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Common to perindopril and indapamide: Concomitant use not recommended: Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Use of perindopril combined with indapamide with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see Warnings).
Concomitant use which requires special care: Baclofen: Increased antihypertensive effect. Monitor blood pressure and adapt antihypertensive dosage if necessary.
Non-steroidal anti-inflammatory medicinal products (NSAIDs) (including aspirin ≥ 3g/day): when ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE-inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Concomitant use which requires some care: Imipramine-like antidepressants (tricyclics), neuroleptics: Increased antihypertensive effect and increased risk of orthostatic hypotension (additive effect).
Linked to perindopril: Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Contraindications, Warnings and Pharmacology: Pharmacodynamics under Actions).
Drugs inducing hyperkalaemia: Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin-II receptor antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalaemia.
Concomitant use contra-indicated (see Contraindications): Aliskiren: In diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase.
Extracorporeal treatments: Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see Contraindications). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Sacubitril/valsartan: The concomitant use of perindopril with sacubitril/valsartan is contra-indicated as the concomitant inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be started until 36 hours after taking the last dose of perindopril therapy. Perindopril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see Contraindications and Warnings).
Concomitant use not recommended: Aliskiren: In patients other than diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase (see Warnings).
Concomitant therapy with ACE inhibitor and angiotensin-receptor blocker: It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, concomitant therapy with an ACE inhibitor and an angiotensin-receptor blocker is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) as compared to use of a single renin-angiotensin-aldosterone system agent. Dual blockade (e.g, by combining an ACE-inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function, potassium levels, and blood pressure (see Warnings).
Estramustine: Risk of increased adverse effects such as angioneurotic oedema (angioedema).
Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see Precautions).
Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium (salts): Hyperkalaemia (potentially lethal), especially in conjunction with renal impairment (additive hyperkalaemic effects). The combination of perindopril with the previously-mentioned drugs is not recommended (see Precautions). If concomitant use is nonetheless indicated, they should be used with caution and with frequent monitoring of serum potassium. For use of spironolactone in heart failure, see "Concomitant use which requires special care" as follows.
Concomitant use which requires special care: Antidiabetic agents (insulin, oral hypoglycaemic agents): Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
Non-potassium-sparing diuretics: Patients on diuretics, and especially those who are volume and/or salt depleted, may experience excessive reduction in blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake prior to initiating therapy with low and progressive doses of perindopril.
In arterial hypertension, when prior diuretic therapy can have caused salt/volume depletion, either the diuretic must be discontinued before initiating the ACE inhibitor, in which case a non-potassium-sparing diuretic can be thereafter reintroduced or the ACE inhibitor must be initiated with a low dosage and progressively increased.
In diuretic-treated congestive heart failure, the ACE inhibitor should be initiated at a very low dosage, possibly after reducing the dosage of the associated non-potassium-sparing diuretic. In all cases, renal function (creatinine levels) must be monitored during the first few weeks of ACE inhibitor therapy.
Potassium-sparing diuretics (eplerenone, spironolactone): With eplerenone or spironolactone at doses between 12.5 mg to 50 mg per day and with low doses of ACE inhibitors: In the treatment of class II-IV heart failure (NYHA) with an ejection fraction <40%, and previously treated with ACE inhibitors and loop diuretics, risk of hyperkalaemia, potentially lethal, especially in case of non-observance of the prescription recommendations about this combination.
Before initiating the combination, check the absence of hyperkalaemia and renal impairment.
Close monitoring of the kalaemia and creatininemia is recommended in the first month of the treatment once a week at the beginning and, monthly thereafter.
Racecadotril: ACE inhibitors (e.g. perindopril) are known to cause angioedema. This risk may be elevated when used concomitantly with racecadotril (a drug used against acute diarrhea).
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema (see Warnings).
Concomitant use which requires some care: Antihypertensive agents and vasodilatators: Concomitant use of these agents may increase the hypotensive effects of perindopril. Concomitant use with nitroglycerin and other nitrates, or other vasodilatators, may further reduce blood pressure.
Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide: Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia (see Warnings).
Anaesthetic drugs: ACE inhibitors may enhance the hypotensive effects of certain anaesthetic drugs (see Precautions).
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): Increased risk of angio-oedema, due to dipeptidyl peptidase IV (DPP-IV) decreased activity by the gliptin, in patients co-treated with an ACE inhibitor.
Sympathomimetics: Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including perindopril.
Linked to indapamide: Concomitant use which requires special care: Torsades de pointes inducing drugs: Due to the risk of hypokalaemia, indapamide should be administered with caution when associated with medicinal products that induced torsades de pointes such as class IA antiarrhythmic agents (quinidine, hydroquinidine, disopyramide); class III antiarrhythmic agents (amiodarone, dofetilide, ibutilide, bretylium, sotalol); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide); other substances such as bepridil, cisapride, diphemanil, IV erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, IV vincamine, methadone, astemizole, terfenadine. Prevention of low potassium levels and correction if necessary: monitoring of the QT interval.
Potassium-lowering drugs: amphotericin B (IV route), glucocorticoids and mineralocorticoids (systemic route), tetracosactide, stimulant laxatives: Increased risk of low potassium levels (additive effect). Monitoring of potassium levels, and correction if necessary; particular consideration required in cases of treatment with digitalis. Non stimulant laxatives should be used.
Digitalis preparations: Low potassium levels favour the toxic effects of digitalis. Potassium levels and ECG should be monitored and treatment reconsidered if necessary.
Allopurinol: concomitant treatment with indapamide may increase the incidence of hypersensitivity reactions to allopurinol.
Concomitant use which requires some care: Potassium-sparing diuretics (amiloride, spironolactone, triamterene): Whilst rational combinations are useful in some patients, hypokalaemia or hyperkalaemia (particularly in patients with renal failure or diabetes) may still occur. Plasma potassium and ECG should be monitored and, if necessary, treatment reviewed.
Metformin: Lactic acidosis due to metformin caused by possible functional renal insufficiency linked to diuretics and in particular to loop diuretics. Do not use metformin when plasma creatinine levels exceed 15 mg/l (135 micromol/l) in men and 12 mg/l (110 micromol/l) in women.
Iodinated contrast media: In cases of dehydration caused by diuretics, there is an increased risk of acute renal insufficiency, particularly when high doses of iodinated contrast media are used. Rehydration should be carried out before the iodinated compound is administered.
Calcium (salts): Risk of increased levels of calcium due to reduced elimination of calcium in the urine.
Ciclosporin, tacrolimus: Risk of increased creatinine levels with no change in circulating levels of ciclosporin, even when there is no salt and water depletion.
Corticosteroids, tetracosactide (systemic route): Reduction in antihypertensive effect (salt and water retention due to corticosteroids).
