Edarbi® [Azilsartan medoxomil]

Brand Takeda GmbH

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Available since: 2019-09-19

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Clinical Pharmacology

Azilsartan medoxomil - the active ingredient of the drug Edarbi - is a specific antagonist of angiotensin II type 1 receptors (AT1). 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 AT1 receptors in various tissues. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldersterone system (RAAS) with effects including vasoconstriction, cardiac stimulation, stimulation of synthesis and release of aldosterone, and, as a result, renal reabsorption of sodium.

The AT1 receptor blockade inhibits the negative regulatory response of angiotensin II to renin secretion, but the resulting increase in plasma renin activity and the level of circulating angiotensin II do not suppress the antihypertensive effect of azilsartan.

The antihypertensive effect of azilsartan medoxomil develops during the first 2 weeks of use, with a maximum therapeutic effect being achieved after 4 weeks. A decrease in blood pressure (BP) after ingestion of a single dose is usually achieved within a few hours and persists for 24 hours.

The syndrome of "cancellation" (a sharp increase in blood pressure after discontinuation of the drug) after a sudden cancellation after prolonged therapy (for 6 months) with Edarbi was not observed.

Safety and efficacy of the drug does not depend on the age of patients, but greater sensitivity to lower blood pressure in some elderly patients cannot be excluded. As with the use of other angiotensin II receptor antagonists and angiotensin converting enzyme (ACE) inhibitors, the antihypertensive effect is less pronounced in patients of the Negroid race (usually a population with low plasma renin activity).

The simultaneous use of Edarbi 40 mg and 80 mg with dihydropyridine blockers of "slow" calcium channels (amlodipine) or thiazide diuretics (chlorthalidone) leads to an additional decrease in blood pressure compared with the antihypertensive drugs used in monotherapy.

Impact on repolarization processes

Edarby's potential to increase the QT / QTc interval was conducted in healthy volunteers during the QT / QTc study. At use of a dose of 320 mg of Edarbi increase in an interval of QT / QTc is not noted.

QTc - corrected (relative to heart rate (HR)) value of QT interval, relative value.

Since the duration of the QT interval depends on the heart rate (lengthening when it is slowed down), it must be corrected for HR to be assessed.

Lengthening of the QT interval reflects the heterogeneity of the processes of repolarization of the ventricular myocardium, and is regarded as an independent indicator, indicating the possibility of the appearance of fatal disturbances of the heart rhythm.

Pharmacokinetics

Suction

Azilsartan medoxomil is a prodrug. After ingestion, it is converted to a pharmacologically active metabolite, azylsartan, during absorption from the gastrointestinal tract by the action of the enzyme carboxymethylene butenolidase in the intestine and liver.

Estimated absolute bioavailability of azilsartan medoxomil when administered orally is approximately 60% according to the concentration profile in the blood plasma. The maximum concentration (Cmax) of azylsartan in plasma is, on average, reached within 1.5 to 3 hours after ingestion. Eating does not affect the bioavailability of azilsartan.

Distribution

The volume of distribution of azilsartan is about 16 liters. Azilsartan binds to plasma proteins (more than 99%), mainly with plasma albumin. The bond with plasma proteins is kept constant when the concentration of azilsartan in the blood plasma is much higher than the range achieved when taking the recommended doses.

Data on the use of the drug during pregnancy and during breastfeeding are not available.Azilsartan penetrates the placenta of pregnant rats and is excreted into the milk of lactating rats. Studies on animals with radioactive labels showed that the amount of azilsartan penetrating the blood-brain barrier is minimal.

Metabolism

Azilsartan is metabolized to two primary metabolites predominantly in the liver. The main metabolite in the blood plasma is formed by O-dealkylation and is designated as the metabolite M-II, the minor metabolite is formed by decarboxylation and is designated as the metabolite M-I. The AUC values (areas under the concentration-time pharmacokinetic curve) for these metabolites in humans are 50% and less than 1%, respectively, compared to azilsartan. M-I and M-II do not affect the pharmacological activity of Edarbi. The main enzyme responsible for the metabolism of azilsartan is the isoenzyme CYP2C9.

Removal

Azilsartan and its metabolites are eliminated from the body, both through the intestines, and the kidneys. Studies have shown that, after oral administration of azilsartan medoxomil, about 55% (mostly in the form of metabolite MI) is found in the feces and about 42% (15% in the form of azilsartan, 19% in the form of metabolite M-II) . The half-life of azilsartan is about 11 hours and the renal clearance is about 2.3 ml / min. The equilibrium concentration of azylsartan is reached within 5 days and its accumulation in the blood plasma does not occur with a single daily application.

Linearity / Nonlinearity

The pharmacokinetics of azilsartan in azilsartan medoxomile is proportional to the dosage in the dose range from 20 mg to 320 mg after a single or multiple ingestion.

Pharmacokinetics in Special Groups

Children

The pharmacokinetics of azilsartan in children under the age of 18 years has not been studied.

Elderly patients

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

Renal failure

In patients with mild, moderate and severe renal failure, the AUC was increased by + 30%, + 25% and + 95%, respectively. An increase (+ 5%) in AUC was not observed in patients with end-stage renal failure on hemodialysis. Clinical data on pharmacokinetics in patients with severe or terminal stage of renal failure are not available. Azilsartan is not excreted from the systemic circulation through hemodialysis.

Liver failure

The use of Edarbi for more than 5 days in patients with mild (grade A on the Child-Pugh scale) or medium (grade B on the Child-Pugh scale) severity of liver failure leads to a slight increase in AUC (1.3 - 1.6 times, respectively ). The pharmacokinetics of Edarbi in patients with severe (grade C on the Child-Pugh scale) degree of liver failure has not been studied.

Gender

The pharmacokinetics of azilsartan in men and women is not significantly different. Dose adjustment based on gender is not required.

Race

The pharmacokinetics of azilsartan are not significantly different depending on the race of the patients. Dose adjustment depending on race is not required.

Indications

Essential hypertension.

Composition

1 tablet 40 mg contains:

Active substance: azilsartan medoxomil potassium - 42.68 mg corresponds to azilsartan medoxomil - 40 mg.

Excipients: mannitol - 95.63 mg, fumaric acid - 2 mg, sodium hydroxide - 0.69 mg, hyprolosis - 5.4 mg, croscarmellose sodium - 13.8 mg, microcrystalline cellulose - 18 mg, magnesium stearate - 1, 8 mg.

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Dosage and Administration

Edarbi is taken orally once a day, regardless of the meal time. The recommended initial dose is 40 mg 1 time per day. If necessary, further reduction of blood pressure can be increased to the maximum dose - 80 mg 1 time per day.

The maximum daily dose is 80 mg.

In the case of inadequate control of blood pressure in monotherapy with Edarbi, its simultaneous use with other antihypertensive drugs is possible, including diuretics (chlorthalidone and hydrochlorothiazide) and dihydropyridine blockers of “slow” calcium channels (amlodipine).

Duration of treatment

Edarbi should be taken daily, without interruption. In case of discontinuation of treatment, the patient should inform the doctor.

If you forget to use the drug

In case of skipping the next dose, the next dose should be taken at the usual time. You should not take a double dose of Edarbi.

Elderly patients (65 years and older)

Correction of the initial dose of the Edarbi drug in elderly patients is not required. However, in patients over the age of 75, a dose of 20 mg may be considered as the initial dose (the risk of arterial hypotension increases).

Patients with impaired renal function

There is no clinical experience of using Edarbi in patients with severe hypertension with impaired severe kidney function and end-stage renal failure, therefore, it is necessary to use the drug in this category of patients with caution. Correction of the dosage regimen is not required in patients with impaired mild to moderate renal function.

Patients with impaired liver function

The use of the drug in patients with severe hepatic impairment is not recommended due to the lack of clinical experience. Due to the limited experience of using Edarbi in patients with mild and moderately impaired liver function, it is recommended to start treatment with a dose of 20 mg 1 time per day and carry it out under close observation.

Reduction in circulating blood volume (BCC)

The drug Edarbi should be prescribed to patients with decreased BCC and / or hyponatremia (for example, patients with prolonged vomiting, diarrhea, or taking large doses of diuretics) only under strict medical supervision. It is also recommended to begin treatment with a dosage of 20 mg 1 time per day.

Heart failure

Due to the lack of clinical experience, Edarbi should be used with caution in patients with hypertension with severe chronic heart failure (functional class IVHA classification IV).

Negroid race

Dose adjustment is not required in patients of the Negroid race. As in the case of other angiotensin II receptor antagonists (AT1) and ACE inhibitors, patients of the Negroid race have a lower BP in comparison with the rest of the population. In this regard, in order to adequately control blood pressure in patients of the Negroid race, an increase in the Edarbi dose and complex therapy more often than in other patients may be necessary.

Adverse reactions

The frequency of adverse reactions was determined in accordance with the recommendations of the World Health Organization:

very often (> 1/10);
often (> 1/100, infrequently (> 1/1000, rarely (> 1/10 000, very rarely (unspecified frequency (frequency cannot be calculated from available data)).

From the nervous system: often - dizziness.

From the side of the vessels: infrequently - pronounced decrease in blood pressure.

From the gastrointestinal tract: often - diarrhea; infrequently - nausea.

Skin and Subcutaneous Tissues: infrequently - 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 creatine phosphokinase; infrequently - an increase in the concentration of creatinine, hyperuricemia.

General violations: infrequently - increased fatigue, peripheral edema.

Description of individual adverse reactions

With the simultaneous use of Edarbi 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 frequent.

With the simultaneous use of Edarbi with amlodipine, the incidence of adverse reactions - peripheral edema - increases from infrequent to frequent, but is less common than with amlodipine monotherapy.

Rarely observed angioedema, swelling of the face, lips and periorbital edema.

As with the use of other angiotensin II receptor antagonists and ACE inhibitors, the simultaneous use of Edarbi with diuretics (such as chlorthalidone) leads to an increase in the increase in creatinine concentration. An increase in the concentration of creatinine with simultaneous use of Edarbi with diuretics is associated with a greater decrease in blood pressure compared to Edarbi monotherapy. 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. The concentration of creatinine in most patients returned to values at baseline, or values that are close to baseline.

When treating Edarbi, there was a slight increase in serum uric acid concentration (10.8 mcmol / L) compared with a placebo (4.3 mcmol / L).

Just as with the use of other RAAS inhibitors, a slight decrease in hemoglobin and hematocrit was observed in monotherapy (decreased on average by about 3 g / l and 1% by volume, respectively).

If any of the side effects indicated in the instruction are aggravated, or you have noticed any other side effects that are not indicated in the instruction, inform your doctor.

Contraindications

Carefully:

Severe chronic heart failure (NYHA class IV);
severe renal failure (creatinine clearance <30 ml="" min="" li="">
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 volume of circulating blood (BCC) (including vomiting, diarrhea), as well as in patients on a diet with restricted salt;
with simultaneous use with large doses of diuretics; - primary hyper aldosteronism;
hyperkalemia;
stenosis of aortic and mitral valves;
hypertrophic obstructive cardiomyopathy (GOKMP);
age over 75 years.

If you have one of these diseases, before taking Edarbi, you should consult with your doctor.

Drug interactions

Lithium

There was a reversible increase in serum lithium concentration and toxicity during simultaneous use of lithium preparations and ACE inhibitors and lithium preparations with angiotensin II receptor antagonists. Therefore, the simultaneous use of azilsartan medoxomil in combination with lithium preparations is not recommended. If necessary, the use of appropriate combination therapy is recommended to regularly monitor the content of lithium in the serum.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

With the simultaneous use of antagonists of angiotensin II and NSAIDs (for example, selective COX-2 inhibitors (cyclooxygenase-2), acetylsalicylic acid (more than 3 g / day) and non-selective NSAIDs, the antihypertensive effect may be reduced. With simultaneous use of antagonists of angiotensin II and NSAIDs may increase the risk of impaired renal function and an increase in the content of potassium in the blood serum.Therefore, at the beginning of treatment, patients are recommended to regularly take a sufficient amount of fluid and monitor renal function.

Preparations of potassium and potassium-sparing diuretics, heparin

The simultaneous use of potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium and other drugs (for example, heparin) with azilsartan medoxomil can lead to an increase in serum potassium. Patients during combination therapy should monitor the content of potassium in the serum.

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

Double blockade of RAAS by angiotensin II receptor antagonists, 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.

Additional Information on Azilsartan Medoxomil Interaction

Pharmacokinetic interactions were not observed with the simultaneous use of azilsartan medoxomil or azilsartan with amlodipine, antacid preparations (magnesium and aluminum hydroxide), chlorthalidone, digoxin, fluconazole, glibenclamide, ketoconazole, metformin and warfarin. Azilsartan medoxomil is converted to a pharmacologically active metabolite azylsartan during absorption from the gastrointestinal tract under the action of the enzyme carboxymethylene butenolidase in the intestine and liver. In vitro studies have shown that interactions based on enzyme inhibition are unlikely.

Diuretics and other antihypertensives

The antihypertensive effect of azilsartan medoxomil therapy can be enhanced when combined with other antihypertensive drugs, including diuretics (chlorthalidone and hydrochlorothiazide), and dihydropyridine blockers of “slow” calcium channels (amlodipine).

Pregnancy and Lactation

Use during pregnancy

Animal studies have shown that azilsartan and M-II penetrate the placental barrier.

Patients planning a pregnancy should begin therapy with alternative antihypertensive drugs with an established safety profile for pregnant women. Immediately after confirming pregnancy, you should stop taking Edarbi® and, if necessary, start a course of treatment with drugs approved for use during pregnancy.

Newborns whose mothers have received Edarbi therapy may develop arterial hypotension, and therefore newborns must be under close medical supervision.

Breast-feeding

There is no information about the ability of azilsartan and / or its metabolites to penetrate into breast milk. Animal studies have shown that azilsartan and M-II are excreted into the milk of lactating rats.

Due to the lack of experience with the use of Edarbi in women during breastfeeding, its use in this category of patients is not recommended. Preferably the use of drugs with the most studied safety profile, especially during the care of a newborn or premature baby.

Special instructions

Activated renin-angiotensin-aldosterone system

Patients whose vascular tone and kidney function depend to a large extent on the activity of the RAAS (for example, in patients with severe chronic heart failure (class IVHA functional class IV), severe renal failure or renal artery stenosis). on RAAS, such as ACE inhibitors and angiotensin II receptor antagonists, 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 applying Edarbi. 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 Edarbi in patients who recently underwent kidney transplantation are not available.

Liver dysfunction

Data on the clinical experience of using Edarbi in patients with severely impaired liver function are not available, therefore, the use of the drug in these patients is not recommended.

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 Edarbi therapy. Hypovolemia should be adjusted before starting treatment with Edarbi or start treatment with a dosage of 20 mg.

Primary hyperaldosteronism

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

Hyperkalemia

Clinical experience with other drugs that affect the RAAS shows that co-administration of Edarbi® with potassium-sparing diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that may increase the potassium content in the blood (for example, heparin), can lead to hyperkalemia in patients with arterial hypertension. Elderly patients, patients with renal insufficiency, diabetes mellitus and / or patients with other concomitant diseases increase the risk of developing hyperkalemia, which can be fatal. In such patients it is recommended to control the content of potassium in the blood serum.

Aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy

When prescribing Edarbi in patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy, caution must be exercised.

Lithium

As in the case of other angiotensin II receptor antagonists, simultaneous use of lithium preparations and Edarbi is not recommended.

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

Based on the pharmacodynamic properties, it is expected that azilsartan medoxomil will have little effect on the ability to drive vehicles and control mechanisms. Care must be taken as with the use of any antihypertensive drugs (risk of developing dizziness and increased fatigue).

Overdosage

The experience of using Edarbi 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: in case of a pronounced decrease in blood pressure, give the patient a “lying down” position, raise his legs, take measures to increase the volume of circulating blood (BCC); symptomatic therapy.

Azilsartan is not excreted from the systemic circulation through dialysis.