Rotazar (Film coated tablets) Irbesartan Rotazar 75 mg, 150 mg, 300 mg COMPOSITION A film coated tablet contains Active ingredient: irbesartan 75 mg, 150 mg or 300 mg. Rotazar 75 mg, 150 mg, 300 mg PHARMACOLOGICAL PROPERTIES PHARMACODYNAMICS Rotazar is an antihypertensive drug, a selective antagonist of angiotensin II receptors (АТ 1 type). It blocks all physiologically significant effects of angiotensin II fulfilled via AT 1-receptors regardless of the source or the pathway of angiotensin II synthesis. Specific antagonistic action against AT 1- receptors results in an increase of plasma renin and angiotensin II levels and in a decrease in plasma aldosterone concentration. If the drug is administered in the recommended doses, no significant alteration of serum potassium ion concentration is observed. Irbesartan does not inhibit kininase II (ACE), via which angiotensin II is formed and bradykinin is degraded to inactive metabolites. Irbesartan does not require metabolic activation for development of its action. Irbesartan decreases arterial pressure (AP) with minimum alteration of heart rate (HR). AP decreases in a dose-dependent manner when the drug is administered in doses up to 300 mg once daily, but further increase in irbesartan dosage results in a negligible potentiation of the hypotensive effect. The peak decrease in AP is achieved within 3-6 hours after oral administration of the drug. The hypotensive effect maintains for not less than 24 hours. AP decrease 24 hours after administration of the recommended doses is 60-70% compared to the peak decrease in diastolic and systolic AP in response to the drug. Once daily administration of the drug in doses of 150-300 mg results in the mean degree of AP reduction (systolic/diastolic) at the end of interdose interval (i.e. 24 hours after administration of the drug) in a supine or a sitting position by 8-13/5-8 mm Hg (respectively) compared to placebo. Once daily administration of the drug in a dose of 150 mg exhibits the same hypotensive effect (AP reduction before administration of the next dose of the drug and the mean decrease in AP over 24 hours) as administration of the same dose divided in 2 doses. The hypotensive action of Rotazar develops within 1-2 weeks; the maximum therapeutic effect is achieved within 4-6 weeks after the beginning of treatment. The antihypertensive effect is
maintained in prolonged therapy as well. After termination of treatment AP gradually returns to the initial value; no withdrawal syndrome has been observed. Irbesartan does not affect serum concentrations of uric acid or excretion of uric acid in urine. Efficiency of Rotazar does not depend on age or gender. PHARMACOKINETICS Absorption After oral administration the drug is well absorbed from the gastrointestinal tract (GIT). The peak plasma irbesartan concentration is achieved within 1.5-2 hours after oral administration. Absolute bioavailability is 60-80%. Concomitant food intake does not significantly influence the bioavailability of the drug. Pharmacokinetics of irbesartan is linear and dose-proportional in the dose interval from 10 to 600 mg; in doses over 600 mg (2 times higher than the maximum recommended dose) irbesartan kinetics becomes non-linear (the absorption decreases). Distribution Plasma protein binding is about 96%. Binding with cellular constituent of blood is insignificant. Distribution volume is 53-93 l. Irbesartan accumulation in plasma in repeated once daily administration is limited (less than 20%). Metabolism Irbesartan is biotransformed in liver by way of oxidation and conjugation with glucuronic acid. Irbesartan is oxidized mainly by isoenzyme CYP2С9; involvement of isoenzyme CYP3A4 in irbesartan metabolism is negligible. The main metabolite present in systemic circulation is irbesartan glucuronide (about 6%). Excretion Total body clearance and renal clearance are 157-176 ml/min and 3-3.5 ml/min, respectively. Terminal elimination half-life (T 1/2) is 11-15 hours. Irbesartan and its metabolites are excreted in bile and urine. After oral administration of 14С-irbesartan about 20% of radioactivity is recovered in urine, and the rest - in faeces. Less than 2% of the administered dose is eliminated in urine as unchanged irbesartan. Pharmacokinetics in particular medical cases Women demonstrate a little higher plasma concentrations of irbesartan (compared to men). Still, no differences in T 1/2 values and accumulation of irbesartan have been observed. No dose adjustment is required for women. The values of AUC and the peak irbesartan concentration were somewhat higher in elderly patients ( 65 years old) than in younger ones, but no reliable differences in terminal T 1/2 have been observed.
Pharmacokinetic parameters of irbesartan in patients with impaired renal function or in patients undergoing hemodialysis do not significantly change. Irbesartan is not eliminated via hemodialysis. Pharmacokinetic parameters of irbesartan in patients with mild or moderate liver cirrhosis do not significantly change. No pharmacokinetic studies have been performed in patients with severe hepatic failure. THERAPEUTİC İNDİCATİONS - essential arterial hypertension; - nephropathy in patients with arterial hypertension and type 2 diabetes mellitus (as part of combined hypotensive therapy). CONTRAINDICATIONS - hypersensitivity to the components of the drug; - hereditary galactose intolerance, lactase deficiency or malabsorption of glucose and galactose; - pregnancy; - lactation; - children and adolescents under 18 years old (efficiency and safety have not been determined). Exercise caution administering the drug in aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy, dehydration, hyponatremia, diarrhea, vomiting, diet with limited consumption of salt, diuretic therapy, bilateral stenosis of renal arteries, unilateral stenosis of the artery of the single present kidney, chronic heart failure of the III-IV functional class according to NYHA classification, IHD and/or atherosclerotic damage of cerebral vessels, hyperkalemia, renal failure, hemodialysis, recent transplantation of a kidney (absence of clinical experience of administration), severe renal failure (absence of clinical experience of administration). ADVERSE EFFECTS Arterial hypertension Central nervous system disorders: common - dizziness. Cardiovascular system disorders: uncommon - tachycardia, skin hyperemia. Respiratory system disorders: uncommon - cough. Gastrointestinal tract disorders: common - nausea, vomiting; uncommon - diarrhea, dyspepsia, heartburn. Reproductive system disorders: uncommon - sexual dysfunction.
General body disorders: common - fatigue; uncommon - chest pain. Abnormal laboratory test results: common - proved increase in CPK level, not accompanied with clinical manifestations on the part of the musculoskeletal system. Arterial hypertension and type 2 diabetes mellitus with kidney damage Apart from the side effects described for patients with arterial hypertension, 0.5% of patients with arterial hypertension, type 2 diabetes mellitus with microalbuminuria and without renal failure reported orthostatic dizziness and orthostatic hypotension during treatment with irbesartan (compared to the frequency of such reactions during treatment with placebo). In > 2% (compared to the frequency during treatment with placebo) of patients with arterial hypertension, type 2 diabetes mellitus with pronounced proteinuria and chronic renal failure the following adverse reactions were observed. Nervous system disorders: common - orthostatic dizziness. Cardiovascular system disorders: common - orthostatic hypotension. Musculoskeletal disorders: common - muscle and bone pain. Abnormal laboratory test results: hyperkalemia during treatment of diabetic patients with irbesartan was observed more frequently than during treatment with placebo. Among diabetic patients with increased AP and microalbuminuria with normal renal function hyperkalemia ( 5.5% mmol/l) was observed in 29.4% of patients treated with irbesartan in a dose of 300 mg (very common) and in 22% of patients in the placebo group. Among diabetic patients with increased AP, chronic renal failure and pronounced proteinuria hyperkalemia ( 5.5% mmol/l) was observed in 46.3% of patients treated with irbesartan (very common) and in 26.3% of patients in the placebo group. 1.7% of patients with increased AP and diabetic nephropathy, treated with irbesartan, demonstrated clinically insignificant decrease in hemoglobin concentration (common). DOSAGE AND ADMİNİSTRATİON The drug is administered orally. The tablet is swallowed whole, followed with water. The initial and maintenance doses are 150 mg once daily regardless the timing of meals. Administration of the drug in such doses ensures better 24-hour control of AP, than in doses of 75 mg daily. But in some cases, especially in patients undergoing hemodialysis or in patients older than 75 years, the initial dose should be 75 mg. In case of insufficient therapeutic effect of Rotazar in a dose of 150 mg once daily the dose may be increased to 300 mg or another antihypertensive drug may be prescribed. Particularly, it was shown that administration of the diuretic hydrochlorothiazide potentiated the effect of Rotazar. Treatment of patients with arterial hypertension and type 2 diabetes mellitus should be started with a dose of 150 mg once daily and gradually increased to 300 mg which is the preferable maintenance dose for treatment of nephropathy.
In patients with water and electrolytic imbalance the circulating blood volume (CBV) should be restored and/or hyponatremia should be eliminated before treatment with the drug. No dose regimen adjustment is required in patients with renal dysfunction. The initial dose for patients undergoing hemodialysis should be 75 mg daily. No dose regimen adjustment is required in patients with mild or moderate hepatic dysfunction. Clinical experience of administration of the drug in patients with severe hepatic dysfunction is absent. Although the recommended initial dose for patients aged over 75 years is 75 mg, no dose adjustment is usually required. PACKAGING Film coated tablets. 14 tablets in a blister. 2 blisters together with a leaflet in a carton box.