Instructions for Irbetan tablets 300 mg No. 20
Composition
active ingredient: 1 tablet contains irbesartan 300 mg;
Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, poloxamer, colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: round tablets with a biconvex surface, white or almost white in color, with a score.
Pharmacotherapeutic group
Angiotensin II receptor antagonists, simple preparations. ATX code C09C A04.
Pharmacological properties
Pharmacodynamics
Mechanism of action: Irbesartan is a potent, orally active, selective angiotensin II (type AT1) receptor antagonist. It can block all the effects of angiotensin II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin II.
Selective antagonism of angiotensin II (AT1) receptors leads to increased levels of renin and angiotensin II in the blood plasma, as well as a decrease in the concentration of aldosterone in the blood plasma.
Irbesartan alone has no significant effect on serum potassium levels when used at recommended doses. Irbesartan does not inhibit angiotensin-converting enzyme (kininase II), the enzyme that catalyzes the formation of angiotensin II and the degradation of bradykinin to inactive metabolites. Irbesartan is active without metabolic activation.
Clinical efficacy.
Arterial hypertension. Irbesartan lowers blood pressure with minimal changes in heart rate. The reduction in blood pressure is dose-dependent with a tendency to plateau at doses above 300 mg. When using the drug in doses of 150-300 mg 1 time per day, blood pressure in the supine or sitting position at the time of minimal drug efficacy (i.e. 24 hours after taking the dose) is on average 8-13/5-8 mm Hg (systolic/diastolic) lower than when using placebo.
The maximum reduction in blood pressure occurs within 3-6 hours after taking the drug, and the blood pressure-lowering effect is maintained for at least 24 hours. When using the recommended doses, the reduction in blood pressure 24 hours after taking the drug is 60-70% of the corresponding maximum diastolic and systolic response. Taking the drug at a dose of 150 mg 1 time per day provides a minimal effect and an average daily result similar to that observed when taking the drug twice a day at the same total daily dose.
The blood pressure-lowering effect of Irbetan develops within 1-2 weeks, with the maximum effect occurring 4-6 weeks after the start of therapy. This antihypertensive effect is maintained during long-term therapy.
After discontinuation of the drug, blood pressure gradually returns to baseline. No rebound hypertension was observed.
The blood pressure-lowering effect of irbesartan and thiazide diuretics is additive. In patients whose blood pressure is not adequately controlled with irbesartan monotherapy, the addition of low-dose hydrochlorothiazide (12.5 mg) once daily to irbesartan resulted in an additional placebo-corrected reduction in blood pressure of 7-10/3-6 mm Hg (systolic/diastolic) at the time of trough.
The efficacy of Irbesartan is not influenced by age or gender. As with other medicinal products that act on the renin-angiotensin system, black patients with hypertension have a significantly lower response to irbesartan monotherapy. When irbesartan is co-administered with low doses of hydrochlorothiazide (e.g. 12.5 mg/day), the antihypertensive response in black patients approaches that of Caucasian patients.
There is no clinically significant effect of the drug on serum uric acid levels or urinary uric acid secretion.
Pharmacokinetics
After oral administration, irbesartan is well absorbed: bioavailability is 60-80%.
The bioavailability of irbesartan is not significantly affected by food intake. Irbesartan is approximately 96% bound to plasma proteins and is not significantly bound to cellular components of the blood. The volume of distribution of irbesartan is 53-93 liters.
After oral or intravenous administration of 14C-irbesartan, 80-85% of the radioactivity circulating in the blood plasma is attributed to unchanged irbesartan.
Irbesartan is metabolized in the liver by glucuronide conjugation and oxidation.
Irbesartan exhibits linear and dose-proportional pharmacokinetics over a dose range of 10 to 600 mg. A less than dose-proportional increase in oral absorption was observed at doses above 600 mg (twice the maximum recommended dose); the mechanism for this is not clear. Peak plasma concentrations are reached 1.5 to 2 hours after oral administration.
The total and renal clearance of the drug are 157-176 and 3-3.5 ml/min, respectively.
The terminal half-life of irbesartan is 11-15 hours. Steady-state plasma concentrations are reached within 3 days after starting once-daily dosing. Limited accumulation of the drug in plasma (<20%) is observed with multiple once-daily dosing of irbesartan. It is known that female hypertensive patients have slightly higher plasma concentrations of irbesartan compared to males. However, no differences in half-life and accumulation of irbesartan were found between males and females. No dose adjustment is required in female patients. AUC and Cmax values of irbesartan were also slightly higher in elderly patients (≥ 65 years) than in young patients (18-40 years).
However, the terminal half-life was not significantly different. No dose adjustment is required in elderly patients.
Irbesartan and its metabolites are excreted in both bile and urine. After both oral and intravenous administration of 14C-irbesartan, approximately 20% of the radioactivity was excreted in the urine and the remainder in the feces. Less than 2% of the dose was excreted in the urine as unchanged irbesartan.
Renal impairment: In patients with renal insufficiency or in patients undergoing hemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered.
Irbesartan is not removed by hemodialysis.
Hepatic impairment: In patients with mild or moderate liver cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered.
Studies in patients with severe hepatic dysfunction have not been conducted.
Indication
Treatment of essential hypertension in adults. Treatment of chronic kidney disease in adult patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive therapy regimen.
Contraindication
Hypersensitivity to the active substance or to any of the excipients (see section "Composition"). Pregnant women and women planning to become pregnant (see section "Use during pregnancy or breastfeeding").
The concomitant use of Irbeta with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal dysfunction (glomerular filtration rate (GFR) < 60 ml/min/1.73 m2) (see section “Interaction with other medicinal products and other forms of interaction”).
Interaction with other medicinal products and other types of interactions
Diuretics and other antihypertensive drugs. The risk of hypotension with irbesartan may be increased when used concomitantly with other antihypertensive drugs, but irbesartan has been safely used with some other antihypertensive drugs, such as beta-blockers, long-acting calcium channel blockers, and thiazide diuretics. Previous treatment with high doses of diuretics may lead to hypovolemia and increase the risk of hypotension after starting Irbesartan (see section "Special warnings and precautions for use").
Aliskiren-containing drugs or ACE inhibitors. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is known to be associated with an increased incidence of adverse events such as hypotension, hyperkalaemia and deterioration of renal function (including acute renal failure) compared with the use of any single agent affecting the RAAS (see sections "Contraindications", "Special instructions for use").
Potassium supplements and potassium-sparing diuretics: Based on experience with other medicinal products that affect the renin-angiotensin system, the concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium levels and is therefore not recommended (see section 4.4).
Non-steroidal anti-inflammatory drugs: When angiotensin II antagonists are used concomitantly with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective non-steroidal anti-inflammatory drugs), attenuation of the antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to worsening of renal function, including acute renal failure, and increases in serum potassium, especially in patients with pre-existing renal impairment. This combination should be used with caution, especially in the elderly.
Patients should be adequately hydrated and may benefit from monitoring of renal function at the start of such combination therapy and periodically thereafter.
Additional information on irbesartan interactions. In clinical studies, hydrochlorothiazide did not alter the pharmacokinetics of irbesartan. Irbesartan is metabolized primarily by CYP2C9 and, to a lesser extent, by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin (a drug metabolized by CYP2C9). The effect of CYP2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan has not been evaluated.
When irbesartan was co-administered with digoxin, the pharmacokinetics of digoxin did not change.
Application features
Intravascular hypovolemia: Patients who are hypovolemic and/or natriuretic due to intensive diuretic therapy, dietary salt restriction, diarrhea, or vomiting may experience symptomatic hypotension, especially after the first dose. Such conditions should be corrected before initiating Irbeta.
Renovascular hypertension: There is an increased risk of severe hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. Therefore, similar effects should be expected with any angiotensin II receptor antagonist.
Renal failure and kidney transplantation. When using the drug in patients with impaired renal function, periodic monitoring of potassium and creatinine levels in the blood serum is recommended. There is no experience with the use of the drug Irbetan in patients who have recently undergone kidney transplantation.
Patients with hypertension, type 2 diabetes and chronic kidney disease. The effects of irbesartan on both the renal and cardiovascular systems were not consistent across subgroups analyzed in the study of patients with end-stage chronic kidney disease. In particular, its benefits were less pronounced in women and non-Caucasian subjects.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS). There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalaemia and deterioration of renal function (including the development of acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see section 4.5). If such dual blockade therapy is considered absolutely necessary, it should be used only under specialist supervision and with frequent monitoring of renal function, electrolytes and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
Hyperkalemia: As with other drugs that affect the renin-angiotensin-aldosterone system, hyperkalemia may occur during treatment with irbesartan, especially in the presence of renal dysfunction, overt proteinuria due to diabetic nephropathy and/or heart failure. Close monitoring of serum potassium levels is recommended in patients at risk of developing this complication (see section 4.5).
Lithium: The concomitant use of lithium and irbesartan is not recommended (see section 4.5).
Primary aldosteronism: Patients with primary aldosteronism usually do not respond to antihypertensive medicinal products that act by inhibiting the renin-angiotensin system. Therefore, the use of Irbesartan is not recommended in such patients.
General precautions: 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 primary renal disease, including renal artery stenosis), the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists that affect this system has been associated with cases of acute hypotension, azotemia, oliguria, or (rarely) acute renal failure. As with any antihypertensive agent, excessive reduction in blood pressure in patients with ischemic cardiopathy or ischemic cardiovascular disease could result in myocardial infarction or stroke.
As with angiotensin-converting enzyme inhibitors, irbesartan and other angiotensin antagonists appear to be less effective in lowering blood pressure in black people than in non-blacks, which may be due to a higher prevalence of low-renin states in the black hypertensive population (see section 5.1).
Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effects of the drug on the ability to drive and use machines have not been conducted. Based on the pharmacodynamic properties of irbesartan, its effect on this ability is unlikely. However, when driving or operating machinery, it should be taken into account that dizziness or increased fatigue may occur during treatment.
Use during pregnancy or breastfeeding
Pregnancy. The drug should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use should be discontinued immediately and replaced with another drug approved for use in pregnant women.
Breastfeeding. As no information is available regarding the use of Irbesartan during breastfeeding, the drug is not recommended for use in these patients and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant. It is not known whether irbesartan or its metabolites are excreted in human milk.
Fertility: Irbesartan had no effect on the fertility of rats and their offspring up to dose levels that caused the first signs of maternal toxicity.
Method of administration and doses
The medicine is intended for oral use.
The usual recommended initial and maintenance dose is 150 mg (1/2 tablet) once daily, without regard to meals. Irbesartan 150 mg once daily usually provides better daily blood pressure control than 75 mg. However, starting treatment with 75 mg should be considered, particularly in patients on haemodialysis and in the elderly over 75 years of age.
In patients not adequately controlled with irbesartan 150 mg once daily, the dose may be increased to 300 mg (1 tablet) or other antihypertensive agents may be added. In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect on the effect of Irbesartan (see section 4.5).
In patients with hypertension and type 2 diabetes, irbesartan therapy should be initiated at a dose of 150 mg once daily and titrated to 300 mg once daily, which is the preferred maintenance dose in the treatment of chronic kidney disease. The benefits of Irbesartan on renal function in patients with hypertension and type 2 diabetes have been demonstrated in studies in which irbesartan was added to other antihypertensive agents, as needed, to achieve target blood pressure.
Special patient groups.
Renal impairment: No dose adjustment is required in patients with renal impairment. For patients undergoing hemodialysis, a lower starting dose (75 mg) should be considered (see section 4.4).
Elderly patients: For patients aged 75 years and over, starting treatment with 75 mg should be considered; dose adjustment is usually not required.
Children
The safety and effectiveness of Irbetan in children (under 18 years of age) have not been established.
The effect of irbesartan has been studied in pediatric populations of patients aged 6 to 16 years, but the data available to date are insufficient to extend the indications for use of the drug to children (see section "Adverse reactions") until further data on this issue become available.
Overdose
When using the drug in adults at doses up to 900 mg/day for 8 weeks, no toxic reactions were observed. The most likely manifestations of an overdose of irbesartan are arterial hypotension and tachycardia; bradycardia may also occur in case of overdose. There is currently no specific information on the treatment of an overdose with the drug. The patient's condition should be constantly monitored, and treatment should be symptomatic and supportive.
Recommended measures include induction of vomiting and/or gastric lavage.
Activated charcoal may be useful in treating overdose.
Irbesartan is not removed by hemodialysis.
Adverse reactions
In placebo-controlled studies in patients with hypertension, the overall incidence of adverse events was similar between irbesartan (56.2%) and placebo (56.5%). Discontinuation of treatment due to any clinical or laboratory adverse event was less frequent in the irbesartan group (3.3%) than in the placebo group (4.5%). The incidence of adverse events was not related to dose (within the recommended dose range), gender, age, race, or duration of treatment.
Among patients with hypertension and diabetes mellitus with microalbuminuria and normal renal function, orthostatic dizziness and orthostatic hypotension while taking the drug were observed in 0.5% of patients (i.e., infrequently), but more often than in the placebo group.
The following are adverse reactions reported in placebo-controlled trials in which 1965 patients with hypertension were treated with irbesartan. Terms marked with an asterisk (*) indicate additional adverse reactions that occurred in > 2% of patients with hypertension, diabetes mellitus, chronic renal failure and overt proteinuria and were more frequent than in the placebo group.
Adverse reactions additionally reported during post-marketing experience are also listed. These adverse reactions were reported spontaneously.
Immune system disorders: hypersensitivity reactions such as angioedema, rash, urticaria.
Metabolic and nutritional disorders: hyperkalemia.
Nervous system: dizziness, orthostatic dizziness, vertigo, headache.
From the side of the organs of hearing and balance: tinnitus.
Cardiac: tachycardia.
Vascular: orthostatic hypotension, hyperemia.
Respiratory, thoracic and mediastinal disorders: cough.
Gastrointestinal: nausea/vomiting, diarrhea, dyspepsia/heartburn, dysgeusia.
From the hepatobiliary system: jaundice, hepatitis, liver dysfunction.
Skin and subcutaneous tissue disorders: leukocytoclastic vasculitis.
Musculoskeletal and connective tissue disorders: musculoskeletal pain, arthralgia, myalgia (in some cases associated with elevated plasma creatine kinase levels), muscle spasms.
Renal and urinary disorders: renal dysfunction, including cases of renal failure in patients at increased risk of this complication (see section "Special warnings and precautions for use").
From the reproductive system and mammary glands: sexual dysfunction.
General disorders and administration site conditions: fatigue, chest pain.
Results: Hyperkalemia* in patients with diabetes mellitus treated with irbesartan occurred more frequently than in patients receiving placebo. In patients with hypertension, diabetes mellitus, microalbuminuria and normal renal function, hyperkalemia (≥ 5.5 mEq/L) was observed in 29.4% of patients in the irbesartan 300 mg group and in 22% of patients in the placebo group. In patients with hypertension, diabetes mellitus, chronic renal failure and overt proteinuria, hyperkalemia (≥ 5.5 mEq/L) was observed in 46.3% of patients in the irbesartan group and in 26.3% of patients in the placebo group.
Significant increases in plasma creatine kinase levels (1.7%) were commonly observed in subjects treated with irbesartan. None of these increases were associated with identifiable musculoskeletal clinical manifestations.
Paediatric population: In a randomised study of 318 hypertensive children and adolescents aged 6 to 16 years, the following adverse reactions were observed during the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this study, the most common laboratory abnormalities were increased creatinine (6.5%) and increased creatine kinase in 2% of treated children.
Expiration date
3 years.
Storage conditions
Store in original packaging at a temperature not exceeding 25 ºС.
Keep out of reach of children.
Packaging
10 tablets in a blister; 2 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "KYIV VITAMIN FACTORY".
Location of the manufacturer and its business address
04073, Ukraine, Kyiv, Kopylivska St., 38.
