Edarbi Clo, 40 mg+12, 5 mg 98 pcs

A combined antihypertensive drug. Edarbi^® Clo contains an angiotensin II receptor antagonist (azilsartan medoxomil) and a thiazide-like diuretic (chlorthalidone). Simultaneous use of the two active agents leads to a more pronounced decrease in BP compared to taking each of them in monotherapy. When administered once daily, effective BP reduction is achieved within 24 hours.

Asilsartan medoxomil is a specific angiotensin II type 1 receptor antagonist (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 of the RAAS, its effects include vasoconstriction, stimulation of aldosterone synthesis and secretion, increased HR and renal sodium reabsorption.

Asilsartan medoxomil is a prodrug for oral administration. It is rapidly converted to the active molecule azilsartan, which selectively inhibits the effects of angiotensin II by blocking its binding to the AT₁ receptor in various tissues, such as vascular smooth muscle and the adrenal gland. Therefore, its action is not related to the pathway of angiotensin II biosynthesis. The AT₂ receptor is also found in many tissues, but it is not involved in the regulation of cardiovascular activity. The affinity of azilsartan for the AT₁ receptor is 10,000 times greater than for the AT₂ receptor.

The inhibition of RAAS activity by ACE inhibitors that inhibit 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 inhibit ACE (kininase II), it should not affect bradykinin activity. Azilsartan does not bind to or block other receptors or ion channels that play an important role in cardiovascular regulation.

Asilsartan dose-dependently suppresses the vasoconstrictor effects of angiotensin II infusion. A single administration of azilsartan at a dose equivalent to 32 mg of azilsartan medoxomil suppressed the maximal vasoconstrictor effects of angiotensin II by approximately 90% at the time of highest concentration, and by approximately 60% 24 h after administration. In healthy volunteers, plasma angiotensin I and angiotensin II concentrations and renin activity increased and aldosterone concentrations decreased after a single oral dose and after repeated doses of azilsartan medoxomil; no clinically significant effect on serum potassium or sodium was found. Overall, the pharmacodynamic properties of azilsartan medoxomil are consistent with AT₁ receptor blocking.

The antihypertensive effect of azilsartan medoxomil develops during the first 2 weeks of use with reaching maximum therapeutic effect after 4 weeks. Decrease in BP after a single oral dose is usually achieved within several hours and maintained for 24 hours.

Chlorthalidone is a thiazide-like diuretic and inhibits active sodium ion reabsorption in the renal tubules (the initial part of the distal convoluted tubule of the nephron), increasing excretion of sodium and chlorine ions and increasing diuresis. In addition, chlorthalidone increases excretion of potassium, magnesium and bicarbonate ions and inhibits calcium ions and uric acid. The antihypertensive effect of chlorthalidone is associated with the elimination of fluid and sodium from the body. Diuretic effect develops 2-3 hours after oral administration of chlorthalidone and lasts for 2-3 days.

The antihypertensive effect of chlortalidone develops gradually with maximum therapeutic effect 2-4 weeks after the start of therapy.

In the clinical studies, the azilsartan medoxomil/chlorthalidone combination was more effective than the combination of azilsartan medoxomil with hydrochlorothiazide or the olmesartan medoxomil/hydrochlorothiazide combination, even though a higher proportion of study participants in the comparison group required dose increases due to insufficient BP control.

In a 12-week double-blind, planned dose-escalation study, the 40-mg/25-mg azilsartan medoxomil/hydrochlorothiazide combination was statistically significantly superior to the 40-mg/25-mg olmesartan medoxomil/hydrochlorothiazide combination in reducing systolic BP in moderate to severe arterial hypertension. Similar results were obtained in all patient subgroups, regardless of age, sex, or race. The azilsartan medoxomil/hlorthalidone combination lowered BP more effectively than the olmesartan medoxomil/hydrochlorothiazide combination in every hour of the 24-hour interval between doses of the drugs, as measured by CMAD (daily blood pressure monitoring).

Indications

Active ingredient

How to take, the dosage

Edarbi® Clo is taken orally once daily regardless of meal time.

The recommended starting dose of Edarbi® Clo is 40 mg azilsartan medoxomil + 12.5 mg chlorthalidone once daily.

If additional BP lowering is necessary, the dose of Edarbi® Clo may be increased to a maximum of 40 mg azilsartan medoxomil + 25 mg chlorthalidone once daily.

Edarbi® Clo should be taken daily, without interruption. If treatment is discontinued, the patient should inform the physician.

If the next dose is missed, the patient should take the next dose at the usual time. Do not take a double dose of Edarbi® Clo.

No withdrawal syndrome has been observed with abrupt discontinuation of azilsartan medoxomil after long-term therapy (for 6 months). However, withdrawal of Edarbi® Clo after long-term therapy should be done gradually, if possible.

In elderly patients (65 years and older), no adjustment of the initial dose of the drug is required.

There is no clinical experience of using Edarbi® Clo in patients with severe arterial hypertension with impaired renal function (CKG less than 30 ml/min), therefore it is not recommended for this category of patients. In patients with mild to moderate renal dysfunction (CKD more than 30 ml/min) no dosage regimen adjustment is required.

The use of the drug in patients with severe hepatic impairment is not recommended since there is no clinical experience of its use (see section Contraindications). Because of the limited experience of use, caution should be exercised when using Edarbi® Clo in patients with mild to moderate hepatic impairment (less than 9 points on the Child-Pugh score), because even slight electrolyte-water balance disorders when taking diuretics can provoke hepatic coma. Active monitoring of these patients is recommended.

In patients with decreased blood circulation, fluid and electrolyte losses should be replenished before starting Edarbi® Clo.

In patients with arterial hypertension with severe chronic heart failure (NYHA class IV), Edarbi® Clo should be used with caution due to lack of clinical experience.

Dose adjustment is not necessary in non-Hispanic patients because the antihypertensive effects of Edarbi® Clo in this patient population are similar to patients of other races.

Interaction

A reversible increase in serum lithium concentration and toxicity during concomitant use of lithium and diuretics and lithium preparations with angiotensin II receptor antagonists (ARA II) have been observed. Therefore, concomitant use of the drug Edarbi® Clo in combination with lithium preparations is not recommended (see section “Special indications”). If it is necessary to use the appropriate combination therapy, regular monitoring of lithium concentration in blood serum is recommended.

In elderly patients and patients with decreased blood circulation (including those receiving diuretics) or with impaired renal function, concomitant use of APA II and NSAIDs may lead to worsening of renal function up to the development of acute renal failure. Therefore, at the beginning of treatment, patients are recommended to take sufficient fluids regularly and monitor renal function. Co-administration of APA II and NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid (more than 3 g/day) and non-selective NSAIDs may weaken antihypertensive effect.

Double RAAS blockade with angiotensin II receptor antagonists, ACE inhibitors, or aliskirenone is associated with an increased risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) compared to monotherapy.

The concomitant use of cardiac glycosides and a diuretic may aggravate the effects of hypokalemia, such as heart rhythm disturbances.

Further information on interactions of azilsartan medoxomil

No pharmacokinetic interaction has been observed with concomitant use of azilsartan medoxomil or azilsartan with amlodipine, antacids (aluminum and magnesium hydroxide), chlorthalidone, digoxin, fluconazole, glibenclamide, ketoconazole, metformin and warfarin.

Asilsartan medoxomil is converted to the pharmacologically active metabolite azilsartan during absorption from the GI tract by the enzyme carboxymethylenbutenolidase in the gut and liver. In vitro studies have shown that interactions based on enzyme inhibition are unlikely.

More information on chlorthalidone interactions

Chlorthalidone potentiates the effects of curare-like muscle relaxants and antihypertensive agents (including guanethidine, methyldopa, beta-adrenoblockers, vasodilators, slow calcium channel blockers), MAO inhibitors.

The concomitant use of chlorthalidone with allopurinol may increase the incidence of hypersensitivity reactions to allopurinol.

Chlorthalidone may increase the risk of amantadine-induced adverse reactions.

The anticholinergic drugs (e.g., atropine, biperiden) may increase the bioavailability of chlorthalidone, decreasing GI motility and evacuation of gastric contents.

The hypokalemic effects of chlorthalidone are enhanced with concomitant use with corticosteroids, ACTH, amphotericin, beta2-adrenoblockers, carbenoxolone. Patients should monitor serum potassium during combination therapy.

It may be necessary to adjust (decrease or increase) the dose of hypoglycemic agents for oral administration and insulin.

The pharmacological effects of calcium salts and vitamin D may increase to clinically significant levels when used concomitantly with chlorthalidone.

Simultaneous use with cyclosporine may increase the risk of hyperuricemia and complications such as gout.

Colestyramine interferes with absorption of chlorthalidone. The pharmacological effect of chlorthalidone may be reduced.

The concomitant use of chlorthalidone with methotrexate and cyclophosphamide may lead to potentiation of the pharmacological effect of anticancer drugs.

Special Instructions

Arterial hypotension with impaired water-electrolyte balance

. Patients with decreased blood circulation and/or with hyponatremia (as a result of vomiting, diarrhea, use of high-dose diuretics or compliance with diet with restriction of table salt intake) may develop clinically significant arterial hypotension after initiation of therapy with Edarbi® Clo. Hypovolemia and water-electrolyte balance should be corrected before starting treatment. Transient arterial hypotension is not a contraindication for further treatment, which can be continued after BP stabilization.

Renal dysfunction

In patients with impaired renal function (CKG greater than 30 ml/min) the drug should be used with caution. It is recommended to monitor potassium content and serum creatinine concentration regularly. Such patients require careful dose selection with continuous monitoring and BP control. Elevated creatinine concentration is more frequently observed in patients with moderate and severe renal dysfunction.

Chlorthalidone may cause azotemia.

In case of progressive worsening of renal function (increased blood urea nitrogen (BUN)), temporary discontinuation of diuretic therapy or its complete withdrawal is recommended.

Double blockade of the RAAS

. Patients in whom vascular tone and renal function are highly dependent on RAAS activity (e.g., patients with severe chronic heart failure (NYHA class IV), severe renal insufficiency or renal artery stenosis), treatment with drugs acting on the RAAS, such as ACE inhibitors and ARA II, is associated with the possibility of acute arterial hypotension, azotemia, oliguria or, in rare cases, acute renal failure. The possibility of these effects cannot be excluded with Edarbi® Clo.

The sharp decrease of BP in patients with ischemic cardiomyopathy or ischemic cerebrovascular disease may lead to myocardial infarction or stroke.

Kidney transplantation

There are no data on the use of Edarbi® Clo in patients who have recently had a kidney transplant.

There are no data about the clinical experience of using Edarbi® Clo in patients with severe liver dysfunction, so it is not recommended for this category of patients (see section “Contraindications”). Due to limited experience of use, caution should be exercised when using Edarbi® Clo in patients with mild to moderate hepatic impairment (less than 9 points on the Child-Pugh score) since even small electrolyte and water imbalances while taking diuretics can provoke hepatic coma. It is recommended to actively monitor these patients.

Primary Hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to therapy with antihypertensive agents that affect the RAAS. Therefore, Edarbi® Clo is not recommended for administration in these patients.

Hypokalemia

Hypokalemia may occur during therapy with chlorthalidone. Serum potassium levels should be monitored regularly. In patients taking cardiac glycosides, hypokalemia may predispose to arrhythmias.

Aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy

Patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy should use caution when prescribing Edarbi® Clo.

Lithium

As with other ARA II drugs, concomitant use of lithium and Edarbi®Klo is not recommended.

Impact on driving and operating machinery

Cautiousness should be exercised when driving vehicles and operating machinery requiring increased attention and responsiveness because there is a risk of dizziness and increased fatigue when using the drug.

Features

Azilsartan medoxomil

Intake

After oral administration, the Cmax of azilsartan in plasma is reached on average within 3 h.

The pharmacokinetic parameters (Tmax, Cmax, AUC value) of azilsartan are similar with and without chlorthalidone.

Distribution

The Vd of azilsartan is about 16 liters. Azilsartan binds to plasma proteins (more than 99%), predominantly to albumin.

Metabolism

Asilsartan is metabolized to two primary metabolites mainly in the liver. The primary metabolite in blood plasma is formed by O-dealkylation and is designated as metabolite M-II; the secondary metabolite is formed by decarboxylation and is designated as metabolite M-I. The AUC values for these metabolites in humans are 50% and less than 1%, respectively, compared with azilsartan. The main enzyme involved in the metabolism of azilsartan is the CYP2C9 isoenzyme.

Contraindications

Side effects

Definition of the frequency of adverse reactions according to WHO recommendations: Very common (>1/10); common (>1/100, <1/10); infrequent (>1/1000, <1/100; rare (>1/10 000, <1/1000); very rare (<1/10 000), including individual reports; unspecified frequency (frequency cannot be calculated from available data).

The combination of azilsartan medoxomil and chlorthalidone

Overdose

Azilsartan medoxomil (monotherapy)

Experience with azilsartan medoxomil in adults at doses up to 320 mg/day for 7 days shows that the drug is well tolerated.

Symptoms: marked decrease in BP, dizziness.

Treatment: if BP significantly decreases, the patient should be transferred to a horizontal position with a low headrest; measures to increase the blood pressure and symptomatic therapy are recommended. Azilsartan is not excreted from systemic blood flow by dialysis.

Chlorthalidone (monotherapy)

Symptoms: nausea, weakness, dizziness, water-electrolyte imbalance.

Treatment: there is no specific antidote. In marked BP decrease the stomach should be flushed; it is recommended to carry out measures to normalize the water-electrolyte balance (infusion therapy); symptomatic therapy.