Telmisartan-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

C09CA07 (Telmisartan)

Active Substance

Telmisartan (Rec.INN registered by WHO)

Dosage Forms

	Telmisartan-SZ	Tablets 40 mg: 14, 28, 30 or 60 pcs.
		Tablets 80 mg: 14, 28, 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat-cylindrical, with a bevel and a score.

Excipients: sodium hydroxide, povidone K30 (medium molecular weight polyvinylpyrrolidone), meglumine, mannitol, magnesium stearate, talc.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
14 pcs. – contour cell packs (1) – cardboard packs.
14 pcs. – contour cell packs (2) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical, with a bevel and a score.

Excipients: sodium hydroxide, povidone K30 (medium molecular weight polyvinylpyrrolidone), meglumine, mannitol, magnesium stearate, talc.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
14 pcs. – contour cell packs (1) – cardboard packs.
14 pcs. – contour cell packs (2) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Angiotensin II receptor antagonist

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system, angiotensin II receptor antagonists

Pharmacological Action

Telmisartan is a specific angiotensin II receptor antagonist (type AT₁), effective when taken orally.

It has a high affinity for the AT₁ receptor subtype of angiotensin II, through which the action of angiotensin II is realized.

It displaces angiotensin II from binding to the receptor, without having an agonist effect on this receptor.

Telmisartan binds only to the AT₁ receptor subtype of angiotensin II.

The binding is long-lasting.

It has no affinity for other receptors, including the AT₂ receptor and other less studied angiotensin receptors.

The functional significance of these receptors, as well as the effect of their possible excessive stimulation by angiotensin II, the concentration of which increases when telmisartan is prescribed, has not been studied.

It reduces the concentration of aldosterone in the blood, does not inhibit plasma renin and does not block ion channels.

Telmisartan does not inhibit angiotensin-converting enzyme (kininase II) (an enzyme that also breaks down bradykinin).

Therefore, an increase in bradykinin-induced side effects is not expected.

In patients, Telmisartan at a dose of 80 mg completely blocks the hypertensive effect of angiotensin II.

The onset of the antihypertensive effect is noted within 3 hours after the first dose of telmisartan.

The effect of the drug persists for 24 hours and remains significant for up to 48 hours.

A pronounced antihypertensive effect usually develops after 4-8 weeks of regular oral administration.

In patients with arterial hypertension, Telmisartan reduces systolic and diastolic blood pressure without affecting heart rate.

In case of abrupt withdrawal of telmisartan, blood pressure gradually returns to the initial level without the development of withdrawal syndrome.

Pharmacokinetics

Absorption

When taken orally, it is rapidly absorbed from the gastrointestinal tract.

Bioavailability is 50%.

When taken simultaneously with food, the decrease in AUC ranges from 6% (at a dose of 40 mg) to 19% (at a dose of 160 mg).

After 3 hours of administration, the concentration in the plasma levels out, regardless of the time of food intake.

Distribution

Binding to plasma proteins is 99.5%, mainly with albumin and α₁-glycoprotein.

V_d is approximately 500 L.

Metabolism

It is metabolized by conjugation with glucuronic acid.

The metabolites are pharmacologically inactive.

Excretion

T_1/2 is more than 20 hours.

It is excreted through the intestines unchanged, renal excretion is less than 2% of the administered dose.

The total plasma clearance is high (900 ml/min) compared to hepatic blood flow (about 1500 ml/min).

Linearity/non-linearity

The pharmacokinetics of telmisartan when taken orally is non-linear: an increase in the concentration of the drug in plasma (C_max and AUC) occurs disproportionately to the increase in dose.

Telmisartan does not accumulate significantly in plasma upon repeated administration.

Pharmacokinetics in special patient groups

Elderly. The pharmacokinetics of telmisartan in elderly patients does not differ from young patients.

No dose adjustment is required.

Renal impairment. In patients with mild, moderate and severe renal impairment, a 2-fold increase in concentration was noted.

However, lower plasma concentrations were observed in patients with renal failure on dialysis.

Telmisartan is highly bound to plasma proteins in patients with renal impairment and cannot be removed by dialysis.

T_1/2 does not change in patients with renal impairment.

Hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment showed an increase in the absolute bioavailability of telmisartan to almost 100%.

In hepatic impairment, T_1/2 does not change.

Gender. There is a difference in plasma concentrations between men and women.

C_max in plasma is approximately 3 times and AUC is approximately 2 times higher in women compared to men without a significant effect on efficacy.

No dose adjustment is required.

Children. The main pharmacokinetic parameters of telmisartan in children aged 6 to 18 years after taking telmisartan at a dose of 1 mg/kg or 2 mg/kg for 4 weeks are generally comparable to the data obtained in the treatment of adults and confirm the non-linearity of telmisartan pharmacokinetics, especially with respect to C_max.

Indications

Adults from 18 years old

• Arterial hypertension;
• Prevention of cardiovascular diseases. Reduction of cardiovascular morbidity in adult patients with:
  • Atherothrombotic cardiovascular disease (history of coronary artery disease (CAD), stroke or peripheral artery disease (PAD));
  • Type 2 diabetes mellitus with confirmed target organ damage.

ICD codes

Dosage Regimen

The drug is taken orally, regardless of the time of food intake.

Arterial hypertension

The recommended initial dose of the drug is 1 tab. (40 mg) once a day.

In some patients, a daily dose of telmisartan of 20 mg (1/2 tablet of the 40 mg drug) is effective.

In cases where the therapeutic effect is not achieved, the maximum recommended dose can be increased to 80 mg once a day.

In addition, Telmisartan can be used in combination with thiazide diuretics (e.g., hydrochlorothiazide) or slow calcium channel blockers (e.g., amlodipine), which have demonstrated an additive antihypertensive effect when used concomitantly with telmisartan.

When deciding to increase the dose, it should be taken into account that the maximum antihypertensive effect is usually achieved within 4-8 weeks after the start of treatment (see section “Pharmacological action”).

Prevention of cardiovascular diseases

The recommended dose is 1 tab. 80 mg once a day.

It is not known whether doses of telmisartan <80 mg are effective in reducing cardiovascular morbidity.

During the initial period of treatment, careful monitoring of blood pressure is recommended; if necessary, adjustment of the dose of blood pressure-lowering drugs may be required.

Special patient groups

Elderly patients

No dose adjustment of the drug is required.

Patients with impaired renal function

There is limited experience with the use of telmisartan in patients with severe renal impairment or in patients on hemodialysis.

Such patients require a lower initial dose – 20 mg (1/2 tab. of 40 mg) (see section “Special instructions”). Patients with mild or moderate renal impairment do not require dose adjustment.

Patients with impaired liver function

The drug Telmisartan-SZ is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see section “Contraindications”).

In patients with mild or moderate hepatic impairment (Child-Pugh class A and B, respectively) the daily dose should not exceed 40 mg (see section “Special instructions”).

Children

The safety and efficacy of the drug Telmisartan-SZ in children aged 0 to 18 years have not been established.

No data available.

Adverse Reactions

Summary of the safety profile

Serious adverse reactions to Telmisartan include anaphylactic reaction and angioedema, which may occur rarely (≥1/10000, but <1/1000) and acute renal failure.

The overall frequency of adverse reactions reported with telmisartan was generally comparable to placebo (41.4% vs. 43.9%) in controlled studies in patients treated for arterial hypertension.

The frequency of adverse reactions did not depend on the dose and did not correlate with the gender, age or race of the patients.

The safety profile of telmisartan in patients treated to reduce cardiovascular morbidity was consistent with the profile obtained in patients with arterial hypertension.

Tabulated summary of adverse reactions

The adverse reactions listed below were obtained from controlled clinical trials in patients with arterial hypertension and from post-marketing observations.

The table also takes into account serious adverse reactions and adverse reactions leading to discontinuation of treatment, reported in 3 long-term clinical trials involving 21642 patients who received Telmisartan to reduce cardiovascular morbidity for 6 years.

Adverse reactions are distributed by system-organ classes with an indication of the frequency of their occurrence according to the WHO classification: very common (≥1/10); common (≥1/100, but <1/10); uncommon (≥1/1000, but <1/100); rare (≥1/10000, but <1/1000); very rare (<1/10000), frequency not known (cannot be estimated from the available data).

Description of selected adverse reactions

Sepsis

In the PRoFESS study, an increased incidence of sepsis was observed with the use of telmisartan compared to placebo.

This phenomenon may be random or related to a mechanism that has not yet been studied (see section “Pharmacological action”).

Arterial hypotension

This adverse reaction occurred frequently in patients with controlled blood pressure who received Telmisartan to reduce cardiovascular morbidity against the background of standard therapy.

Abnormal liver function/liver function disorders

Most cases of abnormal liver function tests/liver function disorders were noted during post-marketing surveillance in Japanese.

In patients of Japanese origin, such adverse reactions were noted more often.

Interstitial lung disease

Cases of interstitial lung disease have been reported from post-marketing experience, temporally associated with the use of telmisartan.

However, a causal relationship has not been established.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration in order to ensure continuous monitoring of the benefit-risk ratio of the drug.

Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to telmisartan or to any of the excipients included in the drug.
• Obstructive diseases of the biliary tract;
• Severe hepatic impairment (Child-Pugh class C);
• Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate and severe renal impairment (GFR <60 ml/min/1.73 m² body surface area);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy;
• Pregnancy;
• Breastfeeding period.

With caution:

• Bilateral renal artery stenosis or stenosis of the artery of a single kidney;
• Mild or moderate hepatic and/or renal impairment;
• Decreased circulating blood volume due to previous diuretic therapy, salt restriction, diarrhea or vomiting;
• Hyponatremia;
• Hyperkalemia;
• Conditions after kidney transplantation;
• Chronic heart failure (CHF);
• Aortic and mitral valve stenosis;
• Hypertrophic obstructive cardiomyopathy (HOCM);
• Primary hyperaldosteronism;
• Use in patients of the Black race.

Use in Pregnancy and Lactation

Pregnancy

The use of the drug Telmisartan-SZ is contraindicated during pregnancy (see section “Contraindications”).

The use of ARBs during the first trimester of pregnancy is not recommended; these drugs should not be used during pregnancy.

If pregnancy is diagnosed, the use of the drug Telmisartan-SZ should be discontinued immediately.

If necessary, alternative therapy should be prescribed (other classes of antihypertensive drugs approved for use during pregnancy).

The use of ARBs in the second and third trimesters of pregnancy is contraindicated.

In preclinical studies of telmisartan, no teratogenic effects were identified, but fetotoxicity was established.

It is known that exposure to ARBs in the second and third trimesters of pregnancy causes fetotoxicity in humans (decreased renal function, oligohydramnios, delayed skull ossification), as well as neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

Women planning pregnancy should be prescribed alternative therapy.

If treatment with ARBs occurred in the second trimester of pregnancy, an ultrasound assessment of renal function and skull condition in the fetus is recommended.

Newborns whose mothers received ARBs should be carefully monitored for arterial hypotension.

Breastfeeding period

Therapy with the drug Telmisartan-SZ is contraindicated during breastfeeding (see section “Contraindications”).

Fertility

There are no data on the effect of telmisartan on human fertility.

In preclinical studies, no effect of telmisartan on male and female fertility was observed.

Use in Hepatic Impairment

The drug should be prescribed with caution in case of impaired liver function.

The use of the drug is contraindicated in severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

There is limited experience with the use of telmisartan in patients with severe renal impairment or in patients on hemodialysis.

Such patients require a lower initial dose – 20 mg (1/2 tab. of 40 mg).

Patients with mild or moderate renal impairment do not require dose adjustment.

The drug should be prescribed with caution in case of bilateral renal artery stenosis or stenosis of the artery of a single kidney, impaired liver and kidney function, condition after kidney transplantation (no experience of use).

Pediatric Use

The use of the drug is contraindicated under the age of 18 years (efficacy and safety have not been established).

Geriatric Use

In elderly patients, no dose adjustment of the drug is required.

Special Precautions

Pregnancy

Angiotensin II receptor antagonists (ARBs) should not be prescribed during pregnancy.

If continuation of ARB therapy is not considered necessary, women planning pregnancy should switch to alternative antihypertensive drugs that have an established safety profile for use during pregnancy.

If pregnancy is diagnosed, treatment with ARBs should be discontinued immediately and, if necessary, alternative therapy should be initiated (see sections “Contraindications” and “Pregnancy and lactation”).

Hepatic Impairment

The drug Telmisartan-SZ should not be used in patients with cholestasis, biliary obstruction, or severe hepatic impairment ( Child-Pugh class C), as Telmisartan is primarily excreted in the bile. In such patients, delayed elimination of the drug from the body is expected. Telmisartan-SZ should be used with caution in patients with mild to moderate hepatic impairment ( Child-Pugh class A and B).

Renovascular Hypertension

When using drugs affecting the renin-angiotensin-aldosterone system (RAAS) in patients with bilateral renal artery stenosis or stenosis of a solitary functioning kidney, there is an increased risk of severe arterial hypotension and renal failure.

Renal Impairment, Post-Kidney Transplant

When using Telmisartan-SZ in patients with renal insufficiency, it is recommended to monitor serum potassium levels and plasma creatinine concentration. There is no experience with the use of telmisartan in patients who have recently undergone kidney transplantation. Telmisartan is not removed from the blood by hemofiltration or hemodialysis.

Reduced Blood Volume

In patients with reduced blood volume ( hypovolemia) and/or hyponatremia due to intensive diuretic therapy, salt-restricted diet, diarrhea, or vomiting, symptomatic arterial hypotension may develop, especially after the first dose of telmisartan. These conditions should be corrected before taking telmisartan. Before starting therapy with telmisartan, disturbances in water and electrolyte balance, especially such as reduced blood volume ( hypovolemia) and/or hyponatremia, must be corrected.

Dual Blockade of the RAAS

There is evidence that the concomitant use of ACE inhibitors, ARBs, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combined use of ACE inhibitors, ARBs, or aliskiren is not recommended.

If therapy with dual blockade of the RAAS is considered absolutely necessary, it should be carried out only under the supervision of a specialist and with careful monitoring of renal function, electrolyte levels, and blood pressure.

ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Other Conditions Associated with RAAS Stimulation

In patients in whom vascular tone and renal function depend predominantly on the activity of the RAAS (e.g., patients with severe chronic heart failure or primary renal disease, including renal artery stenosis), therapy with drugs that affect this system, such as telmisartan, has been associated with acute arterial hypotension, hyperazotemia, oliguria, or, rarely, acute renal failure (see the “Adverse Reactions” section).

Primary Hyperaldosteronism

Patients with primary aldosteronism generally do not respond to antihypertensive drugs that act by inhibiting the RAAS. Therefore, the use of telmisartan is not recommended.

Aortic and/or Mitral Valve Stenosis, HOCM

Caution should be exercised when using telmisartan (like other vasodilators) in patients with aortic and/or mitral stenosis or with hypertrophic obstructive cardiomyopathy (HOCM).

Patients with Diabetes Mellitus Receiving Insulin or Oral Hypoglycemic Drugs

In patients with diabetes mellitus and additional cardiovascular risk, such as coronary artery disease, when using blood pressure-lowering drugs such as ARBs or ACE inhibitors, the risk of fatal myocardial infarction (MI) and sudden cardiovascular death may increase. In patients with diabetes mellitus, coronary artery disease may be asymptomatic and therefore may be undiagnosed. Before starting Telmisartan-SZ in patients with diabetes mellitus, appropriate diagnostic tests, including an exercise test, should be performed to detect and treat coronary artery disease.

When using telmisartan in such patients, hypoglycemia may develop.

It is recommended to regularly monitor blood glucose concentration and, if necessary, adjust hypoglycemic agents.

Hyperkalemia

The use of drugs affecting the RAAS may lead to the development of hyperkalemia, especially in the presence of renal insufficiency and/or heart failure.

In elderly patients, patients with renal insufficiency, patients with diabetes mellitus, patients simultaneously taking other drugs that increase potassium levels, and/or patients with comorbidities, hyperkalemia can be fatal.

When considering the concomitant use of such drugs, the benefit-risk ratio should be assessed.

The main risk factors for the development of hyperkalemia are

• Diabetes mellitus, impaired renal function, age over 70 years;
• Concomitant use of drugs affecting the RAAS and/or causing an increase in serum potassium levels. Drugs that can cause hyperkalemia include potassium-containing salt substitutes, potassium-sparing diuretics (spironolactone, eplerenone, amiloride, triamterene), ACE inhibitors, ARBs, nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, heparin, immunosuppressive agents (cyclosporine and tacrolimus), as well as co-trimoxazole (sulfamethoxazole + trimethoprim);
• Concomitant conditions such as dehydration, acute decompensated heart failure, metabolic acidosis, impaired renal function, sudden progression of renal disease (e.g., infectious diseases), conditions accompanied by tissue necrosis (acute limb ischemia, rhabdomyolysis, extensive trauma).

Patients at high risk of developing hyperkalemia require careful monitoring of serum potassium levels (see the “Drug Interactions” section).

Ethnic Differences

ACE inhibitors and ARBs (including Telmisartan) may have a less pronounced antihypertensive effect in Black patients. This may be due to lower renin activity in hypertension in such patients compared to other races.

Other

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

Effect on Ability to Drive and Operate Machinery

No specific clinical studies have been conducted on the effect of Telmisartan-SZ on the ability to drive vehicles and operate machinery. However, when driving vehicles and working with machinery, the possibility of developing syncope or vertigo should be taken into account, which requires caution.

Overdose

Telmisartan is not removed from the blood by hemofiltration or hemodialysis.

Symptoms

The most pronounced manifestations of telmisartan overdose were arterial hypotension and tachycardia. Bradycardia, dizziness, increased serum creatinine concentration, and acute renal failure have also been reported.

Treatment

Telmisartan is not removed by hemodialysis. The patient should be under close supervision, and treatment should be symptomatic and supportive. The treatment strategy depends on the time elapsed after drug intake and the severity of the symptoms. Recommended measures include induction of vomiting and/or gastric lavage. Administration of activated charcoal may be useful in the treatment of overdose.

Serum electrolyte and creatinine concentrations should be monitored frequently. If arterial hypotension occurs, the patient should be placed in a supine position with legs elevated, and blood volume and electrolyte levels should be rapidly replenished.

Drug Interactions

Digoxin

Concomitant administration of telmisartan and digoxin resulted in a mean increase in the C_max (49%) and trough concentration (C_min) (20%) of digoxin in plasma. When initiating, adjusting the dose, and discontinuing telmisartan, digoxin concentration should be monitored to maintain it within the therapeutic range.

Drugs Causing Hyperkalemia

Like other drugs acting on the RAAS, Telmisartan may provoke hyperkalemia (see the “Special Instructions” section). The risk may increase when combined with other drugs that can also provoke hyperkalemia (potassium-containing dietary supplements and potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs, including selective COX-2 inhibitors, heparin, immunosuppressants (cyclosporine or tacrolimus) and co-trimoxazole (sulfamethoxazole+trimethoprim).

The frequency of hyperkalemia development depends on the presence of risk factors. The risk of hyperkalemia is particularly high with the concomitant use of potassium-sparing diuretics and potassium-containing salt substitutes. Concomitant use with ACE inhibitors or NSAIDs, including selective COX-2 inhibitors, is associated with a lower risk of hyperkalemia, provided that precautionary measures are strictly followed.

Concomitant use is not recommended

Potassium-Sparing Diuretics and Potassium-Containing Salt Substitutes

ARBs, such as Telmisartan, reduce potassium loss caused by diuretics. Potassium-sparing diuretics, such as spironolactone, eplerenone, triamterene, or amiloride, potassium preparations, or potassium-containing salts, can cause a significant increase in serum potassium levels. If their combined use is necessary due to proven hypokalemia, therapy should be conducted with caution under regular monitoring of serum potassium levels.

Lithium

Concomitant use of lithium preparations and ACE inhibitors or ARBs, including Telmisartan, has been associated with a reversible increase in plasma lithium concentration, accompanied by toxic effects. If concomitant use of these drugs is necessary, monitoring of serum lithium salt levels is recommended.

Concomitant use requires special caution

NSAIDs

NSAIDs (e.g., acetylsalicylic acid in doses used for anti-inflammatory treatment, COX-2 inhibitors, and non-selective NSAIDs) may reduce the antihypertensive effect of ARBs.

In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with impaired renal function), concomitant use of ARBs and COX-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such a combination should be prescribed with caution, especially in elderly patients. Patients should receive adequate fluids; furthermore, renal function parameters should be monitored at the start of concomitant use and periodically thereafter.

Ramipril

In one study, co-administration of telmisartan and ramipril resulted in up to a 2.5-fold increase in the AUC_0-24 and C_max of ramipril and ramiprilat. The clinical significance of this observation is unknown.

Loop and Thiazide Diuretics

Previous therapy with high doses of diuretics, including furosemide (a loop diuretic) and hydrochlorothiazide (a thiazide diuretic), may lead to reduced blood volume and an increased risk of arterial hypotension at the start of telmisartan therapy.

Concomitant use requires caution

Other Antihypertensive Agents

The blood pressure-lowering effect of telmisartan may be enhanced by the concomitant intake of other antihypertensive drugs.

Clinical trial data have shown that dual blockade of the RAAS by combined use of ACE inhibitors, ARBs, or aliskiren is associated with a higher incidence of adverse reactions such as arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure) compared to the use of a single agent acting on the RAAS (see the sections “Pharmacological Action”, “Contraindications”, “Special Instructions”).

Based on their pharmacological properties, the following drugs can be expected to enhance the antihypertensive effect of all antihypertensive agents, including Telmisartan: baclofen, amifostine. In addition, orthostatic hypotension may be exacerbated by alcohol, barbiturates, narcotics, or antidepressants.

Systemic Glucocorticosteroids

Glucocorticosteroids reduce the antihypertensive effect of telmisartan.

Storage Conditions

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

Shelf Life

Shelf life is 3 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.