Ordiss N tablets 12.5mg + 16mg, No. 30

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

The method of application and dosage regimen of a particular drug depends on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly observe the compliance of the used dosage form of a particular drug with the indications for use and the dosage regimen.

It is taken orally 1 time / day. A single dose of a combination of candesartan + hydrochlorothiazide ranges from 8 mg / 12.5 mg to 32 mg / 25 mg.

It is recommended to titrate the candesartan dose before transferring the patient to the candesartan + hydrochlorothiazide combination. The main hypotensive effect is achieved, as a rule, in the first 4 weeks after the start of treatment.

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

For patients at risk of arterial hypotension (for example, with reduced BCC), titration of the dose of candesartan is recommended, starting at 4 mg as monotherapy.

In patients with moderate hepatic dysfunction, before starting therapy with this combination, titration of the dose of candesartan is recommended, starting at 2 mg.

hydrochlorothiazide

candesartan

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; 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).

Carefully: impaired renal function (CC> 30 ml / min), liver failure; severe chronic insufficiency; bilateral renal artery stenosis; stenosis of an artery of a single kidney; hemodynamically significant stenosis of the aortic and / or mitral valve; Ischemic heart disease; hypertrophic obstructive cardiomyopathy; decrease in BCC; diabetes; 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, colestiramine, tubocketamide drugs, adocurarinecytotoxic drugs, GCS, ACTH, barbiturates, general anesthetics, epinephrine, iodine-containing drugs, with alcohol.

Clinical and pharmacological group: Antihypertensive combined drug (angiotensin II receptor antagonist + diuretic)

Pharmaco-therapeutic group: Combined antihypertensive agent (angiotensin II receptor antagonist + diuretic)

pharmachologic effect

Combined antihypertensive drug. Contains candesartan, a selective angiotensin II AT1 receptor antagonist, and hydrochlorothiazide, a thiazide diuretic.

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

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

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

After a single dose of the combination candesartan + hydrochlorothiazide, the main hypotensive effect develops within 2 hours. When taken 1 time / day, the combination causes a mild decrease in blood pressure within 24 hours with a slight difference between the maximum and average effect of action. With prolonged treatment, a stable decrease in blood pressure occurs within 4 weeks after starting the drug and can be maintained with a long course of treatment.

Pharmacokinetics

Candesartan

When candesartan is absorbed from the gastrointestinal tract, cilexitil through ether hydrolysis quickly turns into an active substance - candesartan, strongly binds to AT1 receptors and slowly dissociates, does not have agonist properties. The absolute bioavailability of candesartan after oral administration is about 40%. Food intake has no significant effect on AUC, i.e. food does not significantly affect the bioavailability of candesartan.

Cmax in blood plasma is achieved 3-4 hours after taking the tablet form of the drug. With an increase in the dose within the recommended range, the concentration of candesartan increases linearly. The binding of candesartan to blood plasma proteins is more than 99%. The plasma Vd of candesartan is 0.1 L / kg. Candesartan is mainly excreted in the urine and bile unchanged and is only slightly metabolized in the liver. T1 / 2 is approximately 9 hours. Cumulation of candesartan in the body is not 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 ingestion of radioactively labeled candesartan, about 26% of the administered amount is excreted in the urine in the form of candesartan and 7% in the form of an inactive metabolite, while in the feces 56% of the administered amount is found in the form of candesartan and 10% in the form of an inactive metabolite. In patients with mild to moderate renal impairment, the Cmax and AUC of candesartan increased by 50% and 70%, respectively, while T1 / 2 does not change compared with patients with normal renal function. In patients with severe renal impairment and / or on hemodialysis, the Cmax and AUC of candesartan increased by 50% and 110%, respectively, and T1 / 2 increased by 2 times. In patients with mild to moderate hepatic impairment, an increase in the AUC of candesartan was observed by 23%.

Hydrochlorothiazide

After oral administration, the Cmax of hydrochlorothiazide is achieved within 1-3 hours. The absolute bioavailability is assessed by the cumulative renal excretion of hydrochlorothiazide and is about 60%. Plasma protein binding is 40-70%. Vd - 0.8 ± 0.3 l / kg. It is not metabolized in the human body and is excreted in the urine practically unchanged. About 60% of the dose taken orally is excreted within 48 hours. Renal clearance is about 250-300 ml / min. T1 / 2 - 10-15 hours. There is a difference in plasma concentrations in men and women. In women, there is a tendency for a clinically significant increase in the concentration of hydrochlorothiazide in blood plasma. In patients with impaired renal function, the rate of excretion of hydrochlorothiazide is reduced. Studies conducted with the participation of patients with CC 90 ml / min showed that the T1 / 2 of hydrochlorothiazide increases.In patients with reduced renal function T1 / 2, about 34 hours.

Indications

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

Dosage regimen

The method of application and dosage regimen of a particular drug depends on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly observe the compliance of the used dosage form of a particular drug with the indications for use and the dosage regimen.

It is taken orally 1 time / day. A single dose of a combination of candesartan + hydrochlorothiazide ranges from 8 mg / 12.5 mg to 32 mg / 25 mg.

It is recommended to titrate the candesartan dose before transferring the patient to the candesartan + hydrochlorothiazide combination. The main hypotensive effect is achieved, as a rule, in the first 4 weeks after the start of treatment.

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

For patients at risk of arterial hypotension (for example, with reduced BCC), titration of the dose of candesartan is recommended, starting at 4 mg as monotherapy.

In patients with moderate hepatic dysfunction, before starting therapy with this combination, titration of the dose of candesartan is recommended, starting at 2 mg.

Side effect

Candesartan

From the hematopoietic system: very rarely - leukopenia, neutropenia, agranulocytosis.

From the side of 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 - an increase in the activity of hepatic transaminases, impaired liver function, hepatitis.

From the respiratory system: very rarely - cough.

On the part of the skin and subcutaneous tissues: very rarely - skin rash, pruritus, urticaria, angioedema.

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

From the side of the kidneys and urinary tract: very rarely - renal failure.

Hydrochlorothiazide

From the side of 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 the side of metabolism and nutrition: often - hyperglycemia, hyperuricemia, hyponatremia, hypokalemia.

From the nervous system: often - dizziness, vergygo; rarely - sleep disturbances, anxiety, depression, paresthesia.

From the side of the organ of vision: rarely - decreased vision clarity, acute myopia, acute angle-closure glaucoma.

From the side of 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.

On the part of the skin and subcutaneous tissues: infrequently - rash, urticaria, photosensitivity reaction; rarely - toxic epidermal necrolysis, erythematous reactions, recurrence of cutaneous erythematosis.

From the musculoskeletal system: rarely - muscle spasm.

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

Others: often - weakness, increased concentration of cholesterol, triglycerides in blood plasma; rarely - fever, increased concentration of creatinine, urea in the blood plasma.

Contraindications for use

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; 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).

Carefully: impaired renal function (CC> 30 ml / min), liver failure; severe chronic insufficiency; bilateral renal artery stenosis; stenosis of an artery of a single kidney; hemodynamically significant stenosis of the aortic and / or mitral valve; Ischemic heart disease; hypertrophic obstructive cardiomyopathy; decrease in BCC; diabetes; 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, colestiramine, tubocketamide drugs, adocurarinecytotoxic drugs, GCS, ACTH, barbiturates, general anesthetics, epinephrine, iodine-containing drugs, with alcohol.

Application during pregnancy and lactation

Use during pregnancy and breastfeeding is contraindicated.

Application for violations of liver function

Contraindication: severe liver dysfunction.

Application for impaired renal function

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).

Application in children

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

Use in elderly patients

The drug is approved for use in elderly patients

special instructions

The simultaneous use of ACE inhibitors, ARA II or aliskiren increases the risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure). Double blockade of RAAS when using ACE inhibitors, ARA II or aliskiren is not recommended.

If double 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 content and blood pressure. ACE inhibitors and ARA II should not be used concomitantly in patients with diabetic nephropathy.

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

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

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

In patients receiving angiotensin II antagonists, during anesthesia and during surgery, arterial hypotension may develop as a result of RAAS blockade. Very rarely, there may be cases of severe arterial hypotension, requiring IV fluid and / or vasoconstrictor drugs.

Thiazide diuretics should be used with caution in patients with impaired liver function or progressive liver disease. slight fluctuations in fluid volume and electrolyte composition can cause hepatic coma.

Thiazide-based drugs with a diuretic effect 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. Revealed hypercalcemia may be a sign of latent hyperthyroidism. The use of thiazide diuretics should be discontinued pending test results for the parathyroid gland.

Hydrochlorothiazide dose-dependently increases the excretion of potassium, which can cause hypokalemia. This effect of hydrochlorothiazide is less pronounced if it is used simultaneously with candesartan. The risk of hypokalemia is increased in patients with cirrhosis of the liver, increased diuresis, taking fluids with a low salt content, undergoing parallel treatment with corticosteroids or ACTH.

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

The use of thiazide diuretics can change the concentration of glucose in the blood 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 may contribute to the onset of gout in predisposed patients.

Patients whose vascular tone and renal function are predominantly dependent on RAAS activity (for example, patients with severe chronic heart failure, kidney disease, including renal artery stenosis) are especially sensitive to drugs acting on the RAAS. The appointment of such drugs in these patients is accompanied by severe arterial hypotension, azotemia, oliguria, and, less often, acute renal failure. The possibility of the development of these effects is not excluded with the use of angiotensin II receptor antagonists. A sharp decrease in blood pressure in patients with ischemic cardiopathy, cerebrovascular diseases of ischemic origin, when using any antihypertensive drugs, 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.

With the use of thiazide diuretics, cases of exacerbation or onset of symptoms of congestive seborrhea have been noted.

With the use of thiazide diuretics, there have been cases of worsening of the course of systemic lupus erythematosus.

Hydrochlorothiazide can cause an idiosyncratic reaction, leading to the development of acute myopia and secondary angle-closure glaucoma. Symptoms include: sudden loss of vision or eye pain that usually appears within hours or weeks of starting hydrochlorothiazide therapy. If left untreated, acute angle-closure glaucoma can lead to permanent loss of vision. Treatment - stop taking hydrochlorothiazide as soon as possible. If intraocular pressure remains uncontrolled, urgent medical treatment or surgery may be required. Risk factors for the development of acute angle-closure glaucoma are a history of allergic reactions to sulfonamides or benzylpenicillins.

Influence on the ability to drive vehicles and control mechanisms

If undesirable effects from the central nervous system occur during therapy with a combination of candesartan + hydrochlorothiazide, care should be taken when performing actions that require increased concentration of attention and speed of psychomotor reactions.

Drug interactions

With the 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, it is possible to reduce the hypotensive effect of candesartan.

The simultaneous use of a combination of candesartan + hydrochlorothiazide with other antihypertensive drugs enhances the hypotensive effect.

?война¤ блокада –јј— с применением антагонистов рецепторов ангиотензина II (ј–ј II), ингибиторов јѕ‘ или алискирена (ингибитор ренина) может сопровождатьс¤ повышенным риском развити¤ артериальной гипотензии, обморока, гиперкалиемии и нарушени¤ функции почек (в т.ч. острой почечной недостаточности) по сравнению с монотерапией. Ќеобходим регул¤рный контроль ј?, функции почек и содержани¤ электролитов в крови у пациентов, принимающих комбинацию кандесартан+гидрохлоротиазид одновременно с другими лекарственными средствами, вли¤ющими на –јј—.

 андесартан+гидрохлоротиазид не следует примен¤ть одновременно с алискиреном или алискиренсодержащими препаратами у пациентов с сахарным диабетом и/или с нарушением функции почек (— ‘<60 мл/мин/1.73 м2).

ѕри одновременном применении ингибиторов јѕ‘ и ингибиторов дипептидилпептидазы 4 типа (например, вилдаглиптин) возможно повышение риска развити¤ отека  винке.

?ействие гидрохлоротиазида, привод¤щее к потере кали¤, может усиливатьс¤ другими средствами, привод¤щими к потере кали¤ и гипокалиемии, такими как диуретики, слабительные, амфотерицин, карбеноксолон, пенициллин G натрий, производные салициловой кислоты.

ќпыт применени¤ других лекарственных средств, действующих на –јј—, показывает, что сопутствующа¤ терапи¤ калийсберегающими диуретиками, препаратами кали¤, заменител¤ми соли, содержащими калий, и другими средствами, повышающими содержание кали¤ в сыворотке крови (например, гепарин), может приводить к развитию гиперкалиемии.

vипокалиеми¤ и гипомагниеми¤, вызванные приемом диуретических препаратов, предрасполагают к развитию кардиотоксического эффекта сердечных гликозидов и антиаритмических препаратов. ѕри приеме комбинации кандесартан+гидрохлоротиазид параллельно с такими препаратами требуетс¤ контроль содержани¤ кали¤ в плазме крови.

ѕри одновременном применении препаратов лити¤ с ингибиторами јѕ‘ возникает обратимое повышение концентрации лити¤ в сыворотке крови и развитие токсических реакций. ѕодобные реакции могут встречатьс¤ и при использовании антагонистов рецепторов ангиотензина II, в св¤зи с чем рекомендуетс¤ контролировать содержание лити¤ в сыворотке крови.

?иуретический, натрийуретический и гипотензивный эффекты гидрохлоротиазида уменьшаютс¤ при одновременном применении Ќѕ¬—.

¬сасывание гидрохлоротиазида уменьшаетс¤ при применении колестипола, колестирамина.

?ействие недепол¤ризующих миорелаксантов (например, тубокурарина) может быть усилено гидрохлоротиазидом.

“иазидные диуретики могут вызывать повышение содержани¤ кальци¤ в плазме крови в св¤зи с уменьшением его экскреции. ѕри необходимости применени¤ кальцийсодержащих пищевых добавок или витамина D следует контролировать содержание кальци¤ в плазме крови и при необходимости корректировать дозу.

“иазидные диуретики усиливают гипергликемическое действие бета-адреноблокаторов и диазоксида.

јнтихолинергические средства (например, атропин, биперидин) могут увеличивать биодоступность тиазидных диуретиков вследствие снижени¤ моторики ? “. “иазидные диуретики могут увеличить риск неблагопри¤тного действи¤ амантадина.

“иазидные диуретики способны замедлить выведение цитостатических препаратов (таких как циклофосфамид, метотрексат) из организма и усилить их миелоподавл¤ющее действие.

–иск гипокалиемии может увеличитьс¤ при одновременном приеме v — или ј “v.

Ќа фоне применени¤ данной комбинации возможно увеличение частоты развити¤ ортостатической артериальной гипотензии при употреблении алкогол¤, применени¤ барбитуратов или общих анестетиков.

When treating with thiazide diuretics, a decrease in glucose tolerance is possible, and therefore it may be necessary to select a dose of hypoglycemic drugs (including insulin).

Hydrochlorothiazide may reduce the effects of vasoconstrictor amines (eg epinephrine).

Hydrochlorothiazide may increase the risk of developing acute renal failure, especially when combined with high doses of iodinated vehicle .