Coversyl 10 Mg/5 mg Tablets

Coversyl 5 mg and 10 mg are indicated for the treatment of mild to moderate hypertension. Coversyl 5 mg is indicated in congestive heart failure not adequately controlled by conventional therapy with diuretics and digitalis and in whom vasodilatation is indicated.

Posology
Mild to moderate hypertension
The recommended dosage is 5 mg orally taken in the morning before breakfast, which can be increased to a single daily dose of 10 mg if necessary, after one month of treatment. In elderly patients, treatment should be initiated at a dose of 2,5 mg, which may progressively be increased to 5 mg after one month, then to 10 mg if necessary, depending on renal function.

Congestive heart failure
The treatment should be initiated under close medical supervision. Initial dose of 2,5 mg orally as a single daily dose in the morning, which may, in most instances be increased to 5 mg (once blood pressure acceptability has been demonstrated).

Concomitant diuretic therapy in hypertension
Caution is recommended in patients who are currently being treated with diuretics. As the effects of ACE-inhibitors may be potentiated in a situation where hypovolaemia may occur, the diuretic therapy should be discontinued 2 to 3 days prior to initiation of therapy with Coversyl. In the case of combination with a diuretic, it is not advisable to prescribe a potassium salt or a potassium sparing agent before determining the blood potassium, and attention should be paid to possible overdose of the diuretic.

Special populations
Renal insufficiency
In patients with renal insufficiency, the dosage of perindopril must be adjusted in relation to the severity of the insufficiency.

Table 1 Dosage adjustment in renal impairment

• Creatinine clearance > 60 ml/min: 5 mg per day
• Creatinine clearance between 30 and 60 ml/min: 2,5 mg per day
• Creatinine clearance between 15 and 30 ml/min: 2,5 mg every other day
• Haemodialysed patients < 15 ml/min: 2,5 mg on day of dialysis

• Hypersensitivity to any of the ingredients of Coversyl.
• 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).
• Hereditary/idiopathic angioedema (see section 4.4).
• Hypertrophic obstructive cardiomyopathy (HOCM) (see section 4.4).
• Severe renal function impairment (creatinine clearance below 30 ml/min).
• In bilateral renal artery stenosis.
• Renal artery stenosis in patient with a single kidney.
• Aortic stenosis (see section 4.4).
• Concomitant therapy with potassium-sparing diuretics (such as spironolactone, triamterene, amiloride), (see section 4.5).
• Porphyria.
• In combinations with lithium: concomitant use with Coversyl may lead to toxic blood concentration of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The concomitant use of Coversyl with aliskiren-containing products is contraindicated. (see sections 4.4 and 4.5).
• Concomitant use with sacubitril/valsartan (see sections 4.4 and 4.5). Coversyl must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.4 and 4.5).
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5).
• 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.

Should a woman become pregnant while receiving Coversyl, the treatment must be stopped promptly and switched to a different medicine. (see sections 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 increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of Coversyl, angiotensin II receptor blockers or aliskiren is therefore contraindicated (see sections 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. Coversyl and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy (see sections 4.3 and 4.5).

Hypotension
ACE-inhibitors may cause a fall in blood pressure. Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients and is more likely to occur in patients who have been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension (see sections 4.5 and 4.8). In patients with symptomatic heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients with an increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored (see sections 4.2 and 4.8). Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contra-indication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion. In some patients with congestive heart failure, who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with Coversyl. If hypotension becomes symptomatic, a reduction of the dose or discontinuation of perindopril may be necessary.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy
Coversyl should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle, such as aortic stenosis or hypertrophic cardiomyopathy.

Renal impairment
In cases of renal impairment (creatinine clearance < 60 ml/min) the initial Coversyl dosage should be adjusted according to the patientu2019s creatinine clearance (see section 4.2) and then as a function of the patientu2019s response to treatment (see section 4.8). Routine monitoring of potassium and creatinine are part of normal medical practice for these patients. In patients with symptomatic heart failure, hypotension following the initiation of therapy with ACE-inhibitors may lead to some further impairment in renal function. Acute renal failure has been reported in this situation. In patients with bilateral renal artery stenosis, or stenosis of the artery to a solitary kidney, and who have been treated with ACE-inhibitors, increases in blood urea and serum creatinine may occur. This is usually reversible upon discontinuation of therapy. It is especially likely in patients with renal insufficiency. If renovascular hypertension is also present, there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of Coversyl therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, especially when Coversyl was given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Coversyl may be required.

Haemodialysis patients
Anaphylactic reactions have been reported in patients dialysed with high flux membranes and treated concomitantly with an ACE-inhibitor. In these patients, consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.

Kidney transplantation
There is no experience regarding the administration of Coversyl in patients with a recent kidney transplant.

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 (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.

Dual blockade of the RAAS with ARBs, ACE-inhibitors, or aliskiren
Clinical trial data have 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 (see sections 4.3 and 4.4).

Medicines increasing the risk of angioedema
Concomitant use of ACE-inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4). 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 sections 4.3 and 4.4).

Medicines inducing hyperkalaemia
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with Coversyl. Some medicines or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), ACE-inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus and trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. The combination of these medicines increases the risk of hyperkalaemia. Therefore, the combination of Coversyl with the above-mentioned medicines is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

Concomitant use contraindicated (See section 4.3)
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. polyacrylonitrile membranes) and low-density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Fluoroquinolones and ACE-inhibitors/Renin angiotensin receptor blockers
Concomitant use of fluoroquinolones and ACE-inhibitors/Renin angiotensin receptor blockers may precipitate acute kidney injury (see section 4.3). The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).

Pregnancy
Coversyl is contraindicated during pregnancy and lactation. Pregnant women should be informed of the potential hazards to the foetus and must not take Coversyl during pregnancy (see section 4.3). 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 Coversyl should be stopped immediately and if appropriate, alternative therapy should be started. Foetal exposure to ACE-inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spins bifida) and of kidney malformations. ACE-inhibitors, such as Coversyl pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regularity mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in newborns have been reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur. Should exposure to ACE-inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see also section 4.3).

Lactation
It is not known whether perindopril is excreted into human breast milk. Therefore, the use of Coversyl is not recommended in women who are breastfeeding. Coversyl is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Fertility
There was no effect on reproductive performance or fertility.

Coversyl has no direct 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.

a. Summary of safety profile.
The safety profile of perindopril is consistent with the safety profile of ACE-inhibitors: The most frequent adverse events reported in clinical trials and observed with perindopril are: dizziness, headache, paraesthesia, vertigo, visual disturbances, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhoea, dysgeusia, dyspepsia, nausea, vomiting, pruritis, rash, muscle cramps, and asthenia.

b. Tabulated list of adverse reactions.
The following side effects have been observed during treatment with Coversyl and ranked under the following frequency Very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u2265 1/1 000, < 1/100); rare (u2265 1/10 000, < 1/1 000); very rare (< 1/10 000); including isolated reports, not known (cannot be estimated from the available data).

Symptoms associated with overdose of ACE-inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. The recommended treatment of an overdose is an intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. Coversyl may be removed from the general circulation by haemodialysis. Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously. Expected symptoms and signs would be linked to hypotension. Further treatment is symptomatic and supportive.