Ilpio®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ILPIO® (YLPIO®)

Composition:

Active substances: telmisartan and indapamide;

One tablet contains 80 mg of telmisartan and 2.5 mg of indapamide;

Excipients: mannite (E 421), sodium hydroxide, povidone 25, magnesium stearate (E 470b).

Medicinal form. Tablets.

Main physico-chemical properties: round, biconvex tablets of yellowish color with a dividing groove on both sides, diameter 9 mm.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Combined angiotensin II receptor blockers. Angiotensin II receptor blockers (ARBs) and diuretics. Telmisartan and diuretics.

ATC code C09D A07.

Pharmacological Properties

Pharmacodynamics

Telmisartan

Telmisartan is a specific and potent oral antagonist of angiotensin II receptors (AT1 subtype). Telmisartan competitively displaces angiotensin II from its binding sites on AT1 receptors, which mediate the known actions of angiotensin II. Telmisartan has no partial agonistic activity at the AT1 receptor. It selectively binds to AT1 receptors, and this binding is long-lasting. Telmisartan has no affinity for other receptors, including AT2 receptors and other less-characterized angiotensin receptors. The functional role of these receptors is not fully understood, nor is the effect of their potential stimulation by angiotensin II, whose levels increase during telmisartan therapy. Telmisartan reduces plasma aldosterone levels. It does not decrease plasma renin levels and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kininase II), the enzyme responsible for bradykinin degradation. Therefore, potentiation of bradykinin-mediated adverse effects is not expected.

In humans, telmisartan at a dose of 80 mg almost completely inhibits the blood pressure increase induced by angiotensin II. The blocking effect persists for 24 hours and remains detectable up to 48 hours.

Indapamide

Indapamide is a sulfonamide diuretic pharmacologically related to thiazide diuretics. Indapamide inhibits sodium reabsorption in the cortical segment of the renal tubules. This increases urinary excretion of sodium and chloride, and to a lesser extent, potassium and magnesium, resulting in enhanced diuresis.

The antihypertensive effect of indapamide is evident at doses where the diuretic effect is minimal. Moreover, its antihypertensive action persists even in patients with arterial hypertension undergoing hemodialysis.

Indapamide acts at the vascular level through:

• Reducing the contractility of vascular smooth muscle, associated with changes in transmembrane ion exchange (primarily calcium);
• Stimulating the synthesis of prostaglandin PGE2 and prostacyclin PGI2 (a vasodilator and inhibitor of platelet aggregation).

Indapamide reduces left ventricular hypertrophy.

Studies of varying duration (short-, medium-, and long-term) in patients with arterial hypertension have shown that indapamide:

• Does not affect lipid metabolism: triglycerides, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol;
• Does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.

Exceeding the recommended dose does not increase the therapeutic effect of thiazide and thiazide-like diuretics, while the incidence of adverse effects increases. If treatment is insufficiently effective, dose escalation is not recommended.

Pharmacokinetics

Telmisartan

Absorption. Telmisartan is rapidly absorbed, but the extent of absorption is variable. The mean absolute bioavailability of telmisartan is approximately 50%. Administration with food reduces the area under the concentration-time curve (AUC0–∞) by approximately 6% (40 mg) to 19% (160 mg). After 3 hours, plasma concentrations are similar to those observed when telmisartan is taken without food.

Linearity/Non-linearity. The slight reduction in AUC is not considered to diminish therapeutic efficacy. There is no linear relationship between dose and plasma concentration. Cmax and, to a lesser extent, AUC increase disproportionately at doses above 40 mg.

Distribution. Telmisartan is highly bound to plasma proteins (>99.5%), primarily to albumin and alpha-1 acid glycoprotein. The mean volume of distribution at steady state (Vss) is approximately 500 L.

Metabolism. Telmisartan undergoes metabolism via conjugation to form the glucuronide of the parent compound. The pharmacological activity of the conjugate has not been established.

Elimination. Telmisartan exhibits biexponential pharmacokinetics with a terminal elimination half-life >20 hours. Maximum plasma concentration (Cmax) and, to a lesser extent, the area under the plasma concentration-time curve (AUC) increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan with recommended dosing. Plasma concentrations are higher in women than in men, without a corresponding impact on efficacy.

After oral (and intravenous) administration, telmisartan is almost entirely excreted in feces, primarily as unchanged compound. Cumulative renal excretion accounts for <1% of the dose. Total plasma clearance (Cltot) is high (approximately 1000 mL/min), compared to hepatic blood flow (about 1500 mL/min).

Special Patient Populations

Pediatric patients. The pharmacokinetics of two doses of telmisartan were evaluated as a secondary objective in hypertensive patients (n = 57) aged 6 to <18 years, after receiving telmisartan at 1 mg/kg or 2 mg/kg for 4 weeks. Pharmacokinetic objectives included determining steady-state telmisartan levels in children and adolescents and investigating age-related differences. Although the study was too small to reliably assess pharmacokinetics in children under 12 years, the results overall align with data from adults and confirm the nonlinearity of telmisartan parameters, particularly regarding Cmax.

Gender. Plasma Cmax and AUC in women are approximately 3 and 2 times higher, respectively, than in men.

Elderly patients. The pharmacokinetics of telmisartan do not differ between elderly patients and those under 65 years of age.

Patients with renal impairment. In patients with mild to moderate and severe renal impairment, plasma concentrations were approximately doubled. However, in patients with renal impairment undergoing dialysis, lower plasma concentrations were observed. Telmisartan is highly protein-bound in patients with renal impairment and is not dialyzable. The elimination half-life is not altered in patients with renal impairment.

Patients with hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability to approximately 100%. The elimination half-life is not altered in patients with hepatic impairment.

Indapamide

Absorption. Indapamide bioavailability is high—93%.
The time to reach maximum plasma concentration (Tmax) after a 2.5 mg dose is approximately 1–2 hours.

Distribution. Plasma protein binding exceeds 75%.
With regular administration, a stable plasma concentration plateau is achieved compared to levels after a single dose. This plasma concentration remains stable over time without accumulation.

Elimination. Renal clearance accounts for 60–80% of total clearance.
Indapamide is primarily excreted as metabolites; the fraction excreted unchanged in urine is 5%.
The elimination half-life ranges from 14 to 24 hours (average 18 hours).

Special Patient Populations

Patients with renal impairment
In patients with renal impairment, pharmacokinetic parameters are not altered.

Clinical characteristics.

Indications.

Arterial hypertension.

The combined medicinal product ILPIO® may be used in adult patients whose blood pressure is already adequately controlled with the concomitant administration of 80 mg telmisartan and 2.5 mg indapamide.

For this purpose, the administration of two separate telmisartan and indapamide medications is replaced by prescribing ILPIO®.

Contraindications.

• Hypersensitivity to the active substance, other sulphonamides, or to any excipient of the medicinal product (see section "Composition");
• severe renal impairment;
• hepatic encephalopathy or severe hepatic dysfunction;
• obstructive biliary disorders;
• hypokalaemia.

The medicinal product must not be used during pregnancy or in women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy.

Concomitant use of telmisartan and aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (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.

Digoxin

When telmisartan and digoxin are used concomitantly, median increases in digoxin plasma peak concentrations (by 49%) and trough concentrations (by 20%) have been observed. Digoxin levels should be monitored at the beginning of treatment, during dose adjustment, and upon discontinuation of telmisartan/indapamide to maintain them within the therapeutic range.

Like other agents that inhibit the renin-angiotensin-aldosterone system, telmisartan may cause hyperkalaemia (see section "Special warnings and precautions for use"). The risk may increase when used in combination with other agents that may also cause hyperkalaemia (potassium-containing salt substitutes, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim).

Cases of hyperkalaemia depend on associated risk factors. The risk increases with the above-mentioned therapeutic combinations. The risk is particularly high when combined with potassium-sparing diuretics and potassium-containing salt substitutes. Combination with ACE inhibitors or NSAIDs, for example, is less risky provided that the relevant precautions are strictly observed.

Concomitant use not recommended

Potassium-sparing diuretics or potassium supplements. Angiotensin II receptor antagonists, such as telmisartan, reduce potassium loss caused by diuretics. Potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium concentration. If concomitant use is indicated due to documented hypokalaemia, these agents must be used with caution and serum potassium levels should be monitored frequently.

Lithium. Reversible increases in serum lithium concentration and lithium toxicity have been observed when lithium is used concomitantly with ACE inhibitors and angiotensin II receptor antagonists, including telmisartan. If use of this combination is necessary, careful monitoring of serum lithium levels is recommended.

Plasma lithium levels may increase and symptoms of lithium overdose may appear, as with a low-salt diet (reduced urinary lithium excretion). If a diuretic must be prescribed, careful monitoring of plasma lithium levels and adjustment of the lithium dose are required.

Concomitant use requiring caution

Non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs (i.e., acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.

In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), combined use of angiotensin II receptor antagonists and agents that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible.

Non-steroidal anti-inflammatory drugs (for systemic use), including selective COX-2 inhibitors, and high doses of acetylsalicylic acid (≥ 3 g/day):

• may reduce the antihypertensive effect of indapamide;
• in dehydrated patients, increase the risk of acute renal failure (due to reduced glomerular filtration). Before starting treatment, fluid balance should be restored and renal function checked.

Therefore, telmisartan/indapamide should be used with caution, especially in elderly patients. Patients should receive adequate fluid intake; consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.

In one study, concomitant use of telmisartan and ramipril resulted in a 2.5-fold increase in AUC_0–24 and C_max of ramipril and ramiprilat. The clinical significance of this phenomenon is unknown.

Diuretics (thiazide or loop diuretics). Prior treatment with high doses of such diuretics as furosemide (a loop diuretic) and hydrochlorothiazide (a thiazide diuretic) may lead to reduced blood volume and risk of developing arterial hypotension at the start of telmisartan treatment.

Medicinal products that may cause torsades de pointes-type ventricular tachycardia, including:

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide, bretylium);
• certain antipsychotics:
  • phenothiazines (e.g., chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine);
  • benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride);
  • butyrophenones (e.g., droperidol, haloperidol);
• other antipsychotics (e.g., pimozide);
• other medicinal products (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vinca alkaloids, methadone, astemizole, terfenadine).

When indapamide is used with the above-mentioned medicinal products, the risk of ventricular arrhythmias, including torsades de pointes – torsades-type paroxysmal ventricular tachycardia (hypokalaemia being a risk factor), increases.

Before prescribing such a combination, potassium levels should be checked and corrected if necessary. The patient's clinical status, plasma electrolytes, and ECG should be monitored. In the presence of hypokalaemia, medicinal products that do not cause torsades de pointes are recommended.

ACE inhibitors. Sudden onset of arterial hypotension and/or acute renal failure (ARF) may occur in patients with low sodium levels (especially in patients with renal artery stenosis).

Arterial hypertension. If prior diuretic use has led to reduced sodium levels, diuretic therapy should be discontinued 3 days before starting ACE inhibitor treatment, and diuretic therapy should then be resumed if necessary, or the ACE inhibitor should be started at a low initial dose with gradual dose escalation.

In congestive heart failure, ACE inhibitor therapy should be initiated at the lowest dose and possibly after reducing the dose of a previously prescribed potassium-wasting diuretic.

In any case, renal function (plasma creatinine) should be monitored during the first weeks of ACE inhibitor therapy.

Medicinal products that may cause hypokalaemia: glucocorticoids and mineralocorticoids (for systemic use), amphotericin B (intravenous), tetracosactide, stimulant laxatives, increase the risk of hypokalaemia (additive effect). Plasma potassium levels should be monitored and corrected if necessary, with particular attention to concomitant therapy with cardiac glycosides. Non-stimulant laxatives are recommended.

Cardiac glycosides. Hypokalaemia and/or hypomagnesaemia may predispose to digoxin toxicity. Monitoring of plasma potassium and magnesium levels and ECG monitoring are recommended, with treatment adjustment as needed.

Baclofen enhances the antihypertensive effect of the medicinal product. At the start of therapy, the patient's fluid and electrolyte balance should be restored and renal function monitored.

Allopurinol. Concomitant use with indapamide may increase the frequency of allopurinol hypersensitivity reactions.

Concomitant use requiring attention

Other antihypertensive agents. The ability of telmisartan to lower blood pressure may be enhanced by concomitant use of other antihypertensive agents.

Clinical data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalaemia, and reduced renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Special warnings and precautions for use", "Contraindications", and "Pharmacodynamics").

Due to the pharmacological properties of baclofen and amifostine, these medicinal products may enhance the hypotensive effect of all antihypertensive agents, including telmisartan. In addition, orthostatic hypotension may be exacerbated by alcohol consumption, barbiturates, narcotics, and antidepressants.

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). If there is a rationale for prescribing such a combination, the possibility of hypokalaemia or hyperkalaemia (especially in patients with diabetes mellitus or renal impairment) cannot be excluded. Monitoring of plasma potassium levels, ECG monitoring, and therapy adjustment if necessary are required.

Metformin. The risk of lactic acidosis increases if functional renal impairment develops due to diuretic use, especially loop diuretics. Metformin should not be prescribed if plasma creatinine levels exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents. In cases of dehydration caused by diuretic use, the risk of ARF increases, especially with high doses of iodinated contrast agents. Fluid balance should be restored before administering iodinated contrast agents.

Tricyclic antidepressants, neuroleptics. Enhanced antihypertensive effect and risk of orthostatic hypotension due to additive effects.

Calcium salts. Hypercalcaemia may occur due to reduced renal elimination of calcium.

Cyclosporine, tacrolimus. Risk of increased plasma creatinine without effect on circulating cyclosporine levels, even in the absence of reduced water/sodium levels.

Corticosteroids, tetracosactide (systemic action). Reduced antihypertensive effect of indapamide due to water and sodium retention caused by corticosteroids.

Special precautions for use.

Pregnancy

The medicinal product must not be used in pregnant women or in women who are planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, it must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy (see sections "Contraindications" and "Use in pregnancy or lactation").

Angioneurotic intestinal angioedema

Angioneurotic intestinal angioedema has been reported in patients receiving 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, telmisartan/indapamide must be discontinued and appropriate monitoring of the patient should be ensured until complete symptom resolution.

Hepatic impairment

Telmisartan/indapamide must not be administered to patients with cholestasis, obstructive biliary disorders, or severe hepatic impairment (see section "Contraindications"), as telmisartan is primarily eliminated via bile. In patients with these conditions, hepatic clearance of telmisartan is reduced.

Telmisartan/indapamide should be used with caution in patients with mild to moderate hepatic impairment.

Renovascular hypertension

Patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are at increased risk of severe hypotension and renal failure when treated with drugs affecting the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation

In patients with impaired renal function treated with telmisartan, periodic monitoring of serum potassium and creatinine levels is recommended. There is no experience with the use of telmisartan/indapamide in patients who have recently undergone kidney transplantation.

Reduced intravascular fluid volume

Symptomatic hypotension, especially after the first dose of telmisartan/indapamide, may occur in patients with reduced intravascular volume and/or reduced sodium levels due to intensive diuretic therapy, a low-salt diet, diarrhea, or vomiting. These conditions should be corrected before initiating telmisartan/indapamide. Sodium levels and/or intravascular fluid volume should be normalized prior to starting treatment with telmisartan/indapamide.

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

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (up to acute kidney injury).

Therefore, dual blockade 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" and "Pharmacodynamics").

If dual blockade is considered absolutely necessary, it should only be performed under specialist supervision and with continuous careful monitoring of renal function, electrolyte levels, and blood pressure.

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

Other conditions requiring renin-angiotensin-aldosterone system activity

In patients whose vascular tone and renal function primarily depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or significant renal disease, including renal artery stenosis), treatment with drugs affecting this system, such as telmisartan, may lead to acute hypotension, hyperazotemia, oliguria, and rarely, acute kidney injury (see section "Adverse reactions").

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting via blockade of the renin-angiotensin system. Therefore, prescribing telmisartan/indapamide to these patients is not recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, the medicinal product should be used with caution in patients diagnosed with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Diabetic patients treated with insulin or antidiabetic medicinal products

Hypoglycemia may occur during treatment with telmisartan/indapamide in such patients. Blood glucose levels should be monitored, and dose adjustments of insulin or antidiabetic agents may be necessary.

In patients with diabetes and cardiovascular risk (e.g., with concomitant coronary artery disease), the risk of fatal myocardial infarction and sudden cardiovascular death may be higher when treated with antihypertensive agents such as angiotensin II receptor antagonists and ACE inhibitors. Coronary artery disease in diabetic patients may be asymptomatic and thus undiagnosed. Diabetic patients should be carefully evaluated, e.g., by stress testing, to detect and treat concomitant coronary artery disease before initiating treatment.

Hepatic encephalopathy

In patients with impaired liver function, the use of thiazide-like diuretics, particularly in the presence of electrolyte imbalance, may precipitate hepatic encephalopathy, which may progress to hepatic coma. In such cases, diuretic therapy must be discontinued immediately.

Photosensitivity

Cases of photosensitivity reactions have been reported in patients taking thiazide and thiazide-like diuretics (see section "Adverse reactions"). If such reactions occur, diuretic treatment is recommended to be discontinued. If re-administration of diuretics is necessary, vulnerable areas should be protected from sunlight or artificial ultraviolet sources.

Precautions

Water and electrolyte balance

Serum sodium

Serum sodium levels should be monitored before starting treatment and regularly during therapy. Hyponatremia may initially be asymptomatic, so regular monitoring is required. Monitoring should be more frequent in elderly patients and patients with hepatic cirrhosis. Any diuretic may cause hyponatremia, which can sometimes have serious consequences. Hyponatremia with hypovolemia may lead to dehydration and orthostatic hypotension; concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis (this phenomenon is of low frequency and severity).

Serum potassium

Hyperkalemia

Medicinal products affecting the renin-angiotensin-aldosterone system may cause hyperkalemia.

In elderly patients, patients with renal impairment, patients with diabetes, patients receiving other medicinal products that may increase potassium levels, and/or patients with concomitant diseases, hyperkalemia may lead to fatal outcomes.

The benefit-risk ratio must be carefully considered before combining medicinal products that inhibit the renin-angiotensin system.

Key risk factors for hyperkalemia include:

• diabetes, renal impairment, age over 70 years;
• combination therapy with one or more other agents affecting the renin-angiotensin-aldosterone system and/or potassium-containing dietary supplements. Medicinal products or therapeutic groups that may provoke hyperkalemia include potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim;
• intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, worsening renal function, acute deterioration of renal function (e.g., due to infections), and cellular lysis (e.g., acute limb ischemia, acute skeletal muscle necrosis, extensive trauma).

Patients at risk require careful monitoring of serum potassium concentration (see section "Interaction with other medicinal products and other forms of interaction").

Hypokalemia

Decreased serum potassium levels leading to hypokalemia are a major risk with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis, mostly associated with severe concomitant hypokalemia, have been reported. Hypokalemia (< 3.4 mmol/L) must be prevented in certain high-risk patient groups, such as elderly patients, poorly nourished patients, patients taking multiple medications, patients with cirrhosis accompanied by edema and ascites, patients with ischemic heart disease, and patients with heart failure. In these cases, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias.

Patients with congenital or drug-induced prolonged QT interval are also at risk. Hypokalemia, as well as bradycardia, may predispose to severe cardiac rhythm disturbances, including paroxysmal ventricular tachycardia of the torsades de pointes type, which may lead to fatal outcomes.

In all the above cases, more frequent monitoring of serum potassium levels is required. The first test should be performed within the first week of treatment. If hypokalemia is detected, it should be corrected.

Hypokalemia associated with low serum magnesium concentration may be poorly responsive to treatment unless serum magnesium levels are also corrected.

Serum magnesium

Thiazides and related diuretics, including indapamide, have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Serum calcium

Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and lead to a slight and transient increase in serum calcium levels. Marked hypercalcemia may result from previously undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function should be evaluated.

Blood glucose

In patients with diabetes, blood glucose levels should be closely monitored, especially in the presence of hypokalemia.

Uric acid

In patients with elevated uric acid levels, there may be a tendency toward increased frequency of gout attacks.

Renal function and diuretics

Thiazide and thiazide-like diuretics are most effective when renal function is not impaired or only mildly impaired (plasma creatinine < 25 mg/L, i.e., < 220 µmol/L in adults). In elderly patients, plasma creatinine levels should be consistent with age, body weight, and sex.

Hypovolemia

Hypovolemia due to loss of water and sodium from diuretic use at the beginning of treatment may reduce glomerular filtration. This may lead to increased blood urea and creatinine levels. This transient functional renal impairment has no consequences in individuals with normal renal function but may worsen pre-existing renal impairment.

Choroidal effusion, acute myopia (short-sightedness), and secondary angle-closure glaucoma

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical or surgical intervention may be necessary. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Ethnic differences

ACE inhibitors, telmisartan, and other angiotensin II receptor antagonists have been observed to be less effective in reducing blood pressure in Black patients compared to other ethnic groups. This may be explained by a higher prevalence of low-renin states among Black (or of African descent) patients with hypertension.

Others

As with other antihypertensive agents, excessive reduction in blood pressure in patients with ischemic heart disease or ischemic cardiomyopathy may lead to myocardial infarction or stroke.

In athletes, indapamide may result in a positive doping test.

Excipients

The product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially sodium-free.

Use in pregnancy or lactation.

Pregnancy

The medicinal product must not be used in pregnant women or in women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, it must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy (see sections "Contraindications" and "Special precautions for use").

There are no adequate data on the use of this product in pregnant women.

Epidemiological evidence regarding teratogenic risk from ACE inhibitors during the first trimester of pregnancy has not been conclusive, but a small increased risk cannot be excluded. Although there are no controlled epidemiological data on teratogenic risk with angiotensin II receptor antagonists, similar risks may exist for this class of medicinal products. When pregnancy is planned, the product should be replaced in advance with another antihypertensive agent with an established safety profile during pregnancy. If pregnancy is diagnosed, treatment with angiotensin II receptor antagonists must be stopped immediately, and alternative therapy should be initiated if necessary.

It is known that use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy causes fetotoxicity in humans (renal dysfunction, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If angiotensin II receptor antagonists are used starting from the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull ossification is recommended. Infants born to mothers who took angiotensin II receptor antagonists must be closely monitored for hypotension (see sections "Contraindications" and "Special precautions for use").

Data on the use of indapamide in pregnant women are lacking or limited (fewer than 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may reduce the pregnant woman's circulating blood volume and uteroplacental perfusion, potentially leading to fetoplacental ischemia and delayed fetal development. Animal studies have not shown direct or indirect toxic effects on reproductive performance. As a precautionary measure, indapamide should be avoided during pregnancy.

Lactation

Treatment with ILPIO® is not recommended during breastfeeding.

If treatment is necessary and alternative therapy with established safety is unavailable, breastfeeding must be discontinued.

Due to lack of information on the use of telmisartan during lactation, this medicinal product is not recommended for use in breastfeeding women. Alternative therapy with a better-established safety profile is preferred, especially when breastfeeding newborns or preterm infants.

There is insufficient data on the passage of indapamide/metabolites into breast milk. Hypersensitivity to sulfonamide derivatives and hypokalemia may occur. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide-like diuretics, the use of which during breastfeeding is associated with reduced or even suppressed lactation.

Indapamide is not recommended during breastfeeding.

Fertility

Preclinical studies have not shown effects of telmisartan and indapamide on fertility in males or females.

Reproductive toxicity studies showed no effect of indapamide on fertility in male and female rats. No effect on human fertility is expected.

Ability to affect reaction speed when driving or operating machinery.

When driving vehicles or operating machinery, the possibility of dizziness or hypersomnia with antihypertensive therapy, including telmisartan, should be considered.

Indapamide does not affect alertness, but if adverse reactions occur (see section "Adverse reactions"), including symptoms related to reduced blood pressure, especially at the beginning of treatment or when used in combination with another antihypertensive agent, the ability to drive or operate machinery may be impaired.

Dosage and Administration

For oral use.

Dosage

The recommended dose of ILPIO® is one tablet once daily.

In patients whose blood pressure is already controlled with a combination of telmisartan and indapamide, the dose should correspond to their previous treatment regimen.

Special Patient Groups

Renal Impairment (see sections "Special Warnings and Precautions for Use" and "Contraindications")

ILPIO® is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min) and in patients undergoing hemodialysis. No dose adjustment is required in patients with mild to moderate renal impairment. However, thiazide and thiazide-like diuretics are most effective when renal function is normal or only minimally impaired.

Elderly Patients (see section "Special Warnings and Precautions for Use")

No dose adjustment is necessary in elderly patients; however, plasma creatinine levels should be adjusted according to age, body weight, and gender. ILPIO® may be prescribed to elderly patients if renal function is normal or only minimally impaired.

Hepatic Impairment (see sections "Special Warnings and Precautions for Use" and "Contraindications")

Treatment with ILPIO® is contraindicated in patients with severe hepatic impairment.

In patients with mild or moderate hepatic impairment, dose adjustment is required: the maximum daily dose should not exceed 40 mg of telmisartan.

Administration

ILPIO® may be taken regardless of food intake. The tablet should be swallowed whole with a sufficient amount of water or a non-alcoholic beverage. The tablet may be divided into two equal doses.

Storage and Handling Precautions

ILPIO® should be stored in its sealed blister pack. Tablets should be removed from the blister immediately before use.

Pediatric Use

The safety and efficacy of ILPIO® in children and adolescents (under 18 years of age) have not been established. Current available data are described in the section "Pharmacokinetics", but no dosage recommendations can be made.

Overdose

Symptoms. The most prominent symptoms of telmisartan overdose were hypotension and tachycardia; bradycardia, dizziness, increased serum creatinine, and acute kidney injury (AKI) have also been reported.

Indapamide has no toxic effects even at very high doses up to 40 mg. Symptoms of indapamide overdose are primarily due to water-electrolyte disturbances (hyponatremia, hypokalemia). Clinically, nausea, vomiting, hypotension, seizures, somnolence, vertigo, confusion, polyuria, or oliguria progressing to anuria (due to hypovolemia) may occur.

Treatment. Telmisartan is not removed from the body by hemodialysis. Patients should be closely monitored and receive symptomatic and supportive therapy. Management depends on the time since overdose and severity of symptoms. Induction of vomiting and/or gastric lavage is recommended. Activated charcoal may be administered. Serum electrolytes and creatinine levels should be monitored frequently. In case of hypotension, the patient should be placed in a supine position and treated with rapid fluid and electrolyte replacement.

Side effects

Telmisartan

Serious adverse reactions, including anaphylactic reaction and angioedema, may occur in isolated cases (from ≥ 1/10,000 to <1/1,000), and neutropenia has also been observed.

The overall incidence of adverse reactions in patients with arterial hypertension during controlled clinical trials receiving telmisartan was generally comparable to that with placebo (41.4% vs. 43.9%). The incidence of adverse reactions was dose-independent and unrelated to patient sex, age, or race. The safety profile of telmisartan in patients receiving the drug for cardiovascular disease prevention was consistent with the safety profile observed in patients with arterial hypertension.

The adverse reactions listed below are based on results from controlled clinical studies in hypertensive patients and post-marketing reports. This list also includes serious adverse reactions and those leading to discontinuation of the drug during three long-term clinical trials involving 21,642 patients who received telmisartan for cardiovascular disease prevention for up to six years.

Adverse reactions are listed according to their frequency of occurrence: 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 (≥ 1/100,000 to <1/10,000), frequency not known (cannot be estimated from available data).

Within each category, adverse reactions are listed in order of decreasing severity.

Infections and infestations:

Uncommon – urinary tract infections (including cystitis), upper respiratory tract infections (including pharyngitis and sinusitis);

Rare – sepsis, including fatal cases¹.

Blood and lymphatic system disorders:

Uncommon – anaemia;

Rare – eosinophilia, thrombocytopenia.

Immune system disorders:

Rare – anaphylactic reaction, hypersensitivity.

Metabolism and nutrition disorders:

Uncommon – hyperkalaemia;

Rare – hypoglycaemia (in patients with diabetes mellitus).

Psychiatric disorders:

Uncommon – insomnia, depression;

Rare – anxiety.

Nervous system disorders:

Uncommon – syncope;

Rare – somnolence.

Eye disorders:

Rare – visual disturbance.

Ear and labyrinth disorders:

Uncommon – vertigo.

Cardiac disorders:

Uncommon – bradycardia;

Rare – tachycardia.

Vascular disorders:

Uncommon – arterial hypotension², orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders:

Uncommon – dyspnoea, cough;

Very rare – interstitial lung disease³.

Gastrointestinal disorders:

Uncommon – abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting;

Rare – dry mouth, gastric discomfort, dysgeusia;

Frequency not known – intestinal angioedema: intestinal angioedema with symptoms such as abdominal pain, nausea, vomiting, and diarrhoea has been reported after use of similar drugs⁴.

Hepatobiliary disorders:

Rare – hepatic function abnormalities/liver disorders⁵.

Skin and subcutaneous tissue disorders:

Uncommon – pruritus, increased sweating, rash;

Rare – angioedema (including fatal cases), eczema, erythema, urticaria, drug eruption, toxic dermatitis.

Musculoskeletal and connective tissue disorders:

Uncommon – back pain (e.g. sciatica), muscle cramps, myalgia;

Rare – arthralgia, limb pain, tendon pain (symptoms resembling tendinitis).

Renal and urinary disorders:

Uncommon – renal function impairment, including acute renal failure.

General disorders:

Uncommon – chest pain, asthenia (weakness);

Rare – influenza-like symptoms.

Investigations:

Uncommon – increased blood creatinine;

Rare – decreased haemoglobin, increased blood uric acid, increased liver enzymes, increased blood creatine phosphokinase.

^{1, 2, 3, 4, 5} See section "Side effects. Description of selected adverse reactions" for detailed information.

Description of selected adverse reactions

Sepsis. In the PRoFESS study, a higher incidence of sepsis was observed in patients receiving telmisartan compared to those receiving placebo. This may be due to chance or may reflect a process currently not fully understood.

Intestinal angioedema. Cases of intestinal angioedema have been reported following use of angiotensin II receptor antagonists (see section "Special precautions for use").

Hypotension. This adverse reaction was commonly observed in patients with controlled blood pressure who received telmisartan for cardiovascular disease prevention in addition to standard therapy.

Hepatic function abnormalities/liver disorders. According to post-marketing data, most cases of hepatic function abnormalities/liver disorders occurred in patients of Japanese nationality. Patients of Japanese nationality appear to be more susceptible to these adverse reactions.

Interstitial lung disease. Cases of interstitial lung disease have been reported during post-marketing surveillance in temporal association with telmisartan use. However, a causal relationship has not been established.

Indapamide

The most frequently reported adverse reactions with indapamide are hypokalaemia, hypersensitivity reactions (mainly dermatological), particularly in individuals predisposed to allergic and asthmatic reactions, and maculopapular rash.

Adverse reactions are listed according to their frequency of occurrence: 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 (≥ 1/100,000 to <1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Very rare – agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, thrombocytopenia.

Metabolism and nutrition disorders:

Common – hypokalaemia (see section "Special precautions for use");

Uncommon – hyponatraemia (see section "Special precautions for use");

Rare – hypochloraemia;

Rare – hypomagnesaemia;

Very rare – hypercalcaemia.

Nervous system disorders:

Rare – dizziness (vertigo), fatigue, headache, paraesthesia;

Frequency not known – loss of consciousness.

Eye disorders:

Frequency not known – myopia, choroidal effusion, acute angle-closure glaucoma, blurred vision, visual disturbances.

Cardiac disorders:

Very rare – arrhythmia;

Frequency not known – paroxysmal ventricular tachycardia of the torsades de pointes type, which may be fatal (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction").

Vascular disorders:

Very rare – arterial hypotension.

Gastrointestinal disorders:

Uncommon – vomiting;

Rare – nausea, constipation, dry mouth;

Very rare – pancreatitis.

Hepatobiliary disorders:

Very rare – hepatic function abnormalities;

Frequency not known – in patients with hepatic insufficiency, hepatic encephalopathy may occur (see sections "Special precautions for use", "Contraindications"), hepatitis.

Skin and subcutaneous tissue disorders:

Common – hypersensitivity reactions (mainly dermatological in patients predisposed to allergic and asthmatic reactions), maculopapular rash;

Uncommon – purpura;

Very rare – angioedema, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome;

Frequency not known – possible exacerbation of pre-existing systemic lupus erythematosus, photosensitivity reactions (see section "Special precautions for use").

Renal and urinary disorders:

Very rare – renal failure.

Reproductive system and breast disorders:

Uncommon – erectile dysfunction.

Musculoskeletal and connective tissue disorders:

Frequency not known – muscle spasms, muscle weakness, myalgia, rhabdomyolysis.

Investigations:

Frequency not known – QT interval prolongation on electrocardiogram (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction"), increased blood glucose (see section "Special precautions for use"), increased blood uric acid (see section "Special precautions for use"), increased liver enzymes.

Description of selected adverse reactions

During Phase II and III studies comparing 1.5 mg and 2.5 mg doses of indapamide, analysis of plasma potassium levels revealed a dose-dependent effect of indapamide:

• Indapamide 1.5 mg: plasma potassium <3.4 mmol/L was observed in 10% of patients and <3.2 mmol/L in 4% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium was 0.23 mmol/L.
• Indapamide 2.5 mg: plasma potassium <3.4 mmol/L was observed in 25% of patients and <3.2 mmol/L in 10% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium was 0.41 mmol/L.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

3 years. Do not use after the expiry date.

Storage conditions

Store in the original packaging to protect from light.

Keep out of reach and sight of children.

Packaging

10 tablets are placed in a blister made of OPA/Al/PVC film and aluminium foil.

3 or 10 blisters, together with the instruction for medical use, are placed in a cardboard box.

Prescription status

Prescription only.

Manufacturer/Marketing Authorization Holder

PRO.MED.CS Prague, a.s.

Manufacturer’s location and address of place of business/Marketing Authorization Holder’s location

Telčská 377/1, Michle, Prague 4, 140 00, Czech Republic