Edarbi Clo, 40 mg+12, 5 mg 28 pcs

Edarbi® Clo is a combination drug consisting of an angiotensin II receptor antagonist (ARAII – azilsartan medoxomil) and a thiazide-like diuretic (chlorthalidone). Simultaneous use of the two active agents leads to a more pronounced BP reduction compared to that of each of them in monotherapy. When administered once daily, effective BP lowering is achieved within 24 hours.

Asilsartan medoxomil, one of the active ingredients in Edarbi® Clo, is a specific angiotensin II type 1 (AT1) receptor antagonist. Angiotensin II is formed from angiotensin I in a reaction catalyzed by ACE (kininase II). Angiotensin II is the main vasoconstrictor of the RAAS and its effects include vasoconstriction, stimulation of aldosterone synthesis and secretion, increased HR, and renal sodium reabsorption. Azilsartan medoxomil is an oral prodrug. Azilsartan medoxomil is rapidly converted to the active molecule azilsartan, which selectively inhibits the effects of angiotensin II by blocking its binding to AT1 receptors 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 CPS activity. The affinity of azilsartan for the AT1 receptor is 10,000 times higher 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 blocking the AT1 receptor.

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 a few hours and persists for 24 hours.

Chlorthalidone, a thiazide-like diuretic, 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 initiation of therapy.

In the 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, 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 + 25-mg combination of azilsartan medoxomil + chlorthalidone was statistically significantly superior to the 40 + 25-mg combination of olmesartan medoxomil + hydrochlorothiazide in reducing BP in moderate to severe arterial hypertension. Similar results were obtained in all patient subgroups, regardless of age, sex, or race. The combination of azilsartan medoxomil + chlorthalidone lowered BP more effectively than the combination of olmesartan medoxomil + hydrochlorothiazide in each hour of the 24-hour interval between doses of the drugs, as measured by CMAD (daily blood pressure monitoring).

Indications

Essential hypertension (patients who are indicated for combination therapy).

Active ingredient

Composition

film-coated tablets
1 tablet

azilsartan medoxomil potassium 42.68 mg, corresponding to azilsartan medoxomil 40 mg

chlorthalidone 12.5 mg

Associates:

Mannitol – 211.23 mg,

microcrystalline cellulose – 54 mg,

fumaric acid – 2 mg,

sodium hydroxide – 0.69 mg,

hyprolose – 10.8 mg,

crospovidone – 22.5 mg,

magnesium stearate – 3.6 mg.

Composition of the film coating:

Hypromellose 2910 – 7.8 mg, talc – 1.2 mg, titanium dioxide – 0.99 mg, iron oxide red dye – 0.01 mg, macrogol 8000 – 0.18 mg, ink gray F1 purified for labeling trace amounts*.

How to take, the dosage

Ingestion, 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®Klo may be increased to maximum 40 mg of azilsartan medoxomil + 25 mg of chlorthalidone once daily.

The duration of the treatment course. Edarbi® Clo should be taken daily without interruption. If treatment is discontinued, the patient must inform the physician.

Patient special groups

Patients of advanced age (65 years and older). No adjustment of the starting dose of Edarbi®Clo in elderly patients is required.

People with impaired renal function. There is no clinical experience of using Edarbi® Clo in patients with severe arterial hypertension (AH) with impaired renal function (creatinine Cl less than 30 ml/min), therefore it is not recommended to use the drug in this category of patients (see “Contraindications”). There is no need to correct the dosage regimen in patients with mild to moderate renal dysfunction (creatinine Cl over 30 ml/min).

Hepatic impairment. It is not recommended to use the drug in patients with severe hepatic dysfunction due to the lack of clinical experience of use (see “Contraindications”). Due to limited experience of use, Edarbi® Clo should be used with caution in patients with mild to moderate hepatic dysfunction (less than 9 points by Child-Pugh score), because even small electrolyte-water balance disorders when taking diuretics can provoke hepatic coma. It is recommended to actively monitor these patients.

CPU decrease. Fluid and electrolyte losses should be replenished in patients with decreased blood circulatory capacity before starting the use of Edarbi® Clo (see “Special Precautions”).

Heart failure. Because of lack of clinical experience the use of Edarbi® Clo in patients with AH with severe chronic heart failure (functional class IV according to NYHA classification) should be used with caution.

Negroid race. No dose adjustment is required since the antihypertensive effect of Edarbi® Clo in patients of Negro race is similar to that in patients of other races.

Dose skipping

If a dose is missed, the patient should take the next dose at the usual time. Do not take a double dose of Edarbi® Clo. Withdrawal syndrome (rapid increase in BP) following abrupt withdrawal after long-term therapy (for 6 months) with azilsartan medoxomil has not been observed. Nevertheless, withdrawal of Edarbi® Clo after long-term therapy should be done gradually if possible.

Interaction

Lithium. Reversible increase of lithium concentration in blood serum and manifestation of toxicity during concomitant use of lithium preparations and diuretics and lithium preparations with APAII have been noted. Therefore, concomitant use of Edarbi® Clo in combination with lithium preparations is not recommended (see “Cautionary Note”). If it is necessary to use appropriate combination therapy, regular monitoring of lithium concentration in blood serum is recommended.

NSAIDs, including selective COX-2 inhibitors. In elderly patients and patients with decreased blood circulation (including those receiving diuretics) or with impaired renal function, concomitant use of APAII and NSAIDs may lead to worsening of renal function up to 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 APAII and NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid (more than 3 g/day) and non-selective NSAIDs may decrease antihypertensive effect.

Double blockade of the RAAS. Dual RAAS blockade with APAII, ACE inhibitors, or aliskiren is associated with an increased risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) compared with monotherapy.

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

Further information on azilsartan medoxomil interactions

No FKV 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 hypotensive agents (including guanethidine, methyldopa, beta-adrenoblockers, vasodilators, BKK), MAO inhibitors.

The concomitant use of chlorthalidone with allopurinol may lead to an increased 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 effect of chlorthalidone is enhanced with concomitant use with corticosteroids, ACTH, amphotericin, beta2-adrenoblockers, and carbenoxolone. Serum potassium should be monitored in patients during combined 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 hyponatremia (as a result of vomiting, diarrhea, taking high doses of diuretics or dietary restriction of table salt) may develop clinically significant arterial hypotension after starting therapy with Edarbi® Clo. Hypovolemia and water-electrolyte balance should be corrected before treatment start. 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 (creatinine Cl 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), temporary discontinuation of diuretic therapy or complete withdrawal is recommended.

Double blockade of the RAAS

. In patients whose vascular tone and renal function strongly depend on the activity of RAAS (for example, patients with severe chronic heart failure – functional class IV according to NYHA classification, severe degree of renal failure or renal artery stenosis), treatment with drugs acting on RAAS, such as ACE inhibitors and ARAII, is connected with possibility of acute arterial hypotension, azotemia, oliguria or rarely – acute renal failure. The possibility of these effects cannot be excluded with the use of Edarbi® Clo.

A dramatic 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 undergone a kidney transplant.

There are no data on clinical experience with Edarbi® Clo in patients with severe hepatic impairment, so it is not recommended for this category of patients (see “Contraindications”). Due to limited experience, Edarbi® Clo should be used with caution in patients with mild to moderate hepatic impairment (less than 9 points on the Child-Pugh scale), since even small electrolyte-water balance disorders when taking diuretics may provoke hepatic coma. It is recommended to actively monitor these patients.

Primary Hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to therapy with hypotensive drugs that affect the RAAS. Therefore, the drug Edarbi® Clo is not recommended to be administered to these patients.

Hypokalemia

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

Aortic or mitral valve stenosis, GOCMP

Patients with aortic or mitral stenosis or GOCMP should use caution when prescribing Edarbi® Clo.

Lithium

As with other ARAIIs, concomitant use of lithium and Edarbi® Clo is not recommended.

Impact on the ability to drive vehicles and operate machinery. Caution should be exercised when driving vehicles and operating machinery requiring increased attention and responsiveness – risk of dizziness and increased fatigue.

Contraindications

Side effects

Combination of azilsartan medoxomil and chlorthalidone

Blood and lymphatic system disorders: infrequent – anemia.

Nervous system disorders: frequently – dizziness, postural dizziness; infrequently – syncope, paresthesia.

vascular disorders: often – marked decrease of BP.

Gastrointestinal disorders: frequently – diarrhea, nausea; infrequently – vomiting.

Skin and subcutaneous tissue: infrequent – skin rash, itching; rarely – angioedema.

Skeletal, muscular and connective tissue: infrequent – muscle cramps.

Mechanism and nutrition: often – hyperuricemia; infrequent – hypokalemia, potassium increase, hyponatremia, aggravation of gout.

Impact on the results of laboratory and instrumental studies: very often – increase in creatinine concentration; often – increase in urea concentration; infrequent – increase in glucose concentration.

General disorders: frequently – fatigue, peripheral edema.

Asilsartan medoxomil (monotherapy)

Nervous system disorders: frequent – dizziness; infrequent – headache.

vascular disorders: infrequent – marked decrease in BP.

Gastrointestinal disorders: frequently – diarrhea; infrequently – nausea.

Skin and subcutaneous tissue: infrequent – skin rash, itching; rarely – angioedema.

Skeletal, muscular and connective tissue: infrequent – muscle cramps.

Impact on the results of laboratory and instrumental studies: often – increase of CPK activity; infrequent – increase of creatinine concentration, hyperuricemia.

General disorders: infrequent – fatigue, peripheral edema.

Chlorthalidone (monotherapy)

Nervous system disorders: rarely – headache.

Heart: rarely – arrhythmia.

Vascular disorders: often – marked decrease in BP.

The digestive system: often – loss of appetite, gastrointestinal disorders; rarely – constipation, abdominal pain; very rarely – pancreatitis.

Skin and subcutaneous tissue: often – urticaria; rarely – photosensitization, cutaneous vasculitis.

Respiratory system, thoracic and mediastinal organs: rarely – allergic pulmonary edema.

Hepatic and biliary tract disorders: rarely – intrahepatic cholestasis or jaundice.

Renal and urinary tract: rarely – allergic interstitial nephritis.

Blood and lymphatic system disorders: rare – thrombocytopenia, leukopenia, agranulocytosis, eosinophilia.

As to metabolism and nutrition: very often – hyperlipidemia, hypokalemia; often – hypomagnesemia; rarely – hypercalcemia, glucosuria, decompensation of diabetes mellitus; very rarely – hypochloremic alkalosis.

General disorders: often – decreased potency.

Description of individual adverse reactions

When azilsartan medoxomil is used concomitantly with chlorthalidone, the frequency of adverse reactions – marked decrease in BP and increase in creatinine concentration – increases in frequency of occurrence: from infrequent to frequent. This is associated with a more effective BP reduction compared with azilsartan medoxomil monotherapy. Most of these effects were transient or nonprogressive as long as patients continued therapy. After drug withdrawal, most of the increases in creatinine concentrations that did not go away during treatment were reversible.

The increase in uric acid concentration when using Edarbi® Clo is due to its constituent chlorthalidone and depends on the dose of the diuretic. Reports about the development of gout have been infrequent, even with long-term therapy.

The incidence of adverse reactions such as hypokalemia is reduced when azilsartan medoxomil is used concomitantly with chlorthalidone.

If any of the side effects listed in the instructions worsen or if the patient notices any other side effects not listed in the instructions, you should inform your physician.

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 is markedly decreased, put the patient in a supine position, elevate the legs, conduct measures to increase the blood pressure; symptomatic therapy. Azilsartan is not eliminated 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, measures to normalize the water-electrolyte balance should be taken (infusion therapy); symptomatic therapy.