IRBATEL-N 300

INSTRUCTION for medical use of the medicinal product IRBATAL-H 150 (IRBATAL-H 150) IRBATAL-H 300 (IRBATAL-H 150) Composition: irbesartan and hydrochlorothiazide; active substances: 1 tablet contains irbesartan 150 mg and hydrochlorothiazide 12.5 mg or contains irbesartan 300 mg and hydrochlorothiazide 12.5 mg; excipients: lactose monohydrate, sodium croscarmellose, povidone, magnesium stearate, purified water, pigment blend PB – 24899 (iron oxide red (E 172), iron oxide yellow (E 172)). Medicinal form. Tablets. Main physicochemical properties: Irbatal-H 150: oval, biconvex tablets of light pink (peach) colour with speckles, embossed with "L180" on one side and smooth on the other; Irbatal-H 300: oval, biconvex tablets of light pink (peach) colour with speckles, embossed with "L181" on one side and smooth on the other; Pharmacotherapeutic group. Combined angiotensin II inhibitors. ATC code C09D A04. Pharmacological properties. Pharmacodynamics. Irbatal-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, with blood pressure reduction greater than with either component 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 method of angiotensin-II synthesis. Selective antagonism of angiotensin-II receptors (AT1) leads to increased plasma renin levels and angiotensin-II levels, as well as decreased plasma aldosterone concentration. Irbesartan alone, when administered at recommended doses to patients without risk of electrolyte imbalance, does not significantly affect serum potassium levels. Irbesartan does not inhibit ACE (kininase-II), the enzyme that generates angiotensin-II and degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation. Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully understood. Thiazides affect electrolyte reabsorption in renal tubules, directly enhancing the excretion of sodium and chloride in approximately equal amounts. Due to the diuretic effect of hydrochlorothiazide, plasma volume decreases, plasma renin activity increases, aldosterone secretion increases, resulting in increased urinary loss of potassium and bicarbonate and decreased serum potassium concentration. Likely, due to blockade of the renin-angiotensin-aldosterone system when irbesartan is co-administered, there is a tendency to compensate for potassium loss. After administration of hydrochlorothiazide, diuresis begins within 2 hours, peak effect occurs approximately at 4 hours, while its action lasts approximately 6–12 hours. The combination of hydrochlorothiazide and irbesartan results in dose-dependent additional reduction of arterial blood pressure within the therapeutic dose range. Adding 12.5 mg hydrochlorothiazide to 300 mg irbesartan once daily in patients whose condition cannot be adequately controlled with 300 mg irbesartan as monotherapy led to a placebo-adjusted reduction in diastolic blood pressure to a minimum value (24 hours after dose administration) of 6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an overall reduction of systolic/diastolic 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 reduction of mean systolic/diastolic arterial blood pressure, adjusted for placebo effects, to 12.9/6.9 mm Hg (24 hours after administration) in patients with mild to moderate arterial hypertension. Peak effect was observed within 3–6 hours. During ambulatory blood pressure monitoring, the combination of 150 mg irbesartan and 12.5 mg hydrochlorothiazide administered once daily resulted in consistent reduction of arterial blood pressure over 24 hours, with a mean reduction in 24-hour systolic/diastolic arterial blood pressure, without adjustment for placebo effects, of 15.8/10.0 mm Hg. The blood pressure-lowering effect of irbesartan in combination with hydrochlorothiazide is evident after the first dose and lasts for 1–2 weeks, with maximum effect achieved within 6–8 weeks. During long-term studies, the effect of irbesartan/hydrochlorothiazide lasted more than one year. There is information that with use of both irbesartan and hydrochlorothiazide, rebound hypertension was not observed. The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has not been studied. Epidemiological data show that long-term treatment with hydrochlorothiazide reduces the risk of morbidity and mortality from cardiovascular diseases. The effectiveness of the drug does not depend on patient age or gender. In non-Caucasian patients with arterial hypertension, the response to monotherapy with irbesartan, as with other drugs affecting the renin-angiotensin system, is significantly lower. When irbesartan is used in combination with a low dose of hydrochlorothiazide (e.g., 12.5 mg daily), the antihypertensive response in non-Caucasian patients approaches that of other races. Pharmacokinetics. Concomitant administration of hydrochlorothiazide and irbesartan does not affect the pharmacokinetics of either component of the medicinal product. Irbesartan and hydrochlorothiazide are orally active drugs and do not require metabolic conversion for activity. After oral administration, absolute oral bioavailability is 60–80% for irbesartan and 50–80% for hydrochlorothiazide. Food does not affect the bioavailability of the drug. Peak plasma concentration is reached within 1.5–2 hours after oral administration for irbesartan and within 1–2.5 hours for hydrochlorothiazide. Protein binding of irbesartan to plasma proteins is approximately 96%, with low binding to blood cells, which can be neglected. The volume of distribution of irbesartan is 53–93 litres. Hydrochlorothiazide is bound to plasma proteins by 68%, and its confirmed volume of distribution is 0.83–1.14 l/kg. Irbesartan shows linear and dose-proportional pharmacokinetics within the dose range of 10 to 600 mg. Increased absorption was observed at doses below 600 mg; the mechanism is not understood. Total renal clearance is 157–176 and 3.0–3.5 ml/min, respectively. The terminal half-life of irbesartan is 11–15 hours. Steady-state plasma concentration is achieved within 3 days after starting once-daily dosing. Limited accumulation of irbesartan (< 20%) is observed in plasma after repeated daily dosing. In a study, slightly higher plasma concentrations of irbesartan were observed in female patients with arterial hypertension. However, no differences were found in half-life or accumulation of irbesartan. Dose adjustment is not required based on patient age or gender. AUC and Cmax values for irbesartan were also slightly higher in elderly patients (≥ 65 years) than in younger patients (18–40 years). However, the terminal half-life did not differ significantly. Dose adjustment is not required for elderly patients. The mean half-life of hydrochlorothiazide in plasma according to available data is 5–15 hours. After oral administration, unchanged irbesartan in plasma accounts for 80-85%, as determined by the 14C marker. Irbesartan is metabolized in the liver via glucuronidation and oxidation. The main circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies show that irbesartan is primarily oxidized by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has a negligible effect that can be disregarded. Irbesartan and its metabolites are excreted both via the liver and kidneys. 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 in urine as unchanged irbesartan. Hydrochlorothiazide is not metabolized but is rapidly excreted by the kidneys. At least 61% of the oral dose is excreted unchanged within 24 hours. Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier and is excreted in breast milk. Renal impairment. In patients with renal impairment or undergoing hemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by hemodialysis. It has been reported that in patients with creatinine clearance < 20 ml/min, the half-life of hydrochlorothiazide increases to 21 hours. Hepatic impairment. In patients with mild to moderate hepatic cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies in patients with severe hepatic impairment have not been conducted. Clinical characteristics. Indications. Treatment of essential hypertension. This fixed-dose combination is indicated for adult patients whose blood pressure is not adequately controlled with irbesartan or hydrochlorothiazide alone. Contraindications. Hypersensitivity to the active substances or to any of the excipients, or to any substances derived from sulfonamides (hydrochlorothiazide is a sulfonamide derivative). Severe renal impairment (creatinine clearance < 30 ml/min). Persistent hypokalemia, hypercalcemia. Severe hepatic impairment, hepatic cirrhosis, and cholestasis. Concomitant use with aliskiren-containing products in patients with diabetes and in patients with moderate to severe renal impairment (glomerular filtration rate < 60 ml/min/1.73 m²). Concomitant use with angiotensin-converting enzyme (ACE) inhibitors in patients with diabetic nephropathy. Refractory hypokalemia or hypercalcemia. Refractory hyponatremia. Symptomatic hyperuricemia (gout). Anuria. Pregnancy and breastfeeding period. Pediatric age (under 18 years). Interaction with other medicinal products and other types of interactions. Other antihypertensive agents. The antihypertensive effect of the drug may be enhanced by concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (in doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely used with other antihypertensive agents, including calcium channel blockers and β-adrenergic blockers. Prior treatment with high-dose diuretics may lead to reduced blood volume and risk of hypotension when starting irbesartan with thiazide diuretics, unless reduced blood volume has been previously corrected. Aliskiren-containing products. Concomitant use 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 not recommended for all other patients. Lithium preparations. There have been reports of transient increases in serum lithium concentration and toxicity with concomitant use of lithium and angiotensin-converting enzyme inhibitors. To date, very rare cases of such effects have been reported with irbesartan use. Additionally, thiazides reduce renal excretion of lithium, so the risk of lithium toxicity may increase when using the drug. Therefore, combining lithium and Irbatal-H is not recommended (see section "Special precautions for use"). If such combination is necessary, careful monitoring of serum lithium levels is recommended. Medicinal products that deplete potassium. The potassium-depleting effect of hydrochlorothiazide is mitigated by the potassium-sparing effect of irbesartan. However, changes in serum potassium levels are possible due to 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 drugs that inhibit the renin-angiotensin system, concomitant use of potassium-sparing diuretics, additional potassium-containing preparations, 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 whose efficacy is affected by changes in serum potassium levels. Periodic monitoring of serum potassium levels is recommended if the drug is used concomitantly with medicinal products whose toxicity is increased by disturbances in serum potassium levels (such as digitalis glycosides, antiarrhythmic agents). Angiotensin-converting enzyme (ACE) inhibitors. Concomitant use of the drug with ACE inhibitors is contraindicated in patients with diabetic nephropathy and not recommended for all other patients. Non-steroidal anti-inflammatory drugs (NSAIDs). If angiotensin-II antagonists are used concomitantly with NSAIDs (i.e., selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective non-steroidal anti-inflammatory drugs), the antihypertensive effect may be attenuated. As with use of ACE inhibitors, concomitant use of angiotensin-II antagonists and NSAIDs may lead to increased risk of worsening renal function, including acute renal failure, and increased serum potassium levels, especially in patients with pre-existing renal impairment. Combination of angiotensin-II antagonists and NSAIDs should be used with caution, especially in elderly patients. Patients should receive adequate fluid intake, attention should be paid to monitoring renal function after initiation of such combination therapy, and periodically thereafter. Additional information on irbesartan interaction. According to study data, hydrochlorothiazide does not affect the pharmacokinetics of irbesartan. Irbesartan is primarily eliminated via CYP2C9 and to a lesser extent via glucuronidation. No significant pharmacokinetic or pharmacodynamic interaction was observed when irbesartan was used with warfarin, a drug metabolized by CYP2C9. The effect of CYP2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan is not established. Digoxin pharmacokinetics were not altered by concomitant use of irbesartan. Potassium supplements and potassium-sparing diuretics. Based on experience with other drugs affecting the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs 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 interaction. Interaction with the following medicinal products and substances may occur with concomitant use of thiazide diuretics. Alcohol. May cause orthostatic hypotension. Antidiabetic medicinal products (oral preparations and insulin). Dose adjustment of the antidiabetic medicinal product may be required. Metformin should be used with caution due to the risk of lactic acidosis due to possible functional renal impairment caused by hydrochlorothiazide. Cholestyramine and colestipol resins. Absorption of hydrochlorothiazide is impaired in the presence of anion-exchange resins. The drug should be taken at least 1 hour before or 4 hours after taking these medicinal products. Corticosteroids, ACTH. Electrolyte depletion may be reduced, especially hypokalemia may be exacerbated. Digitalis glycosides. Thiazide-induced hypokalemia or hypomagnesemia predisposes to digitalis glycoside-induced cardiac arrhythmias. Non-steroidal anti-inflammatory drugs. NSAID use 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 excluded. Non-depolarizing muscle relaxants (e.g., tubocurarine). The effect of non-depolarizing muscle relaxants may be potentiated by hydrochlorothiazide. Medicinal products for gout. Dose adjustment of gout medications may be required, as hydrochlorothiazide may increase serum uric acid levels. Increased dosage of probenecid or sulfinpyrazone may be needed. 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. If additional calcium-containing preparations or calcium-sparing drugs (e.g., vitamin D) are required, serum calcium levels should be monitored and calcium dosage adjusted accordingly. Carbamazepine. Concomitant use of carbamazepine and hydrochlorothiazide has been associated with risk of symptomatic hyponatremia. Electrolyte levels must be monitored when these drugs are used concomitantly. If possible, diuretics of another class should be used. Medicinal products whose efficacy is affected by changes in serum potassium levels. Periodic monitoring of serum potassium levels and ECG examination is recommended if hydrochlorothiazide is taken concomitantly with drugs whose effects are affected by changes in serum potassium levels (such as digitalis glycosides and antiarrhythmic drugs), and with the following drugs that cause polymorphic tachycardia of the torsade de pointes type (ventricular tachycardia), including some antiarrhythmic drugs, since hypokalemia is a factor predisposing to torsade de pointes tachycardia:

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

Methyldopa. Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa. Salicylates. With high-dose salicylate use, hydrochlorothiazide may enhance its toxic effects on the central nervous system. Cyclosporine. Concomitant use of cyclosporine may exacerbate hyperuricemia and increase the risk of gout-like complications. Alcohol, barbiturates, narcotics, or antidepressants. May potentiate orthostatic arterial hypotension. β-blockers and diazoxide. Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate 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 affect the results of parathyroid function assessment. Specific hypersensitization. Due to ACE inhibition, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom increases. This effect is believed to also occur with other allergens. Iodine-containing contrast agents. In cases of diuretic-induced dehydration, the risk of acute renal failure increases, especially with high doses of iodine-containing contrast agents. Patients require rehydration before administration of iodine-containing agents. Amphotericin B (for parenteral administration), corticosteroids, ACTH, and stimulant laxatives. Hydrochlorothiazide exacerbates electrolyte imbalance, primarily hypokalemia. Anticholinergic agents (e.g., atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by reducing gastrointestinal tract tone and gastric emptying rate. Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides may reduce renal excretion of cytotoxic drugs (e.g., cyclophosphamide, methotrexate) and potentiate their bone marrow suppression effects. Special precautions for use. Low blood pressure – patients with low blood volume. The drug is rarely associated with symptomatic reduction in blood pressure in hypertensive patients without other risk factors for blood pressure reduction. Symptomatic reduction in blood pressure may occur in patients with reduced blood volume and/or sodium content due to intensive diuretic therapy, restricted salt intake, diarrhea, or vomiting. Such conditions should be corrected before starting 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 uniform in all subgroups of patients with advanced chronic kidney disease. In particular, its benefits were less pronounced in women and in individuals not of Caucasian race. Renal artery stenosis – renovascular hypertension. There is an increased risk of severe arterial hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney are treated with ACE inhibitors or angiotensin-II receptor antagonists. Although this has not been observed with use of Irbatal-H, a similar effect should be expected. Renal impairment and kidney transplantation. If the drug is used in patients with impaired renal function, periodic monitoring of serum calcium, creatinine, and uric acid levels is recommended. There is no experience with use of the drug in patients who have recently undergone kidney transplantation. The drug 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 impaired renal function. Dose adjustment is not required for patients with renal impairment with creatinine clearance ≥ 30 ml/min. However, 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 with combination of the drug with aliskiren is not recommended due to increased risk of hypotension, hyperkalemia, and changes in renal function. Concomitant use 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). Hepatic impairment. Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as minor changes in fluid and electrolyte balance may accelerate the onset of hepatic coma. There is no clinical experience with use of the drug in patients with hepatic impairment. Thiazides should be used with caution in liver disorders and progressive liver diseases, as these drugs may cause intrahepatic cholestasis, and even minimal changes in water-salt balance may trigger hepatic coma. 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 for patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy. Primary hyperaldosteronism. In patients with primary hyperaldosteronism, antihypertensive effect is generally not achieved with drugs acting via inhibition of the renin-angiotensin system, so use of the drug is not recommended. Effect on metabolism and endocrine system. Glucose tolerance may be impaired during therapy with thiazide diuretics. Adjustment of insulin or oral hypoglycemic agent dosage may be required for diabetic patients. Signs of latent diabetes may manifest during therapy with thiazide diuretics. Increased cholesterol and triglyceride levels are associated with use of thiazide diuretics; however, with the 12.5 mg dose contained in the drug, minimal or no effect has been reported. Hyperuricemia or signs of gout may occur in some patients receiving thiazide diuretic therapy. Electrolyte imbalance. As with any patients taking diuretics, serum electrolyte levels should be periodically checked. Thiazides, including hydrochlorothiazide, may cause fluid or electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Characteristic signs of fluid or electrolyte imbalance to watch for include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle weakness, decreased blood pressure, oliguria, tachycardia, and gastrointestinal disorders such as nausea or vomiting. Although hypokalemia may develop with use of thiazide diuretics, concomitant therapy with irbesartan may mitigate such hypokalemia. The highest risk of hypokalemia is in patients with hepatic cirrhosis, patients with intensive diuresis, patients orally receiving inadequate amounts of electrolytes, and patients concurrently receiving corticosteroids or ACTH. Conversely, hyperkalemia may occur due to the presence of irbesartan in the drug, especially in the presence of renal impairment and/or heart failure, as well as diabetes. Appropriate monitoring of serum potassium levels is recommended in patients at risk. The drug should be used with caution with potassium-sparing diuretics, additional potassium preparations, or potassium-containing salt substitutes. There is no evidence that irbesartan may mitigate or prevent hyponatremia due to diuretic use. Chloride deficiency is generally mild and usually does not require treatment. Thiazides may reduce calcium excretion in urine and cause transient and slight increase in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate latent hyperparathyroidism. Thiazide use should be discontinued before parathyroid function tests. It has been shown that thiazides increase magnesium excretion in urine, which may lead to hypomagnesemia. Lithium preparations. Concomitant use of lithium preparations and Irbatal-H is not recommended. Anti-doping control. Hydrochlorothiazide contained in this medicinal product may give a positive analytical result in anti-doping control. General warnings. In patients whose vascular tone and renal function primarily depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or initial kidney disease, including renal artery stenosis), treatment with ACE inhibitors or angiotensin-II receptor antagonists affecting this system is associated with acute arterial hypotension, azotemia, oliguria, or rarely acute renal failure. As with use of any antihypertensive agent, excessive reduction of blood pressure in patients with ischemic heart disease or ischemic cardiovascular 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, but they are more likely in patients with such history. Exacerbation or activation of systemic lupus erythematosus has been reported with use of thiazide diuretics. Photosensitivity reactions have been reported with use of thiazide diuretics. If a photosensitivity reaction occurs during treatment, treatment should be discontinued. If re-administration of such diuretics is considered necessary, exposed skin areas should be protected from sunlight or artificial UV radiation. Acute myopia and secondary acute angle-closure glaucoma. Medicinal products containing sulfanilamide or its derivatives may cause idiosyncrasy leading to transient myopia and acute angle-closure glaucoma. Hydrochlorothiazide is a sulfanilamide derivative, but to date only isolated cases of acute angle-closure glaucoma have been reported with use of hydrochlorothiazide. Symptoms of this condition include acute decrease in visual acuity or eye pain. These symptoms usually develop within hours or weeks after starting therapy with this drug. If acute angle-closure glaucoma is left untreated, it may lead to irreversible vision loss in the patient. Upon detection of such a symptom, therapy with this drug should be discontinued as quickly as possible. If intraocular pressure remains uncontrolled after this, pharmacological or surgical treatment may be considered. Risk factors for development of acute angle-closure glaucoma may include history of allergy to sulfanilamide or penicillin. Non-melanoma skin cancer. Results of two recent pharmacoepidemiological studies (based on Danish nationwide data sources, including the Danish Cancer Registry and the Danish National Prescription Registry) showed a cumulative dose-dependent association between hydrochlorothiazide use and development of basal cell carcinoma and squamous cell carcinoma. The photosensitizing effect of hydrochlorothiazide may be the cause 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 check their skin for new lesions and changes in existing ones, and to report any suspicious skin lesions. Suspicious skin lesions should undergo histological examination via biopsy. Patients should be advised to limit sun and UV exposure and use adequate protection when exposed to sun and UV radiation to minimize skin cancer risk. The appropriateness of hydrochlorothiazide use should also be carefully reconsidered in patients with a history of skin cancer (see section "Adverse reactions"). Effect of hydrochlorothiazide on laboratory test results:

• the drug may reduce the level of protein-bound iodine in plasma;
• 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.

Lactose. Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. Use during pregnancy or breastfeeding. Pregnancy. The medicinal product is contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use must be immediately discontinued and replaced with another medicinal product permitted for use during pregnancy. Before planned pregnancy, appropriate alternative treatment with a safety profile recognized for use during pregnancy should be initiated. Breastfeeding. Use of Irbatal-H during breastfeeding is contraindicated. Ability to affect reaction speed when driving or operating machinery. Studies on the effect on the ability to drive vehicles and operate machinery have not been conducted. Given the pharmacodynamic properties of the drug, its effect on this ability is unlikely. When driving vehicles or operating machinery, it should be considered that during treatment of arterial hypertension, drowsiness or fatigue may occur. Method of administration and dosage. The drug is administered once daily, regardless of food intake. Dose titration with individual components (i.e., irbesartan and hydrochlorothiazide) may be recommended. If clinically appropriate, direct transition from monotherapy to fixed combinations may be considered: Irbatal-H 150 mg/12.5 mg may be used in patients whose blood pressure cannot be adequately controlled with hydrochlorothiazide alone or irbesartan at a dose of 150 mg; Irbatal-H 300 mg/12.5 mg may be used in patients whose blood pressure is insufficiently controlled with irbesartan at a dose of 300 mg or with Irbatal-H 150 mg/12.5 mg. Doses exceeding 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. If necessary, Irbatal-H may be used with other antihypertensive medicinal products (see section "Interaction with other medicinal products and other types of interactions"). Renal impairment. Due to the presence of hydrochlorothiazide in the drug, it is not recommended for patients with severe renal function impairment (creatinine clearance < 30 ml/min). In such patients, loop diuretics are preferred over thiazides. Dose adjustment is not required for patients with renal impairment with creatinine clearance ≥ 30 ml/min. Hepatic impairment. Irbatal-H is not recommended for patients with severe hepatic impairment. Thiazides should be used with caution in patients with hepatic impairment. Dose adjustment is not required for patients with mild or moderate hepatic impairment. Elderly patients. No dose adjustment is required for elderly patients. Children. The drug is contraindicated for use in children due to insufficient data on safety and efficacy. Overdose. There is no specific information on treatment of Irbatal-H overdose. The patient should undergo careful monitoring, and treatment should be symptomatic and supportive. Treatment depends on the time elapsed since drug administration and severity of symptoms. Measures to be taken include induction of vomiting and/or gastric lavage. Activated charcoal may be used in treating overdose. Serum electrolyte and creatinine levels should be monitored frequently. In case of arterial hypotension, the patient should be placed in a horizontal position and saline solutions should be administered promptly and fluid volume replenished. The most likely manifestations of irbesartan overdose are arterial hypotension and tachycardia; bradycardia may also occur. Hydrochlorothiazide overdose may lead to acute urinary retention in predisposed patients (e.g., in case of prostatic hyperplasia), tachycardia, weakness, dizziness, muscle spasms, polyuria, oliguria, anuria, hypokalemia, hyponatremia, hypochloremia, alkalosis, increased blood urea nitrogen (mainly renal failure). The most common symptoms of overdose are nausea and drowsiness. Other signs of overdose include confusion, shock, exhaustion, disturbances of consciousness, vomiting, thirst. Hypokalemia may lead to muscle spasms and/or exacerbate cardiac arrhythmia due to concomitant use of digitalis glycosides or certain antiarrhythmic drugs. Irbesartan is not removed by hemodialysis. The extent to which hydrochlorothiazide is removed by hemodialysis is not established. Adverse reactions. Table 1 lists adverse reactions for which information was obtained from spontaneous reports and placebo-controlled studies. The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100, but < 1/10); uncommon (≥ 1/1000, but < 1/100); rare (≥ 1/10000, but < 1/1000); very rare (< 1/10000); frequency not known – frequency cannot be estimated from available data. Adverse reactions are listed in order of decreasing severity. Table 1. Adverse reactions based on placebo-controlled studies and spontaneous reports

Additional information on individual components: In addition to the above-mentioned adverse reactions for the combined medicinal product, the adverse reactions listed in tables 2 and 3 below have been reported in association with individual components of the Irbatall-N medication.

Table 2. Adverse reactions reported during administration of irbesartan alone

In 1.7% of patients with arterial hypertension and advanced diabetic nephropathy treated with irbesartan, a decrease in hemoglobin levels* was observed, which was not clinically significant. Table 3 Adverse reactions reported during treatment with hydrochlorothiazide alone

Dose-dependent adverse effects of hydrochlorothiazide (particularly disturbances of electrolyte balance) may be intensified during dose titration of hydrochlorothiazide. Benign, malignant and unspecified neoplasms (including cysts and polyps). Frequency unknown: non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma). Description of selected adverse reactions. Non-melanoma skin cancer: epidemiological studies have shown an association between the occurrence of non-melanoma skin cancer and cumulative dose of hydrochlorothiazide (cumulative dose-effect) (see section "Special precautions for use"). Shelf life. 2 years. Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children. Packaging. 10 tablets in a blister pack, 10 blisters in a cardboard box. Prescription category. Prescription only. Manufacturer. Alembic Pharmaceuticals Limited. Manufacturer's address and place of business. Panelav, P.V. Tajpura, District: Halol, Taluka: Panchmahal, Gujarat – 389 350, India.