Hyposart (Tablets) Instructions for Use

ATC Code

C09CA06 (Candesartan)

Active Substance

Candesartan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Angiotensin II receptor antagonist

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system, angiotensin II receptor antagonists

Pharmacological Action

Angiotensin II receptor antagonist.

Angiotensin II is the main hormone of the RAAS, which plays an important role in the pathogenesis of arterial hypertension, heart failure and other cardiovascular diseases. The main physiological effects of angiotensin II are vasoconstriction, stimulation of aldosterone production, regulation of water-electrolyte homeostasis and stimulation of cell growth. All these effects are mediated by the interaction of angiotensin II with angiotensin type 1 receptors (AT₁ receptors).

Pharmacodynamic effects

Candesartan is a selective angiotensin II type 1 receptor (AT₁ receptors) antagonist. Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and breaks down bradykinin; does not affect ACE and does not lead to the accumulation of bradykinin or substance P. When comparing candesartan with ACE inhibitors, the development of cough was less common in patients receiving candesartan cilexetil. Candesartan does not bind to receptors of other hormones and does not block ion channels involved in the regulation of the cardiovascular system functions. As a result of blocking AT₁ receptors of angiotensin II, a dose-dependent increase in renin activity, concentrations of angiotensin I, angiotensin II and a decrease in plasma aldosterone concentration occurs.

Clinical efficacy and safety

Arterial hypertension

In arterial hypertension, Candesartan causes a dose-dependent long-term reduction in blood pressure. The antihypertensive effect of the drug is due to a decrease in total peripheral vascular resistance, without changing the heart rate.

There were no cases of marked arterial hypotension after taking the first dose of the drug, as well as withdrawal syndrome (rebound syndrome) after discontinuation of therapy.

The onset of the antihypertensive effect after taking the first dose of candesartan cilexetil usually develops within 2 hours. Against the background of ongoing therapy with the drug in a fixed dose, the maximum reduction in blood pressure is usually achieved within 4 weeks and is maintained throughout the treatment. Candesartan cilexetil, prescribed once a day, provides effective and smooth blood pressure reduction over 24 hours with minor fluctuations in blood pressure between doses of the next dose of the drug. The use of candesartan cilexetil together with hydrochlorothiazide enhances the antihypertensive effect.

Concomitant use of candesartan cilexetil and hydrochlorothiazide (or amlodipine) is well tolerated.

The effectiveness of the drug does not depend on the age and sex of the patients.

Candesartan cilexetil increases renal blood flow and does not change or increases GFR, while renal vascular resistance and filtration fraction decrease. Taking candesartan cilexetil at a dose of 8-16 mg for 12 weeks does not have a negative effect on glucose concentration and lipid profile in patients with arterial hypertension and type 2 diabetes mellitus.

The clinical effect of candesartan cilexetil on the indicator of cardiovascular morbidity and mortality when taken at a dose of 8-16 mg (average dose 12 mg) once a day was studied in a randomized clinical trial involving 4937 elderly patients (age from 70 to 89 years, 21% of patients aged 80 years and older) with mild to moderate arterial hypertension, receiving therapy with candesartan cilexetil for an average of 3.7 years (SCOPE study – Study on COgnition and Prognosis in the Elderly).

Patients received candesartan cilexetil or placebo, if necessary, in combination with other antihypertensive drugs. Both treatment regimens showed effective reduction in systolic and diastolic blood pressure (from 166/90 to 145/80 mm Hg in the group of patients receiving Candesartan, and from 167/90 to 149/82 mm Hg in the control group) against the background of good tolerability. Cognitive function and quality of life remained at a good level in both groups of patients. There were no statistically significant differences in the frequency of cardiovascular complications for the primary endpoint, including cardiovascular death, development of non-fatal myocardial infarction and non-fatal stroke, between these two groups of patients. However, in the group of patients receiving Candesartan, the risk of developing non-fatal stroke was 28% lower than in the control group (relative risk=0.72, 95% confidence interval 0.53-0.99, p=0.04).

Chronic heart failure

According to the results of the CHARM clinical trial program (Candesartan in Heart failure – Assessment of Reduction in Mortality and morbidity) involving 7599 patients, the use of candesartan cilexetil (the average dose was 24 mg/day) led to a reduction in the frequency of fatal outcomes and the need for hospitalization due to chronic heart failure and to an improvement in the systolic function of the left ventricle. The median follow-up duration was 37.7 months.

In the CHARM-Alternative study (n=2028) in patients with reduced left ventricular ejection fraction (LVEF) ≤40%, who did not receive an ACE inhibitor due to intolerance (mainly due to cough – 72%), the combined criterion, which included death from cardiovascular diseases or the first hospitalization for chronic heart failure, was significantly lower in the group of patients receiving Candesartan compared to the placebo group (hazard ratio=0.77, 95% confidence interval 0.67-0.89, p< 0.001). The relative risk reduction was 23%. At the same time, a positive effect of candesartan was noted on each of the components of this combined criterion. The use of candesartan cilexetil led to an improvement in the functional class of chronic heart failure according to the NYHA classification (p=0.008).

In the CHARM-Added study (n=2548) in patients with reduced LVEF ≤ 40% receiving ACE inhibitors, the combined criterion, which included death from cardiovascular diseases or the first hospitalization for chronic heart failure, was significantly lower in the group of patients receiving Candesartan compared to the placebo group (hazard ratio=0.85, 95% confidence interval 0.75-0.96, p=0.011), which corresponded to a 15% reduction in relative risk. The use of candesartan cilexetil led to an improvement in the functional class of chronic heart failure according to the NYHA classification (p=0.020).

In the CHARM-Preserved study (n=3023) in patients with preserved systolic function (LVEF >40%), no statistically significant differences were found in the value of the combined efficacy criterion, which included the frequency of fatal outcomes from cardiovascular diseases or the frequency of first hospitalization for chronic heart failure, in the candesartan and placebo groups (hazard ratio=0.89, 95% confidence interval 0.77-1.03, p=0.118). At the same time, a positive effect of candesartan was noted on one of the components of this combined criterion – a reduction in the frequency of hospitalizations for chronic heart failure.

In the combined analysis of all 3 studies of the CHARM program, no reliable differences in the frequency of fatal outcomes from all causes were obtained in the candesartan and placebo groups (hazard ratio=0.91, 95% confidence interval 0.83-1.00, p=0.055).

The reduction in the frequency of fatal outcomes or the frequency of hospitalizations for chronic heart failure during therapy with candesartan did not depend on age, sex and concomitant therapy.

Candesartan was also effective in patients taking beta-blockers in combination with ACE inhibitors, and the effectiveness of candesartan did not depend on whether the patient was taking the optimal dose of an ACE inhibitor or not.

In patients with chronic heart failure and reduced systolic function of the left ventricle (LVEF≤40%), taking candesartan contributed to a decrease in total peripheral vascular resistance and capillary pressure in the lungs, an increase in renin activity and the concentration of angiotensin II in plasma, as well as a decrease in the level of aldosterone.

Pharmacokinetics

Absorption and distribution

Candesartan cilexetil is a prodrug. Candesartan cilexetil after oral administration is rapidly converted into the active substance – Candesartan, by ester hydrolysis during absorption from the digestive tract, binds firmly to AT₁ receptors and slowly dissociates, has no agonist properties.

The absolute bioavailability of candesartan after oral administration is approximately 40%. The relative bioavailability of the drug in tablet form is approximately 34% compared to the oral solution. Thus, the calculated absolute bioavailability of the tablet form of the drug is 14%. C_max in blood serum is reached 3-4 hours after taking the drug in tablet form.

When the drug dose is increased within the recommended limits, the concentration of candesartan increases linearly.

The pharmacokinetic parameters of candesartan do not depend on the patient’s sex.

Food intake does not have a significant effect on AUC, i.e., simultaneous food intake does not significantly affect the bioavailability of the drug. Candesartan is actively bound to plasma proteins (> 99%). V_d of candesartan is 0.1 l/kg.

Metabolism and excretion

Candesartan is mainly excreted from the body by the kidneys and with bile unchanged and only to a small extent metabolized in the liver. T_1/2 of candesartan is approximately 9 hours. Accumulation in the body is not observed. The total clearance of candesartan is about 0.37 ml/min/kg, while renal clearance is about 0.19 ml/min/kg. Renal excretion of candesartan is carried out by glomerular filtration and active tubular secretion. When taking radioactively labeled candesartan cilexetil orally, about 26% of the administered amount is excreted by the kidneys in the form of candesartan and 7% in the form of an inactive metabolite, while 56% of the administered amount is found in the feces in the form of candesartan and 10% in the form of an inactive metabolite.

Pharmacokinetics in special patient groups

In elderly patients (over 65 years old) C_max and AUC of candesartan increase compared to young patients by approximately 50% and 80%, respectively, compared to young patients. However, the hypotensive effect and the frequency of adverse reactions when using the drug candesartan do not depend on the age of the patients.

Renal insufficiency. In patients with mild or moderate renal impairment, C_max and AUC of candesartan increase by approximately 50% and 70%, respectively, while T_1/2 does not change compared to patients with normal renal function. In patients with severe renal impairment, C_max and AUC increase by 50% and 110%, respectively, and the T_1/2 of the drug doubles. Pharmacokinetics in patients on hemodialysis is similar to that in patients with severe renal impairment.

Hepatic insufficiency. In two studies involving patients with mild or moderate hepatic impairment, an increase in the mean AUC of candesartan by approximately 20% was noted in one study and by 80% in the other. There is no experience of use in patients with severe hepatic impairment.

Indications

For adults aged 18 years and over

• Arterial hypertension;
• Chronic heart failure (CHF) and impaired systolic function of the left ventricle (LVEF ≤40%) as an additional therapy to ACE inhibitors or in case of intolerance to ACE inhibitors (see section “Pharmacological action”).

ICD codes

Dosage Regimen

Tablets

The drug is taken orally, once a day, regardless of the time of meal.

Arterial hypertension

The recommended initial and maintenance dose of Hyposart is 8 mg once a day. The dose can be increased to 16 mg once a day. If blood pressure was not sufficiently reduced after 4 weeks of taking Hyposart at a dose of 16 mg/day, it is recommended to increase the dose to 32 mg once a day.

In case therapy with Hyposart does not lead to a reduction in blood pressure to an optimal level, it is recommended to add a thiazide diuretic to the therapy.

Therapy should be adjusted according to the blood pressure level.

The maximum antihypertensive effect is achieved within 4 weeks from the start of treatment.

In elderly patients there is no need to adjust the initial dose of the drug.

In patients with mild or moderate renal impairment (CC 30-80 ml/min/), including patients on hemodialysis, the initial dose of the drug is 4 mg (1/2 of an 8 mg tablet). The dose should be titrated depending on the therapeutic effect of the drug. Clinical experience with the drug in patients with severe renal impairment or end-stage renal failure (CC<15 ml/min) is limited (see section “Special instructions”).

In patients with mild to moderate hepatic impairment it is recommended to start treatment with a daily dose of 4 mg (1/2 of an 8 mg tablet) once a day. The dose may be increased if necessary. Hyposart is contraindicated in patients with severe hepatic impairment and/or cholestasis(see section “Contraindications”).

Concomitant therapy

The use of Hyposart together with thiazide-type diuretics (for example, hydrochlorothiazide) may enhance the antihypertensive effect of the drug.

Chronic heart failure

The recommended initial dose of Hyposart is 4 mg (1/2 of an 8 mg tablet) once a day. Increasing the dose to 32 mg once a day or to the maximum tolerated dose is carried out by doubling it at intervals of at least 2 weeks (see section “Special instructions”).

Concomitant therapy

Hyposart can be prescribed in combination with other agents used in the therapy of chronic heart failure, for example, ACE inhibitors, beta-blockers, diuretics and cardiac glycosides (see section “Special instructions”).

Children

The safety and efficacy of Hyposart in children and adolescents (under 18 years of age) have not been established (see section “Contraindications”).

Adverse Reactions

Arterial hypertension

Adverse reactions (AR) in clinical trials were moderate and transient and were comparable in frequency to the placebo group. The overall frequency of AR during candesartan administration did not depend on the dose of the drug and the age of the patient. The frequency of therapy discontinuation due to side effects was similar when using candesartan (3.1%) and placebo (3.2%).

In the combined analysis of data from conducted studies, the following ARs were reported, often (>1/100) occurring during candesartan administration. The described ARs were observed with a frequency at least 1% greater than in the placebo group. According to this definition, dizziness/vertigo, weakness, headache and respiratory infections were most often noted.

Tabular summary of adverse reactions

The table below presents ARs noted in clinical trials and post-marketing use.

The frequency of ARs is presented in the following gradation: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000).

Laboratory parameters increased concentration of creatinine and urea, increased potassium content. It is recommended to monitor the concentration of creatinine and the content of potassium in the blood serum.

Contraindications

• Hypersensitivity to candesartan cilexetil or to any of the excipients included in the drug;
• Severe hepatic impairment and/or cholestasis;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety have not been established);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
• Simultaneous use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Simultaneous use with ACE inhibitors in patients with diabetic nephropathy.

With caution

Severe renal failure (CC less than 30 ml/min), bilateral renal artery stenosis or stenosis of the artery of a single kidney, history of kidney transplantation, hemodynamically significant stenosis of the aortic and mitral valve, in patients with cerebrovascular diseases and coronary artery disease, hyperkalemia, in patients with reduced circulating blood volume, with primary hyperaldosteronism (there is not enough data from clinical studies), hypertrophic obstructive cardiomyopathy .

Use in Pregnancy and Lactation

Pregnancy

The use of Hyposart during pregnancy is contraindicated (see section “Contraindications”). Patients taking the drug should be warned about this before planning pregnancy so that they can discuss alternative treatment options with their doctor.

If pregnancy is diagnosed, therapy with Hyposart should be discontinued immediately and, if necessary, alternative treatment should be prescribed. Drugs that have a direct effect on the RAAS can cause fetal developmental disorders or have a negative effect on the newborn, including death, when used during pregnancy.

It is known that therapy with angiotensin II receptor antagonists (ARAs) can cause fetal developmental disorders (impaired renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

Breastfeeding period

It is currently unknown whether Candesartan is excreted in breast milk. However, Candesartan passes into the milk of lactating rats. Due to the possible adverse effects on breastfed infants, Hyposart should not be used during breastfeeding.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment and/or cholestasis.

Use in Renal Impairment

The drug should be prescribed with caution in severe renal impairment (creatinine clearance less than 30 ml/min), in patients on hemodialysis, with bilateral renal artery stenosis or stenosis of the artery of a single kidney, and in patients with a history of kidney transplantation.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age (efficacy and safety have not been established).

Geriatric Use

No initial dose adjustment is required for elderly patients.

Special Precautions

Renal impairment

During therapy with candesartan, as with the use of other agents affecting or acting on the RAAS, some patients may experience impaired renal function.

When using candesartan in patients with arterial hypertension and severe renal failure (creatinine clearance less than 30 ml/min), periodic monitoring of serum potassium and creatinine levels is recommended. Clinical experience with the drug in patients with severe renal impairment or end-stage renal disease is limited (creatinine clearance less than 15 ml/min). In such patients, the dose of Hyposart should be carefully titrated under close blood pressure monitoring.

In patients with chronic heart failure, renal function should be monitored periodically, especially in patients aged 75 years and older, and in patients with impaired renal function.

When increasing the dose of Hyposart, monitoring of potassium levels and creatinine concentration is also recommended.

Clinical trials of candesartan in chronic heart failure did not include patients with serum creatinine >265 µmol/L (>3 mg/dL).

Concomitant use with ACE inhibitors in chronic heart failure

When candesartan is used in combination with ACE inhibitors, the risk of adverse reactions (ARs) may increase, especially impaired renal function and hyperkalemia (see the “Adverse Reactions” section). In these cases, careful observation and monitoring of laboratory parameters is necessary.

Hemodialysis

During hemodialysis, blood pressure may be particularly sensitive to AT₁ receptor blockade due to reduced plasma volume and activation of the RAAS. Therefore, patients on hemodialysis should have candesartan carefully titrated under close blood pressure monitoring.

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, drugs affecting the RAAS, in particular ACE inhibitors, can cause an increase in serum urea and creatinine levels. Similar effects can be expected with the use of angiotensin II receptor antagonists.

Kidney transplantation

Clinical experience with candesartan in patients who have undergone kidney transplantation is limited.

Arterial hypotension

In patients with chronic heart failure, arterial hypotension may develop during therapy with candesartan. As with the use of other drugs affecting the RAAS, the cause of arterial hypotension in patients with hypertension may be a decrease in circulating blood volume, as observed in patients receiving high doses of diuretics. Therefore, caution should be exercised at the beginning of therapy and, if necessary, hypovolemia should be corrected.

Dual blockade of the RAAS

Dual blockade of the RAAS by combining candesartan cilexetil and aliskiren is not recommended due to an increased risk of arterial hypotension, hyperkalemia, and changes in renal function. The concomitant use of angiotensin II receptor antagonists with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients. The concomitant use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see the “Contraindications” section).

General anesthesia and surgery

In patients receiving angiotensin II antagonists, arterial hypotension may develop during general anesthesia and surgery as a result of RAAS blockade. Very rarely, cases of severe arterial hypotension requiring intravenous administration of plasma substitutes and/or vasopressors may occur.

Aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy

When prescribing candesartan, as with other vasodilators, caution should be exercised in patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant stenosis of the aortic or mitral valve.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to antihypertensive therapy affecting the RAAS. Therefore, candesartan is not recommended for such patients.

Hyperkalemia

Clinical experience with other drugs affecting the RAAS shows that the concomitant administration of candesartan with potassium-sparing diuretics, potassium preparations, or potassium-containing salt substitutes, or other drugs that may increase blood potassium levels (e.g., heparin), can lead to the development of hyperkalemia in patients with hypertension.

In patients with chronic heart failure, hyperkalemia may develop during therapy with candesartan. When prescribing candesartan to patients with chronic heart failure, regular monitoring of blood potassium levels is recommended, especially when co-administered with ACE inhibitors and potassium-sparing diuretics.

General

Patients in whom vascular tone and renal function are predominantly dependent on RAAS activity (e.g., patients with severe chronic heart failure or kidney disease, including renal artery stenosis) are particularly sensitive to drugs acting on the RAAS. The administration of such agents in these patients is accompanied by sharp arterial hypotension, azotemia, oliguria, and less frequently, acute renal failure. The possibility of these effects cannot be excluded with the use of angiotensin II receptor antagonists. A sharp decrease in blood pressure in patients with coronary artery disease or atherosclerotic cerebrovascular disease with the use of any antihypertensive agents may lead to myocardial infarction or stroke.

Excipients

Hyposart contains lactose monohydrate. Patients with rare hereditary diseases such as galactose intolerance, lactose intolerance due to lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicinal product.

Effect on ability to drive vehicles and operate machinery

The effect on the ability to drive a car or operate machinery has not been studied, but the pharmacodynamic properties of the drug indicate that there is no such effect.

When driving vehicles and engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions, it should be taken into account that dizziness and increased fatigue may occur when using the drug.

Overdose

Symptoms analysis of the pharmacological properties of the drug suggests that the main manifestation of an overdose may be a clinically significant decrease in blood pressure and dizziness. Isolated cases of drug overdose (up to 672 mg of candesartan cilexetil) have been described, resulting in patient recovery without serious consequences.

Treatment if a clinically significant decrease in blood pressure develops, symptomatic treatment and monitoring of the patient’s condition should be carried out. Place the patient in a supine position, elevate the foot of the bed. If necessary, the circulating blood volume should be increased, for example, by intravenous administration of 0.9% sodium chloride solution. If necessary, sympathomimetic drugs may be prescribed. Candesartan is not removed by hemodialysis.

Drug Interactions

The concomitant use of angiotensin II receptor antagonists with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients. The concomitant use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see the “Contraindications” and “Special Precautions” sections).

Pharmacokinetic studies have examined the combined use of candesartan with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinyl estradiol/levonorgestrel), glibenclamide, nifedipine, and enalapril. No clinically significant pharmacokinetic interaction was identified.

Candesartan is metabolized in the liver to a small extent (by the CYP2C9 isoenzyme). Conducted interaction studies have not revealed an effect of the drug on the CYP2C9 and CYP3A4 isoenzymes. The effect on other cytochrome P450 system isoenzymes has not been studied.

Concomitant use of candesartan with other antihypertensive agents potentiates the antihypertensive effect.

Experience with other drugs acting on the RAAS shows that concomitant therapy with potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes, and other agents that may increase serum potassium levels (e.g., heparin) can lead to the development of hyperkalemia.

When lithium preparations are co-administered with ACE inhibitors, reversible increases in serum lithium concentrations and the development of toxic reactions have been reported. Similar reactions may occur with the use of angiotensin II receptor antagonists, and therefore monitoring of serum lithium concentration is recommended when these drugs are used in combination.

When angiotensin II receptor antagonists and NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid (more than 3 g/day), are used concomitantly, a decrease in the antihypertensive effect may be observed.

As with the use of ACE inhibitors, the concomitant use of angiotensin II receptor antagonists and NSAIDs may increase the risk of impaired renal function, including acute renal failure, and increased serum potassium, especially in patients with reduced renal function. Caution should be exercised when these drugs are used concomitantly, especially in elderly patients and in patients with reduced circulating blood volume. Patients should compensate for fluid loss and have renal function monitored regularly after starting combination therapy and periodically during such therapy.

The bioavailability of candesartan is not affected by food intake.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging (blister pack in a carton), at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.