Candecor^® (Tablets) Instructions for Use

ATC Code

C09DA06 (Candesartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Candesartan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin II receptor antagonists (ARBs), combinations; angiotensin II receptor antagonists and diuretics

Pharmacological Action

A combined antihypertensive drug. It contains candesartan – a selective antagonist of angiotensin II AT₁ receptors and Hydrochlorothiazide – a thiazide diuretic.

Candesartan is a selective antagonist of angiotensin II AT₁ receptors, does not inhibit ACE, which converts angiotensin I to angiotensin II and breaks down bradykinin, and does not lead to the accumulation of bradykinin or substance P. As a result of blocking angiotensin II AT₁ receptors, a dose-dependent increase in the content of renin, angiotensin I, angiotensin II and a decrease in the concentration of aldosterone in the blood plasma occurs. Candesartan does not bind to receptors of other hormones and does not block ion channels involved in the regulation of the cardiovascular system functions.

Hydrochlorothiazide is a thiazide diuretic, the diuretic effect of which is associated with impaired reabsorption of sodium, chloride, potassium, magnesium ions, and water in the distal part of the nephron; it delays the excretion of calcium ions and uric acid. It has antihypertensive properties; the hypotensive effect develops due to the expansion of arterioles. It has practically no effect on normal blood pressure levels.

The combination of candesartan + Hydrochlorothiazide has an additive hypotensive effect. In patients with arterial hypertension, the use of this combination causes an effective and prolonged decrease in blood pressure without an increase in heart rate.

After a single dose of the candesartan + Hydrochlorothiazide combination, the main hypotensive effect develops within 2 hours. When taken once a day, the combination causes a mild decrease in blood pressure over 24 hours with a slight difference between the maximum and average effect of action. With long-term treatment, a stable decrease in blood pressure occurs within 4 weeks after the start of taking the drug and can be maintained during a long course of treatment.

Pharmacokinetics

Candesartan

When absorbed from the gastrointestinal tract, Candesartan cilexetil is rapidly converted by ester hydrolysis into the active substance – candesartan, which binds firmly to AT₁ receptors and dissociates slowly, and has no agonist properties. The absolute bioavailability of candesartan after oral administration is about 40%. Food intake does not have a significant effect on AUC, i.e., food does not significantly affect the bioavailability of candesartan.

C_max in blood plasma is reached 3-4 hours after taking the tablet form of the drug. When the dose is increased within the recommended limits, the concentration of candesartan increases linearly. The binding of candesartan to blood plasma proteins is more than 99%. The plasma V_d of candesartan is 0.1 l/kg. Candesartan is mainly excreted from the body in the urine and bile unchanged and only to a small extent is metabolized in the liver. T_1/2 is approximately 9 hours. No accumulation of candesartan in the body is observed.

The total clearance of candesartan is about 0.37 ml/min/kg, while the renal clearance is about 0.19 ml/min/kg. Renal excretion of candesartan is carried out by glomerular filtration and active tubular secretion.

When taking orally labeled radioactive candesartan, about 26% of the administered amount is excreted in the urine as candesartan and 7% as an inactive metabolite, while 56% of the administered amount is found in the feces as candesartan and 10% as an inactive metabolite. In patients with mild to moderate renal impairment, C_max and AUC of candesartan increased by 50% and 70%, respectively, while T_1/2 did not change compared to patients with normal renal function. In patients with severe renal impairment and/or on hemodialysis, C_max and AUC of candesartan increased by 50% and 110%, respectively, and T_1/2 doubled. In patients with mild to moderate hepatic impairment, an increase in the AUC of candesartan by 23% was noted.

Hydrochlorothiazide

After oral administration, C_max of hydrochlorothiazide is reached within 1-3 hours. Absolute bioavailability is estimated by cumulative renal excretion of hydrochlorothiazide and is about 60%. Binding to blood plasma proteins is 40-70%. V_d is 0.8±0.3 l/kg. It is not metabolized in the human body and is excreted in the urine almost unchanged. About 60% of the orally administered dose is excreted within 48 hours. Renal clearance is about 250-300 ml/min. T_1/2 is 10-15 hours. There is a difference in plasma concentrations between men and women. Women tend to have a clinically significant increase in plasma concentrations of hydrochlorothiazide. In patients with impaired renal function, the excretion rate of hydrochlorothiazide is reduced. Studies involving patients with a CC of 90 ml/min showed that the T_1/2 of hydrochlorothiazide increases. In patients with reduced renal function, T_1/2 is about 34 hours.

Indications

Treatment of arterial hypertension in patients for whom combination therapy with candesartan and hydrochlorothiazide is indicated.

ICD codes

Dosage Regimen

Tablets

Take orally once a day. The single dose of the candesartan + Hydrochlorothiazide combination ranges from 8 mg/12.5 mg to 32 mg/25 mg.

It is recommended to titrate the dose of candesartan before switching the patient to the candesartan + Hydrochlorothiazide combination. The main hypotensive effect is usually achieved within the first 4 weeks after the start of treatment.

Before starting therapy with this combination in patients with mild or moderate renal impairment (GFR >30 ml/min/1.73 m²), including patients on hemodialysis, it is recommended to titrate the dose of candesartan, starting from 4 mg.

For patients at risk of arterial hypotension (for example, with reduced blood volume), it is recommended to titrate the dose of candesartan, starting from 4 mg as monotherapy.

In patients with moderate hepatic impairment, before starting therapy with this combination, it is recommended to titrate the dose of candesartan, starting from 2 mg.

Adverse Reactions

Candesartan

From the hematopoietic system very rarely – leukopenia, neutropenia, agranulocytosis.

From the metabolism very rarely – hyperkalemia, hyponatremia.

From the nervous system often – dizziness; very rarely – headache.

From the digestive system: very rarely – nausea.

From the liver and biliary tract very rarely – increased activity of liver transaminases, impaired liver function, hepatitis.

From the respiratory system: very rarely – cough.

From the skin and subcutaneous tissues very rarely – skin rash, skin itching, urticaria, angioedema.

From the musculoskeletal system very rarely – back pain, arthralgia, myalgia.

From the kidneys and urinary tract very rarely – renal failure.

Hydrochlorothiazide

From the blood system rarely – leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, bone marrow suppression, hemolytic anemia, decreased hemoglobin.

From the immune system rarely – anaphylactic reaction.

From metabolism and nutrition often – hyperglycemia, hyperuricemia, hyponatremia, hypokalemia.

From the nervous system often – dizziness, vertigo; rarely – sleep disorders, anxiety, depression, paresthesia.

From the organ of vision rarely – decreased visual acuity, acute myopia, acute angle-closure glaucoma.

From the cardiovascular system infrequently – postural hypotension; rarely – arrhythmia, vasculitis.

From the respiratory system rarely – respiratory distress syndrome, pneumonitis, pulmonary edema.

From the digestive system infrequently – anorexia, loss of appetite, constipation, diarrhea, irritation of the gastric mucosa; rarely – pancreatitis.

From the liver and biliary tract rarely – intrahepatic cholestatic jaundice.

From the skin and subcutaneous tissues infrequently – rash, urticaria, photosensitivity reaction; rarely – toxic epidermal necrolysis, erythematous-like reactions, recurrence of skin erythema.

From the musculoskeletal system rarely – muscle spasm.

From the urinary system often – glucosuria; rarely – impaired renal function, interstitial nephritis.

Other often – weakness, increased concentration of cholesterol, triglycerides in blood plasma; rarely – fever, increased concentration of creatinine, urea in blood plasma.

Contraindications

Hypersensitivity to candesartan, hydrochlorothiazide and other components of the drug; hypersensitivity to other sulfonamide derivatives; primary hyperaldosteronism; gout; severe renal failure (GFR <30 ml/min/1.73 m²); severe liver dysfunction; cholestasis; refractory hypokalemia; hypercalcemia; condition after kidney transplantation; pregnancy; lactation period (breastfeeding); age under 18 years; simultaneous use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or impaired renal function (GFR <60 ml/min/1.73 m²).

With caution: impaired renal function (CC >30 ml/min), liver failure; severe chronic heart failure; bilateral renal artery stenosis; stenosis of the artery of a single kidney; hemodynamically significant stenosis of the aortic and/or mitral valve; coronary artery disease; hypertrophic obstructive cardiomyopathy; decreased blood volume; diabetes mellitus; cerebrovascular diseases; acute myopia; angle-closure glaucoma; systemic lupus erythematosus; simultaneous use with other antihypertensive drugs, potassium-sparing diuretics, amphotericin, carbenoxolone, penicillin G sodium preparations, salicylic acid derivatives, cardiac glycosides, antiarrhythmic drugs, lithium preparations, NSAIDs, colestipol, cholestyramine, tubocurarine, beta-blockers, anticholinergic drugs, amantadine, cytotoxic drugs, corticosteroids, ACTH, barbiturates, general anesthetics, epinephrine, iodine-containing drugs, with alcohol.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during breastfeeding.

Use in Hepatic Impairment

Contraindication: severe liver dysfunction.

Use in Renal Impairment

Contraindications: severe renal failure (GFR <30 ml/min/1.73 m²); simultaneous use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or impaired renal function (GFR <60 ml/min/1.73 m²).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

Simultaneous use of ACE inhibitors, ARBs or aliskiren increases the risk of arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure). Dual blockade of the RAAS with the use of ACE inhibitors, ARBs or aliskiren is not recommended.

If dual blockade of the RAAS is considered absolutely necessary, then treatment should be carried out only under the supervision of a physician and with regular monitoring of renal function, electrolyte levels and blood pressure. ACE inhibitors and ARBs should not be used simultaneously in patients with diabetic nephropathy.

In patients with renal failure, it is recommended to constantly monitor the levels of potassium, creatinine and uric acid.

Drugs affecting the RAAS (for example, ACE inhibitors) can lead to an increase in blood urea and serum creatinine levels in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney. A similar effect should be expected from angiotensin II receptor antagonists.

In patients with a deficiency of blood volume and/or sodium, symptomatic arterial hypotension may develop, so it is not recommended to use the candesartan + Hydrochlorothiazide combination until these symptoms disappear.

In patients receiving angiotensin II antagonists, arterial hypotension may develop during anesthesia and during surgical interventions as a result of blockade of the RAAS. Very rarely, cases of severe arterial hypotension may occur, requiring intravenous administration of fluid and/or vasoconstrictors.

Patients with impaired liver function or progressive liver disease should use thiazide diuretics with caution, since minor fluctuations in fluid volume and electrolyte composition can cause hepatic coma.

Thiazide-based drugs with diuretic effects can reduce the excretion of calcium ions in the urine and can cause abrupt changes and a slight increase in the concentration of calcium ions in the blood plasma. Detected hypercalcemia may be a sign of latent hyperthyroidism. The use of thiazide diuretics should be discontinued until the results of parathyroid gland tests are obtained.

Hydrochlorothiazide increases potassium excretion in a dose-dependent manner, which can cause hypokalemia. This effect of hydrochlorothiazide is less pronounced when used concomitantly with candesartan. The risk of hypokalemia is increased in patients with liver cirrhosis, increased diuresis, taking fluids with low salt content, and undergoing a parallel course of treatment with corticosteroids or ACTH.

Thiazide diuretics increase magnesium excretion, which can cause hypomagnesemia.

The use of thiazide diuretics can change blood glucose levels up to the manifestation of latent diabetes mellitus. Dose adjustment of hypoglycemic agents, including insulin, may be required.

Thiazide diuretics increase the concentration of uric acid in the blood plasma and can contribute to the occurrence of gout in predisposed patients.

Patients whose vascular tone and renal function predominantly depend on the activity of the RAAS (for example, patients with severe chronic heart failure, kidney disease, including renal artery stenosis) are especially sensitive to drugs acting on the RAAS. The prescription of such drugs in these patients is accompanied by a sharp arterial hypotension, azotemia, oliguria and, less commonly, acute renal failure. The possibility of developing the listed effects cannot be excluded when using angiotensin II receptor antagonists. A sharp decrease in blood pressure in patients with ischemic heart disease, cerebrovascular diseases of ischemic origin when using any antihypertensive agents can lead to the development of myocardial infarction or stroke.

The manifestation of hypersensitivity reactions to hydrochlorothiazide is most likely in patients with bronchial asthma, a history of allergic reactions, which does not exclude the appearance of allergic symptoms in other patients.

Cases of exacerbation or appearance of symptoms of congestive seborrhea have been noted with the use of thiazide diuretics.

Cases of worsening systemic lupus erythematosus have been observed with the use of thiazide diuretics.

Hydrochlorothiazide can cause an idiosyncratic reaction leading to the development of acute myopia and secondary angle-closure glaucoma. Symptoms include: sudden decrease in vision or eye pain, which usually appear within several hours or weeks from the start of hydrochlorothiazide therapy. If left untreated, acute angle-closure glaucoma can lead to permanent vision loss. Treatment is to discontinue hydrochlorothiazide as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for the development of acute angle-closure glaucoma are a history of allergic reaction to sulfonamides or benzylpenicillins.

Effect on the ability to drive vehicles and operate machinery

If adverse effects from the central nervous system occur during therapy with the candesartan + Hydrochlorothiazide combination, caution should be exercised when performing activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

With simultaneous use of angiotensin II receptor antagonists and NSAIDs, including COX-2 inhibitors and non-selective NSAIDs, for example, acetylsalicylic acid more than 3 g/day, a decrease in the hypotensive effect of candesartan is possible.

Simultaneous use of the candesartan + Hydrochlorothiazide combination with other antihypertensive agents enhances the hypotensive effect.

Dual blockade of the RAAS with the use of angiotensin II receptor antagonists (ARBs), ACE inhibitors or aliskiren (renin inhibitor) may be accompanied by an increased risk of arterial hypotension, fainting, hyperkalemia and impaired renal function (including acute renal failure) compared with monotherapy. Regular monitoring of blood pressure, renal function and blood electrolyte levels is necessary in patients taking the candesartan + Hydrochlorothiazide combination simultaneously with other drugs affecting the RAAS.

Candesartan + Hydrochlorothiazide should not be used simultaneously with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or with impaired renal function (GFR <60 ml/min/1.73 m²).

With simultaneous use of ACE inhibitors and dipeptidyl peptidase-4 inhibitors (for example, vildagliptin), the risk of developing angioedema may increase.

The effect of hydrochlorothiazide leading to potassium loss may be enhanced by other agents leading to potassium loss and hypokalemia, such as diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives.

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

Hypokalemia and hypomagnesemia induced by the use of diuretic drugs predispose to the development of the cardiotoxic effect of cardiac glycosides and antiarrhythmic drugs. When taking the candesartan+Hydrochlorothiazide combination concurrently with such drugs, monitoring of plasma potassium levels is required.

With the simultaneous use of lithium preparations with ACE inhibitors, a reversible increase in serum lithium concentration and the development of toxic reactions occur. Similar reactions may also occur with the use of angiotensin II receptor antagonists, and therefore it is recommended to monitor serum lithium levels.

The diuretic, natriuretic, and hypotensive effects of hydrochlorothiazide are reduced with the simultaneous use of NSAIDs.

The absorption of hydrochlorothiazide is reduced when using colestipol, cholestyramine.

The action of non-depolarizing muscle relaxants (e.g., tubocurarine) may be enhanced by hydrochlorothiazide.

Thiazide diuretics can cause an increase in plasma calcium levels due to decreased excretion. If it is necessary to use calcium-containing dietary supplements or vitamin D, plasma calcium levels should be monitored and the dose adjusted if necessary.

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

Anticholinergic agents (e.g., atropine, biperiden) may increase the bioavailability of thiazide diuretics due to decreased gastrointestinal motility. Thiazide diuretics may increase the risk of adverse effects of amantadine.

Thiazide diuretics can slow down the elimination of cytostatic drugs (such as cyclophosphamide, methotrexate) from the body and enhance their myelosuppressive effect.

The risk of hypokalemia may increase with the simultaneous use of corticosteroids or ACTH.

Against the background of using this combination, the frequency of orthostatic arterial hypotension may increase when consuming alcohol, using barbiturates, or general anesthetics.

During treatment with thiazide diuretics, a decrease in glucose tolerance is possible, which may require dose adjustment of hypoglycemic drugs (including insulin).

Hydrochlorothiazide may reduce the effect of vasoconstrictive amines (e.g., epinephrine).

Hydrochlorothiazide may increase the risk of acute renal failure, especially in combination with large doses of iodinated contrast media.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

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