Edarbi, tablets 80 mg 28 pcs

An angiotensin II receptor antagonist. Azilsartan medoxomil is an oral active prodrug that is rapidly converted to active azilsartan by blocking its binding to AT1 receptors in various tissues. Angiotensin II is the main pressor of the renin-angiotensin system with effects including vasoconstriction, stimulation of aldosterone synthesis and release, stimulation of cardiac activity and renal sodium reabsorption.

Blockade of AT1 receptors inhibits the inverse suppressive effect of angiotensin II on renin secretion, but the subsequent increase in circulating plasma renin and angiotensin II concentrations does not override the antihypertensive effect of azilsartan.

When using Edarbi™ in the therapy of arterial hypertension, typical BP dynamics are as follows:
– Mean daily systolic BP decreases by 12.2 mm Hg when taking 20 mg, by 13.4-135 mm Hg when taking 40 mg, by 14.5-14.6 mm Hg when taking 80 mg;
– office systolic BP decreases by 14.3 mm Hg when taking 20 mg, by 14.5-16.4 mm Hg when taking 40 mg, by 16.7-17.6 mm Hg when taking 80 mg.

The hypotensive effect of Edarbi™ is maintained for 24 h after administration.

There is no ricochet hypertension after discontinuation of therapy.

The concomitant administration of Edarbib™ 40 and 80 mg with calcium channel blockers (amlodipine) or thiazide diuretics (chlorthalidone) resulted in additional BP reduction compared to other antihypertensive agents as monotherapy.

Dose-dependent adverse effects, including dizziness, hypotension, and increased serum creatinine concentrations, were more frequently observed when concomitantly administered with diuretics compared to administration of Edarbi™ as monotherapy, and hypokalemia was less frequently observed compared to diuretic monotherapy.

The effect on cardiac repolarization:

There was no evidence of prolongation of QT/QTc intervals when Edarbi™ was administered at doses up to 320 mg/day.

Pharmacokinetics:

After oral administration of azilsartan, medoxomil is rapidly hydrolyzed to active azilsartan in the GI tract and/or during absorption. Based on in vitro studies, carboxymethylene butenolidase has been found to be involved in hydrolysis in the intestine and liver. In addition, plasma esterases are involved in the hydrolysis of azilsartan medoxomil into azilsartan.

The estimated absolute bioavailability of azilsartan medoxomil based on plasma concentrations of azilsartan is approximately 60%. After oral administration of azilsartan medoxomil, the Cmax of azilsartan in plasma is reached within 1.5-3 hours. Food has no effect on the bioavailability of azilsartan.

The Vd of azilsartan is approximately 16 liters. Azilsartan is highly bound to plasma proteins (>99%), mainly to serum albumin. Protein binding is constant at plasma concentrations of azilsartan well above the range achieved at recommended doses. Css of azilsartan is reached within 5 days and there is no plasma cumulation with repeated doses once daily.

Dose proportionality in exposure is established for azilsartan at a dose of azilsartan medoxomil from 20 mg to 320 mg after single or multiple doses.

Asilsartan is metabolized to two major metabolites. The main metabolite in plasma is formed by O-dealkylation and is called metabolite M-II; the second metabolite M-I is formed in lower concentration by decarboxylation. The systemic effects of both metabolites in humans are approximately 50% and less than 1% as such of azilsartan, respectively. M-I and M-II are not involved in the pharmacological activity of Edarbi™. The main enzyme responsible for the metabolism of azilsartan is CYP2C9.

After an oral dose of 14C-labeled azilsartan medoxomil, approximately 55% of the radioactivity is evident in the feces and approximately 42% in the urine; 15% of this dose is excreted in the urine as azilsartan. The T1/2 of azilsartan is approximately 11 h and renal clearance is approximately 2.3 mL/min.

Pharmacokinetics in special patient groups:

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

No increase (+5%) in exposure has been observed in patients with end-stage renal disease on dialysis. However, there is no clinical experience with use in patients with severe renal failure or terminal renal disease. Hemodialysis does not remove azilsartan from the systemic blood stream.

The administration of Edarbi™ for up to 5 days in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment resulted in a slight increase in azilsartan exposure (AUC increased 1.3-1.6-fold). The pharmacokinetics of Edarbi™ in patients with severe hepatic impairment have not been studied.

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

Indications

Hypertension (high blood pressure), Edema

Treatment of essential hypertension in adults.

Active ingredient

Azilsartan medoxomil

Composition

1 tablet:

– azilsartan medoxomil 80 mg

Supplementary substances:

mannitol,

fumaric acid,

sodium hydroxide,

Hydroxypropylcellulose,

sodium croscarmellose,

microcrystalline cellulose,

magnesium stearate.

How to take, the dosage

The tablets should be taken orally regardless of meals.

The recommended starting dose is 40 mg once daily. The dose may be increased to the maximum (80 mg once daily) in patients whose BP is not adequately controlled at lower doses.

The antihypertensive effect is seen at week 2 and the maximum effect is reached by week 4.

If BP is not properly controlled by Edarbi™ monotherapy alone, additional BP reduction may be achieved when Edarbi™ is combined with other antihypertensive medications, including diuretics (such as chlorthalidone and hydrochlorothiazide) and calcium channel blockers (such as amlodipine).

In elderly patients, no special dose selection of Edarby™ is required, although consideration should be given to the 20 mg dose as an initial dose in very elderly persons (>75 years) in whom the risk of hypotension is likely.

Caution should be exercised in patients with severe renal impairment and end-stage renal disease, as there is no experience with Edarbi™ in these patients. Hemodialysis does not remove azilsartan from the circulation. No dose adjustment is required in patients with mild to moderate renal impairment.

Edarbi™ has not been studied in patients with severe hepatic impairment, so its use in this group of patients is not recommended. Since there is limited experience with Edarbi™ in patients with mild to moderate hepatic impairment, close monitoring of these patients is recommended.

In patients with possible decreased RBC or salt depletion (e.g., patients with vomiting, diarrhea, or those taking high doses of diuretics), Edarbib™ should be started under close medical supervision and only after normal RBC has been restored.

Caution should be exercised in patients with arterial hypertension with congestive heart failure, as there is no experience with the use of Edarbi™ in these patients.

Interaction

Unrecommended combinations:

Double blockade of the renin-angiotensin system by angiotensin II receptor antagonists, ACE inhibitors, or aliskiren is associated with an increased risk of arterial hypotension, hyperkalemia, and altered renal function (including acute renal failure) compared with monotherapy.

When lithium and ACE inhibitors are used concomitantly, reversible increases in lithium serum concentrations and toxicity have been reported. A similar effect may occur with angiotensin II receptor antagonists. Due to the lack of experience with concomitant use of azilsartan medoxomil and lithium, their combination is not recommended. If this combination proves necessary, close monitoring of serum lithium concentrations is recommended.

Combinations requiring caution:

NSAIDs (including selective COX-2 inhibitors, acetylsalicylic acid >3 g/day and non-selective NSAIDs) when taken concomitantly with angiotensin II receptor antagonists may reduce antihypertensive effects. In addition, concomitant use of angiotensin II receptor antagonists and NSAIDs may lead to an increased risk of impaired renal function and increased serum potassium concentration. Therefore, adequate hydration and monitoring of renal function is recommended at the beginning of treatment.

The concomitant use of potassium-saving diuretics, potassium preparations, potassium-containing salt substitutes, or other medications (e.g., heparin) may increase potassium concentrations. Serum potassium should be monitored as needed.

Additional information:

No clinically significant interaction of azilsartan medoxomil or azilsartan with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glibenclamide, ketoconazole, metformin and warfarin has been reported.
Azilsartan medoxomil is rapidly hydrolyzed to active azilsartan by esterases in the GI tract and/or during drug absorption. In vitro studies have shown that an interaction based on esterase inhibition is unlikely.

Special Instructions

Activated RAAS:

. In patients in whom vascular tone and renal function are predominantly dependent on RAAS activity (e.g., patients with congestive heart failure, severe renal dysfunction, or renal artery stenosis), treatment with drugs affecting this system, such as ACE inhibitors and angiotensin II receptor antagonists, has been associated with acute arterial hypotension, azotemia, oliguria or, less frequently, acute renal failure. The likelihood of such effects cannot be excluded in Edarbi™.

Caution should be exercised in patients with severe renal dysfunction, congestive heart failure, or renal artery stenosis, as there is no experience with the use of Edarbi™ in these patients.

The excessive reduction of BP in patients with ischemic cardiomyopathy or ischemic cerebrovascular disease may lead to myocardial infarction or stroke.

Kidney transplantation:

There is currently no experience with the use of Edarbi™ in patients who have recently undergone a kidney transplant.

Hepatic impairment:
In patients with severe hepatic impairment, the effects of Edarbi™ have not been studied and therefore its use is not recommended in this group of patients.

Hypotension in patients with water or salt depletion:

In patients with significant decreases in RBC and salt depletion (e.g., patients with vomiting, diarrhea, or taking high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbi™. Hypovolemia should be corrected before starting Edarbi™, or treatment should be initiated under close medical supervision.

Primary Hyperaldosteronism:
Patients with primary hyperaldosteronism usually do not respond to antihypertensive medications that act by inhibiting the renin-angiotensin system. Thus, use of Edarbi™ in these patients is not recommended.
Hyperkalemia:
Based on experience with other drugs that affect the RAAS, concomitant use of Edarbi™ with potassium-saving diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that promote potassium (such as heparin) may result in increased patient serum potassium concentrations. In the elderly, in patients with renal insufficiency, in patients with diabetes and/or in patients with other comorbidities, the risk of hyperkalemia increases, which may be fatal. Potassium concentration should be monitored as needed.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:
Special precautions are recommended in patients with aortic or mitral valve stenosis or with hypertrophic obstructive cardiomyopathy.

Lithium:
As with other angiotensin II receptor antagonists, the combination of lithium and Edarbi™ is not recommended.

Impact on the ability to drive and operate machinery:

Based on pharmacodynamic properties, azilsartan medoxomil is expected to have no significant effect on driving and operating machinery. However, when taking any antihypertensive medication, note that dizziness or fatigue may occasionally occur.

Contraindications

– hypersensitivity to the active substance or to any of the excipients of the drug Edarbi;
– co-administration of aliskiren and azilsartan in patients with diabetes;
– pregnancy;
– lactation;
– children and adolescents under 18 years.

Side effects

When taking Edarbi™, side effects may be mild to moderate. Gender and age have no effect on the frequency of side effects.

The incidence of side effects of the drug is rated as follows: very common (≥1/10), common (≥1/100, Frequent: dizziness, diarrhea, increased blood CFA.

Infrequent: arterial hypotension, feeling of fatigue, peripheral edema*, increased blood creatinine, increased blood uric acid concentration/hyperuricemia.

Rarely: angioedema, including perioral and periorbital edema, decreased hemoglobin concentration and hematocrit.

* – The incidence of peripheral edema was increased when Edarbi™ was used concomitantly with amlodipine, but was lower than when amlodipine was used in monotherapy.

Overdose

There have been no signs of overdose in patients who have taken Edarbi™ 320 mg/day for 7 days.

Symptoms: Arterial hypotension and dizziness.

Treatment: if arterial hypotension has occurred, symptomatic therapy should be started and vital functions should be monitored. Hemodialysis is not effective.

Pregnancy use

Angiotensin II receptor antagonists should not be started during pregnancy. Unless continuation of previously initiated therapy with angiotensin II receptor antagonists is considered important, patients planning to become pregnant should be replaced by an alternative antihypertensive medication that is safe for use in pregnancy. If pregnancy is established, treatment with angiotensin II receptor antagonists should be stopped immediately, and alternative therapy should be initiated if necessary.

As there is no information on the use of Edarbi™ during lactation, the use of the drug is not recommended and alternative therapies with better proven safety characteristics during lactation, especially while nursing a newborn or premature infant, are preferable.