Lorista® h

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Lorista® N (Lorista® N)

Composition:

Active substances: losartan, hydrochlorothiazide;

One film-coated tablet contains 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide;

Excipients: pregelatinized starch, microcrystalline cellulose, lactose monohydrate, magnesium stearate, hypromellose, macrogol 4000, talc, quinoline yellow coloring agent (E 104), titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: yellow, slightly biconvex, oval film-coated tablets with a score line on one side.

Pharmacotherapeutic group. Angiotensin II antagonists and diuretics. Losartan and diuretics.

ATC code C09DA01.

Pharmacological properties.

Pharmacodynamics.

Losartan and hydrochlorothiazide

The antihypertensive effect of the components of the medicinal product is additive; thus, administration of the components together reduces arterial pressure to a greater extent than when administered separately. The effect is considered to result from the combined action of both components. In addition, due to its diuretic effect, hydrochlorothiazide increases plasma renin activity and aldosterone secretion, decreases potassium concentration, and increases angiotensin II levels in plasma. Administration of losartan blocks all physiological effects of angiotensin II and, by suppressing aldosterone effects, may attenuate potassium losses associated with diuretic use.

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

The antihypertensive effect of the medicinal product lasts for 24 hours and is maintained during long-term use. In clinical studies lasting at least one year, the antihypertensive effect was preserved with continuous treatment. Despite a significant reduction in arterial pressure, therapy with the medicinal product did not clinically significantly affect heart rate. In clinical studies, after 12 weeks of treatment, a mean reduction in seated diastolic blood pressure of 13.2 mm Hg was recorded.

The combination of losartan and hydrochlorothiazide is effective in reducing blood pressure in both men and women, in patients of non-African and Caucasian descent, in middle-aged (< 65 years) and elderly patients (≥ 65 years), and is effective at all stages of arterial hypertension.

Losartan

Losartan is a synthetic angiotensin II receptor antagonist (type AT1) for oral use. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system 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), producing 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, 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 for cardiovascular regulation. Additionally, losartan does not affect angiotensin-converting enzyme (kinase II), which is responsible for bradykinin degradation. Therefore, adverse reactions associated with elevated bradykinin concentrations are not observed. Administration of losartan inhibits the negative feedback of angiotensin II on renin formation, resulting in increased plasma renin activity. Increased renin activity leads to elevated angiotensin II levels in plasma. Despite this, 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 main active metabolite have greater 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 the incidence of cough 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 studies 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 without diabetes, administration of losartan potassium 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 (usually < 0.4 mg/dL), which is maintained during long-term therapy.

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

In patients with left ventricular dysfunction, 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, mean arterial pressure, as well as reduced heart rate and circulating levels of aldosterone and noradrenaline. Symptoms of arterial hypotension in this group of patients with heart failure were dose-dependent.

Studies in patients with arterial hypertension

In controlled clinical studies, once-daily administration of losartan to patients with mild to moderate essential hypertension resulted in a statistically significant reduction in systolic and diastolic blood pressure. Blood pressure measurements taken 24 hours after dosing compared to measurements taken 5–6 hours after dosing showed that the blood pressure reduction lasted for 24 hours; the natural circadian rhythm was preserved. The reduction in blood pressure at the end of the dosing interval was 70–80% of the effect observed 5–6 hours after administration.

Discontinuation of losartan in patients with arterial hypertension did not lead to a sudden increase in blood pressure (withdrawal syndrome). Despite a significant reduction in blood pressure, losartan did not clinically significantly affect 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 − reduction in severity of arterial hypertension)

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

The mean follow-up period was 4.8 years.

The primary efficacy endpoint was a composite measure of cardiovascular morbidity and mortality due to cardiovascular events, measured by the reduction in total cardiovascular mortality, stroke, and myocardial infarction. Blood pressure was significantly reduced in both 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 due to a reduction in stroke incidence. Treatment with losartan reduced the risk of stroke by 25% compared to atenolol (p = 0.001, 95% CI: 0.63–0.89). There was no significant difference between treatment groups in the incidence of cardiovascular mortality and myocardial infarction.

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 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 show a significant beneficial effect on renal and/or cardiovascular outcomes or mortality; however, an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these results may also apply to other ACE inhibitors and angiotensin II receptor blockers. Therefore, ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Endpoints) study was designed to evaluate the benefit of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney or cardiovascular disease, or both. The study was prematurely terminated due to a high risk of adverse reactions. Cardiovascular mortality and stroke 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 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 subsequently increases urinary potassium excretion, bicarbonate loss, and decreased serum potassium levels. Possibly, due to blockade of the renin-aldosterone system, concomitant administration of angiotensin II receptor antagonists may help reverse potassium loss associated with thiazide diuretics.

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

Non-melanoma skin cancer

Based on available epidemiological data, there is a cumulative dose-dependent association between hydrochlorothiazide (HCTZ) use and the development of non-melanoma skin cancer (NMSC). In one study population, there were 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), compared to 1,430,833 and 172,462 cases in the control group, respectively. High-dose HCTZ use (>50,000 mg cumulative) was associated with an adjusted odds ratio (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 was observed for both BCC and SCC. Another study demonstrated a possible association between lip cancer (squamous cell carcinoma, SCC) and HCTZ use: 633 cases of lip cancer versus 63,067 in the control group (using a risk-set sampling strategy). A dose-response relationship was demonstrated using an adjusted odds ratio (OR) of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high-dose use (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see also 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 albumin. The volume of distribution of losartan is 34 L. In animal studies, losartan crossed the blood-brain barrier to a small extent or not at all.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental barrier, does not cross the blood-brain barrier, and is excreted in 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) potassium losartan, plasma radioactivity is primarily due to losartan and its active metabolite. In 1% of subjects studied, losartan is only minimally converted to the active metabolite.

In addition to the active metabolite, inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl side chain, and a minor metabolite, 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% 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, with elimination half-lives of 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 an oral dose 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. Based on observations over at least 24 hours, the plasma elimination half-life of hydrochlorothiazide ranges from 5.6 to 14.8 hours. At least 61% of an oral dose is excreted unchanged within 24 hours.

Characteristics in patients

Losartan and hydrochlorothiazide

Plasma concentrations of losartan and its active metabolite, as well as hydrochlorothiazide absorption, in elderly patients with arterial hypertension do not significantly differ from those 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 5 and 1.7 times higher, respectively, than in young volunteers.

Pharmacokinetic studies showed 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.

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

Clinical characteristics.

Indications.

Treatment of arterial hypertension when monotherapy with losartan or monotherapy with hydrochlorothiazide is insufficient.

Contraindications.

• Hypersensitivity to losartan, sulfonamide derivatives (such as hydrochlorothiazide), or to any of the excipients.
• Pregnancy or women who are planning to become pregnant (see section "Use in pregnancy or breastfeeding").
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Anuria.
• Severe hepatic impairment, cholestasis, or obstructive biliary disorders.
• Therapeutically resistant hypokalemia or hypercalcemia.
• Persistent hyponatremia.
• Symptomatic hyperuricemia/gout.
• Concomitant use with aliskiren in patients with diabetes mellitus or renal dysfunction (eGFR <60 mL/min/1.73 m²) (see sections "Special precautions for use" 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 level of the active metabolite. The clinical significance of these interactions has not been evaluated.

As with other agents that block 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 medicinal products that may increase serum potassium levels (e.g., drugs containing trimethoprim) may lead to increased serum potassium levels. Concomitant use is not recommended.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid at 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 with 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. This combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored carefully at the start of concomitant therapy 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.

Arterial hypotension, as a primary or adverse effect, is characteristic of tricyclic antidepressants, neuroleptics, baclofen, and amifostine. Concomitant use of these agents may increase the risk of arterial hypotension.

Studies have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of adverse reactions such as arterial hypotension, hyperkalemia, and renal impairment, including acute renal failure, compared to use of a single RAAS-acting agent (see sections "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 this medicinal product.

Hydrochlorothiazide

The following medicinal products may interact with thiazide diuretics when used concomitantly.

Alcohol, barbiturates, narcotics, or antidepressants

Orthostatic hypotension may be potentiated.

Antidiabetic agents (oral antidiabetics and insulin)

Thiazide use may affect glucose tolerance. Dose adjustment of antidiabetic agents may be necessary. Metformin should be used with caution due to the risk of lactic acidosis caused by possible functional renal impairment associated with hydrochlorothiazide use.

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, ACTH

Increased electrolyte loss, particularly increased risk of hypokalemia.

Pressor amines (e.g., adrenaline)

Reduced response to pressor amines may occur. The degree of reduction is minor, so use of these agents is not contraindicated.

Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine)

Potentiation of response to muscle relaxants may occur.

Lithium preparations

Diuretics reduce renal clearance of lithium and increase the risk of lithium toxicity; concomitant use is not recommended.

Drugs used to treat gout (probenecid, sulfinpyrazone, allopurinol)

Dose adjustment of uricosuric agents may be required because hydrochlorothiazide may increase plasma uric acid concentration. Increased doses of probenecid or sulfinpyrazone may be needed. Concomitant use of thiazides may increase the likelihood of hypersensitivity reactions to allopurinol.

Anticholinergic drugs (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 agents and may potentiate myelosuppressive effects.

Salicylates

When high doses of salicylates are used, hydrochlorothiazide may potentiate their toxic effects on the central nervous system.

Methyldopa

Hemolytic anemia has been reported in isolated cases with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

Concomitant use with cyclosporine increases the risk of hyperuricemia and complications such as gout.

Cardiac glycosides

Hypokalemia or hypomagnesemia induced by thiazides predisposes to arrhythmias caused by cardiac glycosides.

Medicinal products affected by changes in serum potassium levels

Serum potassium concentration and ECG monitoring should be performed periodically when using the combination product losartan/hydrochlorothiazide with medicinal products whose effects depend on plasma potassium levels (e.g., cardiac glycosides and antiarrhythmic agents), as well as with agents that may cause ventricular tachycardia (torsades de pointes), including certain antiarrhythmic drugs, since hypokalemia predisposes to ventricular tachycardia:

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

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 regularly, and the dose of these agents adjusted accordingly.

Effect on laboratory parameters

Due to their effect on calcium metabolism, thiazides may alter results of parathyroid function tests.

Carbamazepine

Risk of symptomatic hyponatremia. Clinical monitoring and laboratory blood tests are required.

Contrast agents containing iodine

There is an increased risk of acute renal failure due to diuretic-induced dehydration, especially with high-dose iodine-containing agents. Fluid balance should be restored in patients prior to administration.

Amphotericin B (parenteral), corticosteroids, adrenocorticotropic hormone, laxatives, and glycyrrhizin (contained in licorice)

Hydrochlorothiazide may potentiate electrolyte imbalance, particularly hypokalemia.

Special precautions for use

Losartan

Angioedema

Careful monitoring is required in patients with a history of angioedema (facial, lip, tongue and/or laryngeal swelling).

Hypotension and hypovolemia

Symptomatic arterial hypotension may occur in patients with depleted circulating volume and/or sodium, such as those undergoing intensive diuretic therapy, salt restriction, diarrhea, or vomiting, particularly after the first dose or dose escalation. Such conditions require correction prior to initiating treatment or a reduced initial dose.

Electrolyte and fluid imbalance

Patients with renal impairment, both diabetic and non-diabetic, frequently develop electrolyte imbalances requiring correction. In clinical trials conducted in patients with type 2 diabetes and nephropathy, hyperkalemia occurred more frequently in the losartan group compared to placebo. Therefore, regular monitoring of serum potassium concentration and creatinine clearance is necessary. Particular caution is required in patients with heart failure and creatinine clearance between 30 and 50 mL/min. Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may increase serum potassium levels (e.g., trimethoprim-containing medications) is not recommended with losartan.

Hepatic impairment

Based on pharmacokinetic data showing significantly increased plasma concentrations of losartan in patients with hepatic cirrhosis, dosage reduction is required in patients with mild to moderate hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment; therefore, the drug is contraindicated in these patients.

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, 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 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.

Renal transplantation

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs that act by inhibiting the renin-angiotensin system. Therefore, losartan tablets are not recommended for these patients.

Ischemic heart disease and cerebrovascular disease

As with other antihypertensive agents, rapid reduction of blood pressure in patients with ischemic heart disease or cerebrovascular disease may precipitate myocardial infarction or stroke.

Heart failure

In patients with heart failure, with or without renal impairment, treatment with losartan, as with other drugs acting on the renin-angiotensin system, carries a risk of severe hypotension and (often acutely) renal failure.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, particular caution is required in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Intestinal angioedema

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

Ethnic considerations

Similar to angiotensin-converting enzyme (ACE) inhibitors, losartan and other angiotensin receptor antagonists are less effective in reducing blood pressure in black patients compared to other racial groups, likely due to a higher prevalence of low renin levels in the black population with hypertension.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Women of childbearing potential who are planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is detected, losartan therapy should be discontinued immediately and, if possible, alternative therapy initiated.

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

Concomitant use of aliskiren with angiotensin II receptor antagonists or ACE inhibitors increases the risk of hypotension, hyperkalemia, and renal impairment, including acute renal failure. Due to dual RAAS blockade, concomitant use of aliskiren with angiotensin II receptor antagonists or ACE inhibitors is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If dual RAAS blockade is clinically necessary, renal function, serum electrolytes, and blood pressure should be closely monitored. Concomitant use of angiotensin II receptor antagonists and ACE inhibitors is not recommended in patients with diabetes mellitus.

Hydrochlorothiazide

Hypotension and fluid and electrolyte imbalance

As with other antihypertensive agents, symptomatic hypotension may occur in some patients receiving the drug. Patients should be monitored for clinical signs of fluid or electrolyte imbalance (e.g., hypovolemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia), which may result from concomitant diarrhea or vomiting. In such patients, serum electrolyte levels should be periodically monitored at regular intervals. In hot weather, hyponatremia of dilution may occur in patients prone to edema.

Metabolic and endocrine effects

Thiazides may alter glucose tolerance. Dose adjustment of antidiabetic agents, including insulin, may be required. Thiazide therapy may unmask latent diabetes mellitus.

Thiazides may reduce calcium excretion in urine and may cause a slight and transient increase in serum calcium levels. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide therapy should be discontinued prior to parathyroid function testing.

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

Thiazide therapy may lead to hyperuricemia and/or gout in some patients. Since losartan reduces urinary excretion of uric acid, losartan in combination with hydrochlorothiazide reduces diuretic-induced hyperuricemia.

Hepatic impairment

Thiazides should be used with caution in patients with hepatic impairment or progressive liver disease, as they may precipitate intrahepatic cholestasis, and minor fluid and electrolyte imbalances may trigger hepatic coma. The drug is contraindicated in patients with severe hepatic impairment.

Non-melanoma skin cancer

In two epidemiological studies based on data from the Danish National Cancer Registry, an increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] was observed with increasing cumulative dose of hydrochlorothiazide (HCTZ). A possible mechanism for NMSC development is the photosensitizing effect of HCTZ.

Patients taking HCTZ should be informed about the risk of NMSC, advised to regularly check their skin for new lesions, and to promptly report any suspicious skin changes. To reduce the risk of skin cancer, patients should be advised on preventive measures, such as limiting exposure to sunlight and ultraviolet radiation and ensuring adequate skin protection when exposed. Any suspicious skin lesions should be promptly evaluated, including biopsy with histological examination. HCTZ use may also require reassessment in patients with a history of NMSC (see also section "Adverse reactions").

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Sulfonamide drugs or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial treatment includes immediate discontinuation of the drug. If intraocular pressure remains uncontrolled, prompt medical or surgical intervention may be required. Risk factors for acute angle-closure glaucoma include a history of sulfonamide or penicillin allergy.

Acute respiratory toxicity

Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening pulmonary function, and hypotension. If ARDS is suspected, treatment with Lorista® N should be discontinued and appropriate therapy initiated. Hydrochlorothiazide should not be prescribed to patients with a previous history of ARDS after hydrochlorothiazide use.

Other conditions

Allergic reactions may occur in patients receiving thiazides, regardless of a history of allergic conditions or bronchial asthma. Exacerbation or recurrence of systemic lupus erythematosus has been reported in patients receiving thiazides.

Special information on certain excipients

The product contains lactose. Patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this product.

Use during pregnancy or breastfeeding

Pregnancy

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

Epidemiological data on teratogenic risk associated with ACE inhibitors during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. 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 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, if possible, alternative therapy initiated.

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

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

Newborns whose mothers received angiotensin II inhibitors should be closely monitored for hypotension, oliguria, and hyperkalemia (see sections "Contraindications", "Special precautions for use").

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. 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 perfusion and cause jaundice, electrolyte imbalance, and thrombocytopenia in the fetus and newborn.

Hydrochlorothiazide should not be used to treat gestational edema, gestational hypertension, or preeclampsia due to the risk of reduced plasma volume and uteroplacental hypoperfusion without beneficial effects on disease course.

Hydrochlorothiazide should not be used to treat hypertension in pregnant women except when alternative therapy is not feasible.

Breastfeeding

Angiotensin II receptor antagonists (ARBs)

The drug is not recommended due to insufficient data on use during breastfeeding. The patient should be switched to alternative antihypertensive therapy with an established safety profile during breastfeeding, especially for newborns or premature infants.

Hydrochlorothiazide

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

Ability to affect the ability to drive and use machines

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

However, dizziness or fatigue may occur during driving or operating machinery while using antihypertensive drugs, particularly at the beginning of treatment or after dose escalation.

Method of Administration and Dosage

LORISTA® N may be used in combination with other antihypertensive agents.

The tablets should be swallowed with a glass of water.

Administration of the drug is not affected by food intake.

The combination of losartan and hydrochlorothiazide should not be used as initial therapy. Whenever possible, it is advisable to titrate the doses of the individual components (losartan and hydrochlorothiazide).

If monotherapy with the individual components of the drug is insufficiently effective, the fixed-dose combination product may be used directly.

Arterial Hypertension

The usual initial and maintenance dose for most patients is 1 tablet of LORISTA® N (50 mg/12.5 mg) once daily. In patients who do not achieve adequate response with 1 tablet of LORISTA® N, the dose may be increased to 2 tablets once daily (in the morning).

Maximum antihypertensive effect is achieved within 3–4 weeks of treatment. The maximum recommended dose is 2 tablets of LORISTA® N once daily.

Use in Patients with Renal Impairment and Patients on Hemodialysis

Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance 30–50 mL/min).

Losartan and hydrochlorothiazide tablets are not recommended for patients on hemodialysis. Losartan/hydrochlorothiazide tablets are contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Use in Patients with Reduced Intravascular Fluid Volume

Deficiency of fluid and/or sodium volume should be corrected prior to initiating therapy with losartan/hydrochlorothiazide tablets.

Use in Patients with Hepatic Impairment

Losartan/hydrochlorothiazide is contraindicated in patients with severe hepatic impairment.

Use in Elderly Patients

Dose adjustment in elderly patients is generally not required.

Children

Experience with the use of this drug in pediatric patients is lacking; therefore, losartan/hydrochlorothiazide should not be used in this patient population.

Overdose

There are no specific data regarding treatment of overdose with this drug. Management of overdose is symptomatic and supportive. The drug should be discontinued and the patient should be closely monitored. If ingestion was recent, induce emesis and implement measures to correct dehydration, electrolyte imbalances, hepatic coma, and arterial hypotension.

Losartan

Human data on losartan overdose are limited. The most likely manifestations of overdose are hypotension and tachycardia; bradycardia may occur due to parasympathetic (vagal) stimulation. Symptomatic hypotension should be managed with supportive therapy.

Losartan and its active metabolite are not significantly removed by hemodialysis.

Hydrochlorothiazide

The most common signs and symptoms of overdose are due to electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. In patients taking cardiac glycosides, hypokalemia may potentiate the development of arrhythmias.

Hydrochlorothiazide is removed by hemodialysis; however, the extent of its removal has not been established.

Adverse Reactions

Adverse reactions that may occur during treatment are classified into frequency groups: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000; not known (cannot be estimated from the available data).

In clinical studies of potassium losartan and hydrochlorothiazide, no adverse reactions were observed that were unusual for this combination of substances. Adverse reactions were limited to those previously observed with losartan potassium and/or hydrochlorothiazide.

During studies in patients with arterial hypertension, dizziness was the only adverse effect related to the active substance occurring in more than 1% of patients (significantly more frequent than in the placebo group).

In addition to these reactions, the following adverse reactions have been reported:

Liver and biliary system

Rare: hepatitis.

Laboratory findings

Rare: hyperkalemia, increased alanine aminotransferase (ALT) levels.

Additional adverse reactions observed with the use of either individual component of the drug and which may represent potential adverse effects of the losartan potassium/hydrochlorothiazide combination are listed below:

Losartan

Blood and lymphatic system disorders

Uncommon: anemia, Schönlein-Henoch 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 swelling of the face, lips, pharynx and/or tongue; history of angioedema with drugs, including ACE inhibitors; urticaria).

Metabolism and nutrition disorders

Uncommon: anorexia, gout.

Psychiatric disorders

Common: insomnia.
Uncommon: anxiety, anxious state, confusion, depression, night terrors, sleep disturbances, somnolence, memory impairment.

Nervous system disorders

Common: headache, dizziness.
Uncommon: nervousness, paresthesia, peripheral neuropathy, tremor, migraine, syncope.
Not known: taste disturbance.

Eye disorders

Uncommon: blurred vision, burning or itching sensation in eyes, conjunctivitis, visual disturbances.

Ear and labyrinth disorders

Uncommon: vertigo, tinnitus.

Cardiac disorders

Uncommon: arterial hypotension, orthostatic hypotension, sternalgia, angina pectoris, second-degree atrioventricular block, cerebrovascular disorders, myocardial infarction, palpitations, arrhythmias (atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation).

Vascular disorders

Uncommon: vasculitis.
Not known: dose-dependent orthostatic effects.

Respiratory, thoracic and mediastinal disorders

Common: cough, upper respiratory tract infections, nasal congestion, sinusitis, sinus abnormalities.
Uncommon: pharyngeal discomfort, pharyngitis, laryngitis, dyspnea, 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: changes in liver function tests.

Skin and subcutaneous tissue disorders

Uncommon: alopecia, dermatitis, dry skin, erythema, flushing, photosensitivity, pruritus, rash, urticaria, increased sweating.

Musculoskeletal and connective tissue disorders

Common: muscle cramps, back pain, leg pain, myalgia.
Uncommon: arm pain, joint swelling, knee pain, bone and muscle pain, shoulder pain, joint 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, increased fatigue, chest pain.
Uncommon: facial swelling, increased temperature.
Not known: influenza-like symptoms, malaise.

Laboratory findings

Common: hyperkalemia, slight decrease in hematocrit and hemoglobin levels.
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)

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.

Vascular disorders

Uncommon: necrotizing angiitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders

Uncommon: respiratory distress, including pneumonitis and pulmonary edema.
Very rare: acute respiratory distress syndrome (ARDS).

Gastrointestinal disorders

Uncommon: inflammation of salivary glands, spasms, 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 systemic 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: increased body temperature, dizziness.

¹ Non-melanoma skin cancer: Based on available epidemiological data, there is a cumulative dose-dependent association between hydrochlorothiazide use and development of NMSC (see "Special 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 the reach of children.

Packaging.

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

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

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's name and address.

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