Telpres plus

Ukraine
Brand name Telpres plus
Form tablets
Active substance / Dosage
telmisartan · 80 mg
hydrochlorothiazide · 12.5 mg
Prescription type prescription only
ATC code
C09DA07
Registration number UA/15949/01/03
Manufacturer Laboratorios Likonsa, S.A. (full production cycle, batch release)
Telpres plus tablets

Table of Contents

INSTRUCTION for medical use of the medicinal product TELPRES PLUS

Composition:

Active substances: telmisartan and hydrochlorothiazide;

One tablet contains telmisartan 40 mg and hydrochlorothiazide 12.5 mg, or telmisartan 80 mg and hydrochlorothiazide 12.5 mg, or telmisartan 80 mg and hydrochlorothiazide 25 mg;

Excipients for dosage 40 mg/12.5 mg: mannitol (E 421), povidone, crospovidone, meglumine, sodium hydroxide, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate (type A), magnesium stearate, iron oxide yellow (E 172);

Excipients for dosage 80 mg/12.5 mg: mannitol (E 421), povidone, crospovidone, meglumine, sodium hydroxide, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate (type A), magnesium stearate, iron oxide red (E 172);

Excipients for dosage 80 mg/25 mg: mannitol (E 421), povidone, crospovidone, meglumine, sodium hydroxide, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate (type A), magnesium stearate, iron oxide yellow (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties:

for dosage 40 mg/12.5 mg: round, biconvex, bilayer uncoated tablets, with a layer ranging from light yellow to yellow on one side and from white to almost white with possible pink inclusions on the other side;

for dosage 80 mg/12.5 mg: round, biconvex, bilayer uncoated tablets, with a layer ranging from light pink to pink on one side and from white to almost white with possible pink inclusions on the other side;

for dosage 80 mg/25 mg: round, biconvex, bilayer uncoated tablets, with a layer ranging from light yellow to yellow on one side and from white to almost white with possible pink inclusions on the other side.

Pharmacotherapeutic group.

Angiotensin II antagonists and diuretics.

ATC code C09DA07.

Pharmacological Properties

Pharmacodynamics

Telpres Plus is a combination of an angiotensin II receptor antagonist (telmisartan) and a thiazide diuretic (hydrochlorothiazide). The combination of these ingredients provides an additive antihypertensive effect, reducing blood pressure more than either component alone. When administered once daily at therapeutic doses, Telpres Plus effectively and gradually reduces arterial blood pressure.

Telmisartan, for oral use, is a potent and specific antagonist of angiotensin II receptors (AT1 subtype). Telmisartan binds with very high affinity to the AT1 receptors, displacing angiotensin II at its binding sites, which are responsible for the known actions of angiotensin II. Telmisartan has no partial agonist activity at the AT1 receptor and 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 possible excessive stimulation by angiotensin II, whose levels increase under the influence of telmisartan. Telmisartan reduces plasma aldosterone levels. It does not inhibit human plasma renin, does not block ion channels, and does not inhibit angiotensin-converting enzyme (ACE) (kininase II), which also degrades bradykinin. Therefore, adverse reactions related to bradykinin are not expected to be enhanced.

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

After the first dose of telmisartan, antihypertensive activity gradually develops within 3 hours. The maximum reduction in blood pressure is achieved within 4–8 weeks of initiating treatment and is maintained during long-term therapy. The antihypertensive effect is sustained over 24 hours after dosing, including during the last 4 hours before the next dose, as confirmed by ambulatory blood pressure monitoring. This is supported by the ratio of telmisartan concentration just before the next dose to Cmax, which is 80% after 40 mg and 80 mg doses of telmisartan in clinical studies. A dose-dependent effect on systolic blood pressure has been observed, while data on diastolic pressure are conflicting.

In patients with arterial hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The contribution of the diuretic and natriuretic effects of the drug to its antihypertensive activity has not yet been fully determined. The antihypertensive efficacy of telmisartan is comparable to that of antihypertensive agents from other classes (as demonstrated in studies comparing telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).

Upon abrupt discontinuation of telmisartan therapy, blood pressure gradually returns to pre-treatment levels over several days, with no evidence of a rebound effect.

Clinical studies have shown that dry cough occurs significantly less frequently with telmisartan than with angiotensin-converting enzyme (ACE) inhibitors.

The effect of telmisartan on mortality and cardiovascular morbidity is unknown.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully understood. Thiazides affect the renal tubular mechanism of electrolyte reabsorption, thereby directly increasing the excretion of sodium and chloride in approximately equimolar amounts. Due to its diuretic effect, hydrochlorothiazide reduces plasma volume, increases plasma renin activity, enhances aldosterone secretion, and leads to increased urinary potassium excretion, loss of bicarbonate, and decreased serum potassium levels. The concomitant use of telmisartan, which blocks the renin-angiotensin-aldosterone system (RAAS), may help counteract the potassium loss associated with hydrochlorothiazide. After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peak effect occurs at approximately 4 hours, and the duration of action lasts about 6–12 hours.

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

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

Based on available epidemiological data, there is a cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer. One study included patients with 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), and 1,430,883 and 172,462 control patients, respectively. High cumulative use of hydrochlorothiazide (total ≥50,000 mg) was associated with an adjusted risk ratio (RR) of 1.29 (95% confidence interval (CI): 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) risk and hydrochlorothiazide exposure: 633 cases of lip cancer (SCC) were identified among 63,067 controls. A clear dose-response relationship was demonstrated with an adjusted RR of 2.1 (95% CI: 1.7–2.6), RR of 3.9 (3.0–4.9) for high cumulative dose (at least 25,000 mg), and RR of 7.7 (5.7–10.5) for the highest cumulative dose (at least 100,000 mg) (see section "Special Warnings and Precautions for Use").

Pharmacokinetics

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

Absorption

Telmisartan

After oral administration, peak plasma concentration (Cmax) of telmisartan is reached within 0.5–1.5 hours. The absolute bioavailability of 40 mg and 160 mg telmisartan is 42% and 58%, respectively. Food slightly reduces telmisartan bioavailability, with a decrease in the area under the concentration-time curve (AUC) ranging from approximately 6% (40 mg dose) to 19% (160 mg dose). Three hours after administration, plasma concentrations are similar regardless of whether telmisartan is taken with or without food. The slight reduction in AUC is not considered to result in a reduction in therapeutic efficacy. The pharmacokinetics of orally administered telmisartan are nonlinear with increasing doses from 20 to 160 mg, with plasma concentrations (Cmax and AUC) increasing disproportionately. Telmisartan does not accumulate significantly in plasma with repeated dosing.

Hydrochlorothiazide

After oral administration of Telpres Plus, Cmax of hydrochlorothiazide is reached approximately within 1–3 hours. Based on cumulative renal excretion of hydrochlorothiazide, absolute bioavailability is approximately 60%.

Distribution

Telmisartan

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

Hydrochlorothiazide

Hydrochlorothiazide is protein-bound in plasma by 68%, and its apparent volume of distribution is 0.83–1.14 L/kg.

Elimination

Telmisartan

After 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. Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide. The glucuronide of the parent compound is the only metabolite identified in humans. After a single dose of 14C-labeled telmisartan, the glucuronide accounts for approximately 11% of the measured radioactivity in plasma. Cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan. Total plasma clearance of telmisartan after oral administration is >1500 mL/min. The terminal elimination half-life is >20 hours.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized in humans and is excreted almost entirely unchanged in urine. Approximately 60% of an oral dose is eliminated unchanged within 48 hours. Renal clearance is approximately 250–300 mL/min. The terminal elimination half-life is 10–15 hours.

Special Patient Populations

Gender

Plasma concentrations of telmisartan are generally 2–3 times higher in women than in men. However, clinical studies have not shown a significantly enhanced effect on blood pressure or an increased incidence of orthostatic hypotension in women. Dose adjustment is not required. Women tend to have higher plasma concentrations of hydrochlorothiazide than men, but this difference is not clinically significant.

Elderly Patients

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

Patients with Renal Impairment

Renal excretion does not significantly affect the clearance of telmisartan. Based on limited experience with telmisartan in patients with renal impairment (creatinine clearance 30–60 mL/min; mean approximately 50 mL/min), dose adjustment is not necessary in these patients. Telmisartan is not removed by hemodialysis. In patients with renal insufficiency, the elimination rate of hydrochlorothiazide is reduced. In typical studies, with a mean creatinine clearance of 90 mL/min, the half-life of hydrochlorothiazide was prolonged. In patients with non-functioning kidneys, the elimination half-life is approximately 34 hours.

Patients with Hepatic Impairment

Pharmacokinetic studies in patients with hepatic impairment have shown an increase in absolute bioavailability to 100%. However, the elimination half-life in patients with hepatic impairment does not change.

Clinical characteristics.

Indications.

Arterial hypertension. Telpres Plus is used as a fixed-dose combination when telmisartan monotherapy does not provide adequate control of arterial pressure.

Contraindications.

  • Hypersensitivity to any component of the medicinal product.
  • Hypersensitivity to other substances which are sulphonamide derivatives (since hydrochlorothiazide is a sulphonamide derivative).
  • Pregnancy or planned pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
  • Cholestatic and biliary obstructive disorders.
  • Severe hepatic dysfunction.
  • Anuria, severe renal impairment (creatinine clearance < 30 mL/min).
  • Refractory hypokalemia/hyponatremia, hypercalcemia.
  • Breastfeeding.
  • Symptomatic hyperuricemia (gout).
  • Pediatric population (under 18 years of age).
  • Concomitant use of telmisartan and aliskiren-containing 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 "Pharmacological properties").

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

Lithium

Reversible increases in serum lithium concentration and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Rare cases of interaction have also been reported with angiotensin II receptor antagonists (including telmisartan/hydrochlorothiazide). Concomitant use of lithium and Telpres Plus is not recommended. If such combination is necessary, careful monitoring of serum lithium levels is recommended.

MEDICINAL PRODUCTS ASSOCIATED WITH POTASSIUM LOSS AND HYPOKALEMIA (e.g., other potassium-wasting diuretics, laxatives, corticosteroids, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, sodium penicillin G, salicylic acid and derivatives).

When these medicinal products are used concomitantly with the combination telmisartan/hydrochlorothiazide, monitoring of plasma potassium levels is recommended. These medicinal products may enhance the effect of hydrochlorothiazide on plasma potassium levels.

MEDICINAL PRODUCTS THAT MAY INCREASE POTASSIUM LEVELS AND CAUSE HYPERKALEMIA (e.g., medicinal products that inhibit the renin-angiotensin system, 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 the combination telmisartan/hydrochlorothiazide, monitoring of plasma potassium levels is recommended. Based on experience with other medicinal products that inhibit the renin-angiotensin system, concomitant use of these medicinal products may lead to increased serum potassium levels and is therefore not recommended.

MEDICINAL PRODUCTS CAUSING DISTURBANCES IN SERUM POTASSIUM LEVELS

Monitoring of serum potassium levels and ECG is recommended when Telpres Plus is used concomitantly with medicinal products that cause disturbances in serum potassium levels (e.g., digoxin glycosides, antiarrhythmic agents), and with medicinal products that may provoke paroxysmal tachycardia of the torsades de pointes type (including certain antiarrhythmic agents), since hypokalemia is a triggering factor for torsades de pointes:

  • 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, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
  • others (e.g., bepridil, cizapride, difemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vinca alkaloids IV).

Digoxin glycosides

Hypokalemia or hypomagnesemia induced by thiazides may predispose to digoxin-induced cardiac arrhythmias.

Digoxin

Concomitant use of telmisartan with digoxin has been associated with increased mean peak (49%) and trough (20%) plasma digoxin concentrations. Monitoring of digoxin levels is necessary 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.

Reports indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) using combinations of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as arterial 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 "Pharmacological properties").

Antidiabetic agents (oral agents and insulin)

Dosage adjustment of antidiabetic agents may be required.

Metformin

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

Cholestyramine and colestipol resins

Absorption of hydrochlorothiazide is impaired in the presence of anion-exchange resins.

Non-steroidal 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 antagonists. In some patients with impaired renal function (including dehydrated patients or elderly patients with renal impairment), concomitant use of angiotensin II receptor antagonists and agents that inhibit cyclooxygenase may lead to deterioration of renal function, including acute renal failure, which is usually reversible. Therefore, such combinations should be used with caution, especially in the elderly. Adequate hydration should be ensured after initiation of combination therapy, and renal function should be closely monitored periodically during treatment.

In one study, concomitant use of telmisartan and ramipril resulted in a 2.5-fold increase in AUC0–24 and 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 enhanced by hydrochlorothiazide.

MEDICINAL PRODUCTS USED FOR TREATMENT OF GOUT (e.g., probenecid, sulfinpyrazone, allopurinol)

Dosage 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. When calcium supplements are required, serum calcium levels should be monitored and dosage adjusted accordingly.

β-blockers and diazoxide

The hyperglycemic effect of β-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 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 effect.

Based on pharmacological properties, baclofen and amifostine are expected to enhance the hypotensive effect of all antihypertensive medicinal products, including telmisartan.

Additionally, orthostatic hypotension may be exacerbated by alcohol, barbiturates, narcotics, or antidepressants.

Salicylates

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

Metildopa

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

Cyclosporine

Concomitant use of cyclosporine may enhance hyperuricemia and increase 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.

Iodinated contrast agents

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

Amphotericin B (parenteral), corticosteroids, ACTH, and stimulant laxatives

Hydrochlorothiazide enhances electrolyte imbalance, predominantly hypokalemia.

Special precautions for use.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. For women planning pregnancy, antihypertensive therapy with established safety profiles in pregnancy should be considered instead of angiotensin II receptor antagonists. If pregnancy is diagnosed, angiotensin II receptor antagonists should be discontinued immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Hepatic impairment

Telpros Plus must not be administered to patients with cholestasis, obstructive biliary disorders, or severe hepatic insufficiency, as telmisartan is primarily excreted via bile. Reduced hepatic clearance of telmisartan may be expected in such patients. Additionally, Telpros Plus should be used with caution in patients with impaired liver function or progressive liver disease, since even minor disturbances in fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with the use of Telpros Plus in patients with hepatic insufficiency.

Renovascular hypertension

There is an increased risk of severe arterial hypotension and renal insufficiency in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney when treated with medicinal products affecting the renin-angiotensin-aldosterone system (RAAS).

Renal impairment and kidney transplantation

Telpros Plus should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min). There is no experience with the use of Telpros Plus in patients who have recently undergone kidney transplantation. As experience with Telpros Plus in patients with mild to moderate renal impairment is limited, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended. Azotemia associated with thiazide diuretics may occur in patients with renal impairment.

Reduced intravascular fluid volume

Symptomatic hypotension, particularly after the first dose, may occur in patients with sodium and/or circulating blood volume depletion due to potent diuretic therapy, dietary salt restriction, diarrhea, or vomiting. Therefore, correction of these conditions is recommended prior to initiating Telpros Plus.

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 (including acute renal failure).

Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

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

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

Other conditions associated with RAAS activation

In patients whose vascular tone and renal function depend primarily on RAAS activity (e.g., patients with severe congestive heart failure or renal diseases, including renal artery stenosis), treatment with drugs affecting this system may result in acute arterial hypotension, hyperazotemia, oliguria, and rarely, acute renal failure.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs that act by suppressing the renin-angiotensin system. Therefore, the use of Telpros Plus is not recommended in such patients.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special 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. In patients with diabetes mellitus, dosage adjustment of insulin or oral hypoglycemic agents may be necessary. Latent diabetes mellitus may become manifest during thiazide therapy. Thiazide therapy has been associated with increased cholesterol and triglyceride levels. However, the 12.5 mg dose contained in Telpros Plus has no such effect or only a minimal one. Hyperuricemia or overt gout may develop in some patients receiving thiazide therapy.

Electrolyte imbalance

Serum electrolyte levels should be periodically monitored in any patient receiving diuretic therapy.

Thiazides, including hydrochlorothiazide, may cause fluid or electrolyte imbalance (e.g., hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs of fluid or electrolyte imbalance include dry mouth, thirst, weakness, lethargy, somnolence, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia

Although hypokalemia may develop during treatment with thiazide diuretics, concomitant therapy with telmisartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia is higher in patients with hepatic cirrhosis, those with marked diuresis, those whose oral electrolyte intake does not meet their needs, and those receiving concomitant corticosteroid or ACTH therapy.

Hyperkalemia

Due to angiotensin II receptor antagonism (AT1) associated with telmisartan, a component of Telpros Plus, hyperkalemia may occur. Clinically significant hyperkalemia due to Telpros Plus 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 cautiously when administered concomitantly with the telmisartan/hydrochlorothiazide combination.

Hyponatremia and hypochloremic alkalosis

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

Hypercalcemia

Thiazides may reduce urinary calcium excretion and may cause periodic and slight increases in serum calcium levels in the absence of calcium metabolism disorders. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide therapy should be discontinued prior to testing parathyroid function.

Hypomagnesemia

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

Ethnic differences

Like all other angiotensin II receptor antagonists, telmisartan is less effective in reducing blood pressure in black patients compared to patients of other races. This may be explained by the higher prevalence of low-renin states among black patients with arterial hypertension.

Other conditions

As with any other antihypertensive agents, excessive reduction in blood pressure in patients with ischemic heart disease or ischemic cerebrovascular disease may precipitate myocardial infarction or stroke.

General disorders

Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with a history of allergy or bronchial asthma.

It is known that the use of thiazide diuretics, including hydrochlorothiazide, may exacerbate systemic lupus erythematosus.

Cases of photosensitivity reactions have been observed during treatment with thiazide diuretics. If photosensitivity reactions occur during therapy, drug discontinuation is recommended. If re-administration of the diuretic is considered necessary, protection of exposed skin areas from sunlight or artificial ultraviolet radiation is recommended.

Acute myopia and secondary angle-closure glaucoma

Medicinal products containing sulfonamide or its derivatives may cause idiosyncratic reactions leading to transient myopia and acute angle-closure glaucoma. Hydrochlorothiazide is a sulfonamide derivative, although only isolated cases of acute angle-closure glaucoma associated with hydrochlorothiazide use have been reported. Symptoms include acute decrease in visual acuity or eye pain. These symptoms typically develop within hours to weeks after starting therapy. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Upon occurrence of such symptoms, therapy with this drug should be discontinued immediately. If intraocular pressure remains uncontrolled, pharmacological or surgical treatment should be considered. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (BCC and SCC) with increasing cumulative dose of hydrochlorothiazide was observed in two epidemiological studies. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for the development of these conditions. Patients taking hydrochlorothiazide alone or in combination with other medicinal products should be informed about the risk of non-melanoma skin cancer and advised to regularly check their skin for new lesions or changes in existing lesions and to promptly report any suspicious skin lesions. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy material. Patients should be advised to limit exposure to sunlight and ultraviolet radiation, and to use appropriate protection when exposed to sunlight or UV radiation to minimize skin cancer risk. Additionally, hydrochlorothiazide-containing products should be prescribed cautiously in patients with a history of skin cancer (see also section "Adverse reactions").

Choroidal effusion, acute myopia, 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 sudden onset of decreased visual acuity or eye pain and typically occur within hours to weeks after starting the drug.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is immediate discontinuation of the drug. If intraocular pressure remains uncontrolled, pharmacological or surgical treatment may be necessary. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Acute respiratory toxicity

Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes to hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening pulmonary condition, and hypotension. If ARDS is suspected, Telpros Plus should be discontinued and appropriate treatment initiated.

Hydrochlorothiazide should not be administered to patients who previously experienced ARDS after taking hydrochlorothiazide.

Effect on laboratory test results:

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

Lactose intolerance

The product contains lactose monohydrate. It should not be administered to patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy

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

There are no data on the use of Telpros Plus during pregnancy.

Epidemiological data on teratogenic risk following use of ACE inhibitors in the first trimester are inconclusive; a slight increase in risk cannot be excluded. Women planning pregnancy should be switched to alternative antihypertensive agents with established safety profiles during pregnancy. Angiotensin II receptor antagonists should be discontinued immediately upon confirmation of pregnancy, and alternative therapy initiated if necessary.

Treatment with angiotensin II receptor antagonists during the second and third trimesters of pregnancy causes fetotoxicity in humans (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If angiotensin II receptor antagonists are used from the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull development is recommended. Newborns of mothers who took angiotensin II receptor antagonists should be closely monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use"). Experience with hydrochlorothiazide use during pregnancy, particularly in the first trimester, is limited.

Hydrochlorothiazide crosses the placental barrier. Due to its pharmacological mechanism of action, hydrochlorothiazide 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 or late toxemia due to the risk of reduced plasma volume and placental hypoperfusion without beneficial effect on disease course.

Hydrochlorothiazide should not be used in pregnant women with significant arterial hypertension except in rare cases where alternative treatment is not possible.

Breastfeeding

Due to lack of information on the use of Telpros Plus during breastfeeding, the use of this product during lactation is not recommended. Alternative therapy with agents with better-established safety profiles should be preferred, especially when breastfeeding newborns or preterm infants. Hydrochlorothiazide passes into breast milk in small amounts. High-dose thiazides, causing intense diuresis, may suppress breast milk production. If Telpros Plus is used during breastfeeding, the lowest possible doses should be administered.

Fertility

No effects of telmisartan and hydrochlorothiazide on fertility in men or women have been observed.

Ability to affect reaction speed when driving or operating machinery

Telpros Plus may affect the ability to drive or operate machinery. Dizziness or somnolence may occur during treatment with Telpros Plus.

Dosage and Administration

Adults

Telpres Plus should be administered to patients whose arterial pressure is not adequately controlled with telmisartan alone. Prior to switching to a fixed-dose combination, the dose of each component should be individually determined. Direct substitution of monotherapy with a fixed-dose combination may be considered based on clinical judgment.

Telpres Plus may be prescribed to patients whose arterial pressure is not adequately controlled with either telmisartan or hydrochlorothiazide alone, or to patients who have previously achieved adequate blood pressure control with separate administration of telmisartan and hydrochlorothiazide.

Telpres Plus 40 mg/12.5 mg may be administered once daily to patients whose arterial pressure is not adequately controlled with Telpres 40 mg tablets.

Telpres Plus 80 mg/12.5 mg may be administered once daily to patients whose arterial pressure is not adequately controlled with Telpres 80 mg tablets.

Special Patient Groups

Patients with Renal Impairment

Renal function should be monitored.

Patients with Hepatic Impairment

For patients with mild to moderate hepatic impairment, the daily dose of Telpres Plus should not exceed 40 mg/12.5 mg.

Telpres Plus is contraindicated in patients with severe hepatic impairment. Thiazides should be administered with caution in patients with hepatic impairment.

Elderly Patients

No dose adjustment is required for elderly patients.

Administration

Telpres Plus tablets should be taken orally once daily with liquid, regardless of food intake.

Safety Measures Prior to Administration

Telpres Plus should be stored in a tightly sealed blister pack, as the tablets are highly hygroscopic. Tablets should be removed from the blister immediately before use.

Children

The safety and efficacy of Telpres Plus in children (under 18 years of age) have not been established; therefore, the drug should not be administered to this patient group.

Overdose

Information regarding telmisartan overdose in humans is limited. The extent to which hydrochlorothiazide can be removed by hemodialysis is not established.

Symptoms

The most prominent manifestations of telmisartan overdose were arterial hypotension and tachycardia. Bradycardia, dizziness, vomiting, increased serum creatinine levels, and acute renal failure have also been reported. Hydrochlorothiazide overdose is associated with electrolyte depletion (hypokalemia, hypochloremia) and hypovolemia due to excessive diuresis. The most common symptoms of overdose include nausea and somnolence. Hypokalemia may lead to muscle cramps and/or exacerbation of cardiac arrhythmias, particularly in patients concurrently receiving digitalis glycosides or certain antiarrhythmic agents.

Treatment

Telmisartan is not removed by hemodialysis. Patients should be closely monitored and receive symptomatic and supportive treatment. Management depends on the time elapsed since drug ingestion and the severity of symptoms. Recommended measures include induction of emesis and/or gastric lavage. Activated charcoal may be used in the management of overdose. Serum electrolyte and creatinine levels should be monitored. In cases of arterial hypotension, the patient should be placed in a supine position and treated with rapid volume and salt repletion.

Adverse Reactions

The most commonly reported adverse effect was dizziness. Serious angioedema has been reported rarely (≥1/10,000 to < 1/1,000).

Fixed-dose combination

A dose-dependent relationship for adverse effects has not been established, and these effects were not related to sex, age, or race.

Adverse reactions reported during all clinical trials and occurring more frequently (p ≤ 0.05) with telmisartan/hydrochlorothiazide combination than with placebo are listed below by system organ classes. Adverse reactions observed with each individual component but not reported during clinical trials of the combination may occur during treatment with Telpres Plus.

Adverse reactions are categorized by frequency as follows: very common (≥1/10); common (≥1/100 to < 1/10); uncommon (≥1/1,000 to < 1/100); rare (≥1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

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

Infections and infestations: rare – bronchitis, pharyngitis, sinusitis.

Immune system disorders: rare – exacerbation or activation of systemic lupus erythematosus.

Metabolism and nutrition disorders: uncommon – hypokalaemia; rare – hyperuricaemia, hyponatraemia.

Psychiatric disorders: uncommon – anxiety; rare – depression.

Nervous system disorders: common – dizziness; uncommon – syncope, paraesthesia; rare – insomnia, sleep disturbances.

Eye disorders: rare – visual disturbance, transient blurred vision.

Ear and labyrinth disorders: uncommon – vertigo.

Cardiac disorders: uncommon – tachycardia, arrhythmia.

Vascular disorders: uncommon – arterial hypotension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnoea; very rare – acute respiratory distress syndrome (ARDS) (including pneumonitis and pulmonary oedema) (see section "Special warnings and precautions for use").

Gastrointestinal disorders: uncommon – diarrhoea, dry mouth, flatulence; rare – abdominal pain, constipation, dyspepsia, vomiting, gastritis.

Hepatobiliary disorders: rare – liver function abnormalities/liver disease.

Skin and subcutaneous tissue disorders: rare – angioedema (including fatal cases), erythema, pruritus, rash, hyperhidrosis, urticaria.

Musculoskeletal and connective tissue disorders: uncommon – back pain, muscle spasms, myalgia; rare – arthralgia, calf muscle cramps, leg pain.

Reproductive system and breast disorders: uncommon – erectile dysfunction.

General disorders and administration site conditions: uncommon – chest pain; rare – influenza-like symptoms, pain.

Investigations: uncommon – increased blood uric acid; rare – increased creatinine, increased blood creatine phosphokinase, increased liver enzymes.

Additional information on individual components.

Adverse reactions previously reported with either component may occur with the telmisartan/hydrochlorothiazide combination, even if not observed during clinical trials of this combination.

Telmisartan

Adverse effects occurred with similar frequency during telmisartan and placebo treatment.

The overall incidence of adverse events with telmisartan (41.4%) was generally comparable to that in the placebo group (43.9%) in placebo-controlled trials. The adverse reactions listed below were collected from studies in patients treated with telmisartan for arterial hypertension and in patients aged 50 years and older at high cardiovascular risk.

Infections and infestations: uncommon – upper respiratory tract infections, urinary tract infections including cystitis; rare – sepsis, including fatal cases.

Blood and lymphatic system disorders: uncommon – anaemia; rare – eosinophilia, thrombocytopenia.

Immune system disorders: rare – hypersensitivity, anaphylactic reactions.

Metabolism and nutrition disorders: uncommon – hyperkalaemia; rare – hypoglycaemia (in diabetic patients).

Cardiac disorders: uncommon – bradycardia.

Nervous system disorders: frequency not known – somnolence.

Respiratory, thoracic and mediastinal disorders: uncommon – cough; rare – interstitial lung disease.

Gastrointestinal disorders: rare – gastric discomfort.

Skin and subcutaneous tissue disorders: rare – eczema, drug eruption, toxic dermatitis.

Musculoskeletal and connective tissue disorders: rare – arthrosis, tendon pain.

Renal and urinary disorders: uncommon – renal failure (including acute renal failure).

General disorders and administration site conditions: uncommon – asthenia.

Investigations: rare – decreased haemoglobin.

Hydrochlorothiazide

Hydrochlorothiazide may cause or worsen hypovolaemia, which may lead to electrolyte imbalance (see section "Special warnings and precautions for use").

Adverse reactions observed with hydrochlorothiazide when used alone are listed below.

Infections and infestations: frequency not known – sialadenitis.

Blood and lymphatic system disorders: rare – thrombocytopenia (sometimes with purpura); frequency not known – aplastic anaemia, haemolytic anaemia, bone marrow suppression, leucopenia, neutropenia, agranulocytosis.

Immune system disorders: frequency not known – anaphylactic reactions, anaphylactic shock, hypersensitivity.

Endocrine disorders: frequency not known – inadequate control of diabetes.

Metabolism and nutrition disorders: common – hypomagnesaemia; rare – hypercalcaemia; very rare – hypochloraemic alkalosis; frequency not known – anorexia, loss of appetite, electrolyte imbalance, hypercholesterolaemia, hyperglycaemia, hypovolaemia, hyperuricaemia (which may provoke gout attacks in patients with asymptomatic disease).

Psychiatric disorders: frequency not known – restlessness, disorientation, somnolence, nervousness, mood changes.

Nervous system disorders: rare – headache; frequency not known – mild dizziness, confusion, convulsions.

Eye disorders: frequency not known – xanthopsia, acute myopia, acute angle-closure glaucoma, choroidal effusion.

Vascular disorders: frequency not known – necrotizing vasculitis.

Gastrointestinal disorders: common – nausea; frequency not known – pancreatitis, gastric discomfort, thirst, nausea.

Hepatobiliary disorders: frequency not known – hepatocellular jaundice, cholestatic jaundice, cholecystitis.

Skin and subcutaneous tissue disorders: frequency not known – lupus-like syndrome, photosensitivity reactions, skin vasculitis, toxic epidermal necrolysis, purpura, Stevens-Johnson syndrome, erythema multiforme.

Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency not known – non-melanoma skin cancer (BCC and SCC) associated with hydrochlorothiazide exposure.

Musculoskeletal and connective tissue disorders: frequency not known – weakness.

Renal and urinary disorders: frequency not known – interstitial nephritis, renal dysfunction, glucosuria, renal failure.

Reproductive system and breast disorders: frequency not known – sexual dysfunction.

General disorders and administration site conditions: frequency not known – malaise.

Investigations: frequency not known – increased triglycerides.

Description of selected adverse reactions

Liver function abnormalities/liver disease

Most cases of liver function abnormalities/liver disease were observed in patients of Japanese nationality. Japanese patients are more susceptible to these adverse reactions.

Sepsis

In the PRoFESS study, a higher incidence of sepsis was observed in patients receiving telmisartan compared to those receiving placebo. This finding may be due to chance or to an unknown mechanism.

Interstitial lung disease

Cases of interstitial lung disease associated with telmisartan have been reported. However, a causal relationship has not been established.

Description of selected adverse reactions: non-melanoma skin cancer for the active substance hydrochlorothiazide: based on available epidemiological data, there is a cumulative dose-dependent association between hydrochlorothiazide and the occurrence of non-melanoma skin cancer (see also sections "Pharmacological properties" and "Special warnings and precautions for use").

Shelf life. 3 years.

Storage conditions.

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

Packaging.

14 tablets in a blister; 2 or 7 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LABORATORIOS LICONSA, S.A.

Manufacturer's address and place of business.

Avda. Miralcampo, 7, Pol. Ind. Miralcampo, Azuqueca de Henares, Guadalajara, 19200, Spain.