Adult: Available preparations:
Perindopril arginine 2.5 mg and indapamide 0.625 mg tab
Perindopril arginine 5 mg and indapamide 1.25 mg tab
Perindopril arginine 10 mg and indapamide 2.5 mg tab
Perindopril tert-butylamine 2 mg and indapamide 0.625 mg tab
Perindopril tert-butylamine 4 mg and indapamide 1.25 mg tab
In patients with blood pressure inadequately controlled on perindopril alone: Initially, 1 tab once daily, preferably in the morning. Dose titrations may be given as fixed combinations (when available) or with individual components, if necessary. Dosage is individualised and adjusted according to patient response.
Renal Impairment
CrCl (mL/min)
Dosage
<30
As 2.5 mg/0.625 mg, 5 mg/1.25 mg perindopril arginine/indapamide, and 2 mg/0.625 mg, 4 mg/1.25 mg perindopril tert-butylamine/indapamide tab: Contraindicated.
30-60
As 2.5 mg/0.625 mg, 5 mg/1.25 mg perindopril arginine/indapamide, and 2 mg/0.625 mg, 4 mg/1.25 mg perindopril tert-butylamine/indapamide tab: Dose adjustments may be needed. Max dose of perindopril arginine component: 2.5 mg daily.
<60
As 10 mg/2.5 mg perindopril arginine/indapamide tab: Contraindicated.
Hepatic Impairment
Severe: Contraindicated.
Administration
Should be taken on an empty stomach.
Contraindications
Hypersensitivity to perindopril, indapamide or sulfonamide-related drugs. History of angioedema due to previous ACE inhibitor treatment, hereditary or idiopathic angioedema, unilateral or bilateral renal artery stenosis, hypokalaemia, hepatic encephalopathy. Patient with extracorporeal treatments leading to contact of blood with negatively charged surfaces. Severe hepatic and moderate to severe renal impairment (depending on fixed-dose combination). Pregnancy and lactation. Concomitant use with aliskiren in patients with diabetes mellitus or moderate to severe renal impairment (GFR <60 mL/min/1.73 m2). Concomitant use with or within 36 hours after the last dose of sacubitril/valsartan.
Special Precautions
Patient with CV disease (e.g. ischaemic heart disease, heart failure, long QT syndrome), cerebrovascular disease, acute cardiac decompensation, hypertrophic cardiomyopathy with outflow tract obstruction, aortic or mitral valve stenosis, prediabetes or diabetes mellitus, dehydrated states, volume depletion, metabolic acidosis, collagen vascular disease (e.g. SLE), cirrhosis; history of gout, penicillin allergy. Patient undergoing major surgery, LDL apheresis with dextran sulfate, and desensitisation treatment with hymenoptera venom. Not recommended for use in patients with primary aldosteronism. Black race. Renal and hepatic impairment. Elderly.
Adverse Reactions
Significant: Cough, hypotension, syncope, photosensitivity, ocular effects (e.g. acute transient myopia, acute angle-closure glaucoma), CNS depression, dysgeusia, SLE exacerbation or activation, dermatologic reactions (e.g. maculopapular pruritic rashes, lichenoid eruptions, psoriasis, pemphigus like rash, rosacea, Stevens-Johnson syndrome), electrolyte disturbances (e.g. hyperkalaemia, hypokalaemia, hypochloraemia, hyponatraemia, hypophosphataemia, hypercalcaemia), increased liver enzymes and serum bilirubin, hepatic encephalopathy, renal function deterioration (e.g. increased BUN and serum creatinine, oliguria, acute renal failure, progressive azotaemia, proteinuria), hyperuricaemia, haematologic effects (e.g. neutropenia with myeloid hypoplasia, agranulocytosis, anaemia, thrombocytopenia). Ear and labyrinth disorders: Vertigo, tinnitus. Eye disorders: Visual impairment. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain, constipation, dyspepsia, dry mouth. General disorders and administration site conditions: Asthenia. Metabolism and nutrition disorders: Anorexia. Musculoskeletal and connective tissue disorders: Muscle cramps. Nervous system disorders: Dizziness, headache, paraesthesia. Respiratory, thoracic and mediastinal disorders: Dyspnoea. Skin and subcutaneous tissue disorders: Maculopapular rash, pruritus. Potentially Fatal: Angioedema with laryngeal oedema, arrhythmias. Rarely, cholestatic jaundice that may progress to fulminant hepatic necrosis; hypersensitivity reactions (e.g. anaphylactic/anaphylactoid reactions).
Patient Counseling Information
Avoid exposure to direct sunlight and UV light; apply sunscreen when going outdoors.
Monitoring Parameters
Monitor blood pressure, serum electrolytes (e.g. Na, K, Ca) and creatinine, BUN; hepatic function at baseline and as clinically indicated; uric acid, blood glucose, urea (in patients at risk of hyperkalaemia); CBC with differential (in patient with collagen vascular disease or renal impairment). Assess pregnancy status.
Overdosage
Symptoms: Hypotension, nausea, vomiting, dizziness, sleepiness, mental confusion, cramps, oliguria leading to anuria, salt and water imbalance (e.g. hyponatraemia, hypokalaemia). Management: Symptomatic and supportive treatment. Immediately empty gastric contents by performing gastric lavage and/or administering activated charcoal. Correct fluid and electrolyte balance as necessary. Place the patient in a supine position with the head lowered in case of significant hypotension. Administer IV saline solutions if necessary.
Drug Interactions
Enhanced antihypertensive effect with other antihypertensive agents, vasodilators, baclofen and TCAs.
Perindopril: Increased risk of lithium toxicity. May diminish antihypertensive effect with NSAIDs and sympathomimetic drugs. Increased risk of adverse effects with angiotensin-receptor blockers and estramustine. May enhance the hypotensive effect of anaesthetics. Increased risk of hyperkalaemia with ciclosporin, heparin, trimethoprim, co-trimoxazole, K-sparing diuretics, K supplements and K-containing salt substitutes. May potentiate hypoglycaemia with insulin and oral hypoglycaemic agents. May increase risk of angioedema with racecadotril, mammalian target of rapamycin (mTOR) inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, vildagliptin). May increase risk of leucopenia with allopurinol, immunosuppressants, corticosteroids, or procainamide. May cause nitritoid reactions with Na aurothiomalate.
Indapamide: Increased risk of hypokalaemia with IV amphotericin B, glucocorticoids, systemic mineralocorticoids, stimulant laxatives, drugs that induce torsades de pointes such as antiarrhythmics (e.g. quinidine, disopyramide, amiodarone, dofetilide), neuroleptics (e.g. chlorpromazine, thioridazine, trifluoperazine, pimozide), benzamides (e.g. amisulpride, sultopride, tiapride), bepridil, cisapride, erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, vincamine, methadone, astemizole, and terfenadine. May potentiate toxic effects of cardiac glycosides (e.g. digitalis). May increase the incidence of allopurinol hypersensitivity. Potentially Fatal: Perindopril: Increased risk of hypotension, hyperkalaemia, and decreased renal function with aliskiren. Increased risk of angioedema with sacubitril/valsartan. Rarely, may cause anaphylactoid reactions with dextran sulfate in LDL apheresis.
Food Interaction
Perindopril: Perindoprilat concentrations may be reduced with food.
Indapamide: Increased orthostatic hypotensive effect with alcohol.
Lab Interference
May cause a false-negative aldosterone/renin ratio (ARR).
Indapamide: May interfere with parathyroid function tests and may decrease the protein bound iodine without signs of thyroid disturbance. May cause a positive result in doping tests.
Action
Description: Perindopril and indapamide both reduce blood pressure via different but complementary mechanisms, exhibiting additive effects with its combined use.
Perindopril, a prodrug of perindoprilat, is an ACE inhibitor that prevents the conversion of angiotensin I to angiotensin II, thereby increasing plasma renin activity and decreasing vasoconstriction and aldosterone secretion.
Indapamide is a diuretic with similar effects as thiazides. It enhances Na, chloride, and water excretion by interfering with the transport of Na ions across the renal tubular epithelium. Onset: Perindopril: 1-2 hours. Pharmacokinetics: Absorption: Perindopril: Rapidly absorbed from the gastrointestinal tract. Food may reduce serum levels and the conversion into perindoprilat. Bioavailability: Approx 65-75% (perindopril); approx 25% (perindoprilat). Time to peak plasma concentration: Approx 1 hour (perindopril); 3-7 hours (perindoprilat).
Indapamide: Rapidly and completely absorbed from the gastrointestinal tract. Bioavailability: 93%. Time to peak plasma concentration: 2 hours. Distribution: Perindopril: Volume of distribution: Approx 0.2 L/kg (perindoprilat). Plasma protein binding: Approx 60% (perindopril); 10-20% (perindoprilat).
Indapamide: Widely distributed into the body. Volume of distribution: 25 L. Plasma protein binding: 71-79%. Metabolism: Perindopril: Extensively metabolised in the liver via hydrolysis to perindoprilat (active form) and inactive metabolites including glucuronides.
Indapamide: Extensively metabolised in the liver. Excretion: Perindopril: Via urine (75%; 4-12% as unchanged drug). Elimination half-life: 25-30 hours or longer (perindoprilat).
Indapamide: Mainly via urine (approx 70%; 7% as unchanged drug); faeces (16-23%). Elimination half-life: Biphasic: Approx 14 hours.
Chemical Structure
Perindopril Source: National Center for Biotechnology Information. PubChem Database. Perindopril, CID=107807, https://pubchem.ncbi.nlm.nih.gov/compound/Perindopril (accessed on Jan. 22, 2020)
Indapamide Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3702, Indapamide. https://pubchem.ncbi.nlm.nih.gov/compound/Indapamide. Accessed Sept. 24, 2020.
C09BA04 - perindopril and diuretics ; Belongs to the class of ACE inhibitors in combination with diuretics. Used in the treatment of cardiovascular disease.
References
Acertil Plus 10 mg/2.5 mg (Servier Hong Kong Ltd). MIMS Hong Kong. http://www.mims.com/hongkong. Accessed 13/11/2020.Acertil Plus 2.5 mg (Servier Hong Kong Ltd). MIMS Hong Kong. http://www.mims.com/hongkong. Accessed 13/11/2020.Anon. Indapamide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 15/10/2020.Anon. Perindopril and Indapamide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 13/10/2020.Anon. Perindopril. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 15/10/2020.Buckingham R (ed). Indapamide. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 13/10/2020.Buckingham R (ed). Perindopril. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 13/10/2020.Coversyl Plus 5 mg/1.25 mg (Servier Malaysia Sdn Bhd). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my/. Accessed 13/10/2020.Perindopril Arginine/Indapamide 5 mg/1.25 mg Film-Coated Tablets (Generics [UK] Limited t/a Mylan). MHRA. https://products.mhra.gov.uk/. Accessed 13/10/2020.Perindopril/Indapamide 2 mg/0.625 mg Tablets (Glenmark Pharmaceuticals Europe Limited). MHRA. https://products.mhra.gov.uk/. Accessed 13/10/2020.Perindopril/Indapamide 4 mg/1.25 mg Tablets (Glenmark Pharmaceuticals Europe Limited). MHRA. https://products.mhra.gov.uk/. Accessed 13/10/2020.
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