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

Edema, Hypertension (high blood pressure)

Essential hypertension.

Active ingredient

Azilsartan medoxomil

Composition

1 tablet contains:

the active ingredient:

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

complementary substances:

Mannitol;

fumaric acid;

sodium hydroxide;

Hyprolose;

croscarmellose sodium;

MCC;

magnesium stearate.

How to take, the dosage

Edarbi is taken orally once a day regardless of the time of meals. The recommended starting dose is 40 mg once daily. If additional BP lowering is necessary, the drug dose can be increased to maximum 80 mg once daily.

The maximum daily dose is 80 mg.

In case of inadequate BP control by Edarbi monotherapy it is possible to use it simultaneously with other hypotensive agents, including diuretics (chlorthalidone and hydrochlorothiazide) and dihydropyridine “slow” calcium channel blockers (amlodipine).

The duration of treatment

Edarbi should be taken daily, without interruption. If treatment is discontinued, the patient should inform the physician.

If you forget to use the medication

If the patient misses another dose, they should take the next dose at the usual time. Do not take a double dose of Edarbi.

Patients in the elderly (65 years and older)

The initial dose of Edarbi does not need to be adjusted in elderly patients. However, in patients over 75 years of age, the dose of 20 mg may be considered as starting dose (increased risk of arterial hypotension).

Patients with impaired renal function

There is no clinical experience of using Edarbi in patients with AH with severe renal impairment and end-stage renal failure, therefore the drug should be used with caution in this category of patients. There is no need to correct the dosage regimen in patients with mild to moderate renal dysfunction.

Patients with hepatic impairment

The use of the drug in patients with severe hepatic impairment is not recommended because of lack of clinical experience. Because of the limited experience with Edarbi in patients with mild to moderate hepatic dysfunction, it is recommended that treatment be started at a dose of 20 mg once daily and monitored closely.

Decreased circulating blood volume (CBC)

Edarbi should be administered to patients with decreased CBC and/or hyponatremia (e.g., patients with prolonged vomiting, diarrhea, or those taking high doses of diuretics) only under strict medical supervision. It is also recommended to start treatment with a dosage of 20 mg once daily.

Heart failure

Because of a lack of clinical experience, caution should be exercised when using Edarbi in patients with AH with severe chronic heart failure (NYHA functional class IV).

Negroid race

There is no need for dose adjustment in patients of the negroid race. As with other angiotensin II receptor antagonists (AT1) and ACE inhibitors, patients of the non-Hispanic race have a smaller decrease in BP compared with the rest of the population. Therefore, increasing the dose of Edarbi and complex therapy more often may be necessary to adequately control BP in non-Hispanic patients than in other patients.

Interaction

Lithium

A reversible increase in serum lithium concentration and toxicity during concomitant use of lithium and ACE inhibitors and lithium preparations with angiotensin II receptor antagonists has been noted. Therefore, concomitant use of azilsartan medoxomil in combination with lithium preparations is not recommended. If appropriate combination therapy is required, regular monitoring of serum lithium content is recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs)

. When concomitant use of angiotensin II antagonists and NSAIDs (e.g., selective COX-2 (cyclooxygenase-2) inhibitors, acetylsalicylic acid (more than 3 g/day) and non-selective NSAIDs) may weaken the antihypertensive effect. Concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of renal dysfunction and increased serum potassium. Therefore, at the beginning of treatment, patients are recommended to take plenty of fluids regularly and to control renal function.

Potassium and potassium-saving diuretics, heparin

The simultaneous use of potassium-saving diuretics, potassium preparations, salt substitutes containing potassium and other drugs (e.g., heparin) with azilsartan medoxomil may lead to increased serum potassium levels. Patients should monitor serum potassium during combination therapy.

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

Dual RAAS blockade with 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.

Preliminary information on interactions of azilsartan medoxomil

No pharmacokinetic interactions have been observed with concomitant 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 to the pharmacologically active metabolite azilsartan during absorption from the gastrointestinal tract by the enzyme carboxymethylenbutenolidase in the gut and liver. In vitro studies have shown that interactions based on enzyme inhibition are unlikely.

Diuretics and other hypotensive agents

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

Special Instructions

Activated renin-angiotensin-aldosterone system

. Patients in whom vascular tone and renal function are highly dependent on RAAS activity (e.g., patients with severe chronic heart failure (NYHA functional class IV), severe renal insufficiency 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 acute arterial hypotension, azotemia, oliguria or rarely acute renal failure. The possibility of these effects cannot be excluded even during the use of Edarbi. Sharp decrease of BP in patients with ischemic cardiomyopathy or ischemic cerebrovascular diseases may lead to development of myocardial infarction or stroke.

Kidney transplantation

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

Hepatic impairment

There are no data on clinical experience with Edarbi in patients with severe hepatic impairment; therefore, use of the drug in this patient population is not recommended.

Hypotension due to electrolyte imbalance

Patients with decreased blood circulation and/or with hyponatremia (as a result of vomiting, diarrhea, taking high doses of diuretics or following a diet with restriction of table salt intake) may develop clinically significant hypotension after start of Edarbi therapy. Hypovolemia should be corrected before starting treatment with Edarbi or treatment should be started at a dosage of 20 mg.

Primary Hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to therapy with hypotensive drugs that affect the RAAS. Therefore, it is not recommended to prescribe Edarbi to these patients.

Hyperkalemia

. Clinical experience with other drugs affecting the RAAS shows that concomitant administration of Edarbi with potassium-saving diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that may increase blood potassium levels (e.g., heparin) may lead to hyperkalemia in patients with arterial hypertension. In elderly patients, patients with renal insufficiency, diabetes mellitus and/or patients with other comorbidities, the risk of hyperkalemia increases, which may be fatal. In such patients it is recommended to monitor serum potassium content.

Aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy

Patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy should use caution when prescribing Edarbi.

Lithium

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

Impact on ability to drive vehicles and other mechanisms requiring increased concentration

Based on pharmacodynamic properties, azilsartan medoxomil is expected to have little effect on the ability to drive and operate machinery. Caution should be exercised as with any hypotensive agents (risk of dizziness and increased fatigue).

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Contraindications

• High sensitivity to the active ingredient and other drug components
• pregnancy
• concurrent use of aliskiren in patients with diabetes;
• age below 18 years of age (efficacy and safety not established);
• severe hepatic dysfunction (greater than 9 points on the Child-Pugh scale) (no experience of use).

With caution:

• Severe chronic heart failure (NYHA functional class IV);
• severe renal failure (creatinine clearance < 30 ml/min);
• bilateral renal artery stenosis and artery stenosis of the only functioning kidney;
• ischemic cardiomyopathy;
• ischemic cerebrovascular disease;
• state after renal transplantation;
situations accompanied by decreased circulating blood volume (CBC) (including vomiting, diarrhea), as well as in patients on a diet with restriction of table salt;
• when used simultaneously with high doses of diuretics; – primary hyperaldosteronism;
• hyperkalemia;
• aortic and mitral valve stenosis;
• hypertrophic obstructive cardiomyopathy (HOCMP);
• age above 75 years.

If you have any of the above conditions, be sure to consult your doctor before taking Edarbi®.

Side effects

Nervous system disorders: often – dizziness.

vascular disorders: infrequent – marked decrease in BP.

Gastrointestinal tract: frequently – diarrhea; infrequently – nausea.

Skin and subcutaneous tissue: infrequent – rash, itching; rarely – angioedema.

Skeletal, muscular and connective tissue: infrequent – muscle cramps.

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

General disorders: infrequent – fatigue, peripheral edema.

Description of individual adverse reactions

In concomitant use of Edarbi with chlorthalidone, the frequency of adverse reactions – marked decrease in BP and increase in creatinine concentration – increases in frequency of occurrence: from infrequent to frequent.

When concomitant use of Edarbi with amlodipine, the frequency of the adverse reaction – peripheral edema – increases from infrequent to frequent, but occurs less frequently than with amlodipine monotherapy.

Rarely, angioedema, which includes edema of the face, lips, and periorbital edema, has been observed.

As with other angiotensin II receptor antagonists and ACE inhibitors, concomitant use of Edarbi with diuretics (e.g., chlorthalidone) leads to increased frequency of creatinine concentration. The increase in creatinine concentration during concomitant use of Edarbi with diuretics is associated with a greater decrease in BP compared with Edarbi monotherapy. Most of these effects were transient or not progressive while patients continued therapy. After withdrawal of the drug, most of the increases in creatinine concentrations that did not go away during treatment were reversible. Creatinine concentrations in most patients returned to values at or near baseline.

There was a slight increase in serum uric acid concentration (10.8 μmol/L) when treated with Edarbi compared with placebo (4.3 μmol/L).

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

If any of the side effects listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

Edarbi has been used in adults in doses up to 320 mg/day for 7 days and is well tolerated.

Symptoms: pronounced BP decrease, dizziness.

Treatment: with a marked decrease in BP, put the patient in the supine position, elevate the legs, conduct measures to increase circulating blood volume (RBC); symptomatic therapy.

Asilsartan is not excreted from systemic blood flow by dialysis.

Pregnancy use

Pregnancy use

In animal studies, azilsartan and M-II have been shown to cross the placental barrier.

Patients planning to become pregnant should initiate therapy with alternative hypotensive drugs with an established safety profile for pregnant women. Immediately after confirmation of pregnancy, Edarbi should be discontinued and, if necessary, treatment with drugs approved for use during pregnancy should be initiated.

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

Breastfeeding

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

Because of the lack of experience in the use of Edarbi in women during breastfeeding, its use in this category of patients is not recommended. The use of drugs with the best studied safety profile is preferable, especially during the period of care of the newborn or premature infant.

Fertility

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