolite)

<!--Identifiers-->
| IUPHAR_ligand = 6367
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 82834-16-0
| ATC_prefix = C09
| ATC_prefix = C09
| ATC_suffix = AA04
| ATC_suffix = AA04
| ATC_supplemental = <br>{{ATC|C09|BA04}} (with [[diuretic]]s)<br>{{ATC|C09|BB04}} (with [[amlodipine]])
| ATC_supplemental = <br />{{ATC|C09|BA04}} (with [[diuretic]]s)<br />{{ATC|C09|BB04}} (with [[amlodipine]])
| PubChem = 107807
| PubChem = 107807
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = APRD01178
| DrugBank = DB00790
| C = 19 | H = 32 | N = 2 | O = 5
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| molecular_weight = 368.468 g/mol
| ChemSpiderID = 96956
| bioavailability = 24%
| UNII_Ref = {{fdacite|changed|FDA}}
| protein_bound = 20%
| UNII = Y5GMK36KGY
| metabolism = Renal
| KEGG_Ref = {{keggcite|correct|kegg}}
| elimination_half-life = 1 hour - 17 hours for perindoprilat (active metabolite)
| KEGG = D03753
| pregnancy_category = D
| ChEBI_Ref = {{ebicite|correct|EBI}}
| legal_status =
| ChEBI = 8024
| routes_of_administration = oral
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1581

<!--Chemical data-->
| C=19 | H=32 | N=2 | O=5
| smiles = O=C(OCC)[C@@H](N[C@H](C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@H]12)C)CCC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H32N2O5/c1-4-8-14(19(25)26-5-2)20-12(3)17(22)21-15-10-7-6-9-13(15)11-16(21)18(23)24/h12-16,20H,4-11H2,1-3H3,(H,23,24)/t12-,13-,14-,15-,16-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = IPVQLZZIHOAWMC-QXKUPLGCSA-N
}}
}}
'''Perindopril''' (trade names '''Coversyl''', '''Aceon''') is a long-acting [[ACE inhibitor]].


'''Perindopril''' is a [[medication]] used to treat [[high blood pressure]], [[heart failure]], or stable [[coronary artery disease]].<ref>{{cite web |url = http://www.racgp.org.au/cmi/gxcperin.pdf |title = Consumer Medicine Information, GenRx Perindopril |work = Clinical Resources, Medicine information for health professionals | publisher = Royal Australian College of General Practitioners |url-status = dead |archive-url = https://web.archive.org/web/20070901023153/http://www.racgp.org.au/cmi/gxcperin.pdf |archive-date = 2007-09-01 }}</ref> As a long-acting [[ACE inhibitor]], it works by relaxing [[Blood vessel|blood vessels]] and decreasing [[blood volume]]. As a [[prodrug]], perindopril is [[hydrolyzation|hydrolyzed]] in the liver to its active [[metabolite]], perindoprilat. It was patented in 1980 and approved for medical use in 1988.<ref name="Fisher_2006">{{cite book| vauthors = Fischer J, Ganellin CR |url= https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA467 |title=Analogue-based Drug Discovery |date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=467 }}</ref>
==Indications==
*Essential [[hypertension]].
*Stable coronary artery disease: reduction of risk of cardiac events in patients with a history of [[myocardial infarction]] and/or revascularization.
*Treatment of symptomatic heart disease or failure.


Perindopril is taken in the form of perindopril arginine (with [[arginine]], brand names include '''Coversyl''', '''Coversum''') or perindopril erbumine (with [[erbumine|erbumine (''tert''-Butylamine)]], brand name '''Aceon'''). Both forms are therapeutically equivalent and interchangeable,<ref>{{cite web |url = http://www.pbs.gov.au/html/healthpro/search/results?term=perindopril&scope=PBS+STATIC&form-type=simple |title = PBS For Health Professionals |work = Pharmaceutical Benefits Scheme |year = 2008 | publisher = Australian Government Department of Health and Ageing |access-date = 2008-09-04 |url-status = dead |archive-url = https://web.archive.org/web/20081030010429/http://www.pbs.gov.au/html/healthpro/search/results?term=perindopril&scope=PBS+STATIC&form-type=simple |archive-date = 2008-10-30}}</ref> but the dose prescribed to achieve the same effect differs between the two forms.
==Dosage and administration==
Perindopril should be taken in the morning before food.
===For hypertension===
4&nbsp;mg once daily, then the dose may be increased to 8&nbsp;mg after 1 month of treatment to improve [[blood pressure]] control or in case of concomitant stable coronary artery disease.


In Australia, it was one of the top 10 most prescribed medications between 2017 and 2023.<ref>{{cite web | title=Medicines in the health system | website=Australian Institute of Health and Welfare | date=2 July 2024 | url=https://www.aihw.gov.au/reports/medicines/medicines-in-the-health-system | access-date=30 September 2024}}</ref>
In Australia, perindopril arginine is available as Coversyl, the generic form perindopril erbumine is also available. The two formulations are equivalent and may be freely substituted for each other<ref>{{cite web|url=http://www.pbs.gov.au/html/healthpro/search/results?term=perindopril&scope=PBS+STATIC&form-type=simple|title=PBS For Health Professionals|work=Pharmaceutical Benefits Scheme|year=2008|author=Australian Government Department of Health and Ageing|accessdate=2008-09-04}}</ref>.
In hypertension, the initiation dose is 5&nbsp;mg perindopril arginine (or 4&nbsp;mg perindopril erbumine) once daily, then the dose may be increased to 10&nbsp;mg perindopril arginine (or 8&nbsp;mg perindopril erbumine) after 1 month of treatment to improve [[blood pressure]] control or in case of concomitant stable coronary artery disease.


==Medical uses==
The ''Anglo-Scandinavian Cardiac Outcomes Trial'' showed the benefits of taking the two drugs Coversyl and [[amlodipine]] together. The 9000 British patients aged 40 to 79 were involved in the five-year trial. Half were given the new drug combination, the rest were given traditional drugs. Coversyl and amlodipine were found to be so effective that the trial was stopped early so that all patients could receive the combination.<ref>{{cite web|url=http://jadn.co.uk/enwiki/w/CoversylAmlodipineForHighBloodPressure.htm|title=What you need to know about the new wonder drug cocktail for high blood pressure...|work=JADN Repository|year=2005|author=Charlotte Harding|accessdate=2007-07-01}}</ref><ref>{{cite web|url=http://www.medscape.com/viewarticle/451914|title=ASCOT: Anglo-Scandinavian Cardiac Outcomes Trial -- Results From The Lipid-Lowering Arm|work=Medscape Today|author=Linda Brookes|year=2003|accessdate=2007-07-01}}</ref>
Perindopril shares the indications of ACE inhibitors as a class, including essential [[hypertension]], stable [[coronary artery disease]] (reduction of risk of cardiac events in patients with a history of [[myocardial infarction]] and/or [[revascularization]]), treatment of symptomatic [[coronary artery disease]] or [[heart failure]], and [[diabetic nephropathy]].<ref name="amh">{{Cite web|title=Australian Medicines Handbook|url=https://amhonline.amh.net.au/auth?page=chapters/cardiovascular-drugs/antihypertensives/ace-inhibitors/perindopril|website=amhonline.amh.net.au|access-date=2020-05-10}}</ref>


===Combination therapy===
===For stable coronary artery disease===
====With indapamide====
A starting dose of 4&nbsp;mg for 2 weeks is recommended, then uptitration to 8&nbsp;mg once daily, depending on acceptability.
{{main|Perindopril/indapamide}}
In combination with [[indapamide]], perindopril has been shown to significantly reduce the progression of [[chronic kidney disease]] and renal complications in patients with type 2 diabetes.<ref>{{cite journal | vauthors = Netchessova TA, Shepelkevich AP, Gorbat TV | collaboration = NIKA Study Group | title = Efficacy of single-pill perindopril/indapamide in patients with hypertension and type 2 diabetes | journal = High Blood Pressure & Cardiovascular Prevention | volume = 21 | issue = 1 | pages = 63–69 | date = March 2014 | pmid = 24357222 | doi = 10.1007/s40292-013-0036-x | s2cid = 20819715 }}</ref><ref>{{cite journal | vauthors = Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B | display-authors = 6 | title = 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 | journal = Lancet | volume = 370 | issue = 9590 | pages = 829–840 | date = September 2007 | pmid = 17765963 | doi = 10.1016/s0140-6736(07)61303-8 | s2cid = 21153924 }}</ref> In addition, the Perindopril pROtection aGainst REcurrent Stroke Study ('''PROGRESS''') found that whilst perindopril monotherapy demonstrated no significant benefit in reducing recurrent strokes when compared to placebo, the addition of low dose indapamide to perindopril therapy was associated with larger reductions in both blood pressure lowering and recurrent [[stroke risk]] in patients with pre-existing [[cerebrovascular disease]], irrespective of their blood pressure.<ref name="PROGRESS">{{cite journal | vauthors = ((PROGRESS Collaborative Group)) | title = Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack | journal = Lancet | volume = 358 | issue = 9287 | pages = 1033–1041 | date = September 2001 | pmid = 11589932 | doi = 10.1016/s0140-6736(01)06178-5 | series = 2001 Sep 29 | s2cid = 10053225 }}</ref><ref>{{cite journal | title = Post-stroke antihypertensive treatment study. A preliminary result | journal = Chinese Medical Journal | volume = 108 | issue = 9 | pages = 710–717 | date = September 1995 | pmid = 8575241 | url = https://pubmed.ncbi.nlm.nih.gov/8575241/ | author1 = PATS Collaborating Group }}</ref> There is evidence to support the use of perindopril and indapamide combination over perindopril monotherapy to prevent strokes and improve mortality in patients with a history of stroke, transient ischaemic attack or other cardiovascular disease.<ref name="PROGRESS"/><ref>{{cite journal | vauthors = Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ | display-authors = 6 | title = Treatment of hypertension in patients 80 years of age or older | journal = The New England Journal of Medicine | volume = 358 | issue = 18 | pages = 1887–1898 | date = May 2008 | pmid = 18378519 | doi = 10.1056/NEJMoa0801369 | doi-access = free }}</ref>


====With amlodipine====
In Australia and the UK, Coversyl is only available as perindopril arginine.
{{anchor|With amlodipine}}
A starting dose of 5&nbsp;mg for 2 weeks is recommended, then uptitration to 10&nbsp;mg once daily, depending on acceptability.
The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm ('''ASCOT-BLA''') was a 2005 landmark trial that compared the effects of the established therapy of the combination of [[atenolol]] and [[bendroflumethiazide]] to the new drug combination of [[amlodipine]] and perindopril (trade names '''Viacoram''', '''AceryCal''' etc.).<ref>{{cite journal | vauthors = Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J | display-authors = 6 | title = Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial | journal = Lancet | volume = 366 | issue = 9489 | pages = 895–906 | date = September 2005 | pmid = 16154016 | doi = 10.1016/S0140-6736(05)67185-1 | s2cid = 26084146 }}</ref> The study of more than 19 000 patients world-wide was terminated earlier than anticipated because it clearly demonstrated a statistically significant improvement in mortality and cardiovascular outcomes with the newer treatment. The combination of amlodipine and perindopril remains in the current treatment guidelines for hypertension and the outcomes of the ASCOT-BLA trial paved the way for further research into combination therapy and newer agents.<ref>{{Cite web |title=Hypertension clinical information and guidelines |location=Australia |work=The Heart Foundation |url=https://www.heartfoundation.org.au/conditions/hypertension |access-date=2020-05-10 |archive-date=2020-05-14 |archive-url=https://web.archive.org/web/20200514021049/https://www.heartfoundation.org.au/conditions/hypertension |url-status=dead }}</ref>


==Contraindications==
===Congestive heart disease===
*Children
Coversyl (perindopril) should be started under close medical supervision at a starting dose of 2&nbsp;mg. This may be increased to 4&nbsp;mg once blood pressure acceptability has been demonstrated.
*[[Pregnancy]]

*[[Lactation]]
In Australia, Coversyl (perindopril arginine) should be started under close medical supervision at a starting dose of 2.5&nbsp;mg. This may be increased to 5&nbsp;mg once blood pressure acceptability has been demonstrated.
*Situations where a patient has a history of hypersensitivity

*[[Kidney failure]]
Elderly patients should start treatment at 2&nbsp;mg daily (2.5&nbsp;mg daily (perindopril arginine) in Australia).

Contraindications include; children, pregnancy, lactation and situations where a patient has a history of hypersensitivity to Coversyl (perindopril).


==Precautions==
==Precautions==
*Assess [[kidneys|renal]] function before and during treatment where appropriate.
*Assess [[kidney]] function before and during treatment where appropriate.
*Renovascular hypertension.
*[[Renovascular hypertension]]
*Surgery/anesthesia.
*Surgery/anesthesia
*An analysis on the PROGRESS trial showed that perindopril has key benefits in reducing cardiovascular events by 30% in patients with chronic kidney disease defined as a CrCl <60ml/min.<ref>{{cite journal | vauthors = Perkovic V, Ninomiya T, Arima H, Gallagher M, Jardine M, Cass A, Neal B, Macmahon S, Chalmers J | display-authors = 6 | title = Chronic kidney disease, cardiovascular events, and the effects of perindopril-based blood pressure lowering: data from the PROGRESS study | journal = Journal of the American Society of Nephrology | volume = 18 | issue = 10 | pages = 2766–2772 | date = October 2007 | pmid = 17804673 | doi = 10.1681/ASN.2007020256 | doi-access = free }}</ref> A 2016 and 2017 meta-analysis review looking at ACE inhibitors demonstrated a reduction in cardiovascular events but also slowed the decline of renal failure by 39% when compared to placebo.<ref name=":0" /><ref>{{cite journal | vauthors = Liu Y, Ma X, Zheng J, Jia J, Yan T | title = Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials | journal = BMC Nephrology | volume = 18 | issue = 1 | pages = 206 | date = June 2017 | pmid = 28666408 | pmc = 5493067 | doi = 10.1186/s12882-017-0605-7 | doi-access = free }}</ref> These studies included patients with moderate to severe kidney disease and those on dialysis.
*Renal failure: the dose should be cautiously adjusted in accordance with the creatinine clearance (refer to complete data sheet). *Symptomatic hypotension is rarely seen, but is more likely in volume-depleted patients, those receiving [[diuretic]]s, or with the first two doses. In diuretic-treated patients, stop the diuretic 3 days before starting Coversyl (perindopril). A diuretic may later be given in combination if necessary; potassium-sparing diuretics are not recommended. Combination with neuroleptics or imipramine-type drugs may increase the hypotensive effect. Serum lithium concentrations may rise during lithium therapy.
*Its renoprotective benefits of decreasing blood pressure and removing filtration pressure is highlighted in a 2016 review.<ref name=":0">{{cite journal | vauthors = Xie X, Liu Y, Perkovic V, Li X, Ninomiya T, Hou W, Zhao N, Liu L, Lv J, Zhang H, Wang H | display-authors = 6 | title = Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials | journal = American Journal of Kidney Diseases | volume = 67 | issue = 5 | pages = 728–741 | date = May 2016 | pmid = 26597926 | doi = 10.1053/j.ajkd.2015.10.011 | doi-access = free }}</ref> ACE inhibitor can result in an initial increase of serum creatinine, but mostly returns to baseline in a few weeks in majority of patients.<ref>{{cite journal | vauthors = Garlo KG, Bates DW, Seger DL, Fiskio JM, Charytan DM | title = Association of Changes in Creatinine and Potassium Levels After Initiation of Renin Angiotensin Aldosterone System Inhibitors With Emergency Department Visits, Hospitalizations, and Mortality in Individuals With Chronic Kidney Disease | journal = JAMA Network Open | volume = 1 | issue = 7 | pages = e183874 | date = November 2018 | pmid = 30646338 | pmc = 6324397 | doi = 10.1001/jamanetworkopen.2018.3874 }}</ref> It has been suggested that increased monitoring, especially in advanced kidney failure, will minimise any related risk and improve long-term benefits.<ref>{{cite journal | vauthors = Ohkuma T, Jun M, Rodgers A, Cooper ME, Glasziou P, Hamet P, Harrap S, Mancia G, Marre M, Neal B, Perkovic V, Poulter N, Williams B, Zoungas S, Chalmers J, Woodward M | display-authors = 6 | title = Acute Increases in Serum Creatinine After Starting Angiotensin-Converting Enzyme Inhibitor-Based Therapy and Effects of its Continuation on Major Clinical Outcomes in Type 2 Diabetes Mellitus | journal = Hypertension | volume = 73 | issue = 1 | pages = 84–91 | date = January 2019 | pmid = 30571562 | doi = 10.1161/HYPERTENSIONAHA.118.12060 | hdl-access = free | s2cid = 58547523 | hdl = 10044/1/66141 }}</ref>
*Use cautiously in patients with sodium or volume depletion due to potential excessive hypotensive effects of [[Renin–angiotensin system|renin-angiotensin]] blockade causing symptomatic [[hypotension]].<ref name="amh"/> Careful monitoring or short-term dose reduction of diuretics prior to commencing perindopril is recommended to prevent this potential effect.<ref name="amh"/> A diuretic may later be given in combination if necessary; potassium-sparing diuretics are not recommended in combination with perindopril due to the risk of [[Hyperkalemia|hyperkalaemia]].<ref name="amh"/>
*Combination with [[neuroleptic]]s or imipramine-type drugs may increase the blood pressure lowering effect. Serum [[lithium]] concentrations may rise during lithium therapy.


==Side effects==
==Side effects==
Side effects are mild, usually at the start of treatment; they include:
Rare and mild, usually at the start of treatment. Cough, fatigue, [[asthenia]], headache, disturbances of mood and/or sleep have been reported. Less often, taste impairment, epigastric discomfort, nausea, abdominal pain, and rash. Reversible increases in blood [[urea]] and [[creatinine]] may be observed. Proteinuria has occurred in some patients. Rarely, angioneurotic [[edema]] and decreases in hemoglobin, red cells, and platelets have been reported.
*Cough
*Fatigue
*Weakness/[[Asthenia]]
*Headache
*Disturbances of mood and/or sleep


Less often
==Composition==
*Taste impairment
Each tablet contains 2&nbsp;mg, 4&nbsp;mg or 8&nbsp;mg of the tert-butylamine salt of perindopril. Perindopril is also available under the trade name [[Coversyl Plus]], containing 4&nbsp;mg of perindopril combined with 1.25&nbsp;mg [[indapamide]].
*[[Epigastric]] discomfort
*Nausea
*Abdominal pain
*Rash


Reversible increases in blood [[urea]] and [[creatinine]] may be observed. [[Proteinuria]] has occurred in some patients. Rarely, angioneurotic [[edema]] and decreases in [[hemoglobin]], red cells, and [[platelets]] have been reported.
In Australia, each tablet contains 2.5&nbsp;mg, 5&nbsp;mg or 10&nbsp;mg of arginine. Perindopril is also available under the trade name [[Coversyl Plus]] and [[Coversyl Plus LD]], containing 5&nbsp;mg of perindopril combined with 1.25&nbsp;mg [[indapamide]] and 2.5&nbsp;mg of perindopril combined with 0.625&nbsp;mg [[indapamide]] respectively.

==Composition==
Each tablet contains 2, 4, or 8&nbsp;mg of the tert-butylamine salt of perindopril. Perindopril is also available under the trade name [[Coversyl Plus]], containing 4&nbsp;mg of perindopril combined with 1.25&nbsp;mg [[indapamide]], a [[thiazide-like diuretic]].


In Australia, each tablet contains 2.5, 5, or 10&nbsp;mg of perindopril arginine. Perindopril is also available under the trade name Coversyl Plus, containing 5&nbsp;mg of perindopril arginine combined with 1.25&nbsp;mg indapamide and [[Coversyl Plus LD]], containing 2.5&nbsp;mg of perindopril arginine combined with 0.625&nbsp;mg indapamide.
The efficacy and tolerability of a fixed-dose combination of perindopril 4mg and amlodipine 5mg, a calcium channel antagonist, has recently been confirmed in a prospective, observational multicenter trial 1250 hypertensive patients.<ref name="test">Bahl VK, Jadhav UM, Thacker HP. Management of Hypertension with the Fixed Combination of Perindopril and Amlodipine in Daily Clinical Practice: Results from the STRONG Prospective, Observational, Multicenter Study. ''American Journal of Cardiovascular Drugs'' May 22, 2009; '''9''' (3): 135-42 [http://adisonline.com/cardiovascular/pages/articleviewer.aspx?year=2009&issue=09030&article=00001&type=abstract Link text] </ref>


The efficacy and tolerability of a fixed-dose combination of 4&nbsp;mg perindopril and 5&nbsp;mg [[amlodipine]], a calcium channel antagonist, has been confirmed in a prospective, observational multicenter trial of 1,250 hypertensive patients.<ref name="test">Bahl VK, Jadhav UM, Thacker HP. Management of Hypertension with the Fixed Combination of Perindopril and Amlodipine in Daily Clinical Practice: Results from the STRONG Prospective, Observational, Multicenter Study. ''American Journal of Cardiovascular Drugs'' May 22, 2009; '''9''' (3): 135-42 [http://adisonline.com/cardiovascular/pages/articleviewer.aspx?year=2009&issue=09030&article=00001&type=abstract Link text] {{Webarchive|url=https://web.archive.org/web/20110707090029/http://adisonline.com/cardiovascular/pages/articleviewer.aspx?year=2009&issue=09030&article=00001&type=abstract |date=2011-07-07 }}</ref> A preparation of the two drugs is available commercially as Coveram.
==Presentation==
Packs of 30 tablets of Coversyl (perindopril) 2&nbsp;mg. Packs of 30 tablets of Coversyl (perindopril) 4&nbsp;mg (scored). Packs of 30 tablets of Coversyl (perindopril) 8&nbsp;mg.


==Society and culture==
Also available under the brand names:
===Brand names===
*Aceon
Perindopril is available under the following brand names among others:
{{columns-list|colwidth=10em|
*Acertil
*Acertil
*Actiprex
*Armix
*Armix
*Idaprex
*Coverene
*Coverene
*Coverex
*Coverex
*Coversum
*Coversum
*Coversyl
*Covinace
*Indapril
*Perindo
*Perineva
*Prenessa
*Prestarium
*Prestarium
*Preterax
*Prexanil
*Prexanil
*Prexum
*Prexum
*Procaptan
*Procaptan
*Provinace
*Pericard
*Percarnil
*Perindal
*Repres
*Relika
}}

===Marketing===
In July 2014, the [[European Commission]] imposed fines of {{Euro|427,700,000}} on [[Laboratoires Servier]] and five companies which produce generics due to Servier's abuse of their dominant market position, in breach of European Union Competition law. Servier's strategy included acquiring the principal source of generic production of perindopril and entering into several pay-for-delay agreements with potential generic competitors.<ref>{{Cite web|url=https://europa.eu/rapid/press-release_IP-14-799_en.htm| work = European Commission | title = Antitrust: Commission fines Servier and five generic companies for curbing entry of cheaper versions of cardiovascular medicine | date = 9 July 2014 }}</ref>


==References==
== References ==
*Bounhoure JP, Bottineau G, Lechat P, ''et al.''. "Value of perindopril in the treatment of chronic congestive heart failure: multicentre double-blind placebo-controlled study." ''Clin Exp Hypertens.'' 1989;A11(suppl 2):575-586.
*Lechat P, Granham SP, Desche P, ''et al.''. "Efficacy and acceptability of perindopril in mild-to-moderate chronic congestive heart failure." ''Am Heart J.'' 1993;126:798-806.
*Morgan T and Anderson A; "Clinical efficacy of perindopril in hypertension." ''Clin Exp Pharmacol Physiol.'' 1992;19:61-65.
*Myers MG; (on behalf of the perindopril multicentre dose-response study group) "A dose-response study of perindopril in hypertension: effects on blood pressure 6 and 24h after dosing." ''Can J Cardiol.'' 1996;12:1191-1196.
*"The 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: randomized, double-blind, placebo controlled, multicentre trial (the EUROPA study)." ''[[The Lancet]]'' 2003;362:782-788.
{{reflist}}
{{reflist}}


== Further reading ==
==External links==
{{refbegin}}
* [http://www.coversyl.com/ Official homepage]
* {{cite journal | vauthors = Wang JG, Pimenta E, Chwallek F | title = Comparative review of the blood pressure-lowering and cardiovascular benefits of telmisartan and perindopril | journal = Vascular Health and Risk Management | volume = 10 | pages = 189–200 | date = 2014 | pmid = 24741317 | pmc = 3983078 | doi = 10.2147/VHRM.S59429 | doi-access = free }}
* {{cite journal | vauthors = Shirley M, McCormack PL | title = Perindopril/amlodipine (Prestalia(®)): a review in hypertension | journal = American Journal of Cardiovascular Drugs | volume = 15 | issue = 5 | pages = 363–370 | date = October 2015 | pmid = 26341621 | doi = 10.1007/s40256-015-0144-1 | s2cid = 40807688 }}
* {{cite journal | vauthors = Bertrand ME, Vlachopoulos C, Mourad JJ | title = Triple Combination Therapy for Global Cardiovascular Risk: Atorvastatin, Perindopril, and Amlodipine | journal = American Journal of Cardiovascular Drugs | volume = 16 | issue = 4 | pages = 241–253 | date = August 2016 | pmid = 27256435 | doi = 10.1007/s40256-016-0175-2 | s2cid = 13318472 }}
* {{cite journal | vauthors = Ancion A, Tridetti J, Nguyen Trung ML, Oury C, Lancellotti P | title = A Review of the Role of Bradykinin and Nitric Oxide in the Cardioprotective Action of Angiotensin-Converting Enzyme Inhibitors: Focus on Perindopril | journal = Cardiology and Therapy | volume = 8 | issue = 2 | pages = 179–191 | date = December 2019 | pmid = 31578675 | pmc = 6828891 | doi = 10.1007/s40119-019-00150-w }}
{{refend}}

== External links ==
{{Commons category-inline}}


{{ACE inhibitors}}
{{ACE inhibitors}}
{{Angiotensin receptor modulators}}


[[Category:ACE inhibitors]]
[[Category:ACE inhibitors]]
[[Category:Alpha-Amino acids]]

[[Category:Carboxamides]]
[[it:Perindopril]]
[[Category:Enantiopure drugs]]
[[hu:Perindopril]]
[[Category:Ethyl esters]]
[[pl:Peryndopryl]]
[[Category:Indoles]]
[[Category:Laboratoires Servier]]
[[Category:Prodrugs]]
[[Category:Propyl compounds]]
[[Category:Secondary amino acids]]

Latest revision as of 00:38, 30 September 2024

Perindopril
Clinical data
Trade namesCoversyl, Coversum, Aceon
AHFS/Drugs.comMonograph
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability24%
Protein binding20%
MetabolismKidney
Elimination half-life1–17 hours for perindoprilat (active metabolite)
Identifiers
  • (2S,3aS,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxopentan-2-yl]amino}propanoyl]-octahydro-1H-indole-2-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.120.843 Edit this at Wikidata
Chemical and physical data
FormulaC19H32N2O5
Molar mass368.474 g·mol−1
3D model (JSmol)
  • O=C(OCC)[C@@H](N[C@H](C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@H]12)C)CCC
  • InChI=1S/C19H32N2O5/c1-4-8-14(19(25)26-5-2)20-12(3)17(22)21-15-10-7-6-9-13(15)11-16(21)18(23)24/h12-16,20H,4-11H2,1-3H3,(H,23,24)/t12-,13-,14-,15-,16-/m0/s1 checkY
  • Key:IPVQLZZIHOAWMC-QXKUPLGCSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease.[2] As a long-acting ACE inhibitor, it works by relaxing blood vessels and decreasing blood volume. As a prodrug, perindopril is hydrolyzed in the liver to its active metabolite, perindoprilat. It was patented in 1980 and approved for medical use in 1988.[3]

Perindopril is taken in the form of perindopril arginine (with arginine, brand names include Coversyl, Coversum) or perindopril erbumine (with erbumine (tert-Butylamine), brand name Aceon). Both forms are therapeutically equivalent and interchangeable,[4] but the dose prescribed to achieve the same effect differs between the two forms.

In Australia, it was one of the top 10 most prescribed medications between 2017 and 2023.[5]

Medical uses

[edit]

Perindopril shares the indications of ACE inhibitors as a class, including essential hypertension, stable coronary artery disease (reduction of risk of cardiac events in patients with a history of myocardial infarction and/or revascularization), treatment of symptomatic coronary artery disease or heart failure, and diabetic nephropathy.[6]

Combination therapy

[edit]

With indapamide

[edit]
Main article: Perindopril/indapamide

In combination with indapamide, perindopril has been shown to significantly reduce the progression of chronic kidney disease and renal complications in patients with type 2 diabetes.[7][8] In addition, the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) found that whilst perindopril monotherapy demonstrated no significant benefit in reducing recurrent strokes when compared to placebo, the addition of low dose indapamide to perindopril therapy was associated with larger reductions in both blood pressure lowering and recurrent stroke risk in patients with pre-existing cerebrovascular disease, irrespective of their blood pressure.[9][10] There is evidence to support the use of perindopril and indapamide combination over perindopril monotherapy to prevent strokes and improve mortality in patients with a history of stroke, transient ischaemic attack or other cardiovascular disease.[9][11]

With amlodipine

[edit]

The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BLA) was a 2005 landmark trial that compared the effects of the established therapy of the combination of atenolol and bendroflumethiazide to the new drug combination of amlodipine and perindopril (trade names Viacoram, AceryCal etc.).[12] The study of more than 19 000 patients world-wide was terminated earlier than anticipated because it clearly demonstrated a statistically significant improvement in mortality and cardiovascular outcomes with the newer treatment. The combination of amlodipine and perindopril remains in the current treatment guidelines for hypertension and the outcomes of the ASCOT-BLA trial paved the way for further research into combination therapy and newer agents.[13]

Contraindications

[edit]

Precautions

[edit]
  • Assess kidney function before and during treatment where appropriate.
  • Renovascular hypertension
  • Surgery/anesthesia
  • An analysis on the PROGRESS trial showed that perindopril has key benefits in reducing cardiovascular events by 30% in patients with chronic kidney disease defined as a CrCl <60ml/min.[14] A 2016 and 2017 meta-analysis review looking at ACE inhibitors demonstrated a reduction in cardiovascular events but also slowed the decline of renal failure by 39% when compared to placebo.[15][16] These studies included patients with moderate to severe kidney disease and those on dialysis.
  • Its renoprotective benefits of decreasing blood pressure and removing filtration pressure is highlighted in a 2016 review.[15] ACE inhibitor can result in an initial increase of serum creatinine, but mostly returns to baseline in a few weeks in majority of patients.[17] It has been suggested that increased monitoring, especially in advanced kidney failure, will minimise any related risk and improve long-term benefits.[18]
  • Use cautiously in patients with sodium or volume depletion due to potential excessive hypotensive effects of renin-angiotensin blockade causing symptomatic hypotension.[6] Careful monitoring or short-term dose reduction of diuretics prior to commencing perindopril is recommended to prevent this potential effect.[6] A diuretic may later be given in combination if necessary; potassium-sparing diuretics are not recommended in combination with perindopril due to the risk of hyperkalaemia.[6]
  • Combination with neuroleptics or imipramine-type drugs may increase the blood pressure lowering effect. Serum lithium concentrations may rise during lithium therapy.

Side effects

[edit]

Side effects are mild, usually at the start of treatment; they include:

  • Cough
  • Fatigue
  • Weakness/Asthenia
  • Headache
  • Disturbances of mood and/or sleep

Less often

  • Taste impairment
  • Epigastric discomfort
  • Nausea
  • Abdominal pain
  • Rash

Reversible increases in blood urea and creatinine may be observed. Proteinuria has occurred in some patients. Rarely, angioneurotic edema and decreases in hemoglobin, red cells, and platelets have been reported.

Composition

[edit]

Each tablet contains 2, 4, or 8 mg of the tert-butylamine salt of perindopril. Perindopril is also available under the trade name Coversyl Plus, containing 4 mg of perindopril combined with 1.25 mg indapamide, a thiazide-like diuretic.

In Australia, each tablet contains 2.5, 5, or 10 mg of perindopril arginine. Perindopril is also available under the trade name Coversyl Plus, containing 5 mg of perindopril arginine combined with 1.25 mg indapamide and Coversyl Plus LD, containing 2.5 mg of perindopril arginine combined with 0.625 mg indapamide.

The efficacy and tolerability of a fixed-dose combination of 4 mg perindopril and 5 mg amlodipine, a calcium channel antagonist, has been confirmed in a prospective, observational multicenter trial of 1,250 hypertensive patients.[19] A preparation of the two drugs is available commercially as Coveram.

Society and culture

[edit]

Brand names

[edit]

Perindopril is available under the following brand names among others:

  • Acertil
  • Actiprex
  • Armix
  • Idaprex
  • Coverene
  • Coverex
  • Coversum
  • Coversyl
  • Covinace
  • Indapril
  • Perindo
  • Perineva
  • Prenessa
  • Prestarium
  • Preterax
  • Prexanil
  • Prexum
  • Procaptan
  • Provinace
  • Pericard
  • Percarnil
  • Perindal
  • Repres
  • Relika

Marketing

[edit]

In July 2014, the European Commission imposed fines of €427,700,000 on Laboratoires Servier and five companies which produce generics due to Servier's abuse of their dominant market position, in breach of European Union Competition law. Servier's strategy included acquiring the principal source of generic production of perindopril and entering into several pay-for-delay agreements with potential generic competitors.[20]

References

[edit]
  1. ^ "Regulatory Decision Summary for APO-Perindopril Arginine". Health Canada. 23 October 2014.
  2. ^ "Consumer Medicine Information, GenRx Perindopril" (PDF). Clinical Resources, Medicine information for health professionals. Royal Australian College of General Practitioners. Archived from the original (PDF) on 2007-09-01.
  3. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 467. ISBN 9783527607495.
  4. ^ "PBS For Health Professionals". Pharmaceutical Benefits Scheme. Australian Government Department of Health and Ageing. 2008. Archived from the original on 2008-10-30. Retrieved 2008-09-04.
  5. ^ "Medicines in the health system". Australian Institute of Health and Welfare. 2 July 2024. Retrieved 30 September 2024.
  6. ^ a b c d "Australian Medicines Handbook". amhonline.amh.net.au. Retrieved 2020-05-10.
  7. ^ Netchessova TA, Shepelkevich AP, Gorbat TV, et al. (NIKA Study Group) (March 2014). "Efficacy of single-pill perindopril/indapamide in patients with hypertension and type 2 diabetes". High Blood Pressure & Cardiovascular Prevention. 21 (1): 63–69. doi:10.1007/s40292-013-0036-x. PMID 24357222. S2CID 20819715.
  8. ^ Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, et al. (September 2007). "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. 370 (9590): 829–840. doi:10.1016/s0140-6736(07)61303-8. PMID 17765963. S2CID 21153924.
  9. ^ a b PROGRESS Collaborative Group (September 2001). "Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack". Lancet. 2001 Sep 29. 358 (9287): 1033–1041. doi:10.1016/s0140-6736(01)06178-5. PMID 11589932. S2CID 10053225.
  10. ^ PATS Collaborating Group (September 1995). "Post-stroke antihypertensive treatment study. A preliminary result". Chinese Medical Journal. 108 (9): 710–717. PMID 8575241.
  11. ^ Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. (May 2008). "Treatment of hypertension in patients 80 years of age or older". The New England Journal of Medicine. 358 (18): 1887–1898. doi:10.1056/NEJMoa0801369. PMID 18378519.
  12. ^ Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. (September 2005). "Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial". Lancet. 366 (9489): 895–906. doi:10.1016/S0140-6736(05)67185-1. PMID 16154016. S2CID 26084146.
  13. ^ "Hypertension clinical information and guidelines". The Heart Foundation. Australia. Archived from the original on 2020-05-14. Retrieved 2020-05-10.
  14. ^ Perkovic V, Ninomiya T, Arima H, Gallagher M, Jardine M, Cass A, et al. (October 2007). "Chronic kidney disease, cardiovascular events, and the effects of perindopril-based blood pressure lowering: data from the PROGRESS study". Journal of the American Society of Nephrology. 18 (10): 2766–2772. doi:10.1681/ASN.2007020256. PMID 17804673.
  15. ^ a b Xie X, Liu Y, Perkovic V, Li X, Ninomiya T, Hou W, et al. (May 2016). "Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials". American Journal of Kidney Diseases. 67 (5): 728–741. doi:10.1053/j.ajkd.2015.10.011. PMID 26597926.
  16. ^ Liu Y, Ma X, Zheng J, Jia J, Yan T (June 2017). "Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials". BMC Nephrology. 18 (1): 206. doi:10.1186/s12882-017-0605-7. PMC 5493067. PMID 28666408.
  17. ^ Garlo KG, Bates DW, Seger DL, Fiskio JM, Charytan DM (November 2018). "Association of Changes in Creatinine and Potassium Levels After Initiation of Renin Angiotensin Aldosterone System Inhibitors With Emergency Department Visits, Hospitalizations, and Mortality in Individuals With Chronic Kidney Disease". JAMA Network Open. 1 (7): e183874. doi:10.1001/jamanetworkopen.2018.3874. PMC 6324397. PMID 30646338.
  18. ^ Ohkuma T, Jun M, Rodgers A, Cooper ME, Glasziou P, Hamet P, et al. (January 2019). "Acute Increases in Serum Creatinine After Starting Angiotensin-Converting Enzyme Inhibitor-Based Therapy and Effects of its Continuation on Major Clinical Outcomes in Type 2 Diabetes Mellitus". Hypertension. 73 (1): 84–91. doi:10.1161/HYPERTENSIONAHA.118.12060. hdl:10044/1/66141. PMID 30571562. S2CID 58547523.
  19. ^ Bahl VK, Jadhav UM, Thacker HP. Management of Hypertension with the Fixed Combination of Perindopril and Amlodipine in Daily Clinical Practice: Results from the STRONG Prospective, Observational, Multicenter Study. American Journal of Cardiovascular Drugs May 22, 2009; 9 (3): 135-42 Link text Archived 2011-07-07 at the Wayback Machine
  20. ^ "Antitrust: Commission fines Servier and five generic companies for curbing entry of cheaper versions of cardiovascular medicine". European Commission. 9 July 2014.

Further reading

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[edit]

Media related to Perindopril at Wikimedia Commons

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