Coversyl Plus 4mg Tablet

Coversyl u00ae Plus is indicated for the treatment of essential hypertension, in patients where blood pressure is not adequately controlled and where fixed combination is considered more appropriate than monotherapy.

Posology The dosage regimen depends upon the individual requirements of the patient and is at the discretion of the medical doctor. One Coversyl u00ae Plus tablet per day as a single dose, preferably to be taken in the morning before a meal.

Special populations Elderly (see section 4.4): It is recommended to start the treatment with only one of the constituents. Patients with renal failure (see section 4.4): In cases of severe renal failure (creatinine clearance below 30 ml/min), treatment is contra-indicated. In patients with a creatinine clearance greater than or equal to 30 ml/min and less than 60 ml/min, it is recommended to start the treatment with only one of the constituents. It is not necessary to change the dose when the creatinine clearance is greater than 60 ml/min. Method of administration Oral use.

This medicine is contraindicated in the following circumstances: Linked to indapamide: u2022 Hypersensitivity to any of the ingredients of Coversyl u00ae Plus or any other ACE-inhibitor. u2022 A history of angioedema related to previous therapy with ACE-inhibitors or angiotensin receptor blockers (ARBs): these patients must never again be given these medicines. (see section 4.4) , u2022 Hereditary or idiopathic angioedema, u2022 Hypertrophic obstructive cardiomyopathy (HOCM), u2022 Severe renal function impairment (creatinine clearance below 30 ml/min), u2022 Bilateral renal artery stenosis, u2022 Renal artery stenosis in patients with a single kidney, u2022 Aortic stenosis (see WARNINGS AND SPECIAL PRECAUTIONS), u2022 Concomitant therapy with potassium-sparing diuretics (such as spironolactone, triamterene, amiloride (see WARNINGS AND SPECIAL PRECAUTIONS and INTERACTIONS), u2022 Porphyria, u2022 Lithium therapy: concomitant administration with Coversyl u00ae Plus may lead to toxic blood concentration of lithium (see section 4.5) , u2022 Concomitant use of Coversyl u00ae Plus with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1,73 mu00b2) (see section 4.4 and 4.5). , u2022 Concomitant use with sacubitril/valsartan (see section 4.4 and 4.5). , u2022 Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5). , u2022 Concomitant use of fluoroquinolones with ACE-inhibitors/Renin angiotensin receptor blockers is contraindicated in patients with moderate to severe renal failure (Creatinine Clearance u2264 30 ml/min) and in elderly patients. u2022 Significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section 4.4) , u2022 Pregnancy and lactation (see section 4.4 and 4.6) , Linked to indapamide: u2022 Hypersensitivity to the active substance or to any other sulphonamides, u2022 Severe renal impairment (creatinine clearance below 30 ml/min), u2022 Hepatic encephalopathy, u2022 Severe hepatic impairment, u2022 Hypokalaemia, u2022 As a general rule, this medicine is inadvisable in combination with non antidysrhythmic agents causing torsades de pointes (see section 4.5) u2022 Lactation (section 4.6). Linked to Coversyl u00ae Plus u2022 Hypersensitivity to any of the excipients listed in section 6.1 Due to the lack of sufficient therapeutic experience, Coversyl u00ae Plus should not be used in: u2022 Dialysis patients u2022 Patients with untreated decompensated heart failure.

Special warnings Common to perindopril and indapamide: Lithium: The combination of lithium with the combination of perindopril and indapamide is usually not recommended (see section 4.5). Linked to perindopril: Should a woman become pregnant while receiving Coversyl u00ae Plus, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine (see section 4.3 and 4.6). 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 may increases the risk of hypotension, hyperkalaemia and decreases renal function (including acute renal failure). Dual blockade of RAAS through the combined use of Coversyl u00ae Plus and aliskiren is therefore contraindicated (see section 4.3 and 4.5). 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 medicines, potassium supplements or potassium-containing salt substitutes: The combination of perindopril and potassium-sparing medicines, potassium supplements or potassium-containing salt substitutes is usually not recommended (see section 4.5). Risk of neutropenia/agranulocytosis/thrombocytopenia/anaemia in immuno-suppressed patients: Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE-inhibitors. In patients with normal renal function and no other complicating factors, neutropenia rarely occurs. 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) (see section 4.5 and 4.8).

Renovascular hypertension: There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE-inhibitors (see section 4.3). 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/Angioneurotic Oedema: Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has rarely been reported in patients receiving treatment with ACE-inhibitors, including perindopril (see section 4.8). This may occur at any time during treatment. In such cases, treatment with Coversyl u00ae Plus should immediately be stopped and the patient should be monitored until the oedema has disappeared. Angioneurotic oedema combined with laryngeal oedema may be fatal. Involvement of tongue, glottis or larynx may lead to an obstruction of the airways. A subcutaneous injection of adrenaline (epinephrine) at 1:1 000 (0,3 ml to 0,5 ml) should be administered quickly and other appropriate measures taken. The prescribing of Coversyl u00ae Plus or any other ACE-inhibitor is then contraindicated in these patients (see section 4.3). Black patients receiving ACE-inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks. Patients with a previous history of angioneurotic oedema, which was not linked to taking an ACE-inhibitor, have an increased risk of angioneurotic oedema with Coversyl u00ae Plus (see section 4.3). Intestinal angioedema has rarely been reported 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 with 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 concomitantly taking mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at an increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). The combination of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see section 4.3). 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 (see section 4.3 and 4.5). Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE-inhibitors may also increase the risk of angioedema (see section 4.5). Hence, a careful benefit-risk assessment is needed before initiating treatment with NEP inhibitors (e.g. racecadotril) in patients on perindopril.

Fluoroquinolones and ACE-inhibitors/Renin angiotensin receptor blockers: Concomitant use of fluoroquinolones and ACE-inhibitors/Renin angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment, with fluoroquinolones or ACE-inhibitors/Renin angiotensin receptor blockers whether used separately or concomitantly.

Anaphylactoid reactions during desensitisation: There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE-inhibitors during desensitisation treatment with hymenoptera (bees, wasps) venom. Coversyl u00ae Plus should be used with caution in allergic patients treated with desensitisation, and avoided in those undergoing venom immunotherapy. However, these reactions could be prevented by temporary withdrawal of Coversyl u00ae Plus for at least 24 hours before treatment in patients who require both ACE-inhibitors and desensitisation.

Anaphylactoid reactions during Low Density Lipoprotein (LDL) apheresis: There have been reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE-inhibitors during low-density lipoprotein apheresis with dextran sulphate adsorption. Coversyl u00ae Plus should be avoided in such patients. However, these reactions could be prevented by temporary withdrawal of Coversyl u00ae Plus for at least 24 hours before treatment in patients who require both ACE-inhibitors and LDL apheresis.

Haemodialysis patients: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., AN 69 u00ae ) 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 medication acting through inhibition of the renin-angiotensin system. Therefore, the use Coversyl u00ae Plus is not recommended.

Linked to indapamide: Hepatic encephalopathy: When liver function is impaired, thiazide diuretics and thiazide-related diuretics may cause hepatic encephalopathy. Administration of Coversyl u00ae Plus should be stopped immediately if this occurs.

Photosensitivity: Cases of photosensitivity reactions have been reported with thiazides and related thiazides diuretics (see section 4.8). 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.

Linked to Coversyl u00ae Plus: Renal insufficiency: In cases of severe renal insufficiency (creatinine clearance < 30 ml/min), treatment is contraindicated (see section 4.3). In patients without pre-existing apparent renal lesions and for whom renal blood tests show functional renal insufficiency, treatment should be stopped and possibly restarted 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. Coversyl u00ae Plus 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 diarrhoea 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 contra-indication to continuation of treatment. After reestablishment of a satisfactory blood volume and blood pressure, treatment can be started again with only one of the constituents.

Potassium levels: The combination of perindopril and indapamide does not prevent the onset of hypokalaemia particularly in diabetic patients or in patients with renal failure. Regular monitoring of plasma potassium levels should be carried out.

Excipients Coversyl u00ae Plus should not be administered to patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

Linked to perindopril: Cough: A dry cough has been reported with the use of ACE-inhibitors. It is characterised by its persistence and by its disappearance when treatment is withdrawn. An iatrogenic aetiology should be considered in the event of this symptom. If the prescription of an ACE-inhibitor is still preferred, continuation of treatment may be considered.

Children: The efficacy and safety of perindopril in children and adolescents, alone or in combination has not been established. 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 oedema and ascites. Blocking the renin-angiotensin-aldosterone system with an ACE-inhibitor may 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 with only one of the constituents and increased progressively.

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.

Patients with known atherosclerosis: The risk of hypotension exists in all patients, but particular care should be taken in patients with ischaemic heart disease or cerebral circulatory insufficiency, with treatment being started with only one of the constituents.

Renovascular hypertension: The treatment of renovascular hypertension is revascularisation. Nonetheless, ACE-inhibitors can be beneficial in patients presenting with renovascular hypertension who are awaiting corrective surgery or when such a surgery is not possible. Treatment should be started in a hospital setting with only one of the constituents 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.

Cardiac failure/severe cardiac insufficiency: In patients with severe cardiac insufficiency (grade IV) or in patients with insulin dependent diabetes mellitus (spontaneous tendency to increased levels of potassium), treatment should be started under medical supervision with only one of the constituents. 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: 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 glycaemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic medication or insulin, namely during the first month of treatment with an ACE-inhibitor (see section 4.5).

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/anaesthesia: Coversyl u00ae Plus may precipitate hypotension during general anaesthesia. It is therefore recommended that treatment with perindopril should be discontinued where possible one day before surgery.

Aortic stenosis / hypertrophic cardiomyopathy: ACE-inhibitors should be used with caution in patients with an obstruction in the outflow tract of the left ventricle.

Hepatic failure: Coversyl u00ae Plus has 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 Coversyl u00ae Plus who develop jaundice or marked elevations of hepatic enzymes should discontinue Coversyl u00ae Plus and receive appropriate medical follow-up (see section 4.8.)

Hyperkalaemia: Elevations in serum potassium have been observed in some patients treated with ACE-inhibitors, including perindopril. Risk factors for the development of hyperkalaemia 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, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other medicines associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole, other ACE-inhibitors, angiotensin-II receptor antagonists, acetylsalicylic acid u2265 3 g/day, COX-2 inhibitors and non-selective NSAIDu2019s, 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. Hyperkalaemia can cause serious, sometimes fatal dysrhythmias. If concomitant use of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see section 4.5).

The most likely adverse event in case of overdose is hypotension, sometimes associated with nausea, vomiting, cramps, dizziness, sleepiness, mental confusion, oliguria, which may progress to anuria (due to hypovolaemia). Salt and water disturbances (low sodium levels, low potassium levels) may occur.

The first measures to be taken consist of rapidly eliminating the product(s) ingested by gastric lavage and/or administration of activated charcoal, then restoring fluid and electrolyte balance in a specialised centre until they return to normal. If marked hypotension occurs, this can be treated by placing the patients in a supine position with the head lowered. If necessary an IV infusion of isotonic saline may be given, or any other method of volaemic expansion may be used. Perindoprilat, the active form of perindopril, can be dialysed.