Edarbi Klo tabs 40mg + 25mg #28

Instruction for use of Edarbi Klo

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Edarbi Klo is a combined antihypertensive drug.

Release form and composition

Edarbi Klo is produced in the form of film-coated tablets: biconvex, round; pale pink with the inscriptions "D / S" and "40 / 12.5" printed on one of the sides in gray ink - dosage 40 mg + 12.5 mg, or gray-pink with inscriptions in gray ink "D / S" and "40/25" - dosage of 40 mg + 25 mg (14 pieces in an aluminum blister, 2 blisters in a cardboard box; 7 pieces in an aluminum blister, 4 blisters in a cardboard box).
1 film-coated tablet contains:
    active substances: azilsartan medoxomil potassium - 42.68 mg (corresponds to azilsartan medoxomil in an amount of 40 mg), chlorthalidone - 12.5 or 25 mg;
    additional components: sodium hydroxide, mannitol, fumaric acid, microcrystalline cellulose, crospovidone, hyprolose, magnesium stearate;
    film shell: titanium dioxide, hypromellose 2910, macrogol 8000, iron dye red oxide, talc, F1 gray ink purified for marking (contains iron dye black oxide, ethanol, butyl alcohol, shellac).

Pharmacodynamics

Edarbi Klo is a combined antihypertensive drug, which includes an angiotensin II receptor antagonist (ARA II) - azilsartan medoxomil, and a thiazide-like diuretic - chlorthalidone. The combined use of these active substances provides a more pronounced decrease in blood pressure (BP) when compared with taking each of them as a monotherapy drug. Taking Edarbi Klo 1 time per day leads to an effective decrease in blood pressure for 24 hours.
Azilsartan medoxomil belongs to the specific ARA type II (AT1). Angiotensin II is formed from angiotensin I in a reaction catalyzed by an angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the main vasoconstrictor factor of the renin-angiotensin-aldosterone system (RAAS), its effect is vasoconstriction, stimulation of aldosterone production, increased heart rate (HR) and sodium reabsorption by the kidneys.
Azilsartan medoxomil is an oral prodrug. The substance is rapidly transformed into an active molecule of azilsartan, which selectively blocks the development of the effects of angiotensin II by inhibiting the connection of the latter with the AT1 receptor in various tissues, including in the adrenal glands and smooth muscles of the vascular walls. As a result, its effect is not associated with the course of the biosynthesis of angiotensin II. The AT2 receptor is localized in many tissues, but does not affect the regulation of the cardiovascular system (CVS). The affinity of azilsartan for the AT1 receptor is 10,000 higher than that for the AT2 receptor.
In the treatment of arterial hypertension, ACE inhibitors are widely used, suppressing the formation of angiotensin II from angiotensin I, and thereby inhibiting the activity of the RAAS. ACE inhibitors also block the breakdown of bradykinin, which is catalyzed by ACE; since azilsartan does not inhibit kininase II, its effect should not extend to the action of bradykinin. The substance also does not affect other receptors or ion channels, which are of great importance in the regulation of CVS.
Azilsartan dose-dependently inhibits the vasoconstrictor effect during infusion of angiotensin II. A single dose of azilsartan in an amount corresponding to 32 mg of azilsartan medoxomil inhibited the maximum vasoconstrictor effect of angiotensin II at the time of the highest concentration by about 90%, and by about 60% - 24 hours after administration. After a single oral dose and after repeated doses of azilsartan medoxomil, healthy volunteers showed an increase in the concentration of angiotensin I and II and renin activity in plasma, as well as a decrease in the level of aldosterone. At the same time, there was no significant change in the serum potassium or sodium level in the blood. The pharmacodynamic properties of azilsartan medoxomil are generally combined with the suppression of AT1 receptors.
The development of the antihypertensive effect of this substance occurs during the first 2 weeks of the course, and the maximum therapeutic effect is noted after 4 weeks. After oral administration of a single dose, a decrease in blood pressure is achieved, as a rule, within a few hours and persists for 24 hours.
Chlorthalidone is a thiazide-like diuretic that inhibits the active reabsorption of sodium ions in the renal tubules (in the initial part of the distal convoluted tubule of the nephron). As a result of this, the active substance increases the excretion of chlorine and sodium ions and enhances diuresis, it also enhances the excretion of magnesium, potassium, bicarbonate ions, and retains uric acid and calcium ions.
The antihypertensive properties of the drug are due to the excretion of sodium and fluid from the body. The diuretic effect is observed 2-3 hours after oral administration of chlorthalidone and persists for 2-3 days. The antihypertensive effect manifests itself gradually and reaches its maximum effect 2–4 weeks after the start of treatment.
In clinical trials, the combined use of azilsartan medoxomil and chlorthalidone was more effective than the combination of azilsartan medoxomil or olmesartan medoxomil with hydrochlorothiazide, despite the fact that more study participants in the comparison group needed an increase in dose due to insufficient blood pressure control. In a double-blind study, during which the dose was routinely increased for 12 weeks, the combined use of azilsartan medoxomil and chlorthalidone (40 and 25 mg, respectively) significantly exceeded the combination of olmesartan medoxomil and hydrochlorothiazide (40 mg and 25 mg, respectively) in reducing systolic BP in the presence of moderate to severe arterial hypertension.
Similar results were observed in all patient subgroups regardless of age, gender or race.
The combination of active ingredients Edarbi Clot lowered blood pressure more effectively than the combined use of olmesartan medoxomil / hydrochlorothiazide in every hour of the 24-hour period between doses of drugs according to 24-hour blood pressure monitoring (ABPM).

Pharmacokinetics

After oral administration of Edarbi Klo in blood plasma, the maximum concentration (Cmax) of azilsartan is determined within approximately 3 hours, the half-life (T½) is approximately 12 hours. Pharmacokinetic parameters of azilsartan, such as Cmax, the period of reaching Cmax (TCmax) and the area under the "concentration-time curve" (AUC), when monotherapy with the drug and when it is combined with chlorthalidone are similar.
The volume of distribution (Vd) of azilsartan is on average 16 liters, the connection with blood plasma proteins (mainly albumin) reaches more than 99%.
In the process of biotransformation of azilsartan, two primary metabolites are formed, mainly in the liver. The main metabolite (M-II) in the blood plasma is formed by O-dealkylation, the minor metabolite (M-I) - by decarboxylation. In humans, the AUC value for these metabolites is 50% and less than 1%, respectively, compared with azilsartan. The metabolism of the latter is provided by the isoenzyme CYP2C9.
Azilsartan and its metabolites are excreted by the kidneys and through the intestines, after oral administration, about 55% of the drug (mostly in the form of the M-I metabolite) is detected in the feces and about 42% (in the form of the main substance - 15%, in the form of the M-II metabolite - 19%) - in the urine. There were no significant differences in the pharmacokinetics of azilsartan in patients of different age and gender. There is no need to adjust the dose according to race.
Chlorthalidone after oral administration is absorbed from the gastrointestinal tract by 60%, on average, Cmax in blood plasma is reached within 12 hours, T½ is 40-50 hours. The AUC value of chlorthalidone is similar both when it is taken together with azilsartan medoxomil and when monotherapy is carried out, while the Cmax when combined is 47% higher.
The bioavailability of Edarbi Klo when taken with food is not clinically significant.
In whole blood, chlorthalidone is predominantly associated with erythrocyte carbonic anhydrase. In blood plasma, about 75% of the substance is associated with its proteins, while 58% - with albumin. Chlorthalidone is excreted mostly unchanged. Data on the comparative amounts of the substance excreted unchanged and in the form of metabolites are not provided.
Since chlorthalidone is a thiazide-like diuretic, it passes into breast milk. There is no information on the differences in the pharmacokinetic parameters of this substance in patients of different sexes, as well as depending on race. Chlorthalidone is excreted more slowly in elderly patients than in young patients, but this decrease is not clinically significant. In the presence of renal failure, accumulation of chlorthalidone may occur.

Indications for use

According to the instructions, Edarbi Klo is recommended for the treatment of essential hypertension in patients for whom combined treatment is indicated.

Contraindications

Absolute:
    severe diabetes mellitus;
    refractory form of hypokalemia;
    severe functional disorders of the liver (over 9 points on the Child-Pugh scale);
    anuria;
    severe renal failure [with creatinine clearance (CC) below 30 ml / min];
    age under 18;
    pregnancy and lactation;
    combined intake of aliskiren and aliskiren-containing agents in patients with diabetes mellitus or moderate / severe renal impairment [with a glomerular filtration rate (GFR) less than 60 ml / min / 1.73 m²];
    hypersensitivity to any of the constituents of the antihypertensive agent.
Relative (Edarbi Klo should be taken with caution):
    cerebrovascular ischemic lesions;
    ischemic cardiomyopathy;
    severe chronic heart failure (CHF) (NYHA functional class IV; due to lack of clinical experience of use);
    hypertrophic obstructive cardiomyopathy (GOKMP);
    mitral and aortic valve stenosis;
    mild / moderate degree of functional impairment of the liver (5-9 points on the Child-Pugh scale);
    impaired renal function (CC above 30 ml / min);
    artery stenosis of a single functioning kidney, bilateral renal artery stenosis;
    condition after kidney transplantation (due to the lack of data on the use);
    hypokalemia;
    hyperuricemia, gout;
    primary hyperaldosteronism;
    systemic lupus erythematosus;
    bronchial asthma;
    conditions leading to a decrease in circulating blood volume (BCC), including diarrhea, vomiting, the use of high doses of diuretics, as well as adherence to a diet with limited table salt;
    over 75 years of age.

Instructions for use: method and dosage

Edarbi Klo is taken orally once a day, regardless of food intake.
At the beginning of treatment, Edarbi Klo 40 + 12.5 mg 1 time per day is usually prescribed.
If it is not possible to achieve adequate control of blood pressure, the dose of the drug can be increased to the maximum possible - 40 mg of azilsartan medoxomil + 25 mg of chlorthalidone 1 time per day.
Edarbi Cloe is required to be taken every day, without interruption. When discontinuing therapy, you should consult your doctor. If the next dose is missed, the next dose must be taken at the usual time, you cannot double the dose.
With a sharp cancellation of azilsartan medoxomil after a long course of treatment (within six months), the development of the withdrawal syndrome was not observed. At the same time, at the end of long-term therapy, it is recommended to cancel Edarbi Klo gradually, if possible.

Side effects

Side effects recorded against the background of the combined use of azilsartan medoxomil and chlorthalidone:
    CVS: often - a significant decrease in blood pressure;
    hematopoietic system: infrequently - anemia;
    digestive system: often - nausea, diarrhea; infrequently - vomiting;
    nervous system: often - dizziness, postural dizziness; infrequently - paresthesia, fainting (syncope);
    skin and subcutaneous tissues: infrequently - itching, skin rash;
    musculoskeletal system: infrequently - muscle spasms;
    allergic reactions: rarely - angioedema;
    laboratory indicators: very often - an increase in the level of creatinine (reversible after the end of the admission); often - an increase in the concentration of urea (depends on the dose of chlorthalidone), an increase in the glucose content;
    metabolism: often - hyperuricemia; infrequently - increased potassium concentration, hypokalemia, exacerbation of gout, hyponatremia;
    general reactions: often - peripheral edema, increased fatigue.
Side effects noted with the use of chlorthalidone in monotherapy:
    CVS: often - a significant decrease in blood pressure; rarely - arrhythmia;
    hematopoietic system: rarely - agranulocytosis, leukopenia, eosinophilia, thrombocytopenia;
    digestive system: often - gastrointestinal disorders, loss of appetite; rarely, abdominal pain, constipation, jaundice, or intrahepatic cholestasis; extremely rare - pancreatitis;
    nervous system: rarely - headache;
    allergic reactions: often - urticaria;
    skin and subcutaneous tissues: rarely - cutaneous vasculitis, photosensitivity;
    respiratory system: rarely - allergic pulmonary edema;
    urinary system: rarely - allergic interstitial nephritis;
    metabolism: very often - hypokalemia, hyperlipidemia; often - hypomagnesemia; rarely - decompensation of concomitant diabetes mellitus, glucosuria, hypercalcemia; extremely rare - hypochloremic alkalosis;
    others: often - weakening of potency.
Side effects reported during monotherapy with azilsartan medoxomil:
    CVS: infrequently - a marked decrease in blood pressure;
    digestive system: often - diarrhea; infrequently - nausea;
    nervous system: often - dizziness; infrequently - headache;
    allergic reactions: rarely - angioedema;
    skin and subcutaneous tissues: infrequently - itching, skin rash;
    musculoskeletal system: infrequently - muscle spasms;
    laboratory parameters: often - increased activity of creatine phosphokinase (CPK); infrequently - hyperuricemia, an increase in creatinine levels;
    general reactions: infrequently - peripheral edema, increased fatigue.

Overdose

When taking azilsartan medoxomil as a monotherapy drug in daily doses up to 320 mg for 7 days, its good tolerance was noted. Overdose symptoms can be dizziness and a pronounced decrease in blood pressure; in this condition, it is necessary to transfer the patient to the supine position, raising his legs. Also, measures are recommended to increase the BCC and conduct symptomatic therapy. The drug is not excreted by dialysis.
When monotherapy with chlorthalidone, overdose symptoms include disturbances in water and electrolyte balance, dizziness, weakness, nausea. If there is a significant decrease in blood pressure, it is recommended to flush the stomach, and infusion (to normalize the water and electrolyte balance) and symptomatic therapy are also prescribed.

Special instructions

In patients with hyponatremia and / or with reduced BCC during treatment with Edarbi Clot, there is a threat of clinically significant arterial hypotension. Before starting therapy, it is required to adequately correct hypovolemia by replenishing the loss of electrolytes and fluid. Transient arterial hypotension is not a contraindication for further administration of the drug; after stabilization of blood pressure, treatment can be continued.
If, during therapy, there is a progressive deterioration in renal function (an increase in the level of urea nitrogen in the blood), it is recommended to temporarily stop or completely stop taking diuretics.
In patients with ischemic cerebral circulation disorders or ischemic cardiomyopathy, a sharp decrease in blood pressure can provoke the development of a stroke or myocardial infarction.
In patients whose renal activity and vascular tone are mainly dependent on the activity of the RAAS, for example, in the presence of severe CHF (IV FC according to the NYHA classification), severe renal failure or renal artery stenosis, therapy with drugs affecting the RAAS (ARA II and ACE inhibitors), may be associated with the appearance of acute arterial hypotension, oliguria, azotemia and, in rare cases, acute renal failure. The development of such complications cannot be ruled out when using Edarbi Klo.
In patients with primary hyperaldosteronism, as a rule, resistance to treatment with antihypertensive drugs that have a depressing effect on the RAAS is noted. As a result, such patients are not recommended to take the drug.
Against the background of treatment with chlorthalidone, there is a possibility of developing hypokalemia, for this reason, it is necessary to regularly monitor the level of potassium in the blood. The onset of hypokalemia in patients receiving cardiac glycosides can lead to arrhythmias.

Influence on the ability to drive vehicles and complex mechanisms

Patients driving vehicles and / or complex mechanisms during the period of using Edarbi Klo need to be careful due to the possible appearance of excessive fatigue and dizziness.

Application during pregnancy and lactation

Taking Edarbi Klo during pregnancy and lactation is contraindicated. There are no data on the use of the drug by pregnant women.
Newborns whose mothers took azilsartan medoxomil need careful medical supervision, as their risk of developing arterial hypotension is aggravated.
Chlorthalidone can enter the umbilical cord blood through the placental barrier and lead to the development of jaundice of the fetus or newborn, thrombocytopenia and other undesirable effects noted in adults.
If pregnancy is confirmed during therapy, the use of Edarbi Klo must be urgently discontinued and, if necessary, replaced with another drug approved for use in pregnant women.
It is not known whether azilsartan and / or its metabolites penetrate into human breast milk, but animal studies have shown the ability of azilsartan and its metabolite M-II to penetrate into the milk of lactating rats. It has been established that chlorthalidone is excreted in breast milk.
If taking the drug is necessary during lactation, you need to stop breastfeeding. During this period, it is advisable to use drugs that have a proven safety profile.

Childhood use

Edarbi Klaw is prohibited from admission to patients under 18 years of age, since there is no information confirming the effectiveness and safety of its use in children and adolescents.

With impaired renal function

In patients with severe renal failure (CC below 30 ml / min), Edarbi Klo are contraindicated, since this category of patients does not have clinical experience of its use.
With mild and moderate impairment of renal function (CC above 30 ml / min), changes in the dosage regimen are not required, but it is recommended to regularly monitor blood pressure, potassium content and serum creatinine concentration.

For violations of liver function

The drug is contraindicated for use in the presence of severe functional liver disorders (over 9 points on the Child-Pugh scale) due to lack of experience in use. Patients with mild and moderate liver dysfunctions (5-9 points on the Child-Pugh scale) should use Edarbi Klo with caution, since even with minor violations of water and electrolyte balance while taking diuretics, the risk of hepatic coma increases. It is required to carefully monitor the condition of patients in this risk group.

Use in the elderly

Elderly patients (over 65 years of age) do not need to adjust the initial dose of Edarbi Klo. Persons over the age of 75 should use an antihypertensive agent with caution.

Drug interactions

    lithium preparations - the serum concentration of lithium in the blood reversibly increases and toxicity is manifested when taken simultaneously with ARA II (this combination is not recommended; if combined use is necessary, the level of lithium should be regularly monitored);
    non-steroidal anti-inflammatory drugs (NSAIDs) - in patients with impaired renal function, elderly patients or with reduced BCC (including those taking diuretics), renal function may deteriorate, including the development of acute renal failure (at the beginning of the course in patients belonging to this group risk, it is recommended to regularly monitor kidney function and drink enough fluid);
    selective inhibitors of COX-2 (cyclooxygenase-2), acetylsalicylic acid (in daily doses of more than 3 g) and non-selective NSAIDs - the antihypertensive effect is weakened;
    ARA II, ACE inhibitors - the threat of hyperkalemia, arterial hypotension and functional disorders of the kidneys (including acute renal failure) caused by double blockade of the RAAS increases;
    cardiac glycosides - due to the influence of a diuretic, the effects of hypokalemia, including cardiac arrhythmias, are aggravated.
Possible interaction of azilsartan medoxomil with other drugs / substances:
    enzyme carboxymethylene butenolidase (in the liver and intestine) - the transformation of azilsartan medoxomil into azilsartan (active metabolite) occurs under the action of this enzyme during absorption from the gastrointestinal tract; according to in vitro studies, interactions based on inhibition of enzymes are unlikely;
    antacids (magnesium and aluminum hydroxide), amlodipine, digoxin, chlorthalidone, glibenclamide, fluconazole, metformin, ketoconazole, warfarin - no pharmacokinetic interaction was observed.
Possible interaction of chlorthalidone with other drugs / substances:
    allopurinol - the frequency of hypersensitivity reactions to this drug increases;
    amantadine - the threat of the development of undesirable effects caused by it is aggravated;
    anticholinergic drugs (biperiden, atropine) - the bioavailability of chlorthalidone increases due to a decrease in gastrointestinal motility and evacuation of stomach contents;
    MAO inhibitors, curariform muscle relaxants, antihypertensive agents (methyldopa, guanethidine, slow calcium channel blockers, vasodilating agents, beta-blockers) - the effect of these agents is enhanced;
    amphotericin, corticosteroids, adrenocorticotropic hormone (ACTH), carbenoxolone, beta2-blockers - the hypokalemic effect of chlorthalidone increases (it is required to control the level of potassium in the serum);
    antidiabetic oral agents and insulin - dose adjustments may be necessary;
    cholestyramine - the absorption of chlorthalidone is impaired and its pharmacological effect decreases;
    cyclophosphamide and methotrexate - it is possible to enhance the pharmacological effect of these drugs;
    cyclosporine - the risk of hyperuricemia and gout may be aggravated;
    vitamin D, calcium salts - the pharmacological effects of these agents may increase to clinically significant.

Terms and conditions of storage

Store in its original packaging in a place protected from light and moisture, out of the reach of children, at a temperature not exceeding 25 ° C.
Shelf life is 3 years.

Reviews

According to reviews, Edarbi Klo is an effective drug used to treat essential hypertension. Patients also note a convenient dosage regimen of the drug and its diuretic effect, which helps relieve edema.
Some reviews indicate the development of adverse reactions, such as severe weakness, vomiting, nausea. Many patients consider the disadvantages of Edarbi Klo too high, in their opinion, the cost of the drug.

Terms of sell

You can buy Edarbi Klo without a prescription from a doctor.