Lozap® plus

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOZAP® PLUS (LOZAP® PLUS)

Composition:

Active substances: losartan potassium, hydrochlorothiazide;

One tablet contains losartan potassium 50 mg, hydrochlorothiazide 12.5 mg;

Excipients: mannitol (E 421), microcrystalline cellulose, sodium croscarmellose, povidone, magnesium stearate, hypromellose, polyethylene glycol 6000, talc, simethicone emulsion, titanium dioxide (E 171), quinoline yellow (E 104), Ponceau 4R (E 124).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, oval, film-coated tablets with a break line on both sides.

Pharmacotherapeutic group. Medicinal products acting on the renin-angiotensin system. Angiotensin II antagonists and diuretics. ATC code C09DA01.

Pharmacological properties.

Mechanism of action.

Lozap® Plus is a combination of losartan and hydrochlorothiazide. In patients with arterial hypertension and left ventricular hypertrophy, losartan, particularly in combination with hydrochlorothiazide, reduces the risk of cardiovascular disease and mortality, as demonstrated by assessment of the combined frequency of cardiovascular events, stroke, and myocardial infarction.

The components of the drug exhibit additive antihypertensive effects, reducing blood pressure to a greater extent than either component alone. Due to its diuretic effect, hydrochlorothiazide increases plasma renin activity (PRA), stimulates aldosterone secretion, increases angiotensin II levels, and decreases serum potassium levels. Losartan blocks all physiological effects of angiotensin II and, by inhibiting aldosterone effects, may reduce potassium loss associated with diuretic use.

Losartan exerts a mild uricosuric effect, which disappears upon discontinuation of the drug.

Hydrochlorothiazide slightly increases serum uric acid levels; the combination of losartan and hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.

Pharmacodynamics.

Losartan

Losartan is a synthetic angiotensin II receptor antagonist (AT1 receptor type) intended for oral administration. Angiotensin II is a potent vasoconstrictor substance and the primary active hormone of the renin-angiotensin system, playing a key role in the pathophysiology of arterial hypertension. Angiotensin II binds to AT1 receptors present in various tissues (e.g., vascular smooth muscle, adrenal glands, kidneys, and heart), leading to a range of important biological effects, including vasoconstriction and stimulation of aldosterone secretion. Angiotensin II also promotes proliferation of smooth muscle cells. Losartan selectively blocks AT1 receptors. In vitro and in vivo studies have demonstrated that losartan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically significant effects of angiotensin II, regardless of its source or origin. Losartan does not bind to receptors of other hormones and does not block them or ion channels important for cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kinase II), the enzyme that degrades bradykinin. Therefore, there is no potentiation of bradykinin-mediated adverse effects.

Administration of losartan suppresses the negative feedback of angiotensin II on renin secretion, resulting in increased PRA. Elevated PRA leads to increased plasma angiotensin II concentration. Despite increased levels of these substances, antihypertensive activity and reduced plasma aldosterone concentration are maintained, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, PRA and angiotensin II levels return to baseline within a three-day period.

Both losartan and its main active metabolite have higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10–40 times more potent than losartan on a per-body-weight basis.

In a study specifically designed to evaluate cough incidence in patients taking losartan compared to those receiving ACE inhibitors, the incidence of cough in patients taking losartan or hydrochlorothiazide was approximately the same and statistically significantly lower than in patients taking ACE inhibitors. Additionally, a pooled analysis of 16 double-blind clinical trials involving 4131 patients showed that the incidence of spontaneously reported cough in patients taking losartan (3.1%) was similar to that in patients receiving placebo (2.6%) or hydrochlorothiazide (4.1%), whereas the incidence of cough in patients taking ACE inhibitors was 8.8%.

Administration of potassium losartan to non-diabetic patients with arterial hypertension and proteinuria significantly reduces proteinuria, as well as fractional excretion of albumin and immunoglobulin IgG. Losartan maintains glomerular filtration rate and reduces plasma filtration fraction. Losartan typically reduces serum uric acid concentration (usually <0.4 mg/dL), and this effect is sustained during long-term therapy.

Losartan does not affect autonomic reflexes and has no prolonged effect on plasma norepinephrine concentration. In patients with left ventricular insufficiency, losartan at doses of 25 mg and 50 mg exerts a positive hemodynamic and neurohormonal effect characterized by increased cardiac output index and reduced pulmonary capillary wedge pressure, decreased systemic vascular resistance, reduced mean systemic arterial pressure and heart rate, and reduced circulating plasma levels of aldosterone and norepinephrine. In such patients with heart failure, the incidence of arterial hypotension was dose-dependent.

Studies in patients with arterial hypertension

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

Discontinuation of losartan in patients with arterial hypertension does not lead to a sudden increase in blood pressure (rebound phenomenon). Although losartan causes pronounced blood pressure reduction, it has no significant effect on heart rate.

Losartan is equally effective in male and female patients, as well as in younger (under 65 years) and older patients with arterial hypertension.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully understood. Thiazides interfere with tubular reabsorption of electrolytes in the kidneys, directly increasing excretion of sodium and chloride in approximately equal amounts. The diuretic effect of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, and enhances aldosterone secretion, leading to increased urinary potassium excretion and bicarbonate loss, as well as increased serum potassium concentration. The renin-aldosterone axis is angiotensin II-mediated; therefore, concomitant use of angiotensin II receptor antagonists may counteract potassium loss associated with thiazide diuretics.

After oral administration, diuresis begins within two hours, reaches a maximum at approximately four hours, and lasts for about 6 to 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 HCTZ and NMSC. One study included a population of 71,533 cases of BCC and 8,629 cases of SCC, with control groups of 1,430,833 and 172,462 cases, respectively. High cumulative use of HCTZ (>50,000 mg) 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 cumulative dose-response relationship was observed for both BCC and SCC. Another study demonstrated a possible association between lip cancer (SCC) and HCTZ use: 633 cases of lip cancer versus 63,067 controls (using a risk-set sampling strategy). A cumulative dose-effect relationship was demonstrated by an adjusted odds ratio (OR) of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) for high use (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see also section "Special warnings and precautions for use").

Pharmacokinetics.

Absorption

Losartan

After oral administration, losartan is well absorbed and undergoes first-pass metabolism in the liver, resulting in the formation of an active carboxylic acid metabolite and inactive metabolites. Systemic bioavailability of losartan in tablet form is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached at 1 hour and 3–4 hours, respectively. Administration of losartan with food did not result in clinically significant changes in plasma concentration profile.

Distribution

Losartan

Losartan and its active metabolite are bound to plasma proteins (primarily albumin) by more than 99%. The volume of distribution of losartan is 34 L. Animal studies have shown that losartan barely crosses the blood-brain barrier.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental barrier (but not the blood-brain barrier) and is excreted in breast milk.

Biotransformation

Losartan

Approximately 14% of the losartan dose is converted into its active metabolite. After oral administration of 14C-labeled losartan, circulating plasma radioactivity is primarily due to losartan and its active metabolite.

In addition to the active metabolite, biologically inactive metabolites are formed, including two major metabolites resulting from hydroxylation of the butyl side chain, and one 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, nearly 4% of the dose is excreted unchanged in urine and nearly 6% as the active metabolite. Losartan and its active metabolite exhibit linear pharmacokinetics after oral administration of doses up to 200 mg.

After administration, plasma concentrations of losartan and its active metabolite decline polyexponentially, with terminal half-lives of approximately 2 hours and 6–9 hours, respectively. With once-daily administration of 100 mg, neither losartan nor its active metabolite accumulate significantly in plasma.

Losartan and its metabolites are excreted via bile and urine. After oral administration of 14C-labeled losartan, approximately 35% of radioactivity is recovered in urine and 58% in feces.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. Plasma monitoring over at least 24 hours showed elimination half-life ranging from 5.6 to 14.8 hours. At least 61% of the administered dose is excreted unchanged within 24 hours.

Characteristics in patients

Losartan-hydrochlorothiazide

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

Losartan

In patients with mild to moderate alcoholic liver cirrhosis, plasma concentrations of losartan and its active metabolite after oral administration were 5 and 1.7 times higher, respectively, than in young healthy male volunteers. Neither losartan nor its active metabolite is removed by hemodialysis.

Clinical characteristics.

Indications.

Arterial hypertension in patients in whom monotherapy with losartan or hydrochlorothiazide does not adequately control blood pressure.

Contraindications.

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

Hypersensitivity to sulfonamide derivatives (such as hydrochlorothiazide).

Refractory hypokalemia or hypercalcemia.

Anuria.

Severe hepatic impairment: cholestasis and biliary obstruction-related disorders.

Refractory hyponatremia.

Symptomatic hyperuricemia/gout.

Pregnancy or women planning to become pregnant (see section "Use in pregnancy or lactation").

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

Concomitant use of Lozap® Plus with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR [glomerular filtration rate] <60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Losartan

Rifampicin and fluconazole have been reported to reduce the level of the active metabolite. The clinical consequences of these interactions have not been studied.

Combining losartan, as with other agents that block angiotensin II or its effects, with potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or potassium-containing salt substitutes may lead to increased serum potassium levels. Concomitant use of such agents is not recommended. As with other medicinal products that impair sodium excretion, this medicinal product may reduce lithium excretion. Therefore, if concomitant administration of lithium salts and angiotensin II receptor antagonists is planned, serum lithium levels should be closely monitored.

When angiotensin II receptor antagonists are used concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., selective cyclooxygenase (COX-2) inhibitors, acetylsalicylic acid at anti-inflammatory doses, and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II receptor antagonists or diuretics and NSAIDs may lead to an increased risk of worsening renal function, including possible acute renal failure, as well as increased serum potassium concentration, particularly in patients with pre-existing reduced renal function. Such drug combinations should be used with caution, especially in elderly patients. The patient should receive adequate fluid intake, and monitoring of renal function should be considered immediately after initiation of concomitant therapy and periodically thereafter.

In some patients with impaired renal function treated with NSAIDs (including selective COX-2 inhibitors), therapy with angiotensin II receptor antagonists may cause further deterioration of renal function. These effects are usually reversible.

Other substances causing arterial hypotension (tricyclic antidepressants, antipsychotics, baclofen, amifostine) may increase the risk of arterial hypotension when used concomitantly with agents that lower blood pressure through therapeutic or adverse effects.

Dual blockade (e.g., use of an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to specifically defined cases with careful monitoring of blood pressure, renal function, and electrolyte levels. Clinical trial data have shown that in patients with atherosclerosis, heart failure, or diabetes with target organ damage, dual blockade of the renin-angiotensin-aldosterone system (RAAS) is associated with a higher incidence of arterial hypotension, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single agent (see sections "Pharmacodynamics", "Contraindications", "Special precautions for use").

Aliskiren should not be used concomitantly with Lozap® Plus in patients with diabetes mellitus. Aliskiren should be avoided together with the medicinal product in patients with renal impairment (GFR < 60 mL/min).

Hydrochlorothiazide

When used concomitantly with:

alcohol, barbiturates, narcotics, and antidepressants – risk of orthostatic hypotension may increase;

antidiabetic agents (oral and insulin) – thiazide use may affect glucose tolerance. Dose adjustment of antidiabetic agents may be required. Metformin should be used with caution due to the risk of lactic acidosis induced by functional renal impairment that may occur under the influence of hydrochlorothiazide;

other antihypertensive agents – additive effect;

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

corticosteroids, adrenocorticotropic hormone (ACTH) – pronounced electrolyte depletion, particularly hypokalemia;

pressor amines (e.g., adrenaline) – reduced response to pressor amines may occur, but not sufficient to preclude their use;

non-depolarizing muscle relaxants (e.g., tubocurarine) – possible potentiation of the muscle relaxant effect;

lithium – diuretics reduce renal clearance of lithium and increase the risk of lithium toxicity; their combined use is not recommended.

Medicinal products for the treatment of gout (probenecid, sulfinpyrazone, and allopurinol)

Dose adjustment of uricosuric agents (for excretion of uric acid from the body) may be required, as hydrochlorothiazide may increase serum uric acid levels. Dose increases of probenecid or sulfinpyrazone may be needed. Concomitant administration with thiazides may increase the frequency of hypersensitivity reactions to allopurinol.

Anticholinergic agents (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 medicinal products and potentiate their myelosuppressive effects.

Salicylates

When salicylates are used at high doses in combination with hydrochlorothiazide, the toxic effect of salicylates on the central nervous system may be enhanced.

Methyldopa

Isolated reports of hemolytic anemia have been documented during concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

Concomitant use with cyclosporine may increase the risk of hyperuricemia and gout-like complications.

Cardiac glycosides (digitalis)

Thiazide-induced hypokalemia or hypomagnesemia may lead to digitalis-induced cardiac arrhythmias.

Medicinal products affected by changes in serum potassium concentration

Periodic monitoring of serum potassium concentration and ECG is recommended when losartan/hydrochlorothiazide is used concomitantly with medicinal products affected by changes in serum potassium concentration (e.g., cardiac glycosides and antiarrhythmic agents), and when subsequently used with medicinal products that may induce polymorphic ventricular tachycardia (torsades de pointes) (including certain antiarrhythmic agents); hypokalemia is a contributing factor to the development of torsades de pointes (polymorphic 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 vinpocetine).

Calcium salts

Thiazide diuretics may increase serum calcium levels by reducing its excretion. If calcium supplementation is necessary, serum calcium levels should be monitored and the calcium dose adjusted accordingly.

Effect of the medicinal product on laboratory test results

Due to the effect of thiazides on calcium metabolism, their use may alter the results of parathyroid function tests (see section "Special precautions for use").

Carbamazepine

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

Iodinated contrast agents

In the presence of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high-dose iodine-containing products. Dehydration should be corrected prior to administration of the medicinal product.

Amphotericin B (parenteral), corticosteroids, ACTH, stimulant laxatives, or glycyrrhizin (contained in licorice)

Hydrochlorothiazide may exacerbate electrolyte imbalances, particularly worsening hypokalemia, hyponatremia, hypochloremia, alkalosis, and elevated blood urea nitrogen (mainly in renal insufficiency).

Beta-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.

Amantadine

Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine.

Special precautions for use.

Losartan

Angioedema

Patients with a history of angioedema (swelling of the face, lips, throat, and/or tongue) should be monitored continuously (see section "Adverse reactions").

Arterial hypotension and intravascular hypovolemia

Symptomatic arterial hypotension, particularly after the first dose, may occur in patients with hypovolemia and/or hyponatremia due to aggressive diuretic therapy, dietary salt restriction, diarrhea, or vomiting. These conditions should be corrected prior to initiating treatment with Losap® Plus (see sections "Contraindications", "Dosage and administration").

Electrolyte imbalance

Electrolyte imbalances are frequently observed in patients with impaired renal function, with or without diabetes mellitus. Plasma potassium levels and creatinine clearance should be carefully monitored, particularly in patients with heart failure and creatinine clearance within the range of 30–50 mL/min. Concomitant use of losartan/hydrochlorothiazide with potassium-sparing diuretics, potassium-containing dietary supplements, or potassium-containing salt substitutes is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic impairment

Pharmacokinetic data indicate that plasma concentrations of losartan are significantly increased in patients with hepatic cirrhosis. Therefore, Losap® Plus should be used with caution in patients with mild to moderate hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Thus, Losap® Plus is contraindicated in patients with severe hepatic impairment (see sections "Pharmacokinetics", "Contraindications", "Dosage and administration").

Renal impairment

Worsening of renal function, including renal failure, has been reported due to inhibition of the renin-angiotensin-aldosterone system (RAAS), particularly in patients whose renal function depends on RAAS activity, such as those with severe heart failure or pre-existing renal dysfunction. As with other medicinal products affecting the RAAS, increases in 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 the drug.

Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Kidney transplantation

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs that act via inhibition of the renin-angiotensin system. Therefore, use of Losap® Plus is not recommended in these patients.

Ischemic heart disease and cerebrovascular disorders

Excessive reduction in blood pressure in patients with ischemic cardiovascular disease or cerebrovascular disorders may lead to myocardial infarction or stroke.

Heart failure

In patients with heart failure, with or without concomitant renal impairment, as with other drugs affecting the renin-angiotensin system, there is a risk of developing severe arterial hypotension and (often acute) renal failure.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilating agents, Losap® Plus should be administered with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Ethnic factors

Like all ACE inhibitors, losartan and other angiotensin antagonists are significantly less effective in reducing blood pressure in black patients compared to patients of other races. This may be due to the higher prevalence of low-renin hypertension in the black population.

Pregnancy

Angiotensin II receptor antagonists (ARBs) should not be used as initial therapy during pregnancy. If continued ARB therapy is considered absolutely necessary, pregnant women or women planning pregnancy should be switched to an alternative antihypertensive agent with a well-established safety profile during pregnancy.

If pregnancy is diagnosed, ARBs should be discontinued immediately, and alternative therapy should be initiated if necessary (see sections "Contraindications", "Use during pregnancy or breastfeeding").

Dual blockade of the RAAS

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

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

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

Hydrochlorothiazide

Arterial hypotension and fluid and electrolyte imbalance

As with other antihypertensive agents, symptomatic arterial hypotension may occur in some patients. Patients should be monitored for clinical signs of fluid and electrolyte imbalance, such as dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia, which may develop during concomitant diarrhea or vomiting. Serum electrolyte levels should be monitored in such patients. Hyponatremia of dilution may develop in patients with edema during hot weather.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In some cases, dosage adjustment of hypoglycemic agents, including insulin, may be required (see section "Interaction with other medicinal products and other forms of interaction"). Latent diabetes mellitus may become overt during thiazide therapy.

Thiazides may reduce urinary excretion of calcium and cause occasional and slight increases in serum calcium levels. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide diuretic therapy should be discontinued before parathyroid function testing.

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

In some patients, thiazide therapy may accelerate the development of hyperuricemia and/or gout. Since losartan reduces uric acid levels, the combination of losartan with hydrochlorothiazide reduces the hyperuricemia induced by diuretic use.

Hepatic impairment

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

Losap® Plus is contraindicated in patients with severe hepatic impairment (see sections "Pharmacokinetics", "Contraindications").

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 doses of hydrochlorothiazide (HCTZ). A possible mechanism for NMSC development may be the photosensitizing effect of HCTZ.

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

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

Hydrochlorothiazide is a sulfonamide. Medicinal products that are sulfonamides or sulfonamide derivatives may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms are characterized by sudden onset of decreased visual acuity or eye pain and usually develop within hours to weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial management includes prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, immediate medical or surgical intervention may be required. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy (see section "Adverse reactions").

Acute respiratory toxicity

Very rare but severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes to hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, pulmonary dysfunction, and hypotension. If ARDS is suspected, the drug should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after taking hydrochlorothiazide.

Laboratory tests

The drug may reduce plasma iodine levels. Treatment should be discontinued prior to laboratory testing for parathyroid function. This medicinal product may increase serum free bilirubin concentration.

Other effects

Hypersensitivity reactions may occur in patients taking thiazide diuretics, even in the absence of prior allergy or bronchial asthma. There have been reports of exacerbation or progression of systemic lupus erythematosus during thiazide diuretic therapy.

Excipients

This medicinal product contains the dye Ponceau 4R, which may cause allergic reactions.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

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

Period of breastfeeding

Angiotensin II receptor antagonists (ARBs)

There is no information on the use of Losap® Plus during breastfeeding; therefore, its use during this period is not recommended. An alternative agent with a more established safety profile during breastfeeding, particularly for newborns and preterm infants, should be considered.

Hydrochlorothiazide

Hydrochlorothiazide is excreted in human breast milk in small amounts. Thiazides in high doses, by increasing diuresis, may suppress breast milk secretion. Use of Losap® Plus during breastfeeding is not recommended. If Losap® Plus is used during this period, the dose should be as low as possible.

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

Studies on the effect of the drug on the ability to drive vehicles or operate machinery have not been conducted. However, patients who intend to drive or operate machinery should be aware that dizziness or somnolence may occasionally occur during antihypertensive therapy, particularly at the beginning of treatment or when the dose is increased.

Dosage and Administration

Lozap® Plus can be administered regardless of food intake. The tablet should be swallowed whole with a glass of water.

Arterial Hypertension

The combination of losartan and hydrochlorothiazide is not intended for initial therapy. It is indicated only for patients in whom blood pressure cannot be adequately controlled with monotherapy using potassium losartan or monotherapy with hydrochlorothiazide. It is recommended to titrate the dose of each component separately (for losartan and hydrochlorothiazide). In clinically appropriate cases, direct transition from monotherapy to the fixed-dose combination may be considered in patients whose blood pressure is not sufficiently controlled.

The usual maintenance dose is 1 tablet once daily. For patients who do not achieve an adequate therapeutic response, the dose may be increased to 2 tablets once daily.

Maximum dose: 2 tablets once daily. A stable antihypertensive effect is usually achieved within 3–4 weeks after initiation of treatment.

Use in Patients with Renal Impairment and Patients on Hemodialysis

In patients with mild to moderate renal impairment (i.e., creatinine clearance of 30–50 mL/min), no initial dose adjustment is required. The use of tablets containing losartan and hydrochlorothiazide is not recommended in patients undergoing hemodialysis. Lozap® Plus should not be used in patients with severe renal impairment (i.e., creatinine clearance < 30 mL/min) (see section "Contraindications").

Use in Patients with Intravascular Hypovolemia

Before administering Lozap® Plus, intravascular hypovolemia and/or hyponatremia should first be corrected.

Use in Patients with Hepatic Impairment

Lozap® Plus is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Use in Elderly Patients

Dose adjustment is generally not required when administering the drug to elderly patients.

Use in Children

Experience with the use of the drug in children and adolescents is lacking; therefore, the drug should not be administered to this patient group.

Children

Safety and efficacy of the drug in children and adolescents have not been established; therefore, Lozap® Plus should not be used in this patient group.

Overdose

There are no data on specific treatment for overdose with this medication. In case of overdose, therapy should be discontinued and the patient should be closely monitored. If the drug was recently ingested, induce vomiting and take measures to prevent dehydration, electrolyte imbalances, hepatic coma, and arterial hypotension. Treatment is symptomatic and supportive.

Losartan

Human data on 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 therapy 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 (polyuria, oliguria, or anuria), alkalosis, increased blood urea nitrogen (primarily due to renal failure). When taken concomitantly with cardiac glycosides, hypokalemia may lead to increased risk of arrhythmias, tachycardia, arterial hypotension, and shock. Other symptoms may include weakness, nausea, vomiting, thirst, confusion, dizziness, muscle cramps, paresthesia, exhaustion, and disturbances of consciousness. Hydrochlorothiazide is removed by hemodialysis, although the extent of removal is not well established.

Adverse Reactions

The adverse reactions listed below are categorized by System Organ Class and frequency of occurrence, which was determined according to the following criteria: 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); frequency not known (cannot be estimated based on available data).

In clinical studies of potassium losartan and hydrochlorothiazide, no adverse reactions specific to the combination of these active substances were observed. The reported adverse reactions were limited to those previously reported with losartan and/or hydrochlorothiazide used separately.

In controlled clinical trials in patients with primary arterial hypertension, dizziness was the only treatment-related adverse reaction occurring at a rate exceeding that with placebo by 1% or more in patients receiving losartan and hydrochlorothiazide.

During post-marketing use of the medicinal product, the following adverse reactions have been reported for potassium losartan/hydrochlorothiazide.

From the nervous system:

Frequency not known – dysgeusia.

From the cardiac system:

Frequency not known – dose-dependent orthostatic effects.

From the hepatobiliary system:

Rare – hepatitis.

From the skin and immune system:

Frequency not known – cutaneous lupus erythematosus.

Investigations:

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

Additional adverse reactions observed with either active ingredient used alone, and which may potentially occur with the combination of losartan/hydrochlorothiazide, include:

Adverse reactions associated with losartan

During clinical trials and post-authorization use of losartan, the following adverse reactions have been reported:

From the blood and lymphatic system:

Uncommon – anemia, Schönlein-Henoch purpura, ecchymosis, hemolysis; frequency not known – thrombocytopenia.

From the immune system:

Rare – hypersensitivity reactions (including anaphylactic reactions, angioedema, laryngeal edema and vocal cord edema leading to airway obstruction, and/or facial, lip, throat, and/or tongue swelling). Angioedema in some of these patients had previously been reported in association with other medicinal products, including ACE inhibitors.

Metabolic and nutritional disorders:

Uncommon – loss of appetite, gout.

From the psychiatric system:

Common – insomnia; uncommon – anxiety, anxiety disorder, panic disorder, confusion, depression, unusual dreams, sleep disorders, somnolence, memory impairment.

From the nervous system:

Common – headache, dizziness; uncommon – nervousness, paresthesia, peripheral neuropathy, tremor, migraine, syncope; frequency not known – dysgeusia.

From the eye:

Uncommon – blurred vision, burning or prickling sensation in the eyes, conjunctivitis, decreased visual acuity;

From the ear and labyrinthine system:

Uncommon – vertigo, tinnitus.

From the heart:

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

From the vascular system:

Uncommon – vasculitis; frequency not known – dose-dependent orthostatic effects.

From the respiratory system, thoracic and mediastinal organs:

Common – cough, upper respiratory tract infections, nasal congestion, sinusitis, sinus disorders; uncommon – throat discomfort, pharyngitis, laryngitis, dyspnea, bronchitis, epistaxis, rhinitis, respiratory congestion and pulmonary congestion; very rare – acute respiratory distress syndrome (ARDS) (see section "Special Warnings and Precautions for Use").

From the gastrointestinal tract:

Common – abdominal pain, nausea, diarrhea, dyspepsia; uncommon – constipation, toothache, dry mouth, flatulence, gastritis, vomiting, intestinal obstruction; frequency not known – pancreatitis.

From the hepatobiliary system:

Frequency not known – abnormal liver function tests.

From the skin and subcutaneous tissue:

Uncommon – alopecia, dermatitis, dry skin, erythema, skin redness, photosensitivity, pruritus, rash, urticaria, excessive sweating.

From the musculoskeletal and connective tissue system:

Common – muscle cramps, back pain, leg pain, myalgia; uncommon – arm pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, hip pain, fibromyalgia, muscle weakness; frequency not known – rhabdomyolysis.

From the renal and urinary system:

Common – renal function impairment, renal failure; uncommon – nocturia, frequent urination, urinary tract infections.

From the reproductive system and breast:

Uncommon – decreased libido, erectile dysfunction/impotence.

General disorders and administration site reactions:

Common – asthenia, increased fatigue, chest pain; uncommon – facial swelling, edema, increased body temperature; frequency not known – influenza-like symptoms, malaise.

Investigations:

Common – hyperkalemia, slight decrease in hematocrit and hemoglobin levels, hypoglycemia; uncommon – slight increase in serum urea and creatinine levels; very rare – increased liver enzymes and bilirubin levels; frequency not known – hyponatremia.

Adverse reactions associated with hydrochlorothiazide

Benign, malignant and unspecified neoplasms (including cysts and polyps):

Frequency not known – non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

From the blood and lymphatic system:

Uncommon – agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia, neutropenia.

From the immune system:

Rare – anaphylactic reactions, anaphylactic shock.

From metabolism and nutrition:

Uncommon – loss of appetite, anorexia, hyperglycemia, bone marrow suppression, hyperuricemia, hypomagnesemia, hypokalemia, hyponatremia, hypercalcemia; with high-dose use, possible increase in blood lipid levels.

From the psychiatric system:

Uncommon – insomnia.

From the nervous system:

Common – headache (cephalalgia).

From the eye:

Uncommon – transient blurred vision, xanthopsia; frequency not known – acute myopia, secondary acute angle-closure glaucoma, choroidal effusion.

From the vascular system:

Uncommon – necrotizing angiitis (vasculitis, cutaneous vasculitis).

From the respiratory system, thoracic and mediastinal organs:

Uncommon – respiratory distress, including pneumonitis and pulmonary edema.

From the gastrointestinal tract:

Uncommon – sialadenitis, dry mouth, spasms, gastric mucosal irritation, nausea, vomiting, diarrhea, constipation.

From the hepatobiliary system:

Uncommon – jaundice (intrahepatic cholestasis), cholecystitis, pancreatitis, hypochloremic alkalosis, which may precipitate hepatic encephalopathy or hepatic coma.

From the skin and subcutaneous tissue:

Uncommon – photosensitivity, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome; frequency not known – cutaneous lupus erythematosus.

From the musculoskeletal and connective tissue system:

Uncommon – muscle cramps, cramps.

From the renal and urinary system:

Uncommon – glucosuria, interstitial nephritis, renal dysfunction, renal failure, decreased glucose tolerance.

From the reproductive system:

Erectile dysfunction/impotence.

General disorders and administration site reactions:

Uncommon – increased body temperature, fever, dizziness.

Description of selected adverse reactions

Non-melanoma skin cancer: Based on available epidemiological data, a cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 30 °C.

Incompatibilities. Not known.

Packaging. No. 10, No. 30 (10x3), No. 30 (15x2), No. 90 (10x9), No. 90 (15x6):

10 tablets in a blister; 1, 3, or 9 blisters in a cardboard box;

15 tablets in a blister; 2 or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "Zentiva".

Manufacturer's address and location of operations.

Kabelovni 130, 102 37 Prague 10, Dolni Měcholupy, Czech Republic.

Marketing Authorization Holder.

LLC "Sanofi-Aventis Ukraine".

Address of the Marketing Authorization Holder.

48-50A Zhylyanska Street, Kyiv, 01033, Ukraine.