Telzap^® Plus (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Sanofi Ilac Sanayi Ve Ticaret, A.S. (Turkey)

Contact Information

SANOFI

ATC Code

C09DA07 (Telmisartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Telmisartan (Rec.INN registered by WHO)

Dosage Form

Telzap® Plus

Tablets 12.5 mg+80 mg: 30 or 90 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white with a yellowish tint, oblong, biconvex, with an engraving “81” on one side.

Excipients: sorbitol, sodium hydroxide, povidone 25, magnesium stearate.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Clinical-Pharmacological Group

Combined antihypertensive drug (diuretic + angiotensin II receptor antagonist)

Pharmacotherapeutic Group

Antihypertensive agent, combination (diuretic + angiotensin II receptor antagonist)

Pharmacological Action

Telzap^® Plus is a combination of hydrochlorothiazide (a thiazide diuretic) and telmisartan (an angiotensin II receptor antagonist (ARB)). The combination of these components provides a more pronounced antihypertensive effect, with a greater reduction in blood pressure than with monotherapy.

The drug, used once daily in therapeutic doses, effectively and gradually reduces blood pressure.

Hydrochlorothiazide

The mechanism of action of thiazide diuretics (thiazides) is not fully understood. Thiazides block the reabsorption of sodium and chloride ions in the early part of the renal tubules. Thus, they increase the excretion of sodium and chloride and, consequently, the removal of water from the body.

As a result of the diuretic action of hydrochlorothiazide, the plasma volume decreases, leading to increased renin activity and plasma aldosterone levels. This increases the excretion of potassium ions in the urine and decreases the potassium level in the blood (hypokalemia). Hydrochlorothiazide also increases the excretion of magnesium ions and decreases the excretion of calcium ions in the urine. Thiazide diuretics reduce the renal excretion of uric acid and increase its level in the blood.

Thiazide diuretics also reduce carbonic anhydrase activity by enhancing the excretion of bicarbonate ions. But this effect is usually weak and does not affect urine pH.

At maximum therapeutic doses, the diuretic/natriuretic effect of all thiazide diuretics is approximately the same. Natriuresis and diuresis occur within 2 hours and reach their maximum approximately 4 hours later. The duration of the diuretic action of hydrochlorothiazide is from 6 to 12 hours.

Hydrochlorothiazide has an antihypertensive effect. Thiazide diuretics do not affect normal blood pressure.

Telmisartan

Telmisartan is a specific angiotensin II receptor antagonist (subtype AT₁), effective when taken orally. Telmisartan has a high affinity for the angiotensin II receptor subtype AT₁, through which the action of angiotensin II is mediated. Telmisartan displaces angiotensin II from its binding to the receptor, showing no agonist properties at the AT₁ receptor. Telmisartan selectively and durably binds to the AT₁ receptor. Telmisartan has no affinity for other receptors, including AT₂ and other less studied AT receptors. The functional role of these receptors, as well as the effect of their possible increased stimulation by angiotensin II, the concentration of which increases under the action of telmisartan, has not been studied. Telmisartan reduces plasma aldosterone concentration, does not inhibit renin, and does not block ion channels. Telmisartan does not inhibit ACE (kininase II), which also breaks down bradykinin. This avoids side effects associated with the action of bradykinin.

In healthy individuals, Telmisartan at a dose of 80 mg almost completely blocks the hypertensive effect of angiotensin II. The inhibitory effect lasts more than 24 hours and persists for up to 48 hours.

The onset of the antihypertensive effect is observed within the first 3 hours after oral administration of telmisartan. The duration of the therapeutic effect of the drug is more than 24 hours and includes the last 4 hours before the next dose according to 24-hour blood pressure monitoring. This is confirmed by measurements taken at the time of maximum effect and immediately before the next dose (the ratio of residual effect to maximum was above 80% for doses of 40 and 80 mg telmisartan in placebo-controlled studies). The maximum antihypertensive effect develops after 4-8 weeks of regular telmisartan administration and is maintained during long-term therapy.

In patients with arterial hypertension, Telmisartan reduces both systolic and diastolic blood pressure without affecting heart rate. According to the results of clinical studies, the effectiveness of the antihypertensive action of telmisartan is comparable to the therapeutic effect of drugs of other classes, such as amlodipine, atenolol, enalapril, Hydrochlorothiazide and lisinopril.

In case of abrupt discontinuation of telmisartan treatment, blood pressure gradually returns to baseline levels without the development of withdrawal syndrome.

The incidence of dry cough was significantly lower with telmisartan compared to ACE inhibitors.

Pharmacokinetics

In healthy individuals, the simultaneous use of hydrochlorothiazide and telmisartan does not affect the pharmacokinetics of each component of the drug.

Absorption

Hydrochlorothiazide. After oral administration, C_max of hydrochlorothiazide in plasma is reached in about 1-3 hours. Considering the cumulative renal excretion of hydrochlorothiazide, the absolute bioavailability is about 60%.

Telmisartan. After oral administration, Telmisartan is rapidly absorbed. C_max of telmisartan after oral administration is reached in 0.5-1.5 hours. The absolute bioavailability at doses of 40 and 160 mg is 42% and 58%, respectively. Food intake slightly reduces the bioavailability of telmisartan, the decrease in AUC value ranges from 6% (40 mg dose) to 19% (160 mg dose). After 3 hours of administration, the plasma concentration levels out regardless of whether the drug was taken with food or on an empty stomach. The slight decrease in AUC does not cause a reduction in the therapeutic efficacy of the drug.

The pharmacokinetics of telmisartan after oral administration is non-linear. After repeated administration, no significant accumulation of telmisartan in plasma was noted.

Distribution

Hydrochlorothiazide. About 68% of hydrochlorothiazide is bound to plasma proteins, its V_d^ss is 0.83-1.14 L/kg.

Telmisartan. Telmisartan is highly bound to plasma proteins (>99.5%), mainly to albumin and alpha-1 acid glycoprotein. The apparent volume of distribution (V_d^ss) at steady state is approximately 500 L.

Metabolism

Hydrochlorothiazide. Hydrochlorothiazide is not metabolized in humans.

Telmisartan. The metabolism of telmisartan occurs by conjugation with glucuronic acid and the formation of a pharmacologically inactive metabolite, acyl glucuronide. After a single dose of ¹⁴C-labeled telmisartan, the acyl glucuronide accounted for approximately 11% of the total radioactive substance in plasma. Cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.

Excretion

Hydrochlorothiazide. Hydrochlorothiazide is excreted almost completely unchanged in the urine. About 60% of the orally administered dose is excreted unchanged within 48 hours. Renal clearance is 250-300 ml/min. T_1/2 of hydrochlorothiazide is 10-15 hours.

Telmisartan. After oral or intravenous administration of ¹⁴C-labeled telmisartan, most of the dose (>97%) is excreted through the intestine with bile; a negligible amount of the substance is excreted by the kidneys (less than 2%). The total plasma clearance of telmisartan after oral administration is >1500 ml/min. T_1/2 of telmisartan is more than 20 hours.

Pharmacokinetics in special patient groups

Gender. Women tend to have higher plasma concentrations of hydrochlorothiazide; this finding is not clinically significant.

Plasma concentrations of telmisartan are 2-3 times higher in women than in men, but no enhancement of the antihypertensive effect is observed in women. No dose adjustment is necessary.

The pharmacokinetics of telmisartan in elderly patients (over 65 years) does not differ from that in young patients.

Patients with renal impairment. In patients with renal failure, the excretion rate of hydrochlorothiazide is reduced. In patients with a removed or single kidney, T_1/2 is about 34 hours. The excretion of telmisartan occurs practically without the participation of the kidneys (less than 2%). Given the experience with the use of the drug for the treatment of patients with mild to moderate renal failure (CC 30-60 ml/min, average – about 50 ml/min), no dose adjustment is required in patients with renal impairment. Telmisartan is not removed during hemodialysis.

Patients with hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to 100%. In patients with hepatic failure, T_1/2 did not change.

Indications

• Arterial hypertension (in the absence of effectiveness of monotherapy with telmisartan or hydrochlorothiazide).

ICD codes

Dosage Regimen

The drug is taken orally once a day, with fluid, regardless of meals.

Patients whose blood pressure cannot be adequately controlled with monotherapy with telmisartan or hydrochlorothiazide should take the drug Telzap^® Plus.

Before switching to a fixed-dose combination, individual dose titration of each component is recommended. In some clinical situations, a direct switch from monotherapy to treatment with a fixed-dose combination may be considered.

The drug Telzap^® Plus, 12.5 mg + 80 mg can be used once a day in patients whose blood pressure cannot be adequately controlled with telmisartan at a dose of 80 mg/day.

Special patient populations

Dose adjustment in patients with mild or moderate renal impairment (CC greater than 30 ml/min) is not required. Periodic monitoring of renal function parameters is recommended.

Concomitant use of telmisartan with aliskiren is contraindicated in patients with renal failure (GFR less than 60 ml/min/1.73 m²) (see section “Contraindications”).

The drug is contraindicated in patients with hepatic impairment.

For elderly patients (over 65 years), no dose adjustment is required.

The drug is contraindicated for use in children and adolescents under 18 years of age due to lack of safety and efficacy data (see section “Contraindications”).

Adverse Reactions

When using the combination Telmisartan+Hydrochlorothiazide, the most frequently reported adverse reaction was dizziness. Serious angioedema occurred rarely (≥1/10000-<1/1000).

The overall incidence of adverse reactions with the Telmisartan+Hydrochlorothiazide combination was comparable to that with telmisartan monotherapy. No dose-dependency of adverse reactions was established, and no relationship with patient gender, age, or race was noted.

According to WHO, adverse effects are classified according to their frequency of occurrence as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10 000, <1/1000), very rare (<1/10 000), including isolated reports; frequency unknown (cannot be estimated from the available data).

Description of selected adverse reactions

Sepsis

In the PROFESS study, the incidence of sepsis in the telmisartan group was higher than in the placebo group. This may be considered a chance finding or the development of a phenomenon associated with a currently unknown mechanism.

Interstitial lung disease

Cases of interstitial lung disease during telmisartan administration have been reported during post-marketing use, but a causal relationship has not been established.

Liver dysfunction/liver injury

The largest number of cases of liver dysfunction or liver injury was identified from the analysis of post-marketing clinical case reports in patients of Japanese ethnicity. Patients of this ethnic group are more susceptible to developing this type of adverse reaction.

Non-melanoma skin cancer and lip cancer

Based on epidemiological study data, a dose-dependent relationship was observed between the cumulative dose of hydrochlorothiazide and the development of non-melanoma skin cancer and lip cancer (see section “Special Precautions”).

Contraindications

• Hypersensitivity to the active substances or any excipients of the drug and to other sulfonamide derivatives;
• Cholestasis and obstructive biliary tract diseases;
• Severe liver dysfunction (Child-Pugh class C);
• Severe renal impairment (CrCl less than 30 ml/min);
• Concomitant use with aliskiren or drugs containing aliskiren in patients with diabetes mellitus and/or moderate to severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy;
• Refractory hypokalemia, hypercalcemia;
• Refractory hyponatremia;
• Hereditary fructose intolerance (contains sorbitol);
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established).

With caution

• Bilateral renal artery stenosis or stenosis of the artery to a single kidney, severe renal impairment;
• Liver dysfunction or progressive liver diseases (Child-Pugh class A and B);
• Reduced blood volume due to prior diuretic therapy, salt restriction, diarrhea, or vomiting;
• Status after kidney transplantation (no experience with use);
• Chronic heart failure NYHA class III-IV;
• Aortic and mitral valve stenosis;
• Idiopathic hypertrophic subaortic stenosis;
• Hypertrophic obstructive cardiomyopathy;
• Diabetes mellitus;
• Primary hyperaldosteronism;
• Gout;
• In patients with renal failure with CrCl greater than 30 ml/min (experience is limited but does not confirm the development of renal side effects, dose adjustment is not required);
• Water-electrolyte imbalance (including hypokalemia, hyponatremia, hyperkalemia, hypercalcemia, hypochloremic alkalosis, hypomagnesemia);
• Prolonged QT interval on ECG;
• Concomitant use of drugs that can cause polymorphic ventricular tachycardia of the ‘torsade de pointes’ type or prolong the QT interval on ECG;
• Concomitant use of lithium preparations, drugs that can cause hypokalemia, cardiac glycosides;
• Hyperparathyroidism;
• History of non-melanoma skin cancer (see section “Special Precautions”);
• History of allergic reactions to penicillin;
• Hyperuricemia;
• Use in patients of Black race;
• Coronary artery disease and cerebrovascular diseases;
• Elderly age (over 65 years);
• Systemic lupus erythematosus.

Use in Pregnancy and Lactation

Pregnancy

Hydrochlorothiazide

There is limited experience with the use of hydrochlorothiazide during pregnancy (especially in the first trimester). Preclinical data on safety are insufficient. Hydrochlorothiazide crosses the placental barrier and is detected in cord blood. Considering the mechanism of pharmacological action of hydrochlorothiazide, its use in the second and third trimesters of pregnancy may impair fetoplacental perfusion and lead to complications in the fetus and newborn such as jaundice, water-electrolyte imbalance and thrombocytopenia. Cases of thrombocytopenia in newborns whose mothers received thiazide diuretics have been described.

The use of hydrochlorothiazide during pregnancy is contraindicated. Hydrochlorothiazide should not be used to treat pregnancy-induced hypertension (edema, arterial hypertension or pre-eclampsia) in the second half of pregnancy, as it increases the risk of reduced blood volume and placental hypoperfusion, but does not have a favorable effect on the course of these pregnancy complications. Diuretics do not prevent the development of pre-eclampsia.

Telmisartan

Treatment with ARBs during pregnancy is contraindicated. The use of ARBs is not recommended in the first trimester of pregnancy and is contraindicated in the second and third trimesters of pregnancy.

No adequate data on the use of telmisartan in pregnant women are available. Animal studies have revealed reproductive toxicity.

Epidemiological evidence of the risk of teratogenic effects after ACE inhibitor use in the first trimester of pregnancy was not conclusive, however, this risk cannot be ruled out. No controlled epidemiological study data on the risk of ARB use are available yet, a similar risk may exist for this class of drugs. Unless long-term treatment with ARBs is absolutely necessary, patients planning pregnancy should choose an alternative antihypertensive drug with a confirmed safety profile for use during pregnancy. Upon confirmation of pregnancy, treatment with angiotensin II receptor antagonists should be discontinued immediately and, if necessary, alternative treatment should be initiated.

Treatment with ARBs in the second and third trimesters of pregnancy has toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and the newborn (renal failure, arterial hypotension and hyperkalemia). When using ARBs from the second trimester of pregnancy, ultrasound examination of the fetal kidneys and skull is recommended.

Infants whose mothers took ARBs should be closely monitored for arterial hypotension.

Breastfeeding period

The use of Telzap^® Plus during breastfeeding is contraindicated; alternative treatment with a more favorable safety profile should be used.

Hydrochlorothiazide passes into breast milk, therefore its use during breastfeeding is contraindicated. If the use of hydrochlorothiazide during lactation is absolutely necessary, breastfeeding should be discontinued.

Fertility

No studies on the effects of the combination of telmisartan and hydrochlorothiazide on human fertility have been conducted.

Use in Hepatic Impairment

The use of the drug is contraindicated in liver dysfunction.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment (CrCl less than 30 ml/min).

The drug should be used with caution in bilateral renal artery stenosis or stenosis of the artery to a single kidney, severe renal impairment, status after kidney transplantation (no experience with use).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age due to lack of safety and efficacy data.

Geriatric Use

The drug should be used with caution in elderly patients (over 65 years of age).

Special Precautions

The use of Telzap^® Plus in patients with acute myocardial infarction is not recommended due to insufficient clinical experience.

Telzap^® Plus should not be used to relieve a hypertensive crisis.

Hydrochlorothiazide

Renal impairment

In patients with renal impairment, Hydrochlorothiazide may cause azotemia. In renal failure, accumulation of hydrochlorothiazide is possible.

In patients with reduced renal function, periodic monitoring of CrCl is necessary. If renal impairment progresses and/or oliguria (anuria) occurs, Hydrochlorothiazide should be discontinued.

Hepatic impairment

When using thiazide diuretics in patients with hepatic impairment, hepatic encephalopathy may develop. The use of thiazides is contraindicated in patients with severe hepatic failure or hepatic encephalopathy. In patients with mild to moderate hepatic insufficiency and/or progressive liver diseases, Hydrochlorothiazide should be used with caution, since even a slight change in water-electrolyte balance and accumulation of ammonium in the blood serum can cause hepatic coma. If symptoms of encephalopathy appear, diuretic use should be discontinued immediately.

Water-electrolyte balance and metabolic disorders

Thiazide diuretics (including Hydrochlorothiazide) can cause a decrease in circulating blood volume (hypovolemia) and water-electrolyte imbalance (including hypokalemia, hyponatremia, hypochloremic alkalosis). Clinical symptoms of water-electrolyte imbalance are dry mouth, thirst, weakness, lethargy, fatigue, drowsiness, restlessness, muscle pain or cramps, muscle weakness, marked decrease in blood pressure, oliguria, tachycardia, arrhythmia and gastrointestinal disorders (such as nausea and vomiting). In patients receiving hydrochlorothiazide therapy (especially during long-term course treatment), clinical symptoms of water-electrolyte imbalance should be identified, and plasma electrolyte levels should be regularly monitored.

Sodium. All diuretic drugs can cause hyponatremia, sometimes leading to serious complications. Hyponatremia and hypovolemia can lead to dehydration and orthostatic hypotension. Concomitant decrease in chloride ions can lead to secondary compensatory metabolic alkalosis, but the frequency and severity of this effect are insignificant. It is recommended to determine plasma sodium levels before starting treatment and regularly monitor this parameter during hydrochlorothiazide administration.

Potassium. When using thiazide and thiazide-like diuretics, there is a risk of a sharp decrease in plasma potassium levels and the development of hypokalemia (potassium concentration less than 3.4 mmol/l). Hypokalemia increases the risk of cardiac rhythm disturbances (including severe arrhythmias) and enhances the toxic effect of cardiac glycosides. Furthermore, hypokalemia (as well as bradycardia) is a condition that contributes to the development of polymorphic ventricular tachycardia of the ‘torsade de pointes’ type, which can be fatal.

Hypokalemia is most dangerous for the following groups of patients: elderly patients, patients simultaneously receiving therapy with antiarrhythmic and non-antiarrhythmic drugs that can cause polymorphic ventricular tachycardia of the ‘torsade de pointes’ type or prolong the QT interval on ECG, patients with hepatic impairment, coronary artery disease, chronic heart failure. Furthermore, patients with a prolonged QT interval are at increased risk. It does not matter whether this prolongation is caused by congenital reasons or by the action of drugs.

In all the cases described above, it is necessary to avoid the risk of hypokalemia and regularly monitor plasma potassium levels. The first measurement of plasma potassium levels should be performed within the first week of starting treatment. If hypokalemia occurs, appropriate treatment should be prescribed. Hypokalemia can be corrected by the use of potassium-containing drugs or by eating foods rich in potassium (dried fruits, fruits, vegetables).

Calcium. Thiazide diuretics can reduce the renal excretion of calcium ions, leading to a slight and temporary increase in plasma calcium levels. In some patients with long-term use of thiazide diuretics, pathological changes in the parathyroid glands with hypercalcemia and hyperphosphatemia have been observed, but without typical complications of hyperparathyroidism (nephrolithiasis, decreased bone mineral density, peptic ulcer). Severe hypercalcemia may be a manifestation of previously undiagnosed hyperparathyroidism.

Due to their effect on calcium metabolism, thiazides can affect laboratory parameters of parathyroid function. Thiazide diuretics (including Hydrochlorothiazide) should be discontinued before testing parathyroid function.

Magnesium. Thiazides have been found to increase renal excretion of magnesium, which can lead to hypomagnesemia. The clinical significance of hypomagnesemia remains unclear.

Glucose. Treatment with thiazide diuretics may impair glucose tolerance. When using hydrochlorothiazide in patients with manifest or latent diabetes mellitus, blood glucose concentration should be regularly monitored. Adjustment of the dose of hypoglycemic drugs may be required.

Uric acid. In patients with gout, the frequency of attacks may increase or the course of gout may worsen. Close monitoring of patients with gout and impaired uric acid metabolism (hyperuricemia) is necessary.

Lipids. When using hydrochlorothiazide, the concentration of cholesterol and triglycerides in plasma may increase.

Choroidal effusion/acute myopia/secondary angle-closure glaucoma

Hydrochlorothiazide (is a sulfonamide) can cause an idiosyncratic reaction leading to the development of acute myopia and an acute attack of secondary angle-closure glaucoma. Symptoms include: sudden decrease in visual acuity or eye pain, which usually occur within several hours or weeks of starting hydrochlorothiazide therapy. If left untreated, acute angle-closure glaucoma can lead to irreversible vision loss. If symptoms appear, hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for developing acute angle-closure glaucoma are: history of allergic reaction to sulfonamides or penicillin.

Immune system disorders

There are reports that thiazide diuretics (including Hydrochlorothiazide) can cause exacerbation or progression of systemic lupus erythematosus, as well as lupus-like reactions.

In patients receiving thiazide diuretics, hypersensitivity reactions may occur even in the absence of a history of allergic reactions or bronchial asthma.

Acute respiratory toxicity

Severe cases of acute respiratory toxicity, including acute respiratory distress syndrome, have been reported after taking hydrochlorothiazide. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. At the onset of the disease, symptoms include shortness of breath, fever, worsening lung condition and hypotension. If acute respiratory distress syndrome is suspected, Telzap^® plus should be discontinued and appropriate treatment should be provided. Hydrochlorothiazide should not be prescribed to patients who have previously experienced acute respiratory distress syndrome after taking hydrochlorothiazide or another thiazide diuretic.

Photosensitivity

There is information on cases of photosensitivity reactions when taking thiazide diuretics. If photosensitivity occurs during hydrochlorothiazide administration, treatment should be discontinued. If continuation of diuretic therapy is necessary, the skin should be protected from exposure to sunlight or artificial ultraviolet rays.

Non-Melanoma Skin Cancer and Lip Cancer

Two pharmacoepidemiological studies conducted using data from the Danish National Cancer Registry demonstrated an association between hydrochlorothiazide intake and an increased risk of non-melanoma skin cancer (NMSC) – basal cell carcinoma and squamous cell carcinoma. The risk of developing NMSC increased with higher cumulative (accumulated) doses of hydrochlorothiazide. A possible mechanism for the development of NMSC is the photosensitizing effect of hydrochlorothiazide. Another study observed a possible association between the risk of lip cancer and the use of hydrochlorothiazide. A clear dose-response relationship was observed for patients who received at least one dose, for patients who received a high dose (≥25,000 mg), and for patients who received the maximum cumulative dose (≥100,000 mg).

Patients taking Hydrochlorothiazide as monotherapy or in combination with other drugs should be informed about the risk of developing NMSC. Such patients are advised to regularly examine their skin for any new suspicious lesions, as well as changes in existing skin lesions.

Any suspicious skin changes should be reported to a doctor immediately. Suspicious skin areas should be examined by a specialist. A histological examination of skin biopsies may be required to clarify the diagnosis.

To minimize the risk of developing NMSC, patients should be advised to follow preventive measures, such as limiting exposure to sunlight and UV rays, and using appropriate protective equipment.

Particular attention should be paid to patients with known risk factors for skin cancer, including: skin phototypes I and II (fair and light skin), a family history of skin cancer, a history of skin damage caused by solar or UV radiation and radiation therapy, smoking, and taking drugs with photosensitizing effects.

In patients with a history of NMSC, the appropriateness of using hydrochlorothiazide should be reconsidered.

Alcohol

Consumption of alcoholic beverages is not recommended during treatment, as ethanol enhances the antihypertensive effect of thiazide diuretics.

Athletes

Hydrochlorothiazide may give a positive result in doping control tests in athletes.

Other

Hydrochlorothiazide should be used with particular caution in patients with severe atherosclerosis of the cerebral and coronary arteries.

Thiazide diuretics may reduce the amount of iodine bound to plasma proteins without signs of thyroid dysfunction.

Telmisartan

Hepatic Impairment

The use of telmisartan is contraindicated in patients with cholestasis, biliary obstruction, or severe hepatic impairment (Child-Pugh class C), since Telmisartan is mainly excreted in the bile. It is assumed that such patients have reduced hepatic clearance of telmisartan. In patients with mild or moderate hepatic impairment (Child-Pugh class A and B), telmisartan should be used with caution (see the “With Caution” subsection in the “Contraindications” section).

Renovascular Hypertension

When treating with drugs affecting the RAAS, patients with bilateral renal artery stenosis or stenosis of the artery to a solitary functioning kidney are at increased risk of severe arterial hypotension and renal failure.

Renal Impairment and Kidney Transplantation

When using telmisartan in patients with impaired renal function, periodic monitoring of plasma potassium and creatinine levels is recommended. There is no clinical experience with the use of telmisartan in patients who have recently undergone kidney transplantation.

Reduced Blood Volume

Symptomatic arterial hypotension, especially after the first dose of telmisartan, may occur in patients with reduced blood volume and/or low plasma sodium levels due to previous diuretic therapy, salt restriction, diarrhea, or vomiting. Such conditions (fluid and/or sodium deficiency) should be corrected before starting telmisartan.

Dual Blockade of the RAAS

The concomitant use of telmisartan with aliskiren or drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate to severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) (see section “Contraindications”) and is not recommended in other patients.

The concomitant use of telmisartan and ACE inhibitors is contraindicated in patients with diabetic nephropathy (see section “Contraindications”) and is not recommended in other patients.

As a result of RAAS inhibition, hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal failure) have been observed in predisposed patients, especially when several drugs acting on this system are used concomitantly. Therefore, dual blockade of the RAAS (e.g., by combining telmisartan with other RAAS antagonists) is not recommended. If dual blockade of the RAAS is necessary, each case should be considered individually and renal function, fluid and electrolyte balance, and blood pressure should be carefully monitored.

Other Conditions Associated with RAAS Stimulation

In patients whose vascular tone and renal function depend predominantly on the activity of the RAAS (e.g., patients with chronic heart failure or kidney disease, including renal artery stenosis or stenosis of the artery to a solitary kidney), the use of drugs affecting this system may be accompanied by the development of acute arterial hypotension, hyperazotemia, oliguria, and in rare cases, acute renal failure.

Primary Hyperaldosteronism

In patients with primary hyperaldosteronism, treatment with antihypertensive drugs that work by inhibiting the RAAS is generally not effective. Therefore, the use of telmisartan is not recommended.

Aortic and Mitral Valve Stenosis, Hypertrophic Obstructive Cardiomyopathy

As with other vasodilators, special caution should be exercised when using telmisartan in patients with aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy.

Patients with Diabetes Mellitus Treated with Insulin or Oral Hypoglycemic Agents

Hypoglycemia may occur in this group of patients during treatment with telmisartan. Blood glucose monitoring should be intensified, as it may be necessary to adjust the dose of insulin or the hypoglycemic agent.

Hyperkalemia

The use of drugs affecting the RAAS may cause hyperkalemia. In elderly patients, patients with renal impairment or diabetes, patients taking drugs that can increase plasma potassium levels, and/or patients with comorbidities, hyperkalemia can be fatal.

When deciding on the concomitant use of drugs affecting the RAAS, the risk-benefit ratio must be assessed.

The main risk factors for hyperkalemia to consider are

• Diabetes mellitus, renal failure, age (patients over 65 years);
• Combination with one or more drugs affecting the RAAS, and/or potassium-containing dietary supplements. Drugs or therapeutic classes of drugs that can cause hyperkalemia are potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, including selective COX-2 inhibitors, heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim;
• Intercurrent diseases, especially dehydration, acute heart failure, metabolic acidosis, renal dysfunction, cytolysis syndrome (e.g., acute limb ischemia, rhabdomyolysis, extensive trauma).

Patients at risk are advised to carefully monitor plasma potassium levels (see section “Drug Interactions”).

Sorbitol

Telza^® Plus contains sorbitol (E420). Patients with rare hereditary fructose intolerance should not take the drug.

Ethnic Differences

As noted for ACE inhibitors, Telmisartan and other ARBs appear to be less effective in lowering blood pressure in black patients than in other races, possibly due to a greater predisposition to low renin activity in this patient population.

Other

In patients with diabetes mellitus treated with insulin or oral hypoglycemic agents, hypoglycemia may develop during the use of telmisartan.

As with other antihypertensive drugs, an excessive decrease in blood pressure in patients with ischemic cardiomyopathy or coronary artery disease may lead to myocardial infarction or stroke.

Effect on Ability to Drive and Use Machines

When driving vehicles and engaging in potentially hazardous activities, it should be taken into account that dizziness and drowsiness may occur while taking Telza^® Plus, which requires caution.

Overdose

No cases of overdose have been identified. Possible symptoms are a combination of overdose symptoms of the individual components.

Hydrochlorothiazide

Symptoms

The most common manifestations of hydrochlorothiazide overdose are increased diuresis, accompanied by acute fluid loss (dehydration) and electrolyte disturbances (hypokalemia, hyponatremia, hypochloremia). Hydrochlorothiazide overdose may manifest with the following symptoms

• Cardiovascular system: tachycardia, decreased blood pressure, shock;
• Nervous system: weakness, confusion, dizziness, calf muscle cramps, paresthesia, impaired consciousness, fatigue;
• Gastrointestinal tract: nausea, vomiting, thirst;
• Renal and urinary tract: polyuria, oliguria, or anuria (due to hemoconcentration);
• Laboratory parameters: hypokalemia, hyponatremia, hypochloremia, alkalosis, increased blood urea nitrogen (especially in patients with renal failure).

Treatment

In case of overdose, symptomatic and supportive therapy is performed. If the drug was taken recently, induction of vomiting or gastric lavage is indicated to remove hydrochlorothiazide. Absorption of hydrochlorothiazide can be reduced by oral administration of activated charcoal. In case of decreased blood pressure or shock, blood volume should be restored by administration of plasma-substituting fluids and electrolyte deficits (potassium, sodium). For respiratory disorders, oxygen inhalation or artificial ventilation is indicated. Fluid and electrolyte balance (especially serum potassium levels) and renal function should be monitored until they normalize. There is no specific antidote. Hydrochlorothiazide is removed by hemodialysis, but the extent of its removal is not established.

Telmisartan

Symptoms

The most pronounced manifestations of telmisartan overdose are arterial hypotension and tachycardia; bradycardia, dizziness, vomiting, increased serum creatinine, and acute renal failure have also been reported.

Treatment

Telmisartan is not removed by hemodialysis. Patients should be carefully monitored and symptomatic as well as supportive treatment should be administered. The treatment approach depends on the time elapsed since drug intake and the severity of symptoms. Recommended measures include induction of vomiting and/or gastric lavage; administration of activated charcoal is advisable. The patient should be placed in a supine position with legs elevated. If necessary, blood volume should be restored, for example, by intravenous administration of 0.9% sodium chloride solution. Sympathomimetic drugs may be prescribed.

Drug Interactions

Hydrochlorothiazide

Not Recommended Drug Combinations

Lithium Preparations

Concomitant use of hydrochlorothiazide and lithium preparations reduces the renal clearance of lithium, which may lead to increased plasma lithium concentrations and increased toxicity. If concomitant use of hydrochlorothiazide is necessary, the dose of lithium preparations should be carefully selected, plasma lithium concentrations should be regularly monitored, and the drug dose should be adjusted accordingly.

Drug Combinations Requiring Special Attention

Drugs That Can Cause Polymorphic Ventricular Tachycardia of the Torsades de Pointes Type

Due to the increased risk of ventricular arrhythmias, especially polymorphic ventricular tachycardia of the torsades de pointes type (risk factor – hypokalemia), Hydrochlorothiazide should be used with particular caution simultaneously with such drugs as

• Class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, procainamide) and Class IC (flecainide);
• Class III antiarrhythmic drugs (dofetilide, ibutilide, bretylium tosilate), sotalol, dronedarone, amiodarone;
• Other (non-antiarrhythmic) drugs such as:
  • Antipsychotics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulpiride, tiapride), butyrophenones (droperidol, haloperidol), pimozide, sertindole;
  • Antidepressants: tricyclic antidepressants, selective serotonin reuptake inhibitors (citalopram, escitalopram);
  • Antibacterial agents: fluoroquinolones (levofloxacin, moxifloxacin, sparfloxacin, ciprofloxacin); macrolides (erythromycin when administered intravenously, azithromycin, clarithromycin, roxithromycin, spiramycin), co-trimoxazole;
  • Antifungal agents: azoles (voriconazole, itraconazole, ketoconazole, fluconazole);
  • Antimalarial agents (quinine, chloroquine, mefloquine, halofantrine, lumefantrine);
  • Antiprotozoal agents (pentamidine when administered parenterally);
  • Antianginal agents (ranolazine, bepridil);
  • Antineoplastic agents (vandetanib, arsenic trioxide, oxaliplatin, tacrolimus);
  • Antiemetic agents (domperidone, ondansetron);
  • Drugs affecting gastrointestinal motility (cisapride);
  • Antihistamines (astemizole, terfenadine, mizolastine);
  • Other drugs (anagrelide, vasopressin, difemanil methyl sulfate, ketanserin, probucol, propofol, sevoflurane, terlipressin, terodiline, cilostazol).

Plasma potassium levels should be determined and corrected if necessary before starting combination therapy with hydrochlorothiazide and the drugs listed above. Clinical monitoring of the patient, plasma electrolyte levels, and ECG parameters are necessary. In patients with hypokalemia, drugs that do not cause polymorphic ventricular tachycardia of the torsades de pointes type should be used.

Drugs That Can Increase the QT Interval

Concomitant use of hydrochlorothiazide with drugs that can increase the QT interval should be based on a careful assessment of the expected benefit and potential risk for each patient (possible increased risk of polymorphic ventricular tachycardia of the torsades de pointes type). When using such combinations, regular ECG recording (to detect QT interval prolongation) and monitoring of blood potassium levels are necessary.

Drugs That Can Cause Hypokalemia: amphotericin B (when administered intravenously), gluco- and mineralocorticoids (when used systemically), tetracosactide (ACTH), glycyrrhizic acid (carbenoxolone, preparations containing licorice root), stimulant laxatives

Increased risk of hypokalemia with concomitant use with hydrochlorothiazide (additive effect). Regular monitoring of plasma potassium levels is necessary, with correction if needed. During therapy with hydrochlorothiazide, it is recommended to use non-stimulant laxatives.

Cardiac Glycosides

Hypokalemia and hypomagnesemia caused by thiazide diuretics enhance the toxicity of cardiac glycosides. When hydrochlorothiazide and cardiac glycosides are used concomitantly, plasma potassium levels, ECG parameters should be regularly monitored, and therapy should be adjusted if necessary.

Drug Combinations Requiring Attention

Other Antihypertensive Drugs

Potentiation of the antihypertensive effect of hydrochlorothiazide (additive effect). It may be necessary to adjust the dose of concurrently prescribed antihypertensive drugs.

Ethanol, Barbiturates, Antipsychotics, Antidepressants, Anxiolytics, Narcotic Analgesics, and General Anesthetics

Possible enhancement of the antihypertensive effect of hydrochlorothiazide and potentiation of orthostatic hypotension (additive effect).

Non-Depolarizing Muscle Relaxants (e.g., tubocurarine)

Possible enhancement of the effect of non-depolarizing muscle relaxants.

Adrenergic Agonists (Pressor Amines)

Hydrochlorothiazide may reduce the effect of adrenergic agonists such as epinephrine and norepinephrine.

NSAIDs, Including Selective COX-2 Inhibitors and High Doses of Acetylsalicylic Acid (>3 g/day)

NSAIDs may reduce the diuretic and antihypertensive effects of hydrochlorothiazide. When used concomitantly, there is a risk of acute renal failure due to decreased GFR. Hydrochlorothiazide may enhance the toxic effect of high doses of salicylates on the central nervous system.

Oral Hypoglycemic Agents and Insulin

Thiazide diuretics affect glucose tolerance (possible development of hyperglycemia) and reduce the effectiveness of hypoglycemic agents (dose adjustment of hypoglycemic agents may be required).

Hydrochlorothiazide and metformin should be used together with caution due to the risk of lactic acidosis against the background of renal impairment caused by hydrochlorothiazide.

Beta-Blockers, Diazoxide

Concomitant use of thiazide diuretics (including Hydrochlorothiazide) with beta-blockers or diazoxide may increase the risk of hyperglycemia.

Drugs Used to Treat Gout (probenecid, sulfinpyrazone, allopurinol)

Dose adjustment of uricosuric drugs may be necessary, as Hydrochlorothiazide increases serum uric acid levels. Thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.

Amantadine

Thiazide diuretics (including Hydrochlorothiazide) may reduce the clearance of amantadine, lead to an increase in amantadine plasma concentration, and increase the risk of its adverse effects.

Anticholinergic drugs (cholinoblockers)

Anticholinergic drugs (e.g., atropine, biperiden) increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate.

Cytotoxic (antineoplastic) drugs

Thiazide diuretics reduce the renal excretion of cytotoxic drugs (e.g., cyclophosphamide and methotrexate) and potentiate their myelosuppressive effect.

Methyldopa

Cases of hemolytic anemia have been described with the concomitant use of hydrochlorothiazide and methyldopa.

Antiepileptic drugs (carbamazepine, oxcarbazepine, topiramate)

Risk of symptomatic hyponatremia. With the concomitant use of hydrochlorothiazide and carbamazepine, patient monitoring and control of serum sodium levels are necessary. With the concomitant use of hydrochlorothiazide and topiramate, serum topiramate levels should also be monitored, and potassium supplements or topiramate dose adjustment should be prescribed if necessary.

Selective serotonin reuptake inhibitors

Concomitant use with thiazide diuretics may potentiate hyponatremia. Monitoring of plasma sodium levels is necessary.

Cyclosporine

Concomitant use of thiazide diuretics and cyclosporine increases the risk of hyperuricemia and exacerbation of gout.

Oral anticoagulants

Thiazide diuretics may reduce the effect of oral anticoagulants.

Iodinated contrast agents

Dehydration while taking thiazide diuretics increases the risk of acute renal failure, especially when using high doses of iodinated contrast agents. Fluid loss must be compensated before using iodinated contrast agents.

Calcium preparations

Concomitant use may lead to an increase in plasma calcium levels and the development of hypercalcemia due to reduced renal excretion of calcium ions. If concomitant use of calcium-containing drugs is necessary, plasma calcium levels should be monitored and the dose of calcium preparations should be adjusted.

Anion exchange resins (cholestyramine and colestipol)

Anion exchange resins reduce the absorption of hydrochlorothiazide. Single doses of cholestyramine and colestipol reduce the gastrointestinal absorption of hydrochlorothiazide by 85% and 43%, respectively.

Telmisartan

Digoxin

Concomitant use of telmisartan with digoxin was associated with a mean increase in digoxin plasma C_max by 49% and C_min by 20%. At the start of treatment, during dose titration, and upon discontinuation of telmisartan treatment, digoxin plasma concentration should be carefully monitored to maintain it within the therapeutic range.

Dual blockade of the RAAS

Concomitant use of telmisartan with aliskiren or drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate to severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of telmisartan with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Clinical trial data have shown that dual blockade of the RAAS due to the combined use of ACE inhibitors, ARBs, or aliskiren is associated with an increased frequency of adverse events such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) compared to the use of only one drug acting on the RAAS.

The risk of hyperkalemia may increase with the concomitant use of other drugs that can cause hyperkalemia (potassium-containing dietary supplements and potassium-containing salt substitutes, potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), NSAIDs, including selective COX-2 inhibitors, heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim.

The frequency of hyperkalemia depends on associated risk factors. The risk increases with the use of the aforementioned combinations and is particularly high with the concomitant use of potassium-sparing diuretics and potassium-containing salt substitutes. The use of telmisartan in combination with ACE inhibitors or NSAIDs presents a lower risk provided that precautions are strictly followed.

Not recommended combinations

Potassium-sparing diuretics or potassium-containing dietary supplements

Angiotensin II receptor antagonists, such as Telmisartan, reduce the diuretic-induced loss of potassium. Potassium-sparing diuretics, e.g., spironolactone, eplerenone, triamterene, or amiloride, potassium-containing dietary supplements, or salt substitutes may lead to a significant increase in plasma potassium levels.

If concomitant use is necessary in the presence of documented hypokalemia, caution should be exercised and plasma potassium levels should be regularly monitored.

Lithium preparations. Reversible increases in plasma lithium concentrations and its toxic effects have occurred with the concomitant use of lithium preparations with ACE inhibitors and ARBs, including Telmisartan. If the use of this drug combination is necessary, careful monitoring of plasma lithium concentrations is recommended.

Combinations requiring caution

NSAIDs

NSAIDs (i.e., acetylsalicylic acid in doses used for anti-inflammatory treatment, COX-2 inhibitors, and non-selective NSAIDs) may weaken the antihypertensive effect of ARBs. In some patients with impaired renal function (e.g., dehydrated patients, elderly patients with impaired renal function), concomitant use of ARBs and drugs that inhibit COX-2 may lead to further deterioration of renal function, including the development of acute renal failure, which is usually reversible. Therefore, concomitant use of drugs should be carried out with caution, especially in elderly patients. Adequate fluid intake should be ensured, and renal function parameters should be monitored at the start of co-administration and periodically thereafter.

Ramipril

Concomitant use of telmisartan and ramipril resulted in an approximately 2.5-fold increase in the AUC and C_max of ramipril and ramiprilat. The clinical significance of this phenomenon has not been established.

Diuretics (thiazide or “loop”)

Previous treatment with high doses of diuretics, such as furosemide (“loop” diuretic) and Hydrochlorothiazide (thiazide diuretic), may lead to hypovolemia and the risk of arterial hypotension at the start of treatment with telmisartan.

Other combinations

Other antihypertensive agents

The effect of telmisartan may be enhanced when used concomitantly with other antihypertensive drugs.

Based on the pharmacological properties of baclofen and amifostine, it can be assumed that they will enhance the therapeutic effect of all antihypertensive agents, including Telmisartan. Furthermore, orthostatic hypotension may be enhanced by the intake of alcohol, barbiturates, narcotics, or antidepressants.

Corticosteroids (for systemic use)

Corticosteroids weaken the antihypertensive effect of telmisartan.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.