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- Availability date:2020-07-30
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cardosal plus is a combination drug that includes an angiotensin ii receptor antagonist (olmesartan medoxomil) and a thiazide diuretic (hydrochlorothiazide). the combination of these components has an additive antihypertensive effect, as a result of which the hell decreases more effectively than when using each of the components separately.
The use of the drug Kardosal plus 1 time per day provides an effective and mild decrease in blood pressure for 24 hours before the next dose.
Olmesartan Medoxomil is a selective angiotensin II receptor antagonist (type AT1) intended for oral administration. Angiotensin II is the main vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS), which plays an important role in the pathophysiology of hypertension. It causes vasoconstriction, induces the synthesis and secretion of aldosterone, stimulates cardiac activity and sodium reabsorption by the kidneys. Olmesartan suppresses the effects of angiotensin II, aimed at narrowing blood vessels and the secretion of aldosterone, blocking AT1-receptor in tissues, including vascular smooth muscle and adrenal glands. The effect of olmesartan is independent of the source or route of synthesis of angiotensin II. Selective binding of olmesartan to AT1-receptors of angiotensin II leads to an increase in the level of renin and the concentration of angiotensin I and II in the blood plasma, as well as to a certain decrease in the concentration of aldosterone in the blood plasma.
In patients with hypertension of olmesartan, medoxomil causes a steady decrease in blood pressure, the degree of which depends on the dose. There were no signs of arterial hypotension after the first use (first-dose effect), tachyphylaxis against the background of prolonged use, and rebound hypertension after a sharp drug withdrawal.
Taking olmesartan medoxomil once a day provides an effective and gentle decrease in blood pressure within 24 hours before the next dose. When using the drug once a day, its antihypertensive effect was approximately the same as as a result of its use 2 times a day in the same dose.
In the case of continuous treatment, the maximum decrease in blood pressure is achieved 8 weeks after the start of treatment, while a significant antihypertensive effect is detected after 2 weeks of treatment.
The effect of olmesartan medoxomil on mortality and the frequency of complications has not been established.
A randomized study of the use of olmesartan and the prevention of diabetic microalbuminuria (ROADMAP) in 4447 patients with type II diabetes (with normal levels of albuminuria and with at least one additional risk factor for cardiovascular disease) was conducted to determine whether olmesartan therapy can delay the onset of microalbuminuria. During an average tracking period of 3.2 years, patients received olmesartan or placebo in addition to other antihypertensive agents (except for ACE inhibitors or angiotensin II receptor antagonists).
The primary endpoint of the study found a significant reduction in the risk of microalbuminuria in favor of olmesartan. After correcting for blood pressure, this risk reduction was statistically insignificant.8.2% (178 of 2160) of the patients in the olmesartan group and 9.8% (210 of 2139) in the placebo group developed microalbuminuria.
At the secondary endpoint, cardiovascular events were observed in 96 (4.3%) patients receiving olmesartan and in 94 (4.2%) placebo patients. The incidence of deaths from cardiovascular diseases was higher in the olmesartan group compared with the placebo group (15 (0.7%) and 3 (0.1%) patients, respectively), despite the similar incidence of nonfatal stroke (14 (0, 6%) and 8 (0.4%) patients, respectively), non-fatal myocardial infarction (17 (0.8%) and 26 (1.2%) patients, respectively) and mortality not associated with cardiovascular causes (11 ( 0.5%) and 12 (0.5%) patients). Total mortality in the olmesartan group was higher (26 (1.2%) and 15 (0.7%) patients), mainly due to higher mortality from cardiovascular causes.
The ORIENT study (The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial) examined the effects of olmesartan on the outcome of renal and cardiovascular diseases in 577 randomized patients in Japan and China with type II diabetes and pronounced nephropathy. During the mean follow-up period of 3.1 years, patients received olmesartan or placebo in addition to other antihypertensive drugs, including ACE inhibitors. The primary combined endpoint (the time of the first appearance of plasma creatinine doubling, end-stage renal disease, death from all causes) was achieved in 116 (41.1%) patients in the olmesartan group and in 129 (45.4%) patients who received placebo ( risk ratio 0.97; 95% confidence interval 0.75–1.24; p = 0.791). The secondary combined endpoint of the cardiovascular event was achieved in 40 (14.2%) patients taking olmesartan, and 53 (18.7%) patients receiving placebo. This combined endpoint of a cardiovascular event included mortality from cardiovascular disease in 10 (3.5%) patients receiving olmesartan and in 3 (1.1%) patients in the placebo group; total mortality was 19 (6.7%) and 20 (7.0%), the development of non-fatal stroke - 8 (2.8%) and 11 (3.9%) and non-fatal myocardial infarction - 3 (1.1%) and 7 (2.5%), respectively.
Hydrochlorothiazide is a diuretic agent of the thiazide series. The mechanism of the antihypertensive effect of thiazide diuretics is not fully understood. Thiazides affect the reabsorption of electrolytes in the renal tubules, thereby enhancing the excretion of sodium and chlorine (at approximately the same level). Acting as a diuretic, hydrochlorothiazide reduces blood plasma volume, resulting in increased plasma renin activity and aldosterone secretion, increased loss of potassium and bicarbonate in the urine, and their concentration in blood plasma decreases. Since the relationship between renin level and aldosterone secretion is mediated by angiotensin II, with the use of hydrochlorothiazide in combination with an angiotensin II receptor antagonist, the loss of potassium in the urine under the action of thiazide diuretics can be reduced. When using hydrochlorothiazide, diuresis occurs approximately 2 hours after administration, the maximum effect is achieved after 4 hours, and the effect persists for 6-12 hours.
According to epidemiological studies, the prolonged use of hydrochlorothiazide as a means of monotherapy helps to reduce the risk of cardiovascular complications and death from them.
Clinical efficacy and safety. Combined therapy of olmesartan with medoxomil and hydrochlorothiazide. With the combination therapy of olmesartan with medoxomil and hydrochlorothiazide, the antihypertensive effect is additively enhanced and, as a rule, exceeds the effects of each component separately. According to the combined data of placebo-controlled studies, as a result of the use of olmesartan medoxomil / hydrochlorothiazide in doses of 20 / 12.5 mg and 20/25 mg, the average decrease in systolic / diastolic blood pressure at the end of the dosing interval (adjusted for the placebo effect) was 12/7, respectively and 16/9 mmHg. Art. Age and gender did not have a clinically significant effect on the effectiveness of combination therapy of olmesartan with medoxomil and hydrochlorothiazide.
When using hydrochlorothiazide in doses of 12.5 and 25 mg in patients whose monotherapy of olmesartan with medoxomil at a dose of 20 mg was insufficient, an additional decrease in the average daily systolic / diastolic blood pressure, measured by ambulatory blood pressure monitoring (by 7/5 and 12 / 7 mm Hg.Art. Compared with the initial values achieved as a result of monotherapy with olmesartan medoxomil). When measuring blood pressure by the traditional method, an additional decrease in the average systolic / diastolic blood pressure at the end of the dosing interval was 11/10 and 16/11 mm Hg, respectively. Art. (compared to the initial values).
The combination therapy of olmesartan with medoxomil and hydrochlorothiazide remained effective for a long period of treatment (1 year). In case of cancellation of olmesartan, medoxomil (used both in combination with hydrochlorothiazide and separately), no rebound hypertension was noted.
The effect of the combined drug olmesartan medoxomil and hydrochlorothiazide on cardiovascular complications and mortality from them is now unknown.
Other information. The simultaneous use of ACE inhibitors and angiotensin II receptor antagonists has been studied in two large-scale randomized controlled trials: ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes). ONTARGET - a study conducted in the history of patients with cardiovascular or cerebrovascular diseases in the history or type II diabetes mellitus with signs of damage to the target organ. VA NEPHRON-D is a study in patients with type II diabetes mellitus and diabetic nephropathy. The studies did not reveal a significant beneficial effect on the outcome of renal and / or cardiovascular diseases and mortality from them, whereas compared with monotherapy, there was an increased risk of developing hyperkalemia, acute kidney damage and / or hypotension. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor antagonists. The combined use of ACE inhibitors and angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) - a study conducted to identify the positive effect of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor antagonists, involving patients with type II diabetes and chronic kidney disease, cardiovascular disease or with both diseases. The study was interrupted earlier due to an increased risk of undesirable consequences. Mortality from cardiovascular disease and the development of stroke were more often observed in the aliskiren group compared with the placebo group. Serious adverse reactions (hyperkalemia, hypotension, and impaired renal function) were more often reported in the aliskiren group compared with the placebo group.
Suction and distribution. Olmesartan medoxomil is a prodrug that, under the action of esterases in the intestinal mucosa and in the blood of the portal vein, turns into an active metabolite - olmesartan. Neither in the blood plasma nor in the excretion products of olmesartan, medoxomil or the lateral part of the medoxomil group in an unchanged state were not detected. The average absolute bioavailability of olmesartan is 25.6%. Following oral administration of olmesartan medoxomil Cmax in plasma is reached after about 2 hours. In the case of a single oral dose of up to 80 mg, the concentration of olmesartan in the blood plasma rises approximately in proportion to the dose. Food has a minimal effect on the bioavailability of olmesartan, so olmesartan medoxomil can be used regardless of food intake. There were no clinically significant differences in the pharmacokinetics of olmesartan in individuals of different sexes. Olmesartan actively binds to blood plasma proteins (99.7%), however, the risk of clinically significant interactions with other drugs due to competition for binding to blood plasma proteins is low (confirmation of this is the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). Olmesartan binds slightly to blood cells. The average volume of distribution after administration is small - 16–29 liters.
Hydrochlorothiazide. In case of oral administration of olmesartan medoxomil in combination with hydrochlorothiazide, median time to reach Cmax hydrochlorothiazide in blood plasma was 1.5–2 g. Hydrochlorothiazide binds to plasma proteins by 68%, and its apparent distribution volume is 0.83–1.14 l / kg.
Metabolism and elimination. Olmesartan Medoxomil. The total clearance of olmesartan for blood plasma is about 1.3 l / h (coefficient of variation of 19%) and is relatively low compared with hepatic blood flow (about 90 l / h). After a single oral administration of olmesartan, medoxomil labeled with an isotope14C, 10–16% of the radioactive label was detected in the urine (most of it within 24 hours after administration); the remainder is in feces. Given that the systemic bioavailability of the drug is 25.6%, it can be calculated that olmesartan is excreted both by the kidneys (approximately 40%) and the hepatobiliary system (approximately 60%).All the radioactive label noted in the excretion products was in olmesartan. No other significant metabolites have been identified. In the intestinal-hepatic circuit, olmesartan practically does not participate. Since most olmesartan is excreted in the bile, it is contraindicated in patients with bile duct obstruction. Final t½ olmesartan after repeated ingestion varies in the range of 10-15 hours. The steady state was achieved after the first few doses; after 14 days of repeated use, no further accumulation of the drug was noted. Renal clearance is about 0.5-0.7 l / h and does not depend on the dose of the drug.
Hydrochlorothiazide. Hydrochlorothiazide in the human body is not metabolized and is almost completely excreted unchanged in the urine. After oral administration, about 60% of the dose is excreted unchanged for 48 hours. Renal clearance is about 250-300 ml / min. Final t½ is about 10-15 hours
The combination of olmesartan medoxomil with hydrochlorothiazide. In the case of the use of hydrochlorothiazide in combination with olmesartan medoxomil, the systemic bioavailability of the former decreases by about 20%, however, such a decrease has no clinical significance. The pharmacokinetics of olmesartan in the case of its use in combination with hydrochlorothiazide does not change.
Pharmacokinetics in individual groups of patients. Patients over the age of 65. In elderly patients (65–75 years) with hypertension, the AUC of olmesartan in equilibrium was approximately 35% higher than in younger patients, and in patients aged ≥75 years — approximately 44% higher. Based on the available data, we can assume that in elderly people (both healthy and with hypertension), the systemic clearance of hydrochlorothiazide is lower than in healthy volunteers.
Impaired renal function. In patients with impaired renal function, mild, moderate and severe AUC of olmesartan in stationary state was 62, respectively; 82 and 179% higher than healthy volunteers. T½ hydrochlorothiazide in patients with impaired renal function is increased.
Impaired liver function. After a single oral administration of AUC olmesartan in patients with impaired liver function of mild and moderate severity, respectively, was 6 and 65% higher than in healthy volunteers from the control group with the same demographic indicators. In healthy volunteers and patients with impaired liver function of mild to moderate severity, the unbound fraction of olmesartan 2 hours after administration was 0.26, respectively; 0.34 and 0.41%. After repeated use, the average AUC of olmesartan in patients with moderate liver dysfunction was 65% higher than in healthy volunteers of the control group with the same demographic parameters. C valuesmax olmesartan in patients with impaired liver function and healthy volunteers were similar. In patients with severe hepatic impairment, the effectiveness of olmesartan medoxomil has not been determined.The pharmacokinetics of hydrochlorothiazide were not significantly affected by impaired liver function.
Interaction with other drugs
Kolesevelam - a drug that binds bile acids. The concomitant use of 40 mg of olmesartan medoxomil and 3750 mg of wheel magnam hydrochloride in healthy volunteers led to a decrease in Cmax by 28% and a decrease in AUC of 39% for olmesartan. Less impact, lower Cmax and AUC by 4 and 15%, respectively, were observed when olmesartan medoxomil was taken 4 hours before the administration of trochelove hydrochloride. T½ olmesartan decreased by 50–52%, regardless of whether the drugs were taken at the same time or if olmesartan was taken 4 hours before the intake of hydromechanical hydrochloride.
Preclinical safety data. The toxic effects of the combination of olmesartan medoxomil and hydrochlorothiazide were evaluated in studies with repeated oral administration of the drug to rats and dogs (up to 6 months).
As in the case of the use of the drug separately, and use with other drugs of the same class, the toxic effect of this combination is directed mainly to the kidneys. In combination with olmesartan medoxomil and hydrochlorothiazide, functional changes in the kidneys were observed (increased levels of urea nitrogen and creatinine in blood plasma). In rats and dogs that were administered a combination with high doses of the components, degeneration and regeneration of the kidneys was observed, possibly due to impaired renal hemodynamics (decreased renal blood flow due to arterial hypotension combined with hypoxia and degeneration of tubule cells). In addition, the use of a combination of olmesartan medoxomil and hydrochlorothiazide led to a decrease in red blood cell counts (the number of red blood cells, hemoglobin and hematocrit) and a decrease in heart weight in rats. These results were also recorded with the use of other antagonists of AT1receptors and ACE inhibitors. They are probably due to the pharmacological effect of olmesartan medoxomil in high doses and are not observed if the drug is used in the recommended therapeutic doses.
In studies of the effects of the combination of olmesartan medoxomil and hydrochlorothiazide, as well as each component individually, no signs of clinically significant genotoxicity were detected.
The carcinogenic effect of the combination of olmesartan medoxomil and hydrochlorothiazide was not studied, since in clinical practice no signs of a carcinogenic effect of the individual components of the drug were detected.
In mice and rats that were injected with olmesartan medoxomil in combination with hydrochlorothiazide, no signs of teratogenic effects were detected. As expected with respect to drugs of this class, in rats that were administered a combination of olmesartan medoxomil and hydrochlorothiazide during pregnancy, a toxic effect on the fetus was observed, which was manifested by a significant decrease in fetal body weight (see CONTRAINDICATIONS and Use during pregnancy and lactation) .
Treatment of essential ag.
The combined drug Cardosal plus is intended for adult patients in whom the use of only one olmesartan medoxomil does not provide a decrease in blood pressure to the required level.
Adults cardosal plus is not the first choice. it is intended for patients in whom the use of olmesartan medoxomil alone at a dose of 20 mg does not provide the necessary level of hell.
Cardosal plus tablets are taken 1 time per day, regardless of food intake.
In the presence of clinical indications, a patient can be transferred from olmesartan monotherapy with medoxomil in a dose of 20 mg immediately to a combination drug, however, it should be borne in mind that the maximum hypotensive effect of olmesartan medoxomil is achieved 8 weeks after the start of treatment.
Titration of a dose of each component is recommended.
The drug Kardosal plus 20 / 12.5 is prescribed for patients in whom the use of olmesartan medoxomil in a dose of 20 mg does not provide the necessary level of blood pressure.
The drug Kardosal plus 20/25 is prescribed for patients in whom the drug Kardosal plus 20 / 12.5 does not provide the necessary level of blood pressure.
Elderly patients (≥65 years old). For elderly patients, the combined drug is recommended to be used in the same dose as ordinary adult patients.
Impaired renal function. In the case of the use of Cardosal plus in patients with impaired renal function of mild to moderate severity (creatinine clearance of 30-60 ml / min), it is recommended to periodically monitor renal function. For patients with severe renal impairment (creatinine clearance 30 ml / min) Cardosal plus is contraindicated.
Impaired liver function. In patients with impaired liver function of mild to moderate severity, Cardosal plus should be used with caution. In patients with impaired liver function of moderate severity of olmesartan, medoxomil is recommended to be used in an initial dose of 10 mg once a day, the maximum dose should not exceed 20 mg once a day. Patients with impaired liver function, already taking diuretics and / or other antihypertensive drugs, it is recommended to control blood pressure and kidney function. There is no experience with olmesartan medoxomil in patients with severely impaired liver function. In patients with severe impaired liver function, as well as with cholestasis and obstruction of the bile ducts, Cardosal plus should not be used.
An allergic reaction (hypersensitivity) to active substances, any of the auxiliary components or other derivatives of sulfonamides (hydrochlorothiazide is also a derivative of sulfanilamides). severe renal impairment (creatinine clearance 30 ml / min). stable hypokalemia, hypercalcemia, hyponatremia and clinically expressed hyperuricemia. severe liver dysfunction, cholestasis and obstructive biliary tract disease. pregnant or women who are planning a pregnancy.simultaneous use of the drug and preparations containing aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (glomerular filtration rate of 60 ml / min / 1.73 m2.
Most often, when using the drug, the following adverse reactions occur: headache (2.9%), dizziness (1.9%), increased fatigue (1.0%).
Hydrochlorothiazide can cause or exacerbate hypovolemia, which can lead to an electrolyte imbalance.
In clinical trials involving 1155 patients taking olmesartan medoxomil / hydrochlorothiazide at a dose of 20 / 12.5 mg or 20/25 mg, and 466 patients receiving placebo (the duration of drug use was up to 21 months), the overall incidence of adverse reactions to the combination therapy of olmesartan with medoxomil / hydrochlorothiazide was approximately the same as with placebo. The incidence of drug withdrawal due to adverse reactions in the group of olmesartan medoxomil / hydrochlorothiazide 20 / 12.5 mg or 20/25 mg (2%) and placebo (3%) was also approximately the same. In general, the frequency of adverse reactions associated with the combination therapy of olmesartan with medoxomil / hydrochlorothiazide (compared with placebo) did not depend on age (patients under 65 years of age compared to patients over 65 years of age), gender or race of patients, although patients are dizzy over the age of 75 years arose more often.
In addition, the safety of the drug when used in high doses was studied in clinical trials involving 3709 patients who took olmesartan medoxomil in combination with hydrochlorothiazide at a dose of 40 mg / 12.5 mg and 40 mg / 25 mg. Adverse reactions noted during clinical trials, in post-marketing studies or information about which was obtained from spontaneous reports, as well as adverse reactions identified with the use of individual components of the drug olmesartan medoxomil and hydrochlorothiazide are shown in the table below.
The following terminology was used to classify the incidence of adverse reactions: very often ≥ (1/10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000 , 1/1000), very rarely (1/10 000), unknown (impossible to estimate based on available data).
|Organs and Systems for MedDRA||Adverse reactions||Frequency|
|Infectious and parasitic diseases||Sialadenitis||Rarely|
|From the hematopoietic and lymphatic system||Aplastic anemia||Rarely|
|Inhibition of bone marrow function||Rarely|
|Neutropenia / Agranulocytosis||Rarely|
|From the immune system||Anaphylactic reactions||Infrequently||Infrequently|
|Malnutrition and metabolism||Anorexia||Infrequently|
|From the psyche||Apathy||Rarely|
|From the central nervous system||Confusion||Often|
|Impaired consciousness, for example, loss of consciousness||Rarely|
|Feeling dizzy / dizzy||Often||Often||Often|
|Loss of appetite||Infrequently|
|On the part of the organ of vision||Decreased tearing||Rarely|
|Transient blurred vision||Rarely|
|Strengthening Existing Myopia||Infrequently|
|Acute myopia, acute angle-closure glaucoma||Unknown|
|On the part of the organ of hearing and the labyrinth||Vertigo||Infrequently||Infrequently||Rarely|
|From the heart||Angina pectoris||Infrequently|
|Heart rhythm disorders||Rarely|
|From the vessels||Embolism||Rarely|
|Necrotizing angiitis (vasculitis)||Rarely|
|On the part of the respiratory system, chest and mediastinum||Bronchitis||Often|
|From the digestive system||Epigastric pain||Infrequently||Often||Often|
|Irritation of the gastric mucosa||Often|
|Paralytic intestinal obstruction||Rarely|
|On the part of the liver and biliary tract||Acute cholecystitis||Rarely|
|Jaundice (against intrahepatic cholestasis)||Rarely|
|On the part of the skin and subcutaneous adipose tissue||Allergic dermatitis||Infrequently|
|Anaphylactic skin manifestations||Rarely|
|Systemic lupus erythematosus skin reactions||Rarely|
|Hemorrhagic rash (purpura)||Infrequently|
|Exacerbation of the skin form of systemic lupus erythematosus||Rarely|
|Toxic epidermal necrolysis|