Telmiста h 80: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TELMISTA® H 40 TELMISTA® H 80 TELMISTA® HD 80 (TELMISTA® H 40 TELMISTA® H 80 TELMISTA® HD 80)

Composition:

Active substances: telmisartan, hydrochlorothiazide;

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

Excipients: meglumine, sodium hydroxide, povidone, lactose monohydrate, sorbitol (E 420), magnesium stearate, mannitol (E 421), mannitol DC (E 421), hydroxypropylcellulose, colloidal anhydrous silicon dioxide, sodium stearyl fumarate, iron oxide red (E 172) – for TELMISTA® H 40 and TELMISTA® H 80 tablets; iron oxide yellow (E 172) – for TELMISTA® HD 80 tablets.

Pharmaceutical form. Tablets.

Main physicochemical properties:

TELMISTA® H 40: two-layer, biconvex, oval tablets, white to almost white or pink-white on one side and pink marbled on the other side.

TELMISTA® H 80: two-layer, biconvex, oval tablets, white to almost white or pink-white on one side and pink marbled on the other side.

TELMISTA® HD 80: two-layer, biconvex, oval tablets, white to yellowish-white on one side and yellow marbled on the other side.

Pharmacotherapeutic group. Angiotensin II antagonists and diuretics. ATC code C09DA07.

Pharmacological Properties

Pharmacodynamics

The fixed combination of telmisartan/hydrochlorothiazide is a combination of the angiotensin II receptor antagonist telmisartan and the thiazide diuretic hydrochlorothiazide. The combination of these components provides an additive antihypertensive effect, reducing arterial pressure to a greater extent than either component alone. Telmisartan/hydrochlorothiazide, when administered once daily within the therapeutic dose range, results in effective and gradual reduction of arterial pressure.

Mechanism of Action

Telmisartan is effective when administered orally and is a specific antagonist of angiotensin II receptors (AT1 subtype). With very high affinity for this receptor subtype, telmisartan displaces angiotensin II from its binding sites on AT1 receptors. It does not exhibit any partial agonistic activity on AT1 receptors. Telmisartan selectively binds to AT1 receptors, and this binding is long-lasting. Telmisartan has no affinity for other receptors, including AT2 and other less-characterized AT receptors. The functional role of these receptors is unknown, as is the potential effect of their possible "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 (ACE) (kinase II), the enzyme that also degrades bradykinin. Therefore, potentiation of bradykinin-mediated adverse effects is not expected.

At a dose of 80 mg, the drug almost completely suppresses the hypertensive effect of angiotensin II in humans. The drug's effect lasts more than 24 hours and can be observed up to 48 hours.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully understood. Thiazide diuretics affect the electrolyte reabsorption mechanism 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, through blockade of the renin-angiotensin-aldosterone system (RAAS), concomitant use of telmisartan may counteract the potassium loss associated with these diuretics. After administration of hydrochlorothiazide, diuresis begins within 2 hours, maximum effect is reached approximately within 4 hours, and the duration of action lasts about 6–12 hours.

Clinical Efficacy and Safety

After administration of the first dose of telmisartan, antihypertensive activity gradually develops over 3 hours. Maximum reduction in arterial pressure is observed within 4–8 weeks after initiation of treatment and is maintained during long-term therapy. The antihypertensive effect remains stable over 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 ratio of trough to peak values exceeds 80% after doses of 40 and 80 mg 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 drugs (demonstrated in clinical trials comparing telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide, losartan, and lisinopril).

Upon abrupt discontinuation of telmisartan therapy, arterial pressure gradually returns to pre-treatment levels over several days, with no evidence of a withdrawal syndrome.

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

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 disease is unknown.

Non-melanoma skin cancer (NMSC)

Available data from epidemiological studies have demonstrated an association between cumulative hydrochlorothiazide dose and NMSC.

Pharmacokinetics

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

Absorption

Telmisartan. After oral administration, maximum plasma concentration (Cmax) 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, with a decrease in the area under the concentration-time curve (AUC) ranging from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). Three hours after administration, plasma concentrations are equivalent regardless of whether telmisartan is taken with or without food. The slight reduction in AUC is not considered to result in reduced therapeutic efficacy. Telmisartan does not significantly accumulate in plasma with repeated dosing.

Hydrochlorothiazide. After oral administration of the telmisartan/hydrochlorothiazide combination, Cmax of hydrochlorothiazide is reached within 1–3 hours. Due to cumulative renal excretion, the absolute bioavailability of hydrochlorothiazide 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 is approximately 500 L, indicating extensive tissue binding.

Hydrochlorothiazide. Hydrochlorothiazide is protein-bound in plasma by 68%, with a volume of distribution of 0.83–1.14 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 telmisartan metabolism.

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. The terminal elimination half-life is more than 20 hours.

Hydrochlorothiazide is excreted almost entirely unchanged in urine. Approximately 60% of an oral dose is excreted unchanged 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 non-linear in the dose range of 20–160 mg, with greater-than-proportional increases in plasma concentrations (Cmax and AUC) as dose increases.

Hydrochlorothiazide exhibits linear pharmacokinetics.

Special Patient Populations

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

Gender. 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 in the incidence of orthostatic hypotension in women. Dose adjustment is not required. Women tend to have higher hydrochlorothiazide concentrations than men, but this has no clinical significance.

Patients with renal impairment. Renal excretion does not affect the elimination of telmisartan. Based on limited experience in patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min, average 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, in patients with a mean creatinine clearance of 90 mL/min, the half-life of hydrochlorothiazide increases. In patients with absent or non-functioning kidneys, the half-life is approximately 34 hours.

Patients with hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment have shown an increase in absolute bioavailability of nearly 100%. The elimination half-life in these patients is unchanged.

Clinical characteristics.

Indications.

Arterial hypertension.

The medicinal product Telmista H 40 or Telmista H 80, tablets in fixed-dose combination (40 mg or 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.

The medicinal product Telmista HD 80 (80 mg telmisartan/25 mg hydrochlorothiazide) is indicated for use in adult patients when treatment with Telmista H 80 (80 mg telmisartan/12.5 mg hydrochlorothiazide) does not provide adequate blood pressure control, or in adult patients whose blood pressure has previously been stabilized with separate administration of telmisartan and hydrochlorothiazide.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Hypersensitivity to other sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative).
Pregnancy and planned pregnancy (see sections "Special precautions for use" and "Use in pregnancy or lactation").
Cholestatic and biliary obstructive disorders.
Severe hepatic impairment.
Anuria, severe renal impairment (creatinine clearance < 30 mL/min).
Refractory hypokalaemia/hyponatraemia, hypercalcaemia.
Lactation period.
Symptomatic hyperuricaemia (gout).
Paediatric population (under 18 years of age).

Concomitant use of telmisartan/hydrochlorothiazide with aliskiren 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 "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Lithium. Reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and angiotensin-converting enzyme (ACE) inhibitors. Rare cases of such interactions have also been reported with angiotensin II receptor antagonists (including telmisartan/hydrochlorothiazide). Concomitant use of lithium and Telmista H or Telmista HD is not recommended (see section "Special precautions for use"). If combination therapy is proven effective, careful monitoring of serum lithium levels is recommended.

Medicinal products associated with potassium depletion and hypokalaemia (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 hydrochlorothiazide/telmisartan combination, monitoring of plasma potassium levels is recommended. These medicinal products may potentiate the effect of hydrochlorothiazide on plasma potassium levels (see section "Special precautions for use").

Medicinal products that may increase sodium levels and cause hyperkalaemia (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 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 medicinal products may lead to increased serum potassium levels; therefore, such combination is not recommended (see section "Special precautions for use").

Medicinal products causing disturbances in serum potassium levels. Periodic monitoring of serum potassium levels and ECG monitoring are recommended when Telmista H or Telmista HD 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 arrhythmias (including certain antiarrhythmics), with hypokalaemia being a triggering factor for ventricular arrhythmias:

Class Ia antiarrhythmic medicinal products (e.g., quinidine, hydroquinidine, disopyramide);
Class III antiarrhythmic medicinal products (e.g., amiodarone, sotalol, dofetilide, ibutilide);
Certain antipsychotics (e.g., thioridazine, chlorpromazine, levopromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
Others (e.g., bepridil, cisapride, difemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vinca alkaloids IV).

Digoxin glycosides. Hypokalaemia or hypomagnesaemia induced by thiazides may lead to digoxin-induced cardiac arrhythmias (see section "Special precautions for use").

Digoxin. Increased mean maximum (49%) and minimum (20%) plasma concentrations of digoxin have been observed during concomitant administration with telmisartan. Monitoring of digoxin levels is necessary at the initiation of telmisartan therapy, during dose adjustments, and upon discontinuation to maintain levels within the therapeutic range.

Other antihypertensive medicinal products. Telmisartan may enhance the hypotensive effect of other antihypertensive medicinal products.

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

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

Metformin. Metformin should be used with caution due to the risk of lactic acidosis when used concomitantly with hydrochlorothiazide.

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

Non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs (acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, non-selective NSAIDs) may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics and 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 in renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be used with caution, especially in elderly patients. Adequate hydration should be ensured after initiation of combination therapy, and renal function should be monitored carefully and periodically.

In one study, concomitant administration of telmisartan and ramipril resulted in a 2.5-fold increase in AUC 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 potentiated by hydrochlorothiazide.

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

Beta-blockers and diazoxide. The hyperglycaemic effect 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 amantadine-related adverse effects.

Cytotoxic medicinal products (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 enhance the hypotensive effect of all antihypertensive medicinal products, including telmisartan. In addition, orthostatic hypotension may be potentiated 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.

Methyldopa. Isolated cases of haemolytic anaemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.

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

Effect of medicinal products on laboratory test results. Due to effects on calcium metabolism, thiazides may affect 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 hyponatraemia.

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 require rehydration prior to administration of iodinated contrast agents.

Amphotericin B (for parenteral use), corticosteroids, ACTH, and stimulant laxatives. Hydrochlorothiazide may exacerbate electrolyte imbalances, predominantly hypokalaemia.

Special precautions for use.

Pregnancy. It is contraindicated to initiate therapy with angiotensin II receptor antagonists during pregnancy. Patients planning pregnancy should be switched to alternative antihypertensive agents with an established safety profile during pregnancy. Angiotensin II receptor antagonists should be discontinued immediately upon confirmation of pregnancy, and alternative therapy should be initiated if necessary (see sections "Contraindications" and "Use in pregnancy or lactation").

Liver dysfunction. Telmista H, Telmista HD should not be prescribed to patients with cholestasis, biliary obstructive disorders, or severe hepatic insufficiency (see section "Contraindications"), as telmisartan is primarily excreted via bile. Hepatic clearance of telmisartan is expected to be reduced in these patients. Telmista H, Telmista HD should be used with caution in patients with impaired liver function or progressive liver disease, as this medication may cause intrahepatic cholestasis, and even minor changes in fluid and electrolyte balance may lead to hepatic coma. There is no clinical experience with the use of telmisartan/hydrochlorothiazide in patients with hepatic insufficiency.

Renal hypertension. There is an increased risk of severe arterial hypotension and renal failure when drugs affecting the RAAS are administered to patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney.

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

Reduced intravascular fluid volume. 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. Such conditions should be corrected before initiating Telmista H, Telmista HD.

Dual blockade of the RAAS.

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

Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").

If dual blockade is considered absolutely necessary, it should be performed only under specialist supervision and 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 requiring RAAS stimulation. In patients whose vascular tone and renal function primarily depend on RAAS activity (e.g., patients with congestive heart failure or significant renal disease, including renal artery stenosis), use of other drugs affecting the RAAS may be associated with acute arterial hypotension, hyperazotemia, oliguria, and 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, use of this medicinal product 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, while hypoglycemia may occur in diabetic patients receiving insulin or antidiabetic therapy and taking telmisartan. Therefore, blood glucose levels should be monitored in these patients; dose adjustment of insulin or hypoglycemic agents may be necessary. Latent diabetes mellitus may be unmasked during thiazide therapy. Increased cholesterol and triglyceride levels are associated with thiazide diuretic therapy; however, minimal or no increase in cholesterol and triglyceride levels has been observed with the use of formulations containing 12.5 mg hydrochlorothiazide. Hyperuricemia or overt gout may occur in some patients receiving thiazide therapy.

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

Hypokalemia. Although hypokalemia may occur with thiazide diuretics, concomitant therapy with telmisartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with liver cirrhosis, those with significant diuresis, those receiving inadequate oral electrolyte supplementation, and those receiving concomitant therapy with corticosteroids or ACTH (see section "Interaction with other medicinal products and other forms of interaction").
Hyperkalemia. Conversely, due to angiotensin II receptor (AT1) antagonism caused by telmisartan – a component of Telmista H, Telmista HD – hyperkalemia may occur. However, clinically significant hyperkalemia due to Telmista H, Telmista HD has not been documented. Risk factors for hyperkalemia include renal insufficiency 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 Telmista H, Telmista HD (see section "Interaction with other medicinal products and other forms of interaction").
Hyponatremia and hypochloremic alkalosis. There is no evidence that Telmista H, Telmista HD reduces diuretic-induced hyponatremia or prevents its occurrence. Chloride deficiency is generally mild and usually does not require treatment.
Hypercalcemia. Thiazides may reduce urinary calcium excretion and cause transient and slight elevation of serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before parathyroid function testing.
Hypomagnesemia. Thiazides have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see section "Interaction with other medicinal products and other forms of interaction").

Sorbitol and lactose monohydrate. The medicinal product contains lactose monohydrate and sorbitol; therefore, it should not be administered to patients with hereditary fructose intolerance and/or hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Race. As with other angiotensin II receptor antagonists, telmisartan is likely less effective in reducing blood pressure in black patients, presumably due to the prevalent low-renin state in this population of hypertensive patients.

Other. As with any other antihypertensive agent, significant 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 are more likely in patients with a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus (SLE) has been observed with thiazide diuretics, including hydrochlorothiazide.

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

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Hydrochlorothiazide, like sulfonamides, 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 several weeks after initiation of treatment. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Treatment with hydrochlorothiazide should be discontinued as soon as possible. Immediate medical, including surgical, treatment may be necessary 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 (NMSC)

In two epidemiological studies based on the Danish National Cancer Registry, an increased risk of NMSC (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) was observed with increasing cumulative dose of hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may be a mechanism in the development of NMSC.

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. The use of hydrochlorothiazide should also be reconsidered in patients with a history of previous NMSC (see section "Adverse reactions").

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 or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening pulmonary function, and hypotension. If ARDS is suspected, telmisartan/hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after taking hydrochlorothiazide.

The drug may affect results of certain laboratory tests:

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

Use during pregnancy or lactation.

Pregnancy

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

There are no data on the use of the combination of telmisartan/hydrochlorothiazide in pregnant women.

Epidemiological evidence regarding teratogenic risk after use of ACE inhibitors during the first trimester of pregnancy is inconclusive, although a slight increase in risk cannot be excluded.

Treatment with angiotensin II receptor antagonists during the second and third trimesters of pregnancy causes fetal toxicity 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 condition is recommended. Newborns whose mothers received angiotensin II receptor antagonists should be closely monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use"). Limited experience exists with the use of hydrochlorothiazide during pregnancy, especially in the first trimester.

Hydrochlorothiazide crosses the placental barrier. Due to the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters may disrupt fetoplacental perfusion and lead to the following intrauterine and neonatal effects: jaundice, electrolyte imbalance in the fetus, 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 positive effect on disease course.

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

Lactation period

As there is no information on the use of Telmista H, Telmista HD during breastfeeding, the drug is contraindicated during lactation; alternative therapy with drugs with a better-established safety profile should be preferred, especially when breastfeeding newborns or preterm infants.

Hydrochlorothiazide is excreted in breast milk in small amounts. Thiazides in high doses, causing intense diuresis, may suppress breast milk production.

Fertility

Preclinical studies did not reveal effects of telmisartan and hydrochlorothiazide on fertility in males or females.

Ability to affect reaction speed when driving or operating machinery.

Telista H, Telmista HD may affect the ability to drive or operate machinery, as dizziness or somnolence may rarely occur during treatment.

Method of Administration and Dosage

Dosage

Telzita H and Telzita HD are prescribed to patients whose blood pressure is not adequately controlled with telmisartan monotherapy. Before switching to treatment with Telzita H or Telzita HD, the dose of each component should be determined. Direct substitution of monotherapy with fixed-dose combinations may be considered.

Telzita H 40 may be prescribed once daily to patients whose blood pressure is not adequately controlled with 40 mg telmisartan tablets.
Telzita H 80 may be prescribed once daily to patients whose blood pressure is not adequately controlled with 80 mg telmisartan tablets.
Telzita HD 80 may be prescribed once daily to patients whose blood pressure is not adequately controlled with Telzita H 80, or to patients whose blood pressure was previously stabilized with separate administration of telmisartan and hydrochlorothiazide.

Renal impairment. Periodic monitoring of renal function is recommended (see section "Special Warnings and Precautions for Use").

Hepatic impairment. In patients with mild to moderate hepatic impairment, the daily dose should not exceed 40 mg/12.5 mg. Telzita H and Telzita HD are contraindicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with hepatic impairment (see section "Special Warnings and Precautions for Use").

Elderly patients. Dose adjustment is not required in elderly patients.

Method of administration.

Telzita H and Telzita HD should be taken orally once daily with liquid, regardless of food intake.

Children.

The safety and efficacy of Telzita H and Telzita HD in children (under 18 years of age) have not been established. Data are lacking.

Overdose.

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

Symptoms. The most likely expected manifestations of telmisartan overdose are arterial hypotension and tachycardia; bradycardia, dizziness, vomiting, elevated serum creatinine, and acute renal failure have also been observed. Hydrochlorothiazide overdose is associated with electrolyte depletion (hypokalemia, hypochloremia) and dehydration due to excessive diuresis. The most common signs and symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of cardiac arrhythmias, particularly in patients receiving digitalis or certain antiarrhythmic drugs.

Treatment. Telmisartan is not removed by hemodialysis. Careful monitoring of the patient is required. Management 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. Electrolyte levels and creatinine should be monitored. In case of arterial hypotension, the patient should be placed in a supine position and treated with saline and volume-expanding solutions.

Adverse Reactions.

Safety profile overview. The commonly observed adverse reaction was dizziness. Severe angioedema may occur rarely (≥1/10,000 – < 1/1,000).

The frequency and nature of adverse reaction reports for Telmista H 80 can be compared to those for Telmista HD 80. The number of adverse reactions is not dose-dependent and has no association with patient gender, age, or race.

Description of adverse reactions

Below are adverse reactions identified during clinical trials of the telmisartan/hydrochlorothiazide combination, listed by system organ class, which occurred more frequently than with placebo. Adverse reactions not observed during clinical studies but expected during treatment with Telmista H and Telmista HD, based on experience with telmisartan or hydrochlorothiazide used separately, are also listed below in separate subsections.

Adverse reactions are categorized by frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data). Adverse reactions are listed in decreasing order of severity.

Infections and infestations:

rare – bronchitis, pharyngitis, sinusitis.

Immune system disorders:

rare – exacerbation or activation of SLE¹.

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 disorders.

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;

rare – respiratory distress syndrome (including pneumonitis and pulmonary oedema).

Gastrointestinal disorders:

uncommon – diarrhoea, dry mouth, flatulence;

rare – abdominal pain, constipation, dyspepsia, vomiting, gastritis.

Hepatobiliary disorders:

rare – liver function disorders/liver disorders².

Skin and subcutaneous tissue disorders:

rare – angioedema (including fatal cases), erythema, pruritus, rash, increased sweating, urticaria.

Musculoskeletal and connective tissue disorders:

uncommon – back pain, muscle cramps, myalgia;

rare – arthralgia, calf muscle cramps, leg pain.

Reproductive system and breast disorders:

uncommon – impotence.

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.

¹ Based on post-marketing surveillance.

² See section "Adverse Reactions. Description of selected adverse reactions".

Additional information on individual components.

Adverse reactions observed with individual components may be potential adverse reactions during treatment with Telmista H and Telmista HD, even if not observed in clinical trials.

Telmisartan

Adverse reactions occurred with similar frequency in patients receiving placebo and telmisartan. Below are additional adverse reactions reported during clinical studies of telmisartan monotherapy in patients with arterial hypertension or 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 cases³.

Blood and lymphatic system disorders:

uncommon – anaemia;

rare – eosinophilia, thrombocytopenia.

Immune system disorders:

rare – hypersensitivity, anaphylactic reactions.

Metabolism and nutrition disorders:

uncommon – hyperkalaemia;

rare – hypokalaemia (in diabetic patients).

Cardiac disorders:

uncommon – bradycardia.

Nervous system disorders:

frequency not known – somnolence.

Respiratory, thoracic and mediastinal disorders:

uncommon – cough;

very rare – interstitial lung disease³.

Gastrointestinal disorders:

rare – gastric discomfort.

Skin and subcutaneous tissue disorders:

rare – eczema, drug dermatitis, 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 levels.

³ See section "Adverse Reactions. Description of selected adverse reactions".

Hydrochlorothiazide

Hydrochlorothiazide may cause or exacerbate hypovolaemia, which may lead to electrolyte imbalance (see section "Special precautions").

Below are adverse reactions occurring with unknown frequency during monotherapy with hydrochlorothiazide.

Infections and infestations:

frequency not known – sialadenitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps):

frequency not known – NMSC (BCC and SCC).

Blood and lymphatic system disorders:

rare – thrombocytopenia (sometimes with purpura);

frequency not known – aplastic anaemia, haemolytic anaemia, bone marrow suppression, leukopenia, neutropenia, agranulocytosis, thrombocytopenia.

Immune system disorders:

frequency not known – anaphylactic reactions, anaphylactic shock, hypersensitivity.

Endocrine disorders:

frequency not known – loss of diabetes control, decreased glucose tolerance, which may lead to manifestation of latent diabetes mellitus.

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, convulsions, confusion.

Eye disorders:

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

Vascular disorders:

frequency not known – necrotizing vasculitis.

Respiratory, thoracic and mediastinal disorders:

very rare – acute respiratory distress syndrome (ARDS) (see section "Special precautions").

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, Stevens-Johnson syndrome, erythema multiforme, purpura.

Musculoskeletal and connective tissue disorders:

frequency not known – weakness.

Renal and urinary disorders:

frequency not known – interstitial nephritis, impaired renal function, glucosuria, renal failure.

Reproductive system and breast disorders:

frequency not known – sexual dysfunction.

General disorders and administration site conditions:

frequency not known – dehydration.

Investigations:

frequency not known – increased triglyceride levels.

Description of selected adverse reactions.

Liver function disorders/liver disorders. Most cases of liver function disorders/liver 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. During a clinical study, a higher incidence of sepsis was observed in patients receiving telmisartan compared to those receiving placebo. This may be due to chance or may indicate an unknown underlying process.

Interstitial lung disease. Cases of interstitial lung disease 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 epidemiological data, a cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed (see sections "Pharmacodynamics" and "Special precautions").

Reporting suspected adverse reactions. Reporting suspected adverse reactions after medicine authorization is important. This allows continued monitoring of the benefit-risk ratio. Healthcare professionals should report suspected adverse reactions in accordance with national regulatory requirements.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30°C, in the original packaging to protect from light.

Keep out of reach and sight of children.

Packaging.

7 tablets per blister; 2, 4, 8, 12, or 14 blisters per cardboard box.

10 tablets per blister; 3, 6, 9, or 10 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of manufacturing site.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.