Teveten®

INSTRUCTIONS for medical use of the medicinal product TEVETEN®

Composition:

Active substance: eprosartan;

1 tablet contains eprosartan mesilate 735.8 mg (equivalent to eprosartan 600 mg);

Excipients: tablet core – lactose monohydrate, microcrystalline cellulose, pregelatinized starch, magnesium stearate, crospovidone; coating – Opadry® White OY-S-9603 (hypromellose (E 464), polyethylene glycol 400, polysorbate 80 (E 433), titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, capsule-shaped, film-coated tablets, marked "5046" on one side and unmarked on the other.

Pharmacotherapeutic group. Simple preparations of angiotensin II antagonists.

ATC code C09CA02.

Pharmacological Properties.

Pharmacodynamics.

Eprosartan is a potent, non-peptide, orally active, non-biphenyl, non-tetrazole angiotensin II receptor blocker that selectively binds to AT1 receptors. Angiotensin II is a potent vasoconstrictor and the primary active hormone of the renin-angiotensin-aldosterone system. It plays a key role in the pathogenesis of arterial hypertension. Angiotensin II binds to AT1 receptors in various organs and tissues (e.g., vascular smooth muscle, adrenal glands, kidneys, heart) and exerts important biological effects such as vasoconstriction, sodium retention, and aldosterone release. Angiotensin II contributes to cardiac and vascular hypertrophy through its effects on vascular and cardiac smooth muscle cell growth.

Eprosartan antagonizes the effects of angiotensin II on blood pressure, renal blood flow, and aldosterone secretion in healthy individuals. The reduction in blood pressure is sustained over 24 hours without postural hypotension following the first dose. Discontinuation of eprosartan treatment does not cause a sudden rebound increase in blood pressure (withdrawal syndrome).

In patients with arterial hypertension, the reduction in blood pressure after eprosartan administration does not alter heart rate.

In the open-label, randomized, prospective MOSES study (Morbidity and Mortality after Stroke, Eprosartan compared with Nitrendipine for Secondary Prevention), 1405 hypertensive patients with a history of cerebrovascular complications were treated either with eprosartan or nitrendipine. In the eprosartan group, 78% of patients received a daily dose of 600 mg and 12% received up to 800 mg per day. In the nitrendipine group, 47% received 10 mg and 42% received 20 mg daily (11% received up to 40 mg). The primary composite endpoint consisted of all-cause mortality, cerebrovascular events (transient ischemic attack, prolonged reversible ischemic neurological deficit, stroke), and cardiovascular events (unstable angina, myocardial infarction, heart failure, pulmonary embolism, and fatal cardiac arrhythmias), including recurrences. Target blood pressure was well achieved and maintained throughout the study in both treatment groups. The primary endpoint showed a significantly better outcome in the eprosartan group (21% risk reduction). In the first analysis of complications, risk reduction was 12% for cerebrovascular and 30% for cardiovascular endpoints. These results were primarily due to a reduced incidence of transient ischemic attack/prolonged reversible ischemic neurological deficit, unstable angina, and heart failure. All-cause mortality was lower in the nitrendipine group. Specifically, 57 of 681 patients died in the eprosartan group compared to 52 of 671 in the nitrendipine group (relative risk 1.07; 95% confidence interval (CI) 0.73–1.56; p = 0.725). Fatal and non-fatal myocardial infarction occurred in 18 patients in the eprosartan group versus 20 in the nitrendipine group, and stroke occurred in 36 versus 42 patients, respectively, indicating the effectiveness of eprosartan compared to nitrendipine. The effect of eprosartan on the primary endpoint was more pronounced in patients not receiving beta-blockers.

In patients with arterial hypertension, eprosartan does not affect fasting plasma levels of glucose, triglycerides, cholesterol, or low-density lipoproteins.

Eprosartan does not interfere with renal autoregulatory mechanisms. In healthy men, eprosartan improves effective renal blood flow. Eprosartan maintains renal function in patients with essential hypertension and in patients with renal impairment. Eprosartan does not reduce glomerular filtration rate in healthy men, in patients with arterial hypertension, or in patients with varying degrees of renal impairment severity. Eprosartan induces a natriuretic effect in healthy individuals on a low-salt diet. Eprosartan can be safely administered to patients with essential hypertension and to those with varying degrees of renal impairment without causing sodium retention or worsening of renal function.

Eprosartan has no significant effect on uric acid excretion.

Eprosartan does not enhance effects related to bradykinin activation mediated by angiotensin-converting enzyme (ACE), such as cough. In a study comparing cough incidence in patients treated with eprosartan versus those receiving an ACE inhibitor, the incidence of persistent dry cough was significantly lower (1.5%) in the eprosartan group than in the ACE inhibitor group (5.4%) (p < 0.05). The incidence of any type of cough was also significantly lower (p < 0.05) in the eprosartan group (21.2%) compared to the ACE inhibitor group (29.9%). In another study evaluating cough incidence in patients with prior cough during ACE inhibitor therapy, the incidence of persistent dry cough was 2.6% in the eprosartan group, 2.7% in the placebo group, and 25% in the ACE inhibitor group. The difference in persistent dry cough incidence between the eprosartan and ACE inhibitor groups was statistically significant (p < 0.01), whereas no such difference was observed between eprosartan and placebo. The incidence of any type of cough was also significantly lower (p < 0.01) with eprosartan compared to ACE inhibitor, and similar to placebo. Additionally, a pooled analysis of results from six double-blind clinical trials involving 1554 patients demonstrated that the incidence of cough reported spontaneously was similar in patients receiving eprosartan (3.5%) and those receiving placebo (2.6%).

Based on data from three clinical trials (n = 791), the antihypertensive effect of eprosartan was at least equivalent to that of the ACE inhibitor enalapril, with a trend toward greater efficacy of eprosartan.

The use of an ACE inhibitor in combination with an angiotensin II receptor blocker was investigated in two large randomized controlled trials (ONTARGET [Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [Veterans Affairs Nephropathy in Diabetes study]).

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes and diabetic nephropathy.

These studies showed no significant benefit on kidney disease and/or cardiovascular outcomes or reduction in mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similarity in pharmacodynamic properties, these findings are relevant for other ACE inhibitors and angiotensin II receptor blockers as well.

Therefore, concomitant use of an ACE inhibitor and an angiotensin II receptor blocker is not recommended in patients with diabetic nephropathy.

The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) was conducted to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or a combination of these conditions. The trial was terminated early due to an increased risk of adverse events. An increased incidence of stroke and fatal outcomes, as well as adverse effects including serious events (hyperkalemia, hypotension, and renal dysfunction), was observed in the aliskiren group compared to the placebo group.

Pharmacokinetics.

The absolute bioavailability of eprosartan after a single oral 300 mg dose is approximately 13% due to its limited absorption. Peak plasma concentration of eprosartan is reached within 1–2 hours after oral administration on an empty stomach. Pharmacokinetic data indicate that plasma concentrations of eprosartan are proportional to the dose when doses between 100 and 200 mg are administered, and less than proportional at doses between 400 and 800 mg. The elimination half-life of eprosartan after oral administration typically ranges from 5 to 9 hours. With chronic administration, eprosartan does not accumulate significantly. Administration of eprosartan with food results in a minor delay in absorption, with less than a 25% change in Cmax and AUC, which is not clinically significant.

Protein binding of eprosartan to plasma proteins is high (approximately 98%) and consistent across the therapeutic concentration range. Protein binding is independent of gender, age, hepatic impairment, or presence of mild to moderate renal impairment, but may be reduced in some patients with severe renal impairment.

In humans, after oral and intravenous administration of 14C-eprosartan, eprosartan was the only compound detected in plasma and feces. Approximately 20% of the radioactive dose of eprosartan is excreted in urine as the acyl glucuronide conjugate, and 80% as unchanged eprosartan.

The volume of distribution of eprosartan is approximately 13 L. Total plasma clearance is approximately 130 mL/min. Eprosartan is excreted in both urine and bile. After intravenous administration of 14C-eprosartan, approximately 61% of radioactivity is recovered in feces and 37% in urine. After oral administration of 14C-eprosartan, approximately 90% of radioactivity is recovered in feces and 7% in urine.

AUC and Cmax values of eprosartan are increased in elderly individuals (on average approximately 2-fold), but this does not require dosage adjustment.

AUC values of eprosartan are increased (on average approximately 40%) without changes in Cmax in patients with hepatic impairment, which also does not require dosage adjustment.

AUC and Cmax values of eprosartan were approximately 30% higher in patients with moderate renal impairment (creatinine clearance 30–59 mL/min) and 50% higher in patients with severe renal impairment (creatinine clearance 5–29 mL/min) compared to individuals with normal renal function. No dosage adjustment is required.

Pharmacokinetics of eprosartan do not differ between women and men.

Clinical characteristics.

Indications

Essential hypertension.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Pregnancy or planned pregnancy (see section "Use in pregnancy or lactation").

Bilateral renal vascular disease with significant hemodynamic impairment or severe stenosis of the renal artery of a single functioning kidney.

Concomitant use of the medicinal product Teveten® with aliskiren-containing products in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacological properties").

Interaction with other medicinal products and other forms of interaction

Due to the observation of increased serum potassium levels in placebo-controlled studies, and based on experience with other drugs affecting the renin-angiotensin-aldosterone system, concomitant use of eprosartan with potassium-sparing diuretics, potassium-containing dietary supplements and salt substitutes, or other drugs that may increase serum potassium levels (e.g., heparin) is expected to lead to increased serum potassium levels.

Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren leads to an increased incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to monotherapy with a drug acting on the renin-angiotensin-aldosterone system (see sections "Contraindications", "Special warnings and precautions for use", and "Pharmacological properties").

The antihypertensive effect of eprosartan may be enhanced by other antihypertensive agents.

There have been reports of toxicity and reversible increases in serum lithium levels when lithium preparations are used concomitantly with ACE inhibitors. A similar effect cannot be excluded with eprosartan; therefore, serum lithium levels should be monitored if eprosartan is used concomitantly with lithium preparations.

Eprosartan does not exhibit in vitro inhibitory effects on human cytochrome P450 enzymes CYP1A, 2A6, 2C9/8, 2C19, 2D6, 2E, and 3A.

As with ACE inhibitors, concomitant use of angiotensin II receptor blockers with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of worsening renal function, including the possibility of acute renal failure, and increased serum potassium levels, particularly in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored at the start of treatment and periodically thereafter.

Concomitant therapy with losartan and the NSAID indomethacin resulted in reduced efficacy of the angiotensin II receptor blocker; a class effect of angiotensin II receptor blockers cannot be excluded.

Special precautions for use.

Hepatic impairment

Extreme caution should be exercised when administering epoasartan to patients with hepatic impairment due to limited experience with this population.

Renal impairment

Dosage adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min). Epoasartan should be used with caution in patients with creatinine clearance < 30 mL/min or in patients undergoing dialysis.

Patients at risk of renal impairment

Some patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe heart failure [NYHA class IV], bilateral renal artery stenosis, or stenosis of the artery of a solitary kidney) are at risk of developing oliguria and/or progressive azotemia, and rarely, acute renal failure during therapy with ACE inhibitors. The likelihood of such complications is higher in patients receiving concomitant diuretic therapy. There is insufficient therapeutic experience to determine the comparable risk of renal function impairment in these vulnerable patients when using angiotensin II receptor blockers such as epoasartan. If epoasartan is prescribed to patients with impaired renal function, renal function should be assessed before initiating treatment and monitored periodically during therapy. If worsening of renal function occurs during treatment, the continued use of epoasartan should be reconsidered.

The following warnings are based on experience with other drugs in this class and also with ACE inhibitors.

Hyperkalemia

Hyperkalemia may occur during treatment with medicinal products affecting the renin-angiotensin-aldosterone system, particularly in the presence of renal impairment and/or heart failure. Appropriate monitoring of serum potassium levels is recommended in patients at risk.

Based on experience with medicinal products affecting the renin-angiotensin-aldosterone system, concomitant use of epoasartan with potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin) may lead to elevated serum potassium levels and therefore requires caution.

Dual blockade of the renin-angiotensin-aldosterone system

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and renal impairment (including acute renal failure). Therefore, dual blockade of the renin-angiotensin-aldosterone system by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacological properties").

If dual blockade therapy is absolutely necessary, it should be administered under strict medical supervision with frequent monitoring of renal function, electrolytes, and blood pressure. Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.

Primary hyperaldosteronism

Treatment with epoasartan is not recommended in patients with primary hyperaldosteronism.

Hypotension

Symptomatic hypotension may occur in patients with significant fluid and/or salt depletion (e.g., due to high-dose diuretic therapy). Such depletion should be corrected prior to initiating treatment with Teveten®.

Coronary artery disease

Experience with the use of epoasartan in patients with coronary artery disease is limited.

Aortic and mitral valve stenosis/hypertrophic cardiomyopathy

As with all vasodilators, epoasartan should be used with caution in patients with aortic or mitral valve stenosis or hypertrophic cardiomyopathy.

Intestinal angioedema

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

Kidney transplantation

There is no experience with the use of epoasartan in patients with recent kidney transplantation.

Use during pregnancy

Therapy with angiotensin II receptor antagonists should not be initiated during pregnancy. Patients planning pregnancy should be switched to alternative antihypertensive therapy with a well-established safety profile in pregnancy. Angiotensin II receptor antagonist therapy should be discontinued immediately upon confirmation of pregnancy, and alternative therapy should be initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Other warnings

As observed with ACE inhibitors, epoasartan and other angiotensin II receptor antagonists appear to be less effective in lowering blood pressure in black patients compared to other racial groups, possibly due to the higher prevalence of low-renin states in the black hypertensive population.

This medicinal product should not be administered to patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

This medicinal product should not be used in pregnant women or women planning pregnancy.

Epidemiological data on the teratogenic risk associated with exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive, although a small increased risk cannot be excluded. Due to the lack of controlled epidemiological studies on the risk associated with angiotensin II receptor antagonists, this risk cannot be excluded for drugs in this class. Patients planning pregnancy should be switched to alternative antihypertensive therapy with a well-established safety profile in pregnancy. Angiotensin II receptor antagonist therapy should be discontinued immediately upon confirmation of pregnancy, and alternative therapy should be initiated if necessary.

It is known that angiotensin II receptor antagonist therapy during the second and third trimesters of human pregnancy causes fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If angiotensin II receptor antagonist exposure occurs during the second trimester of pregnancy, ultrasound evaluation of fetal kidneys and skull bones is recommended.

Newborns whose mothers have used angiotensin II receptor antagonists should be closely monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Teveten® is not recommended for use during breastfeeding due to lack of adequate data. Alternative therapies with established safety profiles during breastfeeding should be preferred, especially when nursing newborns or preterm infants.

Ability to affect the speed of reactions while driving or operating machinery

The effect of epoasartan on the ability to drive or operate machinery has not been studied; however, due to its pharmacodynamic properties, a negative effect on this ability is unlikely. Nevertheless, caution should be exercised, as fatigue and dizziness may occasionally occur during antihypertensive therapy.

Dosage and Administration

The recommended dose for adults is 600 mg of eprosartan once daily (in the morning).

In most patients, maximum reduction of blood pressure is achieved within 2–3 weeks of treatment.

Teveten® can be used as monotherapy or in combination with other antihypertensive agents. In particular, the addition of thiazide diuretics, such as hydrochlorothiazide, or calcium channel blockers, such as sustained-release nifedipine, has demonstrated an additive effect when used with eprosartan.

The drug may be taken regardless of food intake.

Elderly patients

No specific dose adjustment is required for elderly patients.

Patients with hepatic impairment

Experience with use in patients with hepatic insufficiency is limited (see section "Special Warnings and Precautions for Use").

Patients with renal impairment

For patients with moderate or severe renal impairment (creatinine clearance < 60 ml/min), the daily dose should not exceed 600 mg.

Children. The use of this medicinal product in pediatric patients is not recommended due to insufficient safety and efficacy data.

Overdose

Data on human overdose are limited. During the post-marketing period, isolated reports of oral doses up to 12,000 mg have been received. Most patients reported no symptoms. One patient experienced circulatory collapse after ingestion of 12,000 mg of eprosartan. The patient fully recovered. The most likely manifestation of overdose is arterial hypotension. In case of symptomatic hypotension, appropriate supportive therapy should be administered.

Adverse reactions.

In patients receiving eprosartan treatment, the most commonly observed adverse reactions were headache and non-specific gastrointestinal disorders – occurring in approximately 11% and 8% of patients, respectively.

Adverse reactions are listed by frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000).

Immune system disorders:

uncommon: hypersensitivity*.

Nervous system disorders:

very common: headache*;

common: dizziness*.

Vascular disorders:

uncommon: arterial hypotension.

Respiratory, thoracic and mediastinal disorders:

common: rhinitis.

Skin and subcutaneous tissue disorders:

common: allergic skin reactions (including rash, pruritus);

uncommon: angioedema*.

Gastrointestinal disorders:

common: non-specific gastrointestinal disorders: nausea, vomiting, diarrhea.

General disorders and administration site conditions:

common: asthenia.

*Frequency no higher than with placebo.

In addition to adverse reactions identified during clinical trials, the following adverse reactions have been spontaneously reported during post-marketing use of eprosartan, with frequency that cannot be estimated from available data (unknown).

Renal and urinary disorders:

renal dysfunction, including renal failure, in patients at risk (e.g., with renal artery stenosis).

Musculoskeletal and connective tissue disorders:

arthralgia.

Description of selected adverse reactions:

Cases of intestinal angioedema have been reported following administration of angiotensin II receptor blockers (see section "Special precautions for use").

Shelf life. 3 years.

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

Packaging. 14 tablets in a blister pack; 1 or 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Mylan Laboratories SAS, France.

Manufacturer's address and place of business. Route de Belleville, Lieu dit Maillard, 01400, Chatillon-sur-Chalaronne, France.