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Linked to perindopril: Hypotension: ACE inhibitors may cause a fall in blood pressure. Symptomatic hypotension is seen rarely 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 Interactions and Adverse Reactions). In patients at high risk of symptomatic hypotension, blood pressure, renal function and serum potassium should be monitored closely during treatment with Coveram.
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 sodium chloride 9 mg/ml (0.9%) solution. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.
Aortic and mitral valve stenosis/hypertrophic cardiomyopathy: As with other ACE inhibitors, perindopril 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) an individual dose titration with the monocomponents is recommended (see Dosage & Administration).
Routine monitoring of potassium and creatinine are part of normal medical practice for patients with renal impairment (see Adverse Reactions).
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with ACE inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This 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. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when perindopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment.
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 (see Adverse Reactions).
Race: ACE inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
As with other ACE inhibitors, perindopril may be 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.
Cough: Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Surgery/Anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Coveram may block angiotensin II formation secondary to compensatory renin release. The treatment should be discontinued one day prior to the surgery. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
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 dehydratation, 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 drugs associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole). 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 perindopril and any of the previously mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see Interactions).
Diabetic patients: In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see Interactions).
Linked to amlodipine: The safety and efficacy of amlodipine in hypertensive crisis has not been established.
Cardiac failure: Patients with heart failure should be treated with caution.
In a long-term, placebo controlled study in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group (see Pharmacology: Pharmacodynamics under Actions). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
Hepatic impairment: The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.
Renal failure: Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.
Linked to Coveram: All warnings related to each monocomponent, as listed previously, should apply also to the fixed combination of Coveram.
Excipients: Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the total lactase deficiency should not take this medicinal product.
Interactions: The concomitant use of Coveram with lithium, potassium-sparing drugs or potassium supplements, or dantrolene is not recommended (see Interactions).
Effects on ability to drive and use machines: No studies on the effects of Coveram on the ability to drive and use machines have been performed. Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients suffer from dizziness, headache, fatigue, weariness or nausea, the ability to react may be impaired. Caution is recommended especially at the start of treatment.
Use in the Elderly: Linked to amlodipine: In the elderly increase of the dosage should take place with care (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
