Losartan krka

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOSARTAN KRKA (Losartan KRKA)

Composition:

Active substance: losartan;

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

Excipients: celactose (containing lactose monohydrate and powdered cellulose), corn starch, pregelatinized starch, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, talc, propylene glycol, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

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

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

Pharmacotherapeutic group. Simple angiotensin II receptor antagonists.

ATC code C09CA01.

Pharmacological Properties.

Pharmacodynamics.

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

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

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

During losartan therapy, removal 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 primary metabolite have higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10–40 times more potent than losartan.

Long-term effects of losartan on proteinuria in children were studied for 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. Overall, 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 during the extension phase). The dose ranges of 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 safety extension study show that losartan was well tolerated and led to sustained reduction in proteinuria without significant change in glomerular filtration rate (GFR) over 3 years. In normotensive patients (n = 205), enalapril had a numerically greater effect than losartan on proteinuria (-33.0% (95% confidence interval (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 patients with arterial hypertension (n = 49), losartan had a numerically greater effect on proteinuria (-44.5% (95% CI -64.8; -12.4) vs. -39.5% (95% CI -62.5; -2.2)) and GFR (18.9 (95% CI 5.2; 32.5) vs. -13.4 (95% CI -27.3; 0.6) mL/min/1.73 m²).

An open-label clinical 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. One hundred and one 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 children were infants aged 6 to 23 months. The study 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 received the maximum dose (1.4 mg/kg/day, but not exceeding 100 mg/day) of losartan.

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

In summary, mean reduction in blood pressure from 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, respectively, for low-, medium-, and high-dose groups; reduction in diastolic blood pressure (DBP) from baseline to week 3 was -8.2, -5.1, and -6.7 mm Hg, respectively, for low-, medium-, and high-dose groups); however, no statistically significant dose-dependent response for SBP or DBP was observed.

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

Clinical studies in patients with arterial hypertension

Data from controlled clinical trials show that 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 the antihypertensive effect persists over 24 hours; the natural circadian rhythm was preserved. Blood pressure reduction at the end of the dosing interval was 70–80% of the effect observed 5–6 hours after dosing.

Discontinuation of losartan in 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 men and women, and in younger patients (< 65 years) and elderly patients with arterial hypertension.

LIFE study

The LIFE (Losartan Intervention For Endpoint) study evaluated the impact of losartan on cardiovascular morbidity and mortality endpoints in arterial 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 the 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 the target blood pressure.

The mean follow-up duration was 4.8 years.

The primary efficacy endpoint was a composite of cardiovascular morbidity and mortality, measured by reduction in total cardiovascular mortality, stroke, and myocardial infarction. Blood pressure was significantly lower in both groups. Treatment with losartan reduced risk by 13% (p = 0.021, 95% CI 0.77–0.98) compared to atenolol. Thus, the primary composite endpoint was achieved. This result was primarily due 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). No significant differences were observed between treatment groups in cardiovascular mortality or myocardial infarction rates.

Race

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

RENAAL study

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

The objective 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 additional antihypertensive therapy was needed to achieve target blood pressure.

During the study, dose escalation to 100 mg daily was permitted; 72% of patients received losartan 100 mg once daily for a prolonged period. Other antihypertensive agents (diuretics, calcium antagonists, alpha- and beta-receptor blockers, and centrally acting antihypertensives) were used as add-on therapy as needed in both patient groups. The mean observation period was 4.6 years (average 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) reduced risk by 16.1% (p = 0.022) compared to placebo (359 events) in patients reaching the primary composite endpoint.

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

HEAAL study

The HEAAL (Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan) study was a controlled clinical trial involving 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 either losartan 50 mg once daily or losartan 150 mg, in addition to standard therapy without ACE inhibitors.

The mean follow-up duration 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) reduced risk by 10.1% (p = 0.027, 95% CI 0.82–0.99) compared to losartan 50 mg (889 events) in 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 losartan 50 mg. No significant differences in mortality were observed between treatment groups.

Renal impairment, arterial hypotension, and hyperkalemia occurred more frequently in patients receiving losartan 150 mg than in those receiving losartan 50 mg.

ELITE I and ELITE II studies

The ELITE studies were conducted over 48 weeks in 722 patients with NYHA class II–IV heart failure. No difference was observed between losartan- and captopril-treated patients in the ratio of primary endpoints related to long-term changes in renal function.

The observation from ELITE I that losartan reduces 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 three times daily (initial dose 12.5 mg, increased to 25 mg, then 50 mg three times daily). The primary endpoint of this prospective study was all-cause mortality.

This study, involving 3152 patients with NYHA class II–IV heart failure, was designed to compare mortality rates with losartan and captopril (mean observation period 1.5 years).

Data indicate that in both clinical trials (non-placebo-controlled), losartan was better tolerated than captopril in patients with heart failure, as measured by significantly lower rates of treatment discontinuation due to adverse reactions.

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

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

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

These studies did not demonstrate a significant beneficial effect 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. 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 Using Cardio-Renal Endpoints) study was 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.

Pharmacokinetics.

Absorption

After oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. The 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.

Biotransformation

Approximately 14% of losartan is converted to its active metabolite after intravenous or oral administration. After intravenous or oral administration of radiolabeled 14C-losartan potassium, circulating plasma radioactivity is generally associated with losartan and its metabolites. 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 at 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 both in bile and urine. After oral administration/intravenous injection of 14C-labeled losartan, approximately 35%/43% of the radiolabeled drug was recovered in urine and 58%/50% in feces.

Special patient groups

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 hypertension compared to men, while 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 (see sections "Special warnings and precautions for use" 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 concentration-time curve (AUC) of losartan in patients with normal renal function was approximately twice that in patients on hemodialysis.

Plasma concentrations of the active metabolite do not change in patients with renal impairment or in patients 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 to 16 years after once-daily oral administration at doses of 0.54–0.77 mg/kg (mean doses).

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

Pharmacokinetic parameters of the metabolite varied more depending on age group. Differences were statistically significant in preschool children and adolescents. 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 per day – as part of antihypertensive therapy.
• Treatment of chronic heart failure (in patients aged 60 years and older) when the use of ACE inhibitors is considered impossible due to intolerance, particularly cough, or is contraindicated. Patients with heart failure whose condition has stabilized on an ACE inhibitor should not be switched to treatment with losartan. In the treatment of chronic heart failure, the patient's left ventricular ejection fraction must be ≤ 40%, and the condition must be clinically stable.
• Reduction of the risk of stroke in adult patients with hypertension and documented left ventricular hypertrophy by ECG (see section "Pharmacological properties").

Contraindications.

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

Pregnancy or planned pregnancy (see section "Use in pregnancy or lactation"). Breastfeeding. Severe hepatic impairment.

Concomitant use of the medicinal product Losartan KRKA with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction"). Children under 6 years of age.

Interaction with other medicinal products and other forms of interaction.

Other antihypertensive agents may enhance the hypotensive effect of losartan. Medicinal products that may cause arterial hypotension include tricyclic antidepressants, antipsychotics, baclofen, and amifostine. Concomitant use of these agents with antihypertensive agents increases the risk of arterial hypotension. Losartan is metabolized primarily by the cytochrome P450 (CYP) 2C9 system, forming an active carboxylic acid metabolite. 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 agents 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 products), potassium-containing supplements, or potassium-containing salt substitutes may lead to increased serum potassium levels. Concomitant use of such medicinal products is not recommended.

Reversible increases in serum lithium concentrations and the occurrence of lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Such effects have also been reported very rarely with angiotensin II receptor antagonists. Concomitant treatment with lithium and losartan should be undertaken with caution. If such combination therapy is considered necessary, monitoring of serum lithium levels during combination therapy is recommended.

When angiotensin II receptor antagonists are used concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid at anti-inflammatory doses, non-selective NSAIDs), the antihypertensive effect may be attenuated. Concomitant use of angiotensin II antagonists or diuretics with NSAIDs increases the 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 prescribed with caution, especially in elderly patients. Adequate hydration should be ensured, and monitoring of renal function after initiation of concomitant therapy, as well as periodically during treatment, may be advisable.

Clinical trial data have shown that dual blockade of the RAAS pathway by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single agent acting on the RAAS (see sections "Pharmacological properties", "Contraindications", and "Special precautions for use").

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

Special precautions for use.

Increased sensitivity

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

Arterial hypotension and fluid-electrolyte imbalance

Symptomatic arterial hypotension, particularly after initiation or dose escalation of the drug, may occur in patients with reduced intravascular volume or sodium deficiency caused by potent diuretics, salt-restricted diet, diarrhea, or vomiting. These conditions should be corrected prior to starting losartan therapy or the initial dose should be reduced (see section "Adverse reactions"). These recommendations also apply to children aged 6 to 18 years.

Electrolyte imbalance

Electrolyte imbalances are frequently observed in patients with renal dysfunction (with or without diabetes) and should be taken into account. In a study involving patients with type 2 diabetes and nephropathy, the incidence of hyperkalemia was higher with losartan treatment compared to placebo (see section "Adverse reactions"). 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 agents that may increase serum potassium levels (e.g., trimethoprim-containing products) is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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 symptoms completely resolve.

Hepatic impairment

Since pharmacokinetic data indicate a significant increase in plasma losartan concentrations in patients with hepatic cirrhosis, dose reduction should be considered in patients with a history of hepatic dysfunction. There is no therapeutic experience with losartan in patients with severe hepatic impairment; therefore, losartan is contraindicated in such patients (see sections "Pharmacokinetics", "Contraindications", and "Special precautions for use").

Losartan is not recommended for use in children with hepatic impairment (see section "Special precautions for use").

Renal impairment

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

Medicinal products affecting 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 solitary kidney. These changes in renal function may be reversible upon discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Use in children with renal impairment

Losartan is not recommended for use in children with eGFR < 30 mL/min/1.73 m² due to lack of data in this population (see section "Dosage and administration").

Renal function should be monitored regularly during losartan therapy, as deterioration may occur, particularly in patients with concomitant conditions (e.g., fever, dehydration) that may affect renal function.

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

Kidney transplantation

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents that act by suppressing the renin-angiotensin-aldosterone system. Therefore, losartan is not recommended for this patient group.

Coronary artery disease and cerebrovascular disease

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

Heart failure

As with other agents affecting the RAAS, patients with heart failure, with or without renal impairment, are at risk of developing severe hypotension and renal dysfunction (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 symptomatic, life-threatening cardiac arrhythmias. Therefore, losartan should be used with caution in these patients. Concomitant use of losartan with β-blockers should also be approached with caution (see section "Pharmacological properties").

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

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

Other warnings

Losartan and other angiotensin antagonists are less effective in lowering blood pressure in black patients compared to other patients, possibly due to lower renin activity in black patients with hypertension.

The medicinal product Losartan KRKA contains lactose. Patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this product.

Dual blockade of the RAAS

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

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

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

Use during pregnancy or breastfeeding

Pregnancy

Angiotensin II receptor antagonists (ARBs) are contraindicated during pregnancy.

Epidemiological data on teratogenic effects of ACE inhibitors during the first trimester of pregnancy are inconclusive, but an increased risk cannot be excluded. As there are no controlled epidemiological data on the risk of ARBs, such risks may exist. 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 stopped immediately and, if necessary, alternative treatment initiated. It is known that ARB use during the second and third trimesters of pregnancy causes fetotoxic effects (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 of mothers who took ARBs should be closely monitored for the development of arterial hypotension.

Breastfeeding

Losartan is contraindicated during breastfeeding. Alternative treatment with better-established safety profiles is recommended.

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

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

Method of Administration and Dosage

Losartan tablets should be taken with a glass of water. The drug can be administered independently of food intake. Losartan CRKA 50 mg and 100 mg tablets are not intended to be divided. If a lower dosage is required, losartan in another pharmaceutical form should be used.

Arterial Hypertension

The usual initial and maintenance dose for most patients is 50 mg of the drug once daily (1 tablet of Losartan CRKA 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.

Losartan CRKA may be used in combination with other antihypertensive agents, particularly diuretics (e.g., hydrochlorothiazide).

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

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

Heart Failure

For patients with chronic heart failure, the recommended initial dose of losartan is 12.5 mg once daily. The dose is usually titrated at weekly intervals (i.e., 12.5 mg daily, 25 mg daily, 50 mg daily) to the usual maintenance dose of 50 mg (1 tablet of Losartan CRKA) once daily, depending on individual tolerance.

Administer losartan preparations at the appropriate dosage.

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

The recommended initial dose is 50 mg of Losartan CRKA once daily. Depending on changes in blood pressure, low-dose hydrochlorothiazide may be added and/or the dose of Losartan CRKA may be increased to 100 mg once daily.

Use in Patients with Reduced Circulating Blood Volume

Patients with reduced circulating blood volume (e.g., due to treatment with high-dose diuretics) should start therapy with a dose of 25 mg losartan once daily (see section "Special Warnings and Precautions for Use").

Use in Patients with Renal Impairment and Patients Undergoing Hemodialysis

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

Use in Patients with Hepatic Impairment

For patients with a history of hepatic impairment, a lower initial dose should be considered. There is no experience with losartan in patients with severe hepatic impairment; therefore, losartan is contraindicated in such patients (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Pediatric Population

The safety and efficacy of the drug in children aged 6 months to 6 years have not been established. Available data are described in sections "Pharmacodynamics" and "Pharmacokinetics," but dosage recommendations for this patient group cannot be provided.

Pediatric Population (children 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 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 recommended single dose is 50 mg once daily. In exceptional cases, the dose may be increased to a maximum of 100 mg once daily. The use of doses exceeding 1.4 mg/kg (or more than 100 mg) per day has not been studied in children.

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

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

Losartan is also not recommended for use in children with hepatic impairment (see section "Special Warnings and Precautions for Use").

Use in Elderly Patients

Dose adjustment of the initial dose is generally not required in elderly patients, although an initial dose of 25 mg may be considered for patients aged 75 years and older.

Children

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

Overdose.

Symptoms

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

Treatment

Therapeutic measures depend on the time elapsed since drug ingestion, the nature, and severity of symptoms. The primary measure should be stabilization of cardiovascular function. After oral overdose, administration of activated charcoal in an appropriate dose is indicated. Induction of emesis and gastric lavage are also recommended. Subsequently, vital signs should be monitored and corrected as necessary. Losartan and its active metabolites are not removed by hemodialysis.

Adverse Reactions

In controlled clinical trials of essential hypertension involving patients with arterial hypertension and left ventricular hypertrophy, as well as patients with chronic heart failure, arterial hypertension, type 2 diabetes, and renal disease, the most common adverse event reported with losartan was dizziness.

Below are the adverse reactions classified by system organ class and frequency of occurrence: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

Frequency of adverse reactions determined from placebo-controlled clinical trials and post-marketing experience:

Adverse reaction		Frequency of adverse reactions by indication		Other
	Patients with arterial hypertension	Patients with hypertension and left ventricular hypertrophy	Patients with chronic heart failure	Patients with hypertension and type 2 diabetes with kidney disease	Post-marketing experience
From the blood and lymphatic system
anemia			common		frequency unknown
thrombocytopenia					frequency unknown
From the immune system
hypersensitivity reactions, anaphylactic reactions, angioneurotic edema* and vasculitis**					rare
From the psyche
depression					frequency unknown
From the nervous system
dizziness	common	common	common	common
drowsiness	uncommon
headache	uncommon		uncommon
sleep disorders	uncommon
paraesthesia			rare
migraine					frequency unknown
dysgeusia					frequency unknown
From the ear and labyrinth
vertigo	common	common
tinnitus					frequency unknown
From the heart
palpitations	uncommon
angina pectoris	uncommon
syncope			rare
atrial fibrillation			rare
stroke			rare
From the vascular system
(orthostatic) hypotension (including dose-dependent orthostatic effect)║	uncommon		common	common
From the respiratory system, thoracic organs and mediastinum
dyspnea			uncommon
cough			uncommon		frequency unknown
From the gastrointestinal tract
abdominal pain	uncommon
constipation	uncommon
diarrhea			uncommon		frequency unknown
nausea			uncommon
vomiting			uncommon
intestinal angioneurotic edema					rare
From the liver and biliary system
pancreatitis					frequency unknown
hepatitis					rare
liver function disorders					frequency unknown
From the skin and subcutaneous tissue
urticaria			uncommon		frequency unknown
pruritus			uncommon		frequency unknown
rash	uncommon		uncommon		frequency unknown
photosensitivity					frequency unknown
From the musculoskeletal and connective tissue system
myalgia					frequency unknown
arthralgia					frequency unknown
rhabdomyolysis					frequency unknown
From the kidneys and urinary system
renal function disorders			common
renal failure			common
From the reproductive system and mammary glands
erectile dysfunction / impotence					frequency unknown
General disorders
asthenia	uncommon	common	uncommon	common
weakness	uncommon	common	uncommon	common
edema	uncommon
malaise					frequency unknown
Laboratory parameters
hyperkalemia	common		uncommon†	common‡
increased alanine aminotransferase (ALT)§	rare
increased blood urea, creatinine and serum potassium			common
hyponatremia					frequency unknown
hypoglycemia				common

*Including angioedema of the larynx, glottis, face, lips, pharynx, and/or tongue (which may cause airway obstruction); in some of these patients, there have been reports of a history of angioedema associated with the use of other medicinal products, including ACE inhibitors.

**Including Henoch–Schönlein purpura.

║Particularly in patients with reduced blood volume, such as those with severe heart failure or those receiving high doses of diuretics.

† Frequently in patients who received a dose of 150 mg instead of 50 mg.

‡During clinical trials, hyperkalemia > 5.5 mmol/L developed in 9.9% of patients with arterial hypertension and type 2 diabetes receiving losartan, and in 3.4% of patients receiving placebo.

§Usually resolves after discontinuation of treatment.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via 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 and sight of children.

Packaging.

10 tablets per blister, 3 or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and location of operations.

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