Cantab plus

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CANTAB PLUS (CANTABPLUS)

Composition:

Active substances: candesartan cilexetil, hydrochlorothiazide;

One tablet contains 16 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide;

Excipients: lactose monohydrate, maize starch, polyethylene glycol, low-substituted hydroxypropylcellulose, calcium carboxymethylcellulose, yellow iron oxide (E 172), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: elongated light-yellow tablets with a notch on one side.

Pharmacotherapeutic group.

Angiotensin II receptor antagonists and diuretics. ATC code C09DA06.

Pharmacological properties.

Pharmacodynamics.

Candesartan cilexetil is a prodrug that is rapidly converted into the active substance candesartan via complex ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is a selective angiotensin II AT1-receptor antagonist with strong binding and slow dissociation from these receptors. It has no agonist activity.

Candesartan does not affect angiotensin-converting enzyme (ACE) or other enzymatic systems typically associated with the use of ACE inhibitors, as it does not influence the breakdown of kinins into other substances such as substance P. Angiotensin II antagonists do not actually cause cough. Candesartan does not bind to or block receptors of other hormones or ion channels. AT1 receptor antagonism leads to a dose-dependent increase in plasma renin, angiotensin I, and angiotensin II levels, as well as a reduction in plasma aldosterone concentration.

Non-melanoma skin cancer (NMSC)

Epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide use and the occurrence of NMSC. One study included 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), with 1,430,833 and 172,462 patients in the respective control groups. High cumulative hydrochlorothiazide use (total dose ≥50,000 mg) was associated with an adjusted odds ratio (OR) of 1.29 (95% confidence interval (CI): range 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study showed a potential association between lip cancer (SCC) and hydrochlorothiazide exposure: 633 cases of lip cancer were matched with 63,067 controls using a risk-set sampling strategy. A cumulative dose-dependent relationship was demonstrated, with adjusted ORs ranging from 2.1 (95% CI: 1.7–2.6) to OR 3.9 (3.0–4.9) for high cumulative dose (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").

The effect of candesartan cilexetil 16 mg once daily on cardiovascular morbidity and mortality was evaluated in a randomized clinical trial in elderly patients with mild to moderate arterial hypertension. Patients received candesartan or placebo, with additional antihypertensive agents added as needed. Blood pressure decreased from 166/90 to 145/80 mm Hg in the candesartan group and from 167/90 to 149/82 mm Hg in the control group. No statistically significant difference in the number of major cardiovascular events was observed.

Hydrochlorothiazide inhibits sodium reabsorption primarily in the distal renal tubules and promotes excretion of sodium, chloride, and water. Renal excretion of potassium and magnesium increases in a dose-dependent manner, whereas calcium is more extensively reabsorbed. Hydrochlorothiazide reduces plasma and extracellular fluid volume, decreases cardiac output, and lowers blood pressure. With prolonged therapy, reduced peripheral resistance contributes to blood pressure reduction.

Candesartan and hydrochlorothiazide exhibit additive antihypertensive effects. In patients with arterial hypertension, Kantab Plus provides effective and sustained reduction of blood pressure without reflex tachycardia. There is no information on severe or excessive hypotension after the first dose or withdrawal syndrome. After a single dose of Kantab Plus, the onset of antihypertensive effect typically occurs within 2 hours. With continuous treatment, optimal blood pressure reduction is achieved within four weeks and maintained during long-term therapy. When administered once daily, it provides effective and consistent blood pressure reduction for >24 hours with minimal difference between peak and trough effects between doses. The efficacy of Kantab Plus is independent of patient gender and age.

Currently, there are no data on the use of candesartan cilexetil/hydrochlorothiazide in patients with renal disease/nephropathy, reduced left ventricular function/heart failure, or post-myocardial infarction status.

Pharmacokinetics.

Absorption and distribution

Candesartan cilexetil

After oral administration, candesartan cilexetil is converted into the active substance candesartan. Absolute bioavailability is 40%. Mean peak serum concentration (Cmax) is reached within 3–4 hours after tablet intake. Candesartan serum concentration increases linearly with increasing doses within the therapeutic range. No significant differences in candesartan pharmacokinetics were observed. Food intake does not significantly affect the area under the serum concentration-time curve (AUC).

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

Hydrochlorothiazide

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of 70%. Food intake improves absorption by approximately 15%. Bioavailability may be reduced in patients with heart failure and marked edema.

Hydrochlorothiazide plasma protein binding is approximately 60%. The apparent volume of distribution is approximately 0.8 L/kg.

Metabolism and elimination

Candesartan cilexetil

Candesartan is primarily excreted unchanged in urine and bile, with only minor hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 or CYP3A4. Based on in vitro data, no in vivo interactions are expected with drugs whose metabolism depends on CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 isoenzymes of cytochrome P450. The elimination half-life of candesartan is approximately 9 hours. No drug accumulation occurs after repeated multiple dosing. The half-life of candesartan remains unchanged when candesartan cilexetil is administered in combination with hydrochlorothiazide. An increase in AUC (15–18%) and Cmax (23–24%) of candesartan is observed when co-administered with hydrochlorothiazide, but this is not clinically significant. Additionally, dose titration of individual components is recommended before switching to Kantab Plus. No additional accumulation of candesartan occurs after repeated doses of the combination compared to monotherapy.

Total plasma clearance of candesartan is approximately 0.37 mL/min/kg, and renal clearance is approximately 0.19 mL/min/kg. Renal excretion of candesartan occurs via both glomerular filtration and active tubular secretion. After oral administration of 14C-labeled candesartan cilexetil, approximately 26% of the dose is excreted in urine as candesartan and 7% as inactive metabolite, while approximately 56% of the dose is found in feces as candesartan and 10% as inactive metabolite.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized and is excreted primarily unchanged via glomerular filtration and active tubular secretion. The terminal elimination half-life is 8 hours. Approximately 70% of the orally administered dose is excreted in urine within 48 hours. The half-life of hydrochlorothiazide remains unchanged when combined with candesartan cilexetil. No additional accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared to monotherapy.

Pharmacokinetics in special patient populations

Candesartan cilexetil

In elderly patients (over 65 years), Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared to younger patients. However, blood pressure response and incidence of adverse effects after Kantab Plus dosing are similar in young and elderly patients.

In patients with mild to moderate renal impairment, compared to those with normal renal function, Cmax and AUC of candesartan increased by approximately 50% and 70%, respectively, after multiple dosing, but the elimination half-life remained unchanged. In patients with severe renal impairment, these increases were approximately 50% and 110%, respectively. The terminal elimination half-life of candesartan was approximately doubled in patients with severe renal impairment. Pharmacokinetics in patients undergoing hemodialysis was similar to that in patients with severe renal impairment.

The AUC of candesartan in patients undergoing hemodialysis was similar to that observed in patients with severe renal impairment.

In patients with mild to moderate hepatic impairment, an increase in AUC of candesartan by 23% was observed.

Hydrochlorothiazide

The terminal elimination half-life of hydrochlorothiazide is prolonged in patients with renal impairment.

Clinical characteristics.

Indications.

Treatment of essential hypertension in adult patients when blood pressure is not adequately controlled by monotherapy with candesartan cilexetil or hydrochlorothiazide.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients, or to sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative).

Pregnancy or breastfeeding.

Severe renal impairment (creatinine clearance < 30 mL/min/1.73 m² body surface area).

Severe hepatic impairment and/or cholestasis.

Persistent hypokalemia or hypercalcemia.

Gout.

Concomitant use of this medicinal product with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal dysfunction (eGFR <60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Medicinal products used in clinical pharmacokinetic studies include warfarin, digoxin, oral contraceptives (i.e., ethinylestradiol/levonorgestrel), glipizide, and nifedipine. According to the results of these studies, no clinically significant pharmacokinetic interactions were observed.

The potassium-depleting effect of hydrochlorothiazide may be enhanced by other medicinal products associated with potassium loss and development of hypokalemia (e.g., other potassium-losing diuretics, laxatives, amphotericin, carbenoxolone, sodium penicillin G, salicylic acid derivatives, steroids, ACTH).

Concomitant use of the combination drug CANTAB PLUS with potassium-sparing diuretics, potassium supplements, salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., sodium heparin) may lead to increased serum potassium levels. Monitoring of serum potassium levels should be performed when necessary (see section "Special precautions for use").

Hypokalemia caused by diuretics and hypomagnesemia create conditions for possible cardiotoxic effects of cardiac glycosides and antiarrhythmic agents. Therefore, periodic determination of serum potassium levels is recommended when CANTAB PLUS is used concomitantly with such medicinal products, as well as with agents that may provoke torsades de pointes:

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Certain neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sulpiride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other medicinal products (e.g., bepridil, cisapride, disopyramide, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vinca alkaloids).

Cases of reversible increases in serum lithium concentrations and lithium toxicity have been reported when lithium is used concomitantly with angiotensin-converting enzyme (ACE) inhibitors or hydrochlorothiazide. A similar effect has also been observed with angiotensin II receptor antagonists (ARBs). The use of candesartan and hydrochlorothiazide with lithium is not recommended. If such combination therapy is necessary, careful monitoring of serum lithium levels is recommended.

When ARBs are used concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) (i.e., selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and nonselective 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 development of acute renal failure, as well as increased serum potassium levels, particularly in patients with chronic renal impairment. This combination should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter.

NSAIDs reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide.

Colestyramine or colestipol reduce the absorption of hydrochlorothiazide.

Hydrochlorothiazide may enhance the non-depolarizing effect of muscle relaxants (e.g., tubocurarine).

Thiazide diuretics may increase serum calcium levels due to reduced calcium excretion. When calcium or vitamin D supplements are necessary, serum calcium levels should be monitored and dosage adjusted accordingly.

Thiazide diuretics may potentiate the hyperglycemic effect of beta-blockers and diazoxide.

Anticholinergic agents (e.g., atropine, biperiden) may increase the bioavailability of thiazide diuretics by decreasing gastrointestinal motility and gastric emptying rate.

Thiazide diuretics may increase the risk of adverse effects of amantadine.

Thiazide diuretics may reduce renal excretion of cytotoxic medicinal products (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Concomitant intake of alcohol, barbiturates, or anesthetics may exacerbate orthostatic hypotension.

The use of thiazide diuretics may lead to impaired glucose tolerance. Dose adjustment of antidiabetic medicinal products, including insulin, may be required. Metformin should be used with caution due to the risk of lactic acidosis caused by possible functional renal impairment associated with hydrochlorothiazide.

Hydrochlorothiazide may cause reduced arterial response to pressor amines (such as adrenaline), although this effect is insufficient to completely abolish the pressor effect.

Hydrochlorothiazide may increase the risk of acute renal failure, particularly when high doses of iodinated contrast agents are administered.

Concomitant use of cyclosporine may increase the risk of hyperuricemia and complications such as gout.

Concomitant use of baclofen, amifostine, tricyclic antidepressants, or neuroleptics may enhance the antihypertensive effect and may provoke the development of arterial hypotension.

According to clinical trial data, dual blockade of the renin-angiotensin-aldosterone system (RAAS), resulting from combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren, is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single medicinal product affecting the RAAS (see sections "Contraindications", "Special precautions for use").

Special precautions for use.

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

There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalaemia, and deterioration of renal function (including acute renal failure). This results from dual blockade of the RAAS; therefore, combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

If dual blockade therapy is absolutely necessary, it should be administered only under specialist supervision and with frequent, careful monitoring of renal function, electrolyte levels, and blood pressure. Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.

Renal impairment

As with other drugs that inhibit the RAAS, changes in renal function may be expected in susceptible patients receiving the combination drug CANTAB PLUS (see section "Contraindications").

Kidney transplantation

There is insufficient clinical data on the use of CANTAB PLUS in patients who have undergone kidney transplantation.

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, treatment with drugs affecting the RAAS, including angiotensin II receptor antagonists (ARBs), may increase blood urea and serum creatinine levels.

Reduced circulating blood volume (CBV)

Symptomatic arterial hypotension may develop in patients with reduced CBV and/or hypovolaemia, as with other drugs affecting the RAAS. Therefore, use of CANTAB PLUS is not recommended until this condition has been corrected.

Anaesthesia and surgery

During anaesthesia and surgical procedures in patients receiving ARBs, arterial hypotension may develop due to blockade of the renin-angiotensin system (RAS). Very rarely, severe arterial hypotension may require administration of intravenous fluids and/or vasopressors.

Hepatic impairment

Thiazide diuretics should be used with caution in patients with hepatic impairment or progressive liver disease, as minor disturbances in fluid and electrolyte balance may precipitate hepatic coma. There are no clinical experience data on the use of CANTAB PLUS in patients with hepatic impairment.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, particular caution is required when administering to patients with haemodynamically significant aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting via inhibition of the RAAS. Therefore, use of the combination medicinal product CANTAB PLUS is not recommended in these patients.

Electrolyte imbalance

Serum electrolyte levels should be monitored periodically at appropriate intervals. Use of thiazide diuretics, including hydrochlorothiazide, may lead to fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatraemia, hypomagnesaemia, and hypochloraemic alkalosis).

Thiazide diuretics may reduce calcium excretion in urine and may lead to occasional and slightly elevated serum calcium concentrations. Marked hypercalcaemia may be a sign of occult hyperparathyroidism. In such cases, thiazide diuretics should be discontinued until parathyroid function has been investigated.

Hydrochlorothiazide increases urinary potassium excretion in a dose-dependent manner, which may lead to hypokalaemia. In combination with candesartan cilexetil, this effect of hydrochlorothiazide is less pronounced. The risk of hypokalaemia may be higher in patients with liver cirrhosis, those with increased diuresis, those with inadequate oral electrolyte intake, and those receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).

Use of candesartan cilexetil may lead to hyperkalaemia, particularly in the presence of heart failure and/or renal impairment. Concomitant use of the combination drug CANTAB PLUS with ACE inhibitors, aliskiren, potassium-sparing diuretics, potassium supplements, salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., sodium heparin) may lead to increased serum potassium levels. Serum potassium levels should be monitored if necessary.

Thiazide diuretics also increase urinary magnesium excretion, which may lead to hypomagnesaemia.

Effects on metabolism and endocrine system

Use of thiazide diuretics may impair glucose tolerance. Dose adjustment of antidiabetic medicinal products, including insulin, may be required. Latent diabetes mellitus may become manifest during treatment with thiazide diuretics. Increased cholesterol and triglyceride levels have been associated with thiazide diuretic use. However, only minor effects have been observed with doses contained in the combination drug CANTAB PLUS. Thiazide diuretics increase serum uric acid concentration and may precipitate gout in predisposed patients.

Photosensitization

Cases of photosensitization reactions have been reported during use of thiazide diuretics (see section "Undesirable effects"). If a photosensitivity reaction occurs, treatment should be discontinued. If re-treatment is necessary, protection of skin areas exposed to sunlight or artificial UV radiation is recommended.

Non-melanoma skin cancer

In two epidemiological studies based on data from the Danish National Cancer Registry, an increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] was observed with higher cumulative doses of hydrochlorothiazide.

The photosensitizing effect of hydrochlorothiazide may be a likely mechanism for the development of NMSC.

Patients taking hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer and advised to regularly check their skin for new lesions and to promptly report any suspicious skin changes. To minimize the risk of skin cancer, patients should be advised to take preventive measures such as limiting exposure to sunlight and UV radiation, and, when exposed, to ensure adequate skin protection. Any suspicious skin lesions should be promptly evaluated, including histological examination of biopsy material. In patients with a history of NMSC, reconsideration of hydrochlorothiazide use may be appropriate (see section "Undesirable effects").

General conditions

In patients in whom vascular tone and renal function depend predominantly on RAAS activity (e.g., patients with severe congestive heart failure or primary renal failure, including renal artery stenosis), treatment with drugs affecting this system, including ARBs, has been associated with acute hypotension, azotaemia, oliguria, or, rarely, acute renal failure. As with any antihypertensive drug, excessive reduction in blood pressure in patients with ischaemic heart disease or ischaemic cerebrovascular disease may lead to myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, although they are more likely in patients with such conditions.

Exacerbation or development of systemic lupus erythematosus has been reported during treatment with thiazide diuretics.

The antihypertensive effect of CANTAB PLUS may be enhanced by concomitant use of other antihypertensive agents.

This medicinal product contains lactose as an excipient; therefore, patients with rare hereditary forms of galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting treatment.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical or surgical treatment may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Acute respiratory toxicity

Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported. Very rare, severe cases of acute respiratory toxicity, including ARDS, have been reported after hydrochlorothiazide administration. Pulmonary oedema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnoea, fever, worsening of lung condition, and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who have previously experienced ARDS after taking hydrochlorothiazide.

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including candesartan (see section "Undesirable effects"). 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 complete resolution of symptoms.

Pregnancy

Angiotensin II receptor antagonists should not be used during pregnancy. Except in cases where ARB therapy is essential, patients planning pregnancy should switch to alternative antihypertensive medicinal products with an established safety profile during pregnancy. ARBs should be discontinued immediately upon diagnosis of pregnancy, and alternative therapy initiated if necessary (see sections "Contraindications" and "Use during pregnancy and breastfeeding").

Patients with known sugar intolerances should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding

There are very limited data on the use of CANTAB PLUS in pregnant women. These data are insufficient to draw conclusions regarding potential risk to the fetus if used in the first trimester. In humans, fetal renal perfusion, dependent on the development of the renin-angiotensin-aldosterone system, begins in the second trimester. Therefore, the risk to the fetus increases if CANTAB PLUS is used during the second or third trimester of pregnancy. Use of drugs directly acting on the RAS during the second or third trimester of pregnancy may harm the fetus and newborn (hypotension, renal dysfunction, oliguria and/or anuria, oligohydramnios, cranial hypoplasia, intrauterine growth retardation) and may be fatal. Cases of pulmonary hypoplasia, facial abnormalities, and limb contractures have been described. Animal studies with candesartan cilexetil demonstrated fetal renal damage in late gestation and in newborns. This mechanism is considered pharmacologically mediated via effects on the RAAS.

Hydrochlorothiazide may reduce plasma volume and uteroplacental blood flow. It may also cause neonatal thrombocytopenia. Due to the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters may worsen fetoplacental perfusion and lead to fetal and neonatal effects such as jaundice, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used to treat gestational oedema, gestational hypertension, or pre-eclampsia due to the risk of reduced plasma volume and placental hypoperfusion without beneficial effect on disease course.

Hydrochlorothiazide should not be used to treat essential hypertension in pregnant women, except in rare cases where no other treatment is possible.

Given the above information, CANTAB PLUS is contraindicated during pregnancy. If pregnancy is diagnosed during treatment, CANTAB PLUS should be discontinued.

It is unknown whether candesartan cilexetil passes into breast milk, but due to the potential for adverse effects on breastfed infants, CANTAB PLUS should not be used during breastfeeding.

Ability to influence the ability to drive and use machines

The effect of the drug on the ability to drive and operate machinery has not been studied; however, given the pharmacodynamic properties of candesartan, it is unlikely to affect such ability. Dizziness and fatigue, which may occur during treatment, should be taken into account when driving or operating machinery.

Dosage and Administration

Dosage for the treatment of hypertension

The recommended dose of the combined medicinal product CANTAB PLUS is 1 tablet per day. It is recommended to titrate the doses of the individual components (candesartan cilexetil and hydrochlorothiazide). In clinical practice, a direct transition from monotherapy to treatment with the combined preparation CANTAB PLUS may be considered. When switching from hydrochlorothiazide monotherapy, gradual dose titration of candesartan cilexetil is recommended. The combined medicinal product CANTAB PLUS may be prescribed to patients whose blood pressure is not adequately controlled with monotherapy using either candesartan cilexetil or hydrochlorothiazide, or with CANTAB PLUS at lower doses.

The antihypertensive effect is usually achieved within 4 weeks after initiation of treatment.

Special patient groups

Elderly patients

Dose adjustment is not required in elderly patients.

Patients with reduced circulating blood volume (CBV)

In patients at risk of developing arterial hypotension, for example those with possible reduction in CBV, gradual dose titration of candesartan cilexetil is recommended (in such patients, the initial dose of candesartan cilexetil may be 4 mg).

Patients with renal impairment

Gradual dose titration of the drug is recommended in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min/1.73 m² body surface area).

The combined preparation CANTAB PLUS is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m² body surface area) (see section "Contraindications").

Patients with hepatic impairment

Gradual dose titration of candesartan cilexetil is recommended in patients with mild to moderate chronic liver disease. The combined preparation CANTAB PLUS is contraindicated in patients with severe hepatic impairment and/or cholestasis (see section "Contraindications").

Administration method

Oral administration.

The combined medicinal product CANTAB PLUS can be taken independently of food intake.

The bioavailability of candesartan is not affected by food.

There are no data regarding clinically significant interactions between hydrochlorothiazide and food intake.

Children

Safety and efficacy of the drug in children have not been established; therefore, the drug should not be used in this age group.

Overdose

Symptoms

Based on pharmacological analysis, the main manifestations of overdose are likely to include symptomatic hypotension and dizziness. In a reported individual case of overdose (up to 672 mg of candesartan cilexetil), the patient recovered without sequelae.

The primary manifestation of hydrochlorothiazide overdose is acute fluid and electrolyte loss. Other possible symptoms include dizziness, arterial hypotension, thirst, tachycardia, ventricular arrhythmia, sedation/loss of consciousness, and muscle cramps.

Treatment

There is no specific information available on the treatment of CANTAB PLUS overdose. However, the following measures are recommended in case of overdose. Induce vomiting or perform gastric lavage. If symptomatic hypotension occurs, initiate symptomatic treatment and monitor vital functions. The patient should be placed in a supine position with the lower limbs slightly elevated. If this is insufficient, plasma volume should be expanded by infusion, for example, with isotonic saline solution. If necessary, serum electrolyte and acid-base balance should be monitored and corrected. If the above measures are insufficient, symptomatic medications may be used.

Candesartan is not removed by hemodialysis. It is unknown to what extent hydrochlorothiazide is removed by hemodialysis.

Adverse reactions

According to data from controlled clinical studies, adverse reactions associated with the use of the candesartan cilexetil/hydrochlorothiazide combination were mild and transient. Discontinuation of therapy due to adverse effects during the studies occurred at a similar rate with candesartan cilexetil/hydrochlorothiazide combination (2.3–3.3%) and placebo (2.7–4.3%).

Based on clinical trial data, adverse reactions with the fixed-dose combination of candesartan cilexetil/hydrochlorothiazide were consistent with those observed with candesartan cilexetil and/or hydrochlorothiazide administered individually.

Table 1 lists adverse reactions observed with candesartan cilexetil based on clinical trial data and post-marketing experience. In a pooled analysis of clinical trial data in patients with hypertension, adverse reactions were identified based on their incidence being at least 1% higher with candesartan cilexetil than with placebo.

The following classification of frequency is used: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Table 1

Table 2 presents adverse reactions observed during monotherapy with hydrochlorothiazide, usually at doses of 25 mg or higher.

Table 2

Description of individual adverse reactions

Non-melanoma skin cancer: epidemiological data indicate a cumulative dose-dependent association between the use of hydrochlorothiazide and the occurrence of NMSC (see sections "Special precautions" and "Pharmacological properties").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

14 tablets in a blister, 2 or 6 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of operations.

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