Edarbi Clos pills 40 mg + 12.5 mg 28 pieces
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Active ingredients
Azilsartan medoxomil + hlortalidone
Release form
Pills
Composition
Azilsartan medoxomil potassium 42.68 mg, which corresponds to the content of azilsartan medoxomil 40 mg chlorthalidone 12.5 mg Excipients: mannitol - 211.23 mg, microcrystalline cellulose - 54 mg, fumaric acid - 2 mg, sodium hydroxide - 0.69 mg, hyperrolose - 10.8 mg, crospidone - 2 mg, crospidone - crospidone - 2 mg, sodium hydroxide - 0.69 mg mg, magnesium stearate - 3.6 mg. The composition of the film coating: hypromellose 2910 - 7.8 mg, talc - 1.2 mg, titanium dioxide - 0.99 mg, iron dye red oxide - 0.01 mg, macrogol 8000 - 0.18 mg, gray ink F1 purified for labeling - trace amounts *.
Pharmacological effect
Combined antihypertensive drug. The Edarbi Clo drug contains the angiotensin II receptor antagonist (azilsartan medoxomil) and the thiazide-like diuretic (chlorthalidone). The simultaneous use of two active substances leads to a more pronounced decrease in blood pressure compared to taking each of them in monotherapy. When taking the drug 1 time / day, an effective decrease in blood pressure is achieved within 24 hours. Azilsartan medoxomil is a specific antagonist of angiotensin II type 1 receptors (AT1). Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the main vasoconstrictor factor of the RAAS, its action includes vasoconstriction, stimulation of the synthesis and secretion of aldosterone, increase in heart rate and reabsorption of sodium by the kidneys. Azilsartan medoxomil is a prodrug for oral administration. It quickly turns into an active azilsartan molecule, which selectively prevents the development of effects of angiotensin II by blocking its binding to the AT1 receptor in various tissues, for example, in vascular smooth muscle and adrenal glands. Therefore, its action is not related to the biosynthesis of angiotensin II. The AT2 receptor is also found in many tissues, but it does not participate in the regulation of the cardiovascular system. The affinity of azylsartan for the AT1 receptor is 10,000 times higher than that for the AT2 receptor. Inhibition of RAAS activity by means of ACE inhibitors, which suppress the formation of angiotensin II from angiotensin I, is widely used in the treatment of arterial hypertension. ACE inhibitors also inhibit the breakdown of bradykinin, which is catalyzed by ACE. Since azilsartan does not suppress ACE (kininase II), it should not affect the activity of bradykinin.Azilsartan does not bind to other receptors or ion channels that play an important role in the regulation of the cardiovascular system, and does not block them. Azilsartan suppresses the vasoconstrictor effects of angiotensin II infusion in a dose-dependent manner. A single dose of azilsartan at a dose equivalent to 32 mg of azilsartan medoxomil inhibited the maximum vasoconstrictor effect of angiotensin II by about 90% at the time of greatest concentration, and about 60% 24 hours after administration. In healthy volunteers, the concentrations of angiotensin I and angiotensin II and renin activity in the blood plasma increased, and the concentration of aldosterone decreased after a single dose and after repeated doses of azilsartan medoxomil; no clinically significant effect on serum potassium or sodium was detected. In general, the pharmacodynamic properties of azilsartan medoxomil are consistent with blocking of AT1 receptors. The antihypertensive effect of azilsartan medoxomil develops during the first 2 weeks of use, with a maximum therapeutic effect being achieved after 4 weeks. A decrease in blood pressure after oral administration of a single dose is usually achieved within a few hours and lasts for 24 hours. Chlorthalidone, a thiazide-like diuretic, suppresses the active reabsorption of sodium ions in the renal tubules (the initial part of the distal convoluted nephron tubule), increasing the excretion of sodium ions and chlorine and strengthening diuresis. In addition, chlorthalidone increases the excretion of potassium, magnesium and bicarbonate ions, retains calcium ions and uric acid. The antihypertensive effect of chlorthalidone is associated with the elimination of fluids and sodium from the body. The diuretic effect develops 2-3 hours after taking chlorthalidone inside and lasts for 2-3 days. The antihypertensive effect of chlorthalidone develops gradually with the achievement of the maximum therapeutic effect 2-4 weeks after the start of therapy. In clinical studies, the combination of azilsartan medoxomil / chlorthalidone was more effective than the combination of azilsartan medoxomil with hydrochlorothiazide or the combination olmesartan medoxomil / hydrochlorothiazide, despite the fact that a higher proportion of study participants in the comparison group required an increase in dose due to insufficient control of blood pressure.In a double-blind study with a planned dose increase of 12 weeks, the azilsartan medoxomil / chlorthalidone combination in a dose of 40 mg / 25 mg was significantly higher than the olmesartan medoxomil / hydrochlorothiazide combination 40 mg / 25 mg in reducing systolic blood pressure with moderate and severe arterial hypertension. Similar results were obtained in all subgroups of patients, regardless of age, gender or race. The combination of azilsartan medoxomil / chlorthalidone reduced blood pressure more effectively than the combination of olmesartan medoxomil / hydrochlorothiazide in each hour of the 24-hour interval between doses of drugs, according to the data of BPMD (daily monitoring of blood pressure).
Pharmacokinetics
Azilsartan medoxomil Absorption After taking the drug inside the Cmax azilsartan in plasma, on average, is achieved within 3 hours. The pharmacokinetic parameters (Tmax, Cmax, AUC value) of azilsartan are similar both when combined with chlorthalidone and without it. The distribution of Vd azilsartan is about 16 liters. Azilsartan binds to plasma proteins (more than 99%), mainly albumin. Metabolism Azilsartan is metabolized to two primary metabolites predominantly in the liver. The main metabolite in the blood plasma is formed by O-dealkylation and is designated as the metabolite M-II, the minor metabolite is formed by decarboxylation and is designated as the metabolite M-I. The AUC values for these metabolites in humans are 50% and less than 1%, respectively, compared to azilsartan. The main enzyme responsible for the metabolism of azilsartan is the isoenzyme CYP2C9. Azilsartan and its metabolites are eliminated from the body through the intestines and the kidneys. T1 / 2 of azylsartan is about 12 hours. Studies have shown that after oral administration of azilsartan medoxomil, about 55% (mostly as a metabolite MI) is found in the feces and about 42% (15% in the form of azilsartan, 19% in the form of metabolite M-II) - in the urine. Pharmacokinetics in special groups of patients The pharmacokinetics of azilsartan in young (18–45 years) and elderly (65–85 years) patients is not significantly different. In patients with mild, moderate and severe renal insufficiency, the AUC was increased by 30%, 25% and 95%, respectively.An increase (by 5%) in AUC in patients with end-stage renal failure on hemodialysis was not observed. Clinical data on pharmacokinetics in patients with severe or terminal stage of renal failure are not available. Azilsartan is not excreted from the systemic circulation through hemodialysis. The use of azilsartan medoxomil for more than 5 days in patients with mild liver failure (less than 5 points on the Child-Pugh scale) or moderate (less than 9 points on the Child-Pugh scale) degree leads to a slight increase (1.3-1.6 times, respectively). The pharmacokinetics of azilsartan in patients with severe liver failure (more than 9 points on the Child-Pugh scale) has not been studied. The pharmacokinetics of azilsartan in men and women is not significantly different. Dose adjustment based on gender is not required. The pharmacokinetics of azilsartan are not significantly different depending on the race of the patients. Dose adjustment based on race is not required. Chlorthalidone Absorption After taking the drug inside, chlorthalidone is absorbed from the gastrointestinal tract by 60%. Cmax of chlorthalidone in blood plasma on average is achieved within 12 hours. The AUC value of chlorthalidone is similar as with its co-administration with azilsartan medoxomil, and without it. However, Cmax is 47% higher when it is co-administered with azilsartan medoxomil as part of the Edarbi Clo drug. Eating does not have a clinically significant effect on the bioavailability of the drug. Distribution In whole blood, chlorthalidone is associated mainly with red cell carbonic anhydrase. In blood plasma, about 75% of chlorthalidone is associated with plasma proteins, and 58% with albumin. Metabolism and excretion of chlorthalidone is mainly excreted unchanged. Data on comparative amounts of chlorthalidone, displayed in unchanged form and in the form of metabolites, no. Chlorthalidone is mainly excreted by the kidneys in unchanged form. T1 / 2 chlorthalidone is 40-50 hours. As a thiazide-like diuretic, chlorthalidone is excreted in breast milk. Pharmacokinetics in special groups of patients In elderly patients, chlorthalidone is eliminated more slowly than in younger ones, which is presumably associated with age-related changes in renal function and leads to an increase in T1 / 2.Reduced elimination is not clinically significant. In renal insufficiency, chlortalidone may accumulate. No data are available on the pharmacokinetics of chlortalidone in hepatic insufficiency. Data on the differences in pharmacokinetics in men and women are not available. Data on the differences in pharmacokinetics depending on race are not available.
Indications
- Essential hypertension (for patients who are recommended combination therapy).
Contraindications
- Hypersensitivity to active substances and other components of the drug; - refractory hypokalemia; - anuria; - simultaneous use of aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or moderate or severe renal impairment (GFR less than 60 ml / min / 1.73 m2); - severe forms of diabetes; - abnormal liver function (more than 9 points on the Child-Pugh scale), because no experience of use; - renal failure severe (CC less than 30 ml / min), because no experience of use; - age up to 18 years (efficacy and safety have not been established); - pregnancy and breastfeeding period. With care: - severe chronic heart failure (NYHA classification IV FC); - impaired renal function (CC more than 30 ml / min); - violation of liver function of mild and moderate degree (5-9 points on the Child-Pugh scale); - bilateral renal artery stenosis and arterial stenosis of the only functioning kidney; - Ischemic cardiomyopathy; - ischemic cerebrovascular diseases; - condition after kidney transplantation; - conditions accompanied by a decrease in BCC (including vomiting, diarrhea, the use of diuretics in high doses), as well as in patients who follow a diet with restriction of table salt; - primary hyper aldosteronism; - hyperuricemia, gout; - hypokalemia; - bronchial asthma; - Systemic lupus erythematosus; - Aortic and mitral valve stenosis; - hypertrophic obstructive cardiomyopathy (GOKMP); - age over 75 years.
Use during pregnancy and lactation
Experience with the use of the drug Edarbi Clo in pregnant women is absent. The use of the drug during pregnancy and during breastfeeding is not recommended.Newborns whose mothers received azilsartan medoxomil therapy may develop arterial hypotension, and therefore newborns must be under close medical supervision. Chlorthalidone penetrates the placental barrier into umbilical cord blood and can cause fetal or newborn jaundice, thrombocytopenia, and also other undesirable reactions noted in adults. Immediately after confirmation of pregnancy, you should stop using the drug Edarbi Clos and, if necessary, switch to the use of drugs with proven safety of use during pregnancy. There is no information in relation to a person about the ability of azilsartan and / or its metabolites to penetrate into breast milk. Experimental studies on animals revealed that azilsartan and its metabolite M-II are excreted into the milk of lactating rats. Chlorthalidone crosses the placental barrier and is detected in cord blood, fetal blood and breast milk. If necessary, the use of the drug Edarbi Clo during lactation is necessary to stop breastfeeding, or to stop taking the drug. Preferably the use of drugs with a proven safety profile.
Dosage and administration
Edarbi Clo is ingested 1 time / day, regardless of the time of a meal. The recommended initial dose of Edarbi Clo is 40 mg of azilsartan medoxomil + 12.5 mg of chlorthalidone 1 time / day. If it is necessary to further reduce the blood pressure, the dose of Edarbi Clo can be increased to a maximum of 40 mg of azilsartan medoxomil + 25 mg of chlorthalidone 1 time / day. Edarbi Klo should be taken daily, without interruption. In case of termination of treatment, the patient must inform the doctor. In case of skipping the next dose, the next dose should be taken at the usual time. You should not take a double dose of Edarbi Clos. Withdrawal when a sudden discontinuation of azilsartan medoxomil after prolonged therapy (for 6 months) was not observed. However, the elimination of the drug Edarbi Clough after prolonged treatment should be carried out, if possible, gradually. Elderly patients (65 years and older) do not require correction of the initial dose of the drug.There is no clinical experience with the use of the drug Edarbi Klau in patients with arterial hypertension with impaired severe renal function (CC less than 30 ml / min), therefore, it is not recommended to use the drug in this category of patients. Patients with impaired renal function of mild to moderate severity (CC more than 30 ml / min) do not require correction of the dosage regimen. The use of the drug in patients with severe hepatic impairment is not recommended, since there is no clinical experience of use (see the section Contraindications). Due to limited experience, Edarbi Clough should be used with caution in patients with mild and moderately impaired liver function (less than 9 on the Child-Pugh scale), since even small violations of water-electrolyte balance when taking diuretics can provoke a hepatic coma. It is recommended to actively monitor the condition of such patients. In patients with a reduced BCC, before starting the use of the Edarbi Clo drug, it is necessary to compensate for fluid and electrolyte losses. In patients with arterial hypertension with severe chronic heart failure (NYHA FC IV), Edarbi Clough should be used with caution due to the lack of clinical experience. In patients of the Negroid race, dose adjustment is not required, since The antihypertensive effect of Edarbi Clos in this category of patients is similar to its effect in patients of other races.
Side effects
Determination of the frequency of adverse reactions in accordance with the recommendations of the WHO: very often (> 1/10); often (> 1/100, less than 1/10); infrequently (> 1/1000, less than 1/100; rarely (> 1/10 000, less than 1/1000); very rarely (less than 1/10 000), including individual messages; unspecified frequency (the frequency cannot be calculated using the available data). The combination of azilsartan medoxomil and chlorthalidone Frequency Adverse reactions From the hemopoietic system Infrequently Anemia From the nervous system Often Dizziness Postural dizziness Infrequently Faint (syncope) Paresthesia From the side of the cardiovascular system Frequently expressed reduction of HELL in the digestive system note Infrequently Vomiting Skin and subcutaneous tissue Infrequent Skin rash,itching Allergic reactions Rarely Angioedema From the musculoskeletal system Infrequently Muscle spasms Metabolic metabolism Frequently Hyperuricemia Infrequently Hypokalemia Increased potassium content Hyponatremia Exacerbated gout Congestion Laboratory symptoms Very often Increased creatinine concentration Frequently Increased urea concentration Azilsartan medoxomil peripheral edema (monotherapy) Frequency Adverse reactions With one hundred nervous system nerves Often Dizziness Infrequently Headache Of the cardiovascular system Infrequently A pronounced decrease in blood pressure Of the digestive system Often Diarrhea Infrequently Nausea Of the skin and subcutaneous tissues Infrequent Skin rash, itching Allergic reactions Rarely Angioedema Of the musculoskeletal system spasms Laboratory findings Often Increased activity of CPK Infrequently Increased creatinine concentration Hyperuricemia General reactions Infrequently Fatigue Peripherals General swelling Chlorthalidone (monotherapy) Frequency Adverse reactions From the nervous system Rarely Headache From the cardiovascular system Often Severe decrease in blood pressure Rarely Arrhythmia From the digestive system Often Loss of appetite Gastrointestinal disorders Rarely Constipation Abdominal pain Intrahepatic cholestasis or jaundice Very rare Pancreatitis On the part of the skin and subcutaneous tissue Rarely Photosensitization Cutaneous vasculitis Allergic reactions Often Urticaria On the part of the respiratory system Rarely Allergic swelling of the urinary system simultaneous use of azilsartan medoxomil with chlorthalidone frequently that adverse reactions - marked reduction in blood pressure and an increased concentration of creatinine - increases in the frequency of a:"infrequently" to "often". This is associated with a more effective reduction in blood pressure compared with azilsartan monotherapy with medoxomil. Most of these effects were short-term or not progressive, while patients continued therapy. After discontinuation of the drug, most cases of an increase in the concentration of creatinine that were not treated during treatment were reversible. Increasing the concentration of uric acid in the application of the drug Edarbi Clo is due to its constituent chlortalidone and depends on the dose of diuretic. Reports of the development of gout were infrequent, even with prolonged therapy. With the simultaneous use of azilsartan medoxomil with chlorthalidone, the incidence of adverse reactions, such as hypokalemia, is reduced. If any of the above side effects are exacerbated or any other side effects appear, the patient should inform the doctor.
Overdose
Azilsartan medoxomil (monotherapy) Experience using azilsartan medoxomil in adults in doses up to 320 mg / day for 7 days shows that the drug is well tolerated. Symptoms: marked decrease in blood pressure, dizziness. Treatment: with a marked decrease in blood pressure, the patient should be placed in a horizontal position with a low head; It is recommended that measures to increase the BCC and symptomatic therapy. Azilsartan is not excreted from the systemic circulation through dialysis. Chlorthalidone (monotherapy) Symptoms: nausea, weakness, dizziness, disturbances of water and electrolyte balance. Treatment: there is no specific antidote. With a marked decrease in blood pressure should be flushed stomach; recommended measures to normalize water and electrolyte balance (infusion therapy); symptomatic therapy.
Interaction with other drugs
There was a reversible increase in serum lithium concentration and toxicity during simultaneous use of lithium preparations and diuretics and lithium preparations with angiotensin II receptor antagonists (APA II). Therefore, the simultaneous use of the drug Edarbi Clo in combination with lithium preparations is not recommended (see section "Special instructions"). If necessary, the use of appropriate combination therapy is recommended to regularly monitor the concentration of lithium in the serum. In elderly patients and patients with reduced BCC (includingreceiving diuretics) or with impaired renal function, the simultaneous use of ARA II and NSAIDs can lead to deterioration of renal function up to the development of acute renal failure. Therefore, at the beginning of treatment, patients are recommended to regularly take a sufficient amount of fluid and monitor renal function. With the simultaneous use of ARA II and NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid (more than 3 g / day) and non-selective NSAIDs, the antihypertensive effect may be weakened. Double blockade of RAAS antagonists of angiotensin II receptors, ACE inhibitors or aliskiren is associated with an increased risk of arterial hypotension, hyperkalemia and deterioration of renal function (including acute renal failure) compared with monotherapy. The simultaneous use of cardiac glycosides and a diuretic may aggravate the effects of hypokalemia, such as cardiac arrhythmias. Additional information on the interaction of azilsartan medoxomil No pharmacokinetic interaction was observed with the simultaneous use of azilsartan medoxomil or azilsartan with amlodipine, antacid drugs (aluminum and magnesium hydroxide), chlortalidone, digoxin, fluconazole, glibenclamide, ketoconazole, metmeremerase, and a metforme, and a metforme, a digestin, fluconazole, glibenclamide, ketoconazole, acetylmide, anemocarcid, azotine Azilsartan medoxomil is converted to the pharmacologically active metabolite azilsartan during absorption from the gastrointestinal tract under the action of the enzyme carboxymethylene butenolidase in the intestine and liver. In vitro studies have shown that interactions based on enzyme inhibition are unlikely. Additional information on the interaction of chlorthalidone Chlorthalidone enhances the action of curare-like muscle relaxants and antihypertensive drugs (including guanethidine, methyldopa, beta-blockers, vasodilating agents, slow calcium channel blockers), MAO inhibitors. The simultaneous use of chlorthalidone with allopurinol may lead to an increase in the frequency of hypersensitivity reactions to allopurinol. Chlorthalidone may increase the risk of side effects caused by amantadine. Anticholinergic drugs (for example, atropine, biperiden) can increase the bioavailability of chlorthalidone, reducing gastrointestinal motility and the evacuation of stomach contents.The hypokalemic effect of chlortalidone is enhanced with simultaneous use with corticosteroids, ACTH, amphotericin, beta2-blockers, carbenoxolone. Patients during combination therapy should monitor the content of potassium in the serum. It may be necessary to correct (decrease or increase) the dose of hypoglycemic agents for oral administration and insulin. The pharmacological effects of calcium and vitamin D salts may increase to a clinically significant level while being used with chlorthalidone. Simultaneous use with cyclosporine may increase the risk of developing hyperuricemia and such complications as gout. Kolestiramine interferes with the absorption of chlorthalidone. Perhaps a decrease in the pharmacological effect of chlorthalidone. The simultaneous use of chlorthalidone with methotrexate and cyclophosphamide can lead to a potentiation of the pharmacological effect of anticancer drugs.
special instructions
Hypotension against a background of impaired water and electrolyte balance In patients with reduced BCC and / or hyponatremia (as a result of vomiting, diarrhea, use of diuretics in large doses, or following a diet with restricted salt intake), clinically significant arterial hypotension may develop after starting therapy with the drug Edarbi claw. Hypovolemia and water-electrolyte balance should be adjusted before starting treatment. Transient hypotension is not a contraindication to further treatment, which can be continued after stabilization of blood pressure. Renal dysfunction In patients with impaired renal function (CC more than 30 ml / min), the drug should be used with caution. It is recommended to regularly monitor the content of potassium and serum creatinine concentration. Such patients require careful dose selection with constant monitoring and control of blood pressure. Increased creatinine concentrations are more common in patients with moderate and severe renal impairment. Chlorthalidone may cause azotemia. In the case of progressive deterioration of kidney function (increase in blood urea nitrogen (BUN), it is recommended to temporarily stop diuretic therapy or cancel them completely.Double blockade of the RAAS Patients whose vascular tone and kidney function depend to a large extent on the activity of the RAAS (for example, in patients with severe chronic heart failure (NYHA FC IV), severe renal failure or renal artery stenosis) , acting on the RAAS, such as ACE inhibitors and ARA II, is associated with the possibility of the development of acute arterial hypotension, azotemia, oliguria, or, in rare cases, acute renal failure. The possibility of the development of these effects can not be excluded when using the drug Edarbi Clo. A sharp decrease in blood pressure in patients with ischemic cardiomyopathy or ischemic cerebrovascular diseases may lead to the development of myocardial infarction or stroke. Kidney transplantation There are no data on the use of Edarbi Clos in patients who recently underwent kidney transplantation. Liver dysfunction Data on the clinical experience of the use of Edarbi Clough in patients with severely impaired liver function are not available, therefore, the use of the drug in this category of patients is not recommended (see "Contraindications" section). Due to limited experience, Edarbi Clough should be used with caution in patients with mild and moderately impaired liver function (less than 9 on the Child-Pugh scale), since even small violations of water-electrolyte balance when taking diuretics can provoke a hepatic coma. It is recommended to actively monitor the condition of such patients. Primary Hyperaldosteronism Patients with primary hyper aldosteronism are usually resistant to antihypertensive medication therapy that affect the RAAS. In this regard, the drug Edarbi Clo is not recommended to appoint such patients. Hypokalemia With the treatment of chlorthalidone may develop hypokalemia. It is necessary to regularly monitor the content of potassium in the serum. In patients taking cardiac glycosides, hypokalemia may predispose to arrhythmias. Aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy When prescribing the Edarbi Clo drug in patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy, care must be taken. Lithium As in the case of other ARA II, simultaneous use of lithium preparations and EdarbiClo drug is not recommended.Impact on the ability to drive motor vehicles and control mechanisms. Care should be taken when driving and working with mechanisms that require increased attention and speed of reaction, because when using the drug there is a risk of dizziness and fatigue.