Lorista® n 100

INSTRUCTION for medical use of the medicinal product Lorista® H 100 (Lorista® H 100)

Composition:

Active substances: losartan, hydrochlorothiazide;

One film-coated tablet contains 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide;

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, oval, biconvex, film-coated tablets.

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

ATC code C09D A01.

Pharmacological Properties.

Pharmacodynamics.

Losartan and hydrochlorothiazide

The antihypertensive effect of the components of the drug is additive; thus, the use of the drug components together reduces arterial pressure to a greater extent than their separate administration. 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 excretion, decreases potassium concentration, and increases angiotensin II levels in plasma. Administration of losartan blocks all physiological effects of angiotensin II and, by suppressing the effects of aldosterone, may attenuate potassium losses associated with diuretic use.

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

The antihypertensive effect of the drug persists for 24 hours and is maintained during long-term use. In clinical studies lasting at least one year, the antihypertensive effect was maintained with continuous treatment. Despite significant reduction in arterial pressure, therapy with the drug 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 (≥ 65 years) patients, and is effective at all stages of arterial hypertension.

Losartan

Losartan is a synthetic angiotensin II receptor (type AT1) antagonist 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) and produces 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 the 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 breakdown. Therefore, adverse reactions associated with increased bradykinin concentration 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 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 a 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 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 trials involving 4131 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 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 (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 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, mean arterial pressure, as well as reduced heart rate and circulating levels of aldosterone and noradrenaline. Manifestations 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 statistically significant reductions in systolic and diastolic blood pressure. Blood pressure measurements taken 24 hours after drug administration compared to those taken 5–6 hours after administration showed that the antihypertensive effect persists for 24 hours; the natural circadian rhythm was preserved. The blood pressure reduction 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 significant reduction in arterial 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 hypertension)

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was a randomized, double-blind, active-controlled trial involving 9193 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 the target blood pressure (<140/90 mm Hg) was not achieved, hydrochlorothiazide (12.5 mg) was added first, 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 parameter was a composite endpoint of cardiovascular morbidity and mortality due to cardiovascular events, measured as the reduction in total cardiovascular mortality, stroke, and myocardial infarction. Blood pressure was significantly lower 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 the number of strokes. Treatment with losartan reduced the risk of stroke by 25% compared to atenolol (p = 0.001, 95% CI: 0.63–0.89). No significant difference was observed 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 demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these results 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 Disease 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 events. 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 impairment) 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 and bicarbonate loss, leading to 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, a cumulative dose-dependent association has been observed 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 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

Over 99% of losartan and its active metabolite are bound to plasma proteins, primarily albumins. The volume of distribution of losartan is 34 L. In animal studies, losartan crossed 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 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, radioactivity in plasma 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

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; 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 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 liver cirrhosis, plasma concentrations of losartan and its active metabolites were 5 and 1.7 times higher, respectively, than in young 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-origin 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 in patients whose blood pressure is not adequately controlled with losartan or hydrochlorothiazide alone.

Reduction of the risk of cardiovascular disease and mortality in patients with arterial hypertension and left ventricular hypertrophy.

Contraindications.

• Hypersensitivity to losartan, sulfonamide derivatives (such as hydrochlorothiazide), or any excipients.
• Hypokalemia or hypercalcemia resistant to therapy.
• Severe impairment of liver function; cholestasis and biliary obstruction.
• Refractory hyponatremia.
• Symptomatic hyperuricemia/podagra.
• Pregnancy and women planning to become pregnant (see section "Use in pregnancy or breastfeeding").
• Breastfeeding period.
• Severe renal impairment (creatinine clearance <30 mL/min).
• Anuria.
• Concomitant use with aliskiren in patients with diabetes or renal impairment (eGFR <60 mL/min/1.73 m²) (see sections "Special precautions" 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 consequences of these interactions have not been evaluated.

As with other drugs 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 carefully 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 and NSAIDs may lead to worsening of renal function, including possible acute renal failure, and increased serum potassium levels, particularly in patients with renal impairment. Such combinations should be used with caution, especially in elderly patients. Patients require adequate hydration and careful monitoring of renal function 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 typical of tricyclic antidepressants, neuroleptics, baclofen, and amifostine. Concomitant use of these drugs 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 changes in renal function, including acute renal failure, compared to use of a single RAAS-acting agent (see sections "Contraindications" and "Special precautions").

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 intensified.

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 renal functional 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, adrenocorticotropic hormone (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; therefore, use of these agents is not contraindicated.

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

Increased response to muscle relaxants may occur.

Lithium preparations

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

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone, allopurinol)

Dose adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Higher doses of probenecid or sulfinpyrazone may be needed. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol.

Anticholinergic drugs (e.g., atropine, biperiden)

Increased bioavailability of thiazide diuretics 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 used, hydrochlorothiazide may potentiate the toxic effects of salicylates on the central nervous system.

Methyldopa

In rare cases, hemolytic anemia has been reported with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

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

Cardiac glycosides

Thiazide-induced hypokalemia or hypomagnesemia may predispose to cardiac arrhythmias induced by cardiac glycosides.

Medicinal products affected by changes in serum potassium levels

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

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

Calcium salts

Thiazide diuretics may increase serum calcium levels due to reduced excretion. If calcium-increasing agents are required, serum calcium levels should be monitored regularly, and the dose of these agents adjusted accordingly.

Interference with laboratory tests

Due to their effect on calcium metabolism, thiazides may alter the 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 doses of iodine-containing contrast 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 exacerbate 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 pharyngeal swelling).

Hypotension and hypovolemia

Symptomatic hypotension may occur in patients with depleted intravascular volume and/or sodium depletion due to intensive diuretic therapy, salt restriction, diarrhea, or vomiting, especially after the first dose or dose escalation. Such conditions require correction prior to initiating therapy or a reduced initial dose.

Electrolyte and fluid imbalance

Patients with renal impairment, both diabetic and non-diabetic, frequently develop electrolyte imbalances requiring correction. Therefore, regular monitoring of plasma 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 medicinal products that may increase serum potassium levels (e.g., trimethoprim-containing drugs) 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 such patients.

Renal impairment

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

As with other drugs affecting the RAAS, increased blood urea 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 stenock or stenosis of the artery to a single functioning 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 acute) renal failure.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, particular caution should be exercised 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 antagonists are less effective in reducing blood pressure in black patients compared to other racial groups, likely due to the higher prevalence of low renin levels in the black hypertensive population.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. If continuation of angiotensin II receptor antagonist therapy is not considered essential, pregnant women or women 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 blockade of the RAAS, concomitant use of aliskiren with angiotensin II receptor antagonists or ACE inhibitors is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). In cases where 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 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 occur due to 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. Latent diabetes mellitus may become apparent during thiazide therapy.

Thiazides may reduce urinary calcium excretion 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.

Elevated 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 impaired liver function 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

Two epidemiological studies based on data from the Danish National Cancer Registry showed an increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] 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 about preventive measures, such as limiting exposure to sunlight and ultraviolet radiation and ensuring adequate skin protection when such exposure occurs. Any suspicious skin lesions should be promptly evaluated, including biopsy with histological examination. HCTZ use may also require reevaluation 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 to weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial treatment includes prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, urgent 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® H 100 should be discontinued and appropriate therapy initiated. Hydrochlorothiazide should not be prescribed to patients with a previous history of ARDS after hydrochlorothiazide.

Other conditions

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

Special information on certain ingredients

Lorista® H 100 contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breastfeeding.

Pregnancy

Losartan

The drug is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment, the drug should be immediately discontinued and replaced with another medicine approved for use during pregnancy. Epidemiological data on the 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, such a risk is possible for this class of drugs. If continuation of angiotensin II inhibitor therapy 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 immediately discontinued 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, 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 fetal renal function and skull development is recommended.

Newborns whose mothers have taken angiotensin II inhibitors should be closely monitored for hypotension.

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy, particularly 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 or gestational hypertension or preeclampsia due to the risk of reduced plasma volume and uteroplacental hypoperfusion without beneficial effects on the course of the disease.

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. Thiazides in high doses, causing intense diuresis, may suppress lactation. Lorista® H 100 is not recommended during breastfeeding. If Lorista® H 100 is used during breastfeeding, doses should be as low as possible.

Effect on ability to drive vehicles or operate machinery.

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

However, dizziness or fatigue may occur during antihypertensive therapy, particularly at the beginning of treatment or after dose escalation, when driving vehicles or operating machinery.

Dosage and Administration

LORISTA® H 100 may be used concomitantly with other antihypertensive agents.

The tablet should be swallowed with a glass of water.

LORISTA® H 100 may be administered regardless of food intake.

Arterial Hypertension

Losartan and hydrochlorothiazide are not used as initial therapy, but are indicated for patients whose blood pressure is not adequately controlled with losartan or hydrochlorothiazide alone.

Dose titration using individual components (losartan and hydrochlorothiazide) is recommended.

For patients whose blood pressure is not adequately controlled on monotherapy, a decision may be made to switch to combination therapy.

The usual maintenance dose is 1 tablet of LORISTA® H (50 mg/12.5 mg) once daily. For patients who do not achieve sufficient blood pressure control with 1 tablet of LORISTA® H, the dose may be increased to 1 tablet of LORISTA® HD (100 mg/25 mg) once daily.

Maximum dose: 1 tablet of LORISTA® HD (100 mg/25 mg) once daily. The antihypertensive effect is achieved within 3–4 weeks after initiation of therapy.

LORISTA® H 100 is intended for patients who require a proven titrated dose of losartan 100 mg and need additional blood pressure control.

Reduction of Cardiovascular Morbidity and Mortality in Patients with Arterial Hypertension and Left Ventricular Hypertrophy

The usual initial dose is 50 mg of losartan once daily. For patients in whom the target blood pressure level is not achieved with 50 mg of losartan daily, therapy should be adjusted by combining losartan with low-dose hydrochlorothiazide (12.5 mg), and if necessary, further increased to 100 mg losartan/12.5 mg hydrochlorothiazide once daily. If needed, the dose may be increased to 100 mg losartan and 25 mg hydrochlorothiazide once daily.

LORISTA® H, LORISTA® H 100, and LORISTA® HD are alternative medicinal products for patients requiring concomitant administration of losartan and hydrochlorothiazide at corresponding doses.

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). The combination tablet of losartan/hydrochlorothiazide is not recommended for patients undergoing hemodialysis. The drug should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min).

Use in Patients with Reduced Intravascular Volume

Correction of fluid and/or sodium volume depletion should be performed prior to initiating losartan/hydrochlorothiazide therapy.

Use in Patients with Hepatic Impairment

The drug is contraindicated in patients with severe hepatic impairment.

Use in Elderly Patients

Dose adjustment is generally not required in elderly patients.

Children

There is no experience with the use of this drug in children; therefore, the combination of losartan/hydrochlorothiazide should not be used in this patient population.

Overdose

There are no specific data on the treatment of overdose with this drug. Management of overdose is symptomatic and supportive. The drug therapy should be discontinued and the patient's condition should be closely monitored. If the drug was recently ingested, 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 arterial hypotension and tachycardia; bradycardia may result from parasympathetic (vagal) stimulation. In cases of symptomatic hypotension, supportive treatment is indicated.

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

Hydrochlorothiazide

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

Hydrochlorothiazide is removed by hemodialysis, although the extent of 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: ≥1/1000 to <1/100; rare: ≥1/10,000 to <1/1000; very rare: <1/10,000; not known (cannot be estimated from 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 hypertension trials, dizziness was the only adverse effect related to the active substance occurring in more than 1% of patients (significantly more than in the placebo group).

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

Hepatic and biliary system:
Rare – hepatitis.

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

Additional adverse reactions observed with one of the individual components of the medicinal product, which may potentially occur with the combination of losartan potassium/hydrochlorothiazide, are as follows:

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 glottis edema leading to airway obstruction and/or facial, lip, pharyngeal, 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 sensation, 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 – taste disturbance;

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, 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, redness, 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:
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;
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 – reversible blurred vision, 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 – salivary gland inflammation, 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 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:
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 the 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 reach of children.

Packaging.

10 tablets per blister, 3 or 6 blisters per cardboard box.

14 tablets per blister, 2 or 4 blisters per cardboard box.

15 tablets per blister, 2, 4, or 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address.

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