Lotar®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOTAR® (LOTAR®)

Composition:

Active substance: losartan;

One film-coated tablet contains 50 mg or 100 mg of losartan potassium;

Excipients: magnesium stearate; microcrystalline cellulose; pregelatinized starch; sodium starch glycolate (type A); lactose monohydrate;

Coating of 50 mg tablets: hydroxypropylcellulose; titanium dioxide (E 171).

Coating of 100 mg tablets: hydroxypropylcellulose; titanium dioxide (E 171); yellow iron oxide 10 (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg tablets

white, round, biconvex, film-coated tablets with a score line on one side;

100 mg tablets

light-yellow, round, biconvex, film-coated tablets with a score line on one side.

Pharmacotherapeutic group. Simple angiotensin II receptor antagonists.

ATC code C09CA01.

Pharmacological Properties.

Pharmacodynamics.

Losartan is a synthetic angiotensin II receptor antagonist (AT1 type) for oral administration. Angiotensin II is a potent vasoconstrictor and the primary active hormone of the renin-angiotensin system (RAS), playing a key role in the pathophysiology of arterial hypertension. Angiotensin II binds to AT1 receptors present in many tissues (e.g., vascular smooth muscle, adrenal glands, kidneys, and heart), triggering a cascade of 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 vitro and in vivo, losartan and its pharmacologically active metabolite—carboxylic acid (E3174)—block all physiologically significant effects of angiotensin II, regardless of its source or pathway of synthesis.

Losartan does not bind to or block receptors of other hormones or ion channels important for cardiovascular regulation. Losartan does not inhibit angiotensin-converting enzyme (ACE) (kininase II), the enzyme responsible for bradykinin breakdown. As a result, effects not directly related to AT1 receptor blockade (e.g., increased bradykinin effects) have not been associated with losartan use.

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

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

Studies in Patients with Arterial Hypertension

In controlled clinical trials, once-daily administration of losartan to patients with mild to moderate essential hypertension resulted in statistically significant reductions in systolic and diastolic blood pressure. Blood pressure measurements taken 24 hours after dosing, compared to 5–6 hours after dosing, demonstrated sustained blood pressure reduction over 24 hours, with the natural circadian rhythm preserved. Blood pressure reduction at the end of the dosing interval was 70–80% of the effect observed at 5–6 hours post-dose.

Discontinuation of losartan in patients with arterial hypertension did not lead to sudden blood pressure elevation (rebound phenomenon). Despite significant blood pressure reduction, losartan did not have a clinically meaningful effect on heart rate.

Losartan has equivalent efficacy in men and women, as well as in younger (under 65 years) and older patients with arterial hypertension.

The LIFE Study

The LIFE study (Losartan Intervention For Endpoint Reduction in Hypertension) was a randomized, double-blind, active-controlled trial involving 9193 hypertensive patients aged 55 to 80 years with electrocardiographically documented left ventricular hypertrophy. Patients were randomly assigned to treatment with either losartan 50 mg once daily or atenolol 50 mg once daily. If 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 (except ACE inhibitors, angiotensin II antagonists, or beta-blockers) could be added if necessary to achieve 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 a reduction in the overall incidence of cardiovascular death, stroke, and myocardial infarction. Blood pressure was significantly lower in both treatment groups. Treatment with losartan reduced risk by 13.0% (p = 0.021; 95% confidence interval (CI) 0.77–0.98) compared to atenolol. Thus, the primary composite endpoint was achieved. This result was primarily attributable to a reduction in stroke incidence. Treatment with losartan reduced stroke risk by 25% compared to atenolol (p = 0.001; 95% CI 0.63–0.89). There were no significant differences between treatment groups in rates of cardiovascular mortality or myocardial infarction.

Race

In the LIFE study, non-black patients receiving losartan had a higher risk of the primary composite endpoint (i.e., cardiovascular disease, including myocardial infarction and cardiovascular death), particularly stroke, compared to black patients receiving atenolol. Therefore, the results of losartan use compared to atenolol in the LIFE study regarding cardiovascular morbidity and mortality do not apply to non-black patients with arterial hypertension and left ventricular hypertrophy.

The RENAAL Study

The RENAAL study (Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan) was a controlled clinical trial involving 1513 patients with type II diabetes and associated renal disease, 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 treatment with either losartan 50 mg once daily (titrated as needed to achieve appropriate blood pressure) or placebo, against a background of antihypertensive therapy excluding ACE inhibitors, angiotensin II antagonists, or beta-blockers.

During the study, dose escalation to 100 mg daily was permitted; 72% of patients received losartan 100 mg once daily long-term. 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 observation period lasted 4.6 years (mean 3.4 years).

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

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

For individual or combined components of the primary endpoint, results showed a 25.3% reduction in serum creatinine doubling (p = 0.006); a 28.6% reduction in end-stage renal disease (p = 0.009); and a 21% reduction in serum creatinine doubling and end-stage renal disease (p = 0.010). No significant differences in mortality rates were observed between treatment groups. In this study, losartan was generally well tolerated, as indicated by a frequency of treatment discontinuation due to adverse reactions comparable to the placebo group.

The HEAAL Study

The HEAAL study (Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan) was a controlled clinical trial involving 3834 patients aged 18 to 98 years with heart failure class II–IV according to the New York Heart Association (NYHA) classification and intolerance to ACE inhibitors. Patients were randomly assigned to treatment with 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 patient 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 risk by 10.1% (p = 0.027; 95% CI 0.82–0.99) in the number of patients reaching the primary composite endpoint. This result was primarily due to a reduction in hospitalizations for heart failure.

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

Renal impairment, arterial hypotension, and hyperkalemia were observed more frequently in the group receiving losartan 150 mg than in the group receiving losartan 50 mg, but these adverse reactions did not lead to a significant increase in treatment discontinuation rates in the 150 mg group.

The ELITE I and ELITE II Studies

The ELITE studies were conducted over 48 weeks and involved 722 patients with heart failure class II–IV according to the New York Heart Association (NYHA) classification. No difference was observed between patients receiving losartan and those receiving captopril in the ratio of the primary endpoint of long-term changes in renal function.

The observation from ELITE I that losartan use reduced mortality risk 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 once 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 3152 patients with heart failure class II–IV according to NYHA classification, was conducted to assess mortality rates with losartan and captopril (mean observation period 1.5 years). The primary endpoint showed no statistically significant difference between losartan and captopril in reducing all-cause mortality.

Data exist from both clinical trials (non-placebo-controlled) indicating that losartan was better tolerated than captopril in patients with heart failure, as measured by a significantly lower rate of treatment discontinuation due to adverse reactions and significantly less cough.

During 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 Study)) evaluated the use of a combination of an ACE inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study involving patients with prior cardiovascular or cerebrovascular disease or type II diabetes with evidence of target organ damage. VA NEPHRON-D was a study involving patients with type II diabetes and diabetic nephropathy.

These studies did not demonstrate significant beneficial effects on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers due to their similar pharmacodynamic profiles. Therefore, ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Endpoints) was a study designed to evaluate the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type II diabetes and chronic kidney disease or cardiovascular disease, or both. The study was prematurely terminated due to an increased risk of adverse outcomes. The rate of cardiovascular mortality and stroke in the aliskiren group was higher than in the placebo group, and adverse reactions and serious adverse reactions (hyperkalemia, arterial hypotension, and renal dysfunction) occurred more frequently in the aliskiren group than in the placebo group.

Pediatric Population

Arterial Hypertension in Children

A clinical study involving 177 children aged 6 to 16 years with body weight ≥20 kg and glomerular filtration rate >30 mL/min/1.73 m² was conducted to establish the antihypertensive effect of losartan in children. Patients with body weight >20 to <50 kg received losartan at doses of 2.5, 25, or 50 mg/day, and patients with body weight >50 kg received losartan at doses of 5, 50, or 100 mg/day. After 3 weeks, once-daily administration of losartan was shown to produce dose-dependent blood pressure reduction.

Overall, the response to treatment was dose-dependent. The dose-response relationship was particularly evident when comparing the lowest-dose group with the medium-dose group (Period I: -6.2 mm Hg vs. -11.65 mm Hg); the relationship diminished when comparing the medium-dose group with the highest-dose group (Period I: -11.65 mm Hg vs. -12.21 mm Hg). The lowest studied doses of 2.5 mg and 5 mg, corresponding to a mean daily dose of 0.07 mg/kg, did not produce sustained antihypertensive effects.

These results were confirmed in Period II of the study, when after 3 weeks of treatment, patients were randomized to receive either losartan or placebo. Differences in blood pressure increases widened compared to the placebo group and were greatest in the medium-dose group (6.7 mm Hg for medium dose vs. 5.38 mm Hg for highest dose). Minimal increases in diastolic pressure in placebo-treated patients and those receiving the lowest dose of losartan were similar, again confirming the assumption that the lowest dose of losartan does not produce significant antihypertensive effects.

The long-term effects of losartan on growth, sexual maturation, and general development have not been studied. The efficacy of long-term losartan treatment in pediatric patients for reducing cardiovascular morbidity and mortality has also not been established.

The effect of losartan on proteinuria was evaluated in a placebo-controlled and active (amlodipine)-controlled 12-week clinical trial involving children with arterial hypertension (n = 60) and normal blood pressure (n = 246) combined with proteinuria. All patients had proteinuria and glomerular filtration rate (GFR) >30 mL/min/1.73 m².

Proteinuria was defined as a urine protein-to-creatinine ratio ≥0.3. Hypertensive patients (aged 6 to 18 years) were randomized to receive either losartan (n = 30) or amlodipine (n = 30). Normotensive patients (aged 1 to 18 years) were randomized to receive either losartan (n = 122) or placebo (n = 124). Losartan was administered at doses of 0.7 to 1.4 mg/kg (up to a maximum dose of 100 mg/day). Amlodipine was administered at doses of 0.05 to 0.2 mg/kg (up to a maximum dose of 5 mg/day).

Overall, after 12 weeks of treatment, patients receiving losartan showed a statistically significant 36% reduction in proteinuria compared to baseline, versus a 1% increase in the placebo/amlodipine groups (p = 0.001). In hypertensive patients receiving losartan, proteinuria reduction compared to baseline was -41.5% (95% CI -29.9; -51.1) versus +2.4% (95% CI -22.2; 14.1) in the amlodipine group. Reductions in diastolic and systolic blood pressure were greater in the losartan group (-5.5/-3.8 mm Hg) than in the amlodipine group (-0.1/+0.8 mm Hg). In children with normal blood pressure, a small reduction in blood pressure was also observed with losartan (-3.7/-3.4 mm Hg) compared to the placebo group. No significant correlation between proteinuria reduction and blood pressure reduction was observed, although proteinuria reduction in the losartan group may have been partially attributable to blood pressure reduction.

The long-term effect of losartan in children with proteinuria was studied over 3 years in an open-label phase of the same study, to which all patients who completed the 12-week core study were invited. Overall, 268 patients entered the open-label phase and were re-randomized to either losartan (n = 134) or enalapril (n = 134), with 109 patients followed for >3 years (predefined stopping point for >100 patients followed 3 years in the open-label phase). Investigator-determined dose ranges for losartan and enalapril were 0.30–4.42 mg/kg/day and 0.02–1.13 mg/kg/day, respectively. Maximum daily doses of 50 mg for body weight <50 kg and 100 mg for >50 kg were not exceeded for most patients in the open-label phase.

Thus, safety results indicate that losartan was well tolerated and led to sustained reduction in proteinuria without notable change in GFR over 3 years. In normotensive patients (n = 205), enalapril had a numerically greater effect on proteinuria compared to losartan (-33.0% (95% CI -47.2; -15.0) vs. -16.6% (95% CI -34.9; 6.8)) and on GFR (9.4). 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 on GFR (18.9 (95% CI 5.2)).

An open-label clinical trial with dose-ranging was conducted to evaluate the safety and efficacy of losartan in children aged 6 months to 6 years with arterial hypertension. Overall, 101 patients were randomized into one of three different initial doses of losartan in the open-label phase: 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). Of these, 27 were infants defined as children aged 6 to 23 months. The investigational drug was titrated to the next dose level at weeks 3, 6, and 9 for patients who did not achieve target blood pressure and had not yet reached the maximum dose (1.4 mg/kg/day, not exceeding 100 mg/day) of losartan.

Of the 99 patients who received the investigational medicinal product, 90 patients (90.9%) continued into the open-label phase of the study with subsequent visits every 3 months. The mean duration of therapy was 264 days.

As a result, mean blood pressure reduction from baseline was similar across all treatment groups (change from baseline in systolic blood pressure to week 3 was -7.3, -7.6, and -6.7 mm Hg in the low-, medium-, and high-dose groups, respectively; reduction in diastolic blood pressure from baseline to week 3 was -8.2, -5.1, and -6.7 mm Hg in the low-, medium-, and high-dose groups, respectively), but there was no statistically significant dose-dependent response for systolic and diastolic blood pressure.

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 between treatment groups.

Pharmacokinetics.

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

Distribution. The binding of losartan and its active metabolite to plasma proteins, primarily albumin, exceeds 99%. The volume of distribution is 34 L.

Metabolism. Approximately 14% of the losartan dose (after oral or intravenous administration) is converted to its active metabolite. After oral or intravenous administration of radiolabeled (14C) losartan, circulating plasma radioactivity is primarily associated with losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was observed in approximately 1% of subjects studied. Biologically inactive metabolites are also formed.

Elimination. Plasma clearance of losartan and its active metabolite is approximately 600 and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is approximately 74 and 26 mL/min, respectively. After oral administration of losartan, approximately 4% of the dose is excreted unchanged in urine and approximately 6% of the dose is excreted in urine as the active metabolite. Losartan and its active metabolite exhibit linear pharmacokinetics after oral administration of losartan potassium in doses up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially, with terminal half-lives (T1/2) of approximately 2 hours and 6–9 hours, respectively. After single 100 mg dose administration, neither losartan nor its active metabolite accumulate significantly in plasma.

Excretion of losartan and its metabolites occurs via bile and urine. After oral administration of radiolabeled (14C) losartan, approximately 35% of the radioactive label is recovered in urine and 58% in feces. After intravenous administration of radiolabeled (14C) losartan, approximately 43% of the radioactive label is recovered in urine and 50% in feces.

Pharmacokinetics in Special Patient Populations

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

Plasma concentrations of losartan were twice as high in women with arterial hypertension compared to men with arterial hypertension. Concentrations of the active metabolite did not differ between men and women.

After oral administration of losartan in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of losartan and its active metabolite were 5 and 1.7 times higher, respectively, than in young healthy male volunteers (see sections "Special Warnings" and "Dosage and Administration").

Plasma concentrations of losartan in patients with creatinine clearance above 10 mL/min do not differ from those in individuals with normal renal function. The area under the pharmacokinetic curve in patients undergoing hemodialysis is approximately twice that in patients with normal renal function.

Plasma concentration of the active metabolite does not change in patients with renal impairment or in those undergoing hemodialysis.

Neither losartan nor its active metabolite can be removed by hemodialysis.

Pharmacokinetics in Children

The pharmacokinetics of losartan were studied in 50 hypertensive pediatric patients aged 1 month to 16 years after oral administration of approximately 0.54–0.77 mg/kg losartan once daily (mean doses). Results showed that the active metabolite is formed from losartan in all age groups. Pharmacokinetic parameters of losartan after oral administration were approximately similar in infants and toddlers, preschool children, school-age children, and adolescents. Pharmacokinetic parameters of the metabolite differed more between age groups. Differences became statistically significant when comparing preschool children with adolescents. Exposure in infants/toddlers was relatively high.

Clinical characteristics.

Indications.

• Treatment of essential hypertension in adults, as well as in children aged 6 years and older.
• Treatment of kidney disease in adult patients with arterial hypertension and type 2 diabetes mellitus with proteinuria ≥ 0.5 g/day as part of antihypertensive therapy.
• Treatment of chronic heart failure (in patients aged 60 years and older) when angiotensin-converting enzyme (ACE) inhibitors are considered unsuitable due to intolerance, particularly cough, or are contraindicated. Patients with heart failure whose condition has stabilized on ACE inhibitor therapy should not be switched to losartan. The patient must have a left ventricular ejection fraction ≤ 40%, be clinically stable, and be receiving standard therapy for chronic heart failure.
• Reduction of the risk of stroke in adult patients with arterial hypertension and electrocardiographically confirmed left ventricular hypertrophy.

Contraindications.

Hypersensitivity to the active substance or to any of the other components of the medicinal product.

Severe hepatic impairment.

Pregnancy or women planning to become pregnant (see section "Use in pregnancy or breast-feeding").

Concomitant use of losartan with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus and renal dysfunction (GFR [glomerular filtration rate] < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

Interaction with other medicinal products and other forms of interaction.

Other antihypertensive agents may enhance the hypotensive effect of losartan. Concomitant use of drugs (e.g. tricyclic antidepressants, neuroleptics, baclofen, amifostine) that lower blood pressure as a primary or secondary effect may increase the risk of developing arterial hypotension.

Concomitant administration of angiotensin II antagonists and nonsteroidal anti-inflammatory drugs (e.g. selective cyclooxygenase-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses, and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs)) may result in attenuation of the antihypertensive effect. In patients with impaired renal function, concomitant use of angiotensin II antagonists or diuretics and NSAIDs may lead to worsening of renal function, including acute renal failure, and increased serum potassium levels.

This combination should be used with caution, particularly in elderly patients. Patients should be adequately hydrated, and renal function should be monitored after initiation and periodically during concomitant therapy.

Losartan is primarily metabolized by cytochrome P450 (CYP) 2C9 to form the active carboxylic acid metabolite. It has been established that fluconazole (a CYP2C9 inhibitor) reduces the level of the active metabolite by approximately 50%. Concomitant administration of losartan with rifampicin (an enzyme inducer) resulted in a 40% reduction in plasma concentration of the active metabolite. The clinical significance of this effect is unknown. No significant interaction was observed with concomitant administration of fluvastatin (a weak CYP2C9 inhibitor).

As with other agents that block the formation of angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride) or agents that 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 is not recommended.

Elevated and potentially toxic serum lithium concentrations have been reported during concomitant use of lithium with ACE inhibitors. Isolated cases have also been reported with angiotensin II receptor antagonists. Caution should be exercised when using lithium with losartan. If this combination is necessary, monitoring of serum lithium concentrations is recommended.

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

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 losartan tablets.

Special precautions for use.

Hypersensitivity. Angioedema. Patients with a history of angioedema (facial, lip, throat, and/or tongue swelling) must be carefully monitored (see section "Adverse reactions").

Intestinal angioedema.

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

Arterial hypotension and fluid and electrolyte imbalance. Symptomatic hypotension may occur in patients with reduced circulating blood volume (e.g., due to high-dose diuretics, salt restriction, diarrhea, or vomiting). Prior to initiating losartan therapy, circulating blood volume should be corrected or the initial dose reduced (see section "Dosage and administration"). This also applies to children aged 6 years and older.

Fluid and electrolyte imbalance. This is common in patients with renal insufficiency, with or without diabetes mellitus, so particular caution is required when prescribing the drug to these patients. It is known that in patients with type 2 diabetes and nephropathy, the incidence of hyperkalemia is higher with losartan treatment compared to placebo (see section "Adverse reactions"). Serum potassium concentration and creatinine clearance should be closely monitored, especially in patients with heart failure and creatinine clearance between 30 and 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 medications) with losartan is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Double blockade of the RAAS

Evidence shows that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual RAAS blockade with combined use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

In cases of extreme necessity for dual RAAS blockade, it should be performed under specialist supervision with careful monitoring of renal function, electrolyte balance, and blood pressure.

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

Hepatic impairment. Based on pharmacokinetic data indicating significantly increased plasma concentrations of losartan in patients with liver cirrhosis, the dose should be reduced in patients with a history of hepatic dysfunction. Since there is no therapeutic experience with losartan in patients with severe hepatic impairment, its use in this patient group is not recommended (see sections "Pharmacological properties", "Contraindications", and "Dosage and administration"). The drug is not recommended for use in children with hepatic impairment (see section "Dosage and administration").

Renal impairment. Due to inhibition of the RAAS, changes in renal function, including renal failure, have been observed in some patients (particularly in those whose renal function depends on the RAAS, patients with severe heart failure, or pre-existing renal dysfunction). Some drugs acting on the RAAS may increase blood urea nitrogen and serum creatinine levels in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney; these changes may resolve after discontinuation of therapy.

Caution is required when administering losartan to patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney.

Use in children with renal impairment. The drug is not recommended for use in children with eGFR <30 mL/min/1.73 m² due to lack of relevant data (see section "Dosage and administration").

Renal function should be regularly monitored during treatment, as deterioration is possible. This is particularly important when losartan is used in the presence of other conditions (e.g., fever, dehydration) that may affect renal function.

Concomitant use of losartan and ACE inhibitors worsens renal function; therefore, this combination is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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

Primary hyperaldosteronism. Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that inhibit the renin-angiotensin system. Therefore, the use of losartan is not recommended.

In patients with ischemic heart disease and cerebrovascular disorders, excessive reduction in blood pressure during antihypertensive therapy may lead to myocardial infarction or stroke.

In patients with heart failure with or without renal impairment, treatment with drugs acting on the RAS carries a risk of severe arterial hypotension and renal failure (often acute). There is insufficient therapeutic experience with losartan in patients with heart failure and concomitant severe renal impairment, patients with severe heart failure (NYHA class IV), and patients with heart failure and life-threatening symptomatic arrhythmias.

Losartan should be used with caution in these patient groups. Caution is also required when losartan is used concomitantly with β-blockers (see section "Pharmacological properties").

Aortic stenosis, mitral stenosis, and obstructive hypertrophic cardiomyopathy. As with other vasodilating agents, particular caution is required in patients with aortic stenosis, mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Excipients. The drug contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Other warnings. As observed with ACE inhibitors, losartan and other angiotensin antagonists are less effective in patients of Black race compared to patients of other races, possibly due to low renin activity in Black patients with arterial hypertension.

Use during pregnancy or breastfeeding.

Pregnancy. The drug is contraindicated in pregnant women or women planning to become pregnant. If pregnancy occurs during treatment with this medicinal product, it should be discontinued immediately, and if necessary, replaced with another medicinal product approved for use during pregnancy.

Epidemiological data on the teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Since there are no controlled epidemiological data on the risk of angiotensin II receptor antagonists (ARBs), similar risks may exist for this class of drugs. Except when continued ARB therapy is considered essential, alternative antihypertensive therapy with an established safety profile in pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, ARB treatment should be discontinued immediately, and if necessary, alternative therapy initiated.

It is known that ARB use during the second and third trimesters induces fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If ARBs were used during the second trimester of pregnancy, ultrasound examination is recommended to assess renal function and skull ossification.

Newborns whose mothers received ARBs should be closely monitored for the development of arterial hypotension.

Breastfeeding. Since there is no information on the use of losartan during breastfeeding, the drug is not recommended during this period. Alternative therapy with drugs with a better-established safety profile during breastfeeding is preferred, especially during the neonatal period or if the infant is premature.

Ability to influence reaction speed when driving or operating machinery.

It should be remembered that antihypertensive therapy, particularly at the beginning of treatment or after dose escalation, may cause dizziness or somnolence.

Dosage and Administration

The medication should be taken orally, independent of food intake, with one glass of water.

For arterial hypertension, the usual initial and maintenance dose for most patients is 50 mg once daily. The maximum antihypertensive effect is achieved within 3–6 weeks after initiation of therapy. In some patients, the dose may be increased to 100 mg once daily (in the morning) to achieve a greater effect.

The medication may be used both as monotherapy and in combination with other antihypertensive agents, particularly diuretics (e.g., hydrochlorothiazide) (see sections "Pharmacological Properties", "Contraindications", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Special Warnings").

For the treatment of renal disorders in patients with arterial hypertension and type 2 diabetes mellitus with proteinuria ≥0.5 g/day as part of antihypertensive therapy, the standard initial dose is 50 mg once daily. The dose should then be increased to 100 mg once daily after one month of therapy, depending on the degree of blood pressure reduction. The medication may be administered concomitantly with other antihypertensive agents (diuretics, calcium channel blockers, α- and β-adrenergic blockers, centrally acting agents), insulin, and other hypoglycemic agents (sulfonylurea derivatives, glitazones, and glucosidase inhibitors).

The usual initial dose of losartan in heart failure is 12.5 mg once daily (in this case, a medicinal product with appropriate dosing should be used). The dose is generally increased at weekly intervals (e.g., 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 individual tolerance of the medication.

For reducing the risk of cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophy, the standard initial dose is 50 mg once daily. Subsequently, it is recommended to either add low-dose hydrochlorothiazide or increase the losartan dose to 100 mg once daily, depending on the degree of blood pressure reduction.

Special Patient Groups

Patients with reduced blood volume (e.g., those receiving high-dose diuretics): the initial dose should be reduced to 25 mg once daily. Since the film-coated tablet is not divisible, losartan in another dosage form should be used.

Patients with renal impairment and patients on dialysis. Dose adjustment is not required in patients with renal impairment, including those on dialysis.

Patients with hepatic impairment. Patients with a history of liver disease should be prescribed the medication at lower doses. Losartan is contraindicated in patients with severe hepatic impairment due to the lack of therapeutic experience in this patient group.

Use in Children

Children aged 6 months to 6 years. Safety and efficacy in children aged 6 months to 6 years have not been established. Available data are described in the section "Pharmacological Properties", but dosage recommendations cannot be provided.

Children aged 6 to 18 years. 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. The dose should be adjusted based on its effect on blood pressure.

For patients with body weight over 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 medication 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 impaired liver function.

Elderly Patients. Dose adjustment is not required in elderly patients; however, it is recommended to initiate treatment with a 25 mg dose in patients aged 75 years and older.

Children.

Safety and efficacy of losartan in children under 6 years of age have not been established.

Overdose.

There have been no reports of losartan overdose. The most likely symptoms, depending on the amount ingested, include arterial hypotension and tachycardia. Bradycardia may occur due to stimulation of parasympathetic (vagal) innervation.

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

Management depends on the time of drug intake, severity, and type of symptoms. Priority should be given to stabilizing the cardiovascular system. After oral ingestion, activated charcoal is recommended. Close monitoring of vital signs should be performed, and stabilization should be initiated if necessary. Neither losartan nor its active metabolite is removed from the body by hemodialysis.

Adverse Reactions

It is known that losartan has been studied in the following clinical trials:

• a controlled clinical trial involving >3000 adult patients aged 18 years and older with essential hypertension;
• a controlled clinical trial involving 177 children aged 6 to 16 years with hypertension;
• a controlled clinical trial involving >9000 patients aged 55 to 80 years with hypertension and left ventricular hypertrophy (see "LIFE Study" in section "Pharmacological Properties");
• a controlled clinical trial involving >7700 adult patients with chronic heart failure (see "LIFE Study" in section "Pharmacodynamics");
• a controlled clinical trial involving >1500 patients aged 31 years and older with type 2 diabetes and proteinuria (see "RENAAL Study" in section "Pharmacological Properties").

The most commonly reported adverse reaction was dizziness. The frequency of the 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; frequency not known (cannot be estimated from the available data).

Frequency of adverse reactions identified in placebo-controlled clinical trials and during the post-marketing period

∗Including angioedema of the larynx, pharynx, face, lips, glottis and/or tongue (leading to airway obstruction); in some patients there was a history of angioedema (Quincke's edema) associated with the use of other drugs, including ACE inhibitors.

∗∗Including Henoch-Schönlein purpura.

║ Particularly in patients with intravascular dehydration (e.g., in severe heart failure or during treatment with high-dose diuretics).

† Frequently observed in patients receiving 150 mg of losartan instead of 50 mg.

‡ In a clinical study conducted in patients with type 2 diabetes mellitus 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.

§ Usually reversible upon discontinuation of therapy.

The following additional adverse reactions occurred more frequently in patients receiving losartan than placebo (frequency unknown): back pain, urinary tract infections, and influenza-like symptoms.

Renal and urinary disorders: As a consequence of RAAS inhibition, changes in renal function, including renal failure, have been reported in patients at risk; such changes in renal function may be reversible upon discontinuation of therapy (see section "Special precautions").

Children.

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

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: http://aisf.dec.gov.ua/.

Shelf life.

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of reach of children.

Packaging.

Film-coated tablets, 50 mg. 10 tablets in a blister, 3 blisters in a cardboard box.

Film-coated tablets, 100 mg. 15 tablets in a blister, 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ALKALOID AD Skopje.

Manufacturer's address and location of business operations.

Boulevard of Alexander the Great, 12, Skopje, 1000, Republic of North Macedonia.