pharmachologic effect
Angiotensin II receptor antagonist. Angiotensin II is the main enzyme of the RAAS, which is involved in the pathogenesis of arterial hypertension, heart failure and other cardiovascular diseases.
Candesartan is a selective antagonist of angiotensin II receptors, subtype 1 (AT1 receptors). Does not exhibit agonist properties (does not affect ACE and does not lead to the accumulation of bradykinin or substance P, does not bind to receptors of other hormones, does not affect the state of ion channels involved in the regulation of the cardiovascular system). As a result of blocking the AT1 receptors of angiotensin II, there is a compensatory dose-dependent increase in renin activity, the concentration of angiotensin I, angiotensin II and a decrease in the concentration of aldosterone in the blood plasma.
Arterial hypertension
Oral administration of candesartan provides a dose-dependent, smooth decrease in blood pressure due to a decrease in peripheral vascular resistance without a reflex increase in heart rate. There is no data on the development of severe arterial hypotension after taking the first dose or on the development of withdrawal syndrome after cessation of therapy.
The onset of antihypertensive action after taking the first dose of the drug usually develops within 2 hours, the duration of the effect is 24 hours. With ongoing therapy with candesartan at a fixed dose, the maximum reduction in blood pressure is usually achieved within 4 weeks and persists throughout treatment. The addition of the thiazide diuretic hydrochlorothiazide to candesartan enhances its antihypertensive effect.
The patient's age and gender do not affect the effectiveness of the drug. Candesartan increases renal blood flow and does not change or increases glomerular filtration rate, while renal vascular resistance and filtration fraction are reduced.
Candesartan has a less pronounced antihypertensive effect in patients of the Negroid race (a population with predominantly low renin activity in blood plasma).
There are no data on the effect of candesartan on the progression of diabetic nephropathy. In patients with arterial hypertension and type 2 diabetes mellitus, candesartan does not have a negative effect on blood glucose concentrations and lipid profiles.
Heart failure
Therapy with candesartan reduces the mortality rate and the frequency of hospitalization in patients with chronic heart failure (CHF), regardless of age, gender and concomitant therapy, and leads to a decrease in the functional class of CHF according to the NYHA classification.
Candesartan is effective in patients taking concomitant beta-blockers in combination with ACE inhibitors; Moreover, its effectiveness does not depend on the dose of the ACE inhibitor. In patients with CHF and reduced left ventricular systolic function (left ventricular ejection fraction (LVEF) less than 40%), candesartan reduces peripheral vascular resistance and wedge pressure in the pulmonary capillaries.
Pharmacokinetics
Suction and distribution
Candesartan cilexetil is a prodrug. Candesartan cilexetil after oral administration is quickly converted into the active substance - candesartan, through ether hydrolysis. When absorbed from the digestive tract, it binds firmly to AT1 receptors and dissociates slowly, and does not have agonist properties.
The absolute bioavailability of candesartan after oral administration is approximately 40%. Relative bioavailability is approximately 34%. Cmax in blood serum is achieved 3-4 hours after oral administration. Plasma concentration increases linearly with increasing dose in the therapeutic range (up to 32 mg).
The degree of binding to blood plasma proteins is high (more than 99%). Vd of candesartan is 0.13 l/kg. Does not accumulate. The pharmacokinetic parameters of candesartan do not depend on the patient’s age, gender or meal time.
Metabolism and excretion
Candesartan is mainly excreted unchanged from the body by the kidneys and intestines. Slightly metabolized in the liver (20-30%) with the participation of CYP2C9 with the formation of an inactive derivative.
T1/2 of candesartan is approximately 9 hours. The total clearance is about 0.37 ml/min/kg, while the renal clearance of the drug is 0.19 ml/min/kg. After oral administration of 14C-labeled candesartan cilexetil, 26% of the dose was excreted by the kidneys in the form of candesartan and 7% in the form of an inactive metabolite, while 56% of the dose was excreted through the intestines with bile in the form of candesartan and 10% in the form of an inactive metabolite. After a single oral dose, more than 90% of the dose is eliminated within 72 hours.
Pharmacokinetics in special groups of patients
In elderly patients (over 65 years of age), the Cmax and AUC of candesartan increase compared to young patients by approximately 50% and 80%, respectively. However, the blood pressure response and possible side effects when using candesartan do not depend on the age of the patients.
In patients with mild or moderate renal impairment, the Cmax and AUC of candesartan increase by approximately 50% and 70%, respectively, while T1/2 does not change compared to patients with preserved renal function. Pharmacokinetics in patients on hemodialysis are similar to those in patients with severe renal impairment. In patients with severely impaired renal function, Cmax and AUC increase by 50% and 110%, respectively, and T1/2 of the drug increases by 2 times.
In patients with mild or moderate hepatic impairment, the mean AUC of candesartan increased by approximately 20% in one study and 80% in another study. There is no experience of use in patients with severe liver dysfunction.
Ordiss N tablet 12.5mg+16mg cor x30
Ordiss N tablet 12.5mg+16mg x30, ATX code: C09DA06 (Candesartan in combination with diuretics)
Active substances
hydrochlorothiazide Rec.INN WHO registered candesartan Rec.INN WHO registered
Dosage forms
Ordiss N®
Tabletkireg. No.: LP-002097 from 06/10/13 - Indefinitely Re-registration date: 08/03/18
Release form, packaging and composition of Ordiss N®
The tablets are light pink, biconvex, capsule-shaped, with a score line on both sides, engraved “C” on one side and “16” on opposite sides.
1 tab.
candesartan cilexetil 16 mg
hydrochlorothiazide 12.5 mg
Excipients: pregelatinized starch - 15 mg, povidone-K30 - 16 mg, calcium carmellose - 6.6 mg, poloxamer 188 - 1 mg, microcrystalline cellulose - 72 mg, lactose monohydrate - 177.6 mg, red iron oxide dye (E172) - 0.1 mg , magnesium stearate - 3.2 mg.
The tablets are white or almost white, biconvex, capsule-shaped, with a score on both sides, engraved “C” on one side and “32” on opposite sides.
1 tab.
candesartan cilexetil 32 mg
hydrochlorothiazide 12.5 mg
Excipients: pregelatinized starch - 30 mg, povidone-K30 - 32 mg, calcium carmellose - 13.2 mg, poloxamer 188 - 2 mg, microcrystalline cellulose - 148 mg, lactose monohydrate - 363.9 mg, magnesium stearate - 6.4 mg.
The tablets are light pink, biconvex, capsule-shaped, with a line on both sides, on one side there is an engraving of “H” and “25” on opposite sides of the lines, on the other side there is an engraving of “C” and “32” on opposite sides of the lines.
1 tab.
candesartan cilexetil 32 mg
hydrochlorothiazide 25 mg
Excipients: pregelatinized starch - 30 mg, povidone-K30 - 32 mg, calcium carmellose - 13.2 mg, poloxamer 188 - 2 mg, microcrystalline cellulose - 144 mg, lactose monohydrate - 355.2 mg, iron dye red oxide (E172) - 0.2 mg , magnesium stearate - 6.4 mg.
Clinical and pharmacological group: Combined antihypertensive drug. Angiotensin II receptor antagonist + diuretic Pharmacotherapeutic group: Antihypertensive combined drug (angiotensin II receptor blocker + diuretic)
pharmachologic effect
Angiotensin II is the main hormone of the RAAS, which plays an important role in the pathogenesis of arterial hypertension, heart failure and other cardiovascular diseases. The main physiological effects of angiotensin II are vasoconstriction, stimulation of aldosterone production, regulation of fluid and electrolyte status, and stimulation of cell growth. The effects are mediated by the interaction of angiotensin II with angiotensin type 1 receptors (AT1 receptors).
Candesartan is a selective antagonist of AT1 receptors of angiotensin II, does not inhibit ACE, which converts angiotensin I into 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 renin and angiotensin I occurs , angiotensin II and a decrease in the concentration of aldosterone in the blood plasma.
When comparing candesartan with ACE inhibitors, the development of cough was less common in patients receiving candesartan.
Candesartan does not bind to the 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 that inhibits active sodium reabsorption, mainly in the distal renal tubules and increases the excretion of sodium, chlorine and water ions. The excretion of potassium and magnesium by the kidneys increases in a dose-dependent manner, while calcium begins to be reabsorbed in greater quantities than before.
Hydrochlorothiazide reduces the volume of blood plasma and extracellular fluid, reduces the intensity of blood transport by the heart, and lowers blood pressure. During long-term treatment, the hypotensive effect develops due to the dilation of arterioles. Long-term use of hydrochlorothiazide reduces the risk of cardiovascular disease and mortality.
Candesartan and hydrochlorothiazide have a cumulative hypotensive effect. In patients with arterial hypertension, the use of candesartan/hydrochlorothiazide causes an effective and lasting reduction in blood pressure without increasing heart rate. Orthostatic arterial hypotension is not observed when taking the drug for the first time; after treatment, arterial hypertension does not increase.
After a single dose of candesartan/hydrochlorothiazide, the main hypotensive effect develops within 2 hours. The use of the drug once a day effectively and gently reduces blood pressure within 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 starting the drug and can be maintained with a long course of treatment.
In clinical studies, the incidence of side effects, especially cough, was lower with candesartan/hydrochlorothiazide than with a combination of ACE inhibitors and hydrochlorothiazide.
There are currently no data on the use of candesartan/hydrochlorothiazide in patients with renal failure, nephropathy, reduced left ventricular function, acute heart failure and myocardial infarction.
The effectiveness of candesartan/hydrochlorothiazide does not depend on gender or age.
Pharmacokinetics
Suction and distribution
Candesartan. When candesartan is absorbed from the gastrointestinal tract, cilexitil quickly turns into the active substance, candesartan, through ether hydrolysis, binds strongly to AT1 receptors and slowly dissociates, and has no agonist properties. The absolute bioavailability of candesartan after oral administration is about 40%. The relative bioavailability of the tablet form compared to the oral solution is approximately 34%. Thus, the calculated absolute bioavailability of the tablet form of the drug is 14%. Food intake does not have a significant effect on AUC, i.e. food does not significantly affect the bioavailability of the drug.
Cmax in blood plasma is achieved 3-4 hours after taking the tablet form of the drug. As the dose increases within the recommended limits, the concentration of candesartan increases linearly. The binding of candesartan to plasma proteins is more than 99%. Plasma Vd of candesartan is 0.1 l/kg.
The pharmacokinetic parameters of candesartan do not depend on the gender of the patient.
Hydrochlorothiazide. Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 70%. Concomitant meals increase absorption by approximately 15%. Bioavailability may be reduced in patients with heart failure and severe edema.
Plasma protein binding is approximately 60%. Apparent Vd is approximately 0.8 l/kg.
Metabolism and excretion
Candesartan. Candesartan is mainly excreted unchanged from the body by the kidneys and through the intestines with bile 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 radiolabeled candesartan is administered orally, approximately 26% of the administered amount is excreted in the urine as candesartan and 7% as an inactive metabolite, whereas 56% of the administered amount is found in the feces as candesartan and 10% as an inactive metabolite.
Hydrochlorothiazide. Hydrochlorothiazide is not metabolized and is excreted almost entirely as 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 taken together with candesartan. Approximately 70% of the dose taken orally is excreted by the kidneys within 48 hours. When using a combination of drugs, no additional accumulation of hydrochlorothiazide was detected in comparison with monotherapy.
Pharmacokinetics in special clinical situations
Candesartan. In patients over 65 years of age, the Cmax and AUC of candesartan increase by 50% and 80%, respectively, compared with younger patients. However, the hypotensive effect and the incidence of side effects when using candesartan/hydrochlorothiazide do not depend on the age of the patients.
In patients with mild and moderate renal impairment, Cmax and AUC of candesartan increased by 50% and 70%, respectively, while T1/2 did not change compared to patients with normal renal function.
In patients with severe renal impairment and/or those 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, the AUC of candesartan increased by 23%.
Hydrochlorothiazide. T1/2 is longer in patients with renal failure.
Indications for the drug Ordiss N® are the treatment of arterial hypertension in patients who are indicated for combination therapy. ICD-10 codes
Dosage regimen
Ordiss N® should be taken orally 1 time/day, regardless of meals.
The recommended dose is 1 tablet 1 time/day.
It is recommended to titrate the dose of candesartan before transferring the patient from hydrochlorothiazide monotherapy to therapy with Ordiss N®. If necessary, patients are transferred from monotherapy with Ordiss® to therapy with Ordiss N®.
The main hypotensive effect is achieved, as a rule, in the first 4 weeks after the start of treatment.
In elderly patients, no dose adjustment is required.
In patients with mild or moderate renal impairment (creatinine clearance 30-80 ml/min/1.73 m2 body surface area), dose titration is recommended. The drug Ordiss N® is contraindicated in patients with severe renal failure (creatinine clearance <.30 ml/min/1.73 m2 body surface area).
In patients with mild or moderate hepatic impairment, dose titration is recommended. Ordiss N® is contraindicated in patients with severe liver dysfunction and/or cholestasis.
Patients with reduced blood volume: for patients at risk of arterial hypotension, for example, for patients with reduced blood volume, it is recommended to titrate the dose of candesartan (via monotherapy with Ordiss®), starting from 4 mg.
The safety and effectiveness of the drug Ordiss N® in children and adolescents under 18 years of age have not been established.
Side effect
Determination of the frequency of side effects according to WHO recommendations: very often - at least 10%, often - at least 1%, but less than 10%, infrequently - at least 0.1%, but less than 1%, rarely - at least 0.01%, but less 0.1%, very rarely (including individual messages) - less than 0.01%.
Candesartan
From the hematopoietic system: very rarely - leukopenia, neutropenia, agranulocytosis.
Metabolic disorders: 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, itching, urticaria, angioedema.
From the musculoskeletal system: very rarely - back pain, arthralgia, myalgia.
From the kidneys and urinary tract: very rarely - renal failure (see section "Special instructions").
Hydrochlorothiazide
From the blood system: rarely - leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, suppression of bone marrow function, hemolytic anemia, decreased hemoglobin.
From the immune system: rarely - anaphylactic reaction.
Metabolism: often - hyperglycemia, hyperuricemia, hyponatremia, hypokalemia.
From the nervous system: often - dizziness, vergigo, rarely - sleep disturbances, anxiety, depression, paresthesia.
From the organ of vision: rarely - decreased clarity of vision, 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, relapse of cutaneous erythematosis.
From the musculoskeletal system: rarely - muscle spasm.
From the urinary system: often - glucosuria, rarely - renal dysfunction, interstitial nephritis.
Other: often - weakness, increased concentrations of cholesterol, triglycerides in the blood plasma, rarely - fever, increased concentrations 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 dysfunction (GFR <.30 ml/min/1.73 m2), severe liver dysfunction, cholestasis, refractory hypokalemia, hypercalcemia, condition after kidney transplantation, pregnancy, breastfeeding, childhood and adolescence under 18 years of age, 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 ), lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.
With caution: simultaneous use with other antihypertensive drugs, potassium-sparing diuretics, amphotericin, carbenoxolone, sodium penicillin G drugs, salicylic acid derivatives, cardiac glycosides, antiarrhythmic drugs, lithium drugs, NSAIDs, colestipol, cholestyramine, tubocurarine, beta-blockers, anticholinergic drugs, amantadine, cytotoxic drugs, corticosteroids, ACTH, barbiturates, general anesthetics, epinephrine, iodine-containing drugs, alcohol, impaired renal function (creatinine clearance>30 ml/min), liver failure, severe chronic failure, bilateral renal artery stenosis, single artery stenosis kidneys, hemodynamically significant stenosis of the aortic and/or mitral valve, coronary heart disease, hypertrophic obstructive cardiomyopathy, decreased blood volume, diabetes mellitus, cerebrovascular diseases, acute myopia, angle-closure glaucoma, systemic lupus erythematosus, simultaneous use with alcohol.
Use during pregnancy and breastfeeding
The drug Ordiss N® is contraindicated for use during pregnancy and breastfeeding.
Patients taking the drug should be warned about this before planning pregnancy so that they can switch to alternative therapy with a proven safety profile for use during pregnancy. If pregnancy is diagnosed, drug therapy should be stopped immediately. Drugs that affect the RAAS can cause developmental disorders in the fetus and/or have a negative effect on the newborn, including death when using the drug during pregnancy. It is known that therapy with angiotensin II receptor antagonists can cause developmental disorders of the fetus (impaired renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (impaired renal function, arterial hypotension, hyperkalemia).
Experience with the use of hydrochlorothiazide during pregnancy is limited. Hydrochlorothiazide penetrates the placental barrier. Given the mechanism of action of hydrochlorothiazide, its use during pregnancy can cause disturbances in fetoplacental circulation and undesirable effects in the fetus and newborn in the form of jaundice, water-electrolyte imbalance and thrombocytopenia.
It is not known whether candesartan is excreted into breast milk in humans. Candesartan is excreted in the milk of lactating rats. Hydrochlorothiazide is excreted in breast milk.
Use for liver dysfunction
The drug Ordiss N is contraindicated in patients with severe liver failure. Use with caution in cases of moderate renal failure.
Use for impaired renal function Ordiss N is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). Use with caution in cases of moderate renal failure.
Use in children The safety and effectiveness of Ordiss N® in children and adolescents under 18 years of age have not been established.
Use in elderly patients No dose adjustment is required in elderly patients.
special instructions
Concomitant use of ACE inhibitors, ARB II or aliskiren increases the risk of developing arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure). Double blockade of the RAAS when using ACE inhibitors, ARB II or aliskiren is not recommended (see section “Drug Interactions”).
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 levels and blood pressure. ACE inhibitors and ARB II should not be used simultaneously in patients with diabetic nephropathy.
In patients with renal failure, the use of loop diuretics is preferable to thiazide diuretics. For patients with renal failure during therapy with Ordiss N®, it is recommended to constantly monitor the levels of potassium, creatinine and uric acid.
There are no data on the use of Ordiss N® in patients who have recently undergone a kidney transplant.
Drugs that affect the RAAS (eg, ACE inhibitors) may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or arterial stenosis of a solitary kidney. A similar effect should be expected from angiotensin II receptor antagonists.
In patients with BCC and/or sodium deficiency, symptomatic arterial hypotension may develop, so it is not recommended to use the drug Ordiss N® until these symptoms disappear.
In patients receiving angiotensin II antagonists, hypotension may develop during anesthesia and during surgery as a result of blockade of the RAAS. Very rarely, cases of severe arterial hypotension may occur, requiring IV fluids and/or vasoconstrictors.
Patients with impaired liver function or progressive liver disease should use thiazide diuretics with caution, because Minor fluctuations in fluid volume and electrolyte composition can cause hepatic coma. There are no data on the use of Ordiss N® in patients with liver failure.
When prescribing Ordiss N® to patients with obstructive hypertrophic cardiomyopathy or hemodynamically significant stenosis of the aortic or mitral valve, caution should be exercised.
Patients with primary hyperaldosteronism are usually resistant to treatment with antihypertensive drugs that affect the RAAS, therefore, the use of Ordiss N® in such patients is not recommended.
As in all cases of taking drugs that have a diuretic effect, electrolytes in the blood plasma should be monitored.
Thiazide-based drugs that have a diuretic effect can reduce the excretion of calcium ions in the urine and can cause sudden changes and a slight increase in the concentration of calcium ions in the blood plasma.
Thiazides, incl. and hydrochlorothiazide, can cause disturbances in water-salt balance (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia and hypochloremic alkalosis).
Detected hypercalcemia may be a sign of latent hyperparathyroidism.
The use of thiazide diuretics should be discontinued until results of parathyroid tests are available.
Hydrochlorothiazide increases potassium excretion in a dose-dependent manner, which may cause hypokalemia. This effect of hydrochlorothiazide is less pronounced if it is used simultaneously with candesartan. The risk of hypokalemia appears to be increased in patients with liver cirrhosis, increased diuresis, taking fluids with a reduced salt content, and undergoing concurrent treatment with corticosteroids or ACTH.
Based on experience with the use of drugs that affect the RAAS, the concurrent use of Ordiss N® and diuretics that increase potassium excretion can be compensated by the use of nutritional supplements containing potassium or other drugs that can increase the level of potassium in the blood plasma.
The use of Ordiss N® may cause hypokalemia, especially in patients with heart or renal failure (such cases have not been documented).
Thiazide diuretics increase magnesium excretion, 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. Dosage adjustment of hypoglycemic agents, including insulin, may be required.
The use of thiazide diuretics is associated with an increase in cholesterol and triglycerides in the blood plasma. However, when using the drug Ordiss N®, a minimal amount or absence of such effects was observed.
Thiazide diuretics increase plasma uric acid concentrations and may precipitate gout in predisposed patients.
Patients whose vascular tone and renal function are predominantly dependent 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 is accompanied in these patients by severe 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 cardiopathy, cerebrovascular diseases of ischemic origin when using any antihypertensive drugs can lead to the development of myocardial infarction or stroke.
The occurrence 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.
When using thiazide diuretics, there have been cases of exacerbation or the appearance of symptoms of congestive seborrhea.
When using thiazide diuretics, there have been cases of worsening of systemic lupus erythematosus.
Hydrochlorothiazide may 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, usually occurring within hours to weeks of starting hydrochlorothiazide therapy. If left untreated, acute angle-closure glaucoma can lead to permanent vision loss. Treatment is to stop taking 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 an allergic reaction to sulfonamides or benzylpenicillins.
The drug contains lactose, so it should not be taken by patients with rare hereditary diseases manifested by lactose intolerance, lactose deficiency or impaired absorption of glucose and galactose.
Hydrochlorothiazide, which is part of the drug Ordiss N®, can give a positive result when carried out before
Contraindications for use
- Hypersensitivity to candesartan or other components of the drug;
- lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
- pregnancy;
- breastfeeding period;
- children and adolescents under 18 years of age (efficacy and safety have not been established);
- severe liver dysfunction and/or cholestasis;
- simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or impaired renal function (GFR less than 60 ml/min).
With caution: severe renal dysfunction (creatinine clearance less than 30 ml/min), hemodialysis, bilateral renal artery stenosis or stenosis of the artery of a single kidney, hemodynamically significant stenosis of the aortic and/or mitral valve, hypertrophic obstructive cardiomyopathy (HOCM), condition after kidney transplantation, cerebrovascular disorders of ischemic origin and ischemic heart disease, hyperkalemia in patients with reduced blood volume, general anesthesia and surgical interventions (risk of developing arterial hypotension due to blockade of the RAAS), primary hyperaldosteronism.
Ordiss, 16 mg, tablets, 30 pcs.
Concomitant use of ACE inhibitors, ARB II or aliskiren increases the risk of developing arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure). Double blockade of the RAAS when using ACE inhibitors, ARB II or aliskiren is not recommended (see “Interaction”).
If double blockade of the RAAS is considered absolutely necessary, then treatment should only occur under the supervision of a physician and should be accompanied by careful and regular monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and ARB II should not be used simultaneously in patients with diabetic nephropathy.
Renal dysfunction.
During the use of the drug Ordiss®, as with the use of other drugs that inhibit the RAAS, in some cases, renal dysfunction may develop.
When using the drug Ordiss® in patients with arterial hypertension and severe renal failure (GFR less than 30 ml/min/1.73 m2), it is recommended to regularly monitor the potassium content and creatinine concentration in the blood serum. Clinical experience with the drug in patients with end-stage renal failure (GFR less than 15 ml/min/1.73 m2) is limited. In such patients, it is necessary to select the dose of Ordiss® under blood pressure control.
In patients with CHF, renal function should be periodically monitored, especially in patients over 75 years of age and patients with impaired renal function. When increasing the dose, it is also recommended to monitor the potassium content and creatinine concentration in the blood serum.
There is no data on the use of the drug Ordiss® for CHF with a creatinine concentration of more than 265 µmol/l (more than 3 mg/ml).
Hemodialysis.
During hemodialysis, blood pressure may be especially sensitive to AT1 receptor blockade as a result of a decrease in blood volume and activation of the RAAS. Therefore, patients on hemodialysis need to monitor blood pressure and individually select the dose of Ordiss® in accordance with blood pressure levels.
Simultaneous use with ACE inhibitors for CHF. When used simultaneously with ACE inhibitors, the risk of side effects increases, especially renal dysfunction and hyperkalemia. The clinical condition of patients and relevant laboratory parameters should be monitored.
Renal artery stenosis.
Drugs that affect the RAAS (eg ACE inhibitors) may cause increases in serum urea and creatinine concentrations in patients with bilateral renal artery stenosis or arterial stenosis of a solitary kidney. A similar effect can be expected when using ARA II.
Kidney transplantation.
There is no experience with the use of Ordiss® in patients who have recently undergone kidney transplantation.
Arterial hypotension.
In patients with CHF, arterial hypotension may develop when using Ordiss®. It is also possible to develop arterial hypotension in patients with BCC deficiency, for example, when using large doses of diuretics. In this case, before using the drug Ordiss®, it is necessary to correct the blood volume.
General anesthesia and/or surgical interventions.
In patients receiving angiotensin II antagonists, hypotension may develop during general anesthesia and during surgery as a result of blockade of the RAAS. In rare cases, arterial hypotension may be severe, requiring IV fluids and/or vasopressors.
Stenosis of the aortic and/or mitral valves, HOCM.
When using the drug Ordiss® in patients with HOCM or hemodynamically significant stenosis of the aortic or mitral valves, caution should be exercised.
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism are usually resistant to therapy with antihypertensive drugs that affect the RAAS, so the use of Ordisc® in this group of patients is not recommended.
Hyperkalemia.
Concomitant use of Ordiss® with potassium-sparing diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that can increase serum potassium levels (for example, heparin) may lead to the development of hyperkalemia in patients with arterial hypertension.
Hyperkalemia can also develop in patients with CHF taking the drug Ordiss®. During therapy with Ordiss® in patients with CHF, it is recommended to periodically monitor the potassium level in the blood serum, especially with the simultaneous use of ACE inhibitors and potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone (spironolactone derivative).
Are common.
Patients whose vascular tone and renal function primarily depend on the activity of the RAAS (for example, patients with severe CHF, kidney disease, including renal artery stenosis) are especially sensitive to drugs acting on the RAAS. The use of such drugs is accompanied in these patients by severe arterial hypotension, azotemia, oliguria and, less commonly, acute renal failure. The possibility of developing the listed effects is not excluded when using ARA II. 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.
Application in pediatrics.
The safety and effectiveness of using Ordiss® in people under 18 years of age have not been established.
Impact on the ability to drive vehicles and machinery.
If undesirable effects from the central nervous system occur during therapy with Ordiss®, caution should be exercised when performing actions that require increased concentration and speed of psychomotor reactions.
Use during pregnancy and children
The drug Giposart is contraindicated for use during pregnancy, because it has a direct effect on the RAAS and can cause developmental disorders of the fetus (especially in the second and third trimesters of pregnancy) or have a negative effect on the newborn, including death, if the drug was used during pregnancy.
It is known that therapy with angiotensin II receptor antagonists (ARA II) can cause fetal developmental disorders (impaired renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia). If the fact of pregnancy is established, the drug Giposart must be discontinued as quickly as possible.
When planning pregnancy, it is necessary to transfer the patient to adequate alternative therapy.
It is not known whether candesartan is excreted in breast milk, but it is known to be excreted in the milk of lactating rats.
During treatment with Hyposart, breastfeeding should be stopped. Newborns whose mothers took Hyposart during pregnancy should be under close medical supervision due to the likelihood of developing arterial hypotension.
Use in children
The use of the drug is contraindicated in children and adolescents under 18 years of age (efficacy and safety have not been established).
Side effects
Classification of the frequency of side effects: very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports.
Side effects of candesartan are mild and transient. The frequency of side effects does not depend on the dose of the drug and the age of the patient.
From the nervous system: often - dizziness, headache, weakness.
From the cardiovascular system: often - a pronounced decrease in blood pressure.
From the respiratory system: often - respiratory infections, pharyngitis, rhinitis, cough.
From the digestive system: very rarely - nausea, increased activity of liver transaminases, impaired liver function or hepatitis.
From the urinary system: often - impaired renal function, including renal failure in predisposed patients.
From the musculoskeletal system: very rarely - back pain, arthralgia, myalgia.
From the hematopoietic system: very rarely - leukopenia, neutropenia, thrombocytopenia and agranulocytosis.
Laboratory indicators: very rarely - hyperkalemia, hyponatremia, increased creatinine concentration in the blood, hyperuricemia, slight decrease in hemoglobin.
Allergic reactions: very rarely - angioedema, skin rash, itching, urticaria.
Other: exacerbation of gout, “flushes” of blood to the skin of the face.
Drug interactions
The use of candesartan concomitantly with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal failure (GFR <60 ml/min/1.73 m2).
The simultaneous use of candesartan with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinyl estradiol/levonorgestrel), glibenclamide, nifedipine and enalapril has been studied; no clinically significant pharmacokinetic interaction was observed.
Candesartan is slightly metabolized in the liver (via the CYP2C9 isoenzyme). There was no effect on the CYP2C9 and CYP3A4 isoenzymes; the effect on other cytochrome P450 isoenzymes is currently unknown.
Antihypertensive drugs potentiate the antihypertensive effect of candesartan. Experience with the use of other drugs acting on the RAAS shows that the simultaneous use of the drug and potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium preparations, salt substitutes containing potassium, or other drugs that can increase the concentration of potassium in the blood serum ( for example, heparin) can lead to the development of hyperkalemia.
With the simultaneous use of lithium preparations and ACE inhibitors, cases of transient increases in the concentration of lithium in the blood serum and the development of toxic effects have been observed. A similar effect is possible with the simultaneous use of lithium drugs and angiotensin II receptor antagonists, which requires periodic monitoring of the concentration of lithium in the blood serum during the combined use of these drugs.
With simultaneous use of ARA II and NSAIDs, including selective COX-2 inhibitors and non-selective NSAIDs (for example, acetylsalicylic acid at a dose of more than 3 g / day), the antihypertensive effect of candesartan may be reduced.
Double blockade of the RAAS
As with ACE inhibitors, simultaneous use of ARB II and NSAIDs increases the risk of decreased renal function, including the development of renal failure, which leads to hyperkalemia in patients with impaired renal function. This combination should be used with caution, especially in elderly patients. All patients should receive sufficient fluids; it is necessary to monitor renal function at the beginning of therapy and thereafter.
ORDISS N
Pharmacokinetics
Absorption and distribution
of Candesartan.
When candesartan cilexetil is absorbed from the gastrointestinal tract (GIT), it quickly turns into the active substance, candesartan, through ether hydrolysis, binds strongly to AT1 receptors and slowly dissociates, and has no agonist properties. The absolute bioavailability of candesartan after oral administration is about 40%. The relative bioavailability of the tablet form compared to the oral solution is approximately 34%. Thus, the calculated absolute bioavailability of the tablet form of the drug is 14%. Food intake does not have a significant effect on the area under the concentration-time curve (AUC), i.e. food does not significantly affect the bioavailability of the drug.
The maximum concentration in blood plasma (Cmax) is achieved 3-4 hours after taking the tablet form of the drug. As the dose of the drug increases within the recommended limits, the concentration of candesartan increases linearly. The binding of candesartan to plasma proteins is more than 99%. The plasma volume of distribution (Vd) of candesartan is 0.1 l/kg.
The pharmacokinetic parameters of candesartan do not depend on the gender of the patient. Hydrochlorothiazide.
Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 70%. Concomitant food intake increases absorption by approximately 15%. Bioavailability may be reduced in patients with heart failure and severe edema.
Plasma protein binding is approximately 60%. Apparent Vd is approximately 0.8 l/kg.
Metabolism and excretion
Candesartan.
Candesartan is mainly excreted unchanged from the body by the kidneys and through the intestines with bile and is only slightly metabolized in the liver.
The half-life (T1/2) of candesartan is approximately 9 hours. Cumulation of the drug 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 radiolabeled candesartan is administered orally, approximately 26% of the administered amount is excreted in the urine as candesartan and 7% as an inactive metabolite, whereas 56% of the administered amount is found in the feces as candesartan and 10% as an inactive metabolite.
Hydrochlorothiazide.
Hydrochlorothiazide is not metabolized and is excreted almost entirely as 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 used simultaneously with candesartan. Approximately 70% of the dose taken orally is excreted by the kidneys within 48 hours. When using a combination of drugs, no additional accumulation of hydrochlorothiazide was detected in comparison with monotherapy.
Pharmacokinetics in special clinical situations
Candesartan.
In patients over 65 years of age, the Cmax and AUC of candesartan increase by 50% and 80%, respectively, compared with young patients. However, the hypotensive effect and the incidence of side effects when using candesartan/hydrochlorothiazide do not depend on the age of the patients.
In patients with mild and moderate renal impairment, the Cmax AUC of candesartan increased by 50% and 70%, respectively, while the T1/2 of the drug did not change compared to patients with normal renal function.
In patients with severe renal impairment and/or those on hemodialysis, the Cmax of candesartan AUC increased by 50% and 110%, respectively, and T1/2 of the drug increased by 2 times.
In patients with mild to moderate hepatic impairment, the AUC of candesartan increased by 23%.
Hydrochlorothiazide.
T1/2 is longer in patients with renal failure.
Dosage
The drug is taken orally, 1 time/day, regardless of the time of meal.
Arterial hypertension
The recommended initial and maintenance dose of Giposart is 8 mg 1 time / day. If necessary, the dose can be increased to 16 mg 1 time / day. The maximum antihypertensive effect is achieved within 4 weeks of therapy. The maximum daily dose is 32 mg 1 time/day.
If adequate blood pressure control is not achieved at the maximum daily dose, it is recommended to add a thiazide diuretic (eg, hydrochlorothiazide) to therapy. This may enhance the antihypertensive effect of Giposart.
In patients at risk of developing arterial hypotension (including patients with reduced blood volume), it is recommended to start therapy with a dose of 4 mg.
In patients with mild to moderate renal impairment (creatinine clearance 30-80 ml/min/1.73 m2), including patients on hemodialysis, the initial dose of the drug is 4 mg. The dose should be titrated depending on the therapeutic effect. Clinical experience with the use of the drug in patients with severe renal impairment or end-stage renal failure (creatinine clearance less than 15 ml/min) is limited.
The initial daily dose of the drug in patients with mild to moderate liver disease is 4 mg. It is possible to increase the dose if necessary. There is no clinical experience with the use of the drug in patients with severe liver dysfunction and/or cholestasis.
Chronic heart failure
The recommended initial dose of Giposart is 4 mg 1 time / day. An increase to a maximum daily dose of 32 mg 1 time / day or to the maximum tolerated dose is carried out by doubling the dose with an interval of at least 2 weeks.
Elderly patients and patients with impaired renal or liver function do not require adjustment of the initial dose of the drug.
The safety and effectiveness of the drug Giposart in children and adolescents under 18 years of age have not been established.
Concomitant therapy
The drug Giposart can be used simultaneously with other drugs for the treatment of CHF, including ACE inhibitors, beta-blockers, diuretics, cardiac glycosides or combinations of these drugs.
Ordiss®
Renal dysfunction.
During the use of the drug Ordiss®, as with the use of other drugs that inhibit the RAAS, in some cases, renal dysfunction may develop.
When using the drug Ordiss® in patients with arterial hypertension and severe renal failure (creatinine clearance less than 30 ml/min), it is recommended to regularly monitor the potassium content and creatinine concentration in the blood serum. Clinical experience with the drug in patients with end-stage renal failure (creatinine clearance less than 15 ml/min) is limited. When using the drug Ordiss® in such patients, it is necessary to select the dose of the drug Ordiss® under blood pressure control.
In patients with chronic kidney disease, renal function should be periodically monitored, especially in patients over 75 years of age and in patients with impaired renal function. When increasing the dose, it is also recommended to monitor the potassium content and creatinine concentration in the blood serum.
There is no data on the use of the drug Ordiss® for CHF with a creatinine concentration of more than 265 µmol/l (more than 3 mg/ml).
Hemodialysis
. During hemodialysis, blood pressure may be especially sensitive to AT1 receptor blockade as a result of a decrease in blood volume and activation of the RAAS. Therefore, patients on hemodialysis need to monitor blood pressure and individually select the dose of Ordiss® in accordance with blood pressure levels.
Simultaneous use with ACE inhibitors for CHF
. When used simultaneously with ACE inhibitors, the risk of side effects increases, especially renal dysfunction and hyperkalemia. The clinical condition of patients and relevant laboratory parameters should be monitored.
Renal artery stenosis
. Drugs that affect the RAAS (eg, ACE inhibitors) may lead to increased serum urea and creatinine concentrations in patients with bilateral renal artery stenosis or solitary renal artery stenosis. A similar effect can be expected with the use of angiotensin II receptor antagonists.
Kidney
transplantation . There is no experience with the use of Ordiss® in patients who have recently undergone kidney transplantation.
Arterial hypotension
. In patients with CHF, arterial hypotension may develop when using the drug Ordiss®. It is also possible to develop arterial hypotension in patients with BCC deficiency, for example, when using large doses of diuretics. In this case, before using the drug Ordiss®, it is necessary to correct the blood volume.
General anesthesia and/or surgery
. In patients receiving angiotensin II antagonists, hypotension may develop during general anesthesia and during surgery as a result of blockade of the RAAS. In rare cases, hypotension may be severe, requiring intravenous fluids and/or vasopressors.
Stenosis of the aortic and/or mitral valves, HOCM
. When using the drug Ordiss® in patients with HOCM or hemodynamically significant stenosis of the aortic or mitral valves, caution should be exercised.
Primary hyperaldosteronism
. Patients with primary hyperaldosteronism are usually resistant to therapy with antihypertensive drugs that affect the RAAS, so the use of Ordiss® in this group of patients is not recommended. Hyperkalemia. Concomitant use of Ordiss® with potassium-sparing diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that can increase serum potassium levels (for example, heparin) may lead to the development of hyperkalemia in patients with arterial hypertension.
Hyperkalemia can also develop in patients with CHF taking the drug Ordiss®. During therapy with Ordiss® in patients with CHF, it is recommended to periodically monitor the potassium content in the blood serum, especially with the simultaneous use of ACE inhibitors and potassium-sparing diuretics (spironolactone, triamterene, amiloride).
Are common.
Patients whose vascular tone and renal function are predominantly dependent 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 use of such drugs is accompanied in these patients by severe 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 cardiopathy, cerebrovascular diseases of ischemic origin when using any antihypertensive drugs can lead to the development of myocardial infarction or stroke.
Use in pediatrics
. The safety and effectiveness of using Ordiss® in people under 18 years of age have not been established.
Overdose
Symptoms: excessive decrease in blood pressure, dizziness, tachycardia. Isolated cases of drug overdose (up to 672 mg of candesartan cilexetil) have been described, resulting in the recovery of patients without serious consequences.
Treatment: if there is a pronounced decrease in blood pressure, the patient should be placed in a supine position with his legs raised; further - carry out measures aimed at increasing the volume of blood volume (administration of 0.9% sodium chloride solution intravenously). If necessary, sympathomimetic drugs can be prescribed. It is recommended to carry out symptomatic therapy under the control of vital functions of the body. Hemodialysis is ineffective.
