Losartan 50/hydrochlorothiazide 12,5 krka

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOSARTAN 100/HYDROCHLOROTHIAZIDE 12.5 KRKA LOSARTAN 100/HYDROCHLOROTHIAZIDE 25 KRKA LOSARTAN 50/HYDROCHLOROTHIAZIDE 12.5 KRKA (Losartan 100/hydrochlorothiazide 12.5 KRKA) (Losartan 100/hydrochlorothiazide 25 KRKA) (Losartan 50/hydrochlorothiazide 12.5 KRKA)

Composition:

Active substances: losartan, hydrochlorothiazide;

One film-coated tablet contains:

100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, or

100 mg of losartan potassium and 25 mg of hydrochlorothiazide, or

50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide;

Excipients: pregelatinized starch, microcrystalline cellulose, lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycol 4000, talc, quinoline yellow (E 104) – only in Losartan 50/hydrochlorothiazide 12.5 KRKA and Losartan 100/hydrochlorothiazide 25 KRKA, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Losartan 100/hydrochlorothiazide 12.5 KRKA: white, oval, biconvex film-coated tablets;

Losartan 100/hydrochlorothiazide 25 KRKA: yellow, oval, slightly biconvex film-coated tablets;

Losartan 50/hydrochlorothiazide 12.5 KRKA: yellow, oval, slightly biconvex film-coated tablets with a score on one side, which is not intended for dividing the tablet.

Pharmacotherapeutic group. Combined angiotensin II inhibitors. Losartan and diuretics. ATC code C09DA01.

Pharmacological Properties.

Pharmacodynamics.

Losartan/hydrochlorothiazide

The antihypertensive effects of the components of the medicinal product are additive; therefore, the medicinal product reduces blood pressure to a greater extent than its individual components alone. In addition, due to its diuretic effect, hydrochlorothiazide increases plasma renin activity and aldosterone secretion, decreases serum potassium concentration, and increases plasma angiotensin II levels. Administration of losartan blocks all physiological effects of angiotensin II and, by suppressing aldosterone effects, may help reduce potassium loss associated with diuretic use.

Losartan exerts a mild and transient uricosuric effect. Hydrochlorothiazide slightly increases serum uric acid levels; however, the combination of losartan and hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.

The antihypertensive effect of the medicinal product persists for 24 hours. The antihypertensive effect is maintained during continuous treatment. Clinical studies lasting at least one year have demonstrated sustained antihypertensive efficacy with continuous therapy. Despite a significant reduction in blood pressure, treatment with the medicinal product did not have a clinically significant effect on heart rate. In clinical studies, after 12 weeks of treatment, a mean reduction of 13.2 mm Hg in seated diastolic blood pressure was observed.

The combination of losartan/hydrochlorothiazide is effective in lowering blood pressure in both men and women, in patients of non-Black and other racial groups, in younger patients (< 65 years) and elderly patients (≥ 65 years); the medicinal product is effective in patients with any degree of severity of arterial hypertension.

Losartan

Losartan is a synthetic, orally administered angiotensin II receptor (type AT1) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system (RAS) and a key determinant in the pathophysiology of arterial hypertension. Angiotensin II binds to AT1 receptors located in many tissues (e.g., vascular smooth muscle, adrenal glands, kidneys, and heart) and exerts several important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell proliferation.

Losartan selectively blocks the AT1 receptor. In vitro and in vivo, losartan and its pharmacologically active metabolite, the 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 receptors of other hormones or ion channels important in cardiovascular regulation. Additionally, losartan does not affect angiotensin-converting enzyme (kinase II), which is responsible for bradykinin breakdown. Therefore, adverse reactions associated with elevated bradykinin concentrations are not observed. Administration of losartan inhibits the negative feedback of angiotensin II on renin formation, leading to increased plasma renin activity. Increased renin activity results in elevated plasma angiotensin II levels. Despite these increases, antihypertensive activity and reduced plasma aldosterone levels are maintained, indicating effective blockade of the angiotensin II receptor. After discontinuation of losartan therapy, plasma renin activity and angiotensin II concentration return to normal within three days.

Losartan and its primary active metabolite have a significantly higher affinity for the AT1 receptor than for the AT2 receptor. The active metabolite is estimated to be 10–40 times more potent than losartan on a molar basis.

In a study specifically designed to evaluate cough incidence in patients receiving losartan compared to patients receiving ACE inhibitors, the incidence of cough reported by patients receiving losartan or hydrochlorothiazide was similar and significantly lower than in patients receiving ACE inhibitors. Additionally, a pooled analysis of data from 16 double-blind clinical trials involving 4,131 patients showed that the incidence of cough reported by patients receiving losartan (3.1%) was similar to that in patients receiving placebo (2.6%) or hydrochlorothiazide (4.1%), whereas the incidence was 8.8% in patients receiving ACE inhibitors.

In patients with arterial hypertension associated with proteinuria but without diabetes, treatment with potassium losartan significantly reduces proteinuria, as well as fractional excretion of albumin and IgG. Losartan maintains glomerular filtration rate and reduces filtration fraction. Overall, losartan causes a reduction in serum uric acid concentration (typically < 0.4 mg/dL), which persists during long-term therapy.

Losartan does not affect autonomic reflexes and has no prolonged effect on plasma noradrenaline levels.

In patients with left ventricular insufficiency, administration of losartan at doses of 25 mg and 50 mg produced positive hemodynamic and neurohormonal effects, characterized by increased cardiac index and reduced pulmonary capillary wedge pressure, reduced systemic vascular resistance and mean arterial pressure, as well as reduced heart rate and circulating levels of aldosterone and noradrenaline. Incidence of arterial hypotension in this group of patients with heart failure was dose-dependent.

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 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 result in a sudden increase in blood pressure (withdrawal syndrome). Despite a significant reduction in blood pressure, losartan did not have a clinically significant effect on heart rate.

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

LIFE study (Losartan Intervention For Endpoint − study of losartan's effect on reducing severity of arterial hypertension)

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was a randomized, double-blind, active-controlled trial involving 9,193 patients aged 55 to 80 years with arterial hypertension and 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. If needed, other antihypertensive agents (except ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added 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 reduction in total cardiovascular mortality, stroke, and myocardial infarction. Blood pressure was significantly lower in both treatment groups. Treatment with losartan resulted in a 13% reduction in risk (p = 0.021, 95% 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 cardiovascular mortality or myocardial infarction incidence.

Double 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 a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a study involving patients with type 2 diabetes or 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. Due to similar pharmacodynamic properties, these findings 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 ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or both. The study was terminated prematurely due to a high risk of adverse reactions. Cardiovascular mortality and stroke rates were higher in the aliskiren group than in the placebo group, and adverse events and serious adverse events (hyperkalemia, arterial hypotension, and renal dysfunction) occurred more frequently in the aliskiren group than in the placebo group.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive action of thiazide diuretics is not fully understood. Thiazides affect the renal tubular mechanism of electrolyte reabsorption, thereby directly increasing the excretion of sodium and chloride in approximately equal amounts. The diuretic effect of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, and leads to increased potassium excretion in urine, bicarbonate loss, and decreased serum potassium levels. Possibly, due to blockade of the renin-aldosterone system (RAS), concomitant administration of angiotensin II receptor antagonists may help counteract potassium loss associated with thiazide diuretics.

After oral administration, diuresis begins within two hours, reaches its peak at approximately four hours, and lasts 6–12 hours. The antihypertensive effect persists for up to 24 hours.

Non-melanoma skin cancer (NMSC)

Based on available epidemiological data, a cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed. One study included a population of 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), compared with 1,430,833 and 172,462 individuals in the control population, respectively. High cumulative doses of hydrochlorothiazide (≥ 50,000 mg) were associated with an adjusted OR of 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship between cumulative dose and BCC and SCC was observed. Another study suggested a possible association between lip cancer (SCC) and hydrochlorothiazide exposure: 633 cases of lip cancer were compared with 63,067 individuals in the control population using a random sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7–2.6), increasing to 3.9 (3.0–4.9) for high doses (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").

Pharmacokinetics.

Absorption.

Losartan

After oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming one active carboxylic acid metabolite and other pharmacologically inactive metabolites. The systemic bioavailability of losartan is approximately 33%. Maximum concentrations of losartan and its active metabolite are reached approximately 1 hour and 3–4 hours after administration, respectively. Food intake does not cause clinically significant deviations in the pharmacokinetic profile.

Distribution

Losartan

More than 99% of losartan and its active metabolite are bound to plasma proteins, primarily albumins. The volume of distribution of losartan is 34 L. In rat studies, losartan penetrates the blood-brain barrier to a minimal extent or not at all.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental barrier, does not cross the blood-brain barrier, and is excreted into breast milk.

Biotransformation

Losartan

Approximately 14% of an orally or intravenously administered dose of losartan is metabolized to its active metabolite. After oral or intravenous administration of radiolabeled 14C-losartan, plasma radioactivity is associated with losartan and its active metabolite. In 1% of studied individuals, losartan is only minimally converted to its active metabolite.

In addition to the active metabolite, inactive metabolites are formed, including two major metabolites produced by hydroxylation of the butyl chain, and a minor metabolite, the N-2 tetrazole glucuronide.

Elimination

Losartan

The plasma clearance of losartan and its active metabolite is approximately 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, 4% of the administered dose of losartan is excreted unchanged in urine, and 6% is excreted as the active metabolite.

The pharmacokinetic properties of losartan and its active metabolite change linearly with oral doses of potassium losartan up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially; the elimination half-life is approximately 2 hours and 6–9 hours, respectively. With once-daily administration of 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.

Both biliary and renal excretion play a role in the elimination of losartan and its active metabolites. After administration of radiolabeled 14C-losartan, approximately 35% of radioactivity is recovered in urine and 58% in feces.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is rapidly excreted by the kidneys. When plasma concentrations were monitored for at least 24 hours, the plasma half-life of hydrochlorothiazide ranged from 5.6 to 14.8 hours. At least 61% of an oral dose is excreted unchanged within 24 hours.

Characteristics in patients

Losartan/hydrochlorothiazide

Plasma concentrations of losartan and its active metabolite, as well as absorption of hydrochlorothiazide, in elderly patients with arterial hypertension do not differ significantly from those observed in younger patients with arterial hypertension.

Losartan.

After oral administration to patients with mild to moderate alcoholic cirrhosis, plasma concentrations of losartan and its active metabolites were approximately 5 and 1.7 times higher, respectively, than in young healthy volunteers.

Pharmacokinetic studies have shown that in healthy male volunteers of Japanese and non-Japanese origin, the area under the concentration-time curve (AUC) of losartan was similar. However, the AUC of the carboxylic acid metabolite (E-3174) differed between the two groups, with exposure in Japanese volunteers being 1.5 times higher than in non-Japanese volunteers. The clinical significance of these findings is unknown.

Losartan and its active metabolite are not removed by hemodialysis.

Clinical characteristics.

Indications.

Treatment of essential hypertension in patients in whom adequate blood pressure control is not achieved with either losartan alone or hydrochlorothiazide alone.

Contraindications.

Hypersensitivity to losartan, sulfonamide derivatives (such as hydrochlorothiazide), or to any excipients.

Severe renal impairment (creatinine clearance < 30 mL/min).

Anuria.

Severe hepatic impairment; cholestasis.

Obstructive biliary disorders.

Therapeutically resistant hypokalemia or hypercalcemia.

Refractory hyponatremia.

Symptomatic hyperuricemia/gout.

Second and third trimesters of pregnancy (see sections "Special precautions for use" and "Use in pregnancy or breastfeeding").

Children.

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

Interaction with other medicinal products and other forms of interaction.

Losartan

There have been reports that rifampicin and fluconazole reduce the levels of the active metabolite. The clinical consequences of these interactions have not been evaluated.

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

As with other drugs affecting sodium excretion, lithium clearance may be reduced. Therefore, serum lithium levels should be carefully monitored when lithium salts are used concomitantly with angiotensin II receptor antagonists.

Nonsteroidal anti-inflammatory drugs (NSAIDs) (acetylsalicylic acid in anti-inflammatory doses, selective COX-2 inhibitors) and non-selective NSAIDs may reduce the antihypertensive effect of angiotensin II receptor antagonists. Concomitant use of angiotensin II receptor antagonists or diuretics and NSAIDs may lead to worsening of renal function, including possible acute renal failure, and increased serum potassium levels, particularly in patients with impaired renal function. Such combinations should be used with caution, especially in the elderly. Patients should be adequately hydrated and careful monitoring of renal function should be performed at the initiation of concomitant treatment and periodically thereafter.

In some patients with impaired renal function, concomitant use of angiotensin II receptor antagonists and drugs that inhibit cyclooxygenase-2 may lead to further deterioration of renal function. These effects are usually reversible.

Clinical 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 is associated with an increased risk of adverse events such as arterial hypotension, hyperkalemia, and worsening of renal function (including acute renal failure), compared to treatment with a single RAAS-blocking agent (see sections "Pharmacological properties", "Contraindications", and "Special precautions for use").

Other drugs that may cause arterial hypotension as a primary condition or as an adverse effect include tricyclic antidepressants, neuroleptics, baclofen, and amifostine. Concomitant use of these drugs may increase the risk of arterial hypotension.

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

Hydrochlorothiazide

The following medicinal products may interact when taken concomitantly with thiazide diuretics:

Alcohol, barbiturates, narcotics, or antidepressants: orthostatic hypotension may be potentiated;

Antidiabetic agents (oral agents and insulin): thiazide therapy may affect glucose tolerance. Dose adjustment of antidiabetic agents may be required. Metformin should be used with caution due to the risk of lactic acidosis caused by possible functional renal impairment associated with hydrochlorothiazide;

Other antihypertensive agents: additive effect;

Cholestyramine and colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of anion-exchange resins. Single doses of cholestyramine or colestipol bind hydrochlorothiazide and reduce its gastrointestinal absorption by 85% and 43%, respectively;

Corticosteroids, adrenocorticotropic hormone: enhanced electrolyte depletion, particularly hypokalemia;

Pressor amines (e.g., adrenaline): reduced response to pressor amines may occur, but this is insufficient to preclude their use;

Skeletal muscle relaxants, non-depolarizing (e.g., tubocurarine): increased response to muscle relaxants may occur;

Lithium: diuretics reduce renal lithium clearance and increase the risk of lithium toxicity; concomitant use is not recommended;

Medicinal products used to treat gout (probenecid, sulfinpyrazone, and allopurinol): dose adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be needed. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol;

Anticholinergic agents (e.g., atropine, biperiden): increased bioavailability of thiazide diuretics may occur due to reduced gastrointestinal motility and delayed gastric emptying;

Cytotoxic agents (e.g., cyclophosphamide, methotrexate): thiazides may reduce renal excretion of cytotoxic drugs and enhance their myelosuppressive effects;

Salicylates: when high doses of salicylates are administered, hydrochlorothiazide may potentiate the toxic effects of salicylates on the central nervous system (CNS);

Methyldopa: isolated reports of hemolytic anemia have occurred during concomitant use of hydrochlorothiazide and methyldopa;

Cyclosporine: concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-like complications;

Cardiac glycosides: hypokalemia or hypomagnesemia induced by thiazides may predispose to cardiac arrhythmias caused by cardiac glycosides;

Medicinal products affected by disturbances in serum potassium levels: periodic monitoring of serum potassium and ECG is recommended when using losartan/hydrochlorothiazide with medicinal products affected by disturbances in serum potassium levels (such as cardiac glycosides and antiarrhythmic agents), and with medicinal products that may cause ventricular tachycardia «torsades de pointes» (including certain antiarrhythmic agents); hypokalemia is a precipitating factor for ventricular tachycardia «torsades de pointes»:

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Some neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Others (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).

Calcium salts. Thiazide diuretics may increase serum calcium levels due to reduced excretion. If calcium-elevating agents are required, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Interference with laboratory tests

Due to their effect on calcium metabolism, thiazides may interfere with parathyroid function testing (see section "Special precautions for use").

Carbamazepine. Risk of symptomatic hyponatremia. Clinical and biological monitoring is required.

Iodinated contrast media. There is an increased risk of acute renal failure in cases of diuretic-induced dehydration, particularly with high doses of iodinated agents.

The patient's fluid balance should be restored prior to administration of the agent.

Amphotericin B (parenteral), corticosteroids, adrenocorticotropic hormone, stimulant laxatives, and glycyrrhizin (contained in licorice). Hydrochlorothiazide may potentiate electrolyte imbalance, particularly hypokalemia.

Special precautions for use.

Losartan

Angioedema

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

Hypotension and reduced intravascular volume

Symptomatic arterial hypotension may occur in patients who have been intensively treated with diuretics, restricted dietary salt intake, or who have experienced diarrhea or vomiting prior to starting the medication. These conditions should be corrected before initiating treatment (see sections "Dosage and administration", "Contraindications").

Electrolyte imbalances

Electrolyte imbalances are common and require attention, particularly in patients with renal impairment with or without diabetes mellitus. Plasma potassium concentration and creatinine clearance should be carefully monitored, especially in patients with heart failure and creatinine clearance of 30–50 mL/min.

Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., trimethoprim-containing medications) with losartan/hydrochlorothiazide is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic impairment

Based on pharmacokinetic data demonstrating significantly increased plasma concentrations of losartan in patients with cirrhosis, this combination should be used with caution in patients with mild to moderate hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment; therefore, the losartan/hydrochlorothiazide combination is contraindicated in such patients (see sections "Dosage and administration", "Contraindications", "Pharmacokinetics").

Renal impairment

Due to inhibition of the renin-angiotensin-aldosterone system (RAAS), changes in renal function, including renal failure, have been reported (particularly in patients whose renal function depends on RAAS activity, such as those with severe heart failure or pre-existing renal impairment).

As with other drugs affecting the RAAS, increased blood urea nitrogen and serum creatinine have been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning 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 functioning kidney.

Renal transplantation

There is no experience with use in patients who have recently undergone renal transplantation.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond therapeutically to antihypertensive agents acting via RAAS inhibition. Therefore, use of this medication is not recommended in such patients.

Coronary heart disease and stroke

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

Heart failure

In patients with heart failure, with or without renal impairment, there is a risk of severe hypotension and renal dysfunction (often acute), as with other drugs affecting the RAAS.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilating agents, caution should be exercised when prescribing this medication to patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Intestinal angioedema

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

Ethnic characteristics

As with other ACE inhibitors, losartan and other angiotensin II receptor antagonists may be less effective in reducing blood pressure in black patients compared to patients of other races, possibly due to a higher prevalence of low-renin states in black individuals.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. For women planning pregnancy, antihypertensive therapy should be switched to an alternative with an established safety profile during pregnancy. If pregnancy is detected, treatment with this medication should be discontinued immediately and alternative therapy initiated if possible (see sections "Contraindications", "Use during pregnancy or breastfeeding").

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

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and decreased 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 "Pharmacodynamic properties" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.

Hydrochlorothiazide

Hypotension and electrolyte/fluid imbalance

As with other antihypertensive agents, symptomatic hypotension may occur in some patients during treatment. Patients should be monitored for clinical signs of fluid or electrolyte imbalance (e.g., reduced fluid volume, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia), which may result from concomitant diarrhea or vomiting. Periodic serum electrolyte monitoring should be performed at regular intervals in such patients. In hot weather, hyponatremia due to dilution may occur in patients prone to edema.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. Dose adjustment of antidiabetic agents, including insulin, may be required (see section "Interaction with other medicinal products and other forms of interaction"). Latent diabetes mellitus may become manifest during thiazide therapy.

Thiazides may reduce calcium excretion in urine and cause mild, concomitant elevation of serum calcium levels. Marked hypercalcemia may indicate occult hyperparathyroidism.

Thiazide administration should be discontinued prior to parathyroid function testing.

Elevated cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Hyperuricemia and/or gout exacerbation may occur in some patients due to thiazide therapy. Since losartan reduces uric acid levels, the combination of losartan with hydrochlorothiazide may enhance diuretic-induced hyperuricemia.

Hepatic impairment

Thiazides should be used with caution in patients with hepatic impairment or progressive liver disease, as they may cause intrahepatic cholestasis; minor disturbances in fluid and electrolyte balance may later precipitate hepatic coma.

The combination losartan/hydrochlorothiazide is contraindicated in patients with severe hepatic impairment (see sections "Contraindications", "Pharmacokinetics").

Other

Hypersensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma who are taking thiazides. Exacerbation or activation of systemic lupus erythematosus has been reported with thiazide use.

Special information on certain excipients

The formulations contain lactose; therefore, this medication should not be administered to patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

The formulations contain a dye which may cause allergic reactions.

Non-melanoma skin cancer (NMSC)

In two epidemiological studies based on the Danish National Cancer Registry, an increased risk of NMSC (basal cell carcinoma and squamous cell carcinoma) was observed with increasing cumulative doses of hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may be a potential mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly examine their skin for new lesions and promptly report any suspicious skin changes. Preventive measures such as limiting exposure to sunlight and ultraviolet radiation are recommended, and appropriate protective measures should be taken when exposure occurs to minimize the risk of skin cancer. Suspicious skin lesions should be promptly evaluated, including histological examination by biopsy. The continued need for hydrochlorothiazide should also be re-evaluated in patients with a prior history of NMSC (see section "Adverse reactions").

Acute angle-closure glaucoma

Sulfonamide or sulfonamide-derived drugs may cause idiosyncratic reactions leading to acute transient myopia and acute angle-closure glaucoma. Symptoms include decreased visual acuity or eye pain, usually occurring within hours to one week after drug initiation. Untreated acute angle-closure glaucoma may result in permanent vision loss. Treatment with hydrochlorothiazide should be discontinued as soon as possible. Urgent medical, including surgical, intervention may be required if intraocular pressure remains uncontrolled. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Acute respiratory toxicity

Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema typically develops within minutes to hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening pulmonary status, and hypotension. If ARDS is suspected, Losartan 100/hydrochlorothiazide 12.5 KRKA, Losartan 100/hydrochlorothiazide 25 KRKA, or Losartan 50/hydrochlorothiazide 12.5 KRKA should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who have previously experienced ARDS after hydrochlorothiazide.

Use during pregnancy or breastfeeding.

Pregnancy

Use of angiotensin II inhibitors during the first trimester of pregnancy is not recommended (see section "Special precautions for use"). Use of angiotensin II inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications", "Special precautions for use").

Epidemiological findings regarding teratogenic risk associated with ACE inhibitors during the first trimester are inconclusive, but a small increased risk cannot be excluded. To date, there are no controlled epidemiological data on the risk associated with angiotensin II inhibitors; however, a similar risk is possible for this class of drugs if continued therapy with an angiotensin II inhibitor is not considered essential. Women planning pregnancy should be switched to an alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is detected, treatment with an angiotensin II inhibitor should be discontinued immediately and alternative therapy initiated if possible.

It is known that use of angiotensin II inhibitors during the second and third trimesters of pregnancy may cause fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If angiotensin II inhibitors are used during the second trimester of pregnancy, ultrasound assessment of renal function and skull development is recommended.

Newborns whose mothers took angiotensin II inhibitors should be closely monitored for arterial hypotension.

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy is limited, particularly in the first trimester. Animal studies are limited.

Hydrochlorothiazide crosses the placental barrier. Due to its pharmacological mechanism of action, use during the second and third trimesters may impair placental blood flow and cause jaundice, electrolyte imbalance, and thrombocytopenia in the fetus and newborn.

Hydrochlorothiazide should not be used to treat gestational edema, gestational hypertension, or eclampsia due to the risk of reduced placental volume and placental hypoperfusion without beneficial effect on disease course.

Hydrochlorothiazide should not be used to treat arterial hypertension in pregnant women except when alternative treatments are not feasible.

Breastfeeding period

Angiotensin II receptor antagonists (ARBs)

It is unknown whether losartan/hydrochlorothiazide passes into breast milk. Use of this medication during breastfeeding is not recommended. The patient should be switched to an alternative antihypertensive with an established safety profile during breastfeeding, particularly for newborns or preterm infants.

Hydrochlorothiazide

Hydrochlorothiazide passes into breast milk in small amounts. High-dose thiazides causing intense diuresis may suppress lactation. The medication is not recommended during breastfeeding. If used during breastfeeding, doses should be kept as low as possible.

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted on the effect of the medication on the ability to drive or operate machinery.

However, dizziness or somnolence may occur during driving or operating complex machinery, particularly at the beginning of treatment or when the dose is increased, as with other antihypertensive agents.

Dosage and Administration

The combination of losartan/hydrochlorothiazide may be used together with other antihypertensive agents (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetic Properties"). Do not initiate therapy with losartan/hydrochlorothiazide. The drug should be administered to patients whose blood pressure is not adequately controlled with losartan or hydrochlorothiazide alone.

Tablets should be swallowed with a glass of water, regardless of food intake.

In patients whose blood pressure is not sufficiently controlled, initial transition from monotherapy to fixed-dose combination therapy may be considered, if clinically indicated.

Dosage should be determined by titrating the individual components (losartan and hydrochlorothiazide).

Arterial Hypertension

The usual maintenance dose is 1 tablet of Losartan 50/Hydrochlorothiazide 12.5 KRKA once daily. For patients who do not achieve adequate blood pressure control with 1 tablet of Losartan 50/Hydrochlorothiazide 12.5 KRKA, the dose may be increased to 2 tablets of this strength once daily or to 1 tablet of Losartan 100/Hydrochlorothiazide 25 KRKA once daily. The maximum dose is 1 tablet of Losartan 100/Hydrochlorothiazide 25 KRKA once daily. The antihypertensive effect is usually achieved within 3–4 weeks after initiation of therapy.

Losartan 100/Hydrochlorothiazide 12.5 KRKA is intended for patients who are already receiving a titrated dose of 100 mg losartan and require additional blood pressure control.

Use in Patients with Renal Impairment and Patients Undergoing Hemodialysis

No initial dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance 30–50 mL/min). Use of losartan and hydrochlorothiazide is not recommended in patients undergoing hemodialysis. The combination tablet losartan/hydrochlorothiazide should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications").

Use in Patients with Reduced Intravascular Volume

Volume and/or salt depletion should be corrected prior to initiating therapy.

Use in Patients with Hepatic Impairment

The drug is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Use in Elderly Patients

Dose adjustment is generally not required in elderly patients.

Pediatric Population

There is no experience with use of this drug in children. Therefore, the combination of losartan/hydrochlorothiazide should not be used in children (under 18 years of age).

Overdose.

Symptoms

There is no specific information on the treatment of overdose with this drug. Treatment is symptomatic and supportive. Administration of losartan/hydrochlorothiazide should be discontinued and close monitoring of the patient should be instituted. Recommended measures include induction of emesis if ingestion was recent, and treatment of dehydration, electrolyte imbalances, hepatic coma, and arterial hypotension with symptomatic therapy.

Losartan

The most likely manifestation of overdose is hypotension and tachycardia; bradycardia may occur as a result of parasympathetic (vagal) stimulation. If symptomatic hypotension occurs, supportive treatment should be initiated.

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

Hydrochlorothiazide

The principal manifestations and symptoms are due to electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. In patients receiving concomitant cardiac glycosides, hypokalemia may potentiate cardiac arrhythmias.

Hydrochlorothiazide is removed by hemodialysis, although the degree of removal has not been established.

Side effects

The following adverse reactions are classified by system organ class and frequency of occurrence:

• Very common (≥ 1/10);
• Common (≥ 1/100, < 1/10);
• Uncommon (≥ 1/1,000, < 1/100);
• Rare (≥ 1/10,000, < 1/1,000);
• Very rare (< 1/10,000);
• Not known (cannot be estimated from the available data).

During clinical trials with potassium losartan and hydrochlorothiazide, no adverse reactions specific to this combination were observed. Adverse reactions were limited to those previously reported with losartan potassium and/or hydrochlorothiazide.

It is known that in controlled clinical trials in patients with primary arterial hypertension receiving losartan and hydrochlorothiazide, the only adverse reaction associated with the drug was dizziness, reported at a frequency of 1% (which exceeded the frequency of this reaction in the placebo group).

In addition, the following adverse reactions have been reported during the post-marketing period:

• Nervous system disorders:*
  Common – dizziness;

• Hepatobiliary disorders:*
  Rare – hepatitis;

• Laboratory findings:*
  Rare – hyperkalemia, increased ALT levels.

Additional adverse reactions observed with one of the components of the drug and which may be potential adverse reactions with losartan/hydrochlorothiazide are as follows:

Losartan

• Blood and lymphatic system disorders:*
  Uncommon – anemia, Henoch-Schönlein purpura, ecchymosis, hemolysis;
  Not known – thrombocytopenia;

• Immune system disorders:*
  Rare – hypersensitivity reactions (anaphylactic reactions, angioedema including laryngeal and glottal edema leading to airway obstruction and/or facial, lip, throat and/or tongue swelling; history of angioedema with drugs including ACE inhibitors); urticaria;

• Metabolism and nutrition disorders:*
  Uncommon – anorexia, gout;

• Psychiatric disorders:*
  Common – insomnia;
  Uncommon – fear, anxiety disorder, panic disorder, confusion, depression, abnormal dreams, sleep disorders, somnolence, memory impairment;

• Nervous system disorders:*
  Common – headache, dizziness;
  Uncommon – nervousness, paresthesia, peripheral neuropathy, tremor, migraine, loss of consciousness;
  Not known – dysgeusia;

• Eye disorders:*
  Uncommon – blurred vision, burning/stinging in eyes, conjunctivitis, decreased visual acuity;

• Ear and labyrinth disorders:*
  Uncommon – vertigo, tinnitus;

• Cardiac disorders:*
  Uncommon – arterial hypotension, orthostatic hypotension, sternalgia, angina pectoris, cerebrovascular disorders, second-degree AV block, stroke, myocardial infarction, palpitations, arrhythmias (atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation);

• Respiratory, thoracic and mediastinal disorders:*
  Common – cough, upper respiratory tract infections, nasal congestion, sinusitis, sinus disorders;
  Uncommon – pharyngeal discomfort, pharyngitis, laryngitis, dyspnea, shortness of breath, bronchitis, epistaxis, rhinitis, respiratory tract congestion;

• Gastrointestinal disorders:*
  Common – abdominal pain, nausea, diarrhea, dyspepsia;
  Uncommon – constipation, toothache, dry mouth, flatulence, gastritis, vomiting, intestinal obstruction;
  Rare – intestinal angioedema;
  Not known – pancreatitis;

• Hepatobiliary disorders:*
  Not known – hepatic function abnormalities;

• Skin and subcutaneous tissue disorders:*
  Uncommon – alopecia, dermatitis, dry skin, erythema, redness, photosensitivity, pruritus, rash, urticaria, increased sweating;
  Not known – reactivation of cutaneous lupus erythematosus;

• Musculoskeletal and connective tissue disorders:*
  Common – muscle cramps, back pain, leg pain, myalgia;
  Uncommon – arm pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, coxalgia, fibromyalgia, muscle weakness;
  Not known – rhabdomyolysis;

• Renal and urinary disorders:*
  Common – renal function impairment, renal failure;
  Uncommon – nocturia, frequent urination, urinary tract infections;

• Reproductive system and breast disorders:*
  Uncommon – decreased libido, erectile dysfunction/impotence;

• General disorders and administration site conditions:*
  Common – asthenia, fatigue, chest pain;
  Uncommon – facial swelling, fever;
  Not known – influenza-like symptoms, malaise;

• Vascular disorders:*
  Uncommon – vasculitis;
  Not known – dose-dependent orthostatic effect.

• Laboratory findings:*
  Common – hyperkalemia, slight decrease in hematocrit and hemoglobin, hypoglycemia;
  Uncommon – slight decrease in serum urea and creatinine levels;
  Very rare – increased liver enzymes and bilirubin.

Hydrochlorothiazide

• Benign, malignant and unspecified neoplasms (including cysts and polyps)¹:*
  Not known – non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)¹.

• Blood and lymphatic system disorders:*
  Uncommon – agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia;

• Immune system disorders:*
  Rare – anaphylactic reaction;

• Metabolism and nutrition disorders:*
  Uncommon – anorexia, hyperglycemia, hyperuricemia, hypokalemia, hyponatremia;

• Psychiatric disorders:*
  Uncommon – insomnia, mood changes;

• Nervous system disorders:*
  Common – headache;

• Eye disorders:*
  Uncommon – transient visual disturbances, xanthopsia;
  Not known – choroidal effusion, acute myopia, acute angle-closure glaucoma;

• Cardiac disorders:*
  Uncommon – necrotizing angiitis (vasculitis, subcutaneous vasculitis);

• Respiratory, thoracic and mediastinal disorders:*
  Uncommon – respiratory disorders, including pneumonitis and pulmonary edema;
  Very rare – acute respiratory distress syndrome (ARDS);

• Gastrointestinal disorders:*
  Uncommon – sialadenitis, cramps, gastric irritation, nausea, vomiting, diarrhea, constipation;

• Hepatobiliary disorders:*
  Uncommon – jaundice (intrahepatic cholestasis), pancreatitis;

• Skin and subcutaneous tissue disorders:*
  Uncommon – photosensitivity, urticaria, toxic epidermal necrolysis;
  Rare – Stevens-Johnson syndrome, skin reactions resembling cutaneous lupus erythematosus, reactivation of cutaneous lupus erythematosus;

• Musculoskeletal and connective tissue disorders:*
  Uncommon – muscle cramps;

• Renal and urinary disorders:*
  Uncommon – glucosuria, interstitial nephritis, renal function impairment, renal failure;

• General disorders and administration site conditions:*
  Uncommon – fever, dizziness.

¹ Non-melanoma skin cancer: Based on available data from epidemiological studies, an association has been described between cumulative hydrochlorothiazide dose and NMSC (see sections "Special warnings and precautions for use" and "Pharmacological properties").

Shelf life.
5 years.

Storage conditions.
Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture.
Keep out of reach of children.

Packaging.
10 tablets in a blister pack, 3 or 9 blisters in a cardboard box.

Prescription category.
Prescription only.

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

Manufacturer's address and location of operations.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.