Symptoms: when taking irbesartan in adults at doses up to 900 mg / day, no toxicity was found. The available data for amlodipine suggest that a severe overdose may lead to severe peripheral vasodilation and possibly the development of reflex tachycardia. The development of a pronounced and prolonged excessive decrease in blood pressure, up to the development of shock with a fatal outcome, has been reported.
Treatment: the patient should be under close medical supervision. Treatment should be symptomatic and support the main vital functions of the body. There is no specific information on the treatment of an overdose of irbesartan. The proposed measures in drug overdose Approves® include gastric lavage. Administration of activated charcoal by healthy volunteers immediately after or 2 hours after oral administration of 10 mg of amlodipine showed a slight decrease in the absorption of amlodipine. Due to the fact that amlodipine has a high binding to blood proteins, and irbesartan is not eliminated from the body by hemodialysis, it is unlikely that hemodialysis can be useful in overdose. If a very large overdose has occurred, active monitoring of cardiac activity and respiration should be initiated. Frequent blood pressure measurement is necessary. Clinically significant reduction in blood pressure due to an overdose of amlodipine requires active maintenance of cardiovascular activity, including giving an elevated position to the limbs. It is necessary to monitor the BCC and urinary excretion. It may be necessary to administer vasoconstrictive drugs to restore vascular tone and blood pressure (provided that there are no contraindications to their administration). Intravenous administration of calcium gluconate may be useful in eliminating the effects of calcium channel blockage
hypersensitivity to irbesartan, amlodipine and other dihydropyridine derivatives, as well as excipients of the drug,
cardiogenic shock,
clinically significant aortic stenosis,
unstable angina (with the exception of Prinzmetal angina),
concomitant use with drugs containing aliskiren in patients with diabetes mellitus or with moderate to severe renal insufficiency (glomerular filtration rate (GFR) <60 ml / min/1.73 m2 surface of the body) (see "Interaction" and " Special instructions»),
concomitant use with ACE inhibitors in patients with diabetic nephropathy (see "Interaction" and " Special instructions»),
pregnancy,
breastfeeding period,
age under 18 (efficacy and safety not established).
With caution: hypovolemia and hyponatremia, which occur, for example, with intensive diuretic treatment, hemodialysis, dieting with limited salt intake, diarrhea, vomiting (risk of excessive blood pressure reduction, see "Special instructions"), patients whose renal function depends on the activity of RAAS (including with arterial hypertension with stenosis of the renal artery of one or both kidneys, chronic heart failure of the III–IV functional class according to the classification NYHA), treatment with drugs that affect the RAAS has been associated with the development of oliguria and / or progressive azotemia and rarely-acute renal failure and / or death, the risk of which cannot be excluded when taking ARAII, including irbesartan) (see "Special instructions"), chronic heart failure of functional class II–IV according to the classification NYHA non-ischemic etiology (due to the content of amlodipine in the composition of the drug, the use of which in such patients was associated with an increase in reports of the development of pulmonary edema compared with placebo, despite the absence of differences in the frequency of progression of heart failure) (see "Special instructions"), liver failure (risk of increased T1/2 amlodipine-see.
Combination of irbesartan and amlodipine
Based on pharmacokinetic studies in which irbesartan and amlodipine were taken separately and in combination, there was no PQV between irbesartan and amlodipine.
No studies have been conducted on the drug interaction of the drug Aprovask® with other drugs.
Irbesartan
On the basis of these studies in vitro No interactions with drugs that are metabolized by the following cytochrome P450 isoenzymes should be expected: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, or CYP3A4.
Irbesartan is primarily metabolized by the CYP2C9 isoenzyme, however, no significant PCFs were observed during clinical interaction studies when irbesartan was taken simultaneously with warfarin, which is metabolized by the CYP2C9 isoenzyme.
The pharmacokinetic parameters of irbesartan are not impaired when it is co-administered with nifedipine and hydrochlorothiazide.
Irbesartan does not alter the pharmacokinetics of simvastatin, which is metabolized by the CYP3A4 isoenzyme, or digoxin (a P-glycoprotein substrate).
The combination of the drug Approves® with drugs containing aliskiren, it is contraindicated in patients with diabetes mellitus or moderate to severe renal insufficiency (GFR <60 ml / min/1.73 m2 body surface) and is not recommended in other patients.
ACE inhibitors (ACE inhibitors)
The use of the drug Approves® in combination with aCEI, it is contraindicated in patients with diabetic nephropathy and is not recommended for other patients.
Based on experience with other drugs that affect the RAAS, concomitant administration of potassium-sparing diuretics, potassium preparations, or potassium-containing salt may increase the serum potassium concentration, which requires careful monitoring of plasma potassium levels in patients during treatment.
In elderly patients, patients with hypovolemia (due to diuretics) or impaired renal function, concomitant use of NSAIDs, including selective COX-2 inhibitors together with ARAII, including irbesartan, may lead to deterioration of renal function, including the development of acute renal failure. These effects are usually reversible. Renal function should be periodically monitored in patients taking both ARAII and NSAIDs, including selective COX-2 inhibitors.
Lithium. On the background of the combined use of irbesartan with lithium preparations, an increase in the concentration of lithium in the blood plasma and the toxic effect of lithium were described. In patients taking irbesartan together with lithium preparations, the concentration of lithium in the blood plasma should be monitored.
Amlodipine
Amlodipine has been safely combined with thiazide diuretics, beta-blockers, alpha-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin for sublingual use, NSAIDs, antibiotics, and hypoglycemic agents for oral administration.
Data in vitro Studies with human blood plasma have shown that amlodipine does not affect the binding to the protein of digoxin, phenytoin, warfarin or indomethacin.
Cimetidine. Concomitant administration of amlodipine and cimetidine did not interfere with the pharmacokinetics of amlodipine.
Grapefruit juice. Concomitant administration of 240 mg of grapefruit juice with a single 10 mg dose of amlodipine in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil. When combined with amlodipine and sildenafil, each of the drugs independently showed its blood pressure-lowering effect.
Atorvastatin. Simultaneous course administration of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg led to unreliable changes in the pharmacokinetic parameters of atorvastatin in the state of reaching Css.
Digoxin. Concomitant administration of amlodipine with digoxin did not alter the serum digoxin concentration or the renal clearance of digoxin in healthy volunteers.
Warfarin. Simultaneous administration of amlodipine did not change the PV when taking warfarin.
Cyclosporine. Pharmacokinetic studies with cyclosporine demonstrated that amlodipine had no significant effect on the pharmacokinetics of cyclosporine.
Tacrolimus. With the simultaneous use of tacrolimus and amlodipine, it is possible to increase the concentration of tacrolimus in the blood plasma. It is necessary to monitor the concentration of tacrolimus in the blood plasma and, if necessary, adjust its dose.
Simvastatin. concomitant use of amlodipine with simvastatin may increase the exposure of simvastatin, compared with simvastatin monotherapy. With the simultaneous use of simvastatin and amlodipine, it is necessary to limit the daily dose of simvastatin to 20 mg.
Tablets, 5,150 mg: oval biconvex, covered with a white film shell, with the engraving "150/5" on one side.
Tablets, 10 150 mg: oval biconvex, covered with a pink film shell, with the engraving "150/10" on one side.
Tablets, 5 mg 300: oval biconvex, covered with a yellow film shell, with the engraving "300/5" on one side.
Tablets, 10,300 mg: oval biconvex, covered with a white film shell, with a risk and a bevel to the risk on one side.
The frequency of adverse events/reactions (NS / NR) reported in clinical studies on the use of a combination with fixed doses of irbesartan and amlodipine (clinical studies I-ADD, I-COMBINE and I-COMBO), in clinical studies on the use of irbesartan and its post-marketing use, as well as in clinical studies on the use of amlodipine, was defined according to the WHO classification as follows: very often (≥10%), often (≥1 and <10%), infrequently (≥0.1 and <1%), rarely (≥0.01 and <0.1%), very rarely (<0.01%), the frequency is unknown — the available data cannot be used to estimate the frequency of NYA/HP.
The frequency of HP reported in post-marketing use of the drug was defined as the frequency unknown because information about these HP came from spontaneous reports, without specifying the number of patients taking the drug.
In clinical studies, when comparing fixed-dose combinations of amlodipine irbesartan with irbesartan or amlodipine monotherapy, the types and frequency of treatment-related AES that may be associated with the treatment under study were similar to those observed in previous clinical studies or in post-marketing reports with irbesartan and amlodipine monotherapy.
The most common adverse event was peripheral edema, mainly associated with amlodipine.
NSAIDs observed during treatment and possibly associated with the study drug in amlodipine/irbesartan clinical trials (I-ADD, I-COMBINE, and I-COMBO)
General disorders and disorders at the injection site: often-peripheral edema, edema, infrequently-asthenia.
On the part of the organ of hearing and labyrinth disorders: rarely-vertigo.
From the heart: often-a feeling of palpitation, infrequently-sinus bradycardia.
From the nervous system: often-dizziness, headache, drowsiness, infrequently-paresthesia.
From the genitals and breast: infrequently-erectile dysfunction.
From the respiratory system, chest and mediastinal organs: infrequently-cough.
From the side of the vessels: often-orthostatic hypotension, infrequently-excessive decrease in blood pressure.
From the gastrointestinal tract: often-swelling of the gums, infrequently-nausea, pain in the upper abdomen, constipation.
From the kidneys and urinary tract: often-proteinuria, infrequently-azotemia, hypercreatinemia.
From the side of metabolism and nutrition: infrequently-hyperkalemia.
Musculoskeletal and connective tissue disorders: infrequently-joint stiffness, arthralgia, myalgia.
AES observed in the use of irbesartan in clinical trials (including I-ADD, I-COMBINE, and I-COMBO clinical trials) and in its post-marketing use
On the part of the immune system: frequency unknown-hypersensitivity reactions (allergic reactions).
From the side of metabolism and nutrition: the frequency is unknown-hyperkalemia.
On the part of the organ of hearing and labyrinth disorders: often-vertigo, frequency unknown-tinnitus.
From the nervous system: often-dizziness, headache*, infrequently-orthostatic dizziness.
* Frequency of headache occurrence in studies I-ADD, I-COMBINE and I-COMBO it was rated as "infrequent".
From the heart: infrequently-tachycardia.
From the skin and subcutaneous tissues: the frequency is unknown-leukocytoclastic vasculitis.
From the respiratory system, chest and mediastinal organs: infrequently-cough.
From the gastrointestinal tract: often-nausea/vomiting, pain in the upper abdomen, disorders of the tongue, including dysgeusia (perversion of taste), glossodynia (burning sensation and soreness in the tongue), glossitis (inflammation of the tongue), infrequently — diarrhea, dyspepsia, heartburn.
From the liver and biliary tract: the frequency is unknown — jaundice, increased indicators of functional liver tests, hepatitis.
From the skin and subcutaneous tissues: infrequently-alopecia, the frequency is unknown-angioedema, urticaria.
From the musculoskeletal system and connective tissue: the frequency is unknown — myalgia.
From the kidneys and urinary tract: frequency unknown-impaired renal function, including isolated cases of renal failure in patients with risk factors for its development.
From the genitals and breast: infrequently-erectile dysfunction.
General disorders and disorders at the injection site: often — fatigue* edema, rarely — pain in the chest, the frequency is unknown — asthenia.
* The frequency of increased fatigue in studies I-ADD, I-COMBINE and I-COMBO was rated as infrequent.
Injuries, intoxication, and complications of manipulation: frequency unknown-falls.
Adverse events observed with the use of amlodipine in clinical studies (including clinical studies of I-ADD, I-COMBINE and I-COMBO)
From the blood and lymphatic system: very rarely — thrombocytopenia.
On the part of the immune system: very rarely — allergic reactions.
From the side of metabolism and nutrition: very rarely — hyperglycemia.
Mental disorders: infrequently-insomnia, mood lability.
From the nervous system: often-dizziness, headache*, drowsiness, infrequently-hypesthesia, paresthesia, tremor, taste distortions, syncopal states, very rarely-peripheral neuropathy.
* Frequency of headache occurrence in studies I-ADD, I-COMBINE and I-COMBO it was rated as "infrequent".
On the part of the visual organ: infrequently-visual disorders.
On the part of the organ of hearing and labyrinth disorders: infrequently-tinnitus, vertigo.
From the heart: often-a feeling of palpitation, very rarely-myocardial infarction, cardiac arrhythmias, ventricular tachycardia and atrial fibrillation (atrial fibrillation).
From the side of the vessels: often-flushes of blood to the skin with a feeling of heat, redness of the skin*, infrequently-an excessive decrease in blood pressure, very rarely-vasculitis.
* The frequency of redness of the skin in studies I-ADD, I-COMBINE and I-COMBO was rated as infrequent.
From the respiratory system, chest and mediastinal organs: often-cough, infrequently-shortness of breath, rhinitis, very rarely-coughing.
From the digestive system: often-nausea, abdominal pain, glossodynia, glossitis, infrequently-dyspepsia, vomiting, changes in the rhythm of defecation, dryness of the mucous membranes of the oral cavity, very rarely-pancreatitis, gastritis, gum hyperplasia.
From the liver and biliary tract: very rarely-hepatitis, jaundice and increased activity of liver enzymes (mainly associated with cholestasis).
From the skin and subcutaneous tissues: often-contact dermatitis, infrequently-skin rash, itching, purpura, increased sweating, changes in skin pigmentation (the appearance of discolored skin areas), alopecia, very rarely — angioedema, erythema multiforme, urticaria.
Musculoskeletal and connective tissue disorders: infrequently-arthralgia, muscle cramps, myalgia, back pain.
From the kidneys and urinary tract: infrequently-increased frequency of urination, painful urge to urinate, nocturia.
From the genitals and breast: infrequently-impotence, gynecomastia.
General disorders and disorders at the injection site: often-increased fatigue, edema*, peripheral edema, infrequently-chest pain, asthenia, feeling of malaise, pain, rarely-facial edema.
* According to research data I-ADD, I-COMBINE and I-COMBO frequency of occurrence of edema: infrequently.
Laboratory and instrumental data: infrequently — an increase in body mass, reduction of body weight.
According to the recipe.
Excessive blood pressure reduction: patients with hypovolemia and hyponatremia
Irbesartan rarely caused an excessive decrease in blood pressure in patients with hypertension without other comorbidities. As with ACE inhibitors, an excessive decrease in blood pressure with appropriate symptoms can be expected in patients with hypovolemia and hyponatremia, which include patients who are undergoing intensive diuretic therapy, and / or patients with limited salt intake or who are on hemodialysis. Hyponatremia and hypovolemia should be corrected before treatment with the drug Approves® or you should consider using lower initial doses.
CHF
In a long-term placebo-controlled trial (PRAISE-2) amlodipine in patients with CHF of functional class III-IV (according to the classification NYHA) of non-ischemic etiology, amlodipine was associated with an increase in reports of pulmonary edema, despite the absence of a significant difference in the rate of progression of heart failure, compared with placebo.
Liver failure
As with other BMCC medications, T1/2 amlodipine is increased in patients with impaired liver function, and recommendations for its dosage regimen in patients with impaired liver function have not been established. Therefore, the drug Approves® it should be used with caution in such patients.
Hypertensive crisis
The safety and efficacy of the drug Approves® with a hypertensive crisis, they are not established.
Effect on kidney function
Due to the inhibition of RAAS, changes in renal function can be expected in predisposed patients. In patients whose renal function depends on the activity of RAAS (patients with arterial hypertension with stenosis of the renal artery of one or both kidneys or with CHF of functional class III–IV according to the classification NYHAtreatment with other drugs that affect the RAAS has been associated with the development of oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. It is impossible to exclude the possibility of such an effect when using ARAII, including irbesartan.
Elderly patients
In clinical studies, there was no difference in the efficacy or safety of irbesartan in older patients (65 years and older) compared to younger patients.
Children
Safety and efficacy in children have not yet been established.
Dual RAAS blockade with the combination of the drug Approves® with drugs containing aliskiren and with ACE inhibitors
Dual RAAS blockade with the combination of the drug Approves® ACE inhibitors or aliskiren are not recommended, because there is an increased risk of developing a sharp decrease in blood pressure, hyperkalemia and impaired renal function.
In patients with diabetes mellitus or moderate to severe renal insufficiency (with GFR <60 ml / min/1.73 m2 body surface) of the drug Approves® in combination with aliskiren is contraindicated. Patients with diabetic neuropathy are contraindicated in the use of Aprovask® in combination with ACE inhibitors.
Influence on the ability to drive vehicles and work with mechanisms. The effect of the drug Approves® the ability to drive vehicles or engage in other potentially dangerous activities that require increased attention has not been studied. But based on its pharmacodynamic properties, the effect of the drug Approves® this ability is unlikely. But in the event of dizziness, vertigo, weakness, driving vehicles or engaging in other potentially dangerous activities is not recommended.
Arterial hypertension (when monotherapy with irbesartan or amlodipine is ineffective).
Pharmacodynamic properties of each of the active substances included in the composition of the drug Approves® irbesartan and amlodipine, contribute to their additive antihypertensive effect when used in combination compared to that when using each of these drugs separately. Both angiotensin II receptor antagonists (ARAII) and slow calcium channel blockers (BMCC) reduce blood pressure by reducing peripheral vascular resistance, but blocking the flow of calcium into the cell and reducing the vasoconstrictive effect caused by angiotensin II are complementary mechanisms.
Irbesartan
Irbesartan is a selective highly active ARAII (subtype-AT1Angiotensin II is an important component of the RAAS involved in the pathophysiology of hypertension and sodium ion homeostasis. Irbesartan does not require metabolic activation to manifest its action.
Irbesartan blocks the strong vasoconstrictive and aldosterone-secreting effects of angiotensin II due to selective antagonism to angiotensin II receptors (subtype-AT1), located in the cells of the smooth muscles of the vessels and the adrenal cortex. Irbesartan has no agonistic activity with respect to AT1- receptors. Its affinity to AT1-receptors in the 8500 times greater than for the at2- receptors (receptors that have not been shown to be associated with maintaining the balance (homeostasis) of the CCC).
Irbesartan does not inhibit RAAS enzymes (such as renin, ACE), nor does it affect other hormone receptors or ion channels in the CCC involved in the regulation of blood pressure and sodium ion homeostasis. Irbesartan blockade AT1- receptors breaks the feedback loop in the renin-angiotensin system, increasing the plasma concentrations of renin and angiotensin II. When using irbesartan, the plasma concentration of aldosterone decreases, but when using the drug in the recommended doses, there are no significant changes in the content of potassium in the blood serum (the average increase in the content of potassium in the blood serum is less than 0.1 mEq/l). Irbesartan has no significant effect on the concentration of triglycerides, cholesterol or glucose in the blood 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 and becomes significant within 1-2 weeks of treatment with the maximum effect occurring after 4-6 weeks. In long-term observational studies, the effect of irbesartan persisted 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 at doses of 150-300 mg / day resulted in a greater decrease in sAD/dBP (24 hours after dose) in the supine or sitting position (on average by 8-13/5-8 mmHg) than with placebo. The effect of the drug 24 hours after taking the dose was 60-70% of the corresponding maximum reduction in dBP and sBP. Optimal effectiveness in reducing blood pressure for 24 hours is achieved with a single dose of the drug per day.
Blood pressure decreases approximately to the same extent in the standing and lying position. The orthostatic effect is rare, and, as with ACE inhibitors, its occurrence may 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 blood pressure values with irbesartan monotherapy, the addition of small doses of hydrochlorothiazide (12.5 mg) to irbesartan once a day leads to an additional (compared to the effect of placebo addition) decrease in sAD/dBP, determined 24 hours after their administration, by 7-10/3-6 mm Hg. st. accordingly
Age and gender do not affect the effectiveness of irbesartan. As in the case of treatment with other drugs that affect the RAAS, in patients of the black race, a weaker antihypertensive effect is observed with irbesartan monotherapy. When irbesartan is taken with low doses of hydrochlorothiazide (for example, 12.5 mg / day), the antihypertensive effect in patients of the black race approaches that in patients of the Caucasian race.
After the withdrawal of irbesartan, blood pressure gradually returns to its original level. Withdrawal syndrome was not observed when irbesartan was discontinued.
Amlodipine
Amlodipine is a BMCC from the group of dihydropyridine derivatives that inhibits the transmembrane entry of calcium ions into the cells of the myocardium and vascular smooth muscle. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on the smooth muscles of the vessels.
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 following two effects.
Amlodipine expands the peripheral arterioles and thereby reduces the OPSS, the so-called afterload. Since the heart rate when taking amlodipine practically does not increase, this reduction in the load on the heart muscle reduces the energy consumption of the myocardium and its need for oxygen.
The mechanism of antianginal action of amlodipine also seems to be associated with the expansion of the main coronary arteries and coronary arterioles, both in areas of the myocardium with normal blood flow and in ischemic areas of the myocardium. This dilation of the coronary vessels increases the delivery of oxygen to the myocardium in patients with coronary artery spasm (in Prinzmetal angina or variant angina).
In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure in the supine and standing positions 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, a single daily intake of amlodipine when performing a test with physical activity increases the total time of physical activity, the time before the onset of an attack of angina pectoris and the time before the appearance of ST-segment depression on the ECG by 1 mm. In addition, taking the drug reduces the daily number of angina attacks and the daily need for taking nitroglycerin tablets.
No adverse metabolic effects or changes in blood lipid concentrations were observed when taking amlodipine. Amlodipine can be taken in patients with bronchial asthma, diabetes mellitus, and gout.
Clinical evidence for the efficacy of a fixed-dose combination of irbesartan and amlodipine was obtained in two multicenter, prospective, open-label, parallel-group studies with blind evaluation of performance indicators: I-ADD and I-COMBINE. The results of both studies demonstrated significantly greater efficacy of fixed-dose combinations of irbesartan and amlodipine compared to amlodipine monotherapy or irbesartan monotherapy.
Irbesartan
Irbesartan is an oral active drug that does not require biotransformation to manifest its activity. After oral administration, irbesartan is rapidly and completely absorbed. Cmax irbesartan in the blood plasma is reached in 1.5-2 hours after its oral administration. The absolute bioavailability of irbesartan when taken orally is 60-80%. Food intake does not affect the bioavailability of irbesartan.
Irbesartan binds approximately 96% to blood plasma proteins and practically does not bind to the shaped elements of the blood. Vd irbesartan is 53-93 l/kg.
After oral or intravenous administration 14With irbesartan, the proportion of unchanged irbesartan in the blood plasma accounts for 80-85% of the radioactivity circulating in the systemic bloodstream. Irbesartan is metabolized in the liver by conjugation with glucuronic acid and oxidation. The main metabolite found in the systemic circulation is irbesartan glucuronide (approximately 6%). Irbesartan undergoes oxidation, mainly by the cytochrome P450 — CYP2C9 isoenzyme, the CYP3A4 isoenzyme plays a minor role in the metabolism of irbesartan. Irbesartan is not metabolized by most of the isoenzymes commonly involved in drug metabolism, such as CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1, and does not significantly induce or inhibit these isoenzymes. Irbesartan does not inhibit the CYP3A4 isoenzyme
Irbesartan and its metabolites are excreted both by the liver (with bile) and by the kidneys. After oral or intravenous administration 14With irbesartan, about 20% of the radioactivity is detected 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. T1/2 irbesartan is 11-15 hours. The total clearance with intravenous administration of irbesartan is 157-176 ml / min, of which 3-3. 5 ml / min is accounted for by renal clearance.
Irbesartan, when used in the therapeutic dose range, has linear pharmacokinetics. Css it is achieved on the third day after the start of taking the drug 1 time a day. There is a limited accumulation of irbesartan in the blood plasma (<20%) against the background of the course of taking the drug 1 time per day. In women with arterial hypertension, compared with men with arterial hypertension, higher (by 11-44%) plasma concentrations of irbesartan were observed after its single administration, but against the background of the course of irbesartan administration, women and men did not show differences in the accumulation of irbesartan or its T1/2. There were no gender-related differences in the clinical efficacy of irbesartan.
In elderly patients without arterial hypertension (men and women 65-80 years old) with clinically normal kidney and liver function, AUC and Cmax blood plasma concentrations were approximately 20-50% higher than in younger patients (18-40 years), however, T1/2 In young and elderly patients, the results were comparable. There were no significant age-related differences in the clinical efficacy of irbesartan.
In black patients with normal blood pressure, AUC, and T1/2 irbesartan was approximately 20-25% higher than in Caucasian patients with normal blood pressure, but Cmax their irbesartana was almost the same.
In patients with renal insufficiency (regardless of its severity) and in patients on hemodialysis, the pharmacokinetics of irbesartan does not significantly change. Irbesartan is not removed from the blood by hemodialysis.
In patients with hepatic insufficiency due to mild or moderate liver cirrhosis, the pharmacokinetics of irbesartan do not significantly change.
Studies on the efficacy and safety of irbesartan in children have not been conducted.
Amlodipine
After oral administration in therapeutic doses, amlodipine is well absorbed with the achievement of Cmax in the blood-between 6 and 12 hours after taking it. The absolute bioavailability is 64-90%. Food intake does not interfere with the absorption of amlodipine.
Vd amlodipine is approximately 21 l/kg. In research in vitro Approximately 97.5% of amlodipine in the systemic circulation has been shown to bind to plasma proteins.
Amlodipine is intensively metabolized in the liver to form inactive metabolites.
Through the kidneys, 10% of unchanged amlodipine and 60% of its metabolites are excreted, T1/2 from the blood plasma is approximately 35-50 hours at a dosage of 1 time per day.
In older and younger people Cmax amlodipine in the blood is the same. In elderly patients, the clearance of amlodipine tends to decrease, resulting in an increase in AUC and T1/2.
In children 6-12 years old and adolescents 13-17 years old, the clearance of amlodipine when taking the drug 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. Data obtained on the use of the drug in children under 6 years of age are limited.
As in other BMCC, in hepatic insufficiency, an increase in T is possible1/2 amlodipine (see sections «With caution"and" Special instructions").
In patients with CHF (in all age groups), an increase in AUC and T was observed1/2.
Pharmacokinetics of the amlodipine / irbesartan combination in adults
Simultaneous administration of irbesartan and amlodipine in the form of fixed combinations in tablets or in the form of free combinations did not affect the pharmacokinetics of each of the active substances of this combination.
The three fixed dose combinations of amlodipine and irbesartan (10/150 mg, 5/300 mg, and 10/300 mg) are bioequivalent to the free dose combinations (10/150 mg, 5/300 mg, and 10/300 mg), both in terms of rate and degree of absorption. When taken alone or simultaneously at doses of 10 and 300 mg the time to reach the median Cmax amlodipine and irbesartan in the blood plasma remains unchanged, i.e. 5 and 0.75–1 hours after administration, respectively. Similar to Cmax and the AUC of amlodipine and irbesartan when taken separately or simultaneously at doses of 10 and 300 mg are in the same ranges, as a result of which, when taken together, the relative bioavailability of amlodipine is 98%, and irbesartan is 95%. Average value of T1/2 for amlodipine and irbesartan taken alone or in combination, it is almost the same: 58.5 vs. 52.1 hours for amlodipine and 17.6 vs. 17.7 hours for irbesartan. The elimination of amlodipine and irbesartan does not change when they are taken separately or together. The pharmacokinetics of amlodipine and irbesartan were linear when using amlodipine at doses of 5 to 10 mg and irbesartan at doses of 150 to 300 mg.
Pharmacokinetics in the application of the combination of amlodipine/irbesartan in children
There is no information on the use of a fixed combination of amlodipine and irbesartan in children.
At a temperature not exceeding 30 °C.
Keep out of reach of children.
The shelf life of the drug Approves®3 года.Do not use after the expiration date indicated on the package.
| Film-coated tablets | 1 table. |
| the core | |
| active ingredients: | |
| amlodipine besilat | 7 mg |
| (equivalent to 5 mg of amlodipine) | |
| irbesartan | 150 mg |
| excipients: MCC 50 microns-66 mg, croscarmellose sodium-12 mg, hypromellose 6 MPa * s-5 mg, MCC 100 microns-5 mg, silicon dioxide colloidal-2.5 mg, magnesium stearate-2.5 mg | |
| the film shell: Opadry white (hypromellose-62.5%, titanium dioxide (E171) - 31.25%, macrogol 400-6.25%) - 10 mg |
| Film-coated tablets | 1 table. |
| the core | |
| active ingredients: | |
| amlodipine besilat | 14 mg |
| (equivalent to 10 mg of amlodipine) | |
| irbesartan | 150 mg |
| excipients: MCC 50 microns — 54 mg, croscarmellose sodium-12 mg, hypromellose 6 MPa * s-5 mg, MCC 100 microns-10 mg, silicon dioxide-2.5 mg, magnesium stearate-2.5 mg | |
| the film shell: Opadry pink (hypromellose-57.75%, titanium dioxide (E171) — 29.366%, macrogol 400-9.08%, macrogol 8000-3.3%, iron oxide red dye (E172) - 0.504% — - 10 mg |
| Film-coated tablets | 1 table. |
| the core | |
| active ingredients: | |
| amlodipine besilat | 7 mg |
| (equivalent to 5 mg of amlodipine) | |
| irbesartan | 300 mg |
| excipients: MCC 50 microns-132 mg, croscarmellose sodium-24 mg, hypromellose 6 MPa * s-10 mg, MCC 100 microns-17 mg, silicon dioxide-5 mg, magnesium stearate-5 mg | |
| the film shell: Opadry yellow (hypromellose-57.75%, titanium dioxide (E171) — 29.08%, macrogol 400-9.08%, macrogol 8000-3.3%, iron oxide yellow dye (E172) - 0.79%) — 20 mg |
| Film-coated tablets | 1 table. |
| the core | |
| active ingredients: | |
| amlodipine besilat | 14 mg |
| (equivalent to 10 mg of amlodipine) | |
| irbesartan | 300 mg |
| excipients: MCC 50 microns-132 mg, croscarmellose sodium-24 mg, hypromellose 6 MPa * s-10 mg, MCC 100 microns-10 mg, silicon dioxide-5 mg, magnesium stearate-5 mg | |
| the film shell: Opadry white (hypromellose-62.5%, titanium dioxide (E171) - 31.25%, macrogol 400-6.25%) - 20 mg |
Film-coated tablets, 5 mg 150 mg, 10 mg 150 mg, 5 mg 300 mg and 10 mg 300 mg. In a blister of PVC/PE/PVDH/aluminum, 7 pcs. 2 or 4 bl. in a cardboard pack.
When taking irbesartan at doses of ≥50 mg/kg/day (which, based on 1 kg of body weight, is approximately equivalent to the maximum recommended dose of irbesartan in humans (MRDICH) of 300 mg/day), pregnant rats from day 0 to day 20 of gestation had transient effects (slight or moderate dilation of the renal pelvis, hydroureter and / or absence of renal papillae). When taking irbesartan at doses of ≥180 mg/kg/day (approximately equivalent to 4×MRDICH in terms of 1 kg of body weight) in pregnant rats from the 0th to the 20th day of gestation, the development of subcutaneous edema was observed in rat fetuses. Since these developmental abnormalities were not observed when irbesartan was restricted to oral doses of 50, 150, and 450 mg / kg / day in pregnant rats from day 6 to day 15 of gestation, they appear to be late gestational effects of irbesartan. In rabbits, the use of irbesartan at a dose of 30 mg / kg / day was associated with maternal mortality and abortion. The surviving females who received this dose, equivalent to 1.5 x MRDICH per kg of body weight, had a slight increase in fruit resorption and, accordingly, a decrease in the number of live fruits in the litter. Irbesartan was found to penetrate the placental barrier in rats and rabbits
No teratogenic effect of amlodipine was detected in rats and rabbits.
No adequate and well-controlled studies of the drug Approves® in pregnant women. Exposure to the fetus to ACE inhibitors, which were taken by pregnant women in the second and third trimesters of pregnancy, led to damage and death of the developing fetus. Like any other drugs, which act directly on the RAAS, the drug Approves® contraindicated during pregnancy. The Drug Approves® it should not be used in women with childbearing potential, if they do not use effective methods of contraception. In case of pregnancy during treatment with this medication Approves®, you should stop taking it as soon as possible (see "Contraindications ").
The Drug Approves® it is contraindicated during the breastfeeding period (see "Contraindications").
Inside. The tablet is swallowed with water. The Drug Approves® it can be taken both simultaneously with a meal, and on an empty stomach (i.e., regardless of the time of the meal).
Adults. Usual starting and maintenance dose Approves® — 1 table/day. The Drug Approves® It should be used in patients who fail to achieve the target blood pressure values with irbesartan monotherapy or amlodipine monotherapy, or to continue the treatment of patients already taking irbesartan and amlodipine in the form of separate tablets. Doses should be selected individually, first with the use of separate 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 Approves® it is 10,150 or 10,300 mg/day (due to the fact that the maximum daily dose of amlodipine is 10 mg).
Children. The safety and efficacy of the drug Approves® not installed.
Elderly patients and impaired renal function. There is usually no need to reduce the dose in elderly patients (see "Pharmacodynamics") and patients with impaired renal function.
Impaired liver function. The Drug Approves® it should be used with caution, due to the presence of amlodipine in the composition of the drug (see " Contraindications», With caution and "Special Instructions").
C09DB05 Irbesartan Amlodipine
