Telmilax plus: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TELMILAX PLUS (Telmilax plus)

Composition:

Active substances: telmisartan, hydrochlorothiazide;

1 tablet contains telmisartan 40.0 mg and hydrochlorothiazide 12.5 mg, or telmisartan 80.0 mg and hydrochlorothiazide 25.0 mg, or telmisartan 80.0 mg and hydrochlorothiazide 12.5 mg;

Excipients:

excipients of the telmisartan layer: mannite (E 421), povidone (K 25), crospovidone, magnesium stearate, meglumine, sodium hydroxide;

excipients of the hydrochlorothiazide layer: lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate (type A), magnesium stearate, iron oxide yellow (E 172) (for tablets with dosage 40 mg/12.5 mg and 80 mg/25 mg), or iron oxide red (E 172) (for tablets with dosage 80 mg/12.5 mg).

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets 40 mg/12.5 mg: bilayer tablets of round shape with white and yellow layers;

tablets 80 mg/25 mg: bilayer tablets of round shape with white and yellow layers;

tablets 80 mg/12.5 mg: bilayer tablets of round shape with white and pink layers.

Pharmacotherapeutic group.

Angiotensin II antagonists and diuretics. ATC code C09DA07.

Pharmacological properties.

Pharmacodynamics.

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

Mechanism of action

Telmsartan is effective when administered orally and is a specific antagonist of angiotensin II receptors, subtype 1 (AT1). With very high affinity for these receptor subtypes, telmisartan displaces angiotensin II from its binding to AT1 receptors. It has no partial agonistic activity on AT1 receptors. Telmisartan selectively binds to AT1 receptors, and this binding is long-lasting. Telmisartan shows no affinity for other receptors, including AT2 receptors and other less-characterized AT receptors. The functional role of these receptors is unknown, as is the effect of their possible excessive stimulation by angiotensin II, whose levels are increased by 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 (kininase II), the enzyme that also degrades bradykinin. Therefore, potentiation of bradykinin-mediated adverse reactions is not expected.

The drug at a dose of 80 mg almost completely suppresses the hypertensive effect of angiotensin II in humans. The 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, due to blockade of the renin-angiotensin-aldosterone system (RAAS), the concomitant use of telmisartan counteracts the potassium loss associated with these diuretics. After administration of hydrochlorothiazide, diuresis begins within 2 hours, maximum effect is achieved approximately 4 hours after administration, while the duration of action lasts about 6–12 hours.

Pharmacodynamic effects

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

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

Upon abrupt discontinuation of telmisartan treatment, blood pressure gradually returns to pre-treatment levels over several days without signs of rebound hypertension.

The incidence of dry cough was significantly lower in patients treated with telmisartan compared to those receiving angiotensin-converting enzyme (ACE) inhibitors in clinical trials directly comparing the two antihypertensive drugs.

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

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

Non-melanoma skin cancer

Based on available data from epidemiological studies, there is a cumulative dose-dependent association between hydrochlorothiazide and the development of non-melanoma skin cancer.

One study included a population of 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), compared with 1,430,833 and 172,462 control population patients, respectively. High cumulative use of hydrochlorothiazide (≥ 50,000 mg total) was associated with an adjusted hazard ratio (HR) 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 cumulative dose-effect relationship was observed for both BCC and SCC.

Another study showed a possible association between lip cancer (SCC) and hydrochlorothiazide use: 633 patients with lip cancer (SCC) were compared with 63,067 control population patients using a random sampling strategy. A cumulative dose-effect relationship was demonstrated with an adjusted HR of 2.1 (95% CI: 1.7–2.6) at overall use, increasing to HR 3.9 (3.0–4.9) at high use (~25,000 mg) and HR 7.7 (5.7–10.5) at the highest cumulative dose (~100,000 mg) (see also section "Special precautions for use").

Pharmacokinetics.

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

Absorption

Telmsartan. After oral administration, maximum 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 telmisartan bioavailability. The reduction in area under the concentration-time curve (AUC) for telmisartan ranges from approximately 6% (40 mg dose) to about 19% (160 mg dose). Three hours after administration, plasma concentration is similar regardless of whether telmisartan is taken fasting or with food. The slight reduction in AUC is considered not to result in decreased therapeutic efficacy. Telmisartan does not significantly accumulate in plasma with repeated dosing.

Hydrochlorothiazide. After oral administration of Telmilax Plus, maximum concentration of hydrochlorothiazide is reached within 1–3 hours. Due to cumulative renal excretion of hydrochlorothiazide, absolute bioavailability is approximately 60%.

Distribution

Telmsartan. 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%, and its volume of distribution is 0.83–1.14 L/kg.

Biotransformation

Telmsartan 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

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

Telmsartan. The pharmacokinetics of oral telmisartan are non-linear when the dose is increased from 20 mg to 160 mg, with plasma concentrations (Cmax and AUC) increasing disproportionately.

Hydrochlorothiazide exhibits linear pharmacokinetics.

Special patient populations

Elderly patients. The pharmacokinetics of telmisartan do not differ between elderly patients and patients 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 clinically significant increase in blood pressure reduction or 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 telmisartan elimination. Based on limited experience in patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min, average nearly 50 mL/min), dose adjustment is not necessary. Telmisartan is not removed by hemodialysis. In patients with renal insufficiency, the elimination rate of hydrochlorothiazide is reduced. In typical studies, in patients with mean creatinine clearance of 90 mL/min, the elimination half-life of hydrochlorothiazide increases. In patients with a single functioning kidney, the half-life is approximately 34 hours.

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

Clinical characteristics.

Indications.

Arterial hypertension.

Telmilax Plus, tablets, in fixed-dose combination (40 mg or 80 mg telmisartan/12.5 mg hydrochlorothiazide) is indicated for use in adult patients when telmisartan monotherapy does not provide adequate blood pressure control.

Telmilax Plus, tablets, in fixed-dose combination (80 mg telmisartan/25 mg hydrochlorothiazide) is indicated for use in adult patients when treatment with telmisartan/hydrochlorothiazide 80 mg/12.5 mg does not provide adequate blood pressure control, or in adult patients whose blood pressure has been stabilized with telmisartan or hydrochlorothiazide as monotherapy at the corresponding doses.

Contraindications.

Hypersensitivity to the active substances or to any of the components of the medicinal product.
Hypersensitivity to other sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative).
Pregnancy or planned pregnancy (see sections "Special precautions for use", "Use during pregnancy or breastfeeding").
Cholestatic and biliary obstructive disorders.
Severe hepatic impairment.
Anuria, severe renal impairment (creatinine clearance < 30 mL/min).
Refractory hypokalemia/hyponatremia, hypercalcemia.
Breastfeeding period.
Symptomatic hyperuricemia (gout).
Pediatric population (under 18 years of age).

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

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. Cases of such interactions have also been reported with angiotensin II receptor antagonists (including telmisartan/hydrochlorothiazide). Concomitant use of lithium and Telmilax Plus is not recommended. If combination therapy 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, ACTH, amphotericin, carbenoxolone, sodium penicillin G, salicylic acid and its derivatives). Monitoring of plasma potassium levels is recommended when these medicinal products are used concomitantly with the hydrochlorothiazide/telmisartan combination. These medicinal products may potentiate the effect of hydrochlorothiazide on plasma potassium levels (see section "Special precautions for use").

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). Monitoring of plasma potassium levels is recommended when these medicinal products are used concomitantly with the hydrochlorothiazide/telmisartan combination. 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 (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 Telmilax Plus is used concomitantly with the following medicinal products that may cause disturbances in serum potassium levels (e.g., with digitalis glycosides, antiarrhythmic agents) and medicinal products that promote ventricular arrhythmias, as hypokalemia is a triggering factor for such arrhythmias:

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

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

Digoxin. Increased mean maximum (49%) and minimum (20%) plasma concentrations of digoxin have been observed with concomitant use of telmisartan. Digoxin concentrations should be monitored at the beginning of therapy, during dose adjustments, and upon discontinuation of telmisartan therapy to maintain digoxin levels within the therapeutic range.

Other antihypertensive agents. Telmisartan may enhance the hypotensive effect of other antihypertensive agents.

Clinical data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as hypotension, hyperkalemia, and renal impairment (up to acute renal failure) compared to using a single RAAS-acting agent.

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

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

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

Nonsteroidal 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 the antihypertensive effect of angiotensin II receptor antagonists. In some patients with renal impairment (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 possible acute renal failure, which is usually reversible. Therefore, such combinations should be used with caution, particularly in elderly patients. Adequate hydration should be ensured at the start of combination therapy and periodically thereafter, and renal function should be closely monitored.

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., norepinephrine). 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). 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. Monitoring of serum calcium levels and appropriate dose adjustment are recommended if calcium supplements or calcium-sparing medicinal products (e.g., vitamin D) are prescribed.

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

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

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

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

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

Salicylates. At high doses, hydrochlorothiazide may potentiate the toxic effects of salicylates on the central nervous system.

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

Cyclosporine. Concomitant use of cyclosporine may exacerbate 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 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 acute renal failure increases, particularly with high-dose iodinated contrast agents. Patients require rehydration prior to administration of iodinated contrast agents.

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

Special precautions for use.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. For women planning pregnancy, antihypertensive therapy with angiotensin II receptor antagonists should be replaced by alternative antihypertensive treatments with an established safety profile during pregnancy. Angiotensin II receptor antagonists must be discontinued as soon as pregnancy is confirmed, and alternative therapy should be started if necessary (see sections "Contraindications", "Use in pregnancy or lactation").

Hepatic impairment

The medicinal product Telmilax Plus should not be administered to patients with cholestasis, biliary obstructive disorders, or severe hepatic insufficiency (see section "Contraindications"), as telmisartan is primarily excreted via bile. In these patients, a reduced hepatic clearance of telmisartan is expected. Telmilax Plus should be used with caution in patients with hepatic dysfunction or progressive liver disease, as these drugs may cause intrahepatic cholestasis, and even minor disturbances in fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with the use of the telmisartan/hydrochlorothiazide combination in patients with hepatic insufficiency.

Renovascular hypertension

There is an increased risk of severe arterial hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney when treated with medicinal products affecting the RAAS.

Renal impairment and kidney transplantation

Telmilax Plus must not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications"). Experience with the telmisartan/hydrochlorothiazide combination in patients with recently transplanted kidneys is lacking. Limited experience exists with the use of telmisartan/hydrochlorothiazide in patients with mild to moderate renal impairment; therefore, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended. Azotemia associated with thiazide diuretics may occur in patients with renal dysfunction.

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. This condition should be corrected prior to initiating Telmilax 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 (up to acute renal failure). Therefore, dual blockade via combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Pharmacodynamics", "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 with continuous careful monitoring of renal function, electrolyte levels, and blood pressure.

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

Other conditions requiring RAAS activity

In patients whose vascular tone and renal function primarily depend on RAAS activity (e.g., patients with congestive heart failure or severe renal disease, including renal artery stenosis), treatment with medicinal products 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 agents acting via blockade of the renin-angiotensin system. Therefore, the use of Telmilax Plus is not recommended.

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 patients with diabetes receiving insulin or antidiabetic therapy and taking telmisartan. Therefore, blood glucose levels should be monitored in these patients; dose adjustments of insulin or hypoglycemic agents may be necessary. Latent diabetes mellitus may be revealed during thiazide therapy. Increased cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however, with the use of a preparation containing 12.5 mg hydrochlorothiazide, minimal or no increase in cholesterol and triglyceride levels has been observed. Hyperuricemia or overt gout may occur in some patients receiving thiazide therapy.

Electrolyte imbalance

All patients receiving diuretic therapy should have periodic serum electrolyte monitoring. Thiazides, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis). 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 develop during thiazide diuretic therapy, concomitant treatment with telmisartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with hepatic cirrhosis, those with marked diuresis, those receiving inadequate oral electrolyte supplementation, and those on concomitant corticosteroid or ACTH therapy (see section "Interaction with other medicinal products and other forms of interaction").
Hyperkalemia. Conversely, due to angiotensin II receptor (AT1) antagonism caused by telmisartan—a component of Telmilax Plus—hyperkalemia may occur. However, clinically significant hyperkalemia due to telmisartan/hydrochlorothiazide has not been documented. Risk factors for hyperkalemia include renal impairment and/or heart failure and diabetes mellitus. Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes should be used with caution when administered concomitantly with Telmilax Plus (see section "Interaction with other medicinal products and other forms of interaction").
Hyponatremia and hypochloremic alkalosis. There is no evidence that Telmilax Plus reduces or prevents diuretic-induced hyponatremia. Chloride deficiency is generally mild and usually does not require treatment.
Hypercalcemia. Thiazides may reduce urinary calcium excretion and cause a transient and slight increase in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before assessing parathyroid function.
Hypomagnesemia. Thiazides have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesemia (see section "Interaction with other medicinal products and other forms of interaction").

Race

As with other angiotensin II receptor antagonists, telmisartan is likely to be 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, excessive reduction in blood pressure in patients with ischemic heart disease or myocardial ischemia may lead to myocardial infarction or stroke.

General information

An increased likelihood of hypersensitivity reactions to hydrochlorothiazide may occur in patients with a history of allergy or bronchial asthma, particularly in those with such conditions in their medical history. Exacerbation or activation of systemic lupus erythematosus has been observed during treatment 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, drug use should be discontinued. If reinitiation of diuretic therapy is considered necessary, protection of exposed skin from sunlight or artificial ultraviolet radiation is recommended.

Choroidal effusion, acute myopia, and angle-closure glaucoma

Hydrochlorothiazide, a sulfonamide, may cause an idiosyncratic reaction 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 usually 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. Emergency medical, including surgical, treatment may be required if intraocular pressure remains uncontrolled. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) was observed in two epidemiological studies with high cumulative doses of hydrochlorothiazide. A possible mechanism may be the photosensitizing effect of hydrochlorothiazide.

Patients taking hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer 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, are recommended. 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 non-melanoma skin cancer (see section "Adverse reactions").

Acute respiratory toxicity

Very rare, severe 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 lung condition, and arterial hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. The medicinal product should not be prescribed to patients who previously experienced ARDS after hydrochlorothiazide administration.

Lactose monohydrate

Telmilax Plus contains lactose monohydrate. Therefore, this medicinal product should not be administered to patients with hereditary fructose intolerance and/or hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Effects on laboratory test results:

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

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor antagonists (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, telmisartan should be discontinued and appropriate monitoring initiated until symptoms completely resolve.

Use during pregnancy or breastfeeding.

Pregnancy

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

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

Epidemiological evidence on teratogenic risk after ACE inhibitor use during the first trimester of pregnancy is inconclusive, although a small increased risk cannot be excluded. Although there are no controlled epidemiological data on the risk of angiotensin II receptor antagonists, similar risks are possible for this class of drugs.

Until antihypertensive therapy with angiotensin II receptor antagonists is considered appropriate, women 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.

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 condition is recommended. Newborns whose mothers received angiotensin II receptor antagonists should be closely monitored for arterial hypotension (see sections "Contraindications", "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 positive effects on disease progression.

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

Lactation

Due to lack of information on the use of telmisartan/hydrochlorothiazide during breastfeeding, the drug is not recommended 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. High-dose thiazides, causing intense diuresis, may suppress breast milk production. If Telmilax Plus is used during lactation, the lowest possible doses should be administered.

Fertility

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

Ability to drive and use machines

Telmilax Plus may affect the ability to drive and operate machinery. Dizziness or somnolence may occasionally occur during treatment with telmisartan/hydrochlorothiazide.

Method of Administration and Dosage

Dosage

The medicinal product Telmilax Plus is prescribed to patients whose arterial pressure is not sufficiently controlled with telmisartan monotherapy. Prior to switching to Telmilax Plus, the dose of each component should be determined. Direct substitution of monotherapy with fixed-dose combinations may be considered.

Telmilax Plus, 40 mg/12.5 mg tablets, can be administered once daily to patients whose arterial pressure is not adequately controlled with Telmilax 40 mg tablets.
Telmilax Plus, 80 mg/12.5 mg tablets, can be administered once daily to patients whose arterial pressure is not adequately controlled with Telmilax 80 mg tablets.
Telmilax Plus, 80 mg/25 mg tablets, can be administered once daily to patients whose arterial pressure is not adequately controlled with Telmilax Plus 80 mg/12.5 mg, or to adult patients whose blood pressure has been stabilized with telmisartan or hydrochlorothiazide as monotherapy (see section "Indications").

Special Patient Groups

Elderly Patients

No dose adjustment is required for elderly patients.

Patients with Renal Impairment

Regular monitoring of renal function is recommended (see section "Special Precautions").

Patients with Hepatic Impairment

For patients with mild to moderate hepatic impairment, the daily dose of Telmilax Plus should not exceed 40 mg/12.5 mg. Telmilax Plus is contraindicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with hepatic impairment (see section "Special Precautions").

Method of Administration

The medicinal product Telmilax Plus should be taken orally once daily, with liquid, regardless of food intake.

Precautions Prior to Administration

The medicinal product Telmilax Plus should be stored in its sealed blister due to the hygroscopic nature of the tablets. Tablets should be removed from the blister immediately before use.

Children

The safety and efficacy of Telmilax Plus in children (under 18 years of age) have not been established.

Overdose.

Information on 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, increased serum creatinine, and acute renal failure have also been observed. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalemia, hypochloremia) and dehydration due to excessive diuresis. The most common signs and symptoms of overdose include nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of cardiac arrhythmias, particularly in patients receiving concomitant digitalis or certain antiarrhythmic drugs.

Treatment. Telmisartan is not removed by hemodialysis. Careful monitoring of the patient is required. Treatment for overdose symptoms should be symptomatic and supportive. Therapy depends on the time elapsed since overdose and the severity of symptoms. Supportive measures include induction of emesis and/or gastric lavage. Administration of activated charcoal may be beneficial in managing overdose. 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 solutions.

Adverse Reactions

Safety profile description

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

The overall frequency of adverse reactions reported with telmisartan/hydrochlorothiazide was comparable to those reported with telmisartan alone in randomized controlled trials involving 1471 patients randomized to receive telmisartan plus hydrochlorothiazide (835) or telmisartan alone (636). Dose-dependency of adverse reactions was not established, and they did not correlate with patient sex, age, or race.

Description of adverse reactions

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

Adverse reactions are categorized by frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 – <1/10), uncommon (≥ 1/1,000 – < 1/100), rare (≥1/10,000 – < 1/1,000), very rare (<1/10,000), 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 systemic lupus erythematosus¹.

Metabolism and nutrition disorders:

uncommon – hypokalemia;

rare – hyperuricemia, hyponatremia.

Psychiatric disorders:

uncommon – anxiety;

rare – depression.

Nervous system disorders:

common – dizziness;

uncommon – syncope, paresthesia;

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 – dyspnea;

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

Gastrointestinal disorders:

uncommon – diarrhea, 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 level;

rare – increased creatinine level, increased blood creatine phosphokinase level, increased liver enzyme levels.

¹ Based on post-marketing experience.

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

Additional information regarding individual components

Adverse reactions observed with individual components may be potential adverse reactions during use of Telmilax Plus, even if not observed during clinical trials.

Telmisartan

Adverse reactions occurred with similar frequency among patients receiving placebo and telmisartan. The overall frequency of adverse reactions reported with telmisartan (41.4%) was generally comparable to placebo (43.9%) in placebo-controlled studies. Below are additional adverse reactions reported during clinical trials of telmisartan monotherapy in patients with arterial hypertension or in patients aged 50 years or 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 – anemia;

rare – eosinophilia, thrombocytopenia.

Immune system disorders:

rare – hypersensitivity, anaphylactic reactions.

Metabolism and nutrition disorders:

uncommon – hyperkalemia;

rare – hypokalemia (in patients with diabetes mellitus).

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-induced 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 hemoglobin level.

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

Hydrochlorothiazide

Hydrochlorothiazide may cause or exacerbate hypovolemia, 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 – non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Blood and lymphatic system disorders:

rare – thrombocytopenia (sometimes with purpura);

frequency not known – aplastic anemia, hemolytic anemia, bone marrow depression, leukopenia, neutropenia, agranulocytosis.

Immune system disorders:

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

Endocrine disorders:

frequency not known – loss of diabetes control.

Metabolism and nutrition disorders:

common – hypomagnesemia;

rare – hypercalcemia;

very rare – hypochloremic alkalosis;

frequency not known – anorexia, loss of appetite, electrolyte imbalance, hypercholesterolemia, hyperglycemia, hypovolemia, hyperuricemia 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.

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.

Musculoskeletal and connective tissue disorders:

frequency not known – weakness.

Renal and urinary disorders:

frequency not known – interstitial nephritis, renal dysfunction, glucosuria, renal failure.

Respiratory, thoracic and mediastinal disorders:

very rare – ARDS (see section "Special precautions").

Reproductive system and breast disorders:

frequency not known – sexual dysfunction.

General disorders and administration site conditions:

frequency not known – fever.

Investigations:

frequency not known – increased triglyceride levels.

Description of selected adverse reactions

Cases of intestinal angioedema have been reported after administration of angiotensin II receptor antagonists (see section "Special precautions").

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. In the PRoFESS study, a higher incidence of sepsis was observed among 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 have been reported during post-marketing use. However, a causal relationship has not been established.

Non-melanoma skin cancer

Epidemiological data indicate a cumulative, dose-dependent association between hydrochlorothiazide use and non-melanoma skin cancer.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

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

Prescription category. Prescription only.

Manufacturer.

LABORATORIOS LICONSA, S.A.

Manufacturer's location and address of place of business.

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

Marketing Authorization Holder.

M. BIOTECH LIMITED

Marketing Authorization Holder's location.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom