⚠️ Warnings
Candesartan
Pregnancy
Treatment with angiotensin II receptor antagonists (AIIRAs) must not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be switched to alternative antihypertensive treatments with an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs must be stopped immediately and, if appropriate, alternative therapy initiated (see sections 4.3 and 4.6).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren has been shown to increase the risk of hypotension, hyperkalaemia, and reduced 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 (see sections 4.5 and 5.1).
If dual blockade is considered absolutely necessary, it should only be undertaken under specialist supervision and with 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.
Renal impairment
As with other agents that inhibit the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients treated with candesartan.
When candesartan is used in hypertensive patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended. Experience in patients with very severe or end-stage renal impairment (Clcr < 15 ml/min) is limited. In these patients, candesartan should be carefully titrated with close monitoring of blood pressure.
Evaluation of patients with heart failure should include periodic assessment of renal function, particularly in elderly patients aged 75 years or older and in patients with renal impairment. Monitoring of serum creatinine and potassium levels is recommended during candesartan dose titration. Clinical trials in heart failure did not include patients with serum creatinine concentration > 265 μmol/l (> 3 mg/dl).
Concomitant therapy with an ACE inhibitor in heart failure
The risk of adverse reactions, particularly hypotension, hyperkalaemia, and decreased renal function (including acute renal failure), may be increased when Candezek Combi is used in combination with an ACE inhibitor (see section 4.8). The triple combination of an ACE inhibitor, a mineralocorticoid receptor antagonist, and candesartan is also not recommended. Use of these combinations should be undertaken under specialist supervision and with 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.
Haemodialysis
During dialysis, blood pressure may be particularly sensitive to AT1 receptor blockade as a result of reduced plasma volume and activation of the renin-angiotensin-aldosterone system. Therefore, candesartan should be carefully titrated with close monitoring of blood pressure in haemodialysis patients.
Renovascular hypertension
Patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney who are treated with medicinal products affecting the renin-angiotensin-aldosterone system are at increased risk of severe hypotension and renal impairment.
Kidney transplantation
There is no experience with the administration of candesartan in patients with a recent kidney transplant.
Hypotension
Symptomatic hypotension, particularly after the first dose, may occur in patients with volume and/or sodium depletion, e.g. due to intensive diuretic therapy, dietary salt restriction, diarrhoea, or vomiting. Such conditions should be corrected before administration of candesartan. If hypotension occurs during treatment with Candezek Combi, the patient should be placed in the supine position and, if necessary, an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution administered. Treatment may be continued once blood pressure has stabilised.
Anaesthesia and surgery
During anaesthesia and surgery in patients treated with angiotensin II receptor antagonists, hypotension may occur as a result of blockade of the renin-angiotensin system. Very rarely, hypotension may be severe enough to require intravenous fluids and/or vasopressors.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, particular caution is required in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Primary aldosteronism
Patients with primary aldosteronism generally do not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, candesartan is not recommended in such patients.
Hyperkalaemia
The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia. Hyperkalaemia may be fatal in elderly patients, in patients with renal impairment, in patients with diabetes mellitus, in patients receiving concomitant medicinal products that may raise potassium levels, and/or in patients with intercurrent events.
Intestinal angioedema
Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists [including candesartan] (see section 4.8). These patients presented with abdominal pain, nausea, vomiting, and diarrhoea. Symptoms resolved after discontinuation of the angiotensin II receptor antagonist. If intestinal angioedema is diagnosed, candesartan therapy should be suspended and appropriate monitoring instituted until symptoms have completely resolved.
Before initiating treatment with other medicinal products affecting the renin-angiotensin-aldosterone system, the benefit/risk balance should be evaluated. The main risk factors for hyperkalaemia to be considered are:
Diabetes mellitus;
Renal impairment;
Age (> 70 years);
Combination with one or more medicinal products affecting the renin-angiotensin-aldosterone system and/or with potassium supplements;
Potassium-containing salt substitutes;
Potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (ciclosporin or tacrolimus), and trimethoprim;
Intercurrent events, particularly dehydration, acute cardiac decompensation, metabolic acidosis, worsening renal function, sudden deterioration of renal status (e.g. due to infectious disease), cell breakdown (e.g. acute limb ischaemia, rhabdomyolysis, extensive trauma). Serum potassium should be carefully monitored in such patients (see section 4.5).
General
In patients whose vascular tone and renal function depend predominantly on activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products affecting this system has been associated with acute hypotension, azotaemia, oliguria, or, rarely, acute renal failure (see section 4.8). As with any antihypertensive agent, excessive blood-pressure reduction in patients with ischaemic cardiomyopathy or ischaemic cardiovascular disease may precipitate myocardial infarction or stroke.
The antihypertensive effect of candesartan may be enhanced by other medicinal products that lower blood pressure, whether prescribed as antihypertensives or for other indications.
Amlodipine
Hypertensive crisis
The safety and efficacy of amlodipine in hypertensive crisis have not been established.
Heart 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.
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 (see section 5.1).
Hepatic impairment
The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired hepatic function; dosage recommendations have not been established. Candezek Combi should therefore be used with caution in patients with mild to moderate hepatic impairment. For severe hepatic impairment, see section 4.3.
Elderly patients (65 years or older)
In elderly patients, dose increases should be undertaken with caution (see sections 4.2 and 5.2).
Renal failure
Amlodipine may be used in such patients at usual doses. Changes in amlodipine plasma concentrations are not correlated with the degree of renal impairment. Amlodipine is not dialysable.
Lactose intolerance
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
