Instructions Edarbiclor film-coated tablets 40 mg + 12.5 mg blister No. 28
Composition
active ingredients: azilsartan medoxomil, chlorthalidone.
1 tablet contains azilsartan medoxomil potassium 42.68 mg (equivalent to 40 mg azilsartan medoxomil) and chlorthalidone 12.5 mg;
excipients: mannitol (E 421), microcrystalline cellulose, fumaric acid, sodium hydroxide, hydroxypropylcellulose, crospovidone, magnesium stearate, hypromellose 2910, talc, titanium dioxide (E 171), red iron oxide (E 172), polyethylene glycol 8000, gray ink F1.
Dosage form
Film-coated tablets.
Main physicochemical properties: light pink, round, film-coated tablets, with the inscription "A/C" and "40/12.5" on one side.
Pharmacotherapeutic group
Angiotensin II antagonists and diuretics.
ATX code C09D A09.
Pharmacological properties
Pharmacodynamics
The drug EdarbiKlor® is a combination of two antihypertensive agents with complementary mechanisms of blood pressure regulation: the active precursor of the drug substance angiotensin II AT1 receptor antagonist azilsartan medoxomil and the thiazide-like diuretic chlorthalidone.
Mechanism of action and pharmacodynamic effects.
Azilsartan medoxomil is an orally active prodrug that is rapidly converted by esterases in the gastrointestinal tract during absorption to the active molecule azilsartan, which blocks the action of angiotensin II by selectively blocking its binding to the AT1 receptor in many tissues. Angiotensin II is the main pressor agent of the renin-angiotensin system, which has vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal sodium reabsorption.
Blockade of the AT1 receptor inhibits the negative feedback of angiotensin II with renin secretion, as a result of which increases in plasma renin activity and circulating angiotensin II levels do not attenuate the blood pressure-lowering effect of azilsartan.
Chlorthalidone causes diuresis with increased excretion of sodium and chlorine. The site of action of chlorthalidone is the distal part of the renal tubules (the initial section of the convoluted tubule). The diuretic effect of chlorthalidone is due to inhibition of the reabsorption of Na+Cl- ions by counteracting the Na+Cl- cotransporter in this area, which leads to increased excretion of sodium and water.
Effect on cardiac repolarization.
A thorough QT/QTc study was conducted to assess the potential of azilsartan medoxomil to prolong the QT/QTc interval in healthy subjects. No evidence of QT/QTc prolongation was observed with azilsartan medoxomil at a dose of 320 mg.
Cardiovascular disease outcome studies have demonstrated that long-term treatment with chlorthalidone reduces the risk of morbidity and mortality from such diseases.
A study examining the combination of an ACE inhibitor with an angiotensin II receptor antagonist in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with evidence of target organ damage, and in patients with type 2 diabetes mellitus and diabetic nephropathy, did not demonstrate a significant benefit on renal and/or cardiovascular outcomes and mortality, while there was an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared with monotherapy.
A study designed to test the benefit of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin receptor antagonist for patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both, was stopped early due to an increased risk of adverse outcomes.
Pharmacokinetics
Co-administration of azilsartan 80 mg and chlorthalidone 25 mg once daily for 7 days did not affect the PK of these substances in healthy volunteers.
After oral administration of the fixed-dose tablet, the peak plasma concentration (Cmax) of chlorthalidone is 45% higher than that of chlorthalidone and azilsartan as separate tablets. The extent of absorption, as measured by the area under the curve (AUC), of both azilsartan and chlorthalidone after administration of EdarbiClor® is similar to that after administration of azilsartan and chlorthalidone as separate medicinal products.
EdarbiKlor® can be taken regardless of food intake.
The pharmacokinetic properties of the individual components of EdarbiClor® (azilsartan medoxomil/chlorthalidone) are described below according to their brief characteristics.
Absorption.
Azilsartan medoxomil. Azilsartan medoxomil is an orally administered drug that is rapidly converted to the active substance azilsartan by esterases during absorption.
The estimated absolute bioavailability of azilsartan medoxomil is approximately 60%. After oral administration of azilsartan medoxomil, Cmax of azilsartan is reached after 1.5-3 hours. Food intake does not affect the bioavailability of azilsartan (see section "Special instructions").
Chlorthalidone: The estimated bioavailability of chlorthalidone is approximately 64% 8–12 hours after administration. With multiple doses of 50 mg/day, a mean steady-state blood concentration of 7.2 μg/mL (21.2 μmol/L) measured at the end of the 24-hour dosing interval is achieved after 1–2 weeks.
Distribution.
Azilsartan medoxomil. The volume of distribution of azilsartan is approximately 16 liters. Azilsartan is extensively (> 99%) bound to plasma proteins, primarily serum albumin. Plasma protein binding is unchanged over a range of concentrations significantly higher than those achieved at recommended doses.
Chlorthalidone. In whole blood, chlorthalidone is primarily bound to carbonic anhydrase, which is found in red blood cells. In plasma, approximately 76% of chlorthalidone is bound to plasma proteins, primarily albumin. Chlorthalidone crosses the placental barrier and is excreted in breast milk. When a woman received 50 mg of chlorthalidone daily before and after birth, the level of chlorthalidone in fetal whole blood was approximately 15% of that in maternal blood. Chlorthalidone concentrations in amniotic fluid and breast milk were approximately 4% of the maternal blood concentration.
Metabolism.
Azilsartan medoxomil. Azilsartan is metabolized to two major metabolites. The major metabolite in plasma is formed by O-dealkylation and is designated as metabolite M-II, while the minor metabolite is formed by decarboxylation and is designated as metabolite MI. The systemic exposure levels of the major and minor metabolites in humans are approximately 50% and less than 1% of azilsartan, respectively. MI and M-II do not affect the pharmacological activity of azilsartan medoxomil. The major enzyme responsible for the metabolism of azilsartan is CYP2C9.
Chlorthalidone. Metabolism and excretion via the liver and bile play a minor role in elimination. Approximately 70% of chlorthalidone is excreted in the urine and feces within 120 hours, mainly unchanged.
Breeding.
Azilsartan medoxomil. After oral administration of 14C-labeled azilsartan medoxomil, approximately 55% was excreted in the feces and approximately 42% in the urine. Approximately 15% of the drug was excreted in the urine as unchanged azilsartan. The plasma half-life of azilsartan is approximately 11 hours, and renal clearance is approximately 2.3 ml/min. Steady-state concentrations of azilsartan are reached within 5 days, and no accumulation in plasma occurs with repeated once-daily dosing.
Chlorthalidone. The elimination half-life of chlorthalidone from whole blood and plasma averages 50 hours. The half-life after repeated doses remains unchanged. The majority of the absorbed dose of chlorthalidone is excreted by the kidneys, with a mean renal clearance of 60 ml/min.
Linearity/nonlinearity.
Azilsartan medoxomil.
Dose-proportionality to exposure was established for azilsartan over the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing.
Chlorthalidone.
For doses of 25 mg and 50 mg, Cmax values averaged 1.5 μg/mL (4.4 μmol/L) and 3.2 μg/mL (9.4 μmol/L), respectively. For doses up to 100 mg, a proportional increase in AUC was observed.
Special populations.
Elderly patients.
The pharmacokinetics of azilsartan do not differ significantly between young (age range 18–45 years) and elderly (age range 65–85 years) patients.
In elderly patients, chlorthalidone is eliminated more slowly than in healthy young patients, although absorption remains the same. Therefore, caution is recommended when treating very elderly patients (≥ 75 years) with EdarbiClor® (see section 4.2).
Kidney dysfunction.
In patients with mild, moderate and severe renal impairment, the total exposure (AUC) of azilsartan was increased by +30%, +25% and +95%. No increase (+5%) was observed in dialysis patients with end-stage renal disease. However, there is no clinical experience in patients with severe renal impairment (GFR < 30 mL/min/1.73 m2) or end-stage renal disease (see section 4.3). Azilsartan is not removed from the systemic circulation by haemodialysis.
Most of the absorbed dose of chlorthalidone is excreted by the kidneys, but impaired renal function does not alter the pharmacokinetics of chlorthalidone. The rate-limiting factor in the elimination of chlorthalidone from the blood or plasma is likely to be the drug's affinity for carbonic anhydrases found in erythrocytes. Therefore, no dosage adjustment is necessary for patients with mild to moderate renal impairment (GFR ≥ 30–< 90 mL/min/1.73 m2).
Administration of azilsartan medoxomil for 5 days in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment resulted in a small increase in azilsartan exposure (1.3- to 1.6-fold increase in AUC). Azilsartan has not been studied in patients with severe hepatic impairment. Chlorthalidone has not been studied in patients with hepatic impairment.
Due to the chlorthalidone content, EdarbiKlor® is contraindicated for use in patients with severe liver dysfunction (see section "Method of administration and dosage").
Sex.
The pharmacokinetics of azilsartan do not differ significantly between men and women. In a population pharmacokinetic analysis of patients with hypertension treated with EdarbiClor®, men had lower exposure (Cmax and AUC) than women (≤ 30%). The differences in pharmacokinetics are not considered clinically significant.
No dose adjustment is required based on gender.
Racial affiliation.
The pharmacokinetics of azilsartan do not differ significantly between Caucasian and Negroid patients. In a population pharmacokinetic analysis of patients with arterial hypertension treated with EdarbiClor®, no effect of race on the pharmacokinetics of azilsartan or chlorthalidone was detected.
No dose adjustment is necessary based on race.
Indication
Treatment of hypertension in adults whose blood pressure is not adequately controlled with azilsartan medoxomil monotherapy.
Contraindication
- Hypersensitivity to the active substance or other components of the drug;
- anuria;
- therapy-resistant hypercalcemia, hyponatremia;
- severe liver and kidney dysfunction (creatinine clearance < 30 ml/min);
- symptomatic hyperuricemia;
- pregnancy;
- do not use together with aliskiren-containing drugs in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2).
Interaction with other medicinal products and other types of interactions
Combinations that are not recommended for use.
Lithium. Increased serum lithium concentrations and toxicity have been reported during concomitant use of lithium and angiotensin II receptor antagonists. Serum lithium levels should be monitored during concomitant use. Diuretics such as chlorthalidone reduce renal clearance of lithium, increasing its toxicity. Monitoring of lithium levels is recommended when using EdarbiKlor®.
Due to the lack of experience with the concomitant use of EdarbiKlor® and lithium, this combination is not recommended. If the use of such a combination proves necessary, monitoring of serum lithium levels should be considered.
Caution should be exercised with concomitant use.
Non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), acetylsalicylic acid > 3 g/day) and non-selective NSAIDs. In elderly patients, in patients with hypovolemia (including patients receiving diuretics) and in patients with impaired renal function, the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, and angiotensin II receptor antagonists, including azilsartan, may lead to deterioration of renal function, including the development of acute renal failure, and an increase in serum potassium. Therefore, adequate hydration and monitoring of renal function at the beginning of treatment are recommended.
With the simultaneous use of angiotensin II receptor antagonists with NSAIDs (selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), the antihypertensive effect of EdarbiKlor® may be weakened.
Potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels. Given the experience with other drugs that affect the RAAS, the use of EdarbiKlor® with potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g. heparin) may lead to increases in serum potassium levels in patients with arterial hypertension (see section "Special instructions").
Digitalis: Concomitant use of digitalis may exacerbate the adverse effects of hypokalemia (see section 4.4).
Additional information.
The drug EdarbiClor®.
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) with the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared with the use of a single RAAS-acting agent (see sections 5.1, 5.2 and 5.4).
No drug interaction studies have been conducted with EdarbiClor®, although drug interaction studies have been conducted with azilsartan medoxomil and chlorthalidone.
Azilsartan medoxomil: No clinically significant drug interactions were observed in studies of concomitant use of azilsartan medoxomil or azilsartan with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone, and warfarin.
Azilsartan medoxomil is an active prodrug that is rapidly hydrolyzed by esterases to the active molecule azilsartan in the gastrointestinal tract and/or during absorption of the drug (see section 5.1). In vitro studies have shown that interactions based on esterase inhibition are unlikely.
Chlorthalidone. Diuretics potentiate the effects of curare derivatives and antihypertensive agents (e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium antagonists, ACE and ARB inhibitors).
The hypokalemic effect of chlorthalidone may be potentiated by corticosteroids, ACTH, β2-agonists, amphotericin, and carbenoxolone.
Allopurinol: Concomitant use of chlorthalidone may increase the incidence of hypersensitivity reactions to allopurinol.
Amantadine: Chlorthalidone may increase the risk of side effects caused by amantadine.
Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of chlorthalidone by reducing gastrointestinal motility and gastric emptying rate.
Antidiabetic drugs (oral agents and insulin): Dose adjustment of antidiabetic drugs may be required.
Calcium salts: The pharmacological effects of both calcium salts and vitamin D may be increased to clinically significant levels when co-administered with chlorthalidone.
Cyclosporine: Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-like complications.
Cholestyramine: Absorption of chlorthalidone is impaired in the presence of anion exchange resins. A reduction in pharmacological effect may be expected.
Cytotoxic agents: Concomitant use may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
Diazoxide: The hyperglycemic effect of diazoxide may be potentiated by chlorthalidone.
Application features
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
If dual blockade is considered absolutely necessary, this therapy should only be used under specialist supervision and with frequent close monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
The renin-angiotensin-aldosterone system is activated.
In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with congestive heart failure or renal disease including bilateral renal artery stenosis), treatment with drugs that affect this system, such as ACE inhibitors and angiotensin II receptor antagonists, has been associated with acute hypotension, azotemia, oliguria and, rarely, acute renal failure. The possibility of such effects cannot be excluded with the use of EdarbiKlor®.
Evaluation of patients with hypertension with activated RAAS should include periodic assessment of renal function and electrolyte levels.
Excessive reduction in blood pressure in patients with ischemic cardiomyopathy or ischemic cerebrovascular disease may lead to myocardial infarction or stroke.
Kidney dysfunction.
Chlorthalidone, which is part of the drug EdarbiKlor®, should not be used in severe renal insufficiency (GFR < 30 ml/min/1.73 m2) (see section "Contraindications"). No dose adjustment is required for patients with mild to moderate renal impairment.
Chlorthalidone should be used with caution in patients with impaired renal function, as chlorthalidone may precipitate azotemia. If progressive renal failure becomes evident, consideration should be given to reducing or discontinuing diuretic therapy.
Kidney transplantation.
To date, there is no experience with the use of EdarbiClor® in patients who have recently undergone kidney transplantation.
Liver dysfunction.
Chlorthalidone, which is part of the drug EdarbiKlor®, should not be used in severe hepatic insufficiency (see section "Contraindications").
There is limited experience with the use of EdarbiKlor® in patients with mild to moderate hepatic impairment; however, based on PK studies, no dose adjustment is necessary in patients with mild to moderate hepatic impairment. Minor changes in fluid and electrolyte balance caused by thiazide diuretics may precipitate hepatic coma. Therefore, close monitoring is recommended (see section 5.1).
Hypotension in patients with volume and/or salt depletion.
In patients with possible intravascular volume depletion or salt depletion (e.g. patients experiencing vomiting, diarrhea, or receiving high doses of diuretics), EdarbiKlor® should be initiated under close medical supervision (see section 4.2). Volume depletion and/or salt depletion should be corrected before initiating treatment with EdarbiKlor®.
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that act through inhibition of the renin-angiotensin system. Therefore, EdarbiKlor® is not recommended for use in such patients.
Electrolyte imbalance.
Serum electrolyte levels should be measured periodically in patients receiving diuretic therapy.
Thiazides may cause fluid and electrolyte disturbances (including hypokalemia, hypercalcemia, hyponatremia, and hypochloremic alkalosis). Warning signs of fluid and electrolyte disturbances include dry mouth, thirst, asthenia, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8). Fluid and electrolyte disturbances should be corrected before initiating treatment with EdarbiKlor®.
Hypokalemia.
Hypokalemia is a dose-dependent adverse reaction that may occur with chlorthalidone monotherapy. Concomitant use with azilsartan medoxomil has been shown to reduce chlorthalidone-associated hypokalemia. Concomitant use of digitalis may exacerbate the adverse effects of hypokalemia. Hypokalemia should be corrected before initiating treatment with EdarbiClor®.
Hyperkalemia.
Due to the antagonism of the angiotensin II receptor component of EdarbiKlor®, azilsartan medoxomil, hyperkalemia may develop. Although clinically significant hyperkalemia has not been reported with EdarbiKlor®, risk factors for the development of hyperkalemia include renal and/or cardiac insufficiency, as well as diabetes mellitus. Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes should be administered with caution with EdarbiKlor® (see section “Interaction with other medicinal products and other forms of interaction”).
Hyponatremia and hypochloremic alkalosis.
Thiazides have been shown to cause hyponatremia. EdarbiClor® should not be used in patients with refractory hyponatremia (see Contraindications). Chloride deficiency is usually mild and does not usually require treatment.
Hypercalcemia.
Thiazides may reduce urinary calcium excretion and cause occasional and minor increases in serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may indicate latent hyperparathyroidism. Thiazides should be discontinued before performing parathyroid function tests. EdarbiKlor® should not be used in patients with hypercalcemia (see Contraindications).
Hypomagnesemia.
Thiazides have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see section “Interaction with other medicinal products and other types of interactions”).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.
As with other drugs that cause vasodilation or fluid volume depletion, special caution is indicated in patients with aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy.
Metabolic and endocrine effects.
Thiazide therapy may impair glucose tolerance, so adjustment of insulin dose or antidiabetic therapy may be necessary. Latent diabetes mellitus may become manifest during thiazide therapy. Elevations in cholesterol and triglycerides have been associated with thiazide therapy.
Some patients receiving chlorthalidone or other thiazide diuretics may develop hyperuricemia or manifest overt gout. EdarbiClor® should not be used in patients with symptoms of hyperuricemia (see section "Contraindications").
Pregnancy.
EdarbiKlor® should not be used during pregnancy (see section “Contraindications”).
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).
Diuretics should not be used to treat edema or hypertension during pregnancy (see section “Use during pregnancy or breastfeeding”).
Lithium.
As with other angiotensin II receptor antagonists, the combination of lithium and EdarbiKlor® is not recommended (see section “Interaction with other medicinal products and other types of interactions”).
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma.
Drugs containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours to weeks of starting the drug.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The main treatment is to stop the medication as soon as possible. If the intraocular pressure remains uncontrolled, urgent medical or surgical treatments may be necessary. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Use during pregnancy or breastfeeding
Pregnancy.
EdarbiKlor® should not be used during pregnancy (see sections “Contraindications” and “Special instructions”).
The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section "Special warnings and precautions for use"). The use of angiotensin II receptor antagonists is contraindicated in the second and third trimesters of pregnancy (see sections "Contraindications" and "Special warnings and precautions for use"). Thiazides are contraindicated during pregnancy (see sections "Contraindications" and "Special warnings and precautions for use"). |
There are no clinical data on the use of EdarbiClor® in pregnant women. Animal studies have shown reproductive toxicity.
Azilsartan medoxomil.
Epidemiological data on the risk of teratogenicity following exposure to angiotensin-converting enzyme inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Although there are no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of medicinal products. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor antagonists during the second and third trimesters of pregnancy is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see sections 4.3 and 4.4).
Chlorthalidone.
Diuretics should not be used to treat edema or hypertension during pregnancy because their use may be associated with hypovolemia, increased blood viscosity, and decreased placental perfusion. Diuretics such as chlorthalidone have been shown to cross the placental barrier and appear in cord blood. Fetal bone marrow depression, thrombocytopenia, and fetal and neonatal jaundice have been reported in association with thiazide-like diuretics.
There is no information on the use of EdarbiClor® or azilsartan medoxomil during breastfeeding. However, chlorthalidone is excreted in human milk and therefore the use of EdarbiClor® is not recommended during breastfeeding. Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
Fertility.
There are no data on the effect of EdarbiClor® on human fertility. Preclinical studies have shown that azilsartan medoxomil does not affect male or female fertility in rats.
Ability to influence reaction speed when driving vehicles or other mechanisms
Given the pharmacodynamic properties of EdarbiKlor®, it is expected that the drug will have a negligible effect on the speed of reaction when driving or using other mechanisms. However, when using any antihypertensive drug, the possibility of dizziness or increased fatigue should be taken into account.
Method of administration and doses
The drug EdarbiKlor® is intended for oral use; tablets can be taken regardless of meals.
The recommended initial dose for adults is 1 tablet (40/12.5 mg) once daily. The antihypertensive effect is mainly evident within 1–2 weeks of treatment. After 2–4 weeks of treatment, the dose may be increased to 40/25 mg if necessary to achieve the target blood pressure.
Special patient groups.
Kidney dysfunction.
Chlorthalidone, which is part of the drug EdarbiKlor®, should not be used in patients with severe renal insufficiency (GFR < 30 ml/min/1.73 m2) and anuria (see section "Contraindications"). There is no experience with the use of the drug EdarbiKlor® in patients with a recent kidney transplant. For patients with mild (estimated GFR 60-90 ml/min/1.73 m2) and moderate (estimated GFR 30-60 ml/min/1.73 m2) degree of renal insufficiency, dose adjustment of the drug is not required.
Liver dysfunction.
Chlorthalidone, which is a component of EdarbiClor®, should not be used in patients with severe hepatic impairment (see section “Contraindications”). There is limited experience with the use of EdarbiClor® in patients with mild to moderate hepatic impairment; however, no adjustment of the initial dose of EdarbiClor® is required in patients with mild to moderate hepatic impairment.
Thiazides should be used with caution in patients with impaired hepatic function (see sections "Contraindications" and "Special Instructions for Use"). Minor changes in fluid and electrolyte balance in the body caused by thiazide diuretics can cause hepatic coma. Close monitoring is recommended.
Elderly patients.
No dose adjustment of EdarbiKlor® is required for elderly patients; caution should be exercised and close monitoring should be performed in elderly patients (over 75 years of age), who may be at increased risk of adverse events.
Depletion of intravascular fluid volume.
In patients with intravascular volume or salt depletion (e.g. patients who have been vomiting, diarrhoea or are taking high doses of diuretics), EdarbiKlor® should be initiated under close medical supervision only after adequate volume has been restored (see section "Special warnings and precautions for use").
A transient hypotensive reaction due to volume depletion does not preclude further treatment of patients, which can usually be continued without any particular difficulty after stabilization of blood pressure and volume.
