Silardaf

Treatment of essential hypertension in adults.

Treatment of hypertension in children and adolescents aged 6 to <18 years.

Treatment of adult patients with heart failure and impaired left ventricle systolic function (left ventricular ejection fraction ≤ 40%) when ACE-inhibitors are not tolerated or as add-on therapy to ACE-inhibitors in patients with symptomatic heart failure, despite optimal therapy, when mineralocorticoid receptor antagonists are not tolerated.

Hypertension

Silardaf is indicated for the treatment of hypertension in adults and in children 1 to < 17 years of age, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Silardaf may be used alone or in combination with other antihypertensive agents.

Heart Failure

Silardaf is indicated for the treatment of heart failure (NYHA class II-IV) in adults with left ventricular systolic dysfunction (ejection fraction ≤ 40%) to reduce cardiovascular death and to reduce heart failure hospitalizations. Silardaf also has an added effect on these outcomes when used with an ACE inhibitor.

Posology in hypertension

The recommended initial dose and usual maintenance dose of Silardaf is 8 mg once daily.

Most of the antihypertensive effect is attained within 4 weeks. In some patients whose blood pressure is not adequately controlled, the dose can be increased to 16 mg once daily and to a maximum of 32 mg once daily. Therapy should be adjusted according to blood pressure response.

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

Older people

No initial dosage adjustment is necessary in older people.

Patients with intravascular volume depletion

An initial dose of 4 mg may be considered in patients at risk for hypotension, such as patients with possible volume depletion.

Patients with renal impairment

The starting dose is 4 mg in patients with renal impairment, including patients on haemodialysis. 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).

Patients with hepatic impairment

An initial dose of 4 mg once daily is recommended in patients with mild to moderate hepatic impairment. The dose may be adjusted according to response. Silardaf is contraindicated in patients with severe hepatic impairment and/or cholestasis.

Black patients

The antihypertensive effect of candesartan is less pronounced in black patients than in non- black patients. Consequently, uptitration of Silardaf and concomitant therapy may be more frequently needed for blood pressure control in black than non-black patients.

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 some 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 some 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), Silardaf treatment should be initiated under close medical supervision and a lower starting dose than the general starting dose above should be considered.

Silardaf has not been studied in children with glomerular filtration rate less than 30 ml/min/1.73m2.

Black paediatric patients

The antihypertensive effect of candesartan is less pronounced in black patients than in nonblack patients..

Children aged 1 year to <6 years

The safety and efficacy in children aged 1 to <6 years of age has not been established.

Silardaf is contraindicated in children aged below 1 year.

Posology in heart failure

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

Silardaf can be administered with other heart failure treatment, including ACE- inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicinal products. Silardaf may be co-administered with an ACE-inhibitor in patients with symptomatic heart failure despite optimal standard heart failure therapy when mineralocorticoid receptor antagonists are not tolerated. The combination of an ACE- inhibitor, a potassium-sparing diuretic and Silardaf is not recommended and should be considered only after careful evaluation of the potential benefits and risks.

Special patient populations

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

Paediatric population

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

Method of administration

Oral use.

Silardaf should be taken once daily with or without food.

The bioavailability of candesartan is not affected by food.

Adult Hypertension

Dosage must be individualized. Blood pressure response is dose related over the range of 2 to 32 mg. The usual recommended starting dose of Silardaf is 16 mg once daily when it is used as monotherapy in patients who are not volume depleted. Silardaf can be administered once or twice daily with total daily doses ranging from 8 mg to 32 mg. Larger doses do not appear to have a greater effect, and there is relatively little experience with such doses. Most of the antihypertensive effect is present within 2 weeks, and maximal blood pressure reduction is generally obtained within 4 to 6 weeks of treatment with Silardaf.

Use in Hepatic Impairment: Initiate with 8 mg Silardaf in patients with moderate hepatic insufficiency. Dosing recommendations cannot be provided for patients with severe hepatic insufficiency.

Silardaf may be administered with or without food.

If blood pressure is not controlled by Silardaf alone, a diuretic may be added. Silardaf may be administered with other antihypertensive agents.

Pediatric Hypertension 1 To < 17 Years Of Age

Silardaf may be administered once daily or divided into two equal doses. Adjust the dosage according to blood pressure response. For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate Silardaf under close medical supervision and consider administration of a lower dose.

Children 1 to < 6 Years Of Age

The dose range is 0.05 to 0.4 mg/kg per day. The recommended starting dose is 0.20 mg/kg (oral suspension).

Children 6 to < 17 Years Of Age

For those less than 50 kg, the dose range is 2 to 16 mg per day. The recommended starting dose is 4 to 8 mg. For those greater than 50 kg, the dose range is 4 to 32 mg per day. The recommended starting dose is 8 to 16 mg.

Doses above 0.4 mg/kg (1 to < 6 year olds) or 32 mg (6 to < 17 year olds) have not been studied in pediatric patients.

An antihypertensive effect is usually present within 2 weeks, with full effect generally obtained within 4 weeks of treatment with Silardaf.

Children < 1 year of age must not receive Silardaf for hypertension.

All pediatric patients with a glomerular filtration rate less than 30 ml/min/1.73m² should not receive Silardaf since Silardaf has not been studied in this population.

For children who cannot swallow tablets, an oral suspension may be substituted as described below:

Preparation Of Oral Suspension

Silardaf oral suspension can be prepared in concentrations within the range of 0.1 to 2.0 mg/mL. Typically, a concentration of 1 mg/mL will be suitable for the prescribed dose. Any strength of Silardaf tablets can be used in the preparation of the suspension.

Follow the steps below for preparation of the suspension. The number of tablets and volume of vehicle specified below will yield 160 mL of a 1 mg/mL suspension.

• Prepare the vehicle by adding equal volumes of Ora-Plus® (80 mL) and Ora-Sweet SF® (80 mL) or, alternatively, use, ¹Ora-Blend SF® (160 mL).
• Add a small amount of vehicle to the required number of Silardaf tablets (five 32 mg tablets) and grind into a smooth paste using a mortar and pestle.
• Add the paste to a preparation vessel of suitable size.
• Rinse the mortar and pestle clean using the vehicle and add this to the vessel. Repeat, if necessary.
• Prepare the final volume by adding the remaining vehicle.
• Mix thoroughly.
• Dispense into suitably sized amber PET bottles.
• Label with an expiry date of 100 days and include the following instructions:

Store at room temperature (below 30°C/86°F). Use within 30 days after first opening. Do not use after the expiry date stated on the bottle.

Do not freeze.

Shake well before each use.

Adult Heart Failure

The recommended initial dose for treating heart failure is 4 mg once daily. The target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient.

Severe hepatic impairment and/or cholestasis.

Children aged below 1 year.

The concomitant use of Silardaf with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²).

Silardaf is contraindicated in patients who are hypersensitive to candesartan.

Do not co-administer aliskiren with Silardaf in patients with diabetes.

Renal impairment

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

When Silardaf 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 Silardaf 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 Silardaf, 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

hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when Silardaf is used in combination with an ACE-inhibitor. 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 Silardaf 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 Silardaf in patients with a recent kidney transplantation.

Hypotension

Hypotension may occur during treatment with Silardaf 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 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 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 Silardaf is not recommended.

Hyperkalaemia

Concomitant use of Silardaf 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. Silardaf, hyperkalaemia may occur. Periodic monitoring of serum potassium is recommended. The combination of an ACE inhibitor, a potassium-sparing diuretic (e.g. spironolactone) and Silardafis not recommended and should be considered only after careful evaluation of the potential benefits and risks.

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 other medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, 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.

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 angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

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.

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.

Pediatric population

Use in paediatric patients including patients with renal impairment

Candesartan Krka has not been studied in children with a glomerular filtration rate less than 30 ml/min/1.73m².

For children with possible intravascular volume depletion (e.g. patients treated with diuretics, particularly those with impaired renal function), candesartan treatment should be initiated under close medical supervision and a lower starting dose should be considered.

In post-menarche patients the possibility of pregnancy should be evaluated on a regular basis. Appropriate information should be given and/or action taken to prevent the risk of exposure during pregnancy.

This medicinal product contains lactose monohydrate.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure and death. When pregnancy is detected, discontinue Silardaf as soon as possible.

Oral doses ≥ 10 mg of candesartan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring.

The 10-mg/kg/day dose in rats is approximately 2.8 times the maximum recommended daily human dose (MRHD) of 32 mg on a mg/m² basis (comparison assumes human body weight of 50 kg). Candesartan cilexetil given to pregnant rabbits at an oral dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/m² basis) caused maternal toxicity (decreased body weight and death) but, in surviving dams, had no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development. No maternal toxicity or adverse effects on fetal development were observed when oral doses up to 1000 mg of candesartan cilexetil/kg/day (approximately 138 times the MRHD on a mg/m² basis) were administered to pregnant mice.

Morbidity In Infants

Children < 1 year of age must not receive Silardaf for hypertension. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys.

Hypotension

Silardaf can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Patients with symptomatic hypotension may require temporarily reducing the dose of Silardaf, diuretic or both, and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with Silardaf.

In the CHARM program (heart failure patients), hypotension was reported in 18.8% of patients on Silardaf versus 9.8% of patients on placebo. The incidence of hypotension leading to drug discontinuation in Silardaf-treated patients was 4.1% compared with 2.0% in placebo-treated patients. In the CHARM-Added program, where candesartan or placebo was given in addition to ACE inhibitors, hypotension was reported in 22.6% of patients treated with Silardaf versus 13.8% treated with placebo.

Monitoring of blood pressure is recommended during dose escalation and periodically thereafter.

Major Surgery/Anesthesia

Hypotension may occur during major surgery and anesthesia in patients treated with angiotensin II receptor antagonists, including Silardaf, 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.

Impaired Renal Function

Monitor renal function periodically in patients treated with Silardaf. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend, in part, on the activity of the renin-angiotensin system (e.g., patient with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia or acute renal failure when treated with Silardaf. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Silardaf.

In the CHARM program (heart failure patients), the incidence of abnormal renal function (e.g., creatinine increase) was 12.5% in patients treated with Silardaf versus 6.3% in patients treated with placebo. The incidence of abnormal renal function (e.g., creatinine increase) leading to drug discontinuation in Silardaf-treated patients was 6.3% compared with 2.9% in placebo-treated patients. In the CHARM-Added program, where candesartan or placebo was given in addition to ACE inhibitors, the incidence of abnormal renal function (e.g., creatinine increase) was 15% in patients treated with Silardaf versus 9% in patients treated with placebo.

Hyperkalemia

Drugs that inhibit the renin-angiotensin system can cause hyperkalemia.

Concomitant use of Silardaf with drugs that increase potassium levels may increase the risk of hyperkalemia.

Monitor serum potassium periodically.

In the CHARM program (heart failure patients), the incidence of hyperkalemia was 6.3% in patients treated with Silardaf versus 2.1% in patients treated with placebo. The incidence of hyperkalemia leading to drug discontinuation in Silardaf-treated patients was 2.4% compared with 0.6% in placebo-treated patients. In the CHARM-Added program where candesartan or placebo was given in addition to ACE inhibitors, the incidence of hyperkalemia was 9.5% in patients treated with Silardaf versus 3.5% in patients treated with placebo.

Patient Counseling Information

Advise patient to read FDA-approved patient labeling (PATIENT INFORMATION).

Pregnancy

Advise female patients of childbearing age should be told about the consequences of exposure to Silardaf during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage, whereas mice received the drug by dietary administration. These (maximally-tolerated) doses of candesartan cilexetil provided systemic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg).

Candesartan and its O-deethyl metabolite tested positive for genotoxicity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. Candesartan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. Candesartan cilexetil was evaluated in the Ames test, the in vitro mouse lymphoma cell and rat hepatocyte unscheduled DNA synthesis assays and the in vivo mouse micronucleus test, in each case with negative results. Candesartan cilexetil was not evaluated in the CHL chromosomal aberration or CHO gene mutation assay.

Fertility and reproductive performance were not affected in studies with male and female rats given oral doses of up to 300 mg/kg/day (83 times the maximum daily human dose of 32 mg on a body surface area basis).

Use In Specific Populations

Pregnancy

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Silardaf as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Silardaf, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Silardaf for hypotension, oliguria, and hyperkalemia.

Labor And Delivery

The effect of Silardaf on labor and delivery in humans is unknown.

Nursing Mothers

It is not known whether candesartan is excreted in human milk, but candesartan has been shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue Silardaf, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to Silardaf

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

The antihypertensive effects of Silardaf were evaluated in hypertensive children 1 to < 17 years of age in randomized, double-blind clinical studies. The pharmacokinetics of Silardaf have been evaluated in pediatric patients 1 to < 17 years of age.

Children < 1 year of age must not receive Silardaf for hypertension.

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 Silardaf (3.1%) and placebo (3.2%).

In a pooled analysis of clinical trial data of hypertensive patients, the following adverse reactions with Silardaf were defined based on an incidence of adverse events with Silardaf 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.

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

The frequencies used in the tables throughout this section 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)

Laboratory findings

In general, there were no clinically important influences of Silardaf 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 Silardaf. However, in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.

Paediatric population

The safety of Silardaf was monitored in 255 hypertensive children and adolescents, aged 6 to <18 years old, during a 4 week clinical efficacy study and a 1 year open label study. In nearly all different system organ classes, the frequency of adverse events in children are within common/uncommon range. Whilst the nature and severity of the adverse events are similar to those in adults (see the table above), the frequency of all adverse events are higher in children and adolescent, particularly in:

- Headache, dizziness and upper respiratory tract infection, are “very common” (ie, >1/10) in children and common (> 1/100 to < 1/10) in adults.

- Cough is “very common” (ie, > 1/10) in children and very rare (<1/10,000) in adults.

- Rash is “common” (ie, >1/100 to <1/10) in children and “very rare” (<1/10,000) in adults.

- Hyperkalemia, hyponatraemia and abnormal liver function are uncommon (> 1/1,000 to < 1/100) in children and very rare (< 1/10,000) in adults.

- Sinus arrhythmia, Nasopharyngitis, pyrexia are “common” (ie, >1/100 to <1/10) and oropharyngeal pain is “very common” (ie, >1/10) in children; but none are reported in adults. However these are temporary and widespread childhood illnesses.

The overall safety profile for Silardaf in paediatric patients does not differ significantly from the safety profile in adults.

Treatment of heart failure

The adverse experience profile of Silardaf 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 Silardaf in doses up to 32 mg (n=3,803) to placebo (n=3,796), 21.0% of the Silardaf 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 Silardaffor the indication of heart failure. Periodic monitoring of serum creatinine and potassium is recommended.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adult Hypertension

Silardaf has been evaluated for safety in more than 3600 patients/subjects, including more than 3200 patients treated for hypertension. About 600 of these patients were studied for at least 6 months and about 200 for at least 1 year. In general, treatment with Silardaf was well tolerated. The overall incidence of adverse events reported with Silardaf was similar to placebo.

The rate of withdrawals due to adverse events in all trials in patients (7510 total) was 3.3% (i.e., 108 of 3260) of patients treated with Silardaf as monotherapy and 3.5% (i.e., 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (i.e., 57 of 2350) of patients treated with Silardaf and 3.4% (i.e., 35 of 1027) of patients treated with placebo.

The most common reasons for discontinuation of therapy with Silardaf were headache (0.6%) and dizziness (0.3%).

The adverse events that occurred in placebo-controlled clinical trials in at least 1% of patients treated with Silardaf and at a higher incidence in candesartan cilexetil (n = 2350) than placebo (n = 1027) patients included back pain (3% vs. 2%), dizziness (4% vs. 3%), upper respiratory tract infection (6% vs. 4%), pharyngitis (2% vs. 1%), and rhinitis (2% vs. 1%).

Pediatric Hypertension

Among children in clinical studies, 1 in 93 children age 1 to < 6 and 3 in 240 age 6 to < 17 experienced worsening renal disease. The association between candesartan and exacerbation of the underlying condition could not be excluded.

Heart Failure

The adverse event profile of Silardaf in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM program, comparing Silardaf in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued Silardaf for adverse events vs. 16.1% of placebo patients.

Postmarketing Experience

The following adverse reactions were identified during post-approval use of Silardaf. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following have been very rarely reported in post-marketing experience:

Digestive: Abnormal hepatic function and hepatitis.

Hematologic: Neutropenia, leukopenia, and agranulocytosis.

Immunologic: Angioedema

Metabolic and Nutritional Disorders: Hyperkalemia, hyponatremia.

Respiratory system disorders: Cough

Skin and Appendages Disorders: Pruritus, rash and urticaria.

Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

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 Silardaf), 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.

No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg.

The most likely manifestation of overdosage with Silardaf would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Candesartan cannot be removed by hemodialysis.

Treatment: To obtain up-to-date information about the treatment of overdose, consult your Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics in your patient.

Pharmacotherapeutic group: Angiotensin II antagonists, plain, ATC code: C09CA06.

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.

Pharmacodynamic effects

Silardaf 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 Silardaf. 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 serious or exaggerated first dose hypotension or rebound effect after cessation of treatment.

After administration of a single dose of Silardaf, 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. Silardaf 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 Silardaf 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 Silardaf is used together with hydrochlorothiazide, the reduction in blood pressure is additive. An increased antihypertensive effect is also seen when Silardaf 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 Silardaf reduced urinary albumin excretion (albumin/creatinine ratio, mean 30%, 95%CI 15-42%). There are currently no data on the effect of candesartan on the progression to diabetic nephropathy.

The effects of Silardaf 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 Silardaf 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 149/82mmHg 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).

Paediatric population - hypertension

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 Silardaf 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 Silardaf. 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 Silardaf in a ratio of 1: 2: 2: 2. For children who weighed < 50 kg, the doses of Silardaf were 2, 8, or 16 mg once daily. In children who weighed > 50 kg, the Silardaf 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.

Heart failure

Treatment with Silardaf 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 Silardaf (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 Silardaf (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 0.67-0.89, 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% CI0.70-0.92, 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 Silardaf 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 0.75-0.96, 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 0.78-0.98, 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 Silardaf 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 0.77-1.03, 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 0.79-0.98, p=0.018) and all three studies HR 0.91 (95%CI 0.83-1.00, 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.

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.

Candesartan inhibits the pressor effects of angiotensin II infusion in a dose-dependent manner. After 1 week of once daily dosing with 8 mg of candesartan cilexetil, the pressor effect was inhibited by approximately 90% at peak with approximately 50% inhibition persisting for 24 hours.

Plasma concentrations of angiotensin I and angiotensin II, and plasma renin activity (PRA), increased in a dose-dependent manner after single and repeated administration of candesartan cilexetil to healthy subjects, hypertensive, and heart failure patients. ACE activity was not altered in healthy subjects after repeated candesartan cilexetil administration. The once-daily administration of up to 16 mg of candesartan cilexetil to healthy subjects did not influence plasma aldosterone concentrations, but a decrease in the plasma concentration of aldosterone was observed when 32 mg of candesartan cilexetil was administered to hypertensive patients. In spite of the effect of candesartan cilexetil on aldosterone secretion, very little effect on serum potassium was observed.

Hypertension

Adults

In multiple-dose studies with hypertensive patients, there were no clinically significant changes in metabolic function, including serum levels of total cholesterol, triglycerides, glucose, or uric acid. In a 12-week study of 161 patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension, there was no change in the level of HbA1c.

Heart Failure

In heart failure patients, candesartan ≥ 8 mg resulted in decreases in systemic vascular resistance and pulmonary capillary wedge pressure.

Absorption and distribution

Following oral administration, Silardaf is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of Silardaf. 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 (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 0.1 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 Silardaf, 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 Silardaf in young and elderly patients.

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 t_1/2 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 t_1/2 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 candesartan of approximately 20% in one study and 80% in the other study. 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 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. 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 Silardaf have not been investigated in paediatric patients <1 year of age.

Distribution

The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins ( > 99%) and does not penetrate red blood cells. The protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that candesartan crosses the blood-brain barrier poorly, if at all. It has also been demonstrated in rats that candesartan passes across the placental barrier and is distributed in the fetus.

Metabolism and Excretion

Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.

Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of ¹⁴C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of ¹⁴C-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of candesartan.

Adults

Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT1 subtype angiotensin II receptor antagonist. Candesartan is mainly excreted unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. The elimination half-life of candesartan is approximately 9 hours. After single and repeated administration, the pharmacokinetics of candesartan are linear for oral doses up to 32 mg of candesartan cilexetil. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing.

Following administration of candesartan cilexetil, the absolute bioavailability of candesartan was estimated to be 15%. After tablet ingestion, the peak serum concentration (Cmax) is reached after 3 to 4 hours. Food with a high fat content does not affect the bioavailability of candesartan after candesartan cilexetil administration.

Pediatrics

In children 1 to 17 years of age, plasma levels are greater than 10–fold higher at peak (approximately 4 hours) than 24 hours after a single dose.

Children 1 to < 6 years of age, given 0.2 mg/kg had exposure similar to adults given 8 mg.

Children > 6 years of age had exposure similar to adults given the same dose.

The pharmacokinetics (Cmax and AUC) were not modified by age, sex or body weight.

Candesartan cilexetil pharmacokinetics have not been investigated in pediatric patients less than 1 year of age.

From the dose-ranging studies of candesartan cilexetil, there was a dose related increase in plasma candesartan concentrations.

The renin-angiotensin system (RAS) plays a critical role in kidney development. RAS blockade has been shown to lead to abnormal kidney development in very young mice. Children < 1 year of age must not receive Silardaf. Administering drugs that act directly on the renin-angiotensin system (RAS) can alter normal renal development.

Geriatric and Sex

The pharmacokinetics of candesartan have been studied in the elderly ( ≥ 65 years) and in both sexes. The plasma concentration of candesartan was higher in the elderly (Cmax was approximately 50% higher, and AUC was approximately 80% higher) compared to younger subjects administered the same dose. The pharmacokinetics of candesartan were linear in the elderly, and candesartan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration. No initial dosage adjustment is necessary. There is no difference in the pharmacokinetics of candesartan between male and female subjects.

Renal Insufficiency

In hypertensive patients with renal insufficiency, serum concentrations of candesartan were elevated. After repeated dosing, the AUC and Cmax were approximately doubled in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73m²) compared to patients with normal kidney function. The pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. Candesartan cannot be removed by hemodialysis. No initial dosage adjustment is necessary in patients with renal insufficiency.

In heart failure patients with renal impairment, AUC0-72h was 36% and 65% higher in mild and moderate renal impairment, respectively. Cmax was 15% and 55% higher in mild and moderate renal impairment, respectively.

Pediatrics

Silardaf pharmacokinetics have not been determined in children with renal insufficiency.

Hepatic Insufficiency

The pharmacokinetics of candesartan were compared in patients with mild and moderate hepatic impairment to matched healthy volunteers following a single oral dose of 16 mg candesartan cilexetil. The increase in AUC for candesartan was 30% in patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with moderate hepatic impairment (Child-Pugh B). The increase in Cmax for candesartan was 56% in patients with mild hepatic impairment and 73% in patients with moderate hepatic impairment. The pharmacokinetics after candesartan cilexetil administration have not been investigated in patients with severe hepatic impairment. No initial dosage adjustment is necessary in patients with mild hepatic impairment. In hypertensive patients with moderate hepatic impairment, consideration should be given to initiation of Silardaf at a lower dose.

Heart Failure

The pharmacokinetics of candesartan were linear in patients with heart failure (NYHA class II and III) after candesartan cilexetil doses of 4, 8, and 16 mg. After repeated dosing, the AUC was approximately doubled in these patients compared with healthy, younger patients. The pharmacokinetics in heart failure patients is similar to that in healthy elderly volunteers.