Expiration date: 02/2025

Release form, composition

Pills Ardyss N lenticular, capsulorraphy, light pink color, with valium on both sides. On one side is engraved "C" and "16" on opposite sides risks.

1 tablet contains:

• candesartan 16 mg
  
• hydrochlorothiazide 12.5 mg
  

Excipients:

starch pregelatinization 15 mg, povidone (K-30) 16 mg, carmellose calcium 6.6 mg, poloxamer 188 1 mg, microcrystalline cellulose 72 mg of lactose monohydrate 177.6 mg, colorant iron oxide red (E172) 0.1 mg magnesium stearate 3.2 mg.

Pharm group:

Antihypertensive drug.

Formdata:

Angiotensin II is the main hormone of the renin-angiotensin-aldosterone system (RAAS), which plays an important role in the pathogenesis of hypertension, congestive heart failure and other cardiovascular diseases. The major physiological effects of angiotensin II are vasoconstriction, stimulation of aldosterone production, regulation of water and electrolyte status and stimulation of cell growth. Effects mediated by interaction of angiotensin II with angiotensin receptors type 1 (AT1 receptors).

Candesartan is a selective AT1 antagonist-angiotensin II receptor, does not inhibit angiotensin converting enzyme (ACE) involved in the conversion of angiotensin I to angiotensin II, which destroys bradykinin, does not lead to accumulation of bradykinin or substance p. In the blocking AT1-receptors of angiotensin II occurs a dose-dependent increase in the content of renin, angiotensin I, angiotensin II and reduced concentration of aldosterone in blood plasma.

When candesartan in comparison with ACE inhibitors the development of cough was less frequent in patients treated with candesartan.

Candesartan is not associated with other hormone receptors and does not block ion channels involved in the regulation of the functions of the cardiovascular system.

Hydrochlorothiazide - tiazidopodobnye diuretic, inhibits active sodium reabsorption mainly in the distal renal tubules and increases secretion of sodium ions, chlorine and water. The allocation of potassium and magnesium by the kidneys is enhanced depending on the dose, while the calcium starts to reabsorbiruetsa in larger quantities than before.

Hydrochlorothiazide reduces plasma volume of blood and extracellular fluid, reduces the intensity of transport of blood by the heart, lowers blood pressure (BP). During long-term treatment, hypotensive effect develops due to the expansion of the arterioles. Prolonged use of hydrochlorothiazide reduces the risk of cardiovascular diseases and mortality.

Candesartan and hydrochlorothiazide have summarized hypotensive effect. In patients with hypertension the use of candesartan in/hydrochlorothiazide elicits effective and long-lasting decrease in blood pressure without increasing heart rate (HR). Orthostatic hypotension first dose of the drug is not observed, after the end of treatment arterial hypertension is not increased.

After a single dose of candesartan in/hydrochlorothiazide main hypotensive effect develops within 2 h. the drug 1 time per day effectively and gently lowers blood pressure for 24 hours with little difference between the maximum and the average effect of the action. With prolonged treatment stable blood pressure reduction occurs within 4 weeks after start of treatment and can be maintained with prolonged treatment.

In clinical studies, the incidence of side effects, especially cough, were less common with candesartan in the application/hydrochlorothiazide than in the employment of a combination of ACE inhibitors with hydrochlorothiazide.

Currently, there are no data on the use of candesartan in/hydrochlorothiazide in patients with renal insufficiency, nephropathy, reduced left ventricular function, acute heart failure and myocardial infarction.

The effectiveness of candesartan in/hydrochlorothiazide does not depend on gender and age.

Pharmacokinetics:

Absorption and distribution:

Candesartan

When absorption from the gastrointestinal tract (GIT) of candesartan in cilexitil through the ethereal hydrolysis is rapidly converted to the active substance candesartan, is strongly associated with AT1-receptor and slowly dissociates, has the properties of the agonist. The absolute bioavailability of candesartan in after oral is about 40%. The relative bioavailability of tablets compared to an oral solution is approximately 34%. Thus, the estimated absolute bioavailability of a tablet form of the drug is 14%. Food intake has no significant effect on area under the curve "concentration-time" (AUC), i.e., food does not significantly affect the bioavailability of the drug.

The maximum concentration in plasma (Cmax) is reached 3-4 hours after taking a tablet form of the drug. With increasing doses within the recommended limits of concentration of candesartan in increases linearly. The candesartan in binding with blood plasma proteins - 99%. Plasma volume of distribution (Vd) of candesartan in is 0.1 l/kg.

Pharmacokinetic parameters of candesartan in do not depend on the sex of the patient.

Hydrochlorothiazide

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 70%. Concomitant food intake increases the absorption by approximately 15%. Bioavailability may be reduced in patients with cardiac failure and pronounced edema.

Linking blood plasma proteins is approximately 60%. Apparent Vd is approximately 0.8 l/kg.

Metabolism and excretion:

Candesartan

Candesartan is mainly excreted in the urine and bile in an unmodified form and only to a minor extent metabolised in the liver. The elimination half-life (T1/2) of candesartan in approximately 9 h. drug Accumulation in the body is not observed.

Total clearance of candesartan in is around 0,37 ml/min/kg, with renal clearance of about 0.19 ml/min/kg of candesartan in Renal excretion is by glomerular filtration and active tubular secretion.

Ingestion of radioactively-labeled candesartan in about 26% of the administered amount is excreted in the urine as candesartan in, and 7% as an inactive metabolite, whereas in the feces is detected 56% of the administered amount in the form of candesartan in, and 10% as the inactive metabolite.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized and is excreted almost entirely in the form of the active form of the drug by glomerular filtration and active tubular secretion in the proximal nephron. T1/2 is about 8 hours and does not change when co-administered with candesartan. About 70% dose of the inside, excreted by the kidneys within 48 hours When using combinations of drugs revealed no additional accumulation of hydrochlorothiazide compared with monotherapy.

Pharmacokinetics in special clinical cases:

Candesartan

Pharmacokinetic parameters of candesartan in do not depend on the sex of the patient.

In patients older than 65 years Cmax and AUC of candesartan in increase by 50% and 80%, respectively, compared to the young patients. However, the hypotensive effect and the incidence of side effects when using candesartan in/hydrochlorothiazide do not depend on the age of the patients.

In patients with slight and moderate impaired renal function Cmax and AUC of candesartan in increased by 50% and 70%, respectively, whereas AT1 of the drug is not changed compared to patients with normal renal function.

In patients with severe impairment of renal function and/or hemodialysis Cmax and AUC of candesartan in increased by 50% and 110%, respectively, while T1/2 of the drug increased in 2 times.

In patients with easy and moderate hepatic impairment there was an increase in the AUC of candesartan in 23%.

Hydrochlorothiazide

T1/2 was longer in patients with renal insufficiency.

Indications: — treatment of hypertension in patients who have shown combination therapy.

Category effects on the fetus: the product of Ardyss N is contraindicated during pregnancy and breastfeeding.

Contraindications: 

• hypersensitivity to candesartan, hydrochlorothiazide and other components of the drug;
  
• pregnancy;
  
• the period of breastfeeding;
  
• lactose intolerance;
  
• lactase deficiency;
  
• syndrome glucose-galactose malabsorption;
  
• primary hyperaldosteronism;
  
• gout;
  
• severe impaired renal function (creatinine clearance (CC) less than 30 ml/min);
  
• severe liver dysfunction;
  
• cholestasis;
  
• resistant hypokalemia, hypocalcemia;
  
• the condition after kidney transplantation;
  
• children up to age 18 years.
  

With caution:

Concomitant use with other antihypertensive drugs, clinesperpage diuretics, amphotericin, carbenoxolone, penicillin-sodium salt of derivatives of salicylic acid, cardiac glycosides, antiarrhythmic drugs, drugs lithium, nonsteroidal anti-inflammatory drugs (NSAIDs), colestipol, cholestyramine, tubocurarine, beta-blockers, anticholinergic drugs, amantadine, cytotoxic drugs, glucocorticosteroids (GCS), adrenocorticotropic hormone (ACTH), alcohol, barbiturates, General anesthetics, epinephrine, iodine supplements; the insufficiency of liver and kidney moderate.

Dosing: 

Inside, regardless of meals. The recommended dose is 1 tablet 1 time per day. It is recommended that the dose titration of candesartan in before the transfer of the patient to therapy with Ardyss N. If necessary, patients are transferred from ionotherapy with candesartan therapy drug Ardis N. The main hypotensive effect is achieved, usually within the first 4 weeks after start of treatment.

In patients with impaired renal function is preferable to the use of loop diuretics compared with the thiazide. Before the start of drug therapy, Ardis N patients with easy or moderate impaired renal function (QC over 30 ml/min), including patients on hemodialysis, the recommended dose titration of candesartan in. starting with 4 mg.

The drug Ardyss N is contraindicated in patients with renal failure, severe (CC less than 30 ml/min).

For patients with risk of hypotension (for example, with a reduced volume of circulating blood (BCC)), it is recommended that the titration of candesartan in doses ranging from 4 mg.

In patients with hepatic impairment average degree before the start of drug therapy, Ardis II recommended dose titration of candesartan in, starting with 2 mg. in Patients with impaired liver function, severe drug use, Ardyss N is contraindicated.

In patients older dose adjustment is not required.

Adverse effects: the incidence of adverse effects classified according to the recommendations of the world health organization: very often - not less than 10%; often - at least 1% but less than 10%; rarely, at least 0.1% but < 1%; rare - not less than 0.01%, but less than 0.1%; very rare (including isolated cases) - less than 0.01%.

Candesartan:

From the side of blood system: rarely - leukopenia, neutropenia, agranulocytosis.

From the metabolic and nutritional: rarely - hyperkalemia, hyponatremia.

From the Central nervous system (CNS): often - dizziness; very rarely - headache.

Gastrointestinal: very rarely - nausea.

The liver and biliary tract: rarely - increased activity of "liver" transaminases, abnormal liver function, hepatitis.

From Coogi and subcutaneous tissue: very rare - rash, itching, hives, angioedema.

On the part of the musculoskeletal system and connective tissue: very rare back pain, arthralgia, myalgia.

The kidneys and urinary tract: rarely - renal failure.

Hydrochlorothiazide:

From the side of blood system: rarely - leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, suppression of bone marrow function, hemolytic anemia.

The immune system: rarely - anaphylactic reaction.

From the metabolic and nutrition: often - hyperglycemia, hyperuricemia, hyponatremia, hypokalemia.

CNS: frequently - dizziness, vertigo, rarely - sleep disorders, restlessness, depression, paresthesia.

Side of body: rare - reduced vision clarity.

Of the cardiovascular system: rare- postural hypotension; rare - arrhythmia, vasculitis.

The respiratory system of the chest and mediastinum: a rare-respiratory distress syndrome, pneumonitis, pulmonary edema.

Gastrointestinal: rarely - anorexia, loss of appetite, constipation, diarrhea, irritation of the mucous membrane of the stomach; rare - pancreatitis.

The liver and biliary tract: a rare intrahepatic cholestatic jaundice.

The skin and subcutaneous tissue: rare - rash, urticaria, photosensitivity reactions; rarely toxic epidermal necrolysis, artematopodidae reactions, recurrence of erythematous skin.

On the part of the musculoskeletal system and connective tissue: rare - muscle spasm.

The kidneys and mochevyvodjashchih ways: often, glycosuria; rare - violation of the kidney, interstitial nephritis.

Other: often - fatigue, increasing the concentration of cholesterol and triglycerides in the blood plasma; rarely - fever, increased concentration of creatinine in plasma.

Overdose: Symptoms: analysis of pharmacological properties of the drug suggests that the main manifestation of an overdose may be clinically significant decrease in blood pressure, dizziness. Described isolated cases of overdose (up to 672 mg candesartan in), and ended with the recovery of patients without severe consequences. The main manifestation of an overdose of hydrochlorothiazide is acute loss of fluid and electrolytes. Also observed symptoms such as dizziness, decrease in blood pressure. dry mouth, tachycardia, ventricular arrhythmia, loss of consciousness and muscle spasms.

Treatment: with the development of clinically expressed lower AD should be symptomatic treatment and monitor the patient's condition. To lay the patient on his back and lift his legs. If necessary, increase the BCC, for example, by the intravenous administration of isotonic sodium chloride solution. If necessary, can be assigned sympathomimetic means. Excretion of hydrochlorothiazide and candesartan in by hemodialysis is unlikely.

Special instructions: 

In patients with renal failure the application "loop" diuretics thiazide is preferable. For patients with renal insufficiency during therapy with the drug, Ardyss N it is recommended to constantly monitor the content of potassium, creatinine and uric acid.

Data on the use of drugs, Ardyss N in patients who recently had a kidney transplant, no.

Drugs that affect the RAAS (e.g., ACE inhibitors) may lead to an increase of urea in blood and the content of serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. A similar effect should be expected from the antagonists of angiotensin II receptors.

In patients with a deficit BCC and/or sodium may develop symptomatic arterial hypotension, therefore, it is not recommended to use the drug, Ardyss N to the disappearance of these symptoms.

Patients receiving antagonist of angiotensin II, during anesthesia and during surgery may develop hypotension due to the blockade of RAAS. Very rarely observed cases of severe hypotension requiring I/V administration of fluids and/or a vasoconstrictor.

Patients with impaired hepatic function or progressive liver disease should use thiazide diuretics with caution, because minor fluctuations of fluid volume and electrolyte composition can cause hepatic coma. Data on the use of drugs, Ardyss N in patients with hepatic insufficiency are absent.

In appointing the drug, Ardyss N patients with obstructive hypertrophic cardiomyopathy or hemodynamically significant aortic stenosis or mitral valve should be used with caution.

Patients with primary hyperaldosteronism is usually resistant to therapy with antihypertensive agents that affect the RAAS, therefore, to assign such patients the drug Ardyss N is not recommended.

As in all cases of reception of drugs with diuretic action, you should monitor the performance of the electrolytes in the blood plasma.

Preparations on the basis of thiazides, having diuretic effect, can reduce the secretion of calcium ions with urine and can cause abrupt changes and a slight increase in the concentration of calcium ions in the blood plasma.

Thiazides, including hydrochlorothiazide, may cause a violation of water-salt balance (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia, and gipohloremichesky alkaloz).

Revealed hypercalcemia may be a sign of hidden hyperthyroidism. The use of a thiazide diuretic should be discontinued until the results of the analyses of the study parathyroid glands.

Hydrochlorothiazide dose-dependently increases the secretion of potassium and can cause hypokalemia. Such action of hydrochlorothiazide is manifested less if you use it in combination with candesartan. The risk of hypokalemia is increased in patients with liver cirrhosis, increased diuresis, the host liquid with low salt content, running parallel to the course of treatment with glucocorticoids or ACTH.

Based on the experience of the use of drugs, affecting the RAAS, the parallel use of the drug, Ardyss N and diuretic drugs that increase the secretion of potassium can be compensated by the use of food additives containing potassium or other drugs that can increase potassium levels in the blood plasma. The application of the product Ardyss N may cause hypokalemia, especially in patients with cardiac or renal insufficiency (such cases are documented not reported).

Thiazide diuretics increase the excretion of magnesium, which can cause hypomagnesemia.

The use of thiazide diuretics can change the amount of glucose in the blood up to the manifestation of latent flowing of diabetes. You may need to adjust the dose of hypoglycemic agents, including insulin.

With the use of thiazide diuretics associated increase in cholesterol and triglyceride levels in plasma. However, the use of the drug, Ardyss N was observed a minimal amount or absence of such effects. Thiazide diuretics increase uric acid concentrations in blood plasma and can contribute to padapai in predisposed patients. Patients in whom vascular tone and renal function depend predominantly on the activity of the RAAS (e.g., patients with severe chronic heart failure, renal disease, including renal artery stenosis), are particularly sensitive to drugs acting on the RAAS. The purpose of such drugs is accompanied in these patients, abrupt hypotension, azotemia, oliguria and rarely acute renal failure. The possibility of the development of the listed effects are not excluded and the use of antagonists of angiotensin II receptors. A sharp decrease in blood pressure in patients with ischemic cardiomyopathy, cerebrovascular diseases ischemic when using any antihypertensive funds 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, allergic reactions in history that does not exclude the occurrence of allergic symptoms in other patients. If you are using a thiazide diuretic there were cases of aggravation or appearance of congestive symptoms of seborrhea.

If you are using thiazide diuretics have been cases of deterioration in the current systemic lupus erythematosus.

The drug contains lactose, therefore it should not be taken by patients with rare hereditary diseases, manifested in the lack of tolerance to lactose, lactase deficiency or malabsorption of glucose and lactose. Use in Pediatrics

The safety and efficacy of the drug, Ardyss N in children and adolescents under the age of 18 years not installed.

Effects on ability to drive vehicles and management mechanisms

If you experience unwanted effects from the CNS during therapy with the drug, Ardyss N be careful when performing actions that require high concentration and psychomotor speed reactions.