Edarby Clos - instructions for use, doses, side effects, contraindications

Active substanceAzilsartan medoxomil + ChlortalidoneAzilsartan medoxomil + Chlortalidone

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Dosage form: & nbspfilm coated tablets

Composition:

1 tablet with a dosage of 40 mg + 12.5 mg contains:

Active substance: azilpsartan medoxomil potassium 42.68 mg corresponds to azilsartan medoxomil 40 mg; chlorthalidone 12.5 mg;

Excipients: mannitol 21 1.23 mg, microcrystalline cellulose 54 mg, fumaric acid 2 mg, sodium hydroxide 0.69 mg, giprolose 10.8 mg, crospovidone 22.5 mg, magnesium stearate 3.6 mg.

Film Sheath: 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 amounts¹.

1 tablet with a dosage of 40 mg + 25 mg contains:

Active substance: azilpsartan medoxomil potassium 42.68 mg corresponds to azilsartan medoxomil 40 mg; chlorthalidone 25 mg;

Excipients: mannitol 198.73 mg, microcrystalline cellulose 54 mg, fumaric acid 2 mg, sodium hydroxide 0.69 mg, giprolose 10.8 mg, crospovidone 22.5 mg, magnesium stearate 3.6 mg.

Film Sheath: hypromellose 2910 7.8 mg, talc 1.2 mg, titanium dioxide 0.94 mg, iron dye oxide red 0.06 mg, macrogol 8000 0.18 mg, gray ink F1 purified for marking trace amounts¹.

¹ Inks gray F1 purified for labeling contain: shellac 26%, iron dye oxide black 10%, butyl alcohol 38%, ethanol 26%.

Description:

Tablets 40 mg +12.5 mg:

Round biconvex tablets coated with a film coating of pale pink color with inscriptions "D / C" and "40 / 12.5" on one side with gray ink.

Tablets 40 mg +25 mg:

Round biconvex tablets coated with a film coat of grayish-pink color with inscriptions "D / C" and "40/25" on one side with gray ink.

Pharmacotherapeutic group:A combined hypotensive drug (angiotensin II receptor antagonist + diuretic)

ATX: & nbsp

C.09.D.A.09 Azilsartan medoxomil and diuretics

Pharmacodynamics:

Edarby® Clos is a combination drug that contains an antagonist receptors of angiotensin II (azilsartan medoxomil) and a thiazide-like diuretic (chlorthalidone). Simultaneous application of the two active substances leads to a more pronounced decrease in blood pressure (BP), compared with the reception of each of them in monotherapy. When taking the drug once a day, an effective BP reduction is achieved within 24 hours.

Azilsartan medoxomil - one of the active substances of the drug Edarby ® Clo - is a specific antagonist of angiotensin II type 1 (AT 1) receptors. Angiotensin II is formed from angiotensin 1 in a reaction catalyzed by an angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the main vasoconstrictor of RAAS (renin-angiotensin-aldosterone system), its action includes vasoconstriction, stimulation of synthesis and secretion of aldosterone, increased heart rate (HR) and sodium reabsorption in nights.

Azolsartan medoxomil is a prodrug for oral administration. Azilsartan medoxomil quickly turns into an active molecule of azilsartan, which selectively prevents the development of the effects of angiotensin II by blocking its binding to receptors AT1 in various tissues, for example, in smooth muscles of blood vessels and adrenal glands. Therefore, its effect is not related to the pathway of biosynthesis of angiotensin II.

The AT2 receptor is also found in many tissues, but it does not participate in the regulation of the cardiovascular system. Affinity of azilsartan to the receptor AT1 is 10,000 times higher than to 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 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, which play an important role in the regulation of the cardiovascular system, and does not block them.

Azilsartan dose-dependently suppresses the vasoconstrictive effects of angiotensin II infusion. A single dose of azilsartan in a dose equivalent to 32 mg of azilsartan medoxomil suppressed the maximum vasoconstrictive effect of angiotensin II by approximately 90% at the time of greatest concentration, and approximately 60% at 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 aldosterone concentration decreased after a single oral intake and after repeated doses of azilsartan medoxomil; there was no clinically significant effect on the potassium or sodium content in the blood serum. In general, the pharmacodynamic properties of azilsartan medoxomil are consistent with the blocking of the AT1 receptor.

The antihypertensive effect of azilsartan medoxomil develops during the first 2 weeks of use with the maximum therapeutic effect achieved after 4 weeks. Reduction of blood pressure after ingestion of a single dose is usually achieved within a few hours and persists for 24 hours.

Chlorthalidone - thiazide-like diuretic - suppresses the active reabsorption of sodium ions in the renal tubules (the initial part of the distal convoluted tubule of the nephron), increasing the excretion of sodium and chlorine ions and enhancing diuresis. Besides, chlorthalidone increases the excretion of potassium, magnesium and bicarbonate, delays calcium ions and uric acid. The anti-hypertensive effect of chlorthalidone is associated with the removal of liquid and sodium from the body. Diuretic effect develops 2-3 hours after chlorthalidone intake and remains for 2-3 days.

The antihypertensive effect of chlorthalidone develops gradually with the achievement of maximum therapeutic effect in 2-4 weeks after the initiation of therapy.

In clinical trials, the combination of azilsartan medoxomil / chlorthalidone was more effective,than a combination of azilsartan medoxomil with hydrochlorothiazide or a combination of olmesartan medoxomil / hydrochlorothiazide, although a higher proportion of participants in the comparison group required an increase in dose due to insufficient control of blood pressure (BP).

In a double-blind study with a planned dose increase of 12 weeks, the combination of azilsartan medoxomil / chlorthalidone at a dose of 40 mg / 25 mg statistically significantly exceeded the combination of olmesartan medoxomil / hydrochlorothiazide 40 mg / 25 mg in reducing systolic blood pressure with moderate and severe degree of hypertension. Similar results were obtained in all subgroups of patients, regardless of age, gender or race. The combination of azilsartan medoxomil / chlorthalidone lowered blood pressure more efficiently than the combination of olmesartan medoxomil / hydrochlorothiazide at each hour of the 24-hour interval between doses of the drugs, according to the BPM (24-hour blood pressure monitoring).

Pharmacokinetics:

Suction

Azilsartan medoxomil

After taking the drug inside the maximum concentration (C_max) of azilsartan in blood plasma is achieved on average within 3 hours. The half-life (T_1/2) of azilsartan is about 12 hours.

Pharmacokinetic parameters (time to reach the maximum concentration (TC_max), FROM_max, value AUC (the areas under the pharmacokinetic curve "concentration-time") of azilsartan are similar both when it is taken together with chlorthalidone and without it.

Chlorthalidone

After taking the drug inside chlorthalidone It is absorbed from the gastrointestinal tract by 60%. FROM_m_Oh Chlorthalidone in blood plasma is achieved on average within 12 hours. T_1/2Chlorthalidone is about 45 h.

Value AUC Chlortalidone is similar to both with its joint administration with azilsartan medoxomil, and without it. However, C_max47% higher with his joint admission with azilsartan medoxomil in the preparation Edarbio Clos.

The ingestion of food does not have a clinically significant effect on the bioavailability of the Edarb® Clos.

Distribution

Azilsartan medoxomil

The volume of distribution of azilsartan is about 16 liters. Azilsartan binds to blood plasma proteins (more than 99%), mainly with albumens of blood plasma.

Chlorthalidone

In whole blood chlorthalidone is mainly associated with the erythrocyte carbonic anhydrase. In blood plasma, approximately 75% of chlorthalidone is associated with blood plasma proteins, with 58 % - from albumin.

Metabolism

Azilsartan medoxomil

Azilsartan is metabolized to two primary metabolites, mainly in the liver. The main metabolite in the blood plasma is formed by O-dealkylation and is designated as a metabolite of M-II, a secondary metabolite is formed by decarboxylation and is referred to as metabolite M-I. Values AUC for these metabolites in humans is correspondingly 50% and less than 1% compared to azilsartan. The main enzyme that provides the metabolism of azilsartan is isoenzyme CYP2C9.

Chlorthalidone

Chlortalidone is mainly excreted unchanged. There are no data on the comparative amounts of chlorthalidone, which is excreted unchanged and in the form of metabolites.

Excretion

Azilsartan medoxomil

Azilsartan and its metabolites are excreted from the body, both through the intestine, and by the kidneys. Studies have shown that after ingestion of azilsartan medoxomil, about 55% (mainly in the form of the metabolite M-I) is found in feces and about 42% (15% - in the form of azilsartan, 19% - in the form of metabolite M-II) - in the urine.

Chlorthalidone

Chlortalidone is mainly excreted by the kidneys unchanged. T_1/2Chlorotalidone is 40-50 hours. Being a thiazide-like diuretic, chlorthalidone excreted in breast milk.

Pharmacokinetics in special groups

Elderly patients

Azilsartan medoxomil

The pharmacokinetics of azilsartan in young (18-45 years) and elderly (65-85 years) patients is not significantly different.

Chlorthalidone

Chlorthalidone in elderly patients is excreted more slowly than in young patients, which, presumably, is associated with age-related changes in kidney function and leads to an increase in T_1/2. Reduction of elimination is not clinically significant.

Renal insufficiency

Azilsartan medoxomil

In patients with mild, moderate and severe degree of renal failure AUC was increased by + 30%, + 25% and + 95% respectively. Increases (+ 5%) AUC in patients with terminal stage of renal failure, on hemodialysis, ns was observed. Clinical data on pharmacokinetics in patients with severe degree or terminal stage of renal failure are absent.

Azilsartan is not excreted from the systemic blood flow through hemodialysis. Chlorthalidone

Possible accumulation of chlorthalidone.

Liver failure

Azilsartan medoxomil

The use of azilsartan medoxomil for more than 5 days in patients with mild (less than 5 on the Child-Pugh score) or an average (less than 9 on the Child-Pugh scale) severity of liver failure leads to a slight increase AUC (in 1.3 - 1.6 times, respectively). The pharmacokinetics of azilsartan in patients with severe (more than 9 on the Child-Pugh scale) degree of hepatic insufficiency has not been studied.

Chlorthalidone

Data on the pharmacokinetics of meth.

Gender identity

Azilsartan medoxomil

The pharmacokinetics of azilsartan in men and women is not significantly different. Correction of dose depending on sex is not required.

Chlorthalidone

There are no data on pharmacokinetics.

Race

Azilsartan medoxomil

The pharmacokinetics of azilsartan, depending on the race of the patients, is not significantly different. Correction of dose depending on race is not required.

Chlorthalidone

There are no data on pharmacokinetics.

Indications:

Essential hypertension (patients who are shown combined therapy).

Contraindications:

- hypersensitivity to active substances and other components of the drug;

- refractory hypokalemia;

- anuria;

- pregnancy and the period of breastfeeding (see section Application in pregnancy and during breastfeeding);

- simultaneous administration of aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or moderate or severe renal dysfunction (glomerular filtration rate less than 60 ml / min / 1.73 m²);

- severe forms of diabetes mellitus;

- age under 18 years (effectiveness and safety not established);

- violations of liver function severe (more than 9 points on the scale Child-Pugh) (no experience of use).

- renal failure of severe degree (creatinine clearance (CK) less than 30 ml / min) (no experience of use)

Carefully:

- severe chronic heart failure (IV functional class by classification NYHA);

- impaired renal function (QC more than 30 ml / min);

- impaired liver function of mild to moderate degree (5-9 points on the Child-Pugh scale);

- bilateral stenosis of the renal arteries and stenosis of the artery of a single functioning kidney;

- ischemic cardiomyopathy;

- ischemic cerebrovascular disease;

- condition after kidney transplantation;

- conditions accompanied by a decrease in the volume of circulating blood (01 (K) (including vomiting, diarrhea, high doses of diuretics), as well as in patients who follow a diet with restriction of table salt;

- primary hyperaldosteronism;

- 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 you have one of the listed diseases, before taking the drug Edarby® Clo necessarily consult with your doctor.

Pregnancy and lactation:

The experience of using the drug Edarb® Clo in pregnant women is absent. Taking the drug during pregnancy and during breastfeeding is not recommended.

Application during pregnancy

In newborns, whose mothers received treatment with azilsartanom medoxomil, can develop arterial hypotension, in connection with which, newborns must be under careful medical supervision.

Chlortalidone penetrates the placental barrier into the umbilical cord blood and can cause jaundice of the fetus or newborn, thrombocytopenia and also other unwanted reactions noted in adults.

Immediately after the pregnancy is confirmed, stop using the Edarb® Clos and, if necessary, switch to the use of drugs with proven safety during pregnancy.

Breast-feeding

There is no information on a person about the ability of azilsartan and / or its metabolites to enter breast milk. In animal studies, it has been found that azilsartan and its metabolite M-II are excreted in the milk of lactating rats. Chlorthalidone penetrates the placental barrier and is detected in the umbilical cord blood, fetal blood and breast milk.

If you need to use the drug Edarby Clos during lactation, you must stop breastfeeding or stop taking the drug. Preferably use drugs with a proven safety profile.

Dosing and Administration:

The drug Edarby® Clos is taken orally once a day regardless of time food intake.

The recommended initial dose of Edarb® Clo is 40 mg of azilsartan medoxomil + 12.5 mg of chlorthalidone once a day.

If it is necessary to further reduce blood pressure, the dose of Edarb® Clos can be increased to a maximum of 40 mg of azilsartan medoxomil plus 25 mg of chlorthalidone once a day.

Duration of treatment

The drug Edarby® Clos should be taken daily, without interruption. In the event of discontinuation of treatment, the patient should inform the physician about this.

Special Groups

Patients of advanced age (65 years and older)

It is not necessary to correct the initial dose of Edarb® Clos in elderly patients.

Patients with impaired renal function

There is no clinical experience with the use of Edarb® Clo in patients with arterial hypertension (AH) with impaired renal function of severe degree (QC less than 30 ml / min), therefore it is not recommended to use the drug in this category of patients (see section Contraindications).

There is no need for correction of the dosing regimen in patients with impaired renal function of mild and moderate severity (QC more than 30 ml / min).

Patients with impaired hepatic function

It is not recommended to use the drug in patients with severe liver dysfunction due to lack of clinical experience (see section Contraindications).

Because of limited experience, the use of Edarb® Clos should be used with caution in patients with mild to moderate liver function impairment (less than 9 on the Child-Pugh scale), since even small disturbances of the electrolyte balance in diuretics can provoke a hepatic coma. It is recommended to actively monitor condition of such patients.

Reduction of the volume of circulating blood (BCC)

It is necessary to compensate for fluid and electrolyte losses in patients with reduced BCC before starting the use of Edarb® Clos (see Special instructions).

Heart failure

Due to the lack of clinical experience, the use of Edarb® Clos should be used with caution in patients with AH with severe chronic heart failure (class IV functional class NYHA).

Negroid race

Dose correction is not required, since the antihypertensive effect of the Edarby® Clo drug in patients of the Negroid race is similar to its effect in patients of other races.

Dose skip

If you miss a dose, the patient should take the next dose at the usual time. Do not take a double dose of Edarb® Clos. Syndrome "cancellation" (a sharp increase in blood pressure after drug withdrawal) after a sudden withdrawal after prolonged therapy (within 6 months) of azilsartan medoxomil was not observed. Nevertheless, the elimination of the Edarb® Clos after prolonged treatment should be carried out, if possible, gradually.

Side effects:

The frequency of adverse reactions was determined in accordance with the recommendations of the World Health Organization: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100, rarely (> 1/10 000, <1/1000), very rarely (<1/10 000), including individual messages; unspecified frequency (frequency can not be calculated by available data).

The combination of azilsartan medoxomil and chlorthalidone

System of organs	Frequency	Adverse Reactions
Violations of the blood and lymphatic system	Infrequently	Anemia
Disturbances from the nervous system	Often	Dizziness Postural dizziness
Disturbances from the nervous system	Infrequently	Fainting (syncope) Paresthesia
Vascular disorders	Often	Marked decrease in blood pressure
Infringements from gastrointestinal tract	Often	Diarrhea Nausea
Infringements from gastrointestinal tract	Infrequently	Vomiting
Disturbances from the skin and subcutaneous tissue	Infrequently	Skin rash, itching
Disturbances from the skin and subcutaneous tissue	Rarely	Angioedema
Disturbances from musculoskeletal and connective tissue	Infrequently	Muscle spasms
Disorders from the metabolism and nutrition	Often	Hyperuricemia
Disorders from the metabolism and nutrition	Infrequently	Hypokalemia Increase of potassium content Hyponatremia Exacerbation of gout
Impact on results laboratory and instrumental research	Often	Increase in concentration creatinine
	Often	Increase in concentration urea
	Infrequently	Increase in glucose concentration
Common violations	Often	Increased fatigue, peripheral edema

Azilsartan medoxomil (monotherapy)

System of organs	Frequency	Adverse Reactions
Disturbances from the nervous system	Often	Dizziness
Disturbances from the nervous system	Infrequently	Headache
Vascular disorders	Infrequently	Marked decrease in blood pressure
Disorders from the gastrointestinal tract	Often	Diarrhea
Disorders from the gastrointestinal tract	Infrequently	Nausea
Disturbances from the skin and subcutaneous tissues	Infrequently	Skin rash, itching
Disturbances from the skin and subcutaneous tissues	Rarely	Angioedema
Disturbances from musculoskeletal and connective tissue	Infrequently	Muscle spasms
Impact on the results of laboratory and instrumental studies	Often	Increase in activity of creatine phosphokinase
	Infrequently	Increase in the concentration of creatinine Hyperuricemia
Common violations	Infrequently	Increased fatigue Peripheral edema

Chlortalidone (monotherapy)

System of organs	Frequency	Adverse Reactions
Disturbances from the nervous system	Rarely	Headache
Heart Disease	Rarely	Arrhythmia
Hvascular collapse	Often	Marked decrease in blood pressure
Disorders from the digestive system	Often	Loss of appetite, gastrointestinal disorders
	Rarely	Constipation, abdominal pain
	Rarely	Pancreatitis
Disturbances from the skin and subcutaneous tissue	Often	Hives
Disturbances from the skin and subcutaneous tissue	Rarely	Photosensitivity Cutaneous vasculitis
Disturbances from the respiratory system, chest and mediastinal organs	Rarely	Allergic pulmonary edema
Disorders from the side of the liver and biliary tract	Rarely	Intrahepatic cholestasis or jaundice
Renal impairment and urinary tract	Rarely	Allergic interstitial nephritis
Blood disorders and lymphatic system	Rarely	Thrombocytopenia Leukopenia Agranulocytosis Eosinophilia
Violations from the exchange substances and nutrition	Often	Hyperlipidemia Hypokalemia
	Often	Hypomagnesemia
	Rarely	Hypercalcemia Glucosuria Decompensation of existing diabetes mellitus
	Rarely	Hypochloremic alkalosis
Common violations	Often	Decreased potency

Description of individual adverse reactions

With the simultaneous use of azilsartan medoxomil with chlorthalidone, the frequency of adverse reactions is a marked decrease in blood pressure and an increase in concentration

creatinine - increases in the frequency of occurrence: from infrequently to often. This is due to a more effective decrease in blood pressure compared with the monotherapy of azilsartan medoxomil. Most of these effects were transient or non-progressive, as long as patients continued therapy. After drug withdrawal, the majority of cases of increase in creatinine concentration that did not pass during treatment were reversible.

The increase in the concentration of uric acid with the use of the drug Edarb® Clos is due to the chlorothalidone included in it anddepends on the dose of the diuretic. Reports of gout development were infrequent even with prolonged therapy.

With simultaneous use of azilsartan medoxomil with chlorthalidone, the incidence of an adverse reaction, such as hypokalemia, decreases.

Have any of the side effects listed in the manual aggravated, or you notice any other side effects not listed in the instructions, inform the doctor about it.

Overdose:

Azilsartan medoxomil (monotherapy)

The experience with the use of 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 blood pressure, dizziness.

Treatment: With a pronounced decrease in blood pressure, give the patient a "lying down" position, raise the legs, carry out measures to increase 01 (K; symptomatic therapy.) Azilsartan is not excreted from the systemic blood flow by dialysis.

Chlortalidone (monotherapy)

Symptoms: nausea, weakness, dizziness, disturbance of water-electrolyte balance.

Treatment: there is no specific antidote. With a pronounced decrease in blood pressure, flush the stomach, carry out measures to normalize the water-electrolyte balance (infusion therapy); symptomatic therapy.

Interaction:

Lithium

There was a reversible increase in serum lithium concentration and toxicity during simultaneous use of lithium and diuretics and lithium preparations with angiotensin II receptor antagonists (APAII). Therefore, simultaneous use of the drug Edarby® Clos in combination with lithium preparations is not recommended (see section Special instructions). If it is necessary to use the appropriate combination therapy, regular monitoring of the concentration of lithium in the blood serum is recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of COX-2 (cyclooxygenase-2)

In elderly patients and patients with reduced BCC (including those receiving diuretics) or with disturbed function of the nights, simultaneous application of APAII and NSAIDs can lead to impaired renal function until the development of acute renal failure. Therefore, at the beginning of treatment, patients are advised to take a regular intake of a sufficient amount of fluid and monitor the function of the kidneys. With the simultaneous use of APAII and NSAIDs, including selective inhibitors of COX-2, acetylsalicylic acid (more than 3 g / day) and nonselective NSAIDs may attenuate the antihypertensive effect.

Double blockade of the renin-angiotensin-aldosterone system (RAAS)

Double blockade of RAAS ARAII, 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

Simultaneous use of cardiac glycosides and diuretic can aggravate the effects of hypokalemia, such as heart rhythm disturbances.

Additional information on the interaction of azolsartan medoxomil

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

Azolsartan medoxomil is converted into the pharmacologically active metabolite azilsartan during absorption from the gastrointestinal tract by the action of the enzyme carboxymethylenebutepolydase in the gut and liver. Research in vitro showed that interactions based on inhibition of enzymes are unlikely.

Additional information on the interaction of chlorthalidone

Chlortalidone intensifies the action of curare-like muscle relaxants and hypotensive funds (including guanethidine, methyldopy, beta-blockers, vasodilating agents, blockers of "slow" calcium channels), monoamine oxidase inhibitors (MAO).

The simultaneous use of chlorthalidone with allopurinol may increase the incidence of hypersensitivity reactions allopurinol. Chlorthalidone may increase the risk of adverse reactions caused by amantadine.

Anticholinergic drugs (eg, atropine, biperidene) can increase the bioavailability of chlorthalidone, reducing the motility of the gastrointestinal tract and evacuating the contents of the stomach.

Hypokalemic action of chlorthalidone is enhanced with simultaneous application with corticosteroids, adrenocorticotropic hormone, amphotericin, beta-2-adrenoblockers, carbenoxolone. Patients should be monitored for serum potassium during combined therapy.

It may be necessary to correct (decrease or increase) the dose of hypoglycemic agents for ingestion and insulin.

The pharmacological effects of calcium and vitamin D salts can increase to a clinically significant level when applied simultaneously with chlorthalidone. Simultaneous use with cyclosporine may increase the risk of hyperuricemia and complications such as gout.

Kolestyramin breaks the absorption of chlorthalidone. It is possible to reduce the pharmacological effect of chlorthalidone.

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

Special instructions:

Arterial hypotension on the background of disturbance of water-electrolyte balance

In patients with reduced BCC and / or hyponatremia (as a result of vomiting, diarrhea, taking large doses of diuretics, or adherence to a diet with restricted intake of sodium chloride), clinically significant hypotension may develop after initiating therapy with Edarb® Clos. Hypovolemia and water electrolyte balance should be adjusted before treatment. Transient arterial hypotension is not a contraindication to further treatment, which can be continued after stabilization of blood pressure.

Impaired renal function

In patients with impaired renal function (QC more than 30 ml / min), use the drug with caution. It is recommended to regularly monitor the potassium content and serum creatinine concentration. Such patients require a careful dose selection with constant monitoring and control of blood pressure. Increase in creatinine concentration is more often observed in patients with moderate and severe renal dysfunction.

Chlortalidone can cause azotemia.

In the case of progressive deterioration of kidney function (increased blood urea nitrogen (AMC), temporary discontinuation of diuretic therapy or their complete elimination is recommended.

Double blockade of the renin-angiotensin-aldosterone system

Patients in whom vascular tone and renal function depend largely on RAAS activity (for example, in patients with severe chronic heart failure (IV functional class by classification NYHA), severe renal failure or stenosis of the renal arteries), treatment with drugs acting on 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 developing these effects can not be ruled out with the use of the drug Edarby® Clos.

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

Kidney Transplantation

Data on the use of Edarb® Clos in patients who have recently undergone kidney transplantation are not available.

Impaired liver function

Data on the clinical experience with the use of the Edarb® Clo preparation in patients with impaired hepatic function are not available, therefore, the use of the drug in this category of patients is not recommended (see section Contraindications). Due to limited experience with use, Edarby® Clos should be used with caution in patients with mild or moderate liver function impairment (less than 9 on the Child-Pugh scale), since even small disturbances of the electrolyte balance can be triggered by diuretics when administered to the hepatic coma. It is recommended to actively monitor the condition of such patients.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to therapy with antihypertensive drugs that affect RAAS. Therefore, it is not recommended to administer Edarb® Clos to such patients.

Hypokalemia

When chlorthalidone is used, hypokalemia may develop. It is necessary to regularly monitor the potassium content in the blood serum. In patients taking cardiac glycosides, hypokalemia may predispose to arrhythmias.

Stenosis of the aortic or mitral valve, hypertrophic obstructive cardiomyopathy

Care should be taken when administering Edarb® Clos to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Lithium

As in the case of other ARAPs, simultaneous use of lithium preparations and Edarby Clos preparation is not recommended (see section Interaction with other drugs).

Effect on the ability to drive transp. cf. and fur:

Care must be taken when driving vehicles and working with mechanisms that require increased attention and quick reaction: the risk of dizziness and fatigue.

Form release / dosage:

Film coated tablets 40 mg + 12.5 mg, 40 mg + 25 mg.

Packaging:

For 7 tablets in the AL blister with a desiccant built into the PE layer. For 4 blisters together with instructions for use are placed in a pack of cardboard.

Storage conditions:

Keep in dry the dark place at a temperature of no higher than 25 ° C in the original packaging.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002941

Date of registration:02.04.2015

The owner of the registration certificate:Takeda Pharmaceuticals USA, Inc.Takeda Pharmaceuticals USA, Inc. USA

Manufacturer: & nbsp

TAKEDA PHARMACEUTICAL COMPANY, Limited Japan

Representation: & nbspTakeda Pharmaceuticals Ltd.Takeda Pharmaceuticals Ltd.

Information update date: & nbsp14.08.2015

Illustrated instructions

Instructions

Edarby® Clos (Edarbi® Klo)