Lorista

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

Composition:

Active substance: losartan;

One film-coated tablet contains 12.5 mg, 25 mg, 50 mg, or 100 mg of losartan potassium;

Excipients: celactose (containing lactose monohydrate and powdered cellulose), corn starch, pregelatinized starch, microcrystalline cellulose, anhydrous colloidal silicon dioxide, magnesium stearate, hypromellose, talc, propylene glycol, titanium dioxide (E 171), quinoline yellow dye (E 104) – only for 12.5 mg and 25 mg tablets.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

12.5 mg tablets: yellow, oval, slightly biconvex film-coated tablets;

25 mg tablets: yellow, oval, slightly biconvex film-coated tablets, with a score line on one side;

50 mg tablets: white, round, slightly biconvex film-coated tablets with bevelled edges and a score line on one side;

100 mg tablets: white, oval, slightly biconvex film-coated tablets.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. 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, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system and one of the most important factors in the pathophysiology of arterial hypertension. Angiotensin II binds to the AT1 receptor, located 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, kininase II), the enzyme responsible for bradykinin degradation. As a result, there is no increase in bradykinin-mediated adverse effects. During losartan therapy, elimination of the negative feedback of angiotensin II 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 main metabolite have higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10–40 times more potent than losartan.

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 those taken 5–6 hours after dosing, demonstrated that blood pressure reduction persisted over 24 hours; the natural circadian rhythm was preserved. The reduction in blood pressure at the end of the dosing interval was 70–80% of the effect observed 5–6 hours after dosing.

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

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

LIFE Study (Losartan Intervention For Endpoint reduction in hypertension)

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study 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 necessary, the dose of losartan or atenolol was increased to 100 mg daily. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II antagonists, or beta-blockers) could be added as needed 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 the reduction in total incidence of fatal cardiovascular events, stroke, and myocardial infarction. Blood pressure was significantly lower in both treatment groups. Treatment with losartan reduced risk by 13% (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 the risk of stroke by 25% compared to atenolol (p = 0.001, 95% CI 0.63–0.89).

There were no significant differences between treatment groups in the incidence of fatal cardiovascular events or myocardial infarction.

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. However, the results of the LIFE study regarding cardiovascular morbidity/mortality with losartan compared to atenolol do not apply to black patients with hypertension and left ventricular hypertrophy.

RENAAL Study

The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan) study was a controlled clinical trial involving 1513 patients with type 2 diabetes and nephropathy, with or without hypertension. 751 patients were treated with losartan.

The aim of the study was 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 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 long-term. Other antihypertensive agents (diuretics, potassium antagonists, alpha- and beta-receptor antagonists, and centrally acting antihypertensives) were used as add-on therapy as needed in both patient groups. The duration of follow-up was 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 reduced risk in the losartan group: 25.3% reduction in serum creatinine doubling (p = 0.006); 28.6% reduction in renal failure (p = 0.009); 21% reduction in serum creatinine doubling and renal failure (p = 0.010). There were no significant differences between treatment groups in mortality.

HEAAL Study

The HEAAL (Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan) study was a controlled clinical trial involving 3834 patients aged 18 to 98 years with NYHA class II–IV heart failure and intolerance to ACE inhibitors. Patients were randomly assigned to treatment with losartan 50 mg once daily or 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 from heart failure or hospitalization due to heart failure.

Treatment with losartan 150 mg (828 events) compared to 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 the risk of heart failure by 13.5% (p = 0.025, 95% CI 0.76–0.98) compared to 50 mg. There were no significant differences between losartan treatment groups in mortality.

Renal failure, arterial hypotension, and hyperkalemia were observed more frequently in the group receiving losartan 150 mg than in the group receiving 50 mg.

ELITE I and ELITE II Studies

The ELITE studies were conducted over 48 weeks and involved 722 patients with NYHA class II–IV heart failure. 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 in 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, the effect of 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.

In a study involving 3152 patients with NYHA class II–IV heart failure and a mean follow-up of 1.5 years, mortality rates were assessed with losartan versus captopril.

In both clinical trials (non-placebo-controlled), losartan was better tolerated than captopril, as evidenced by a significantly lower rate of treatment discontinuation due to adverse reactions.

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 trial), evaluated the use of combination therapy with an ACE inhibitor and an angiotensin II receptor blocker.

ONTARGET was a trial involving patients with cardiovascular or cerebrovascular disease history or type 2 diabetes with target organ damage. VA NEPHRON-D was a trial involving patients with type 2 diabetes or diabetic nephropathy.

These studies did not show significant beneficial effects on kidney and/or cardiovascular outcomes or mortality reduction; however, there was an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension compared to monotherapy. Given the similar pharmacodynamic properties, these results may also apply 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 was 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, or both. The study was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke 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 than in the placebo group.

Hypertension in Children

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

Overall, a dose-response relationship was observed. The dose-response relationship was very evident when comparing the low-dose group to the medium-dose group (Period I: –6.22 mm Hg vs –11.65 mm Hg), but was attenuated 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 of 2.5 mg and 5 mg, corresponding to a mean daily dose of 0.07 mg/kg, did not demonstrate consistently effective antihypertensive activity.

These results were confirmed during Period II of the study, when patients were randomized to continue losartan or 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 patients receiving placebo and those continuing losartan at the lowest dose in each group, again indicating that the lowest dose in each group did not have a significant antihypertensive effect.

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

In children with hypertension (N = 60) and normotension (N = 246) with proteinuria, the effect of losartan on proteinuria was evaluated in a 12-week placebo- and active-controlled (amlodipine) clinical trial. Proteinuria was defined as a urine protein/creatinine ratio ≥ 0.3. Hypertensive patients (aged 6 to 18 years) were randomized to receive losartan (n = 30). Normotensive patients (aged 1 to 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 (up to a maximum dose of 100 mg/day). Amlodipine was administered at doses of 0.05–0.2 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 group (p ≤ 0.001). In hypertensive patients receiving losartan, baseline proteinuria decreased by –41.5% (95% CI –29.9; –51.1) versus +2.4% (95% CI –22.2; 14.1) in the amlodipine group. Reduction in both systolic and diastolic blood pressure was greater in the losartan group (–5.5/–3.8 mm Hg) compared to the amlodipine group (–0.1/+0.8 mm Hg). In normotensive children, a small reduction in blood pressure was observed 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 may have partially contributed to proteinuria reduction in the losartan group.

Long-term effects of losartan in children with proteinuria were studied over up to 3 years in an open-label extension phase of the same study, which included all patients who completed the 12-week baseline study. A total of 268 patients were enrolled in the open-label extension phase; they were re-randomized into two groups: to receive losartan (N = 134) or enalapril (N = 134), and 109 patients were followed for ≥ 3 years (pre-specified endpoint: > 100 patients completing 3 years of follow-up in the extension phase). Dose ranges for losartan and enalapril, as determined by the investigator, 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 body weight > 50 kg were not exceeded for most patients during the extension phase.

Thus, results from the extension phase, conducted for safety evaluation, show that losartan was well tolerated and caused sustained reduction in proteinuria without significant change in glomerular filtration rate (GFR) over 3 years. In normotensive patients (n = 205), enalapril had a 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 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; 32.5) vs –13.4 (95% CI –27.3; 0.6) mL/min/1.73 m²].

An open-label clinical trial was conducted to determine the optimal dose and to 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 different 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). Of these, 27 were aged 6–23 months. The study drug was titrated to the next dose level at weeks 3, 6, and 9 for patients who had not achieved target blood pressure and had not yet received the maximum dose of losartan (1.4 mg/kg/day, but not exceeding 100 mg/day).

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

In summary, mean blood pressure reduction compared to baseline was similar across all treatment groups (change in systolic blood pressure (SBP) from baseline 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 (DBP) from baseline to week 3 was –8.2, –5.1, and –6.7 mm Hg in the low-, medium-, and high-dose groups, respectively); however, no statistically significant dose-dependent response for SBP and 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 carboxylic acid metabolite and inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached at approximately 1 hour and 3–4 hours, respectively.

Distribution

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

Metabolism

Approximately 14% of losartan is converted to the active metabolite after intravenous or oral administration. After intravenous or oral administration of radiolabeled 14C-losartan potassium, radioactivity in circulating plasma is typically characterized by losartan and its metabolite. Minimal conversion of losartan to its active metabolite was observed in approximately 1% of cases.

In addition to the active metabolite, inactive metabolites are also formed.

Elimination

The plasma clearance of losartan and its active metabolite is 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is approximately 74 mL/min and 26 mL/min, respectively. After oral administration, approximately 4% of the dose is excreted unchanged in urine and approximately 6% of the dose is excreted in urine as the active metabolite. The pharmacokinetic properties of losartan and its active metabolite are linear following oral doses of losartan potassium up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially, with terminal half-lives of approximately 2 hours and 6–9 hours, respectively. At a dose of 100 mg once daily, losartan and its active metabolite do not accumulate significantly in plasma.

Losartan and its metabolites are excreted via both bile and urine. After oral administration/intravenous injection of 14C-labeled losartan, approximately 35%/43% of radioactivity was recovered in urine and 58%/50% in feces.

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 hypertensive women compared to men, whereas plasma concentrations of the active metabolite did not differ significantly between men and women.

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

Plasma concentrations of losartan in patients with creatinine clearance above 10 mL/min do not differ from those in individuals with normal renal function. However, the area under the concentration-time curve (AUC) of losartan was approximately twice as high in patients with normal renal function compared to patients on hemodialysis.

Plasma concentrations of the active metabolite do not change in patients with impaired renal function or in those on hemodialysis.

Losartan and its active metabolite cannot be removed by hemodialysis.

Pharmacokinetics in Children

The pharmacokinetics of losartan were studied in 50 children with arterial hypertension aged 1 month to 16 years after once-daily oral administration at doses of 0.54 to 0.77 mg/kg (mean doses).

Results showed that the active metabolite of losartan is formed in patients of all age groups. Findings indicate approximately similar pharmacokinetic parameters of losartan after oral administration in neonates, preschool, and school-aged children.

Pharmacokinetic parameters of the metabolite varied more depending on age group. Differences between preschool children and adolescents were statistically significant. Exposure in neonates and children under 2 years of age was relatively high.

Clinical characteristics.

Indications.

• Treatment of essential hypertension in adults, as well as in children aged 6 years and older.
• Treatment of renal disease in adult patients with 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. Patients must have a left ventricular ejection fraction ≤ 40 %, clinically stable condition, and should be receiving standard therapy for chronic heart failure.
• Reduction of the risk of stroke in adult patients with hypertension and documented left ventricular hypertrophy by ECG.

Contraindications.

Hypersensitivity to losartan or to any other component of the medicinal product.

Pregnant women or women planning to become pregnant (see section "Use in pregnancy or lactation"). Severe hepatic impairment. Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²) (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Other antihypertensive agents may enhance the hypotensive effect of losartan. Other drugs that may cause hypotension include tricyclic antidepressants, antipsychotics, baclofen, and amifostine. The primary or secondary effect of concomitant use of these drugs with antihypertensive agents may be an increased risk of arterial hypotension. Losartan is metabolized primarily via the cytochrome P450 (CYP) 2C9 enzyme system to form the active carboxylic acid metabolite. Clinical studies have shown that fluconazole (a CYP2C9 inhibitor) reduces exposure to the active metabolite by approximately 50 %. Concomitant use of losartan and rifampicin (an enzyme inducer) has been shown to reduce plasma concentrations of the active metabolite by 40 %. The clinical significance of this effect is unknown. There is no difference in exposure when losartan is used concomitantly with fluvastatin (a weak CYP2C9 inhibitor). 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 serum potassium levels (such as heparin, trimethoprim-containing drugs), or potassium-containing supplements, or potassium-containing salt substitutes may lead to increased serum potassium levels. Concomitant use of such agents is not recommended. Reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Such effects have also been very rarely reported with angiotensin II receptor antagonists. Concomitant treatment with lithium and losartan should be undertaken with caution. If such combination therapy is considered necessary, serum lithium levels should be monitored during combination treatment.

When angiotensin II receptor antagonists are used concomitantly with nonsteroidal anti-inflammatory drugs (e.g., selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid at anti-inflammatory doses, nonselective NSAIDs), the antihypertensive effect may be attenuated. Concomitant use of angiotensin II antagonists or diuretics with NSAIDs may lead to an increased risk of worsening renal function, including possible development of acute renal failure, as well as increased serum potassium levels, particularly in patients with pre-existing renal impairment. Such combinations should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered after initiation of concomitant therapy and periodically during treatment.

Studies have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of adverse reactions such as hypotension, hyperkalemia, and changes in renal function, including acute renal failure, compared to use of a single agent acting on the renin-angiotensin-aldosterone system (see sections "Contraindications" and "Special warnings and precautions for use").

Grapefruit juice contains components that inhibit CYP450 enzymes and may reduce the concentration of the active metabolite of losartan, thereby decreasing its therapeutic effect. Grapefruit juice should be avoided during losartan tablet administration.

Special precautions for use.

Angioedema

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

Arterial hypotension and fluid-electrolyte imbalance

Symptomatic arterial hypotension, particularly after administration of the first dose or dose escalation, may occur in patients with reduced intravascular volume or sodium deficiency caused by potent diuretics, dietary salt restriction, diarrhea, or vomiting. These conditions should be corrected prior to initiating treatment with Lorista® or require a reduced initial dose. The same recommendations 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, the incidence of hyperkalemia was higher with losartan compared to placebo. Therefore, plasma potassium concentration and creatinine clearance should be monitored regularly, especially in patients with heart failure and creatinine clearance of 30–50 mL/min.

Concomitant use of losartan with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may increase serum potassium levels (e.g., trimethoprim-containing medications) is not recommended.

Intestinal angioedema

Intestinal angioedema has been reported in patients receiving angiotensin II receptor antagonists, including losartan (see section "Adverse reactions"). These patients experienced symptoms such as abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, the drug should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Hepatic impairment

Based on pharmacokinetic data indicating significantly increased plasma concentrations of losartan in patients with liver 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, losartan should not be used in such patients.

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

Renal impairment

Changes in renal function, including renal failure, have been reported and are associated with inhibition of the renin-angiotensin system (particularly in patients whose renal function depends on the renin-angiotensin-aldosterone system, i.e., patients with severe heart failure or pre-existing renal impairment).

Drugs affecting the renin-angiotensin-aldosterone system 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 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 children with renal impairment

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

Renal function should be monitored regularly during losartan therapy, as deterioration may occur. This is particularly important when losartan is used in the presence of other pathological 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.

Kidney transplantation

There is no experience regarding the safety of using the drug in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

Antihypertensive drugs acting via inhibition of the renin-angiotensin system generally do not produce an effect in patients with primary hyperaldosteronism. Therefore, Lorista® is not recommended for this patient group.

Coronary artery disease and cerebrovascular disorders

As with other antihypertensive drugs, excessive reduction in blood pressure in patients with ischemic coronary artery disease or cerebrovascular disorders may lead to myocardial infarction or stroke.

Heart failure

As with other drugs affecting the renin-angiotensin-aldosterone system, there is a risk of severe arterial hypotension and (often acute) renal function impairment in patients with heart failure, with or without renal impairment.

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 symptomatic, life-threatening cardiac arrhythmias. Therefore, losartan should be used with caution in these patient groups. Concomitant use of losartan with β-blockers should be done with caution.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

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

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Except when continuation of ARB therapy is considered necessary, alternative antihypertensive therapy with an established safety profile during pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, ARB therapy should be discontinued immediately and, if necessary, alternative treatment initiated.

Other warnings and precautions

As established for angiotensin-converting enzyme (ACE) inhibitors, losartan and other angiotensin antagonists are less effective in reducing blood pressure in patients of Black race compared to other patients, possibly due to low renin activity in this group of patients with hypertension.

Special information about certain excipients

Lorista® contains lactose. This medication should not be administered to patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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

Concomitant use of aliskiren with angiotensin II receptor antagonists or ACE inhibitors increases the risk of arterial hypotension, hyperkalemia, and renal function changes, including acute renal failure. Due to dual blockade of the renin-angiotensin-aldosterone system (RAAS), concomitant use of aliskiren with angiotensin II receptor antagonists or ACE inhibitors is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). In cases of extreme necessity for dual RAAS blockade, renal function, blood electrolyte levels, and blood pressure should be closely monitored. Concomitant use of angiotensin II receptor antagonists and ACE inhibitors is not recommended in patients with diabetes mellitus.

Use during pregnancy or breastfeeding

Pregnancy

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

Epidemiological data on the teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, although 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 continuation of ARB therapy is considered necessary, alternative antihypertensive therapy with an established safety profile during pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, ARB therapy should be discontinued immediately and, if necessary, alternative treatment initiated. It is known that ARB use during the second and third trimesters of pregnancy causes fetal toxicity (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, an ultrasound examination is recommended to assess renal function and skull ossification.

Newborns whose mothers used ARBs should be monitored frequently for the development of arterial hypotension.

Breastfeeding

Due to lack of any information on the use of losartan during breastfeeding, losartan is not recommended. Alternative medications with better-established safety profiles during breastfeeding should be preferred, especially when nursing newborns or preterm infants.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect of the drug on the ability to drive or operate machinery have not been conducted. However, the possibility of adverse reactions such as dizziness and somnolence, especially at the beginning of treatment and during dose escalation, should be considered.

Method of Administration and Dosage

Lozartan tablets should be taken with a glass of water.

The administration of the drug is independent of food intake.

Arterial Hypertension

The usual initial and maintenance dose for most patients is 50 mg of the drug once daily (1 tablet of Lorista® 50 mg). Maximum antihypertensive effect is achieved within 3 to 6 weeks after initiation of treatment. For some patients, increasing the dose to 100 mg once daily (in the morning) may be beneficial.

Lorista® can be used in combination with other antihypertensive agents, particularly diuretics (e.g., hydrochlorothiazide).

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

The usual initial dose is 50 mg (1 tablet of Lorista®) once daily. The dose may be increased to 100 mg once daily depending on blood pressure levels after 1 month of treatment. Lorista® can be used with other antihypertensive agents (e.g., diuretics, calcium channel blockers, α- or β-receptor blockers, and centrally acting agents), as well as with insulin and other commonly used hypoglycemic agents (e.g., sulfonylureas, glitazones, and glucosidase inhibitors).

Heart Failure

The usual initial dose of Lorista® in patients with chronic heart failure is 12.5 mg once daily. The dose is generally titrated at weekly intervals (i.e., 12.5 mg daily, 25 mg daily, 50 mg daily) up to the usual maintenance dose of 50 mg (1 tablet of Lorista®) once daily, depending on individual tolerability.

Reduction of Stroke Risk in Patients with Arterial Hypertension and Electrocardiographically Documented Left Ventricular Hypertrophy

The usual initial dose is 50 mg of lozartan (1 tablet of Lorista® 50 mg) once daily. Depending on blood pressure response, low-dose hydrochlorothiazide should be added and/or the dose of Lorista® increased to 100 mg once daily.

Special Patient Groups

Use in Patients with Reduced Circulating Volume

In patients with reduced circulating volume (e.g., due to treatment with high-dose diuretics), therapy should be initiated at a dose of 25 mg once daily.

Use in Patients with Renal Impairment and Patients Undergoing Hemodialysis

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

Use in Patients with Hepatic Impairment

A lower initial dose should be considered for patients with a history of hepatic impairment. There is no experience in treating patients with severe hepatic impairment; therefore, lozartan is contraindicated in this patient group.

Pediatric Population

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

Patients aged 6 to 18 years. For children who can swallow tablets and whose body weight is more than 20 kg and less than 50 kg, the recommended dose is 25 mg once daily. In exceptional cases, the dose may be increased up to the maximum of 50 mg once daily. The dose should be adjusted according to its effect on blood pressure. For patients with body weight above 50 kg, the usual single dose is 50 mg once daily. In exceptional cases, the dose may be increased up to the 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.

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

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

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

Use in Elderly Patients

Generally, no adjustment of the initial dose is required for elderly patients, although consideration should be given to initiating treatment with a dose of 25 mg in patients aged 75 years and older.

Children

Lozartan is not recommended for use in children under 6 years of age due to limited data in this patient group.

Overdose.

Symptoms

Data on lozartan overdose are limited. Depending on the degree of intoxication, symptoms such as arterial hypotension, tachycardia, and possibly bradycardia may occur.

Treatment

Therapeutic measures depend on the time elapsed since drug ingestion, and the nature and severity of symptoms. Priority should be given to stabilizing cardiovascular function. After oral overdose, administration of activated charcoal in an appropriate dose is indicated. Induction of vomiting and gastric lavage are recommended procedures. Subsequently, vital signs should be monitored frequently and corrected as necessary. Lozartan and its active metabolites are not removed by hemodialysis.

Adverse Reactions

The most commonly reported adverse reaction during clinical trials was dizziness.

Children

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

Arterial Hypertension

Nervous system disorders: dizziness, somnolence, headache, insomnia, muscle cramps.

Cardiac disorders: palpitations, angina pectoris.

Vascular disorders: symptomatic hypotension (especially in patients with intravascular volume depletion, e.g., in patients with severe heart failure or those receiving high-dose diuretic therapy), dose-dependent orthostatic effect.

Skin and subcutaneous tissue disorders: rash.

Gastrointestinal disorders: abdominal pain, dyspepsia, constipation.

Respiratory, thoracic and mediastinal disorders: cough, rhinitis, sinusitis, pharyngitis, upper respiratory tract infection.

General disorders and administration site conditions: asthenia, weakness, edema.

Investigations: Changes in standard laboratory parameters were rarely associated with losartan tablets. ALT levels were infrequently elevated and usually returned to normal after discontinuation of the drug. Hyperkalemia (serum potassium > 5.5 mmol/L) was observed in 1.5% of patients with arterial hypertension.

Patients with Left Ventricular Hypertrophy

Nervous system disorders: dizziness.

Ear and labyrinth disorders: vertigo.

General disorders and administration site conditions: asthenia/weakness.

Chronic Heart Failure

Nervous system disorders: dizziness, headache, paresthesia.

Cardiac disorders: syncope, atrial fibrillation, stroke.

Vascular disorders: arterial hypotension, including dose-dependent orthostatic effect.

Respiratory, thoracic and mediastinal disorders: dyspnea.

Gastrointestinal disorders: diarrhea, nausea, vomiting.

Skin and subcutaneous tissue disorders: urticaria, pruritus, rash.

Renal and urinary disorders: impaired renal function, renal failure.

General disorders and administration site conditions: asthenia/weakness.

Investigations: hyperkalemia, increased blood urea nitrogen, serum creatinine, and serum potassium.

Arterial Hypertension and Type 2 Diabetes with Renal Disease

Nervous system disorders: dizziness.

Vascular disorders: arterial hypotension.

General disorders and administration site conditions: asthenia/weakness.

Investigations: hypoglycemia, hyperkalemia.

Additional Adverse Reactions

Blood and lymphatic system disorders: anemia.

Cardiac disorders: syncope, palpitations.

Vascular disorders: orthostatic hypotension.

Gastrointestinal disorders: diarrhea.

Musculoskeletal and connective tissue disorders: back pain.

Renal and urinary disorders: urinary tract infections.

General disorders and administration site conditions: influenza-like symptoms.

Investigations: hyperkalemia (in patients with type 2 diabetes and nephropathy).

Post-Marketing Surveillance

Blood and lymphatic system disorders: anemia, thrombocytopenia.

Ear and labyrinth disorders: tinnitus.

Immune system disorders: rarely – hypersensitivity reactions (anaphylactic reactions, angioedema, including laryngeal and glottis edema leading to airway obstruction and/or swelling of the face, lips, throat, and/or tongue); in some patients, history of angioedema associated with other drugs, including ACE inhibitors; vasculitis, including Henoch-Schönlein purpura.

Nervous system disorders: migraine, dysgeusia.

Respiratory, thoracic and mediastinal disorders: cough.

Gastrointestinal disorders: rarely – intestinal angioedema; diarrhea, pancreatitis, vomiting.

General disorders and administration site conditions: malaise.

Hepatobiliary disorders: hepatitis, hepatic function abnormalities.

Skin and subcutaneous tissue disorders: urticaria, pruritus, rash, photosensitivity, erythroderma.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia, rhabdomyolysis.

Reproductive system and breast disorders: erectile dysfunction/impotence.

Renal and urinary disorders: as a consequence of renin-angiotensin-aldosterone system inhibition, changes in kidney function, including renal failure, have been reported in patients at risk; such changes in renal function may be reversible upon discontinuation of therapy.

Psychiatric disorders: depression.

Investigations: hyponatremia.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after drug registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf Life

5 years.

Storage Conditions

Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging

10 tablets in a blister; 3, 6, or 9 blisters in a cardboard box;

14 tablets in a blister; 1, 2, 4, 6, or 7 blisters in a cardboard box.

Prescription Category By prescription only.

Manufacturer

KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

TAD Pharma GmbH, Germany / TAD Pharma GmbH, Germany.

Manufacturer's Name and Address of the Place of Business

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany / Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany.