Edarbiclor® [Azilsartan, Chlortalidon]

Pharmacological properties

Mechanism of action. the active substances of the drug edarbiclor affect two separate mechanisms involved in the regulation of hell. thiazide and thiazide-like diuretics act primarily on the distal part of the tubules of the kidneys (the initial part of the tubules), inhibiting the reabsorption of nacl ions (counteracting the cotransporter na + cl–) and promoting reabsorption of ca ++ (using an unknown mechanism). increased excretion of na + and water into the cortical collecting tube and / or increase in flow rate lead to increased secretion and excretion to + and n +.

Azilsartan Medoxomil. Angiotensin II is formed from angiotensin I as a result of the reaction catalyzed by ACE (kinase II). Angiotensin II is the main pressor agent of the renin-angiotensin system, which affects vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Azilsartan blocks the vasoconstrictor and aldosterone secretory effects of angiotensin II due to the selective blocking of the binding of angiotensin II to the AT receptor₁ in many tissues, such as the smooth muscles of blood vessels and adrenal glands. Thus, its effect does not depend on the synthesis of angiotensin II.

AT receptor₂ also present in many tissues, however, there is no evidence of a connection between this receptor and cardiovascular homeostasis. Azilsartan has an AT receptor affinity₁10,000 times higher than AT receptor₂.

Blockade of the renin-angiotensin system using ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the breakdown of bradykinin, a reaction that catalyzes ACE. Since azilsartan is not inhibited by ACE (kinase II), it should not affect bradykinin levels. It is still unknown whether this difference is clinically relevant. Azilsartan does not bind or block other receptors or ion channels that are important for cardiovascular regulation.

Angiotensin II receptor blockade inhibits the negative feedback of angiotensin II to renin secretion. As a result, increased plasma renin activity and the level of angiotensin II circulating in the blood do not weaken the effect of azilsartan on blood pressure.

Chlortalidone. Chlortalidone causes diuresis with increased excretion of sodium and chlorine. The place of action of chlortalidone is the distal part of the tubules of the kidneys (the initial section of the tubules) due to the suppression of reabsorption of NaCl ions (counteracting the Na cotransporter⁺ Cl^—) and promoting Ca reabsorption⁺⁺ (using an unknown mechanism). Increased Na Excretion⁺ and water to the cortical collecting duct and / or increase in flow rate leads to increased secretion and excretion of K⁺ and H⁺. The diuretic effect of chlortalidone leads to a decrease in extracellular fluid volume, blood plasma volume, cardiac output, total metabolic sodium, glomerular filtration rate and renal plasma flow. Despite the fact that the mechanism of action of chlortalidone and related drugs is not fully understood, it is believed that hyponatremia and hypovolemia are the basis of its antihypertensive effect.

Pharmacodynamics EdarbiClor tablets is an effective medicine for lowering blood pressure. Both azilsartan medoxomil and chlortalidone lower blood pressure by lowering the total peripheral vascular pressure using complementary mechanisms.

Azilsartan Medoxomil. Azilsartan inhibits the pressor effects of angiotensin II infusion depending on the dose. A single dose of azilsartan, equivalent to 32 mg of azilsartan medoxomil, inhibited the maximum pressor effect by about 90% at the peak and 60% after 24 hours.Plasma angiotensin I and II concentrations and plasma renin activity increased, while plasma aldosterone concentration decreased after a single and repeated administration of azilsartan medoxomil to healthy individuals; no clinically significant effects on the level of potassium or sodium in blood plasma were detected.

Chlortalidone. The diuretic effect of chlortalidone begins in about 2.6 hours and lasts up to 72 hours.

Pharmacokinetics After oral administration of the drug EdarbiClor, azilsartan and chlortalidone reach their peak plasma concentrations after 3 and 1 h, respectively. Speed, C_max, Tmax (time to reach maximum concentration) and the degree of absorption of AUC of azilsartan are similar when used alone or with chlortalidone. AUC absorption of chlortalidone is similar when used alone or with azilsartan medoxomil; however indicator C_max chlortalidone in the drug EdarbiClor is 45-47% higher.

Eating did not have a clinically significant effect on the bioavailability of azilsartan or chlortalidone, which are components of the drug EdarbiClor.

Absorption. Azilsartan Medoxomil. Azilsartan medoxomil is a medication for oral use, which, when absorbed, quickly turns under the influence of esterases into the active substance azilsartan.

Azilsartan medoxomil is not detected in blood plasma after oral administration. The dose-proportionality to exposure was established for azilsartan in the dose range of azilsartan medoxomil from 20 to 320 mg after single or multiple administration.

The estimated bioavailability of azilsartan medoxomil is about 60%. Following oral administration of azilsartan medoxomil C_max azilsartan is reached after 1.5–3 hours. Eating does not affect the bioavailability of azilsartan.

Distribution. Azilsartan Medoxomil. The volume of distribution of azilsartan is about 16 liters. Azilsartan intensively (99%) binds to plasma proteins, mainly plasma albumin. Binding to blood plasma proteins does not change in the range of concentrations significantly higher than those achieved when used in recommended doses.

In rats, the minimal radioactivity associated with azilsartan penetrates the BBB. Azilsartan crosses the placental barrier of pregnant female rats and is distributed in the fetus.

Chlortalidone. In whole blood, chlortalidone primarily binds to carbonic anhydrase, which is found in red blood cells. In blood plasma, about 75% of chlortalidone binds to plasma proteins, 58% of the drug binds to albumin. Chlortalidone crosses the placental barrier and passes into breast milk. If a woman received 50 mg of chlortalidone daily before and after giving birth, the level of chlortalidone in the fetal whole blood was about 15% of that in maternal blood. The concentrations of chlortalidone in amniotic fluid and breast milk were about 4% of the concentration in the mothers blood.

Metabolism and excretion. Azilsartan Medoxomil. Azilsartan is metabolized to two major metabolites. When used as monotherapy or in combination with chlortalidone, the half-life of azilsartan medoxomil from blood plasma is 11–13 hours. The main metabolite in blood plasma is formed by O-dealkylation, it is designated as metabolite M-II, while the secondary metabolite is formed with using decarboxylation, it is designated as metabolite MI. The levels of systemic exposure of the main and secondary metabolites in humans are about 50% and less than 1% of azilsartan, respectively. M-I and M-II do not affect the pharmacological activity of azilsartan medoxomil. The main enzyme that is responsible for the metabolism of azilsartan is CYP 2C9.

Following oral administration of azilsartan medoxomil labeled with a radioactive isotope ¹⁴C, about 55% was excreted from the body with feces and approximately 42% - with urine. About 15% of the drug was excreted in the urine in unchanged form of azilsartan. T_½ plasma azilsartan is about 11 hours, and renal clearance is about 2.3 ml / min. The equilibrium concentration of azilsartan is achieved within 5 days, during repeated use of the drug in the regime of 1 time per day, accumulation in the blood plasma does not occur.

Chlortalidone. When used as monotherapy or in combination with azilsartan, medoxomil with T_½ plasma chlortalidone is 42–45 hours.

T_½ after taking repeated doses, it remains unchanged. Most of the absorbed dose of chlortalidone is excreted from the body by the kidneys, while the average renal clearance is 46–70 ml / min. Conversely, metabolism and excretion through the liver and bile play an insignificant role in the excretion of this substance. Approximately 60–70% of chlortalidone is excreted in urine and feces within 120 hours, mainly unchanged.

Indications

Ag treatment to lower blood pressure:

• in patients in whom blood pressure is not adequately controlled by monotherapy;
• as an initial therapy for patients who require combination antihypertensive therapy.

Application

Edarbiclor is intended for oral use, tablets can be taken regardless of food intake.

The recommended starting dose for adults is 1 tablet (40 / 12.5 mg) once a day. The antihypertensive effect is manifested mainly within 1-2 weeks of treatment. After 2–4 weeks of treatment, the dose, if necessary, can be increased to 40/25 mg in order to achieve the target level of blood pressure.

The use of the drug EdarbiClor in a dose above 40/25 mg is impractical.

The drug EdarbiClor can be used to provide an additional decrease in blood pressure in patients in whom hypertension is not sufficiently controlled against the background of monotherapy with an angiotensin II receptor antagonist or diuretic. Patients who do not have adequate control while taking azilsartan medoxomil at a dose of 80 mg can achieve an additional clinical decrease in systolic / diastolic blood pressure by 13/6 mm Hg. Art. after the appointment of the drug EdarbiClor in a dose of 40 / 12.5 mg. Patients who do not have adequate control while taking chlortalidone at a dose of 25 mg can achieve an additional clinical decrease in blood pressure by 10/7 mm Hg. Art. after the appointment of the drug EdarbiClor in a dose of 40 / 12.5 mg.

EdarbiClor can be used as first-line therapy if the patient requires complex therapy to achieve the target level of blood pressure.

Patients for whom doses of the individual components of the drug (azilsartan medoxomil and chlortalidone) have already been selected can receive an appropriate dose of EdarbiClor in return.

If necessary, the drug EdarbiClor can be prescribed along with other antihypertensive drugs.

Before starting treatment with EdarbiClor, it is necessary to correct hypovolemia, if any, especially in patients with impaired renal function and in patients receiving high doses of diuretics (see SPECIAL INSTRUCTIONS).

Patients who have a dose-limiting adverse reaction to chlorthalidone may be given EdarbiClor starting with a low dose of chlortalidone (see SPECIAL INSTRUCTIONS).

Special patient groups. Impaired renal function. Safety and efficacy of EdarbiClor in patients with severe renal failure (estimated glomerular filtration rate (GFR) 30 ml / min / 1.73 m²) are not installed. For patients with mild (estimated GFR 60–90 ml / min / 1.73 m²) and moderate (estimated GFR 30-60 ml / min / 1.73 m²) the degree of renal failure dose adjustment is not required.

Chlortalidone. Chlortalidone may cause azotemia.

Impaired liver function. Azilsartan Medoxomil.For patients with mild to moderate hepatic insufficiency, dose adjustment is not required. The effect of azilsartan medoxomil in patients with severe hepatic impairment has not been studied.

Chlortalidone. Minor changes in the water-electrolyte balance can contribute to the development of hepatic coma in patients with impaired liver function or progressive liver disease.

Elderly patients. For elderly patients, dose adjustment of EdarbiClor is not required.

Contraindications

Hypersensitivity to the active substance or other components of the drug; anuria therapy-resistant hypokalemia, hypercalcemia, hyponatremia; severe violations of the liver and kidneys (creatinine clearance 30 ml / min); cholestasis, bile duct obstruction; During pregnancy and breastfeeding; do not use together with aliskiren-containing agents in patients with diabetes mellitus; childhood; contraindicated for women planning a pregnancy.

Side effects

Azilsartan Medoxomil. Adverse reactions likely to be associated with treatment, which were identified in controlled clinical trials with a frequency of ≥0.3% and higher than in the placebo group, are given below.

From the gastrointestinal tract: diarrhea, nausea.

General disorders: asthenia, fatigue.

From the musculoskeletal system and connective tissue: muscle spasm.

From the nervous system: dizziness, postural dizziness.

From the respiratory system: cough.

Metabolic and nutritional disorders: hyponatremia.

From the cardiovascular system: arterial hypotension.

Chlortalidone. In clinical studies of chlortalidone, the following adverse reactions were observed: rash, headache, dizziness, gastrointestinal upset, and increased levels of uric acid and cholesterol.

Changes in laboratory indicators. In a factorial study, clinically significant changes from standard laboratory parameters with the use of recommended doses of EdarbiClor were infrequent.

Indicators of kidney function. An increase in blood creatinine is a known pharmacological effect of antagonists of the renin-angiotensin-aldosterone system, such as angiotensin II receptor antagonists and ACE inhibitors, and is associated with a degree of decrease in blood pressure. The frequency of a subsequent increase in creatinine level by ≥50% from the initial level and more than the upper limit of the norm in patients taking the recommended doses of EdarbiClor was 2.0% compared with 0.4 and 0.3% with the use of azilsartan medoxomil and chlortalidone, respectively . An increase in creatinine was usually transient or non-progressive and reversible and was associated with a more pronounced decrease in blood pressure.

With the use of the drug EdarbiClor, an increase in blood urea nitrogen was observed on average up to 5.3 mg / dl, compared with 1.5 mg / dl when taking azilsartan medoxomil and 2.5 mg / dl when taking chlortalidone.

Post-marketing period. The following adverse reactions were observed: nausea, fainting, loss of consciousness, rash, itching, angioedema. Since the data on these reactions relate to a group of patients of an indefinite volume, it is not always possible to reliably estimate their frequency or to establish the presence of a causal relationship with the use of the drug.

special instructions

Fetotoxicity. azilsartan medoxomil. the use of drugs that affect the renin-angiotensin system in the second and third trimester of pregnancy leads to impaired renal function of the fetus, increased morbidity and mortality of the fetus and newborns. oligohydramnios, which occurs as a result of this treatment, may be associated with pulmonary hypoplasia and deformation of the bones of the skeleton in the fetus.Potential adverse events in newborns include: cranial hypoplasia, anuria, hypotension, renal failure, and death. if pregnancy is detected, edarbiclor should be discontinued as soon as possible.

Chlortalidone. Thiazides cross the placental barrier and end up in umbilical cord blood. Undesirable effects in the fetus and newborns include jaundice and thrombocytopenia.

Arterial hypotension in patients with hypovolemia or deficiency of salts in the body. In patients with an activated renin-angiotensin system, namely, in patients with hypovolemia or a deficiency of salts in the body (for example, patients receiving high doses of diuretics), symptomatic arterial hypotension may occur after starting treatment with EdarbiClor. It is not advisable for such patients to prescribe more than one remedy as initial therapy, therefore, before starting treatment with EdarbiClor, BCC should be adjusted. If arterial hypotension still occurs, the patient must be given a horizontal position and, if necessary, inject a physiological solution of sodium chloride infusion. A transient hypotensive reaction is not a contraindication for further treatment, which can usually be successfully continued after stabilization of blood pressure.

Renal function impairment. In patients with renal failure, renal function monitoring should be performed. In case of signs of progression of renal failure, a decision should be made to suspend or completely discontinue treatment with EdarbiClor.

Azilsartan Medoxomil. Due to inhibition of the renin-angiotensin system in patients with individual hypersensitivity taking EdarbiClor, a change in renal function can be expected. In patients whose renal function depends on the activity of the renin-angiotensin system (for example, patients with severe congestive heart failure, renal artery stenosis or hypovolemia), treatment with ACE inhibitors and angiotensin receptor antagonists is associated with oliguria or progressive azotemia, as well as in rare cases , with the development of acute renal failure and death. Similar effects can be expected in patients taking EdarbiClor.

In studies of the effects of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, an increase in plasma creatinine or blood urea nitrogen level was observed. Experience with the long-term use of azilsartan medoxomil in patients with unilateral or bilateral renal artery stenosis is not yet available, but similar results can be expected.

Chlortalidone. In patients with kidney disease, chlortalidone may cause azotemia. In the case of signs of progression of renal failure, which is determined by an increase in the level of urea nitrogen in the blood, a decision should be made to suspend or completely cancel treatment with a diuretic.

Violation of the level of serum electrolytes. Thiazide diuretics can cause hyponatremia and hypokalemia. Medicines that inhibit the renin-angiotensin system can cause hyperkalemia. Hypokalemia is a dose-dependent adverse reaction that can develop with the use of chlortalidone. The simultaneous use of digitalis can increase the adverse effect of hypokalemia. Plasma electrolyte levels should be checked periodically.

EdarbiClor reduces hypokalemia associated with the use of chlortalidone. Among patients with normal baseline potassium levels, a decrease (to less than 3.4 mmol / L) was observed in 1.7% of patients taking EdarbiClor, in 0.9% of patients taking azilsartan medoxomil, and 13.4% of patients taking chlortalidone.

Hyperuricemia Chlortalidone. The use of chlortalidone or other thiazide diuretics can lead to hyperuricemia or the manifestation of overt gout in individual patients.

Use during pregnancy and lactation. Pregnancy. The use of angiotensin II antagonists is contraindicated in pregnant women or women planning a pregnancy. The use of drugs that affect the renin-angiotensin system in the II and III trimester of pregnancy leads to impaired renal function of the fetus, increased morbidity and mortality of the fetus and newborns. The oligohydramnios that occurs as a result of this treatment may be associated with pulmonary hypoplasia and deformation of the bones of the skeleton in the fetus. Potential adverse events in newborns include cranial hypoplasia, anuria, arterial hypotension, renal failure, and death. When diagnosing pregnancy, EdarbiClor should be discontinued as soon as possible. The above adverse clinical consequences are usually associated with the use of antihypertensive drugs in the II and III trimester of pregnancy. Most epidemiological studies that studied changes in the fetus after the use of antihypertensive drugs in the first trimester of pregnancy did not notice any special effects in drugs that affect the renin-angiotensin system, compared with other antihypertensive drugs. To optimize the clinical consequences for the mother and the fetus, proper treatment of maternal hypertension during pregnancy with drugs with a studied safety profile is necessary.

It is necessary to carefully observe infants who have had a history of intrauterine exposure to EdarbiClor, since arterial hypotension, oliguria and hyperkalemia may occur.

Lactation. It is not known whether azilsartan is excreted in breast milk, but low concentrations of azilsartan are excreted in animal milk after lactation, and thiazide-like diuretics, such as chlortalidone, are excreted in breast milk. Given the potential for side effects in breast-fed infants, a decision must be made regarding discontinuing breastfeeding or discontinuing the drug, taking into account the importance of this drug to the mother.

Children. The drug EdarbiClor is not prescribed for children, since there are no data on the safety and effectiveness of use in children (under the age of 18 years).

The ability to influence the reaction rate when driving vehicles or other mechanisms. There is no data on the effect of the drug on the speed of psychomotor reactions when driving vehicles or other mechanisms, but the possibility of dizziness or increased fatigue should be taken into account.

Interactions

The pharmacokinetics of azilsartan medoxomil and chlortalidone does not change with simultaneous use.

A study of the interaction of the drug EdarbiClor with other drugs has not been conducted, although studies have been conducted on the interaction of azilsartan medoxomil and chlortalidone with other drugs.

Azilsartan Medoxomil. In studies with the simultaneous use of azilsartan medoxomil or azilsartan with amlodipine, antacids, chlortalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone and warfarin, no clinically significant drug interactions were detected. Thus, azilsartan medoxomil can be used simultaneously with these drugs.

NSAIDs, including selective COX-2 inhibitors. In elderly patients, in patients with hypovolemia (including patients taking diuretics) and in patients with impaired renal function, the simultaneous use of NSAIDs, including selective COX-2 inhibitors,and angiotensin II receptor antagonists, including azilsartan, can lead to impaired renal function, including the development of acute renal failure. These effects are usually reversible. In patients receiving the drug EdarbiClor and NSAIDs, it is necessary to periodically monitor renal function.

NSAIDs, including selective COX-2 inhibitors, can weaken the antihypertensive effect of the drug EdarbiClor.

Double blockade of the renin-angiotensin system. Double blockade of the renin-angiotensin system by angiotensin receptor antagonists, ACE inhibitors, or aliskiren is associated with an increased risk of hypotension, hyperkalemia, and changes in kidney function (including acute renal failure) compared with monotherapy with these drugs. Most patients who receive a combination of two inhibitors of the renin-angiotensin system do not receive additional benefits compared to monotherapy with these agents. The simultaneous use of inhibitors of the renin-angiotensin system should be avoided. In patients receiving the drug EdarbiClor and other drugs that affect the renin-angiotensin system, careful monitoring of blood pressure, renal function and electrolyte levels should be carried out.

Aliskiren and EdarbiClor should not be given to patients with diabetes mellitus at the same time. The use of aliskiren and the drug EdarbiClor should be avoided in patients with impaired renal function (glomerular filtration rate of 60 ml / min).

Chlortalidone. Under the influence of diuretics, for example, chlortalidone, the renal clearance of lithium decreases, which increases its toxicity. When using the drug EdarbiClor, monitoring of the level of lithium in the body is recommended.

Lithium. With the simultaneous use of lithium and angiotensin II receptor antagonists, an increase in serum lithium concentration and the occurrence of its toxicity have been reported. It is necessary to monitor the level of lithium in blood serum while using these drugs.

Overdose

Azilsartan Medoxomil. there is limited evidence of an overdose of the drug in humans. During controlled clinical trials involving healthy volunteers of azilsartan, medoxomil, which was used in doses of up to 320 mg once a day for 7 days, was well tolerated. in case of an overdose, it is necessary to carry out maintenance therapy taking into account the clinical condition of the patient. azilsartan is not excreted by dialysis.

Chlortalidone. Symptoms of acute overdose include nausea, weakness, dizziness, and electrolyte imbalance. The oral LD50 level of the drug in animals is more than 25,000 mg / kg body weight. The minimum lethal dose for humans has not been established. There is no specific antidote to the drug. Gastric lavage followed by maintenance therapy is recommended. If necessary, a solution of glucose and sodium chloride with potassium can be added to this therapy, which should be administered iv with caution.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° C.

UA / CVM / 1018/0009