Edarbi, tablets 20 mg 28 pcs

A specific angiotensin II type 1 receptor antagonist (AT₁). Azilsartan medoxomil is a prodrug. It rapidly converts 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 RAAS with effects including vasoconstriction, cardiac stimulation, stimulation of aldosterone synthesis and release, and consequent renal sodium reabsorption.

At_{1 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 BP after a single oral dose is usually achieved within several hours and maintained for 24 hours.

No withdrawal syndrome has been observed after abrupt discontinuation of long-term therapy (over 6 months) with Edarbi^®.

The safety and efficacy of the drug are not dependent on the age of patients, but greater sensitivity to BP reduction in some elderly patients cannot be excluded.

As with other angiotensin II receptor antagonists and ACE inhibitors, the antihypertensive effect is less pronounced in patients of non-Hispanic race (usually a population with low plasma renin activity). Concomitant use of Edarbi^® 40 mg and 80 mg with dihydropyridine slow calcium channel blockers (amlodipine) or thiazide diuretics (chlorthalidone) leads to additional BP reduction compared to therapy with antihypertensive agents used in monotherapy.

The effect on repolarization processes

The evaluation of the potential of Edarbi^® to prolong the QT/QT_c interval was performed in healthy volunteers during the QT/QT_c study. No increase in the QT/QT_c interval was observed with the use of Edarbi^® at a dose of 320 mg. QT_c is the corrected (relative to HR) value of the QT interval, a relative value. Because the QT interval duration depends on heart rate (lengthening as it slows down), it must be corrected relative to HR to estimate it.

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

Indications

Edema, Hypertension (high blood pressure)

• essential hypertension.

Active ingredient

Azilsartan medoxomil

How to take, the dosage

The drug is taken orally once a day regardless of meals.

The recommended starting dose is 40 mg once daily. If additional BP lowering is necessary, the drug dose may be increased to a maximum of 80 mg once daily. The maximum daily dose is 80 mg.

In case of inadequate BP control when using Edarbi^® as monotherapy it is possible its simultaneous use with other antihypertensive agents, including diuretics (chlorthalidone and hydrochlorothiazide) and dihydropyridine slow calcium channel blockers (amlodipine).

The drug Edarbi^® should be taken daily without interruption. If the patient discontinues treatment, he should inform his physician.

If the next dose is missed, the patient should take the next dose at the usual time. Do not take a double dose of Edarbi^®.

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 the starting dose (increased risk of arterial hypotension).

No dosing adjustment is required in patients with mild to moderate renal dysfunction. There is no clinical experience of using Edarbi^® in patients with severe renal dysfunction and end-stage renal failure, therefore the drug should be used with caution in this category of patients. ® in patients with mild to moderate hepatic impairment it is recommended to start the treatment at dose of 20 mg once daily with close monitoring. Its use in patients with severe hepatic impairment is not recommended because of lack of clinical experience.

The drug Edarbi^® should be administered to patients with decreased blood circulation and/or hyponatremia (e.g., patients with prolonged vomiting, diarrhea, or those taking high-dose diuretics) only under close medical supervision. It is recommended to start treatment with a dosage of 20 mg once daily.

Because of lack of clinical experience, caution should be exercised when using Edarbi^® in patients with severe chronic heart failure (functional class IV according to NYHA classification).

Dose adjustment is not required in non-Hispanic patients. 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. As a result, non-Hispanic patients may require an increased dose of Edarbi^® and complex therapy more often than other patients to adequately control BP.

Interaction

A reversible increase in serum lithium concentration and toxicity have been observed with concomitant use of lithium and ACE inhibitors and lithium preparations with angiotensin II receptor antagonists. Therefore, concomitant use of azilsartan medoxomil in combination with lithium preparations is not recommended. If it is necessary to use this combination, regular monitoring of lithium in blood serum is recommended.

The simultaneous use of angiotensin II antagonists and NSAIDs (e.g., selective COX-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.

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

Double blockade of the RAAS 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.

No pharmacokinetic interactions have been observed when azilsartan medoxomil or azilsartan is used concomitantly with amlodipine, antacids (magnesium and aluminum hydroxide), chlorthalidone, digoxin, fluconazole, glibenclamide, ketoconazole, metformin and warfarin.

Asilsartan medoxomil is converted to the pharmacologically active metabolite azilsartan during absorption from the GI tract by the enzyme carboxymethylenbutenolidase in the intestine and liver. In vitro studies have shown that interactions based on enzyme inhibition are unlikely.

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

Special Instructions

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 with the use of Edarbi^®.

The sharp decrease in BP in patients with ischemic cardiomyopathy or ischemic cerebrovascular disease may lead to the development of myocardial infarction or stroke.

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

There are no data about clinical experience of using Edarbi^® in patients with severe hepatic impairment, therefore the use of the drug in this category of patients is not recommended.

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

Patients with primary hyperaldosteronism are usually resistant to therapy with hypotensive drugs affecting the RAAS. Therefore, Edarbi^® is not recommended for administration in these patients.

The clinical experience with other drugs that affect the RAAS shows that simultaneous administration of Edarbi^® with potassium-saving diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that may increase potassium in the blood (e.g., heparin) may lead to hyperkalemia in patients with arterial hypertension. Elderly patients, patients with renal insufficiency, patients with diabetes and/or patients with other comorbidities have an increased risk of hyperkalemia, which may be fatal. In such patients it is recommended to monitor serum potassium content.

When using Edarbi^® in patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy, caution should be exercised.

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

Impact on driving and operating machinery

Based on pharmacodynamic properties, azilsartan medoxomil is expected to have negligible effect on driving and operating machinery. Caution should be exercised as with any antihypertensive medication (risk of dizziness and increased fatigue).

Contraindications

• severe hepatic dysfunction (more than 9 points on the Child-Pugh scale) (no experience of use);
• pregnancy;
• concomitant administration of aliskiren in patients with diabetes mellitus;
• age under 18 years of age (efficacy and safety not established);
• high sensitivity to the active substance and other components of the drug.

With caution, the drug should be used in severe chronic heart failure (functional class IV according to NYHA classification); severe renal failure (CK <30 ml/min); Bilateral stenosis of the renal arteries and stenosis of the artery of the only functioning kidney; ischemic cardiomyopathy; ischemic cerebrovascular diseases; conditions after renal transplantation; conditions accompanied with reduction of the circulatory bases (including

In combination with high-dose diuretics; primary hyperaldosteronism; hyperkalemia; aortic and mitral valve stenosis; hypertrophic obstructive cardiomyopathy (HACMI); patients aged over 75 years.

Side effects

The frequency of adverse reactions was determined according to WHO recommendations: Very common (>1/10); common (>1/100, <1/10); infrequent (>1/1000, <1/100); rare (>1/10 000, <1/1000); very rare (<1/10 000), including individual reports; unspecified frequency (frequency cannot be calculated from available data).

Nervous system disorders: often – dizziness.

Cardiovascular system disorders: infrequent – marked decrease in BP.

Gastrointestinal system: frequently – diarrhea; infrequently – nausea.

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

Muscular system: infrequent – muscle cramps.

Laboratory and instrumental disorders: often – increase of CPK activity; infrequent – increase of creatinine concentration, hyperuricemia.

Others: infrequent – fatigue, peripheral edema.

Description of individual adverse reactions

When 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 incidence 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. Increased creatinine concentration when concomitant use of Edarbi^® with diuretics is associated with a more pronounced decrease in BP compared to monotherapy with Edarbi^®. Most of these effects were transient or nonprogressive 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.

Treatment with Edarbi^® showed a slight increase in serum uric acid concentration (10.8 μmol/L) compared to placebo (4.3 μmol/L).

As with other RAAS inhibitors, a slight decrease in hemoglobin and hematocrit was observed with Edarbi^® as monotherapy (decreased on average by approximately 3 g/L and 1 vol.%, respectively).

If any of the side effects listed in the instructions worsen, or if the patient notes other side effects not listed in the instructions, this should be reported to the physician.

Overdose

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

Symptoms: marked decrease in BP, dizziness.

Treatment: with marked BP decrease, the patient should be transferred to a horizontal position with a low headrest; measures to increase the blood pressure and symptomatic therapy are recommended. Hemodialysis is ineffective.