Candesar

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

Composition:

Active substance: candesartan;

1 tablet contains 32 mg of candesartan cilexetil;

Excipients: lactose monohydrate; corn starch; hydroxypropylcellulose; macrogol; calcium carboxymethylcellulose; magnesium stearate; iron oxide red (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties: mottled oval pink tablets, engraved with "C" and "12" on both sides of the break line on one side and with a break line on the other side.

Pharmacotherapeutic group.

Agents acting on the renin-angiotensin system. Angiotensin II receptor antagonists, plain. ATC code C09CA06.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system, playing a role in the pathophysiological mechanism of hypertension, heart failure, and other cardiovascular diseases. It is also involved in the pathogenesis of organ 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 a selective angiotensin II receptor (AT1 subtype) antagonist with strong binding and slow dissociation from the receptor. It has no agonistic activity.

Candesartan does not inhibit angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II and degrades bradykinin. There is no effect on ACE 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.

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 oral solution is approximately 34%. Thus, the calculated absolute bioavailability of the tablet is 14%. The mean peak serum concentration (Cmax) is reached 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 the pharmacokinetics of candesartan have been 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 a minor contribution from hepatic metabolism (CYP2C9). Based on in vitro data, no in vivo interactions are expected with drugs whose metabolism depends on the cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. The terminal half-life of candesartan is approximately 9 hours. There is no accumulation after multiple dosing.

The total plasma clearance of candesartan is approximately 0.37 mL/min/kg, with renal clearance of about 0.19 mL/min/kg. Renal elimination of candesartan occurs 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 dosage forms 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 administration, but 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 twice as long in patients with severe renal impairment. The AUC of candesartan in patients undergoing hemodialysis is similar to that in patients with severe renal impairment.

In two studies including patients with moderate hepatic impairment, mean AUC of candesartan increased by approximately 20% in one study and by 80% in another (see section "Dosage and administration"). There is no experience with the use of the drug in patients with severe hepatic impairment.

Clinical characteristics.

Indications.

Treatment of essential hypertension in adults.

Treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤ 40%): in cases of intolerance to ACE inhibitors or as add-on therapy to ACE inhibitor therapy in symptomatic heart failure despite optimal treatment, and in cases of intolerance to mineralocorticoid receptor antagonists.

Contraindications.

Hypersensitivity to candesartan cilexetil or to any of the excipients.

Severe hepatic impairment and/or cholestasis.

Concomitant use of the medicinal product Kandesar and medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR [glomerular filtration rate] < 60 mL/min/1.73 m²).

Pregnancy or breastfeeding. Planning of pregnancy. Pediatric age.

Interaction with other medicinal products and other forms of interactions.

Medicinal products studied in clinical pharmacokinetic trials include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glipizide, 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").

Elevated serum lithium concentrations and toxicity have been reported with concomitant use of lithium and ACE inhibitors. A similar effect may occur with the use of ARBs II. Concomitant use of candesartan with lithium is not recommended. If combination therapy is considered necessary, careful monitoring of serum lithium levels is recommended.

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

As with ACE inhibitors, concomitant use of ARBs II and NSAIDs increases the risk of worsening renal function, including 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 renal function should be monitored 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 hypotension, hyperkalemia, and worsening 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 indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and deterioration in renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended. If dual blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.

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

Renal impairment

As with other drugs that inhibit the renin-angiotensin-aldosterone system, changes in renal function may be expected in susceptible patients receiving Candesart.

When Candesart is administered to patients with hypertension and impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Experience with the use of the drug 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 selected cautiously, 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.

Concomitant therapy with ACE inhibitors in heart failure

The risk of adverse reactions, particularly hypotension, hyperkalemia, and worsening renal function (including acute renal failure), increases 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. Such combinations should be used only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.

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

Hemodialysis

During dialysis, blood pressure may be particularly sensitive to AT1-receptor blockade due to reduced plasma volume and activation of the renin-angiotensin-aldosterone system. Therefore, the dose of Candesart should be selected cautiously in patients undergoing hemodialysis, with monitoring of blood pressure.

Renal artery stenosis

Drugs affecting the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (ARBs), may increase serum uric acid and creatinine levels in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Kidney transplantation

Experience with the use of Candesart in patients with recently transplanted kidneys is lacking.

Arterial hypotension

In patients with heart failure, treatment with Candesart may lead to hypotension. It may also occur in patients with arterial hypertension who have intravascular volume depletion, such as those receiving high-dose diuretics. Therapy should be initiated cautiously, and measures 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.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting through suppression of the renin-angiotensin-aldosterone system. Therefore, the use of Candesart in this population is not recommended.

Hyperkalemia

Concomitant use of Candesart with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may increase potassium levels (e.g., heparin) may lead to elevated serum potassium levels in patients with hypertension. Serum potassium levels should be appropriately monitored.

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; its use should be considered only after careful evaluation of potential benefits and risks.

General

In patients in whom vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other drugs affecting this system has been associated with acute hypotension, azotemia, oliguria, or rarely, acute renal failure. The possibility of such effects cannot be excluded with ARBs. 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 prescribed as antihypertensives or used for other indications.

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

Use during pregnancy or breastfeeding

Use of this medicinal product during pregnancy is contraindicated. Candesart is not recommended for use during breastfeeding.

Pregnancy

Epidemiological data on the teratogenic risk associated with ACE inhibitors in the first trimester of pregnancy do not allow definitive conclusions; however, a slight increase in risk cannot be excluded. Since controlled epidemiological data on the risk of using ARBs are lacking, similar risks may exist with this class of drugs. Alternative antihypertensive therapy with an established safety profile during pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, treatment with ARBs should be discontinued immediately, and alternative therapy initiated if necessary.

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

Breastfeeding

Due to the lack of information on the use of Candesart during breastfeeding, Candesart is not recommended. Alternative therapies with better-established safety profiles during breastfeeding should be preferred, especially when nursing 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 considered that dizziness or increased fatigue may occasionally occur during treatment with Candesart.

Administration and Dosage

Candesar should be taken once daily, regardless of food intake. Food does not affect the bioavailability of candesartan.

The tablet may be divided into two equal parts.

The medicinal product Candesar, 32 mg tablets, is not intended for initial treatment of essential hypertension or heart failure.

Dosing in essential hypertension

The recommended initial and usual maintenance dose of the medicinal product Candesar is 8 mg once daily. In most patients, the antihypertensive effect is achieved within 4 weeks. For 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 can 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 of circulating blood

For patients at risk of developing arterial hypotension, such as dehydrated patients, an initial dose of 4 mg may be appropriate (see section "Special precautions").

Patients with impaired renal function

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

Patients with impaired liver function

For patients with mild to moderate hepatic impairment, the recommended initial dose is 4 mg once daily. The dose may be adjusted according to 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 increasing the dose 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 in 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 can 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 intolerance to mineralocorticoid receptor antagonists, Candesar may be used concomitantly with ACE inhibitors. Combination of an ACE inhibitor, a potassium-sparing diuretic, and Candesar is not recommended; such combination may be considered only after careful assessment of potential benefits and risks (see sections "Special precautions", "Undesirable effects", and "Pharmacological properties").

Special patient groups

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

Children. Safety and efficacy of Candesar in children have not been established.

Overdose.

Symptoms

Based on the pharmacological properties of the medicinal product, the main manifestations of overdose are likely to be symptomatic hypotension and dizziness. In some cases of overdose (with doses up to 672 mg of candesartan cilexetil), recovery without complications has been reported.

Treatment

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

Adverse reactions.

Treatment of arterial hypertension

Adverse reactions observed during clinical studies were mild and transient. No correlation between the overall incidence of adverse events and dose or age was noted. 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 data from studies involving patients with hypertension, adverse reactions were defined as adverse events occurring with a frequency at least 1% higher with candesartan cilexetil than with placebo. According to this definition, the most commonly reported adverse reactions were dizziness/vertigo, headache, and respiratory tract infections.

The table below presents adverse reactions reported during clinical trials and post-marketing surveillance.

The following frequency definitions are used in the tables of this section: 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).

Laboratory test results

In most cases, the medicinal product Candesar had no clinically significant effect on routine laboratory parameters. As with other inhibitors of the renin-angiotensin-aldosterone system, a slight decrease in hemoglobin levels has been observed. Routine monitoring of laboratory parameters is usually not required in patients receiving Candesar. However, periodic monitoring of serum potassium and creatinine levels is recommended for patients with renal impairment.

The table below presents adverse reactions reported during clinical trials and post-marketing surveillance.

Laboratory test results

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 tablets per blister, 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Manufacturer's address.

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