Aprovasc pills 5 mg + 150 mg 28 pcs
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Active ingredients
Amlodipine + Irbesartan
Release form
Pills
Composition
Amlodipine besylate 7 mg; which corresponds to the content of amlodipine 5 mg; irbesartan 150 mg; excipients: microcrystalline cellulose 50 microns - 66 mg, croscarmellose sodium - 12 mg, hypromellose 6 mpa.s - 5 mg, microcrystalline cellulose 100 microns - 5 mg, colloidal silicon dioxide - 2.5 mg, magnesium stearate - 2.5 mg; film coating composition: white opadry (hypromellose - 62.5%, titanium dioxide (e171) - 31.25%, macrogol 400 - 6.25%) - 10 mg.
Pharmacological effect
Combined antihypertensive drug. The pharmacodynamic properties of each of the active substances that make up Aprovask, irbesartan and amlodipine, contribute to their additive antihypertensive effect when used in combination as compared to those of each of these drugs separately. Both angiotensin II receptor antagonists (ARA II) and slow calcium channel blockers reduce blood pressure by reducing peripheral vascular resistance, blocking calcium in the cell and reducing angiotensin II caused by exposure to vasoconstrictor action, complement each other; Irbesartan; Irbesartan; selectively active APA II (subtype-AT1). Angiotensin II is an important component of the RAAS, which is involved in the pathophysiology of the development of arterial hypertension and in the homeostasis of sodium ions. Irbesartan does not need metabolic activation to manifest its action. Irbesartan blocks a strong vasoconstrictor and aldosterone-secreting action of angiotensin II due to selective antagonism of angiotensin II receptors (AT1 subtype) located in the cells of the vascular smooth muscle and the adrenal cortex. Irbesartan has no agonistic activity towards AT1 receptors. Its affinity for AT1 receptors is 8,500 times greater than for AT2 receptors (receptors that have not been shown to be linked to maintaining cardiovascular balance [homeostasis]) .; Irbesartan does not inhibit RAAS enzymes (such as renin, ACE) and also does not affect other hormone receptors or ion channels in the cardiovascular system, which are involved in the regulation of blood pressure and sodium ion homeostasis.The blockade with AT1 receptor irbesartan breaks the feedback loop in the renin-angiotensin system, increasing plasma concentrations of renin and angiotensin II. When using irbesartan, the plasma concentration of aldosterone is reduced, however, when using the drug in recommended doses, there is no significant change in the serum potassium content (the average increase in serum potassium is less than 0.1 mEq / l). Irbesartan has no significant effect on the concentration of triglycerides, cholesterol or glucose in serum. Irbesartan does not affect serum uric acid concentrations or the excretion of uric acid by the kidneys. The antihypertensive effect of irbesartan develops after the first dose is taken and becomes significant within 1-2 weeks of treatment with a maximum effect occurring after 4-6 weeks. In long-term observational studies, the effect of irbesartan was maintained for more than 1 year. A single dose of irbesartan at doses up to 900 mg / day caused a dose-dependent decrease in blood pressure. A single dose of irbesartan in doses of 150-300 mg / day led to a greater decrease in systolic (AAD) / diastolic (DBP) blood pressure (24 hours after a dose) in the supine or sitting position (an average of 8-13 / 5-8 mm Hg. Art.), than that when receiving a placebo. The effect of the drug 24 hours after the dose was 60-70% of the corresponding maximum reduction in DBP and SBP. Optimum efficacy in reducing blood pressure over 24 hours is achieved with a single dose of the drug per day. Blood pressure decreases by approximately the same degree in the standing and lying position. The orthostatic effect is rare, and, as with the use of ACE inhibitors, its occurrence can be expected in patients with hyponatremia or hypovolemia. The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients who fail to achieve the target BP values with monotherapy with irbesartan, adding small doses of hydrochlorothiazide (12.5 mg) to the administration of irbesartan 1 time / day results in an additional (compared to the placebo effect) decrease in 24 h after taking them, at 7-10 / 3-6 mm Hg. Art., respectively.; Age and gender do not affect the effectiveness of irbesartan.As in the case of treatment with other drugs that affect the RAAS, patients of the Negroid race have a weaker antihypertensive effect in monotherapy with irbesartan. When irbesartan is taken with small doses of hydrochlorothiazide (for example, 12.5 mg / day), the antihypertensive effect in patients of the Negroid race approaches that in patients of the Caucasian race.; After the withdrawal of irbesartan, blood pressure gradually returns to its original level. No withdrawal syndrome was observed when discontinuing irbesartan.; Amlodipine; Amlodipine is a blocker of slow calcium channels from the group of dihydropyridine derivatives, which inhibits the transmembrane entry of calcium ions into the cells of myocardium and vascular smooth muscle. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle. The exact mechanism by which amlodipine reduces the frequency and severity of angina attacks is not fully established, but amlodipine reduces myocardial ischemia due to the two effects listed below. 1) Amlodipine expands peripheral arterioles and due to this reduces the round focal system, the so-called afterload. Since Amlodipine heart rate is almost not increased, this reduction in the load on the heart muscle reduces the energy consumption of the myocardium and its oxygen demand. 2) The mechanism of the antianginal action of amlodipine also appears to be associated with the expansion of the main coronary arteries and coronary arterioles, as in myocardial zones with normal blood flow, and in the ischemic zones of the myocardium. This expansion of the coronary vessels increases the delivery of oxygen to the myocardium in patients with spasm of the coronary arteries (with Prinzmetal angina pectoris or variant angina pectoris) .; In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure in the prone position and standing for 24 hours Due to the slow onset of its action, amlodipine is not intended for the relief of hypertensive crises. In patients with angina pectoris, amlodipine is taken once daily during the course of the test with physical tion load increases the overall execution time of exercise, the time until an attack of angina and time before the ST-segment depression on the ECG depth of 1 mm.In addition, taking the drug reduces the daily number of strokes and the daily need for taking nitroglycerin pills. When taking amlodipine, there were no undesirable metabolic effects or changes in blood lipid concentrations. Amlodipine can be prescribed to patients with asthma, diabetes mellitus and gout. Clinical evidence of the efficacy of a combination of fixed-dose irbesartan and amlodipine was obtained in two multicenter, prospective, open-label studies of parallel groups with blind assessment of performance indicators: I-ADD and I-COMBINE studies . The results of both studies showed a significantly higher efficacy of combinations with fixed doses of irbesartan and amlodipine compared with amlodipine monotherapy or irbesartan monotherapy.
Pharmacokinetics
Irbesartan; Absorption; Irbesartan is a drug that is active when taken orally, which does not need biotransformation to show its activity. After oral administration, irbesartan is rapidly and completely absorbed. Cmax of irbesartan in blood plasma is achieved within 1.5-2 hours after ingestion. The absolute bioavailability of irbesartan when administered orally is 60-80%. Eating does not affect the bioavailability of irbesartan.; Distribution; Binding to plasma proteins is approximately 96%, irbesartan is almost not associated with blood cells. Vd irbesartan is 53-93 l / kg.; After ingestion or in / in the introduction of 14C irbesartan, the proportion of unchanged irbesartan in the blood plasma accounts for 80-85% of the radioactivity circulating in the systemic circulation.; Metabolism; acid and oxidation. Irbesartan glucuronide is the main metabolite in the systemic circulation (approximately 6%). Irbesartan undergoes oxidation, mainly with the participation of CYP2C9 isoenzyme; CYP3A4 isoenzyme plays a minor role in the metabolism of irbesartan. Irbesartan is not metabolized by most isoenzymes commonly involved in drug metabolism, such as CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1 isoenzymes, and does not reliably induce or inhibit these isoenzymes. Irbesartan does not inhibit CYP3A4 isoenzyme.; Elimination; T1 / 2 of irbesartan is 11-15 hours.The total clearance for on / in the introduction of irbesartan is 157-176 ml / min, of which 3-3.5 ml / min is accounted for by the renal clearance.; Irbesartan and its metabolites are excreted both by the liver (with bile) and the kidneys. After ingestion or after intravenous administration of 14C of irbesartan, about 20% of the radioactivity is found in the urine with a small residual amount in the feces. Less than 2% of the dose is excreted by the kidneys as unchanged irbesartan.; Irbesartan, when used in the therapeutic range of doses, has linear pharmacokinetics. Css is achieved on the third day after the start of taking the drug 1 time / day. There is a limited accumulation of irbesartan in the blood plasma (<20%) on the background of a course of taking the drug 1 time / day; Pharmacokinetics in special clinical situations; In women with arterial hypertension, compared with men with arterial hypertension, higher (11 44%) plasma concentrations of irbesartan after a single dose, but against the background course of irbesartan in women and men, there were no differences in the accumulation of irbesartan or in its T1 / 2. Gender-related differences in the clinical efficacy of irbesartan were not observed. In elderly patients without hypertension (men and women) (65-80 years old) with clinically normal kidney and liver function, plasma AUC and Cmax were approximately 20-50% higher than in younger patients (18–40 years), however, T1 / 2 in younger and elderly patients were comparable. No significant, age-related differences in the clinical efficacy of irbesartan were observed.; Negroid patients with normal blood pressure - AUC and T1 / 2 irbesartan were approximately 20–25% higher than in European patients with normal blood pressure, but Cmax irbesartan was almost the same. In patients with renal insufficiency (regardless of its severity) and in patients on hemodialysis, the pharmacokinetics of irbesartan did not change significantly. Irbesartan is not removed from the blood by hemodialysis. In patients with hepatic insufficiency due to cirrhosis of the liver, mild or moderate severity does not significantly change the pharmacokinetics of irbesartan.; The efficacy and safety of irbesartan in children has not been established. amlodipine is well absorbed, Cmax in the blood is achieved 6-12 hours after administration. Absolute bioavailability is 64-90%. Meal does not disturb the absorption of amlodipine.; Distribution; Amlodipine Vd is approximately 21 l / kg.In vitro studies have shown that binding of amlodipine in the systemic circulation to plasma proteins is approximately 97.5%; Metabolism and excretion; Amlodipine is extensively metabolized in the liver to form inactive metabolites; T1 / 2 from blood plasma is approximately 35-50 h when taking 1 time / day. 10% of unchanged amlodipine and 60% of its metabolites are excreted by the kidneys.; Pharmacokinetics in special clinical cases; In elderly and younger people, the time to achieve Cmax of amlodipine in the blood is the same. In elderly patients, the clearance of amlodipine tends to decrease, as a result of which the AUC and T1 / 2 increase. In children 6–12 years old and adolescents between 13 and 17 years old, the clearance of amlodipine when taken orally was 22.5 and 27.4 l / h, respectively in boys and 16.4 and 21.3 l / h, respectively, in girls. There was a large variability in the systemic exposure of amlodipine in different children and adolescents. The data obtained on the use of the drug in children under 6 years of age are limited.; Like other slow calcium channel blockers, an increase in amlodipine T1 / 2 is possible in liver failure. An increase in patients with chronic heart failure (in all age groups) was observed AUC and T1 / 2.; Pharmacokinetics when using the combination of irbesartan / amlodipine in adults; Simultaneous administration of irbesartan and amlodipine in the form of fixed combinations in pills or as free combinations had no effect on the pharmacokinetics of each of the active ingredients of this combination.; The three fixed dose combinations of irbesartan and amlodipine (150 mg / 10 mg, 300 mg / 5 mg and 300 mg / 10 mg) are bioequivalent free dose combinations (150 mg / 10 mg, 300 mg / 5 mg and 300 mg / 10 mg), both in terms of speed and degree of absorption. When taken separately or at the same time in doses of 300 mg and 10 mg, the time until reaching the median Cmax of irbesartan and amlodipine in the blood plasma remains unchanged , that is, 0.75-1 h and 5 h after administration, respectively. Similarly, Cmax and AUC of irbesartan and amlodipine when taken separately or at the same time in doses of 300 mg and 10 mg are in the same ranges, resulting in a joint reception of the relative bioavailability of irbesartan is 95%, and amlodipine - 98%; Average T1 / 2 for irbesartan and amlodipine, taken individually or in combination, is almost the same: 17.6 hours versus 17.7 hours for irbesartan and 58.5 hours versus 52.1 hours for amlodipine.Irbesartan and amlodipine removal does not change when they are taken separately or together. The pharmacokinetics of irbesartan and amlodipine were linear when using irbesartan in doses of 150 mg to 300 mg and amlodipine in doses of 5 mg to 10 mg. Pharmacokinetics when using a combination of irbesartan / amlodipine in children; No information is available on the use of the fixed combination of irbesartan and amlodipine in children.
Indications
- Arterial hypertension (with the ineffectiveness of monotherapy with irbesartan or amlodipine).
Contraindications
- hypersensitivity to irbesartan, amlodipine and other derivatives of dihydropyridine, as well as to the excipients of the drug ;; - cardiogenic shock ;; - clinically significant aortic stenosis ;; - unstable stenocardia (with the exception of Prinzmetal stenocardia); - pregnancy, feeding ;; - children and adolescents under 18 years of age (efficacy and safety have not been established) ;; - simultaneous use with drugs containing aliskiren, in patients with diabetes mellitus or with moderately pronounced th and severe renal failure (GFR <60 ml / min / 1.73 m2) ;; - simultaneous use with ACE inhibitors in patients with diabetic nephropathy.; With caution:; In patients with hypovolemia and hyponatremia, such as those with intensive diuretic therapy , hemodialysis, diet restriction of salt intake, diarrhea, vomiting. In patients whose kidney function depends on the activity of the RAAS (such as patients with arterial hypertension with renal artery stenosis of one or both of the kidneys, patients with chronic cardiac failure III-IV functional class NYHA), treatment with drugs affecting the RAAS was associated with the development of oliguria and / or progressive azotemia and rarely acute renal failure and / or death, the risk of which cannot be ruled out when taking ARA II , including irbesartan); In patients with chronic heart failure of the II-IV functional class according to the NYHA classification of non-ischemic etiology (due to the content of amlodipine in the composition, the use of which in such p the number of patients was associated with an increase in reports of pulmonary edema compared with placebo,despite the absence of differences in the frequency of progression of heart failure); in patients with liver failure (risk of increased T1 / 2 amlodipine); in patients with renal insufficiency and after kidney transplantation (because of the content of irbesartan in the composition of the drug) and blood creatinine concentrations); after a recent kidney transplantation (lack of experience with the clinical use of irbesartan) .; Patients with aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy (GOKMP); Patients with IHD and / or clinically significant atherosclerosis of the cerebral vessels enhancement of ischemic disorders, up to the development of acute myocardial infarction and stroke); in patients with SSSU (due to the content of amlodipine in the composition of the preparation).
Dosage and administration
The drug is taken orally. The pill is swallowed with water. Aprovask can be taken both simultaneously with a meal, and on an empty stomach (that is, regardless of the time of the meal); Usually, the initial and maintenance dose of the drug Aprovask is 1 tab./day. Aprovasc should be used in patients in whom it is not possible to achieve the target values of blood pressure in monotherapy with irbesartan or monotherapy with amlodipine, or to continue treatment of patients already taking irbesartan and amlodipine in the form of individual pills. Doses should be selected individually, first with the use of individual drugs irbesartan and amlodipine. Doses are selected depending on the response of blood pressure to the therapy and the target value of blood pressure. The maximum recommended dose of the drug Aprovask is 150 mg / 10 mg or 300 mg / 10 mg per day (due to the fact that the maximum daily dose of amlodipine is 10 mg). As a rule, in elderly patients and in patients with impaired renal function dose reduction is not required.; Aprovask should be used with caution in patients with impaired liver function, due to the presence of amlodipine in the formulation.