Aprovel pills 150 mg 14 pcs
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Active ingredients
Irbesartan
Release form
Pills
Composition
Irbesartan 150 mg Excipients: lactose monohydrate - 51 mg, microcrystalline cellulose - 27 mg, croscarmellose sodium - 12 mg, hypromellose - 5 mg, magnesium stearate - 2.5 mg, silicon dioxide - 2.5 mg. The composition of the film shell: white opadry - 10 mg (lactose monohydrate - 36%, hypromellose - 28%, macrogol 3000 - 10%, titanium dioxide (E171) - 26%), carnauba wax - less than 50 μg.
Pharmacological effect
Antihypertensive drug, selective angiotensin II receptor antagonist (type AT1). Irbesartan does not require metabolic activation to acquire pharmacological activity. Angiotensin II is an important component of the RAAS and is involved in the pathogenesis of arterial hypertension, as well as sodium homeostasis. Irbesartan blocks all physiologically significant effects of angiotensin II, regardless of the source or route of its synthesis, including pronounced vasoconstrictor effect and increased secretion of aldosterone, realized through receptors like AT1, located on the surface of vascular smooth muscle cells and in the adrenal cortex. Irbesartan does not possess agonistic activity against AT1 receptors and has a much greater (more than 8500 times) affinity for AT1 receptors than with AT2 receptors (receptors that are not associated with the regulation of the cardiovascular system). Irbesartan does not inhibit RAAS enzymes (such as renin, ACE) and does not affect the receptors of other hormones or ion channels involved in the regulation of blood pressure and sodium homeostasis. Blocking irbesartan AT1 receptors interrupts the feedback circuit in the renin-angiotensin system, which leads to an increase in plasma concentrations of renin and angiotensin II. After taking irbesartan in recommended doses, the plasma concentration of aldosterone decreases, without significantly affecting the content of potassium in the blood serum (the average value of its increase is less than 0.1 mEq / l). Irbesartan has no significant effect on serum concentrations of triglycerides, cholesterol and glucose. Irbesartan does not affect the concentration of uric acid in the blood serum or the rate of excretion of uric acid by the kidneys. The antihypertensive effect of irbesartan is already apparent after taking its first dose and becomes significant within 1-2 weeks of taking, its maximum antihypertensive effect is achieved by 4-6 weeks of treatment. In long-term clinical studies, the antihypertensive effect of irbesartan has been observed for more than one year.The antihypertensive effect of the daily administration of irbesartan in doses up to 900 mg per day for a day is dose-dependent. Irbesartan, when taken once daily in doses of 150-300 mg, lowers blood pressure, measured in the supine or sitting position at the end of the inter-dose interval (24 hours after taking a dose of irbesartan, i.e. before taking the next dose of irbesartan), on average 8 -13 / 5-8 mm Hg st. (systolic / diastolic blood pressure) compared with placebo. The antihypertensive effect of irbesartan before taking the next dose is 60-70% of the maximum reduction in diastolic and systolic blood pressure. The optimal decrease in blood pressure within 24 hours is achieved by taking irbesartan 1 time per day. Irbesartan approximately equally reduces blood pressure in the standing and lying position. Orthostatic effects are rarely observed, however, as with the use of ACE inhibitors, in patients with hyponatremia and / or hypovolemia, an excessive decrease in blood pressure with clinical manifestations is possible. The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients with insufficient blood pressure reduction with monotherapy with irbesartan, adding low doses of hydrochlorothiazide (12.5 mg) to its administration once a day results in an additional blood pressure reduction of 7-10 / 3-6 mm Hg. (systolic / diastolic) compared with placebo. The effectiveness of irbesartan does not depend on age or gender. As with the use of other drugs that affect RASS, the antihypertensive effect of irbesartan in patients of the negroid race is noticeably less pronounced; however, when using irbesartan along with low doses of hydrochlorothiazide (for example, 12.5 mg / day) effectiveness to that in patients of the Caucasian race. After cancellation of irbesartan, blood pressure returns to the initial level gradually. Cancellation syndrome is not observed. In a multicenter, randomized, controlled active substance (amlodipine) and placebo, a double-blind clinical study of IDNT, conducted in 1,715 patients with arterial hypertension and type 2 diabetes (proteinuria 900 mg / day and serum creatinine in the range of 1.0-3.0 mg / d) a decrease (compared with placebo) by 20% (p = 0.024) and a decrease (compared with amlodipine) by 23% (p = 0.006) in the relative risk of the first occurrence of any of the following conditions: a doubling of serum creatinine,development of end-stage renal failure or death from any of the causes (when a comparable reduction in blood pressure is achieved when using irbesartan and amlodipine). A multicenter, randomized, placebo-controlled, double-blind clinical study on the effects of irbesartan on microalbuminuria in patients with arterial hypertension and type 2 diabetes mellitus (IRMA 2), conducted in 590 patients with arterial hypertension and diabetes mellitus type 2 having microalbama 20-200 mcg / min, 30-300 mg / day and normal renal function (serum creatinine concentration is less than 1.5 mg / dL in men and less than 1.1 mg / dL in women), the effect of long-term treatment (within 2 years) of the drug was evaluated Volume Aprovel on the progression of clinically significant proteinuria. When taking the drug at a dose of 300 mg / day, the relative risk of developing clinically significant proteinuria (compared to placebo, p = 0.0004) was reduced by 70%, and at a dose of 150 mg, the relative risk of developing clinically significant proteinuria (compared with placebo, p = 0.085) by 39%. A slowdown in the progression of clinically significant proteinuria was noted already after 3 months and continued throughout the 2-year period of the clinical study. The decrease in CC within 24 hours between the treatment groups was not significantly different. Microalbuminuria regression to normal albuminuria (less than 20 mcg / min; less than 30 mg / day) was more frequently observed in the Aprovel group at a dose of 300 mg (34%) compared with the placebo group (21%).
Pharmacokinetics
Absorption After oral administration, irbesartan is rapidly and completely absorbed. Cmax of irbesartan in blood plasma is achieved within 1.5-2 hours after ingestion. Absolute bioavailability is 60-80%. Simultaneous food intake does not significantly affect the bioavailability of the drug. Distribution Plasma protein binding is approximately 96%. Binding to cellular components of blood is insignificant. Vd - 53-93 l. With daily intake of irbesartan 1 time / day, Css is reached after 3 days, while its limited accumulation in plasma is observed (less than 20%). Metabolism After ingestion or in / in the introduction of 14C-irbesartan, 80-85% of the radioactivity in the circulating plasma falls on unchanged irbesartan.Irbesartan is biotransformed in the liver by oxidation and conjugation with glucuronic acid. Irbesartan oxidation occurs mainly with the participation of the CYP2C9 isoenzyme, the participation of CYP3A4 isoenzyme in the metabolism of irbesartan is insignificant. The main metabolite in the systemic circulation is irbesartan glucuronide (about 6%). Irbesartan is not metabolized by most isoenzymes, which are usually involved in drug metabolism (CYP1A1, CYP1A2, CYP2A6, CYP2B6 CYP2D6 or CYP2E1 isoenzymes) and does not cause their inhibition or induction. Irbesartan does not induce and does not inhibit the CYP3A4 isoenzyme. Withdrawal Irbesartan and its metabolites are excreted from the body, both through the intestines (with bile) and the kidneys. The final T1 / 2 is 11-15 hours. The total clearance and the renal clearance of intravenous irbesartan are 157-176 ml / min and 3-3.5 ml / min, respectively. After ingestion or in / in the introduction of 14C-irbesartan, about 20% of the radioactivity is found in the urine, and the rest in the feces. Less than 2% of the administered dose is excreted in the urine as unchanged irbesartan. Pharmacokinetics in special clinical situations Slightly higher plasma concentrations of irbesartan are found in women (compared to men). However, differences in T1 / 2 and accumulation of irbesartan were not identified. Correction of the dose of irbesartan in women is not required. There were no differences in the effects of irbesartan depending on gender. The AUC and Cmax values of irbesartan in elderly patients (65–80 years) with clinically normal renal and liver function were approximately 20–50% higher than in younger patients (18–40 years). The values of the final T1 / 2 were comparable. No age-related differences in the effects of irbesartan were observed. In patients with impaired renal function or patients undergoing hemodialysis, the pharmacokinetics of irbesartan do not significantly change. Irbesartan is not removed from the body during hemodialysis. In patients with hepatic insufficiency (due to cirrhosis of the liver), mild (functional class A or 5-6 points on the Child-Pugh scale) and moderate (functional class B or 7-9 points on the Child-Pugh scale), the pharmacokinetic parameters of irbesartan do not change significantly . In patients with impaired renal function or patients undergoing hemodialysis, the pharmacokinetics of irbesartan do not significantly change. Irbesartan is not excreted through hemodialysis.In volunteers without arterial hypertension, AUC and T1 / 2 irbesartan in representatives of the Negroid race were approximately 20–25% higher than in representatives of the Caucasoid race; Their irbesartan was almost the same as that of the Caucasians.
Indications
- arterial hypertension (as monotherapy and in combination with other antihypertensive drugs, for example, thiazide diuretics, beta-blockers, blockers of slow-acting calcium channels); - nephropathy with arterial hypertension and type 2 diabetes mellitus (as part of a combination antihypertensive therapy).
Contraindications
- liver failure severe (functional class C or more than 9 points on the Child-Pugh scale) (lack of experience in clinical use); - simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or with moderate to severe renal insufficiency (GFR less than 60 ml / min / 1.73 m2 of body surface); - simultaneous use with ACE inhibitors in patients with diabetic nephropathy; - pregnancy; - lactation period (breastfeeding); - children's and teenage age up to 18 years (efficiency and safety are not established); - hereditary intolerance to galactose, lactase deficiency or glucose / galactose malabsorption syndrome; - hypersensitivity to the drug. With caution - with aortic stenosis or mitral valve, hypertrophic obstructive cardiomyopathy; - with hypovolemia, hyponatremia, arising, for example, with intensive treatment with diuretics, hemodialysis, diarrhea, vomiting, diet with limited consumption of salt, (the danger of excessive reduction of blood pressure); - in patients with renal function, depending on the activity of the RAAS, such as patients with arterial hypertension with bilateral or unilateral stenosis of the renal arteries or patients with chronic heart failure III-IV functional class (according to the NYHA classification); - in ischemic heart disease and / or clinically significant atherosclerosis of cerebral vessels (with an excessive decrease in blood pressure, there is a risk of increased ischemic disorders,up to the development of acute myocardial infarction and stroke); - in case of renal failure (control of potassium and concentration of creatinine in the blood is required), recent kidney transplantation (lack of experience in clinical use); - with simultaneous use of NSAIDs, including selective COX-2 inhibitors (increased risk of impaired kidney function, including the possibility of developing acute renal failure and increasing serum potassium, especially in elderly patients, patients with hypovolemia [including patients taking diuretics] or in patients with impaired renal function); - when used in combination with ACE inhibitors or aliskiren, because, compared with monotherapy, with a double blockade of RAAS, there is an increased risk of developing an excessive decrease in blood pressure, hyperkalemia and renal dysfunction.
Use during pregnancy and lactation
Experience in the use of the drug Aprovel during pregnancy is missing. The use of ACE inhibitors in the II and III trimesters of pregnancy caused damage and death of the developing fetus. Therefore, during pregnancy, irbesartan, as well as any other drug that acts directly on the RAAS, is contraindicated. Transition to appropriate alternative therapy of antihypertensive drugs with an established safety profile during pregnancy should be carried out before the beginning of pregnancy planning. When diagnosing pregnancy during treatment, the drug should be immediately canceled. It is not known whether irbesartan is excreted in breast milk. Aprovel is contraindicated during lactation (breastfeeding). Therefore, after assessing the ratio of the estimated benefits of taking the drug for the mother and the potential risk to the baby, either breastfeeding or taking Aprovel should be stopped.
Dosage and administration
The drug is taken orally, regardless of the meal. The pill is swallowed whole with water. The initial dose is, as a rule, 150 mg 1 time / day. With insufficient therapeutic effect when using the drug Aprovel at a dose of 150 mg 1 time / day, the dose can be increased to 300 mg, or additional use of a diuretic (for example, hydrochlorothiazide at a dose of 12.5 mg) or another antihypertensive drug (for example, beta-adrenergic blocker, slow long-acting calcium channel). In patients with nephropathy with hypertension and type 2 diabetes, the preferred maintenance dose is 300 mg 1 time / day.In general, elderly patients do not require a dose reduction. In patients who took the drug Aprovel in clinical studies, in general, there was no difference in efficacy and safety between patients aged 65 years and older and younger patients. In patients with mild and moderately impaired liver function, dose reduction is usually not required. Experience with the use of the drug in patients with severe liver failure is absent. In patients with renal insufficiency (regardless of severity), dose reduction is not required. In patients with severe hypovolemia and / or hyponatremia, such as patients receiving intensive diuretic therapy, or who are on hemodialysis, hypovolemia and hyponatremia should be adjusted before the start of the use of the drug Aprovel.
Side effects
Determination of the frequency of adverse reactions (according to the WHO classification): very often (1/10), often (1/100, less than 1/10), infrequently (1/1000, less than 1/100), rarely (1/10 000, less 1/1000), very rarely (less than 1/10 000, including individual messages), the frequency is unknown (according to the available data, it is not possible to determine the frequency of occurrence of an undesirable phenomenon). The safety of the drug Aprovel has been studied in clinical studies in approximately 5,000 patients, including 1,300 patients with arterial hypertension who took the drug for more than 6 months, and 400 patients who took the drug for 1 year or more. Adverse events in patients taking Aprovel were usually mild and transient, and their frequency did not depend on the dose taken, as well as on gender, age and race. In placebo-controlled studies in which 1965 patients took irbesartan (on average for 1-3 months), discontinuation of treatment due to the development of any clinical or laboratory adverse reactions was required in 3.3% of patients taking Aprovel and in 4.5 % of patients taking placebo (the differences were statistically significant). Adverse events observed in placebo-controlled clinical trials with the use of the drug Aprovel in hypertension, probably or possibly related to his or her admission, or without an established relationship with the drug. placeboThe nervous system: often - dizziness, headache; infrequently - orthostatic dizziness. Since the cardiovascular system: infrequently - tachycardia, flushing to the skin of the face, swelling. On the part of the respiratory system: Infrequently - cough. On the part of the digestive system: often - nausea / vomiting; infrequently - diarrhea, dyspepsia / heartburn. On the part of the reproductive system: infrequently - sexual dysfunction. General reactions: often - increased fatigue; infrequently - pain in the chest. From the laboratory parameters: during controlled clinical trials in patients with arterial hypertension no clinically significant changes in laboratory parameters were observed. No special monitoring of laboratory parameters is required for hypertensive patients receiving Aprovel. Adverse events observed in controlled clinical trials when using Aprovel in patients with nephropathy in hypertension and type 2 diabetes (clinical studies IDNT and IRMA 2) Adverse events were similar to those in patients with arterial hypertension except for orthostatic symptoms ( orthostatic dizziness and orthostatic hypotension). On the part of the nervous system: very often - dizziness (10.2%) (when taking placebo 6%); often - orthostatic dizziness (5.4%) (when taking placebo 2.7%). Since the cardiovascular system: often - orthostatic hypotension (5.4%) (when taking placebo 3.2%). The percentage of treatment discontinuation due to orthostatic symptoms when taking the drug Aprovel compared with placebo was 0.3% for vertigo versus 0.5%, 0.2% for orthostatic vertigo and 0.0% for orthostatic hypotension and 0.0% respectively. On the part of laboratory parameters: hyperkalemia was more often observed with patients with hypertension and diabetes when receiving irbesartan than with placebo. In the IDNT clinical trial, the percentage of patients with hyperkalemia (> 6 mEq / L) when taking the drug Aprovel was 18.6% versus 6.0% when taking placebo. In a clinical study of IRMA, 2 percent of patients with hyperkalemia> 6 mEq / L was 1.0% when taking the drug Aprovel, and hyperkalemia was not observed in the placebo group. In a clinical study of IDNT, the frequency of discontinuation of treatment due to the development of hyperkalemia with the use of the drug Aprovel and placebo was 2.1% and 0.36%, respectively.In a clinical study of IRMA, the frequency of discontinuing treatment due to the development of hyperkalemia when taking the drug Aprovel and placebo was 0.5% and 0%, respectively. Adverse events observed with post-marketing use of the drug Aprovel On the part of the immune system: very rarely (as with all angiotensin II receptor antagonists) - allergic reactions such as urticaria, angioneurotic edema. The following adverse events have been identified with the use of irbesartan since the release of Aprovel to the market. On the part of the organ of hearing and labyrinth disorders: the frequency is unknown - ringing in the ears. On the part of the liver and biliary tract: the frequency is unknown - increased activity of liver enzymes and concentration of bilirubin in the blood, hepatitis, jaundice. On the part of metabolism: the frequency is unknown - hyperkalemia. On the part of the nervous system: the frequency is unknown - vertigo. On the part of the musculoskeletal system: the frequency is unknown - myalgia. From the urinary system: the frequency is unknown - impaired renal function, including cases of renal failure in patients at risk. General reactions: frequency unknown - asthenia.
Overdose
When using the drug in adult patients at a dose of up to 900 mg / day for 8 weeks did not reveal any toxicity. Treatment: in case of overdose, it is recommended to induce vomiting and / or gastric lavage. Constant monitoring of the patient’s condition should be established and, if necessary, symptomatic and supportive therapy should be carried out. Irbesartan is not excreted through hemodialysis. There is no specific information regarding the treatment of overdose.
Interaction with other drugs
Based on these in vitro studies, interactions of irbesartan with drugs that are metabolized with the participation of isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2E1 or CYP3A4 are not expected. Irbesartan is mainly metabolized with the participation of the CYP2C9 isoenzyme and, to a lesser extent, is glucuronized. No significant pharmacokinetic and pharmacodynamic interactions were observed with the combined use of irbesartan with warfarin, a drug that is metabolized with the participation of the CYP2C9 isoenzyme.Irbesartan does not change the pharmacokinetics of digoxin and simvastatin. The combined use of irbesartan with hydrochlorothiazide or nifedipine does not change the pharmacokinetics of irbesartan. With drugs containing aliskiren The combination of the drug Aprovel with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or with moderate to severe renal insufficiency (GFR less than 60 ml / min / 1.73 m2 of body surface), and its use is not recommended in other patients. With ACE inhibitors Use of the drug Aprovel in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients. With potassium preparations and potassium-sparing diuretics, heparin On the basis of the experience obtained with the use of other drugs that affect the RAAS, the simultaneous use of irbesartan with potassium preparations; potassium-containing salt substitutes; potassium-sparing diuretics or other drugs that can increase the content of potassium in the blood plasma (heparin) can sometimes significantly increase the serum concentration of potassium, which requires careful monitoring of serum potassium in patients during treatment. With NSAIDs, including selective COX-2 inhibitors With the simultaneous use of angiotensin II receptor antagonists and NSAIDs (including selective COX-2 inhibitors), the hypotensive effect of irbesartan can be reduced. In elderly patients, patients with hypovolemia, or in patients with impaired renal function, the use of NSAIDs, including COX-2 inhibitors, simultaneously with angiotensin II receptor antagonists, including irbesartan, can lead to deterioration of renal function, including the possible development of acute renal failure. These effects are usually reversible. Kidney function should be periodically monitored in patients who simultaneously take irbesartan and NSAIDs, including COX-2 inhibitors. With lithium preparations, an increase in serum lithium concentration and an increase in its toxicity have been reported with simultaneous use of lithium salts with irbesartan. With diuretics and other antihypertensive drugs. With simultaneous use of irbesartan and other antihypertensive drugs, it is possible to enhance the antihypertensive effect.Irbesartan without any undesirable consequences was used simultaneously with other antihypertensive drugs, such as beta-blockers, blockers of slow-acting calcium channels and long-acting thiazide diuretics. Prior treatment with high-dose diuretics can lead to hypovolemia and increase the risk of an excessive decrease in blood pressure at the beginning of treatment with Aprovel.
special instructions
Excessive decrease in blood pressure The use of the drug Aprove has so far rarely been accompanied by an excessive decrease in blood pressure in patients with arterial hypertension without concomitant diseases. As with the use of ACE inhibitors, an excessive decrease in blood pressure, accompanied by clinical symptoms, can develop in patients with hyponatremia / hypovolemia (for example, as a result of intensive diuretic therapy, diarrhea or vomiting, diet with restricted salt intake), as well as in patients on hemodialysis. Before starting the use of the drug Aprovel, it is necessary to correct hypovolemia and / or hyponatremia. Patients with renal function, depending on the activity of the RAAS As a result of inhibition of the RAAS, impaired renal function can be expected in susceptible patients. In patients with kidney function, depending on the activity of the RAAS (patients with arterial hypertension and renal artery stenosis of one or both kidneys or patients with chronic heart failure III and IV functional class according to the NYHA classification), treatment with Aprovel was associated with oliguria and / or progressive azotemia and rarely with acute renal failure and / or death. Renal failure and kidney transplantation When using the drug Aprovel in patients with renal insufficiency, periodic monitoring of the concentration of potassium and serum creatinine is recommended. There are no clinical data on the use of the drug Aprovel in patients who have had a kidney transplant. Arterial hypertension and diabetes mellitus type 2 with kidney damage The beneficial effect in slowing the progression of renal and cardiovascular lesions observed in the use of the drug Aprovel had different severity in different groups of patients: it was less pronounced in women and patients not related to the Caucasian race.In a clinical study of IDNT, patients with arterial hypertension and type 2 diabetes with proteinuria (900 mg / day), in the subgroup of patients with a high risk of renal artery stenosis, none of the patients taking Aprovel had a sharp early increase in creatinine concentration serum associated with renal artery stenosis. Double blockade of RAAS with the combination of the drug Aprovel with ACE inhibitors or aliskiren Double blockade of the RAAS when using the combination of the drug Aprovel with aliskiren is not recommended, because compared to monotherapy, there is an increased risk of a sharp decrease in blood pressure, the development of hyperkalemia and renal dysfunction. The use of the drug Aprovel in combination with aliskiren is contraindicated in patients with diabetes or renal failure with GFR less than 60 ml / min / 1.73 m2 of body surface. The use of the drug Aprovel in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients. Hyperkalemia Hyperkalemia may develop with the use of the drug Aprovel (as with the use of other drugs that affect the RAAS), especially in patients with renal insufficiency and / or heart disease. In such patients, adequate monitoring of serum potassium is recommended. Stenosis of the aortic or mitral valve, obstructive hypertrophic cardiomyopathy As with the use of other vasodilators, when administering the drug Aprovel to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy, caution is required. Primary Hyperaldosteronism Patients with primary hyper aldosteronism usually do not respond to antihypertensive drugs that inhibit RAAS. Therefore, the use of the drug Aprovel in such cases is impractical. CHD and / or clinically significant atherosclerosis of the cerebral vessels. As with the use of other antihypertensive drugs, a significant decrease in blood pressure in patients with IHD and / or severe cerebral atherosclerosis can lead to the development of myocardial infarction or stroke. Treatment should be under the control of blood pressure.Use in Pediatrics To date, the safety and efficacy of the drug in patients of childhood and adolescence has not been established. The impact on the ability to drive vehicles and control mechanisms The influence of the drug Aprovel on the ability to drive vehicles or other potentially dangerous activities requiring increased attention has not been studied. However, based on the pharmacodynamic properties of the drug Aprovel, its effect on this ability is unlikely. In the event of dizziness and weakness, attention may be reduced and psychomotor reactions slow down. With the development of such side effects, the doctor decides on the possibility of practicing any potentially dangerous activities.