Ranacand

CHARACTERISTICS OF THE MEDICINAL PRODUCT

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 lactose monohydrate.
16 mg: Each tablet contains 151.5 mg of lactose monohydrate.
Full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

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

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

The medicinal product Ranacand is used:

• In the treatment of primary arterial hypertension in adults.
• In the treatment of arterial hypertension in children and adolescents from 6 to <18 years of age.< li>
• 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 additional medication to ACE inhibitors in patients with persistent symptoms of heart failure, despite optimal therapy, when mineralocorticoid receptor antagonists are not tolerated (see sections 4.3, 4.4, 4.5, and 5.1).

4.2 Posology and Method of Administration

Dosing in Arterial Hypertension

The recommended initial dose and usual maintenance dose is 8 mg once daily.
The full antihypertensive effect is achieved within 4 weeks of starting treatment. If treatment with a dose of 8 mg does not provide adequate blood pressure control, the dose should be increased to 16 mg once daily, or to a maximum dose of 32 mg once daily. Treatment should be adjusted according to blood pressure response.
The medicinal product Ranacand can be used in combination with other blood pressure-lowering medications (see sections 4.3, 4.4, 4.5, and 5.1).
It has been observed that the use of hydrochlorothiazide in combination with any dose of the medicinal product Ranacand results in additional blood pressure reduction.
Elderly patients
There is no need to adjust the initial dose in elderly patients.
Use in patients with reduced intravascular volume
In patients at risk of hypotension, such as patients with possible reduced intravascular volume, it is recommended to consider starting treatment with a dose of 4 mg (see section 4.4).
Use in patients with renal impairment
In patients with renal impairment, including those undergoing hemodialysis, the initial dose is 4 mg.
The dose should be increased according to the patient's response to treatment.
Data for patients with very 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 initial dose is 4 mg once daily. The dose should be adjusted according to the patient's response to treatment.
The medicinal product Ranacand should not be used in patients with severe hepatic impairment and/or cholestasis (see sections 4.3 and 5.2).
Use in black patients
In black patients, the antihypertensive effect of candesartan is weaker than in patients of other races. Therefore, in black patients, it may be necessary to increase the dose of the medicinal product Ranacand more frequently than in patients of other races in order to achieve blood pressure control (see section 5.1).
Children and adolescents
Children and adolescents from 6 to <18 years of age:
The recommended initial dose is 4 mg once daily.

• Patients with a body weight <50 kg: in patients with insufficient blood pressure control, the dose can be increased to a maximum of 8 mg once daily.< li>
• Patients with a body weight ≥50 kg: in patients with insufficient blood pressure control, the dose can be increased to 8 mg once daily, and then to 16 mg once daily, if necessary (see section 5.1). The use of doses greater than 32 mg has not been studied in children and adolescents.

Most of the blood pressure-lowering effect is achieved within 4 weeks.
In children with possible reduced circulating blood volume (e.g., patients receiving diuretics, especially those with renal impairment), treatment should be started under close medical supervision, and consideration should be given to using a lower initial dose than specified above (see section 4.2).
No studies have been conducted on the use of the medicinal product Ranacand in children with a glomerular filtration rate of less than 30 ml/min/1.73 m² (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 under 6 years of age

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

Dosing in Heart Failure

The usual recommended initial dose of the medicinal product Ranacand is 4 mg once daily.
This dose can be increased to a target dose of 32 mg once daily (maximum dose) or to the maximum tolerated dose by doubling the dose at intervals of at least 2 weeks (see section 4.4). The assessment of the patient's condition with heart failure should also include an assessment of renal function, including monitoring of potassium and creatinine levels in the serum.
The medicinal product Ranacand can be used in combination with other medications used in the treatment of heart failure, including ACE inhibitors, beta-blockers, diuretics, and digitalis glycosides, or a combination of these medicinal products. Ranacand can be administered in combination with an ACE inhibitor to patients with persistent symptoms of heart failure, despite optimal standard therapy for heart failure, when mineralocorticoid receptor antagonists are not tolerated. However, the combination of ACE inhibitors, potassium-sparing diuretics (e.g., spironolactone), and the medicinal product Ranacand should not be recommended. The use of these combinations 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 populations
There is no need to adjust the initial dose 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 administered once daily, regardless of meals.
Food intake 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 trimester 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 <60 ml min 1.73 m²) (see sections 4.5 and 5.1).< li>

4.4 Special Warnings and Precautions for Use

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) (ang. Renin-Angiotensin-Aldosterone-system, RAAS).
There is evidence that the concomitant use of ACE inhibitors, angiotensin receptor blockers (ARBs), or aliskiren increases the risk of hypotension, hyperkalemia, and renal impairment (including acute renal failure). Therefore, the use of dual blockade of the RAAS system by concomitant use of ACE inhibitors, angiotensin receptor blockers, or aliskiren is not recommended (see sections 4.5 and 5.1).
If the use of dual blockade of the RAAS system is absolutely necessary, it should be carried out under the supervision of a specialist, and the patient's vital signs, such as renal function, electrolyte levels, and blood pressure, should be closely monitored.
In patients with diabetic nephropathy, the concomitant use of ACE inhibitors and angiotensin receptor blockers should not be used.
Intestinal angioedema
In patients treated with angiotensin receptor blockers, including candesartan, intestinal angioedema has been reported (see section 4.8). In these patients, abdominal pain, nausea, vomiting, and diarrhea occurred. The symptoms resolved after discontinuation of the angiotensin receptor blocker. If a patient is diagnosed with intestinal angioedema, treatment with candesartan should be discontinued and appropriate monitoring should be initiated until the symptoms resolve completely.
Renal impairment
As with other inhibitors of the renin-angiotensin-aldosterone system, treatment with the medicinal product Ranacand may be associated with changes in renal function in susceptible patients.
During treatment with the medicinal product Ranacand in patients with arterial hypertension and renal impairment, it is recommended to periodically monitor serum potassium and creatinine levels.
Data on the use of the medicinal product Ranacand in patients with very severe or end-stage renal impairment (creatinine clearance <15 ml min) are limited. in these patients, the dose of medicinal product ranacand should be increased with caution, close monitoring blood pressure.
Monitoring of patients with heart failure should include periodic monitoring of renal function, especially in patients over 75 years of age and in patients with renal impairment.
It is recommended to monitor serum creatinine and potassium levels during dose escalation of the medicinal product Ranacand. Clinical trials in heart failure did not include patients with serum creatinine levels >265 μmol/l (>3 mg/dl).
Use in children and adolescents, including those with renal impairment
The use of the medicinal product Ranacand in children with a glomerular filtration rate of less than 30 ml/min/1.73 m² has not been studied (see section 4.2).
Combination with ACE inhibitors in heart failure
The risk of adverse reactions, in particular hypotension, hyperkalemia, and worsening of renal function (including acute renal failure), may increase when Ranacand is used in combination with an ACE inhibitor.
A triple combination of an ACE inhibitor, a mineralocorticoid receptor antagonist, and candesartan is also not recommended. The use of these combinations should be carried out under the supervision of a specialist, and the patient's renal function, electrolyte levels, and blood pressure should be closely monitored.
Concomitant use of ACE inhibitors and angiotensin receptor blockers is not recommended in patients with diabetic nephropathy.
Hemodialysis
During hemodialysis, blockade of the angiotensin II receptor may cause significant changes in blood pressure due to decreased plasma volume and increased activity of the renin-angiotensin-aldosterone system. Therefore, in hemodialysis patients, the dose of the medicinal product Ranacand should be increased with caution, with close monitoring of blood pressure.
Renal artery stenosis
In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, other medicinal products affecting the renin-angiotensin-aldosterone system, such as angiotensin receptor blockers, may cause increased urea and creatinine levels in the serum.
Kidney transplantation
Clinical data on the use of the medicinal product Ranacand in patients who have undergone kidney transplantation are limited.
Hypotension
During treatment with the medicinal product Ranacand in patients with heart failure, hypotension may occur. Hypotension may also occur in patients with arterial hypertension with reduced intravascular volume, such as patients taking high doses of diuretics. Caution should be exercised when starting treatment and hypovolemia should be corrected.
In children with possible reduced circulating blood volume (e.g., patients receiving diuretics, especially those with renal impairment), treatment should be started under close medical supervision, and consideration should be given to using a lower initial dose (see section 4.2).
Anesthesia and surgery
In patients treated with angiotensin receptor blockers, during anesthesia and surgery, hypotension may occur due to inhibition of the renin-angiotensin-aldosterone system. In rare cases, hypotension may be severe and may require intravenous fluids and/or vasopressors.
Aortic and mitral stenosis (hypertrophic cardiomyopathy with outflow obstruction from the left ventricle)
Caution should be exercised in patients with hemodynamically significant aortic or mitral stenosis or hypertrophic cardiomyopathy with outflow obstruction from the left ventricle.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism are generally resistant to the antihypertensive effects of medicinal products that act through the inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of the medicinal product Ranacand is not recommended in these cases.
Hyperkalemia
Based on experience with other medicinal products affecting the renin-angiotensin-aldosterone system, it has been found that during concomitant use of the medicinal product Ranacand and 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), hyperkalemia may occur in patients with arterial hypertension. Monitoring of potassium levels is recommended.
In patients with heart failure treated with the medicinal product Ranacand, hyperkalemia may occur. Periodic monitoring of serum potassium levels is recommended. Concomitant use of ACE inhibitors, potassium-sparing diuretics (e.g., spironolactone), and the medicinal product Ranacand is not recommended. The use of these combinations should be preceded by a thorough assessment of the potential benefits and risks for the patient.
General
In patients in whom the tension of the vessels and renal function are significantly dependent on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal disease as the underlying disease, including renal artery stenosis), treatment with other medicinal products affecting this system may lead to the occurrence of acute hypotension, azotemia, oliguria, or, less frequently, acute renal failure. The use of these medicinal products should be carried out under close medical supervision.
As with other antihypertensive medicinal products, excessive reduction of blood pressure in patients with coronary heart disease or cerebrovascular disease may lead to myocardial infarction or stroke.
The antihypertensive effect of candesartan may be enhanced by the concomitant use of another antihypertensive medicinal product, regardless of whether the medicinal product is prescribed to lower blood pressure or for other indications.
Pregnancy
The use of AIIRA is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin receptor blockers is contraindicated in the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

• 4.3 and 4.4).

The results of epidemiological studies on the risk of teratogenic effects after the use of ACE inhibitors in the first trimester of pregnancy are inconclusive; however, a small increase in risk cannot be excluded. While data from controlled epidemiological studies on the risk of using angiotensin receptor blockers (AIIRA) are not available, a similar risk may exist for this class of medicinal products. If treatment with angiotensin receptor blockers is not considered necessary, in women planning pregnancy, alternative antihypertensive therapy with an established safety profile during pregnancy should be initiated. In the event of pregnancy, treatment with AIIRA should be discontinued immediately and, if appropriate, alternative therapy should be initiated (see sections 4.3 and 4.6).
Women of childbearing potential should be regularly assessed for the possibility of pregnancy. It is necessary to provide the patient with appropriate information and/or take appropriate action to prevent exposure to the medicinal product during pregnancy (see sections 4.3 and 4.6).
Excipients
The medicinal product contains lactose. The medicinal product should not be used in patients with rare hereditary galactose intolerance, lactase deficiency (Lapp lactase deficiency), or glucose-galactose malabsorption syndrome (see section 6.1).

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

Clinical pharmacokinetic studies were conducted with the following compounds:
hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e., ethinyl estradiol/levonorgestrel), glibenclamide, nifedipine, and enalapril. No interactions of clinical significance were observed.
During concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin), monitoring of potassium levels is recommended (see section 4.4).
Transient increases in lithium levels and the occurrence of lithium toxicity have been observed during concomitant use of lithium preparations and ACE inhibitors. A similar effect may occur during concomitant use of angiotensin receptor blockers. Concomitant use of candesartan and lithium is not recommended. If combination therapy with lithium is necessary, monitoring of lithium levels in the serum is recommended.
When angiotensin receptor blockers are used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs), a decrease in antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of angiotensin receptor blockers and NSAIDs may lead to an increased risk of renal impairment, including acute renal failure, and an increase in serum potassium levels, especially in patients with pre-existing poor renal function. During concomitant use of these medicinal products, caution should be exercised, especially in elderly patients. Patients should be adequately hydrated, and consideration should be given to monitoring renal function after starting combination therapy and periodically thereafter.
Clinical trials have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin receptor blockers, or aliskiren is associated with a higher frequency of adverse events, such as hypotension, hyperkalemia, and renal impairment (including acute renal failure), compared with the use of a medicinal product from the RAAS inhibitor class as monotherapy (see sections 4.3, 4.4, and 5.1).
Children and adolescents
Interaction studies have been conducted only in adult patients.

4.6 Pregnancy and Lactation

Pregnancy
The use of AIIRA is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin receptor blockers is contraindicated in the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

• 4.3 and 4.4).

The results of epidemiological studies on the risk of teratogenic effects after the use of ACE inhibitors in the first trimester of pregnancy are inconclusive; however, a small increase in risk cannot be excluded. While data from controlled epidemiological studies on the risk of using angiotensin receptor blockers (AIIRA) are not available, a similar risk may exist for this class of medicinal products. If treatment with angiotensin receptor blockers is not considered necessary, in women planning pregnancy, alternative antihypertensive therapy with an established safety profile during pregnancy should be initiated. In the event of pregnancy, treatment with AIIRA should be discontinued immediately and, if appropriate, alternative therapy should be initiated (see sections 4.3 and 4.6).
It is known that the use of AIIRA in the second and third trimesters of pregnancy has a toxic effect on the human fetus (renal impairment, oligohydramnios, delayed skull ossification) and newborns (renal failure, hypotension, hyperkalemia) (see section 5.3).
If AIIRA is used from the second trimester of pregnancy, it is recommended to perform an ultrasound scan to monitor renal function and skull development.
Newborns whose mothers have taken AIIRA should be closely monitored for hypotension (see sections 4.3 and 4.4).
Breastfeeding
Due to the lack of available data on the use of candesartan during breastfeeding, the use of candesartan is not recommended. It is preferable to use a therapy with a better established safety profile during breastfeeding, especially in newborns or preterm infants.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Undesirable Effects

Hypertension
Undesirable effects observed in controlled clinical trials were mild and transient. The overall frequency of undesirable effects did not show a relationship to dose or age of the patient. The frequency of withdrawal from treatment due to undesirable effects was similar for candesartan cilexetil (3.1%) and placebo (3.2%).
In an analysis of data from clinical trials in patients with hypertension, undesirable effects related to the use of candesartan cilexetil were defined as those that occurred at least 1% more frequently than after placebo administration. According to this definition, the most common undesirable effects were dizziness, headache, and respiratory tract infections.
Below is a list of undesirable effects collected from clinical trials and post-marketing experience.

Laboratory findings
Generally, no significant clinical effect of the medicinal product Ranacand on routine laboratory tests has been found. As with other medicinal products that inhibit the renin-angiotensin-aldosterone system, a slight decrease in hemoglobin levels has been observed.
Usually, there is no need to perform routine laboratory tests in patients treated with the medicinal product Ranacand. However, in patients with renal impairment, it is recommended to periodically monitor serum potassium and creatinine levels.
Children and adolescents
The safety of candesartan cilexetil was monitored in 255 children and adolescents with hypertension aged 6 to <18 years in a 4-week clinical efficacy trial and 1-year open-label study (see section 5.1). within almost all system organ classes, the frequency of undesirable effects children was similar to or lower than that adults table above). while nature severity events are those observed adult patients, is higher adolescents, particular:< p>

• headache, dizziness, and respiratory tract infections occurring "very commonly" (≥1/10 patients) in children and "commonly" (≥1/100 to <1>
• cough occurring "very commonly" (≥1/10 patients) in children and "very rarely" (<1>
• rash occurring "commonly" (≥1/100 to <1>
• hyperkalemia, hyponatremia, and abnormal liver function occurring "uncommonly" (≥1/1,000 to <1>
• sinusitis, nasopharyngitis, and fever occurring "commonly" (≥1/100 to <1>

The overall safety profile of candesartan cilexetil in children and adolescents is similar to that in adult patients.
Heart failure
The safety profile of candesartan in adult patients with heart failure is based on the pharmacological properties of the medicinal product and the condition of the patients. In the CHARM clinical trial, which compared the effects of candesartan cilexetil in doses up to 32 mg (n = 3803) with placebo (n = 3796), 21.0% of patients in the candesartan cilexetil group and 16.1% of patients in the placebo group discontinued treatment due to undesirable effects. The most common undesirable effects were hyperkalemia, hypotension, and renal impairment. These effects occurred more frequently in patients over 70 years of age, diabetics, or patients taking another medicinal product affecting the renin-angiotensin-aldosterone system, in particular ACE inhibitors and (or) spironolactone. The following is a list of undesirable effects collected from clinical trials and post-marketing experience.

Laboratory findings
In patients treated with the medicinal product Ranacand for heart failure, hyperkalemia and renal impairment may occur. Periodic monitoring of serum creatinine and potassium levels is recommended (see section 4.4).
Reporting of suspected adverse reactions
After the medicinal product has been placed on the market, it is important to report any suspected adverse reactions. Healthcare professionals are asked to report any suspected adverse reactions via the Department of Adverse Reaction Monitoring 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 can also be reported to the marketing authorization holder.

4.9 Overdose

Symptoms
Based on pharmacological data, it can be concluded that the main symptoms of overdose are symptomatic hypotension and dizziness. Single cases of overdose have been reported (up to 672 mg of candesartan cilexetil), in which the recovery of adult patients was uneventful.
Treatment
In the event of symptomatic hypotension, supportive treatment should be initiated, and vital functions should be monitored. The patient should be placed in a supine position, with legs elevated. If this is not sufficient, the circulating volume should be increased by administering an intravenous infusion of, for example, an isotonic saline solution. If this measure is not effective, sympathomimetic drugs can be administered.
Candesartan is not removed by hemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

The pharmacotherapeutic group: angiotensin II receptor antagonists, plain
ATC code: C09 CA 06.
Mechanism of action
Angiotensin II is the main hormone of the renin-angiotensin-aldosterone system acting on
vessels and has significant importance in the pathophysiology of hypertension, heart failure, and
other cardiovascular diseases. It also plays a significant role in the pathogenesis of end-organ
hypertrophy and damage. The main physiological actions of angiotensin II, such as vasoconstriction,
stimulation of aldosterone secretion, regulation of water-electrolyte balance, and stimulation of cell
growth, are mediated by the type 1 (AT1) receptor.
Pharmacodynamic effects
Candesartan cilexetil is a prodrug suitable for oral administration. During absorption from the
gastrointestinal tract, it is rapidly converted by hydrolysis to the active form - candesartan.
Candesartan is an angiotensin II receptor antagonist that acts selectively on AT1 receptors,
characterized by strong binding to the receptor and slow dissociation of this bond. It has no
agonistic activity.
Candesartan does not inhibit ACE activity, which causes the conversion of angiotensin I to
angiotensin II and the breakdown of bradykinin. Candesartan does not affect ACE activity and does
not enhance the effects of bradykinin or substance P. Controlled clinical trials comparing candesartan
with ACE inhibitors showed that the frequency of cough in patients taking candesartan cilexetil was
lower. Candesartan does not bind to other hormone receptors or ion channels important in the
regulation of the cardiovascular system and does not block them. The antagonistic effect on angiotensin
II receptors (AT1) causes a dose-dependent increase in plasma renin, angiotensin I, and angiotensin II
concentrations, as well as a decrease in plasma aldosterone concentration.
Clinical efficacy and safety
Hypertension
In hypertension, candesartan causes a dose-dependent, long-lasting decrease in blood pressure.
The antihypertensive effect is the result of a decrease in total peripheral resistance without a
reflex increase in heart rate. There are no reports of significant or exacerbated hypotension after the
first dose or a rebound effect after treatment discontinuation.
After a single dose of candesartan cilexetil, the antihypertensive effect usually occurs within 2 hours.
During long-term treatment, the full antihypertensive effect with any dose usually occurs within four
weeks and is maintained during long-term treatment. Meta-analysis results showed that the average
increase in treatment efficacy after dose escalation from 16 mg to 32 mg once daily was negligible.
However, analyzing interindividual differences, some patients may expect greater than average treatment
efficacy. Taking candesartan cilexetil once daily provides effective and smooth blood pressure reduction
lasting over 24 hours, with a small difference between maximum and minimum drug effects between
doses. The antihypertensive effect and tolerance of candesartan and losartan were compared in two
randomized, double-blind trials involving 1268 patients with mild or moderate hypertension. The
maximum blood pressure reduction was 13.1/10.5 mmHg (systolic/diastolic) with candesartan cilexetil
32 mg once daily and 10.0/8.7 mmHg with losartan potassium 100 mg once daily (the difference in blood
pressure reduction was 3.1/1.8 mmHg, p<0.0001/p<0.0001).
During concomitant administration of candesartan cilexetil and hydrochlorothiazide, the
antihypertensive effects of these drugs are additive. Enhanced antihypertensive effect is also achieved
when candesartan cilexetil is administered concomitantly with amlodipine or felodipine.
The antihypertensive effect of drugs that inhibit the renin-angiotensin-aldosterone system in black
patients (who typically have lower plasma renin activity) is weaker than in patients of other races.
This also applies to candesartan. In an open-label clinical trial involving 5156 patients with elevated
diastolic blood pressure, blood pressure reduction during candesartan treatment was significantly lower
in black patients than in patients of other races (respectively, 14.4/10.3 mmHg versus 19.0/12.7 mmHg,
p<0.0001/p<0.0001).
Candesartan increases renal blood flow, without affecting glomerular filtration rate or increasing it,
but causes a decrease in renal vascular resistance and filtration fraction. In a 3-month clinical trial
conducted in patients with hypertension and type 2 diabetes with microalbuminuria, it was shown that
during antihypertensive treatment with candesartan cilexetil, urinary albumin excretion (albumin-to-
creatinine ratio, mean 30%, 95% confidence interval 15-42%) decreased. Currently, there are no data
on the effect of candesartan on the development of diabetic nephropathy.
In a randomized clinical trial, Study on Cognition and Prognosis in the Elderly, lasting an average of
3.7 years, involving 4937 patients with mild and moderate hypertension (aged 70-89 years; 21% of
patients were 80 years old or older), the effect of candesartan cilexetil administered once daily at doses
of 8-16 mg (average dose 12 mg) on cardiovascular morbidity and mortality was investigated. Patients
received candesartan cilexetil or placebo, and additionally, if necessary, other antihypertensive drugs.
In the group of patients taking candesartan, blood pressure was reduced from 166/90 to 145/80 mmHg,
while in the control group from 167/90 to 149/82 mmHg.
In the primary endpoint of the study, which was severe cardiovascular events (cardiovascular death,
stroke, and non-fatal myocardial infarction), no statistically significant difference was found. In the group
of patients taking candesartan, 26.7 events per 1000 patient-years were reported, while in the control
group, 30 events per 1000 patient-years (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), investigated the concomitant use of an ACE inhibitor with an angiotensin II receptor
antagonist.
The ONTARGET trial was conducted in patients with cardiovascular diseases, cerebrovascular diseases
in history, or type 2 diabetes with proven end-organ damage. The VA NEPHRON-D trial was conducted
in patients with type 2 diabetes and diabetic nephropathy.
These trials showed no significant beneficial effect on renal parameters and (or) outcomes in terms of
cardiovascular morbidity and mortality, while an increased risk of hyperkalemia, acute kidney injury, and
(or) hypotension was observed compared to monotherapy. Due to the similarities in the pharmacodynamic
properties of these drugs, the aforementioned results are also relevant for other ACE inhibitors and
angiotensin II receptor antagonists.
Therefore, in patients with diabetic nephropathy, ACE inhibitors and angiotensin II receptor antagonists
should not be used concomitantly.
The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease
Endpoints) was designed to investigate the benefits of adding aliskiren to standard treatment with an ACE
inhibitor or an 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 an increased risk of adverse events. Cardiovascular deaths
and strokes occurred more frequently in the group receiving aliskiren compared to the placebo group.
The group receiving aliskiren also reported more frequent adverse events, including serious adverse events
(hyperkalemia, hypotension, and kidney failure), compared to the placebo group.
Children and adolescents – hypertension
The antihypertensive effect of candesartan was evaluated in children with 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, of whom 74% had kidney disease, were randomized to receive
an oral dose of candesartan cilexetil suspension of 0.05, 0.20, or 0.40 mg/kg body weight once daily.
The primary method of analysis was the assessment of the slope of the 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 compared to baseline values in the three dose groups of candesartan cilexetil. However, since there
was no placebo control group in the study, the actual magnitude of the drug's effect on blood pressure
remains uncertain, making it difficult to make a binding assessment of the benefit-risk ratio in this age
group.
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 ratio of 1:2:2:2. In children weighing <50 kg, candesartan cilexetil
doses were 2, 8, or 16 mg once daily. In children weighing >50 kg, candesartan cilexetil doses were 4,
16, or 32 mg once daily. Candesartan, in doses analyzed together, reduced sitting systolic blood pressure
(SiSBP) by 10.2 mmHg (P<0.0001) and sitting diastolic blood pressure (SiDBP) (P=0.0029) by 6.6 mmHg,
compared to baseline values. In the placebo group, a decrease in SiSBP by 3.7 mmHg (p=0.0074) and a
decrease in SiDBP by 1.80 mmHg (p=0.0992) compared to baseline values were also observed. Despite
a significant placebo effect, all individual doses of candesartan (and all combined doses) showed significant
superiority over placebo. The maximum response in terms of blood pressure reduction in children weighing
<50 kg and>50 kg was achieved at doses of 8 mg and 16 mg, respectively, and above these doses, the
response reached a plateau.
Of the patients enrolled in the study, 47% were black children, and 29% were girls; the mean age ± SD
was 12.9 ± 2.6 years. In children aged 6 to <17 years, a trend towards smaller effect of the drug on
blood pressure was observed in black patients compared to patients of other races.
Heart failure
The CHARM study (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity)
showed 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 study, conducted in a double-blind manner, involved patients with chronic heart
failure belonging to NYHA classes 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 with optimal treatment for chronic heart failure were randomly assigned to the placebo group or
the candesartan cilexetil group (with doses increased gradually from 4 mg or 8 mg once daily to 32 mg
once daily, or the maximum tolerated dose; the average dose was 24 mg) and were observed for a median
of 37.7 months. After 6 months of treatment, 63% of patients still taking candesartan cilexetil (89%)
received the maximum dose of 32 mg.
In the CHARM-Alternative study, cardiovascular mortality or first hospitalization due to chronic heart
failure, evaluated as a composite endpoint, was significantly lower after candesartan administration
compared to placebo (HR 0.77, 95% CI 0.67-0.89, p<0.001). This corresponds to a 23% reduction in
relative risk. The composite endpoint occurred in 33.0% (95% CI: 30.1 to 36.0) of patients taking
candesartan and 40.0% (95% CI: 37.0 to 43.1) of patients taking placebo, an absolute difference of
7.0% (95% CI: 11.2 to 2.8). In this study, one patient out of 14 treated with candesartan avoided
cardiovascular death or hospitalization due to heart failure. Overall mortality from any cause and first
hospitalization due to heart failure, evaluated as a composite endpoint, were also significantly lower after
candesartan administration (HR 0.80, 95% CI 0.70-0.92, p = 0.001). The composite endpoint occurred
in 36.6% (95% CI: 33.7 to 39.7) of patients taking candesartan and 42.7% (95% CI: 39.6 to 45.8) of
patients taking placebo, an absolute difference of 6.0% (95% CI: 10.3 to 1.8). Candesartan had a
beneficial effect on reducing both components of the composite endpoint, i.e., mortality and morbidity
(hospitalization due to chronic heart failure). As a result of treatment with candesartan cilexetil, the
condition of patients according to the NYHA classification improved (p = 0.008).
In the CHARM-Added study, cardiovascular mortality and first hospitalization due to chronic heart failure,
evaluated as a composite endpoint, were significantly lower after candesartan administration compared to
placebo (HR 0.85, 95% CI 0.75-0.96, p = 0.011). These results correspond to a 15% reduction in
relative risk. The composite endpoint occurred in 37.9% (95% CI: 35.2 to 40.6) of patients taking
candesartan and 42.3% (95% CI: 39.6 to 45.1) of patients taking placebo, an absolute difference of
4.4% (95% CI: 8.2 to 0.6). In this study, one patient out of 23 treated with candesartan avoided
cardiovascular death or hospitalization due to heart failure. Overall mortality from any cause and first
hospitalization due to heart failure, evaluated as a composite endpoint, were also significantly lower after
candesartan administration (HR 0.87, 95% CI 0.78-0.98, p = 0.021). The composite endpoint occurred
in 42.2% (95% CI: 39.5 to 45.0) of patients taking candesartan and 46.1% (95% CI: 43.4 to 48.9) of
patients taking placebo, an absolute difference of 3.9% (95% CI: 7.8 to 0.1). Candesartan had a
beneficial effect on reducing both components of the composite endpoint, i.e., mortality and morbidity.
As a result of treatment with candesartan cilexetil, the condition of patients according to the NYHA
classification improved (p = 0.020).
In the CHARM-Preserved study, cardiovascular mortality and first hospitalization due to chronic heart
failure, evaluated as a composite endpoint, were not statistically lower (HR 0.89, 95% CI 0.77-1.03, p
= 0.118).
Overall mortality was not statistically significant when evaluated separately in each of the three CHARM
studies. However, overall mortality was also evaluated jointly in the CHARM-Alternative and CHARM-
Added studies (HR 0.88, 95% CI 0.79-0.98, p = 0.018) and in all three studies (HR 0.91, 95% CI 0.83-
1.00, p = 0.055).
The beneficial effect of candesartan on reducing cardiovascular mortality and the frequency of
hospitalizations due to chronic heart failure did not depend on age, sex, or other concomitantly used
drugs. Candesartan was effective in patients also taking β-blockers and ACE inhibitors, and the efficacy of
candesartan was observed regardless of the use of ACE inhibitors in 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 reduces plasma aldosterone
concentration.

5.2 Pharmacokinetic Properties

Absorption and distribution
After oral administration, candesartan cilexetil is converted to the active form - candesartan.
The absolute bioavailability of candesartan after oral administration of candesartan cilexetil is about 40%.
The relative bioavailability of candesartan after oral administration of a tablet is about 34% compared to
an oral solution, with very little interindividual variability. The estimated absolute bioavailability after
oral administration of a tablet is 14%. The mean maximum concentration in serum (Cmax) occurs 3-4
hours after tablet administration. The concentration of candesartan in serum increases linearly with
increasing doses in the range of therapeutic doses. No sex-related differences in the pharmacokinetics of
candesartan are observed.
Candesartan is strongly bound to plasma proteins (more than 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, and only a small fraction is metabolized in
the liver (CYP2C9). Available interaction studies do not show an effect on CYP2C9 and CYP3A4. In vitro
studies do not show interactions with drugs whose metabolism depends on cytochrome P450 isoenzymes
CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and such interactions are not
expected in vivo. The elimination half-life of candesartan is about 9 hours. Candesartan does not
accumulate after multiple dosing.
The total clearance of candesartan is about 0.37 ml/min/kg body weight, including renal clearance of
0.19 ml/min/kg body weight. Candesartan is excreted by the kidneys through both glomerular filtration and
active tubular secretion. After oral administration of candesartan cilexetil labeled with the C isotope,
about 26% of the dose is excreted in the urine as candesartan, and 7% as an inactive metabolite, while
in the feces, 56% of the dose is detected as candesartan, and 10% as an inactive metabolite.
Pharmacokinetics in special patient groups
Compared to younger patients, in elderly patients (over 65 years), Cmax and AUC of candesartan increase
by about 50% and 80%, respectively. However, the blood pressure response and the frequency of adverse
events are similar after candesartan administration in younger and elderly patients (see section 4.2).
In patients with mild to moderate renal impairment, Cmax and AUC of candesartan increase by about 50%
and 70%, respectively, during multiple dosing, but the elimination half-life does not change compared to
patients with normal renal function. In patients with severe renal impairment, these values increase by
about 50% and 110%, respectively. The elimination half-life of candesartan in the elimination phase was
about twice as long in patients with severe renal impairment. The AUC of candesartan in patients on
hemodialysis and in patients with severe renal impairment were similar.
In two studies involving patients with mild to moderate liver impairment, an increase in the average AUC
of candesartan by about 20% was observed in one study and by about 80% in the other study (see section
4.2). There are no data on severe liver impairment.
Children and adolescents
The pharmacokinetic properties of candesartan were evaluated in children with hypertension aged 1 to
<6 years and 6 to <17 in two pharmacokinetic studies with a single dose.
In children aged 1 to <6 years, 10 children with a body weight of to <25 kg received single dose of
candesartan cilexetil oral suspension of 0.2 mg/kg body weight. No correlation was observed between Cmax
and AUC depending on 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 dose of 16 mg candesartan cilexetil in
tablet form. No correlation was observed between Cmax and AUC depending on age. However, body weight
appears to correlate significantly with Cmax (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 similar to that in adults who received the same dose of the
drug was observed. The pharmacokinetics of candesartan cilexetil have not been studied in children under
1 year of age.

5.3 Preclinical Safety Data

There is no evidence of systemic or toxic effects on target organs at clinically relevant doses. Preclinical
safety studies conducted in mice, rats, dogs, and monkeys showed the effect of candesartan at high doses
on the kidneys and red blood cell parameters. Candesartan caused a decrease in red blood cell count
(erythrocytes, hemoglobin, hematocrit). The effect of candesartan on the kidneys (i.e., interstitial nephritis,
tubular dilation, acidophilic casts; increased urea and creatinine levels in the blood) may be due to the
decrease in blood pressure, which caused disturbances in renal blood flow. Additionally, candesartan
causes hyperplasia/hypertrophy of the juxtaglomerular apparatus. It is believed that these changes were
caused by the pharmacological action of candesartan. No hyperplasia/hypertrophy of the juxtaglomerular
apparatus has been observed in humans taking candesartan at therapeutic doses.
In preclinical studies in normotensive newborns and young rats, candesartan caused a decrease in body
weight and heart weight. As in adult animals, it is believed that these effects result from the pharmacological
action of candesartan. At the lowest dose of 10 mg/kg body weight, exposure to candesartan was 12 to 78
times higher than the concentrations observed in children aged 1 to <6 years who received candesartan
cilexetil at a dose of 0.2 mg/kg body weight, and 7 to 54 times higher than the concentrations observed
in children aged 6 to <17 years who received candesartan cilexetil at a dose of 16 mg. since the
concentration at which no effects are observed has not been determined, the safety margin for these effects
on heart weight and the clinical significance of this interaction remain unknown.
Toxic effects on the fetus were observed in the later stages of pregnancy (see section 4.6).
Candesartan, at therapeutic doses, did not show mutagenic or clastogenic effects in in vitro and in vivo
studies on mutagenicity.
Candesartan does not have carcinogenic effects.
The renin-angiotensin-aldosterone system plays a critical role in the development of the kidney in fetal
life. It has been shown that blocking the renin-angiotensin-aldosterone system leads to abnormal kidney
development in very young mice. The administration of drugs that directly affect the renin-angiotensin-
aldosterone system may disrupt normal kidney development.
Therefore, children under 1 year of age should not take candesartan (see section 4.3).

6. Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate
Cornstarch
Hydroxypropylcellulose (low-substituted)
Macrogol 6000
Calcium carmellose
Iron oxide, red (E 172)
Magnesium stearate

6.2 Incompatibilities

None.

6.3 Shelf Life

2 years

6.4 Special Precautions for Storage

No special storage precautions.

6.5 Nature and Contents of Container

PVC/PE/PVDC/Aluminum blister pack 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 medicinal product or waste material should be disposed of in accordance with local
regulations.

7. Marketing Authorization Holder

Responsible for Batch Release

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

8. Marketing Authorization Number

8 mg: Marketing Authorization No. 17089
16 mg: Marketing Authorization No. 17090

9. Date of First Authorization and/or Line Extensions

Date of Last Renewal

Date of first authorization: 04.08.2010
Date of last renewal: 13.04.2016

10. Date of Revision of the Text

Summary of Product Characteristics

• 18.06.2025