Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 24, 17489, Greifswald, Germany
Pharmacotherapeutic group: Angiotensin II antagonists, plain
ATC code: C09CA06
Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension, heart failure and other cardiovascular disorders. It also has a role in the pathogenesis of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 (AT1) receptor.
Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an AIIRA, selective for AT1 receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. There is no effect on ACE and no potentiation of bradykinin or substance P. In controlled clinical trials comparing candesartan with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The antagonism of the angiotensin II (AT1) receptors results in dose related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
In hypertension, candesartan causes a dose-dependent, long-lasting reduction in arterial blood pressure. The antihypertensive action is due to decreased systemic peripheral resistance, without reflex increase in heart rate. There is no indication of serious or exaggerated first dose hypotension or rebound effect after cessation of treatment.
After administration of a single dose of candesartan cilexetil, onset of antihypertensive effect generally occurs within 2 hours. With continuous treatment, most of the reduction in blood pressure with any dose is generally attained within four weeks and is sustained during long-term treatment. According to a meta-analysis, the average additional effect of a dose increase from 16 mg to 32 mg once daily was small. Taking into account the inter-individual variability, a more than average effect can be expected in some patients. Candesartan cilexetil once daily provides effective and smooth blood pressure reduction over 24 hours, with little difference between maximum and trough effects during the dosing interval. The antihypertensive effect and tolerability of candesartan and losartan were compared in two randomised, double-blind studies in a total of 1,268 patients with mild to moderate hypertension. The trough blood pressure reduction (systolic/diastolic) was 13.1/10.5 mmHg with candesartan cilexetil 32 mg once daily and 10.0/8.7 mmHg with losartan potassium 100 mg once daily (difference in blood pressure reduction 3.1/1.8 mmHg, p<0.0001/p<0.0001).
When candesartan cilexetil is used together with hydrochlorothiazide, the reduction in blood pressure is additive. An increased antihypertensive effect is also seen when candesartan cilexetil is combined with amlodipine or felodipine.
Medicinal products that block the renin-angiotensin-aldosterone system have less pronounced antihypertensive effect in black patients (usually a low-renin population) than in non-black patients. This is also the case for candesartan. In an open label clinical experience trial in 5,156 patients with diastolic hypertension, the blood pressure reduction during candesartan treatment was significantly less in black than non-black patients (14.4/10.3 mmHg vs 19.0/12.7 mmHg, p<0.0001/p<0.0001).
Candesartan increases renal blood flow and either has no effect on or increases glomerular filtration rate while renal vascular resistance and filtration fraction are reduced. In a 3-month clinical study in hypertensive patients with type 2 diabetes mellitus and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion (albumin/creatinine ratio, mean 30%, 95%CI 15‑42%). There is currently no data on the effect of candesartan on the progression to diabetic nephropathy.
The effects of candesartan cilexetil 8‑16 mg (mean dose 12 mg), once daily, on cardiovascular morbidity and mortality were evaluated in a randomised clinical trial with 4,937 elderly patients (aged 70‑89 years; 21% aged 80 or above) with mild to moderate hypertension followed for a mean of 3.7 years (Study on COgnition and Prognosis in the Elderly). Patients received candesartan cilexetil or placebo with other antihypertensive treatment added as needed. The blood pressure was reduced from 166/90 to 145/80 mmHg in the candesartan group, and from 167/90 to 149/82 mmHg in the control group. There was no statistically significant difference in the primary endpoint, major cardiovascular events (cardiovascular mortality, non-fatal stroke and non-fatal myocardial infarction). There were 26.7 events per 1000 patient-years in the candesartan group versus 30.0 events per 1000 patient-years in the control group (relative risk 0.89, 95%CI 0.75 to 1.06, p=0.19).
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
The antihypertensive effects of candesartan were evaluated in hypertensive children aged 1 to <6 years and 6 to <17 years in two randomised, double-blind multicentre, 4 week dose ranging studies. In children aged 1 to <6 years, 93 patients, 74% of whom had renal disease, were randomised to receive an oral dose of candesartan cilexetil suspension 0.05, 0.20 or 0.40 mg/kg once daily. The primary method of analysis was slope of the change in systolic blood pressure (SBP) as a function of dose. SBP and diastolic blood pressure (DBP) decreased 6.0/5.2 to 12.0/11.1 mmHg from baseline across the three doses of candesartan cilexetil. However, since there was no placebo group, the true magnitude of blood pressure effect remains uncertain which makes a conclusive assessment of benefit-risk balance difficult in this age group.
In children aged 6 to <17 years, 240 patients were randomised to receive either placebo or low, medium, or high doses of candesartan cilexetil in a ratio of 1: 2: 2: 2. For children who weighed <50 kg, the doses of candesartan cilexetil were 2, 8, or 16 mg once daily. In children who weighed >50 kg, the candesartan cilexetil doses were 4, 16 or 32 mg once daily. Candesartan at pooled doses reduced SiSBP by 10.2 mmHg (P<0.0001) and SiDBP (P=0.0029) by 6.6 mmHg, from the base line. In the placebo group, there was also a reduction of 3.7 mmHg in SiSBP (p=0.0074) and 1.80 mmHg for SiDBP (p=0.0992) from the baseline. Despite the large placebo effect, all individual candesartan doses (and all doses pooled) were significantly superior to placebo. Maximum response in reduction of blood pressure in children below and above 50 kg was reached at 8mg and 16 mg doses, respectively and the effect plateaued after that point. Of those enrolled, 47% were black patients and 29% were female; mean age +/- SD was 12.9 +/- 2.6 years.
In children aged 6 to < 17 years there was a trend for a lesser effect on blood pressure in black patients compared to non-black patients.
Treatment with candesartan cilexetil reduces mortality, reduces hospitalisation due to heart failure, and improves symptoms in patients with left ventricular systolic dysfunction as shown in the Candesartan in Heart failure – Assessment of Reduction in Mortality and morbidity (CHARM) programme.
This placebo controlled, double-blind study programme in chronic heart failure (CHF) patients with NYHA functional class II to IV consisted of three separate studies: CHARM-Alternative (n=2,028) in patients with LVEF ≤40% not treated with an ACE inhibitor because of intolerance (mainly due to cough, 72%), CHARM-Added (n=2,548) in patients with LVEF ≤ 40% and treated with an ACE inhibitor, and CHARM-Preserved (n=3,023) in patients with LVEF > 40%. Patients on optimal CHF therapy at baseline were randomised to placebo or candesartan cilexetil (titrated from 4 mg or 8 mg once daily to 32 mg once daily or the highest tolerated dose, mean dose 24 mg) and followed for a median of 37.7 months. After 6 months of treatment 63% of the patients still taking candesartan cilexetil (89%) were at the target dose of 32 mg.
In CHARM-Alternative, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo, hazard ratio (HR) 0.77 (95%CI: 0.67 to 0.89, p<0.001). This corresponds to a relative risk reduction of 23%. Of candesartan patients 33.0% (95%CI: 30.1 to 36.0) and of placebo patients 40.0% (95%CI: 37.0 to 43.1) experienced this endpoint, absolute difference 7.0% (95%CI: 11.2 to 2.8). Fourteen patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan, HR 0.80 (95%CI: 0.70 to 0.92, p=0.001). Of candesartan patients 36.6% (95%CI: 33.7 to 39.7) and of placebo patients 42.7% (95%CI: 39.6 to 45.8) experienced this endpoint, absolute difference 6.0% (95%CI: 10.3 to 1.8). Both the mortality and morbidity (CHF hospitalisation) components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.008).
In CHARM-Added, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo, HR 0.85 (95%CI: 0.75 to 0.96, p=0.011). This corresponds to a relative risk reduction of 15%. Of candesartan patients 37.9% (95%CI: 35.2 to 40.6) and of placebo patients 42.3% (95%CI: 39.6 to 45.1) experienced this endpoint, absolute difference 4.4% (95%CI: 8.2 to 0.6). Twenty-three patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan, HR 0.87 (95%CI: 0.78 to 0.98, p=0.021). Of candesartan patients 42.2% (95%CI: 39.5 to 45.0) and of placebo patients 46.1% (95%CI: 43.4 to 48.9) experienced this endpoint, absolute difference 3.9% (95%CI: 7.8 to 0.1). Both the mortality and morbidity components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.020).
In CHARM-Preserved, no statistically significant reduction was achieved in the composite endpoint of cardiovascular mortality or first CHF hospitalisation, HR 0.89 (95%CI: 0.77 to 1.03, p=0.118).
All-cause mortality was not statistically significant when examined separately in each of the three CHARM studies. However, all-cause mortality was also assessed in pooled populations, CHARM-Alternative and CHARM-Added, HR 0.88 (95%CI: 0.79 to 0.98, p=0.018) and all three studies, HR 0.91 (95%CI: 0.83 to 1.00, p=0.055).
The beneficial effects of candesartan were consistent irrespective of age, gender and concomitant medication. Candesartan was effective also in patients taking both beta-blockers and ACE inhibitors at the same time, and the benefit was obtained whether or not patients were taking ACE inhibitors at the target dose recommended by treatment guidelines.
In patients with CHF and depressed left ventricular systolic function (left ventricular ejection fraction, LVEF ≤ 40%), candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases aldosterone levels.
Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34% with very little variability. The estimated absolute bioavailability of the tablet is therefore 14%. The mean peak serum concentration (Cmax) is reached 3‑4 hours following tablet intake. The candesartan serum concentrations increase linearly with increasing doses in the therapeutic dose range. No gender related differences in the pharmacokinetics of candesartan have been observed. The area under the serum concentration versus time curve (AUC) of candesartan is not significantly affected by food.
Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution of candesartan is 0.1 l/kg.
The bioavailability of candesartan is not affected by food.
Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4. Based on in vitro data, no interaction would be expected to occur in vivo with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life of candesartan is approximately 9 hours. There is no accumulation following multiple doses.
Total plasma clearance of candesartan is about 0.37 ml/min/kg, with a renal clearance of about 0.19 ml/min/kg. The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of 14C-labelled candesartan cilexetil,approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the inactive metabolite.
In the elderly (over 65 years) Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively in comparison to young subjects. However, the blood pressure response and the incidence of adverse events are similar after a given dose of Blopress in young and elderly patients (see section 4.2).
In patients with mild to moderate renal impairment Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively, but t½ was not altered, compared to patients with normal renal function. The corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal t½ of candesartan was approximately doubled in patients with severe renal impairment. The AUC of candesartan in patients undergoing haemodialysis was similar to that in patients with severe renal impairment.
In two studies, both including patients with mild to moderate hepatic impairment, there was an increase in the mean AUC of candesartanof approximately 20% in one study and 80% in the other study(see section 4.2). There is no experience in patients with severe hepatic impairment.
The Pharmacokinetic properties of candesartan were evaluated in hypertensive children aged 1 to <6 years and 6 to <17 years in two single dose PK studies.
In children aged 1 to <6 years, 10 children weighing 10 to <25 kg received a single dose of 0.2 mg/kg, oral suspension. There was no correlation between Cmax and AUC with age or weight. No clearance data has been collected; therefore the possibility of a correlation between clearance and weight/age in this population is unknown.
In children aged 6 to <17 years, 22 children received a single dose of 16 mg tablet. Half the subjects were below and half were above 12 years of age.There was no correlation between Cmax and AUC with age. However weight seems to significantly correlate with Cmax (p=0.012) and AUC (p=0.011). No clearance data, has been collected, therefore the possibility of a correlation between clearance and weight/age in this population is unknown.
Children >6 years of age had exposure similar to adults given the same dose.
The pharmacokinetics of candesartan cilexetil have not been investigated in paediatric patients <1 year of age.
There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In preclinical safety studies candesartan had effects on the kidneys and on red cell parameters at high doses in mice, rats, dogs and monkeys. Candesartan caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). Effects on the kidneys (such as interstitial nephritis, tubular distension, basophilic tubules; increased plasma concentrations of urea and creatinine) were induced by candesartan which could be secondary to the hypotensive effect leading to alterations of renal perfusion. Furthermore, candesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells. These changes were considered to be caused by the pharmacological action of candesartan. For therapeutic doses of candesartan in humans, the hyperplasia/hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
In preclinical studies in normotensive neonatal and juvenile rats, candesartan caused a reduction in body weight and heart weight. As in adult animals, these effects are considered to result from the pharmacological action of candesartan. At the lowest dose of 10 mg/kg exposure to candesartan was between 12 and 78 times the levels found in children aged 1 to <6 who received candesartan cilexetil at a dose of 0.2 mg/kg and 7 to 54 times those found in children aged 6 to <17 who received candesartan cilexetil at a dose of 16 mg. As a no observed effect level was not identified in these studies, the safety margin for the effects on heart weight and the clinical relevance of the finding is unknown.
Foetotoxicity has been observed in late pregnancy (see section 4.6).
Data from in vitro and in vivo mutagenicity testing indicates that candesartan will not exert mutagenic or clastogenic activities under conditions of clinical use.
There was no evidence of carcinogenicity.
The renin‑angiotensin‑aldosterone system plays a critical role in kidney development in utero. Renin‑angiotensin‑aldosteron e system blockade has been shown to lead to abnormal kidney development in very young mice. Administering drugs that act directly on the renin‑angiotensin‑aldosterone system can alter normal renal development. Therefore, children aged less than 1 year should not receive Blopress (see section 4.3).
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