⚠️ Warnings
Candesartan
Pregnancy
Treatment with angiotensin II receptor antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy must be switched to alternative antihypertensive treatment with an established safety profile for use in pregnancy. When pregnancy is diagnosed, AIIRA treatment must be stopped immediately, and, if appropriate, alternative treatment should be started (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 decreased renal function (including acute renal failure). Dual blockade of the 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, 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.
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 renal impairment or end-stage renal disease (Clcr < 15 ml/min) is limited. In these patients, candesartan should be carefully titrated with close monitoring of blood pressure.
Assessment of patients with heart failure should include periodic evaluation of renal function, especially in elderly patients aged 75 years and over and in patients with renal impairment. During dose titration of candesartan, monitoring of serum creatinine and potassium is recommended. Clinical trials in heart failure did not include patients with serum creatinine >265 μmol/l (> 3 mg/dl).
Concomitant treatment with an ACE inhibitor in heart failure
The risk of adverse effects, especially hypotension, hyperkalaemia, and decreased renal function (including acute renal failure), may increase when Bilamcar is used in combination with an ACE inhibitor (see section 4.8). Triple combination of an ACE inhibitor, a mineralocorticoid receptor antagonist, and candesartan is also not recommended. Use of these combinations should be 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.
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 in patients on haemodialysis with close monitoring of blood pressure.
Renovascular hypertension
Patients with bilateral renal artery stenosis or stenosis of the artery supplying a single functioning kidney who are treated with agents affecting the renin-angiotensin-aldosterone system are at increased risk of severe hypotension and renal impairment.
Renal transplantation
There is no experience with the administration of candesartan in patients with a recent kidney transplant.
Hypotension
Symptomatic hypotension, especially after the first dose, may occur in patients who are volume- and/or sodium-depleted, e.g. by intensive diuretic therapy, dietary salt restriction, diarrhoea, or vomiting. These conditions should be corrected before administration of candesartan. If hypotension occurs with Bilamcar, the patient should be placed in the supine position and, if necessary, an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution should be given. Treatment can continue once blood pressure has been stabilised.
Anaesthesia and surgery
During anaesthesia and surgery in patients treated with angiotensin II receptor antagonists, hypotension may occur due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe enough to warrant the use of intravenous fluids and/or vasopressors.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special 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 agents acting through inhibition of the renin-angiotensin system. Therefore, the use of candesartan is not recommended in these patients.
Hyperkalaemia
Administration 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 concomitantly treated with other medicinal products that may increase 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. On discontinuation of the angiotensin II receptor antagonist, the symptoms resolved. If intestinal angioedema is diagnosed, candesartan treatment should be discontinued and appropriate monitoring should be initiated until the symptoms have completely resolved.
Before considering initiation of treatment with other medicinal products that affect the renin-angiotensin-aldosterone system, the benefit-risk ratio should be evaluated. The main risk factors for hyperkalaemia that should be considered are:
Diabetes mellitus,
Renal impairment,
Age (> 70 years),
Combination with one or more medicinal products that affect the renin-angiotensin-aldosterone system and/or with potassium supplements.
Salt substitutes containing potassium,
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 of renal function, sudden deterioration of renal condition (e.g. in infectious diseases), cell lysis (e.g. in acute limb ischaemia, rhabdomyolysis, extensive trauma). In these patients, serum potassium should be carefully monitored (see section 4.5).
General
In patients whose vascular tone and renal function depend predominantly on the 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 that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (see section 4.8). As with any antihypertensive agents, excessive blood pressure reduction in patients with ischaemic cardiomyopathy or ischaemic cardiovascular disease could result in myocardial infarction or stroke.
The antihypertensive effect of candesartan may be enhanced by other blood pressure-lowering medicinal products, 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 compared with 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 hepatic impairment; dosage recommendations have not been established. Bilamcar 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, doses should be increased with caution (see sections 4.2 and 5.2).
Renal failure
Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations do not correlate 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 product.
