Ordiss, 16 mg tablets 30 pcs

Pharmacotherapeutic group: angiotensin II receptor antagonist.

ATX code: C09CA06

Pharmacological properties

Pharmacodynamics

Angiotensin II is the main component (hormone) of the renin-angiotensin-aldosterone system (RAAS), which is involved in the pathogenesis of arterial hypertension (AH), heart failure and other cardiovascular diseases.

Candesartan is a selective angiotensin II receptor antagonist, subtype 1 (AT1 receptor). It does not exhibit agonist properties (does not affect angiotensin-converting enzyme (ACE) and does not lead to accumulation of bradykinin or substance P, does not bind to receptors of other hormones, does not affect ion channels involved in regulation of cardiovascular system activity). As a result of blocking of AT1-receptors of angiotensin II there is a compensatory dose-dependent increase of renin activity, concentration of angiotensin I, angiotensin II and decrease of plasma concentration of aldosterone.

Arterial hypertension

The oral administration of candesartan provides a dose-dependent, smooth decrease in BP by reducing total peripheral vascular resistance (TPR) without a reflex increase in heart rate (HR). There are no data about the development of significant rterial hypotension after the first dose or about the development of “withdrawal” after discontinuation of therapy.

The onset of antihypertensive effect after the first dose of the drug usually develops within 2 hours, the duration of effect is 24 hours. Against the background of continuing therapy with candesartan in a fixed dose, maximum BP reduction is usually achieved within 4 weeks and persists throughout treatment.

The addition of the thiazide diuretic hydrochlorothiazide to candesartan increases its antihypertensive effect.

The patient’s age and gender do not affect the effectiveness of the drug. Increases renal blood flow and does not alter or increase glomerular filtration rate, whereas renal vascular resistance and filtration fraction decrease.

Candesartan has a less pronounced antihypertensive effect in patients of non-hypertensive race (a population with predominantly low plasma renin activity).

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 has no adverse effect on blood glucose concentration and lipid profile.

Chronic Heart Failure

Therapy with candesartan decreases mortality rate and hospitalization rate in patients with chronic heart failure (CHF) regardless of age, sex and concomitant therapy and leads to reduction of NYHA functional class of CHF.

Candesartan is effective in patients taking simultaneously beta-adrenoblockers in combination with ACE inhibitors, and its effectiveness is independent of the ACE inhibitor dose. In patients with CHF and reduced left ventricular systolic function (left ventricular ejection fraction (LVEF) less than 40%), candesartan reduces O

Pharmacokinetics

Extraction and distribution. On absorption from the gastrointestinal tract (GIT), candesartan cilexetyl is rapidly converted by ester hydrolysis to the active substance, candesartan, binds firmly to AT1 receptors and dissociates slowly, 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 estimated absolute bioavailability of the tablet form of the drug is 14%. Food intake has no significant effect on the area under the curve “concentration-time” (AUC), i.e. food has no significant effect on the bioavailability of the drug.

The maximum plasma concentration (Cmax) is reached 3-4 hours after taking the tablet form of the drug. When increasing the drug dose within the recommended limits, the concentration of candesartan increases linearly. Binding of candesartan to plasma proteins is more than 99%. Plasma volume of distribution (Vd) of candesartan is 0.1 l/kg.

Pharmacokinetic parameters of candesartan are independent of patient gender.

Metabolism and excretion. Candesartan is primarily excreted unchanged by the kidneys and through the intestine and only to a minor extent is metabolized in the liver.

The half-life (T1/2) of candesartan is approximately 9 h. There is no accumulation of the drug in the body.

The total clearance of candesartan is approximately 0.37 ml/min/kg, with renal clearance of approximately 0.19 ml/min/kg. Renal excretion of candesartan is by glomerular filtration and active tubular secretion.

In oral administration of radioactively labeled candesartan, approximately 26% of the administered amount is excreted by the kidneys as candesartan and 7% as an inactive metabolite, while 56% of the administered amount is found in the feces as candesartan and 10% as an inactive metabolite.

Pharmacokinetics in special clinical cases. Pharmacokinetic parameters of candesartan are independent of patient gender.

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

In patients with mild to moderate renal impairment, the Cmax and AUC of candesartan increased by 50% and 70%, respectively, whereas the T1/2 of the drug was not altered compared to 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 the T1/2 of the drug was doubled.

In patients with mild to moderate hepatic impairment, there was a 23% increase in the AUC of candesartan.

Indications

– Arterial hypertension.
– Chronic heart failure and left ventricular systolic dysfunction (decreased RVF ≤ 40%) as adjunctive therapy to angiotensin-converting enzyme inhibitors (ACE) or when ACE inhibitors are intolerant (see section “Pharmacodynamics”).

Active ingredient

Composition

How to take, the dosage

Ordiss® should be taken once daily regardless of meals.

Hypertension

The recommended starting and maintenance dose of Ordiss® is 8 mg once daily. In patients who require further reduction of blood pressure (BP), it is recommended to increase the dose to 16 mg once daily. Patients who have not been able to reduce their blood pressure sufficiently after 4 weeks of Ordiss® at a dose of 16 mg once daily are recommended to increase the dose to 32 mg once daily. Maximal antihypertensive effect is reached within 4 weeks from the beginning of treatment.

If therapy with Ordiss® does not lower BP to optimal levels, a different regimen is recommended.

The therapy should be adjusted according to blood pressure levels.

Elderly patients

In elderly patients there is no need to adjust the initial dose of the drug.

Patients with impaired renal function

. In patients with mild to moderate renal impairment (creatinine clearance 30-80 ml/min/1.73 m2 body surface area), including patients on hemodialysis, the initial dose of the drug is 4 mg/day (½ tablet of 8 mg). The dose should be titrated depending on the therapeutic effect of the drug.

The clinical experience with the drug in patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m2 body surface area) or end-stage renal failure (creatinine clearance less than 15 ml/min) is limited (see section “Special Precautions”).

Patients with hepatic impairment

In patients with mild to moderate hepatic impairment, we recommend starting treatment with a daily dose of 4 mg once daily (½ tablet of 8 mg). It is possible to increase the dose if necessary. Ordiss® is contraindicated in patients with severe liver dysfunction and/or cholestasis (see section “Contraindications”).

Companion therapy

The use of Ordiss® together with thiazide-type diuretics (e.g. hydrochlorothiazide) may increase the antihypertensive effect of Ordiss®.

Hypovolemia

The recommended starting dose of Ordiss® is 4 mg (½ tablet of 8 mg) once daily.

Chronic heart failure (CHF)

The recommended starting dose of Ordiss® is 4 mg (½ 8 mg tablet) once daily. The dose is increased to 32 mg once daily or to the maximum tolerated dose by doubling the dose at intervals of at least 2 weeks (see section “Cautions”).

Patient Special Groups

Patients who are elderly and have impaired renal or hepatic function or hypovolemia do not need to change the starting dose of the drug.

Application in children and adolescents

The safety and effectiveness of Ordiss® in children and adolescents (

Adrenoblockers, diuretics, and cardiac glycosides (see See section “Special indications”, “Pharmacodynamics”).

Interaction

Dual RAAS blockade with angiotensin II receptor antagonists (ARA II), ACE inhibitors or aliskiren (direct renin inhibitor) may be associated with an increased risk of hypotension, syncope, hyperkalemia and renal function disorders (including acute renal failure) compared to monotherapy. Regular monitoring of BP, renal function and blood electrolytes in patients taking concomitantly candesartan and other drugs affecting the RAAS is necessary.

Candesartan is contraindicated concomitantly with aliskiren or aliskiren containing drugs in patients with diabetes and/or with moderate or severe renal function impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and not recommended in other patients.
Concomitant use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.
Concomitant use of ACE inhibitors and dipeptidyl peptidase type 4 inhibitors (e.g., vildagliptin) may increase the risk of Quincke’s edema. No clinically significant drug interactions have been found with candesartan and hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril. Candesartan is slightly metabolized in the liver with the participation of CYP2C9 isoenzyme. Interaction studies have shown no effect of candesartan on CYP2C9 and CYP3A4 isoenzymes, the effect on other cytochrome P450 isoenzymes has not been studied. Concomitant use of candesartan with other hypotensive agents increases antihypertensive effect.
Experience with other drugs acting on RAAS shows that concomitant therapy with potassium-saving diuretics, potassium supplements, table salt substitutes containing potassium and other agents that increase serum potassium (e.g., heparin) may lead to hyperkalemia.
Concomitant use of lithium preparations and ACE inhibitors leads to reversible increase of lithium concentration in blood serum and development of toxic reactions. Such reactions may also occur when using angiotensin II receptor antagonists, in connection with which it is recommended to monitor the lithium content in blood serum.
Concomitant use with non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2), acetylsalicylic acid (more than 3 g / day) and non-selective NSAIDs, may reduce the antihypertensive effect of candesartan, and may also lead to increased risk of renal function disorders, including development of acute renal failure and increased serum potassium levels. The combination of these drugs should be used with caution, especially in elderly patients.

Special Instructions

The concomitant use of ACE inhibitors, ARA II or aliskiren increases the risk of hypotension, hyperkalemia and renal dysfunction (including acute renal failure). Dual RAAS blockade with concomitant use of ACE inhibitors, ARA II and drugs containing aliskiren is contraindicated in patients with diabetes and/or with moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients, (see “Interaction with other patients”).
If dual RAAS blockade is considered absolutely necessary, the treatment should only be performed under medical supervision and should be accompanied by thorough and regular monitoring of renal function, electrolytes and blood pressure. Simultaneous use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients. During the use of Ordiss®, as well as during the use of other drugs that inhibit the RAAS, renal dysfunction may develop in some cases.
During use of Ordiss® in patients with severe arterial hypertension and renal insufficiency (FFR 3 mg/ml).
Hemodialysis. During hemodialysis, BP may be particularly sensitive to AT1-receptor blockade as a result of decreased ODC and RAAS activation. Therefore, patients on hemodialysis should monitor their blood pressure and adjust the dose of Ordiss® individually according to their blood pressure. Concomitant use with ACE inhibitors in CHF. Concomitant use with ACE inhibitors increases the risk of side effects, especially renal dysfunction and hyperkalemia. The clinical condition of patients and relevant laboratory parameters should be monitored.
Renal artery stenosis. The drugs affecting the RAAS (e.g., ACE inhibitors) may cause increased serum concentrations of urea and creatinine in patients with bilateral renal artery stenosis or arterial stenosis of the single kidney. A similar effect may be expected with the use of angiotensin II receptor antagonists.
Kidney transplantation. There is no experience in using Ordiss® in patients with recent kidney transplantation.
Arterial hypotension. Patients with CHF when using Ordiss® may develop arterial hypotension. The development of arterial hypotension is also possible in patients with circulatory blood pressure deficit, for example, when using high doses of diuretics. In this case, BCC correction should be performed prior to the use of Ordiss® .
General anesthesia and/or surgical interventions. Patients receiving angiotensin II antagonists during general anesthesia and surgical interventions may develop arterial hypotension as a result of RAAS blockade. In rare cases, arterial hypotension may be severe, requiring intravenous administration of fluid and/or vasopressor agents.
Aortic and/or mitral valve stenosis, GOCMP. Caution should be exercised when using Ordiss® in patients with GOCMP or hemodynamically significant aortic or mitral valve stenosis.
Primary hyperaldosteronism. Patients with primary hyperaldosteronism are usually resistant to therapy with hypotensive agents that affect the RAAS, therefore, it is not recommended to use Ordiss® in this group of patients.
Hyperkalemia. Concomitant use of Ordiss® with potassium-saving diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that may increase the serum potassium content (e.g. heparin), may lead to hyperkalemia in patients with arterial hypertension.

Hyperkalemia may also develop in patients with CHF taking Ordiss® . Against the background of Ordiss® therapy in CHF patients it is recommended to perform periodic control of serum potassium, especially in case of simultaneous use of ACE inhibitors and potassium saving diuretics (spironolactone, triamterene, amiloride, eplerenone (spironolactone derivative)). Patients in whom vascular tone and renal function mainly depend on RAAS activity (e.g., patients with severe chronic heart failure, renal diseases, including renal artery stenosis) are especially sensitive to the drugs acting on RAAS. The use of such drugs in these patients is accompanied by severe arterial hypotension, azotemia, oliguria and, less frequently, acute renal failure. The possibility of these effects is not excluded by the use of angiotensin II receptor antagonists. Sharp decrease of BP in patients with ischemic cardiopathy, cerebrovascular diseases of ischemic genesis while using any hypotensive agents can lead to myocardial infarction or stroke. The safety and effectiveness of the use of Ordiss® under 18 years of age has not been established.

If any undesirable effect of the drug on driving and operating machinery occurs, caution should be exercised when carrying out activities requiring increased concentration and rapid psychomotor reaction during treatment with Ordiss®.

Synopsis

Contraindications

Hypersensitivity to candesartan and other drug components; lactose intolerance; lactase deficiency; glucose-galactose malabsorption syndrome; severe hepatic impairment and/or cholestasis; pregnancy; breastfeeding period; childhood age below 18 years; concomitant use with aliskiren or drugs containing

Aliskiren, in patients with diabetes mellitus and/or moderate or severe impairment of renal function (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 body surface area), simultaneous use with ACE inhibitors in patients with diabetic nephropathy.

With caution

. Hemodynamically significant aortic and mitral valve stenosis, cerebrovascular disease, coronary heart disease (CHD), hypertrophic obstructive cardiomyopathy (HOCMP), condition after kidney transplantation, bilateral renal artery stenosis or stenosis of the artery of a single kidney, primary hyperaldosteronism, severe renal failure (creatinine clearance (CK) less than 30 ml/min), hemodialysis, hyperkalemia; in patients with decreased circulating blood volume (DCV), general anesthesia and surgical interventions (risk of arterial hypotension due to RAAS blockade).

Side effects

Arterial hypertension

Side effects in clinical trials were moderate and transient. The overall incidence of side effects with candesartan was independent of the drug dose, sex and age of the patient. The incidence of discontinuation of therapy due to side effects was similar for candesartan cilexetil (3.1%) and placebo (3.2%). A pooled analysis of data from clinical trials in patients with arterial hypertension identified adverse reactions with candesartan cilexetil that occurred at least 1% more frequently than in the placebo group. The most commonly reported adverse reactions were dizziness/vertigo, headache, and respiratory infections.

The following are the adverse reactions reported in clinical trials and post-registration use: Very frequently, 1/10 appointments (>10%), frequently, from 1/100 appointments ( >1% and < 10%), infrequently, from 1/1000 appointments ( >0.1% and < 1%), rarely, from 1/10000 appointments ( > 0.01% and < 0.1%) , very rarely, from < 1/10000 appointments (< 0.01%), frequency unknown (cannot be determined from available data).

Infectious and parasitic infections: often – respiratory infections.

Disorders of the blood and lymphatic system: very rarely – leukopenia, neutropenia, agranulocytosis.

Disorders of metabolism and nutrition: very rarely – hyperkalemia, hyponatremia.

Nervous system disorders: frequently – dizziness/vertigo, headache. Disorders of the respiratory system, thorax and mediastinum: very rarely – cough.

Gastrointestinal tract disorders: very rare – nausea; frequency unknown – diarrhea.

Hepatic and biliary tract disorders: very rare – increased activity of “liver” enzymes, liver dysfunction or hepatitis.

Skin and subcutaneous tissue disorders: very rarely – angioedema, skin rash, itching, urticaria.

Skeletal-muscular system and connective tissue disorders: very rarely – back pain, arthralgia, myalgia.

Repnal and urinary tract disorders: frequently – renal dysfunction, including renal failure in predisposed patients.

Laboratory findings: In general, no clinically significant changes in standard laboratory parameters have been observed with candesartan cilexetil. As with other drugs affecting the RAAS, a slight decrease in hemoglobin was observed. Regular monitoring of laboratory parameters is usually not required when using candesartan. However, in patients with impaired renal function, periodic monitoring of serum potassium and creatinine concentration is recommended.

Chronic Heart Failure

The side effects observed with candesartan in adult patients with chronic heart failure were consistent with the pharmacological properties of the drug and depended on the patient’s condition. The clinical studies compared candesartan cilexetil in doses up to 32 mg (n=3803) with placebo (n=3796); 21% of patients in the candesartan cilexetil group and 16.1% of patients in the placebo group discontinued treatment because of adverse reactions. The most common adverse reactions were hyperkalemia, arterial hypotension, and renal dysfunction. These reactions occurred most frequently in patients older than 70 years of age, with diabetes mellitus, or in patients treated with other drugs that affect the RAAS, particularly ACE inhibitors and/or spironolactone.

The following are the adverse reactions reported in clinical trials and post-registration use: very frequently, 1/10 prescriptions (>10%), frequently, from 1/100 prescriptions ( >1% and < 10%), infrequently, from 1/1000 prescriptions ( >0.1% and < 1%), rarely, from 1/10000 prescriptions ( > 0.01% and < 0.1%) , very rarely, from < 1/10000 appointments (< 0.01%), frequency unknown (cannot be determined from available data).

Disorders of the blood and lymphatic system: very rarely – leukopenia, neutropenia, agranulocytosis.

Disorders of metabolism and nutrition: often – hyperkalemia, very rarely – hyponatremia.

Skin and subcutaneous tissue disorders: very rarely – angioedema, skin rash, itching, urticaria.

Nervous system disorders: very rarely – dizziness, headache.

Disorders of the respiratory system, the thorax and mediastinum: very rarely – cough.

Gastrointestinal tract disorders: very rare – nausea; frequency unknown – diarrhea.

vascular disorders: frequently – arterial hypotension.

Hepatic and biliary tract disorders: very rarely – increased activity of “liver” enzymes, liver dysfunction or hepatitis.

Muscular system and connective tissue disorders: very rarely – back pain, arthralgia, myalgia.

Repnal and urinary tract disorders: frequently – renal dysfunction, including renal failure in predisposed patients.

Laboratory findings: Frequently, hyperkalemia and impaired renal function are observed in treated heart failure. Periodic monitoring of potassium and serum creatinine concentration is recommended.

Overdose

Symptoms: analysis of the pharmacological properties of the drug suggests that the main manifestation of overdose may be clinically pronounced decreased BP, dizziness. There have been individual cases of overdose of the drug (up to 672 mg of candesartan), which ended in recovery of patients without severe consequences.

Treatment: if clinically pronounced BP decrease develops, symptomatic treatment should be administered and the patient’s condition monitored. Place patient on back and elevate legs. If necessary, increase the BOD, e.g., by intravenous injection of 0.9% sodium chloride solution. Sympathomimetic agents may be used if necessary. Excretion of candesartan by hemodialysis is ineffective.

Pregnancy use

Similarities