Izgrev

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IZGREV (IZGREV)

Composition:

Active substances: irbesartan, hydrochlorothiazide;

One film-coated tablet contains irbesartan 150 mg and hydrochlorothiazide 12.5 mg, or irbesartan 300 mg and hydrochlorothiazide 12.5 mg;

Excipients:

Inner granulate: lactose monohydrate; microcrystalline cellulose type 101; pregelatinized starch; poloxamer 188; sodium croscarmellose;

Outer granulate: sodium croscarmellose, microcrystalline cellulose type 102, magnesium stearate;

Film coating: Opadry® Pink 03A34089, containing: hypromellose, titanium dioxide (E171), purified stearic acid, microcrystalline cellulose (E460), yellow iron oxide (E172), red iron oxide (E172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: light pink, elongated, biconvex film-coated tablets.

Pharmacotherapeutic group. Combined angiotensin II inhibitors.

ATC code C09DA04.

Pharmacological Properties

Pharmacodynamics

Izrev 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 angiotensin II receptor antagonist (AT1 subtype). It blocks all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or pathway of angiotensin II synthesis. Selective antagonism of angiotensin II (AT1) receptors leads to increased plasma renin and angiotensin II levels, as well as decreased plasma aldosterone concentration. When administered alone at recommended doses, irbesartan does not significantly affect serum potassium levels in patients without risk of electrolyte imbalance (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction"). 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 mechanism of the antihypertensive effect of thiazide diuretics is not fully understood. Thiazides affect electrolyte reabsorption mechanisms in the renal tubules, directly enhancing the excretion of sodium and chloride in approximately equal amounts. Due to the diuretic effect of hydrochlorothiazide, plasma volume decreases, leading to increased plasma renin activity and aldosterone secretion, resulting in increased urinary loss of potassium and bicarbonate and decreased serum potassium concentration. When irbesartan is co-administered, the renin-angiotensin-aldosterone system blockade likely counteracts potassium loss. After hydrochlorothiazide administration, diuresis begins within 2 hours, peak effect occurs around 4 hours, and the duration of action lasts approximately 6–12 hours.

The combination of hydrochlorothiazide and irbesartan produces dose-dependent additional reductions in arterial blood pressure within the therapeutic dose range. Adding 12.5 mg hydrochlorothiazide to 300 mg irbesartan once daily in patients whose blood pressure was not adequately controlled with 300 mg irbesartan alone resulted in a placebo-adjusted reduction in diastolic blood pressure at trough (24 hours after dosing) of 6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide led to an overall reduction in systolic/diastolic blood pressure of 13.6/11.5 mm Hg, unadjusted for placebo effects.

Based on limited clinical data (7 out of 22 patients), patients whose blood pressure is not controlled with the 300 mg/12.5 mg dose may respond to treatment by titration to 300 mg/25 mg. In these patients, gradual reductions in both systolic arterial pressure (SAP) and diastolic arterial pressure (DAP) were observed (13.3 and 8.3 mm Hg, respectively).

With once-daily administration of 150 mg irbesartan and 12.5 mg hydrochlorothiazide, mean placebo-adjusted reductions in systolic/diastolic blood pressure of 12.9/6.9 mm Hg (at 24 hours post-dose) were observed in patients with mild to moderate arterial hypertension. Peak effect occurred at 3–6 hours. According to ambulatory blood pressure monitoring, once-daily administration of 150 mg irbesartan and 12.5 mg hydrochlorothiazide provided consistent blood pressure reduction over 24 hours, with a mean 24-hour reduction in systolic/diastolic blood pressure of 15.8/10 mm Hg, unadjusted for placebo. The trough-to-peak ratio for irbesartan/hydrochlorothiazide 150 mg/12.5 mg, assessed by ambulatory monitoring, was 100%. The trough-to-peak ratios determined by office blood pressure measurements were 68% and 76%, respectively. These 24-hour effects occurred without excessive blood pressure reduction relative to peak values, providing safe and effective blood pressure control throughout the dosing interval.

In patients whose condition was not adequately controlled with 25 mg hydrochlorothiazide alone, adding irbesartan resulted in an additional mean reduction in systolic/diastolic blood pressure, unadjusted for placebo, of 11.1/7.2 mm Hg.

The blood pressure-lowering effect of irbesartan in combination with hydrochlorothiazide begins after the first dose and persists for 1–2 weeks, with maximum effect achieved within 6–8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide lasted longer than one year. Although not specifically studied for the irbesartan/hydrochlorothiazide combination, rebound hypertension has not been observed with either irbesartan or hydrochlorothiazide.

The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has not been studied. Clinical trial data have shown that long-term treatment with hydrochlorothiazide reduces cardiovascular mortality.

There are no differences in response to irbesartan/hydrochlorothiazide based on age or gender. As with other drugs affecting the renin-angiotensin system, patients of non-Black race with hypertension show a significantly greater response to irbesartan monotherapy. When irbesartan is used in combination with a low dose of hydrochlorothiazide (e.g., 12.5 mg daily), the antihypertensive response in Black patients approaches that observed in other racial groups.

The efficacy and safety of the irbesartan/hydrochlorothiazide combination as initial therapy in severe arterial hypertension (defined as systolic arterial pressure (SAP) ≥ 160 mm Hg) were evaluated in a multicenter, randomized, double-blind, active-controlled, 8-week study.

A total of 697 patients were randomized in a 2:1 ratio to receive either irbesartan/hydrochlorothiazide 150 mg/12.5 mg or irbesartan 150 mg, with systematic titration (based on response to lower dose) after one week to irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively.

Among the study population, 58% were male. The mean patient age was 52.5 years, 13% were ≥65 years, and only 2% were ≥75 years. Twelve percent (12%) of patients had diabetes mellitus, 34% had hyperlipidemia, and the most common cardiovascular disease was stable angina in 3.5% of participants. The primary objective of this study was to compare the proportion of patients achieving controlled SAP (SAP < 90 mm Hg) at week 5 of treatment. Forty-seven percent (47.2%) of patients receiving the combination achieved SAP < 90 mm Hg compared to 33.2% of patients receiving irbesartan (p = 0.0005). Mean baseline blood pressure was approximately 172/113 mm Hg in each treatment group, and the reduction in SAP/DAP at five weeks was 30.8/24.0 mm Hg and 21.1/19.3 mm Hg for irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001).

The types and frequency of adverse reactions reported in patients receiving the combination were similar to the adverse reaction profile observed in patients receiving monotherapy. During the 8-week treatment period, no episodes of loss of consciousness occurred in either treatment group. Hypotension was observed in 0.6% and 0% of patients, and dizziness in 2.8% and 3.1% of patients in the combination and monotherapy groups, respectively.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large randomized controlled trials [ONTARGET (the telmisartan monotherapy and ramipril combination trial) and VA NEPHRON-D (veterans nephropathy in diabetes)] evaluated the use of a combination of an ACE inhibitor with an angiotensin II receptor blocker. ONTARGET studied patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D study included patients with type 2 diabetes and diabetic nephropathy.

These trials did not demonstrate significant benefits in renal and/or cardiovascular outcomes or mortality reduction; instead, they showed an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared to monotherapy. Given the similar pharmacodynamic properties, these findings are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

Therefore, ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

The ALTITUDE trial (aliskiren treatment in type 2 diabetes with cardiovascular and renal endpoints) was designed to evaluate the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was terminated prematurely due to an increased risk of adverse outcomes. Cardiovascular events and stroke were more frequent in the aliskiren group than in the placebo group, and adverse events and serious adverse events of interest (hyperkalemia, hypotension, and renal dysfunction) occurred more frequently in the aliskiren group than in the placebo group.

Non-melanoma skin cancer font

Epidemiological data indicate a cumulative, dose-dependent association between hydrochlorothiazide use and non-melanoma skin cancer. One study evaluated 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC) among 1,430,833 and 172,462 control patients, respectively. High cumulative doses of hydrochlorothiazide (>50,000 mg) were associated with an adjusted odds ratio (OR) of 1.29 (95% CI [confidence interval]: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear cumulative dose-response relationship was observed for both BCC and SCC. Another study demonstrated an association between lip cancer (SCC) and hydrochlorothiazide use: 633 cases of lip cancer among 63,067 individuals in the control group (using a risk-stratified sampling strategy). A cumulative dose-response relationship was demonstrated by an adjusted odds ratio (OR) of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) at high dose (~25,000 mg) and OR 7.7 (5.7–10.5) at the highest cumulative dose (~100,000 mg) (see also section "Special warnings and precautions for use").

Pharmacokinetics

Co-administered hydrochlorothiazide and irbesartan do not affect each other's pharmacokinetics.

Absorption

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

Distribution

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

Linearity/Non-linearity

Irbesartan exhibits linear and dose-proportional pharmacokinetics within the dose range of 10 to 600 mg. Less than proportional increases in oral absorption were observed at doses above 600 mg; the mechanism is not fully understood. Total systemic clearance and renal clearance are 157–176 mL/min and 3–3.5 mL/min, respectively. The terminal half-life of irbesartan is 11–15 hours. Steady-state plasma concentrations are achieved within 3 days of once-daily dosing. Limited accumulation (<20%) of irbesartan is observed in plasma after repeated daily dosing. Slightly higher plasma concentrations of irbesartan were observed in female hypertensive patients compared to males. However, no significant differences in half-life or accumulation were observed. Dose adjustment is not required for female patients. Area under the concentration-time curve (AUC) and maximum concentration (Cmax) values of irbesartan were slightly higher in elderly patients (≥65 years) than in younger patients (18–40 years). However, the terminal half-life was not significantly different. Dose adjustment is not required for elderly patients. The mean half-life of hydrochlorothiazide in plasma is 5–15 hours.

Biotransformation

After oral or intravenous administration of 14C-irbesartan, 80–85% of circulating plasma radioactivity is attributable to unchanged irbesartan. 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 has a negligible effect.

Elimination

Irbesartan and its metabolites are excreted both via bile and urine. After oral or 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 orally administered 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

Pharmacokinetic parameters of irbesartan are not significantly altered in patients with renal impairment or those undergoing hemodialysis. Irbesartan is not removed by hemodialysis. In patients with creatinine clearance <20 mL/min, the half-life of hydrochlorothiazide has been reported to increase 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.

Preclinical safety data

Irbesartan/hydrochlorothiazide

The potential toxicity of the irbesartan/hydrochlorothiazide combination after oral administration was evaluated in rats and macaques in studies lasting up to 6 months. No toxicological findings of relevance to therapeutic use in humans were observed.

The following changes observed in rats and macaques receiving irbesartan/hydrochlorothiazide at doses of 10/10 and 90/90 mg/kg/day were also observed with individual administration of irbesartan or hydrochlorothiazide and/or were secondary to blood pressure reduction (no significant toxicological interactions were observed):

• Renal changes characterized by slight increases in serum urea and creatinine levels and juxtaglomerular apparatus hyperplasia/hypertrophy, which are direct consequences of irbesartan's interaction with the renin-angiotensin system;
• Slight reductions in erythrocyte parameters (erythrocytes, hemoglobin, hematocrit);
• Gastric color changes, ulcers, and focal necrosis of the gastric mucosa—observed in several rats during a 6-month toxicity study with irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques;
• Decreased serum potassium levels with hydrochlorothiazide, which was less pronounced when hydrochlorothiazide was administered in combination with irbesartan.

Most of the above effects are likely related to the pharmacological activity of irbesartan (inhibition of angiotensin II-induced suppression of renin release with stimulation of renin-producing cells) and are also observed with ACE inhibitors. These findings are unlikely to be relevant to the therapeutic use of irbesartan/hydrochlorothiazide in humans.

No teratogenic effects were observed in rats receiving the combination of irbesartan and hydrochlorothiazide at doses causing maternal toxicity. The effect of the irbesartan/hydrochlorothiazide combination on fertility has not been evaluated in animal studies, as there is no evidence of adverse effects of irbesartan or hydrochlorothiazide alone on fertility in animals or humans. However, another angiotensin II antagonist affected fertility parameters in animal studies when administered alone or in combination with hydrochlorothiazide at lower doses.

No evidence of mutagenicity or clastogenicity of the irbesartan/hydrochlorothiazide combination was found. The carcinogenic potential of the irbesartan/hydrochlorothiazide combination has not been evaluated in animal studies.

Irbesartan

No evidence of abnormal systemic toxicity or target organ toxicity was observed at clinically relevant doses. In preclinical safety studies, high doses of irbesartan (>250 mg/kg/day in rats and >100 mg/kg/day in macaques) caused reductions in erythrocyte parameters (erythrocytes, hemoglobin, hematocrit). At very high doses (>500 mg/kg/day), irbesartan induced degenerative renal changes in rats and macaques (such as interstitial nephritis, tubular dilatation, basophilic tubules, increased plasma urea and creatinine concentrations). These changes are considered secondary to the hypotensive effect of the drug, leading to reduced renal perfusion. Additionally, irbesartan induced juxtaglomerular cell hyperplasia/hypertrophy (in rats at >90 mg/kg/day, in macaques at >10 mg/kg/day). These changes are considered to be pharmacologically mediated. Juxtaglomerular hyperplasia/hypertrophy has no clinical significance in humans receiving therapeutic doses of irbesartan.

No evidence of mutagenicity, clastogenicity, or carcinogenicity was found.

In animal studies, even orally administered doses of irbesartan that caused some toxicity (50–650 mg/kg/day), including mortality (at the highest doses), did not affect fertility or reproductive performance in male and female rats. No significant effects on the number of corpora lutea, implantations, or live fetuses were observed. Irbesartan did not affect offspring survival, development, or reproduction. Radiolabeled irbesartan was detected in the fetuses of rats and rabbits in animal studies.

Irbesartan is excreted in the milk of lactating rats.

Animal studies with irbesartan revealed transient toxic effects (increased renal pelvis cavitation, hydronephrosis, or subcutaneous edema) in rat fetuses, which resolved after birth. In rabbits, abortion or early resorption occurred at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in rats or rabbits.

Hydrochlorothiazide

Despite some evidence of genotoxic or carcinogenic effects in certain experimental models, extensive human experience with hydrochlorothiazide has not demonstrated an increased risk of tumor development.

Clinical characteristics

Indications. For the 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 (see section "Pharmacological properties").

Contraindications

• Hypersensitivity to the active substances or to any of the excipients, or to any sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide derivative).
• Second and third trimesters of pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Refractory hypokalemia, hypercalcemia.
• Severe hepatic impairment, biliary cirrhosis, and cholestasis.

The concomitant use of the medicinal product Izgrev with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate [GFR] < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacological properties").

Interaction with other medicinal products and other forms of interaction

Other antihypertensive agents. The antihypertensive effect of Izgrev may be enhanced when used concomitantly with 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-blockers. Prior treatment with high-dose diuretics may lead to volume depletion and risk of hypotension upon initiation of irbesartan with thiazide diuretics, unless volume depletion has been previously corrected (see section "Special precautions for use").

Aliskiren-containing products or angiotensin-converting enzyme (ACE) inhibitors. Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to monotherapy acting on the RAAS (see sections "Dosage and administration", "Contraindications", "Special precautions for use", "Pharmacological properties").

Lithium-containing medicines. Reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Such effects have been reported very rarely with irbesartan. In addition, thiazides reduce renal clearance of lithium; therefore, the risk of lithium toxicity may be increased during treatment with Izgrev. Hence, concomitant use of lithium and Izgrev 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 counterbalanced by the potassium-sparing effect of irbesartan. However, the influence of hydrochlorothiazide on serum potassium levels may be enhanced 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, 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 (see section "Special precautions for use").

Medicinal products whose effects depend on serum potassium levels. Periodic monitoring of serum potassium levels is recommended when Izgrev is used concomitantly with medicinal products whose toxicity increases with deviations in serum potassium levels (e.g., digitalis glycosides, antiarrhythmics).

Angiotensin-converting enzyme (ACE) inhibitors. Concomitant use of Izgrev 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 non-selective NSAIDs), attenuation of the antihypertensive effect may occur.

As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs increases the 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 of such combination therapy and periodically thereafter.

Repaglinide: irbesartan may inhibit OATP1B1. In a clinical study, irbesartan increased Cmax and AUC of repaglinide (an OATP1B1 substrate) by 1.8-fold and 1.3-fold, respectively, when administered 1 hour prior to repaglinide. In another study, no significant pharmacokinetic interaction was observed during concomitant use of these two drugs. Therefore, dose adjustment of the antidiabetic agent, including repaglinide, may be necessary (see section "Special precautions for use").

Additional information on irbesartan interactions

Studies indicate that hydrochlorothiazide does not interfere with the pharmacokinetics of irbesartan. Irbesartan is primarily metabolized by CYP2C9 and to a lesser extent via glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin, which is metabolized by CYP2C9. The effect of CYP2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan has not been established. Concomitant administration of irbesartan did not alter the pharmacokinetics of digoxin.

Additional information on hydrochlorothiazide interactions

The following medicinal products may interact with thiazide diuretics when used concomitantly:

Alcohol: may potentiate orthostatic hypotension.

Antidiabetic medicinal products (oral agents and insulin): dose adjustment of the antidiabetic agent may be required (see section "Special precautions for use").

Cholestyramine and colestipol resins: absorption of hydrochlorothiazide is reduced in the presence of anion-exchange resins. Izgrev should be taken at least 1 hour before or 4 hours after such agents.

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

Cardiac glycosides: hypokalemia or hypomagnesemia induced by thiazides may predispose to digitalis-induced cardiac arrhythmias (see section "Special precautions for use").

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 reduced, but not to the extent that their use is precluded.

Non-depolarizing muscle relaxants (e.g., tubocurarine): the action of non-depolarizing muscle relaxants may be potentiated by hydrochlorothiazide.

Medicinal products for the treatment of gout: dosage adjustment of antigout agents may be necessary, as hydrochlorothiazide may increase serum uric acid levels. Dose increases of probenecid or sulfinpyrazone may be required. Concomitant use with thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.

Calcium salts: thiazide diuretics may increase serum calcium levels due to reduced excretion. If calcium supplements or calcium-retaining agents (e.g., vitamin D preparations) are required, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Carbamazepine: concomitant use of carbamazepine with hydrochlorothiazide is associated with a risk of symptomatic hyponatremia. Electrolyte levels should be monitored during concomitant use. If possible, another class of diuretics should be considered.

Other interactions: 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 reactions caused by cytotoxic agents (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Special precautions for use

Hypotension in patients with volume depletion. Isgreve rarely causes symptomatic reduction in arterial pressure in patients with hypertension who have no other risk factors for low blood pressure. Symptomatic hypotension may occur in patients whose blood volume and/or sodium levels are reduced due to intensive diuretic therapy, restricted dietary salt intake, diarrhea, or vomiting. Such conditions should be corrected prior to initiating Isgreve therapy.

Renal artery stenosis — renovascular hypertension. The effects of irbesartan on renal and cardiovascular function were not consistent across all subgroups in a study involving patients with advanced chronic kidney disease. In particular, its benefits were less pronounced in women and in individuals of non-Caucasian race.

There is an increased risk of severe hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney when treated with ACE inhibitors or angiotensin II receptor antagonists. A similar effect should be anticipated with the use of Isgreve.

Renal impairment and kidney transplantation. When Isgreve is administered to patients with impaired renal function, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended. There is no experience with the use of Isgreve in patients who have recently undergone kidney transplantation. Isgreve 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 (see section "Contraindications"). 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).

Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and renal dysfunction (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacological properties"). If dual blockade therapy is considered absolutely necessary, it should be performed only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of Isgreve 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 fluid and electrolyte imbalances may precipitate hepatic coma. There is no clinical experience with the use of Isgreve 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 fluid and electrolyte balance may trigger hepatic coma. Hydrochlorothiazide is contraindicated in patients with severe hepatic impairment.

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients treated with angiotensin II receptor antagonists (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, Isgreve should be discontinued and appropriate monitoring initiated until symptoms completely resolve.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilating agents, special precautions should be taken 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 suppressing the renin-angiotensin system. Therefore, use of Isgreve is not recommended in such patients.

Effects on metabolism and endocrine system. Thiazide diuretics may impair glucose tolerance. Thiazide therapy may unmask latent diabetes mellitus. Irbesartan may cause hypoglycemia, particularly in patients with diabetes mellitus. For patients treated with insulin or antidiabetic agents, appropriate monitoring of blood glucose levels should be considered.

Dose adjustment of insulin or antidiabetic agents may be required if indicated (see section "Interaction with other medicinal products and other forms of interaction").

Thiazide diuretics have been associated with increased cholesterol and triglyceride levels; however, at the 12.5 mg dose contained in Isgreve, this effect was minimal or absent.

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

Electrolyte imbalance. Serum electrolyte levels should be periodically monitored in patients receiving diuretics.

Thiazides, including hydrochlorothiazide, may cause disturbances in fluid or electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Characteristic signs of fluid or electrolyte imbalance to watch for include dry mouth, thirst, weakness, lethargy, somnolence, restlessness, muscle pain or cramps, muscle weakness, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.

Although hypokalemia may develop during thiazide diuretic therapy, concomitant treatment with irbesartan may attenuate diuretic-induced hypokalemia. The highest risk of hypokalemia occurs in patients with hepatic cirrhosis, those with marked diuresis, those receiving inadequate oral electrolyte supplementation, and those concurrently receiving corticosteroids or ACTH. Conversely, hyperkalemia may occur due to the presence of irbesartan in Isgreve, particularly in patients with renal impairment and/or heart failure, as well as those with diabetes mellitus. Appropriate monitoring of serum potassium levels is recommended in such high-risk patients. Concomitant use of potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes with Isgreve should be done with caution (see section "Interaction with other medicinal products and other forms of interaction").

There is no evidence that irbesartan attenuates or prevents diuretic-induced hyponatremia. Chloride deficiency is generally mild and usually does not require treatment.

Thiazides may reduce urinary calcium excretion and cause transient and slight elevation of serum calcium levels in the absence of calcium metabolism disorders. Marked hypercalcemia may indicate latent hyperparathyroidism. Thiazide use should be discontinued before assessing parathyroid function.

Thiazides have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia.

Lithium preparations. Concomitant use of lithium and Isgreve is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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

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 affecting this system may lead to acute hypotension, azotemia, oliguria, or rarely, acute renal failure (see section "Interaction with other medicinal products and other forms of interaction"). As with any antihypertensive agent, excessive reduction in blood pressure in patients with ischemic heart disease or cerebrovascular disease may lead to myocardial infarction or stroke. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported during thiazide diuretic therapy.

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

Pregnancy. Treatment with angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. Women planning pregnancy should switch to alternative antihypertensive therapy with an established safety profile during pregnancy, unless continued treatment with ACE inhibitors is considered essential.

If pregnancy is diagnosed, treatment with ACE inhibitors should be discontinued immediately and, if necessary, alternative therapy initiated (see sections "Contraindications" and "Adverse reactions").

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Hydrochlorothiazide is a sulfonamide and may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of myopia or eye pain and typically occur within hours to weeks after starting treatment. Untreated acute angle-closure glaucoma may lead to permanent vision loss. Hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure cannot be controlled, immediate medical or surgical treatment may be required. Risk factors for developing angle-closure glaucoma include a history of allergy to sulfonamides or penicillin (see section "Adverse reactions").

Non-melanoma skin cancer. In two epidemiological studies based on data from the Danish National Cancer Registry, an increased risk of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) was observed with increasing cumulative doses of hydrochlorothiazide.

The likely mechanism for non-melanoma skin cancer (NMSC) development is the photosensitizing effect of hydrochlorothiazide.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly check their skin for new lesions and promptly report any suspicious skin changes. Patients should be informed about preventive measures such as limiting exposure to sunlight and ultraviolet radiation and using appropriate protection to minimize the risk of skin cancer.

Suspicious skin lesions should be promptly evaluated, possibly including histological examination of biopsy material. Re-evaluation of hydrochlorothiazide therapy may also be necessary for patients with a history of NMSC (see also section "Adverse reactions").

Acute respiratory toxicity. Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported following hydrochlorothiazide use. Pulmonary edema typically develops within minutes or hours. Early symptoms include dyspnea, fever, worsening pulmonary function, and arterial hypotension. If ARDS is suspected, Isgreve should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS after taking hydrochlorothiazide.

Excipients. The medicinal product contains lactose. One 150 mg tablet contains 26 mg of lactose monohydrate; one 300 mg tablet contains 52 mg of lactose monohydrate. This medicinal product should not be administered to patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy

Angiotensin II receptor antagonists (ARBs)

ARBs are not recommended during the first trimester of pregnancy (see section "Special precautions for use"). Use of ARBs is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on teratogenic risk with ACE inhibitors during the first trimester of pregnancy are inconclusive. However, a small increased risk cannot be excluded. Although there are no controlled epidemiological data on the risk of angiotensin II receptor antagonists, such a risk may exist. Women planning pregnancy should switch to alternative antihypertensive therapy with an established safety profile during pregnancy, unless continued treatment with ACE inhibitors is considered essential. If pregnancy is diagnosed, treatment with ACE inhibitors should be discontinued immediately and, if necessary, alternative therapy initiated.

It is known that use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy induces human fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia) (see section "Pharmacological properties").

If angiotensin II receptor antagonists were used from the second trimester of pregnancy, ultrasound assessment of renal function and skull ossification is recommended.

Newborns whose mothers received ARBs should be closely monitored for hypotension (see sections "Contraindications" and "Special precautions for use").

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy, especially during the first trimester, is limited. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Due to its pharmacological mechanism of action, use of hydrochlorothiazide during the second and third trimesters may impair fetoplacental perfusion and cause effects in the fetus and newborn such as jaundice, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational edema, gestational hypertension, or preeclampsia due to the risk of reduced plasma volume and placental hypoperfusion, and lack of beneficial effect on disease course.

Hydrochlorothiazide should not be used to treat essential hypertension in pregnant women except in rare cases when no other treatment is possible.

Since Isgreve contains hydrochlorothiazide, it is not recommended for use during the first trimester of pregnancy. Women planning pregnancy should switch to appropriate alternative therapy.

Breastfeeding

Angiotensin II receptor antagonists

Due to lack of adequate information, use of Isgreve during breastfeeding is not recommended. Alternative therapies with a better-established safety profile during lactation should be preferred, especially when nursing newborns or preterm infants.

It is unknown whether irbesartan or its metabolites are excreted in breast milk.

Available pharmacodynamic/toxicological data from rat studies indicate excretion of irbesartan or its metabolites into milk (see section "Pharmacological properties" for details).

Hydrochlorothiazide

Hydrochlorothiazide is excreted in small amounts in breast milk. Thiazides in high doses, leading to marked diuresis, may suppress breast milk production. Use of Isgreve during breastfeeding is not recommended. If Isgreve is used during lactation, doses should be as low as possible.

Fertility

Irbesartan had no effect on fertility or offspring of rats up to dose levels causing the first signs of toxicity in the parents (see section "Pharmacological properties").

Ability to affect driving and use of machinery

No studies on the effect of Isgreve on the ability to drive or operate machinery have been conducted. Given its pharmacodynamic properties, its effect on this ability is unlikely. However, when driving or operating machinery, it should be considered that treatment for hypertension may cause somnolence, dizziness, or fatigue.

Dosage and Administration

Izreve is administered once daily, independent of food intake.

Dose titration of the individual components (i.e., irbesartan and hydrochlorothiazide) is recommended.

When clinically appropriate, direct transition from monotherapy to fixed-dose combinations is possible:

• Izreve 150 mg / 12.5 mg may be used in patients whose blood pressure is not adequately controlled with either hydrochlorothiazide alone or irbesartan 150 mg;
• Izreve 300 mg / 12.5 mg may be used in patients whose blood pressure is not sufficiently controlled with irbesartan 300 mg or with the medicinal product Izreve 150 mg / 12.5 mg.

Doses exceeding 300 mg irbesartan / 25 mg hydrochlorothiazide once daily are not recommended.

If necessary, Izreve may be used concomitantly with other antihypertensive medicinal products (see sections "Contraindications", "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction", "Pharmacological Properties").

Renal impairment. Due to the presence of hydrochlorothiazide in Izreve, the product is not recommended for patients with severe renal impairment (creatinine clearance < 30 mL/min). In treating such patients, preference should be given to loop diuretics rather than thiazides. Dose adjustment is not required for patients with renal impairment and creatinine clearance ≥ 30 mL/min (see sections "Contraindications", "Special Warnings and Precautions for Use").

Hepatic impairment. Izreve is not recommended for patients with severe hepatic impairment. Thiazides should be used with caution in patients with hepatic impairment. Dose adjustment of Izreve is not required in patients with mild to moderate hepatic impairment (see section "Contraindications").

Elderly patients: Dose adjustment of the medicinal product is not required for elderly patients.

Children. The medicinal product should not be used in children (under 18 years of age) due to insufficient data on safety and efficacy.

Overdose

There is no specific information on the treatment of overdose with the medicinal product Izreve.

Careful patient monitoring should be performed, and treatment should be symptomatic and supportive, depending on the time elapsed since drug administration and the severity of symptoms. Induction of emesis and/or gastric lavage, administration of activated charcoal may be necessary. Serum electrolyte and creatinine levels should be monitored frequently. In case of arterial hypotension, the patient should be placed in a supine position and promptly administered saline solutions and fluid volume replacement.

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

Hydrochlorothiazide overdose is associated with decreased electrolyte levels (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. The most common symptoms of overdose are nausea and drowsiness. Hypokalemia may cause muscle cramps and/or exacerbation of cardiac arrhythmias, particularly in patients receiving concomitant digitalis glycosides or certain antiarrhythmic medicinal products.

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

Adverse Reactions

Among 898 hypertensive patients receiving various doses of irbesartan/hydrochlorothiazide (from 37.5 mg / 6.25 mg to 300 mg / 25 mg) in placebo-controlled studies, adverse reactions were observed in 29.5% of patients. The most commonly reported adverse reactions were dizziness (5.6%), fatigue (4.9%), nausea/vomiting (1.8%), and urinary disorders (1.4%). In addition, increases in blood urea nitrogen (2.3%), creatine kinase (1.7%), and creatinine (1.1%) were also frequently observed in the studies.

Table 1 lists adverse reactions identified from spontaneous reports and placebo-controlled studies.

The frequency of adverse reactions was classified as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency category, adverse reactions are listed in order of decreasing severity.

In addition to the above-mentioned adverse reactions observed during the use of the combined medicinal product, adverse reactions which occurred during the use of individual components — irbesartan and hydrochlorothiazide — may also occur.

Non-melanoma skin cancer: Based on available epidemiological data, a cumulative dose-dependent association has been identified between hydrochlorothiazide and non-melanoma skin cancer (see sections "Special precautions for use" and "Pharmacological properties").

Dose-dependent adverse reactions to hydrochlorothiazide (especially electrolyte imbalances) may be intensified during dose titration of hydrochlorothiazide.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store below 30 °C.

Keep out of reach and sight of children.

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

Prescription status. Prescription only.

Manufacturer: JSC "Chaikapharma High-Quality Medicines".

Manufacturer's address and location of its business operations:

1 Hristo Mihaylov Blvd, Sofia 1172, Bulgaria.