Irbetan-n: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IRBETAN-H (IRBETAN-H)

Composition:

Active substances: irbesartan, hydrochlorothiazide;

One tablet contains 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose;
pregelatinized starch; magnesium stearate; colloidal anhydrous silicon dioxide; iron oxide red (E 172); iron oxide yellow (E 172)

One tablet contains 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide;

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex tablets of orange-pink color with white specks. The presence of specks of dark-colored dye is permissible.

Pharmacotherapeutic group. Combined angiotensin-II inhibitors.

ATC code C09D A04.

Pharmacological Properties

Pharmacodynamics

Irbesartan-H is a combination of the angiotensin-II receptor antagonist irbesartan and the thiazide diuretic hydrochlorothiazide. The combination of these components provides an additive antihypertensive effect, resulting in a greater reduction in arterial blood pressure than with either component administered alone.

Irbesartan is a potent, orally active, selective antagonist of angiotensin-II receptors (AT1 subtype). It blocks all actions of angiotensin-II mediated via the AT1 receptor, regardless of the source or pathway of angiotensin-II synthesis. Selective antagonism of angiotensin-II (AT1) receptors leads to increased plasma levels of renin and angiotensin-II, as well as decreased plasma aldosterone concentration. When administered at recommended doses to patients without risk of electrolyte imbalance, irbesartan alone does not significantly affect serum potassium levels. Irbesartan does not inhibit ACE (kininase-II), the enzyme responsible for generating angiotensin-II and degrading bradykinin into inactive metabolites. Irbesartan does not require metabolic activation.

Hydrochlorothiazide is a thiazide diuretic. The precise mechanism of the antihypertensive effect of thiazide diuretics is not fully understood. Thiazides affect electrolyte reabsorption in the renal tubules, directly enhancing the excretion of sodium and chloride in approximately equal amounts. Due to its diuretic effect, hydrochlorothiazide reduces plasma volume, increases plasma renin activity, and stimulates aldosterone secretion, leading to increased urinary loss of potassium and bicarbonate and a decrease in serum potassium concentration. When irbesartan is co-administered, blockade of the renin-angiotensin-aldosterone system (RAAS) likely counteracts potassium loss.

After oral administration, diuresis with hydrochlorothiazide begins within 2 hours, peaks at approximately 4 hours, and lasts for about 6–12 hours.

The combination of hydrochlorothiazide and irbesartan produces a dose-dependent additional reduction in arterial blood pressure within the therapeutic dose range. Adding 12.5 mg hydrochlorothiazide to 300 mg irbesartan once daily in patients whose condition is not adequately controlled with 300 mg irbesartan as monotherapy resulted in a placebo-corrected reduction in diastolic blood pressure of up to 6.1 mm Hg at the minimum value (24 hours after dose administration). The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an overall reduction in systolic/diastolic blood pressure of 13.6/11.5 mm Hg, without adjustment for placebo effects.

Administration once daily of 150 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in a placebo-adjusted reduction in mean systolic/diastolic blood pressure of 12.9/6.9 mm Hg (measured 24 hours after dose administration) in patients with mild to moderate arterial hypertension. Peak effect occurred within 3–6 hours. Ambulatory blood pressure monitoring showed that the combination of 150 mg irbesartan and 12.5 mg hydrochlorothiazide administered once daily provided consistent blood pressure reduction over 24 hours, with a mean reduction in 24-hour systolic/diastolic blood pressure of 15.8/10.0 mm Hg, without adjustment for placebo effects.

The blood pressure-lowering effect of irbesartan in combination with hydrochlorothiazide begins after the first dose, persists for 1–2 weeks, and reaches maximum effect within 6–8 weeks. In long-term studies, the effect of irbesartan/hydrochlorothiazide lasted for periods exceeding one year. There is evidence that rebound hypertension does not occur upon discontinuation of either irbesartan or hydrochlorothiazide.

The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has not been studied. Epidemiological data indicate that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular morbidity and mortality.

The efficacy of the drug is independent of patient age or sex. In patients of non-Black race, the response to monotherapy with irbesartan, as with other drugs affecting the renin-angiotensin system (RAS), is significantly lower. However, when irbesartan is combined with a low dose of hydrochlorothiazide (e.g., 12.5 mg daily), the antihypertensive response in patients of non-Black race approaches that observed in patients of other races.

Pharmacokinetics

Concomitant administration of hydrochlorothiazide and irbesartan does not affect the pharmacokinetics of either component.

Both irbesartan and hydrochlorothiazide are orally active and do not require biotransformation for activity. After oral administration, the absolute oral bioavailability is 60–80% for irbesartan and 50–80% for hydrochlorothiazide. Food does not affect the bioavailability of the drug. Peak plasma concentrations are reached within 1.5–2 hours after administration for irbesartan and within 1–2.5 hours for hydrochlorothiazide.

Plasma protein binding of irbesartan is approximately 96%, with negligible binding to blood cells. The volume of distribution of irbesartan ranges from 53 to 93 liters. Hydrochlorothiazide is 68% bound to plasma proteins, with a confirmed volume of distribution of 0.83–1.14 L/kg.

Irbesartan exhibits linear and dose-proportional pharmacokinetics within the dose range of 10–600 mg. Increased absorption has been observed at doses below 600 mg; the mechanism is not fully understood. Total renal clearance is 157–176 mL/min for irbesartan and 3.0–3.5 mL/min for hydrochlorothiazide. The terminal elimination half-life of irbesartan is 11–15 hours. Steady-state plasma concentrations are achieved within 3 days of initiating once-daily dosing. Limited accumulation (<20%) of irbesartan is observed in plasma after repeated daily dosing. In clinical studies, slightly higher plasma concentrations of irbesartan were observed in female patients with arterial hypertension. However, no significant differences were observed in elimination half-life or accumulation. Dosage adjustment is not required based on patient age or sex. AUC and Cmax values for irbesartan were also slightly higher in elderly patients (≥65 years) compared to younger patients (18–40 years). However, the terminal half-life was not significantly different. Dose adjustment is not necessary for elderly patients. The mean elimination half-life of hydrochlorothiazide in plasma, based on available data, ranges from 5 to 15 hours.

After oral administration, 80–85% of irbesartan in plasma remains unchanged, as determined by 14C labeling. Irbesartan is metabolized in the liver via glucuronidation and oxidation. The main circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidized by the cytochrome P450 enzyme CYP2C9; CYP3A4 plays a minor role that can be neglected. Irbesartan and its metabolites are excreted both hepatically and renally. After both oral and intravenous administration of 14C-irbesartan, approximately 20% of radioactivity is excreted in urine, and the remainder in feces. Less than 2% of the dose is excreted unchanged in urine. Hydrochlorothiazide is not metabolized but is rapidly excreted by the kidneys. At least 61% of an oral dose is excreted unchanged within 24 hours. Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier and is excreted into breast milk.

Renal impairment: Pharmacokinetic parameters of irbesartan are not significantly altered in patients with renal impairment or those undergoing hemodialysis. Irbesartan is not removed by hemodialysis. It has been reported that in patients with creatinine clearance <20 mL/min, the elimination half-life of hydrochlorothiazide increases to 21 hours.

Hepatic impairment: Pharmacokinetic parameters of irbesartan are not significantly altered in patients with mild to moderate hepatic cirrhosis. Studies in patients with severe hepatic impairment have not been conducted.

Clinical characteristics.

Indications.

Treatment of essential hypertension.

This fixed-dose combination is indicated in adult patients whose blood pressure is not adequately controlled with irbesartan or hydrochlorothiazide alone.

Contraindications.

Hypersensitivity to the active substances or to sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative).
Severe renal impairment (creatinine clearance < 30 mL/min).
Persistent hypokalemia, hypercalcemia.
Severe hepatic impairment, liver cirrhosis, and cholestasis.
Concomitant use of Irbetan-N with aliskiren-containing products in patients with diabetes or moderate to severe renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²).
Concomitant use of Irbetan-N with angiotensin-converting enzyme (ACE) inhibitors in patients with diabetic nephropathy.
Refractory hypokalemia or hypercalcemia.
Refractory hyponatremia.
Symptomatic hyperuricemia (gout).
Anuria.
Pregnancy or breastfeeding.
Pediatric age.

Interaction with other medicinal products and other forms of interaction.

Other antihypertensive agents. The antihypertensive effect of Irbetan-N may be enhanced when used concomitantly with other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely used with other antihypertensive agents, including calcium channel blockers and beta-blockers. Prior treatment with high-dose diuretics may lead to reduced blood volume and risk of hypotension upon initiation of irbesartan with thiazide diuretics, unless volume depletion has been previously corrected.

Aliskiren-containing products. Concomitant use of Irbetan-N with aliskiren-containing products is contraindicated in patients with diabetes and in patients with moderate to severe renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) and is not recommended in all other patients.

Lithium. Cases of transient increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. There have been very rare reports of similar effects with irbesartan. In addition, thiazides reduce renal lithium excretion; therefore, the risk of lithium toxicity may be increased when this product is used concomitantly. Thus, combination of lithium and Irbetan-N is not recommended. If such combination is necessary, careful monitoring of serum lithium levels is advised.

Medicinal products that deplete potassium. The potassium-depleting effect of hydrochlorothiazide is counterbalanced by the potassium-sparing effect of irbesartan. However, the effect of hydrochlorothiazide on serum potassium levels may be influenced by other medicinal products associated with potassium loss and hypokalemia (e.g., other potassium-wasting diuretics, laxatives, amphotericin, carbenoxolone, sodium penicillin G). Conversely, based on experience with other agents that inhibit the renin-angiotensin system (RAS), concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., sodium heparin) may lead to increased serum potassium levels. Appropriate monitoring of serum potassium levels is recommended in patients at risk.

Medicinal products affected by changes in serum potassium levels. Periodic monitoring of serum potassium levels is recommended when the product is used concomitantly with medicinal products whose toxicity is increased by disturbances in serum potassium levels (e.g., cardiac glycosides, antiarrhythmic agents).

Angiotensin-converting enzyme (ACE) inhibitors. Concomitant use of Irbetan-N with ACE inhibitors is contraindicated in patients with diabetic nephropathy and not recommended in all other patients.

Nonsteroidal anti-inflammatory drugs (NSAIDs). When angiotensin-II antagonists are used concomitantly with NSAIDs (i.e., selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and nonselective NSAIDs), a reduction in antihypertensive effect may occur.

As with ACE inhibitors, concomitant use of angiotensin-II antagonists and NSAIDs may lead to an increased risk of worsening renal function, including possible development of acute renal failure, and increased serum potassium levels, particularly in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored after initiation and during treatment.

Additional information on irbesartan interactions. Studies have shown that the pharmacokinetics of irbesartan are not affected by hydrochlorothiazide. Irbesartan is primarily metabolized by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interaction was observed when irbesartan was coadministered with warfarin, a drug metabolized by CYP2C9. The effect of CYP2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan has not been established. Coadministration of irbesartan did not alter the pharmacokinetics of digoxin.

Potassium supplements and potassium-sparing diuretics. Based on experience with other agents affecting the renin-angiotensin system (RAS), 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 increased serum potassium levels and is therefore not recommended.

Additional information on hydrochlorothiazide interactions. Possible interactions with the following medicinal products when used concomitantly with thiazide diuretics:

Alcohol: may cause orthostatic hypotension.

Antidiabetic agents (oral agents and insulin): dosage adjustment of antidiabetic agents may be required.

Metformin should be used with caution due to the risk of lactic acidosis associated with possible hydrochlorothiazide-induced functional renal impairment.

Cholestyramine and colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of anion-exchange resins. Irbetan-N should be taken at least 1 hour before or 4 hours after administration of these agents.

Corticosteroids, adrenocorticotropic hormone (ACTH): electrolyte depletion may be increased, particularly hypokalemia may be exacerbated.

Cardiac glycosides: thiazide-induced hypokalemia or hypomagnesemia may predispose to cardiac arrhythmias induced by cardiac glycosides.

Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics in some patients.

Pressor amines (e.g., noradrenaline): the effect of pressor amines may be attenuated, but not to the extent that their use is precluded.

Nondepolarizing muscle relaxants (e.g., tubocurarine): the effect of nondepolarizing muscle relaxants may be enhanced by hydrochlorothiazide.

Antigout agents: dosage adjustment of antigout agents may be necessary because hydrochlorothiazide may increase serum uric acid levels. The dose of probenecid or sulfinpyrazone may need to be increased. Concomitant use of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Calcium salts: thiazide diuretics may increase serum calcium levels due to reduced excretion. When additional calcium-containing preparations or calcium-conserving agents (e.g., vitamin D therapy) are required, serum calcium levels should be monitored and calcium dosing adjusted accordingly.

Carbamazepine. Concomitant use of carbamazepine and hydrochlorothiazide has been associated with a risk of symptomatic hyponatremia. Electrolyte levels should be monitored when these agents are used together. If possible, diuretics of another class should be used.

Medicinal products whose effects are influenced by changes in serum potassium levels.

Periodic monitoring of serum potassium levels and ECG monitoring are recommended when hydrochlorothiazide is used concomitantly with medicinal products whose effects are influenced by changes in serum potassium levels (such as cardiac glycosides and antiarrhythmic agents), and with the following agents associated with polymorphic ventricular tachycardia (torsades de pointes) (including some antiarrhythmic agents), since hypokalemia is a contributing factor to the development of torsades de pointes:

Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
Certain neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
Other medicinal products (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vinca alkaloids).

Methyldopa. Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.

Salicylates. At high doses, salicylates may have their toxic effects on the central nervous system enhanced by hydrochlorothiazide.

Cyclosporine. Concomitant use of cyclosporine may enhance hyperuricemia and increase the risk of gout-like complications.

Alcohol, barbiturates, narcotics, or antidepressants. May enhance orthostatic hypotension.

Beta-blockers and diazoxide. Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycemic effect of diazoxide.

Amantadine. Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine.

Effect of medicinal products on laboratory test results. Due to effects on calcium metabolism, thiazides may influence the assessment of parathyroid function.

Specific hyposensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom may increase due to ACE inhibition. This effect may also occur with other allergens.

Iodinated contrast agents. In cases of diuretic-induced dehydration, the risk of acute renal failure is increased, particularly with high-dose iodinated contrast agents. Patients require rehydration prior to administration of iodinated agents.

Amphotericin B (parenteral), corticosteroids, ACTH, and stimulant laxatives. Hydrochlorothiazide enhances electrolyte imbalance, predominantly hypokalemia.

Other forms of interaction: the hyperglycemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Anticholinergic agents (e.g., atropine, beperidone) may increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate.

Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides may reduce renal excretion of cytotoxic agents (e.g., cyclophosphamide, methotrexate) and enhance their myelosuppressive effects.

Special precautions for use.

Reduced blood pressure – patients with low blood volume. Irbesartan-H rarely causes symptomatic reduction in blood pressure in patients with arterial hypertension who have no other risk factors for hypotension. Symptomatic reduction in blood pressure may occur in patients whose blood volume and/or sodium levels have been reduced due to intensive diuretic therapy, restricted dietary salt intake, diarrhoea, or vomiting. Such conditions should be corrected before initiating treatment with the drug.

Patients with arterial hypertension, type 2 diabetes, and chronic kidney disease. The effect of irbesartan on renal and cardiovascular function was not consistent across all subgroups participating in the analysis conducted within the study involving patients with advanced chronic kidney disease. In particular, its benefits were less pronounced in women and in individuals of non-Caucasian race.

Renal artery stenosis – renovascular hypertension. There is an increased risk of severe hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney when treated with ACE inhibitors or angiotensin-II receptor antagonists.

Renal impairment and kidney transplantation. When the drug is administered to patients with impaired renal function, periodic monitoring of serum calcium, creatinine, and uric acid levels is recommended. There is no experience with the use of the drug in patients who have recently undergone kidney transplantation. Irbesartan-H should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min). Azotemia associated with thiazide diuretics may occur in patients with renal dysfunction. Dose adjustment is not required in patients with renal impairment whose creatinine clearance is ≥ 30 mL/min. This fixed-dose combination should be used with caution in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min but < 60 mL/min).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Dual RAAS blockade by combining Irbesartan-H with aliskiren is not recommended due to increased risk of hypotension, hyperkalaemia, and changes in renal function. Concomitant use of Irbesartan-H with aliskiren-containing medicinal products is contraindicated in patients with diabetes and in patients with moderate to severe renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²).

Hepatic impairment. Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with the use of Irbesartan-H in patients with hepatic impairment.

Thiazides should be used cautiously in patients with liver disorders and progressive liver disease, as these drugs may cause intrahepatic cholestasis, and even minimal changes in water and electrolyte balance may trigger hepatic encephalopathy. Hydrochlorothiazide is contraindicated in patients with severe hepatic impairment.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilating agents, special precautions are required in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents that act by inhibiting the renin-angiotensin system (RAS). Therefore, the use of Irbesartan-H in such patients is not recommended.

Effects on metabolism and the endocrine system. Glucose tolerance may be impaired during therapy with thiazide diuretics, and latent diabetes mellitus may become manifest. Dose adjustments of insulin or oral hypoglycaemic agents may be necessary in diabetic patients.

Elevated levels of cholesterol and triglycerides have been associated with thiazide diuretic therapy; however, with the 12.5 mg dose of hydrochlorothiazide contained in Irbesartan-H, minimal or no effect has been reported.

Hyperuricaemia or signs of gout may occur in some patients receiving thiazide diuretic therapy.

Electrolyte imbalance. As with any patients receiving diuretics, serum electrolyte levels should be periodically monitored at appropriate intervals.

Thiazides, including hydrochlorothiazide, may cause disturbances in fluid or electrolyte balance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Characteristic signs of fluid or electrolyte imbalance to be monitored include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular weakness, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.

Although hypokalaemia may develop during treatment with thiazide diuretics, concomitant therapy with irbesartan may attenuate the hypokalaemia induced by diuretics. The risk of hypokalaemia is highest in patients with liver cirrhosis, those undergoing intensive diuresis, patients taking inadequate oral electrolyte supplements, or those receiving concomitant corticosteroid or ACTH therapy. Conversely, hyperkalaemia may occur due to the presence of irbesartan in Irbesartan-H, particularly in patients with renal impairment and/or heart failure, as well as diabetes mellitus. Appropriate monitoring of serum potassium levels is recommended in patients at risk. Caution is required when combining potassium-sparing diuretics with potassium supplements or potassium-containing salt substitutes.

There is no evidence that irbesartan attenuates or prevents hyponatraemia induced by diuretics. Chloride deficiency is generally mild and usually does not require treatment.

Thiazides may reduce calcium excretion in urine and may cause a transient and slight increase in serum calcium levels in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may indicate latent hyperparathyroidism. Thiazide therapy should be discontinued before assessing parathyroid function. Data indicate that thiazides increase magnesium excretion in urine, which may lead to hypomagnesaemia.

Lithium preparations. Concomitant use of lithium and Irbesartan-H is not recommended.

Anti-doping control. Hydrochlorothiazide contained in this medicinal product may yield a positive analytical result in anti-doping tests.

General warnings. In patients whose vascular tone and renal function depend primarily 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 angiotensin-II receptor antagonists may lead to acute hypotension, azotemia, oliguria, or acute renal failure.

As with any antihypertensive agent, excessive reduction in blood pressure in patients with ischaemic heart disease or ischaemic cerebrovascular disease may lead to myocardial infarction or stroke. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, although they are more likely in patients with such a history. Exacerbation or activation of systemic lupus erythematosus has been reported during treatment with thiazide diuretics.

Photosensitivity reactions have been reported with thiazide diuretics. If a photosensitivity reaction occurs during treatment, therapy should be discontinued. If re-administration of such diuretics is considered necessary, protection of exposed skin areas from sunlight or artificial UV radiation is recommended.

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin-II receptor blockers [including irbesartan] (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhoea. Symptoms resolved after discontinuation of angiotensin-II receptor blockers. If intestinal angioedema is diagnosed, irbesartan should be discontinued and appropriate monitoring initiated until symptoms completely resolve.

Acute myopia and secondary acute angle-closure glaucoma. Medicinal products containing sulfonamide or its derivatives may cause idiosyncrasy leading to transient myopia and acute angle-closure glaucoma. Hydrochlorothiazide is a sulfonamide derivative; however, only isolated cases of acute angle-closure glaucoma associated with hydrochlorothiazide use have been reported to date. Symptoms of this condition include acute decrease in visual acuity or eye pain. These symptoms typically develop within hours or weeks after starting therapy with this drug. If left untreated, acute angle-closure glaucoma may lead to irreversible vision loss. Upon detection of such symptoms, therapy with this drug should be discontinued immediately. If intraocular pressure remains uncontrolled, pharmacological or surgical treatment should be considered. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Effects of hydrochlorothiazide on laboratory test results:

The drug may decrease plasma protein-bound iodine levels;
Treatment with the drug should be discontinued before laboratory testing to assess parathyroid function;
The drug may increase the concentration of free bilirubin in serum.

Non-melanoma skin cancer. Results from two recent pharmacoepidemiological studies (based on Danish nationwide data sources, including the Danish Cancer Registry and the Danish Prescription Registry) showed a cumulative dose-dependent association between hydrochlorothiazide use and the occurrence of basal cell carcinoma and squamous cell carcinoma.

The photosensitizing effect of hydrochlorothiazide may contribute to the development of these conditions. Patients taking hydrochlorothiazide alone or in combination with other medicinal products should be informed about the risk of non-melanoma skin cancer and advised to regularly examine their skin for new lesions or changes in existing ones and to report any suspicious skin changes.

Suspicious skin lesions should undergo histological examination via biopsy. Patients should be advised to limit exposure to sunlight and UV radiation and to use appropriate protection when exposed to sunlight or UV radiation to minimize the risk of skin cancer.

The continued use of hydrochlorothiazide should also be carefully reconsidered in patients with a history of skin cancer (see section "Adverse reactions").

Lactose. The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Acute respiratory toxicity

Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported. Very rare, severe cases of acute respiratory toxicity, including ARDS, have been reported after hydrochlorothiazide administration. Pulmonary oedema usually develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnoea, fever, worsening of lung condition, and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after taking hydrochlorothiazide.

Use during pregnancy or breastfeeding.

Pregnancy. Use of this medicinal product during pregnancy is contraindicated. Upon diagnosis of pregnancy, treatment with angiotensin-II receptor antagonists (ARBs) should be stopped immediately, and alternative therapy should be initiated if necessary.

Breastfeeding. Use of Irbesartan-H during breastfeeding is contraindicated.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect on the ability to drive or operate machinery have been conducted. Based on the pharmacodynamic properties of the drug, its effect on this ability is unlikely. However, when driving or operating machinery, it should be considered that somnolence or fatigue may occur during treatment of arterial hypertension.

Dosage and Administration

The medicinal product should be taken once daily, independent of food intake.

If clinically indicated, direct transition from monotherapy to fixed combinations may be considered:

Irbetan-H 150 mg/12.5 mg can be used in patients whose blood pressure is not adequately controlled with hydrochlorothiazide alone or with irbesartan 150 mg alone.
Irbetan-H 300 mg/12.5 mg can be used in patients whose blood pressure is not adequately controlled with irbesartan 300 mg or with Irbetan-H 150 mg/12.5 mg.

If necessary, Irbetan-H may be used concomitantly with other antihypertensive medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Renal impairment. Due to the presence of hydrochlorothiazide, the medicinal product is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min). Loop diuretics, rather than thiazides, are preferred in the treatment of such patients. Dose adjustment is not required in patients with renal impairment and creatinine clearance ≥ 30 mL/min.

Hepatic impairment. Irbetan-H is not recommended in patients with severe hepatic impairment. Thiazides should be used with caution in patients with hepatic impairment. Dose adjustment is not required in patients with mild to moderate hepatic impairment.

Elderly patients. No dose adjustment is necessary in elderly patients.

Children.

The medicinal product is not recommended for use in children due to insufficient data on safety and efficacy.

Overdose.

There is no specific information on the treatment of overdose with Irbetan-H. The patient should be closely monitored, and treatment should be symptomatic and supportive. Management depends on the time elapsed since drug intake and the severity of symptoms. Recommended measures include induction of vomiting and/or gastric lavage. Administration of activated charcoal may be beneficial. Serum electrolytes and creatinine levels should be monitored frequently. In case of arterial hypotension, the patient should be placed in a supine position, and intravenous saline solutions and fluid volume replacement should be promptly administered.

The most likely manifestations of irbesartan overdose are arterial hypotension and tachycardia; bradycardia is also possible.

Hydrochlorothiazide overdose is associated with electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to pronounced diuresis. The most common signs and symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or may exacerbate cardiac arrhythmias, particularly when digitalis glycosides or certain antiarrhythmic medicinal products are used concomitantly.

Irbesartan is not removed by hemodialysis. The extent to which hydrochlorothiazide is removed by hemodialysis has not been established.

Adverse reactions.

Irbesartan/hydrochlorothiazide combination.

In patients with arterial hypertension receiving various doses of irbesartan/hydrochlorothiazide (range from 37.5 mg/6.25 mg to 300 mg/25 mg), the most commonly observed adverse reactions were dizziness, increased fatigue, nausea, vomiting, disturbances in urination, elevated blood urea nitrogen, creatine kinase, and creatinine levels.

Immune system disorders: hypersensitivity reactions, including angioedema, rash, urticaria.

Cardiovascular system disorders: loss of consciousness, arterial hypotension, tachycardia, edema, ECG changes, orthostatic hypotension, hyperemia.

Nervous system disorders: dizziness, orthostatic dizziness, headache.

Ear and labyrinth disorders: sensation of ringing or buzzing in the ears, vertigo.

Respiratory system disorders: cough.

Gastrointestinal disorders: nausea, vomiting, diarrhea, heartburn, abdominal pain, dyspepsia, dysgeusia.

Renal and urinary disorders: urinary disorders, impaired renal function, including isolated cases of renal failure in patients at risk.

Musculoskeletal system disorders: limb edema, arthralgia, myalgia.

Metabolism and nutrition disorders: hyperkalemia.

General disorders: increased fatigue, dry mouth, asthenia.

Hepatobiliary disorders: jaundice, hepatitis, hepatic function abnormalities.

Reproductive system disorders: sexual dysfunction, libido changes.

Skin and subcutaneous tissue disorders: pruritus, leukocytoclastic vasculitis.

Laboratory investigations: increased blood urea nitrogen (BUN), creatinine and creatine kinase levels; decreased serum potassium and sodium levels.

Individual components.

The adverse reactions listed below are associated with the individual components of the medicinal product Irbetan-H — irbesartan and hydrochlorothiazide — when used separately.

Adverse reactions reported during treatment with irbesartan alone

Gastrointestinal disorders: rarely – intestinal angioedema.

General disorders: chest pain.

In patients with advanced-stage arterial hypertension and diabetic nephropathy treated with irbesartan, a reduction in hemoglobin levels was observed, although it was not clinically significant.

Adverse reactions reported during treatment with hydrochlorothiazide alone

Cardiovascular system disorders: cardiac arrhythmias, orthostatic hypotension, postural hypotension, necrotizing angiitis.

Blood and lymphatic system disorders: aplastic anemia, bone marrow suppression, neutropenia, agranulocytosis, hemolytic anemia, leukopenia, thrombocytopenia.

Nervous system disorders: vertigo, paresthesia, unsteady gait, restlessness, headache, seizures, confusion.

Eye disorders: transient visual disturbances, xanthopsia, acute onset of myopia, and secondary acute angle-closure glaucoma.

Respiratory, thoracic and mediastinal disorders: very rare – acute respiratory distress syndrome (ARDS) (see section "Special precautions").

Gastrointestinal disorders: pancreatitis, anorexia, diarrhea, constipation, gastric mucosal irritation, sialadenitis, loss of appetite, dry mouth, thirst, nausea, vomiting, cholecystitis.

Renal and urinary disorders: interstitial nephritis, impaired renal function, renal failure.

Skin and subcutaneous tissue disorders: anaphylactic reactions including shock, toxic epidermal necrolysis, necrotic angiitis (vasculitis, cutaneous vasculitis), skin reactions resembling systemic lupus erythematosus, recurrence of cutaneous lupus erythematosus, photosensitivity reactions, rash, urticaria, purpura, Stevens-Johnson syndrome.

Musculoskeletal system disorders: weakness, muscle spasms and pain.

Hepatobiliary disorders: jaundice (intrahepatic cholestatic jaundice).

Psychiatric disorders: depression, sleep disturbances, disorientation, somnolence, nervousness, mood changes.

Laboratory findings: electrolyte imbalance (including hypokalemia and hyponatremia); hyperuricemia, which may provoke gout attacks in patients with asymptomatic disease; glucosuria; hyperglycemia; increased cholesterol and triglyceride levels; reduced glucose tolerance, potentially leading to manifestation of latent diabetes mellitus; hypochloremic alkalosis, which may induce hepatic encephalopathy or hepatic coma.

General disorders: fever, exhaustion, sexual disorders.

Dose-dependent adverse effects of hydrochlorothiazide (particularly electrolyte imbalance) may be intensified when the dose of hydrochlorothiazide is titrated upward.

Benign and malignant neoplasms (including cysts and polyps): Frequency not known: non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Description of selected adverse reactions

Non-melanoma skin cancer: epidemiological studies indicate a cumulative dose-effect relationship between hydrochlorothiazide exposure and the occurrence of non-melanoma skin cancer (cumulative dose-effect) (see section "Special precautions").

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets in a blister; 3 blisters per pack.

Prescription status. Prescription only.

Manufacturer: JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of business activity:

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Website: www.vitamin.com.ua.