Micardisplus®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİCARDİSPLUS® (MICARDISPLUS®)

Composition:

Active substances: telmisartan, hydrochlorothiazide;

One tablet contains telmisartan 80 mg and hydrochlorothiazide 12.5 mg;

Excipients: povidone (E 1201); meglumine; sodium hydroxide; sorbitol (E 420); magnesium stearate (E 470b); microcrystalline cellulose; iron oxide red (E 172); sodium starch glycolate; lactose monohydrate; maize starch.

Pharmaceutical form. Tablets.

Main physico-chemical properties: elongated white-red biconvex two-layer tablets with possible red specks in the white layer. The white side has an imprint «Н8» and the Boehringer Ingelheim company logo.

Pharmacotherapeutic group.

Angiotensin II receptor blockers (ARBs) and diuretics. ATC code С09D А07.

Pharmacological properties.

Pharmacodynamics.

MICARDIS PLUS is a combination of an angiotensin II receptor blocker (telmisartan) and a thiazide diuretic (hydrochlorothiazide). The combination of these components provides an additive antihypertensive effect, reducing arterial pressure to a greater extent than either component alone. When MICARDIS PLUS tablets are administered once daily within the therapeutic dose range, effective and gradual reduction of arterial pressure is observed.

Mechanism of action.

Telmisartan is effective when administered orally; it is a specific blocker of angiotensin II receptors of the AT1 subtype. With its very high affinity for these receptors, telmisartan displaces angiotensin II from its binding sites on AT1 receptors. It exhibits no partial agonist activity at AT1 receptors. Telmisartan selectively binds to AT1 receptors. The binding is long-lasting. Telmisartan has no affinity for other receptors, including AT2 and other less-characterized angiotensin receptors. The functional role of these receptors is unknown, as is the effect of their potential "overstimulation" by angiotensin II, whose levels increase under the influence of telmisartan. Telmisartan reduces plasma aldosterone levels. Telmisartan does not inhibit human plasma renin and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kinase II), an enzyme that also degrades bradykinin. Therefore, potentiation of bradykinin-mediated adverse effects is not expected.

In healthy volunteers, telmisartan at a dose of 80 mg almost completely inhibits the hypertensive effect of angiotensin II in humans. The inhibitory effect lasts more than 24 hours and persists up to 48 hours.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully understood. Thiazide diuretics affect electrolyte reabsorption mechanisms in renal tubules, thereby directly increasing the excretion of sodium and chloride in approximately equivalent amounts. Due to the diuretic effect of hydrochlorothiazide, plasma volume decreases, plasma renin activity increases, and aldosterone secretion increases, resulting in increased urinary excretion of potassium and bicarbonates and decreased serum potassium levels. Possibly, due to blockade of the renin-angiotensin-aldosterone system, the concomitant administration of telmisartan counteracts the potassium loss associated with these diuretics. After administration of hydrochlorothiazide, diuresis begins within 2 hours, maximum effect is reached approximately 4 hours after administration, and the duration of action lasts approximately 6–12 hours.

Pharmacodynamic effects.

After the first dose of telmisartan, antihypertensive activity gradually develops over 3 hours. Maximum reduction in arterial pressure is usually observed after 4–8 weeks of treatment and is maintained during long-term therapy. The hypotensive effect remains stable for 24 hours after drug intake, including the last 4 hours before the next dose. This is confirmed by blood pressure measurements at peak effect and immediately before the next dose (the trough-to-peak ratio exceeds 80% after doses of 40 mg and 80 mg of telmisartan in placebo-controlled clinical trials).

In patients with arterial hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of telmisartan is comparable to that of other classes of antihypertensive agents (demonstrated in clinical trials comparing telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).

Upon abrupt discontinuation of telmisartan therapy, arterial pressure gradually returns to pre-treatment levels over several days, without signs of withdrawal syndrome.

In clinical trials comparing two antihypertensive treatment regimens, the incidence of dry cough was significantly lower in patients receiving telmisartan than in those receiving angiotensin-converting enzyme inhibitors.

In the "Prevention Regimen for Effectively Avoiding Second Strokes" (PRoFESS) study in patients aged 50 years or older who had recently experienced a stroke, sepsis occurred more frequently with telmisartan (0.70%) compared to placebo (0.49%) [RR 1.43 (95% confidence interval 1.00–2.06)]; the rate of fatal sepsis was higher in patients receiving telmisartan (0.33%) compared to those receiving placebo (0.16%) [RR 2.07 (95% confidence interval 1.14–3.76)].

The observed increased incidence of sepsis with telmisartan may be due to chance or to a mechanism not yet established.

Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular morbidity and mortality.

The effect of the fixed-dose combination of telmisartan/hydrochlorothiazide on mortality and cardiovascular disease is unknown.

Non-melanoma skin cancer

Available data from epidemiological studies have demonstrated an association between cumulative hydrochlorothiazide dose and non-melanoma skin cancer.

Pharmacokinetics.

Co-administration of hydrochlorothiazide and telmisartan does not affect the pharmacokinetics of these drugs in healthy volunteers.

Absorption.

Telmisartan. After oral administration, peak plasma concentration of telmisartan is reached within 0.5–1.5 hours. Absolute bioavailability of telmisartan at doses of 40 mg and 160 mg is 42% and 58%, respectively. Food slightly reduces the bioavailability of telmisartan; the reduction in area under the concentration-time curve (AUC) for telmisartan ranges from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). Three hours after administration, plasma concentrations are similar whether telmisartan is taken on an empty stomach or with food. The slight reduction in AUC is not considered to result in reduced therapeutic efficacy. Telmisartan does not accumulate significantly in plasma with repeated dosing.

Hydrochlorothiazide. After oral administration of the fixed-dose combination, peak plasma concentration of hydrochlorothiazide is reached within 1–3 hours. Due to cumulative renal excretion of hydrochlorothiazide, absolute bioavailability is approximately 60%.

Distribution.

Telmisartan is highly bound to plasma proteins (>99.5%), primarily to albumin and alpha-1-acid glycoprotein. The volume of distribution is approximately 500 L, indicating extensive tissue binding.

Hydrochlorothiazide is bound to plasma proteins by 64%, and the volume of distribution is 0.8 ± 0.3 L/kg.

Metabolism.

Telmisartan is metabolized via conjugation to form a pharmacologically inactive acylglucuronide. The glucuronide of the parent compound is the only metabolite identified in humans. After administration of a single dose of 14C-labeled telmisartan, the glucuronide accounts for approximately 11% of measured radioactivity in plasma. Cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.

Hydrochlorothiazide is not metabolized in humans.

Elimination.

Telmisartan. After intravenous or oral administration of 14C-labeled telmisartan, the majority of the dose (>97%) is excreted in feces via biliary excretion. Only a negligible amount is found in urine. Total plasma clearance of telmisartan after oral administration exceeds 1500 mL/min. Terminal elimination half-life is more than 20 hours.

Hydrochlorothiazide is excreted almost entirely unchanged in urine. Approximately 60% of an oral dose is eliminated within 48 hours. Renal clearance is approximately 250–300 mL/min. Terminal elimination half-life is 10–15 hours.

Linearity/Non-linearity.

Telmisartan. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range of 20–160 mg, with greater-than-proportional increases in plasma concentration (Cmax and AUC) as dose increases. Telmisartan does not accumulate significantly in plasma with repeated dosing.

Hydrochlorothiazide exhibits linear pharmacokinetics.

Pharmacokinetics in special patient populations.

Elderly patients. The pharmacokinetics of telmisartan do not differ between elderly and younger patients.

Sex. Plasma concentrations of telmisartan are generally 2–3 times higher in women than in men. However, clinical trial data show no significant increase in blood pressure reduction or orthostatic hypotension in women. Dose adjustment is not required. Women tend to have higher plasma concentrations of hydrochlorothiazide than men, but this has no clinical significance.

Patients with renal impairment. Lower plasma concentrations were observed in patients with dialysis-dependent renal failure. In patients with renal impairment, telmisartan is highly bound to plasma proteins and is not removed by dialysis. Elimination half-life is not altered in patients with impaired renal function. The elimination rate of hydrochlorothiazide is reduced in patients with renal impairment. In a typical study in patients with a mean creatinine clearance of 90 mL/min, the elimination half-life of hydrochlorothiazide increased. In patients with absent or removed kidneys, the elimination half-life is approximately 34 hours.

Patients with hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability to nearly 100%. Elimination half-life is not altered in these patients.

Clinical characteristics.

Indications.

Essential hypertension.

MIKARDIS PLUS, tablets, in a fixed-dose combination (80 mg telmisartan / 12.5 mg hydrochlorothiazide) is indicated for use in adult patients when treatment with telmisartan as monotherapy does not provide adequate blood pressure control.

Contraindications.

• Hypersensitivity to any of the active substances or to any of the excipients of the medicinal product (see section "Composition").
• Hypersensitivity to other sulfonamide derivatives (since hydrochlorothiazide is a sulfonamide derivative).
• Pregnancy or planned pregnancy (see sections "Special precautions for use" and "Use in pregnancy or lactation").
• Cholestasis and biliary obstructive disorders.
• Severe hepatic impairment.
• Severe renal impairment (creatinine clearance < 30 mL/min), anuria.
• Refractory hypokalemia/hyponatremia, hypercalcemia.
• Breastfeeding.
• Symptomatic hyperuricemia (gout).
• Pediatric population (under 18 years of age).

Concomitant use of telmisartan/hydrochlorothiazide and aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

Interaction with other medicinal products and other forms of interaction.

Litium. When lithium is used concomitantly with angiotensin-converting enzyme inhibitors, reversible increases in serum lithium concentration and lithium toxicity have been reported. Isolated cases of interaction have been reported with angiotensin II receptor blockers (including telmisartan/hydrochlorothiazide). Concomitant use of lithium and telmisartan/hydrochlorothiazide is not recommended (see section "Contraindications"). If combination therapy is necessary, careful monitoring of serum lithium levels is recommended during concomitant use.

Medicinal products associated with potassium loss and hypokalemia (e.g., other potassium-wasting diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, sodium penicillin G, salicylic acid and derivatives). When these medicinal products are used concomitantly with hydrochlorothiazide-telmisartan combination, monitoring of plasma potassium levels is recommended. These medicinal products may potentiate the effect of hydrochlorothiazide on serum potassium levels (see section "Special precautions for use").

Iodinated contrast agents

In cases of diuretic-induced dehydration, the risk of acute renal failure is increased, particularly with high doses of iodinated contrast agents. Patients should be adequately rehydrated prior to administration of iodinated contrast agents.

Medicinal products that may increase potassium levels and cause hyperkalemia (e.g., angiotensin-converting enzyme inhibitors, potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, cyclosporine, or other medicinal products such as sodium heparin). When these medicinal products are used concomitantly with hydrochlorothiazide-telmisartan combination, monitoring of plasma potassium levels is recommended. Based on experience with other medicinal products that inhibit the renin-angiotensin system, concomitant use of these agents may lead to increased serum potassium levels and is therefore not recommended (see section "Special precautions for use").

Medicinal products causing disturbances in serum potassium levels. Periodic monitoring of serum potassium levels and ECG is recommended when telmisartan/hydrochlorothiazide is used concomitantly with the following medicinal products that may cause disturbances in serum potassium levels (e.g., with digoxin glycosides, antiarrhythmic agents) and medicinal products that promote ventricular tachyarrhythmias (including certain antiarrhythmics), where hypokalemia is a triggering factor:

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Certain antipsychotics (e.g., thioridazine, chlorpromazine, levopromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Others (e.g., bepridil, cisapride, difemanyl, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine IV).

Digoxin glycosides. Hypokalemia or hypomagnesemia induced by thiazides may predispose to digoxin-induced cardiac arrhythmias (see section "Special precautions for use").

Digoxin. When telmisartan is used concomitantly with digoxin, increases in mean peak (49%) and trough (20%) plasma digoxin concentrations have been observed. Digoxin levels should be monitored at the initiation of therapy, during dose adjustments, and upon discontinuation of telmisartan therapy to maintain levels within the therapeutic range.

Other antihypertensive agents. Telmisartan may enhance the hypotensive effect 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 hypotension, hyperkalemia, and reduced renal function (including acute renal failure) compared to use of a single RAAS-acting agent (see sections "Special precautions for use", "Contraindications", and "Pharmacodynamics").

Antidiabetic agents (oral agents and insulin). Dose adjustment of antidiabetic agents may be required (see section "Special precautions for use").

Metformin. Metformin should be used with caution due to the risk of lactic acidosis caused by possible renal impairment associated with hydrochlorothiazide use.

Cholestyramine and colestipol resins. Absorption of hydrochlorothiazide is reduced in the presence of ion-exchange resins.

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs (including acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs) may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics and the antihypertensive effect of angiotensin II receptor blockers. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of angiotensin II receptor blockers and agents that inhibit cyclooxygenase may lead to further deterioration of renal function, including potentially reversible acute renal failure. Therefore, such combinations should be used with caution, particularly in elderly patients. Adequate hydration and careful monitoring of renal function should be ensured after initiation of combination therapy and periodically during treatment.

In one study, concomitant use of telmisartan and ramipril resulted in a 2.5-fold increase in the area under the concentration-time curve (AUC0–24) and maximum plasma concentration (Cmax) of ramipril and ramiprilat. The clinical significance of this observation remains unknown.

Vasoactive amines (e.g., noradrenaline). The effect of vasoactive amines may be reduced.

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

Medicinal products used for the treatment of gout (e.g., probenecid, sulfinpyrazone, allopurinol). Dose adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be necessary. Concomitant use of thiazides 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-conserving agents (e.g., vitamin D therapy) are required, serum calcium levels should be monitored and doses adjusted accordingly.

Beta-blockers and diazoxide. The hyperglycemic effects of beta-blockers and diazoxide may be enhanced by thiazides.

Anticholinergic medicinal products (e.g., atropine, biperiden) may increase the bioavailability of thiazide diuretics by increasing gastrointestinal motility and gastric emptying.

Amantadine. Thiazides may increase the risk of adverse effects associated with amantadine.

Cytotoxic agents (e.g., cyclophosphamide, methotrexate). Thiazides may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Due to pharmacological properties, baclofen and amifostine are expected to potentiate the hypotensive effect of all antihypertensive agents, including telmisartan. Additionally, orthostatic hypotension may be exacerbated by alcohol, barbiturates, narcotics, or antidepressants.

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

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

Cyclosporine. Concomitant use of cyclosporine may increase hyperuricemia and the risk of complications such as gout.

Effect of medicinal products on laboratory test results. Due to their effect on calcium metabolism, thiazides may influence the assessment of parathyroid gland function (see section "Special precautions for use").

Carbamazepine. Clinical and biological monitoring is required due to the risk of symptomatic hyponatremia.

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

Special precautions for use.

Pregnancy. Therapy with angiotensin II receptor blockers should not be initiated during pregnancy. If treatment with angiotensin II receptor blockers is considered necessary, patients planning pregnancy should be switched to an alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is diagnosed, angiotensin II receptor blockers should be discontinued immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Hepatic impairment. Telmisartan/hydrochlorothiazide should not be administered to patients with cholestasis, biliary obstructive disorders, or severe hepatic insufficiency (see section "Contraindications"), as telmisartan is primarily excreted via bile. Reduced hepatic clearance of telmisartan is expected in these patients.

Telmisartan/hydrochlorothiazide should be used with caution in patients with impaired liver function or progressive liver disease, as even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with the use of telmisartan/hydrochlorothiazide in patients with hepatic insufficiency.

Renovascular hypertension. There is an increased risk of severe hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney when treated with drugs affecting the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation. Telmisartan/hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications"). There is no experience with the use of telmisartan/hydrochlorothiazide in patients with a recently transplanted kidney. Limited experience exists with the use of telmisartan/hydrochlorothiazide in patients with mild to moderate renal impairment; therefore, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended. Azotemia associated with thiazide diuretics may occur in patients with renal impairment.

Telmisartan is not removed from the blood by hemofiltration and is not dialyzable.

Patients with reduced intravascular fluid volume and/or sodium. Symptomatic hypotension, particularly after the first dose, may occur in patients with reduced fluid and/or sodium volume due to diuretic therapy, dietary salt restriction, diarrhea, or vomiting. Before initiating treatment with MİCARDIS PLUS, such conditions, especially reduced intravascular fluid volume and/or sodium, should be corrected.

Hyponatremia, sometimes accompanied by neurological symptoms (nausea, progressive disorientation, apathy), has been observed during hydrochlorothiazide therapy.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Evidence indicates that concomitant use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (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" and "Pharmacodynamics").

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

ACE inhibitors and angiotensin II receptor blockers should 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 depend primarily on the activity of the renin-angiotensin-aldosterone system (e.g., patients with congestive heart failure or severe renal disease, including renal artery stenosis), treatment with drugs affecting this system may lead to acute hypotension, hyperazotemia, oliguria, or rarely, acute renal failure (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, the use of telmisartan/hydrochlorothiazide is not recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilators, particular caution is required when treating patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Metabolic and endocrine effects. Thiazide therapy may reduce glucose tolerance, while hypoglycemia may develop in diabetic patients receiving insulin or antidiabetic therapy along with telmisartan. Therefore, blood glucose levels should be monitored in these patients; dose adjustments of insulin or hypoglycemic agents may be necessary. Latent diabetes mellitus may be unmasked during thiazide therapy.

Elevated cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however, with the use of a preparation containing 12.5 mg hydrochlorothiazide, minimal or no increase in cholesterol and triglycerides has been observed. Hyperuricemia or overt gout may occur in some patients receiving thiazide therapy.

Electrolyte imbalance. All patients receiving diuretic therapy should have periodic determination of serum electrolyte levels. Thiazides, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (including hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting (see section "Adverse reactions").

• Hypokalemia. Although hypokalemia may develop during thiazide diuretic therapy, concomitant therapy with telmisartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with hepatic cirrhosis, those with marked diuresis, those receiving inadequate oral electrolyte supplementation, and those receiving concomitant corticosteroid or ACTH therapy (see section "Interaction with other medicinal products and other forms of interaction").
• Hyperkalemia. Conversely, due to angiotensin II receptor (AT1) antagonism caused by telmisartan, hyperkalemia may occur. However, clinically significant hyperkalemia due to telmisartan/hydrochlorothiazide has not been documented. Risk factors for hyperkalemia include renal impairment and/or heart failure and diabetes mellitus. Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes should be used with caution when administered concomitantly with telmisartan/hydrochlorothiazide (see section "Interaction with other medicinal products and other forms of interaction").
• Hypochloremic alkalosis. Chloride deficiency is usually mild and generally does not require treatment.
• Hypercalcemia. Thiazides may reduce urinary calcium excretion and lead to slight increases in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide therapy should be discontinued before parathyroid function tests are performed.
• Hypomagnesemia. Thiazides have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesemia (see section "Interaction with other medicinal products and other forms of interaction").

Race. As with other angiotensin II receptor blockers, telmisartan is less effective in lowering blood pressure in patients of black ethnicity, likely due to the prevalent low renin state in this population with hypertension.

Ischemic heart disease. As with any other antihypertensive agent, excessive reduction in blood pressure in patients with ischemic heart disease or myocardial ischemia may lead to myocardial infarction or stroke.

General information. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, although more likely in those with such conditions in their history. Exacerbation or activation of systemic lupus erythematosus has been observed during treatment with thiazide diuretics, including hydrochlorothiazide.

Photosensitivity reactions have been reported during treatment with thiazide diuretics (see section "Adverse reactions"). If photosensitivity reactions occur during treatment, drug discontinuation is recommended. If reinitiation of diuretic therapy is considered necessary, protection of exposed skin from sunlight or artificial ultraviolet radiation is recommended.

Choroidal effusion, acute myopia, and angle-closure glaucoma. Hydrochlorothiazide, a sulfonamide, may cause hypersensitivity reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma.

Symptoms include sudden onset of decreased visual acuity or eye pain and typically occur from several hours to weeks after initiation of treatment. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Hydrochlorothiazide therapy should be discontinued as soon as possible. Immediate medical or surgical intervention may be required if intraocular pressure remains uncontrolled. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Non-melanoma skin cancer. In two epidemiological studies based on the Danish National Cancer Registry, an increased risk of non-melanoma skin cancer (NMSC) (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) was observed with increasing cumulative dose of hydrochlorothiazide (see section "Adverse reactions"). The photosensitizing effect of hydrochlorothiazide may be a mechanism underlying NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and should regularly examine their skin for new lesions and promptly report any suspicious skin changes. Preventive measures such as limiting exposure to sunlight and ultraviolet radiation should be considered. Patients should be advised to use adequate protection against such exposure to minimize the risk of skin cancer. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy specimens. Hydrochlorothiazide use should also be reconsidered in patients with a history of NMSC (see section "Adverse reactions").

Acute respiratory toxicity. Very rare but severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema typically develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening lung function, and hypotension. If ARDS is suspected, MİCARDIS PLUS should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS after hydrochlorothiazide.

Intestinal angioedema. Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers (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, telmisartan therapy should be discontinued and appropriate monitoring initiated until complete symptom resolution.

Lactose. Each tablet contains lactose (the product contains 112 mg lactose monohydrate, equivalent to 107 mg anhydrous lactose per tablet). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Sorbitol. MİCARDIS PLUS (80 mg/12.5 mg tablets) contains 338 mg sorbitol per tablet. Patients with hereditary fructose intolerance should not take this medicinal product.

Each tablet contains less than 1 mmol sodium (23 mg), which is considered essentially sodium-free.

The drug may affect the results of the following laboratory tests:

• the drug may reduce plasma protein-bound iodine levels;
• treatment with the drug should be discontinued before laboratory testing to assess parathyroid gland function;
• the drug may increase free bilirubin concentration in serum.

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product approved for use (see sections "Contraindications" and "Special precautions for use").

There are no data on the use of telmisartan/hydrochlorothiazide in pregnant women. Animal studies have shown reproductive toxicity.

Epidemiological evidence regarding teratogenic risk after ACE inhibitor use during the first trimester of pregnancy is inconclusive; however, a small increased risk cannot be excluded. Although there are no controlled epidemiological data on the risk of angiotensin II receptor blockers, similar risks are possible for this class of drugs. Until angiotensin II receptor blocker therapy is considered appropriate, women planning pregnancy should be switched to alternative antihypertensive drugs with an established safety profile during pregnancy. If pregnancy is diagnosed, angiotensin II receptor blockers should be discontinued immediately and alternative therapy initiated if necessary.

Treatment with angiotensin II receptor blockers during the second and third trimesters of pregnancy causes fetotoxicity in humans (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If angiotensin II receptor blockers were used from the second trimester of pregnancy, ultrasound monitoring of fetal kidney function and skull condition is recommended. Newborns whose mothers took angiotensin II receptor blockers should be closely monitored for hypotension (see sections "Contraindications" and "Special precautions for use").

Limited experience exists with hydrochlorothiazide use during pregnancy, particularly in the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placental barrier. Due to the pharmacological mechanism of hydrochlorothiazide, its use during the second and third trimesters may impair fetoplacental perfusion and lead to intrauterine and neonatal effects such as jaundice, fetal electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used for edema or pregnancy-induced hypertension, including preeclampsia, due to the risk of plasma volume reduction and placental hypoperfusion without positive effect on disease course.

Hydrochlorothiazide should not be used in pregnant women with significant hypertension except in rare cases where no other treatment is possible.

Breastfeeding

As there is no information on the use of telmisartan/hydrochlorothiazide during breastfeeding, its use during this period is not recommended; alternative therapy with drugs with a better-established safety profile should be preferred, especially when breastfeeding newborns or preterm infants.

Hydrochlorothiazide is excreted in small amounts in breast milk. High-dose thiazides causing intense diuresis may suppress breast milk production. The use of telmisartan/hydrochlorothiazide during breastfeeding is contraindicated.

Fertility

No studies on the effect on human fertility with the fixed-dose combination or individual components have been conducted.

Preclinical studies did not reveal effects of telmisartan or hydrochlorothiazide on male or female fertility.

Ability to affect reaction speed when driving or operating machinery.

MİCARDIS PLUS may affect the ability to drive or operate machinery. Treatment with antihypertensive drugs, particularly telmisartan/hydrochlorothiazide, may cause dizziness, syncope, or vertigo.

Patients experiencing these adverse effects should avoid potentially hazardous activities such as driving or operating machinery.

Method of Administration and Dosage.

Dosage

Fixed-dose combination therapy is indicated for patients whose blood pressure is not adequately controlled with telmisartan alone. The dose of each component should be determined before switching to a fixed-dose combination. Direct substitution of monotherapy with fixed-dose combinations may be considered if clinically justified. MICARDISPLUS 80 mg/12.5 mg may be administered once daily to patients whose blood pressure is not adequately controlled on MICARDIS 80 mg tablets.

Elderly patients. No dosage adjustment is required for elderly patients.

Renal impairment. Experience in patients with mild to moderate renal impairment is limited, but does not indicate adverse renal effects; therefore, dosage adjustment is not considered necessary. Periodic monitoring of renal function is recommended (see section "Special precautions for use"). Due to the presence of hydrochlorothiazide, fixed-dose combination therapy is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications").

Telmisartan is not removed from blood by hemofiltration and is not dialyzable.

Hepatic impairment. MICARDISPLUS should be used with caution in patients with mild to moderate hepatic impairment. The dose of telmisartan should not exceed 40 mg once daily. Fixed-dose combination therapy is contraindicated in patients with severe hepatic dysfunction (see section "Contraindications"). Thiazides should be used with caution in patients with hepatic impairment (see section "Special precautions for use").

Method of administration.

MICARDISPLUS should be taken orally once daily, swallowing the tablet whole with liquid. MICARDISPLUS can be taken independently of food intake.

Precautions prior to administration.

MICARDISPLUS should be stored in its sealed blister pack due to the hygroscopic nature of the tablets. Tablets should be removed from the blister pack immediately before use.

Children

The safety and efficacy of MICARDISPLUS in patients under 18 years of age have not been established. Use of MICARDISPLUS in pediatric patients is not recommended.

Overdose

Information regarding telmisartan overdose in humans is limited. The extent to which hydrochlorothiazide is removed by hemodialysis is unknown.

Symptoms. The most likely expected manifestations of telmisartan overdose are arterial hypotension and tachycardia; bradycardia, dizziness, vomiting, increased serum creatinine, and acute renal failure have also been observed. Overdose with hydrochlorothiazide may lead to electrolyte depletion (hypokalemia, hypochloremia) and hypovolemia due to excessive diuresis. The most common symptoms of overdose include nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of cardiac arrhythmias, particularly in patients receiving concomitant digoxin or certain antiarrhythmic agents.

Treatment. Telmisartan is not removed by hemofiltration and is not dialyzable. Careful monitoring of the patient is required. Treatment of overdose symptoms should be symptomatic and supportive. Therapy depends on the time of ingestion and severity of symptoms. Supportive measures include induction of emesis and/or gastric lavage. Administration of activated charcoal may be beneficial in managing overdose. Frequent monitoring of serum electrolytes and creatinine levels is recommended. In case of arterial hypotension, the patient should be placed in a supine position and treated with measures aimed at rapid restoration of salt and fluid volume.

Adverse reactions.

Safety profile overview. The most common adverse reaction is dizziness. Serious angioedema may occur rarely (≥1/10,000 – < 1/1,000).

Overall, the frequency of reported adverse reactions for telmisartan/hydrochlorothiazide is comparable to that reported for telmisartan alone in a randomized controlled trial involving 1,471 patients receiving either the combination of telmisartan and hydrochlorothiazide (835 patients) or telmisartan alone (636 patients). The number of adverse effects was not dose-dependent and showed no association with gender, age, or race.

List of adverse reactions in table form

Adverse reactions reported in all clinical trials and occurring more frequently (p ≤ 0.05) with telmisartan plus hydrochlorothiazide than with placebo are listed below by organ system class. Adverse reactions not observed during clinical trials may occur during treatment with telmisartan/hydrochlorothiazide and are based on the experience of using telmisartan or hydrochlorothiazide individually.

Known adverse reactions associated with the use of each component separately, but not observed in clinical trials with the medicinal product MİCARDIS PLUS, may represent potential adverse reactions during its use.

Adverse reactions classified by frequency of occurrence are defined as follows: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1,000 – < 1/100), rare (≥ 1/10,000 – < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

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

Table 1

Adverse reactions (according to MedDRA, based on data from placebo-controlled trials and post-marketing surveillance)

1 Based on reports during post-marketing use.

2 See subsections below for additional information.

a Adverse reactions occurred with similar frequency in patients receiving placebo and telmisartan. The overall incidence of adverse reactions reported with telmisartan (41.4%) was generally comparable to that with placebo (43.9%) in placebo-controlled trials. The adverse reactions listed above were observed in all clinical trials involving patients receiving telmisartan for hypertension or patients aged 50 years and older at high risk of cardiovascular disease.

Description of selected adverse reactions.

Hepatic function impairment/liver function disorders. Most cases of hepatic function impairment/liver function disorders reported during the post-marketing period with telmisartan occurred in patients of Japanese nationality. These patients appear to be more susceptible to these adverse reactions.

Sepsis. In the PRoFESS study, cases of sepsis were observed more frequently in patients receiving telmisartan than in those receiving placebo. This may be due to chance or may indicate a process with an unknown mechanism (see section "Pharmacodynamics").

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

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and pharmaceutical workers, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 7 tablets per blister; 4 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Boehringer Ingelheim Pharma GmbH & Co.KG

or

Boehringer Ingelheim Hellas Single Member S.A.

Manufacturer's location and address of place of business.

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany

or

5th km Paiania-Markopoulo, Koropi Attiki, 19441, Greece.