Ranacand

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Ranacand, 8 mg, tablets
Ranacand, 16 mg, tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 8 mg of candesartan cilexetil.
Each tablet contains 16 mg of candesartan cilexetil.
Excipient with known effect:
8 mg: Each tablet contains 75.8 mg of monohydrate lactose.
16 mg: Each tablet contains 151.5 mg of monohydrate lactose.
For a complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet
8 mg: Pink, marbled tablet, capsule-shaped, approximately 9.1 mm in length and 4.6 mm in width, with embossed marking "C" and "10" on both sides of the break line on one side, and a break line on the other side.
The tablet can be divided into halves.
16 mg: Pink, marbled tablet, capsule-shaped, approximately 11.7 mm in length and 5.1 mm in width, with embossed marking "C" and "11" on both sides of the break line on one side, and a break line on the other side.
The tablet can be divided into halves.

4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Ranacand is indicated:

• For the treatment of primary essential hypertension in adults.
• For the treatment of hypertension in children and adolescents aged 6 to <18 years.
• For the treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤40%), when ACE inhibitors are not tolerated, or as an add-on to ACE inhibitor therapy in patients with persistent symptoms of heart failure despite optimal treatment, when mineralocorticoid receptor antagonists are not tolerated (see sections 4.3, 4.4, 4.5 and 5.1).

4.2 Dosage and Administration

Dosage in Hypertension
The recommended starting dose and usual maintenance dose is 8 mg once daily.
Full antihypertensive effect is achieved within 4 weeks after initiation of treatment. If blood
pressure is not adequately controlled with the 8 mg dose, the dose should be increased to 16 mg
once daily, or up to the maximum dose of 32 mg once daily. Treatment should be adjusted based
on blood pressure response. The medicinal product Ranacand may be used concomitantly with
other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1).
An additional reduction in blood pressure has been observed when hydrochlorothiazide is used
concomitantly with any dose of the medicinal product Ranacand.

Elderly patients
No initial dosage adjustment is necessary in elderly patients.

Use in patients with reduced intravascular volume
In patients at risk of hypotension, such as those in whom reduced intravascular volume is likely,
treatment should be initiated with a dose of 4 mg (see section 4.4).

Use in patients with renal impairment
The initial dose in patients with renal impairment, including those undergoing hemodialysis, is 4 mg.
The dose should be increased according to the patient's response to treatment.
Data in patients with severe or end-stage renal impairment (creatinine clearance < 15 ml/min) are limited (see section 4.4).

Use in patients with hepatic impairment
In patients with mild to moderate hepatic impairment, the recommended starting dose is 4 mg once daily. The dose should be adjusted according to the patient's response to treatment.
The medicinal product Ranacand must not be used in patients with severe hepatic impairment and (or) cholestasis (see sections 4.3 and 5.2).

Use in black patients
The antihypertensive effect of candesartan is weaker in black patients than in patients of other races. Therefore, in black patients, dose escalation of the medicinal product Ranacand and/or concomitant combination therapy may be required more frequently than in patients of other races to achieve blood pressure control (see section 5.1).

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

• Patients with body weight <50 kg: in patients with inadequate blood pressure control, the dose may be increased up to a maximum of 8 mg once daily.
• Patients with body weight ≥50 kg: in patients with inadequate blood pressure control, the dose may be increased to 8 mg once daily, and then to 16 mg once daily, if necessary (see section 5.1). Doses higher than 32 mg have not been studied in children and adolescents.

Most of the blood pressure-lowering effect is achieved within 4 weeks.
In children with possible reduced blood volume (e.g., patients receiving diuretics, particularly those with renal impairment), treatment with the medicinal product Ranacand should be initiated under strict medical supervision, and a lower starting dose than that stated above should be considered (see section 4.4).
Studies on the use of the medicinal product Ranacand in children with glomerular filtration rate below 30 ml/min/1.73 m² have not been conducted (see section 4.4).

Black children and adolescents
The antihypertensive effect of candesartan is weaker in black patients than in patients of other races (see section 5.1).

Children aged below 1 year to <6 years

• The safety and efficacy of the medicinal product in children aged 1 to <6 years have not been established. Currently available data are described in section 5.1, but no dosage recommendations can be made.
• The use of the medicinal product Ranacand in children below 1 year of age is contraindicated (see section 4.3).

Dosage in Heart Failure
The usual recommended starting dose of the medicinal product Ranacand is 4 mg once daily.
This dose may be increased to the target dose of 32 mg once daily (maximum dose) or to the highest tolerated dose by doubling the dose at intervals of at least 2 weeks (see section 4.4). Assessment of the patient with heart failure should also include evaluation of renal function, including monitoring of serum potassium and creatinine levels.
The medicinal product Ranacand may be used concomitantly with other drugs used in the treatment of heart failure, including in combination with ACE inhibitors, β-blockers, diuretics and digitalis glycosides, or with combinations of these medicinal products. Ranacand may be administered in combination with an ACE inhibitor in patients with persistent symptoms of heart failure despite optimal standard heart failure therapy, when mineralocorticoid receptor antagonists are not tolerated. Concomitant use of ACE inhibitors, potassium-sparing diuretics (e.g., spironolactone) and the medicinal product Ranacand is not recommended. Concomitant administration of the above-mentioned drugs should be preceded by a thorough assessment of the potential benefits and risks for the patient (see sections 4.4, 4.8 and 5.1).

Special patient groups
No initial dose adjustment is necessary in elderly patients or in patients with reduced intravascular volume, renal impairment, or mild to moderate hepatic impairment.

Children and adolescents
The safety and efficacy of the medicinal product in the treatment of heart failure in children and adolescents under 18 years of age have not been established. Data are not available.

Administration
Oral administration.
The medicinal product Ranacand should be taken once daily, regardless of meals.
Food does not affect the bioavailability of candesartan cilexetil.

4.3 Contraindications

• Hypersensitivity to candesartan cilexetil or to any of the excipients listed in section 6.1.
• Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
• Severe hepatic impairment and (or) cholestasis.
• Children under 1 year of age (see section 5.3).
• Concomitant use of the medicinal product Ranacand with products containing aliskiren is contraindicated in patients with diabetes or renal impairment (glomerular filtration rate, GFR <60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
Evidence indicates that concomitant use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or aliskiren increases the risk of hypotension, hyperkalaemia, and renal impairment (including acute kidney injury). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin receptor blockers, or aliskiren is not recommended (see sections 4.5 and 5.1).
If dual blockade of the RAAS is considered absolutely necessary, it should be performed under specialist supervision only, with close monitoring of vital parameters such as renal function, electrolyte levels, and blood pressure.
Concomitant use of ACE inhibitors and angiotensin receptor blockers is not recommended in patients with diabetic nephropathy.

Intestinal angioedema
Cases of intestinal angioedema have been reported in patients treated with angiotensin receptor blockers, including candesartan (see section 4.8). These patients experienced abdominal pain, nausea, vomiting, and diarrhoea. Symptoms resolved after discontinuation of angiotensin receptor blockers. If intestinal angioedema is diagnosed, treatment with candesartan should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Renal impairment
As with other inhibitors of the renin-angiotensin-aldosterone system, changes in renal function may be expected during treatment with Ranacand in susceptible patients.
When using Ranacand in patients with hypertension and impaired renal function, periodic monitoring of serum potassium and creatinine concentrations is recommended.
Data on the use of Ranacand in patients with severe or end-stage renal impairment (creatinine clearance < 15 ml/min) are limited. In these patients, the dose of Ranacand should be increased cautiously with simultaneous monitoring of blood pressure.
Patients with heart failure should be monitored periodically for renal function, particularly in those aged 75 years or older and in patients with impaired renal function. Monitoring of serum creatinine and potassium levels is recommended when increasing the dose of Ranacand. Clinical trials in heart failure did not include patients with serum creatinine > 265 μmol/l (>3 mg/dl).

Use in children and adolescents, including those with impaired renal function
The use of Ranacand in children with a glomerular filtration rate below 30 ml/min/1.73 m² has not been studied (see section 4.2).

Combination therapy with ACE inhibitors in heart failure
The risk of adverse effects, particularly hypotension, hyperkalaemia, and worsening renal function (including acute renal failure), may increase when Ranacand is used concomitantly with an ACE inhibitor.
Triple combination therapy with an ACE inhibitor, a mineralocorticoid receptor antagonist, and candesartan is also not recommended. Such combinations should be used under specialist supervision with close monitoring of renal function, electrolyte levels, and blood pressure.
Concomitant use of ACE inhibitors and angiotensin receptor blockers is not recommended in patients with diabetic nephropathy.

Haemodialysis
During dialysis, blockade of AT receptors may lead to significant blood pressure changes due to reduced plasma volume and increased activity of the renin-angiotensin-aldosterone system. Therefore, in haemodialysed patients, the dose of Ranacand should be increased cautiously with simultaneous monitoring of blood pressure.

Renal artery stenosis
In patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney, other medicinal products affecting the renin-angiotensin-aldosterone system, such as angiotensin receptor blockers, may increase serum urea and creatinine levels.

Kidney transplantation
Clinical data on the use of Ranacand in patients after kidney transplantation are limited.

Hypotension
Hypotension may occur during treatment with Ranacand in patients with heart failure. Hypotension may also occur in hypertensive patients with reduced intravascular volume, e.g., patients receiving high doses of diuretics. Caution should be exercised when initiating treatment, and hypovolaemia should be corrected.
In children with potential reduction in circulating blood volume (e.g., patients treated with diuretics, particularly those with impaired renal function), treatment should be initiated under strict medical supervision, and consideration should be given to using a lower starting dose (see section 4.2).

Anaesthesia and surgical procedures
In patients treated with angiotensin receptor blockers, arterial hypotension may occur during anaesthesia and surgical procedures due to inhibition of the renin-angiotensin-aldosterone system. In rare cases, hypotension may be severe and may require intravenous fluids and/or vasoconstrictor drugs.

Aortic and mitral valve stenosis (hypertrophic cardiomyopathy with left ventricular outflow tract obstruction)
Particular caution is required in patients with hemodynamically significant aortic or mitral valve stenosis or hypertrophic cardiomyopathy with left ventricular outflow tract obstruction.

Primary hyperaldosteronism
Patients with primary hyperaldosteronism are generally unresponsive to antihypertensive medicinal products acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of Ranacand is not recommended in such cases.

Hyperkalaemia
Based on experience with other medicinal products affecting the renin-angiotensin-aldosterone system, concomitant use of Ranacand with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin, cotrimoxazole also known as trimethoprim/sulfamethoxazole) may lead to increased serum potassium levels in patients with hypertension. Serum potassium levels should be monitored.
Hyperkalaemia may occur in patients with heart failure treated with Ranacand. Periodic monitoring of serum potassium levels is recommended. Combination of ACE inhibitors, potassium-sparing diuretics (e.g., spironolactone), and Ranacand is not recommended. Concomitant use of these agents should be preceded by a thorough assessment of potential benefits and risks for the individual patient.

General
In patients in whom vascular tone and renal function are highly dependent on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal disease as the underlying condition, including renal artery stenosis), treatment with other medicinal products affecting this system may lead to acute hypotension, azotaemia, oliguria, or, less frequently, acute renal failure. Similar effects cannot be excluded during treatment with angiotensin receptor blockers. As with other antihypertensive agents, excessive reduction of blood pressure in patients with ischaemic heart disease or cerebrovascular disease may result in myocardial infarction or stroke.
The antihypertensive effect of candesartan may be enhanced by concomitant use of other antihypertensive agents, regardless of whether the agent is prescribed for blood pressure reduction or its use is indicated for other reasons.

Pregnancy
Treatment with angiotensin II receptor antagonists (AIIRA) should not be initiated during pregnancy. If continuation of AIIRA treatment is not considered necessary, women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. Upon confirmation of pregnancy, AIIRA treatment must be discontinued immediately and, if appropriate, alternative therapy initiated (see sections 4.3 and 4.6).
Women of childbearing potential should be regularly assessed for the possibility of pregnancy. Adequate information should be provided to the patient and/or appropriate measures taken to prevent exposure to the medicinal product during pregnancy (see sections 4.3 and 4.6).

Excipients
The medicinal product contains lactose. It should not be used in patients with rare hereditary problems of galactose intolerance, Lapp-type lactase deficiency, or glucose-galactose malabsorption (see section 6.1).

4.5 Interactions with other medicinal products and other forms of interactions

Pharmacokinetic clinical studies have been conducted with the following compounds:
hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol /
levonorgestrel), glibenclamide, nifedipine, and enalapril. No clinically significant interactions were observed.

When potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products increasing potassium levels (e.g. heparins) are used concomitantly, serum potassium levels should be monitored (see section 4.4).

Transient increases in serum lithium concentrations and symptoms of lithium toxicity have been observed during concomitant use of lithium and ACE inhibitors. A similar effect may occur with concomitant use of angiotensin II receptor antagonists. Candesartan is not recommended to be used with lithium. If combination therapy with lithium is necessary, monitoring of serum lithium concentrations is recommended.

When angiotensin II receptor antagonists are used concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDs), attenuation of antihypertensive effect may occur.

As with ACE inhibitors, concomitant use of angiotensin II receptor antagonists and NSAIDs may lead to increased risk of deterioration in renal function, including possible acute renal failure, and increased serum potassium concentration, particularly in patients with pre-existing impaired renal function. Caution should be exercised when administering these drugs concomitantly, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored after initiating combination therapy, followed by periodic monitoring.

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS), through concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren, is associated with a higher frequency of adverse events such as hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to monotherapy with a single RAAS-acting agent (see sections 4.3, 4.4, and 5.1).

Children and adolescents
Interaction studies have been performed only in adult patients.

4.6 Pregnancy and lactation

Pregnancy
The use of angiotensin II receptor antagonists (AIIRA) is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological study results regarding the risk of teratogenic effects following the use of ACE inhibitors during the first trimester of pregnancy have been inconclusive; however, a small increased risk cannot be ruled out. Although controlled epidemiological data on the risk associated with the use of angiotensin II receptor antagonists (AIIRA) are unavailable, a similar risk may exist for this class of medicinal products. If antihypertensive treatment with angiotensin II receptor antagonists is not considered essential, patients planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. Upon confirmation of pregnancy, treatment with AIIRA should be discontinued immediately and, if appropriate, alternative treatment should be initiated.
It is known that the use of AIIRA during the second and third trimesters of pregnancy has toxic effects on the human fetus (renal dysfunction, oligohydramnios, delayed skull ossification) and on newborns (renal failure, hypotension, hyperkalemia) (see section 5.3).
If AIIRA are used from the second trimester of pregnancy onwards, ultrasonographic examination to monitor renal function and skull development is recommended.
Infants whose mothers have taken AIIRA should be carefully monitored for the development of hypotension (see sections 4.3 and 4.4).

Breast-feeding
Due to the lack of available data on the use of candesartan during breast-feeding, candesartan is not recommended. It is preferable to use therapies with better-established safety profiles during breast-feeding, especially when nursing newborns or preterm infants.

4.7 Effects on the ability to drive and use machines

Studies on the effect on the ability to drive and operate machinery have not been conducted.
However, the possibility of dizziness or fatigue occurring during candesartan treatment should be taken into account.

4.8 Undesirable effects

Hypertension treatment
Adverse effects observed in controlled clinical trials were mild and transient. The overall incidence of adverse events showed no dependence on dose or patient age. The frequency of discontinuation due to adverse events was similar for candesartan cilexetil (3.1%) and placebo (3.2%).
In the analysis of data collected from clinical trials in hypertensive patients, adverse events considered to be related to candesartan cilexetil treatment were defined as those occurring at least 1% more frequently than with placebo. According to this definition, the most commonly occurring adverse events were dizziness and headache, as well as respiratory tract infections.
Below is a summary of adverse events collected based on clinical trials and post-marketing experience.
The frequency of adverse events in all tables in section 4.8 has been classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (frequency cannot be estimated from the available data).

Laboratory findings
Generally, no clinically significant effect of the medicinal product Ranacand on the results of routine laboratory tests has been observed. As with other drugs inhibiting the renin-angiotensin-aldosterone system, a slight decrease in hemoglobin concentration has been observed. Routine laboratory monitoring is usually not required in patients treated with Ranacand. However, in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.

Children and adolescents
The safety of candesartan cilexetil has been evaluated in 255 children and adolescents with arterial hypertension aged 6 to <18 years in a 4-week efficacy study and a one-year open-label study (see section 5.1). The frequency of adverse reactions within nearly all body systems and organs falls within the range of "common" to "uncommon". While the nature and severity of adverse events are similar to those observed in adult patients (see table above), the frequency of all adverse reactions is higher in children and adolescents, particularly for:

• Headache, dizziness, upper respiratory tract infection occurring "very commonly" (≥1/10 patients) in children and "commonly" (≥1/100 to <1/10 patients) in adults.
• Cough occurring "very commonly" (≥1/10 patients) in children and "very rare" (<1/10,000 patients) in adults.
• Rash occurring "commonly" (≥1/100 to <1/10 patients) in children and "very rare" (<1/10,000 patients) in adults.
• Hyperkalemia, hyponatremia, and abnormal liver function occurring "uncommonly" (≥1/1,000 to <1/100 patients) in children and "very rare" (<1/10,000 patients) in adults.
• Sinus arrhythmia, nasopharyngitis, fever occurring "commonly" (≥1/100 to <1/10 patients), and oral cavity and throat pain occurring "very commonly" (≥1/10 patients) in children, but not reported in adults. However, these are transient phenomena and very common in children.

The overall safety profile of candesartan cilexetil in children and adolescents does not differ significantly from that in adult patients.

Heart failure treatment
The adverse reaction profile of candesartan in adult patients with heart failure is consistent with the pharmacological properties of the drug and the underlying medical condition. In the CHARM clinical trial comparing candesartan cilexetil up to 32 mg (n = 3803) with placebo (n = 3796), treatment was discontinued due to adverse reactions in 21.0% of patients receiving candesartan cilexetil and 16.1% of those receiving placebo. The most frequently reported adverse reactions were hyperkalemia, hypotension, and renal dysfunction. These occurred more frequently in patients aged 70 years and older, in diabetic patients, and in patients receiving other medicinal products acting on the renin-angiotensin-aldosterone system, particularly ACE inhibitors and (or) spironolactone.
Below is a summary of adverse reactions collected from clinical trials and post-marketing experience.

Laboratory test results
Hyperkalemia and renal dysfunction are commonly observed in patients treated with the medicinal product Ranacand for heart failure. Periodic monitoring of serum creatinine and potassium levels is recommended (see section 4.4).

Reporting suspected adverse reactions
After marketing authorization of the medicinal product, it is important to report suspected adverse reactions. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the Department of Monitoring of Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl .
Adverse reactions may also be reported to the marketing authorization holder.

4.9 Overdose

Symptoms
Based on pharmacological data, it can be inferred that the main symptoms of overdose are symptomatic hypotension and dizziness. Isolated cases of overdose (up to 672 mg of candesartan cilexetil) have been reported, in which adult patients recovered without complications.

Management
In the event of symptomatic hypotension, symptomatic treatment should be initiated and vital functions monitored. The patient should be placed in a supine position with legs elevated. If this is insufficient, plasma volume should be increased by intravenous infusion, e.g. with isotonic saline solution. If this measure is ineffective, sympathomimetic drugs may be administered.
Candesartan is not removed by hemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action
Angiotensin II is the primary hormone of the renin-angiotensin-aldosterone system acting on blood vessels and plays a key role in the pathophysiology of arterial hypertension, heart failure, and other cardiovascular diseases. It also plays an important role in the pathogenesis of end-organ hypertrophy and damage. The main physiological effects of angiotensin II, such as vasoconstriction, stimulation of aldosterone secretion, regulation of water-electrolyte balance, and stimulation of cell growth, are mediated via the type 1 receptor (AT\textsubscript{1}).

Pharmacodynamic action
Candesartan cilexetil is a prodrug suitable for oral administration. During absorption from the gastrointestinal tract, it is rapidly hydrolyzed to its active form, candesartan. Candesartan is a selective antagonist of angiotensin II receptors acting on AT\textsubscript{1} receptors, characterized by strong receptor binding and slow dissociation from this binding. It has no agonistic activity.

Candesartan does not inhibit ACE activity, which converts angiotensin I into angiotensin II and degrades bradykinin. Candesartan does not affect ACE activity and does not potentiate the effects of bradykinin or substance P. Controlled clinical trials comparing candesartan with ACE inhibitors have shown a lower incidence of cough in patients taking candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation. Antagonistic action at angiotensin II (AT\textsubscript{1}) receptors leads to dose-dependent increases in plasma renin, angiotensin I, and angiotensin II concentrations, and a decrease in plasma aldosterone concentration.

Clinical efficacy and safety of use

Arterial hypertension
In arterial hypertension, candesartan produces dose-dependent, long-lasting reduction in blood pressure. The antihypertensive effect results from reduced total peripheral resistance without reflex tachycardia. There are no reports of significant or marked hypotension after the first dose or a "rebound" effect upon discontinuation of treatment.

After administration of a single dose of candesartan cilexetil, antihypertensive effects usually occur within 2 hours. During long-term treatment, the full antihypertensive effect at any dose is usually achieved within four weeks and maintained during prolonged therapy. Results of a meta-analysis showed that the average increase in efficacy after increasing the dose from 16 mg to 32 mg once daily was minimal. However, considering inter-individual differences, greater than average efficacy may be expected in some patients. Once-daily administration of candesartan cilexetil provides effective and smooth blood pressure reduction maintained for over 24 hours, with a small difference between maximum and minimum effects between consecutive doses.

The antihypertensive effect and tolerability of candesartan and losartan were compared in two randomized, double-blind trials involving 1268 patients with mild to moderate arterial hypertension. The maximum reduction in blood pressure was 13.1/10.5 mmHg (systolic/diastolic) with candesartan cilexetil 32 mg once daily and 10.0/8.7 mmHg with potassium losartan 100 mg once daily (difference in blood pressure reduction was 3.1/1.8 mmHg, p<0.0001/p<0.0001).

The antihypertensive effects of candesartan cilexetil and hydrochlorothiazide are additive when used concomitantly. Enhanced antihypertensive effect is also achieved when candesartan cilexetil is used concomitantly with amlodipine or felodipine.

The antihypertensive effect of drugs inhibiting the renin-angiotensin-aldosterone system is weaker in black patients (who generally have lower plasma renin activity) compared to patients of other races. This also applies to candesartan. In an open-label clinical trial involving 5156 patients with elevated diastolic blood pressure, the reduction in blood pressure during treatment with candesartan was significantly smaller in black patients than in patients of other races (14.4/10.3 mmHg vs. 19.0/12.7 mmHg, p<0.0001/p<0.0001).

Candesartan increases renal blood flow without affecting or increasing glomerular filtration coefficient, while decreasing renal vascular resistance and filtration fraction. In a 3-month clinical trial in patients with arterial hypertension and type 2 diabetes with microalbuminuria, treatment with candesartan cilexetil reduced urinary albumin excretion (albumin-to-creatinine clearance ratio, mean reduction 30%, 95% confidence interval 15–42%). Currently, there are no data on the effect of candesartan on the development of diabetic nephropathy.

In the randomized clinical trial Study on Cognition and Prognosis in the Elderly, lasting a mean of 3.7 years and involving 4937 patients with mild to moderate arterial hypertension (aged 70–89 years; 21% aged 80 years or older), the effect of once-daily candesartan cilexetil at doses of 8–16 mg (mean dose 12 mg) on morbidity and mortality due to cardiovascular diseases was evaluated. Patients received either candesartan cilexetil or placebo, and if necessary, additional antihypertensive drugs. In the candesartan group, blood pressure decreased from 166/90 to 145/80 mmHg, compared to a reduction from 167/90 to 149/82 mmHg in the control group. For the primary endpoint of the study—serious cardiovascular events (death due to cardiovascular disease, stroke, and non-fatal myocardial infarction)—no statistically significant difference was observed. The event rate was 26.7 events per 1000 patient-years in the candesartan group and 30 events per 1000 patient-years in the control group (relative risk 0.89, 95% CI 0.75 to 1.06, p = 0.19).

Two large randomized, controlled clinical trials, ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes), evaluated the concomitant use of an ACE inhibitor with angiotensin II receptor antagonists.

The ONTARGET trial included patients with cardiovascular disease, cerebrovascular disease, or type 2 diabetes with documented target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.

These trials showed no significant beneficial effect on renal parameters and (or) cardiovascular morbidity and mortality outcomes, while an increased risk of hyperkalemia, acute kidney injury, and (or) hypotension was observed compared to monotherapy. Due to similarities in pharmacodynamic properties of these drugs, these findings are also relevant for other ACE inhibitors and angiotensin II receptor antagonists.

Therefore, concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.

The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was designed to evaluate the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease and/or cardiovascular disease. The trial was prematurely terminated due to increased risk of adverse events. Cardiovascular deaths and strokes occurred more frequently in the aliskiren group compared to the placebo group. The aliskiren group also experienced more frequent adverse events, including serious adverse events (hyperkalemia, hypotension, and renal failure), compared to the placebo group.

Children and adolescents – arterial hypertension
The antihypertensive effect of candesartan was evaluated in children with arterial hypertension aged 1 to <6 years and 6 to <17 years in two randomized, double-blind, multicenter, 4-week clinical trials.

In children aged 1 to <6 years, 93 patients (74% of whom had kidney disease) were randomized to receive oral candesartan cilexetil suspension at doses of 0.05, 0.20, or 0.40 mg/kg body weight once daily. The primary analysis method was assessment of the slope of change in systolic blood pressure (SBP) as a function of dose. SBP and diastolic blood pressure (DBP) decreased by 6.0/5.2 to 12.0/11.1 mmHg from baseline across the three candesartan cilexetil dose groups. However, because the trials lacked a placebo control group, the actual magnitude of the drug's effect on blood pressure remains uncertain, making a definitive benefit-risk assessment in this age group difficult.

In children aged 6 to <17 years, 240 patients were randomized to receive placebo or low, medium, or high doses of candesartan cilexetil in a 1:2:2:2 ratio. In children with body weight <50 kg, candesartan cilexetil doses were 2, 8, or 16 mg once daily. In children with body weight >50 kg, doses were 4, 16, or 32 mg once daily. Candesartan, when all doses were analyzed together, reduced seated systolic blood pressure (SiSBP) by 10.2 mmHg (P<0.0001) and seated diastolic blood pressure (SiDBP) by 6.6 mmHg (P=0.0029) from baseline. In the placebo group, SiSBP decreased by 3.7 mmHg (p=0.0074) and SiDBP by 1.80 mmHg (p=0.0992) from baseline. Despite a significant placebo effect, all individual candesartan doses (and all combined doses) showed significant superiority over placebo. The maximal blood pressure-lowering response in children with body weight below and above 50 kg was achieved at doses of 8 mg and 16 mg, respectively, with response plateauing above these doses.

Among patients included in the trials, 47% were black children and 29% were girls; mean age ± SD was 12.9 ± 2.6 years. In children aged 6 to <17 years, a trend toward reduced drug effect on blood pressure was observed in black patients compared to patients of other races.

Heart failure
The CHARM (Candesartan in Heart failure – Assessment of Reduction in Mortality and morbidity) trial demonstrated that treatment with candesartan cilexetil reduces mortality, the need for hospitalization due to heart failure, and improves the condition of patients with impaired left ventricular systolic function.

This placebo-controlled, double-blind trial included patients with chronic heart failure classified as NYHA class II to IV and consisted of three separate studies: CHARM-Alternative (n = 2028), involving patients not previously treated with ACE inhibitors due to intolerance (mainly due to cough, 72%), with LVEF ≤ 40%; CHARM-Added (n = 2548), involving patients previously treated with ACE inhibitors, with LVEF ≤ 40%; and CHARM-Preserved (n = 3023), involving patients with LVEF > 40%. Patients receiving optimal treatment for chronic heart failure were randomly assigned to placebo or candesartan cilexetil (doses gradually increased 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 patients still taking candesartan cilexetil (89%) were receiving the highest dose of 32 mg.

In the CHARM-Alternative trial, cardiovascular mortality or first hospitalization due to chronic heart failure, evaluated as a composite endpoint, was significantly lower with candesartan compared to placebo (HR 0.77, 95% CI 0.67–0.89, p<0.001). This corresponds to a 23% relative risk reduction. The endpoint was reached by 33.0% (95%CI: 30.1 to 36.0) of patients receiving candesartan and 40.0% (95%CI: 37.0 to 43.1) of those receiving placebo, an absolute difference of 7.0% (95%CI: 11.2 to 2.8). In this trial, one in every 14 patients treated with candesartan avoided cardiovascular death or hospitalization due to heart failure. All-cause mortality and first hospitalization due to heart failure, evaluated as a composite endpoint, was also significantly lower with candesartan (HR 0.80, 95% CI 0.70–0.92, p = 0.001). The composite endpoint was reached by 36.6% (95%CI: 33.7 to 39.7) of patients receiving candesartan and 42.7% (95%CI: 39.6 to 45.8) of those receiving placebo, an absolute difference of 6.0% (95%CI: 10.3 to 1.8). Candesartan reduced both components of the composite endpoint—mortality and morbidity (hospitalization due to chronic heart failure). Treatment with candesartan cilexetil improved patients' condition as assessed by NYHA classification (p = 0.008).

In the CHARM-Added trial, cardiovascular mortality or first hospitalization due to chronic heart failure, evaluated as a composite endpoint, was significantly lower with candesartan compared to placebo (HR 0.85, 95% CI 0.75–0.96, p = 0.011). These results correspond to a 15% relative risk reduction. The composite endpoint was reached by 37.9% (95%CI: 35.2 to 40.6) of patients receiving candesartan and 42.3% (95%CI: 39.6 to 45.1) of those receiving placebo, an absolute difference of 4.4% (95%CI: 8.2 to 0.6). In this trial, one in every 23 patients treated with candesartan avoided cardiovascular death or hospitalization due to heart failure. All-cause mortality and first hospitalization due to chronic heart failure, evaluated as a composite endpoint, were also significantly lower with candesartan (HR 0.87, 95% CI 0.78–0.98, p = 0.021). The composite endpoint was reached by 42.2% (95%CI: 39.5 to 45.0) of patients receiving candesartan and 46.1% (95%CI: 43.4 to 48.9) of those receiving placebo, an absolute difference of 3.9% (95%CI: 7.8 to 0.1). Candesartan favorably reduced both components of the composite endpoint—mortality and morbidity. Treatment with candesartan cilexetil improved patients' condition as assessed by NYHA classification (p = 0.020).

In the CHARM-Preserved trial, cardiovascular mortality or first hospitalization due to chronic heart failure, evaluated as a composite endpoint, was not statistically significantly lower (HR 0.89, 95% CI 0.77–1.03, p = 0.118).

All-cause mortality was not statistically significant when evaluated separately in each of the three CHARM trials. However, all-cause mortality was also evaluated collectively in the CHARM-Alternative and CHARM-Added trials (HR 0.88, 95% CI 0.79–0.98, p = 0.018) and in all three trials (HR 0.91, 95% CI 0.83–1.00, p = 0.055).

The beneficial effect of candesartan in reducing cardiovascular mortality and frequency of hospitalization due to chronic heart failure was independent of age, sex, and other concomitant medications. Candesartan was effective also in patients concurrently receiving β-blockers and ACE inhibitors, and the efficacy of candesartan was demonstrated regardless of whether ACE inhibitors were used at target doses according to recommended treatment regimens.

In patients with chronic heart failure and impaired left ventricular function (left ventricular ejection fraction, LVEF ≤ 40%), candesartan reduces peripheral vascular resistance and pulmonary capillary pressure, increases plasma renin activity and angiotensin II concentration, and decreases plasma aldosterone concentration.

5.2 Pharmacokinetic properties

Absorption and distribution
After oral administration, candesartan cilexetil is converted into its active form – candesartan.
The absolute bioavailability of candesartan following administration as an oral solution of candesartan cilexetil is approximately 40%. The relative bioavailability of candesartan after tablet administration, compared to the oral solution, is approximately 34%, with very low inter-individual variability. The estimated absolute bioavailability after tablet administration is 14%. Mean peak serum concentration (C_) occurs 3–4 hours after tablet intake. Serum concentrations of candesartan increase linearly with increasing dose within the therapeutic dose range. No gender-related differences in the pharmacokinetics of candesartan have been observed. Food intake does not significantly affect the area under the plasma concentration-time curve (AUC) for candesartan.
Candesartan is highly bound to plasma proteins (over 99%). The apparent volume of distribution of candesartan is 0.1 L/kg body weight.
The bioavailability of candesartan is not affected by food intake.

Metabolism and elimination
Candesartan is excreted mainly unchanged in urine and bile, with only a small portion metabolized in the liver (CYP2C9). Available interaction studies have shown no effect on CYP2C9 and CYP3A4. In vitro studies have not revealed interactions with drugs whose metabolism depends on cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, and such interactions are not expected in vivo. The elimination half-life of candesartan is approximately 9 hours. Candesartan does not accumulate after multiple dosing.
Total clearance of candesartan is approximately 0.37 mL/min/kg body weight, of which renal clearance is 0.19 mL/min/kg body weight. Renal excretion of candesartan occurs via both glomerular filtration and active tubular secretion. After oral administration of radiolabeled (C_) candesartan cilexetil, approximately 26% of the dose is excreted in urine as candesartan and 7% as inactive metabolite, whereas in feces, 56% of the dose is recovered as candesartan and 10% as inactive metabolite.

Pharmacokinetics in special patient populations
Compared to younger patients, in elderly individuals (over 65 years of age), C_ and AUC of candesartan increase by approximately 50% and 80%, respectively. However, the blood pressure response and the frequency of adverse effects are similar after administration of candesartan doses in both young and elderly patients (see section 4.2).
In patients with mild to moderate renal impairment, C_ and AUC of candesartan increase by approximately 50% and 70%, respectively, during multiple dosing, while t_ remains unchanged compared to patients with normal renal function. In patients with severe renal impairment, these values increase by approximately 50% and 110%, respectively. The elimination half-life (t_) of candesartan was about twice as long in patients with severe renal impairment. AUC values for candesartan in patients undergoing hemodialysis and in those with severe renal impairment were similar.
In two studies involving patients with mild to moderate hepatic impairment, an increase in mean AUC of candesartan of approximately 20% was observed in one study and approximately 80% in the other (see section 4.2). There are no data available for patients with severe hepatic impairment.

Children and adolescents
The pharmacokinetic properties of candesartan were evaluated in children with hypertension aged 1 to <6 years and 6 to <17 years in two pharmacokinetic studies using single doses.
In children aged 1 to <6 years, 10 children with body weight between 10 and <25 kg received a single oral suspension dose of 0.2 mg/kg body weight. No correlation between C_ and AUC was observed with respect to age or body weight of the child. No data on clearance were collected; therefore, the possibility of a correlation between clearance and body weight/age in this population remains unknown.
In children aged 6 to <17 years, 22 children received a single 16 mg tablet dose. No correlation between C_ and AUC was observed with respect to age. However, body weight appeared to significantly correlate with C_ (p=0.012) and AUC (p=0.011). No data on clearance were collected; therefore, the possibility of a correlation between clearance and body weight/age in this population remains unknown.
In children over 6 years of age, exposure was found to be similar to that in adults receiving the same dose of the drug.
The pharmacokinetics of candesartan cilexetil has not been studied in children under 1 year of age.

5.3 Preclinical safety data

There is no evidence of systemic abnormalities or toxic effects on target organs following administration of clinically relevant doses. Preclinical safety studies conducted in mice, rats, dogs, and monkeys showed effects of candesartan, given in high doses, on the kidneys and red blood cell parameters. Candesartan caused a reduction in red blood cell count (erythrocytes, hemoglobin, hematocrit). Renal effects of candesartan (i.e. interstitial nephritis, tubular dilatation, basophilic casts; increased plasma concentrations of urea and creatinine) may be attributed to reduced blood pressure, leading to disturbances in renal perfusion. Additionally, candesartan causes hyperplasia/hypertrophy of juxtaglomerular apparatus cells. These changes are considered to result from the pharmacological action of candesartan. Hyperplasia/hypertrophy of juxtaglomerular apparatus cells has not been observed in humans receiving candesartan at therapeutic doses.

In preclinical studies in normotensive neonatal and young rats, candesartan caused reduced body weight and heart weight. As in adult animals, these effects are considered to result from the pharmacological action of candesartan. At the lowest dose tested of 10 mg/kg body weight, exposure to candesartan was 12 to 78 times higher than concentrations observed in children aged 1 to <6 years receiving candesartan cilexetil at a dose of 0.2 mg/kg body weight, and 7 to 54 times higher than concentrations observed in children aged 6 to <17 years receiving candesartan cilexetil at a dose of 16 mg. Since no no-effect level was established in these studies, the safety margin for these effects on heart weight and the clinical relevance of this effect remain unknown.

Toxic effects on the fetus were observed in late pregnancy (see section 4.6).

Candesartan did not show mutagenic or clastogenic activity in in vitro and in vivo studies on mutagenicity at therapeutic doses.

Candesartan does not exhibit carcinogenic activity.

The renin-angiotensin-aldosterone system plays a critical role in fetal kidney development. Inhibition of the renin-angiotensin-aldosterone system has been shown to lead to abnormal kidney development in very young mice. Administration of drugs acting directly on the renin-angiotensin-aldosterone system may impair normal kidney development. For this reason, children under 1 year of age should not receive candesartan (see section 4.3).

6. PHARMACEUTICAL DATA

6.1 List of excipients

Monohydrate lactose
Corn starch
Hydroxypropylcellulose (low substituted)
Macrogol 6000
Calcium carmellose
Iron oxide, red (E 172)
Magnesium stearate

6.2 Pharmaceutical incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions during storage

No special requirements for storage conditions.

6.5 Type and content of container

PVC/PE/PVDC/Aluminium blister in a cardboard box.
Pack sizes: 7, 14, 15, 20, 28, 30, 50, 56, 90, 98, 100 tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and preparation of the medicinal product

for use
Any unused residues of the medicinal product or its waste must be disposed of in accordance
with local regulations.

7. MARKETING AUTHORISATION HOLDER

Ranacand (Poland) Sp. z o.o.
ul. Idzikowskiego 16
00-710 Warsaw

8. MARKETING AUTHORISATION NUMBER

8 mg: Authorisation number 17089
16 mg: Authorisation number 17090

9. DATE OF FIRST AUTHORISATION OR RENEWAL OF THE AUTHORISATION

I DATE OF RENEWAL OF THE AUTHORISATION
Date of first authorisation: 04.08.2010
Date of latest renewal: 13.04.2016

10. DATE OF ADOPTION OR PARTIAL CHANGE OF THE TEXT

SUMMARY OF PRODUCT CHARACTERISTICS
18.06.2025