Instructions for Cantab tablets 16 mg blister No. 28
Composition
active ingredient: candesartan cilexetil;
1 tablet contains candesartan cilexetil 8 mg or 16 mg or 32 mg;
Excipients: lactose monohydrate, corn starch, polyethylene glycol 8000, low-substituted hydroxypropylcellulose, calcium carboxymethylcellulose, red iron oxide (E 172), magnesium stearate.
Dosage form
Pills.
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 C09C A06.
Pharmacological properties
Pharmacodynamics.
Angiotensin II is the main vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS), which plays a role in the pathophysiological mechanism of the development of arterial hypertension, heart failure and other cardiovascular diseases. The main physiological effects of angiotensin II, such as vasoconstriction, stimulation of aldosterone, regulation of salt and water homeostasis and stimulation of cell growth, occur with the participation of type 1 receptors (AT1).
Candesartan cilexetil is an orally administered prodrug. It is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist (ARB) that is selective for the AT1 receptor, with tight binding and slow dissociation from the receptor. It does not exhibit agonist activity.
Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and destroys bradykinin. No effect on ACE or enhancement of bradykinin or substance P was observed. In studies comparing candesartan with ACE inhibitors, the incidence of cough was lower in patients taking candesartan cilexetil. Candesartan does not bind to or block receptors for other hormones or ion channels important in the regulation of the cardiovascular system. Antagonism of angiotensin II (AT1) receptors leads to a dose-dependent increase in plasma renin, angiotensin I and angiotensin II levels, as well as a decrease in plasma aldosterone concentrations.
Arterial hypertension
In hypertension, candesartan causes a dose-dependent long-term reduction in blood pressure. The antihypertensive effect is due to a decrease in systemic peripheral resistance without a reflex increase in heart rate. There is no evidence of serious or increased arterial hypotension after the first dose or of a withdrawal syndrome after discontinuation of treatment.
After a single dose of candesartan cilexetil, the onset of the antihypertensive effect is observed in most cases within 2 hours. With long-term treatment, the main reduction in blood pressure is usually achieved within four weeks at all doses and is maintained during long-term treatment. According to the meta-analysis, the average additional effect when increasing the dose from 16 mg to 32 mg 1 time per day was small. Taking into account interindividual differences, a more pronounced than average effect can be expected in some patients. Candesartan cilexetil, when administered once daily, provides effective and smooth blood pressure reduction over 24 hours with a small difference between maximum and minimum effects during the dosing interval.
An additive reduction in blood pressure is observed when candesartan cilexetil is used together with hydrochlorothiazide. An enhanced antihypertensive effect is also observed when candesartan cilexetil is combined with amlodipine or felodipine.
Drugs that block the renin-angiotensin-aldosterone system tend to have a less pronounced antihypertensive effect in black patients (who usually constitute a low-renin population) than in non-blacks. This is also true for candesartan.
Candesartan increases renal blood flow and/or has no effect on or increases 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, reduces hospitalizations for heart failure, and improves 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 concentrations, and reduces aldosterone levels.
Pharmacokinetics.
After oral administration of candesartan cilexetil, it is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after oral administration of candesartan cilexetil solution. The relative bioavailability of the tablet formulation compared to the same oral solution is approximately 34% with very little variability. The calculated absolute bioavailability of the tablet is 14%. The mean peak serum concentration (Cmax) is reached 3-4 hours after tablet administration. The serum concentration of candesartan increases linearly with increasing doses within the therapeutic dosage range. No differences in the pharmacokinetics of candesartan depending on the patient's gender have been identified. The area under the serum concentration-time curve (AUC) of candesartan is not significantly affected by food.
Candesartan is highly bound to plasma proteins (more than 99%). The estimated volume of distribution of candesartan is 0.1 l/kg.
The bioavailability of candesartan is not affected by food.
Metabolism and excretion
Candesartan is excreted mainly unchanged in the urine and bile and only to a minor extent by hepatic metabolism (CYP2C9). Based on in vitro data, no in vivo interactions with drugs metabolized by the cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 are expected. The terminal elimination 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 a renal clearance of approximately 0.19 ml/min/kg. Candesartan is eliminated by the kidneys by both glomerular filtration and active tubular secretion. Following oral administration of 14C-labelled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite, while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as an inactive metabolite.
Pharmacokinetics in special patient populations
In elderly patients (aged 65 years and older), the Cmax and AUC of candesartan were increased by approximately 50% and 80%, respectively, compared with young patients. However, the blood pressure response and the incidence of adverse events were similar after dosing in young and elderly patients.
In patients with mild and moderate renal impairment, Cmax and AUC of candesartan increased with repeated dosing by approximately 50% and 70%, respectively, but the mean elimination half-life (t1/2) remained unchanged compared to patients with normal renal function. The 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. The AUC of candesartan in patients on hemodialysis was close to that in patients with severe renal impairment.
There is no experience with the use of the drug in patients with severe hepatic insufficiency.
Indication
Treatment of essential hypertension in adults.
Treatment of heart failure and left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 40%) in adult patients as add-on therapy to treatment with angiotensin-converting enzyme (ACE) inhibitors or in cases of intolerance to ACE inhibitors.
Contraindication
Hypersensitivity to candesartan cilexetil or to any of the excipients.
Severe hepatic insufficiency and/or cholestasis.
In patients with diabetes mellitus or impaired renal function (GFR <60 ml/min/1.73 m2), the simultaneous use of Cantab and drugs containing aliskiren is contraindicated.
Interaction with other medicinal products and other types of interactions
Drugs studied in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinyl estradiol/levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically significant pharmacokinetic interactions were observed with these drugs.
Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products (e.g. heparin) may increase potassium levels. Potassium levels should be monitored appropriately.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium and ACE inhibitors.
A similar effect may be observed with AIIRAs. The use of candesartan with lithium is not recommended. If the combination is confirmed, careful monitoring of serum lithium levels is recommended.
As with ACE inhibitors, concomitant use of ARBs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure and an increase in serum potassium, particularly in patients with compromised renal function at the start of treatment. The combination should be used with caution, especially in elderly patients. The patient should be adequately hydrated and attention should be paid to monitoring renal function after initiation of concomitant therapy and periodically thereafter.
Clinical trial data suggest that dual blockade of the RAAS through the 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 with the use of a RAAS-acting agent alone.
Application features
Dual blockade of RAAS
There is evidence that the 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 through the combined use of 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 and 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.
Kidney failure
As with other RAAS-inhibiting agents, changes in renal function may be expected in susceptible patients taking the drug.
When using the drug in patients with arterial hypertension and renal failure, periodic monitoring of serum potassium and creatinine levels is recommended.
Experience in patients with very severe or end-stage renal disease (creatinine clearance <15 ml/min) is limited. In such patients, the dose should be adjusted with caution and blood pressure should be closely monitored.
Monitoring of patients with heart failure should include periodic assessment of renal function, especially in elderly patients (aged 75 years and over) and in patients with impaired renal function. Monitoring of serum creatinine and potassium is recommended during dose adjustment. Patients with serum creatinine > 265 μmol/L (> 3 mg/dL) should not be enrolled in clinical trials in heart failure.
Concomitant therapy with ACE inhibitors in heart failure
The risk of adverse reactions, especially hypotension, worsening of renal function (including acute renal failure) and hyperkalemia, may increase when the drug is used in combination with ACE inhibitors. The triple combination of an ACE inhibitor, a mineralocorticoid receptor antagonist and candesartan is also not recommended. The use of these combinations should only be carried out under specialist supervision and with frequent and 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.
Hemodialysis
During dialysis, blood pressure may be particularly sensitive to AT1 receptor blockade due to decreased plasma volume and activation of the RAAS. Therefore, in patients undergoing hemodialysis, the dose of the drug should be adjusted carefully, with blood pressure monitoring.
Renal artery stenosis
Medicinal products that affect the RAAS, including angiotensin II receptor antagonists (ARBs), may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.
Kidney transplantation
There is no experience with the use of the drug in patients with a recent kidney transplant.
Arterial hypotension
In patients with heart failure, hypotension may occur during treatment with the drug. It may also develop in patients with hypertension and intravascular dehydration due to high doses of diuretics. Therapy should be initiated with caution and measures should be taken to correct hypovolemia.
Anesthesia and surgical interventions
In patients receiving angiotensin II antagonists, hypotension may occur during anesthesia and surgery as a result of blockade of the renin-angiotensin system. Very rarely, hypotension may be severe and require intravenous fluids and/or the use of vasoconstrictors.
Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)
As with other vasodilators, it should be used with caution in patients with hemodynamically significant aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Patients with primary hyperaldosteronism are generally unresponsive to antihypertensive drugs that act by inhibiting the RAAS. Therefore, the use of the drug in such patients is not recommended.
Hyperkalemia
Concomitant use of the drug with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that may increase potassium levels (e.g. heparin) may lead to an increase in serum potassium levels in patients with arterial hypertension. Potassium levels should be monitored appropriately.
Hyperkalemia may occur in patients with heart failure receiving the drug. Periodic monitoring of serum potassium is recommended. The combination of ACE inhibitors, potassium-sparing diuretics (e.g. spironolactone) and candesartan is not recommended and should be used only after careful consideration of the potential benefits and risks.
General
In patients whose vascular tone and renal function depend predominantly on the activity of the RAAS (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products that affect this system has been associated with acute hypotension, azotemia, oliguria, and rarely acute renal failure. The possibility of similar effects cannot be excluded with ARBs. As with any antihypertensive agent, excessive reduction in blood pressure in patients with ischaemic cardiopathy or ischaemic cerebrovascular disease could result in myocardial infarction or stroke.
The antihypertensive effect of candesartan may be enhanced by other medicinal products with blood pressure-lowering properties, whether prescribed as antihypertensives or used for other indications.
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy
AIIRAs should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments that have a
A safety profile for use in pregnancy has been established. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.
In postmenarcheal patients, the possibility of becoming pregnant should be assessed on a general basis. Appropriate information should be provided and/or measures should be taken to prevent the risk of exposure to the drug during pregnancy (see sections “Contraindications” and “Use during pregnancy or lactation”).
Use during pregnancy or breastfeeding
The use of the drug during pregnancy is contraindicated. Cantab is not recommended for use during breastfeeding.
Pregnancy
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy is inconclusive, but a small increased risk cannot be excluded. In the absence of controlled epidemiological data on the risk with ARBs, similar risks may exist for this class of drugs. Unless continued ARB therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, ARB treatment should be stopped immediately, and, if appropriate, alternative therapy should be started.
Newborns whose mothers have received ARVIs require careful observation for arterial hypotension (see sections "Contraindications" and "Special Instructions").
Breastfeeding period
Since there is no information on the use of the drug during breastfeeding, Cantab is not recommended for use and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies have been conducted on the effects of candesartan on the ability to drive and use machines. However, it should be taken into account that dizziness or fatigue may occur during treatment with the drug.
Method of administration and doses
Method of application
Take internally.
The drug should be taken once a day, regardless of food intake.
Food intake does not affect the bioavailability of candesartan.
The recommended initial dose and usual maintenance dose of the drug is 8 mg 1 time per day. In most cases, the antihypertensive effect is achieved within 4 weeks. In some patients with insufficient blood pressure control, the dose may be increased to 16 mg 1 time per day and a maximum of 32 mg 1 time per day. Therapy requires correction according to the blood pressure response.
The maximum daily dose is 32 mg.
The drug can also be used in combination with other antihypertensive agents. The addition of hydrochlorothiazide has been shown to provide an additional antihypertensive effect with various doses of the drug.
Use in elderly patients.
Initial dose adjustment is not necessary when used in elderly patients.
Use in patients with decreased intravascular volume of circulating fluid.
A starting dose of 4 mg may be considered in patients at risk of hypotension, such as those with possible dehydration.
Use in renal insufficiency.
The initial dose in patients with renal insufficiency, including patients on hemodialysis, is 4 mg. The dose should be adjusted according to the response to treatment. Experience in patients with very severe or end-stage renal failure (creatinine clearance <15 ml/min) is limited.
Use in case of hepatic insufficiency.
A starting dose of 4 mg once daily is recommended for patients with mild to moderate hepatic impairment. The dose may be adjusted based on response to treatment. The drug is contraindicated in patients with severe hepatic impairment and/or cholestasis.
Application depending on race.
The antihypertensive effect of candesartan is less pronounced in black patients than in non-black patients. Therefore, the need for increased doses of the drug and the need for concomitant therapy to control blood pressure may occur more often in black patients than in non-black patients.
Dosage for heart failure.
The usual recommended starting dose of Cantab is 4 mg (1/2 tablet of Cantab 8 mg) once daily. Increases to the target dose of 32 mg once daily (maximum dose) or the highest tolerated dose are made by doubling the dose at intervals of at least 2 weeks. Examination of patients with heart failure should always include assessment of renal function, including monitoring of serum creatinine and potassium.
The drug can be used with other drugs for the treatment of heart failure, including ACE inhibitors, β-blockers, diuretics and digitalis or a combination of these drugs. The combination of ACE inhibitors, potassium-sparing diuretics (e.g. spironolactone) and the drug is not recommended; it should be used only after careful assessment of the potential benefits and risks.
Special categories of patients.
Initial dose adjustment is not necessary when using the drug in elderly patients or in patients with intravascular dehydration or renal insufficiency, or mild to moderate hepatic insufficiency.
Children.
The safety and efficacy of Cantab in children from birth to 18 years of age for the treatment of heart failure have not been established. Data are lacking.
Method of application
For oral use.
Cantab should be taken once a day, regardless of food intake.
Food intake does not affect the bioavailability of candesartan.
Children.
The safety and effectiveness of Cantab in children have not been established.
Overdose
Symptoms: Given the pharmacological properties of the drug, the main manifestations of overdose are likely to be symptomatic hypotension and dizziness. In isolated cases of overdose (up to 672 mg candesartan cilexetil) patients have been reported to recover without sequelae.
Treatment: If symptomatic hypotension develops, symptomatic treatment should be instituted and vital signs monitored. The patient
should be placed in a supine position with the lower extremities elevated. If this is not sufficient, plasma volume should be increased by infusion, e.g.
0.9% sodium chloride solution. If the above measures are not sufficient, you can
Sympathomimetic drugs should be used. Candesartan is not removed by hemodialysis.
Side effects
Treatment of arterial hypertension
Adverse reactions observed during the studies were mild and transient. No relationship of the overall incidence of adverse events to dose or age was found.
Table 1 presents adverse reactions reported during clinical trials and post-marketing surveillance.
The following frequency definitions have been used: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000) and very rare (< 1/10,000).
Table 1
| System classes | Frequency | Undesirable effect |
| Infections and infestations | often | Respiratory tract infections |
| Blood and lymphatic system disorders | very rarely | Leukopenia, neutropenia and agranulocytosis |
| Metabolism and nutrition | very rarely | Hyperkalemia, hyponatremia |
| often | Dizziness/vertigo, headache |
| Respiratory, thoracic and mediastinal disorders | very rarely | Cough |
| From the digestive tract | very rarely | Nausea |
| Liver and biliary tract disorders | very rarely | Elevated liver enzymes, liver dysfunction, or hepatitis |
| Skin and subcutaneous tissue disorders | very rarely | Angioedema, rash, urticaria, pruritus |
| Musculoskeletal and connective tissue disorders | very rarely | Back pain, arthralgia, myalgia |
| Renal and urinary disorders | very rarely | Deterioration of renal function, including renal failure in susceptible patients |
Laboratory test results
In most cases, there was no clinically significant effect of the drug on routine laboratory parameters. As with other RAAS inhibitors, a slight decrease in hemoglobin levels was noted. Usually, there is no need for constant monitoring of laboratory parameters for patients taking the drug. However, periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal insufficiency.
Table 2 presents data on adverse reactions observed during studies and post-marketing surveillance.
Heart failure treatment
The adverse reaction profile of Cantab in adult patients with heart failure was consistent with the pharmacological properties of the drug and the patient's medical condition. The most frequently reported adverse reactions were hyperkalemia, hypotension, and renal dysfunction. These events were more common in patients aged 70 years or older, diabetic patients, or patients receiving other drugs that affect the RAAS, including ACE inhibitors and/or spironolactone.
Table 2
| System classes | Frequency | Undesirable effect |
| Blood and lymphatic system disorders | very rarely | Leukopenia, neutropenia and agranulocytosis |
| Metabolism and nutrition | often | Hyperkalemia |
| very rarely | Hyponatremia |
| From the nervous system | very rarely | Dizziness, headache |
| Respiratory system | very rarely | Cough |
| From the vascular side | often | Arterial hypotension |
| Respiratory, thoracic and mediastinal disorders | very rarely | Cough |
| From the digestive tract | very rarely | Nausea |
| Liver and biliary tract disorders | very rarely | Elevated liver enzymes, liver dysfunction, or hepatitis |
| Skin and subcutaneous tissue disorders | very rarely | Angioedema, rash, urticaria, pruritus |
| Musculoskeletal and connective tissue disorders | very rarely | Back pain, arthralgia, myalgia |
| Renal and urinary disorders | often | Deterioration of renal function, including renal failure in susceptible patients |
Laboratory test results
Hyperkalemia and renal failure are common in patients treated for heart failure. Periodic monitoring of serum creatinine and potassium levels is recommended.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after a medicinal product has been authorised is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging.
Keep out of reach of children.
Packaging
8 mg: 14 tablets in a blister, 2 or 4 or 7 blisters in a cardboard box.
16 mg and 32 mg: 14 tablets in a blister, 2 or 4 or 6 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
NOBEL ILACH SANAI VE TJARET A.Sh.
Address
Sankaklar Quarter, Eski Akcakoca Ave., No. 299, 81100 Duzce, Turkey.
