Edarbi® [Azilsartan]

Pharmacological properties

azilsartan medoxomil is an active drug precursor for oral use. the precursor quickly turns into the active molecule of azilsartan, which, due to the blocking of the processes of binding of angiotensin ii to at1 receptors in many tissues, acts as a selective antagonist of the effects of angiotensin ii. angiotensin ii - the main blocking agent of the renin-angiotensin system; the effects of angiotensin ii include vasoconstriction, stimulation of the synthesis and release of aldosterone, stimulation of the heart and sodium reabsorption in the kidneys.

AT receptor blocking₁ leads to inhibition of the negative inverse effect of angiotensin II on renin secretion, but an increase in plasma renin activity and angiotensin II levels in the systemic circulation, which arise due to receptor blocking and do not prevent the development of the hypotensive effect of azilsartan.

Pharmacokinetics After oral administration of azilsartan, medoxomil is rapidly hydrolyzed in the digestive tract and / or during absorption to the active substance (azilsartan).

In vitro studies show that the carboxymethylenebutenolidase enzyme is involved in hydrolysis in the intestinal tract and liver. Plasma esterases are also involved in the hydrolysis of azilsartan medoxomil to azilsartan.

Absorption. Based on the concentration of azilsartan in plasma, the calculated absolute oral bioavailability of azilsartan medoxomil is about 60%. Following oral administration of azilsartan medoxomil C_max plasma azilsartan is reached in 1.5–3 hours. Food does not affect the bioavailability of azilsartan.

Distribution. The volume of distribution of azilsartan is about 16 liters. Azilsartan intensively (99%) binds to plasma proteins, mainly with albumin. Binding to blood plasma proteins does not change in the range of concentrations significantly higher than those achieved when used in recommended doses.

Biotransformation. Metabolic cleavage of azilsartan leads to the formation of two major metabolites. The main metabolite in blood plasma is formed by O-dealkylation, it is referred to as metabolite M-II. The minor metabolite, which is formed as a result of decarboxylation, is referred to as metabolite M-I. The levels of systemic exposure of the main and secondary metabolites in humans were ≈50 and 1% of the exposure level of azilsartan, respectively. M-I and M-II do not have an additional effect on the pharmacological effect of azilsartan medoxomil. Azilsartan metabolism mainly occurs due to the enzyme CYP 2C9.

Following oral administration of 5 mg of azilsartan medoxomil labeled with a radioactive isotope ¹⁴C, about 55% of the radioactivity was excreted from the body with feces and about 42% - with urine. About 15% of the drug was excreted in the urine as unchanged azilsartan. T_½ plasma azilsartan is about 11 hours, and renal clearance is about 2.3 ml / min. The equilibrium concentration of azilsartan is reached within 5 days, and during repeated administration of the drug in the regime of 1 time per day cumulation in the blood plasma is not observed.

Linearity / nonlinearity. In the dose range of azilsartan medoxomil from 20 to 320 mg after taking single or multiple doses, the dependence of the exposure of azilsartan on the dose taken was established.

Characteristics in specific patient subgroups

Children. The pharmacokinetics of azilsartan in children (under the age of 18 years) has not been investigated.

Elderly patients. Significant differences in the pharmacokinetics of azilsartan in young people (aged 18–45 years) and elderly people (65–85 years) were not detected.

Impaired renal function.In patients with mild, moderate, and severe renal impairment, total exposure to azilsartan (AUC) increased by 30; 25 and 95% respectively. In patients with end-stage renal failure during dialysis, no increase in exposure was noted (+ 5%). At the same time, there is no clinical experience with the use of the drug in patients with severe impaired renal function or end-stage renal failure. Azilsartan is not removed from the systemic circulation during hemodialysis.

Impaired liver function. Edarbi treatment of patients with mild (Child A-Pugh class) or moderate (Child-Pugh class B) liver dysfunction for no more than 5 days led to a slight increase in the exposure of azilsartan (increase in AUC by 1.3-1.6 times ) The use of the drug Edarbi for the treatment of patients with severe hepatic impairment has not been investigated.

Floor. Significant differences in the pharmacokinetics of azilsartan in men and women were not detected. There is no need for dose adjustment depending on the patient’s gender.

Racial affiliation. Significant differences in the pharmacokinetics of azilsartan in patients of the Caucasian and Negroid race were not detected. There is no need for dose adjustment depending on the race of the patient.

Indications

Treatment of essential hypertension in adults.

Application

Edarbi is intended for oral use, tablets can be taken regardless of food intake.

The recommended starting dose is 40 mg once daily.

For patients in whom this dose does not adequately control blood pressure, the dose can be increased to the maximum recommended dose of 80 mg once a day.

A stable antihypertensive effect is achieved within 2 weeks of treatment. The maximum effect is achieved after 4 weeks of taking the drug.

If during monotherapy with Edarbi, it is not possible to achieve adequate control of blood pressure, an additional decrease in blood pressure can be achieved through combination treatment with other antihypertensive drugs, including diuretics (for example, chlortalidone and hydrochlorothiazide) and calcium channel blockers.

Elderly patients (from 65 years old) do not need to adjust the initial dose of Edarbi. However, for patients over the age of 75 years with a risk of arterial hypotension, the possibility of using the drug in a dose of 20 mg should be considered (see Pharmacokinetics).

Impaired renal function. Use with caution Edarbi in patients with hypertension and severe renal impairment or end-stage renal failure, since there is no experience with the use of the drug in such patients. Azilsartan is not removed from the systemic circulation during hemodialysis. Patients with mild or moderate renal failure do not require dose adjustment.

Impaired liver function. Studies on the use of Edarbi in patients with severely impaired liver function have not been carried out, therefore, the drug is not recommended for use in patients of this group.

Since the experience of using Edarbi in patients with mild to moderate impaired liver function is limited, it is recommended to carefully monitor the condition of such patients and consider the possibility of using the drug in an initial dose of 20 mg.

Intravascular volume deficiency. For patients with a possible intravascular volume deficiency or salt depletion (for example, patients with vomiting, diarrhea, or patients who receive high doses of diuretics), Edarbi is prescribed under the supervision of a doctor, you should also consider the possibility of using an initial dose of 20 mg.

Patients of the Negroid race. There is no need for dose adjustment, although these patients have a less pronounced decrease in blood pressure compared with patients of a different race. This usually applies to other angiotensin II receptor blockers and ACE inhibitors.For this population, a more frequent increase in the dose of Edarbi and concomitant therapy may be required.

Contraindications

Hypersensitivity to the active substance or other components of the drug. pregnancy or women planning a pregnancy (see use during pregnancy and lactation). do not use edarbi with drugs containing aliskiren in patients with diabetes mellitus or impaired renal function (glomerular filtration rate of 60 ml / min / 1.73 m2).

Side effects

Undesirable effects by frequency of occurrence are classified into the following categories: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000 and 1/1000), very rarely (1/10 000), including isolated cases.

In each organ-organ class, adverse reactions are indicated in decreasing order of their clinical value.

From the nervous system: often - dizziness.

From the vascular system: infrequently - hypotension.

From the alimentary canal: often - diarrhea; infrequently - nausea.

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

From the musculoskeletal system and connective tissue: infrequently - muscle spasms.

General disorders: infrequently - fatigue, peripheral edema.

Laboratory studies: often - increased levels of CPK in the blood; infrequently - increased levels of creatinine in the blood, increased levels of uric acid in the blood / hyperuricemia.

Description of individual adverse reactions. During the combined use of Edarbi and chlortalidone, the frequency of increase in blood creatinine and hypotension increased from infrequently to often.

During the combined use of Edarbi and amlodipine, the incidence of peripheral edema increased from infrequently to often, but was lower than that characteristic of amlodipine in monotherapy.

Laboratory research

Serum creatinine level. In randomized, placebo-controlled trials of monotherapy with the drug, the frequency of increase in serum creatinine after treatment with Edarbi did not differ from that in the placebo group. The simultaneous use of Edarbi and diuretics, such as chlortalidone, led to a higher frequency of increased creatinine levels. This observation is consistent with known facts for other angiotensin II receptor blockers and ACE inhibitors. An increase in creatinine during the combined use of Edarbi and diuretics is associated with a more pronounced decrease in blood pressure compared with the use of one of these drugs. Most episodes of increased creatinine levels were temporary or did not progress with continued treatment. After cessation of treatment, creatinine levels in most cases normalize on their own.

Uric acid. When using Edarbi, a slight average increase in the level of uric acid in the blood plasma was noted compared with placebo (10.8 μmol / L versus 4.3 μmol / L).

Hemoglobin and hematocrit. In placebo-controlled studies of monotherapy with the drug, a slight decrease in the level of hemoglobin and hematocrit was noted (about 3 g / l and 1 vol.%, Respectively). This effect has also been observed with other inhibitors of the renin-angiotensin-aldosterone system (RAAS).

special instructions

Activation of raas. in patients whose vascular tone and renal function mainly depend on RAAS activity (for example, patients with congestive heart failure, severe renal failure or renal artery stenosis), treatment with drugs that affect RAAS (for example, APF inhibitors and angiotensin ii receptor blockers) was associated with the occurrence of acute arterial hypotension, azotemia, oliguria or, in rare cases, arr. it is impossible to exclude the occurrence of such phenomena in the application of edarbi.

Use with caution Edarbi for the treatment of patients with hypertension and severe renal impairment, congestive heart failure or renal artery stenosis, since there is no experience with the drug for the treatment of such patients.

An excessive decrease in blood pressure in patients with coronary artery disease or ischemic cerebrovascular accident can lead to myocardial infarction or stroke.

Double blockade of RAAS. The combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and impaired renal function (including acute renal failure). Therefore, the double blockade of RAAS due to the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see INTERACTIONS). If necessary, therapy with double blockade should be carried out under the supervision of a doctor and monitoring renal function, electrolyte levels and blood pressure. Patients with diabetic nephropathy should not take ACE inhibitors together with angiotensin II receptor blockers.

Kidney transplant To date, there is no experience with the use of Edarbi in patients who have recently undergone kidney transplantation.

Impaired liver function. The use of Edarbi for the treatment of patients with severe hepatic impairment has not been investigated, therefore this drug is not recommended for patients of this group.

Arterial hypotension in patients with bcc deficiency and / or salt depletion. In patients with severe BCC deficiency and / or salt depletion (for example, patients with diarrhea, vomiting, or patients taking high doses of diuretics), symptomatic hypotension may occur after starting treatment with Edarbi. Prior to treatment, measures must be taken to compensate for hypovolemia or treatment should be started under close medical supervision. You should also consider prescribing an initial dose of 20 mg.

Primary hyperaldosteronism. In patients with primary aldosteronism, there is usually no response to treatment with antihypertensive drugs, the mechanism of action of which is to suppress the renin-angiotensin-aldosterone system. Thus, the use of Edarbi in such patients is not recommended.

Hyperkalemia Based on the experience of using other drugs that affect RAAS, the simultaneous use of Edarbi with potassium-sparing diuretics, potassium-containing additives, salt substitutes with potassium, or other drugs that can increase the level of potassium in the blood (for example, heparin) can lead to an increase in the level of potassium in the blood of patients with hypertension. In elderly patients, with renal failure, with diabetes mellitus and / or with other concomitant diseases, the risk of hyperkalemia (which can be fatal) increases. If necessary, potassium levels should be monitored.

Stenosis of aortic and mitral valves, obstructive hypertrophic cardiomyopathy. Treatment of patients with aortic or mitral valve stenosis or with hypertrophic obstructive cardiomyopathy requires special care.

Lithium. As with other angiotensin II receptor blockers, Edarbi should not be prescribed simultaneously with lithium preparations.

Use during pregnancy and lactation

Pregnancy. The drug should not be used in pregnant women or women who are planning a pregnancy. If pregnancy is confirmed during treatment, the use of the drug should be stopped immediately and another drug prescribed for use in pregnant women should be prescribed.

Data on the use of Edarbi in pregnant women are not available. Animal studies have revealed reproductive toxicity.

Epidemiological data do not indicate a risk of teratogenicity as a result of exposure to ACE inhibitors during the first trimester of pregnancy, but a slight increase in risk cannot be ruled out. Due to the lack of controlled epidemiological data regarding the risk associated with angiotensin II receptor blockers, this risk cannot be excluded for drugs of this class. Patients planning a pregnancy should switch to alternative antihypertensive therapy, which has a more studied safety profile for use in pregnant women.

Therapy with angiotensin II receptor blockers in women in the II and III trimester of pregnancy can lead to fetotoxicity (decreased kidney function, oligohydramnios, delayed ossification of the skull bones) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If it is necessary to use angiotensin II receptor blockers in the second trimester of pregnancy, ultrasound is recommended to determine renal function and ossification of the bones of the skull in the fetus.

Infants whose mothers have used angiotensin II receptor blockers should be carefully monitored for hypotension (see CONTRAINDICATIONS, SPECIAL INDICATIONS).

Breastfeeding. The drug is not recommended for use during lactation due to the lack of relevant data. During breastfeeding, it is advisable to begin alternative treatment with a more studied safety profile, especially during feeding a newborn or premature baby.

Fertility. There are no data on the effect of azilsartan medoxomil on human reproductive function. According to the results of preclinical studies, azilsartan did not affect the reproductive function of female and male rats.

Children. There is no data on the use of the drug in children (under 18 years old).

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Given the pharmacodynamic characteristics of the drug, azilsartan medoxomil may have a negligible effect on the reaction rate when driving vehicles or working with other mechanisms. However, while taking any antihypertensive drug, you need to know about the possible occurrence of dizziness or fatigue.

Interactions

Not recommended combinations

Lithium. With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the concentration of lithium in serum and a reversible increase in the severity of toxic manifestations were noted. With angiotensin II receptor blockers, a similar effect is possible. Due to the lack of experience with the simultaneous use of azilsartan medoxomil and lithium preparations, this combination of drugs is not recommended. If necessary, the simultaneous administration of these drugs should carefully monitor the level of lithium in the blood serum.

Combinations to be used with caution

NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid at a dose of 3 g / day and non-selective NSAIDs. With the simultaneous use of NSAIDs (that is, selective COX-2 inhibitors, for example, 3 g / day acetylsalicylic acid and non-selective NSAIDs) and angiotensin II receptor blockers, it is possible to weaken the severity of the hypotensive effect of the latter. In addition, the simultaneous use of angiotensin II receptor blockers and NSAIDs may increase the risk of impaired renal function and potassium levels in the blood. Thus, it is recommended at the beginning of treatment to ensure adequate hydration of the patient and control of renal function.

Potassium-sparing diuretics, potassium-containing supplements, salt substitutes with potassium, and other substances that can increase the level of potassium in the blood.Potassium-sparing diuretics, potassium-containing supplements, potassium-containing salt substitutes, and other drugs (such as heparin) can increase blood potassium levels while it is used. If necessary, serum potassium levels should be monitored.

Additional Information. Clinical studies have shown that the dual blockade of RAAS with the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of developing arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) as compared to monotherapy with the active RAAS agent (see CONTRAINDICATIONS, SPECIAL INSTRUCTIONS).

In studies of the use of azilsartan, medoxomil or azilsartan in combination with amlodipine, antacids, chlortalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin and warfarin, no clinically significant drug interactions were recorded.

Azilsartan medoxomil is rapidly hydrolyzed by digestive tract esterases and / or during absorption to the active substance azilsartan. In vitro studies indicate a low probability of interactions based on inhibition of esterases.

Overdose

Symptoms based on pharmacological properties, it can be expected that the main manifestations of an overdose will be symptomatic hypotension and dizziness. in controlled clinical trials involving healthy individuals, participants received edarbi in a dose of up to 320 mg once a day for 7 days. these doses were well tolerated by study participants.

Treatment. With the development of symptomatic hypotension, substitution therapy should be started and basic vital signs monitored. Azilsartan is not excreted by hemodialysis.

Storage conditions

It does not require special storage conditions. Store in the original packaging.

UA / CVM / 1018/0009