Expiration date: 06/2025

Film-coated tablets 40 mg/12.5 mg and 40 mg/25 mg

Composition

1 tablet of 40 mg / 12.5 mg contains

active ingredients: azilsartan medoxomil potassium 42.68 mg (equivalent to azilsartan medoxomil free acid 40.0 mg)

chlorthalidone 12.5 mg

excipients: mannitol, microcrystalline cellulose, fumaric acid, sodium hydroxide, hydroxypropyl cellulose, crospovidone, magnesium stearate

Film shell: hypromellose 2910, titanium dioxide (E 171), talc, polyethylene glycol 8000, iron oxide red (E 172), grey F1 purified ink*

1 tablet of 40 mg / 25 mg contains

active ingredients: azilsartan medoxomil potassium 42.68 mg (equivalent to azilsartan medoxomil free acid 40.0 mg)

chlorthalidone 25 mg

excipients: mannitol, microcrystalline cellulose, fumaric acid, sodium hydroxide, hydroxypropyl cellulose, crospovidone, magnesium stearate

Film shell: hypromellose 2910, titanium dioxide (E 171), talc, polyethylene glycol 8000, iron oxide red (E 172), grey F1 purified ink*

* The composition of F1 grey ink purified for marking: shellac – 26%, black iron oxide – 10%, butanol – 38%, ethanol – 26%.

Description

Round biconvex tablets, coated with a pale pink film, with the inscription "A / C" and "40/12.5" on one side of the tablet (for a dosage of 40 mg / 12.5 mg).

Round biconvex tablets, coated with a gray-pink film, with the inscription "A/C" and "40/25" on one side of the tablet (for a dosage of 40 mg / 25 mg).

Pharmacotherapeutic group

Drugs that affect the renin-angiotensin system. Angiotensin II antagonists in combination with other drugs. Angiotensin II antagonists in combination with diuretics. Azilsartan medoximil and diuretics.

ATX code C09DA09

Pharmacological properties

Pharmacokinetics

Suction

After ingestion of Edarbi Klo, peak plasma concentrations of azilsartan and chlorthalidone are reached after 3 and 1 hours, respectively. The rate (Cmax and Tmax) and the degree of absorption (AUC) of azilsartan are similar when taken together with and without chlorthalidone. The AUC of chlorthalidone is similar when taken with and without azilsartan medoxomil; however, the Cmax of chlorthalidone, when taken with azilsartan medoxomil, was 47% higher. The half-life (T1/2) of azilsartan and chlorthalidone is approximately 12 and 45 hours, respectively.

Food intake does not affect the bioavailability of Edarbi Klo.

Azilsartan medoxomil

During absorption in the gastrointestinal tract of azilsartan, medoxomil is rapidly hydrolyzed to active azilsartan. Azilsartan medoxomil is not detectable in plasma after oral administration. The proportionality of the dose for azilsartan was established in the dose range of azilsartan medoxomil from 20 to 320 mg after a single or multiple administration. The estimated absolute bioavailability of azilsartan after taking azilsartan medoxomil is approximately 60%. After oral administration of azilsartan medoxomil, the Cmax of azilsartan in plasma is reached within 1.5-3 hours. Food intake does not affect the bioavailability of azilsartan.

Distribution

Azilsartan medoxomil

The volume of distribution of azilsartan is approximately 16 liters. Azilsartan binds strongly to plasma proteins (>99%) mainly with albumin. Binding to plasma proteins is constant even at concentrations of azilsartan in plasma, far exceeding the achieved values at recommended doses.

Chlorthalidone

In whole blood, chlorthalidone binds mainly to the carbonic anhydrase of erythrocytes. In plasma, approximately 75% of chlorthalidone is bound to plasma proteins, and 58% of the drug is bound to albumin.

Metabolism and elimination

Azilsartan medoxomil

Azilsartan is metabolized to two main metabolites. The main metabolite in plasma is formed by O-disalkylation and is called the M-II metabolite, the other M-I metabolite is formed in a lower concentration by decarboxylation. The systemic effect of both metabolites in the human body is approximately 50% and less than 1%, respectively. M-I and M-II are not involved in the pharmacological activity of azilsartan medoxomil. The main enzyme responsible for the metabolism of azilsartan is CYP2C9.

After an oral dose of 14C-labeled azilsartan medoxomil, approximately 55% of the radioactive substance was detected in feces and approximately 42% in urine, while 15% of the dose was excreted in urine as azilsartan. The half-life of azilsartan is approximately 11 hours, and the renal clearance is approximately 2.3 ml/min. Steady-state levels of azilsartan are reached within 5 days, while accumulation in plasma with repeated single daily administration does not occur.

Chlorthalidone

The drug is mainly excreted unchanged by the kidneys. Other ways of elimination of the drug have not yet been established. There is no data on the comparative amounts of chlorthalidone, excreted unchanged and in the form of metabolites, the concentration of the drug in biological fluids, the degree of accumulation by individual organs or the fetal body, or penetration through the blood-brain barrier.

Mechanism of action

The action of the active substances of the drug Edarbi Klo is directed at two separate mechanisms involved in the regulation of blood pressure. Azilsartan blocks vasoconstrictive and sodium-retaining effects of angiotensin II on cardiac muscle, vascular smooth muscle, as well as on adrenal and renal cells. Chlorthalidone provides diuresis with increased excretion of sodium and chloride in the cortical segment of the ascending knee of the Henle loop.

Azilsartan medoxomil

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzymes (ACE, kinase II). Angiotensin II is the main vasoconstrictor of the renin-angiotensin system (RAS), and its effects include vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal sodium reabsorption. Azilsartan inhibits the vasoconstrictor effect and the effect associated with the secretion of aldosterone by selectively blocking the binding of angiotensin II to the AT1 receptor in tissues such as vascular smooth muscle and adrenal glands. Thus, its effect does not depend on the pathway of angiotensin II synthesis.

AT2 receptors are found in many tissues, however, there is no evidence of the connection of this receptor with cardiovascular homeostasis yet. Azilsartan is characterized by more than 10,000-fold affinity of binding to the AT1 receptor than to the AT2 receptor.

The suppression of RAS by ACE inhibitors blocking the biosynthesis of angiotensin II from angiotensin I is widely used in the treatment of hypertension. ACE inhibitors also inhibit the breakdown of bradykinin, which is catalyzed by ACE. Since azilsartan does not suppress ACE (kinase II), it should not affect bradykinin levels. Azilsartan does not bind or block other receptors or ion channels that play an important role in the regulation of the cardiovascular system.

Angiotensin II receptor blockade inhibits the negative regulatory response of angiotensin II to renin secretion, however, the observed increase in plasma renin activity and circulating angiotensin II levels does not suppress the effect of azilsartan on blood pressure.

Chlorthalidone

Chlorthalidone provides diuresis with increased excretion of sodium and chloride. The place of action is the cortical segment of the ascending knee of the Henle loop. The diuretic effect of chlorthalidone leads to a decrease in the volume of extracellular fluid, plasma volume, cardiac output, total sodium exchange, glomerular filtration rate, renal plasma flow. Although the mechanism of action of chlorthalidone and related drugs has not been fully studied, a decrease in sodium levels and fluid volume, apparently, provide the basis for its antihypertensive effect.

Pharmacodynamics

Azilsartan medoxomil and chlorthalidone reduce blood pressure by reducing peripheral resistance, but through complementary mechanisms.

Azilsartan medoxomil

Azilsartan, depending on the dose, inhibits the vasoconstrictive effects of angiotensin II.

A single dose of azilsartan at a dose equivalent to 32 mg of azilsartan medoxomil inhibited the maximum vasoconstrictive effect of angiotensin II by about 90% at the time of the highest concentration, and by about 60% 24 hours after administration. The concentrations of angiotensin I and angiotensin II and the activity of renin in blood plasma increased, and the concentration of aldosterone decreased after a single oral administration and after repeated doses of azilsartan medoxomil; no clinically significant effect on the content of potassium or sodium in blood serum was found.

Chlorthalidone

The diuretic effect of chlorthalidone begins after about 2.6 hours and lasts for 72 hours.

Indications for use

Edarbi Klo is a combination of an angiotensin II receptor blocker (ARB) and a thiazide–like diuretic indicated for use in the treatment of arterial hypertension in order to reduce blood pressure:

in patients in whom it is impossible to ensure blood pressure control when using monotherapy

as a means of initial therapy in patients who may need several medications to achieve the required blood pressure level

Method of administration and dosage

The recommended starting dose of Edarbi Klo is 40/12.5 mg orally once a day. Basically, the antihypertensive effect manifests itself within 1-2 weeks. After 2-4 weeks of therapy, if necessary, the dose can be increased to 40/25 mg to achieve the target blood pressure. Taking the drug in doses above 40/25 mg is probably not characterized by additional benefits.

The drug Edarbi Klo can be used to further reduce blood pressure in patients in whom it is impossible to ensure proper control of blood pressure when using ARBs or diuretics as monotherapy. In patients whose blood pressure was not controlled when taking 80 mg of azilsartan medoxomil, when switching to Edarbi Klo at a dose of 40/12.5 mg, there may be an additional decrease in office blood pressure by 13/6 mmHg (systolic / diastolic). When switching to taking Edarbi Klo at a dose of 40/12.5 mg, patients who did not have proper blood pressure control with the use of chlorthalidone at a dose of 25 mg may experience an additional decrease in office blood pressure by 10/7 mm Hg (systolic / diastolic).

The drug Edarbi Klo can be used as a means of initial therapy in patients who may need several drugs to achieve the required blood pressure level.

Patients who have had titration of individual components (azilsartan medoxomil and chlorthalidone) can instead receive an appropriate dose of Edarbi Klo. The drug Edarbi Klo can be taken regardless of food intake.

The drug Edarbi Klo can be taken with other antihypertensive agents as needed.

Before starting treatment with Edarbi Klo, it is necessary to correct the reduced volume of fluid, especially in patients with impaired renal function or in patients receiving high-dose diuretics.

Patients experiencing dose-limiting adverse reactions during chlorthalidone therapy can be transferred to Edarbi Klo, initially with a lower dose of chlorthalidone.Special patient groups

Elderly patients

Correction of the dose of Edarbi Klo in elderly patients is not required. Of the total number of patients in clinical trials with Edarbi Klo, 24% were elderly patients (65 years or older); 5.7% were aged 75 years or older. In terms of the safety or efficacy of the drug, no general differences were found between older and younger patients, however, a higher level of sensitivity in some older people cannot be excluded.

Children's age

The safety and efficacy of Edarbi Klo in patients under the age of 18 has not been established.

Patients with impaired renal function

The safety and efficacy of Edarbi Klo in patients with severe renal impairment (GFR <30 ml/min / 1.73 m2) have not been established. Dose adjustment in patients with impaired renal function of mild (GFR 60-90 ml/min / 1.73 m2) or moderate (GFR 30-60 ml / min / 1.73 m2) degree is not required.

Taking chlorthalidone can provoke azotemia.

Patients with impaired liver function

Azilsartan medoxomil

Dose adjustment in patients with mild or moderate hepatic impairment is not required. The use of azilsartan medoxomil in patients with severe hepatic insufficiency has not been studied.

Chlorthalidone

Minor changes in the balance of fluid and electrolytes can provoke hepatic coma in patients with impaired liver function or progressive liver disease.

Side effects

The section "Special instructions" includes more detailed information about the following potential adverse reactions in connection with taking the drug Edarbi Klo, azilsartan medoxomil or chlorthalidone:

• embryotoxicity
• arterial hypotension in patients with reduced fluid volume or salt levels
• impaired renal function
• hypokalemia
• hyperuricemia
• Clinical research experience

The safety assessment of Edarbi Klo was performed in studies involving more than 3,900 patients with arterial hypertension. More than 700 patients were treated for at least 6 months and more than 280 patients for at least 1 year. Adverse reactions, as a rule, were mild in severity and transient.

General adverse reactions when taking Edarbi Klo were observed more often in at least 2% of patients participating in an 8-week factorial study compared with groups of patients taking azilsartan medoxomil or chlorthalidone (Table 1).

Arterial hypotension and fainting were observed in 1.7% and 0.3% of patients treated with Edarbi Klo.

8.3% of patients receiving Edarbi Klo at the recommended doses stopped participating in the study due to adverse reactions, compared with 3.2% of patients receiving azilsartan medoxomil and 3.2% of patients receiving chlorthalidone. The most common reasons for discontinuation of therapy with Edarbi Klo included an increase in serum creatinine (3.6%) and dizziness (2.3%).

Azilsartan medoxomil

In total, 4814 patients who received azilsartan medoxomil in clinical trials at doses of 20, 40 or 80 mg were studied for safety. This number includes 1,704 patients who have been receiving the drug for at least 6 months, of which 588 have been receiving treatment for at least 1 year. As a rule, adverse reactions were characterized by mild severity, did not depend on the administered dose and were comparable, regardless of age, gender and race.

The frequency of adverse reactions ≥ 0.3% in more than 3,300 patients; the nature of reactions is described below:

• gastrointestinal disorders: diarrhea, nausea;
• common complications and complications at the injection site: asthenia, fatigue;
• disorders of the musculoskeletal system and connective tissue: muscle spasms;
• disorders of the nervous system: dizziness, postural dizziness;
• disorders of the respiratory system, chest and mediastinal organs: cough;

Chlorthalidone

In clinical trials with chlorthalidone, the following adverse reactions were observed: rash, headache, dizziness, gastrointestinal disorders and increased levels of uric acid and cholesterol.

Results of clinical laboratory studies of the drug Edarbi Klo

In a factorial study, clinically significant changes in standard laboratory parameters were observed infrequently when Edarbi Klo was administered at the recommended doses.

Parameters of kidney function:

An increase in blood creatinine is a known pharmacological effect of such blockers of the renin-angiotensin aldosterone system (RAAS) as ARBs and ACE inhibitors and is associated with a decrease in blood pressure. The frequency of consecutive cases of increased creatinine levels ≥ 50% of the baseline and > the upper limit of normal (HGN) was 2.0% in patients receiving Edarbi Klo at the recommended doses, compared with 0.4% and 0.3% in the treatment of azilsartan with medoxomil and chlorthalidone, respectively. The increase in creatinine levels was usually temporary, reversible, or did not progress, and was associated with a significant decrease in blood pressure.

An average increase in blood urea nitrogen (AMC) was observed in the treatment with Edarbi Klo (5.3 mg/dl) compared with the AMC values in the treatment of azilsartan with medoxomil (1.5 mg/dl) and chlorthalidone (2.5 mg/dl).

Post-registration application experience

During the use of the drug Edarbi Klo in the post-registration period , the following adverse reactions were detected:

• nausea
• rash
• itching
• Quincke's edema

Due to the fact that information about these reactions is received voluntarily from the population, it is not always possible to reliably estimate the frequency of occurrence of such reactions or establish a causal relationship with taking the drug.

Contraindications

• hypersensitivity to azilsartan medoxomil or chlorthalidone or to any auxiliary substance
• anuria
• pregnancy and lactation
• in diabetes mellitus, do not prescribe simultaneously with aliskiren
• children under 18 years of age

Drug interactions

Edarby Clo

The pharmacokinetics of azilsartan medoxomil and chlorthalidone do not change when taken together. Studies of the interaction of the drug Edarbi Klo with other drugs have not been conducted, however, azilsartan medoxomil and chlorthalidone were subjected to such studies.

Azilsartan medoxomil

No clinically significant drug interactions were observed in studies of azilsartan medoxomil or azilsartan in combination with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone and warfarin. The data obtained indicate in favor of the possible use of azilsartan medoxomil in conjunction with the listed drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors)

In elderly patients, patients with decreased fluid volume (including patients treated with diuretics), or patients with impaired renal function, concomitant administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including azilsartan, may lead to deterioration of renal function, including possible acute kidney failure. These effects are usually reversible. It is necessary to periodically monitor kidney function in patients receiving Edarbi Klo and NSAID treatment.

The antihypertensive effect of Edarbi Klo may be weakened by the action of NSAIDs, including selective COX-2 inhibitors.

Double blockade of RACES

Double blockade of RAS with angiotensin receptor blockers, ACE inhibitors or aliskiren is associated with an increased risk of hypotension, hyperkalemia and changes in renal function (including acute renal failure) compared with monotherapy. Most patients receiving a combination of two RAS inhibitors do not benefit from any additional benefits compared to monotherapy. In general, the combined use of RAS inhibitors should be avoided. It is necessary to ensure careful monitoring of blood pressure, kidney function and electrolyte levels in patients receiving the drug Edarbi Klo and other agents affecting RAS.

Aliskiren should not be prescribed together with the drug Edarbi Klo to patients with diabetes mellitus. Avoid using aliskiren with Edarbi Klo in patients with renal insufficiency (GFR <60 ml/min).

Chlorthalidone

The renal clearance of lithium decreases when taking diuretics such as chlorthalidone, while increasing the risk of increasing the concentration of lithium to the level of toxicity. When using the drug Edarbi Klo, it is necessary to ensure proper monitoring of lithium levels.

Lithium

An increase in the concentration of lithium in the blood serum and an increase in its concentration to the level of toxicity was recorded during concomitant administration of lithium with angiotensin II receptor agonists. With concomitant use, proper monitoring of lithium levels should be ensured.

Special instructions

Hypotension in patients with hypovolemia or decreased electrolytes

In patients with activated ASD, for example, in patients with hypovolemia or a decrease in electrolytes (as observed in the treatment with diuretics in high doses), symptomatic hypotension may occur after the start of treatment with Edarbi Klo. Such patients are probably not suitable candidates for starting therapy with more than one drug; therefore, before taking Edarbi Klo, correction of hypovolemia should be provided. With the development of hypotension, the patient should be placed in a supine position and, if necessary, provide intravenous infusion of saline solution. A temporary hypotensive reaction is not a contraindication for further treatment, and taking the drug can usually be resumed without any difficulty after blood pressure stabilizes.

Impaired renal function

Edarby Clo

It is necessary to monitor the deterioration of renal function in patients with impaired renal function. If there are signs of progression of renal insufficiency, it is necessary to consider suspending or discontinuing the use of Edarbi Klo.

Azilsartan medoxomil

At-risk patients receiving Edarbi Klo may experience changes in renal function due to the inhibition of RAS. In patients whose renal function may depend on the activity of the renin-angiotensin system (for example, patients with severe heart failure, renal artery stenosis or reduced fluid volume), treatment with ACE inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results can be expected in patients taking the drug Edarbi Klo.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, an increase in serum creatinine or AMC was recorded. Long-term use of azilsartan medoxomil in patients with unilateral or bilateral renal artery stenosis is not practiced, but similar results are possible.

Chlorthalidone

In patients with kidney disease, chlorthalidone can provoke the development of azotemia. With an obvious progression of kidney failure, as may be indicated by an increased level of AMC, it is necessary to consider suspending or discontinuing diuretic therapy.

Hypokalemia

Chlorthalidone

Hypokalemia is a dose-dependent adverse reaction to taking chlorthalidone. Concomitant use of digitalis preparations may exacerbate the negative side effects of hypokalemia.

The drug Edarbi Klo weakens the degree of hypokalemia caused by taking chlorthalidone. In patients with normal baseline potassium levels, a decrease in potassium levels (less than 3.4 mmol/L) was observed in 1.7% of patients treated with Edarbi Klo, 0.9% of patients treated with azilsartan medoxomil and 13.4% of patients treated with chlorthalidone.

Hyperuricemia

Chlorthalidone

In some patients, taking chlorthalidone or other thiazide diuretics may provoke the development of hyperuricemia or obvious gout.

A rare age

Newborns exposed to the intrauterine effects of the drug Edarbi Klo: with oliguria or hypotension, it is necessary to maintain blood pressure and kidney function. An exchange blood transfusion or dialysis may be required.

Pregnancy and lactation

Category D when using medicines by pregnant women.

The use of drugs that affect ASD in the second and third trimesters of pregnancy reduces the renal function of the fetus and increases the morbidity and mortality rates of the fetus and newborn. The lack of water caused by such medications may be associated with hypoplasia of the lungs and skeletal deformities of the fetus. Potential side effects in newborns include cranial hypoplasia, anuria, hypotension, renal failure, and death. If pregnancy is detected, taking the drug Edarbi Klo should be stopped as soon as possible. The listed adverse outcomes are usually associated with the use of drugs in the second and third trimester of pregnancy. Most epidemiological studies aimed at studying fetal abnormalities after taking antihypertensive drugs by the mother in the first trimester did not indicate any differences between drugs that affect ASD from other antihypertensive drugs. During pregnancy, it is necessary to ensure proper control of maternal hypertension levels to optimize maternal and fetal outcomes.

In the absence of an alternative to therapy with drugs affecting ASD for a particular patient, it is necessary to inform the mother about the potential risk to the fetus. To assess the state of the intraamnial environment, it is necessary to perform a series of ultrasound. If water scarcity is detected, the use of the drug Edarbi Klo should be discontinued, except in cases where the life of the mother depends on the treatment with the drug. It is considered advisable to check the condition of the fetus, taking into account the week of pregnancy. However, patients and doctors should be aware that signs of lack of water may appear only after irreversible fetal disorders. It is necessary to ensure careful monitoring of newborns exposed to intrauterine exposure to Edarbi Klo for the development of hypotension, oliguria and hyperkalemia.

Chlorthalidone

Thiazides penetrate the placental barrier and are found in umbilical cord blood. Adverse reactions include jaundice and thrombocytopenia in the fetus or newborn.

Breastfeeding

The fact of azilsartan excretion in breast milk has not been established, however, azilsartan is excreted in low concentrations in the milk of nursing rats, and chlorthalidone is excreted in breast milk. In view of the possibility of adverse effects on a breastfed child, a decision should be made regarding the termination of breastfeeding or taking the drug, taking into account the importance of the drug for the mother.

Features of the drug's effect on the ability to drive a vehicle or potentially dangerous mechanisms

It is necessary to be careful when driving vehicles and working with mechanisms that require increased attention and responsiveness: the risk of dizziness and increased fatigue.

Overdose

Data on overdose in humans is limited.

Azilsartan medoxomil

Data on overdose in humans is limited. Within the framework of controlled clinical trials involving healthy subjects, single daily doses of azilsartan medoxomil in the amount of up to 320 mg, which were administered for 7 days, were well tolerated. In case of overdose, supportive therapy should be prescribed taking into account the clinical condition of the patient. Azilsartan does not undergo dialysis.

Chlorthalidone

Symptoms of acute overdose include nausea, weakness, dizziness and electrolyte imbalance. Minimum Lethal Dose (MLD) the person is not installed. There are no specific antidotes, but gastric lavage with subsequent supportive treatment is recommended. If necessary, such treatment may include intravenous administration of dextrose-salt solution with potassium with due care.

Release form

7 tablets in a contour cell packaging made of aluminum foil with a moisture absorber built into the polyethylene layer.

4 contour packages together with instructions for medical use in the state and Russian languages are put into a cardboard pack.

Storage conditions

In a dry, protected from light place at a temperature not exceeding 25 ° C

Keep out of reach of children!

Shelf life

3 years

Do not use the drug after the expiration date