Edarbi, tablets 40 mg 28 pcs

Pharmacodynamics

Asilsartan medoxomil, the active ingredient in Edarbi, is a specific angiotensin II type 1 (AT1) receptor antagonist. Azilsartan medoxomil is an oral prodrug. Azilsartan medoxomil is rapidly converted to the active molecule azilsartan, which selectively inhibits the effects of angiotensin II by blocking its binding to AT1 receptors in various tissues. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldesterone system (RAAS) with effects including vasoconstriction, cardiac stimulation, stimulation of aldosterone synthesis and release, and consequent renal sodium reabsorption.

At1-receptor blockade inhibits the negative regulatory response of angiotensin II to renin secretion, but the resulting increase in plasma renin activity and circulating angiotensin II levels does not suppress the antihypertensive effect of azilsartan.

The antihypertensive effect of azilsartan medoxomil develops during the first 2 weeks of use with reaching maximum therapeutic effect after 4 weeks. Decrease in blood pressure (BP) after a single oral dose is usually achieved within a few hours and maintained for 24 hours.

The “withdrawal” syndrome (a sharp increase in BP after drug withdrawal) after abrupt withdrawal after long-term therapy (within 6 months) with Edarbi has not been observed.

The safety and efficacy of the drug do not depend on the age of patients, but a greater sensitivity to BP lowering in some elderly patients cannot be excluded. As with other angiotensin II receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors, the antihypertensive effect is less pronounced in non-Hispanic patients (typically a population with low plasma renin activity).

The simultaneous use of Edarbi 40 mg and 80 mg with dihydropyridine “slow” calcium channel blockers (amlodipine) or thiazide diuretics (chlorthalidone) results in additional BP reduction compared to hypotensive agents used in monotherapy.

The effect on repolarization processes

The potential of Edarbi to prolong the QT/QTc interval was evaluated in healthy volunteers during the QT/QTc study. No increase in the QT/QTc interval was observed with the 320 mg dose of Edarbi.

The QTc is the corrected (relative to heart rate (HR)) value of the QT interval, a relative value.

Because QT interval length is dependent on heart rate (lengthening as the heart rate slows), it must be correlated to HR to assess it.

Lengthening of the QT interval reflects heterogeneity in ventricular myocardial repolarization processes and is considered as an independent indicator of the potential for fatal heart rhythm disturbances.

Pharmacokinetics

Azilsartan medoxomil is a prodrug. After oral administration, it is converted to the pharmacologically active metabolite azilsartan during absorption from the gastrointestinal tract by the enzyme carboxymethylene butenolidase in the gut and liver.

The estimated absolute bioavailability of azilsartan medoxomil with oral administration is approximately 60% according to the plasma concentration profile. The maximum plasma concentration (Cmax) of azilsartan is reached on average within 1.5 to 3 hours after oral administration. Food intake 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%), predominantly to plasma albumins. Binding to plasma proteins remains constant at plasma concentrations of azilsartan well above the range achieved with the recommended doses.

There are no data on the use of the drug during pregnancy and breastfeeding. Azilsartan penetrates the placenta of pregnant rats and is excreted into the milk of lactating rats. Studies on animals with radioactive tags have shown that the amount of azilsartan penetrating the blood-brain barrier is minimal.

Metabolism

Asilsartan is metabolized to two primary metabolites mainly in the liver. The primary metabolite in blood plasma is formed by O-dealkylation and is designated as metabolite M-II; the secondary metabolite is formed by decarboxylation and is designated as metabolite M-I. The AUC (area under the pharmacokinetic concentration-time curve) values 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 CYP2C9 isoenzyme.

Asilsartan and its metabolites are excreted from the body both through the intestine and the kidneys. Studies have shown that after oral administration of azilsartan medoxomil, about 55% (mainly as metabolite M-I) is detected in the feces and about 42% (15% as azilsartan, 19% as metabolite M-II) in the urine. The elimination half-life of azilsartan is about 11 h and renal clearance is about 2.3 ml/min. The equilibrium concentration of azilsartan is reached within 5 days and there is no plasma cumulation with single daily administration.

Linearity/Nonlinearity

The pharmacokinetics of azilsartan in azilsartan medoxomil is proportional to dosage over a dose range of 20 mg to 320 mg after single or multiple oral doses.

Pharmacokinetics in special groups

Pharmacokinetics of azilsartan in children under 18 years of age have not been studied.

Elderly patients

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

Renal failure

In patients with mild, moderate and severe renal failure, AUC was increased by + 30%, + 25% and + 95%, respectively. No increase (+ 5%) in AUC was observed in patients with terminal renal failure on hemodialysis. There are no clinical data on pharmacokinetics in patients with severe or terminal renal failure. Azilsartan is not excreted from the systemic bloodstream by hemodialysis.

Hepatic failure

The use of Edarbi for more than 5 days in patients with mild (Child-Pugh grade A) or moderate (Child-Pugh grade B) hepatic failure leads to a slight increase in AUC (1.3 to 1.6 times, respectively). Pharmacokinetics of Edarbi® in patients with severe (Child-Pugh class C) hepatic failure has not been studied.

Gender identity

The pharmacokinetics of azilsartan in men and women are not significantly different. There is no need to adjust the dose according to gender.

Raciality

The pharmacokinetics of azilsartan do not differ significantly by patient race. No dose adjustment based on race is required.

Indications

Essential hypertension.

Pharmacological effect

Pharmacodynamics

Azilsartan medoxomil, the active ingredient of Edarbi, is a specific antagonist of angiotensin II type 1 receptors (AT1). Azilsartan medoxomil is an oral prodrug. Azilsartan medoxomil is rapidly converted to the active azilsartan molecule, which selectively prevents the development of the effects of angiotensin II by blocking its binding to AT1 receptors in various tissues. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldesterone system (RAAS) with effects including vasoconstriction, cardiac stimulation, stimulation of aldosterone synthesis and release, and consequent renal sodium reabsorption.

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

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

Withdrawal syndrome (a sharp increase in blood pressure after discontinuation of the drug) after sudden withdrawal after long-term therapy (for 6 months) with Edarbi was not observed.

The safety and effectiveness of the drug do not depend on the age of the patients, but greater sensitivity to lowering blood pressure in some elderly patients cannot be excluded. As with other angiotensin II receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors, the antihypertensive effect is less pronounced in black patients (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 reduction in blood pressure compared to antihypertensive drugs used in monotherapy.

Influence on repolarization processes

Edarby’s potential to prolong the QT/QTc interval was assessed in healthy volunteers during a QT/QTc study. When using a dose of 320 mg of Edarbi, no increase in the QT/QTc interval was noted.

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

Since the duration of the QT interval depends on the heart rate (lengthening as it slows down), it must be corrected for heart rate to be assessed.

Prolongation 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 fatal cardiac arrhythmias.

Pharmacokinetics

Suction

Azilsartan medoxomil is a prodrug. After oral administration, it is converted into the pharmacologically active metabolite azilsartan during absorption from the gastrointestinal tract under the action of the enzyme carboxymethylenebutenolidase in the intestine and liver.

The estimated absolute bioavailability of azilsartan medoxomil when administered orally is approximately 60% based on plasma concentration profiles. The maximum concentration (Cmax) of azilsartan in blood plasma is on average reached within 1.5 – 3 hours after taking the drug orally. Food intake does not affect the bioavailability of azilsartan.

Distribution

The volume of distribution of azilsartan is about 16 liters. Azilsartan binds to blood plasma proteins (more than 99%), mainly to blood plasma albumin. The binding to plasma proteins remains constant when the concentration of azilsartan in the blood plasma significantly exceeds the range achieved when taking recommended doses.

There are no data on the use of the drug during pregnancy and breastfeeding. Azilsartan crosses the placenta of pregnant rats and is excreted into the milk of lactating rats. Radiolabeled animal studies have shown that the amount of azilsartan that crosses the blood-brain barrier is minimal.

Metabolism

Azilsartan is metabolized to two primary metabolites primarily in the liver. The main metabolite in blood plasma is formed by O-dealkylation and is designated as metabolite M-II, the minor metabolite is formed by decarboxylation and is designated as metabolite M-I. The AUC (area under the concentration-time pharmacokinetic curve) values ​​for these metabolites in humans are respectively 50% and less than 1% 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 CYP2C9 isoenzyme.

Removal

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

Linearity/Nonlinearity

The pharmacokinetics of azilsartan in azilsartan medoxomil are dose proportional over a dose range of 20 mg to 320 mg following single or multiple oral doses.

Pharmacokinetics in special groups

Children

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

Elderly patients

The pharmacokinetics of azilsartan in young (18–45 years) and elderly (65–85 years) patients does not differ significantly.

Kidney failure

In patients with mild, moderate and severe renal impairment, AUC was increased by +30%, +25% and +95%, respectively. No increase (+5%) in AUC was observed in patients with end-stage renal disease on hemodialysis. Clinical data on pharmacokinetics in patients with severe or end-stage renal failure are not available. Azilsartan is not removed from the systemic circulation by hemodialysis.

Liver failure

Use of Edarbi for more than 5 days in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) 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 (class C on the Child-Pugh scale) degree of liver failure have not been studied.

Gender

The pharmacokinetics of azilsartan in men and women is not significantly different. No dose adjustment is required depending on gender.

Race

The pharmacokinetics of azilsartan do not differ significantly depending on the race of patients. No dose adjustment is required based on race.

Special instructions

Activated renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend to a large extent on the activity of the RAAS (for example, in patients with severe chronic heart failure (NYHA functional class IV), severe renal failure or renal artery stenosis), treatment with drugs acting on the 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 developing the listed effects cannot be excluded when using 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 transplant

There are no data on the use of Edarbi in patients who have recently undergone kidney transplantation.

Liver dysfunction

There are no data on clinical experience with the use of Edarbi in patients with severe liver dysfunction, therefore the use of the drug in this category of patients is not recommended.

Arterial hypotension due to water and electrolyte imbalance

In patients with reduced blood volume and/or hyponatremia (as a result of vomiting, diarrhea, taking large doses of diuretics, or following a diet with limited sodium intake), clinically significant arterial hypotension may develop after initiation of Edarbi therapy. Hypovolemia should be corrected before starting treatment with Edarbi or starting 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 for such patients.

Hyperkalemia

Clinical experience with other drugs that affect the RAAS shows that the simultaneous administration of Edarbi with potassium-sparing diuretics, potassium supplements or salt substitutes containing potassium, or other drugs that can increase the level of potassium in the blood (for example, heparin) can lead to hyperkalemia in patients with arterial hypertension. Elderly patients, patients with renal failure, 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 monitor serum potassium levels.

Aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy

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

Lithium

As with other angiotensin II receptor antagonists, simultaneous use of lithium and Edarbi is not recommended.

Impact on the ability to drive vehicles and other mechanisms that require increased concentration

Based on the pharmacodynamic properties, it is expected that azilsartan medoxomil will have a slight effect on the ability to drive vehicles and operate machinery. Caution must be exercised, as with any antihypertensive drugs (risk of dizziness and fatigue).

Active ingredient

Azilsartan medoxomil

Composition

1 tablet contains:

active ingredient:

azilsartan medoxomil potassium 42.68 mg, which corresponds to azilsartan medoxomil – 40 mg,

excipients:

mannitol;

fumaric acid;

sodium hydroxide;

hyprolose;

croscarmellose sodium;

MCC;

magnesium stearate.

Pregnancy

Use during pregnancy

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

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

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

Breast-feeding

There is no information on the ability of azilsartan and/or its metabolites to pass 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. It is preferable to use drugs with the best studied safety profile, especially during the period of caring for a newborn or premature baby.

Fertility

There are no data on the effects of Edarbi on fertility in humans. Preclinical studies have shown no effect on male or female fertility in rats.

Contraindications

Hypersensitivity to the active substance and other components of the drug;
pregnancy;
simultaneous use of aliskiren in patients with diabetes mellitus;
age under 18 years (efficacy and safety have not been established);
severe liver dysfunction (more than 9 points on the Child-Pugh scale) (no experience with use).

With caution:

Severe chronic heart failure (IV functional class according to the NYHA classification);
severe renal failure (creatinine clearance <30 ml/min); bilateral renal artery stenosis and stenosis of the artery of the only functioning kidney; ischemic cardiomyopathy; ischemic cerebrovascular diseases; condition after kidney transplantation; conditions accompanied by a decrease in circulating blood volume (CBV) (including vomiting, diarrhea), as well as in patients on a diet with limited salt; when used simultaneously with large doses of diuretics; - primary hyperaldosteronism; hyperkalemia; stenosis of the aortic and mitral valves; hypertrophic obstructive cardiomyopathy (HOCM); age over 75 years.

If you have one of the listed diseases, be sure to consult your doctor before taking Edarbi®.

Side Effects

From the nervous system: often – dizziness.

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

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

From the skin and subcutaneous tissues: infrequently – rash, itching; rarely – angioedema.

From the musculoskeletal and connective tissue side: infrequently – muscle spasms.

Influence on the results of laboratory and instrumental studies: often – increased activity of creatine phosphokinase; infrequently – increased creatinine concentration, hyperuricemia.

General disorders: infrequently – increased fatigue, peripheral edema.

Description of selected adverse reactions

With simultaneous use of Edarbi with chlorthalidone, the frequency of adverse reactions – a pronounced decrease in blood pressure and an increase in creatinine concentration – increases in frequency: from infrequent to frequent.

With simultaneous use of Edarbi with amlodipine, the frequency of an undesirable reaction – peripheral edema – increases from infrequent to frequent, but is less common than with amlodipine monotherapy.

Angioedema, including swelling of the face, lips and periorbital edema, is rare.

As with the use of other angiotensin II receptor antagonists and ACE inhibitors, the simultaneous use of Edarbi with diuretics (for example, chlorthalidone) leads to an increased incidence of increased creatinine concentrations. An increase in creatinine concentration 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-lived or did not progress as long as patients continued therapy. After discontinuation of the drug, most cases of increase in creatinine concentration that did not go away during treatment were reversible. Creatinine concentrations returned to baseline values ​​or values ​​close to baseline in most patients.

When treated with Edarbi, a slight increase in serum uric acid concentration was observed (10.8 µmol/l) compared to placebo (4.3 µmol/l).

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

If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Interaction

Lithium

A reversible increase in serum lithium concentrations and toxicity were observed during concomitant 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 it is necessary to use appropriate combination therapy, regular monitoring of lithium levels in the blood serum is recommended.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

With the simultaneous use of angiotensin II antagonists 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 weakened. With simultaneous use of angiotensin II antagonists and NSAIDs, the risk of renal dysfunction and an increase in serum potassium may increase. Therefore, at the beginning of treatment, patients are advised to regularly take sufficient fluids and monitor kidney function.

Potassium supplements and potassium-sparing diuretics, heparin

Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other drugs (for example, heparin) with azilsartan medoxomil may lead to an increase in serum potassium levels. Patients should monitor serum potassium levels during combination therapy.

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

Dual blockade of the RAAS with angiotensin II receptor antagonists, ACE inhibitors, or aliskiren is associated with an increased risk of arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure) compared with monotherapy.

Additional interaction information for azilsartan medoxomil

No pharmacokinetic interactions were observed with simultaneous use of azilsartan medoxomil or azilsartan with amlodipine, antacids (magnesium and aluminum hydroxide), chlorthalidone, digoxin, fluconazole, glibenclamide, ketoconazole, metformin and warfarin. Azilsartan medoxomil is converted into the pharmacologically active metabolite azilsartan during absorption from the gastrointestinal tract under the action of the enzyme carboxymethylenebutenolidase in the intestine and liver. In vitro studies have shown that interactions based on enzyme inhibition are unlikely.

Diuretics and other antihypertensive drugs

The antihypertensive effect of azilsartan medoxomil therapy can be enhanced when used in combination with other antihypertensive drugs, including diuretics (chlorthalidone and hydrochlorothiazide) and dihydropyridine slow calcium channel blockers (amlodipine).

Overdose

Experience with the use of 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: with a pronounced decrease in blood pressure, place the patient in a “lying” position, raise his legs, take measures to increase the volume of circulating blood (CBV); symptomatic therapy.

Azilsartan is not removed from the systemic circulation by dialysis.

Storage conditions

Store in original packaging to protect from light and moisture at a temperature not exceeding 25° C.

Shelf life

3 years.

Manufacturer

Takeda Island Limited, Ireland