Co-irbesan®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CO-IRBESAN® (CO-IRBESAN)

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: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, coating *Opadry Pink OY – 34948.

*Composition of Opadry Pink OY – 34948 coating: hypromellose (2910), polyethylene glycol 400, titanium dioxide (E 171), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

tablets 150 mg/12.5 mg: oval, biconvex, pink, film-coated tablets with a break line on one side;

tablets 300 mg/12.5 mg: elongated, pink, film-coated tablets with a break line on one side.

Pharmacotherapeutic group.

Combined angiotensin II inhibitors. ATC code C09DA04.

Pharmacological Properties

Pharmacodynamics

Co-Irbesan® 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 blood pressure than with either component alone.

Irbesartan is a potent, orally active, selective antagonist of the angiotensin-II receptor (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 receptors (AT1) leads to increased plasma renin and angiotensin-II levels, as well as reduced plasma aldosterone concentration. When used at recommended doses in patients without risk of electrolyte imbalance, irbesartan alone has no significant effect on 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 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 its diuretic action, hydrochlorothiazide reduces plasma volume, increases plasma renin activity, and stimulates aldosterone secretion, resulting in increased urinary excretion of potassium and bicarbonate and decreased serum potassium concentration. However, due to blockade of the renin-angiotensin-aldosterone system when irbesartan is co-administered, there is a tendency to counteract potassium loss. After oral administration, diuresis begins within 2 hours, peak effect occurs at approximately 4 hours, and the duration of action lasts about 6–12 hours.

The combination of hydrochlorothiazide and irbesartan results in a dose-dependent additional reduction in arterial pressure within the therapeutic dose range. Adding 12.5 mg hydrochlorothiazide to 300 mg irbesartan once daily in patients inadequately controlled on 300 mg irbesartan alone resulted in a placebo-corrected reduction in diastolic blood pressure to a trough value (24 hours after dosing) of 6.1 mm Hg. 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, not adjusted for placebo effects.

Based on limited clinical data (7 out of 22 patients), patients not adequately controlled on the 300 mg/12.5 mg combination may respond to dose titration to 300 mg/25 mg. In such patients, gradual reductions in arterial pressure were observed in both systolic (SAT) and diastolic (DAT) blood pressure (13.3 and 8.3 mm Hg, respectively).

Administration once daily of 150 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in a mean placebo-corrected reduction in systolic/diastolic blood pressure of 12.9/6.9 mm Hg (24 hours after dosing) in patients with mild to moderate arterial hypertension. Peak effect occurred within 3–6 hours. Ambulatory blood pressure monitoring showed that co-administration of 150 mg irbesartan and 12.5 mg hydrochlorothiazide once daily resulted in consistent blood pressure reduction over 24 hours, with a mean 24-hour reduction in systolic/diastolic blood pressure of 15.8/10 mm Hg, not adjusted for placebo. The transition from trough to peak effect for the 150 mg/12.5 mg formulation, as measured by ambulatory monitoring, was 100%. The trough-to-peak effects measured during office visits were 68% and 76%, respectively. These 24-hour effects occur without excessive blood pressure reduction relative to peak levels, providing safe and effective blood pressure control over the 24-hour dosing interval.

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

The antihypertensive effect of irbesartan in combination with hydrochlorothiazide is evident after the first dose and persists for 1–2 weeks, with maximum effect achieved within 6–8 weeks. During long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide persisted for periods longer than one year. Although not specifically studied for Co-Irbesan®, rebound hypertension has not been observed with either irbesartan or hydrochlorothiazide upon discontinuation.

The effect of irbesartan combined with 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 Co-Irbesan® based on age or gender. As with other drugs affecting the renin-angiotensin system, patients of Black race with hypertension have a lower response to irbesartan monotherapy. However, when irbesartan is combined with a low dose of hydrochlorothiazide (e.g., 12.5 mg daily), the antihypertensive response in these patients approaches that seen in patients of other races.

The efficacy and safety of Co-Irbesan® as initial therapy in severe arterial hypertension (defined as DBP ≥ 110 mm Hg) were evaluated in a multicenter, randomized, double-blind, active-controlled, 8-week, multi-arm study.

47% of patients receiving the combination therapy achieved a trough DBP < 90 mm Hg, compared to 33.2% of patients receiving irbesartan alone (p=0.0005). Mean baseline blood pressure was approximately 172/113 mm Hg in each group, and the reduction in SBP/DBP at week 5 was 30.8/24.0 mm Hg and 21.1/19.3 mm Hg, respectively, for the irbesartan/hydrochlorothiazide and irbesartan groups (P < 0.0001).

Clinical trial data indicate that the type and frequency of adverse events reported in patients treated with the combination product were similar to the adverse event profile of patients receiving monotherapy. No cases of syncope were reported during the studies. Hypotension occurred in 0.6% and 0% of patients, and dizziness in 2.8% and 3.1% of patients, respectively, in the combination and monotherapy groups.

Pharmacokinetics

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

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

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.

Irbesartan exhibits linear and dose-proportional pharmacokinetics over the dose range of 10–600 mg. Increased absorption has been observed at doses below 600 mg, although the mechanism is not fully understood. Total systemic clearance is 157–176 mL/min for irbesartan and 3–3.5 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 once-daily dosing. Limited accumulation (< 20%) of irbesartan is observed in plasma after repeated daily dosing. Slightly higher plasma concentrations of irbesartan have been observed in female hypertensive patients. However, no differences in half-life or accumulation were observed. Dose adjustment is not required for female patients. 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 required for elderly patients. The mean elimination half-life of hydrochlorothiazide from plasma, according to reported data, ranges from 5 to 15 hours.

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 plays a minor role that can be neglected. Irbesartan and its metabolites are excreted both hepatically and renally. After either 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 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. In patients with creatinine clearance < 20 mL/min, the elimination 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 impairment due to liver 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, to any of the excipients, or to any substance derived from sulfonamides (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 Co-Irbesan® with aliskiren-containing products in patients with diabetes mellitus and in patients with moderate to severe renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²).

Concomitant use of Co-Irbesan® with angiotensin-converting enzyme (ACE) inhibitors in patients with diabetic nephropathy.

Refractory hypokalemia or hypercalcemia.

Refractory hyponatremia.

Symptomatic hyperuricemia (gout).

Anuria.

Pregnancy and breastfeeding.

Pediatric age.

Interaction with other medicinal products and other forms of interaction.

Other antihypertensive agents. The antihypertensive effect of Co-Irbesan® 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-adrenergic blockers. Prior treatment with high-dose diuretics may lead to volume depletion and increase the risk of hypotension upon initiation of irbesartan with thiazide diuretics, unless volume depletion has been previously corrected.

Aliskiren-containing products. Concomitant use of Co-Irbesan® with aliskiren-containing products is contraindicated in patients with diabetes mellitus 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-containing medicines. Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant use of lithium with ACE inhibitors. Rare cases of similar effects have been reported with irbesartan. In addition, thiazides reduce renal lithium excretion; therefore, the risk of lithium toxicity may be increased when Co-Irbesan® is used. Thus, concomitant use of lithium and Co-Irbesan® is not recommended (see section "Special precautions for use"). If such combination is necessary, careful monitoring of serum lithium levels is recommended.

Medicinal products causing potassium loss. The potassium-lowering effect of hydrochlorothiazide is counterbalanced by the potassium-sparing effect of irbesartan. However, the potassium-lowering effect of hydrochlorothiazide 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 elevated serum potassium levels. Appropriate monitoring of serum potassium levels is recommended in patients at risk.

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

ACE inhibitors. Concomitant use of Co-Irbesan® 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 nonsteroidal anti-inflammatory drugs), a reduction in antihypertensive effect may occur.

As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening renal function, including possible development of acute renal failure, and may elevate serum potassium levels, particularly in patients with pre-existing renal impairment. The combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored after initiation and periodically thereafter.

Additional information on irbesartan interactions. Pharmacokinetic studies show that hydrochlorothiazide does not affect the pharmacokinetics of irbesartan. Irbesartan is primarily metabolized by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interaction was observed when irbesartan was co-administered with warfarin, a drug metabolized by CYP2C9. The effect of CYP2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan has not been established. Concurrent administration 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, 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. Interactions with the following medicinal products may occur when used concomitantly with thiazide diuretics.

Alcohol. May cause orthostatic hypotension.

Antidiabetic agents (oral agents and insulin). Dosage adjustment of the antidiabetic agent 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. Co-Irbesan® should be taken at least 1 hour before or 4 hours after administration of these medicinal products.

Corticosteroids, ACTH. May increase electrolyte depletion, particularly hypokalemia.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs). 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 contraindicated.

Non-depolarizing muscle relaxants (e.g., tubocurarine): The effect of non-depolarizing muscle relaxants may be enhanced by hydrochlorothiazide.

Antigout agents. Dosage adjustment of antigout agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be needed. When used concomitantly with thiazide diuretics, the incidence of hypersensitivity reactions to allopurinol may increase.

Calcium salts. Thiazide diuretics may increase serum calcium levels due to reduced excretion. If calcium supplements or calcium-retaining agents (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 a risk of symptomatic hyponatremia. Electrolyte levels should be monitored when these agents are used together. If possible, diuretics of another class should be considered.

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 that may cause torsades de pointes (ventricular tachycardia) (including certain antiarrhythmic agents), as hypokalemia is a contributing factor in 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, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other medicinal products (e.g., bepridil, cisapride, difemanyl, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).

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

Salicylates. When high doses of salicylates are used, hydrochlorothiazide may enhance their toxic effects on the central nervous system.

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

Alcohol, barbiturates, narcotics, or antidepressants. May potentiate orthostatic 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 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 hypersensitivity. The risk and severity of anaphylactic and anaphylactoid reactions to insect venom are increased during ACE inhibition. This effect may also occur with other allergens.

Iodine-containing contrast agents. In cases of diuretic-induced dehydration, the risk of acute renal failure is increased, particularly with high doses of iodine-containing contrast agents. Patients require rehydration prior to administration of iodine-containing agents.

Amphotericin B (parenteral), corticosteroids, ACTH, and stimulant laxatives. Hydrochlorothiazide may exacerbate electrolyte imbalances, particularly hypokalemia.

Other forms of interaction. The hyperglycemic effect of β-blockers and diazoxide may be enhanced by thiazides.

Anticholinergic agents (e.g., atropine, biperiden) may increase the bioavailability of thiazide-type 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.

Hypotension – patients with reduced blood volume. Co-Irbesan® is rarely associated with symptomatic reduction in blood pressure in patients with hypertension without other risk factors for hypotension. Symptomatic hypotension may occur in patients in whom blood volume and/or sodium levels are reduced due to intensive diuretic therapy, restricted dietary salt intake, diarrhoea, or vomiting. Such conditions should be corrected prior to initiating treatment with Co-Irbesan®.

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 in the analysis conducted within 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.

Renal artery stenosis – renovascular hypertension: There is an increased risk of severe hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney are treated with ACE inhibitors or angiotensin II receptor antagonists. A similar effect should be anticipated when using Co-Irbesan®.

Renal impairment and kidney transplantation. Periodic monitoring of serum calcium, creatinine, and uric acid levels is recommended when Co-Irbesan® is administered to patients with renal impairment. There is no experience with the use of Co-Irbesan® in patients who have recently undergone kidney transplantation. Co-Irbesan® 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 impairment. Dose adjustment is not required in patients with renal impairment and 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 blockade of the RAAS by combining Co-Irbesan® with aliskiren is not recommended due to an increased risk of hypotension, hyperkalemia, and changes in renal function. Concomitant use of Co-Irbesan® with aliskiren-containing products is contraindicated in patients with diabetes and in those 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 Co-Irbesan® in patients with hepatic impairment.

Thiazides should be used cautiously in hepatic disorders and progressive liver disease, as these agents may cause intrahepatic cholestasis, and even minimal changes in fluid and electrolyte balance may provoke 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 caution is required in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism. Antihypertensive effects are generally not achieved with drugs acting via inhibition of the renin-angiotensin system in patients with primary hyperaldosteronism; therefore, use of Co-Irbesan® is not recommended.

Effects on metabolism and endocrine system. Thiazide diuretics may impair glucose tolerance. Dose adjustments of insulin or oral hypoglycemic agents may be necessary in diabetic patients. Thiazide therapy may unmask latent diabetes mellitus.

Elevated cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however, at the 12.5 mg dose contained in Co-Irbesan®, minimal or no effect has been reported.

Hyperuricemia or symptoms of gout may occur in some patients receiving thiazide diuretics.

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

Thiazides, including hydrochlorothiazide, may cause disturbances in fluid or electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs and symptoms suggestive of fluid or electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular 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 undergoing intensive diuresis, those taking inadequate oral electrolyte supplements, and those receiving concomitant corticosteroid or ACTH therapy. Conversely, hyperkalemia may occur due to the presence of irbesartan in Co-Irbesan®, particularly in the presence of renal impairment and/or heart failure, as well as diabetes mellitus. Appropriate monitoring of serum potassium levels is recommended in patients at risk. Co-Irbesan® should be used with caution when combined with potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes.

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 may cause a 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 prior to parathyroid function testing.

Thiazides have been shown to increase magnesium excretion in urine, potentially leading to hypomagnesemia.

Lithium preparations. Concomitant use of lithium and Co-Irbesan® is not recommended.

Antidoping control. Hydrochlorothiazide contained in this medicinal product may yield positive analytical results in antidoping controls.

General warnings. In patients in whom 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 underlying renal disease, including renal artery stenosis), treatment with ACE inhibitors or angiotensin II receptor antagonists affecting this system has been associated with acute hypotension, azotemia, oliguria, or rarely, acute renal failure. 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 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 thiazide diuretic therapy.

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.

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, although only isolated cases of acute angle-closure glaucoma have been reported with hydrochlorothiazide use to date. Symptoms include acute visual impairment or eye pain. These symptoms typically develop within hours or weeks after starting therapy. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. If such symptoms occur, the drug should be discontinued immediately. If intraocular pressure remains uncontrolled, pharmacological or surgical treatment should be considered. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Acute respiratory toxicity

Very rare, severe cases of acute respiratory toxicity, including ARDS, have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening 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.

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 diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, irbesartan should be discontinued and appropriate monitoring initiated until complete symptom resolution.

Effects of hydrochlorothiazide on laboratory test results:

• the drug may decrease plasma protein-bound iodine levels;
• treatment should be discontinued prior to laboratory testing for parathyroid function;
• the drug may increase serum free bilirubin concentration.

Lactose. This medicinal product is contraindicated in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy.

This medicinal product is contraindicated in pregnancy or in women planning to become pregnant. If pregnancy is confirmed during treatment with this product, therapy should be immediately discontinued and replaced with another medicinal product approved for use during pregnancy.

Breastfeeding.

ARB II. Since information on the use of Co-Irbesan® in women during breastfeeding is lacking, its use is contraindicated in these patients. Alternative medicinal products with better-established safety profiles during breastfeeding should be preferred, especially when nursing newborns or preterm infants.

Hydrochlorothiazide. Hydrochlorothiazide is excreted in human breast milk in small amounts. Thiazides in high doses cause pronounced diuresis and may therefore suppress milk production. Thus, the use of Co-Irbesan® during breastfeeding is contraindicated.

Ability to influence 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 Co-Irbesan®, its effect on this ability is unlikely. However, when driving or operating machinery, it should be considered that during antihypertensive therapy, drowsiness, dizziness, or increased fatigue may occur.

Method of Administration and Dosage

Co-Irbesan® is administered once daily, independent of food intake.

Dose titration with individual components (i.e., irbesartan and hydrochlorothiazide) may be recommended.

When clinically appropriate, direct transition from monotherapy to fixed-dose combinations may be considered:

Co-Irbesan® 150 mg/12.5 mg may be used in patients whose blood pressure cannot be adequately controlled with either hydrochlorothiazide alone or irbesartan 150 mg;

Co-Irbesan® 300 mg/12.5 mg may be used in patients whose blood pressure is not sufficiently controlled with irbesartan 300 mg or with Co-Irbesan® 150 mg/12.5 mg.

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

If necessary, Co-Irbesan® may be used concomitantly with other antihypertensive medicinal products.

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

Hepatic impairment. Co-Irbesan® is not recommended for patients with severe hepatic impairment. Thiazides should be used with caution in patients with hepatic impairment. Dose adjustment of Co-Irbesan® is not required in patients with mild to moderate hepatic impairment.

Elderly patients: dose adjustment is not required for elderly patients.

Children.

The drug is not administered to children (under 18 years of age) due to insufficient data on safety and efficacy.

Overdose.

There is no specific information on the treatment of Co-Irbesan® overdose.

The patient should be closely monitored, and treatment should be symptomatic and supportive. Management depends on the time elapsed since ingestion and the severity of symptoms. Recommended measures include induction of emesis and/or gastric lavage. Activated charcoal may be used in the treatment of overdose. Serum electrolytes 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 repletion.

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

Overdose of hydrochlorothiazide may lead to acute urinary retention in predisposed patients (e.g., in case of benign prostatic hyperplasia), tachycardia, weakness, dizziness, muscle cramps, polyuria, oliguria, anuria, hypokalemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen levels (mainly due to renal impairment). The most common symptoms of overdose are nausea and drowsiness. Other signs of overdose include confusion, shock, exhaustion, disturbances of consciousness, vomiting, and thirst.

Hypokalemia may lead to muscle cramps and/or exacerbate cardiac arrhythmia when used concomitantly with cardiac 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.

Table 1 lists adverse reactions reported via 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). Adverse reactions are listed in order of decreasing severity.

Table 1. Adverse reactions based on placebo-controlled studies and spontaneous reports
Laboratory findings	Common Uncommon	Increase in blood urea nitrogen (BUN), creatinine, and creatine kinase. Decrease in serum potassium and sodium levels.
Cardiac disorders	Uncommon	Loss of consciousness, arterial hypotension, tachycardia, edema. ECG changes.
Nervous system disorders	Common Uncommon Frequency not known	Dizziness. Orthostatic dizziness. Headache.
Ear and labyrinth disorders	Frequency not known	Sensation of noise/ringing in the ears. Vertigo.
Respiratory, thoracic and mediastinal disorders	Frequency not known	Cough.
Gastrointestinal disorders	Common Uncommon Rare Frequency not known	Nausea/vomiting. Diarrhea. Heartburn. Abdominal pain. Angioneurotic edema of the intestine. Dyspepsia, dysgeusia.
Renal and urinary disorders	Common Frequency not known	Urinary disorders. Renal dysfunction, including isolated cases of renal failure in patients at risk (see section "Special precautions").
Musculoskeletal and connective tissue disorders	Uncommon Not known	Limb edema. Arthralgia, myalgia.
Metabolism and nutrition disorders	Frequency not known	Hyperkalemia.
Vascular disorders	Common Uncommon	Orthostatic hypotension Hyperemia.
General disorders	Common Uncommon Frequency not known	Increased fatigue. Dry mouth. Asthenia.
Immune system disorders	Frequency not known	Hypersensitivity reactions, including angioneurotic edema, rash, urticaria.
Hepatobiliary disorders	Uncommon Frequency not known	Jaundice. Hepatitis, hepatic dysfunction.
Reproductive system and breast disorders	Uncommon	Sexual dysfunction, changes in libido.
Skin and subcutaneous tissue disorders	Common Frequency not known	Pruritus. Leukocytoclastic vasculitis.

Additional information on individual components: in addition to the adverse reactions listed above for the combined medicinal product and other adverse reactions previously reported for one of the individual components, potential adverse reactions to irbesartan and hydrochlorothiazide may occur. The adverse reactions reported to be associated with the individual components of Co-Irbesan® are listed in tables 2 and 3 below.

Table 2. Adverse reactions reported during use of irbesartan alone
General disorders and administration site conditions	Uncommon	Chest pain.

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
Clinical trial findings	Frequency not known	Electrolyte imbalance (including hypokalemia and hyponatremia (see section "Special precautions")), hyperuricemia, which may provoke gout attacks in patients with asymptomatic disease, glucosuria, hyperglycemia, increased levels of cholesterol and triglycerides. Decreased glucose tolerance, which may lead to manifestation of latent diabetes mellitus. Hypochloremic alkalosis, which may induce hepatic encephalopathy or hepatic coma.
Cardiac disorders	Frequency not known	Cardiac arrhythmias. Orthostatic hypotension
Blood and lymphatic system disorders	Very rare Frequency not known	Aplastic anemia. Suppression of bone marrow function, neutropenia/agranulocytosis, hemolytic anemia, leukopenia, thrombocytopenia.
Nervous system disorders	Frequency not known	Dizziness, paresthesia, unsteady gait, restlessness, headache, seizures, confusion.
Eye disorders	Frequency not known	Transient visual disturbances, xanthopsia, acute myopia, and secondary acute angle-closure glaucoma.
Respiratory, thoracic and mediastinal disorders	Very rare	Acute respiratory distress syndrome (ARDS), including pneumonitis and pulmonary edema (see section "Special precautions").
Gastrointestinal disorders	Frequency not known	Pancreatitis, anorexia, diarrhea, constipation, gastric mucosal irritation, sialadenitis, loss of appetite, dry mouth, thirst, nausea, vomiting, cholecystitis.
Renal and urinary disorders	Frequency not known	Interstitial nephritis, impaired kidney function, renal failure.
Skin and subcutaneous tissue disorders	Frequency not known	Anaphylactic reactions, including shock, toxic epidermal necrolysis, necrotizing angiitis (vasculitis, cutaneous vasculitis); skin reactions resembling systemic lupus erythematosus; recurrence of cutaneous lupus erythematosus, photosensitivity reactions, rash, urticaria, purpura, Stevens-Johnson syndrome.
Musculoskeletal and connective tissue disorders	Frequency not known	Weakness, muscle spasms and pain.
Vascular disorders	Frequency not known	Postural hypotension. Necrotizing vasculitis
General disorders	Frequency not known	Malaise. Exhaustion. Sexual dysfunction.
Hepatobiliary disorders	Frequency not known	Jaundice (intrahepatic cholestatic jaundice).
Psychiatric disorders	Frequency not known	Depression, sleep disturbances, disorientation, drowsiness, nervousness, mood changes.

Dose-dependent adverse effects of hydrochlorothiazide (particularly electrolyte imbalance) may be enhanced during dose titration of hydrochlorothiazide.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

14 tablets in a blister, 2 blisters in a cardboard pack.

15 tablets in a blister, 6 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address.

Sankaklar Quarter, Eskikarakoca Avenue, No. 299, 81100, Duzce, Turkey.