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Edarbyclor® [azilsartan medoxomil/chlorthalidone]

Brand Takeda GmbH

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Available since: 2019-09-19

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Clinical Pharmacology

Edarby^® Clo is a combination drug that consists of an angiotensin II receptor antagonist (ARAII - azilsartan medoxomil) and a thiazide-like diuretic (chlorthalidone). The simultaneous use of two active substances leads to a more pronounced decrease in blood pressure compared with that when taking each of them in monotherapy. When taking the drug once a day, an effective decrease in blood pressure is achieved within 24 hours.

Azilsartan medoxomil - one of the active ingredients of the drug Edarbi^® Clo - is a specific antagonist of angiotensin II type 1 receptors (AT₁). Angiotensin II is formed from angiotensin I in a reaction catalyzed by 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, increased heart rate and reabsorption of sodium by the kidneys. Azilsartan medoxomil is a prodrug for oral administration. Azilsartan medoxomil quickly turns into an active azilsartan molecule, which selectively prevents the development of the effects of angiotensin II by blocking its binding to the AT receptors₁ in various tissues, such as vascular smooth muscle and adrenal glands. Therefore, its action is not related to the biosynthesis of angiotensin II.

AT receptor₂ It is also found in many tissues, but it does not participate in the regulation of CVS activity. The affinity of azylsartan to the receptor AT₁ 10,000 times higher than the AT receptor₂.

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 inhibit 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 CAS, 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; clinically significant effect on the content of potassium or sodium in serum was not detected. In general, the pharmacodynamic properties of azilsartan medoxomil are consistent with blocking the AT receptor₁.

The antihypertensive effect of azilsartan medoxomil develops during the first 2 weeks of use, with a maximum therapeutic effect being achieved after 4 weeks. Reduction 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 increasing 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 orally and persists 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 of 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 blood pressure control.

In a double-blind study with a planned dose increase of 12 weeks, the combination of azilsartan medoxomil + chlorthalidone at a dose of 40 + 25 mg was statistically significantly superior to the combination of olmesartan medoxomil + hydrochlorothiazide 40 + 25 mg in reducing sAD in patients with moderate to 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).

Indications

Essential hypertension (patients for whom combination therapy is indicated).

Composition

Excipients: mannitol - 211.23 mg, microcrystalline cellulose - 54 mg, fumaric acid - 2 mg, sodium hydroxide - 0.69 mg, hyprolosis - 10.8 mg, crospovidone - 22.5 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 marking trace amounts *.

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Dosage and Administration

Orally, 1 time per day, regardless of meal times.

The recommended initial dose of the drug Edarbi^® Clo is 40 mg of azilsartan medoxomil + 12.5 mg of chlorthalidone 1 time per day. If necessary, further reduction of blood pressure dose of the drug Edarbi^®Clo can be increased to a maximum of 40 mg of azilsartan medoxomil + 25 mg of chlorthalidone 1 time per day.

Duration of treatment. Drug edarbi^® Clos should be taken daily, without interruption. In case of discontinuation of treatment, the patient should inform the doctor.

Special patient groups

Elderly patients (65 years and older). Correction of the initial dose of the drug Edarbi is not required.^®Clos in elderly patients.

Impaired renal function. No clinical experience with the drug Edarbi^® Clos in patients with arterial hypertension (AH) with severe renal impairment (Cl creatinine less than 30 ml / min), therefore, it is not recommended to use the drug in this category of patients (see "Contraindications"). Correction of the dosing regimen is not required in patients with impaired mild to moderate renal function (Cl creatinine more than 30 ml / min).

Liver dysfunction. The use of the drug in patients with severe hepatic impairment is not recommended due to the lack of clinical experience (see "Contraindications"). Due to limited experience, Edarbi should be used with caution.^® Klau in patients with impaired liver function of mild and moderate degree (less than 9 points on the Child-Pugh scale), since even small violations of water and electrolyte balance when taking diuretics can provoke hepatic coma. It is recommended to actively monitor the condition of such patients.

Reduced bcc. It is necessary to compensate for the loss of fluid and electrolytes in patients with reduced BCC before starting the use of Edarbi^® Clos (see "Special Instructions").

Heart failure. Due to the lack of clinical experience, Edarbi should be used with caution.^® Clo in hypertensive patients with severe CHF (functional class IV by NYHA classification).

Skip dose

In case of skipping the next dose, the next dose should be taken at the usual time. Do not take a double dose of Edarbi^® Clos. Withdrawal syndrome (a sharp increase in blood pressure) after a sudden cancellation after prolonged therapy (for 6 months) azilsartan medoxomil was not observed. However, the abolition of the drug Edarbi^® Clos after prolonged treatment should be carried out as gradually as possible.

Adverse reactions

Combination of azilsartan medoxomil and chlorthalidone

From the side of blood and lymphatic system: infrequently - anemia.

On the part of the nervous system: often - dizziness, postural dizziness; infrequently - syncope, paresthesia.

On the part of the vessels: often - a pronounced decrease in blood pressure.

On the part of the digestive tract: often - diarrhea, nausea; infrequently - vomiting.

On the part of the skin and subcutaneous tissues: infrequently - skin rash, itching; rarely - angioedema.

From the musculoskeletal and connective tissue: infrequently - muscle spasms.

Metabolism and nutrition: often - hyperuricemia; infrequently - hypokalemia, increased potassium levels, hyponatremia, exacerbation of the course of gout.

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

General disorders: often - fatigue, peripheral edema.

Azilsartan medoxomil (monotherapy)

On the part of the nervous system: often - dizziness; infrequently - headache.

On the part of the vessels: infrequently - a pronounced decrease in blood pressure.

On the part of the digestive tract: often - diarrhea; infrequently - nausea.

On the part of the skin and subcutaneous tissues: infrequently - skin rash, itching; rarely - angioedema.

From the musculoskeletal and connective tissue: infrequently - muscle spasms.

Impact on the results of laboratory and instrumental studies: often - increased activity of CPFC; infrequently - an increase in the concentration of creatinine, hyperuricemia.

General disorders: infrequently - increased fatigue, peripheral edema.

Chlorthalidone (monotherapy)

From the nervous system: rarely - a headache.

Cardiac: rarely - arrhythmia.

On the part of the vessels: often - a pronounced decrease in blood pressure.

On the part of the digestive system: often - loss of appetite, gastrointestinal disorders; rarely - constipation, abdominal pain; very rarely - pancreatitis.

On the part of the skin and subcutaneous tissues: often - urticaria; rarely photosensitivity, cutaneous vasculitis.

On the part of the respiratory system, chest organs and mediastinum: rarely - allergic pulmonary edema.

On the part of the liver and biliary tract: rarely - intrahepatic cholestasis or jaundice.

On the part of the kidneys and urinary tract: rarely - allergic interstitial nephritis.

On the part of the blood and lymphatic system: rarely - thrombocytopenia, leukopenia, agranulocytosis, eosinophilia.

Metabolism and nutrition: very often - hyperlipidemia, hypokalemia; often - hypomagnesemia; rarely - hypercalcemia, glycosuria, decompensation of existing diabetes; very rarely - hypochloremic alkalosis.

General disorders: often - reduced potency.

Description of individual adverse reactions

With simultaneous use of azilsartan medoxomil with chlorthalidone, the frequency of adverse reactions - a pronounced decrease in blood pressure and an increase in the concentration of creatinine - increases in frequency of occurrence: from infrequent 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 when using the drug Edarbi^® Clos is due to its chlorthalidone 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 side effects indicated in the instructions are aggravated or the patient has noticed any other side effects that are not indicated in the instructions, you should inform your doctor.

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 (glomerular filtration rate less than 60 ml / min / 1.73 m²);
severe diabetes;
severe liver function abnormalities (more than 9 points on the Child-Pugh scale) (no experience of use);
renal failure severe (Cl creatinine less than 30 ml / min) (no experience with the application);
pregnancy and breastfeeding period (see “Use during pregnancy and lactation);
age up to 18 years (efficacy and safety have not been established).
With care: severe chronic heart failure (NYHA class IV functional class); impaired renal function (Cl creatinine more than 30 ml / min); hepatic impairment of mild and moderate degree (5–9 points on the Child-Pugh scale); bilateral renal artery stenosis and arterial stenosis of a single functioning kidney; ischemic cardiomyopathy; ischemic cerebrovascular diseases; condition after kidney transplantation; conditions accompanied by a decrease in the bcc (includingvomiting, diarrhea, taking high doses of diuretics), as well as a diet with salt restriction; primary hyper aldosteronism; hyperuricemia and gout; bronchial asthma; systemic lupus erythematosus; stenosis of the aortic and mitral valve; hypertrophic obstructive cardiomyopathy (GOKMP); age over 75 years; hypokalemia. If a patient has one of the listed diseases, before taking Edarbi^® Clo should be consulted with a doctor.

Drug interactions

Lithium. A reversible increase in the concentration of lithium in the serum and a manifestation of toxicity during the simultaneous use of lithium preparations and diuretics and lithium preparations with ARAII were noted. Therefore, the simultaneous use of the drug Edarbi^® Clo in combination with lithium preparations is not recommended (see “Special Instructions”). If necessary, the use of appropriate combination therapy is recommended to regularly monitor the concentration of lithium in the serum.

NSAIDs, including selective COX-2 inhibitors. In elderly patients and patients with reduced BCC (including receiving diuretics) or with impaired renal function, the simultaneous use of APAII and NSAIDs can lead to a deterioration in 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 simultaneous use of APAII and NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid (more than 3 g / day) and non-selective NSAIDs, the antihypertensive effect may be reduced.

Double blockade of RAAS. Double blockade of RAAS 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.

Cardiac glycosides. The simultaneous use of cardiac glycosides and a diuretic may aggravate the effects of hypokalemia, such as cardiac arrhythmias.

Additional Information on Azilsartan Medoxomil Interaction

No PCF was observed with simultaneous use of azilsartan medoxomil or azilsartan with amlodipine, antacid preparations (aluminum and magnesium hydroxide), chlorthalidone, digoxin, fluconazole, glibenclamide, ketoconazole, metformin and warfarin.

Azilsartan medoxomil is converted to the pharmacologically active metabolite azylsartan during absorption from the gastrointestinal tract under the action of the enzyme carboxymethylene butenolidase in the intestine and liver. Research in vitro showed that interactions based on enzyme inhibition are unlikely.

Additional Information on Chlorthalidone Interaction

Chlorthalidone enhances the action of curare-like muscle relaxants and antihypertensive drugs (including guanethidine, methyldopa, beta-blockers, vasodilating agents, BPC), 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 adverse reactions caused by amantadine.

Anticholinergic drugs (for example, atropine, biperiden) can increase the bioavailability of chlorthalidone, reducing the motility of the gastrointestinal tract and the evacuation of stomach contents.

The hypokalemic effect of chlortalidone is enhanced when used simultaneously with corticosteroids, ACTH, amphotericinin, beta₂-adrenoblockers, carbenoxolone. Patients during combination therapy should monitor the content of potassium in the serum.

Correction (decrease or increase) in the dose of hypoglycemic agents for oral administration and insulin may be required.

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.

Pregnancy and Lactation

Experience with the use of the drug^® Clos in pregnant women is absent. Taking the drug during pregnancy and during breastfeeding is not recommended.

Newborns whose mothers received azilsartan medoxomil therapy may develop hypotension, and therefore newborns should 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 should stop taking the drug Edarbi^® Clo and, if necessary, switch to the use of drugs with proven safety of use during pregnancy.

There is no information regarding a person about the ability of azilsartan and / or its metabolites to penetrate into breast milk. In animal studies, it has been revealed that azilsartan and its metabolite MII are excreted into the milk of lactating rats. Chlorthalidone penetrates the placental barrier and is detected in umbilical cord blood, fetal blood and breast milk. If necessary, use the drug Edarbi^® Clos during lactation must stop breastfeeding or taking the drug. Preferably the use of drugs with a proven safety profile.

Special instructions

Arterial hypotension on the background of impaired water and electrolyte balance

In patients with reduced BCC and / or hyponatremia (as a result of vomiting, diarrhea, taking large doses of diuretics or following a diet with restricted salt intake), clinically significant hypotension may develop after starting treatment with Edarbi^® Clos. 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 (Cl creatinine 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 a progressive deterioration in renal function (an increase in blood urea nitrogen, it is recommended to temporarily discontinue diuretic therapy or cancel them completely.

Double blockade of RAAS

Patients whose vascular tone and kidney function depend to a large extent on the activity of the RAAS (for example, patients with severe CHF - IV functional class by classification NYHA, severe renal failure or renal artery stenosis), treatment of drugs acting on the RAAS, such as ACE inhibitors and APAII, is associated with the possibility of developing acute arterial hypotension, azotemia, oliguria, or rarely acute renal failure. The possibility of the development of these effects can not be excluded when using the drug Edarbi^® Clos.

A sharp decrease in blood pressure in patients with ischemic cardiomyopathy or ischemic cerebrovascular diseases can lead to the development of myocardial infarction or stroke.

Kidney transplantation

Data on the use of the drug Edarbi^® Clos in patients who recently underwent kidney transplantation are absent.

Liver dysfunction

Data on the clinical experience of the drug Edarbi^® Klo in patients with severely impaired liver function are absent, therefore, the use of the drug in this category of patients is not recommended (see "Contraindications"). Due to limited experience, Edarbi should be used with caution.^® Klau in patients with impaired liver function of mild and moderate degree (less than 9 points on the Child-Pugh scale), since even small violations of water and electrolyte balance when taking diuretics can provoke hepatic coma. It is recommended to actively monitor the condition of such patients.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to treatment with antihypertensive drugs that affect the RAAS. In this regard, the drug Edarbi^® Clo is not recommended to appoint such patients.

Hypokalemia

When therapy with 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.

Stenosis of the aortic or mitral valve, GOKMP

When prescribing the drug Edarbi^® Care must be exercised in patients with aortic or mitral stenosis or GOKMP.

Lithium

As in the case of other APAII, the simultaneous use of lithium and Edarbi preparations is not recommended.^® Clos.

Influence on ability to steer vehicles and work with mechanisms. Care must be taken when driving and working with mechanisms that require increased attention and responsiveness - the risk of dizziness and fatigue.

Overdosage

Azilsartan medoxomil (monotherapy)

The experience with 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 pronounced decrease in blood pressure to give the patient a prone position, lift the legs, to carry out measures to increase the BCC; 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 pronounced decrease in blood pressure, flush the stomach, take measures to normalize water and electrolyte balance (infusion therapy); symptomatic therapy.