Edarby® (Edarbi®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAzilsartan medoxomilAzilsartan medoxomil
Dosage form: & nbsppills
Composition:

1 tablet of 20 mg contains:

Active substance: azilsartan medoxomil potassium 21.34 mg corresponds to azilsartan medoxomil 20 mg

Excipients: mannitol 47.815 mg, fumaric acid 1 mg, sodium hydroxide 0.345 mg, giprolose 2.7 mg, croscarmellose sodium 6.9 mg, cellulose microcrystalline 9 mg, magnesium stearate 0.9 mg.

1 tablet of 40 mg contains:

Active substance: azilsartan medoxomil potassium 42.68 mg corresponds to azilsartan medoxomil 40 mg

Excipients: mannitol 95.63 mg, fumaric acid 2 mg, sodium hydroxide 0.69 mg, giprolose 5.4 mg, croscarmellose sodium 13.8 mg, microcrystalline cellulose 18 mg, magnesium stearate 1.8 mg.

1 tablet of 80 mg contains:

Active substance: azilsartan medoxomil potassium 85.36 mg corresponds to azilsartan medoxomil 80 mg

Excipients: mannitol 191.26 mg, fumaric acid 4 mg, sodium hydroxide 1.38 mg, giprolose 10.8 mg, croscarmellose sodium 27.6 mg, cellulose microcrystalline 36 mg, magnesium stearate 3.6 mg.

Description:

Tablets of 20 mg:

From white to almost white, round biconvex tablets with engraving "ASL" on one side and "20" on the other.

Tablets 40 mg:

From white to almost white, round biconvex tablets with engraving "ASL" on one side and "40" on the other.

Tablets 80 mg:

From white to almost white, round biconvex tablets with engraving "ASL" on one side and "80" on the other.

Pharmacotherapeutic group:Angiotensin II receptor antagonist
ATX: & nbsp

C.09.C.A.09   Azilsartan medoxomil

Pharmacodynamics:

Azilsartan medoxomil, the active substance of the Edarb® preparation, is a specific antagonist of angiotensin II type 1 receptors (AT1). Azilsartan medoxomil is a prodrug for oral administration. Azilsartan medoxomil quickly turns into an active molecule of azilsartan, which selectively prevents the development of the effects of angiotensin II by blocking its binding to the AT receptors1 in various tissues. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldehsterone system (RAAS) with effects including vasoconstriction, cardiac stimulation, synthesis stimulation and aldosterone release, and as a consequence, renal sodium reabsorption.

Blockade AT1-receptor inhibits the negative regulatory response of angiotensin II to renin secretion,but the final increase in plasma activity of renin and the level of circulating angiotensin II 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. Reduction of blood pressure (BP) after ingestion of a single dose is usually achieved within a few hours and persists for 24 hours.

Syndrome "cancellation" (a sharp increase in blood pressure after drug withdrawal) after a sudden withdrawal after prolonged therapy (for 6 months) with Edarb® was not observed.

The safety and effectiveness of the drug do not depend on the age of the patients, but a greater sensitivity to lowering blood pressure in some elderly patients can not be ruled out. As with the use of other angiotensin II receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors, the antihypertensive effect is less pronounced in patients of the Negroid race (usually a population with low renin activity in the blood plasma).

Simultaneous application of Edarb® 40 mg and 80 mg with dihydropyridine blockers of "slow" calcium channels (amlodipine) or thiazide diuretics (chlorthalidone) leads to an additional decrease in blood pressure in comparison with antihypertensive agents used in monotherapy (see section Interaction with other drugs).

Influence on repolarization processes

Evaluation of the Edarby® potential to increase the interval QT/QTc was conducted in healthy volunteers during the study QT/QTc. When applying a dose of 320 mg

Edarby® interval increases QT/QTc not noted. QTc - Corrected (relative to the heart rate (heart rate)) interval value QT, relative value. Since the duration of the interval QT depends on the frequency of the heart rate (lengthening when it slows down), for evaluation, it must be corrected for the heart rate. Interval lengthening QT reflects the heterogeneity of the processes of repolarization of the ventricular myocardium, and is regarded as an independent indicator indicating the possible occurrence of fatal cardiac arrhythmias.

Pharmacokinetics:

Suction

Azolsartan medoxomil is a prodrug. After oral administration, it becomes a pharmacologically active metabolite of azilsartan during absorption from the gastrointestinal tract by the action of the enzyme carboxymethylenebutenolidase in the gut and liver.

Estimated absolute bioavailability of azilsartan medoxomil for oral administration is approximately 60 % according to the profile of concentrations in the blood plasma. The maximum concentration (CmOh) of azilsartan in blood plasma is achieved on average within 1.5 - 3 hours after ingestion. Eating 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 with albumens of blood plasma. The association with blood plasma proteins remains constant at a concentration of azilsartan in the blood plasma, which is significantly higher than the range achieved with the intake of recommended doses.

Data on the use of the drug during pregnancy and during breastfeeding are absent. Azilsartan penetrates the placenta of pregnant rats and is excreted into the milk of lactating rats (see section Application during pregnancy and during breastfeeding).

Studies on animals with radioactive labels showed that the amount of azilsartan penetrating the blood-brain barrier is minimal.

Metabolism

Azilsartan is metabolized to two primary metabolites, mainly in the liver. The main metabolite in the blood plasma is formed by O-dealkylation and is referred to as the metabolite M-II, a secondary metabolite is formed by decarboxylation and is referred to as a metabolite of M-I. Values AUC (area under the pharmacokinetic curve "concentration-time") for these metabolites in humans is 50% and less than 1%, respectively, compared with azilsartan. M-I them-II do not affect the pharmacological activity of Edarb®. The main enzyme that provides the metabolism of azilsartan is isoenzyme CYP2C9.

Excretion

Azilsartan and its metabolites are excreted from the body, both through the intestine, and by the kidneys. Studies have shown that after ingestion of azilsartan medoxomil, about 55% (mainly in the form of the metabolite M-I) is found in feces and about 42% (15% - in the form of azilsartan, 19% - in the form of metabolite M-II) - in the 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 reached within 5 days and its cumulation in the blood plasma with a single daily application does not occur.

Linearity / Nonlinearity

The pharmacokinetics of azilsartan in azilsartan medoxomil is proportional to the dosage in the dose range from 20 mg to 320 mg after single or multiple oral administration.

Pharmacokinetics in special groups

Children

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

Elderly patients

Pharmacokinetics of azilsartan in young (18-45 years) and elderly (65 - 85 years) patients is not significantly different.

Renal insufficiency

In patients with mild, moderate and severe degree of renal failure AUC was increased by + 30%, + 25% and + 95% respectively. Increases (+ 5 %) AUC in patients with terminal stage of renal failure, on hemodialysis, was not observed. Clinical data on pharmacokinetics in patients with severe degree or terminal stage of renal failure are absent.

Azilsartan is not excreted from the systemic blood flow through hemodialysis.

Liver failure

The use of EDARBY ® for more than 5 days in patients with mild (class A on the Child-Pugh scale) or moderate (class B on the Child-Pugh scale) severity of liver failure leads to a slight increase AUC (in 1.3 - 1.6 times, respectively). The pharmacokinetics of Edarb® in patients with severe (grade C on the Child-Pugh scale) degree of hepatic insufficiency has not been studied.

Gender identity

The pharmacokinetics of azilsartan in men and women is not significantly different. Correction of dose depending on sex is not required.

Race

The pharmacokinetics of azilsartan depending on the race of patients is not significantly different. Dose adjustments are not required depending on the race.

Indications:

Essential hypertension.

Contraindications:

- hypersensitivity to the active substance and other components of the drug;

- pregnancy;

- simultaneous administration of aliskiren in patients with diabetes mellitus;

- age under 18 years (effectiveness and safety not established);

- severe violations of the liver (more than 9 points on the scale Child-Pugh) (no experience of use).

Carefully:

- severe chronic heart failure (IV functional class by classification NYHA);

- severe renal insufficiency (creatinine clearance <30 mL / min);

- bilateral stenosis of the renal arteries and stenosis of the artery of a single functioning kidney;

- ischemic cardiomyopathy;

- ischemic cerebrovascular disease;

- condition after kidney transplantation;

- conditions, accompanied by a decrease in the volume of circulating blood (bcc) (including vomiting, diarrhea), as well as in patients who observe a diet with restriction of table salt;

- with simultaneous use with high doses of diuretics;

- primary hyperaldosteronism;

- hyperkalemia;

- Stenosis of the aortic and mitral valves;

- hypertrophic obstructive cardiomyopathy (GOKMP);

- age over 75 years.

If you have any of these diseases, consult your doctor before taking Edarby.

Pregnancy and lactation:

Application during pregnancy

In animal studies, it has been found that azilsartan and M-II penetrate through the placental barrier.

Patients planning a 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 Edarb® and, if necessary, begin treatment with drugs approved for use during pregnancy.

In newborns, whose mothers received therapy with Edarby®, hypotension may develop, and therefore newborns should be under careful medical supervision.

Breast-feeding

There is no information on the ability of azilsartan and / or its metabolites to enter breast milk. In animal studies, it has been found that azilsartan and M-II are excreted in the milk of lactating rats.

Due to the lack of experience with the use of Edarb® in women during breastfeeding, its use in this category of patients is not recommended. Preferably the use of drugs with the most studied safety profile, especially during the care of a newborn or premature baby.

Fertility

There are no data on the effect of Edarb® on fertility in humans. Preclinical studies showed no effect on male or female fertility in rats.

Dosing and Administration:

Edarby® is taken orally once a day, regardless of the time of ingestion. The recommended initial dose is 40 mg once a day. If it is necessary to further reduce blood pressure, the dose of the drug can be increased to a maximum of 80 mg once a day.

The maximum daily dose is 80 mg.

In case of inadequate control of blood pressure in monotherapy with Edarb® it is possible to use it simultaneously with other antihypertensive agents, including diuretics (chlorthalidone and hydrochlorothiazide) and dihydropyridine blockers of "slow" calcium channels (amlodipine).

Duration of treatment

Edarb® should be taken daily, without interruption. In the event of discontinuation of treatment, the patient should inform the physician about this.

Dose skip

If you miss a dose, the patient should take the next dose at the usual time. Do not take a double dose of Edarb®.

Special Groups

Patients of advanced age (65 years and older)

It is not necessary to correct the initial dose of Edarb® in elderly patients. However, in patients older than 75 years, a dose of 20 mg can be considered as an initial (increases the risk of developing arterial hypotension).

Patients with impaired renal function

There is no clinical experience with the use of Edarb® in patients with AH with impaired renal function and severe end-stage renal failure, so use the drug in this patient category should be used with caution.

It is not necessary to correct the dosing regimen in patients with impaired renal function of mild to moderate severity.

Patients with impaired hepatic function

It is not recommended to use the drug in patients with severe hepatic dysfunction due to lack of clinical experience (see section Contraindications).

Because of the limited experience with the use of Edarb® in patients with impaired liver function of mild and moderate severity, it is recommended to start treatment at a dose of 20 mg once a day and monitor it carefully.

Reduction of the volume of circulating blood (BCC)

The Edarby® drug should be given to patients with reduced BCC and / or hyponatremia (eg, patients with prolonged vomiting, diarrhea, or taking large doses of diuretics) only under strict medical supervision. It is also recommended to start treatment with a dosage of 20 mg once a day.

Heart failure

Due to the lack of clinical experience, Edarb® should be used with caution in patients with AH with severe chronic heart failure (class IV functional class NYHA).

Negroid race

Do not require dose adjustment in patients of the Negroid race. As in the case of other angiotensin II receptor antagonists (AT1) and ACE inhibitors, a decrease in blood pressure is observed in patients of the Negroid race in comparison with the rest of the population. In this regard, for an adequate control of blood pressure in patients of the Negroid race, an increase in the dose of Edarb® and complex therapy may be necessary more often than in other patients.

Side effects:

The frequency of adverse reactions was determined in accordance with the recommendations of the World Health Organization: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100, rarely (> 1/10 000, <1/1000), very rarely (<1/10 000), including individual messages; unspecified frequency (frequency can not be calculated by available data).

System of organs

Frequency

Adverse Reactions

Infringements from

Often

Dizziness

nervous system



Infringements from

Infrequently

Marked decrease in blood pressure

vessels



Infringements from

Often

Diarrhea

gastrointestinal tract

Infrequently

Nausea

Disturbances from the skin and

Infrequently

Rash, itching

subcutaneous tissue



Rarely

Angioedema



Disturbances from musculoskeletal and connective tissue

Infrequently

Muscle spasms



Impact on the results of laboratory and instrumental studies

Often

Increase in activity of creatine phosphokinase


Infrequently

Increase in concentration

creatinine

Hyperuricemia


Common violations

Infrequently

Increased fatigue, peripheral edema


Description of individual adverse reactions

With the simultaneous use of Edarby® with chlorthalidone, the incidence of adverse reactions-a marked decrease in blood pressure and an increase in creatinine-increases in frequency: from infrequent to frequent.

With the simultaneous use of EDARBY® with amlodipine, the frequency of the undesired reaction-peripheral edema-increases from infrequent to frequent, but is less common than with amlodipine monotherapy.

Rarely angioedema is observed, including edema of the face, lips and periorbital edema.

As with the use of other angiotensin II receptor antagonists and ACE inhibitors, the simultaneous use of Edarb® with diuretics (eg, chlorthalidone) leads to more cases of increased creatinine concentration. An increase in the concentration of creatinine with the simultaneous use of EDARBI® with diuretics is associated with a large decrease in blood pressure as compared with the monotherapy of EDARBY®.Most of these effects were transient or non-progressive, as long as patients continued therapy. After drug withdrawal, the majority of cases of increase in creatinine concentration that did not pass during treatment were reversible. The creatinine concentration in most patients returned to values ​​on the baseline, or values ​​close to the baseline.

In the treatment of Edarby®, a slight increase in serum uric acid concentration (10.8 μmol / L) was observed compared with placebo (4.3 μmol / L).

As with other RAAS inhibitors, a small decrease in hemoglobin and hematocrit was observed in monotherapy (on average, they decreased by about 3 g / L and 1% by volume, respectively).

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

Overdose:

The experience of using Edarb® in adults at 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, give the patient a "lying down" position, raise the legs, carry out measures to increase the volume of circulating blood (BCC); symptomatic therapy.

Azilzartan is not excreted from the systemic blood flow through dialysis.

Interaction:

Lithium

There was a reversible increase in serum lithium concentration and toxicity during simultaneous use of lithium preparations and ACE inhibitors and lithium preparations with angiotensin II receptor antagonists. Therefore, simultaneous use of azilsartan medoxomil in combination with lithium preparations is not recommended (see section Special instructions). If it is necessary to use the appropriate combination therapy, regular monitoring of the lithium content in serum is recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs)

With simultaneous use of angiotensin II antagonists and NSAIDs (for example, selective inhibitors of COX-2 (cyclooxygenase-2), acetylsalicylic acid (more than 3 g / day) and non-selective NSAIDs), the antihypertensive effect may be attenuated. With simultaneous use of angiotensin II antagonists and NSAIDs, the risk of renal dysfunction and increased serum potassium levels may increase.Therefore, at the beginning of treatment, patients are advised to take a regular intake of a sufficient amount of fluid and monitor the function of the kidneys.

Potassium preparations and potassium-sparing diuretics, heparin

Simultaneous use of potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium and other medicines (eg, heparin) with azilsartan medoxomil can lead to an increase in serum potassium content (see section Special instructions). Patients should be monitored for serum potassium during combined therapy.

Double blockade of angiotensin-aldosterone system (RAAS)

Double blockade of 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 information on the interaction of azolsartan medoxomil

No pharmacokinetic interactions were observed with the simultaneous use of azilsartan medoxomil or azilsartan with amlodipine,antacid preparations (magnesium and aluminum hydroxide), chlorthalidone, digoxin, fluconazole, glibenclamide, ketoconazole, metformin and warfarin.

Azolsartan medoxomil is converted into the pharmacologically active metabolite azilsartan during absorption from the gastrointestinal tract by the action of the enzyme carboxymethylenebutenolidase in the gut and liver. Research in vitro showed that interactions based on inhibition of enzymes are unlikely.

Diuretics and other antihypertensives

The antihypertensive effect of the therapy with azilsartan medoxomil can be strengthened when combined with other antihypertensive agents, including diuretics (chlorthalidone and hydrochlorothiazide), and dihydropyridine blockers of "slow" calcium channels (amlodipine).

Special instructions:

Activated renin-angiotensin-aldosterone system

Patients who have vascular tone and kidney function depend to a large extent on the activity of RAAS (for example, in patients with severe chronic heart failure (class IV functional class NYHA), severe renal failure or stenosis of the renal arteries), treatment with drugs acting on 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 these effects can not be ruled out when using Edarby®.

A sharp decrease in blood pressure in patients with ischemic cardiomyopathy or ischemic cerebrovascular disease can lead to the development of myocardial infarction or stroke.

Kidney Transplantation

Data on the use of Edarb® in patients who have recently undergone kidney transplantation are not available.

Impaired liver function

Data on the clinical experience of the use of Edarb® in patients with severe hepatic impairment are absent, therefore, the use of the drug in this category of patients is not recommended.

Arterial hypotension on the background of disturbance of water-electrolyte balance

In patients with reduced RT (K and / or hyponatremia (as a result of vomiting, diarrhea,receiving large doses of diuretics, or adherence to a diet with restricted intake of table salt), clinically significant arterial Hypotension after initiation of therapy with Edarb®. Hypovolemia should be adjusted before starting treatment with Edarb® or starting treatment with a dosage of 20 mg.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to therapy with antihypertensive drugs that affect RAAS. In this regard, Edarby® is not recommended for such patients.

Hyperkalemia

Clinical experience with other drugs that affect RAAS shows that simultaneous administration of Edarby® with potassium-sparing diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that may increase the potassium content of the blood (eg, heparin) can lead to Hyperkalemia in patients with arterial hypertension. In elderly patients, patients with renal insufficiency, diabetes mellitus and / or patients with other concomitant diseases, the risk of developing hyperkalemia increases, which can be fatal.In such patients it is recommended to monitor the potassium content in the blood serum.

Stenosis of aortic or mitral valves, hypertrophic obstructive cardiomyopathy

Care should be taken when administering Edarby® to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Lithium

As with other angiotensin II receptor antagonists, simultaneous use of lithium preparations and Edarb® preparation is not recommended (see section Interaction with other drugs).

Effect on the ability to drive transp. cf. and fur:

Based on pharmacodynamic properties, it is expected that azilsartan medoxomil will slightly affect the ability to drive motor transport and management mechanisms. Care should be taken, as with any antihypertensive drug (risk of dizziness and fatigue).

Form release / dosage:

Tablets of 20 mg, 40 mg and 80 mg.

Packaging:

By 14 tablets in an AL blister with a built in PE layer desiccant. By 1, 2, 3, 4 or 7 blisters together with instructions for use are placed in a cardboard pack.

Storage conditions:

Store in the original packaging to protect from light and moisture at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription
Registration number:LP-002359
Date of registration:03.02.2014
The owner of the registration certificate:Takeda Global Research and Development Sente (Europe) LimitedTakeda Global Research and Development Sente (Europe) Limited United Kingdom
Manufacturer: & nbsp
Representation: & nbspTakeda Pharmaceuticals Ltd.Takeda Pharmaceuticals Ltd.
Information update date: & nbsp14.08.2015
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