Candesar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KANDESAR (CANDESAR)

Composition:

Active substance: candesartan;

1 tablet contains 4 mg, 8 mg, or 16 mg of candesartan cilexetil;

Excipients:

lactose monohydrate; corn starch, calcium carboxymethylcellulose, hydroxypropylcellulose, polyethylene glycol 6000, magnesium stearate, iron oxide red (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties:

4 mg tablets: mottled pink, capsule-shaped tablets, embossed with "С9" on one side and a deep score line on the other side;

8 mg tablets: mottled pink, capsule-shaped tablets, embossed with "С" and "10" on both sides of the score line on one side and a score line on the other side;

16 mg tablets: mottled pink, capsule-shaped tablets, embossed with "С" and "11" on both sides of the score line on one side and a score line on the other side;

Pharmacotherapeutic group. Angiotensin II receptor antagonists. ATC code C09C A06.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS), playing a role in the pathophysiological mechanism of arterial hypertension, heart failure, and other cardiovascular diseases. It also contributes to the pathogenesis of hypertrophy and target organ damage. The main physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis, and cell growth stimulation, are mediated via type 1 (AT1) receptors.

Pharmacodynamic effects

Candesartan cilexetil is an orally active prodrug. It is rapidly converted into the active substance candesartan by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist (ARA-II), selectively blocking AT1 receptors, with strong binding and slow dissociation from the receptor. It has no agonistic activity.

Candesartan does not inhibit the angiotensin-converting enzyme (ACE), which converts angiotensin I into angiotensin II and degrades bradykinin. There is no effect on ACE activity or potentiation of bradykinin or substance P. In controlled clinical trials comparing candesartan with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not bind to or block receptors of other hormones or ion channels important in cardiovascular regulation. Antagonism of angiotensin II receptors (AT1) leads to dose-dependent increases in plasma levels of renin, angiotensin I, and angiotensin II, as well as a reduction in plasma aldosterone concentration.

Clinical efficacy and safety

Arterial hypertension

In arterial hypertension, candesartan produces a dose-dependent, long-lasting reduction in blood pressure. The antihypertensive effect results from a reduction in systemic vascular resistance without reflex tachycardia. There is no evidence of severe or excessive hypotension after the first dose or withdrawal syndrome upon discontinuation of treatment.

After a single dose of candesartan cilexetil, the onset of antihypertensive effect is typically observed within 2 hours. With long-term treatment, the main reduction in blood pressure is usually achieved within 4 weeks and maintained during prolonged therapy. According to meta-analysis data, the average additional effect of increasing the dose from 16 mg to 32 mg once daily was minimal. Considering individual variability, a more pronounced effect may be expected in some patients compared to the average. Candesartan cilexetil administered once daily provides effective and gradual blood pressure reduction over 24 hours, with minimal difference between maximum and minimum effects during the dosing interval. The antihypertensive effect and tolerability of candesartan and losartan were compared in two randomized, double-blind studies involving a total of 1268 patients with mild to moderate arterial hypertension. The mean reduction in blood pressure (systolic/diastolic) was 13.1/10.5 mm Hg with 32 mg of candesartan cilexetil once daily and 10.0/8.7 mm Hg with 100 mg of losartan potassium once daily (difference in blood pressure reduction 3.1/1.8 mm Hg, p<0.0001/p<0.0001).

When candesartan cilexetil is used concomitantly with hydrochlorothiazide, an additional reduction in blood pressure is observed. An enhanced antihypertensive effect is also noted when candesartan cilexetil is combined with amlodipine or felodipine.

Medicinal products that block the RAAS have a less pronounced antihypertensive effect in patients of non-Black race (typically patients with low renin levels) compared to patients of other races. This also applies to candesartan.

Candesartan increases renal blood flow and does not affect or increases glomerular filtration rate by reducing renal vascular resistance and filtration fraction. In a 3-month clinical study involving patients with arterial hypertension, type 2 diabetes, and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion. Currently, there are no data on the effect of candesartan on the progression of diabetic nephropathy.

The effect of candesartan cilexetil at doses of 8–16 mg (mean dose 12 mg) once daily on cardiovascular morbidity and mortality was evaluated in a randomized clinical trial involving 4937 elderly patients (aged 70–89 years; 21% aged 80 years or older) with mild to moderate arterial hypertension, with a mean duration of 3.7 years (Study on COgnition and Prognosis in the Elderly – SCOPE). Patients received candesartan cilexetil or placebo in addition to other antihypertensive therapy, which was added as needed. Blood pressure decreased from 166/90 to 145/80 mm Hg in the candesartan treatment group and from 167/90 to 149/82 mm Hg in the control group. There was no statistically significant difference in the number of major cardiovascular events in the primary endpoint. There were 26.7 events per 1000 patient-years in the candesartan group versus 30 events per 1000 patient-years in the control group.

Heart failure

Treatment with candesartan cilexetil reduces mortality, reduces hospitalizations due to heart failure, and alleviates symptoms in patients with left ventricular systolic dysfunction, as demonstrated in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity) program.

This placebo-controlled, double-blind research program involving patients with chronic heart failure (CHF) in New York Heart Association (NYHA) functional classes II–IV consisted of three separate studies: CHARM-Alternative (n=2028) involving patients with left ventricular ejection fraction (LVEF) ≤ 40% who were not treated with ACE inhibitors due to intolerance (mainly due to cough, 72%), CHARM-Added (n=2548) involving patients with LVEF ≤ 40% who were receiving ACE inhibitors, and CHARM-Preserved (n=3023) involving patients with LVEF ≥ 40%.

In the CHARM-Alternative study, the composite endpoint of cardiovascular mortality or first hospitalization due to CHF was significantly lower with candesartan compared to placebo (relative risk reduced by 23%). The composite endpoint of all-cause mortality or first hospitalization due to CHF was also significantly reduced in the candesartan group, with an absolute difference of 6%. Both components of these composite endpoints—mortality and morbidity (hospitalization due to CHF)—support the beneficial effect of candesartan. Treatment with candesartan cilexetil improved NYHA functional class (p=0.008).

In the CHARM-Added study, the composite endpoint of cardiovascular mortality or first hospitalization due to CHF was significantly reduced in the candesartan group compared to placebo (relative risk reduced by 15%). The composite endpoint of all-cause mortality or first hospitalization due to CHF was also significantly reduced in the candesartan group, with an absolute difference of 3.9%. Both components of these composite endpoints—mortality and morbidity—support the beneficial effect of candesartan. Treatment with candesartan cilexetil improved NYHA functional class (p=0.020).

In the CHARM-Preserved study, no statistically significant reduction in the composite endpoints of cardiovascular mortality or first hospitalization due to CHF was achieved.

All-cause mortality was not statistically significant when analyzed separately in each of the three CHARM studies. However, all-cause mortality was also evaluated in the combined population of 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 positive effects of candesartan were consistent regardless of age, sex, and concomitant medication. Candesartan was also effective in patients receiving beta-blockers and ACE inhibitors simultaneously, with a positive effect observed independently of whether patients were receiving ACE inhibitors at the target dose recommended in the product information.

In patients with CHF and reduced left ventricular systolic function (LVEF ≤ 40%), candesartan reduces systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and reduces aldosterone levels.

Pharmacokinetics.

Absorption and distribution

After oral administration, candesartan cilexetil is converted into the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after oral administration of a candesartan cilexetil solution. The relative bioavailability of the tablet formulation compared to the same oral solution is approximately 34% with very low variability. Thus, the calculated absolute bioavailability of the tablet is 14%. The mean maximum serum concentration (Cmax) is reached within 3–4 hours after tablet intake. Serum concentrations of candesartan increase linearly with increasing doses within the therapeutic dose range. No gender-related differences in candesartan pharmacokinetics were observed. Food intake does not affect the area under the serum concentration-time curve (AUC) of candesartan.

Candesartan is highly bound to plasma proteins (over 99%). The apparent volume of distribution of candesartan is 0.1 L/kg.

Food intake does not affect the bioavailability of candesartan.

Metabolism and elimination

Candesartan is primarily excreted unchanged in urine and bile, with only minor hepatic metabolism (CYP2C9). According to in vitro data, no in vivo interactions are expected with drugs whose metabolism depends on the CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 isoenzymes of cytochrome P450. The terminal half-life of candesartan is approximately 9 hours. There is no accumulation after multiple doses.

The total plasma clearance of candesartan is approximately 0.37 mL/min/kg, with renal clearance of about 0.19 mL/min/kg. Candesartan is eliminated by the kidneys via both glomerular filtration and active tubular secretion. After oral administration of a radiolabeled 14C candesartan cilexetil dose, approximately 26% of the dose is excreted in urine as candesartan and 7% as an inactive metabolite, while approximately 56% of the dose is recovered in feces as candesartan and 10% as an inactive metabolite.

Pharmacokinetics in special patient populations

In elderly patients (aged 65 years and older), Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared to younger patients. However, the blood pressure response and incidence of adverse effects after administration of Candesar are similar in younger and elderly patients (see section "Dosage and administration").

In patients with mild to moderate renal impairment, Cmax and AUC of candesartan increase by approximately 50% and 70%, respectively, upon repeated dosing, while t1/2 remains unchanged compared to patients with normal renal function. Corresponding changes in patients with severe renal impairment are approximately 50% and 110%, respectively. The terminal t1/2 of candesartan is approximately doubled in patients with severe renal impairment. AUC of candesartan in patients undergoing hemodialysis is similar to that in patients with severe renal impairment.

In two studies involving patients with moderate hepatic impairment, an increase in mean AUC of candesartan of approximately 20% was observed in one study and 80% in another (see section "Dosage and administration"). Experience with the use of the drug in patients with severe hepatic impairment is lacking.

Clinical characteristics.

Indications.

Treatment of essential hypertension in adults.

Treatment of adult patients with heart failure and impaired systolic function of the left ventricle (left ventricular ejection fraction ≤ 40%) as add-on therapy to ACE inhibitors or in cases of intolerance to ACE inhibitors.

Contraindications.

Hypersensitivity to candesartan cilexetil or to any of the excipients.

Severe hepatic impairment and/or cholestasis.

Concomitant use of the medicinal product Candesar and medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR <60 ml/min/1.73 m²).

Interaction with other medicinal products and other forms of interaction.

Medicinal products studied in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glyburide, nifedipine, and enalapril. No clinically significant pharmacokinetic interactions with these medicinal products were observed.

Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products (e.g. heparin) may increase potassium levels. Monitoring of potassium levels should be performed appropriately (see section "Special precautions for use").

Increased serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. A similar effect may occur with angiotensin II receptor antagonists (ARBs). Concomitant use of candesartan with lithium is not recommended. If combination therapy is deemed necessary, careful monitoring of serum lithium levels is recommended.

When ARBs are used concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs) (i.e. selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs), a reduction in antihypertensive effect may occur.

As with ACE inhibitors, concomitant use of ARBs and NSAIDs may lead to an increased risk of worsening renal function, including possible acute renal failure, and hyperkalemia, particularly in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be performed after initiation of concomitant therapy and periodically thereafter.

Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse events such as arterial hypotension, hyperkalemia, and worsening of renal function (including acute renal failure), compared to use of a single medicinal product acting on the RAAS.

Special precautions for use.

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

Evidence exists that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and deterioration of renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended. If dual blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision and with frequent, careful monitoring of renal function, electrolytes, and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Renal impairment

As with other medicinal products that inhibit the RAAS, changes in renal function may be expected in susceptible patients receiving Candesart.

When Candesart is administered to patients with arterial hypertension and impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Experience with the use of Candesart in patients with very severe or end-stage renal impairment (creatinine clearance <15 mL/min) is limited. In such patients, the dose of Candesart should be carefully titrated with monitoring of blood pressure.

Evaluation of patients with heart failure should include periodic assessment of renal function, particularly in elderly patients (aged 75 years and older) and in patients with impaired renal function. Monitoring of serum creatinine and potassium levels is recommended during dose titration of Candesart. Clinical trials in heart failure did not include patients with serum creatinine levels >265 µmol/L (>3 mg/dL).

Concomitant therapy with ACE inhibitors in heart failure

The risk of adverse reactions, particularly hypotension, hyperkalemia, and worsening of renal function (including acute renal failure), may increase when Candesart is used in combination with ACE inhibitors. Triple combination therapy with an ACE inhibitor, a mineralocorticoid receptor antagonist, and candesartan is also not recommended. The use of these combinations should be carried out only under specialist supervision and with frequent, careful monitoring of renal function, electrolytes, and blood pressure.

ACE inhibitors should not be used concomitantly with angiotensin II receptor antagonists in patients with diabetic nephropathy.

Hemodialysis

During dialysis, blood pressure may be particularly sensitive to blockade of AT1 receptors due to reduced plasma volume and activation of the RAAS. Therefore, in patients undergoing hemodialysis, the dose of Candesart should be carefully titrated with monitoring of blood pressure.

Renal artery stenosis

Medicinal products affecting the RAAS, including ARAsII, may increase serum uric acid and creatinine levels in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney.

Kidney transplantation

Experience with the use of Candesart in patients who have recently undergone kidney transplantation is limited.

Hypotension

In patients with heart failure, treatment with Candesart may result in hypotension. Hypotension may also occur in patients with arterial hypertension who have intravascular volume depletion, such as those receiving high doses of diuretics. Therapy should be initiated cautiously, and measures should be taken to correct hypovolemia.

Anesthesia and surgery

In patients treated with angiotensin II antagonists, hypotension may occur during anesthesia and surgical procedures due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe and require intravenous fluid administration and/or vasopressor agents.

Stenosis of aortic and mitral valves (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, particular caution is advised in patients with hemodynamically significant stenosis of the aortic or mitral valve or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting through inhibition of the RAAS. Therefore, the use of Candesart in this patient group is not recommended.

Hyperkalemia

Concomitant use of Candesart with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products capable of increasing potassium levels (e.g., heparin) may lead to elevated serum potassium levels in patients with arterial hypertension. Appropriate monitoring of potassium levels should be performed.

Hyperkalemia may occur in patients with heart failure treated with Candesart. Periodic monitoring of serum potassium levels is recommended. The combination of an ACE inhibitor, a potassium-sparing diuretic (e.g., spironolactone), and Candesart is not recommended; such use should be considered only after careful assessment of potential benefits and risks.

General

In patients in whom vascular tone and renal function depend predominantly on RAAS activity (e.g., patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products affecting this system has been associated with acute hypotension, azotemia, oliguria, and rarely, acute renal failure. The possibility of such effects cannot be excluded with the use of ARAsII. As with any antihypertensive agent, excessive reduction in blood pressure in patients with ischemic cardiomyopathy or cerebrovascular disease may lead to myocardial infarction or stroke.

The antihypertensive effect of candesartan may be enhanced by other medicinal products that have blood pressure-lowering properties, regardless of whether they are used as antihypertensives or for other indications.

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

Pregnancy

Initiation of ARAsII during pregnancy is not recommended. Unless continued therapy with ARAsII is considered essential, alternative antihypertensive therapy with an established safety profile in pregnancy should be prescribed for women planning pregnancy. If pregnancy is diagnosed, treatment with ARAsII should be discontinued immediately, and alternative therapy initiated if necessary.

In postmenarchal women, the possibility of pregnancy should be assessed on a general basis. Appropriate information and/or measures to prevent fetal exposure to the drug should be provided (see sections "Contraindications" and "Use in pregnancy or lactation").

Use during pregnancy or breastfeeding

Use of the drug during pregnancy is contraindicated. Candesart is not recommended for use during breastfeeding.

Pregnancy

Epidemiological data on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy do not allow definitive conclusions, but a slight increase in risk cannot be excluded. Since controlled epidemiological data on the risk associated with ARAsII use are lacking, similar risks may exist for this class of medicinal products. Unless continued therapy with ARAsII is considered essential, alternative antihypertensive therapy with an established safety profile in pregnancy should be prescribed for women planning pregnancy. If pregnancy is diagnosed, treatment with ARAsII should be discontinued immediately, and alternative therapy initiated if necessary.

Newborns whose mothers have taken ARAsII require careful monitoring for hypotension (see sections "Contraindications" and "Special precautions for use").

Lactation

Due to lack of information on the use of Candesart during breastfeeding, Candesart is not recommended during this period. Alternative therapies with better-established safety profiles during breastfeeding should be preferred, especially when breastfeeding newborns or preterm infants.

Ability to influence reaction speed when driving or operating machinery

Studies on the effect of candesartan on the ability to drive vehicles or operate machinery have not been conducted. However, it should be noted that dizziness or increased fatigue may occasionally occur during treatment with Candesart.

Dosage and Administration

Dosing for arterial hypertension

The recommended initial and usual maintenance dose of Candesar is 8 mg once daily. In most patients, the antihypertensive effect is achieved within 4 weeks. In some patients with inadequate blood pressure control, the dose may be increased to 16 mg once daily and up to a maximum of 32 mg once daily. Therapy should be adjusted according to blood pressure response. Candesar may also be used in combination with other antihypertensive agents (see sections "Contraindications", "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Pharmacological properties"). It has been observed that adding hydrochlorothiazide provides additional antihypertensive effect with various doses of Candesar.

Elderly patients

No initial dose adjustment is required for elderly patients.

Patients with reduced intravascular volume

In patients at risk of developing arterial hypotension, such as those with possible dehydration, consideration may be given to initiating treatment with a dose of 4 mg (see section "Special precautions").

Patients with renal impairment

The initial dose for patients with renal impairment, including those on hemodialysis, is 4 mg. The dose should be titrated according to the treatment response. Experience with the use of Candesar in patients with very severe renal impairment or at end-stage renal disease (creatinine clearance <15 mL/min) is limited (see section "Special precautions").

Patients with hepatic impairment

For patients with mild to moderate hepatic impairment, the recommended initial dose is 4 mg once daily. The dose may be adjusted according to the treatment response. Candesar is contraindicated in patients with severe hepatic impairment and/or cholestasis (see sections "Contraindications" and "Pharmacological properties").

Patients of non-Caucasian race

The antihypertensive effect of candesartan is less pronounced in patients of non-Caucasian race compared to patients of other races. Therefore, the need for higher doses of Candesar and concomitant therapy to control blood pressure may occur more frequently in patients of non-Caucasian race than in patients of other races (see section "Pharmacological properties").

Dosing for heart failure

The usual recommended initial dose of Candesar is 4 mg once daily. Dose escalation to the target dose of 32 mg once daily (maximum dose) or the highest tolerated dose should be achieved by doubling the dose at intervals of at least 2 weeks (see section "Special precautions"). Evaluation of patients with heart failure should always include assessment of renal function, including monitoring of serum creatinine and potassium. Candesar may be used in combination with other medications for the treatment of heart failure, including ACE inhibitors, beta-blockers, diuretics, and digoxin, or combinations thereof. In patients with symptoms of heart failure despite optimal standard heart failure therapy, and in those intolerant to mineralocorticoid receptor antagonists, Candesar may be used concomitantly with ACE inhibitors. The combination of an ACE inhibitor, a potassium-sparing diuretic, and Candesar is not recommended; such combination should be considered only after careful evaluation of potential benefits and risks (see sections "Special precautions", "Adverse reactions", and "Pharmacological properties").

Special patient groups

No initial dose adjustment is required for elderly patients or for patients with reduced intravascular blood volume, or with renal impairment, or with mild to moderate hepatic impairment.

Children

The safety and efficacy of Candesar in children from birth to 18 years of age for the treatment of heart failure have not been established. Data are lacking.

Administration

For oral use.

Candesar should be taken once daily, regardless of food intake.

Food intake does not affect the bioavailability of candesartan.

Overdose

Symptoms

Given the pharmacological properties of the drug, the main manifestations of overdose are likely to be symptomatic hypotension and dizziness. Recovery without complications has been reported in some cases of overdose (with doses up to 672 mg of candesartan cilexetil).

Treatment

In case of symptomatic hypotension, symptomatic treatment should be initiated and vital signs should be monitored. The patient should be placed in a supine position with elevated legs. If this is insufficient, plasma volume should be expanded by infusion, for example, with isotonic saline solution. If the above measures are inadequate, sympathomimetic agents may be used. Candesartan is not removed by hemodialysis.

Adverse Reactions

Treatment of arterial hypertension

Adverse reactions observed during controlled clinical trials were mild and transient. No association between the overall incidence of adverse events and either dose or age was observed. The number of cases of treatment discontinuation due to adverse events was similar with candesartan cilexetil (3.1%) and placebo (3.2%).

In a pooled analysis of clinical trial data involving patients with arterial hypertension, adverse reactions associated with candesartan cilexetil were defined as those adverse events occurring with a frequency at least 1% higher than with placebo. According to this definition, the most commonly reported adverse reactions were dizziness/vertigo, headache, and respiratory tract infections.

The adverse reactions reported during clinical trials and post-marketing surveillance are listed in the table below.

In the tables in the section "Adverse Reactions", the following frequency definitions are used: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (≤ 1/10,000).

System organ class	Frequency	Adverse effect
Infections and infestations	Common	Respiratory tract infections
Blood and lymphatic system disorders	Very rare	Leukopenia, neutropenia, and agranulocytosis
Metabolism and nutrition disorders	Very rare	Hyperkalemia, hyponatremia
Nervous system disorders	Common	Dizziness/vertigo, headache
Respiratory, thoracic and mediastinal disorders	Very rare	Cough
Gastrointestinal disorders	Very rare	Nausea
Hepatobiliary disorders	Very rare	Elevated liver enzymes, hepatic dysfunction, or hepatitis
Skin and subcutaneous tissue disorders	Very rare	Angioedema, rash, urticaria, pruritus
Musculoskeletal and connective tissue disorders	Very rare	Back pain, arthralgia, myalgia
Renal and urinary disorders	Very rare	Renal dysfunction, including acute renal failure in susceptible patients (see section "Special precautions for use")

Laboratory test results

In most cases, there was no clinically significant effect of Candesal on routine laboratory parameters. As with other inhibitors of the RAS, a slight decrease in hemoglobin levels has been observed. Routine monitoring of laboratory parameters is generally not required for patients receiving Candesar. However, in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended.

Treatment of heart failure

The adverse reaction profile of Candesar in adult patients with heart failure was consistent with the pharmacological properties of the drug and the underlying health status of the patients. In the CHARM clinical program, which compared candesartan cilexetil at doses up to 32 mg (n=3803) with placebo (n=3796), 21% of patients in the candesartan cilexetil treatment group and 16.1% of patients in the placebo group discontinued treatment due to adverse events. The most commonly reported adverse reactions were hyperkalemia, arterial hypotension, and renal dysfunction. These events were more frequently observed in patients over 70 years of age, patients with diabetes mellitus, or patients receiving other medications affecting the RAS, particularly ACE inhibitors and/or spironolactone.

The table below lists adverse reactions reported during clinical studies and post-marketing surveillance.

System Organ Class	Frequency	Adverse Effect
Blood and lymphatic system disorders	Very rare	Leukopenia, neutropenia, and agranulocytosis
Metabolism and nutrition disorders	Common	Hyperkalemia
	Very rare	Hypotremia
Nervous system disorders	Very rare	Dizziness, headache
Vascular disorders	Common	Arterial hypotension
Respiratory, thoracic and mediastinal disorders	Very rare	Cough
Gastrointestinal disorders	Very rare	Nausea
Hepatobiliary disorders	Very rare	Elevated liver enzymes, liver function abnormalities, or hepatitis
Skin and subcutaneous tissue disorders	Very rare	Angioedema, rash, urticaria, pruritus
Musculoskeletal and connective tissue disorders	Very rare	Back pain, arthralgia, myalgia
Renal and urinary disorders	Common	Renal dysfunction, including renal failure in susceptible patients (see «Special precautions»).

Laboratory test results

Hyperkalemia and renal function impairment were commonly observed in patients receiving Candesar for the indication of heart failure. Periodic monitoring of serum creatinine and potassium levels is recommended (see section "Dosage and Administration").

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C in a dry place out of reach of children.

Packaging. 10 tablets in a blister pack. 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Address of the manufacturer and its manufacturing site.

V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India