Hypertension

Since this drug may cause excessively decreased blood pressure, this drug should not be used as an initial therapy for hypertension.

Posology

The recommended dose of Clodipan is 1 capsule per day.

The fixed dose combination is not suitable for initiation therapy. Dose adjustment, if necessary, should be done with the individual components

Before switching to Clodipan patients should be controlled on stable doses of the individual components taken at the same time.

The dose of Clodipan should be based on the doses of the individual components of the combination at the time of switching.

Special populations

Elderly (aged 65 years or older)

No dose adjustment is necessary for elderly patients. Caution is required when increasing the dosage. Limited information is available on use in the very elderly patients.

Renal impairment

No dose adjustment is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and creatinine is advised in moderate renal impairment. Caution is advised because of limited experience available in patients with severe or end-stage renal impairment (Clcr<15 mL/min) or on haemodialysis.

Changes in amlodipine plasma concentrations are not correlated with stage of renal impairment, therefore the usual dosage is recommended. Amlodipine and candesartan cilexetil are not dialysable. See also section 4.4.

Hepatic impairment

In patients with mild to moderate hepatic impairment Clodipan should be administered with caution. Clodipan is contraindicated in patients with severe hepatic impairment and/or cholestasis (see sections 4.3, 4.4 and 5.2).

Paediatric population

The safety and efficacy of Clodipan in children aged below 18 years have not been established. No data are available.

Methods of administration

Oral use.

Clodipan can be taken with or without food. It is recommended to take Clodipan with some liquid.

Candesartan

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist 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 angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see section 4.3 and 4.6).

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

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased 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 therapy 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 inhibiting 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. There is limited experience in patients with very severe or end-stage renal disease (Clcr < 15 mL/min). In these patients candesartan 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 75 years or older, and patients with impaired renal function. 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 therapy with an ACE-inhibitor in heart failure

The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when Clodipan 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 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, candesartan should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney when treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Kidney transplantation

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

Hypotension

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of candesartan. If hypotension occurs with Clodipan, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution for infusion. Treatment can be continued once blood pressure has been stabilised.

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 may be 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 aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of candesartan is not recommended.

Hyperkalaemia

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia. Hyperkalaemia may be fatal in the elderly, in patients with renal insufficiency, in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.

Before considering the concomitant use of medicinal products that affect the renin-angiotensin aldosterone system, the benefit risk ratio 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 other medicinal products that affect the renin-angiotensin aldosterone system and/or potassium supplements.

-  Salt substitutes containing potassium,

-  Potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporin or tacrolimus), and trimethoprim.

-  Intercurrent events, in particular dehydratation, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extensive trauma).

Serum potassium should be monitored closely in these patients (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 medicinal product, excessive reduction of blood pressure in patients with ischaemic cardiomyopathy or ischaemic cardiovascular 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.

Amlodipine

Hypertensive crisis

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.

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

Amlodipine half-life is prolonged and AUC values are higher in patients with impaired liver function; dose recommendations have not been established. Clodipan should therefore be used with caution in patients with mild to moderate hepatic impairment. For severe hepatic impairment, see section 4.3.

Elderly (aged 65 years or older)

In the elderly increase of the dosage should take place with care (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 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 medicine.

No interactions between the two components of this fixed dose combinations have been observed in clinical studies.

Interactions linked to candesartan/amlodipine to be taken into account with concomitant use.

Other antihypertensive medicinal products

The blood pressure lowering effect of Clodipan can be increased by concomitant use of other antihypertensive medicinal products.

Medicinal products with blood pressure lowering potential

Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including Clodipan, e.g. baclofen, amifostine, neuroleptics or antidepressants. Furthermore, orthostatic hypotension may be aggravated by alcohol.

Corticosteroids (systemic use)

Reduction of the antihypertensive effect.

Interactions linked to candesartan

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.

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products (e.g. heparin) that may increase potassium level

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).

Lithium

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.

NSAIDs

When AIIRAs are administered simultaneously with non-steroidal anti-inflammatory drugs (NSAIDs) (i.e. selective COX-2 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 blockade of the renin-angiotensin-aldosterone-system (RAAS)

Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACE- inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Interactions linked to amlodipine

Effects of other medicinal products on amlodipine:

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic (PK) variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.

CYP3A4 inducers

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant use particularly with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse were observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of amlodipine on other medicinal products:

Tacrolimus

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Cyclosporine

No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of cyclosporine were observed.

Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dose reductions should be made as necessary.

Simvastatin

Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. The dose of simvastatin to be limited to 20 mg daily in patients on amlodipine.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Pregnancy

Linked to candesartan/amlodipine

Clodipan is not recommended during the first trimester of pregnancy as no data are available and safety profile has not been established for both amlodipine and candesartan. Use in early pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

Clodipan is contraindicated during the second and third trimesters of pregnancy due to candesartan content.

Linked to candesartan

The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections

4.3 and 4.4). Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (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 foetal renal function and skull is recommended.

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). 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.

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

Linked to amlodipine

The safety of amlodipine in human pregnancy has not been established.

In animal studies, reproductive toxicity was observed at high doses (see section 5.3).

Breast-feeding

Linked to candesartan/amlodipine

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

Linked to amlodipine

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 – 7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of amlodipine therapy to the mother.

Fertility

Linked to candesartan/amlodipine

No information is available regarding potential effect of candesartan and amlodipine on fertility.

Linked to candesartan

Animal studies have shown that candesartan cilexetil had no adverse effect on fertility in rats (see section 5.3)

Linked to amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

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 candesartan.

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.

Summary of the safety profile

Fixed dose combination

No clinical studies have been performed. Undesirable effects observed for particular active ingredients are described below.

Adverse reactions previously reported with one of the individual components (candesartan or amlodipine) may be potential adverse reactions with Clodipan as well, even if not observed in clinical trials or during the post-marketing period.

Candesartan

Treatment of hypertension

In controlled clinical studies with candesartan for treatment of hypertension 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% higher than the incidence seen with placebo. By this definition, the most commonly reported adverse reactions were dizziness/vertigo, headache and respiratory infection.

Amlodipine

The most commonly reported adverse reactions during treatment were oedema (very common) somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, and fatigue (common).

Tabulated list of adverse reactions

The frequencies used in the tables throughout section 4.8 are:

-        very common (≥ 1/10),

-     common (≥ 1/100 to < 1/10),

-     uncommon (≥ 1/1,000 to < 1/100),

-     rare (≥ 1/10,000 to < 1/1,000)

-     very rare (< 1/10,000),

-     not known (cannot be estimated from the available data).

Candesartan

The Table 1 below presents adverse reactions from clinical trials and post-marketing experience.

Table 1

Laboratory findings

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 candesartan. However, in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.

Amlodipine

Within each frequency grouping, adverse reactions in Table 2 are presented in order of decreasing seriousness.

Table 2

*mostly consistent with cholestasis

To reports any side effect(s):

Saudi Arabia:

Other GCC States:

Symptoms

There is no experience of overdose with the fixed dose combination candesrtan/amlodipine in humans.

Available data suggest that gross overdose of amlodipine could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

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

Treatment

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, sodium chloride 9 mg/ml (0.9%) solution for infusion. Sympathomimetic medicinal products may be administered if the above-mentioned measures are not sufficient.

Candesartan is not removed by haemodialysis.

Clinically significant hypotension due to amlodipine overdose calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output.

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine.

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II antagonists and calcium channel blockers; ATC code: C09DB07

Clodipan combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: an angiotensin II receptor antagonist, candesartan cilexetil and a dihydropyridinic calcium channel blocker, amlodipine.

The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

Candesartan cilexetil

Mechanism of action

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.

Pharmacodynamic effects

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.

Clinical efficacy and safety

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 seriousor 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).

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

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.

Amlodipine

Mechanism of action

Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic burden by the following two actions:

1)  Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.

2)  The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).

Pharmacodynamic effects

In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.

In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1 mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.

Candesartan cilexetil

Absorption and distribution

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 capsule formulation compared with the same oral solution is approximately 34% with very little variability. The estimated absolute bioavailability of the capsule is therefore 14%. The mean peak serum concentration (Cmax) is reached 3-4 hours following capsule 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.

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 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.

Pharmacokinetics in special populations

Elderly (aged 65 years or older)

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 candesartan in young and elderly patients (see section 4.2).

Renal impairment

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 half life (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.

Hepatic 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.

Amlodipine

Absorption and distribution

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64% and 80%.

The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

The bioavailability of amlodipine is not affected by food intake.

Biotransformation and elimination

The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

Pharmacokinetics in special populations

Hepatic impairment

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.

Renal impairment

Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.

Elderly (aged 65 years or older)

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.

Preclinical data available for the components of this fixed dose combination are reported below.

Candesartan

Reproductive toxicty

There was no evidence of 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.

Foetotoxicity has been observed in late pregnancy (see section 4.6).

Carcinogenesis, mutagenesis

Data from in vitro and in vivo mutagenicity studies indicates that candesartan will not exert mutagenic or clastogenic activities under conditions of clinical use.

There was no evidence of carcinogenicity.

Amlodipine Reproductive toxicity

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at doses approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

Impairment of fertility

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10mg on a mg/m² basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

*Based on patient weight of 50 kg

Capsule content

Lactose monohydrate

Maize starch

Carmellose calcium

Macrogol Type 8000

Hydroxypropylcellulose/type: EXF, 250-800 cps

Hydroxypropylcellulose/type: LF, 65-175 cps

Magnesium stearate

Capsule shell (8 mg/5 mg, 8 mg /10 mg)

Quinoline yellow (E 104)

Iron oxide yellow (E 172)

Titanium dioxide (E 171)

Gelatin

Capsule shell (16 mg/5 mg)

Quinoline yellow (E 104)

Titanium dioxide (E 171)

Gelatin

Capsule shell (16 mg/10 mg)

Titanium dioxide (E 171)

Gelatin

Printing ink (8 mg/10 mg, 16 mg/ 5 mg)

Shellac (E904)

Iron oxide black (E172)

Propylene glycol

Ammonia solution, concentrated

Potassium hydroxide

Not applicable.

Do not store above 30 ºC.

PA/Aluminium/PVC/Aluminium blisters in a carton box.

Pack sizes of 28 hard capsules (each blister contains 7 hard capsules).

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