COVERSYL PLUS Perindopril Arginine / Indapamide 10mg / 2.5mg Film-Coated Tablet 30's

5 mg/1.25 mg: Treatment of essential hypertension, in adults, in patients whose blood pressure is not adequately controlled on perindopril alone.
10 mg/2.5 mg: Substitution therapy for the treatment of essential hypertension, in patients already controlled with Perindopril and Indapamide given concurrently at the same dose level.

 

One Perindopril arginine + Indapamide (Coversyl Plus) film-coated tablet per day as a single dose, preferably to be taken in the morning, and before a meal.
Hepatic impairment: In severe hepatic impairment, treatment is contraindicated.
In patients with moderate hepatic impairment, no dose modification is required.
Method of administration: Oral use.
Missed Dose: It is important to take this medicine every day as regular treatment is more effective. However, if a dose of Perindopril arginine + Indapamide (Coversyl Plus) is forgotten, take the next dose at the usual time. Do not take a double dose to make up for a forgotten dose.
5 mg/1.25 mg: When possible, individual dose titration with the components is recommended. Perindopril arginine + Indapamide (Coversyl Plus) should be used when blood pressure is not adequately controlled on Perindopril arginine + Indapamide (Preterax) 2.5mg/625mcg film-coated tablet (where available). When clinically appropriate, direct change from monotherapy to Perindopril arginine + Indapamide (Coversyl Plus) film-coated tablet may be considered.
Elderly: Treatment should be initiated after considering blood pressure response and renal function.
Renal impairment: In severe renal impairment (creatinine clearance below 30 ml/min), treatment is contraindicated.
In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), it is recommended to start treatment with the adequate dosage of the free combination.
In patients with creatinine clearance greater than or equal to 60 ml/min, no dose modification is required.
Usual medical follow-up will include frequent monitoring of creatinine and potassium.
Pediatric population: The safety and efficacy of perindopril arginine/indapamide in the pediatric population have not yet been established. No data are available.
Perindopril arginine + Indapamide (Coversyl Plus) should not be used in children and adolescents.
10 mg/2.5 mg: Elderly: In elderly, the plasma creatinine must be adjusted in relation to age, weight and gender. Elderly patients can be treated if renal function is normal and after considering blood pressure response.
Renal impairment: In severe and moderate renal impairment (creatinine clearance below 60 ml/min), treatment is contraindicated.
Usual medical follow-up will include frequent monitoring of creatinine and potassium.
Pediatric population: The safety and efficacy of Perindopril arginine + Indapamide (Coversyl Plus) in children and adolescents have not yet been established. No data are available. Perindopril arginine + Indapamide (Coversyl Plus) should not be used in children and adolescents.

 

Overdosage

Should be taken on an empty stomach: Preferably taken in the morning.

Linked to perindopril: Hypersensitivity to the active substance or to any other ACE inhibitor; History of angioedema (Quincke's edema) associated with previous ACE inhibitor therapy; Hereditary/idiopathic angioedema; Second and third trimesters of pregnancy; Concomitant use of Perindopril arginine + Indapamide (Coversyl Plus) 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 leading to contact of blood with negatively charged surfaces; Significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney.
Linked to indapamide: Hypersensitivity to the active substance or to any other sulphonamides; Hepatic encephalopathy; Severe hepatic impairment; Hypokalemia; As a general rule, this medicine is inadvisable in combination with non antiarrhythmic agents causing torsades de pointes; Lactation.
5 mg/1.25 mg: Severe renal impairment (creatinine clearance below 30 ml/min).
10 mg/2.5 mg: Severe and moderate renal impairment (creatinine clearance below 60 ml/min).
Linked to Perindopril arginine + Indapamide (Coversyl Plus): Hypersensitivity to any of the excipients.
Due to the lack of sufficient therapeutic experience, Perindopril arginine + Indapamide (Coversyl Plus) should not be used in: Dialysis patients; Patients with untreated decompensated heart failure.

Special warnings: Common to perindopril and indapamide: Lithium: The combination of lithium and the combination of perindopril and indapamide is usually not recommended.
Linked to perindopril: Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Potassium-sparing drugs, potassium supplements or potassium-containing salt substitutes: The combination of perindopril and potassium-sparing drugs, potassium supplements or potassium-containing salt substitutes is usually not recommended.
Neutropenia/agranulocytosis/thrombocytopenia/anemia: Neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Perindopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy. If perindopril is used in such patients, periodical monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (e.g. sore throat, fever).
Renovascular hypertension: There is an increased risk of hypotension and renal insufficiency when patient with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only minor changes in serum creatinine even in patients with unilateral renal artery stenosis.
Hypersensitivity/angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including perindopril. This may occur at any time during treatment. In such cases perindopril should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should be administered promptly.
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment).
The combination of perindopril with sacubitril/valsartan is 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. If treatment with sacubitril/valsartan is stopped, perindopril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan. Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE inhibitors may also increase the risk of angioedema. Hence, a careful benefit-risk assessment is needed before initiating treatment with NEP inhibitors (e.g. racecadotril) in patients on perindopril.
Anaphylactoid reactions during desensitization: There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (bees, wasps) venom. ACE inhibitors should be used with caution in allergic patients treated with desensitization, and avoided in those undergoing venom immunotherapy. However these reactions could be prevented by temporary withdrawal of ACE inhibitor for at least 24 hours before treatment in patients who require both ACE inhibitors and desensitization.
Anaphylactoid reactions during LDL apheresis: Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.
Hemodialysis patients: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g., AN 69) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Primary aldosteronism: Patients with primary hyperaldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of this product is not recommended.
Use in Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.
Linked to indapamide: Hepatic encephalopathy: When liver function is impaired, thiazide diuretics and thiazide-related diuretics may cause hepatic encephalopathy. Administration of the diuretic should be stopped immediately if this occurs.
Photosensitivity: Cases of photosensitivity reactions have been reported with thiazides and related thiazide diuretics. If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.
Precautions for use: Common to perindopril and indapamide: Renal impairment: 5 mg/1.25 mg: In cases of severe renal impairment (creatinine clearance < 30 ml/min), treatment is contraindicated.
10 mg/2.5 mg: In cases of severe and moderate renal impairment (creatinine clearance < 60 ml/min), treatment is contraindicated.
In certain hypertensive patients without pre-existing apparent renal lesions and for whom renal blood tests show functional renal insufficiency, treatment should be stopped and possibly restarted either at a low dose or with one constituent only.
In these patients, usual medical follow-up will include frequent monitoring of potassium and creatinine, after two weeks of treatment and then every two months during therapeutic stability period. Renal failure has been reported mainly in patients with severe heart failure or underlying renal failure including renal artery stenosis.
The drug is usually not recommended in case of bilateral renal artery stenosis or a single functioning kidney.
Hypotension and water and electrolyte depletion: There is a risk of sudden hypotension in the presence of pre-existing sodium depletion (in particular in individuals with renal artery stenosis). Therefore systematic testing should be carried out for clinical signs of water and electrolyte depletion, which may occur with an intercurrent episode of diarrhea or vomiting. Regular monitoring of plasma electrolytes should be carried out in such patients.
Marked hypotension may require the implementation of an intravenous infusion of isotonic saline.
Transient hypotension is not a contraindication to continuation of treatment. After re-establishment of a satisfactory blood volume and blood pressure, treatment can be started again either at a reduced dose or with only one of the constituents.
Potassium levels: The combination of perindopril and indapamide does not prevent the onset of hypokalemia particularly in diabetic patients or in patients with renal failure. As with any antihypertensive agent containing a diuretic, regular monitoring of plasma potassium levels should be carried out.
Excipients: Perindopril arginine + Indapamide (Coversyl Plus) should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Linked to perindopril: Cough: A dry cough has been reported with the use of angiotensin converting enzyme inhibitors. It is characterized by its persistence and by its disappearance when treatment is withdrawn. An iatrogenic etiology should be considered in the event of this symptom. If the prescription of an angiotensin converting enzyme inhibitor is still preferred, continuation of treatment may be considered.
Risk of arterial hypotension and/or renal insufficiency (in cases of cardiac insufficiency, water and electrolyte depletion, etc): Marked stimulation of the renin-angiotensin-aldosterone system has been observed particularly during marked water and electrolyte depletions (strict sodium-free diet or prolonged diuretic treatment), in patients whose blood pressure was initially low, in cases of renal artery stenosis, congestive heart failure or cirrhosis with edema and ascites.
The blocking of this system with an angiotensin converting enzyme inhibitor may therefore cause, particularly at the time of the first administration and during the first two weeks of treatment, a sudden drop in blood pressure and/or an increase in plasma levels of creatinine, showing a functional renal insufficiency. Occasionally this can be acute in onset, although rare, and with a variable time to onset.
In such cases, the treatment should then be initiated at a lower dose and increased progressively.
Atherosclerosis: The risk of hypotension exists in all patients but particular care should be taken in patients with ischemic heart disease or cerebral circulatory insufficiency, with treatment being started at a low dose.
Renovascular hypertension: The treatment for renovascular hypertension is revascularization. Nonetheless, angiotensin converting enzyme inhibitors can be beneficial in patients presenting with renovascular hypertension who are awaiting corrective surgery or when such a surgery is not possible.
5 mg/1.25 mg: If Perindopril arginine + Indapamide (Coversyl Plus) is prescribed to patients with known or suspected renal artery stenosis, treatment should be started in a hospital setting at a low dose and renal function and potassium levels should be monitored, since some patients have developed a functional renal insufficiency which was reversed when treatment was stopped.
10 mg/2.5 mg: Treatment with Perindopril arginine + Indapamide (Coversyl Plus) 10mg/2.5mg is not appropriate in patients with known or suspected renal artery stenosis because treatment should be started in a hospital setting at a dose lower than the Perindopril arginine + Indapamide (Coversyl Plus) 10mg/2.5mg one.
Cardiac failure/severe cardiac insufficiency: 5 mg/1.25 mg: In patients with severe cardiac insufficiency (grade IV), treatment should be started under medical supervision with a reduced initial dose. Treatment with beta-blockers in hypertensive patients with coronary insufficiency should not be stopped: the ACE inhibitor should be added to the beta-blocker.
10 mg/2.5 mg: In patients with severe cardiac insufficiency (grade IV), treatment with Perindopril arginine + Indapamide (Coversyl Plus) is not appropriate because treatment should be started under medical supervision with a reduced initial dose. Treatment with beta-blockers in hypertensive patients with coronary insufficiency should not be stopped: the ACE inhibitor should be added to the beta-blocker
Diabetic patients: 5 mg/1.25 mg: In patients with insulin dependent diabetes mellitus (spontaneous tendency to increased levels of potassium), treatment should be started under medical supervision with a reduced initial dose.
The glycemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.
10 mg/2.5 mg: In patients with insulin dependent diabetes mellitus (spontaneous tendency to increased levels of potassium), treatment with Perindopril arginine + Indapamide (Coversyl Plus) is not appropriate because treatment should be started under medical supervision with a reduced initial dose. Treatment with beta-blockers in hypertensive patients with coronary insufficiency should not be stopped: the ACE inhibitor should be added to the beta-blocker. The glycemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.
Ethnic differences: As with other angiotensin converting enzyme inhibitors, perindopril is apparently less effective in lowering blood pressure in black people than in non Blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.
Surgery/anesthesia: Angiotensin converting enzyme inhibitors can cause hypotension in cases of anesthesia, especially when the anesthetic administered is an agent with hypotensive potential.
It is therefore recommended that treatment with long-acting angiotensin converting enzyme inhibitors such as perindopril should be discontinued where possible one day before surgery.
Aortic or mitral valve stenosis/hypertrophic cardiomyopathy: ACE inhibitors should be used with caution in patient with an obstruction in the outflow tract of the left ventricle.
Hepatic failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Hyperkalemia: Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril. Risk factors for the development of hyperkalemia include those with renal insufficiency, worsening of renal function, age (> 70 years), diabetes mellitus, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparins, other ACE inhibitors, angiotensin-II receptor antagonists, acetylsalicylic acid ≥ 3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal arrhythmias. If concomitant use of the previously-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
Use in Children: The efficacy and tolerability of perindopril in children and adolescents, alone or in combination, have not been established.
Use in the Elderly: Renal function and potassium levels should be tested before the start of treatment. The initial dose is subsequently adjusted according to blood pressure response, especially in cases of water and electrolyte depletion, in order to avoid sudden onset of hypotension.
Linked to indapamide: Water and electrolyte balance: Sodium levels: These should be tested before treatment is started, then at regular intervals. Reduction in sodium levels can be initially asymptomatic and regular testing is therefore essential. Testing should be more frequent in elderly and cirrhotic patients. Any diuretic treatment may cause hyponatremia, sometimes with very serious consequences. Hyponatremia with hypovolemia may be responsible of dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis: the incidence and degree of this effect are slight.
Potassium levels: Potassium depletion with hypokalemia is a major risk with thiazide diuretics and thiazide-related diuretics. The risk of onset of lowered potassium levels (< 3.4 mmol/l) should be prevented in some high risk populations such as elderly and/or malnourished subjects, whether or not they are taking multiple medications, cirrhotic patients with edema and ascites, coronary patients and patients with heart failure. In such cases hypokalemia increases the cardiac toxicity of cardiac glycosides and the risk of rhythm disorders.
Subjects presenting with a long QT interval are also at risk, whether the origin is congenital or iatrogenic. Hypokalemia, as with bradycardia, acts as a factor which favors the onset of severe rhythm disorders, in particular torsades de pointes, which may be fatal.
In all cases more frequent testing of potassium levels is necessary. The first measurement of plasma potassium levels should be carried out during the first week following the start of treatment.
If low potassium levels are detected, correction is required.
Calcium levels: Thiazide diuretics and thiazide-related diuretics may reduce urinary excretion of calcium and cause a mild and transient increase in plasma calcium levels. Markedly raised levels of calcium may be related to undiagnosed hyperparathyroidism. In such cases the treatment should be stopped before investigating the parathyroid function.
Blood glucose: Monitoring of blood glucose is important in diabetic patients, particularly when potassium levels are low.
Uric acid: Tendency to gout attacks may be increased in hyperuricemic patients.
Renal function and diuretics: Thiazide diuretics and thiazide-related diuretics are only fully effective when renal function is normal or only slightly impaired (creatinine levels lower than approximately 25 mg/l, i.e. 220 µmol/l for an adult).
In the elderly the value of plasma creatinine levels should be adjusted to take account of the age, weight and sex of the patient, according to the Cockroft formula: cl_cr = (140-age) x body weight/0.814 x plasma creatinine level with: age expressed in years; body weight in kg; plasma creatinine level in micromol/l.
This formula is suitable for an elderly male and should be adapted for women by multiplying the result by 0.85.
Hypovolemia, resulting from the loss of water and sodium caused by the diuretic at the start of treatment, causes a reduction in glomerular filtration. It may result in an increase in blood urea and creatinine levels. This transitory functional renal insufficiency is of no adverse consequence in patients with normal renal function but may however worsen a pre-existing renal impairment.
Athletes: Athletes should note that this product contains an active substance which may cause a positive reaction in doping tests.
Acute myopia and secondary angle-closure glaucoma: Sulfonamide, or sulfonamide derivative, drugs can cause an idiosyncratic reaction resulting in transient myopia and acute angle-closure glaucoma. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Driving and using machines: 5 mg/1.25 mg: Neither the two active substances nor Perindopril arginine + Indapamide (Coversyl Plus) affect alertness but individual reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or in combination with another antihypertensive medication. As a result, the ability to drive or operate machinery may be impaired.
10 mg/2.5 mg: The two active substances, individually or combined in Perindopril arginine + Indapamide (Coversyl Plus), have no influence on the ability to drive and use machines but individual reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or in combination with another antihypertensive medication.
As a result the ability to drive or operate machinery may be impaired.

 

Use In Pregnancy & Lactation

Like all medicines, Perindopril arginine + Indapamide (Coversyl Plus) can cause side effects, although not everybody gets them.
Summary of safety profile: The administration of perindopril inhibits the renin-angiotensin-aldosterone axis and tends to reduce the potassium loss caused by indapamide.
The most commonly reported adverse reactions observed are: With perindopril: dizziness, headache, paresthesia, dysgeusia, visual impairment, vertigo, tinnitus, hypotension, cough, dyspnea, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, pruritus, rash, muscle cramps and asthenia.
With indapamide: hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions and maculopapular rashes.
5 mg/1.25 mg: Four percent of the patients on treatment with Perindopril arginine + Indapamide (Coversyl Plus) 5mg/1.25mg experience hypokalemia (potassium level < 3.4 mmol/l).
10 mg/2.5 mg: Six percent of the patients on treatment with Perindopril arginine + Indapamide (Coversyl Plus) 10mg/2.5mg experience hypokalemia (potassium level < 3.4 mmol/l).
Tabulated list of adverse reactions: The following undesirable effects have been observed during clinical trials and/or post-marketing use and ranked under the following frequency: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data). (See Tables A and B.)

Seek medical attention immediately at the first sign of any adverse drug reaction.

 

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.
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, hyperkalemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.
Drugs inducing hyperkalemia: Some drugs or therapeutic classes may increase the occurrence of hyperkalemia: 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 hyperkalemia.
Concomitant use contraindicated: Aliskiren: In diabetic or impaired renal patients, risk of hyperkalemia, 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 hemofiltration 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. 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 contraindicated 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.
Concomitant use not recommended: Aliskiren: In patients other than diabetic or impaired renal patients, risk of hyperkalemia, worsening of renal function and cardiovascular morbidity and mortality increase.
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, hyperkalemia, 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.
Estramustine: Risk of increased adverse effects such as angioneurotic edema (angioedema).
Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalemia.
Potassium-sparing diuretics (e.g. triamterene, amiloride…), potassium (salts): Hyperkalemia (potentially lethal), especially in conjunction with renal impairment (additive hyperkalemic effects). The combination of perindopril with the previously-mentioned drugs is not recommended. 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 hypoglycemic agents): Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood-glucose lowering effect with risk of hypoglycemia. 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 hyperkalemia, potentially lethal, especially in cse of non-observance of the prescription recommendations about this combination.
Before initiating the combination, check the absence of hyperkalemia and renal impairment.
Close monitoring of the kalemia 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.
Concomitant use which requires some care: Antihypertensive agents and vasodilators: Concomitant use of these agents may increase the hypotensive effects of perindopril. Concomitant use with nitroglycerin and other nitrates, or other vasodilators, 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.
Anesthetic drugs: ACE inhibitors may enhance the hypotensive effects of certain anesthetic drugs.
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): Increased risk of angioedema, 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 hypokalemia, 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 favor 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, hypokalemia or hyperkalemia (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).

Storage

Action

ACE Inhibitors/Direct Renin Inhibitors / Diuretics