Trosan

INSTRUCTION for medical use of the medicinal product TROSAN (TROSAN)

Composition:

Active substance: losartan potassium;

1 tablet contains 25 mg, or 50 mg, or 100 mg of losartan potassium;

Excipients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch, low-substituted hydroxypropylcellulose, magnesium stearate, Opadry White 20A58900.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: white or almost white, oval, biconvex, film-coated tablets, marked with "5" and "7" on both sides of the break line on one side and "J" with the break line on the other side;

50 mg tablets: white or almost white, oval, biconvex, film-coated tablets, marked with "E" on one side and "4" and "6" on both sides of the break line on the other side;

100 mg tablets: white or almost white, oval, biconvex, film-coated tablets, embossed with the symbol "E" on one side and "47" on the other side.

Pharmacotherapeutic group. Angiotensin II receptor antagonists, plain preparations.

ATC code C09CA01.

Pharmacological Properties

Pharmacodynamics

Losartan is a synthetic angiotensin II receptor antagonist (type AT1) for oral administration. Angiotensin II is a potent vasoconstrictor and the primary active hormone of the renin-angiotensin-aldosterone system (RAAS), playing a key role in the pathophysiology of arterial hypertension. Angiotensin II binds to the AT1 receptor, present in many tissues (e.g., vascular smooth muscle, adrenal glands, kidneys, and heart), mediating several important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates proliferation of smooth muscle cells.

Losartan selectively binds to the AT1 receptor. In both in vitro and in vivo conditions, losartan and its pharmacologically active metabolite—carboxylic acid (E-3174)—block all physiologically significant effects of angiotensin II, regardless of its source or pathway of synthesis.

Losartan does not bind to or block other hormone receptors or ion channels important for cardiovascular regulation. Losartan does not inhibit angiotensin-converting enzyme (ACE) (kinase II), the enzyme responsible for bradykinin breakdown. For this reason, there is no increase in bradykinin-mediated adverse effects.

During losartan administration, the removal of angiotensin II’s negative feedback on renin secretion leads to increased plasma renin activity (PRA). This increase in PRA results in elevated plasma angiotensin II levels. Despite this rise, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan therapy, plasma renin activity and angiotensin II levels return to baseline values within 3 days.

Both losartan and its primary metabolite have higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10–40 times more potent than losartan.

Clinical Studies in Patients with Arterial Hypertension

Controlled clinical trials have demonstrated that once-daily administration of losartan in patients with mild to moderate essential hypertension results in statistically significant reductions in systolic and diastolic blood pressure. Blood pressure measurements taken 24 hours after dosing, compared to those taken 5–6 hours after dosing, showed that the antihypertensive effect persists over 24 hours, with the natural circadian rhythm preserved. The blood pressure reduction at the end of the dosing interval was 70–80% of the effect observed 5–6 hours after dosing.

Discontinuation of losartan in hypertensive patients did not lead to a sudden increase in blood pressure (withdrawal syndrome). Despite significant blood pressure reduction, losartan had no clinically meaningful effect on heart rate.

Losartan is equally effective in men and women, and in younger patients (<65 years) and elderly patients with arterial hypertension.

LIFE Study

The LIFE (Losartan Intervention For Endpoint) study evaluated the impact of losartan on reducing cardiovascular morbidity and mortality in patients with hypertension.

The LIFE study was a randomized, double-blind, active-controlled trial involving 9,193 hypertensive patients aged 55 to 80 years with left ventricular hypertrophy on ECG. Patients were randomly assigned to treatment with either losartan 50 mg once daily or atenolol 50 mg once daily. If the target blood pressure (<140/90 mm Hg) was not achieved, hydrochlorothiazide (12.5 mg) was added initially, and if needed, the dose of losartan or atenolol was increased to 100 mg daily. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists, or beta-blockers) could be added as needed to achieve the target blood pressure.

The mean duration of follow-up was 4.8 years.

The primary efficacy endpoint was a composite of cardiovascular morbidity and mortality due to cardiovascular events, measured as the reduction in total cardiovascular mortality, stroke, and myocardial infarction. Blood pressure was significantly lower in both treatment groups. Treatment with losartan reduced the risk by 13% (p = 0.021, 95% CI 0.77–0.98) compared to atenolol, thus achieving the primary composite endpoint. This benefit was primarily due to a reduction in stroke incidence. Stroke risk was reduced by 25% with losartan compared to atenolol (p = 0.001, 95% CI 0.63–0.89). There were no significant differences between treatment groups in cardiovascular mortality or myocardial infarction rates.

Race

In the LIFE study, among non-black patients receiving losartan, there was a higher incidence of cardiovascular events (including myocardial infarction and mortality), particularly stroke, compared to non-black patients receiving atenolol.

RENAAL Study

The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan) study was a controlled clinical trial involving 1,513 patients with type 2 diabetes and nephropathy, with or without hypertension. 751 patients were treated with losartan.

The study aimed to demonstrate the nephroprotective benefits of losartan beyond blood pressure reduction.

Patients with proteinuria and serum creatinine levels of 1.3–3.0 mg/dL were randomly assigned to receive either losartan 50 mg once daily or placebo. ACE inhibitors, angiotensin II antagonists, or beta-blockers were excluded if needed to achieve target blood pressure.

During the study, the dose could be increased to 100 mg daily; 72% of patients received losartan 100 mg once daily for a prolonged period. Other antihypertensive agents (diuretics, potassium antagonists, alpha- and beta-receptor blockers, and centrally acting antihypertensives) were used as add-on therapy as needed in both patient groups. The mean duration of follow-up was 4.6 years (average 3.4 years).

The primary endpoint was a composite of doubling of serum creatinine, end-stage renal disease (dialysis or kidney transplantation), or death.

Treatment with losartan (327 events) compared to placebo (359 events) reduced the risk by 16.1% (p = 0.022) in patients reaching the primary composite endpoint.

For individual or combined secondary endpoints, results showed a 25.3% risk reduction in the losartan group for serum creatinine increase (p = 0.006); a 28.6% reduction in renal failure (p = 0.009); and a 21% reduction in serum creatinine increase and renal failure (p = 0.010). No significant differences in mortality were observed between treatment groups.

HEAAL Study

The HEAAL (Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan) study was a controlled clinical trial involving 3,834 patients aged 18 to 98 years with NYHA class II–IV heart failure and intolerance to ACE inhibitors. Patients were randomly assigned to receive either losartan 50 mg once daily or losartan 150 mg once daily, on a background of conventional therapy without ACE inhibitors.

The mean duration of follow-up was 4.7 years. The primary endpoint was a composite of death due to heart failure or hospitalization for heart failure.

Treatment with losartan 150 mg (828 events) compared to losartan 50 mg (889 events) reduced the risk by 10.1% (p = 0.027, 95% CI 0.82–0.99) in patients reaching the primary composite endpoint. This benefit was primarily due to a reduction in hospitalizations for heart failure.

Treatment with losartan 150 mg reduced the risk of heart failure events by 13.5% (p = 0.025, 95% CI 0.76–0.98) compared to losartan 50 mg. No significant differences in mortality were observed between treatment groups.

Renal impairment, hypotension, and hyperkalemia were more frequently observed in the group receiving losartan 150 mg compared to the group receiving losartan 50 mg.

ELITE I and ELITE II Studies

The ELITE studies, conducted over 48 weeks in 722 patients with NYHA class II–IV heart failure, showed no difference between losartan and captopril in the primary endpoint of long-term changes in renal function.

The observation from ELITE I that losartan reduced mortality compared to captopril was not confirmed in the subsequent ELITE II study, as described below.

In the ELITE II study, losartan 50 mg once daily (initial dose 12.5 mg, increased to 25 mg, then 50 mg once daily) was compared to captopril 50 mg three times daily (initial dose 12.5 mg, increased to 25 mg, then 50 mg three times daily). The primary endpoint of this prospective study was all-cause mortality.

This study, involving 3,152 patients with NYHA class II–IV heart failure, aimed to compare mortality rates with losartan versus captopril (mean follow-up 1.5 years). No statistically significant difference was observed between losartan and captopril in reducing all-cause mortality.

Data from both clinical trials (non-placebo-controlled) indicate that losartan was better tolerated than captopril, as measured by a significantly lower rate of therapy discontinuation due to adverse reactions.

In the ELITE II study, increased mortality was observed in a small subgroup (22% of total heart failure patients) who were receiving beta-blockers at baseline.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

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 trial)—evaluated the use of ACE inhibitor combined with angiotensin II receptor blocker.

ONTARGET involved patients with prior cardiovascular or cerebrovascular disease or type 2 diabetes with target organ damage. VA NEPHRON-D involved patients with type 2 diabetes and diabetic nephropathy.

These studies showed no significant benefit on renal and/or cardiovascular outcomes or mortality, but an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared to monotherapy. Given the similar pharmacodynamic properties, these findings are applicable to other ACE inhibitors and angiotensin II receptor blockers. Therefore, ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

The ALTITUDE (Aliskiren Trial in Type 2 Diabetes with Cardiovascular and Renal Disease) study, designed to evaluate the benefits of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney or cardiovascular disease, was prematurely terminated due to increased risk of adverse outcomes. Cardiovascular mortality and stroke rates were higher in the aliskiren group than in the placebo group, and adverse and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) occurred more frequently in the aliskiren group.

Children

Hypertension in Children

The antihypertensive effect of losartan was demonstrated in a clinical study involving 177 children aged 6 to 16 years with hypertension, body weight >20 kg, and glomerular filtration rate >30 mL/min/1.73 m². Patients with body weight 20–50 kg received 2.5, 25, or 50 mg of losartan daily; those with body weight ≥50 kg received 5, 50, or 100 mg daily. After three weeks of once-daily losartan administration, blood pressure decreased in a dose-dependent manner.

Overall, a dose-response relationship was observed. The dose-response was very evident when comparing the low-dose group to the medium-dose group (Period I: -6.2 mm Hg vs. -11.65 mm Hg), but it weakened when comparing the medium-dose group to the high-dose group (Period I: -11.65 mm Hg vs. -12.21 mm Hg). The lowest studied doses (2.5 mg and 5 mg), corresponding to a mean daily dose of 0.07 mg/kg, did not show consistently stable antihypertensive efficacy.

These results were confirmed during Period II of the study, when patients were randomized to continue losartan or switch to placebo after three weeks of treatment. The difference in blood pressure increase compared to placebo was greatest in the medium-dose group (6.70 mm Hg for medium dose vs. 5.38 mm Hg for high dose). The increase in minimum diastolic blood pressure was similar in placebo recipients and those continuing losartan at the lowest dose in each group, again indicating that the lowest dose in each group lacked significant antihypertensive effect.

The long-term effects of losartan on growth, sexual maturation, and general development have not been studied. The long-term efficacy of antihypertensive therapy with losartan in childhood for reducing cardiovascular morbidity and mortality has not been established.

In a 12-week placebo- and active-controlled (amlodipine) clinical study, the effect of losartan on proteinuria was evaluated in children with hypertension (N=60) and normotensive children (N=246) with proteinuria (defined as urine protein/creatinine ratio ≥0.3). Hypertensive children (aged 6–18 years) were randomized to receive losartan (n=30) or amlodipine (n=30). Normotensive children (aged 1–18 years) were randomized to receive losartan (n=122) or placebo (n=124). Losartan was administered at doses of 0.7–1.4 mg/kg (maximum 100 mg daily). Amlodipine was administered at doses of 0.05–0.2 mg/kg (maximum 5 mg daily).

After 12 weeks, patients receiving losartan showed a statistically significant 36% reduction in proteinuria compared to baseline, versus a 1% increase in the placebo/amlodipine group (p≤0.001). Hypertensive patients receiving losartan showed a 41.5% reduction in baseline proteinuria (95% CI -29.9; -51.1) versus a 2.4% increase (95% CI -22.2; 14.1) in the amlodipine group. Reductions in both systolic and diastolic blood pressure were greater in the losartan group (-5.5/-3.8 mm Hg) compared to amlodipine (-0.1/+0.8 mm Hg). Normotensive children showed a slight blood pressure reduction in the losartan group (-3.7/-3.4 mm Hg) compared to placebo. No significant correlation was observed between proteinuria reduction and blood pressure, although blood pressure reduction in the losartan group may have been partially influenced by proteinuria reduction.

Long-term effects of losartan in children with proteinuria were studied for up to 3 years in an open-label extension phase of the same study, involving all patients who completed the 12-week core study. A total of 268 patients were enrolled in the open-label extension and re-randomized into two groups: losartan (n=134) or enalapril (n=134), with 109 patients followed for ≥3 years (pre-specified endpoint: >100 patients completing 3 years of follow-up). Dose ranges for losartan and enalapril, at the investigator’s discretion, were 0.30–4.42 mg/kg/day and 0.02–1.13 mg/kg/day, respectively. Maximum daily doses (50 mg for body weight <50 kg and 100 mg for body weight >50 kg) were not exceeded for most patients during the extension phase.

Thus, results from the extension safety study show that losartan was well tolerated and led to sustained reduction in proteinuria without notable change in glomerular filtration rate (GFR) over 3 years. In normotensive patients (n=205), enalapril had a numerically greater effect than losartan on proteinuria (-33.0% (95% CI -47.2; -15.0) vs. -16.6% (95% CI -34.9; 6.8)) and on GFR (9.4 (95% CI 0.4; 18.4) vs. -4.0 (95% CI -13.1; 5.0) mL/min/1.73 m²). In hypertensive patients (n=49), losartan had a numerically greater effect on proteinuria (-44.5% (95% CI -64.8; -12.4) vs. -39.5% (95% CI -62.5; -2.2)) and GFR (18.9 (95% CI 5.2; 32.5) vs. -13.4 (95% CI -27.3; 0.6) mL/min/1.73 m²).

An open-label clinical study was conducted to determine the optimal dose and evaluate the safety and efficacy of losartan in children aged 6 months to 6 years with arterial hypertension. 101 patients were randomized to receive one of three initial doses of losartan in an open-label design: low dose 0.1 mg/kg/day (n=33), medium dose 0.3 mg/kg/day (n=34), or high dose 0.7 mg/kg/day (n=34). Among them, 27 were infants aged 6–23 months. The study drug was titrated to the next dose level at weeks 3, 6, and 9 for patients not achieving target blood pressure and not yet on maximum dose (1.4 mg/kg/day, but not exceeding 100 mg daily).

Of the 99 patients who received the study drug, 90 (90.9%) continued into the extension treatment phase with follow-up visits for an additional 3 months. The mean duration of therapy was 264 days.

In summary, mean blood pressure reduction from baseline was similar across all treatment groups (change in systolic blood pressure (SBP) from baseline to week 3: -7.3, -7.6, and -6.7 mm Hg for low, medium, and high dose groups, respectively; change in diastolic blood pressure (DBP): -8.2, -5.1, and -6.7 mm Hg, respectively), but no statistically significant dose-dependent response in SBP or DBP was observed.

Losartan at doses up to 1.4 mg/kg was generally well tolerated in children with arterial hypertension aged 6 months to 6 years after 12 weeks of treatment. The overall safety profile was comparable across treatment groups.

Pharmacokinetics

Absorption

After oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming the active metabolite, carboxylic acid, and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. The mean peak concentrations of losartan and its active metabolite are reached at 1 hour and 3–4 hours, respectively.

Distribution

Losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters.

Biotransformation

Approximately 14% of an intravenous or oral dose of losartan is converted to its active metabolite. In addition to the active metabolite, inactive metabolites are formed.

Elimination

The plasma clearance of losartan and its active metabolite is approximately 600 mL/min and 50 mL/min, respectively. The renal clearance of losartan and its active metabolite is approximately 74 mL/min and 26 mL/min, respectively. After oral administration, about 4% of the dose is excreted unchanged in urine, and about 6% is excreted in urine as the active metabolite. The pharmacokinetics of losartan and its active metabolite after oral doses not exceeding 200 mg are linear.

After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially, with terminal elimination half-lives of approximately 2 hours and 6–9 hours, respectively. With once-daily dosing of 100 mg losartan, no significant accumulation occurs in plasma.

Excretion of losartan and its metabolites occurs via biliary and urinary routes. After oral administration of radiolabeled (14C) losartan in humans, approximately 35% of radioactivity was recovered in urine and 58% in feces.

Special Patient Populations

Plasma concentrations of losartan and its active metabolite do not differ significantly in elderly hypertensive patients compared to younger hypertensive patients.

In women with hypertension, plasma levels of losartan are twice as high as in men, while plasma levels of the active metabolite do not differ between men and women.

In patients with mild to moderate alcoholic cirrhosis, plasma levels of losartan and its active metabolite after oral administration are approximately 5 and 1.7 times higher, respectively, than in young male volunteers.

Plasma concentrations of losartan are unchanged in patients with creatinine clearance above 10 mL/min. In patients undergoing hemodialysis, the area under the plasma concentration-time curve (AUC) of losartan is twice as high as in patients with normal renal function. Plasma concentrations of the active metabolite remain unchanged in patients with renal impairment or those on hemodialysis.

Losartan and its active metabolite are not removed by hemodialysis.

Children

Pharmacokinetics of losartan were studied in 50 patients aged >1 month to <16 years with arterial hypertension receiving once-daily oral doses of approximately 0.54 to 0.77 mg/kg (mean doses). Results showed that the active metabolite is formed in patients of all age groups. Pharmacokinetic parameters of losartan after oral administration were approximately similar in infants and toddlers, preschool children, school-aged children, and adolescents. Pharmacokinetic parameters of the metabolite showed greater variability across age groups, with statistically significant differences observed when comparing preschool children and adolescents. Exposure in infants/toddlers was relatively high.

Clinical characteristics.

Indications.

• Treatment of essential hypertension in adults, as well as in children and adolescents aged 6–18 years.
• Treatment of kidney disease in adult patients with hypertension and type 2 diabetes mellitus with proteinuria ≥ 0.5 g per day – as part of antihypertensive therapy.
• Treatment of chronic heart failure in adult patients when the use of angiotensin-converting enzyme (ACE) inhibitors is considered impossible due to intolerance, particularly cough, or is contraindicated. Patients with heart failure whose condition has stabilized on ACE inhibitor therapy should not be switched to losartan treatment. The patient must have a left ventricular ejection fraction ≤ 40%, a clinically stable condition, and be on established therapy for chronic heart failure.
• Reduction of the risk of stroke in adult patients with arterial hypertension and left ventricular hypertrophy confirmed by ECG.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Special precautions for use").
• Pregnancy or women planning to become pregnant (see section "Use during pregnancy or breastfeeding").
• Severe hepatic impairment.
• Concomitant use of losartan with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus and renal impairment (glomerular filtration rate [GFR] < 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.

Other antihypertensive agents may enhance the hypotensive effect of losartan. Concomitant use of drugs that may reduce blood pressure due to adverse reactions (e.g., tricyclic antidepressants, neuroleptics, baclofen, amifostine) may increase the risk of arterial hypotension.

Losartan is primarily metabolized by cytochrome P450 (CYP) 2C9 to its active metabolite, carboxylic acid. It has been established that fluconazole (a CYP2C9 inhibitor) reduces the conversion of losartan to its active metabolite by approximately 50%, and concomitant treatment with losartan and rifampicin (an enzyme inducer) results in a 40% reduction in plasma concentration of the active metabolite of losartan. The clinical significance of these effects is unknown. No differences in exposure were observed during concomitant treatment with fluvastatin (a weak CYP2C9 inhibitor) and losartan.

As with other drugs that block angiotensin II or its effects, concomitant use of agents that retain potassium in the body (e.g., potassium-sparing diuretics: spironolactone, triamterene, amiloride) or that may increase potassium levels (e.g., heparin, trimethoprim-containing preparations), potassium supplements, or potassium-containing salt substitutes may lead to increased serum potassium levels. Concomitant use of such medicinal products is not recommended.

Cases of reversible increases in serum lithium concentrations and lithium toxicity have been reported during concomitant use of lithium and ACE inhibitors. Such effects have very rarely occurred with angiotensin II receptor antagonists. Concomitant administration of lithium and losartan should be done with caution. If concomitant use is necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use of angiotensin II antagonists and non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses, and non-selective NSAIDs) may result in attenuation of the antihypertensive effect. Concomitant use of angiotensin II antagonists or diuretics and NSAIDs may increase the risk of renal impairment, including the possibility of acute renal failure, as well as increased serum potassium levels, particularly in patients with pre-existing renal impairment. Combined therapy should be prescribed with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored closely after initiation of concomitant therapy and periodically thereafter.

Data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse events such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) compared to use of a single agent affecting the RAAS (see sections "Contraindications", "Special precautions for use", "Pharmacological properties").

Grapefruit juice contains components that inhibit CYP450 enzymes and may reduce the concentration of the active metabolite of losartan, potentially diminishing its therapeutic effect. Grapefruit juice should be avoided during treatment with tablets containing losartan.

Special precautions for use.

Hypersensitivity.

Angioedema. Patients with a history of angioedema (facial, lip, laryngeal, and/or tongue swelling) should be closely monitored.

Hypotension and fluid/electrolyte imbalance.

Symptomatic hypotension may occur in patients with reduced fluid volume and/or excessive sodium loss due to intensive diuretic therapy, salt-free diet, diarrhea, or vomiting, especially after the first dose of losartan or following dose escalation. Prior to initiating Trosan, these conditions should be corrected or a lower initial dose should be used (see "Dosage and administration"). These recommendations also apply to children aged 6 to 18 years.

Electrolyte imbalance.

Electrolyte imbalances are frequently observed in patients with renal impairment (with or without diabetes mellitus) and should be taken into account. In a clinical trial involving patients with type 2 diabetes and nephropathy, hyperkalemia occurred more frequently with losartan than with placebo. Therefore, careful monitoring of plasma potassium levels and creatinine clearance values is required, especially in patients with heart failure and creatinine clearance of 30–50 mL/min. Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may increase serum potassium concentration (e.g., trimethoprim-containing products) with losartan is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic impairment.

Based on pharmacokinetic data showing significantly increased plasma concentrations of losartan in patients with hepatic cirrhosis, dose reduction should be considered in patients with a history of hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment; therefore, Trosan should not be prescribed to patients with severe hepatic dysfunction or to children with liver failure.

Renal impairment.

Changes in renal function, including renal failure, have been reported as a result of renin-angiotensin-aldosterone system (RAAS) inhibition, particularly in patients whose renal function depends on RAAS activity (e.g., patients with severe heart failure or pre-existing renal impairment).

As with other drugs affecting the RAAS, increases in blood urea nitrogen and serum creatinine have been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. These changes in renal function may be reversible upon discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney.

Use in pediatric patients with renal impairment.

Trosan is not recommended for use in children with glomerular filtration rate (GFR) <30 mL/min/1.73 m² due to lack of data.

Renal function should be closely monitored during treatment, as it may deteriorate, especially in the presence of other conditions (e.g., fever, dehydration) that may impair renal function.

Concomitant use of losartan and ACE inhibitors may worsen renal function. Therefore, combination therapy is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Renal transplantation.

There are no data on the use of the drug in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism.

Antihypertensive agents acting via inhibition of the renin-angiotensin system are generally ineffective in patients with primary hyperaldosteronism. Therefore, use of Trosan in such patients is not recommended.

Ischemic heart disease and cerebrovascular disorders.

As with other antihypertensive agents, excessive reduction in blood pressure in patients with ischemic cardiovascular or cerebrovascular disease may lead to myocardial infarction or stroke.

Heart failure.

As with other drugs acting on the renin-angiotensin system, patients with heart failure, with or without renal involvement, are at risk of developing severe hypotension and (often acute) renal failure.

There is insufficient therapeutic experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA class IV), and in patients with heart failure and life-threatening cardiac arrhythmias. Therefore, Trosan should be used with caution in these patient groups. Caution is also advised when losartan is used in combination with β-blockers.

Aortic and mitral valve stenosis / obstructive hypertrophic cardiomyopathy.

Like other vasodilators, the drug should be administered with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption.

Trosan should not be taken by patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Pregnancy.

Initiation of the drug during pregnancy is not recommended. For patients planning pregnancy, if continued therapy with Trosan is not considered necessary, an alternative antihypertensive treatment with an established safety profile during pregnancy should be initiated. Upon confirmation of pregnancy, losartan therapy should be discontinued immediately and, if necessary, alternative therapy started (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Other warnings and precautions.

Losartan and other angiotensin receptor antagonists are undoubtedly less effective in lowering blood pressure in black patients compared to other racial groups, likely due to the higher prevalence of low-renin status among black patients with hypertension.

Dual blockade of the RAAS

Evidence shows that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

If dual RAAS blockade is absolutely necessary, it should be performed under specialist supervision with close monitoring of renal function, electrolyte balance, and blood pressure.

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

Combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²).

Use during pregnancy or breastfeeding.

Pregnancy

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

Epidemiological data on the teratogenic risk of ACE inhibitors used during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. Due to the lack of controlled epidemiological data on the risk associated with angiotensin II receptor antagonists (ARBs), similar risks may apply to this class of drugs. Unless continued ARB therapy is considered urgently necessary, patients planning pregnancy should be switched to alternative antihypertensive agents with a well-established safety profile during pregnancy. Upon diagnosis of pregnancy, losartan should be discontinued immediately and, if necessary, alternative therapy initiated.

It is known that ARBs used during the second and third trimesters of human pregnancy cause fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal complications (renal failure, hypotension, hyperkalemia).

If losartan was used from the second trimester of pregnancy, ultrasound examination of the fetal kidneys and skull is recommended.

Newborns whose mothers took losartan during pregnancy should be closely monitored for signs of hypotension (see also sections "Contraindications" and "Special precautions for use").

Breastfeeding

Since there is no information on the use of losartan during breastfeeding, the drug is not recommended. Preferred alternatives with a better-established safety profile during breastfeeding should be considered, especially during the neonatal period or if the infant is premature.

Ability to influence reaction speed when driving or operating machinery.

No studies have been conducted on the effect of the drug on the ability to drive or operate machinery. However, the possibility of adverse reactions such as dizziness and somnolence, particularly at the beginning of treatment and during dose escalation, should be considered.

Dosage and Administration

The medicinal product should be taken independently of food intake, with a glass of water.

Trosan is not available in a 12.5 mg dosage; therefore, patients requiring a losartan dose lower than 25 mg should be prescribed the drug in an appropriate dosage form.

Arterial Hypertension

The usual initial and maintenance dose for most patients is 50 mg of the drug once daily. The maximum antihypertensive effect is achieved within 3–6 weeks after initiation of treatment. For some patients, increasing the dose to 100 mg once daily (in the morning) may be beneficial.

The drug may be used in combination with other antihypertensive agents, particularly diuretics (e.g., hydrochlorothiazide) (see sections "Contraindications", "Special Warnings and Precautions for Use", "Pharmacological Properties").

Patients with Arterial Hypertension and Type 2 Diabetes Mellitus (Proteinuria ≥ 0.5 g/day)

The usual initial dose is 50 mg of the drug once daily. The dose may be increased to 100 mg once daily depending on blood pressure levels one month after initiation of treatment. Losartan may be used concomitantly with other antihypertensive agents (e.g., diuretics, calcium channel blockers, α- or β-receptor blockers, centrally acting agents), as well as with insulin and other widely used hypoglycemic agents (e.g., sulfonylurea derivatives, glitazones, and glucosidase inhibitors).

Heart Failure

The usual initial dose of losartan for patients with heart failure is 12.5 mg once daily. The dose is usually titrated at weekly intervals (i.e., 12.5 mg daily, 25 mg daily, 50 mg daily, 100 mg daily) up to a maximum dose of 150 mg once daily, depending on patient tolerance.

Reduction of Stroke Risk in Patients with Arterial Hypertension and Left Ventricular Hypertrophy Confirmed by ECG

The usual initial dose is 50 mg of losartan once daily. Depending on blood pressure response, a low dose of hydrochlorothiazide may be added and/or the losartan dose increased to 100 mg once daily.

Special Patient Groups

Use in Patients with Reduced Circulating Blood Volume (CBV)

In patients with reduced CBV (e.g., due to high-dose diuretic therapy), consideration should be given to initiating treatment with a 25 mg once-daily dose (see section "Contraindications").

Use in Patients with Renal Impairment and Patients Undergoing Hemodialysis

No initial dose adjustment is required when administering losartan to patients with renal impairment or to those undergoing hemodialysis.

Use in Patients with Hepatic Impairment

For patients with a history of hepatic impairment, a lower initial dose should be considered. There is no experience with losartan in patients with severe hepatic impairment; therefore, losartan is contraindicated in this patient group (see section "Contraindications").

Use in Elderly Patients

Usually, no initial dose adjustment is required for elderly patients; however, initiating treatment with a 25 mg dose should be considered for patients aged 75 years and older.

Children

The safety and efficacy of the drug in children aged 6 months to 6 years have not been established. Available data are presented in the section "Pharmacological Properties", but no dosing recommendations can be provided.

For children who can swallow tablets and whose body weight is more than 20 kg but less than 50 kg, the recommended dose is 25 mg once daily. In exceptional cases, the dose may be increased to a maximum of 50 mg once daily. Dose adjustments should be made based on the effect on blood pressure.

For patients with body weight exceeding 50 kg, the usual dose is 50 mg once daily. In exceptional cases, the dose may be increased to a maximum of 100 mg once daily. Doses exceeding 1.4 mg/kg (or more than 100 mg) per day have not been studied in children.

Losartan is not recommended for use in children under 6 years of age due to insufficient data on its use in this patient group.

The drug is not recommended for use in children with eGFR < 30 mL/min/1.73 m² due to lack of relevant data.

Losartan is also not recommended for use in children with hepatic impairment.

Children

Data on the safety and efficacy of the drug in children aged 6 months to 6 years have not been established. Available data are presented in the section "Pharmacological Properties", but no dosing recommendations for children under 6 years of age can be provided.

Overdose

Symptoms of intoxication. Cases of drug overdose have not been reported. The most likely symptoms, depending on the extent of overdose, would be arterial hypotension and tachycardia. Bradycardia may occur due to stimulation of parasympathetic (vagal) innervation.

Treatment of intoxication

In case of symptomatic arterial hypotension, supportive therapy should be administered.

Treatment depends on the time elapsed since drug ingestion and on the nature and severity of symptoms.

The primary measure should be stabilization of cardiovascular function. After oral ingestion, administration of activated charcoal in an appropriate dose is indicated. Vital signs should be monitored frequently thereafter, and adjustments made as necessary. Losartan and its active metabolites are not removed by hemodialysis.

Adverse reactions

Losartan has been evaluated in clinical studies as follows:

• In a controlled clinical study involving >3000 adult patients aged 18 years and older with essential hypertension.
• In a controlled clinical study involving 177 children aged 6 to 16 years with hypertension.
• In a controlled clinical study involving >9000 patients aged 55 to 80 years with arterial hypertension and left ventricular hypertrophy.
• In controlled clinical studies involving >7700 adult patients with chronic heart failure.
• In a controlled clinical study involving >1500 patients aged 31 years and older with type 2 diabetes and proteinuria.

In these clinical studies, the most commonly reported adverse reaction was dizziness.

The frequency of adverse reactions listed below is defined as follows: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10000 to <1/1000; very rare: <1/10000; not known (cannot be estimated from available data).

Frequency of adverse reactions identified in placebo-controlled clinical trials and during post-marketing use of losartan.

* Including laryngeal edema, vocal cords, face, lips, pharynx and/or tongue (causing airway obstruction); some of these patients had a history of angioneurotic edema with other medicinal products, including ACE inhibitors.

** Includes Henoch–Schönlein purpura.

║Especially in patients with intravascular hypovolemia, e.g. in patients with severe heart failure or in patients receiving high-dose diuretic therapy.

†This adverse reaction was more frequent among patients receiving 150 mg of losartan than 50 mg.

‡In a clinical trial involving patients with type 2 diabetes and nephropathy, hyperkalemia (>5.5 mmol/L) was observed in 9.9% of patients receiving losartan tablets and in 3.4% of patients receiving placebo.

§This adverse reaction usually resolved after discontinuation of losartan.

The following additional adverse reactions occurred more frequently in patients receiving losartan than in patients receiving placebo (frequency not known): back pain, urinary tract infections, and influenza-like symptoms.

Renal and urinary disorders

In patients at increased risk, changes in renal function due to inhibition of the RAAS, including cases of renal failure, have been reported; these changes in renal function may be reversible upon discontinuation of the drug (see section "Special warnings and precautions for use").

Paediatric population

The adverse reaction profile in children is similar to that in adult patients. Data on adverse reactions in children are limited.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national adverse reaction reporting systems.

Shelf life.

3 years.

Storage conditions.

Keep out of reach and sight of children. Store at a temperature not exceeding 25 °C.

Packaging.

25 mg tablets: 10 tablets in a blister, 3 blisters in a cardboard box.

50 mg tablets: 10 tablets in a blister, 3 blisters in a cardboard box.

100 mg tablets: 10 tablets in a blister, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited – Unit III / Aurobindo Pharma Limited – Unit III

Manufacturer's address and location of operations.

Survey No: 313, 314 – Blocks I, II, III, IV, Bachupally Village, Quthubullapur Mandal, Medchal District, Telangana, 500090, India / Survey no: 313, 314 – Block I, II, III, IV, Bachupally Village, Quthubullapur Mandal, Medchal District, Telangana, 500090, India