Properties
What is it?
Composition: Each film-coated tablet contains 300 mg of Irbesartan and 13.89 mg of Amlodipine Besylate, equivalent to 10 mg of Amlodipine, as active ingredients; contains Celactose 80 and Croscarmellose Sodium as excipients; contains Titanium Dioxide (E171) and Iron Yellow Oxide (E172) as colorants. Pharmacological characteristics: Pharmacodynamic characteristics: Pharmacotherapeutic group: Angiotensin-II antagonists and calcium channel blockers. Irbapin is a combination of Irbesartan, an angiotensin-II receptor antagonist, and Amlodipine, a calcium channel blocker. Irbesartan Irbesartan is an orally active, potent, and selective angiotensin-II receptor (subtype AT1) antagonist. Irbesartan blocks all effects of angiotensin-II mediated through AT1 receptors, regardless of its source or mechanism of action. Selective antagonism of angiotensin-II (AT1) receptors leads to an increase in plasma renin and angiotensin-II concentrations and a decrease in plasma aldosterone concentration. At recommended doses, during monotherapy with Irbesartan in patients without a predisposition to electrolyte imbalance, serum potassium concentrations do not change significantly. Irbesartan does not inhibit ACE (kininase II), the enzyme that converts angiotensin-II and breaks down bradykinin to inactive metabolites. Metabolic activation of Irbesartan is not required for its action. Pharmacodynamic effects Clinical action Irbesartan: Hypertension: Irbesartan lowers blood pressure with minimal changes in heart rate. Doses exceeding 300 mg once daily have a dose-dependent effect on blood pressure reduction. At doses of 150-300 mg once daily, the reduction in blood pressure (systolic/diastolic) at the end of the dosing interval (i.e., 24 hours after administration) in the patient's horizontal or vertical position is on average 8-13/5-8 mmHg higher compared to placebo. Maximum blood pressure reduction is achieved 3-6 hours after administration, and the hypotensive effect is maintained for at least 24 hours. At the recommended dose, the blood pressure reduction after 24 hours is 60-70% of the maximum reduction in diastolic and systolic blood pressure. Administration of 150 mg once daily results in the same hypotensive effect as the same dose divided into two administrations, with an average 24-hour interval. The hypotensive effect of Irbesartan develops within 1-2 weeks, with maximum therapeutic effect achieved 4-6 weeks after the start of treatment. The antihypertensive effect is maintained with long-term treatment. After discontinuation of Irbesartan treatment, blood pressure gradually returns to baseline levels, with no recurrence of hypertension. The efficacy of Irbesartan is not dependent on age or sex. As with other drugs acting on the renin-angiotensin system, hypertensive black patients show a lower response to Irbesartan monotherapy. When Irbesartan is administered with a low dose of hydrochlorothiazide (e.g., 12.5 mg daily), the antihypertensive effect in black patients is similar to that observed in non-black patients. No clinically significant effect on serum uric acid levels or urinary uric acid excretion was observed. Type 2 Diabetes Mellitus with Arterial Hypertension and Kidney Disease: The study "Effect of Irbesartan on Microalbuminuria in Patients with Type 2 Diabetes Mellitus and Arterial Hypertension (IRMA 2)" showed that Irbesartan at a dose of 300 mg delays the progression of overt proteinuria in patients with microalbuminuria. IRMA 2 was a placebo-controlled, double-blind, morbidity study in patients with type 2 diabetes, microalbuminuria (30-300 mg/day), and normal kidney function (serum creatinine <1.5 mg/dL in men and <1.3 mg/dL in women). The primary endpoint was the progression of overt proteinuria (defined as urinary albumin excretion rate of ≥300 mg/day and an increase in urinary albumin excretion rate of at least 30% compared to baseline). Additional antihypertensive agents (excluding ACE inhibitors, angiotensin-II receptor agonists, and dihydropyridine calcium blockers) were added as needed to achieve the target blood pressure. Since blood pressure levels were similar in all treatment groups, few patients (5.2%) in the 300 mg Irbesartan treatment group reached the endpoint of overt proteinuria compared to the placebo group (14.9%) or the 150 mg Irbesartan treatment group (9.7%). The relative risk reduction compared to placebo (p=0.0004) was 70% at the higher dose. Improvement in glomerular filtration rate (GFR) was not assessed during the first three months of treatment. Slowing of clinical proteinuria progression was observed within three months and continued for over 2 years. Return to normoalbuminuria at baseline (Use of the drug in patients with heart failure Hemodynamic studies and controlled clinical trials using exercise testing showed that amlodipine in functional class II-III according to NYHA does not worsen the condition of patients with chronic heart failure, as confirmed by exercise tolerance, left ventricular ejection fraction, and clinical symptoms. In placebo-controlled studies (PRAISE) involving patients with NYHA functional class III-IV heart failure receiving digoxin, diuretics, and ACE inhibitors, amlodipine did not increase the risk of death or the overall risk of death and complications associated with heart failure. In subsequent long-term, placebo-controlled studies (PRAISE-2) in patients with NYHA functional class III-IV chronic heart failure without clinical or objective signs of ischemic heart disease, receiving ACE inhibitors, digitalis, and diuretics, amlodipine did not affect mortality from all causes and cardiovascular pathology. In the same patients, amlodipine administration was associated with an increase in the incidence of pulmonary edema, although no significant difference in worsening of heart failure was observed compared to placebo. Treatment to Prevent Heart Attack (ALLHAT) The Randomized Double-Blind Trial of Disease and Mortality, "Antihypertensive and Hypolipidemic Treatment Trial to Prevent Heart Attack" (ALLHAT), was conducted to compare the effects of more modern drugs: 2.5-10 mg/day amlodipine (calcium channel blocker) or 10-40 mg/day lisinopril (ACE inhibitor) as first-line agents with 12.5-25 mg/day of the thiazide diuretic, chlorthalidone, for the treatment of mild to moderate hypertension. A total of 33,357 patients aged 55 years or older with hypertension were randomized and followed for an average of 4.9 years. Patients had at least one additional risk factor for ischemic heart disease, a history of myocardial infarction or stroke (>6 months prior to study entry), or other documented atherosclerotic cardiovascular disease (total 51.5%); type 2 diabetes mellitus (36.1%); high-density lipoprotein cholesterol <35 mg/dL (11.6%); left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), including current smoking (21.9%). The primary endpoint was the combination of fatal ischemic heart disease and non-fatal myocardial infarction. There was no significant difference in the incidence of the primary endpoint between amlodipine and chlorthalidone therapy: RR 0.98 95% confidence interval [0.90-1.07] p=0.65. Among secondary endpoints, heart failure (a component of the cardiovascular endpoint composite) was significantly higher in the amlodipine group than in the chlorthalidone group (10.2% vs. 7.7%, RR 1.38, 95% confidence interval [1.25-1.52] p<0.001). However, no significant difference in all-cause mortality was found between amlodipine and chlorthalidone therapy: RR 0.96 95% confidence interval [0.89-1.02] p=0.20. Amlodipine Amlodipine is a dihydropyridine calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle. The mechanism of the antihypertensive effect of amlodipine is due to its direct relaxant effect on vascular smooth muscle. The primary mechanism by which amlodipine relieves angina is not fully understood, but amlodipine reduces the total ischemic burden by the following two mechanisms: 1) Amlodipine dilates peripheral arterioles and thus reduces total peripheral resistance (afterload), against which the heart has to work. Heart rate remains stable, and this unloading of the heart reduces myocardial oxygen consumption and demand. 2) The mechanism of action of amlodipine also includes dilation of the main coronary arteries and coronary arterioles in both normal and ischemic regions. Such dilation increases myocardial oxygen supply in patients with coronary artery spasm (Prinzmetal's or variant angina). In patients with hypertension, a single daily dose of amlodipine provides a clinically significant reduction in blood pressure for 24 hours in both the horizontal and vertical positions. Due to its slow onset of action, acute hypotension is not characteristic of amlodipine administration. In patients with angina, a single daily dose of amlodipine increases exercise tolerance, delays the onset of anginal attacks and 1 mm ST segment depression, and reduces the frequency of anginal attacks and nitroglycerin use. Amlodipine does not adversely affect metabolism and plasma lipid profile, making it suitable for the treatment of patients with bronchial asthma, diabetes mellitus, and gout. Use of the drug in patients with ischemic heart disease (IHD) The efficacy of amlodipine in preventing clinical events in patients with ischemic heart disease (IHD) was studied in an independent, multicenter, randomized, double-blind, placebo-controlled trial involving 1997 patients, comparing amlodipine with enalapril for the prevention of thrombosis (CAMELOT). In this study, 663 patients received 5-10 mg of amlodipine for 2 years, 673 patients received 10-20 mg of enalapril, and 655 patients received placebo in combination with standard therapy, including statins, beta-blockers, diuretics, and aspirin. The primary efficacy results are presented in Table 1. The study results show that amlodipine treatment reduced the frequency of hospitalization for angina and also reduced the frequency of revascularization procedures in patients with IHD. Table 1. Incidence of Clinically Significant Outcomes in the CAMELOT Study Cardiovascular Complication, Number (%) Amlodipine vs. Placebo Outcome Amlodipine Placebo Enalapril Relative Risk (95% CI) P-value Primary Endpoint Adverse Cardiovascular Events 110 (16.6) 151 (23.1) 136 (20.2) 0.69 (0.54 – 0.88) .003 Individual Components Coronary Artery Revascularization 78 (11.8) 103 (15.7) 95 (14.1) 0.73 (0.54-0.98) .03 Hospitalization for Angina 51 (7.7) 84 (12.8) 86 (12.8) 0.58 (0.41-0.82) .002 Non-fatal Myocardial Infarction 14 (2.1) 19 (2.9) 11 (1.6) 0.73 (0.37-1.46) .37 Stroke or Transient Ischemic Attack 6 (0.9) 12 (1.8) 8 (1.2) 0.50 (0.19-1.32) .15 Cardiovascular Death 5 (0.8) 2 (0.3) 5 (0.7) 2.46 (0.48-12.7) .27 Hospitalization for Congestive Heart Failure 3 (0.5) 5 (0.8) 4 (0.6) 0.59 (0.14-2.47) .46 Resuscitation After Cardiac Arrest 0 4 (0.6) 1 (0.1) Not Specified .04 Newly Diagnosed Peripheral Arterial Disease 5 (0.8) 2 (0.3) 8 (1.2) 2.6 (0.50-13.4) .24 Abbreviations: CHF - Congestive Heart Failure; CI – Confidence Interval; MI - Myocardial Infarction; TIA - Transient Ischemic Attack. Use of the drug in patients with heart failure Hemodynamic studies and controlled clinical trials using exercise testing showed that amlodipine in functional class II-III according to NYHA does not worsen the condition of patients with chronic heart failure, as confirmed by exercise tolerance, left ventricular ejection fraction, and clinical symptoms. In placebo-controlled studies (PRAISE) involving patients with NYHA functional class III-IV heart failure receiving digoxin, diuretics, and ACE inhibitors, amlodipine did not increase the risk of death or the overall risk of death and complications associated with heart failure. In subsequent long-term, placebo-controlled studies (PRAISE-2) in patients with NYHA functional class III-IV chronic heart failure without clinical or objective signs of ischemic heart disease, receiving ACE inhibitors, digitalis, and diuretics, amlodipine did not affect mortality from all causes and cardiovascular pathology. In the same patients, amlodipine administration was associated with an increase in the incidence of pulmonary edema. Treatment to Prevent Heart Attack (ALLHAT) The Randomized Double-Blind Trial of Disease and Mortality, "Antihypertensive and Hypolipidemic Treatment Trial to Prevent Heart Attack" (ALLHAT), was conducted to compare the effects of more modern drugs: 2.5-10 mg/day amlodipine (calcium channel blocker) or 10-40 mg/day lisinopril (ACE inhibitor) as first-line agents with 12.5-25 mg/day of the thiazide diuretic, chlorthalidone, for the treatment of mild to moderate hypertension. A total of 33,357 patients aged 55 years or older with hypertension were randomized and followed for an average of 4.9 years. Patients had at least one additional risk factor for ischemic heart disease, a history of myocardial infarction or stroke (>6 months prior to study entry), or other documented atherosclerotic cardiovascular disease (total 51.5%); type 2 diabetes mellitus (36.1%); high-density lipoprotein cholesterol <35 mg/dL (11.6%); left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), including current smoking (21.9%). The primary endpoint was the combination of fatal ischemic heart disease and non-fatal myocardial infarction. There was no significant difference in the incidence of the primary endpoint between amlodipine and chlorthalidone therapy: RR 0.98 95% confidence interval [0.90-1.07] p=0.65. Among secondary endpoints, heart failure (a component of the cardiovascular endpoint composite) was significantly higher in the amlodipine group than in the chlorthalidone group (10.2% vs. 7.7%, RR 1.38, 95% confidence interval [1.25-1.52] p<0.001). However, no significant difference in all-cause mortality was found between amlodipine and chlorthalidone therapy: RR 0.96 95% confidence interval [0.89-1.02] p=0.20. Use in children (6 years and older) A study involving 268 children aged 6 to 17 years, predominantly with secondary arterial hypotension, compared amlodipine at doses of 2.5 mg and 5.0 mg with placebo. The study showed that both doses of the drug significantly lowered systolic blood pressure compared to placebo. The difference between the two doses was statistically insignificant. The long-term effects of amlodipine on growth, sexual maturation, and overall development have not been studied. The long-term effects of amlodipine therapy in childhood on cardiovascular morbidity and mortality in adulthood have also not been established. Pharmacokinetics General characteristics Irbesartan Absorption: After oral administration, Irbesartan is well absorbed: absolute bioavailability is approximately 60-80%. Food intake does not affect the bioavailability of Irbesartan. Food intake does not affect the bioavailability of Irbapyrine. Distribution: Plasma protein binding is approximately 96%, with negligible binding to blood cell components. The volume of distribution of Irbesartan is 53-93 liters. After oral administration or intravenous infusion of 14C-labeled Irbesartan, 80-85% of circulating plasma radioactivity can be attributed to unchanged Irbesartan. Linearity: With therapeutic doses of 10-600 mg, Irbesartan exhibits linear and dose-proportional pharmacokinetics; at doses up to 600 mg (a dose twice the recommended maximum dose), a less than proportional increase in oral absorption was observed; the mechanism of this is unknown. Peak plasma concentrations are reached 1.5-2 hours after oral administration. Biotransformation: Irbesartan is metabolized in the liver via glucuronide oxidation and conjugation. The main metabolite in systemic circulation is Irbesartan glucuronide (approximately 6%). In vitro studies with cytochrome P450 enzymes have shown that Irbesartan is primarily oxidized by CYP2C9, while the involvement of CYP3A4 isoenzyme in Irbesartan metabolism is negligible. With therapeutic doses of 10-600 mg, Irbesartan exhibits linear and dose-proportional pharmacokinetics; at doses up to 600 mg (a dose twice the recommended maximum dose), a less than proportional increase in oral absorption was observed; the mechanism of this is unknown. Peak plasma concentrations are reached 1.5-2 hours after oral administration. Elimination: Total body and renal clearance are 157-176 and 3-3.5 mL/min, respectively. The average terminal half-life of Irbesartan is 11-15 hours. Steady-state plasma concentrations are reached within 3 days of initiating once-daily dosing. With repeated administration of the drug at this dose, limited accumulation of Irbesartan in plasma is observed (less than 20%). In the study, somewhat higher plasma concentrations of Irbesartan were observed in female patients. However, no difference in the half-life and accumulation of Irbesartan was observed. Dose adjustment was not necessary in female patients. AUC and Cmax values for Irbesartan were slightly higher in elderly patients (>65 years) compared to younger patients (18-40 years). However, the terminal half-life of the drug did not change significantly. Dose adjustment was not necessary in elderly patients. Irbesartan and its metabolites are excreted in bile and urine. After oral administration or intravenous infusion of 14C-labeled Irbesartan, approximately 20% of radioactivity is found in urine, and the remainder in feces. Less than 2% of the administered dose is excreted unchanged in the urine. The terminal half-life of the drug in plasma is 35-50 hours, and steady-state concentrations are achieved with once-daily dosing. Patient characteristics: Renal impairment: In patients with renal insufficiency or on hemodialysis, the pharmacokinetic parameters of Irbesartan do not change significantly. Irbesartan administration is not interrupted during hemodialysis. Hepatic impairment: The pharmacokinetic parameters of Irbesartan do not change significantly in patients with mild to moderate cirrhosis. Studies have not been conducted in patients with severe hepatic insufficiency. Amlodipine Absorption, distribution, and plasma protein binding: After oral administration of therapeutic doses, amlodipine is well absorbed into the bloodstream, with peak plasma concentrations observed 6-12 hours after administration. Absolute bioavailability ranges from 64% to 80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins. Food intake does not affect the bioavailability of amlodipine. Biotransformation / Elimination The terminal half-life in plasma is approximately 35-50 hours and is maintained with once-daily dosing. Amlodipine is extensively metabolized in the liver to inactive metabolites; the drug is excreted in urine as 10% of the parent compound and 60% as metabolites. Hepatic impairment There is very limited clinical data on amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have reduced amlodipine clearance, leading to a prolonged half-life and an increase in AUC of approximately 40% to 60%. Elderly The time to reach peak plasma concentration of amlodipine is similar in the elderly and young. However, in elderly patients, amlodipine clearance is reduced, leading to an increased area under the curve (AUC) and half-life. An increase in AUC and half-life was expected in patients with congestive heart failure in this patient group. Dose adjustment is not necessary in elderly patients. Storage conditions: The drug should be stored at a temperature not exceeding 250C, in its original packaging. Keep the drug out of reach of children. Expiration date: 2 years Dispensing rule: Pharmaceutical product group II, dispensed with prescription form №3