Pharmacological properties
Pharmacodynamics. Irbesartan is a potent oral selective angiotensin II receptor antagonist (ARA II - type AT1). It is believed that it blocks all physiologically significant effects of angiotensin II mediated through the AT1 receptor, regardless of the source or pathway of angiotensin II synthesis. Selective antagonistic action against angiotensin II receptors (AT1) leads to an increase in the concentration of renin and angiotensin II and a decrease in the concentration of aldosterone in the blood plasma. When using the drug in recommended doses, the level of potassium in the blood serum does not change significantly. Irbesartan does not inhibit APF (kininase II) - the enzyme that produces angiotensin II, carries out metabolic degradation of bradykinin with the formation of inactive metabolites. To manifest its effect, irbesartan does not require metabolic activation.
Clinical efficacy in hypertension. Irbesartan reduces blood pressure with minimal change in heart rate. The reduction in blood pressure when taken once a day is dose-dependent, with a tendency to plateau at a dose of 300 mg. Doses of 150-300 mg when taken once a day reduce blood pressure in the supine or sitting position at the end of the drug's action (i.e. 24 hours after taking the drug) by an average of 8-13 / 5-8 mm Hg. (systolic / diastolic) more than placebo.
The maximum reduction in blood pressure is achieved 3-6 hours after taking the drug, the hypotensive effect persists for at least 24 hours.
24 hours after taking the recommended doses, the blood pressure reduction is 60-70% compared to the maximum reduction in diastolic and systolic blood pressure. Taking the drug at a dose of 150 mg once a day causes an effect (at the minimum of action and on average over 24 hours) similar to that when dividing this daily dose into 2 doses.
The antihypertensive effect of the drug Converium is manifested within 1-2 weeks, and the maximum effect is achieved at 4-6 weeks from the start of treatment. The antihypertensive effect is maintained during long-term treatment. After discontinuation of treatment, blood pressure gradually returns to baseline. Withdrawal syndrome in the form of an increase in the severity of hypertension after discontinuation of the drug has not been noted.
Irbesartan, when given with thiazide diuretics, has an additive hypotensive effect. In patients who were not adequately controlled with irbesartan monotherapy, co-administration of a lower dose of hydrochlorothiazide (12.5 mg) with irbesartan once daily resulted in a more pronounced reduction in blood pressure of at least 7-10/3-6 mm Hg (systolic/diastolic) compared with placebo.
Pharmacokinetics. After oral administration, irbesartan is well absorbed: studies have shown that the absolute bioavailability is about 60-80%. Simultaneous food intake does not significantly affect the bioavailability of irbesartan. Binding to plasma proteins is ≈96%, while binding to blood cells is insignificant. The volume of distribution is 53-93 l. After oral or intravenous administration of 14 C irbesartan, 80-85% of the radioactivity circulating in the blood plasma is unchanged irbesartan. Irbesartan is metabolized in the liver by conjugation with glucuronide and oxidation. The main circulating metabolite in the blood is irbesartan-glucuronide (≈6%). In vitro data indicate that irbesartan is oxidized mainly by the cytochrome P450 enzyme CYP 2C9; the CYP 3A4 isoenzyme had almost no effect on it.
The pharmacokinetics of irbesartan in the dose range of 10-600 mg is linear and proportional to the dose taken. A less proportional increase in absorption when taken orally is noted at a dose of 600 mg (2 times higher than the maximum recommended dose); the mechanism of this is unknown. C max in blood plasma is achieved 1.5-2 h after oral administration of the drug. Total and renal clearance are 157-176 and 3-3.5 ml/min, respectively. The final T ½ of irbesartan is 11-15 h. Equilibrium plasma concentrations are achieved 3 days after the start of the drug once a day. When used once a day, the cumulation of irbesartan in blood plasma is low (20%). In the course of the study, women with hypertension had a slightly higher concentration of irbesartan in blood plasma. However, there were no differences in T½ and accumulation of irbesartan. There is no need to change the dose for women. In elderly patients (65 years), the AUC and Cmax values for irbesartan were slightly higher than in young patients (18-40 years). However, the final T½ did not change significantly. There is no need to change the dose of the drug for elderly patients.
Irbesartan and its metabolites are excreted via the bile and kidneys. After oral or intravenous administration of 14C irbesartan, ≈20% of the radioactive label is recovered in the urine, the remainder in the feces. Less than 2% of the administered dose of irbesartan is excreted unchanged in the urine.
Renal impairment: In patients with renal impairment or in patients undergoing hemodialysis, the pharmacokinetic parameters of irbesartan do not change significantly. Irbesartan is not removed from the body by hemodialysis.
Hepatic impairment. The pharmacokinetic parameters of irbesartan are not significantly altered in patients with mild or moderate cirrhosis. Studies in patients with severe hepatic impairment have not been conducted.
Indication
Essential hypertension. AG in patients with kidney disease and type 2 diabetes mellitus as part of antihypertensive therapy.
Application
The usual starting and maintenance dose is 150 mg once daily with or without food. Converium 150 mg once daily usually provides better 24-hour control than 75 mg. However, a 75 mg dose may be used at the start of therapy, especially in patients on haemodialysis or in patients over 75 years of age.
For patients whose blood pressure is not adequately controlled with 150 mg once daily, the dose of Converium may be increased to 300 mg once daily or another antihypertensive agent may be added. In particular, it has been shown that the addition of a diuretic such as hydrochlorothiazide to Converium therapy has an additive effect.
For patients with hypertension and type 2 diabetes, treatment should begin with a dose of 150 mg of irbesartan once daily, then increase to a dose of 300 mg once daily, which is the optimal maintenance dose for the treatment of patients with kidney disease.
The drug Converium has a positive nephroprotective effect on the kidneys in patients with hypertension and type 2 diabetes. To achieve the target blood pressure level, irbesartan is used as an adjunct to other antihypertensive agents if necessary.
Renal insufficiency. No dosage adjustment is required for patients with impaired renal function. Individuals on hemodialysis should be given the drug at a low initial dose (75 mg).
Intravascular volume depletion. Volume depletion/circulating blood volume and/or sodium depletion should be corrected prior to initiating Converium.
Hepatic impairment: No dose adjustment is required for patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment.
Elderly patients: Although treatment of patients over 75 years of age should be initiated at a dose of 75 mg, dose adjustment is usually not required.
Pediatric Use: Irbesartan is not recommended for use in children and adolescents due to a lack of data on its safety and efficacy.
Contraindication
Hypersensitivity to any component of the drug. Pregnancy and breastfeeding. Children. Galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
Side effects
The frequency of the following adverse reactions was defined as follows: very common (1/10), common (1/100, 1/10), uncommon (1/1000, 1/100), rare (1/1000, 1/100), very rare (1/10,000). Within each grouping, adverse reactions are presented in order of decreasing importance.
From the nervous system: often - dizziness.
From the cardiovascular system: infrequently - tachycardia, hyperemia.
Respiratory, thoracic and mediastinal disorders: infrequently - cough.
On the part of the digestive system: often - nausea, vomiting; infrequently - diarrhea, dyspepsia / heartburn.
From the reproductive system and mammary glands: infrequently - sexual dysfunction.
General condition and conditions at the injection site: often - fatigue; infrequently - chest pain.
Laboratory studies: often - a significant increase in the level of CPK in the blood plasma, which was not accompanied by clinical manifestations from the musculoskeletal system.
Hypertension in patients with kidney disease and type 2 diabetes mellitus. In addition to the side effects described above, orthostatic dizziness and orthostatic hypotension have been observed in diabetic patients with hypertension who had microalbuminuria and normal renal function (uncommon side effects).
In patients with diabetes mellitus with hypertension who had chronic renal failure and severe proteinuria, the following additional side effects were noted.
From the nervous system: often - orthostatic dizziness.
Vascular disorders: often - orthostatic hypotension.
Musculoskeletal and connective tissue disorders: often - pain in bones and muscles.
Laboratory studies. Hyperkalemia was more common in diabetic patients taking irbesartan. When using 300 mg of irbesartan in diabetic patients with hypertension, who had microalbuminuria and normal renal function, hyperkalemia (5.5 mEq / mol) was observed in 29.4% (very common side effects). In diabetic patients with arterial hypertension and chronic renal failure and severe proteinuria, who took irbesartan, hyperkalemia (5.5 mEq / mol) was observed in 46.3% (very common side effects). A decrease in hemoglobin levels, which had no clinical significance, was observed in patients with hypertension and progressive diabetic nephropathy, who took irbesartan (frequent side effects).
Immune system disorders: As with other ARBs, hypersensitivity reactions such as rash, urticaria, and angioedema have been reported rarely.
Metabolism and nutrition disorders: hyperkalemia.
From the nervous system: headache.
Hearing and vestibular disorders: tinnitus.
On the part of the digestive system: dysgeusia (change in taste).
Hepatobiliary disorders: hepatitis, liver dysfunction.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia (in some cases associated with increased CPK levels in blood plasma), muscle cramps.
Renal and urinary system: renal dysfunction, including renal failure in patients at high risk (see Precautions).
Skin and subcutaneous tissue disorders: leukocytoclastic vasculitis.
Adverse reactions in pediatrics. In children and adolescents aged 6-16 years with hypertension, the following side effects were noted: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). The most frequently observed deviations from the norm of the following laboratory parameters were: increased creatinine levels (6.5%) and CPK levels in 2% of patients in this age group.
Special instructions
Intravascular volume depletion. Symptomatic hypotension, especially after the first dose, may occur in patients with reduced intravascular volume and/or sodium depletion due to intensive diuretic therapy, a salt-restricted diet, diarrhea, or vomiting. These conditions should be corrected before initiating Converium.
Renovascular hypertension. When using drugs that affect the renin-angiotensin-aldosterone system, there is an increased risk of severe hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney. Although no such cases have been identified with the use of the drug Converium, similar effects can be expected with the use of ARA II.
Renal insufficiency and kidney transplantation. When using Converium in patients with impaired renal function, regular monitoring of potassium and creatinine plasma levels is recommended. There is no experience with the use of Converium in patients with recent kidney transplantation.
Patients with hypertension, kidney disease, and type 2 diabetes
Hyperkalemia. As with other drugs that affect the renin-angiotensin-aldosterone system, hyperkalemia may develop during treatment with Converium, especially in the presence of renal insufficiency, severe proteinuria due to diabetic nephropathy and/or heart failure. Close monitoring of plasma potassium concentrations is recommended in patients at risk.
Lithium. The simultaneous use of lithium and Converium is not recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilators, the drug should be used with extreme caution in patients with aortic or mitral valve stenosis, obstructive hypertrophic cardiomyopathy.
Primary aldosteronism: Patients with primary aldosteronism usually do not respond clinically to antihypertensive drugs that act by inhibiting the renin-angiotensin system. Therefore, the use of Converium in the treatment of such patients is not recommended.
General: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with ACE inhibitors or ARBs that affect this system has been associated with acute hypotension, azotemia, oliguria and occasionally acute renal failure. As with any antihypertensive agent, excessive reduction in blood pressure in patients with coronary artery disease or ischemic cardiovascular disease may result in myocardial infarction or stroke. Like ACE inhibitors, irbesartan and other angiotensin antagonists appear to be less effective in lowering blood pressure in blacks than in non-blacks, possibly because low-renin states are more common in the black hypertensive population. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy and breastfeeding.
Pregnancy. ARA II is not recommended for use during pregnancy.
There are no epidemiological data to support a teratogenic risk with the use of ACE inhibitors in the first trimester of pregnancy; however, even the slightest possibility of risk cannot be excluded. Since there are no controlled epidemiological data on the risk with the use of ARA II, similar risks may exist for drugs of this group.
If pregnancy is diagnosed, the use of ARA II should be discontinued and, if necessary, replaced by alternative therapy.
It has been confirmed that the use of ARA II in the II and III trimesters of pregnancy causes fetotoxicity in humans (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
When using ARA II from the second trimester of pregnancy, it is recommended to perform an ultrasound scan of the kidneys and skull bones.
Infants whose mothers have taken ARA II should be monitored closely for the development of hypotension.
Breastfeeding period The use of the drug Converium is contraindicated during breastfeeding.
Children: The safety and efficacy of the drug in children and adolescents have not been established.
The ability to influence the reaction rate when driving vehicles or working with other mechanisms has not been studied. The pharmacokinetic properties of irbesartan indicate that such an effect is unlikely.
When driving or operating other machinery, it should be taken into account that dizziness and fatigue are possible during treatment with the drug.
Interactions
Diuretics and other antihypertensive agents. Other antihypertensive agents may enhance the hypotensive effect of irbesartan; however, Converium has been safely administered with other antihypertensive agents such as β-blockers, long-acting calcium channel blockers and thiazide diuretics. Previous treatment with a high dose of diuretic may lead to dehydration and increase the risk of hypotension at the start of treatment with Converium.
Potassium supplements and potassium-sparing diuretics. Experience with other medicinal products that affect the renin-angiotensin-aldosterone system suggests that concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other medicinal products that may increase plasma potassium levels (e.g. heparin) may lead to increases in plasma potassium levels. Therefore, the concomitant use of such medicinal products with Converium is not recommended.
Lithium. Transient increases in plasma lithium concentrations and toxicity have been reported with concomitant use of lithium with ACE inhibitors. In isolated cases, similar effects have been observed with irbesartan. Therefore, this combination is not recommended. If necessary, careful monitoring of plasma lithium levels is recommended.
NSAIDs. With the simultaneous use of ARA II with NSAIDs (for example, with selective COX-2 inhibitors, acetylsalicylic acid (3 g / day) and non-selective NSAIDs) may be a decrease in the severity of the antihypertensive effect.
As with ACE inhibitors, concomitant use of ARA II and NSAIDs may increase the risk of renal dysfunction, including acute renal failure, and may lead to increases in serum potassium, especially in patients with impaired renal function. This combination should be used with caution, especially in the elderly. Adequate hydration and monitoring of renal function should be considered at the beginning of combination therapy and periodically thereafter.
Additional information on irbesartan interactions. Hydrochlorothiazide does not affect the pharmacokinetics of irbesartan. Irbesartan is metabolized primarily by CYP 2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin, which is metabolized by CYP 2C9. The effect of CYP 2C9 inducers, such as rifampicin, on the pharmacokinetics of irbesartan has not been studied. The pharmacokinetics of digoxin were not altered by co-administration with irbesartan.
Overdose
Experience with the drug in the treatment of adults at a dose of up to 900 mg/day for 8 weeks has not revealed toxicity of the drug. The most likely manifestations of overdose may be hypotension and tachycardia; bradycardia may also be a manifestation of overdose. There are no specific data on the treatment of overdose with the drug Converium. Patients require careful observation, treatment should be symptomatic and supportive. Therapeutic measures: induce vomiting and / or perform gastric lavage. In case of overdose, the use of activated charcoal may be useful. Irbesartan is not removed by hemodialysis.
Storage conditions
In the original packaging at a temperature not exceeding 25 °C.
