Cantab

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KANTAB (CANTAB)

Composition:

Active substance: candesartan cilexetil;

1 tablet contains 8 mg, 16 mg, or 32 mg of candesartan cilexetil;

Excipients: lactose monohydrate, corn starch, polyethylene glycol 8000, low-substituted hydroxypropyl cellulose, calcium carboxymethylcellulose, iron oxide red (E 172), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

8 mg tablets: round, dark pink tablets, with a break line on one side;

16 mg, 32 mg tablets: round, pink tablets, with a break line on one side.

Pharmacotherapeutic group.

Angiotensin II receptor antagonists. ATC code C09CA06.

Pharmacological properties.

Pharmacodynamics.

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

Candesartan cilexetil is a prodrug suitable for oral administration. 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 antagonist (ARB II) with high affinity for AT1 receptors, exhibiting tight binding and slow dissociation from the receptor. It has no agonistic activity.

Candesartan does not inhibit angiotensin-converting enzyme (ACE), which converts angiotensin I into angiotensin II and degrades bradykinin. No influence on ACE or potentiation of bradykinin or substance P has been observed. In comparative studies between candesartan and 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 at angiotensin II receptors (AT1) leads to a dose-dependent increase in plasma levels of renin, angiotensin I, and angiotensin II, as well as a reduction in plasma aldosterone concentration.

Arterial hypertension

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

After a single dose of candesartan cilexetil, onset of the antihypertensive effect is typically observed within 2 hours in most cases. With long-term treatment, the main reduction in blood pressure at all doses is usually achieved within four weeks and is 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 inter-individual variability, a more pronounced than average effect may be expected in some patients. When administered once daily, candesartan cilexetil provides effective and smooth blood pressure reduction over 24 hours, with minimal difference between maximum and minimum effects during the dosing interval.

When candesartan cilexetil is used concomitantly with hydrochlorothiazide, an additional reduction in blood pressure is observed. Enhanced antihypertensive effects are also seen when candesartan cilexetil is combined with amlodipine or felodipine. Antihypertensive agents that block the renin-angiotensin-aldosterone system generally have a less pronounced effect in patients of non-black race (who typically belong to populations with low renin levels) compared to other racial groups. This also applies to candesartan.

Candesartan increases or has no effect on, or may increase, renal blood flow and/or glomerular filtration rate (GFR) by reducing renal vascular resistance and filtration fraction. There are no data on the effect of candesartan on the progression of diabetic nephropathy.

Heart failure

Treatment with candesartan cilexetil reduces mortality, decreases hospitalizations due to heart failure, and alleviates symptoms in patients with left ventricular systolic dysfunction.

In patients with chronic heart failure (CHF) and reduced left ventricular systolic function (left ventricular ejection fraction, LVEF ≤ 40%), candesartan reduces systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases 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% following oral administration of a solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared to the same oral solution is about 34%, with very low variability. 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 differences in candesartan pharmacokinetics based on patient sex have been observed. The area under the serum concentration-time curve (AUC) of candesartan is not significantly affected by food intake.

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

The bioavailability of candesartan is not altered by food.

Metabolism and elimination

Candesartan is primarily excreted unchanged in urine and bile, with only minor hepatic metabolism (via CYP2C9). Based on in vitro studies, 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 doses.

Total plasma clearance of candesartan is approximately 0.37 mL/min/kg, with renal clearance of about 0.19 mL/min/kg. Renal excretion of candesartan occurs via both glomerular filtration and active tubular secretion. After oral administration of radiolabeled 14C-candesartan cilexetil, 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 were increased by approximately 50% and 80%, respectively, compared to younger patients. However, blood pressure response and incidence of adverse events were similar after dosing in younger and elderly patients.

In patients with mild to moderate renal impairment, Cmax and AUC of candesartan increased by approximately 50% and 70%, respectively, upon repeated dosing, while the mean half-life (t1/2) remained unchanged compared to patients with normal renal function. Corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal t1/2 of candesartan was approximately doubled in patients with severe renal impairment. AUC of candesartan in patients undergoing hemodialysis was similar to that in patients with severe renal impairment.

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 heart failure and left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 40%) in adults, as additional therapy to treatment with angiotensin-converting enzyme (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 Cantab and medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (GFR <60 mL/min/1.73 m²).

Interaction with other medicinal products and other forms of interaction.

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

Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products (e.g., heparin) may increase potassium levels. Serum potassium levels should therefore be appropriately monitored.

Cases of reversible increases in serum lithium concentrations and lithium toxicity have been reported during concomitant use of lithium and ACE inhibitors.

A similar effect may occur with the use of ARBs. Concomitant use of candesartan and lithium is not recommended. If combination therapy is considered necessary, careful monitoring of serum lithium levels is recommended.

When ARBs are administered concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., 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 an increase in serum potassium levels, particularly in patients with pre-existing impaired renal function. This combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and attention should be paid to monitoring renal function 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, hyperkalaemia, and deterioration of renal function (including acute renal failure), compared to treatment with a single medicinal product acting on the RAAS.

Special precautions for use.

Dual blockade of the RAAS

Evidence exists that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalaemia, and deterioration of 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 carried out only under specialist supervision and with frequent, careful monitoring of renal function, electrolytes, 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 agents acting on the RAAS, changes in renal function may be expected in sensitive patients receiving the drug.

When used in patients with hypertension and renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.

Experience with 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 should be carefully adjusted with careful 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 patients with impaired renal function. Monitoring of serum creatinine and potassium levels is recommended during dose titration. Patients with serum creatinine levels > 265 μmol/L (> 3 mg/dL) should not be included in clinical heart failure studies.

Concomitant therapy with ACE inhibitors in heart failure

The risk of adverse reactions, particularly hypotension, worsening of renal function (including acute renal failure), and hyperkalaemia, may increase when the drug is used in combination with ACE inhibitors. Triple combination therapy with an ACE inhibitor, a mineralocorticoid receptor antagonist, and candesartan is also not recommended. 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 blockers in patients with diabetic nephropathy.

Haemodialysis

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

Renal artery stenosis

Drugs affecting the RAAS, including angiotensin II receptor antagonists (ARBs), may increase blood urea and serum creatinine levels in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Kidney transplantation

There is no experience with use of the drug in patients who have recently undergone kidney transplantation.

Arterial hypotension

In patients with heart failure, arterial hypotension may occur during treatment with the drug. It may also develop in patients with hypertension and intravascular dehydration due to high-dose diuretic therapy. Therapy should be initiated cautiously, and measures taken to correct hypovolaemia.

Anaesthesia and surgery

In patients taking angiotensin II antagonists, arterial hypotension may occur during anaesthesia 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, caution should be exercised when administering the drug to patients with haemodynamically significant aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting via inhibition of the RAAS. Therefore, use of the drug in such patients is not recommended.

Hyperkalaemia

Concomitant use of the drug 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 hypertension. Serum potassium levels should be appropriately monitored.

Hyperkalaemia may occur in patients with heart failure receiving the drug. Periodic monitoring of serum potassium levels is recommended. Combination therapy with ACE inhibitors, potassium-sparing diuretics (e.g. spironolactone), and candesartan is not recommended and should be used only after careful assessment of potential benefits and risks.

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including candesartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, candesartan should be discontinued and appropriate monitoring initiated until symptoms have completely resolved.

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, azotaemia, oliguria, and rarely, acute renal failure. Such effects cannot be excluded with ARBs. As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic heart disease or ischaemic cerebrovascular disease may lead to myocardial infarction or stroke.

The antihypertensive effect of candesartan may be enhanced by other medicinal products that lower blood pressure, regardless of whether they are prescribed as antihypertensives or for other indications.

The drug 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 ARBs during pregnancy is not recommended. Except in cases where continuation of ARB therapy is considered absolutely necessary, alternative antihypertensive treatment with an established safety profile in pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, ARB therapy should be discontinued immediately and, if necessary, alternative therapy initiated.

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

Use during pregnancy or breastfeeding.

The use of the drug during pregnancy is contraindicated. Candesartan is not recommended for use during breastfeeding.

Pregnancy

Epidemiological data on teratogenic risk following exposure to ACE inhibitors during the first trimester of pregnancy do not allow definitive conclusions, but a small increased risk cannot be excluded. Since controlled epidemiological data on the risk with ARBs are lacking, similar risks may exist for this class of medicinal products. Except in cases where continuation of ARB therapy is considered absolutely necessary, alternative antihypertensive treatment with an established safety profile in pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, ARB therapy should be discontinued immediately and, if necessary, alternative therapy initiated.

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

Breastfeeding

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

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect of candesartan on the ability to drive or operate machinery have been conducted. However, it should be noted that dizziness or increased fatigue may occur during treatment with the drug.

Dosage and Administration

Administration

For oral use.

The medication should be taken once daily, regardless of food intake.

Food intake does not affect the bioavailability of candesartan.

Dosage in arterial hypertension.

The recommended initial and usual maintenance dose is 8 mg once daily. In most patients, the antihypertensive effect is achieved within 4 weeks. In some patients with insufficient 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.

Maximum daily dose – 32 mg.

The drug may also be used in combination with other antihypertensive agents. It has been shown that adding hydrochlorothiazide provides an additional antihypertensive effect with various doses of the drug.

Use in elderly patients.

Initial dose adjustment is not required in elderly patients.

Use in patients with reduced intravascular fluid volume.

An initial dose of 4 mg may be considered in patients at risk of developing arterial hypotension, such as those who may be dehydrated.

Use in renal impairment.

The initial dose in patients with renal impairment, including those on hemodialysis, is 4 mg. The dose should be titrated according to 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.

Use in hepatic impairment.

In 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. The drug is contraindicated in patients with severe hepatic impairment and/or cholestasis.

Use according to race.

The antihypertensive effect of candesartan is less pronounced in Black patients compared to patients of other races. Therefore, the need for dose escalation and concomitant therapy to control blood pressure may occur more frequently in Black patients than in individuals of other races.

Dosage in heart failure.

The usual recommended initial dose of Catab is 4 mg (1/2 tablet of Catab 8 mg) once daily. Titration 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. Evaluation of patients with heart failure should always include assessment of renal function, including monitoring of serum creatinine and potassium levels.

The drug may be used concomitantly with other medications for the treatment of heart failure, including ACE inhibitors, β-blockers, diuretics, and digoxin, or combinations thereof. The combination of ACE inhibitors, potassium-sparing diuretics (e.g., spironolactone), and this drug is not recommended and should be used only after careful assessment of potential benefits and risks.

Special patient groups.

Initial dose adjustment is not required when administering the drug to elderly patients or to patients with intravascular dehydration, renal impairment, or mild to moderate hepatic impairment.

Children.

The safety and efficacy of Catab 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.

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

Food intake does not affect the bioavailability of candesartan.

Children.

The safety and efficacy of Catab in children have not been established.

Overdose.

Symptoms. Given the pharmacological properties of the drug, the main manifestation of overdose is likely to be symptomatic arterial hypotension and dizziness. In individual cases of overdose (up to 672 mg of candesartan cilexetil), recovery without sequelae has been reported.

Treatment. If symptomatic arterial hypotension develops, symptomatic treatment should be initiated and vital signs 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 0.9% sodium chloride solution. If the above measures are inadequate, sympathomimetic drugs may be used. Candesartan is not removed by hemodialysis.

Adverse reactions.

Treatment of arterial hypertension

Adverse reactions observed during studies were mild and transient. No correlation between the overall frequency of adverse events and dose or age was identified.

Table 1 lists adverse reactions reported during clinical studies and post-marketing surveillance.

The following frequency definitions were used: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), and very rare (< 1/10,000).

Table 1

System Classes	Frequency	Adverse Reaction
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, intestinal angioedema
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	Worsening of kidney function, including renal failure in susceptible patients

Laboratory test results

In most cases, clinically significant effects of the drug on routine laboratory parameters were not observed. As with other RAAS inhibitors, a slight decrease in hemoglobin levels has been noted. Usually, patients taking the drug do not require continuous monitoring of laboratory parameters. However, in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.

Table 2 presents data on adverse reactions observed during clinical studies and post-marketing surveillance.

Treatment of heart failure

The adverse reaction profile of CANTAB in adult patients with heart failure was consistent with the pharmacological properties of the drug and the health status of the patients. The most commonly reported adverse reactions were hyperkalemia, arterial hypotension, and renal function disorders. These events were more frequently observed in patients aged 70 years and older, patients with diabetes mellitus, or patients receiving other medicinal products affecting the RAAS, particularly ACE inhibitors and/or spironolactone.

Table 2

System classes	Frequency	Adverse effect
Blood and lymphatic system disorders	very rare	Leukopenia, neutropenia and agranulocytosis
Metabolism and nutrition disorders	common	Hyperkalaemia
	very rare	Hypotension
Nervous system disorders	very rare	Dizziness, headache
Respiratory system disorders	very rare	Cough
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, impaired liver function 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	Worsening of kidney function, including renal failure in susceptible patients

Laboratory test results

Hyperkalemia and renal failure are commonly observed in patients receiving the drug for heart failure. Periodic monitoring of serum creatinine and potassium levels is recommended.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continued monitoring of the benefit-risk balance of the drug. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

8 mg: 14 tablets in a blister, 2, 4, or 7 blisters in a cardboard package.

16 mg and 32 mg: 14 tablets in a blister, 2, 4, or 6 blisters in a cardboard package.

Prescription category. Prescription only.

Manufacturer. NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of operations.

Sankaklar Quarter, Eskisehir Yolu Akcakoca Street No: 299, 81100 Duzce, Turkey.