CANDEZA is indicated for the:

•      Treatment of essential hypertension in adults.

•      The treatment of hypertension in children and adolescents aged 6 to <18 years.

•      Treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction≤40%) as add-on therapy to Angiotensin Converting Enzyme (ACE) inhibitors or when ACE inhibitors are not tolerated(see section 5.1).

Posology in Hypertension

Paediatric Population:
Children and adolescents aged 6 to < 18 years:
The recommended starting dose is 4 mg once daily.

·         For patients weighing < 50 kg: In patients whose blood pressure is not adequately controlled, the dose can be increased to a maximum of 8 mg once daily.

·         For patients weighing ≥ 50 kg: In patients whose blood pressure is not adequately controlled, the dose can be increased to 8 mg once daily and then to 16 mg once daily if needed.
Doses above 32 mg have not been studied in paediatric patients.
Most of the antihypertensive effect is attained within 4 weeks.
For children with possible intravascular volume depletion (e.g., patients treated with diuretics, particularly those with impaired renal function), CANDEZA treatment should be initiated under close medical supervision and a lower starting dose than the general starting dose above should be considered.
Black paediatric patients:
The antihypertensive effect of candesartan is less pronounced in black patients than in non-black patients.
Children aged below 1 year to < 6 years:

·         The safety and efficacy in children aged 1 to < 6 years of age has not been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.

·         CANDEZA is contraindicated in children aged below 1 year (see section 4.3).

The recommended initial dose and usual maintenance dose of CANDEZA is 8 mg once daily. Most of the antihypertensive effect is attained within4 weeks. In some patients whose blood pressure is not adequately controlled, the dose can be increased to 16mg once daily and to a maximum of 32 mg once daily. Therapy should be adjusted according to blood pressure response.

CANDEZA may also be administered with other antihypertensive agents. Addition of hydrochlorothiazide has been shown to have an additive antihypertensive effect with various doses of CANDEZA.

Elderly population

No initial dose adjustment is necessary in elderly patients.

Patients with intravascular volume depletion

An initial dose of4 mg maybe considered in patients at risk for hypotension, such as patients with possible volume depletion (see section 4.4).

Patients with renal impairment

The starting dose is 4 mg in patients with renal impairment, including patients on haemodialys is. The dose should be titrated according to response. There is limited experience in patients with very severe or end-stage renal impairment (Cl_creatinine<15 ml/min) (see section 4.4).

Patients with hepatic impairment

An initial dose of4 mg once daily is recommended in patients with mild to moderate hepatic impairment. The dose may be adjusted according to response. CANDEZA is contraindicated in patients with severe hepatic impairment and/or cholestasis (see sections 4.3and 5.2).

Black patients

The antihypertensive effect of candesartan is less pronounced in black patients than in non-black patients. Consequently, up titration of CANDEZA and concomitant therapy may be more frequently needed for blood pressure control in black patients than in non-black patients (see section 5.1).

Posology in Heart Failure

The usual recommended initial dose of CANDEZA is 4 mg once daily. Up-titration to the target dose of 32mg once daily (maximum dose) or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks (see section 4.4). Evaluation of patients with heart failure should always comprise assessment of renal function including monitoring of serum creatinine and potassium.

CANDEZA can be administered with other heart failure treatment, including ACE inhibitors, beta blockers, diuretics and digitalis or a combination of these medicinal products. The combination of an ACE inhibitor, a potassium sparing diuretic (e.g. spironolactone) and CANDEZA is not recommended and should be considered only after careful evaluation of the potential benefits and risks (see sections 4.4, 4.8 and5.1).

Special patient populations

No initial dose adjustment is necessary for elderly patients or in patients with intravascular volume depletion or renal impairment or mild to moderate hepatic impairment.

Paediatric Population

The safety and efficacy of CANDEZA in children aged between birth and 18 years have not been established in the treatment of hypertension and heart failure. No data are available.

Method of administration

Oral use.

CANDEZA should be taken once daily with or without food. The bioavailability of candesartan is not affected by food.

Renal impairment

As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function maybe anticipated in susceptible patients treated with CANDEZA.

When CANDEZA is used in hypertensive patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended. There is limited experience in patients with very severe or end-stage renal impairment (Cl_creatinine<15 ml/min).In these patients CANDEZA should be carefully titrated with thorough monitoring of blood pressure.

Evaluation of patients with heart failure should include periodic assessments of renal function, especially in elderly patients 75years or older, and patients with impaired renal function. During dose titration of CANDEZA, monitoring of serum creatinine and potassium is recommended. Clinical trials in heart failure did not include patients with serum creatinine >265µmol/l (>3mg/dl).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Combination therapy of ACEI and ARB drugs may cause an increased risk of hyperkalemia, worsening of the kidney function and hypotension. Therefore, this combination should not be used, especially in patients with kidney problems.

Concomitant therapy with an ACE inhibitor in heart failure

The risk of adverse reactions, especially renal function impairment and hyperkalaemia, may increase when CANDEZA is used in combination with an ACE inhibitor (see section 4.8). Patients with such treatment should be monitored regularly and carefully.

Haemodialysis

During dialysis the 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, CANDEZA should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis.

Renal artery stenosis

Medicinal products that affect the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (AIIRAs), may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Kidney transplantation

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

Hypotension

Hypotension may occur during treatment with CANDEZA in heart failure patients. It may also occur in hypertensive patients with intravascular volume depletion such as those receiving high dose diuretics. Caution should be observed when initiating therapy and correction of hypovolemia should be attempted.

Anaesthesia and surgery

Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockade of the renin-angiotensin system. Very rarely, hypotension maybe severe such that it may warrant the use of intravenous fluids and/or vasopressors.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicinal products acting through inhibition of the renin- angiotensin-aldosterone system. Therefore, the use of CANDEZA is not recommended in this population.

Hyperkalaemia

Concomitant use of CANDEZA with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g.heparin) may lead to increases in serum potassium in hypertensive patients. Monitoring of potassium should be undertaken as appropriate.

In heart failure patients treated with CANDEZA, hyperkalaemia may occur. Periodic monitoring of serum potassium is recommended. The combination of an ACE inhibitor, a potassium sparing diuretic (e.g. spironolactone) and CANDEZA is not recommended and should be considered only after careful evaluation of the potential benefits and risks.

General

In patients whose vascular tone an drenal 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 renalartery stenosis), treatment with other medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguriaor, rarely, acute renal failure. The possibility of similar effects cannot be excluded with AIIRAs. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

The antihypertensive effect of candesartan may be enhanced by other medicinal products with blood pressure lowering properties, whether prescribed as an antihypertensive or prescribed for other indications.

CANDEZA contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Pregnancy

AIIRAs should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically significant pharmacokinetic interactions with these medicinal products have been identified.

Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products (e.g. heparin) may increase potassium levels. Monitoring of potassium should be undertaken as appropriate (see section 4.4).

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. A similar effect may occur with AIIRAs. Use of candesartan with lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

When AIIRAs are administered simultaneously with non-steroidal anti-inflammatory drugs (NSAIDs) (i.e. selective COX2 inhibitors, acetylsalicylic acid(>3 g/day)and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.

As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Dual RAAS blockade

The combination of aliskiren with ARBs or ACEis is contraindicated in patients with diabetes mellitus or renal impairment.

Dual blockade (e.g. by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should not be used, especially in patients with kidney problems.

Pregnancy

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with AIIRAs, similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation)and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4).

Lactation

Because no information is available regarding the use of CANDEZA during breast- feeding, CANDEZA is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or pre term infant.

No studies on the effects of candesartan on the ability to drive and use machines have been performed. However, it should be taken into account that occasionally dizziness or weariness may occur during treatment with CANDEZA.

Treatment of Hypertension

In controlled clinical studies adverse reactions were mild and transient. The overall incidence of adverse events showed no association with dose or age. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil(3.1%) and placebo (3.2%).

In a pooled analysis of clinical trial data of hypertensive patients, adverse reactions with candesartan cilexetil were defined based on an incidence of adverse events with candesartan cilexetil at least 1%higherthan the incidence seen with placebo. By this definition, the most commonly reported adverse reactions were dizziness/vertigo, headache and respiratory infection.

The table below presents adverse reactions from clinical trials and post-marketing experience.

The frequencies used in the tables throughout section 4.8 are: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10000,<1/1000) and very rare (<1/10000).

Laboratory findings

In general, there were no clinically important influences of CANDEZA on routine laboratory variables. As for other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin have been seen. No routine monitoring of laboratory variables is usually necessary for patients receiving CANDEZA. However, in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.

Treatment of Heart Failure

The adverse experience profile of CANDEZA in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM clinical programme, comparing CANDEZA in doses up to32 mg(n=3,803) to placebo(n=3,796), 21.0%of the candesartan cilexetil group and 16.1% of the placebo group discontinued treatment because of adverse events. The most commonly reported adverse reactions were hyperkalaemia, hypotension and renal impairment. These events were more common in patients over 70 years of age, diabetics, or subjects who received other medicinal products which affect the renin-angiotensin- aldosterone system, in particular an ACE inhibitor and/or spironolactone.

The table below presents adverse reactions from clinical trials and post-marketing experience.

Laboratory findings

Hyperkalaemia and renal impairment are common in patients treated with CANDEZA for the indication of heart failure. Periodic monitoring of serum creatinine and potassium is recommended (see section 4.4).

To report any side effect(s):

Symptoms

Based on pharmacological considerations, the main manifestation of an overdose is likely to be symptomatic hypotension and dizziness. In individual case reports of overdose (of up to 672 mg candesartan cilexetil) patient recovery was uneventful.

Management

If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by infusion of, for example, isotonic saline solution. Sympathomimetic medicinal products may be administered if the above-mentioned measures are not sufficient.

Candesartan is not removed by haemodialysis.

Pharmacotherapeutic group:

3.4.2.2 – Cardiovascular system. Anti-hypertensive. Renin-angiotensin axis modifiers. AngiotensinII receptor antagonists

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 AT1receptors, 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 rennin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.

Hypertension

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 from16 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 over24 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 candesartancilexetil32 mg once daily and 10.0/8.7 mmHg with losartan potassium100 mg once daily(difference in bloodpressurereduction3.1/1.8 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%CI15-42%). 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 80orabove) with mild to moderate hypertension followed for a mean of 3.7years (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 from166/90 to 145/80 mmHg in the candesartan group, and from167/90to149/82 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 were26.7 events per 1000 patient-years in the candesartan group versus 30.0 events per 1000 patient-years in the control group (relative risk0.89, 95%CI0.75 to 1.06, p=0.19).

Heart Failure

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%andtreated 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 (titratedfrom4 mg or 8 mg once dailyto 32 mg once daily or the highest tolerated dose, mean dose 24 mg) and followed for a median of 37.7months.

After 6 months of treatment 63%of the patients still taking candesartan cilexetil (89%)were at the target dose of 32mg.

In CHARM-Alternative, the composite end point 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 of23%. Of candesartan patients 33.0% (95%CI: 30.1 to36.0)and of placebo patients 40.0%(95%CI: 37.0 to 43.1) experienced this end point, absolute difference 7.0% (95%CI: 11.2to 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: 0.70to 0.92,p=0.001). Of candesartan patients36.6%(95%CI: 33.7to 39.7) and of placebo patients 42.7% (95%CI: 39.6 to45.8)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 end points 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 end point of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo, HR 0.85 (95%CI: 0.75 to0.96,p=0.011).This corresponds to a relative risk reduction of 15%. Of candesartan patients 37.9% (95%CI: 35.2to 40.6) and of placebo patients 42.3% (95%CI:39.6 to45.1)experienced this end point, absolute difference 4.4% (95%CI: 8.2 to0.6).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 end point 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 end point, 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.

Absorption and distribution

Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately40% after an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same oral solutionisapproximately34% with very little variability. The estimated absolute bioavailability of the tablet is therefore 14%.The mean peak serum concentration (C_max) 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 0.1l/kg.

The bioavailability of candesartan is not affected by food.

Biotransformation and elimination

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 approximately9 hours. There is no accumulation following multiple doses.

Total plasma clearance of candesartan is about0.37 ml/min/kg, with a renal clearance of about0.19 ml/min/kg.  The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oraldoseof¹⁴Clabelledcandesartan 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.

Pharmacokinetics in special populations

In the elderly (over 65 years) C_max 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 CANDEZA in young and elderly patients (see section 4.2).

In patients with mild to moderate renal impairment C_max and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively, but t½was 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 t½of candesartan was approximately doubled in patients with severe renal impairment. The AUC of candesartanin 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 candesartan of 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.

Paediatric population

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 C_max 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. There was no correlation between C_max and AUC with age. However weight seems to significantly correlate with C_max (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.

Foetal toxicity 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.

CANDEZA 4 and 8 mg tablets:

Docusate sodium

Sodium Laurilsulfate

Carmellose calcium

Pregelatinised Starch

Hydroxypropyl cellulose

Lactose Monohydrate

Magnesium Stearate

CANDEZA 16 and 32 mg tablets:

Docusate sodium

Sodium Laurilsulfate

Carmellose calcium

Pregelatinised Starch

Hydroxypropylcellulose

Lactose Monohydrate

Magnesium Stearate

Iron oxide red (E172)

Not applicable.

Store below 30ºC.

4mg tablets: Blister packages of PVC/PVDC-Alu with 28 tablets.

8mg tablets: Blister packages of PVC/PVDC-Alu with 28 tablets.

16 mg tablets: Blister packages of PVC/PVDC-Alu with 28 tablets.

32 mg tablets: Blister packages of PVC/PVDC-Alu with 28 tablets.

Any unused product or waste material should be disposed of in accordance with local requirements